Nils P. Hailer

Uncemented and cemented primary total hip arthroplasty in the Swedish Hip Arthroplasty Register.

Background and purpose Since the introduction of total hip arthroplasty (THA) in Sweden, both components have most commonly been cemented. A decade ago the frequency of uncemented fixation started to increase, and this change in practice has continued. We therefore analyzed implant survival of cemented and uncemented THA, and whether the modes of failure differ between the two methods of fixation. Patients and methods All patients registered in the Swedish Hip Arthroplasty Register between 1992 and 2007 who received either totally cemented or totally uncemented THA were identified (n = 170,413). Kaplan-Meier survival analysis with revision of any component, and for any reason, as the endpoints was performed. Cox regression models were used to calculate risk ratios (RRs) for revision for various reasons, adjusted for sex, age, and primary diagnosis. Results Revision-free 10-year survival of uncemented THA was lower than that of cemented THA (85% vs. 94%, p < 0.001). No age or diagnosis groups benefited from the use of uncemented fixation. Cox regression analysis confirmed that uncemented THA had a higher risk of revision for any reason (RR = 1.5, 95% CI: 1.4–1.6) and for aseptic loosening (RR = 1.5, CI: 1.3–1.6). Uncemented cup components had a higher risk of cup revision due to aseptic loosening (RR = 1.8, CI: 1.6–2.0), whereas uncemented stem components had a lower risk of stem revision due to aseptic loosening (RR = 0.4, CI: 0.3–0.5) when compared to cemented components. Uncemented stems were more frequently revised due to periprosthetic fracture during the first 2 postoperative years than cemented stems (RR = 8, CI: 5–14). The 5 most common uncemented cups had no increased risk of revision for any reason when compared with the 5 most commonly used cemented cups (RR = 0.9, CI: 0.6–1.1). There was no significant difference in the risk of revision due to infection between cemented and uncemented THA. Interpretation Survival of uncemented THA is inferior to that of cemented THA, and this appears to be mainly related to poorer performance of uncemented cups. Uncemented stems perform better than cemented stems; however, unrecognized intraoperative femoral fractures may be an important reason for early failure of uncemented stems. The risk of revision of the most common uncemented cup designs is similar to that of cemented cups, indicating that some of the problems with uncemented cup fixation may have been solved.

Proliferation of microglia and astrocytes in the dentate gyrus following entorhinal cortex lesion: a quantitative bromodeoxyuridine-labelling study.

Entorhinal cortex lesion of adult rats induces glial activation and proliferation in the deafferented dentate molecular layer. Double‐labelling immunocytochemistry for the astrocyte‐specific antigen glial fibrillary acidic protein or the microglial cell marker Griffonia simplicifolia isolectin B4 with bromodeoxyuridine detection revealed that microglia counts and the proliferation rate in the ipsilateral dentate gyrus reached a maximum in the molecular layer at 3 days post‐lesion (dpl) and returned to control levels by 30 dpl. Astrocyte counts in the ipsilateral dentate gyrus peaked at 30 dpl, with maximum proliferation at 7 dpl. At 100 dpl the astrocyte count had reverted to control levels. Glial proliferation was not restricted to the ipsilateral molecular layer but also occurred to some degree in the granule cell layer and the contralateral dentate gyrus. Thus entorhinal cortex lesion induces a rapid microglia reaction and long‐lasting astrocyte activation in the deafferented termination zone of the perforant path. We conclude that glial proliferation after entorhinal cortex lesion follows a complex temporal and spatial pattern that coincides with processes of neuronal and axonal reorganization.

The risk of revision due to dislocation after total hip arthroplasty depends on surgical approach, femoral head size, sex, and primary diagnosis: An analysis of 78,098 operations in the Swedish Hip Arthroplasty Register

Background and purpose The effects of patient-related and technical factors on the risk of revision due to dislocation after primary total hip arthroplasty (THA) are only partly understood. We hypothesized that increasing the femoral head size can reduce this risk, that the lateral surgical approach is associated with a lower risk than the posterior and minimally invasive approaches, and that gender and diagnosis influence the risk of revision due to dislocation. Patients and methods Data on 78,098 THAs in 61,743 patients performed between 2005 and 2010 were extracted from the Swedish Hip Arthroplasty Register. Inclusion criteria were a head size of 22, 28, 32, or 36 mm, or the use of a dual-mobility cup. The covariates age, sex, primary diagnosis, type of surgical approach, and head size were entered into Cox proportional hazards models in order to calculate the adjusted relative risk (RR) of revision due to dislocation, with 95% confidence intervals (CI). Results After a mean follow-up of 2.7 (0–6) years, 399 hips (0.5%) had been revised due to dislocation. The use of 22-mm femoral heads resulted in a higher risk of revision than the use of 28-mm heads (RR = 2.0, CI: 1.2–3.3). Only 1 of 287 dual-mobility cups had been revised due to dislocation. Compared with the direct lateral approach, minimally invasive approaches were associated with a higher risk of revision due to dislocation (RR = 4.2, CI: 2.3–7.7), as were posterior approaches (RR = 1.3, CI: 1.1–1.7). An increased risk of revision due to dislocation was found for the diagnoses femoral neck fracture (RR = 3.9, CI: 3.1–5.0) and osteonecrosis of the femoral head (RR = 3.7, CI: 2.5–5.5), whereas women were at lower risk than men (RR = 0.8, CI: 0.7–1.0). Restriction of the analysis to the first 6 months after the index procedure gave similar risk estimates. Interpretation Patients with femoral neck fracture or osteonecrosis of the femoral head are at higher risk of dislocation. Use of the minimally invasive and posterior approaches also increases this risk, and we raise the question of whether patients belonging to risk groups should be operated using lateral approaches. The use of femoral head diameters above 28 mm or of dual-mobility cups reduced this risk in a clinically relevant manner, but this observation was not statistically significant.

Astrocytic factors deactivate antigen presenting cells that invade the central nervous system.

We hypothesized that CNS tissue has the potential to deactivate invading monocytes/macrophages in order to maintain the immune privilege of the brain, and furthermore, that astrocytes are the cells that initiate monocyte/macrophage deactivation. To test this hypothesis, fluorescent prelabeled rat spleen macrophages with typical amoeboid morphology were transferred into organotypic hip‐pocampal slice cultures (OHSCs), where they gradually developed a ramified morphology similar to the appearance of resting microglial cells. This morphological transformation also occurred if macrophages or monocytes were co‐cultured with mixed glial cultures or with astrocytoma cells, and ramification was accompanied by reduced expression of adhesion molecules leukocyte function antigen (LFA)‐1, intercellular adhesion molecule (ICAM)‐1, and major histocompatibility complex (MHC)‐class‐II molecules. Moreover, treatment of macrophages with astrocyte culture supernatant effectively down‐regulated the LPS‐induced expression of adhesion‐ and MHC‐class‐II‐molecules. Astrocyte supernatant‐induced inhibition of adhesion and MHC‐class‐II‐molecule expression was mimicked by transforming growth factor (TGF)‐β1, furthermore, this inhibitory effect was diminished by simultaneous treatment with neutralizing anti‐TGF‐β‐antibodies. In conclusion, our results suggest that astrocyte‐derived, soluble factors that are present in the CNS microenvironment deactivate invading macrophages, thus contributing to the maintenance of CNS immune‐privilege following impairment of blood‐brain‐barrier (BBB) integrity.

Interleukin-1β exacerbates and interleukin-1 receptor antagonist attenuates neuronal injury and microglial activation after excitotoxic damage in organotypic hippocampal slice cultures

The effects of interleukin (IL)‐1β and IL‐1 receptor antagonist (IL‐1ra) on neurons and microglial cells were investigated in organotypic hippocampal slice cultures (OHSCs). OHSCs obtained from rats were excitotoxically lesioned after 6 days in vitro by application of N‐methyl‐d‐aspartate (NMDA) and treated with IL‐1β (6 ng/mL) or IL‐1ra (40, 100 or 500 ng/mL) for up to 10 days. OHSCs were then analysed by bright field microscopy after hematoxylin staining and confocal laser scanning microscopy after labeling of damaged neurons with propidium iodide (PI) and fluorescent staining of microglial cells. The specificity of PI labeling of damaged neurons was validated by triple staining with neuronal and glial markers and it was observed that PI accumulated in damaged neurons only but not in microglial cells or astrocytes. Treatment of unlesioned OHSCs with IL‐1β did not induce neuronal damage but caused an increase in the number of microglial cells. NMDA lesioning alone resulted in a massive increase in the number of microglial cells and degenerating neurons. Treatment of NMDA‐lesioned OHSCs with IL‐1β exacerbated neuronal cell death and further enhanced microglial cell numbers. Treatment of NMDA‐lesioned cultures with IL‐1ra significantly attenuated NMDA‐induced neuronal damage and reduced the number of microglial cells, whereas application of IL‐1ra in unlesioned OHSCs did not induce significant changes in either cell population. Our findings indicate that: (i) IL‐1β directly affects the central nervous system and acts independently of infiltrating hematogenous cells; (ii) IL‐1β induces microglial activation but is not neurotoxic per se; (iii) IL‐1β enhances excitotoxic neuronal damage and microglial activation and (iv) IL‐1ra, even when applied for only 4 h, reduces neuronal cell death and the number of microglial cells after excitotoxic damage.

ACTIVATED MICROGLIAL CELLS MIGRATE TOWARDS SITES OF EXCITOTOXIC NEURONAL INJURY INSIDE ORGANOTYPIC HIPPOCAMPAL SLICE CULTURES

The aim of this study was to analyse microglial reactions to excitotoxic N‐methyl‐d‐aspartic acid (NMDA)‐induced degeneration of rat dentate and hippocampal neurons in vitro. We used a migration model combining the techniques of microglial single cell culture and organotypic hippocampal slice culture (OHSC). Site‐specific oxidative damage in OHSCs was induced by pretreatment with 50 μm NMDA. Neuronal injury determined by propidium iodide (PI) uptake included the hippocampal cell layers of the dentate gyrus (DG) and the cornu ammonis (CA). Fluorescence‐prelabelled microglial cells with ameboid morphology were transferred onto the OHSC and migrated predominantly to the prelesioned cell layers of DG and CA when compared with unlesioned areas of the OHSC. In NMDA pretreated slices, microglial cells clustered around degenerating granule cells in the DG and pyramidal cells in the CA. This effect was significantly inhibited in unlesioned slice cultures and in NMDA‐exposed cultures that were pretreated with the NMDA‐antagonist MK‐801. Our observations suggest that microglia – attracted by the presence of stimuli provided by NMDA‐induced neuronal death – migrate specifically towards these lesioned neurons.

Vitamin E induces ramification and downregulation of adhesion molecules in cultured microglial cells

Microglial cells in the healthy adult CNS possess a characteristic ramified morphology and show little or no expression of major histocompatibility complex (MHC) or adhesion molecules. In contrast, microglial cells isolated from newborn rat brains inevitably show a nonramified amoeboid morphology and express immunoeffector molecules, such as MHC class I and II, and various adhesion molecules thought to be markers of microglial activation. Furthermore, they produce large amounts of oxygen radicals. Treatment of cultured microglial cells with the antioxidants vitamin E (α‐tocopherol) and vitamin C (ascorbic acid) induced a ramified microglial morphology after 48 h in vitro, otherwise only seen in healthy adult CNS tissue or in co‐culture with astrocytes. Morphological transformation of microglial cells was quantified by morphometric analysis and was found to be statistically significant. Ramification of microglia induced by vitamin E was accompanied by downregulated expression of adhesion molecules leukocyte function antigen‐1, very late antigen‐4, and intercellular adhesion molecule‐1, as assessed by FACS analysis and immunocytochemistry. Moreover, cell numbers of microglia treated with vitamin E remained stable within 7 days in vitro, whereas untreated controls showed a cell loss of 81.5%. These data show that vitamin E acts as a protective compound in dissociated microglial cell cultures. In conclusion, our results suggest that vitamin E and vitamin C shift microglial morphology toward ramification and induce an immunological deactivation. These changes seem to be mediated by oxidative mechanisms. GLIA 22:180–188, 1998.

Morphological features of the entorhinal-hippocampal connection.

The goal of this review in an overview of the structural elements of the entorhinal-hippocampal connection. The development of the dendrites of hippocampal neurons will be outlined in relation to afferent pathway specificity and the mature dendritic structure compared. Interneurons will be contrasted to pyramidal cells in terms of processing of physiological signals and convergence and divergence in control of hippocampal circuits. Mechanisms of axonal guidance and target recognition, target structures, the involvement of receptor distribution on hippocampal dendrites and the involvement of non-neuronal cellular elements in the establishment of specific connections will be presented. Mechanisms relevant for the maintenance of shape and morphological specializations of hippocampal dendrites will be reviewed. One of the significant contexts in which to view these structural elements is the degree of plasticity in which they participate, during development and origination of dendrites, mature synaptic plasticity and after lesions, when the cells must continue to maintain and reconstitute function, to remain part of the circuitry in the hippocampus. This review will be presented in four main sections: (1) interneurons-development, role in synchronizing influence and hippocampal network functioning; (2) principal cells in CA1, CA3 and dentate gyrus regions-their development, function in terms of synaptic integration, differentiating structure and alterations with lesions; (3) glia and glia/neuronal interactions-response to lesions and developmental guidance mechanisms; and (4) network and circuit aspects of hippocampal morphology and functioning. Finally, the interwoven role of these various elements participating in hippocampal network function will be discussed.

Astrocytic factors protect neuronal integrity and reduce microglial activation in an in vitro model of N-methyl-d-aspartate-induced excitotoxic injury in organotypic hippocampal slice cultures

Acute CNS lesions lead to neuronal injury and a parallel glial activation that is accompanied by the release of neurotoxic substances. The extent of the original neuronal damage can therefore be potentiated in a process called secondary damage. As astrocytes are known to secrete immunomodulatory and neuroprotective substances, we investigated whether astrocytic factors can attenuate the amount of neuronal injury as well as the degree of microglial activation in a model of excitotoxic neurodegeneration. Treatment of organotypic hippocampal slice cultures with N‐methyl‐d‐aspartate (NMDA) resulted in a reproducible loss of viable granule cells, partial destruction of the regular hippocampal cytoarchitecture and a concomitant accumulation of amoeboid microglial cells at sites of neuronal damage. Astrocyte‐conditioned media reduced the amount of NMDA‐induced neuronal injury by 45.3%, diminished the degree of microglial activation and resulted in an improved preservation of the hippocampal cytoarchitecture. Transforming growth factor (TGF)‐β failed to act as a neuroprotectant and even enhanced the amount of neuronal injury by 52.5%. Direct effects of astrocytic factors on isolated microglial cells consisted of increased microglial ramification and down‐regulated expression of intercellular adhesion molecule‐1, whereas incubation with TGF‐β had no such effects. In summary, our findings show that hitherto unidentified astrocyte‐derived factors that are probably not identical with TGF‐β can substantially enhance neuronal survival, either by eliciting direct neuroprotective effects or by modulating the microglial response to neuronal injury.

Dual-mobility cups for revision due to instability are associated with a low rate of re-revisions due to dislocation 228 patients from the Swedish Hip Arthroplasty Register

Background and purpose Revision total hip arthroplasty (THA) due to recurrent dislocations is associated with a high risk of persistent instability. We hypothesized that the use of dual-mobility cups would reduce the risk of re-revision due to dislocation after revision THA. Patients and methods 228 THA cup revisions (in 228 patients) performed due to recurrent dislocations and employing a specific dual-mobility cup (Avantage) were identified in the Swedish Hip Arthroplasty Register. Kaplan-Meier survival analysis was performed with re-revision due to dislocation as the primary endpoint and re-revision for any reason as the secondary endpoint. Cox regression models were fitted in order to calculate the influence of various covariates on the risk of re-revision. Results 58 patients (25%) had been revised at least once prior to the index cup revision. The surgical approach at the index cup revision was lateral in 99 cases (44%) and posterior in 124 cases (56%). Median follow-up was 2 (0–6) years after the index cup revision, and by then 18 patients (8%) had been re-revised for any reason. Of these, 4 patients (2%) had been re-revised due to dislocation. Survival after 2 years with the endpoint revision of any component due to dislocation was 99% (95% CI: 97–100), and it was 93% (CI: 90–97) with the endpoint revision of any component for any reason. Risk factors for subsequent re-revision for any reason were age between 50–59 years at the time of the index cup revision (risk ratio (RR) = 5 when compared with age > 75, CI: 1–23) and previous revision surgery to the relevant joint (RR = 1.7 per previous revision, CI: 1–3). Interpretation The risk of re-revision due to dislocation after insertion of dual-mobility cups during revision THA performed for recurrent dislocations appears to be low in the short term. Since most dislocations occur early after revision THA, we believe that this device adequately addresses the problem of recurrent instability. Younger age and prior hip revision surgery are risk factors for further revision surgery. However, problems such as potentially increased liner wear and subsequent aseptic loosening may be associated with the use of such devices in the long term.