Chronic, high-dose, oral prednisone has been the mainstay of myasthenia gravis treatment for decades and has proven to be highly beneficial in many, toxic in some way to all, and not effective in a significant minority. No patient characteristics or biomarkers are predictive of treatment response leading to many patients suffering adverse effects with no benefit. Presently, measurements of treatment response, whether taken from clinician or patient perspective, are appreciated to be limited by lack of good correlation, which then complicates correlation to biological measures. Treatment response may be limited because disease mechanisms are not influenced by corticosteroids, limits on dosage because of adverse effects, or individual differences in corticosteroids. This review evaluates potential mechanisms that underlie lack of response to glucocorticoids in patients with myasthenia gravis.
In densely populated colonies of the bacterium Pseudomonas fluorescens Pf0-1, diverse mutations in the rsmE gene are naturally selected by solving the problem of overcrowding. Here, we show that RsmE-regulated secretions function together to create and protect space of low cell density.
Objective: To study 24-hour urine metabolic abnormalities in patients with obstructive sleep apnea syndrome (OSAS), diagnosed by polysomnography. The purpose was to identify whether OSAS is independently associated with a distinctive set of 24-hour urine studies in a cohort of stone formers. Patients and Methods: Using our institutional stone database (2013–2017), 1132 consecutive patients with 24-hour urine collections were identified. After applying our exclusion criteria, the final cohort consisted of 376 patients of which 45 patients had OSAS. Descriptive statistics were used to compare 24-hour urine parameters between patients with and without OSAS. Logistic regression models were used to assess the association between OSAS and 24-hour urine parameters. Results: On univariate analysis, patients with OSAS were older (57.7 versus 48.2, p < 0.001) with a higher body mass index (BMI) (35 versus 27.8, p < 0.001), and higher likelihood of diabetes mellitus (DM) (57.8 versus 10.6%, p < 0.001) and hypertension (HTN) (60% versus 23.9%, p < 0.001). Patients with OSAS had higher 24-hour total amount of urine volume (2018 versus 1818 ml, p = 0.03), calcium (279.7 versus 208 mg, p = 0.02), oxalate (41.6 versus 31.3 mg, p < 0.001), yet lower 24-hour urine pH (5.75 versus 6.03, p = 0.001). On multivariable linear regression analysis, OSAS did not affect any of the 24-hour urinary parameters. Conclusion: OSAS is a prevalent comorbidity among nephrolithiasis patients. We found no major differences in 24-hour urine parameters between nephrolithiasis patients with OSAS and those without OSAS. Further study is needed to determine whether the severity of OSAS and compliance with treatment play a role in the pathogenesis of stone formation. Level of evidence: 2b
Cells in microbial communities on surfaces live and divide in close proximity, which greatly enhances the potential for social interactions. Spatiogenetic structures manifest through competitive and cooperative interactions among the same and different genotypes within a shared space, and extracellular secretions appear to function dynamically at the forefront. A previous experimental evolution study utilizing Pseudomonas fluorescens Pf0-1 colonies demonstrated that diverse mutations in the rsmE gene are repeatedly and exclusively selected through the formation of a dominant spatial structure. RsmE’s primary molecular function is translation repression, and its homologs regulate various social and virulence phenotypes. Pseudomonas spp. possess multiple paralogs of Rsm proteins, and RsmA, RsmE, and RsmI are the most prevalent. Here, we demonstrate that the production of a mucoid polymer and a biosurfactant are exclusively regulated through RsmE, contradicting the generalized notion of functional redundancy among the Rsm paralogs. Furthermore, we identify the biosurfactant as the cyclic lipopeptide gacamide A. Competition and microscopy analyses show that the mucoid polymer is solely responsible for creating a space of low cellular density, which is shared exclusively by the same genotype. Gacamide A and other RsmE-regulated products appear to establish a physical boundary that prevents the encroachment of the competing genotype into the newly created space. Although cyclic lipopeptides and other biosurfactants are best known for their antimicrobial properties and reducing surface tension to promote the spreading of cells on various surfaces, they also appear to help define spatial structure formation within a dense community.
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