Host defense, dendritic cells and the human lung

Host defense mechanisms protect the body against microorganisms and other foreign structures. These mechanisms can be divided in nonspecific, or innate, and specific, or acquired, immunity. In both branches of immunity the several types of leukocytes (white blood cells) play a dominant role. Nonspecific defense comprises the natural barriers that protect against invading microorganisms, the complement system, and various types of white blood cells including granulocytes, monocytes, macrophages and natural killer cells that are able to neutralize microorganisms and foreign material by phagocytosis and/or killing. The natural barriers consist of the epithelial surfaces of the body, such as the skin and the bronchial epithelium. In the lung, junctional complexes between bronchial epithelial cells physically prevent the invasion of microorganisms. In addition, microorganisms and other particles are removed from the respiratory tract by the "tapis roulant": the mucus film propelled towards the oropharyngeal cavity by the cilia of the epithelial cells. The mucus not only serves as vehicle for particle transport, but also contains antibacterial and antiviral proteins. Specific immunity involves the recognition of foreign structures (antigens), the discrimination between self and non-self, and the generation of immunologic memory. A crucial step in the initiation of an immune response is the presentation of antigens to and the stimulation of T cells. Cells capable of antigen-presentation and the stimulation of T cells are called antigenpresenting cells (APC) and comprise monocytes, macrophages, B cells and in particular dendritic cells (DC). Recognition of the presented antigen by the T cell and the generation of costimulatory signals by the APC result in proliferation, cytokine production and a change in marker expression of the T cell. The T cells thereby regulate the activation of several eff

Binding of corticosteroid receptors to rat hippocampus nuclear matrix

AbstractIn rat hippocampus, the mineralocorticoid receptor and the glucocorticoid receptor bind corticosterone with high affinity. We have studied the association of these receptors with the nuclear matrix both after in vivo and in vitro administration of radiolabelled corticosterone to hippocampus cells. It was found that in vivo 100% and in vitro 60% of the corticosterone that specifically bound to rat hippocampus nuclei was attached to the nuclear matrix. A selective glucocorticoid receptor agonist did not compete for corticosterone binding. This indicates that this binding was mediated by the mineralocorticoid receptor rather than the glucocorticoid receptor

Etiology of nocturia response in men with diminished bladder capacity

Aims: To test the hypothesis that patients with nocturia owing to diminished global or nocturnal bladder capacity improve via increased bladder capacity. Methods: This is a retrospective analysis of voiding diaries completed at a VA urology clinic between 2008-2017. Inclusion required patients aged at least 18 years, male, undergoing treatment for nocturia, and having completed at least two 24-hour voiding diaries >= 1 month apart. Patients were divided into two cohorts: responders (any decline in nocturia) and non-responders (no change or any increase in nocturia). Patients were further sub-stratified as having low global bladder capacity (maximum voided volume [MVV] = 200 mL). Wilcoxon rank-sum was applied with a Bonferroni correction to test significance. Results: Forty pre- and post-treatment diaries from 27 patients, and 19 pre- and post-treatment diaries from 17 patients were identified as having low global and low nocturnal bladder capacity, respectively. Nocturia responders with low global bladder capacity demonstrated significant decline compared to non-responders in nocturnal urine volume (NUV) (-140 vs +75, P < 0.01) and nocturnal bladder capacity index (NBCi) (-0.59 vs +0.23, P < 0.01). Patients with low nocturnal bladder capacity similarly demonstrated decreased NUV (-30 vs +160, P = 0.04) and NBCi (-1.4 vs +0.33, P < 0.01). There was no significant change in MVV or NMVV for either group. Conclusions: Treatment directed at lowering nocturnal urine production and enabling patients to consistently void at capacity is a rational strategy to treat nocturia in patients with low bladder capacity

The role of strigolactones in P deficiency induced transcriptional changes in tomato roots

BACKGROUND: Phosphorus (P) is an essential macronutrient for plant growth and development. Upon P shortage, plant responds with massive reprogramming of transcription, the Phosphate Starvation Response (PSR). In parallel, the production of strigolactones (SLs)—a class of plant hormones that regulates plant development and rhizosphere signaling molecules—increases. It is unclear, however, what the functional link is between these two processes. In this study, using tomato as a model, RNAseq was used to evaluate the time-resolved changes in gene expression in the roots upon P starvation and, using a tomato CAROTENOID CLEAVAGE DIOXYGENASES 8 (CCD8) RNAi line, what the role of SLs is in this. RESULTS: Gene ontology (GO)-term enrichment and KEGG analysis of the genes regulated by P starvation and P replenishment revealed that metabolism is an important component of the P starvation response that is aimed at P homeostasis, with large changes occurring in glyco-and galactolipid and carbohydrate metabolism, biosynthesis of secondary metabolites, including terpenoids and polyketides, glycan biosynthesis and metabolism, and amino acid metabolism. In the CCD8 RNAi line about 96% of the PSR genes was less affected than in wild-type (WT) tomato. For example, phospholipid biosynthesis was suppressed by P starvation, while the degradation of phospholipids and biosynthesis of substitute lipids such as sulfolipids and galactolipids were induced by P starvation. Around two thirds of the corresponding transcriptional changes depend on the presence of SLs. Other biosynthesis pathways are also reprogrammed under P starvation, such as phenylpropanoid and carotenoid biosynthesis, pantothenate and CoA, lysine and alkaloids, and this also partially depends on SLs. Additionally, some plant hormone biosynthetic pathways were affected by P starvation and also here, SLs are required for many of the changes (more than two thirds for Gibberellins and around one third for Abscisic acid) in the gene expression. CONCLUSIONS: Our analysis shows that SLs are not just the end product of the PSR in plants (the signals secreted by plants into the rhizosphere), but also play a major role in the regulation of the PSR (as plant hormone). SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12870-021-03124-0

Increased numbers of dendritic cells in the bronchial mucosa of atopic asthmatic patients: Downregulation by inhaled corticosteroids

Background. Dendritic cells (DC) are the most potent antigen-presenting cells (APC) and stimulators of T cells. Dendritic cells are also likely to be essential for the initiation of allergic immune responses in the lung. However, there are not many data on the presence of dendritic cells in the airways of patients with atopic asthma and on the effects of corticosteroid-treatment on such dendritic cells. Objective. We investigated the distribution of dendritic cells in the bronchial epithelium and mucosa of 16 non-smoking atopic asthmatic patients and eight healthy control subjects using detailed immunohistochemistry (CD1a, HLA-DR, L25 as markers for dendritic cells). Methods. Eleven asthmatics were treated for 2.5 years with bronchodilators only and five with bronchodilators and inhaled beclomethasone dipropionate (BDP), 800 μg daily. The patients were randomly sampled from a double-blind multicentre study. Results. There were higher numbers of CD1a+ DC (P = 0.003), L25+ DC (P = 0.002) and HLA-DR expression (P = 0.042) in the bronchial mucosa of asthmatic patients compared with healthy controls. After 2.5 years of treatment, we found a significant increase in flow expiratory volume in 1 second (FEV1) (P = 0.009) and a significant decrease in hyperresponsiveness (PC20 histamine) (P = 0.013) in the corticosteroid group (n = 5) compared with the bronchodilator group (n = 11). This clinical improvement in the corticosteroid-treated group was accompanied by significantly lower numbers of CD1a+ DC (P=0.008), and HLA-DR expression (P=0.028) in the bronchial mucosa than in the bronchodilator-treated group. Conclusion. Our data suggest that dendritic cells are involved in asthmatic inflammation and that corticosteroids may downregulate the number of dendritic

Enrichment and characterization of dendritic cells from human bronchoalveolar lavages

In the present study about 0.3% to 1.6% of human bronchoalveolar lavage (BAL) cells were identified as typical dendritic cells (DC), having an irregular outline, lobulated nucleus, and clear distinguishable acid phosphatase activity or EBM11 (anti-CD68) reactivity in a spot near the nucleus. After DC enrichment, using transient adherence to plastic, FcR-panning, and a density metrizamide gradient, a population containing 7-8% typical DC was obtained. This DC-enriched low density fraction, containing the highest percentages of DC, very strongly induced T cell proliferation in an allogeneic mixed leucocyte reaction (MLR), which was significantly higher than that induced by other partly (un)fractionated BAL cells. These data indicate that DC seem to be the major accessory cells in the BAL fluid, and therefore may be important in the regulation of T cell immune responses in the lung

Implications of resampling data to address the class imbalance problem (IRCIP): an evaluation of impact on performance between classification algorithms in medical data

Objective When correcting for the "class imbalance" problem in medical data, the effects of resampling applied on classifier algorithms remain unclear. We examined the effect on performance over several combinations of classifiers and resampling ratios. Materials and Methods Multiple classification algorithms were trained on 7 resampled datasets: no correction, random undersampling, 4 ratios of Synthetic Minority Oversampling Technique (SMOTE), and random oversampling with the Adaptive Synthetic algorithm (ADASYN). Performance was evaluated in Area Under the Curve (AUC), precision, recall, Brier score, and calibration metrics. A case study on prediction modeling for 30-day unplanned readmissions in previously admitted Urology patients was presented. Results For most algorithms, using resampled data showed a significant increase in AUC and precision, ranging from 0.74 (CI: 0.69-0.79) to 0.93 (CI: 0.92-0.94), and 0.35 (CI: 0.12-0.58) to 0.86 (CI: 0.81-0.92) respectively. All classification algorithms showed significant increases in recall, and significant decreases in Brier score with distorted calibration overestimating positives. Discussion Imbalance correction resulted in an overall improved performance, yet poorly calibrated models. There can still be clinical utility due to a strong discriminating performance, specifically when predicting only low and high risk cases is clinically more relevant. Conclusion Resampling data resulted in increased performances in classification algorithms, yet produced an overestimation of positive predictions. Based on the findings from our case study, a thoughtful predefinition of the clinical prediction task may guide the use of resampling techniques in future studies aiming to improve clinical decision support tools.Orthopaedics, Trauma Surgery and Rehabilitatio