Publications

Occlusive vasculopathy with intimal hyperplasia and plexogenic arteriopathy are severe histopathological changes characteristic of pulmonary arterial hypertension (PAH). Although a phenotypic switch in pulmonary endothelial cells (ECs) has been suggested to play a critical role in the formation of occlusive lesions, the pathobiology of this process is poorly understood. The goal of this study was to identify novel molecular mechanisms associated with EC dysfunction and PAH-associated bone morphogenetic protein receptor 2 (BMPR2) deficiency during PAH pathogenesis. A bioinfomatics approach, patient samples, and in vitro experiments were used. By combining a metaanalysis of human idiopathic PAH (iPAH)-associated gene-expression microarrays and a unique gene expression-profiling technique in rat endothelium, our bioinformatics approach revealed a PAH-associated dysregulation of genes involving chromatin organization, DNA metabolism, and repair. Our hypothesis that altered DNA repair and loss of genomic stability play a role in PAH was supported by in vitro assays where pulmonary ECs from patients with iPAH and BMPR2-deficient ECs were highly susceptible to DNA damage. Furthermore, we showed that BMPR2 expression is tightly linked to DNA damage control because excessive DNA damage leads to rapid down-regulation of BMPR2 expression. Moreover, we identified breast cancer 1 (BRCA1) as a novel target for BMPR2 signaling and a novel modulator of pulmonary EC homeostasis. We show here that BMPR2 signaling plays a critical role in the regulation of genomic integrity in pulmonary ECs via genes such as BRCA1. We propose that iPAH-associated EC dysfunction and genomic instability are mediated through BMPR2 deficiency-associated loss of DNA damage control.

There is significant evidence that Th2 (T helper 2)-mediated inflammation supports the pathogenesis of both human and experimental animal models of pulmonary hypertension (PH). A key immune regulator is vascular endothelial growth factor (VEGF), which is produced by Th2 inflammation and can itself contribute to Th2 pulmonary responses. In this study, we interrogated the role of VEGF signaling in a murine model of schistosomiasis-induced PH with a phenotype of significant intrapulmonary Th2 inflammation, vascular remodeling, and elevated right ventricular pressures. We found that VEGF receptor blockade partially suppressed the levels of the Th2 inflammatory cytokines interleukin (IL)-4 and IL-13 in both the lung and the liver after Schistosoma mansoni exposure and suppressed pulmonary vascular remodeling. These findings suggest that VEGF positively contributes to schistosomiasis-induced vascular inflammation and remodeling, and they also provide evidence for a VEGF-dependent signaling pathway necessary for pulmonary vascular remodeling and inflammation in this model.

Previous studies have demonstrated the utility of fluorescence in situ hybridization (FISH) as an ancillary method in the diagnostic workup of histopathologically ambiguous melanocytic neoplasms. A combination of probes targeting 3 loci on chromosome 6 and 1 on 11q has been reported to distinguish unequivocal melanomas and nevi with a sensitivity and specificity of 87% and 96%, respectively. However, information on how FISH should be integrated into routine clinical testing is limited. We report our experience of FISH testing of 804 ambiguous melanocytic lesions performed as part of routine workup at University of California, San Francisco. The main category (47% of all cases) for which FISH testing was requested was Spitz tumors. Other categories included the distinction of possible melanoma from combined nevi (9%), acral or mucosal nevi (9%), Clark/dysplastic nevi (7%), and blue or deep penetrating nevi (6%) and to assess the possibility of nevoid melanoma (4%). Of the ambiguous tumors successfully tested, 88% received a more definitive benign or malignant final diagnosis. Of the 630 cases that tested negative by FISH, the final diagnosis was benign in 489 (78%) cases, ambiguous in 91 cases (14%), and malignant in 50 cases (8%). A positive FISH result was observed in 124 cases, with a final diagnosis of melanoma in 117 (94%). One (1%) FISH-positive case had an equivocal final diagnosis, and 6 (5%) were interpreted, despite the positive FISH result, as melanocytic nevi. We conclude that FISH testing can help reduce the number of equivocal diagnoses in ambiguous melanocytic neoplasms, in particular if FISH testing is positive, and discuss the challenges and limitations of FISH in clinical practice.

OBJECTIVES

To examine the impact of preoperative coronal plane deformity on functional and radiographic outcomes on endosteal strut augmentation of proximal humerus fracture fixation.

DESIGN

Single surgeon, retrospective analysis of a prospective database. Case series.

SETTING

Academic level 1 trauma center.

PATIENTS/PARTICIPANTS

Seventy-two patients with isolated proximal humerus fractures fulfilled all inclusion/exclusion criteria with a minimum follow-up of 12 months.

INTERVENTION

Proximal humerus open reduction internal fixation with a laterally placed proximal humeral locking plate and endosteal placement of an allograft fibula treated through the anterolateral approach.

MAIN OUTCOME MEASUREMENTS

Global functional outcome as determined by the Disabilities of the Arm, Shoulder and Hand (DASH) score and Short Form 36 physical function. Shoulder-specific functional outcome as determined by the Constant-Murley and the University of California Los Angeles shoulder scores.

RESULTS

The mean age was 62 years old (range, 26-90 years). There were 32 varus fractures (neck-shaft angle, 110.8 degrees) and 40 valgus fractures (neck-shaft angle, 168.9 degrees). There was no significant difference in the initial postoperative (varus: 132.5 degrees, valgus: 135.5 degrees) and final (varus: 129.9 degrees, valgus: 132.2 degrees) neck-shaft angles or change in humeral height (varus: 0.94 mm, valgus: 1.48 mm). There were no significant differences in functional outcomes [Constant (varus: 85.2, valgus: 88.7) DASH (varus: 21.4, valgus: 13.9), University of California Los Angeles (28.6, varus 30.4), and Short Form 36 (varus: 66.8, valgus: 59.1)]. There were 2 patients in the valgus group and 3 patients in the varus group with an asymptomatic humeral head screw penetration (mean Constant 84.5, DASH 9.5). There was 1 deep infection in the varus group and 2 in the valgus group necessitating implant removal after fracture union. There was 1 case of avascular necrosis in the valgus group (DASH 19.4, Constant 73).

CONCLUSIONS

There were no significant differences in complication rates, radiographic, or clinical outcomes between fractures presenting with preoperative varus coronal displacement compared with those presenting with valgus coronal displacement. The equivalent outcomes may be attributed to the uniform operative technique and fibular strut augmentation used by the primary surgeon.

LEVEL OF EVIDENCE

Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.