Bactericidal Permeability-Increasing Protein (BPI) Inhibits Mycobacterium tuberculosis Growth.

Bactericidal permeability-increasing protein (BPI) is a multifunctional cationic protein produced by neutrophils, eosinophils, fibroblasts, and macrophages with antibacterial anti-inflammatory properties. In the context of Gram-negative infection, BPI kills bacteria, neutralizes the endotoxic activity of lipopolysaccharides (LPSs), and, thus, avoids immune hyperactivation. Interestingly, BPI increases in patients with Gram-positive meningitis, interacts with lipopeptides and lipoteichoic acids of Gram-positive bacteria, and significantly enhances the immune response in peripheral blood mononuclear cells. We evaluated the antimycobacterial and immunoregulatory properties of BPI in human macrophages infected with Mycobacterium tuberculosis. Our results showed that recombinant BPI entered macrophages, significantly reduced the intracellular growth of M. tuberculosis, and inhibited the production of the proinflammatory cytokine tumor necrosis factor-alpha (TNF-α). Furthermore, BPI decreased bacterial growth directly in vitro. These data suggest that BPI has direct and indirect bactericidal effects inhibiting bacterial growth and potentiating the immune response in human macrophages and support that this new protein's broad-spectrum antibacterial activity has the potential for fighting tuberculosis.

Reduced IL-8 Secretion by NOD-like and Toll-like Receptors in Blood Cells from COVID-19 Patients.

Severe inflammatory responses are associated with the misbalance of innate and adaptive immunity. TLRs, NLRs, and cytokine receptors play an important role in pathogen sensing and intracellular control, which remains unclear in COVID-19. This study aimed to evaluate IL-8 production in blood cells from COVID-19 patients in a two-week follow-up evaluation. Blood samples were taken at admission (t1) and after 14 days of hospitalization (t2). The functionality of TLR2, TLR4, TLR7/8, TLR9, NOD1, and NOD2 innate receptors and IL-12 and IFN-γ cytokine receptors was evaluated by whole blood stimulation with specific synthetic receptor agonists through the quantification of IL-8, TNF-α, or IFN-γ. At admission, ligand-dependent IL-8 secretion was 6.4, 13, and 2.5 times lower for TLR2, TLR4, and endosomal TLR7/8 receptors, respectively, in patients than in healthy controls. Additionally, IL-12 receptor-induced IFN-γ secretion was lower in COVID-19 patients than in healthy subjects. We evaluated the same parameters after 14 days and observed significantly higher responses for TLR2, TLR4, TLR7/8, TLR9, and NOD1, NOD2, and IFN-γ receptors. In conclusion, the low secretion of IL-8 through stimulation with agonists of TLR2, TLR4, TLR7/8, TLR9, and NOD2 at t1 suggests their possible contribution to immunosuppression following hyperinflammation in COVID-19 disease.

Transcultural adaptation of the revised caregiving appraisal scale (RCAS) in the Spanish population.

AIM: To develop a transcultural adaptation of the Revised Caregiving Appraisal Scale among Spanish caregivers of dependent older people and to test the psychometric properties of the scale. DESIGN: Cross-sectional study. METHODS: The Revised Caregiving Appraisal Scale was transculturally adapted to the Spanish population following the methodology of direct and back translation. The Spanish version of the Revised Caregiving Appraisal Scale was administered to a total of 182 family caregivers of older dependent people. The study began in January 2016 and ended in December of the same year. The construct validity was studied by means of the scree plot and parallel analysis. The exploratory factorial analysis was carried out, and the correlation between factors was studied. To verify the reliability of the process, Cronbach's alpha and homogeneity were calculated by the corrected total item correlation. The validity of the convergent criterion was studied by means of the Pearson correlation coefficient, using the Zarit Caregiver Load Interview and the Family Satisfaction Scale as the gold standard. RESULTS: The construct validity revealed three factors: 'Subjective Burden' (15 items), 'Satisfaction' (7 items) and 'Competence' (3 items). The Cronbach alpha was .86 for 'Subjective Burden', .74 for 'Satisfaction' and .74 for 'Competence'. The corrected total item correlation was greater than .25. The validity of the convergent criterion of the 'Subjective Burden' and 'Competence' factors with the 'Zarit Caregiver's Load Interview' presented a very high statistically significant correlation, unlike 'Satisfaction' which presented a low positive correlation with the 'Family Satisfaction Scale'. CONCLUSION: The Spanish version of the Revised Caregiving Appraisal Scale is a valid and reliable scale according to the tests performed on a random sample of family caregivers of older dependent people in Spain. IMPACT: This scale will enable the simultaneous assessment of negative ('Subjective Burden' and 'Competence') and positive ('Satisfaction') perceptions among family caregivers of older dependent people.

Impact of Active Video Games on Body Mass Index in Children and Adolescents: Systematic Review and Meta-Analysis Evaluating the Quality of Primary Studies.

OBJECTIVE: To study the impact of active video games on Body Mass Index (BMI) in children and adolescents. DESIGN AND METHODS: A systematic review and meta-analysis. Data were pooled in meta-analysis using the method of random effects or fixed effects, as appropriate, after examination of statistical heterogeneity. Data sources and eligibility criteria for selecting studies. A comprehensive literature research was conducted in Medline (PubMed), ISI web of Knowledge, and SCOPUS up to April 2018, in relation to clinical trials (both controlled and non-controlled) in children and adolescents, whose intervention was based on active video games. RESULTS: The overall intragroup effect of the intervention based on active video games was in favor of the intervention, reaching statistical significance using the fixed effects model: (standardized mean difference (SMD) = -0.138; 95% CI (-0.237 to -0.038), p = 0.007 and was of borderline statistical significance in the random effects model: SMD= -0.191; 95% CI (-0.386 to 0.003), p = 0.053. The individual results of the determinations of the 15 included studies for this analysis showed a high heterogeneity among them (I2 = 82.91%). When the intervention was applied to children and adolescents with greater than or equal to 85 (overweight or obese) BMI percentile showed a greater effect in favor of the active video games: SMD= -0.483, p = 0.012. The overall intra-group effect in the control group was close to zero (SMD = 0.087). With respect to the non-standardized mean difference (MD) between groups, it was also in favor of active video games for both BMI (Kg/m2): DM = -0.317, 95% CI (-0.442 to -0.193), p = < 0.001 and BMI z-score: DM = -0.077, 95% CI (-0.139 to -0.016), p = 0.013. CONCLUSIONS: Our meta-analysis show a statistically significant effect in favor of using active video games on BMI in children and adolescents. The clinical relevance of this positive effect must be evaluated.

Resolvin D1 (RvD1) and maresin 1 (Mar1) contribute to human macrophage control of M. tuberculosis infection while resolving inflammation.

Resolvins and protectins counter inflammation, enhance phagocytosis, induce bactericidal/permeability-increasing protein (BPI) expression, and restore inflamed tissue to homeostasis. Because modulating the inflammation/antiinflammation balance is important in Mycobacterium tuberculosis infection, we evaluated the effects of resolvins and protectins on human macrophages infected in vitro. Monocyte-derived macrophages were infected with M. tuberculosis H37Rv at a multiplicity of infection (MOI) of 5 and treated 1 h post-infection in vitro with 100 nM LXA4, RvD1, RvD2, PD1 or 150 nM Mar1. After 24 h, cytokine production was measured by Luminex, and BPI and cathelicidin LL37 expression was determined by real-time PCR. Macrophage bactericidal activity was assessed by colony-forming units (CFUs) 3 days posttreatment. Nuclear translocation of Nrf2 was assessed by ELISA, NFκB translocation was determined by imaging cytometry, and BPI production was determined by fluorescence microscopy. We found that all lipids reduced LPS-dependent and M. tuberculosis-induced TNF-α production. RvD1 and Mar1 also induced a significant reduction in M. tuberculosis intracellular growth. RvD1 and Mar1 elicited distinct immunomodulatory patterns. RvD1 induced upregulation of both antimicrobial effector genes (BPI and LL37) and cytokines (GM-CSF and IL-6). Mar1 induced only BPI overexpression. RvD1 and Mar1 induced NFκB nuclear translocation, but only Mar1 induced Nrf2 translocation. Inhibition of G protein-coupled receptor signaling in infected macrophages abrogated the regulatory effects of RvD1. In conclusion, RvD1 and Mar1 modulate the anti-inflammatory and antimicrobial properties of M. tuberculosis-infected human macrophages. Since both proresolving lipids are inducible and synthesized from dietary components, they have immunotherapeutic potential against tuberculosis when inflammation is uncontrolled.

Loperamide Restricts Intracellular Growth of Mycobacterium tuberculosis in Lung Macrophages.

New approaches for improving tuberculosis (TB) control using adjunct host-directed cellular and repurposed drug therapies are needed. Autophagy plays a crucial role in the response to TB, and a variety of autophagy-inducing drugs that are currently available for various medical conditions may serve as an adjunct treatment in pulmonary TB. Here, we evaluated the potential of loperamide, carbamazepine, valproic acid, verapamil, and rapamycin to enhance the antimicrobial immune response to Mycobacterium tuberculosis (Mtb). Human monocyte-derived macrophages (MDMs) and murine alveolar cells (MACs) were infected with Mtb and treated with loperamide, carbamazepine, valproic acid, verapamil, and rapamycin in vitro. Balb/c mice were intraperitoneally administered loperamide, valproic acid, and verapamil, and MACs were infected in vitro with Mtb. The induction of autophagy, the containment of Mtb within autophagosomes and the intracellular Mtb burden were determined. Autophagy was induced by all of the drugs in human and mouse macrophages, and loperamide significantly increased the colocalization of microtubule-associated protein 1 light chain 3 with Mtb in MDMs. Carbamazepine, loperamide, and valproic acid induced microtubule-associated protein 1 light chain 3 and autophagy related 16- like protein 1 gene expression in MDMs and in MACs. Loperamide also induced a reduction in TNF-α production. Loperamide and verapamil induced autophagy, which was associated with a significant reduction in the intracellular growth of Mtb in MACs and alveolar macrophages. The intraperitoneal administration of loperamide and valproic acid induced autophagy in freshly isolated MACs. The antimycobacterial activity in MACs was higher after loperamide treatment and was associated with the degradation of p62. In conclusion, loperamide shows potential as an adjunctive therapy for the treatment of TB.

Multisensory Stimulation as an Intervention Strategy for Elderly Patients With Severe Dementia: A Pilot Randomized Controlled Trial.

The objective of this study was to compare the effect of multisensory stimulation environment (MSSE) and one-to-one activity sessions in the symptomatology of elderly individuals with severe dementia. Thirty-two participants were randomly assigned to the following 3 groups: MSSE, activity, and control group. The MSSE and activity groups participated in two 30-minute weekly sessions over 16 weeks. Pre-, mid-, and posttrial; 8-week follow-up behavior; mood; cognitive status; and dementia severity were registered. Patients in the MSSE group demonstrated a significant improvement in the Neuropsychiatric Inventory and Bedford Alzheimer Nursing Severity Scale scores compared with the activity group. Both MSSE and activity groups showed an improvement during the intervention in the Cohen-Mansfield Agitation Inventory aggressive behavior factor and total score, with no significant differences between groups. The MSSE may have better effects on neuropsychiatric symptoms and dementia severity in comparison with one-to-one activity sessions in patients with severe dementia.

Humoral and cellular responses to a non-adjuvanted monovalent H1N1 pandemic influenza vaccine in hospital employees.

BACKGROUND: The efficacy of the H1N1 influenza vaccine relies on the induction of both humoral and cellular responses. This study evaluated the humoral and cellular responses to a monovalent non-adjuvanted pandemic influenza A/H1N1 vaccine in occupationally exposed subjects who were previously vaccinated with a seasonal vaccine. METHODS: Sixty healthy workers from a respiratory disease hospital were recruited. Sera and peripheral blood mononuclear cells (PBMCs) were obtained prior to and 1 month after vaccination with a non-adjuvanted monovalent 2009 H1N1 vaccine (Influenza A (H1N1) 2009 Monovalent Vaccine Panenza, Sanofi Pasteur). Antibody titers against the pandemic A/H1N1 influenza virus were measured via hemagglutination inhibition (HI) and microneutralization assays. Antibodies against the seasonal HA1 were assessed by ELISA. The frequency of IFN-γ-producing cells as well as CD4+ and CD8+ T cell proliferation specific to the pandemic virus A/H1N peptides, seasonal H1N1 peptides and seasonal H3N2 peptides were assessed using ELISPOT and flow cytometry. RESULTS: At baseline, 6.7% of the subjects had seroprotective antibody titers. The seroconversion rate was 48.3%, and the seroprotection rate was 66.7%. The geometric mean titers (GMTs) were significantly increased (from 6.8 to 64.9, p < 0.05). Forty-nine percent of the subjects had basal levels of specific IFN-γ-producing T cells to the pandemic A/H1N1 peptides that were unchanged post-vaccination. CD4+ T cell proliferation in response to specific pandemic A/H1N1 virus peptides was also unchanged; in contrast, the antigen-specific proliferation of CD8+ T cells significantly increased post-vaccination. CONCLUSION: Our results indicate that a cellular immune response that is cross-reactive to pandemic influenza antigens may be present in populations exposed to the circulating seasonal influenza virus prior to pandemic or seasonal vaccination. Additionally, we found that the pandemic vaccine induced a significant increase in CD8+ T cell proliferation.

Manejo del paciente pluripatológico en una unidad de hospitalización domiciliaria / Managing the patient with multimorbidity in a hospital at home unit

No disponible

Human {beta}-defensin 2 is expressed and associated with Mycobacterium tuberculosis during infection of human alveolar epithelial cells.

To determine the role of human beta-defensin 2 (HBD-2) in human tuberculosis, we studied the in vitro induction of HBD-2 gene expression by Mycobacterium tuberculosis H37Rv infection in the human lung epithelial cell line A549, in alveolar macrophages (AM), and in blood monocytes (MN) by reverse transcription-PCR. We also studied the induction of HBD-2 gene expression by mannose lipoarabinomannan (manLAM) from M. tuberculosis. Intracellular production of HBD-2 peptide was detected by immunocytochemistry and electron microscopy. Our results demonstrated that there was induction of HBD-2 mRNA in A549 cells after infection with M. tuberculosis at various multiplicities of infection (MOI) and that there was stimulation with manLAM. AM expressed the HBD-2 gene only at a high MOI with M. tuberculosis. MN did not express HBD-2 at any of the experimental M. tuberculosis MOI. Immunostaining revealed the presence of intracellular HBD-2 peptide in A549 cells following infection with M. tuberculosis, and the staining was more intense in areas where there were M. tuberculosis clusters. By using electron microscopy we also demonstrated production of HBD-2 after M. tuberculosis infection and adherence of HBD-2 to the membranes of M. tuberculosis. Alveolar epithelial cells are among the first cells to encounter M. tuberculosis following aerogenic infection. As HBD-2 has been shown to control growth of M. tuberculosis and has chemotactic activity, our results suggest that HBD-2 induction by M. tuberculosis may have a role in the pathogenesis of human tuberculosis.