Faculty Bibliography

The pharmacological manipulation of liver X receptors (LXRs) has been an attractive therapeutic strategy for atherosclerosis treatment as they control reverse cholesterol transport and inflammatory response. This study presents the development and efficacy of nanoparticles (NPs) incorporating the synthetic LXR agonist GW3965 (GW) in targeting atherosclerotic lesions. Collagen IV (Col IV) targeting ligands are employed to functionalize the NPs to improve targeting to the atherosclerotic plaque, and formulation parameters such as the length of the polyethylene glycol (PEG) coating molecules are systematically optimized. In vitro studies indicate that the GW-encapsulated NPs upregulate the LXR target genes and downregulate proinflammatory mediator in macrophages. The Col IV-targeted NPs encapsulating GW (Col IV-GW-NPs) successfully reaches atherosclerotic lesions when administered for 5 weeks to mice with preexisting lesions, substantially reducing macrophage content ( approximately 30%) compared to the PBS group, which is with greater efficacy versus nontargeting NPs encapsulating GW (GW-NPs) ( approximately 18%). In addition, mice administered the Col IV-GW-NPs do not demonstrate increased hepatic lipid biosynthesis or hyperlipidemia during the treatment period, unlike mice injected with the free GW. These findings suggest a new form of LXR-based therapeutics capable of enhanced delivery of the LXR agonist to atherosclerotic lesions without altering hepatic lipid metabolism.

PURPOSE: Fracture nonunion is a common problem for today's orthopaedic surgeon. However, many techniques are currently available for the treatment of long-bone nonunion. This video demonstrates the use of iliac crest bone graft and plate stabilization in the setting of a hypertrophic femoral nonunion. METHODS: Treatment of femoral nonunion after intramedullary nail fixation using compression plating and bone grafting is a reliable technique for reducing pain, improving function, and achieving radiographic union. Furthermore, the use of autologous bone graft, in particular iliac crest bone graft, has provided reliable clinical results. RESULTS: In this video, we present the case of a hypertrophic femoral nonunion treated with supplemental bone grafting in addition to plate and screw fixation. CONCLUSIONS: Although femoral nonunions are a relatively rare occurrence, they can be reasonably treated using stabilization and supplemental bone grafting. Iliac crest bone graft provides for excellent results when used for treatment of a fracture nonunion.

OBJECTIVE: This research examined the frequency of and characteristics associated with three forms of violence among persons with mental illness-violence directed at others, self-directed violence, and violence directed at them by others. METHODS: Previously unreported data from a follow-up sample of 951 patients from the MacArthur Violence Risk Assessment Study were analyzed to characterize involvement in violence directed at others, self-directed violence, and violence directed at them by others. RESULTS: Most patients (58%) experienced at least one form of violence, 28% experienced at least two forms, and 7% experienced all three forms. Several diagnostic, social, and historical variables distinguished the groups. CONCLUSIONS: Given the substantial overlap among the three forms of violence, clinicians should routinely screen patients who report one form for the occurrence of the other two. Co-occurrence of several forms of violence may require a package of interventions with components geared to each.

Remarkable strides have been made in the treatment of ischemic heart disease in decades. As the initial loss of cardiomyocytes associated with myocardial infarction serves as an impetus for myocardial remodeling, the ability to replace these cells with healthy counterparts would represent an effective treatment for many forms of cardiovascular disease. The discovery of cardiac stem cells (that can differentiate into multiple lineages) highlighted the possibility for development of cell-based therapeutics to achieve this ultimate goal. Recent research features cardiac stem cell maintenance, proliferation, and differentiation, as well as direct reprogramming of various somatic cells into cardiomyocytes, all within the context of the holy grail of regeneration of the injured heart. Much work remains to be done, but the future looks bright!

Background and Rationale: Mutations in Plakophilin-2 (PKP2) are the most common cause of ARVC, an inherited disease characterized by fibro- or fibrofatty infiltration of RV predominance, ventricular arrhythmias and sudden death in the young. The relation between PKP2 expression and the heart transcriptome in vivo, is unknown. Furthermore, while splicing misregulation has been associated with other inherited diseases, PKP2-dependent exon usage differences remain unexplored. We generated a murine line of cardiac-restricted, tamoxifen activated PKP2 deficiency ("PKP2-cKO") and defined PKP2- dependent exon usage in adult non-failing hearts. Methods and Results: The first disease manifestation was an increase in RV area, detected by echocardiography 14 days after tamoxifen injection (14 days post-injection or "dpi"), followed by marked RV dilation and reparative fibrosis (21 dpi), then bi-ventricular dilated cardiomyopathy (28 dpi), heart failure and death (30-50 dpi). To capture the earliest molecular events, hearts 14 dpi were used for RNAseq and exon usage. Comparing RV vs LV revealed minor changes in transcript abundance, but significant differences in alternative splicing (AS) program. We found ~75% of differentially spliced exons flanked by sequences that bind RBFox2, an RNA-binding protein that acts as central AS regulator of the adult heart, and that is necessary to maintain cardiac structure. Western blot analysis at 14 dpi and thereafter showed reduced abundance of RBFox2. RNAseq at 21 dpi showed that in addition to RBFox2, transcripts were reduced for RBFox1, MBNL1, MBNL2 and RBM20 (also molecules that control the AS program). Exon usage analysis at 21 dpi identified massive AS misregulation, similar to that of a failing heart, even though ejection fraction at this stage was ~50%. Misregulated genes included several involved in electrical rhythm and intracellular calcium homeostasis. Conclusion: We generated a model of PKP2-dependent ARVC. Our studies point to a previously unrecognized association between a desmosomal molecule, a splicing regulator, and the control of electrical and mechanical function. AS misregulation may be a substrate for sudden unexpected arrhythmic death in the young

The migration of primordial germ cells (PGCs) from their place of origin to the embryonic gonad is an essential reproductive feature in many animal species. In Drosophila melanogaster, a single G protein-coupled receptor, Trapped in endoderm 1 (Tre1), mediates germ cell polarization at the onset of active migration and directs subsequent migration of PGCs through the midgut primordium. How these different aspects of cell behavior are coordinated through a single receptor is not known. We demonstrate that two highly conserved domains, the E/N/DRY and NPxxY motifs, have overlapping and unique functions in Tre1. The Tre1-NRY domain via G protein signaling is required for reading and responding to guidance and survival cues controlled by the lipid phosphate phosphatases Wunen and Wunen2. In contrast, the Tre1-NPIIY domain has a separate role in Rho1- and E-cadherin-mediated polarization at the initiation stage independent of G protein signaling. We propose that this bifurcation of the Tre1 G protein-coupled receptor signaling response via G protein-dependent and independent branches enables distinct spatiotemporal regulation of germ cell migration.

Atherosclerosis, the major cause of cardiovascular disease, is a chronic inflammatory disease characterized by the accumulation of lipids and inflammatory cells in the artery wall. Aberrant expression of microRNAs has been implicated in the pathophysiological processes underlying the progression of atherosclerosis. Here, we define the contribution of miR-21 in hematopoietic cells during atherogenesis. Interestingly, we found that miR-21 is the most abundant miRNA in macrophages and its absence results in accelerated atherosclerosis, plaque necrosis, and vascular inflammation. miR-21 expression influences foam cell formation, sensitivity to ER-stress-induced apoptosis, and phagocytic clearance capacity. Mechanistically, we discovered that the absence of miR-21 in macrophages increases the expression of the miR-21 target gene, MKK3, promoting the induction of p38-CHOP and JNK signaling. Both pathways enhance macrophage apoptosis and promote the post-translational degradation of ABCG1, a transporter that regulates cholesterol efflux in macrophages. Altogether, these findings reveal a major role for hematopoietic miR-21 in atherogenesis.

BACKGROUND: The number of hip fractures is rising as life expectancy increases. As such, the number of centenarians sustaining these fractures is also increasing. The purpose of this study was to determine whether patients who are >/=100 years old and sustain a hip fracture fare worse in the hospital than those who are younger. METHODS: Using a large database, the New York Statewide Planning and Research Cooperative System (SPARCS), we identified patients who were >/=65 years old and had been treated for a hip fracture over a 12-year period. Data on demographics, comorbidities, and treatment were collected. Three cohorts were established: patients who were 65 to 80 years old, 81 to 99 years old, and >/=100 years old (centenarians). Outcome measures included hospital length of stay, estimated total costs, and in-hospital mortality rates. RESULTS: A total of 168,087 patients with a hip fracture were identified, and 1,150 (0.7%) of them had sustained the fracture when they were >/=100 years old. Centenarians incurred costs and had lengths of stay that were similar to those of younger patients. Despite the similarities, centenarians were found to have a significantly higher in-hospital mortality rate than the younger populations (7.4% compared with 4.4% for those 81 to 99 years old and 2.6% for those 65 to 80 years old; p < 0.01). Male sex and an increasing number of medical comorbidities were found to predict in-hospital mortality for centenarians sustaining extracapsular hip fractures. No significant predictors of in-hospital mortality were identified for centenarians who sustained femoral neck fractures. An increased time to surgery did not influence the odds of in-hospital mortality. CONCLUSIONS: Centenarians had increased in-hospital mortality, but the remaining short-term outcomes were comparable with those for the younger cohorts with similar fracture patterns. For this extremely elderly population, time to surgery does not appear to affect short-term mortality rates, suggesting a potential benefit to preoperative optimization. LEVEL OF EVIDENCE: Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence.