The increase and persistence of inflammation in community-acquired pneumonia (CAP) patients can lead to higher mortality. Biomarkers capable of measuring this inadequate inflammatory response are ...likely candidates to be related with a bad outcome. We investigated the association between concentrations of several inflammatory markers and mortality of CAP patients.
This was a prospective study of hospitalised CAP patients in a Spanish university hospital. Blood tests upon admittance and in the early-stage evolution (72-120 hours) were carried out, where C-reactive protein, procalcitonin, proadrenomedullin, copeptin, white blood cell, Lymphocyte Count Percentage (LCP), Neutrophil Count Percentage (NCP) and Neutrophil/Lymphocyte Ratio (NLR) were measured. The outcome variable was mortality at 30 and 90 days. Statistical analysis included logistic regression, ROC analysis and area-under-curve test.
154 hospitalised CAP patients were included. Patients who died during follow-up had higher levels of procalcitonin, copeptin, proadrenomedullin, lower levels of LCP, and higher of NCP and NLR. Remarkably, multivariate analysis showed a relationship between NCP and mortality, regardless of age, severity of CAP and comorbidities. AUC analysis showed that NLR and NCP at admittance and during early-stage evolution achieved a good diagnostic power. ROC test for NCP and NLR were similar to those of the novel serum biomarkers analysed.
NLR and NCP, are promising candidate predictors of mortality for hospitalised CAP patients, and both are cheaper, easier to perform, and at least as reliable as the new serum biomarkers. Future implementation of new biomarkers would require comparison not only with classic inflammatory parameters like White Blood Cell count but also with NLR and NCP.
Patients with community-acquired pneumonia (CAP) undergo a dysregulated host response that is related to mortality. MicroRNAs (miRNAs) participate in this response, but their expression pattern and ...their role as biomarkers in CAP have not been fully characterized.
A prospective observational study was performed in a cohort of 153 consecutive patients admitted to hospital with CAP. Clinical and analytical variables were collected, and the main outcome variable was 30-day mortality. Small RNA was purified from plasma of these patients obtained on the first day of admission, and miRNA expression was analyzed by RT-PCR. Univariate and multivariate analyses were carried out through the construction of a logistic regression model. The proposed model was compared with established prognostic clinical scales using ROC curve analysis.
The mean age of the patients included was 74.7 years SD 15.9. Their mean PSI was 100.9 SD 34.6 and the mean modified Charlson index was 2.9 SD 3.0. Both miR-146a and miR-16-5p showed statistically significant association with 30-day mortality after admission due to CAP (1.10 vs. 0.23 and 51.74 vs. 35.23, respectively), and this association remained for miR-16-5p in the multivariate analysis adjusted for age, gender and history of bronchoaspiration (OR 0.95, p = 0.021). The area-under-the-curve (AUC) of our adjusted multivariate model (AUC = 0.954 95%CI 0.91-0.99), was better than those of prognostic scales such as PSI (AUC = 0.799 0.69-0.91) and CURB-65 (AUC = 0.722 0.58-0.86).
High levels of miR-146a-5p and miR-16-5p upon admission due to CAP are associated with lower mortality at 30 days of follow-up. Both miRNAs could be used as biomarkers of good prognosis in subjects hospitalized with CAP.
Previous studies provided evidence of the benefits of omega-3 polyunsaturated fatty acids (ω-3 PUFA) on the cardiovascular system and inflammation. However, its possible effect on skeletal muscle is ...unknown. This study aimed to evaluate whether ω-3 PUFA reverses the dysregulation of metabolic modulators in the skeletal muscle of rats on a high-fat obesogenic diet. For this purpose, an animal model was developed using male Wistar rats with a high-fat diet (HFD) and subsequently supplemented with ω-3 PUFA. Insulin resistance was assessed, and gene and protein expression of metabolism modulators in skeletal muscle was also calculated using PCR-RT and Western blot. Our results confirmed that in HFD rats, zoometric parameters and insulin resistance were increased compared to SD rats. Furthermore, we demonstrate reduced gene and protein expression of peroxisome proliferator-activated receptors (PPARs) and insulin signaling molecules. After ω-3 PUFA supplementation, we observed that glucose (24.34%), triglycerides (35.78%), and HOMA-IR (40.10%) were reduced, and QUICKI (12.16%) increased compared to HFD rats. Furthermore, in skeletal muscle, we detected increased gene and protein expression of PPAR-α, PPAR-γ, insulin receptor (INSR), insulin receptor substrate 1 (ISR-1), phosphatidylinositol-3-kinase (PI3K), and glucose transporter 4 (GLUT-4). These findings suggest that ω-3 PUFAs decrease insulin resistance of obese skeletal muscle.
Lower respiratory infections are among the top ten causes of death worldwide. Since pathogen to cell adhesion is a crucial step in the infection progress, blocking the interaction between eukaryotic ...receptors and bacterial ligands may enable the pathogenesis process to be stopped. Cell surface glycosaminoglycans (GAGs) are known to be mediators in the adhesion of diverse bacteria to different cell types, making it of interest to examine their involvement in the attachment of various pathogenic bacteria to lung cells, including epithelial cells and fibroblasts.
The function of cell surface GAGs in bacterial adhesion was studied by reducing their levels through inhibiting their biosynthesis and enzymatic degradation, as well as in binding competition experiments with various species of GAGs. The participation of the different bacterial adhesins in attachment was evaluated through competition with two peptides, both containing consensus heparin binding sequences. Blocking inhibition assays using anti-syndecans and the enzymatic removal of glypicans were conducted to test their involvement in bacterial adhesion. The importance of the fine structure of GAGs in the interaction with pathogens was investigated in competition experiments with specifically desulfated heparins.
The binding of all bacteria tested decreased when GAG levels in cell surface of both lung cells were diminished. Competition experiments with different types of GAGs showed that heparan sulfate chains are the main species involved. Blocking or removal of cell surface proteoglycans evidenced that syndecans play a more important role than glypicans. The binding was partially inhibited by peptides including heparin binding sequences. Desulfated heparins also reduced bacterial adhesion to different extents depending on the bacterium and the sulfated residue, especially in fibroblast cells.
Taken together, these data demonstrate that the GAG chains of the cell surface are involved in the adhesion of bacterial adhesins to lung cells. Heparan sulfate seems to be the main species implicated, and binding is dependent on the sulfation pattern of the molecule. These data could facilitate the development of new anti-infective strategies, enabling the development of new procedures for blocking the interaction between pathogens and lung cells more effectively.
Previous studies have evaluated the association between sickle cell disease (SCD) and periodontal disease; however, their effect on the periodontal parameters remains unclear. This systematic review ...aimed to investigate whether individuals with sickle cell disease (SCD) increase the risks of periodontal disease more than those without. For the selection of eligible studies, an electronic search was conducted in the MEDLINE/PubMed, Web of Science, Cochrane Library, and Scopus databases. The meta-analysis was based on the inversion of variance using the mean difference (MD) of the continuous outcomes. The quality assessment of included studies was performed using the JBI Critical Appraisal Tools. In total, 13 studies and 2381 participants were included in the qualitative analysis, while 9 studies were considered for the meta-analysis. The meta-analysis indicated that patients with SCD present similar Plaque Index, Clinical Attachment Level, Bleeding on Probing, and Probing Depth when compared to healthy patients (p > .05). However, the Gingival Index was higher for patients with SCD (p = .0002; MD: 0.20). Compared to healthy patients, patients with SCD did not have an increase in periodontal parameters, except for the gingival index. However, further well-designed studies are recommended to reassess the association between SCD and periodontal diseases.
Innate immunity to Candida albicans depends upon the recognition of molecular patterns on the fungal cell wall. However, the masking of major components such as β-glucan seems to be a mechanism that ...fungi have evolved to avoid immune cell recognition through the dectin-1 receptor. Although the role of C. albicans mitogen-activated protein kinase (MAPK) pathways as virulence determinants has been established previously with animal models, the mechanism involved in this behavior is largely unknown. In this study we demonstrate that a disruption of the C. albicans extracellular signal-regulated kinase (ERK)-like 1 (CEK1)-mediated MAPK pathway causes enhanced cell wall β-glucan exposure, triggering immune responses more efficiently than the wild type, as measured by dectin-1-mediated specific binding and human dendritic cell (hDC)- and macrophage-mediated phagocytosis, killing, and activation of intracellular signaling pathways. At the molecular level, the disruption of CEK1 resulted in altered spleen tyrosine kinase (Syk), Raf-1, and ERK1/2 activations together with IκB degradation on hDCs and increased dectin-1-dependent activator protein 1 (AP-1) activation on transfected cells. In addition, concurring with these altered pathways, we detected increased reactive oxygen species production and cytokine secretion. In conclusion, the CEK1-mediated MAPK pathway is involved in β-glucan exposure in a fungal pathogen, hence influencing dectin-1-dependent immune cell recognition, thus establishing this fungal intracellular signaling route as a promising novel therapeutic target.
Chromosomal translocations in tumors frequently produce fusion genes coding for chimeric proteins with a key role in oncogenesis. Recent reports described a BCR-JAK2 fusion gene in fatal chronic and ...acute myeloid leukemia, but the functional behavior of the chimeric protein remains uncharacterized. We used fluorescence in situ hybridization and reverse transcription polymerase chain reaction (RT-PCR) assays to describe a BCR-JAK2 fusion gene from a patient with acute lymphoblastic leukemia. The patient has been in complete remission for six years following treatment and autologous transplantation, and minimal residual disease was monitored by real-time RT-PCR. BCR-JAK2 codes for a protein containing the BCR oligomerization domain fused to the JAK2 tyrosine-kinase domain. In vitro analysis of transfected cells showed that BCR-JAK2 is located in the cytoplasm. Transduction of hematopoietic Ba/F3 cells with retroviral vectors carrying BCR-JAK2 induced IL-3-independent cell growth, constitutive activation of the chimeric protein as well as STAT5 phosphorylation and translocation to the nuclei, where Bcl-xL gene expression was elicited. Primary mouse progenitor cells transduced with BCR-JAK2 also showed increased proliferation and survival. Treatment with the JAK2 inhibitor TG101209 abrogated BCR-JAK2 and STAT5 phosphorylation, decreased Bcl-xL expression and triggered apoptosis of transformed Ba/F3 cells. Therefore, BCR-JAK2 is a novel tyrosine-kinase with transforming activity. It deregulates growth factor-dependent proliferation and cell survival, which can be abrogated by the TG101209 inhibitor. Moreover, transformed Ba/F3 cells developed tumors when injected subcutaneously into nude mice, thus proving the tumorigenic capacity of BCR-JAK2 in vivo. Together these findings suggest that adult and pediatric patients with BCR-ABL-negative leukemia and JAK2 overexpression may benefit from targeted therapies.
•The associated oral manifestations in HIV patients remain present even in the HAART era.•Periodontal disease with or without mobility were the predominant oral lesions in the patients of this ...study.•No relationship was found between oral lesions, TCD4+ and TCD8+ cell count, TCD4:TCD8 ratio, or viral load.•There is a protective effect of duration of treatment with relation to periodontal disease with mobility.
This study aimed to assess the prevalence of oral lesions in patients living with HIV infection and their association with CD4 count, viral load, and antiretroviral therapy in patients with HIV.
A cross-sectional study was conducted on a sample of 161 patients attending the… All the patients were examined for their oral lesions, current CD4 counts, type, and duration of the therapy. Data analyses were carried out using Chi-Square, Student T/Mann-Whitney, and logistic regression tests.
Oral lesions were observed in 58.39% of patients with HIV. Periodontal disease with 78 (48.45%) or without mobility 79 (49.07%) was observed more frequently, followed by hyperpigmentation of oral mucosa 23 (14.29%), Linear Gingival Erythema (LGE) 15 (9.32%), candidiasis pseudomembranous 14 (8.70%). Oral Hairy Leukoplakia (OHL) was observed only in 3 (1.86%). A relationship between periodontal disease with dental mobility and smoking was found (p=0.04), as well duration of treatment (p=1.53e-3) and age (p=0.02). Hyperpigmentation was related to race (p=0.01) and smoking (p=1.30e-6). CD4 count, CD4:CD8 ratio, viral load, or type of treatment were not associated with oral lesions. Logistic regression showed that the duration of treatment has a protective effect on the periodontal disease with dental mobility (OR = 0.28 −2.27 to −0.25; p-value=0.03), independent of age or smoking. To hyperpigmentation, the best model included smoking (OR=8.47 1.18–3.10, p= 1.31e-5), without race or type and duration of treatment.
Among HIV patients undergoing antiretroviral treatment, oral lesions can be observed, predominantly periodontal disease. Pseudomembranous candidiasis and oral hairy leukoplakia were also observed. No relationship was found between associated oral manifestations in HIV patients and the start of the treatment, TCD4+ and TCD8+ cell count, TCD4:TCD8 ratio, or viral load. The data indicate that there is a protective effect of duration of treatment with relation to periodontal disease with mobility and that hyperpigmentation seems to be more related to smoking than type and duration of treatment.
Level 3 (OCEBM Levels of Evidence Working Group*. "The Oxford 2011 Levels of Evidence").
We compared in an inducible expression system the individual effect of US2, US6 and US11 human cytomegalovirus (HCMV) proteins on HLA‐E and HLA class Ia surface expression, assessing in parallel ...their influence on target susceptibility to NK cell clones. To this end, the RPMI 8866 B lymphoma cell line (HLA‐A2, HLA‐A3, HLA‐B7, HLA‐Cw7, HLA‐ER, HLA‐EG) was stably cotransfected with the ecdysone receptor, together with the US sequences under the control of an ecdysone‐inducible promoter. Biosynthesis of viral proteins was turned on by incubating transfectants with Ponasterone A. US6 down‐regulated expression of all class I molecules, hampering target resistance to NK cell clones controlled by the CD94/NKG2A, KIR2DL2 and/or CD85j (ILT2 or LIR‐1) inhibitory receptors. By contrast, US11 reduced the surface levels of class Ia molecules but preserved HLA‐E; this rendered US11+ cells sensitive to NK clones under the control of KIR2DL2 and/or CD85j, while their resistance to CD94/NKG2A+KIR2DL2– effector cells was maintained. US2 preserved as well HLA‐E expression but selectively targeted class Ia molecules; in fact, HLA‐A and HLA‐C allotypes were down‐modulated whereas HLA‐B7 remained unaltered. US2+ targets became sensitive to KIR2DL2+ cells but remained resistant to CD94/NKG2A+CD85j+ NK clones. The differential effects of US proteins on HLA class Ia and HLA‐E likely reflect the evolutionary adaptation of HCMV to counteract NK‐mediated surveillance.
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