The 2023 Austrian-Swiss-German Fellowship.

ABSTRACT: The Austrian-Swiss-German Fellowship was set up in 1978 to facilitate a program through which surgeons from the German-speaking countries of Austria, Switzerland, and Germany could visit the United Kingdom, Canada, and the United States of America. In 2023, surgeons Brian Mullis and Satish Kutty, representing the American Orthopaedic Association and the British Orthopaedic Association, respectively, visited centers in Austria, Switzerland, and Germany over the course of 4 weeks. This article describes their journey and experiences.

Sequencing batch reactor technology for landfill leachate treatment: A state-of-the-art review.

Landfill has become an underlying source of surface and groundwater pollution if not efficiently managed, due to the risk of leachate infiltration into to land and aquifers. The generated leachate is considered a serious environmental threat for the public health, because of the toxic and recalcitrant nature of its constituents. Thus, it must be collected and appropriately treated before being discharged into the environment. At present, there is no single unit process available for proper leachate treatment as conventional wastewater treatment processes cannot achieve a satisfactory level for degrading toxic substances present. Therefore, there is a growing interest in examination of different leachate treatment processes for maximum operational flexibility. Based on leachate characteristics, discharge requirements, technical possibilities, regulatory requirements and financial considerations, several techniques have been applied for its degradation, presenting varying degrees of efficiency. Therefore, this article presents a comprehensive review of existing research articles on the pros and cons of various leachate degradation methods. In line with environmental sustainability, the article stressed on the application and efficiency of sequencing batch reactor (SBR) system treating landfill leachate due to its operational flexibility, resistance to shock loads and high biomass retention. Contributions of integrated leachate treatment technologies with SBR were also discussed. The article further analyzed the effect of different adopted materials, processes, strategies and configurations on leachate treatment. Environmental and operational parameters that affect SBR system were critically discussed. It is believed that information contained in this review will increase readers fundamental knowledge, guide future researchers and be incorporated into future works on experimentally-based SBR studies for leachate treatment.

Differences in right ventricular-pulmonary vascular coupling and clinical indices between repaired standard tetralogy of Fallot and repaired tetralogy of Fallot with pulmonary atresia.

PURPOSE: The purpose of this study was to compare ventricular vascular coupling ratio (VVCR) between patients with repaired standard tetralogy of Fallot (TOF) and those with repaired TOF-pulmonary atresia (TOF-PA) using cardiovascular magnetic resonance (CMR). MATERIALS AND METHODS: Patients with repaired TOF aged>6 years were prospectively enrolled for same day CMR, echocardiography, and exercise stress test following a standardized protocol. Sanz's method was used to calculate VVCR as right ventricle (RV) end-systolic volume/pulmonary artery stroke volume. Regression analysis was used to examine associations with exercise test parameters, New York Heart Association (NYHA) class, RV size and biventricular systolic function. RESULTS: A total of 248 subjects were included; of these 222 had repaired TOF (group I, 129 males; mean age, 15.9±4.7 [SD] years [range: 8-29 years]) and 26 had repaired TOF-PA (group II, 14 males; mean age, 17.0±6.3 [SD] years [range: 8-29 years]). Mean VVCR for all subjects was 1.54±0.64 [SD] (range: 0.43-3.80). Mean VVCR was significantly greater in the TOF-PA group (1.81±0.75 [SD]; range: 0.78-3.20) than in the standard TOF group (1.51±0.72 [SD]; range: 0.43-3.80) (P=0.03). VVCR was greater in the 68 NYHA class II subjects (1.79±0.66 [SD]; range: 0.75-3.26) compared to the 179 NYHA class I subjects (1.46±0.61 [SD]; range: 0.43-3.80) (P<0.001). CONCLUSION: Non-invasive determination of VVCR using CMR is feasible in children and adolescents. VVCR showed association with NYHA class, and was worse in subjects with repaired TOF-PA compared to those with repaired standard TOF. VVCR shows promise as an indicator of pulmonary artery compliance and cardiovascular performance in this cohort.

Adsorption kinetics of colour removal from palm oil mill effluent using wastewater sludge carbon in column studies.

Treated palm oil mill effluents (POME) is of great concern as it still has colour from its dissolved organics which may pollute receiving water bodies. In this study, the removal of colour from treated palm oil mill effluent were investigated through adsorption studies using carbon derived from wastewater sludge (WSC). Sludge from activated sludge plants were dried and processed to produce WSC. In this study, three different bed depths of WSC were used: 5 cm, 10 cm, and 15 cm. For each bed depth, the flowrate was varied at three different values: 100 mL/hr, 50 mL/hr and 25 mL/hr. It was found that at bed depth of 5 cm, the breakthrough curves were occurred at 360 min, 150 min and 15 min for flowrates of 25, 50 and 100 mL/hr respectively. It was observed that at a particular depth the exhaustion time for column reduced as flow rate increases. Kinetic models, Adams-Bohart and Yoon-Nelson were used to analyze the performance of the adsorption. It was found that rate constant for Adams Bohart model decreased with the increase in bed depth. Adsorption capacity obtained from Adams-Bohart model ranged from 2676.19 mg/L up to 8938.78 mg/L. The maximum adsorption capacity increases with smaller bed depth. For Yoon-Nelson model, the rate constant decreases with increase in bed depth. The required time for 50% breakthrough obtained from the models ranged from 17.01 to 104.17 minutes for all three bed depths. The reduction of colour was found to be effective at all bed depths. The experimental data was best described by both models as with higher values of correlation coefficient (R2).

A Restricted Role for FcγR in the Regulation of Adaptive Immunity.

By their interaction with IgG immune complexes, FcγR and complement link innate and adaptive immunity, showing functional redundancy. In complement-deficient mice, IgG downstream effector functions are often impaired, as well as adaptive immunity. Based on a variety of model systems using FcγR-knockout mice, it has been concluded that FcγRs are also key regulators of innate and adaptive immunity; however, several of the model systems underpinning these conclusions suffer from flawed experimental design. To address this issue, we generated a novel mouse model deficient for all FcγRs (FcγRI/II/III/IV-/- mice). These mice displayed normal development and lymphoid and myeloid ontogeny. Although IgG effector pathways were impaired, adaptive immune responses to a variety of challenges, including bacterial infection and IgG immune complexes, were not. Like FcγRIIb-deficient mice, FcγRI/II/III/IV-/- mice developed higher Ab titers but no autoantibodies. These observations indicate a redundant role for activating FcγRs in the modulation of the adaptive immune response in vivo. We conclude that FcγRs are downstream IgG effector molecules with a restricted role in the ontogeny and maintenance of the immune system, as well as the regulation of adaptive immunity.

Fetal myocardial deformation in maternal diabetes mellitus and obesity.

OBJECTIVE: Experimental evidence suggests that changes in the fetal myocardium result from intrauterine effects of maternal diabetes mellitus and obesity. The aim of this study was to assess fetal cardiac function using two-dimensional speckle-tracking echocardiography to determine the effects of maternal diabetes and obesity on the fetal myocardium. METHODS: Comparative cross-sectional evaluation of myocardial function in fetuses of mothers with diabetes mellitus (FDM) or obesity (FO) and normal gestational age-matched control fetuses (FC) was performed using two-dimensional speckle-tracking echocardiography at two centers. RESULTS: In total, 178 fetuses (82 FDM, 26 FO and 70 FC) met the enrolment criteria. Mean gestational age at assessment was similar among groups: 25.3 ± 5.1 weeks for FDM, 25.0 ± 4.6 weeks for FO and 25.1 ± 4.9 weeks for FC. Mean maternal body mass index was significantly higher in FDM and FO groups compared with the FC group. Statistically significant differences in fetal cardiac function were detected between FDM and FC for global longitudinal strain (mean ± SD, -21.4 ± 6.5% vs -27.0 ± 5.2%; P < 0.001), global circumferential strain (mean ± SD, -22.6 ± 6.5% vs -26.2 ± 6.8%; P = 0.002), average longitudinal systolic strain rate (median, -1.4 (interquartile range (IQR), -1.7 to -1.1)/s vs -1.6 (IQR, -2.0 to -1.4)/s; P = 0.001) and average circumferential systolic strain rate (median, -1.4 (IQR, -1.9 to -1.1)/s vs -1.6 (IQR, -2.1 to -1.3)/s; P = 0.006). Cases of non-obese FDM also had abnormal strain parameters compared with FC. Global longitudinal strain (mean ± SD, -21.1 ± 7.5%) and average circumferential systolic strain rate (median, -1.3 (IQR, -1.8 to -1.1)/s) were significantly lower in FO compared with FC. CONCLUSIONS: Unfavorable changes occur in the fetal myocardium in response to both maternal diabetes mellitus and obesity. The long-term prognostic implications of these changes require further study. Copyright © 2016 ISUOG. Published by John Wiley & Sons Ltd.

Regulation of autoantibody activity by the IL-23-TH17 axis determines the onset of autoimmune disease.

The checkpoints and mechanisms that contribute to autoantibody-driven disease are as yet incompletely understood. Here we identified the axis of interleukin 23 (IL-23) and the TH17 subset of helper T cells as a decisive factor that controlled the intrinsic inflammatory activity of autoantibodies and triggered the clinical onset of autoimmune arthritis. By instructing B cells in an IL-22- and IL-21-dependent manner, TH17 cells regulated the expression of ß-galactoside α2,6-sialyltransferase 1 in newly differentiating antibody-producing cells and determined the glycosylation profile and activity of immunoglobulin G (IgG) produced by the plasma cells that subsequently emerged. Asymptomatic humans with rheumatoid arthritis (RA)-specific autoantibodies showed identical changes in the activity and glycosylation of autoreactive IgG antibodies before shifting to the inflammatory phase of RA; thus, our results identify an IL-23-TH17 cell-dependent pathway that controls autoantibody activity and unmasks a preexisting breach in immunotolerance.

Multiple differences between patients who initiate fish oil supplementation post-myocardial infarction and those who do not: the TRIUMPH Study.

The utility of fish oil supplements (FOS) in patients who survive an acute myocardial infarction (MI) remains controversial, with randomized trials showing less benefit than observational studies would suggest. The differences in the characteristics of MI patients who use FOS in routine clinical care are unknown but may help explain this discrepancy. We used data from a 24-site registry study in which extensive information was available on 4340 MI patients at admission and 1, 6, and 12 months postdischarge. After excluding those using FOS at admission (n = 651), those who died before the 1-month follow-up visit (n = 63), and those with missing data at 1 month (n = 1228), 2398 remained. Of them, 377 (16%) started FOS within 1 month of their MI. We analyzed 53 patient characteristics associated with FOS use. We observed differences (P < .001) in 20 demographic, socioeconomic, treatment, disease severity, and health status domains. The FOS users were more likely than nonusers to be white, married, financially secure, highly educated, and eating fish. They also had a higher ejection fraction at discharge, were more likely to have had in-hospital percutaneous coronary interventions, and were more likely to have participated in cardiac rehabilitation programs. The FOS users were less likely to have a history of diabetes, alcohol abuse, stroke, MI, and angina. In conclusion, post-MI patients who initiate FOS within 1 month of discharge in routine clinical practice differ substantially from those who do not. These differences are strongly associated with a better post-MI prognosis and may illuminate several sources of unmeasured confounding in observational studies.

Patient attendance at a UK dental hospital emergency clinic.

A questionnaire survey was performed within a dental emergency clinic at a London teaching hospital to determine patients' reasons for attendance and satisfaction with their care. Questionnaires were distributed to all patients registering for the dental emergency clinic over a four week period. A total of 1,058 questionnaires were returned, with an average satisfaction score of 9.3/10. The majority of patients (58%) reported symptomatic dental attendance. Common reasons for irregular attendance were lack of perceived 'need' for care and concerns about cost of care. Patients with irregular attendance were significantly more likely to report their past dental care had been affected by cost than regular attenders. Fifty-one percent of all respondents had tried to make an appointment with a dentist prior to attending the emergency clinic, and 21% of patients with a GDP reporting difficulty accessing urgent care at their practice. Forty-nine percent of patients attending the emergency clinic were referred to oral surgery clinics. Overall, this survey revealed high levels of satisfaction with care in this dental emergency clinic. Patients' reasons for attendance at the clinic can be considered in terms of 'push' and 'pull' factors, deterring them from primary dental care and drawing them into secondary/tertiary care environments.

Cardiovascular magnetic resonance feature-tracking assessment of myocardial mechanics: Intervendor agreement and considerations regarding reproducibility.

AIM: To assess intervendor agreement of cardiovascular magnetic resonance feature tracking (CMR-FT) and to study the impact of repeated measures on reproducibility. MATERIALS AND METHODS: Ten healthy volunteers underwent cine imaging in short-axis orientation at rest and with dobutamine stimulation (10 and 20 µg/kg/min). All images were analysed three times using two types of software (TomTec, Unterschleissheim, Germany and Circle, cvi(42), Calgary, Canada) to assess global left ventricular circumferential (Ecc) and radial (Err) strains and torsion. Differences in intra- and interobserver variability within and between software types were assessed based on single and averaged measurements (two and three repetitions with subsequent averaging of results, respectively) as determined by Bland-Altman analysis, intraclass correlation coefficients (ICC), and coefficient of variation (CoV). RESULTS: Myocardial strains and torsion significantly increased on dobutamine stimulation with both types of software (p<0.05). Resting Ecc and torsion as well as Ecc values during dobutamine stimulation were lower measured with Circle (p<0.05). Intra- and interobserver variability between software types was lowest for Ecc (ICC 0.81 [0.63-0.91], 0.87 [0.72-0.94] and CoV 12.47% and 14.3%, respectively) irrespective of the number of analysis repetitions. Err and torsion showed higher variability that markedly improved for torsion with repeated analyses and to a lesser extent for Err. On an intravendor level TomTec showed better reproducibility for Ecc and torsion and Circle for Err. CONCLUSIONS: CMR-FT strain and torsion measurements are subject to considerable intervendor variability, which can be reduced using three analysis repetitions. For both vendors, Ecc qualifies as the most robust parameter with the best agreement, albeit lower Ecc values obtained using Circle, and warrants further investigation of incremental clinical merit.

A single functional group substitution in c5a breaks B cell and T cell tolerance and protects against experimental arthritis.

OBJECTIVE: A deficiency in C5 protects against arthritis development. However, there is currently no approach successfully translating these findings into arthritis therapy, as by targeting the key component, C5a. The aim of this study was to develop a vaccination strategy targeting C5a as therapy for patients with rheumatoid arthritis. METHODS: An anti-C5a vaccine was generated by incorporating the unnatural amino acid p-nitrophenylalanine (4NPA) into selected sites in the murine C5a molecule. C5a-4NPA variants were screened for their immunogenicity in mice on different arthritis-susceptible class II major histocompatibility complex (MHC) backgrounds. A candidate vaccine was tested for its impact on disease in a murine model of collagen-induced arthritis (CIA). Immunity toward endogenous C5a as well as type II collagen was monitored and characterized. RESULTS: Replacing a single tyrosine residue in position 35 (Y(35) ) with 4NPA allowed the generation of an anti-C5a vaccine, which partly protected mice against the development of CIA while strongly ameliorating the severity of clinical disease. Although differing in just 3 atoms from wild-type C5a (wtC5a), C5aY(35) 4NPA induced loss of T cell and B cell tolerance toward the endogenous protein in mice expressing class II MHC H-2(q) molecules. Despite differential B cell epitope recognition, antibodies induced by both wtC5a and C5aY(35) 4NPA neutralized C5a. Thus, anti-wtC5a IgG titers during arthritis priming were potentially of critical importance for disease protection, because high titers of C5a-neutralizing antibodies after disease onset were unable to reverse the course of arthritis. CONCLUSION: The results of this study suggest that the most effective anti-C5a treatment in arthritis can be accomplished using a preventive vaccination strategy, and that treatment using conventional biologic or small molecule strategies targeting the C5a/C5aR axis may miss the optimal window for therapeutic intervention during the subclinical priming phase of the disease.

Smart consultation for musculoskeletal trauma: accuracy of using smart phones for fracture diagnosis.

INTRODUCTION: Musculoskeletal trauma occupies a significant proportion of the daily workload of most Emergency and Radiology departments. The diagnosis and management of patients with musculoskeletal trauma often require assessment of radiographs along with clinical assessment. With the advent of smart phones we hypothesised that they could be used as a means of smarter communication, particularly for the transfer of radiographic images between healthcare professionals. PATIENTS AND METHOD: We performed a cross sectional study using thirty radiographs each of the distal radius, ankle and hip. The study was approved by Ethics Committee and all data were anonymized in accordance to Caldicott guidelines and data protection act 1998. Photographs of radiographs were taken using an iphone camera and sent to three independent Orthopaedic Registrars via Multimedia messaging service (MMS). Each Registrar independently assessed these images on their smart phone display in their own time and recorded the specific diagnosis along with the classification of fractures and specific treatment plan. The accuracy of diagnosis on smart phone was measured against the radiology report; and inter observer agreement was assessed among registrars for classification and treatment plan. RESULTS: The overall accuracy of fracture diagnosis was 97.7% with sensitivity of 100% and specificity of 94.4%. The inter observer agreement analysis showed kappa (k) values of 0.67, 0.67 and 0.71 for classification of wrist, ankle and hip fractures respectively showing substantial agreement while kappa values for management plan were 0.65, 0.88 and 0.65 for the three fractures respectively showing substantial to near perfect agreement. CONCLUSION: This study suggests that smart phone can be used as a safe and accurate tool for skeletal trauma consultation among oncall doctors and can help reduce the waiting time in emergency departments.

Collagen antibody-induced arthritis evokes persistent pain with spinal glial involvement and transient prostaglandin dependency.

OBJECTIVE: Pain is one of the most debilitating symptoms reported by rheumatoid arthritis (RA) patients. While the collagen antibody-induced arthritis (CAIA) model is used for studying the effector phase of RA pathologic progression, it has not been evaluated as a model for studies of pain. Thus, this study was undertaken to examine pain-like behavior induced by anticollagen antibodies and to assess the effect of currently prescribed analgesics for RA. In addition, the involvement of spinal glia in antibody-induced pain was explored. METHODS: CAIA was induced in mice by intravenous injection of a collagen antibody cocktail, followed by intraperitoneal injection of lipopolysaccharide. Disease severity was assessed by visual and histologic examination. Pain-like behavior and the antinociceptive effect of diclofenac, buprenorphine, gabapentin, pentoxifylline, and JNK-interacting protein 1 were examined in mechanical stimulation experiments. Spinal astrocyte and microglia reactivity were investigated by real-time polymerase chain reaction and immunohistochemistry. RESULTS: Following the induction of CAIA, mice developed transient joint inflammation. In contrast, pain-like behavior was observed prior to, and outlasted, the visual signs of arthritis. Whereas gabapentin and buprenorphine attenuated mechanical hypersensitivity during both the inflammatory and postinflammatory phases of arthritis, diclofenac was antinociceptive only during the inflammatory phase. Spinal astrocytes and microglia displayed time-dependent signs of activation, and inhibition of glial activity reversed CAIA-induced mechanical hypersensitivity. CONCLUSION: CAIA represents a multifaceted model for studies exploring the mechanisms of pain induced by inflammation in the articular joint. Our findings of a time-dependent prostaglandin and spinal glial contribution to antibody-induced pain highlight the importance of using appropriate disease models to assess joint-related pain.

Genetic control of antibody production during collagen-induced arthritis development in heterogeneous stock mice.

OBJECTIVE: To identify genetic factors driving pathogenic autoantibody formation in collagen-induced arthritis (CIA), a mouse model of rheumatoid arthritis (RA), in order to better understand the etiology of RA and identify possible new avenues for therapeutic intervention. METHODS: We performed a genome-wide analysis of quantitative trait loci controlling autoantibody to type II collagen (anti-CII), anti-citrullinated protein antibody (ACPA), and rheumatoid factor (RF). To identify loci controlling autoantibody production, we induced CIA in a heterogeneous stock-derived mouse cohort, with contribution of 8 inbred mouse strains backcrossed to C57BL/10.Q. Serum samples were collected from 1,640 mice before arthritis onset and at the peak of the disease. Antibody concentrations were measured by standard enzyme-linked immunosorbent assay, and linkage analysis was performed using a linear regression-based method. RESULTS: We identified loci controlling formation of anti-CII of different IgG isotypes (IgG1, IgG3), antibodies to major CII epitopes (C1, J1, U1), antibodies to a citrullinated CII peptide (citC1), and RF. The anti-CII, ACPA, and RF responses were all found to be controlled by distinct genes, one of the most important loci being the immunoglobulin heavy chain locus. CONCLUSION: This comprehensive genetic analysis of autoantibody formation in CIA demonstrates an association not only of anti-CII, but interestingly also of ACPA and RF, with arthritis development in mice. These results underscore the importance of non-major histocompatibility complex genes in controlling the formation of clinically relevant autoantibodies.

Crystal structure of an arthritogenic anticollagen immune complex.

OBJECTIVE: In rheumatoid arthritis, joint inflammation and cartilage destruction are mediated by autoantibodies directed to various self antigens. Type II collagen (CII)-specific antibodies are likely to play a role in this process and have been shown to induce experimental arthritis in susceptible animals. The purpose of this study was to reveal how arthritogenic autoantibodies recognize native CII in its triple-helical conformation. METHODS: Site-directed mutagenesis and crystallographic studies were performed to reveal crucial contact points between the CII antibody and the triple-helical CII peptide. RESULTS: The crystal structure of a pathogenic autoantibody bound to a major triple-helical epitope present on CII was determined, allowing a first and detailed description of the interactions within an arthritogenic complex that is frequently occurring in both mice and humans with autoimmune arthritis. The crystal structure emphasizes the role of arginine residues located in a commonly recognized motif on CII and reveals that germline-encoded elements are involved in the interaction with the epitope. CONCLUSION: The crystal structure of an arthritogenic antibody binding a triple-helical epitope on CII indicates a crucial role of germline-encoded and arginine residues as the target structures.

Pathogenic autoreactive B cells are not negatively selected toward matrix protein collagen II.

We have addressed the importance of B cell tolerance to collagen type II, a matrix protein, which is a target in rheumatoid arthritis (RA) and its mouse models. We generated a germline-encoded anti-collagen type II (CII) IgH replacement anti-C1 B cell mouse strain (ACB) to investigate how B cell tolerance to CII, a matrix protein, is subverted and to further understand pathogenesis of RA. Phenotypic analysis revealed that CII-specific B cells were surprisingly neither deleted nor anergized. Instead, they were readily detected in all lymphoid organs. Spontaneously produced autoantibodies could bind directly to cartilage surface without detectable pathology. However, exaggerated arthritis was seen after injection of anti-CII Abs specific for other epitopes. In addition, Abs from CII-specific hybridomas generated from ACB mice induced arthritis. Interestingly, IgH/L chain sequence data in B cell hybridomas revealed a lack of somatic mutations in autoreactive B cells. The ACB model provides the first possibility, to our knowledge, to study B cell tolerance to a matrix protein, and the observations made in the study could not be predicted from previous models. B cell-reactive epitopes on CII are largely shared between human RA and rodent CII-induced arthritis; this study, therefore, has important implications for further understanding of pathological processes in autoimmune diseases like RA.

Inhibiting the C5-C5a receptor axis.

Activation of the complement system is a major pathogenic event that drives various inflammatory responses in numerous diseases. All pathways of complement activation lead to cleavage of the C5 molecule generating the anaphylatoxin C5a and, C5b that subsequently forms the terminal complement complex (C5b-9). C5a exerts a predominant pro-inflammatory activity through interactions with the classical G-protein coupled receptor C5aR (CD88) as well as with the non-G protein coupled receptor C5L2 (GPR77), expressed on various immune and non-immune cells. C5b-9 causes cytolysis through the formation of the membrane attack complex (MAC), and sub-lytic MAC and soluble C5b-9 also possess a multitude of non-cytolytic immune functions. These two complement effectors, C5a and C5b-9, generated from C5 cleavage, are key components of the complement system responsible for propagating and/or initiating pathology in different diseases, including paroxysmal nocturnal hemoglobinuria, rheumatoid arthritis, ischemia-reperfusion injuries and neurodegenerative diseases. Thus, the C5-C5a receptor axis represents an attractive target for drug development. This review provides a comprehensive analysis of different methods of inhibiting the generation of C5a and C5b-9 as well as the signalling cascade of C5a via its receptors. These include the inhibition of C5 cleavage through targeting of C5 convertases or via the C5 molecule itself, as well as blocking the activity of C5a by neutralizing antibodies and pharmacological inhibitors, or by targeting C5a receptors per se. Examples of drugs and naturally occurring compounds used are discussed in relation to disease models and clinical trials. To date, only one such compound has thus far made it to clinical medicine: the anti-C5 antibody eculizumab, for treating paroxysmal nocturnal hemoglobinuria. However, a number of drug candidates are rapidly emerging that are currently in early-phase clinical trials. The C5-C5a axis as a target for drug development is highly promising for the treatment of currently intractable major human diseases.

Intracapsular fracture of the proximal femur fracture after hip resurfacing treated by cannulated screws.

Fracture of the neck of the femur after resurfacing arthroplasty usually leads to failure and conversion to a total hip replacement. We describe an intracapsular fracture of the femoral neck sustained after hip resurfacing which was treated by cannulated screws, resulting in union and retention of the resurfacing implant. The result at follow-up three years later was very satisfactory with a Harris hip score of 99.

Secretory lysosome targeting and induced secretion of human soluble TNF-alpha receptor in murine hematopoietic cells in vivo as a principle for immunoregulation in inflammation and malignancy.

OBJECTIVE: Systemic administration of immunotherapeutics often gives rise to severe side effects. A local deposition, using secretory lysosomes of hematopoietic cells as vehicles for delivery, can overcome this problem. In the present study, the validity of this concept was investigated using retroviral transduction of the human soluble tumor necrosis factor-alpha receptor 1 (hsTNFR1) into murine bone marrow cells, followed by transfer of the genetically modified cells into irradiated mice. MATERIALS AND METHODS: Bone marrow cells from donor mice were transduced with retroviral vector containing cDNA for hsTNFR1, together with a transmembrane domain and a tyrosine-sorting signal in order to facilitate the endoplasmic reticulum export and to achieve secretory lysosome loading. Expression of hsTNFR1 in recipient mice was investigated using flow cytometry and Western blot. Enzyme-linked immunosorbent assay was used to measure levels of tumor necrosis factor-alpha, hsTNFR1, and murine TNFR1. RESULTS: Stable long-term expression of hsTNFR1 was achieved in transplanted mice. Hematopoietic cells, such as natural killer, T and B cells, and neutrophils contained hsTNFR1. Exposure of lipopolysaccaride (in vivo) or phorbole-myristrate esterase (in vitro) induced significant secretion of hsTNFR1. Release of endogeneous murine sTNFR1 did not differ between cells transduced with hsTNFR1 or an "empty" vector. CONCLUSION: Long-term expression in vivo and inducible secretion of hsTNFR1 in murine hematopoietic cells support the potential use of storage organelles in hematopoietic cells as vehicles for targeting inflamed/malignant sites with therapeutically active agents.