C-type lectin receptors sense a diversity of endogenous and exogenous ligands that may trigger differential responses. Here, we have found that human and mouse Mincle bind to a ligand released by ...Leishmania, a eukaryote parasite that evades an effective immune response. Mincle-deficient mice had milder dermal pathology and a tenth of the parasite burden compared to wild-type mice after Leishmania major intradermal ear infection. Mincle deficiency enhanced adaptive immunity against the parasite, correlating with increased activation, migration, and priming by Mincle-deficient dendritic cells (DCs). Leishmania triggered a Mincle-dependent inhibitory axis characterized by SHP1 coupling to the FcRγ chain. Selective loss of SHP1 in CD11c+ cells phenocopies enhanced adaptive immunity to Leishmania. In conclusion, Leishmania shifts Mincle to an inhibitory ITAM (ITAMi) configuration that impairs DC activation. Thus, ITAMi can be exploited for immune evasion by a pathogen and may represent a paradigm for ITAM-coupled receptors sensing self and non-self.
Display omitted
•Leishmania releases a proteinaceous ligand that binds human and mouse Mincle•Clec4e−/− mice show enhanced immunity with reduced parasite burden and pathology•Leishmania inhibits activation and migration of DCs in a Mincle-dependent manner•Leishmania shifts Mincle to an inhibitory FcRγ/SHP1 axis in DCs
Iborra et al. show 90% reduced parasitemia during Leishmania infection in Mincle-deficient mice. These mice have an enhanced adaptive response through increased DC activation and migration. Leishmania releases a proteinaceous ligand for Mincle, triggering an inhibitory ITAM signaling axis that involves Mincle, FcRγ chain, and SHP1.
Breast cancer is a heterogeneous disease comprising a variety of entities with various genetic backgrounds. Estrogen receptor-positive, human epidermal growth factor receptor 2-negative tumors ...typically have a favorable outcome; however, some patients eventually relapse, which suggests some heterogeneity within this category. In the present study, we used proteomics and miRNA profiling techniques to characterize a set of 102 either estrogen receptor-positive (ER+)/progesterone receptor-positive (PR+) or triple-negative formalin-fixed, paraffin-embedded breast tumors. Protein expression-based probabilistic graphical models and flux balance analyses revealed that some ER+/PR+ samples had a protein expression profile similar to that of triple-negative samples and had a clinical outcome similar to those with triple-negative disease. This probabilistic graphical model-based classification had prognostic value in patients with luminal A breast cancer. This prognostic information was independent of that provided by standard genomic tests for breast cancer, such as MammaPrint, OncoType Dx and the 8-gene Score.
The exposure of human monocytes to the gram-negative endotoxin LPS provokes them to enter a transient state in which they are refractory to further stimulation by LPS. This phenomenon is known as ...‘endotoxin tolerance’ (ET) and it is characterized by a decrease in leukocyte proinflammatory cytokine production in response to LPS. In the present study, we have analyzed the expression of IRAK-M mRNA and protein in a human model of ET using human monocytes isolated from peripheral blood. In these monocyte cultures, IRAK-M mRNA was expressed 6
h after stimulation with different doses of LPS. However, endotoxin pretreatment induced a more immediate up-regulation of IRAK-M gene expression, transcripts appearing only one hour after a second LPS-challenge, and the production of high levels of IRAK-M protein in these tolerant monocytes. We also analyzed the response of monocytes isolated from septic patients within a temporal tolerance timeframe when stimulated ex vivo with LPS. In contrast to monocytes from healthy volunteers and patients outside of the tolerance timeframe, monocytes from septic patients rapidly expressed IRAK-M mRNA when stimulated with LPS ex vivo. Moreover, the expression of IRAK-M mRNA was more rapidly induced in the presence of a PI3K inhibitor, suggesting a connection between these two kinases. Thus, our data indicate that IRAK-M could play a pivotal role in the process of ET in human monocytes and provide evidence that PI3K is involved in regulating its expression.
In patients with epilepsy health education has a positive influence on self-management of the disease, improves prognosis and enhances patient well-being. The aim of this study was to evaluate an ...educational intervention using instructional clips in patients with epilepsy in a video-electroencephalographic monitoring unit.
We conducted a randomised clinical trial with two groups (intervention and control). Adult patients with epilepsy admitted to the video-electroencephalographic monitoring unit were recruited. Nine videos about the diagnosis and treatment of epilepsy, together with recommendations on lifestyle, were produced and administered to the intervention group while admitted. Patients' knowledge of their disease was assessed by means of a questionnaire designed specifically for this study. A pre-assessment was conducted at the beginning of the study, at hospital discharge and at three months, and the knowledge of epilepsy in the two groups was compared at each time considered in the study.
Sixty-six patients were included, with a mean age of 39 ± 14.7 years (range: 17-76) and a median of 8 years since disease onset (range: 1-60 years). Fifty-three per cent of the patients were women. Focal epilepsy was the most frequent type (95.5%). The mean score on the pre-intervention test was 57.2 ± 15.3. Patients who received the educational intervention showed better post-test scores at discharge from hospital (81.8 ± 11.2 versus 62.8 ± 13.7; p = 0.001) and at three months (76 ± 9.6 versus 63.2 ± 12.8; p = 0.001).
The EPICAP educational intervention using instructional clips significantly improves patients' knowledge of epilepsy-related diagnostic, therapeutic and lifestyle issues.
Although blood monocytes possess significant cytotoxic activity against tumor cells, tumor-infiltrating monocytes are commonly deactivated in cancer patients. Monocytes pre-exposed to tumor cells ...show significantly decreased expression levels of TNF-alpha, IL-12p40, and IL-1R-associated kinase (IRAK)-1. Activation of the Ser/Thr kinase IRAK-1 is an important event in several inflammatory processes. By contrast, another IRAK family member, IRAK-M, negatively regulates this pathway, and is up-regulated in cultures of endotoxin-tolerant monocytes and in monocytes from septic patients within the timeframe of tolerance. In this study, we show that IRAK-M expression is enhanced at the mRNA and protein level in human monocytes cultured in the presence of tumor cells. IRAK-M was induced in monocytes upon coculturing with different tumor cells, as well as by fixed tumor cells and medium supplemented with the supernatant from tumor cell cultures. Moreover, blood monocytes from patients with chronic myeloid leukemia and patients with metastasis also overexpressed IRAK-M. Low concentrations of hyaluronan, a cell surface glycosaminoglycan released by tumor cells, also up-regulated IRAK-M. The induction of IRAK-M by hyaluronan and tumor cells was abolished by incubation with anti-CD44 or anti-TLR4 blocking Abs. Furthermore, down-regulation of IRAK-M expression by small interfering RNAs specific for IRAK-M reinstates both TNF-alpha mRNA expression and protein production in human monocytes re-exposed to a tumor cell line. Altogether, our findings indicate that deactivation of human monocytes in the presence of tumor cells involves IRAK-M up-regulation, and this effect appears to be mediated by hyaluronan through the engagement of CD44 and TLR4.
Clinical orthopaedic use of calcium phosphate cement has been limited due to its slow resorption rate, but a new macroporous α-tricalcium phosphate (α-TCP) bone cement has been designed to accelerate ...resorption and to increase bone ingrowth. To assess its clinical potential, the in vivo behaviour of α-TCP was evaluated in a critical-size defect drilled in the femoral condyles of 36 adult female New Zealand rabbits. Macroporous or standard cement was injected immediately after preparation of the defect. The foaming agent was albumen, which gave up to 75% porosity. The rabbits were divided into three groups and the lesions examined histopathologically at 1, 4 and 12 weeks.
No inflammatory reaction was detected at any time period following implantation with either macroporous or standard cement. At 12 weeks, the area of the implanted macroporous cement was approximately 35% of the initial lesion size. Bone growth and revascularisation was observed inside the central pores of the macroporous cement, not only at the margins, as was found with standard calcium phosphate cement. The results indicated that both cements were osteoconductive, biocompatible and biodegradable but their different physicochemical and biological properties had a marked influence on their post-implant behaviour.
Adherence to Enhanced Recovery Protocols (ERPs) is associated with faster functional recovery, better patient satisfaction, lower complication rates and reduced length of hospital stay. Understanding ...institutional barriers and facilitators is essential for improving adherence to ERPs. The purpose of this study was to identify institutional factors associated with adherence to an ERP for colorectal surgery.
A secondary analysis of a nationwide study was conducted including 686 patients who underwent colorectal surgery across twenty-one institutions in Spain. Adherence to ERPs was calculated based upon the components recommended by the Enhanced Recovery After Surgery (ERAS®) Society. Institutional characteristics (i.e., case volume, ERP duration, anesthesia staff size, multidisciplinary meetings, leadership discipline) were captured from each participating program. Multivariable regression was performed to determine characteristics associated with adherence.
The median adherence to ERAS was 68.2% (IQR 59.1%–81.8%). Multivariable linear regression revealed that anesthesiologist leadership (+5.49%, 95%CI +2.81% to +8.18%, P < 0.01), duration of ERAS implementation (+0.46% per year, 95%CI +0.06% to +0.86%, P < 0.01) and the use of regular multidisciplinary meetings (+4.66%, 95%CI +0.06 to +7.74%, P < 0.01) were independently associated with greater adherence. Case volume (−2.38% per 4 cases weekly, 95%CI -3.03 to −1.74, P < 0.01) and number of anesthesia providers (−1.19% per 10 providers, 95%CI +2.23 to −8.18%, P < 0.01) were negatively associated with adherence.
Adherence to ERPs is strongly associated with anesthesiology leadership, regular multidisciplinary meetings, and program duration, whereas case volume and the size of the anesthesia staff were potential barriers. These findings highlight the importance of strong leadership, experience and establishing a multidisciplinary team when developing an ERP for colorectal surgery.
•Qualitative research suggests that institutional factors may be influencing adherence with Enhanced Recovery Protocols.•This multicenter study demonstrated that anesthesiology leadership, multidisciplinary meetings, and program duration are facilitators to ERP adherence.•The number of anesthesiologists and case volume were potential barriers to adherence with ERP guidelines.•Self-declared ERAS institutions should tailor quality improvement initiatives to specific program-level factors, particularly in settings with high case volume and large anesthesia staff sizes.
PDF
