BAFF and APRIL are innate immune mediators that trigger immunoglobulin G (IgG) and IgA class-switch recombination (CSR) in B cells by engaging the receptor TACI. The mechanism that underlies CSR ...signaling by TACI remains unknown. Here we found that the cytoplasmic domain of TACI encompasses a conserved motif that bound MyD88, an adaptor that activates transcription factor NF-kappaB signaling pathways via a Toll-interleukin 1 (IL-1) receptor (TIR) domain. TACI lacks a TIR domain, yet triggered CSR via the DNA-editing enzyme AID by activating NF-kappaB through a Toll-like receptor (TLR)-like MyD88-IRAK1-IRAK4-TRAF6-TAK1 pathway. TACI-induced CSR was impaired in mice and humans lacking MyD88 or the kinase IRAK4, which indicates that MyD88 controls a B cell-intrinsic, TIR-independent, TACI-dependent pathway for immunoglobulin diversification.
The broad and heterogeneous clinical spectrum that characterizes common variable immunodeficiency (CVID) is associated with quite different disease course and prognosis, highlighting the need to ...develop tools that predict complications. We developed a multianalyte VISUAL score (variable immunodeficiency score upfront analytical link) aimed to predict severity using individual CVID patient data at baseline of a cohort of 50 CVID patients from two different centers in Portugal and Spain. We retrospectively applied VISUAL to the CVID clinical severity scores proposed by Ameratunga and Grimbacher after 15 years follow-up of our cohort. VISUAL score at CVID diagnosis showed adequate performance for predicting infectious and non-infectious severe complications (Cluster B). Compared to switched memory B lymphocyte phenotype alone, VISUAL provided a more accurate identification of clinically meaningful outcome, with significantly higher sensitivity (85% vs 55%, p = 0.01), and negative predictive value (77% vs 58%) and AUC of the ROC curves (0.72 vs 0.64), with optimal cut-off level of 10. For every increase of 1 point in the VISUAL scale, the odds of being in the higher risk category (Cluster B) increased in 1.3 (p = 0.005) for Ameratunga's severity score and 1.26 (p = 0.004) for Grimbacher's severity score. At diagnosis of CVID, VISUAL score ≥ 10 showed 8.94-fold higher odds of severe prognosis than below this threshold. Kaplan-Meier estimates for the VISUAL ≥ 10 points showed significantly earlier progression to Cluster B than those with VISUAL < 10 (p = 0.0002). This prognostic laboratory score might allow close monitoring and more aggressive treatment in patients with scores ≥ 10 on a personalized basis approach. Further studies are needed to prospectively validate VISUAL score.
MyD88 is a key downstream adapter for most Toll-like receptors (TLRs) and interleukin-1 receptors (IL-1Rs). MyD88 deficiency in mice leads to susceptibility to a broad range of pathogens in ...experimental settings of infection. We describe a distinct situation in a natural setting of human infection. Nine children with autosomal recessive MyD88 deficiency suffered from life-threatening, often recurrent pyogenic bacterial infections, including invasive pneumococcal disease. However, these patients were otherwise healthy, with normal resistance to other microbes. Their clinical status improved with age, but not due to any cellular leakiness in MyD88 deficiency. The MyD88-dependent TLRs and IL-1Rs are therefore essential for protective immunity to a small number of pyogenic bacteria, but redundant for host defense to most natural infections.
Autosomal recessive interleukin-1 receptor-associated kinase (IRAK)-4 and myeloid differentiation factor (MyD)88 deficiencies impair Toll-like receptor (TLR)- and interleukin-1 receptor-mediated ...immunity. We documented the clinical features and outcome of 48 patients with IRAK-4 deficiency and 12 patients with MyD88 deficiency, from 37 kindreds in 15 countries.The clinical features of IRAK-4 and MyD88 deficiency were indistinguishable. There were no severe viral, parasitic, and fungal diseases, and the range of bacterial infections was narrow. Noninvasive bacterial infections occurred in 52 patients, with a high incidence of infections of the upper respiratory tract and the skin, mostly caused by Pseudomonas aeruginosa and Staphylococcus aureus, respectively. The leading threat was invasive pneumococcal disease, documented in 41 patients (68%) and causing 72 documented invasive infections (52.2%). P. aeruginosa and Staph. aureus documented invasive infections also occurred (16.7% and 16%, respectively, in 13 and 13 patients, respectively). Systemic signs of inflammation were usually weak or delayed. The first invasive infection occurred before the age of 2 years in 53 (88.3%) and in the neonatal period in 19 (32.7%) patients. Multiple or recurrent invasive infections were observed in most survivors (n = 36/50, 72%).Clinical outcome was poor, with 24 deaths, in 10 cases during the first invasive episode and in 16 cases of invasive pneumococcal disease. However, no death and invasive infectious disease were reported in patients after the age of 8 years and 14 years, respectively. Antibiotic prophylaxis (n = 34), antipneumococcal vaccination (n = 31), and/or IgG infusion (n = 19), when instituted, had a beneficial impact on patients until the teenage years, with no seemingly detectable impact thereafter.IRAK-4 and MyD88 deficiencies predispose patients to recurrent life-threatening bacterial diseases, such as invasive pneumococcal disease in particular, in infancy and early childhood, with weak signs of inflammation. Patients and families should be informed of the risk of developing life-threatening infections; empiric antibacterial treatment and immediate medical consultation are strongly recommended in cases of suspected infection or moderate fever. Prophylactic measures in childhood are beneficial, until spontaneous improvement occurs in adolescence.
...the process of self-translation indeed allows for a kind of recreation usually denied to other forms of translations. In 1937, in "Constructions in Analysis," he compares the psychoanalyst and the ...archeologist since they use the residuals of wreckage to recompose what was already buried (260); that is, under the ruins of a city once covered in ashes, as in the case of Pompeii, the essence is preserved. herefore, in a way, nothing is lost in the psyche, even though it may be presented only as "memory traces" ("Letter 52" 207), as ruins. he memory that the patient recovers is not the same as the original, nor is it a new one. his process, which is quite similar to a translation, implies an inevitable loss as well as a gain, as new arrangements can always be constructed. ...the birthmark, literally a mark, can actually be read as a trace of the "true" identity of Kristina when she seeks her origins: "Who gave me my birthmark?" (Fault Lines 262)/ "Qui m'a donné mon grain de beauté?" (Lignes de Faille 329). ...she suspects that she does not belong to that family and her "real" identity and memories are actually being reconstructed by an "other"-through quotations marks, by her brother. he only proof she really has is the birthmark, the trace and the inscription, which cannot be translated. ...our memory and unconscious registers would not be readymade, but constructed through an incessant process of translation. hat is exactly the conclusion that Freud reaches in "Letter 46" of 1896, when he situates the origins of neurosis by the diferent periods in which the experiences-scenes-were marked as signs or traces that could be transposed into words.
Chronic granulomatous disease (CGD) is a primary immunodeficiency caused by mutations in the phagocyte reactive oxygen species (ROS)-producing NOX2 enzyme complex and characterized by recurrent ...infections associated with hyperinflammatory and autoimmune manifestations. A translational, comparative analysis of CGD patients and the corresponding ROS-deficient Ncf1(m1J) mutated mouse model was performed to reveal the molecular pathways operating in NOX2 complex deficient inflammation.
A prominent type I interferon (IFN) response signature that was accompanied by elevated autoantibody levels was identified in both mice and humans lacking functional NOX2 complex. To further underline the systemic lupus erythematosus (SLE)-related autoimmune process, we show that naïve Ncf1(m1J) mutated mice, similar to SLE patients, suffer from inflammatory kidney disease with IgG and C3 deposits in the glomeruli. Expression analysis of germ-free Ncf1(m1J) mutated mice reproduced the type I IFN signature, enabling us to conclude that the upregulated signaling pathway is of endogenous origin.
Our findings link the previously unexplained connection between ROS deficiency and increased susceptibility to autoimmunity by the discovery that activation of IFN signaling is a major pathway downstream of a deficient NOX2 complex in both mice and humans.
We conclude that the lack of phagocyte-derived oxidative burst is associated with spontaneous autoimmunity and linked with type I IFN signature in both mice and humans.
Aim. The aim of the study was to evaluate, by means of the push-out test, the effect of the anatomical customization of the fiber post on the bond strength of a self-adhesive resin cement. Methods. ...Twelve endodontically treated, human, upper central incisors were randomly divided into two groups (n=6): control (glass fiber posts cemented with Relyx® U200) and customized (glass fiber posts anatomically customized with translucent composite resin cemented with Relyx U200). The roots were sectioned into three slices, cervical, middle, and apical, and photographed with a digital camera attached to a stereomicroscopic loupe. The images were analyzed by software, for evaluation of the cement line. The slices were subsequently submitted to the push-out test until the post had completely extruded, and the fracture mode was analyzed with a stereomicroscopic loupe. Results. The results showed significant differences between the groups in the different root thirds in relation to the area occupied by air bubbles (p<0.05). Bond strength, when all the thirds are considered, was 8.77 ± 4.89 MPa for the control group and 16.96 ± 4.85 MPa for the customized group. Conclusion. The customized group showed greater bond resistance than the control group and a more uniform cement layer.
Pachydermoperiostosis, a rare condition, is characterized by pachydermia, finger clubbing, and periostosis. We present an unusual treatment for frontal rhytids, for which we used a tissue expander ...that contributed to thinning of the skin and the depth of the rhytids prior to frontal lifting. The results were maintained after one year.
Pachydermoperiostosis, a rare condition, is characterized by pachydermia, finger clubbing, and periostosis. We present an unusual treatment for frontal rhytids, for which we used a tissue expander that contributed to thinning of the skin and the depth of the rhytids prior to frontal lifting. The results were maintained after one year.
•KFLC can be determined in CSF samples by sensitive automated methods.•Several neuro-inflammatory conditions that can mimic MS were included as controls.•Most MS cases showed K index ≥ 7.25, ...including some cases with negative OCBs.•K index can provide valuable support to the analysis of OCB results.•Selecting samples for OCB detection can improve analytical workflow (K index ≥ 2.55)
Automated, technically simple analytical methods offering objective results are highly valued in clinical laboratories. Kappa free light chains (KFLC) in cerebrospinal fluid (CSF) are promising multiple sclerosis (MS) biomarkers, particularly kappa (K) index.
KFLC were determined in CSF and serum samples of patients diagnosed with MS, clinically/radiologically isolated syndrome (N, 39), and controls (N, 152; inflammatory and non-inflammatory neurological disorders). Diagnostic performance of several KFLC parameters, previously determined oligoclonal band (OCB) testing, and IgG index, was assessed. A K index decision threshold for sample screening was identified and reduction in performed OCB analyses estimated accordingly.
Higher KFLC parameters were detected in the MS group and K index performed best among them (AUC 0.92). At a 7.25 cut-off it showed better sensitivity (85% vs. 77%) though less specificity (88% vs. 91%) than OCBs. Comparatively, IgG index’s performance was inferior (AUC 0.83). A decision K index threshold of 2.55 (97% sensitivity) would reduce OCB testing by 52% in the studied population.
The proposed 7.25 cut-off could assist MS diagnostics and identify some false negative cases from OCB studies. Sequential algorithms using K index for the decision to perform OCB detection would improve laboratory efficiency and substantially reduce costs.
Easy access to the Internet enables the creation of many online applications. In this sense, questionnaires were developed to evaluate the usability of health area online applications: the National ...Usability-Focused Health Information System Scale (NuHISS), the Enlight, and the User Version of the Mobile Application Rating Scale (uMARS). Those scales do not have a Portuguese (Brazil) version which is adequate to Brazil's culture. As a consequence, they can not be properly used in Brazil.
To translate and cross-cultural adapt the NuHISS, Enlight, and uMARS to Portuguese (Brazil).
A methodological study involving the translation and cross-cultural adaptation of the questionnaires NuHISS, Enlight, and uMARS was conducted following international guidelines recommendations. The questionnaires pass trough an initial translation, translation synthesis, back translation, expert committee, and a pre-final version test.
Thirdy-two health professionals analyzed NuHiss, Enlight, and uMARS translated and cross-cultural adapted Portuguese (Brazil) version. There was conceptual equivalence between the translated and original versions, and no significant adaptations were needed during the translation process. 93.8% of professionals assume that the language is cohesive and 96.9% of them consider that the content is cohesive.
The NuHISS, Enlight, and uMARS were successfully translated and cross-culturally adapted to Portuguese (Brazil) and can be properly applied in Brazil. Brazilian health professionals should use the questionnaires NuHISS, Enlight, and uMARS to evaluate health area applications usability.
PDF
