Citations

Background: Tibial slope angle is a nonmodifiable risk factor for anterior cruciate ligament (ACL) injury. However, the mechanical role of varying tibial slopes during athletic tasks has yet to be clinically quantified. Purpose: To examine the influence of posterior tibial slope on knee joint loading during controlled, in vitro simulation of the knee joint articulations during athletic tasks. Study Design: Descriptive laboratory study. Methods: A 6 degree of freedom robotic manipulator positionally maneuvered cadaveric knee joints from 12 unique specimens with varying tibial slopes (range, −7.7° to 7.7°) through drop vertical jump and sidestep cutting tasks that were derived from 3-dimensional in vivo motion recordings. Internal knee joint torques and forces were recorded throughout simulation and were linearly correlated with tibial slope. Results: The mean (±SD) posterior tibial slope angle was 2.2° ± 4.3° in the lateral compartment and 2.3° ± 3.3° in the medial compartment. For simulated drop vertical jumps, lateral compartment tibial slope angle expressed moderate, direct correlations with peak internally generated knee adduction ( r = 0.60-0.65), flexion ( r = 0.64-0.66), lateral ( r = 0.57-0.69), and external rotation torques ( r = 0.47-0.72) as well as inverse correlations with peak abduction ( r = −0.42 to −0.61) and internal rotation torques ( r = −0.39 to −0.79). Only frontal plane torques were correlated during sidestep cutting simulations. For simulated drop vertical jumps, medial compartment tibial slope angle expressed moderate, direct correlations with peak internally generated knee flexion torque ( r = 0.64-0.69) and lateral knee force ( r = 0.55-0.74) as well as inverse correlations with peak external torque ( r = −0.34 to −0.67) and medial knee force ( r = −0.58 to −0.59). These moderate correlations were also present during simulated sidestep cutting. Conclusion: The investigation supported the theory that increased posterior tibial slope would lead to greater magnitude knee joint moments, specifically, internally generated knee adduction and flexion torques. Clinical Relevance: The knee torques that positively correlated with increased tibial slope angle in this investigation are associated with heightened risk of ACL injury. Therefore, the present data indicated that a higher posterior tibial slope is correlated to increased knee loads that are associated with heightened risk of ACL injury.

Abstract Human induced pluripotent stem cells (iPSCs) and derived progeny provide invaluable regenerative platforms, yet their clinical translation has been compromised by their biosafety concern. Here, we assessed the safety of transplanting patient-derived iPSC-generated pancreatic endoderm/progenitor cells. Transplantation of progenitors from iPSCs reprogrammed by lentiviral vectors (LV-iPSCs) led to the formation of invasive teratocarcinoma-like tumors in more than 90% of immunodeficient mice. Moreover, removal of primary tumors from LV-iPSC progeny-transplanted hosts generated secondary and metastatic tumors. Combined transgene-free (TGF) reprogramming and elimination of residual pluripotent cells by enzymatic dissociation ensured tumor-free transplantation, ultimately enabling regeneration of type 1 diabetes-specific human islet structures in vivo. The incidence of tumor formation in TGF-iPSCs was titratable, depending on the oncogenic load, with reintegration of the cMYC expressing vector abolishing tumor-free transplantation. Thus, transgene-free cMYC-independent reprogramming and elimination of residual pluripotent cells are mandatory steps in achieving transplantation of iPSC progeny for customized and safe islet regeneration in vivo. Significance Pluripotent stem cell therapy for diabetes relies on the safety as well as the quality of derived insulin-producing cells. Data from this study highlight prominent tumorigenic risks of induced pluripotent stem cell (iPSC) products, especially when reprogrammed with integrating vectors. Two major underlying mechanisms in iPSC tumorigenicity are residual pluripotent cells and cMYC overload by vector integration. This study also demonstrated that combined transgene-free reprogramming and enzymatic dissociation allows teratoma-free transplantation of iPSC progeny in the mouse model in testing the tumorigenicity of iPSC products. Further safety assessment and improvement in iPSC specification into a mature β cell phenotype would lead to safe islet replacement therapy for diabetes.

Considerable evidence implicates cellular senescence in the biology of aging and chronic disease. Diet and exercise are determinants of healthy aging; however, the extent to which they affect the behavior and accretion of senescent cells within distinct tissues is not clear. Here we tested the hypothesis that exercise prevents premature senescent cell accumulation and systemic metabolic dysfunction induced by a fast-food diet (FFD). Using transgenic mice that express EGFP in response to activation of the senescence-associated p16INK4a promoter, we demonstrate that FFD consumption causes deleterious changes in body weight and composition as well as in measures of physical, cardiac, and metabolic health. The harmful effects of the FFD were associated with dramatic increases in several markers of senescence, including p16, EGFP, senescence-associated β-galactosidase, and the senescence-associated secretory phenotype (SASP) specifically in visceral adipose tissue. We show that exercise prevents the accumulation of senescent cells and the expression of the SASP while nullifying the damaging effects of the FFD on parameters of health. We also demonstrate that exercise initiated after long-term FFD feeding reduces senescent phenotype markers in visceral adipose tissue while attenuating physical impairments, suggesting that exercise may provide restorative benefit by mitigating accrued senescent burden. These findings highlight a novel mechanism by which exercise mediates its beneficial effects and reinforces the effect of modifiable lifestyle choices on health span.

Though the public consciousness is typically focused on factors such as psychology, penis size, and the presence of the “G‐spot,” there are other anatomical and neuro‐anatomic differences that could play an equal, or more important, role in the frequency and intensity of orgasms. Discovering these variations could direct further medical or procedural management to improve sexual satisfaction. The aim of this study is to review the available literature of anatomical sexual variation and to explain why this variation may predispose some patients toward a particular sexual experience. In this review, we explored the available literature on sexual anatomy and neuro‐anatomy. We used PubMed and OVID Medline for search terms, including orgasm, penile size variation, clitoral variation, Grafenberg spot, and benefits of orgasm. First we review the basic anatomy and innervation of the reproductive organs. Then we describe several anatomical variations that likely play a superior role to popular known variation (penis size, presence of g‐spot, etc). For males, the delicate play between the parasympathetic and sympathetic nervous systems is vital to achieve orgasm. For females, the autonomic component is more complex. The clitoris is the primary anatomical feature for female orgasm, including its migration toward the anterior vaginal wall. In conclusions, orgasms are complex phenomena involving psychological, physiological, and anatomic variation. While these variations predispose people to certain sexual function, future research should explore how to surgically or medically alter these. Clin. Anat. 29:665–672, 2016. © 2016 Wiley Periodicals, Inc.

Background: Delivering specialty care remotely directly into people's homes can enhance access for and improve the healthcare of individuals with chronic conditions. However, evidence supporting this approach is limited. Materials and Methods: Connect.Parkinson is a randomized comparative effectiveness study that compares usual care of individuals with Parkinson's disease in the community with usual care augmented by virtual house calls with a Parkinson's disease specialist from 1 of 18 centers nationally. Individuals in the intervention arm receive four virtual visits from a Parkinson's disease specialist over 1 year via secure, Web-based videoconferencing directly into their homes. All study activities, including recruitment, enrollment, and assessments, are conducted remotely. Here we report on interest, feasibility, and barriers to enrollment in this ongoing study. Results: During recruitment, 11,734 individuals visited the study's Web site, and 927 unique individuals submitted electronic interest forms. Two hundred ten individuals from 18 states enrolled in the study from March 2014 to June 2015, and 195 were randomized. Most participants were white (96%) and college educated (73%). Of the randomized participants, 73% had seen a Parkinson's disease specialist within the previous year. Conclusions: Among individuals with Parkinson's disease, national interest in receiving remote specialty care directly into the home is high. Remote enrollment in this care model is feasible but is likely affected by differential access to the Internet.

Abstract Purpose: First-in-human phase I trial to determine the safety, pharmacokinetics, and antitumor activity of BIND-014, a novel, tumor prostate-specific membrane antigen (PSMA)–targeted nanoparticle, containing docetaxel. Experimental Design: Patients with advanced solid tumors received BIND-014 every three weeks (n = 28) or weekly (n = 27), with dose levels ranging from 3.5 to 75 mg/m2 and 15 to 45 mg/m2, respectively. Results: BIND-014 was generally well tolerated, with no unexpected toxicities. The most common drug-related toxicities (>20% of patients) on either schedule included neutropenia, fatigue, anemia, alopecia, and diarrhea. BIND-014 demonstrated a dose-linear pharmacokinetic profile, distinct from docetaxel, with prolonged persistence of docetaxel-encapsulated circulating nanoparticles. Of the 52 patients evaluable for response, one had a complete response (cervical cancer on the every three week schedule) and five had partial responses (ampullary adenocarcinoma, non–small cell lung, and prostate cancers on the every-three-week schedule, and breast and gastroesophageal cancers on the weekly schedule). Responses were noted in both PSMA-detectable and -undetectable tumors. Conclusions: BIND-014 was generally well tolerated, with predictable and manageable toxicity and a unique pharmacokinetic profile compared with conventional docetaxel. Clinical activity was noted in multiple tumor types. The recommended phase II dose of BIND-014 is 60 mg/m2 every three weeks or 40 mg/m2 weekly. Clin Cancer Res; 22(13); 3157–63. ©2016 AACR.