Significance of NT-pro-BNP in acute exacerbation of COPD patients without underlying left ventricular dysfunction

Muhammad Adrish,1 Varalaxmi Bhavani Nannaka,2 Edison J Cano,3 Bharat Bajantri,1 Gilda Diaz-Fuentes1 1Division of Pulmonary and Critical Care Medicine, Bronx-Lebanon Hospital Center, Icahn School of Medicine at Mount Sinai, 2Department of Critical Care Medicine, Montefiore Medical Center, The University Hospital for Albert Einstein College of Medicine, 3Department of Medicine, Bronx-Lebanon Hospital Center, Icahn School of Medicine at Mount Sinai, Bronx, NY, USA Background: B-type natriuretic peptide (BNP) and the N-terminal fragment of pro-BNP (NT-pro-BNP) are established biomarkers of heart failure. Increased levels of natriuretic peptide (NP) have been associated with poor outcomes in acute exacerbation of COPD (AECOPD); however, most studies did not address the conditions that can also increase NT-pro-BNP levels. We aimed to determine if NT-pro-BNP levels correlate with outcomes of AECOPD in patients without heart failure and other conditions that can affect NT-pro-BNP levels.Methods: We conducted a retrospective study in patients hospitalized for AECOPD with available NT-pro-BNP levels and normal left ventricular ejection fraction. We compared patients with normal and elevated NT-pro-BNP levels and analyzed the clinical and outcome data.Results: A total of 167 of 1,420 (11.7%) patients met the study criteria. A total of 77% of male patients and 53% of female patients had elevated NT-pro-BNP levels (P=0.0031). NT-pro-BNP levels were not associated with COPD severity and comorbid illnesses. Log-transformed NT-pro-BNP levels were positively associated with echocardiographically estimated right ventricular systolic pressure (r=0.3658; 95% confidence interval [CI]: 0.2060–0.5067; P<0.0001). Patients with elevated NT-pro-BNP levels were more likely to require intensive care (63% vs 43%; P=0.0207) and had a longer hospital length of stay (P=0.0052). There were no differences in the need for noninvasive positive pressure ventilation (P=0.1245) or mechanical ventilation (P=0.9824) or in regard to in-hospital mortality (P=0.5273).Conclusion: Patients with AECOPD and elevated NT-pro-BNP levels had increased hospital length of stay and need for intensive care. Based on our study, serum NT-pro-BNP levels cannot be used as a biomarker for increased mortality or requirement for invasive or noninvasive ventilation in this group of patients. Keywords: acute exacerbation of COPD, NT-pro-BNP, natriuretic peptide, COP

The battle between rotavirus and its host for control of the interferon signaling pathway.

Viral pathogens must overcome innate antiviral responses to replicate successfully in the host organism. Some of the mechanisms viruses use to interfere with antiviral responses in the infected cell include preventing detection of viral components, perturbing the function of transcription factors that initiate antiviral responses, and inhibiting downstream signal transduction. RNA viruses with small genomes and limited coding space often express multifunctional proteins that modulate several aspects of the normal host response to infection. One such virus, rotavirus, is an important pediatric pathogen that causes severe gastroenteritis, leading to ~450,000 deaths globally each year. In this review, we discuss the nature of the innate antiviral responses triggered by rotavirus infection and the viral mechanisms for inhibiting these responses

Single-Cell Mass Cytometry Analysis of Human Tonsil T Cell Remodeling by Varicella Zoster Virus

Although pathogens must infect differentiated host cells that exhibit substantial diversity, documenting the consequences of infection against this heterogeneity is challenging. Single-cell mass cytometry permits deep profiling based on combinatorial expression of surface and intracellular proteins. We used this method to investigate varicella-zoster virus (VZV) infection of tonsil T cells, which mediate viral transport to skin. Our results indicate that VZV induces a continuum of changes regardless of basal phenotypic and functional T cell characteristics. Contrary to the premise that VZV selectively infects T cells with skin trafficking profiles, VZV infection altered T cell surface proteins to enhance or induce these properties. Zap70 and Akt signaling pathways that trigger such surface changes were activated in VZV-infected naive and memory cells by a T cell receptor (TCR)-independent process. Single-cell mass cytometry is likely to be broadly relevant for demonstrating how intracellular pathogens modulate differentiated cells to support pathogenesis in the natural host

Rotavirus interactions with innate signaling pathways.

<p>Viral nucleic acids may be recognized in a host cell by membrane-bound Toll-like receptors (TLR3) or cytoplasmic RIG-I-like receptors (RLRs). When activated by nucleic-acid binding, RLRs recruit and activate the signaling adaptor molecule IPS-1, which recruits a signaling complex that activates latent cytoplasmic transcription factors such as interferon regulatory factor 3 (IRF3) and nuclear factor-κB (NF-κB). TLR3 activation stimulates the recruitment of the adaptor TRIF, which acts as a platform for a variety of signaling molecules that also phosphorylate IRF3 or NF-κB. When signaled, the C-terminus of IRF3 is phosphorylated, causing a conformational change that leads to dimerization and nuclear translocation. NF-κB is held inactive by inhibitor of NF-κB (IκB). Signals generated during viral infection cause phosphorylation of IκB, followed by ubiquitination (orange circles) and proteasomal degradation mediated by the SKP-CUL-F-box-β-TrCP (SCF^β-TrCP) E3 ubiquitin ligase complex. NF-κB subsequently translocates to the nucleus. IRF3 and NF-κB bind to the IFN-β promoter in a cooperative manner with c-Jun/ATF-2 forming an enhanceosome complex initiating the transcription of IFN-β mRNA. Additional transcription factors, including IRF7, are induced by IFN-β and can also bind to the IFN-β promoter to enhance the transcription of IFN-β and IFN-α genes. PI3K activity may be required for mediating TLR3 and RIG-I signaling by an unknown mechanism (dashed line). PKR responds to dsRNA binding by phosphorylating eIF2α, which ultimately inhibits translation initiation. PKR is also thought to promote the secretion of IFN-β by an unknown mechanism (dashed line). Rotavirus can antagonize innate signaling pathways through several avenues (shown in red), the primary one representing the NSP1-induced degradation of IRF3 and IRF7. Some NSP1 proteins are also known to induce the degradation of β-TrCP. Rotavirus NSP3 can also impede antiviral responses by suppressing the translation of host mRNAs generated from IFN-stimulated genes. By sequestering viral RNAs within viroplasms, the virus can prevent their recognition by PKR, RIG-I, MDA-5, and other sensors that upregulate antiviral responses.</p

Overview of the rotavirus replication cycle.

<p>During entry into the cell, the outermost protein layer of the triple-layered virion is lost. Polymerase complexes in the core of the resultant double-layered particle produce viral mRNAs that are capped but lack poly(A) tails. Viral proteins and RNAs accumulate in protected sites of the cytoplasm called viroplasms where nascent particle assembly takes place. Interaction of newly formed polymerase complexes with the core capsid protein triggers genome replication, which is followed by addition of the intermediate protein layer of the virion. Double-layered particles bud into the endoplasmic reticulum, acquiring their outer capsid. After release through lysis or trafficking, the attachment spike must be cleaved by trypsin-like proteases in the intestinal lumen to activate the virus for subsequent infection.</p