Predictive Factors for and Complications of Bronchiectasis in Common Variable Immunodeficiency Disorders

Bronchiectasis is a frequent complication of common variable immunodeficiency disorders (CVID). In a cohort of patients with CVID, we sought to identify predictors of bronchiectasis. Secondly, we sought to describe the impact of bronchiectasis on lung function, infection risk, and quality of life. We conducted an observational cohort study of 110 patients with CVID and an available pulmonary computed tomography scan. The prevalence of bronchiectasis was 53%, with most of these patients (54%) having mild disease. Patients with bronchiectasis had lower median serum immunoglobulin (Ig) concentrations, especially long-term IgM (0 vs 0.25 g/l; p < 0.01) and pre-treatment IgG (1.3 vs 3.7 g/l; p < 0.01). CVID patients with bronchiectasis had worse forced expiratory volume in one second (2.10 vs 2.99 l; p < 0.01) and an annual decline in forced expiratory volume in one second of 25 ml/year (vs 8 ml/year in patients without bronchiectasis; p = 0.01). Patients with bronchiectasis also reported more annual respiratory tract infections (1.77 vs 1.25 infections/year, p = 0.04) and a poorer quality of life (26 vs 14 points in the St George's Respiratory Questionnaire; p = 0.02). Low serum immunoglobulin M concentration identifies patients at risk for bronchiectasis in CVID and may play a role in pathogenesis. Bronchiectasis is relevant because it is associated with frequent respiratory tract infections, poorer lung function, a greater rate of lung function decline, and a lower quality of life

Altered Microbiota, Impaired Quality of Life, Malabsorption, Infection, and Inflammation in CVID Patients With Diarrhoea

© Copyright © 2020 van Schewick, Nöltner, Abel, Burns, Workman, Symes, Guzman, Proietti, Bulashevska, Moreira, Soetedjo, Lowe and Grimbacher. Background: Diarrhoea is the commonest gastrointestinal symptom in patients with common variable immunodeficiency (CVID). Objective: The aim of this study was to describe the prevalence and clinical presentation of chronic and recurrent diarrhoea in the Royal-Free-Hospital (RFH) London CVID cohort, including symptoms, infections, level of inflammation, and microbial diversity. Methods: A cross-sectional study of adult CVID patients (139 out of 172 diagnosed with CVID completed the screening questionnaire). Those with diarrhoea ≥6 days/month had stool and blood samples analysed and completed the short Inflammatory Bowel Disease Questionnaire (sIBDQ). BMI, spleen-size, lymphocytes and gut-microbial diversity were compared. Due to logistical and clinical restraints, not all patients could be analysed on all measures. Results: 46/139 (33.1%) patients had current significant diarrhoea. In patients with past or present diarrhoea, BMI was lower (median 23.7 vs. 26, p = 0.005), malabsorption more common (57.97 vs. 35.71%, p = 0.011). CD4+ lymphocytes were higher in patients with diarrhoea (p = 0.028; n = 138), but CD4+ naïve lymphocytes were significantly higher in non-diarrhoea patients (p = 0.009, N = 28). Nine patients had confirmed or probable current gastrointestinal infections. Calprotectin was >60 μg/g in 13/29 with significant diarrhoea including 9 without infection. SIBDQ revealed a low median score of 4.74. Microbial alpha diversity was significantly lower in CVID patients compared to healthy household controls. There was no significant difference in alpha diversity in relation to antibiotic intake during the 6 weeks prior to providing samples. Conclusion: Patients with CVID and significant diarrhoea had infections, raised calprotectin, malabsorption, a lower BMI, an impaired quality of life (comparable to active IBD), and they differed from non-diarrhoea patients in their lymphocyte phenotyping. Furthermore, microbial diversity was altered. These findings strongly imply that there may be an inflammatory nature and a systemic predisposition to diarrhoea in CVID, which necessitates further investigation

Optimal Control of Saccades by Spatial-Temporal Activity Patterns in the Monkey Superior Colliculus

A major challenge in computational neurobiology is to understand how populations of noisy, broadly-tuned neurons produce accurate goal-directed actions such as saccades. Saccades are high-velocity eye movements that have stereotyped, nonlinear kinematics; their duration increases with amplitude, while peak eye-velocity saturates for large saccades. Recent theories suggest that these characteristics reflect a deliberate strategy that optimizes a speed-accuracy tradeoff in the presence of signal-dependent noise in the neural control signals. Here we argue that the midbrain superior colliculus (SC), a key sensorimotor interface that contains a topographically-organized map of saccade vectors, is in an ideal position to implement such an optimization principle. Most models attribute the nonlinear saccade kinematics to saturation in the brainstem pulse generator downstream from the SC. However, there is little data to support this assumption. We now present new neurophysiological evidence for an alternative scheme, which proposes that these properties reside in the spatial-temporal dynamics of SC activity. As predicted by this scheme, we found a remarkably systematic organization in the burst properties of saccade-related neurons along the rostral-to-caudal (i.e., amplitude-coding) dimension of the SC motor map: peak firing-rates systematically decrease for cells encoding larger saccades, while burst durations and skewness increase, suggesting that this spatial gradient underlies the increase in duration and skewness of the eye velocity profiles with amplitude. We also show that all neurons in the recruited population synchronize their burst profiles, indicating that the burst-timing of each cell is determined by the planned saccade vector in which it participates, rather than by its anatomical location. Together with the observation that saccade-related SC cells indeed show signal-dependent noise, this precisely tuned organization of SC burst activity strongly supports the notion of an optimal motor-control principle embedded in the SC motor map as it fully accounts for the straight trajectories and kinematic nonlinearity of saccades

Linear ensemble-coding in midbrain superior colliculus specifies the saccade kinematics

Recently, we proposed an ensemble-coding scheme of the midbrain superior colliculus (SC) in which, during a saccade, each spike emitted by each recruited SC neuron contributes a fixed minivector to the gaze-control motor output. The size and direction of this ‘spike vector’ depend exclusively on a cell’s location within the SC motor map (Goossens and Van Opstal, in J Neurophysiol 95: 2326–2341, 2006). According to this simple scheme, the planned saccade trajectory results from instantaneous linear summation of all spike vectors across the motor map. In our simulations with this model, the brainstem saccade generator was simplified by a linear feedback system, rendering the total model (which has only three free parameters) essentially linear. Interestingly, when this scheme was applied to actually recorded spike trains from 139 saccade-related SC neurons, measured during thousands of eye movements to single visual targets, straight saccades resulted with the correct velocity profiles and nonlinear kinematic relations (‘main sequence properties– and ‘component stretching’) Hence, we concluded that the kinematic nonlinearity of saccades resides in the spatial-temporal distribution of SC activity, rather than in the brainstem burst generator. The latter is generally assumed in models of the saccadic system. Here we analyze how this behaviour might emerge from this simple scheme. In addition, we will show new experimental evidence in support of the proposed mechanism

A competitive integration model of exogenous and endogenous eye movements

We present a model of the eye movement system in which the programming of an eye movement is the result of the competitive integration of information in the superior colliculi (SC). This brain area receives input from occipital cortex, the frontal eye fields, and the dorsolateral prefrontal cortex, on the basis of which it computes the location of the next saccadic target. Two critical assumptions in the model are that cortical inputs are not only excitatory, but can also inhibit saccades to specific locations, and that the SC continue to influence the trajectory of a saccade while it is being executed. With these assumptions, we account for many neurophysiological and behavioral findings from eye movement research. Interactions within the saccade map are shown to account for effects of distractors on saccadic reaction time (SRT) and saccade trajectory, including the global effect and oculomotor capture. In addition, the model accounts for express saccades, the gap effect, saccadic reaction times for antisaccades, and recorded responses from neurons in the SC and frontal eye fields in these tasks. © The Author(s) 2010

Impact of Intermediate Hyperglycemia and Diabetes on Immune Dysfunction in Tuberculosis

Supplementary Data: Supplementary materials are available at Clinical Infectious Diseases online at https://academic.oup.com/cid/article/72/1/69/5857148#274319223 . Consisting of data provided by the authors to benefit the reader, the posted materials are not copyedited and are the sole responsibility of the authors, so questions or comments should be addressed to the corresponding author.Copyright © The Author(s) 2020. Background: People with diabetes have an increased risk of developing active tuberculosis (TB) and are more likely to have poor TB-treatment outcomes, which may impact on control of TB as the prevalence of diabetes is increasing worldwide. Blood transcriptomes are altered in patients with active TB relative to healthy individuals. The effects of diabetes and intermediate hyperglycemia (IH) on this transcriptomic signature were investigated to enhance understanding of immunological susceptibility in diabetes-TB comorbidity. Methods: Whole blood samples were collected from active TB patients with diabetes (glycated hemoglobin [HbA1c] ≥6.5%) or IH (HbA1c = 5.7% to <6.5%), TB-only patients, and healthy controls in 4 countries: South Africa, Romania, Indonesia, and Peru. Differential blood gene expression was determined by RNA-seq (n = 249). Results: Diabetes increased the magnitude of gene expression change in the host transcriptome in TB, notably showing an increase in genes associated with innate inflammatory and decrease in adaptive immune responses. Strikingly, patients with IH and TB exhibited blood transcriptomes much more similar to patients with diabetes-TB than to patients with only TB. Both diabetes-TB and IH-TB patients had a decreased type I interferon response relative to TB-only patients. Conclusions: Comorbidity in individuals with both TB and diabetes is associated with altered transcriptomes, with an expected enhanced inflammation in the presence of both conditions, but also reduced type I interferon responses in comorbid patients, suggesting an unexpected uncoupling of the TB transcriptome phenotype. These immunological dysfunctions are also present in individuals with IH, showing that altered immunity to TB may also be present in this group. The TB disease outcomes in individuals with IH diagnosed with TB should be investigated further.European Union’s Seventh Framework Programme (FP7 2007-2013 - Health) under grant agreement No 305279

Mesenchymal stem cell transplantation as a potential therapy for refractory lupus nephritis: A systematic review

Abstract Background Lupus nephritis (LN) results in high morbidity and mortality in patients with systemic lupus erythematosus. Refractory cases of standard immunosuppressive therapy have been recorded. Mesenchymal stem cell transplantation (MSCT) shows potential use in autoimmune diseases. We aim to review MSCT in the treatment of refractory LN. Methods Published articles were systematically extracted from the databases in May 2022. The quality of the studies was assessed using the Oxford Centre for Evidence‐Based Medicine critical appraisal checklist. Results Four studies were included. All studies recruit severe or refractory LN patients and show significant improvement in post‐MSCT 24‐h proteinuria. However, the improvement of renal function after MSCT is inconsistent between studies after a 1‐month follow‐up, with one study showing deterioration of the estimated glomerular filtration rate after 3 months and one study showing an increase in serum creatinine at 6 and 9 months. Moreover, all studies show improvement in Systemic Lupus Erythematosus Disease Activity Index scores after MSCT, while two studies show that a decrease in anti‐double‐stranded DNA (anti‐dsDNA) levels after MSCT is only evident for up to 1‐month period. Conclusions MSCT can be effective, especially in severe or refractory LN. More randomized‐controlled trials are needed to support this evidence

Rifampicin Alters Metformin Plasma Exposure but Not Blood Glucose Levels in Diabetic Tuberculosis Patients

Contains fulltext : 202131.pdf (publisher's version ) (Open Access

Emergent self-organizing feature map for recognizing road sign images

Road sign recognition system remains a challenging part of designing an Intelligent Driving Support System. While there exist many approaches to classify road signs, none have adopted an unsupervised approach. This paper proposes a way of Self-Organizing feature mapping for recognizing a road sign. The emergent self-organizing map (ESOM) is employed for the feature mapping in this study. It has the capability of visualizing the distance structures as well as the density structure of high-dimensional data sets, in which the ESOM is suitable to detect non-trivial cluster structures. This paper discusses the usage of ESOM for road sign detection and classification. The benchmarking against some other commonly used classifiers was performed. The results demonstrate that the ESOM approach outperforms the others in conducting the same simulations of the road sign recognition. We further demonstrate that the result obtained with ESOM is significantly more superior than traditional SOM which does not take into the boundary effect like ESOM did