Citations

Abstract Rationale Lymphangioleiomyomatosis (LAM) is a progressive cystic lung disease that predominantly affects women and can worsen with pregnancy, estrogen treatment, and the menstrual cycle, suggesting an important role for estrogen in disease pathogenesis. Objectives To assess the efficacy and safety of the aromatase inhibitor letrozole in the treatment of LAM. Methods Seventeen postmenopausal women with LAM were enrolled in this phase II trial and randomized to receive letrozole 2.5 mg daily (n = 9) or placebo (n = 8) for a period of 12 months. Five patients in each group were also taking sirolimus at baseline and remained on the drug throughout the treatment period. Lung function, exercise capacity, quality of life, and serum vascular endothelial growth factor D (VEGF-D) were measured at baseline and at 3-month intervals. Results Fifteen patients completed the study. Two patients withdrew. There were no differences in adverse events in the letrozole and placebo groups. The target enrollment of 25 patients per arm was not met, so the efficacy of letrozole could not be assessed as planned. After adjusting for sirolimus use, we found that the rate of change in FEV1 for all subjects was −3 ± 3 ml/mo (P = 0.4), and for serum VEGF-D, the rate of change was −0.024 ± 0.009 pg/ml/mo (P = 0.015), showing a steeper decline in the letrozole group (−0.029 ± 0.013; P = 0.025). All patients who were taking sirolimus had a reduction in VEGF-D levels from baseline to the last visit, compared with only half of the patients who were not taking sirolimus. In a post hoc analysis, eight matched letrozole-treated–placebo-treated pairs were constructed, six of which demonstrated better FEV1 improvement for the letrozole-treated patients. Conclusions Letrozole treatment appears to be safe and well tolerated in postmenopausal patients with LAM, including those taking sirolimus. Enrollment in this trial was compromised by the publication of an effective treatment (sirolimus) in the same month as the study opened, resulting in limited power to detect treatment effects. Post hoc matched pairs exploration studies provide tentative support for additional studies of letrozole in LAM. Considering the reduced rate of lung function decline in postmenopausal patients, future studies will likely require enhanced study designs, such as selective enrollment of those with prognostic biomarkers predictive of decline. Clinical trial registered with www.clinicaltrials.gov (NCT01353209).

Abstract Follicular Th (Tfh) cells are a distinct subset of Th cells that help B cells produce class-switched antibodies. Studies have demonstrated that Tfh cells are highly prone to HIV infection and replication. However, the molecular mechanisms underlying this phenomenon are largely unclear. Here, we show that murine and human Tfh cells have diminished constitutive expression of IFN-stimulated genes (ISGs) inclusive of antiviral resistance factor MX dynamin-like GTPase 2 (MX2) and IFN-induced transmembrane 3 (IFITM3) compared with non-Tfh cells. A lower antiviral resistance in Tfh was consistent with a higher susceptibility to retroviral infections. Mechanistically, we found that BCL6, a master regulator of Tfh cell development, binds to ISG loci and inhibits the expression of MX2 and IFITM3 in Tfh cells. We demonstrate further that inhibition of the BCL6 BR-C, ttk, and bab (BTB) domain function increases the expression of ISGs and suppresses HIV infection and replication in Tfh cells. Our data reveal a regulatory role of BCL6 in inhibiting antiviral resistance factors in Tfh cells, thereby promoting the susceptibility Tfh cells to viral infections. Our results indicate that the modulation of BCL6 function in Tfh cells could be a potential strategy to enhance Tfh cell resistance to retroviral infections and potentially decrease cellular reservoirs of HIV infection.

The absence of a positive family history (PFH) in 10%–25% of patients poses a diagnostic challenge for autosomal dominant polycystic kidney disease (ADPKD). In the Toronto Genetic Epidemiology Study of Polycystic Kidney Disease, 210 affected probands underwent renal function testing, abdominal imaging, and comprehensive PKD1 and PKD2 mutation screening. From this cohort, we reviewed all patients with and without an apparent family history, examined their parental medical records, and performed renal imaging in all available parents of unknown disease status. Subsequent reclassification of 209 analyzed patients revealed 72.2% (151 of 209) with a PFH, 15.3% (32 of 209) with de novo disease, 10.5% (22 of 209) with an indeterminate family history, and 1.9% (four of 209) with PFH in retrospect. Among the patients with de novo cases, we found two families with germline mosaicism and one family with somatic mosaicism. Additionally, analysis of renal imaging revealed that 16.3% (34 of 209) of patients displayed atypical PKD, most of which followed one of three patterns: asymmetric or focal PKD with PFH and an identified PKD1 or PKD2 mutation (15 of 34), asymmetric and de novo PKD with proven or suspected somatic mosaicism (seven of 34), or focal PKD without any identifiable PKD1 or PKD2 mutation (eight of 34). In conclusion, PKD without an apparent family history may be due to de novo disease, missing parental medical records, germline or somatic mosaicism, or mild disease from hypomorphic PKD1 and PKD2 mutations. Furthermore, mutations of a newly identified gene for ADPKD, GANAB , and somatic mosaicism need to be considered in the mutation-negative patients with focal disease.

Purpose To determine the rate of return of young amateur athletes to sport after hip arthroscopy, their clinical outcomes, and pathologic risk factors for worse outcomes 2 years after surgery. Methods This study included all patients between age 13 and 23 who participated in a sport prior to surgery with intent to return who underwent hip arthroscopy after failure of comprehensive nonoperative management for whom 2‐year outcome scores were available. Outcomes collected retrospectively included modified Harris Hip Score (mHHS) and the Hip Outcome Scores (HOS) subscales for activities of daily living (ADL) and sport (HOS Sport). In addition, sport played, return to sport rates, and Tegner Scores were measured preinjury and postoperatively. Descriptive statistics were used to present demographic data. A priori analysis was used to determine the sample size needed to show minimal clinically important differences for mHHS, HOS ADL, and HOS Sport. Results The study population included 50 patients with a mean age of 17.8 years. Athletes returned to sport at a rate of 92% (46/50). At a mean follow‐up of 34 months, the mean mHHS, HOS ADL, and HOS Sport outcome scores were 85, 91, and 80 for the entire study group; 87, 92, and 84 for the group that returned to sport; and 67, 82, and 41 for the group that did not return to sport, respectively. Median preinjury and postoperative Tegner levels were 8 and 7, respectively. Labral takedown and reattachment was associated with lower HOS ADL ( P = .01) and HOS Sport scores ( P = .02). Conclusions Athletes returned to sport at a high rate (92%; 46/50) after hip arthroscopy and perform activities at near preinjury levels. In this group of athletes, arthroscopic labral repair with chondrolabral preservation, which reflected less severe chondrolabral pathology, performed better than labral repair with takedown and reattachment. Level of Evidence Level IV, therapeutic case series.

Study Design: Multicenter retrospective case series and review of the literature. Objective: To determine the rate of esophageal perforations following anterior cervical spine surgery. Methods: As part of an AOSpine series on rare complications, a retrospective cohort study was conducted among 21 high-volume surgical centers to identify esophageal perforations following anterior cervical spine surgery. Staff at each center abstracted data from patients’ charts and created case report forms for each event identified. Case report forms were then sent to the AOSpine North America Clinical Research Network Methodological Core for data processing and analysis. Results: The records of 9591 patients who underwent anterior cervical spine surgery were reviewed. Two (0.02%) were found to have esophageal perforations following anterior cervical spine surgery. Both cases were detected and treated in the acute postoperative period. One patient was successfully treated with primary repair and debridement. One patient underwent multiple debridement attempts and expired. Conclusions: Esophageal perforation following anterior cervical spine surgery is a relatively rare occurrence. Prompt recognition and treatment of these injuries is critical to minimizing morbidity and mortality.

ObjectivesCurrently, there are no cardiovascular (CV) preprocedure screening parameters for patients undergoing in‐office laryngeal procedures (IOLP). Studies have shown significant changes in CV measures for IOLP. The aim was to develop and evaluate a pre‐IOLP CV screening protocol.MethodsReview of IOLP literature and consultation with an anesthesiologist and cardiologist led to the development of CV parameters and questions related to four metabolic equivalents (METS) of work as a patient‐screening tool before IOLP. A separate cohort was screened with only a modified CV protocol. All patients were screened for heart rate (HR) and blood pressure (BP) elevation prior to the procedure. Need for further CV evaluation was characterized as systolic blood pressure BP >160, diastolic BP >100, and/or HR >110 beats/minute. Patients whose BP/HR exceeded these values were referred to their primary care physician (PCP) before re‐screening. If parameters were exceeded again at the second screen, then the procedure was done under monitored anesthesia care.ResultsThe first study phase included 56 patients. The fail rate was 40% largely related to four METS of work. The second study phase included 440 patients. The screen fail rate was 15 patients of 572 (2.6%). Of these, 12 patients of 132 (9.1%) failed the initial screen and were sent to their PCP for further evaluation, and five of 440 (1.4%) patients failed on the day of the procedure. Overall, five of 440 (1.5%) patients would qualify to have their site of service changed for their laryngology procedure from an unmonitored to a monitored setting due to the prescreening criteria.ConclusionFew patients needed further workup based upon the in‐office CV parameters set in this study. Patients with CV risk factors were identified by the screening protocol. Having established hemodynamic parameters in place may improve the safety of IOLP with a very low physician burden.Level of Evidence2b Laryngoscope, 127:1845–1849, 2017

Airway inflammation is a hallmark of asthma, triggering airway smooth muscle (ASM) hyperreactivity and airway remodeling. TNFα increases both agonist-induced cytosolic Ca2+ concentration ([Ca2+]cyt) and force in ASM. The effects of TNFα on ASM force may also be due to an increase in Ca2+ sensitivity, cytoskeletal remodeling, and/or changes in contractile protein content. We hypothesized that 24 h of exposure to TNFα increases ASM force by changing actin and myosin heavy chain (MyHC) content and/or polymerization. Porcine ASM strips were permeabilized with 10% Triton X-100, and force was measured in response to increasing concentrations of Ca2+ (pCa 9.0 to 4.0) in control and TNFα-treated groups. Relative phosphorylation of the regulatory myosin light chain (p-MLC) and total actin, MLC, and MyHC concentrations were quantified at pCa 9.0, 6.1, and 4.0. Actin polymerization was quantified by the ratio of filamentous to globular actin at pCa 9.0 and 4.0. For determination of total cross-bridge formation, isometric ATP hydrolysis rate at pCa 4.0 was measured using an enzyme-coupled NADH-linked fluorometric technique. Exposure to TNFα significantly increased force across the range of Ca2+ activation but did not affect the intrinsic Ca2+ sensitivity of force generation. The TNFα-induced increase in ASM force was associated with an increase in total actin, MLC, and MyHC content, as well as an increase in actin polymerization and an increase in maximum isometric ATP hydrolysis rate. The results of this study support our hypothesis that TNFα increases force generation in ASM by increasing the number of contractile units (actin-myosin content) contributing to force generation.