Citations

ABSTRACT Purpose. To determine whether treatment of symptomatic convergence insufficiency (CI) has an effect on Academic Behavior Survey (ABS) scores. Methods. The ABS is a six‐item survey developed by the Convergence Insufficiency Treatment Trial Group that quantifies the frequency of adverse school behaviors and parental concern about school performance on an ordinal scale from 0 (never) to 4 (always) with total scores ranging from 0 to 24. The ABS was administered at baseline and after 12 weeks of treatment to the parents of 218 children aged 9 to 17 years with symptomatic CI, who were enrolled in the Convergence Insufficiency Treatment Trial and randomized into (1) home‐based pencil push‐ups; (2) home‐based computer vergence/accommodative therapy and pencil push‐ups; (3) office‐based vergence/accommodative therapy with home reinforcement; and (4) office‐based placebo therapy with home reinforcement. Participants were classified as successful (n = 42), improved (n = 60), or non‐responder (n = 116) at the completion of 12 weeks of treatment using a composite measure of the symptom score, nearpoint of convergence, and positive fusional vergence. Analysis of covariance methods were used to compare the mean change in ABS between response to treatment groups while controlling for the ABS score at baseline. Results. The mean ABS score for the entire group at baseline was 12.85 (SD = 6.3). The mean ABS score decreased (improved) in those categorized as successful, improved, and non‐responder by 4.0, 2.9, and 1.3 points, respectively. The improvement in the ABS score was significantly related to treatment outcome (p < 0.0001), with the ABS score being significantly lower (better) for children who were successful or improved after treatment as compared to children who were non‐responders (p = 0.002 and 0.043, respectively). Conclusions. A successful or improved outcome after CI treatment was associated with a reduction in the frequency of adverse academic behaviors and parental concern associated with reading and school work as reported by parents.

The study of hemodynamic alterations following the creation of an arteriovenous fistula (AVF) is relevant to vascular adaptive responses and hemodialysis access dysfunction. This study examined such alterations in a murine AVF created by anastomosing the carotid artery to the jugular vein. AVF blood flow was markedly increased due to reduced AVF vascular resistance. Despite such markedly increased basal blood flow, AVF blood flow further increased in response to acetylcholine. This AVF model exhibited increased cardiac output and decreased systemic vascular resistance; the kidney, in contrast, exhibited decreased blood flow and increased vascular resistance. Augmentation in AVF blood flow was attended by increased arterial heme oxygenase-1 (HO-1) mRNA and protein expression, the latter localized to smooth muscle cells of the AVF artery; AVF blood flow was substantially reduced in HO-1−/− mice compared with HO-1+/+ mice. Finally, in a murine model of a representative disease known to exhibit impaired hemodynamic responses (sickle cell disease), the creation of an AVF was attended by decreased AVF flow and impaired AVF function. We conclude that this AVF model exhibits markedly increased AVF blood flow, a vasodilatory reserve capacity, increased cardiac output, decreased renal blood flow, and a dependency on intact hemodynamic responses, in general, and HO-1 expression, in particular, in achieving and maintaining AVF blood flow. We suggest that these findings support the utility of this model in investigating the basis for and the consequences of hemodynamic stress, including shear stress, and the pathobiology of hemodialysis AVF dysfunction.

Abstract Transplantation of pluripotent stem cells has proven beneficial in heart failure, yet the proteomic landscape underlying repair remains largely uncharacterized. In a genetic model of dilated cardiomyopathy elicited by pressure overload in the KCNJ11 (potassium inwardly rectifying channel, subfamily J, member 11) null mutant, proteome-wide profiles were here resolved by means of a systems approach prior to and following disease manifestation in the absence or presence of embryonic stem cell treatment. Comparative two-dimensional gel electrophoresis revealed a unique cardiomyopathic proteome in the absence of therapy, remodeled in response to stem cell treatment. Specifically, linear ion trap quadrupole-Orbitrap mass spectrometry determined the identities of 93 and 109 differentially expressed proteins from treated and untreated cardiomyopathic hearts, respectively. Mapped protein–protein relationships and corresponding neighborhoods incorporated the stem cell-dependent subproteome into a nonstochastic network with divergent composition from the stem cell-independent counterpart. Stem cell intervention produced a distinct proteome signature across a spectrum of biological processes ranging from energetic metabolism, oxidoreductases, and stress-related chaperones to processes supporting protein synthesis/degradation, signaling, and transport regulation, cell structure and scaffolding. In the absence of treatment, bioinformatic interrogation of the disease-only proteome network prioritized adverse cardiac outcomes, ablated or ameliorated following stem cell transplantation. Functional and structural measurements validated improved myocardial contractile performance, reduced ventricular size and decreased cardiac damage in the treated cohort. Unbiased systems assessment unmasked “cardiovascular development” as a prioritized biological function in stem cell-reconstructed cardiomyopathic hearts. Thus, embryonic stem cell treatment transformed the cardiomyopathic proteome to demote disease-associated adverse effects and sustain a procardiogenic developmental response, supplying a regenerative substrate for heart failure repair.

Abstract Purpose: The growth of non–Hodgkin lymphomas can be influenced by tumor–immune system interactions. Cytotoxic T-lymphocyte antigen 4 (CTLA-4) is a negative regulator of T-cell activation that serves to dampen antitumor immune responses. Blocking anti–CTLA-4 monoclonal antibodies improves host resistance to immunogenic tumors, and the anti–CTLA-4 antibody ipilimumab (MDX-010) has clinical activity against melanoma, prostate, and ovarian cancers. Experimental Design: We did a phase I trial of ipilimumab in patients with relapsed/refractory B-cell lymphoma to evaluate safety, immunologic activity, and potential clinical efficacy. Treatment consisted of ipilimumab at 3 mg/kg and then monthly at 1 mg/kg × 3 months (dose level 1), with subsequent escalation to 3 mg/kg monthly × 4 months (dose level 2). Results: Eighteen patients were treated, 12 at the lower dose level and 6 at the higher dose level. Ipilimumab was generally well tolerated, with common adverse events attributed to it, including diarrhea, headache, abdominal pain, anorexia, fatigue, neutropenia, and thrombocytopenia. Two patients had clinical responses; one patient with diffuse large B-cell lymphoma had an ongoing complete response (&gt;31 months), and one with follicular lymphoma had a partial response lasting 19 months. In 5 of 16 cases tested (31%), T-cell proliferation to recall antigens was significantly increased (&gt;2-fold) after ipilimumab therapy. Conclusions: Blockade of CTLA-4 signaling with the use of ipilimumab is well tolerated at the doses used and has antitumor activity in patients with B-cell lymphoma. Further evaluation of ipilimumab alone or in combination with other agents in B-cell lymphoma patients is therefore warranted. (Clin Cancer Res 2009;15(20):6446–53)

Purpose Single-fraction image-guided intensity-modulated radiation therapy (IG-IMRT) allows for tumoricidal treatment of traditionally radioresistant cancers while sparing critical adjacent structures. Risk of vertebral fracture after IG-IMRT for spinal metastases has not been defined. Patients and Methods We evaluated 62 consecutive patients undergoing single fraction IG-IMRT at 71 sites for solid organ metastases. A neuroradiologist and three spine surgeons evaluated prospectively obtained magnetic resonance/computed tomography (CT) imaging studies for post-treatment fracture development and tumor recurrence. Results Fracture progression was noted in 27 vertebrae (39%). Multivariate logistic regression analysis showed that CT appearance, lesion location, and percent vertebral body involvement independently predicted fracture progression. Lesions located between T10 and the sacrum were 4.6 times more likely to fracture than were lesions above T10 (95% CI, 1.1 to 19.7). Lytic lesions were 6.8 times more likely to fracture than were sclerotic and mixed lesions (95% CI, 1.4 to 33.3). As percent vertebral body involvement increased, odds of fracture also increased. Patients with fracture progression had significantly higher narcotic use, change in Karnofsky performance score, and a strong trend toward higher pain scores. Local tumor progression occurred in seven patients and contributed to one fracture. Obesity, posterior element involvement, bisphosphonate use, and local kyphosis did not confer increased risk. Conclusion Vertebral fracture is common after single fraction IG-IMRT for metastatic spine lesions. Lytic disease involving more than 40% of the vertebral body and location at or below T10 confer a high risk of fracture, the presence of which yields significantly poorer clinical outcomes. These results may help clinicians identify high-risk patients who would benefit from prophylactic vertebro- or kyphoplasty.

Rationale : Induced pluripotent stem cells (iPS) allow derivation of pluripotent progenitors from somatic sources. Originally, iPS were induced by a stemness-related gene set that included the c-MYC oncogene. Objective : Here, we determined from embryo to adult the cardiogenic proficiency of iPS programmed without c-MYC, a cardiogenicity-associated transcription factor. Methods and Results : Transgenic expression of 3 human stemness factors SOX2, OCT4, and KLF4 here reset murine fibroblasts to the pluripotent ground state. Transduction without c-MYC reversed cellular ultrastructure into a primitive archetype and induced stem cell markers generating 3-germ layers, all qualifiers of acquired pluripotency. Three-factor induced iPS (3F-iPS) clones reproducibly demonstrated cardiac differentiation properties characterized by vigorous beating activity of embryoid bodies and robust expression of cardiac Mef2c, α-actinin, connexin43, MLC2a, and troponin I. In vitro isolated iPS-derived cardiomyocytes demonstrated functional excitation-contraction coupling. Chimerism with 3F-iPS derived by morula-stage diploid aggregation was sustained during prenatal heart organogenesis and contributed in vivo to normal cardiac structure and overall performance in adult tumor-free offspring. Conclusions : Thus, 3F-iPS bioengineered without c-MYC achieve highest stringency criteria for bona fide cardiogenesis enabling reprogrammed fibroblasts to yield de novo heart tissue compatible with native counterpart throughout embryological development and into adulthood.

Background— Nuclear reprogramming provides an emerging strategy to produce embryo-independent pluripotent stem cells from somatic tissue. Induced pluripotent stem cells (iPS) demonstrate aptitude for de novo cardiac differentiation, yet their potential for heart disease therapy has not been tested. Methods and Results— In this study, fibroblasts transduced with human stemness factors OCT3/4, SOX2, KLF4, and c-MYC converted into an embryonic stem cell–like phenotype and demonstrated the ability to spontaneously assimilate into preimplantation host morula via diploid aggregation, unique to bona fide pluripotent cells. In utero, iPS-derived chimera executed differentiation programs to construct normal heart parenchyma patterning. Within infarcted hearts in the adult, intramyocardial delivery of iPS yielded progeny that properly engrafted without disrupting cytoarchitecture in immunocompetent recipients. In contrast to parental nonreparative fibroblasts, iPS treatment restored postischemic contractile performance, ventricular wall thickness, and electric stability while achieving in situ regeneration of cardiac, smooth muscle, and endothelial tissue. Conclusions— Fibroblasts reprogrammed by human stemness factors thus acquire the potential to repair acute myocardial infarction, establishing iPS in the treatment of heart disease.