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Guidelines for the treatment of pulmonary arterial hypertension (PAH) recommend sequential add‐on therapy for patients who deteriorate or fail to improve clinically. However, it is not known whether these patients also benefit from transitioning from inhaled prostacyclins to parenteral prostacyclins. We sought to characterize PAH patients receiving inhaled treprostinil who were transitioned to parenteral treprostinil. We conducted a multicenter retrospective study at 7 PAH centers and collected reasons, methods, safety, and outcome of patients transitioned from inhaled treprostinil to parenteral treprostinil. Twenty‐six patients with pulmonary hypertension in group 1, 4, or 5 transitioned from inhaled treprostinil to parenteral treprostinil (10 intravenous, 16 subcutaneous). Twenty‐four patients were also on one or two oral therapies. Reasons for transition were clinical deterioration, lack of clinical improvement, and pregnancy (19, 6, and 1 patients, respectively). Transitions occurred in hospital, clinic, or home (17, 7, and 2 patients, respectively). Parenteral infusion was started after the last inhaled treatment at maintenance dose (13 patients), after the inhaled therapy was downtitrated to 18 μg (6 patients), or with an overlap of inhaled downtitration with parenteral uptitration (7 patients). The transition was safe; side effects included symptoms of prostacyclin overdose. Patients were followed for 3–18 months. At 3 months, 8 patients improved, 17 maintained their functional class, and 1 continued to deteriorate. In conclusion, selected PAH patients can be safely transitioned from inhaled treprostinil to parenteral treprostinil using a variety of methodologies in different settings with the expectation that patients will improve or at least remain clinically stable.

Objectives: Arthroscopy is being used more frequently as a treatment for intra-articular hip pathology due to femoroacetabular impingement (FAI). Prior to surgery, intra-articular anesthetic injection is commonly performed as a diagnostic test to localize the source of pain. Currently, there is a paucity of data correlating post-injection pain relief and functional outcomes after hip arthroscopy for FAI. The purpose of this study is to determine whether the amount of pain relief after preoperative intra-articular anesthetic injection predicts clinical and functional outcomes following hip arthroscopy with minimum one year follow-up. We hypothesize that increased pain relief (>50%) will correlate with better outcomes after surgery. Methods: The records of patients undergoing hip arthroscopy for FAI at our institution between April 2007 and April 2012 were reviewed. We identified patients who underwent pre-operative intra-articular anesthetic injection and subsequent hip arthroscopy. Inclusion criteria were: ultrasound or fluoroscopic guided intra-articular anesthetic injection performed at our institution, documented pre- and post-injection Numerical Rating Scale (NRS) pain scores, no prior ipsilateral hip surgery, and minimum 1 year follow-up. Pre-operative radiographs were reviewed and degree of osteoarthritis was determined using the Tonnis classification system. Outcomes were assessed with Modified Harris Hip Score (MHHS) and Hip Outcome Score (HOS). Univariate and multivariate models were performed to assess whether percent pain relief correlated with outcome scores. Results: 57 hips in 55 patients met our inclusion criteria and included 37 females (67%) and 18 males (33%) with a mean age of 42.6 ± 14.7 (range 15-68) years. 8 patients had Tonnis grade 0, 35 had Tonnis grade 1, and 14 had Tonnis grade 2. Mean pain relief after intra-articular injection was 74.4 ± 31.9 (range 0-100) percent. 13 patients (23%) had ≤50% pain relief while 44 (77%) had >50% pain relief. Outcome scores were obtained at a mean 25.5 (range 12- 60) months. Mean MHHS, HOS-ADL, and HOS-Sport scores were 82.1 ± 17.4 (range 42.9-100), 85.0 ± 16.6 (range 39.7-100), and 71.8 ± 28.1 (range 11.1-100) respectively. There was no correlation between percent pain relief and MHHS, HOS-ADL, or HOS-Sport scores. There was no significant difference in outcome scores between those with ≤50% and >50% pain relief. When adjusting for Tonnis grade there was no correlation between percent relief and any of the outcome scores measured. Conclusion: In patients undergoing hip arthroscopy for FAI, our data indicates that the amount of pain relief from intra-articular anesthetic injection does not correlate with minimum 1 year clinical and functional outcomes even when adjusting for Tonnis grade. Although pain relief did not predict outcomes in our study, we still believe it is a useful diagnostic tool to localize the source of pain in patients considering hip arthroscopy.

Purpose The purpose of this study was to determine failure rates, functional outcomes, and risk factors for failure after revision anterior shoulder stabilization surgery in high‐risk adolescent athletes. Methods Adolescent athletes who underwent primary anterior shoulder stabilization were reviewed. Patients undergoing subsequent revision stabilization surgery were identified and analyzed. Failure rates after revision surgery were assessed by Kaplan‐Meier analysis. Failure was defined as recurrent instability requiring reoperation. Functional outcomes included the Marx activity score; American Shoulder and Elbow Surgeons score; and University of California, Los Angeles score. The characteristics of patients who required reoperation for recurrent instability after revision surgery were compared with those of patients who required only a single revision to identify potential risk factors for failure. Results Of 90 patients who underwent primary anterior stabilization surgery, 15 (17%) had failure and underwent revision surgery (mean age, 16.6 years; age range, 14 to 18 years). The mean follow‐up period was 5.5 years (range, 2 to 12 years). Of the 15 revision patients, 5 (33%) had recurrent dislocations and required repeat revision stabilization surgery at a mean of 50 months (range, 22 to 102 months) after initial revision. No risk factors for failure were identified. The Kaplan‐Meier reoperation‐free estimates were 86% (95% confidence interval, 67% to 100%) at 24 months and 78% (95% confidence interval, 56% to 100%) at 48 months after revision surgery. The mean final Marx activity score was 14.8 (range, 5 to 20); American Shoulder and Elbow Surgeons score, 82.1 (range, 33 to 100); and University of California, Los Angeles score, 30.8 (range, 16 to 35). Conclusions At 5.5 years' follow‐up, adolescent athletes had a high failure rate of revision stabilization surgery and modest functional outcomes. We were unable to convincingly identify specific risk factors for failure of revision surgery. Level of Evidence Level IV, retrospective therapeutic case series.

Recombinant virus vaccines are often less effective due to immunodominant responses against endogenous vector antigens. However, the use of small RNA virus vectors provides an opportunity to limit host exposure to endogenous virus antigens and focus immune responses on the desired vaccine antigen. Using the Daniel's strain of Theiler's murine encephalomyelitis virus, we have identified strategies to modulate responses to endogenous viral proteins by manipulating the host CD8+ T-cell repertoire prior to infection or through the use of mutations introduced into the virus genome. Both of these approaches enhance responses to vaccine antigens introduced into the picornavirus. However, the use of mutant immunodominant epitopes provides an opportunity for enhancing vaccine responses without further manipulation of the host. Using this strategy, we demonstrate that modification of the consensus MHC class I anchor residue within the virus genome can promote enhanced immunity to foreign antigens and self-antigens embedded in the virus genome.

SummaryBackgroundThe presence of germline mutations in sporadic pheochromocytomas and paragangliomas (SPPs) may change the clinical management of both index patients and their family members. However, the frequency of germline mutations in SPPs is unknown.ObjectiveTo describe the frequency of germline mutations in SPPs and to determine the value of testing index patients and their family members for these mutations.MethodsWe searched databases through June 2012 for observational studies of patients with SPPs who underwent germline genetic testing. The criteria used to define sporadic tumours were (i) the absence of a family history of PCC/PG, (ii) the absence of syndromic features, (iii) the absence of bilateral disease and (iv) the absence of metastatic disease.ResultsWe included 31 studies including 5031 patients (mean age 44). These patients received tests for any of these ten mutations: SDHAF2, RET, SDHD, SDHB, SDHC, VHL, TMEM127, MAX, Isocitrate Dehydrogenase Mutation (IDH) and NF1. The overall frequency of germline mutation in SPP was 551 of 5031 or 11%; when studies with patients fulfilling four criteria for sporadic tumours were used, the frequency was 171 of 1332 or 13%. The most common germline mutation was SDHB 167 of 3611 (4·6%). Little outcome data were available to assess the benefits of genetic testing in index cases and family members.ConclusionsThe frequency of germline mutations in SPPs is approximately 11–13% and the most common mutations affect less than 1 in 20 patients. The value of testing for germline mutations in patients with SPPs and their family members is unknown, as the balance of potential benefits and harms remains unclear.

AbstractPurposeAssessment of hip internal rotation (IR) is a critical element in the evaluation of a painful hip, yet there currently exists no consistent method of determining this measurement. The purpose of this study is to report the intra‐rater and inter‐rater reliability of active and passive hip IR measurement using a digital inclinometer.MethodsTwenty‐five subjects (8 men, 17 women) with asymptomatic hip joints, and no known pathology between the ages of 22 and 42 participated. Two examiners measured hip IR for each subject using a digital inclinometer while visually monitoring pelvic motion. Measurements included passive IR, active IR, and active IR while internally rotating both legs simultaneously. Statistical analysis was performed including intra‐rater and inter‐rater reliability.ResultsThere was no significant difference in measured IR values. Mean range of motion values for all techniques and both examiners ranged from 30.7° to 32.8°. Intra‐rater reliability for examiner 1 ranged from 0.84 to 0.92. Inter‐rater reliability ranged from 0.89 to 0.93. Of the methods utilized, active IR of a single leg was the most responsive technique with a minimal detectable change value of 5.4°.ConclusionsClinical assessment of hip IR range of motion can be performed efficiently and reliably with a digital inclinometer along with visual monitoring of the pelvis for unwanted motion. Findings from this study support unilateral active hip IR in a seated position as a reliable and responsive technique for obtaining hip IR measurements.Level of evidenceIII.

AbstractImproving the effectiveness of adipose‐tissue derived human mesenchymal stromal/stem cells (AMSCs) for skeletal therapies requires a detailed characterization of mechanisms supporting cell proliferation and multi‐potency. We investigated the molecular phenotype of AMSCs that were either actively proliferating in platelet lysate or in a basal non‐proliferative state. Flow cytometry combined with high‐throughput RNA sequencing (RNASeq) and RT‐qPCR analyses validate that AMSCs express classic mesenchymal cell surface markers (e.g., CD44, CD73/NT5E, CD90/THY1, and CD105/ENG). Expression of CD90 is selectively elevated at confluence. Self‐renewing AMSCs express a standard cell cycle program that successively mediates DNA replication, chromatin packaging, cyto‐architectural enlargement, and mitotic division. Confluent AMSCs preferentially express genes involved in extracellular matrix (ECM) formation and cellular communication. For example, cell cycle‐related biomarkers (e.g., cyclins E2 and B2, transcription factor E2F1) and histone‐related genes (e.g., H4, HINFP, NPAT) are elevated in proliferating AMSCs, while ECM genes are strongly upregulated (>10‐fold) in quiescent AMSCs. AMSCs also express pluripotency genes (e.g., POU5F1, NANOG, KLF4) and early mesenchymal markers (e.g., NES, ACTA2) consistent with their multipotent phenotype. Strikingly, AMSCs modulate expression of WNT signaling components and switch production of WNT ligands (from WNT5A/WNT5B/WNT7B to WNT2/WNT2B), while upregulating WNT‐related genes (WISP2, SFRP2, and SFRP4). Furthermore, post‐proliferative AMSCs spontaneously express fibroblastic, osteogenic, chondrogenic, and adipogenic biomarkers when maintained in confluent cultures. Our findings validate the biological properties of self‐renewing and multi‐potent AMSCs by providing high‐resolution quality control data that support their clinical versatility. J. Cell. Biochem. 115: 1816–1828, 2014. © 2014 Wiley Periodicals, Inc.