The Migration Pattern of a Short-Tapered Femoral Stem Correlates with the Occurrence of Cortical Hypertrophies: A 10-Year Longitudinal Study Using Ein Bild Röntgen Analyse-Femoral Component Analysis.

Background: Shorter hip stems have shown promising mid-term results but lack long-term data. High rates of distal cortical hypertrophy (CH) have been described, suggesting a more diaphyseal load transmission. This study aimed to determine patient-specific and surgery-related factors influencing CH and their impact on 10-year outcomes. Methods: It included 100 consecutive total hip arthroplasties (THAs) using the Fitmore stem (Zimmer, Warsaw, Indiana), with clinical and radiographic follow-ups at 1, 2, 5, and at least 10 years post-surgery. Results: No revisions were performed due to aseptic loosening after a mean of 11.6 years (range: 10-13.5 years). CH was observed in 26% of hips, primarily in Gruen zones 3 and 5. There was no significant difference in the Harris Hip Score between patients with and without CH. Larger stem sizes and greater axial subsidence significantly correlated with CH occurrence (OD 1.80, (1.13-1.92), p = 0.004; OD 1.47, (1.04-2.08), p = 0.028). The Fitmore stem demonstrated excellent survival rates and favorable outcomes over 10 years. Conclusions: Despite a lower CH rate compared to other studies, significant correlations with stem size and subsidence were identified. This study underscores the importance of patient selection and achieving high primary stability to maintain the metaphyseal anchoring concept.

Concerns about the histological assessment in a mouse model of human celiac disease.

Commentary on: Abadie V et al. IL­15, gluten and HLA­DQ8 drive tissue destruction in coeliac disease. Nature. 2020; 578: 600­604

In vitro adhesion, pilus expression, and in vivo amelioration of antibiotic-induced microbiota disturbance by Bifidobacterium spp. strains from fecal donors.

Fecal microbiota transplantation (FMT) is used routinely to treat recurrent Clostridioides difficile infection (rCDI) and investigated as a treatment for numerous conditions associated with gut microbiota alterations. Metagenomic analyses have indicated that recipient colonization by donor bacteria may be associated with favorable clinical outcomes. Bifidobacteria are abundant gut commensals associated with health. We have previously demonstrated that Bifidobacterium strains transferred in FMT can colonize recipients in long term, at least for a year, and recovered such strains by cultivation. This study addressed in vitro adhesion and pilus gene expression of long-term colonizing Bifidobacterium strains from FMT donors as well as in vivo colonization and capability to ameliorate antibiotic-induced microbiota disturbance. RNA-Seq differential gene expression analysis showed that the strongly adherent B. longum strains DY_pv11 and DX_pv23 expressed tight adherence and sortase-dependent pilus genes, respectively. Two B. longum strains, adherent DX_pv23 and poorly adhering DX_pv18, were selected to address in vivo colonization and efficacy to restore antibiotic-disturbed microbiota in C57BL/6 murine model. DX_pv23 colonized mice transiently with a rate comparable to that of the B. animalis BB-12 used as a reference. Although long-term colonization was not observed with any of the three strains, 16S rRNA gene profiling revealed that oral administration of DX_pv23 enhanced the recovery of antibiotic-disturbed microbiota to the original configuration significantly better than the other strains. The findings suggest that selected strains from FMT donors, such as DX_pv23 in this study, may have therapeutic potential by in vitro expression of colonization factors and boosting endogenous gut microbiota.

Intranasal administration of adenoviral vaccines expressing SARS-CoV-2 spike protein improves vaccine immunity in mouse models.

The ongoing SARS-CoV-2 pandemic is controlled but not halted by public health measures and mass vaccination strategies which have exclusively relied on intramuscular vaccines. Intranasal vaccines can prime or recruit to the respiratory epithelium mucosal immune cells capable of preventing infection. Here we report a comprehensive series of studies on this concept using various mouse models, including HLA class II-humanized transgenic strains. We found that a single intranasal (i.n.) dose of serotype-5 adenoviral vectors expressing either the receptor binding domain (Ad5-RBD) or the complete ectodomain (Ad5-S) of the SARS-CoV-2 spike protein was effective in inducing i) serum and bronchoalveolar lavage (BAL) anti-spike IgA and IgG, ii) robust SARS-CoV-2-neutralizing activity in the serum and BAL, iii) rigorous spike-directed T helper 1 cell/cytotoxic T cell immunity, and iv) protection of mice from a challenge with the SARS-CoV-2 beta variant. Intramuscular (i.m.) Ad5-RBD or Ad5-S administration did not induce serum or BAL IgA, and resulted in lower neutralizing titers in the serum. Moreover, prior immunity induced by an intramuscular mRNA vaccine could be potently enhanced and modulated towards a mucosal IgA response by an i.n. Ad5-S booster. Notably, Ad5 DNA was found in the liver or spleen after i.m. but not i.n. administration, indicating a lack of systemic spread of the vaccine vector, which has been associated with a risk of thrombotic thrombocytopenia. Unlike in otherwise genetically identical HLA-DQ6 mice, in HLA-DQ8 mice Ad5-RBD vaccine was inferior to Ad5-S, suggesting that the RBD fragment does not contain a sufficient collection of helper-T cell epitopes to constitute an optimal vaccine antigen. Our data add to previous promising preclinical results on intranasal SARS-CoV-2 vaccination and support the potential of this approach to elicit mucosal immunity for preventing transmission of SARS-CoV-2.

Acetabular orientation in triple pelvic osteotomy: is intraoperative fluoroscopy reliable?

PURPOSE: In pelvic osteotomies, unfavorable balancing of the anterior and posterior acetabular wall can affect the longevity of the natural joint. This raises the question, whether intraoperative fluoroscopy is sufficiently accurate. The objective was to assess the correlation between acetabular parameters [lateral center edge angle (LCEA), acetabular index (AI), anterior wall index (AWI), posterior wall index (PWI)] acquired on intraoperative fluoroscopic images and postoperative pelvic radiographs and to analyze intra- and interobserver reliability of these parameters. METHODS: A retrospective examination was conducted on 206 consecutive cases (176 patients) after triple pelvic osteotomy (TPO). Every patient received a pre- and postoperative pelvic radiograph in supine position in exactly the same technique. A highly standardized surgical sequence allowed consistent intraoperative fluoroscopic imaging. LCAE, AI, PWI and AWI were measured by an experienced orthopedic surgeon and an orthopedic surgeon in training. Statistics comprised a priori power analysis, Bland-Altman analysis and intraclass correlation coefficient (ICC). RESULTS: A total of 165 cases were included. ICC between the parameters of the fluoroscopic images and postoperative radiographs was for LCEA: 0.935, AI: 0.936, AWI: 0.725 and PWI: 0.878. Intraobserver ICC for all parameters ranged from 0.953 to 0.989, interobserver ICC from 0.798 to 0.968, respectively. CONCLUSION: In the surgical treatment of hip dysplasia by means of TPO, intraoperative fluoroscopic imaging has proven to be reliable and accurate. Intraobserver correlation was excellent for all parameters. The correlation between the intraoperative fluoroscopic images and postoperative radiographs ranged from good to excellent, with the lowest values for the acetabular wall indices (AWI and PWI).

Hijacking the human complement inhibitor C4b-binding protein by the sporozoite stage of the Plasmodium falciparum parasite.

The complement system is considered the first line of defense against pathogens. Hijacking complement regulators from blood is a common evasion tactic of pathogens to inhibit complement activation on their surfaces. Here, we report hijacking of the complement C4b-binding protein (C4bp), the regulator of the classical and lectin pathways of complement activation, by the sporozoite (SPZ) stage of the Plasmodium falciparum parasite. This was shown by direct binding of radiolabeled purified C4bp to live SPZs as well as by binding of C4bp from human serum to SPZs in indirect immunofluorescence assays. Using a membrane-bound peptide array, peptides from the N-terminal domain (NTD) of P. falciparum circumsporozoite protein (CSP) were found to bind C4bp. Soluble biotinylated peptide covering the same region on the NTD and a recombinantly expressed NTD also bound C4bp in a dose-dependent manner. NTD-binding site on C4bp was mapped to the CCP1-2 of the C4bp α-chain, a common binding site for many pathogens. Native CSP was also co-immunoprecipitated with C4bp from human serum. Preventing C4bp binding to the SPZ surface negatively affected the SPZs gliding motility in the presence of functional complement and malaria hyperimmune IgG confirming the protective role of C4bp in controlling complement activation through the classical pathway on the SPZ surface. Incorporating the CSP-C4bp binding region into a CSP-based vaccine formulation could induce vaccine-mediated immunity that neutralizes this immune evasion region and increases the vaccine efficacy.

Impaired immunity and high attack rates caused by SARS-CoV-2 variants among vaccinated long-term care facility residents.

INTRODUCTION: Long-term care facilities (LTCF) residents are at high risk for severe coronavirus disease 2019 (COVID-19), and therefore, COVID-19 vaccinations were prioritized for residents and personnel in Finland at the beginning of 2021. METHODS: We investigated COVID-19 outbreaks in two LTCFs, where residents were once or twice vaccinated. After the outbreaks we measured immunoglobulin G (IgG) antibodies to severe acute respiratory syndrome coronavirus 2 spike glycoprotein, neutralizing antibody (NAb) titers, and cell-mediated immunity markers from residents and healthcare workers (HCWs). RESULTS: In LTFC-1, the outbreak was caused by an Alpha variant (B.1.1.7) and the attack rate (AR) among once vaccinated residents was 23%. In LTCF-2 the outbreak was caused by a Beta variant (B.1.351). Its AR was 47% although all residents had received their second dose 1 month before the outbreak. We observed that vaccination had induced lower IgG concentrations, NAb titers and cell-mediated immune responses in residents compared to HCWs. Only 1/8 residents had NAb to the Beta variant after two vaccine doses. CONCLUSIONS: The vaccinated elderly remain susceptible to breakthrough infections caused by Alpha and Beta variants. The weaker vaccine response in the elderly needs to be addressed in vaccination protocols, while new variants capable of evading vaccine-induced immunity continue to emerge.

[Contemporary indications for aseptic revision total hip arthroplasty]. / Aktuelle Indikationen zum aseptischen Hüft-TEP-Wechsel.

BACKGROUND: Hip arthroplasties and revision procedures will continue to rise over the next decades. In 2020 in Germany, 75% of all revision surgeries involved an exchange of at least one component; exchanges of all components were carried out in 27.5% of the revisions. The most common failure modes were aseptic loosening, infections, periprosthetic fractures, instabilities, and metal-related pathologies. INDICATIONS: Aseptic loosening remains the most common reason for revision. However, the indications for hip arthroplasty revisions have changed over time, with a decrease in revisions due to aseptic loosening and an increase in revisions due to infection and periprosthetic fracture. The rate of dislocations remained approximately constant over the past decade, with international differences. Metal-associated pathologies will continue to play a significant role in revision hip arthroplasty.

Residual dysplasia of the hip after successful ultrasound-monitored treatment: how does an infant's hip evolve?

Despite that normal values for the hip joint are reached at the end of ultrasound-monitored-treatment, the development of the acetabulum can be compromised during the growth phase. The acetabular index (AI) measured on a pelvic radiograph has been proven to be a reliable parameter. The aim of this study is to gain a better understanding of the dynamics of once-treated, residually dysplastic hips. This should be achieved by radiographically following these hips up to a milestone-examination at the end of preschool age. A total of 120 hips of consecutive 60 infants were included in this examination, each presenting with a residual developmental dysplasia of the hips (DDH) after successful ultrasound-monitored harness treatment. Radiographic follow-up was assessed retrospectively around 18 months, 3 years and 6 years of age, and the AI was measured. The age-dependent Tönnis classification was applied. The hips were assigned normal, mildly or severely dysplastic. Dependent t -test for paired samples indicated a highly significant improvement of the AI-values, including from the first to the second and from the second to the third follow-up. The percentage distribution into the Tönnis classification changed remarkably: in the first follow-up, 36 of the 120 hips were evaluated 'severely dysplastic', in the third follow-up only 1. On the other hand, three hips underwent acetabuloplasty. Even after normal values have been achieved at the end of ultrasound-monitored treatment, there remains a risk of residual dysplasia of the hips. Particularly, when the first radiographic examination shows nonphysiological findings, further close-meshed follow-up is recommended. Level of evidence: retrospective study of therapeutic outcome, consecutive patients, level II.

Defining 'undersizing' in short-stem total hip arthroplasty: the importance of sufficient contact with the lateral femoral cortex.

INTRODUCTION: Undersizing is 1 of the main reasons for early implant failure. Adequate sizing in short-stem total hip arthroplasty can be challenging and, so far, lacks key decision criteria. METHODS: We included 191 calcar-guided short stems. All patients underwent standardised digital anteroposterior imaging pre- and post-surgery and during follow-up. Preoperative planning was performed digitally. Planned stem sizes were retrospectively assessed and compared with the implanted sizes. Additionally, adequate sizing was analysed by determining whether the stem made intraoperative contact with the lateral distal femoral cortex. Implant migration was assessed by Ein-Bild-Roentgen-Analysis Femoral-Component-Analysis 5 years after surgery. Influence of different Dorr types and postoperative centrum-collum-diaphyseal angle (CCD) categories on lateral femoral cortical contact were analysed. Additionally, the Harris Hip Score (HHS) was assessed at final follow-up. Stem-revision rate was documented. RESULTS: Implanted stems were at least 2 sizes smaller than those at the preoperative planning in 49 (25.7%) cases. The stem made contact with the lateral distal femoral cortex in only 130 hips (68.1%). Mean subsidence was significantly higher in the no-contact group (2.07 mm, range -7.7 to 1.7) than in the contact group (1.23 mm, range -4.5 to 1.8) at the final follow-up (p = 0.0018). Stems at least 2 sizes smaller than those at preoperative planning showed a significantly higher prevalence of non-contact (46.9% vs. 26.8%) (p = 0.009). Those undersized stems were more likely found in varus hips. No influence of the Dorr classification and the different CCD categories on the probability of achieving sufficient cortical contact was found. HHS showed no intergroup differences. CONCLUSIONS: Stems that did not make intraoperative contact with the lateral femoral cortex showed significantly increased axial migration at mid-term follow-up. Thus, the investigated criteria regarding the definition of undersizing in short-stem THA should be acknowledged. No obvious mid-term consequences were noted regarding revision rate. Long-term results are mandatory.

Common Laboratory Mice Are Susceptible to Infection with the SARS-CoV-2 Beta Variant.

Small animal models are of crucial importance for assessing COVID-19 countermeasures. Common laboratory mice would be well-suited for this purpose but are not susceptible to infection with wild-type SARS-CoV-2. However, the development of mouse-adapted virus strains has revealed key mutations in the SARS-CoV-2 spike protein that increase infectivity, and interestingly, many of these mutations are also present in naturally occurring SARS-CoV-2 variants of concern. This suggests that these variants might have the ability to infect common laboratory mice. Herein we show that the SARS-CoV-2 beta variant attains infectibility to BALB/c mice and causes pulmonary changes within 2-3 days post infection, consistent with results seen in other murine models of COVID-19, at a reasonable virus dose (2 × 105 PFU). The findings suggest that common laboratory mice can serve as the animal model of choice for testing the effectiveness of antiviral drugs and vaccines against SARS-CoV-2.

Biomechanics of a calcar loading and a shortened tapered femoral stem: Comparative in-vitro testing of primary stability and strain distribution.

PURPOSE: The most common femoral short stems available on the market can, in principle, be divided with regard to their anchoring concepts into a calcar loading and a shortened tapered design. The purpose of this study was to compare the primary stability and stress-shielding of two short stems, which correspond to these two different anchoring concepts. METHODS: Using seven paired fresh frozen human cadaver femurs, primary axial and rotational stabilities under dynamic load (100-1600 N) were evaluated by miniature displacement transducers after 100,000 load cycles. Changes in cortical strains were measured before and after implantation of both stem types to detect implant-specific load transmission and possible stress-shielding effects. RESULTS: Reversible and irreversible micromotions under dynamic load displayed no significant differences between the two implants. Implantation of either stem types resulted in a reduction of cortical strains in the proximal femur, which was less pronounced for the calcar loading implant. CONCLUSIONS: Both short stems displayed comparable micromotions far below the critical threshold above which osseointegration may disturbed. Neither short stem could avoid proximal stress-shielding. This effect was less pronounced for the calcar loading short stem, which corresponds to a more physiological load transmission.

Abductor Muscle Force after Straight-Stem Compared to Short-Stem Total Hip Arthroplasty through a Modified Direct Lateral Approach: Functional Assessment of 70 Consecutive Patients of a Randomized Controlled Clinical Trial.

Because of preservation of proximal femoral bone stock and minimized soft tissue trauma, short-stem implants are becoming increasingly important in total hip arthroplasty (THA). The postulated advantage regarding the functional outcome has not been verified. We hypothesized an increased abductor muscle strength by the use of a short-stem design. Seventy consecutive patients of a randomized clinical trial were included. Of these, 67 patients met the inclusion criteria after 12 months. Thirty-five patients received a standard straight stem and 32 patients a short-stem femoral component. All surgeries were performed by a modified direct lateral approach. Isometric muscle strength of the hip abductors was evaluated preoperatively 3 and 12 months after surgery. Harris hip score (HHS) and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) scores were evaluated. After three months, there were no differences between the two groups; the abductor force was comparable to the preoperative initial values. After 12 months, a significant increase in muscle strength for the short stem patient group compared to preoperative baseline values was measured (straight-stem THA, 0.09 Nm/kg ± 0.4, p = 0.32; short-stem THA, 0.2 Nm/kg ± 0.3, p = 0.004). Comparison of the 12-month postoperative total HHS and WOMAC revealed no significant differences between both groups. A significant increase in hip abductor muscle strength 12 months after short-stem THA compared to conventional-stem THA was observed.

Biomechanics of a cemented short stem: a comparative in vitro study regarding primary stability and maximum fracture load.

PURPOSE: In total hip arthroplasty, uncemented short stems have been used more and more frequently in recent years. Especially for short and curved femoral implants, bone-preserving and soft tissue-sparing properties are postulated. However, indication is limited to sufficient bone quality. At present, there are no curved short stems available which are based on cemented fixation. METHODS: In this in vitro study, primary stability and maximum fracture load of a newly developed cemented short-stem implant was evaluated in comparison to an already well-established cemented conventional straight stem using six pairs of human cadaver femurs with minor bone quality. Primary stability, including reversible micromotion and irreversible migration, was assessed in a dynamic material-testing machine. Furthermore, a subsequent load-to-failure test revealed the periprosthetic fracture characteristics. RESULTS: Reversible and irreversible micromotions showed no statistical difference between the two investigated stems. All short stems fractured under maximum load according to Vancouver type B3, whereas 4 out of 6 conventional stems suffered a periprosthetic fracture according to Vancouver type C. Mean fracture load of the short stems was 3062 N versus 3160 N for the conventional stems (p = 0.84). CONCLUSION: Primary stability of the cemented short stem was not negatively influenced compared to the cemented conventional stem and no significant difference in fracture load was observed. However, a clear difference in the fracture pattern has been identified.

Urinary Excretion of Iohexol as a Permeability Marker in a Mouse Model of Intestinal Inflammation: Time Course, Performance and Welfare Considerations.

Intestinal permeability (IP) tests are used to assess intestinal damage in patients and research models. The probe iohexol has shown advantages compared to 51Cr-EDTA or absorbable/nonabsorbable sugars. During IP tests, animals are housed in metabolic cages (MCs) to collect urine. We examined the performance of an iohexol IP test in mice. Rag1-/- (C57BL/6) mice of both sexes were divided into controls or treatment groups, the latter receiving injections of effector/memory T cells to induce intestinal inflammation. After two, four and five weeks (W), a single dose of iohexol was orally administered. Urine was collected seven times over 24 h in MCs. Iohexol concentration was measured by ELISA. Intestinal histological damage was scored in duodenal sections. In control and treated mice of both sexes, urinary excretion of iohexol peaked at 4 h. From W2 to W4/W5, urinary iohexol excretion increased in treated mice of both sexes, consistent with development of duodenitis in this model. Positive correlations were observed between the urinary excretion of iohexol in W4/W5 and the histological severity of duodenitis in treated male mice. We conclude that a 6 h cumulative urine sample appears sufficient to evaluate small IP to iohexol in this mouse model, improving animal welfare by reducing cage periods.

Mid-term gender-specific differences in periprosthetic bone remodelling after implantation of a curved bone-preserving hip stem.

BACKGROUND: The implant-specific periprosthetic bone remodelling in the proximal femur is considered to be an important factor influencing the long-term survival of cementless hip stems. Particularly data of gender-specific differences regarding bone-preserving stems are very rare in literature and mainly limited to short-term investigations. Therefore, we investigated at mid-term one arm of a prospective randomised study to evaluate if there is an influence of gender on implant-specific stress shielding after implantation of a curved bone preserving hip stem (Fitmore) 5 years postoperatively. HYPOTHESIS: We hypothesised there will be no gender-specific differences in periprosthetic bone remodelling. PATIENTS AND METHODS: A total of 20 female and 37 male patients underwent total hip arthroplasty using the Fitmore stem. Clinical, radiological as well as osteodensitometric examinations were performed preoperatively, 7 days and 3, 12 and 60 months postoperatively. Clinical data collection included the Western Ontario and McMaster Universities Arthritis Index (WOMAC) and the Harris Hip Score (HHS). Periprosthetic bone mineral density (BMD) was measured using Dual Energy X-ray Absorptiometry (DXA) and the periprosthetic bone was divided into 7 regions of interest (ROI) for analysis. The results at 3, 12 and 60 months were compared with the first postoperative measurement after 7 days to obtain a percentage change. RESULTS: Periprosthetic BMD showed a decrease in all 7 ROIs for both groups 5 years postoperatively referred to the baseline value, except ROI 3 (0.8%, p=0.761), representing the distal lateral part of the stem, and ROI 5 (0.3%, p=0.688), representing the distal medial part of the stem in the male cohort. Significant gender differences were found in ROI 1 (-16.0% vs. -3.5%, p=0.016) and ROI 6 (-9.9% vs. -2.1%, p=0.04) in favour of the male patients. Clinical results showed no significant gender differences 5 years postoperatively with regard to WOMAC (mean 0.4 (±0.8, 0-3.3) in women vs. 0.3 (±0.8, 0-4.2) in men, p=0.76) and HHS (mean 93.0 (±9.7, 66.0-100.0) in women vs. 93.9 (±11.5, 53.0-100.0) in men, p=0.36). CONCLUSION: Proximal stress shielding was observed independent of gender 5 years postoperatively. However, there was a significantly lower bone loss proximal lateral and medial below the calcar in male patients, indicating a more physiological load transfer. [ClinicalTrials.gov identifier: NCT03147131 (Study ID D.3067-244/10). Registered 10 May 2017 - retrospectively registered, https://clinicaltrials.gov/ct2/show/NCT03147131?term=Bieger&draw=2&rank=1] LEVEL OF EVIDENCE: IV; prospective study without control group.

No evidence of autoimmunity to human OX1 or OX2 orexin receptors in Pandemrix-vaccinated narcoleptic children.

Narcolepsy type 1, likely an immune-mediated disease, is characterized by excessive daytime sleepiness and cataplexy. The disease is strongly associated with human leukocyte antigen (HLA) DQB1∗06:02. A significant increase in the incidence of childhood and adolescent narcolepsy was observed after a vaccination campaign with AS03-adjuvanted Pandemrix influenza vaccine in Nordic and several other countries in 2010 and 2011. Previously, it has been suggested that a surface-exposed region of influenza A nucleoprotein, a structural component of the Pandemrix vaccine, shares amino acid residues with the first extracellular domain of the human OX2 orexin/hypocretin receptor eliciting the development of autoantibodies. Here, we analyzed, whether H1N1pdm09 infection or Pandemrix vaccination contributed to the development of autoantibodies to the orexin precursor protein or the OX1 or OX2 receptors. The analysis was based on the presence or absence of autoantibody responses against analyzed proteins. Entire OX1 and OX2 receptors or just their extracellular N-termini were transiently expressed in HuH7 cells to determine specific antibody responses in human sera. Based on our immunofluorescence analysis, none of the 56 Pandemrix-vaccinated narcoleptic patients, 28 patients who suffered from a laboratory-confirmed H1N1pdm09 infection or 19 Pandemrix-vaccinated controls showed specific autoantibody responses to prepro-orexin, orexin receptors or the isolated extracellular N-termini of orexin receptors. We also did not find any evidence for cell-mediated immunity against the N-terminal epitopes of OX2. Our findings do not support the hypothesis that the surface-exposed region of the influenza nucleoprotein A would elicit the development of an immune response against orexin receptors.

Mid-term migration pattern of a calcar-guided short stem: A five-year EBRA-FCA-study.

BACKGROUND: Short-term results of several short-stem designs have indicated early axial migration. Mid- and long-term results for most designs are lacking. The objective of this study was to evaluate the mid-term migration pattern of a calcar-guided short stem five years postoperative. METHODS: Implant migration of 191 calcar-guided short stems was assessed by Ein-Bild-Roentgen-Analysis Femoral-Component- Analysis (EBRA-FCA) 5 years after surgery. Migration pattern of the whole group was analyzed and compared to the migration pattern of implants potentially being "at hazard" with a subsidence of more than 1.5 mm at 2 years postoperatively. Influence of preoperative Dorr types (A vs. B vs. C), age (<70 vs. >70 years), gender (female vs. male), weight (<90 kg vs. >90 kg), BMI (<30 vs. >30) and uni-vs. bilateral procedures on mid-term migration pattern was analyzed. Additionally outcome of varus- and valgus stem alignment was assessed. RESULTS: Mean axial subsidence was 1.5 mm (SD 1.48 mm) at final follow-up. Two years after surgery 73 short stems were classified "at hazard". Of these stems, 69 cases showed secondary stabilisation in the following period, whereas 4 cases presented unstable with more than 1 mm of further subsidence. Stem revision was not required neither in the group of implants with early stabilisation nor the group with pronounced early onset migration. Male gender and heavy-weight patients had a significant higher risk for axial migration, as well as extensive valgus stem alignment, whereas for Dorr type B, compared to A, no statistical difference could be observed. CONCLUSIONS: In most cases, even in the group of stems being "at hazard", settling could be documented. While different Dorr types did not show a statistically significant impact on axial migration, particularly in male and heavy-weight patients the risk of continuous subsidence is increased. In those 4 cases with further migration, undersizing of the stem could be recognized. At present, clinical consequences are still uncertain.

Gliadin Nanoparticles Induce Immune Tolerance to Gliadin in Mouse Models of Celiac Disease.

BACKGROUND & AIMS: Celiac disease could be treated, and potentially cured, by restoring T-cell tolerance to gliadin. We investigated the safety and efficacy of negatively charged 500-nm poly(lactide-co-glycolide) nanoparticles encapsulating gliadin protein (TIMP-GLIA) in 3 mouse models of celiac disease. Uptake of these nanoparticles by antigen-presenting cells was shown to induce immune tolerance in other animal models of autoimmune disease. METHODS: We performed studies with C57BL/6; RAG1-/- (C57BL/6); and HLA-DQ8, huCD4 transgenic Ab0 NOD mice. Mice were given 1 or 2 tail-vein injections of TIMP-GLIA or control nanoparticles. Some mice were given intradermal injections of gliadin in complete Freund's adjuvant (immunization) or of soluble gliadin or ovalbumin (ear challenge). RAG-/- mice were given intraperitoneal injections of CD4+CD62L-CD44hi T cells from gliadin-immunized C57BL/6 mice and were fed with an AIN-76A-based diet containing wheat gluten (oral challenge) or without gluten. Spleen or lymph node cells were analyzed in proliferation and cytokine secretion assays or by flow cytometry, RNA sequencing, or real-time quantitative polymerase chain reaction. Serum samples were analyzed by gliadin antibody enzyme-linked immunosorbent assay, and intestinal tissues were analyzed by histology. Human peripheral blood mononuclear cells, or immature dendritic cells derived from human peripheral blood mononuclear cells, were cultured in medium containing TIMP-GLIA, anti-CD3 antibody, or lipopolysaccharide (controls) and analyzed in proliferation and cytokine secretion assays or by flow cytometry. Whole blood or plasma from healthy volunteers was incubated with TIMP-GLIA, and hemolysis, platelet activation and aggregation, and complement activation or coagulation were analyzed. RESULTS: TIMP-GLIA did not increase markers of maturation on cultured human dendritic cells or induce activation of T cells from patients with active or treated celiac disease. In the delayed-type hypersensitivity (model 1), the HLA-DQ8 transgenic (model 2), and the gliadin memory T-cell enteropathy (model 3) models of celiac disease, intravenous injections of TIMP-GLIA significantly decreased gliadin-specific T-cell proliferation (in models 1 and 2), inflammatory cytokine secretion (in models 1, 2, and 3), circulating gliadin-specific IgG/IgG2c (in models 1 and 2), ear swelling (in model 1), gluten-dependent enteropathy (in model 3), and body weight loss (in model 3). In model 1, the effects were shown to be dose dependent. Splenocytes from HLA-DQ8 transgenic mice given TIMP-GLIA nanoparticles, but not control nanoparticles, had increased levels of FOXP3 and gene expression signatures associated with tolerance induction. CONCLUSIONS: In mice with gliadin sensitivity, injection of TIMP-GLIA nanoparticles induced unresponsiveness to gliadin and reduced markers of inflammation and enteropathy. This strategy might be developed for the treatment of celiac disease.