Quality of Life in Patients With Chronic Rhinosinusitis and Sleep Dysfunction Undergoing Endoscopic Sinus Surgery: A Pilot Investigation of Comorbid Obstructive Sleep Apnea.

Importance: Patients with chronic rhinosinusitis (CRS) have reduced sleep quality linked to their overall well-being and disease-specific quality of life (QOL). Other primary sleep disorders also affect QOL.

Objective: To determine the impact of comorbid obstructive sleep apnea (OSA) on CRS disease-specific QOL and sleep dysfunction in patients with CRS following functional endoscopic sinus surgery.

Topical cathelicidin (LL-37) an innate immune peptide induces acute olfactory epithelium inflammation in a mouse model.

Background: Cathelicidin (LL-37) is an endogenous innate immune peptide that is elevated in patients with chronic rhinosinusitis (CRS). The role of LL-37 in olfactory epithelium (OE) inflammation remains unknown. We hypothesized that: (1) LL-37 topically delivered would elicit profound OE inflammation; and (2) LL-37 induced inflammation is associated with increased infiltration of neutrophils and mast cells.

6-Hydroxy-1,2,4-triazine-3,5(2H,4H)-dione Derivatives as Novel D-Amino Acid Oxidase Inhibitors.

A series of 2-substituted 6-hydroxy-1,2,4-triazine-3,5(2H,4H)-dione derivatives were synthesized as inhibitors of D-amino acid oxidase (DAAO). Many compounds in this series were found to be potent DAAO inhibitors, with IC50 values in the double-digit nanomolar range. The 6-hydroxy-1,2,4-triazine-3,5(2H,4H)-dione pharmacophore appears metabolically resistant to O-glucuronidation unlike other structurally related DAAO inhibitors.

Cognitive dysfunction associated with pain and quality of life in chronic rhinosinusitis.

Background: Cognitive dysfunction and its relationship to both pain and disease-specific quality of life (QOL) in chronic rhinosinusitis (CRS) have not been investigated previously. We sought to analyze the correlations of pain and disease-specific QOL with cognitive function in CRS.

Methods: Adults with CRS were prospectively enrolled in a cross-sectional study.

Familial risk of pediatric chronic rhinosinusitis.

Objectives/hypothesis: To determine the risk of chronic rhinosinusitis (CRS) in relatives of children with a diagnosis of CRS.

Study Design: Retrospective observational cohort study with population-based matched controls.

Methods: A unique genealogical database linked to medical records was used to identify subjects ≤12 years old with a diagnosis of CRS from 1996 to 2011.

Selective CNS Uptake of the GCP-II Inhibitor 2-PMPA following Intranasal Administration.

Glutamate carboxypeptidase II (GCP-II) is a brain metallopeptidase that hydrolyzes the abundant neuropeptide N-acetyl-aspartyl-glutamate (NAAG) to NAA and glutamate. Small molecule GCP-II inhibitors increase brain NAAG, which activates mGluR3, decreases glutamate, and provide therapeutic utility in a variety of preclinical models of neurodegenerative diseases wherein excess glutamate is presumed pathogenic. Unfortunately no GCP-II inhibitor has advanced clinically, largely due to their highly polar nature resulting in insufficient oral bioavailability and limited brain penetration.

Characterization of facial pain associated with chronic rhinosinusitis using validated pain evaluation instruments.

Background: Prior investigations into facial pain associated with chronic rhinosinusitis (CRS) have yielded important results, but have yet to use pain-specific outcome measures. This study seeks to characterize facial pain associated with CRS using validated pain-specific instruments.

Methods: Adults with CRS were enrolled into a prospective, cross-sectional study along with control participants presenting with non-CRS diagnoses.

Outcomes of complete vs targeted approaches to endoscopic sinus surgery.

Background: Functional endoscopic sinus surgery (FESS) was historically predicated on targeted widening of narrow anatomic structures that caused postobstructive persistent sinus inflammation. It is now clear that chronic rhinosinusitis (CRS) is a multifactorial disease with subsets of patients which may require a more extensive surgical approach. This study compares quality-of-life (QOL) and disease severity outcomes after FESS based on the extent of surgical intervention.

Familial risk of chronic rhinosinusitis with and without nasal polyposis: genetics or environment.

Background: Chronic rhinosinusitis (CRS) is a highly prevalent inflammatory condition, with significant effects on morbidity and quality of life, yet little is known about its pathogenesis. Preliminary evidence suggests there is a heritable component to the multifactorial etiology of CRS; however, our understanding of this genetic susceptibility is limited.

Methods: Using an extensive genealogical database linked to medical records, the risk of CRS with nasal polyps (CRSwNP) and without polyps (CRSsNP) was calculated for relatives and spouses of adult probands (1638 CRSwNP and 24,200 CRSsNP patients diagnosed between 1996 and 2011) and were compared to random population controls matched 5:1 on sex and birth year from Cox regression models.

Neurological sequelae induced by alphavirus infection of the CNS are attenuated by treatment with the glutamine antagonist 6-diazo-5-oxo-l-norleucine.

Recovery from encephalomyelitis induced by infection with mosquito-borne alphaviruses is associated with a high risk of lifelong debilitating neurological deficits. Infection of mice with the prototypic alphavirus, Sindbis virus, provides an animal model with which to study disease mechanisms and examine potential therapeutics. Infectious virus is cleared from the brain within a week after infection, but viral RNA is cleared slowly and persists for the life of the animal.

Bioanalysis of 6-diazo-5-oxo-l-norleucine in plasma and brain by ultra-performance liquid chromatography mass spectrometry.

Glutamine is an abundant amino acid that plays pivotal roles in cell growth, cell metabolism, and neurotransmission. Dysregulation of glutamine-using pathways has been associated with pathological conditions such as cancer and neurodegenerative diseases. 6-Diazo-5-oxo-l-norleucine (DON) is a reactive glutamine analog that inhibits enzymes affecting glutamine metabolism such as glutaminase, 2-N-amidotransferase, l-asparaginase, and several enzymes involved in pyrimidine and purine de novo synthesis.

Longitudinal improvement and stability of the SNOT-22 survey in the evaluation of surgical management for chronic rhinosinusitis.

Background: Patients with chronic rhinosinusitis (CRS) have significant quality-of-life (QOL) improvements following endoscopic sinus surgery (ESS). These improvements remain stable and persist between 6 months and 20 months as measured by the Rhinosinusitis Disability Index and the Chronic Sinusitis Survey. There has yet to be an evaluation of the longitudinal stability of the 22-item Sino-Nasal Outcome Test (SNOT-22) after ESS in patients with CRS.

Structure-Metabolism Relationships in the Glucuronidation of d-Amino Acid Oxidase Inhibitors.

Representative d-amino acid oxidase (DAAO) inhibitors were subjected to in vitro liver microsomal stability tests in the absence or presence of uridine diphosphate glucuronic acid (UDPGA). While carboxylate-based DAAO inhibitors displayed little glucuronidation, most DAAO inhibitors containing α-hydroxycarbonyl moiety exhibited nearly complete glucuronidation within 30 min. The one exception was 6-[2-(3,5-difluorophenyl)ethyl]-4-hydroxypyridazin-3(2H)-one 10, which exhibited some degree of resistance to glucuronidation by liver microsomes from mice, rats, and humans.

Peptidomimetics of Arg-Phe-NH2 as small molecule agonists of Mas-related gene C (MrgC) receptors.

A series of Arg-Phe-NH2 peptidomimetics containing an Arg mimetic were synthesized and tested as agonists of human MrgX1, rat MrgC, and mouse MrgC11 receptors. As predicted from the previously established species specificity, these peptidomimetics were found to be devoid of MrgX1 agonist activity. In contrast, these compounds acted as agonists of MrgC and/or MrgC11 with varying degrees of potency.

Investigation of change in cardinal symptoms of chronic rhinosinusitis after surgical or ongoing medical management.

Background: Chronic rhinosinusitis (CRS) has been defined as inflammation of the paranasal sinuses lasting at least 12 weeks with corresponding 2 or more "cardinal symptoms" that include: (1) nasal obstruction; (2) thick nasal discharge; (3) facial pain/pressure; and (4) reduction or loss of sense of smell. Although prior studies have investigated symptoms of CRS after sinus surgery, none have compared the outcomes of these specific symptoms to ongoing medical therapy.

Methods: Patients with CRS were prospectively enrolled into a multi-institutional, comparative effectiveness, cohort study.

Differential expression of innate immunity genes in chronic rhinosinusitis.

Background: Prior research has identified several components of the innate immune system that may play a significant role in chronic rhinosinusitis (CRS), but the role of innate immunity in patients with CRS is poorly understood. The objective of this study was to determine differential expression of innate immunity genes in the mucosa of patients with CRS with nasal polyposis (CRSwNP) and CRS without nasal polyposis (CRSsNP) when compared with controls.

Methods: Control patients (n = 9) and patients with CRS (n = 36) who failed medical management were prospectively enrolled.

Stabilization of cellular RNA in blood during storage at room temperature: a comparison of cell-free RNA BCT(®) with K3EDTA tubes.

Background: Messenger RNA (mRNA) expression levels in blood cells are important in disease diagnosis, prognosis and biomarker discovery research. Accurate measurements of intracellular mRNA levels in blood cells depend upon several pre-analytical factors, including delays in RNA extraction from blood after phlebotomy. Dramatic changes in mRNA expression levels caused by delays in blood sample processing may render such samples unsuitable for gene expression analysis.

Sleep and quality of life improvements after endoscopic sinus surgery in patients with chronic rhinosinusitis.

Background: Recent investigation has demonstrated that approximately 75% of patients with medically refractory chronic rhinosinusitis (CRS) report abnormal sleep quality, with strong correlation between worse sleep quality and more severe CRS disease severity. It remains unknown whether the treatment effect of endoscopic sinus surgery (ESS) for CRS results in appreciable sleep quality improvements.

Methods: Adult patients (aged ≥18 years) with a current diagnosis of recalcitrant chronic rhinosinusitis (CRS), who voluntarily elected ESS as the next treatment modality (n = 301), were prospectively evaluated within 4 academic, tertiary care centers using treatment outcome instruments: the Rhinosinusitis Disability Index, the 22-item Sinonasal Outcome Test, the 2-item Patient Health Questionnaire, and the Pittsburgh Sleep Quality Index (PSQI) both before and after ESS.

Comparative effectiveness of medical and surgical therapy on olfaction in chronic rhinosinusitis: a prospective, multi-institutional study.

Background: Evidence comparing the impact of medical and surgical management of chronic rhinosinusitis on olfactory function is limited. This study evaluates olfactory outcomes in patients who failed initial medical management and elect either continued medical management or endoscopic sinus surgery (ESS) followed by medical management.

Methods: Adult subjects were prospectively enrolled into a nonrandomized, multi-institutional cohort.

Stabilization of circulating tumor cells in blood using a collection device with a preservative reagent.

Background: The enumeration and characterization of circulating tumor cells (CTCs) in the blood of cancer patients is useful for cancer prognostic and treatment monitoring purposes. The number of CTCs present in patient blood is very low; thus, robust technologies have been developed to enumerate and characterize CTCs in patient blood samples. One of the challenges to the clinical utility of CTCs is their inherent fragility, which makes these cells very unstable during transportation and storage of blood samples.

Design, synthesis, and pharmacological evaluation of fluorinated tetrahydrouridine derivatives as inhibitors of cytidine deaminase.

Several 2'-fluorinated tetrahydrouridine derivatives were synthesized as inhibitors of cytidine deaminase (CDA). (4R)-2'-Deoxy-2',2'-difluoro-3,4,5,6-tetrahydrouridine (7a) showed enhanced acid stability over tetrahydrouridine (THU) 5 at its N-glycosyl bond. As a result, compound 7a showed an improved oral pharmacokinetic profile with a higher and more reproducible plasma exposure in rhesus monkeys compared to 5.

Predictors of olfactory dysfunction in rhinosinusitis using the brief smell identification test.

Objectives/hypothesis: Associations between olfactory function to quality-of-life (QOL) and disease severity in patients with rhinosinusitis is poorly understood. We sought to evaluate and compare olfactory function between subgroups of patients with rhinosinusitis using the Brief Smell Identification Test (B-SIT).

Study Design: Cross-sectional evaluation of a multicenter cohort.

δ-Thiolactones as prodrugs of thiol-based glutamate carboxypeptidase II (GCPII) inhibitors.

δ-Thiolactones derived from thiol-based glutamate carboxypeptidase II (GCPII) inhibitors were evaluated as prodrugs. In rat liver microsomes, 2-(3-mercaptopropyl)pentanedioic acid (2-MPPA, 1) was gradually produced from 3-(2-oxotetrahydrothiopyran-3-yl)propionic acid (5), a thiolactone derived from 1. Compound 1 was detected in plasma at concentrations well above its IC50 for GCPII following oral administration of 5 in rats.

Antisomnogenic cytokines, quality of life, and chronic rhinosinusitis: a pilot study.

Objectives/hypothesis: Sleep disturbance, reduced quality of life (QOL), and other components of "sickness behavior" in patients with chronic rhinosinusitis (CRS) are poorly understood. These complex changes in central behavior are due to the effects of immune mediators acting in the brain. We hypothesized that immune mediators that have been associated with CRS are also associated with sickness behavior, somnifacient complaints, and CRS disease-specific QOL.