Nonallergic Rhinopathy: A Comprehensive Review of Classification, Diagnosis, and Treatment.

Chronic nonallergic rhinitis syndromes encompass various conditions, of which vasomotor rhinitis is the most common form, representing approximately 80% of patients, also referred to as nonallergic rhinopathy (NAR), nasal hyperreactivity, neurogenic rhinitis, or idiopathic rhinitis. Expert panels have recommended replacing vasomotor rhinitis terminology because it is more descriptive of this condition that is characterized by symptoms triggered by chemical irritants and weather changes through chemosensors, mechanosensors, thermosensors, and/or osmosensors activated through different transient receptor potential calcium ion channels. Elucidating the specific role of transient receptor potential vanilloid 1, triggered by capsaicin, has been an important advancement in better understanding the pathophysiology of NAR because it has now been shown that downregulation of transient receptor potential vanilloid 1 receptors by several therapeutic compounds provides symptomatic relief for this condition. The classification of NAR is further complicated by its association with allergic rhinitis referred to as mixed rhinitis, which involves both immunoglobulin E-mediated and neurogenic mechanistic pathways. Comorbidities associated with NAR, including rhinosinusitis, headaches, asthma, chronic cough, and sleep disturbances, underscore the need for comprehensive management. Treatment options for NAR include environmental interventions, pharmacotherapy, and in refractory cases, surgical options, emphasizing the need for a tailored approach for each patient. Thus, it is extremely important to accurately diagnose NAR because inappropriate therapies lead to poor clinical outcomes and unnecessary health care and economic burdens for these patients. This review provides a comprehensive overview of NAR subtypes, focusing on classification, diagnosis, and treatment approaches for NAR.

Chronic Urticaria and Angioedema: Masqueraders and Misdiagnoses.

Chronic urticaria is a common condition presenting with intensely pruritic wheals. Although individual lesions resolve within 24 hours, by definition, chronic urticaria lasts for a duration of at least 6 weeks. Both spontaneous and inducible forms exist. In the spontaneous variant, chronic urticaria occurs in the absence of clearly identifiable triggers. In chronic inducible urticaria, specific triggers may include dermatographism, cholinergic (heat), cold, exercise, delayed pressure, and solar. Extensive laboratory evaluation for chronic spontaneous urticaria is not required unless indicated by clinical history or physical examination. Angioedema describes sudden onset of localized edema involving the deep layers of the skin and submucosal tissues. It can be seen in isolation or in conjunction with chronic urticaria. Angioedema typically resolves slower than wheals, taking up to 72 hours or longer. Histamine- and bradykinin-mediated forms exist. Both chronic urticaria and angioedema have many mimics, and a broad range of differential diagnoses should be considered. Importantly, an incorrect diagnosis may have significant implications for the additional investigation, treatment, and prognosis of the affected patient. The aim of this article is to discuss the characteristics of chronic urticaria and angioedema, and an approach to the investigation and diagnosis of their mimics.

Establishment of a Host-to-Host Transmission Model for Mycobacterium avium subsp. hominissuis Using Caenorhabditis elegans and Identification of Colonization-Associated Genes.

Mycobacterium avium subsp. hominissuis (M. avium) is a member of the non-tuberculous mycobacteria (NTM), and is a common cause of lung infection in patients with chronic NTM lung conditions. M. avium is an environmental bacterium believed to be transmitted from environmental sources. In this work we used a recently developed model in Caenorhabditis elegans to ask whether M. avium can be transmitted from host-to-host, and the bacterial genes associated with host colonization. Infection of C. elegans was carried out by placing the nematode in cultured with M. avium. Bacteria eliminated from the intestines of infected C. elegans were used to infect naïve nematodes. In parallel experiments, to identify colonization associated genes, a transposon library of M. avium was screened for the ability to bind to HEp-2 mucosal cells. Thirty clones were identified and five selected clones with impaired adherence to HEp-2 epithelial cells were used to infect C. elegans to determine the degree of colonization. It was determined that M. avium eliminated from infected C. elegans were able to colonize a naïve C. elegans with high efficiency. Thirty of the most adherence-deficient M. avium clones obtained from the HEp-2 cell screening were sequenced to identify the location of the transposon. Many of the genes associated with the bacterial cell wall synthesis were shown to be inactivated in the selected mutants. Five out of the 30 bacterial clones were then used to infect C. elegans. All five mutants had impaired ability to colonize C. elegans compared with the wild type bacteria (decrease of 1.5-2.0 logs, p < 0.05). The limitation of this work is that the model can be used for initial screening, but other more complex systems should be used to confirm the findings. C. elegans can be used as a model to test for M. avium adherence/colonization-associated virulence determinants. All the tested adherence-deficient clones that were examined had impaired ability to colonize the host C. elegans, and some can be potentially used to prevent colonization.

Establishing Caenorhabditis elegans as a model for Mycobacterium avium subspecies hominissuis infection and intestinal colonization.

The nematode Caenorhabditis elegans has become a model system for studying the disease interaction between pathogens and the host. To determine whether the transparent nematode could serve as a useful model for Mycobacterium avium subspecies hominissuis (MAH) infection of the intestinal tract, worms were fed MAH and assayed for the effects of the bacterial infection on the worm. It was observed during feeding that viable MAH increases in the intestinal lumen in a time dependent manner. Ingestion of MAH was deemed non-toxic to worms as MAH-fed populations have similar survival curves to those fed E. coli strain OP50. Pulse-chase analysis using E. coli strain OP50 revealed that MAH colonize the intestinal tract, as viable MAH remain within the intestine after the assay. Visualization of intestinal MAH using histology and transmission electron microscopy demonstrates that MAH localizes to the intestinal lumen, as well as establishes direct contact with intestinal epithelium. Bacterial colonization appears to have a detrimental effect on the microvilli of the intestinal epithelial cells. The MAH ΔGPL/4B2 strain with a mutation in glycopeptidolipid production is deficient in binding to human epithelial cells (HEp-2), as well as deficient in its ability to bind to and colonize the intestinal tract of C. elegans as efficiently as wild-type MAH. These data indicate the C. elegans may serve as a useful model system for MAH pathogenesis and in determining the mechanisms used by MAH during infection and colonization of the intestinal epithelium.

Bloom syndrome radials are predominantly non-homologous and are suppressed by phosphorylated BLM.

Biallelic mutations in BLM cause Bloom syndrome (BS), a genome instability disorder characterized by growth retardation, sun sensitivity and a predisposition to cancer. As evidence of decreased genome stability, BS cells demonstrate not only elevated levels of spontaneous sister chromatid exchanges (SCEs), but also exhibit chromosomal radial formation. The molecular nature and mechanism of radial formation is not known, but radials have been thought to be DNA recombination intermediates between homologs that failed to resolve. However, we find that radials in BS cells occur over 95% between non-homologous chromosomes, and occur non-randomly throughout the genome. BLM must be phosphorylated at T99 and T122 for certain cell cycle checkpoints, but it is not known whether these modifications are necessary to suppress radial formation. We find that exogenous BLM constructs preventing phosphorylation at T99 and T122 are not able to suppress radial formation in BS cells, but are able to inhibit SCE formation. These findings indicate that BLM functions in 2 distinct pathways requiring different modifications. In one pathway, for which the phosphorylation marks appear dispensable, BLM functions to suppress SCE formation. In a second pathway, T99 and T122 phosphorylations are essential for suppression of chromosomal radial formation, both those formed spontaneously and those formed following interstrand crosslink damage.