Citations

Background— Excitation-contraction coupling in striated muscle requires proper communication of plasmalemmal voltage-activated Ca 2+ channels and Ca 2+ release channels on sarcoplasmic reticulum within junctional membrane complexes. Although previous studies revealed a loss of junctional membrane complexes and embryonic lethality in germ-line junctophilin-2 (JPH2) knockout mice, it has remained unclear whether JPH2 plays an essential role in junctional membrane complex formation and the Ca 2+ -induced Ca 2+ release process in the heart. Our recent work demonstrated loss-of-function mutations in JPH2 in patients with hypertrophic cardiomyopathy. Methods and Results— To elucidate the role of JPH2 in the heart, we developed a novel approach to conditionally reduce JPH2 protein levels using RNA interference. Cardiac-specific JPH2 knockdown resulted in impaired cardiac contractility, which caused heart failure and increased mortality. JPH2 deficiency resulted in loss of excitation-contraction coupling gain, precipitated by a reduction in the number of junctional membrane complexes and increased variability in the plasmalemma–sarcoplasmic reticulum distance. Conclusions— Loss of JPH2 had profound effects on Ca 2+ release channel inactivation, suggesting a novel functional role for JPH2 in regulating intracellular Ca 2+ release channels in cardiac myocytes. Thus, our novel approach of cardiac-specific short hairpin RNA–mediated knockdown of junctophilin-2 has uncovered a critical role for junctophilin in intracellular Ca 2+ release in the heart.

Background: Medial elbow distraction during pitching as the primary mechanism contributing to adaptations in ulnar collateral ligament (UCL) appearance during magnetic resonance imaging (MRI) evaluation has not been established. Hypothesis: Uninjured high school–aged pitchers with unilateral adaptations of the UCL exhibit a higher peak internal elbow adduction moment than those without UCL adaptations. Study Design: Cohort study (Prevalence); Level of evidence, 2. Methods: Twenty uninjured, asymptomatic high school–aged pitchers underwent bilateral elbow MRI examinations. Three-dimensional motion analysis testing was performed to collect throwing arm biomechanics as participants pitched from an indoor mound. Nonparametric tests were performed to compare peak internal elbow adduction moment in uninjured participants with and without adaptations in UCL appearance and to determine the nature of the relationship between the peak internal adduction moment and UCL appearance. Results: Uninjured participants with UCL thickening exhibited a higher peak internal elbow adduction moment of 53.3 ± 6.8 N·m compared with uninjured participants without adaptations in UCL appearance, 38.8 ± 10.9 N·m ( P = .05), as higher moments were correlated with ligament thickening (correlation coefficient, 0.45) ( P = .02). Conclusion: This study establishes the association between medial elbow distraction captured by the internal adduction moment during pitching and UCL adaptations visible during MRI evaluation.

Generalized periodic epileptiform discharges can occur in a variety of epileptic syndromes and herald impending seizures. Such discharges are also extremely rare in children. Cerebral visual impairment can be associated with generalized and partial onset seizures, particularly those involving the occipital lobe. The authors present a case of a 10-month-old boy whose electroencephalogram revealed generalized periodic epileptiform discharges following resolution of status epilepticus. Such discharges warranted further monitoring, during which he experienced 2 additional seizures. He also was discovered to have cerebral visual impairment, which slowly resolved following termination of seizure activity. The child was subsequently found to have a de novo mutation of the sodium channel, voltage-gated, type I, alpha subunit (SCN1A) gene consistent with Dravet syndrome.

SP/KLF (Specificity protein/Krüppel-like factor) transcription factors comprise an emerging group of proteins that may behave as tumour suppressors. Incidentally, many cancers that display alterations in certain KLF proteins are also associated with a high incidence of KRAS (V-Ki-ras2 Kirsten rat sarcoma viral oncogene homologue) mutations. Therefore in the present paper we investigate whether SP/KLF proteins suppress KRAS-mediated cell growth, and more importantly, the potential mechanisms underlying these effects. Using a comprehensive family-wide screening of the 24 SP/KLF members, we discovered that SP5, SP8, KLF2, KLF3, KLF4, KLF11, KLF13, KLF14, KLF15 and KLF16 inhibit cellular growth and suppress transformation mediated by oncogenic KRAS. Each protein in this subset of SP/KLF members individually inhibits BrdU (5-bromo-2-deoxyuridine) incorporation in KRAS oncogenic-mutant cancer cells. SP5, KLF3, KLF11, KLF13, KLF14 and KLF16 also increase apoptosis in these cells. Using KLF11 as a representative model for mechanistic studies, we demonstrate that this protein inhibits the ability of cancer cells to form both colonies in soft agar and tumour growth in vivo. Molecular studies demonstrate that these effects of KLF11 are mediated, at least in part, through silencing cyclin A via binding to its promoter and leading to cell-cycle arrest in S-phase. Interestingly, similar to KLF11, KLF14 and KLF16 mechanistically share the ability to modulate the expression of cyclin A. Collectively, the present study stringently defines a distinct subset of SP/KLF proteins that impairs KRAS-mediated cell growth, and that mechanistically some members of this subset accomplish this, at least in part, through regulation of the cyclin A promoter.

Uncertainty in the duration of surgical procedures can cause long patient wait times, poor utilization of resources, and high overtime costs. We compare several heuristics for scheduling an Outpatient Procedure Center. First, a discrete event simulation model is used to evaluate how 12 different sequencing and patient appointment time‐setting heuristics perform with respect to the competing criteria of expected patient waiting time and expected surgical suite overtime for a single day compared with current practice. Second, a bi‐criteria genetic algorithm (GA) is used to determine if better solutions can be obtained for this single day scheduling problem. Third, we investigate the efficacy of the bi‐criteria GA when surgeries are allowed to be moved to other days. We present numerical experiments based on real data from a large health care provider. Our analysis provides insight into the best scheduling heuristics, and the trade‐off between patient and health care provider‐based criteria. Finally, we summarize several important managerial insights based on our findings.

Abstract Immune thrombocytopenia (ITP) is commonly encountered in clinical practice. In 1996 the American Society of Hematology published a landmark guidance paper designed to assist clinicians in the management of this disorder. Since 1996 there have been numerous advances in the management of both adult and pediatric ITP. These changes mandated an update in the guidelines. This guideline uses a rigorous, evidence-based approach to the location, interpretation, and presentation of the available evidence. We have endeavored to identify, abstract, and present all available methodologically rigorous data informing the treatment of ITP. We provide evidence-based treatment recommendations using the GRADE system in those areas in which such evidence exists. We do not provide evidence in those areas in which evidence is lacking, or is of lower quality—interested readers are referred to a number of recent, consensus-based recommendations for expert opinion in these clinical areas. Our review identified the need for additional studies in many key areas of the therapy of ITP such as comparative studies of “front-line” therapy for ITP, the management of serious bleeding in patients with ITP, and studies that will provide guidance about which therapy should be used as salvage therapy for patients after failure of a first-line intervention.

Abstract Purpose: Malignant peripheral nerve sheath tumors (MPNST) are highly aggressive sarcomas with variable patient survival and few known prognostically relevant genomic biomarkers. To identify survival-associated genomic biomarkers, we performed high-resolution array-based comparative genomic hybridization (aCGH) on a large set of MPNSTs. Experimental Design: Candidate gene alterations identified by aCGH in 38 MPNSTs were validated at the DNA, RNA, and protein levels on these same tumors and an independent set of 87 MPNST specimens. Results: aCGH revealed highly complex copy number alterations, including both previously reported and completely novel loci. Four regions of copy number gain were associated with poor patient survival. Candidate genes in these regions include SOX5 (12p12.1), NOL1 and MLF2 (12p13.31), FOXM1 and FKBP1 (12p13.33), and CDK4 and TSPAN31 (12q14.1). Alterations of these candidate genes and several others of interest (ERBB2, MYC and TP53) were confirmed by at least 1 complementary methodology, including DNA and mRNA quantitative real-time PCR, mRNA expression profiling, and tissue microarray-based fluorescence in situ hybridization and immunohistochemistry. Multivariate analysis showed that CDK4 gain/amplification and increased FOXM1 protein expression were the most significant independent predictors for poor survival in MPNST patients (P < 0.05). Conclusions: Our study provides new and independently confirmed candidate genes that could serve as genomic biomarkers for overall survival in MPNST patients. Clin Cancer Res; 17(7); 1924–34. ©2011 AACR.