Outcome-based commissioning of knee arthroplasty in the NHS: system error in a national monitoring programme and the unintended consequences on achieving the Best Practice Tariff.

AIMS: Our unit was identified as a negative outlier in the national patient-reported outcome measures (PROMs) programme, which has significant funding implications. As a centre that carries out a high volume of unicompartmental knee arthroplasty (UKA), our objectives were: 1) to determine whether the PROMs programme included primary UKA when calculating the gain in Oxford Knee Score (OKS); and 2) to determine the impact of excluding primary UKA on calculated OKS gains for primary knee arthroplasty. MATERIALS AND METHODS: National PROMs data from England (2012 to 2016) were analyzed. Inclusion of UKA cases in the national PROMs programme was determined using clinical codes. Local OKS gain was calculated for UKA and TKA and compared with the published PROMs results for 2012/13. RESULTS: Use of the recommended codes for primary UKA excluded 99.6% of UKAs locally and 97% nationally from PROMs programme analysis. Inclusion of primary UKAs in PROMs analysis improved our OKS gain from 15.1 (below average) to 16.3 (above average) for 2012/13 for primary knee arthroplasty. CONCLUSION: Exclusion of UKA patients from the PROMs programme is a nationwide issue that potentially introduces bias when comparing OKS gain between centres. Where commissioning decisions are based on routinely collected data, it is imperative that the underlying methodology is appropriate to generate valid results.

Hemiarthroplasty using cemented or uncemented stems of proven design: a comparative study.

National Institute of Clinical Excellence guidelines state that cemented stems with an Orthopaedic Data Evaluation Panel (ODEP) rating of > 3B should be used for hemiarthroplasty when treating an intracapsular fracture of the femoral neck. These recommendations are based on studies in which most, if not all stems, did not hold such a rating. This case-control study compared the outcome of hemiarthroplasty using a cemented (Exeter) or uncemented (Corail) femoral stem. These are the two prostheses most commonly used in hip arthroplasty in the UK. Data were obtained from two centres; most patients had undergone hemiarthroplasty using a cemented Exeter stem (n = 292/412). Patients were matched for all factors that have been shown to influence mortality after an intracapsular fracture of the neck of the femur. Outcome measures included: complications, re-operations and mortality rates at two, seven, 30 and 365 days post-operatively. Comparable outcomes for the two stems were seen. There were more intra-operative complications in the uncemented group (13% vs 0%), but the cemented group had a greater mortality in the early post-operative period (n = 6). There was no overall difference in the rate of re-operation (5%) or death (365 days: 26%) between the two groups at any time post-operatively. This study therefore supports the use of both cemented and uncemented stems of proven design, with an ODEP rating of 10A, in patients with an intracapsular fracture of the neck of the femur.

Corail uncemented hemiarthroplasty with a Cathcart head for intracapsular hip fractures.

The National Institute for Health and Clinical Excellence (NICE) guidelines from 2011 recommend the use of cemented hemi-arthroplasty for appropriate patients with an intracapsular hip fracture. In our institution all patients who were admitted with an intracapsular hip fracture and were suitable for a hemi-arthroplasty between April 2010 and July 2012 received an uncemented prosthesis according to our established departmental routine practice. A retrospective analysis of outcome was performed to establish whether the continued use of an uncemented stem was justified. Patient, surgical and outcome data were collected on the National Hip Fracture database. A total of 306 patients received a Cathcart modular head on a Corail uncemented stem as a hemi-arthroplasty. The mean age of the patients was 83.3 years (SD 7.56; 46.6 to 94) and 216 (70.6%) were women. The mortality rate at 30 days was 5.8%. A total of 46.5% of patients returned to their own home by 30 days, which increased to 73.2% by 120 days. The implant used as a hemi-arthroplasty for intracapsular hip fracture provided satisfactory results, with a good rate of return to pre-injury place of residence and an acceptable mortality rate. Surgery should be performed by those who are familiar with the design of the stem and understand what is required for successful implantation.

Gemella haemolysans spondylodiscitis: a report of two cases.

We report on two cases of infective spondylodiscitis caused by Gemella haemolysans in otherwise healthy patients. This organism has only rarely been identified as a cause of bone and joint infection, with only two previous reports of infective spondylodiscitis. We describe the clinical features, investigations and treatment options.

Activities and interactions among phospholipases A2 during thapsigargin-induced S49 cell death.

The purpose of this study was to determine the roles of calcium-dependent phospholipase A2 (cPLA2) and calcium-independent phospholipase A2 (iPLA2) in thapsigargin-induced membrane susceptibility to secretory phospholipase A2 (sPLA2) and programmed cell death. 3H-arachidonic acid release was observed in the presence of thapsigargin. This release was inhibited partially by an inhibitor of iPLA2 (BEL) and completely by an inhibitor of both cPLA2 and iPLA2 (MAFP) suggesting that these enzymes were active during apoptosis. The process of cell death did not require the activity of either enzyme since neither inhibitor impeded the progression of apoptosis. However, both inhibitors increased the susceptibility of the membrane to sPLA2 in the presence of thapsigargin. In the case of BEL, this effect appeared to involve direct induction of apoptosis in a sub-population of the cells independent of the action of iPLA2. In conclusion, the results suggested that cPLA2 and iPLA2 are active during thapsigargin-induced apoptosis in S49 cells and that cPLA2 tempers the tendency of the cells to become susceptible to sPLA2 during apoptosis.

Multiple remote-US preexposures and the blocking effect produced by a proximal-US.

Weanling, young-adult, and old-age Wistar albino rats were used to determine whether number of unconditioned stimulus (US) presentations, given 24 h or more (remote preexposure) prior to conditioning, alters the blocking effect of a single-US preexposure given 2 h before (proximal) taste aversion conditioning. As the number of remote-US preexposures increased from 0 to 6, the ability of the proximal-US preexposure to block conditioning initially increased then decreased for all age groups. Of the models put forth to explain US preexposure effects on conditioned taste aversion (CTA), only Wagner's information processing model adequately explained the reduction of the blocking effect of the proximal-US preexposure produced as a result of increasing remote-US preexposures.

Mechanisms by which elevated intracellular calcium induces S49 cell membranes to become susceptible to the action of secretory phospholipase A2.

Exposure of S49 lymphoma cells to exogenous group IIA or V secretory phospholipase A2 (sPLA2) caused an initial release of fatty acid followed by resistance to further hydrolysis by the enzyme. This refractoriness was overcome by exposing cells to palmitoyl lysolecithin. This effect was specific in terms of lysophospholipid structure. Induction of membrane susceptibility by lysolecithin involved an increase in cytosolic calcium and was duplicated by incubating the cells with calcium ionophores such as ionomycin. Lysolecithin also activated cytosolic phospholipase A2 (cPLA2). Inhibition of this enzyme attenuated the ability of lysolecithin (but not ionomycin) to induce susceptibility to sPLA2. Lysolecithin or ionomycin caused concurrent hydrolysis of both phosphatidylethanolamine and phosphatidylcholine implying that transbilayer movement of phosphatidylethanolamine occurred upon exposure to these agents but that susceptibility is not simply due to exposure of a preferred substrate (i.e. phosphatidylethanolamine) to the enzyme. Microvesicles were apparently released from the cells upon addition of lysolecithin or ionomycin. Both these vesicles and the remnant cell membranes were susceptible to sPLA2. Together these data suggest that lysolecithin induces susceptibility through both cPLA2-dependent and -independent pathways. Whereas elevated cytosolic calcium was required for both pathways, it was sufficient only for the cPLA2-independent pathway. This cPLA2-independent pathway involved changes in cell membrane structure associated with transbilayer phospholipid migration and microvesicle release.

Low body temperature affects associative processes in long-trace conditioned flavor aversion.

A series of experiments examined the effect of low body temperature on the associative process in long-trace conditioned flavor aversion. Experiment 1 demonstrated that maintaining a low body temperature between conditioned stimulus (CS) and unconditioned stimulus (US) administration facilitates the associative process and allows a flavor aversion to be conditioned in young rats over an interval that would normally not support conditioning. Experiments 2 and 3 demonstrated that this was due neither to lingering systemic saccharin serving as a CS nor to a cold induced enhancement of US intensity. Experiment 4 demonstrated that inducing hypothermia at various times during a 3-h CS-US interval results in an apparent delay of reinforcement gradient. We propose that a cold induced decrease in metabolic rate slows the internal clock that governs the perception of time and that the CS-US association depends upon perceived contiguity rather than upon an external clock-referenced contiguity.

Phosphorylation of rat muscle acetyl-CoA carboxylase by AMP-activated protein kinase and protein kinase A.

This study was designed to compare functional effects of phosphorylation of muscle acetyl-CoA carboxylase (ACC) by adenosine 3',5'-cyclic monophosphate-dependent protein kinase (PKA) and by AMP-activated protein kinase (AMPK). Muscle ACC (272 kDa) was phosphorylated and then subjected to sodium dodecyl sulfate-polyacrylamide gel electrophoresis followed by autoradiography. Functional effects of phosphorylation were determined by measuring ACC activity at different concentrations of each of the substrates and of citrate, an activator of the enzyme. The maximal velocity (Vmax) and the Michaelis constants (Km) for ATP, acetyl-CoA, and bicarbonate were unaffected by phosphorylation by PKA. Phosphorylation by AMPK increased the Km for ATP and acetyl-CoA. Sequential phosphorylation by PKA and AMPK, first without label and second with label, appeared to reduce the extent of label incorporation, regardless of the order. The activation constant (Ka) for citrate activation was increased to the same extent by AMPK phosphorylation, regardless of previous or subsequent phosphorylation by PKA. Thus muscle ACC can be phosphorylated by PKA but with no apparent functional effects on the enzyme. AMPK appears to be the more important regulator of muscle ACC.

Mechanisms by which thionin induces susceptibility of S49 cell membranes to extracellular phospholipase A2.

Whereas cells normally resist attack by PLA2, they become susceptible under certain pathological conditions. To ascertain the regulatory mechanisms that induce cellular susceptibility to PLA2, the effect of thionin on S49 cells was examined in the presence of PLA2. Thionin alone was unable to evoke hydrolysis of the lipid bilayer. Likewise, the addition of PLA2 alone caused production of only a minimal amount of free fatty acid. However, thionin and PLA2 together resulted in significant hydrolysis of the cell membrane. Thionin caused perturbation of the bilayer structure as suggested by the changes in the emission spectra of laurdan and the permeability of the membrane to propidium iodide. These changes correlated quantitatively with the susceptibility of the lipid bilayer to PLA2. Furthermore, thionin induced a modest increase in intracellular Ca2+. The source of this Ca2+ was the extracellular fluid since EDTA in the extracellular medium inhibited the Ca2+ influx. Moreover, cobalt chloride, a universal Ca2+ channel blocker, prevented the rise in intracellular Ca2+, the uptake of propidium iodide, and the susceptibility to PLA2 induced by thionin. In contrast, the changes in the laurdan emission caused by the thionin were not affected by the cobalt. Furthermore, incubation of the cells with the calcium ionophore A23187 also caused the cells to become susceptible to PLA2. We hypothesize that thionin causes S49 cell membranes to become susceptible to PLA2 by a Ca2+-dependent perturbation of the bilayer structure.

Candida endocarditis. A treatable form of pacemaker infection.

Fungal endocarditis is a rare complication of permanent pacemaker implantation. In all reports we have identified, this infection has been fatal, diagnosed postmortem. We present a patient in whom early echocardiographic diagnosis resulted in curative surgical and antimicrobial therapy. Fungal endocarditis is an unusual, but treatable complication of permanent pacemakers.

Crosslinkage of B lymphocyte surface immunoglobulin by anti-Ig or antigen induces prolonged oscillation of intracellular ionized calcium.

Our results indicate that B lymphocytes stimulated with anti-Ig or antigen exhibit repetitive [Ca2+]i transients which persist for hours. The magnitude of these transients favors an important and ongoing role for [Ca2+]i elevation in antigen driven B cell activation. Repetitive Ca2+ transients may prove to be a prevalent mechanism of Ca2+ signaling. In preliminary experiments (with L. E. Samelson and R. D. Klausner), we have observed Ca2+ transients in cloned T cells stimulated with antigen. Woods et al. have described repetitive free Ca2+ transients in hepatocytes stimulated with extracellular ligands promoting glycogenolysis, and suggest that the intervals of base-line [Ca2+]i levels explain the absence of mitochondrial overload in chronically stimulated cells. These considerations apply equally to B lymphocytes and recommend caution in delineating the range of Ca2+-mediated functions by prolonged coculture of cells with Ca2+ ionophores. Our experiments were done in a simple recording chamber with one cell type. No cell interactions were observed. Given the variety of indicator dyes now available, the technical approach we present, augmented by a more sophisticated recording chamber, is a potentially powerful tool for examining the intrinsic, and T- or accessory cell-dependent, physiology of B cell differentiation.

Flow cytometric analysis of murine splenic B lymphocyte cytosolic free calcium response to anti-IgM and anti-IgD.

The accurate measurement of ionized intracellular calcium [Ca++]i in single cells by flow cytometry with the use of a new fluorescent calcium chelator, indo-1, is described. We have developed a dependable in situ calibration technique that indicates a resting [Ca++]i in lymphocytes of 100 nM. The enhanced fluorescence of this probe permits its use at sufficiently low cytoplasmic concentrations that buffering of [Ca++]i transients does not occur. The [Ca++]i response of small resting B lymphocytes to crosslinking of surface antigen receptors by anti-immunoglobulin is heterogeneous. With maximal stimulus, the peak [Ca++]i response occurs in 10 to 20 seconds with most cells reaching levels greater than/1 microM. Mean [Ca++]i falls to between 300 and 800 nM by 100 seconds where it remains for more than 10 min. Anti-delta is a more potent stimulus of increased [Ca++]i than anti-mu in terms of both [Ca++]i level and fraction of B cells responding. Whether this is due to the greater density of surface IgD than IgM, a difference in signal transduction efficiency, or both, is not yet known. Surface immunoglobulin receptors are present in great excess. Less than 3% of surface immunoglobulin is crosslinked at the peak of the [Ca++]i response.

The B lymphocyte calcium response to anti-Ig is diminished by membrane immunoglobulin cross-linkage to the Fc gamma receptor.

We report the cytosolic free calcium, [Ca2+]i, responses of single murine B lymphocytes to whole and F(ab')2 fragments of anti-Ig measured in the flow cytometer with indo-1, a new fluorescent chelator of calcium. The principle advantages of this recording system are these: Indo-1 is highly fluorescent; hence, loading concentrations that introduce artifacts in the reported [Ca2+]i signal may be avoided. The measurement of [Ca2+]i by fluorescence ratio corrects for nonuniform dye uptake, making possible quantitative estimates of [Ca2+]i in single cells and an assessment of the variability of population responses. Baseline recordings of unstimulated lymphocytes indicated a narrow, stable range of [Ca2+]i (75 to 125 nM). The [Ca2+]i rise induced by various anti-Ig preparations exhibited considerable heterogeneity. The initial mean value for F(ab')2 anti-Ig-stimulated cells peaked above 1 microM and was due only to the release of Ca2+ from intracellular stores. A steady state elevation of [Ca2+]i was reached by 5 min and persisted for hours. Cells stimulated with intact anti-Ig reached similar initial peak [Ca2+]i values, but then declined toward baseline. This difference was due to membrane Ig-IgG Fc receptor (mIg-Fc gamma R) cross-linkage, because blocking the Fc gamma R with a monoclonal antibody made the [Ca2+]i responses to F(ab')2 and intact anti-Ig identical. The attenuation of the [Ca2+]i signal by mIg-Fc gamma R cross-linkage is proceeded by a corresponding Fc gamma-mediated reduction in anti-Ig-induced inositol trisphosphate elevation. These findings outline a biochemical basis for mIg- and Fc gamma R-mediated activation and regulation intrinsic to the B cell, and demonstrate the advantages of indo-1 over quin2 for fluorescent measurement of [Ca2+]i in small cells.

Voltage-sensitive cyanine dye fluorescence signals in lymphocytes: plasma membrane and mitochondrial components.

The origin of the cyanine dye fluorescence signal in murine and human peripheral blood leukocytes was investigated using the oxa- and indo-carbocyanines di-O-C5(3) and di-I-C5(3). Fluorescence signals from individual cells suspended with nanomolar concentrations of the dyes were measured in a flow cytometer modified to permit simultaneous four-parameter analysis (including two-color fluorescence or fluorescence polarization measurements). The contributions of mitochondrial membrane potential (psi m) and plasma membrane potential (psi pm) to the total voltage-sensitive fluorescence signal were found to depend on the equilibrium extracellular dye concentration, manipulated in these experiments by varying the ratio of dye to cell density. Hence, conditions could be chosen that amplified either the psi m or the psi pm component. Selective depolarization of lymphocytes or polymorphonuclear leukocytes (PMN) in mixed cell suspensions demonstrated that defining the partition of dye between cells and medium is requisite to assessing the heterogeneity of cell responses by cyanine dye fluorescence. At extracellular dye concentrations exceeding 5 nM in equilibrated cell suspensions, both mitochondrial and plasma membrane dye toxicity were observed. In murine splenic lymphocytes, plasma membrane toxicity (dye-induced depolarization) was selective for the B lymphocytes. Certain problems in calibration of psi pm with valinomycin at low dye concentrations and perturbations of psi pm by mitochondrial inhibitors are presented. These findings address the current controversy concerning psi m and psi pm measurement in intact cells by cyanine dye fluorescence. The finding of selective toxicity at low cyanine dye concentrations suggest that purported differences in resting psi m among cells or changes in psi pm with cell activation may reflect variable susceptibility to dye toxicity rather than intrinsic cell properties.

Lymphocyte membrane potential and Ca2+-sensitive potassium channels described by oxonol dye fluorescence measurements.

A method is described for quantitative measurement of lymphocyte transmembrane electrical potential difference (psi) by flow cytometric recording of the oxonol dye fluorescence of single cells. Both the simultaneous collection and analysis of multiple optical parameters and the use of a negatively charged oxonol probe allowed more accurate measurement of psi than may be obtained by bulk cell suspension techniques employing cationic voltage indicators. Mouse spleen and human blood lymphocyte psi was calculated to be -70 mV. T and B lymphocytes maintain a constant psi as extracellular K+ is varied from 2 to 10 mM and the deviation from K+ equilibrium potentials (EK) is shown to result from Na+ permeability. At [K+]o values greater than 10 mM, lymphocytes behave as K+ electrodes. Examination of lymphocyte subsets showed that hyperpolarization induced by the Ca2+ ionophore A23187 occurs only in T cells. This response was identified as activation of a Ca2+-sensitive K+ channel by pharmacologic manipulations. Hence, T cells depolarized by 4-aminopyridine (4-AP, 10 mM) were observed to return to resting psi by A23187-induced elevation of [Ca2+]i. Cells depolarized by quinine (100 microM) were unaffected by A23187. The Ca2+-activated channel does not contribute to resting psi in T cells since it may be selectively blocked by quinine (20 microM) or modulated by calmodulin antagonists (5 microM trifluperazine) without affecting resting psi.

Intrathecal IgG synthesis and blood-brain barrier impairment in patients with systemic lupus erythematosus and central nervous system dysfunction.

Paired serum and cerebrospinal fluid specimens from 19 patients with SLE and central nervous system dysfunction were studied with respect to cerebrospinal fluid IgG index (a measure of intrathecal IgG synthesis), isoelectric focusing using immunoperoxidase staining techniques to detect oligoclonal IgG, and determination of the cerebrospinal fluid/serum albumin quotient (Q albumin) as a measure of blood-brain barrier integrity. Twenty-five patients without neurologic disease and 70 patients with a variety of non-SLE neurologic disorders were also studied for comparison. Of most interest was the observation that 42 percent of the patients with SLE had cerebrospinal fluid oligoclonal IgG, usually in association with elevation of the cerebrospinal fluid IgG index. In addition, two of the cerebrospinal fluid specimens that exhibited oligoclonal IgG also had increased titers of alpha-interferon. Q albumin was normal (under 9.0) in 12 of 13 patients with SLE, who had seizure, psychosis, or cranial neuropathy as principal central nervous system manifestations (mean +/- SD = 5.3 +/- 2.4), but was significantly elevated (mean +/- SD = 27.4 +/- 18.8, p less than 0.001) in five of six patients with diffuse, major central nervous system injury, for example, encephalopathy with coma, transverse myelopathy, paraparesis. Blood-brain barrier impairment was not correlated either with presence of circulating immune complexes or with other clinical or serologic evidence for extra-central nervous system disease activity. Taken together, the data suggest that, within the limitations of the techniques used, impairment of the blood-brain barrier in SLE may be secondary to the central nervous system lesion, rather than a result of systemic immune complex injury. In addition, substantial evidence is provided for an ongoing humoral immune response within the central nervous system in this disorder, which, in certain patients, may be associated with the production of intrathecal alpha-interferon.