Adenosine metabolized from extracellular ATP promotes type 2 immunity through triggering A2BAR signaling in intestinal epithelial cells.

Intestinal nematode parasites can cross the epithelial barrier, causing tissue damage and release of danger-associated molecular patterns (DAMPs) that may promote host protective type 2 immunity. We investigate whether adenosine binding to the A2B adenosine receptor (A2BAR) on intestinal epithelial cells (IECs) plays an important role. Specific blockade of IEC A2BAR inhibits the host protective memory response to the enteric helminth, Heligmosomoides polygyrus bakeri (Hpb), including disruption of granuloma development at the host-parasite interface. Memory T cell development is blocked during the primary response, and transcriptional analyses reveal profound impairment of IEC activation. Extracellular ATP is visualized 24 h after inoculation and is shown in CD39-deficient mice to be critical for the adenosine production mediating the initiation of type 2 immunity. Our studies indicate a potent adenosine-mediated IEC pathway that, along with the tuft cell circuit, is critical for the activation of type 2 immunity.

Sterile particle-induced inflammation is mediated by macrophages releasing IL-33 through a Bruton's tyrosine kinase-dependent pathway.

Initiation of the innate sterile inflammatory response that can develop in response to microparticle exposure is little understood. Here, we report that a potent type 2 immune response associated with the accumulation of neutrophils, eosinophils and alternatively activated (M2) macrophages was observed in response to sterile microparticles similar in size to wear debris associated with prosthetic implants. Although elevations in interleukin-33 (IL-33) and type 2 cytokines occurred independently of caspase-1 inflammasome signalling, the response was dependent on Bruton's tyrosine kinase (BTK). IL-33 was produced by macrophages and BTK-dependent expression of IL-33 by macrophages was sufficient to initiate the type 2 response. Analysis of inflammation in patient periprosthetic tissue also revealed type 2 responses under aseptic conditions in patients undergoing revision surgery. These findings indicate that microparticle-induced sterile inflammation is initiated by macrophages activated to produce IL-33. They further suggest that both BTK and IL-33 may provide therapeutic targets for wear debris-induced periprosthetic inflammation.

B Cells Produce the Tissue-Protective Protein RELMα during Helminth Infection, which Inhibits IL-17 Expression and Limits Emphysema.

Emphysema results in destruction of alveolar walls and enlargement of lung airspaces and has been shown to develop during helminth infections through IL-4R-independent mechanisms. We examined whether interleukin 17A (IL-17A) may instead modulate development of emphysematous pathology in mice infected with the helminth parasite Nippostrongylus brasiliensis. We found that transient elevations in IL-17A shortly after helminth infection triggered subsequent emphysema that destroyed alveolar structures. Furthermore, lung B cells, activated through IL-4R signaling, inhibited early onset of emphysematous pathology. IL-10 and other regulatory cytokines typically associated with B regulatory cell function did not play a major role in this response. Instead, at early stages of the response, B cells produced high levels of the tissue-protective protein, Resistin-like molecule α (RELMα), which then downregulated IL-17A expression. These studies show that transient elevations in IL-17A trigger emphysema and reveal a helminth-induced immune regulatory mechanism that controls IL-17A and the severity of emphysema.

Pla2g1b Places Worms in Peril.

The determinants of helminth resistance are not well understood. In this issue of Cell Host & Microbe, Entwistle et al. (2017) provide intriguing evidence that a phospholipase A2 (Pla2gb1) produced by epithelial cells can impair larval development in helminths, providing a novel mechanism contributing to intestinal nematode resistance.

Identifying the third dimension in 2D fluoroscopy to create 3D cardiac maps.

Three-dimensional cardiac mapping is important for optimal visualization of the heart during cardiac ablation for the treatment of certain arrhythmias. However, many hospitals and clinics worldwide cannot afford the high cost of the current mapping systems. We set out to determine if, using predefined algorithms, comparable 3D cardiac maps could be created by a new device that relies on data generated from single-plane fluoroscopy and patient recording and monitoring systems, without the need for costly equipment, infrastructure changes, or specialized catheters. The study included phantom and animal experiments to compare the prototype test device, Navik 3D, with the existing CARTO 3 System. The primary endpoint directly compared: (a) the 3D distance between the Navik 3D-simulated ablation location and the back-projected ground truth location of the pacing and mapping catheter electrode, and (b) the same distance for CARTO. The study's primary objective was considered met if the 95% confidence lower limit was greater than 0.75% for the Navik 3D-CARTO difference between the 2 distances, or less than or equal to 2 mm. Study results showed that the Navik 3D performance was equivalent to the CARTO system, and that accurate 3D cardiac maps can be created using data from equipment that already exists in all electrophysiology labs.

Outcomes of a Modular Intercalary Endoprosthesis as Treatment for Segmental Defects of the Femur, Tibia, and Humerus.

BACKGROUND: Resection of diaphyseal bone tumors for local tumor control and stabilization often results in an intercalary skeletal defect and presents a reconstructive challenge for orthopaedic surgeons. Although many options for reconstruction have been described, relatively few studies report on the functional outcomes and complications of patients treated with modular intercalary endoprostheses. QUESTIONS/PURPOSES: The objectives of this study were to examine clinical outcomes after reconstruction with a modular intercalary endoprosthesis with a specific focus on (1) the rate of complication or failure; (2) differences in complication rates by anatomic site; (3) functional results as assessed by the Musculoskeletal Tumor Society System (MSTS); and (4) differences in complication rate between patients treated with cemented versus noncemented fixation. METHODS: We conducted a retrospective chart review of patients treated with a modular intercalary endoprosthesis from three musculoskeletal oncology centers from 2008 to 2013. The indication for use of this intercalary endoprosthesis was segmental bone loss from aggressive or malignant tumor with sparing of the joint above and below and deemed unsuitable for biologic reconstruction. No other implant was used for this indication during this period. During this period, 41 patients received a total of 44 intercalary implants, which included 18 (40%) humeri, 5 (11%) tibiae, and 21 (48%) femora. There were 27 (66%) men and 14 (34%) women with a mean age of 63 years (range, 18­91 years). Eight patients (20%) had primary bone tumors and 33 (80%) had metastatic lesions. Thirty-five (85%) patients were being operated on as an initial treatment and six (15%) for revision of a previous reconstruction. Twenty-nine (66%) procedures had cemented stem fixation and 15 (34%) were treated with noncemented fixation. The overall mean followup was 14 months (range, 1­51 months). Patients with primary tumors had a mean followup of 19 months (range, 4­48 months) and patients with metastatic disease had a mean followup of 11 months (range, 1­51 months). Causes of implant failure were categorized according to Henderson et al. [19] into five types as follows: Type I (soft tissue failure), Type II (aseptic loosening), Type III (structural failure), Type IV (infection), and Type V (tumor progression). At 2 years of followup, 38 (93%) of these patients were accounted for with three (7%) lost to followup. MSTS functional assessment was available for 39 of 41 patients (95%). RESULTS: At latest followup of these 41 patients, 14 (34%) patients were dead of disease, two patients (5%) dead of other causes, seven (17%) are continuously disease-free, one (2%) shows no evidence of disease, and 17 (41%) are alive with disease. There were 12 (27%) nononcologic complications. Five (11%) of these were Type II failures occurring in noncemented implants between the stem and bone, and six (14%) were Type III failures occurring in cemented implants at the clamp-rod implant interface. One patient developed a deep infection (2%, Type IV failure) and underwent removal of the implant. Additionally, one patient (2%, Type V failure) was treated by amputation after local progression of his metastatic disease. Complications were more common in femoral reconstructions than in tibial or humeral reconstructions. Twelve of 21 patients (57%) with femoral reconstructions had complications versus 0% of tibial or humeral reconstructions (0 of 23; odds ratio [OR], 62; 95% confidence interval [CI], 3­1154; p < 0.0001). The mean overall MSTS score was 77%. Implants with cemented fixation (29) had higher mean MSTS scores when compared with implants with noncemented (15) fixation (84% versus 66%, p = 0.0017). The complication rate was 33% in noncemented cases and 21% in cemented cases (p = 0.39); however, Type II failure at the bone-stem interface was associated with noncemented fixation and Type III failure at the clamp-rod interface was associated with cemented fixation (OR, 143; 95% CI, 2.413­8476; p = 0.0022). CONCLUSIONS: The results of this study indicate that this modular intercalary endoprosthesis yields equivalent results to other studies of intercalary endoprostheses in terms of MSTS scores. We found that patients treated with intercalary endoprostheses in the femur experienced more frequent complications than those treated for lesions in either the humerus or tibia and that the femoral complication rate of this endoprosthesis is higher when compared with other studies of intercalary endoprostheses for femoral reconstruction. Further studies are still needed to determine the long-term outcomes of this endoprosthesis in patients with primary tumors where longevity of the implant is of more importance than in the metastatic setting. We recommend cemented fixation for this intercalary modular endoprostheses because this provides improved MSTS scores and allows immediate return to weightbearing, which is of advantage to metastatic patients with limited lifespans. Level of Evidence: Level III, therapeutic study.