Lupus autoantibodies initiate neuroinflammation sustained by continuous HMGB1:RAGE signaling and reversed by increased LAIR-1 expression.

Cognitive impairment is a frequent manifestation of neuropsychiatric systemic lupus erythematosus, present in up to 80% of patients and leading to a diminished quality of life. In the present study, we used a model of lupus-like cognitive impairment that is initiated when antibodies that crossreact with excitatory neuronal receptors penetrate the hippocampus, causing immediate, self-limited, excitotoxic death of hippocampal neurons, which is then followed by a significant loss of dendritic complexity in surviving neurons. This injury creates a maladaptive equilibrium that is sustained in mice for at least 1 year. We identified a feedforward loop of microglial activation and microglia-dependent synapse elimination dependent on neuronal secretion of high mobility group box 1 protein (HMGB1) which binds the receptor for advanced glycation end products (RAGE) and leads to microglial secretion of C1q, upregulation of interleukin-10 with consequent downregulation of leukocyte-associated immunoglobulin-like receptor 1 (LAIR-1), an inhibitory receptor for C1q. Treatment with a centrally acting angiotensin-converting enzyme inhibitor or with an angiotensin-receptor blocker restored a healthy equilibrium, microglial quiescence and intact spatial memory.

T cells instruct myeloid cells to produce inflammasome-independent IL-1ß and cause autoimmunity.

The cytokine interleukin (IL)-1ß is a key mediator of antimicrobial immunity as well as autoimmune inflammation. Production of IL-1ß requires transcription by innate immune receptor signaling and maturational cleavage by inflammasomes. Whether this mechanism applies to IL-1ß production seen in T cell-driven autoimmune diseases remains unclear. Here, we describe an inflammasome-independent pathway of IL-1ß production that was triggered upon cognate interactions between effector CD4+ T cells and mononuclear phagocytes (MPs). The cytokine TNF produced by activated CD4+ T cells engaged its receptor TNFR on MPs, leading to pro-IL-1ß synthesis. Membrane-bound FasL, expressed by CD4+ T cells, activated death receptor Fas signaling in MPs, resulting in caspase-8-dependent pro-IL-1ß cleavage. The T cell-instructed IL-1ß resulted in systemic inflammation, whereas absence of TNFR or Fas signaling protected mice from CD4+ T cell-driven autoimmunity. The TNFR-Fas-caspase-8-dependent pathway provides a mechanistic explanation for IL-1ß production and its consequences in CD4+ T cell-driven autoimmune pathology.

Ultrasound Neuromodulation of an Anti-Inflammatory Pathway at the Spleen Improves Experimental Pulmonary Hypertension.

BACKGROUND: Inflammation is pathogenically implicated in pulmonary arterial hypertension; however, it has not been adequately targeted therapeutically. We investigated whether neuromodulation of an anti-inflammatory neuroimmune pathway involving the splenic nerve using noninvasive, focused ultrasound stimulation of the spleen (sFUS) can improve experimental pulmonary hypertension. METHODS: Pulmonary hypertension was induced in rats either by Sugen 5416 (20 mg/kg SQ) injection, followed by 21 (or 35) days of hypoxia (sugen/hypoxia model), or by monocrotaline (60 mg/kg IP) injection (monocrotaline model). Animals were randomized to receive either 12-minute-long sessions of sFUS daily or sham stimulation for 14 days. Catheterizations, echocardiography, indices of autonomic function, lung and heart histology and immunohistochemistry, spleen flow cytometry, and lung single-cell RNA sequencing were performed after treatment to assess the effects of sFUS. RESULTS: Splenic denervation right before induction of pulmonary hypertension results in a more severe disease phenotype. In both sugen/hypoxia and monocrotaline models, sFUS treatment reduces right ventricular systolic pressure by 25% to 30% compared with sham treatment, without affecting systemic pressure, and improves right ventricular function and autonomic indices. sFUS reduces wall thickness, apoptosis, and proliferation in small pulmonary arterioles, suppresses CD3+ and CD68+ cell infiltration in lungs and right ventricular fibrosis and hypertrophy and lowers BNP (brain natriuretic peptide). Beneficial effects persist for weeks after sFUS discontinuation and are more robust with early and longer treatment. Splenic denervation abolishes sFUS therapeutic benefits. sFUS partially normalizes CD68+ and CD8+ T-cell counts in the spleen and downregulates several inflammatory genes and pathways in nonclassical and classical monocytes and macrophages in the lung. Differentially expressed genes in those cell types are significantly enriched for human pulmonary arterial hypertension-associated genes. CONCLUSIONS: sFUS causes dose-dependent, sustained improvement of hemodynamic, autonomic, laboratory, and pathological manifestations in 2 models of experimental pulmonary hypertension. Mechanistically, sFUS normalizes immune cell populations in the spleen and downregulates inflammatory genes and pathways in the lung, many of which are relevant in human disease.

A Multiplexed System for Quantitative Comparisons of Chromatin Landscapes.

Genome-wide profiling of histone modifications can provide systematic insight into the regulatory elements and programs engaged in a given cell type. However, conventional chromatin immunoprecipitation and sequencing (ChIP-seq) does not capture quantitative information on histone modification levels, requires large amounts of starting material, and involves tedious processing of each individual sample. Here, we address these limitations with a technology that leverages DNA barcoding to profile chromatin quantitatively and in multiplexed format. We concurrently map relative levels of multiple histone modifications across multiple samples, each comprising as few as a thousand cells. We demonstrate the technology by monitoring dynamic changes following inhibition of p300, EZH2, or KDM5, by linking altered epigenetic landscapes to chromatin regulator mutations, and by mapping active and repressive marks in purified human hematopoietic stem cells. Hence, this technology enables quantitative studies of chromatin state dynamics across rare cell types, genotypes, environmental conditions, and drug treatments.

Restoring tolerance to ß-cells in Type 1 diabetes: Current and emerging strategies.

Type 1 diabetes (T1D) results from insulin insufficiency due to islet death and dysfunction following T cell-mediated autoimmune attack. The technical feasibility of durable, functional autologous islet restoration is progressing such that it presents the most likely long-term cure for T1D but cannot succeed without the necessary counterpart of clinically effective therapeutic strategies that prevent grafted islets' destruction by pre-existing anti-islet T cells. While advances have been made in broad immunosuppression to lower off-target effects, the risk of opportunistic infections and cancers remains a concern, especially for well-managed T1D patients. Current immunomodulatory strategies in development focus on autologous Treg expansion, treatments to decrease antigen presentation and T effector (Teff) activation, and broad depletion of T cells with or without hematopoietic stem cell transplants. Emerging strategies harnessing the intensified DNA damage response present in expanding T cells, exacerbating their already high sensitivity to apoptosis to abate autoreactive Teff cells.

Cognitive dysfunction in SLE: An understudied clinical manifestation.

Neuropsychiatric lupus (NPSLE) is a debilitating manifestation of SLE which occurs in a majority of SLE patients and has a variety of clinical manifestations. In the central nervous system, NPSLE may result from ischemia or penetration of inflammatory mediators and neurotoxic antibodies through the blood brain barrier (BBB). Here we focus on cognitive dysfunction (CD) as an NPSLE manifestation; it is common, underdiagnosed, and without specific therapy. For a very long time, clinicians ignored cognitive dysfunction and researchers who might be interested in the question struggled to find an approach to understanding mechanisms for this manifestation. Recent years, however, propelled by a more patient-centric approach to disease, have seen remarkable progress in our understanding of CD pathogenesis. This has been enabled through the use of novel imaging modalities and numerous mouse models. Overall, these studies point to a pivotal role of an impaired BBB and microglial activation in leading to neuronal injury. These insights suggest potential therapeutic modalities and make possible clinical trials for cognitive impairment.

"Back Rx, a personalized mobile phone application for discogenic chronic low back pain: a prospective pilot study".

BACKGROUND: Intervertebral disc pathology is the most common identifiable cause of chronic lower back pain (CLBP). There are limited conservative alternatives to treat discogenic axial CLBP. Back Rx is a mobile application (app) developed to treat patients with this condition, following the Back Rx exercise program, assisted by a virtual coach. METHODS: Patients 18 to 65 years of age, with axial CLBP (more than 3 months), and evidence of lumbar disc pathology by magnetic resonance imaging (MRI) were enrolled to the study. Patients' symptomatology was prospectively evaluated at baseline and after 3 months of using the Back Rx app. The main outcome of the study was back pain evaluated using the visual analog scale (VAS) for pain. Secondary outcomes were the patient's functionality, the weekly pain medication intake, the patients' adherence to the app, and the patients´ satisfaction rate. RESULTS: Seventy-five patients with CLBP were enrolled in the study. All patients had a statistically significant improvement from baseline to final follow-up in the average VAS scores, and the functionality evaluations. Average VAS scores decreased from 5.17 ± 2.1 at baseline to 3.8 ± 2.6 at final follow-up (P = 0.016). Patients showed a significant decrease in the number of pain medications taken during a week (P = 0.001). Overall compliance with the app was 52%, and 65% of the patients rated the overall experience as good or excellent. CONCLUSION: The Back Rx app decreased pain and increased function in patients with discogenic axial CLBP compared to their baseline status. Further measures are needed to increase patients' compliance with the app and the Back Rx program. TRIAL REGISTRATION: Retrospectively registered in 2/2/2017 NCT03040310 (ClinicalTrials.gov).

Does Low Back Pain Improve Following Total Hip Arthroplasty?

BACKGROUND: Frequently, patients indicated for total hip arthroplasty (THA) present with low back pain (LBP) and hip pain. The purpose of this study was to compare patients whose back pain resolved after THA with those where back pain did not resolve and identify how to predict this using spinopelvic parameters. METHODS: We reviewed a series of 500 patients who underwent THA for unilateral hip osteoarthritis by 2 surgeons. Patients underwent biplanar standing and sitting EOS radiographs pre-operatively. Patients with previous spine surgery or femoral neck fracture were excluded. Demographic data was analyzed at baseline. The Oswestry Disability Index (ODI) scores were calculated pre-operatively and at 1 year postoperatively. Spinopelvic parameters included, pelvic incidence and sacral slope (SS) change from standing to sitting. RESULTS: Two hundred and four patients (41%) had documented LBP before THA. The Oswestry Disability Index (ODI) for patients improved from 38.9 ± 17.8 pre-operatively to 17.0 ± 10.6 at 1 year post-operatively (P < .001). At 1- and 2-year follow-up, resolution of back pain occurred in 168 (82.4%) and 187 (91.2%) patients, respectively. Pelvic incidence was not predictive of back pain resolution. All patients whose back pain resolved had a sacral slope change from standing to sitting of >10°, while those patients whose back pain did not resolve had a change of <10°. CONCLUSION: This study demonstrates that symptomatic low back pain (LBP) resolves in 82% of patients after THA. The results of this study may be used to counsel patients on back pain and its resolution following total hip replacement.

Cognitive Impairment in SLE: Mechanisms and Therapeutic Approaches.

A wide range of patients with systemic lupus erythematosus (SLE) suffer from cognitive dysfunction (CD) which severely impacts their quality of life. However, CD remains underdiagnosed and poorly understood. Here, we discuss current findings in patients and in animal models. Strong evidence suggests that CD pathogenesis involves known mechanisms of tissue injury in SLE. These mechanisms recruit brain resident cells, in particular microglia, into the pathological process. While systemic immune activation is critical to central nervous system injury, the current focus of therapy is the microglial cell and not the systemic immune perturbation. Further studies are critical to examine additional potential therapeutic targets and more specific treatments based on the cause and progress of the disease.

EOS Imaging is Accurate and Reproducible for Preoperative Total Hip Arthroplasty Templating.

BACKGROUND: Templating is a critical part of preoperative planning for total hip arthroplasty (THA). The accuracy of templating on images acquired with EOS is unknown. This study sought to compare the accuracy and reproducibility of templating for THA using EOS imaging to conventional digital radiographs. METHODS: Forty-three consecutive primary unilateral THAs were retrospectively templated, six months postoperatively, using preoperative 2D EOS imaging and conventional radiographs. Two blinded observers templated each case for acetabular and femoral component size and femoral offset. The retrospectively templated sizes were compared to the sizes selected during surgery. Interobserver agreement was calculated, and the influence of demographic variables was explored. RESULTS: EOS templating predicted the exact acetabular and femoral size in 71% and 66% of cases, respectively, and to within one size in 98% of cases. The acetabular and femoral component size was more likely to be templated to the exact size using EOS compared to conventional imaging (P < .05). The femoral component offset choice was accurately predicted in 83% of EOS cases compared to 80% of conventional templates (P = .341). Component size and offset were not influenced by patient age, gender, laterality, or BMI. Interobserver agreement was excellent for acetabular (Cronbach's alpha = 0.94) and femoral (Cronbach's alpha = 0.96) component size. CONCLUSIONS: Preoperative templating for THA using EOS imaging is accurate, with an excellent interobserver agreement. EOS exposes patients to less radiation than traditional radiographs, and its three-dimensional applications should be explored as they may further enhance preoperative plans.

High Offset Stems Are Protective of Dislocation in High-Risk Total Hip Arthroplasty.

BACKGROUND: Spinal stiffness has been shown to increase risk of dislocation due to impingement and instability. Increasing anteversion of the acetabular component has been suggested to prevent dislocation, but little has been discussed in terms of femoral or global offset restoration. The purpose of this study is to quantify dislocation rates after primary THA using standard versus high-offset femoral components and to determine how differences in offset affect impingement-free range of motion in a stiff spine cohort using a novel impingement model. METHODS: A total of 12,365 patients undergoing THA from 2016 to 2018 were retrospectively reviewed to determine dislocation rates and utilization of standard- versus high-offset stems. For 50 consecutive patients with spinal stiffness, a CT-based computer software impingement modeling system assessed bony or prosthetic impingement during simulated range of motion. The model was run 5 times for each patient with varying offsets. Range of motion was simulated in each scenario to determine the degree at which impingement occurred. RESULTS: There were 51 dislocations for a 0.41% dislocation rate. Total utilization of high-offset stems in the entire cohort was 49%. Of those patients who sustained a dislocation, 49 (96%) utilized a standard-offset stem. The impingement modeling demonstrated 5 degrees of added range of motion until impingement for every 1 mm offset increase. CONCLUSION: In the impingement model, high-offset stems facilitated greater ROM before bony impingement and resulted in lower dislocation rates. In the setting of high-risk THA due to spinal stiffness, surgeons should consider the use of high-offset stems and pay attention to offset restoration.

Early Recovery Outcomes in Patients Undergoing Total Hip Arthroplasty Through a Posterior Approach With Modified Postoperative Precautions.

BACKGROUND: Recent data suggest that a modified, more lenient set of precautions after total hip arthroplasty (THA) performed through the posterolateral approach may safely allow more patient movement and exercise in the immediate postoperative period. We hypothesize that 1) patients undergoing THA given modified precautions will demonstrate a fast-track return to functional activity and 2) wrist-based activity trackers will provide valuable information on postoperative activity levels. METHODS: We prospectively enrolled patients undergoing THA. Patients were given a wrist-based, commercially available activity tracker to wear 1 week preoperatively and 6 weeks postoperatively. Postoperative hip precautions included only the avoidance of the "leg-shaving" position of combined hip flexion, adduction, and internal rotation. Linear mixed models were used to analyze the change in steps and Hip Disability and Osteoarthritis Outcome Score-Junior (HOOS)-JR data. Pearson correlation coefficients were used to describe the relationship between average steps and HOOS-JR scores over time. RESULTS: Eighty-two patients were enrolled. Seventy-four percent returned to work by week 4. Seventy-six percent of left THA patients returned to driving by week 4. At 6 weeks, 23% of survey respondents were taking pain medication and 26% were using assistive devices. Average daily steps were 1098 at week 1, 2491 at week 2, 4130 at week 3, 4850 at week 4, 5712 at week 5, and 6069 at week 6. A significant correlation (R: -0.981) was found between increased weekly steps and improved HOOS-JR scores after THA (P < .001). CONCLUSION: Defining expected recovery timelines for patients undergoing THA helps surgeons counsel their patients preoperatively. Our study demonstrates an expected pathway for recovery after THA by using modified precautions that will be more clearly outlined with ongoing clinical data analysis.

Dying to protect: cell death and the control of T-cell homeostasis.

T cells play a critical role in immune responses as they specifically recognize peptide/MHC complexes with their T-cell receptors and initiate adaptive immune responses. While T cells are critical for performing appropriate effector functions and maintaining immune memory, they also can cause autoimmunity or neoplasia if misdirected or dysregulated. Thus, T cells must be tightly regulated from their development onward. Maintenance of appropriate T-cell homeostasis is essential to promote protective immunity and limit autoimmunity and neoplasia. This review will focus on the role of cell death in maintenance of T-cell homeostasis and outline novel therapeutic strategies tailored to manipulate cell death to limit T-cell survival (eg, autoimmunity and transplantation) or enhance T-cell survival (eg, vaccination and immune deficiency).

Manipulating DNA damage-response signaling for the treatment of immune-mediated diseases.

Antigen-activated lymphocytes undergo extraordinarily rapid cell division in the course of immune responses. We hypothesized that this unique aspect of lymphocyte biology leads to unusual genomic stress in recently antigen-activated lymphocytes and that targeted manipulation of DNA damage-response (DDR) signaling pathways would allow for selective therapeutic targeting of pathological T cells in disease contexts. Consistent with these hypotheses, we found that activated mouse and human T cells display a pronounced DDR in vitro and in vivo. Upon screening a variety of small-molecule compounds, we found that potentiation of p53 (via inhibition of MDM2) or impairment of cell cycle checkpoints (via inhibition of CHK1/2 or WEE1) led to the selective elimination of activated, pathological T cells in vivo. The combination of these strategies [which we termed "p53 potentiation with checkpoint abrogation" (PPCA)] displayed therapeutic benefits in preclinical disease models of hemophagocytic lymphohistiocytosis and multiple sclerosis, which are driven by foreign antigens or self-antigens, respectively. PPCA therapy targeted pathological T cells but did not compromise naive, regulatory, or quiescent memory T-cell pools, and had a modest nonimmune toxicity profile. Thus, PPCA is a therapeutic modality for selective, antigen-specific immune modulation with significant translational potential for diverse immune-mediated diseases.

Stiffness After Total Knee Arthroplasty: Is It a Result of Spinal Deformity?

BACKGROUND: There are no studies to date analyzing the effect of spinal malalignment on outcomes of total knee arthroplasty (TKA). Knee flexion is a well-described lower extremity compensatory mechanism for maintaining sagittal balance with increasing spinal deformity. The purpose of this study was to determine whether a subset of patients with poor range of motion (ROM) after TKA have unrecognized spinal deformity, predisposing them to knee flexion contractures and stiffness. METHODS: We retrospectively evaluated a consecutive series of patients who underwent manipulation under anesthesia (MUA) for poor ROM after TKA. Using standing full-length biplanar images, knee alignment and spinopelvic parameters were measured. Patients were stratified by pelvic incidence minus lumbar lordosis as a measure of spinal sagittal alignment with a mismatch of ≥10° defined as abnormal, and we calculated the incidence of sagittal spinal deformity. RESULTS: Average ROM before MUA was extension 3° and flexion 83°. About 62% of patients had a pelvic incidence minus lumbar lordosis mismatch of ≥10°. In the spinal deformity group, post-MUA ROM was improved for flexion only, whereas both flexion and extension were improved in the nondeformity group. CONCLUSION: Compensatory knee flexion because of sagittal spinal deformity may predispose to poor ROM after TKA. Patients with clinical suspicion should be worked up preoperatively and counseled accordingly.

Stability and uniqueness of clonal immunoglobulin CDR3 sequences for MRD tracking in multiple myeloma.

Minimal residual disease (MRD) tracking, by next generation sequencing of immunoglobulin sequences, is moving towards clinical implementation in multiple myeloma. However, there is only sparse information available to address whether clonal sequences remain stable for tracking over time, and to what extent light chain sequences are sufficiently unique for tracking. Here, we analyzed immunoglobulin repertoires from 905 plasma cell myeloma and healthy control samples, focusing on the third complementarity determining region (CDR3). Clonal heavy and/or light chain expression was identified in all patients at baseline, with one or more subclones related to the main clone in 3.2%. In 45 patients with 101 sequential samples, the dominant clonal CDR3 sequences remained identical over time, despite differential clonal evolution by whole exome sequencing in 49% of patients. The low frequency of subclonal CDR3 variants, and absence of evolution over time in active multiple myeloma, indicates that tumor cells at this stage are not under selective pressure to undergo antibody affinity maturation. Next, we establish somatic hypermutation and non-templated insertions as the most important determinants of light chain clonal uniqueness, identifying a potentially trackable sequence in the majority of patients. Taken together, we show that dominant clonal sequences identified at baseline are reliable biomarkers for long-term tracking of the malignant clone, including both IGH and the majority of light chain clones.

Pelvic pitch and roll during total hip arthroplasty performed through a posterolateral approach. A potential source of error in free-hand cup positioning.

PURPOSE: Intraoperative pelvic motion can alter the perceived cup inclination and version during non-navigated THA. We quantified pelvic motion during different phases of primary THA performed in the lateral decubitus through a posterolateral approach. METHODS: Pelvic roll (rotation of the coronal plane) and pitch angles (rotation parallel to the coronal plane) were studied in 75 patients undergoing THA for osteoarthritis by four arthroplasty surgeons. Ten steps of surgery were defined. Angular motion was recorded with a miniature surgical device that utilizes inertial sensors. RESULTS: The mean absolute roll ranged from 0.03° detected at the end of surgery to 4.13° detected during acetabular exposure. The mean absolute pitch ranged from 0.05° detected at the end of surgery to 2.54° detected during hip dislocation. The maximum pelvic roll and pitch detected during surgery averaged 17.62° (SD: 5.08) and 9.3° (SD: 3.39) respectively. Absolute roll and pitch angles were not affected by patient's BMI, sex, pre-operative hip motion, or surgeon. Before cup insertion, the greatest mean change in roll was observed during acetabular exposure (10.02° anteriorly), and for pitch was observed during dislocation (1.88° caudally). CONCLUSION: During THA performed through a posterolateral approach, there is a progressive anterior pelvic roll that peaks before cup insertion. This can lead to underestimation of cup anteversion during non-navigated THA. The anterior roll does not completely correct, even when all retractors and external forces acting on the pelvis are removed. Pelvic pitch that could affect the perceived cup inclination occurs to a lesser extent than pelvic roll.

Total Hip Arthroplasty Patients With Fixed Spinopelvic Alignment Are at Higher Risk of Hip Dislocation.

BACKGROUND: Sitting radiographs have been used as a pre-operative tool to plan patient-specific total hip arthroplasty (THA) component position that would improve hip stability. Previous work has demonstrated that spinal mobility may impact functional acetabular position when seated. We sought to determine whether patients who dislocate following THA have different sitting spinopelvic alignment or acetabular component orientation compared to patients who did not dislocate. METHODS: A consecutive series of 1000 patients underwent post-operative low-dose biplanar spine-to-ankle lateral radiographs in standing and sitting positions 1 year following THA. Twelve patients (1% of all patients) experienced hip dislocation. Patients were categorized as having normal lumbar spines (without radiographic arthrosis) or as having lumbar multi-level degenerative disc disease. Measurements of spinopelvic alignment parameters (including sacral slope, lumbar lordosis, and proximal femur angles) and acetabular component orientation in sitting position (functional inclination and functional anteversion) were performed. RESULTS: Patients who dislocated had significantly less spine flexion, less change in pelvic tilt, and more hip flexion from standing to sitting positions compared to patients with normal spines. In sitting position, dislocators had acetabular components with less functional inclination and less functional anteversion. CONCLUSION: This study demonstrates that patients with fixed spinopelvic alignment from standing to sitting position are at higher risk of hip dislocation. Imaging patients from standing to sitting position using this technique can provide valuable information on whether a patient has fixed spinopelvic alignment with postural changes and is therefore at higher risk of dislocation.

Hepatic MDR3 expression impacts lipid homeostasis and susceptibility to inflammatory bile duct obstruction in neonates.

BackgroundHeterozygous mutations in the gene ABCB4, encoding the phospholipid floppase MDR3 (Mdr2 in mice), are associated with various chronic liver diseases. Here we hypothesize that reduced ABCB4 expression predisposes to extrahepatic biliary atresia (EHBA).MethodsLivers from neonatal wild-type (wt) and heterozygous Mdr2-deficient mice were subjected to mass spectrometry-based lipidomics and RNA sequencing studies. Following postnatal infection with rhesus rotavirus (RRV), liver immune responses and EHBA phenotype were assessed. Hepatic microarray data from 40 infants with EHBA were mined for expression levels of ABCB4.ResultsPhosphatidylcholine (PC) and phosphatidylethanolamine (PE) were increased, whereas the PC/PE ratio was decreased in neonatal Mdr2+/- mice compared with wt mice. Following RRV challenge, hepatic expression of IFNγ and infiltration with CD8+ and NK+ lymphocytes were increased in Mdr2+/- mice. Plasma total bilirubin levels and prevalence of complete ductal obstruction were higher in these mice. In infants with EHBA, hepatic gene expression of ABCB4 was downregulated in those with an inflammatory compared with a fibrosing molecular phenotype.ConclusionDecreased expression of ABCB4 causes dysregulation in (phospho)lipid homeostasis, and predisposes to aberrant pro-inflammatory lymphocyte responses and an aggravated phenotype of EHBA in neonatal mice. Downregulated ABCB4 is associated with an inflammatory transcriptome signature in infants with EHBA.

Rigid Patient Positioning is Unreliable in Total Hip Arthroplasty.

BACKGROUND: To our knowledge, no study has assessed the ability of rigid patient positioning devices to afford arthroplasty surgeons with ideal acetabular orientation throughout surgery. The purpose of this study is to use robotic arm-assisted computer navigation to assess the reliability of pelvic position in total hip arthroplasty performed on patients positioned with rigid positioning devices. METHODS: A prospective cohort of 100 hips (94 patients) underwent robotic-guided total hip arthroplasty in the lateral decubitus position from the posterior approach, 77 stabilized by universal lateral positioner, and 23 by peg board. Before reaming, computed tomography-templated computer software generated true values of pelvic anteversion and inclination based on the position of the robot arm registered to the patient's preoperative pelvic computed tomography. RESULTS: Mean alteration in anteversion and inclination values was 1.7° (absolute value, 5.3°; range, -20° to 20°) and 1.6° (absolute value, 2.6°; range, -8° to 10°), respectively. And 22% of anteversion values were altered by >10° and 41% by >5°. There was no difference between hip positioners used (P = .36). Anteversion variability was correlated with body mass index (P = .02). CONCLUSION: Despite the use of rigid patient positioning devices-a lateral hip positioner or peg board-this study reveals clinically important malposition of the pelvis in many cases, especially with regard to anteversion. These results show a clear need to pay particular attention to anatomic landmarks or computer-assisted techniques to assure accurate acetabular cup positioning. Patient positioning should not be solely trusted.