Inflammasome-independent NLRP3 augments TGF-ß signaling in kidney epithelium.

Tubulointerstitial inflammation and fibrosis are strongly associated with the outcome of chronic kidney disease. We recently demonstrated that the NOD-like receptor, pyrin domain containing-3 (NLRP3) contributes to renal inflammation, injury, and fibrosis following unilateral ureteric obstruction in mice. NLRP3 expression in renal tubular epithelial cells (TECs) was found to be an important component of experimental disease pathogenesis, although the biology of NLRP3 in epithelial cells is unknown. In human and mouse primary renal TECs, NLRP3 expression was increased in response to TGF-ß1 stimulation and associated with epithelial-mesenchymal transition (EMT) and the expression of α-smooth muscle actin (αSMA) and matrix metalloproteinase (MMP) 9. TGF-ß1-induced EMT and the induction of MMP-9 and αSMA were significantly decreased in mouse Nlrp3(-/-) renal TECs, suggesting a role for Nlrp3 in TGF-ß-dependent signaling. Although apoptosis-associated speck-like protein containing a CARD domain(-/-) TECs demonstrated a phenotype similar to that of Nlrp3(-/-) cells in response to TGF-ß1, the effect of Nlrp3 on MMP-9 and αSMA expression was inflammasome independent, as IL-1ß, IL-18, MyD88, and caspase-1 were dispensable. Smad2 and Smad3 phosphorylation in response to TGF-ß1 was attenuated in Nlrp3(-/-) and apoptosis-associated speck-like protein containing a CARD domain(-/-) cells, accounting for the dampened EMT and TGF-ß1 responsiveness in these cells. Consistent with these findings, overexpression of NLRP3 in 293T cells resulted in increased Smad3 phosphorylation and activity. Taken together, these data support a novel and direct role for NLRP3 in promoting TGF-ß signaling and R-Smad activation in epithelial cells independent of the inflammasome.

A retrospective evaluation of minimally invasive ponto surgery (MIPS) in two pediatric centers.

BACKGROUND: Percutaneous bone anchored hearing systems have been used effectively for over forty years with low rates of complications. Minimally Invasive Ponto Surgery (MIPS) is a surgical technique performed through a puncture hole that has been reported to minimize soft tissue trauma and decrease operative time. Due to it being a relatively new procedure there remains a paucity of pediatric outcomes data. METHODS: Pediatric patients from two tertiary pediatric otolaryngology centers between 2016 and 2019 who underwent MIPS were included in this study. Charts were retrospectively reviewed for indications for surgery, implant and abutment type, overlying skin thickness, skin-to-skin time, Holgers score at three, six and twelve months, revision surgery and time to abutment fitting. RESULTS: Fourteen patients, two with bilateral procedures met inclusion criteria (mean age = 8.07 ± 2.87years). The mean overlying skin thickness was 5.13 ± 3.18mm. 9.44% of visits had an adverse skin reactionOne patient required surgery forskin overgrowth. One implant loss (6.3%) was reported, following trauma to the abutment. Mean MIPS skin to skin times were 12.4 ± 2.6 min, markedly different that the Baha® Attract and Connect which were 56 and 53 min, respectively. CONCLUSION: This study represents the largest pediatric MIPS cohort to date, and our results are similar to published adult studies.

Retrospective review of dosing trends in botulinum toxin injections for the treatment of adductor spasmodic dysphonia in a long-term cohort.

BACKGROUND: Botulinum toxin A (BT) is the gold standard treatment for adductor spasmodic dysphonia (AdSD) with established use for greater than thirty years. The spasmodic dysphonia (SD) literature would benefit from additional long-term cohort data, especially in the Canadian population. The goals of this study were to evaluate whether BT dosage required to achieve acceptable voice shifts over time and to elucidate differences in the subgroups of patients receiving unilateral vocal fold (UVF) injections. METHODS: Patient records were retrospectively reviewed at the regional tertiary Voice Clinic for AdSD patients from 1996 to 2017 to identify AdSD patients treated with serial BT injections. Descriptive statistics, paired t-tests for time between treatments and ANOVA tests were used to evaluate trends in subgroup age. RESULTS: One-hundred and twenty-six patients (61% female, mean age = 53 ± 15.5 years) met inclusion criteria and received laryngeal EMG-guided BT injections for up to twenty-two years and as many as 79 treatments. The mean total BT dosage for our population was 1.54 ± 0.35 Units per side. The majority of subjects had decreasing doses over time with a small subgroup having slowly increasing doses. Comparing treatment dosages between unilateral and bilateral injection groups, injection dosage per vocal fold was 1.65 ± 0.62 with time between injections was significantly shorter for the unilateral injection group (mean = 105 days, SD ± 19.8 days, p = 0.005) compared to the bilateral injection subgroup (137 ± 35.7 days, p < 0.005). The mean age of the unilateral injection population as younger at 42.4 ± 11.8 years (p = 0.004). CONCLUSION: The majority of patients in this study had decreasing BT injection dosages over time, with a smaller proportion having slowly increasing doses, thought to be likely relating to disease severity. The unilateral vocal fold injections were well tolerated despite needing more frequent injections, and found to be more prevalent in the younger age group.

Safety of long-term high-volume sinonasal budesonide irrigations for chronic rhinosinusitis.

BACKGROUND: Off-label high-volume sinonasal budesonide irrigations are commonly used during the management of chronic rhinosinusitis (CRS). Although short-term use (4 to 8 weeks) has been demonstrated to be safe, the long-term effects on the hypothalamic-pituitary-adrenal (HPA) axis remain unclear. The objective of this study is to determine whether CRS patients using long-term (minimum greater than 12 months) budesonide sinonasal irrigations have evidence of HPA axis suppression. METHODS: Patients with CRS being managed with high-volume sinonasal budesonide irrigations were recruited from 2 tertiary level rhinology clinics between March 2014 and July 2015. Inclusion criteria were as follows: (1) adult (age greater than 18 years); (2) guideline-based diagnosis of CRS; (3) previous endoscopic sinus surgery; (4) minimum of twice daily high-volume sinonasal budesonide irrigation (concentration of 1 mg per irrigation; total daily dose of 2 mg); and (5) a minimum of 12-month duration. Exclusion criteria included systemic corticosteroid use within 3 months of HPA axis testing. The primary outcomes were morning (am) serum cortisol levels and, when indicated, cosyntropin stimulation levels. RESULTS: A total of 35 patients fulfilled eligibility criteria and underwent HPA axis testing. Mean duration of budesonide sinonasal irrigation therapy use was 38.2 months (2.9 years). The mean ± standard deviation (SD) am serum cortisol was 431.2 ± 146.9 nmol/L (normal, 200 to 650 nmol/L). Subsequent cosyntropin stimulation tests, in indicated patients (n = 19), demonstrated no evidence of HPA axis suppression. CONCLUSION: Outcomes from this study suggest that daily high-volume sinonasal budesonide irrigations fail to produce evidence of HPA axis suppression with prolonged courses lasting longer than 2 years.