Nitric oxide and its metabolites in the critical phase of illness: rapid biomarkers in the making

The potential of nitric oxide (NO) as a rapid assay biomarker, one that could provide a quantum leap in acute care, remains largely untapped. NO plays a crucial role as bronchodilator, vasodilator and inflammatory mediator. The main objective of this review is to demonstrate how NO is a molecule of heavy interest in various acute disease states along the emergency department and critical care spectrum: respiratory infections, central nervous system infections, asthma, acute kidney injury, sepsis, septic shock, and myocardial ischemia, to name just a few. We discuss how NO and its oxidative metabolites, nitrite and nitrate, are readily detectable in several body compartments and fluids, and as such they are associated with many of the pathophysiological processes mentioned above. With methods such as high performance liquid chromatography and chemiluminescence these entities are relatively easy and inexpensive to analyze. Emphasis is placed on diagnostic rapidity, as this relates directly to quality of care in acute care situations. Further, a rationale is provided for more bench, translational and clinical research in the field of NO biomarkers for such settings. Developing standard protocols for the aforementioned disease states, centered on concentrations of NO and its metabolites, can prove to revolutionize diagnostics and prognostication along a spectrum of clinical care. We present a strong case for developing these biomarkers more as point-of-care assays with potential of color gradient test strips for rapid screening of disease entities in acute care and beyond. This will be relevant to global health

Early Disruption of the Microbiome Leading to Decreased Antioxidant Capacity and Epigenetic Changes: Implications for the Rise in Autism

Currently, 1 out of every 59 children in the United States is diagnosed with autism. While initial research to find the possible causes for autism were mostly focused on the genome, more recent studies indicate a significant role for epigenetic regulation of gene expression and the microbiome. In this review article, we examine the connections between early disruption of the developing microbiome and gastrointestinal tract function, with particular regard to susceptibility to autism. The biological mechanisms that accompany individuals with autism are reviewed in this manuscript including immune system dysregulation, inflammation, oxidative stress, metabolic and methylation abnormalities as well as gastrointestinal distress. We propose that these autism-associated biological mechanisms may be caused and/or sustained by dysbiosis, an alteration to the composition of resident commensal communities relative to the community found in healthy individuals and its redox and epigenetic consequences, changes that in part can be due to early use and over-use of antibiotics across generations. Further studies are warranted to clarify the contribution of oxidative stress and gut microbiome in the pathophysiology of autism. A better understanding of the microbiome and gastrointestinal tract in relation to autism will provide promising new opportunities to develop novel treatment modalities

Towards nitric oxide based diagnostics: call to action

The discovery in the 1980s of the mammalian biosynthesis of nitric oxide (NO) and its roles in the immune, cardiovascular and nervous systems[1] established a startling new paradigm in the history of cellular signaling mechanisms. NO is one of the most important signaling molecules in the body and is involved in virtually every organ system, where it is responsible for modulating an astonishing variety of effects[1]. One can then imagine the host of diseases or conditions that might be caused or affected by the body\u27s dysregulation of NO production and signaling. As a highly reactive free radical, NO is implicated in a variety of pathophysiological processes, a few of which are mentioned inFigure 1. Maintaining NO homeostasis is crucial for optimal health and disease prevention, and developing novel and accurate biomarkers for NO production or availability will probably lead to better diagnostics and treatment strategies for a host of human diseases and have a profound effect on public health. In this letter, we make a strong case for the need for rapid validation of useful and accurate NO based biomarkers for diagnostic and prognostic utility in the clinical setting

Preclinical and clinical otoprotective applications of cell-penetrating peptide D-JNKI-1 (AM-111)

There is a growing interest in the auditory community to develop novel prophylactic and therapeutic drugs to prevent permanent sensorineural hearing loss following acute cochlear injury. The jun-N-terminal protein kinase (JNK) pathway plays a crucial role in acute sensory hearing loss. Blocking the JNK pathway using the cell-penetrating peptide D-JNKI-1 (AM-111/brimapitide) has shown promise as both a prophylactic and therapeutic agent for acute cochlear injury. A number of pre-clinical and clinical studies have determined the impact of D-JNKI-1 on acute sensorineural hearing loss. Given the inner-ear selective therapeutic profile, local route of administration, and ability to diffuse across cellular membranes rapidly using both active and passive transport makes D-JNK-1 a promising oto-protective drug. In this review article, we discuss the application of D-JNKI-1 in various auditory disorders as well as its pharmacological properties and distribution in the cochlea. •Jun-N-terminal protein kinase pathway (JNK) is involved in acute sensorineural hearing loss.•Blocking JNK pathway using cell-penetrating peptide D-JNKI-1 (AM-111; brimapitide) is oto-protective.•D-JNKI-1 is a prophylactic and therapeutic agent that provides protection against permanent sensorineural hearing loss from acute cochlear injury

Planktonic Growth of Pseudomonas aeruginosa around a Dual-Species Biofilm Supports the Growth of Fusobacterium nucleatum within That Biofilm

Purpose. The goal of this study was to understand the potential interaction between Pseudomonas aeruginosa and Fusobacterium nucleatum within the middle ear. Methods. We examined the microbiota of ear fluid and tympanostomy tubes (TTs) obtained from patients with posttympanostomy tube otorrhea. We also examined biofilms formed by P. aeruginosa and F. nucleatum, singly or together, under aerobic or anaerobic conditions. Results. While the facultative anaerobe P. aeruginosa dominated the bacterial population within the ear fluid, strict anaerobes, including F. nucleatum, dominated bacterial populations within the TTs. F. nucleatum was able to grow under aerobic conditions only in the presence of P. aeruginosa, whose growth reduced the level of dissolved oxygen within the broth to nearly anoxic condition within 4 h after inoculation. The presence of P. aeruginosa allowed F. nucleatum to maintain its growth for 72 h within the dual-species biofilm but not within the planktonic growth. Visualization of the biofilms revealed coaggregation of P. aeruginosa and F. nucleatum. Conclusion. Extrapolation of these results suggests that, within the middle ear fluid, the growth of P. aeruginosa produces the anaerobic conditions required for the growth of F. nucleatum, both within effusion and within biofilms

A biomarker-based approach to infectious disease in the pediatric emergency department

In modern pediatric emergency medicine, biomarker-based assays that enable quick bedside diagnostics and subsequent disease management can be valuable. There is a growing need for novel, disease-specific biomarkers that can improve the outcome of pediatric infectious diseases commonly encountered in the emergency department (ED). Viral respiratory infections, central nervous system infections, sepsis, and septic shock are acute disease states frequently encountered in the ED. In this review, we describe a host of novel biomarkers, including a diverse set of cytokines, chemokines, and nitric oxide–based metabolites. Based on disease pathophysiology, a rationale is provided for a molecular- or biomarker-based approach in the ED. Throughout this review, emphasis is placed on diagnostic rapidity because this relates directly to timeliness and quality of care in a busy ED. Once the biomarkers become more clinically available, in a rapid ED setting as bedside point-of-care assays, quality of care will be enhanced, not only by means of diagnostics but also in prognosticating severity of illness