Long-term results of the lateral resurfacing elbow arthroplasty.

Aims: The aim of this study was to report the long-term outcome and implant survival of the lateral resurfacing elbow (LRE) arthroplasty in the treatment of elbow arthritis. Patients and Methods: We reviewed a consecutive series of 27 patients (30 elbows) who underwent LRE arthroplasty between December 2005 and January 2008. There were 15 women and 12 men, with a mean age of 61 years (25 to 82). The diagnosis was primary hypotrophic osteoarthritis (OA) in 12 patients (14 elbows), post-traumatic osteoarthritis (PTOA) in five (five elbows) and rheumatoid arthritis (RA) in ten patients (11 elbows). The mean clinical outcome scores including the Mayo Elbow Performance Score (MEPS), the American Shoulder and Elbow Surgeons elbow score (ASES-e), the mean range of movement and the radiological outcome were recorded at three, six and 12 months and at a mean final follow-up of 8.3 years (7.3 to 9.4). A one sample t-test comparing pre and postoperative values, and survival analysis using the Kaplan-Meier method were undertaken. Results: A statistically significantly increased outcome score was noted for the whole group at each time interval. This was also significantly increased at each time in each of the subgroups (OA, RA, and PTOA). Implant survivorship was 100%. Conclusion: We found that the LRE arthroplasty, which was initially developed for younger patients with osteoarthritis, is an effective form of surgical treatment for a wider range of patients with more severe degenerative changes, irrespective of their cause. It is therefore a satisfactory alternative to total elbow arthroplasty (TEA) and has lower rates of complications in the subgroups of patients we have studied. It does not require activities to be restricted to the same extent as following TEA. Based on this experience, we now recommend LRE arthroplasty rather than TEA as the primary form of implant for the treatment of patients with OA of the elbow. Cite this article: Bone Joint J 2018;100-B:338-45.

Assessing the impact of dabigatran and warfarin on health-related quality of life: results from an RE-LY sub-study.

BACKGROUND: Anticoagulation is recommended in patients with atrial fibrillation (AF) to prevent strokes. Vitamin K antagonists, such as warfarin, are associated with numerous practical limitations--frequent anticoagulation monitoring, lifestyle and dietary restrictions--that complicate patient management and may impact health-related quality of life (HRQoL). This study derived HRQoL estimates for AF patients receiving warfarin or dabigatran etexilate (dabigatran), a new oral anticoagulant not requiring anticoagulation monitoring, during one year of stable treatment, i.e. in the absence of outcome events, such as strokes or major bleedings. METHODS: Changes in HRQoL over time and between treatments were assessed using the EQ-5D (utility and Visual Analogue Scale (VAS) scores) at baseline, 3 and 12 months in a sub-group of 1435 patients participating in the RE-LY trial. RE-LY was a phase III study that compared the safety and efficacy of warfarin, dabigatran 150 mg bid and dabigatran 110 mg bid for stroke prevention in patients with AF. RESULTS: Utilities ranged from 0.805 (dabigatran 150 mg bid) to 0.811 (dabigatran 110 mg bid) at baseline, and did not change over the one year observation period. No differences between the dabigatran groups and warfarin were statistically significant except for the dabigatran 150 mg bid group at 3 months. Similarly, none of the within-group or between-group differences in VAS scores were statistically significant. CONCLUSIONS: Over the course of one year, all anticoagulated patients without outcome events (e.g. strokes or major bleedings) had stable HRQoL. Scores between dabigatran and warfarin were comparable, which was unexpected given the known complexities of warfarin treatment.

Glucocorticoid ultradian rhythmicity directs cyclical gene pulsing of the clock gene period 1 in rat hippocampus.

In vivo glucocorticoid (GC) secretion exhibits a distinctive ultradian rhythmicity. The lipophilic hormone can rapidly diffuse into cells, although only the pulse peak is of sufficient amplitude to activate the low affinity glucocorticoid receptor (GR). Discrete pulses readily access brain regions such as the hippocampus where GR expression is enriched and known to regulate neuronal function, including memory and learning processes. In the present study, we have tested the hypothesis that GR brain targets are responsive to ultradian GC rhythmicity. We have used adrenalectomised rats replaced with pulses of corticosterone to determine the transcriptional effects of ultradian pulses in the hippocampus. Confocal microscopy confirmed that each GC pulse results in transient GR nuclear localisation in hippocampal CA1 neurones. Concomitant GR activation and DNA binding was demonstrated by synthetic glucocorticoid response element oligonucleotide binding, and verified for the Clock gene Period 1 promoter region by chromatin immunoprecipitation assays. Strikingly each GC pulse induced a 'burst' of transcription of Period 1 measured by heterogeneous nuclear RNA quantitative polymerase chain reaction. The net effect of pulsatile GC exposure on accumulation of the mature transcript was also assessed, revealing a plateau of mRNA levels throughout the time course of pulsatile exposure, indicating the pulse timing works optimally for steady state Per1 expression. The plateau dropped to baseline within 120 min of the final pulse, indicating a relatively short half-life for hippocampal Per1. The significance of this strict temporal control is that any perturbation to the pulse frequency or duration would have rapid quantitative effects on the levels of Per1. This in turn could affect hippocampal function, especially circadian related memory and learning processes.

MHC class II expression is regulated in dendritic cells independently of invariant chain degradation.

We have investigated the mechanisms that control MHC class II (MHC II) expression in immature and activated dendritic cells (DC) grown from spleen and bone marrow precursors. Degradation of the MHC II chaperone invariant chain (Ii), acquisition of peptide cargo by MHC II, and delivery of MHC II-peptide complexes to the cell surface proceeded similarly in both immature and activated DC. However, immature DC reendocytosed and then degraded the MHC II-peptide complexes much faster than the activated DC. MHC II expression in DC is therefore not controlled by the activity of the protease(s) that degrade Ii, but by the rate of endocytosis of peptide-loaded MHC II. Late after activation, DC downregulated MHC II synthesis both in vitro and in vivo.

Cutting edge: intravenous soluble antigen is presented to CD4 T cells by CD8- dendritic cells, but cross-presented to CD8 T cells by CD8+ dendritic cells.

Mouse spleen contains three distinct mature dendritic cell (DC) populations (CD4(+)8(-), CD4(-)8(-), and CD4(-)8(+)) which retain a capacity to take up particulate and soluble AGS: Although the three splenic DC subtypes showed similar uptake of injected soluble OVA, they differed markedly in their capacity to present this Ag and activate proliferation in OVA-specific CD4 or CD8 T cells. For class II MHC-restricted presentation to CD4 T cells, the CD8(-) DC subtypes were more efficient, but for class I MHC-restricted presentation to CD8 T cells, the CD8(+) DC subtype was far more effective. This differential persisted when the DC were activated with LPS. The CD8(+) DC are therefore specialized for in vivo cross-presentation of exogenous soluble Ags into the class I MHC presentation pathway.

The development, maturation, and turnover rate of mouse spleen dendritic cell populations.

Three distinct subtypes of dendritic cells (DC) are present in mouse spleen, separable as CD4(-)8alpha(-), CD4(+)8alpha(-), and CD4(-)8alpha(+) DC. We have tested whether these represent stages of development or activation within one DC lineage, or whether they represent separate DC lineages. All three DC subtypes appear relatively mature by many criteria, but all retain a capacity to phagocytose particulate material in vivo. Although further maturation or activation could be induced by bacterially derived stimuli, phagocytic capacity was retained, and no DC subtype was converted to the other. Continuous elimination of CD4(+)8(-) DC by Ab depletion had no effect on the levels of the other DC subtypes. Bromodeoxyuridine labeling experiments indicated that all three DC subtypes have a rapid turnover (half-life, 1.5-2.9 days) in the spleen, with none being the precursor of another. The three DC subtypes showed different kinetics of development from bone marrow precursors. The CD8alpha(+) spleen DC, apparently the most mature, displayed an extremely rapid turnover based on bromodeoxyuridine uptake and the fastest generation from bone marrow precursors. In conclusion, the three splenic DC subtypes behave as rapidly turning over products of three independent developmental streams.

CD4 and CD8 expression by dendritic cell subtypes in mouse thymus and spleen.

The dendritic cells (DC) of mouse spleen and thymus were examined for expression of CD4 and CD8. Provided care was taken to avoid selective extraction or selective depletion of DC subpopulations, three main types of DC were detected in mouse spleen: a major new population of CD4+8- DEC-205low CD11bhigh DC, together with the previously described CD4-8- DEC-205low CD11bhigh DC and CD4-8alphaalpha+ DEC-205high CD11blow DC. The CD4 on the surface of the CD4+ splenic DC subpopulation was produced by the DC themselves, and CD4 RNA transcripts were present. Likewise, the CD8alpha on the surface of the splenic CD8+ DC was shown to be a product of the DC themselves, in agreement with earlier evidence. All three spleen DC types would be considered as mature, based on expression of CD80, CD86, and CD40 as well as on T cell stimulating function. Mouse thymuses appeared to contain two DC types; both were DEC-205highCD11blow, but they differed in the level of CD8alphaalpha expression. However, as well as this authenticated marker expression, immunofluorescent staining was also found to reflect a series of artifacts, due to the autofluorescence of contaminating cells and due to pickup of CD4 and CD8alphabeta. By constructing mice chimeric for the hemopoietic lineages using mixtures of wild-type bone marrow with CD4null or CD8alphanull bone marrow, a marked pickup by thymic DC of Ags derived from thymocytes was demonstrated.

Intercellular adhesion molecule-1 expression in endothelial cells is activated by cytomegalovirus immediate early proteins.

BACKGROUND: Human cytomegalovirus (HCMV) infection is associated with allograft vasculopathy and rejection. One potential mechanism is vascular injury from immunologically mediated processes. HCMV infection has been shown to increase the constitutive expression of intercellular adhesion molecule-1 (ICAM-1). The objective of this study was to determine the molecular basis of HCMV enhanced ICAM-1 gene expression in endothelial cells using human umbilical vein endothelial cells (HUVECs) as a model. METHODS: HUVECS were infected with HCMV virus and the level of ICAM-1 mRNA determined over time. HUVECS were then transiently transfected with plasmid constructs containing ICAM-1 and HCMV immediate early (IE) gene sequences and the effect of IE proteins on ICAM-1 promoter expression determined. Antibodies to cytokines known to be affected by HCMV IE proteins or to modulate ICAM-1 expression were added to determine if cytokines were mediating ICAM-1 expression. RESULTS: Infection of HUVECs with HCMV resulted in a rapid rise in ICAM-1 mRNA levels, suggesting that the viral IE proteins were involved in gene activation. The HCMV IE1 and IE2 proteins synergistically activated both transfected and endogenous ICAM-1 gene expression. The addition of antibodies to interleukin-1, tumor necrosis factor-a, transforming growth factor-beta, or interleukin-6 had no effect on the IE protein-mediated increase in ICAM-1 expression. Deletion analysis of the ICAM-1 gene promoter revealed that a minimum of 370 base pairs of 5' flanking sequences was required for maximal transactivation by IE proteins; mutation analysis showed that an NFkappaB site at base pairs -187 to -178 was not required for promoter activation. CONCLUSIONS: These results demonstrate that HCMV regulates the heterologous ICAM-1 gene promoter in endothelial cells not via cellular cytokine production, but rather by a direct effect of IE proteins, and supports a model in which HCMV IE gene products interact with ICAM-1 promoter elements to increase gene expression.

Research capacity in UK primary care.

BACKGROUND: Moves towards a 'primary care-led' National Health Service (NHS) and towards evidence-based care have focused attention upon the need for evaluative research relating to the structure, delivery, and outcome of primary health care in the United Kingdom (UK). This paper describes work carried out to inform the Department of Health Committee on Research and Development (R&D) in Primary Care (Mant Committee). AIM: To describe the extent and nature of current research capacity in primary care in the UK and to identify future needs and priorities. METHOD: Funding data were requested from NHS National Programmes, NHS Executive Regional Offices, the Department of Health (DoH), Scottish Office, Medical Research Council, and some charities. A postal survey was sent to relevant academic departments, and appropriate academic journals were reviewed from 1992 to 1996. In addition, interviews were conducted with academic and professional leaders in primary care. RESULTS: Overall, total annual primary care R&D spend by the NHS and the DoH was found to be 7% of the total spend, although annual primary care R&D spend differs according to funding source. Journals relating to primary care do not, with some notable exceptions (e.g. British Journal of General Practice, Family Practice), have high academic status, and research into primary care by academic departments is, with perhaps the exception of general practice, on a small scale. The research base of most primary care professions is minimal, and significant barriers were identified that will need addressing if research capacity is to be expanded. CONCLUSION: There are strong arguments for the development of primary care research in a 'primary care-led' NHS in the UK. However, dashes for growth or attempts to expand capacity from the present infrastructure must be avoided in favour of endeavours to foster a sustainable, long-term research infrastructure capable of responding meaningfully to identified needs.

Age related somatic mitochondrial DNA deletions in bone.

BACKGROUND: It has been suggested that the accumulation of damage to mitochondrial DNA is a major cause of age related, degenerative disease. Aging is known to cause bone loss leading to a fall in bone mineral density and disruption of bone microarchitecture. However, despite the evidence of age related bone loss, no attempt has been made to detect specific deletions of mitochondrial DNA in the bone of aged individuals. AIMS: To detect bone specific, age related deletions in mitochondrial DNA. METHOD: Blood leucocytes and bone biopsies from patients who had undergone orthopaedic surgery were used as a source of mitochondrial DNA and screened for deletions using the polymerase chain reaction. RESULTS: Although no deletions were detected in the blood mitochondrial DNA, specific deletions in bone mitochondrial DNA were found in three of five elderly subjects. CONCLUSION: The findings of this study suggest that there could be a link between mitochondrial DNA deletions and free radical induced apoptosis of bone cells in the development of age related bone loss.

Evolution of mouse hepatitis virus (MHV) during chronic infection: quasispecies nature of the persisting MHV RNA.

Coronavirus infection of mice has been used extensively as a model for the study of acute encephalitis and chronic demyelination. To examine the evolution of coronavirus RNA during chronic demyelinating infection, we isolated RNA from intracerebrally inoculated mice at 4, 6, 8, 13, 20, and 42 days postinfection and used reverse transcription-polymerase chain reaction amplification methods (RT-PCR) to detect viral sequences. RNA sequences from two viral structural genes, the spike gene and the nucleocapsid gene, were detected throughout the chronic infection. In contrast, infectious virus was not detectable from brain homongenates beyond 13 days postinfection. These results indicate that coronavirus RNA persists in the brain at times when infectious virus is not detected. To determine if genetic changes were occurring during viral replication in the host, we cloned and sequenced the RT-PCR products from the spike and nucleocapsid regions and analyzed the sequences for mutations. Sequencing of the cloned products revealed that a variety of mutant forms of viral RNA persisted in the CNS, including point mutants, deletion mutants, and termination mutants. The mutations accumulated during persistent infection in both the spike and the nucleocapsid sequences, with greater than 65% of the mutations encoding amino acid changes. These results show that a diverse population or quasispecies consisting of mutant and deletion variant viral RNAs (which may not be capable of producing infectious virus particles) persists in the central nervous system of mice during chronic demyelinating infection. The implications of these results for the role of persistent viral genetic information in the pathogenesis of chronic demyelination are discussed.

Mutations associated with viral sequences isolated from mice persistently infected with MHV-JHM.

Mouse hepatitis virus JHM (JHMV or MHV-4) induces subacute and chronic demyelination in rodents and has been studied as a model human demyelinating diseases, such a multiple sclerosis. However, despite intensive investigation, the state of JHMV during chronic disease is poorly understood. Using reverse transcription-polymerase chain reaction amplification (RT-PCR) to "rescue" viral RNA, we have found that JHMV-specific sequences persist for at least 787 days after intracerebral inoculation of experimental mice. Analysis of persisting viral RNA reveals that it is extensively mutated, and we hypothesize that the mutations observed reflect adaptation of the viral quasispecies to low-level intracellular replication during chronic disease.

Characterization of a subtype of primary osteoclastoma: extracellular calcium but not calcitonin inhibits aggressive HLA-DR-positive osteoclastoma possessing 'functional' calcitonin receptors.

We report here a case of primary osteoclastoma that despite possessing HLA-DR-positive status and 'functional' calcitonin receptors, exhibited aggressive in vitro and in vivo bone resorptive activity. In the osteoclast bone slice assay employing scanning electron microscopy, the giant cell-mediated bone resorption was uninhibited by salmon calcitonin (10 nM) and significantly inhibited by raised extracellular calcium (20 mM). In Fura-2AM based microspectrofluorimetric assays, the presence of the 'functional' calcitonin receptors was ascertained by a rise in intracellular calcium induced by calcitonin and high extracellular calcium. These findings provide evidence for a hitherto unrecognized subtype of giant cells that have HLA-DR-positive status, exhibit avid bone resorptive activity, but remain insensitive to calcitonin despite possessing calcitonin receptors.

Pseudoaneurysm of the superficial femoral artery. An unusual complication following rotationplasty.

A 21 year old man presented with pain and swelling around the right knee. Staging studies and open biopsy provided a diagnosis of malignant fibrous histiocytoma, stage II B. A wide local excision followed by prosthetic reconstruction was not possible because of extensive involvement of the quadriceps muscle with tumor. Therefore the patient underwent wide local excision of the tumor and rotationplasty, providing functionally a transtibial amputation. Postoperatively (Day 44) a critical ischaemia of the foot developed, and angiography revealed a pseudoaneurysm of the superficial femoral artery at the level of the tibial condyle. The patient underwent successful arterial reconstruction and the bones united. The etiology of this pseudoaneurysm appears to be related to the presence of the coiled superficial femoral artery abutting the medial tibial condyle flare. This complication may be prevented by ensuring that the condylar flare be contoured, and then an adequate cushion of soft tissue be interposed between artery and bone at this level.

An anatomic study of the axis of elbow movement in the coronal plane: Relevance to component alignment in elbow arthroplasty.

We have performed an anatomic study on cadaveric material identifying a relationship between the posterior cortex of the distal humerus and the axis of movement of the elbow joint with reference to the coronal plane. This study was performed on 11 cadaveric upper limbs in which the axis of movement relative to the coronal plane was identified and confirmed with an external fixator. The relation between this plane and the tangential plane of the posterior cortex of the distal humerus was investigated. Observations made at points progressively proximal to the humeral epicondyles demonstrated that the tangential plane of the posterior humeral cortex became increasingly inclined medially until it became parallel to the coronal axis of movement of the elbow joint at a point 25 to 35 mm proximal to the medial epicondyle of the humerus. The relevance of this observation to the orientation of the humeral component of a total elbow joint replacement arthroplasty is discussed.

Elbow lengthening after total prosthetic arthroplasty: Observations and clinical implications.

We have carried out a radiologic study to determine the effect on limb length of inserting the components of a total elbow joint replacement arthroplasty. The preoperative and postoperative radiographs of 27 consecutive patients undergoing total elbow joint replacement arthroplasty with the Kudo prosthesis were studied. In all cases lengthening across the elbow was found. Both ulnar and humeral lengthening were observed. A mean length increase of 8.6 mm (range 2 to 17 mm) was recorded. Ulnar lengthening contributed to overall lengthening by a significantly greater amount than humeral lengthening. We correlated the degree of lengthening observed with clinical measurements in this series of patients but found no significant differences. Operative maneuvers are suggested to accommodate this length increase, to achieve soft-tissue balance, and to avoid potential complications such as ulnar neuropathy and joint instability.