Citations

Background: Heterozygote carriers of potentially pathogenic variants in the cystic fibrosis transmembrane conductance regulator ( CFTR ) gene have increased asthma risk. However, the frequency and impact of CFTR variation among individuals with asthma is unknown. Objective: To determine whether potentially pathogenic CFTR variants associate with disease severity and whether individuals with two potentially pathogenic variants exist in a severe asthma-enriched cohort . Methods : We analyzed sequencing data spanning a 190.5Kb region of CFTR in participants from the Severe Asthma Research Program (SARP1-3). Potentially pathogenic, rare CFTR variants (frequency<0.05) were classified as CF-causing or of varying clinical consequences (VVCC) (CFTR2.org). Regression-based models tested for association between CFTR genotypes (0-2 potentially pathogenic variants) and severity outcomes. Results: Of 1401 participants, 9.5% (134) had one potentially pathogenic variant, occurring more frequently in non-Hispanic white (NHW, 10.1% [84 of 831]) compared to African American individuals (AA, 5.2% [22 of 426]). We found ≥2 potentially pathogenic CFTR variants in 1.4% (19); 0.5% (4) of NHW and 2.8% (12) of AA. Potentially pathogenic CFTR variant genotypes (≥1 or ≥2 variants) were not cumulatively associated with lung function or exacerbations. In NHW, we found three F508del compound heterozygotes with F508del and a VVCC (two 5T;TG12[c.1210-11T>G] and one Arg1070Trp) and a homozygote for the VVCC, 5T;TG12. Conclusions: We found potentially pathogenic CFTR variants within a severe asthma-enriched cohort , including three compound heterozygote genotypes variably associated with CF in NHW individuals. These findings provide the rationale for CFTR sequencing and phenotyping of CF-related traits in individuals with severe asthma.

Abstract Inhibitory receptors have a critical role in the regulation of immunity. Siglecs are a family of primarily inhibitory receptors expressed by immune cells that recognize specific sialic acid modifications on cell surface glycans. Many tumors have increased sialic acid incorporation. Overexpression of the sialyltransferase ST8Sia6 on tumors led to altered immune responses and increased tumor growth. In this study, we examined the role of ST8Sia6 on immune cells in regulating antitumor immunity. ST8Sia6 knockout mice had an enhanced immune response to tumors. The loss of ST8Sia6 promoted an enhanced intratumoral activation of macrophages and dendritic cells, including upregulation of CD40. Intratumoral regulatory T cells exhibited a more inflammatory phenotype in ST8Sia6 knockout mice. Using adoptive transfer studies, the change in regulatory T cell phenotype was not cell intrinsic and depended on the loss of ST8Sia6 expression in APCs. Thus, ST8Sia6 generates ligands for Siglecs that dampen antitumor immunity.

Abstract In-stent stenosis has a reported prevalence of 14% to 19% at 1-yr follow-up after carotid stenting and is associated with an increased risk of acute ischemic stroke. 1,2 Risk factors include female sex, diabetes, and dyslipidemia. Cutting balloon angioplasty is a safe and effective treatment modality for the treatment of carotid in-stent stenosis, and alternative treatment options include observation with medical management and placement of another stent. 3,4 The authors present the case of a 61-yr-old man with carotid in-stent restenosis and progressive worsening on serial imaging with ultrasound. The patient had a history of carotid stenting for symptomatic stenosis 6 mo prior and was maintained on aspirin and clopidogrel. In light of the progressive worsening, the in-stent stenosis was confirmed on computed tomography (CT) angiogram. The options were discussed with the patient and he consented for treatment with cutting balloon angioplasty. Final angiogram showed improvement of the luminal diameter with a residual stenosis of 15%. The patient tolerated the procedure well and was discharged home on postoperative day 1. Follow-up ultrasound demonstrated moderate improvement in peak systolic velocities, and the plan is to continue observation with a clinical follow-up and repeat carotid Dopplers at 3 mo.

Abstract The immune system contains a series of checks and balances that maintain tolerance and prevent autoimmunity. Sialic acid-binding Ig-type lectins (Siglecs) are cell surface receptors found on immune cells and inhibit inflammation by recruiting protein tyrosine phosphatases to ITIMs. Islet-resident macrophages express Siglec-E, and Siglec-E expression decreases on islet-resident macrophages as insulitis progresses in the NOD mouse. The sialyltransferase ST8Sia6 generates α-2,8-disialic acids that are ligands for Siglec-E in vivo. We hypothesized that engaging Siglec-E through ST8Sia6-generated ligands may inhibit the development of immune-mediated diabetes. Constitutive overexpression of ST8Sia6 in pancreatic β cells mitigated hyperglycemia in the multiple low-dose streptozotocin model of diabetes, demonstrating that engagement of this immune receptor facilitates tolerance in the setting of inflammation and autoimmune disease.

BackgroundDistal iliotibial band friction syndrome (ITBFS) is a common cause of knee pain in endurance athletes. Nonsurgical treatment is usually successful, but surgery is occasionally required for recalcitrant cases. No published studies to date have evaluated the feasibility of an ultrasound‐guided (USG) partial iliotibial band (ITB) release.ObjectiveTo determine the feasibility of an USG partial ITB release using a cutting wire. A secondary aim was to assess whether adjacent structures were damaged. We hypothesized that the posterior distal ITB could be partially transected with a cutting wire under USG with no injury to adjacent structures.DesignCadaveric study.SettingQuaternary‐care academic institute.ParticipantsTen cadaveric knees ranging from 76‐89 years old with a mean body mass index of 21.9 kg/m2.InterventionsOne physician sonographer performed USG releases of the posterior ITBs at the level of the lateral femoral epicondyle with a cutting wire. Dissection was carried out by an independent second physician to assess for primary and secondary outcomes.Main Outcome Measures(1) Release of the posterior border of the ITB; (2) width of the release; (3) evaluation for any injury to adjacent structures; (4) technical difficulty of the procedure (0 = no difficulty, 10 = most difficult procedure possible); (5) duration of time it took to complete the procedure.ResultsAll 10 knees had the posterior border of the ITB transected. Mean release length was 16 mm (range 15‐17), which was within 1 mm of the target release length of 15 mm. No adjacent structures were damaged.ConclusionA USG release of the posterior ITB utilizing a cutting wire is feasible and safe in a cadaveric model. Translational research is warranted to determine how these results apply to the clinical setting.

Background: Adductor longus tendinopathy is a well-known etiology of chronic groin pain in elite athletes. Surgery is indicated for those who fail conservative treatment. No studies to date have evaluated the feasibility of an ultrasound-guided release of the proximal adductor longus tendon. Purpose/Hypothesis: The primary aim of this study was to determine the feasibility of an ultrasound-guided selective adductor longus release with a cutting wire. A secondary aim was to determine safety by avoiding injury to adjacent structures. We hypothesized that the proximal adductor longus tendon can be released under ultrasound guidance with a cutting wire without injury to adjacent neurovascular or genitourinary structures. Study Design: Descriptive laboratory study. Methods: Ten adductor longus tendons (5 cadaveric specimens) from 4 males and 1 female between 76 and 89 years of age with a mean body mass index of 21.9 kg/m 2 (range, 16.8-29.6 kg/m 2 ) were used during this study. A single experienced physician sonographer performed ultrasound-guided proximal adductor longus tendon releases on all cadaveric specimens using a cutting wire. Dissection was performed by a second physician to determine the completeness of the tendon transections and to detect injury to adjacent neurovascular or genitourinary structures. Results: All 10 adductor longus tendons were transected. Eight of 10 transections were complete, whereas in 2 transections, >99% of the tendon was transected. There were no injuries to adjacent genitourinary or neurovascular structures. Conclusion: Ultrasound-guided adductor tendon release is feasible and safe in a cadaveric model. Further translational research should be performed to determine whether these results can be replicated in the clinical setting. Clinical Relevance: Adductor longus tendinopathy frequently requires surgical intervention and prolonged time away from sport. The present study suggests that a selective adductor longus tendon release can be performed with ultrasound guidance. This procedure warrants further translational research to explore its use in clinical practice.

Abstract Intricate life-versus-death decisions are programmed during T cell development, and the regulatory mechanisms that coordinate their activation and repression are still under investigation. In this study, HDAC3-deficient double-positive (DP) thymocytes exhibit a severe decrease in numbers. The thymic cortex is rich in ATP, which is released by macrophages that clear apoptotic DP thymocytes that fail to undergo positive selection. We demonstrate that HDAC3 is required to repress expression of the purinergic receptor P2X7 to prevent DP cell death. HDAC3-deficient DP thymocytes upregulate the P2X7 receptor, increasing sensitivity to ATP-induced cell death. P2rx7/HDAC3-double knockout mice show a partial rescue in DP cell number. HDAC3 directly binds to the P2rx7 enhancer, which is hyperacetylated in the absence of HDAC3. In addition, RORγt binds to the P2rx7 enhancer and promotes P2X7 receptor expression in the absence of HDAC3. Therefore, HDAC3 is a critical regulator of DP thymocyte survival and is required to suppress P2X7 receptor expression.