Loss of NBEAL2 function leads to grey platelet syndrome (GPS), a bleeding disorder characterized by macro-thrombocytopenia and α-granule-deficient platelets. A proportion of patients with GPS develop ...autoimmunity through an unknown mechanism, which might be related to the proteins NBEAL2 interacts with, specifically in immune cells. Here we show a comprehensive interactome of NBEAL2 in primary T cells, based on mass spectrometry identification of altogether 74 protein association partners. These include LRBA, a member of the same BEACH domain family as NBEAL2, recessive mutations of which cause autoimmunity and lymphocytic infiltration through defective CTLA-4 trafficking. Investigating the potential association between NBEAL2 and CTLA-4 signalling suggested by the mass spectrometry results, we confirm by co-immunoprecipitation that CTLA-4 and NBEAL2 interact with each other. Interestingly, NBEAL2 deficiency leads to low CTLA-4 expression in patient-derived effector T cells, while their regulatory T cells appear unaffected. Knocking-down NBEAL2 in healthy primary T cells recapitulates the low CTLA-4 expression observed in the T cells of GPS patients. Our results thus show that NBEAL2 is involved in the regulation of CTLA-4 expression in conventional T cells and provide a rationale for considering CTLA-4-immunoglobulin therapy in patients with GPS and autoimmune disease.
Abstract Loss of NBEAL2 function leads to grey platelet syndrome (GPS), a bleeding disorder characterized by macro-thrombocytopenia and α-granule-deficient platelets. A proportion of patients with ...GPS develop autoimmunity through an unknown mechanism, which might be related to the proteins NBEAL2 interacts with, specifically in immune cells. Here we show a comprehensive interactome of NBEAL2 in primary T cells, based on mass spectrometry identification of altogether 74 protein association partners. These include LRBA, a member of the same BEACH domain family as NBEAL2, recessive mutations of which cause autoimmunity and lymphocytic infiltration through defective CTLA-4 trafficking. Investigating the potential association between NBEAL2 and CTLA-4 signalling suggested by the mass spectrometry results, we confirm by co-immunoprecipitation that CTLA-4 and NBEAL2 interact with each other. Interestingly, NBEAL2 deficiency leads to low CTLA-4 expression in patient-derived effector T cells, while their regulatory T cells appear unaffected. Knocking-down NBEAL2 in healthy primary T cells recapitulates the low CTLA-4 expression observed in the T cells of GPS patients. Our results thus show that NBEAL2 is involved in the regulation of CTLA-4 expression in conventional T cells and provide a rationale for considering CTLA-4-immunoglobulin therapy in patients with GPS and autoimmune disease.
Summary
β‐thalassemia is an haemoglobinopathy characterized by a defective synthesis of the β‐globin chain. To assess the current state of health of paediatric patients with β‐thalassemia, data from ...the French national registry regarding children born between 2005 and 2020 with β‐thalassemia intermedia (TI) or major (TM) were collected. A total of 237 patients (median age 7.1 years at last visit) were analysed, of whom 156 (65.8%) were born in France and 162 (68.4%) had a TM phenotype. The probability of survival for children with TM born in France was 98.3% at 15 years. Fifty‐four (22.8%) children received a haematopoietic stem cell transplant with a success rate of 88.8%. Hepatic and cardiac iron overload monitoring in non‐transplanted patients showed moderate overload in 15.7% (18/115) and 7.1% (7/99) of cases, respectively, while clinical complications were found in only 4 patients with TM (hepatic in 3 cases). At last visit, mean ferritinemia was 1293 ng/ml (±759). Overall, less than 10% of children underwent splenectomy. No significant impact of the disease on growth or academic achievement was observed. Deferasirox was the main first‐line chelator, prescribed in 78.2% of cases, with side effects reported in 11.7% of instances.
A robust nickel-catalyzed oxidative isocyanide insertion/C–H amination by reaction of readily available N-uracil-amidines with isocyanides affording polysubstituted pyrimidouracils has been reported. ...The reaction proceeds in moderate to quantitative yield, under mild conditions (i.e., green solvent, air atmosphere, moderate temperature). The broad range of structurally diverse isocyanides and N-uracil-amidines that are tolerated make this method an interesting alternative to the currently available procedures toward pyrimidouracils.
Cochlear implant (CI) users can only access limited pitch information through their device, which hinders music appreciation. Poor music perception may not only be due to CI technical limitations; ...lack of training or negative attitudes toward the electric sound might also contribute to it. Our study investigated with an implicit (indirect) investigation method whether poorly transmitted pitch information, presented as musical chords, can activate listeners' knowledge about musical structures acquired prior to deafness. Seven postlingually deafened adult CI users participated in a musical priming paradigm investigating pitch processing without explicit judgments. Sequences made of eight sung-chords that ended on either a musically related (expected) target chord or a less-related (less-expected) target chord were presented. The use of a priming task based on linguistic features allowed CI patients to perform fast judgments on target chords in the sung music. If listeners' musical knowledge is activated and allows for tonal expectations (as in normal-hearing listeners), faster response times were expected for related targets than less-related targets. However, if the pitch percept is too different and does not activate musical knowledge acquired prior to deafness, storing pitch information in a short-term memory buffer predicts the opposite pattern. If transmitted pitch information is too poor, no difference in response times should be observed. Results showed that CI patients were able to perform the linguistic task on the sung chords, but correct response times indicated sensory priming, with faster response times observed for the less-related targets: CI patients processed at least some of the pitch information of the musical sequences, which was stored in an auditory short-term memory and influenced chord processing. This finding suggests that the signal transmitted via electric hearing led to a pitch percept that was too different from that based on acoustic hearing, so that it did not automatically activate listeners' previously acquired musical structure knowledge. However, the transmitted signal seems sufficiently informative to lead to sensory priming. These findings are encouraging for the development of pitch-related training programs for CI patients, despite the current technological limitations of the CI coding.
Bloodstream infections are a leading cause of mortality. Their detection relies on blood cultures (BCs) but time to positivity is often between tens of hours and days. d-lactate is a metabolite ...widely produced by bacteria but very few in human. We aimed to evaluate d-lactate, d-lactate/l-lactate ratio and d-lactate/total lactate ratio in plasma as potential early biomarkers of bacteraemia on a strictly biological standpoint.
A total of 228 plasma specimens were collected from patients who had confirmed bacteraemia (n = 131) and healthy outpatients (n = 97). Specific l-lactate and d-lactate analyses were performed using enzymatic assays and analytical performances of d-lactate, d-lactate/total lactate and d-lactate/l-lactate ratios for the diagnosis of bacteraemia were assessed.
A preliminary in vitro study confirmed that all strains of Escherichia coli, Klebsiella pneumoniae and Staphylococcus aureus were able to produce d-lactate at significant levels. In patients, plasma d-lactate level was the most specific biomarker predicting a bacteraemia profile with a specificity and predictive positive value of 100% using a cut-off of 131 μmol.L−1. However, sensitivity and negative predictive value were rather low, estimated at 31% and 52%, respectively. d-lactate displayed an Area Under Receiver Operating Characteristic (AUROC) curve of 0.696 with a P value < 0.0001. There was no difference of d-lactate levels between BCs bottles positive for Gram-positive or Gram-negative bacteria (p = 0.55).
d-lactate shows promise as a specific early biomarker of bacterial metabolism. The development of rapid automated assays could raise clinical applications for infectious diseases diagnosis including early bacteraemia prediction.
Aims
Clinical outcomes of diabetic macular edema (DME) have been widely described, but data on diabetic retinopathy perceptions by diabetes patients are limited. The aim of this survey was to explore ...the lived experience, knowledge, fears and expectations about disease, and treatment in patients with diabetes and macular edema treated with intravitreal injections (IVTI) and to characterize patient profiles.
Methods
Cross-sectional survey including a preliminary qualitative phase (20 patients with DME, treated or treatment-naive, 5 female and 15 male, age 36–74 years) followed by a quantitative survey (116 patients treated with IVTI for DME). Data ASKIA Analyze (version 5.3.3.5) was used for descriptive statistics, and R software (version 3.4.1) for multiple correspondence analysis.
Results
The qualitative phase identified the wording used by patients and information helpful to propose modalities of response in the quantitative phase. In the quantitative survey (116 patients, mean age 66.6 years), most patients were treated with anti-vascular endothelial growth factor. Overall, 71.9% reported that the disease negatively affected their daily activities and 33.1% considered that regular visits to the ophthalmologist were disrupting their life. Treatment expectations differed significantly between patients in terms of disease experience (visit and injection schedules), fears and feelings, and relationship with physicians, allowing three patient profiles to be identified: “Worried” patients (
n
= 45) felt isolated and were worried about the need for repeated treatment and possible side effects. They were mainly active men aged < 60 with type I diabetes (T1D) and DME diagnosed for > 2 years; “Curious” patients (
n
= 21) experienced insufficient support and requested more information on their disease and existing treatments. They were mainly single women aged 60–69 years; “Passive” patients (
n
= 50) felt sufficiently informed by their ophthalmologist and were not concerned by DME. They were older (mean age: 70 years) and mainly type 2 diabetic men.
Conclusions
Patients with diabetes and macular edema treated with IVTI form a heterogeneous group regarding fears and expectations. Different patient profiles were identified and need to be confirmed in larger studies. A better understanding of psychological profiles may optimize compliance of diabetic patients.
The present study was aimed to compare gain and speech intelligibility measured in quiet and in noise between the Signia hearing aid and the Vibrant Soundbridge (VSB), both devices using the same ...sound processing technology.
A prospective longitudinal study was performed. Six patients with a steeply sloping high-frequency hearing loss were selected.
The protocol comprised 3 months' hearing aid use, VSB implantation, and 3 months' VSB use.
Patient performances were evaluated unaided and aided by audiologic assessments, including free-field thresholds and word recognition tasks in quiet and in noise.
Statistical analysis revealed a slight decrease in overall frequencies in pure-tone audiometry after surgery; however, this decrease did not exceed 5 dB and was not different from the changes that occurred in the contralateral nonimplanted ear. The measures of aided and unaided hearing thresholds showed statistically significant larger gains with the VSB than with the hearing aid. In quiet, speech performances were poorer unaided than with either device. Because of ceiling effects, statistically significant higher scores with the VSB than with the hearing aid were only observed at the lowest intensity level. In noise, speech intelligibility was reported to be better with the VSB compared with both unaided and with the hearing aid at 5 signal-to-noise ratios.
This prospective study demonstrated that direct-drive stimulation provided by the VSB allows better speech performances than acoustic stimulation for rehabilitation of patients with steeply sloping high-frequency hearing losses.
The purpose of this study was to determine the prognostic value of circulating secretory phospholipase A2 (sPLA2) activity in patients with acute coronary syndromes (ACS).
The plasma level of type ...IIA sPLA2 is a risk factor for coronary artery disease (CAD) and is associated with adverse outcomes in patients with stable CAD. The prognostic impact of sPLA2 in patients with ACS is unknown.
Secretory phospholipase A2 antigen levels and activity were measured in plasma samples of 446 patients with ACS, obtained at the time of enrollment.
Baseline sPLA2 activity was associated with the risk of death and myocardial infarction (MI). The unadjusted rate of death and MI increased in a stepwise fashion with increasing tertiles of sPLA2 activity (p < 0.0001). The association remained significant in the subgroup of patients who had MI with ST-segment elevation (p = 0.014) and the subgroup of patients who had unstable angina or non–ST-segment elevation MI (p < 0.002). After adjustment for clinical and biological variables, the hazard ratios for the combined end point of death or MI in the third tertile of sPLA2 compared with the first and second tertiles was 3.08 (95% confidence interval, 1.37 to 6.91, p = 0.006).
A single measurement of plasma sPLA2 activity at the time of enrollment provides strong independent information to predict recurrent events in patients with ACS.
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