Vascular Smooth Muscle as a Therapeutic Target in Disease Pathology

Our circulatory system is composed of numerous elements that are responsible for transport of blood and delivery of essential nutrients and gases to vital downstream tissues. Among these components that make up our circulation is vascular smooth muscle (VSM), the primary muscular and contractile element of blood vessels and regulator of many blood vessel functions. This is of particular importance as cardiovascular disease (CVD), the number one killer of individuals in America and worldwide, is primarily vascular in origin. Logically, identifying and characterizing feasible targets that could control CVD are highly appealing and much desired. With this in mind and given its centrality in control of vascular physiology, VSM has gained wide attention as a plausible target to combat elements of CVD. This book chapter focuses on VSM as a potential therapeutic target against CVD and will provide overview of vascular anatomy and physiology and brief discussions about the pivotal roles of VSM in CVD pathology, the influence of abnormal blood flow mechanics and hemodynamics in CVD, neural control of VSM and the vasculature, and possible novel cellular and molecular signaling targets that could be used to control and/or minimize CVD. This chapter hopes to serve as a valuable resource for basic and applied scientists as well as clinicians interested in understanding the crucial roles that VSM plays in vessel physiology and pathology

Time‐lapse photogrammetry reveals hydrological controls of fine‐scale High‐Arctic glacier surface roughness evolution

In a warming Arctic, as glacier snowlines rise, short- to medium-term increases in seasonal bare-ice extent are forecast for the next few decades. These changes will enhance the importance of turbulent energy fluxes for surface ablation and glacier mass balance. Turbulent energy exchanges at the ice surface are conditioned by its topography, or roughness, which has been hypothesized to be controlled by supraglacial hydrology at the glacier scale. However, current understanding of the dynamics in surface topography, and the role of drainage development, remains incomplete, particularly for the transition between seasonal snow cover and well-developed, weathered bare-ice. Using time-lapse photogrammetry, we report a daily timeseries of fine (millimetre)-scale supraglacial topography at a 2 m2 plot on the Lower Foxfonna glacier, Svalbard, over two 9-day periods in 2011. We show traditional kernel-based morphometric descriptions of roughness were ineffective in describing temporal change, but indicated fine-scale albedo feedbacks at depths of ~60 mm contributed to conditioning surface topography. We found profile-based and two-dimensional estimates of roughness revealed temporal change, and the aerodynamic roughness parameter, z0, showed a 22–32% decrease from ~1 mm following the exposure of bare-ice, and a subsequent 72–77% increase. Using geostatistical techniques, we identified ‘hole effect’ properties in the surface elevation semivariograms, and demonstrated that hydrological drivers control the plot-scale topography: degradation of superimposed ice reduces roughness while the inception of braided rills initiates a subsequent development and amplification of topography. Our study presents an analytical framework for future studies that interrogate the coupling between ice surface roughness and hydro-meteorological variables and seek to improve parameterizations of topographically evolving bare-ice areas

High tibial osteotomy results in improved frontal plane knee moments, gait patterns and patient reported outcomes

Purpose The purpose of this study was to quantify changes in knee loading in the three clinical planes, compensatory gait adaptations and patient-reported outcome measures (PROMS) resulting from opening wedge high tibial osteotomy (HTO). Methods Gait analysis was performed on 18 participants (19 knees) with medial osteoarthritis (OA) and varus alignment pre- and post-HTO, along with 18 controls, to calculate temporal, kinematic and kinetic measures. Oxford Knee Score, Knee Outcome Survey and visual analogue pain scores were collected. Paired and independent sample tests identified changes following surgery and deviations from controls. Results HTO restored frontal and transverse plane knee joint loading to that of the control group, while reductions remained in the sagittal plane. Elevated frontal plane trunk sway (p = 0.031) and reduced gait speed (p = 0.042), adopted as compensatory gait changes pre-HTO, were corrected by the surgery. PROMs significantly improved (p ≤ 0.002). Centre of pressure (COP) was lateralised relative to the knee post-HTO (p < 0.001). Energy absorbed in the sagittal plane significantly increased post-HTO (p = 0.007), whilst work done in the transverse plane reduced (p ≤ 0.008). Pre-operative gait deviations from the control group that were retained post-HTO included smaller sagittal (p = 0.003) knee range of motion during gait, greater stance duration (p = 0.008) and altered COP location (anterior to the knee) in early stance (p = 0.025). Conclusions HTO surgery restored frontal and transverse plane knee loading to normal levels and improved PROMs. Gait adaptations known to reduce knee loading employed pre-HTO were not retained post-HTO. Some gait features were found to differ between post-HTO subjects and controls

Culture change in elite sport performance teams: Examining and advancing effectiveness in the new era

Reflecting the importance of optimizing culture for elite teams, Fletcher and Arnold (2011) recently suggested the need for expertise in culture change. Acknowledging the dearth of literature on the specific process, however, the potential effectiveness of practitioners in this area is unknown. The present paper examines the activity's precise demands and the validity of understanding in sport psychology and organizational research to support its delivery. Recognizing that sport psychologists are being increasingly utilized by elite team management, initial evidence-based guidelines are presented. Finally, to stimulate the development of ecologically valid, practically meaningful knowledge, the paper identifies a number of future research directions

The ASCIZ-DYNLL1 axis promotes 53BP1-dependent non-homologous end joining and PARP inhibitor sensitivity

53BP1 controls a specialized non-homologous end joining (NHEJ) pathway that is essential for adaptive immunity, yet oncogenic in BRCA1 mutant cancers. Intra-chromosomal DNA double-strand break (DSB) joining events during immunoglobulin class switch recombination (CSR) require 53BP1. However, in BRCA1 mutant cells, 53BP1 blocks homologous recombination (HR) and promotes toxic NHEJ, resulting in genomic instability. Here, we identify the protein dimerization hub—DYNLL1—as an organizer of multimeric 53BP1 complexes. DYNLL1 binding stimulates 53BP1 oligomerization, and promotes 53BP1’s recruitment to, and interaction with, DSB-associated chromatin. Consequently, DYNLL1 regulates 53BP1-dependent NHEJ: CSR is compromised upon deletion of Dynll1 or its transcriptional regulator Asciz, or by mutation of DYNLL1 binding motifs in 53BP1; furthermore, Brca1 mutant cells and tumours are rendered resistant to poly-ADP ribose polymerase (PARP) inhibitor treatments upon deletion of Dynll1 or Asciz. Thus, our results reveal a mechanism that regulates 53BP1-dependent NHEJ and the therapeutic response of BRCA1-deficient cancers

Recombinant IFN-α2a-NGR exhibits higher inhibitory function on tumor neovessels formation compared with IFN-α2a in vivo and in vitro

Purpose We compared the efficacy of ofatumumab (O) versus rituximab (R) in combination with cisplatin, cytarabine, and dexamethasone (DHAP) salvage treatment, followed by autologous stem-cell transplantation (ASCT) in patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL). Patients and Methods Patients with CD201 DLBCL age >= 18 years who had experienced their first relapse or who were refractory to first-line R-CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone)-like treatment were randomly assigned between three cycles of R-DHAP or O-DHAP. Either O 1,000 mg or R 375 mg/m2 was administered for a total of four infusions (days 1 and 8 of cycle 1; day 1 of cycles 2 and 3 of DHAP). Patients who experienced a response after two cycles of treatment received the third cycle, followed by high-dose therapy and ASCT. Primary end point was progression-free survival (PFS), with failure to achieve a response after cycle 2 included as an event. Results Between March 2010 and December 2013, 447 patients were randomly assigned. Median age was 57 years (range, 18 to 83 years); 17% were age >= 65 years; 63% had stage III and IV disease; 71% did not achieve complete response (CR) or experience response for, 1 year on first-line R-CHOP. Response rate for O-DHAP was 38% (CR, 15%) versus 42% (CR, 22%) for R-DHAP. ASCT on protocol was completed by 74 patients (33%) in the O arm and 83 patients (37%) in the R arm. PFS, event-free survival, and overall survival were not significantly different between O-DHAP versus R-DHAP: PFS at 2 years was 24% versus 26% (hazard ratio [HR], 1.12; 95% CI, 0.89 to 1.42; P = .33); event-free survival at 2 years was 16% versus 18% (HR, 1.10; P=.35); and overall survival at 2 years was 41% versus 38% (HR, 0.90; P=.38). Positron emission tomography negativity before ASCT was highly predictive for superior outcome. Conclusion No difference in efficacy was found between O-DHAP and R-DHAP as salvage treatment of relapsed or refractory DLBCL. (C) 2016 by American Society of Clinical Oncolog

The utilization of an ocular wound chamber on corneal epithelial wounds

Purpose Currently available ocular moisture chambers are not adequate to manage the treatment of periocular burns, corneal injuries, and infection. The purpose of these studies was to demonstrate that a flexible, semi-transparent ocular wound chamber device adapted from technology currently used on dermal wounds is safe for use on corneal epithelial injuries. Materials and methods A depilatory cream (Nair™, 30 seconds) was utilized to remove the excess hair surrounding the left eyes of anesthetized Institute Armand Frappier (IAF) hairless, female guinea pigs (Crl:HA-Hrhr). A 4 mm corneal epithelium defect was created using a corneal rust ring remover (Algerbrush®II). Epithelial defects were either left untreated or the eyes were fitted with an ocular wound chamber and 0.5 mL of hydroxypropyl methylcellulose (HPMC) gel (GenTeal®) or HPMC liquid (GenTeal®) was injected into each chamber (N=5 per group). At 0, 24, 48, and 72 hours fluorescein and optical coherence tomography imaging was collected and the intraocular pressure (IOP) was measured. H&E staining was performed on corneal and eyelid skin samples and evaluated by a veterinary pathologist. Results: Corneal epithelial wounds demonstrated 100% closure rates when left untreated or treated with an ocular wound chamber containing HPMC gel at 72 hours while wounds treated with an ocular wound chamber containing HPMC liquid were 98% healed. No significant differences were found in corneal thickness and wound healing, IOP, or eyelid skin pathology in any treatment group when compared to controls. Conclusions: This study indicates that adapted wound chamber technology can be safely used on sterile, corneal epithelial wounds without adverse effects on periocular or ocular tissue when filled with a liquid or gel

Willingness to act upon beliefs about 'treatment as prevention' among Australian gay and bisexual men

HIV 'treatment as prevention' (TasP) is highly effective in reducing HIV transmission in serodiscordant couples. There has been little examination of gay and bisexual men's attitudes towards TasP, particularly regarding men's willingness to act on beliefs about TasP. We conducted an online cross-sectional survey of Australian men in late 2012 to investigate knowledge and beliefs about new developments in HIV prevention. Amongst 839 men (mean age 39.5 years), men tended to disagree that TasP was sufficiently effective to justify reduced condom use, although HIV-positive men had more favourable attitudes. Only a minority of men were aware of any evidence for TasP; and one-quarter incorrectly believed that evidence for the effectiveness of TasP already existed for the homosexual population. One-fifth (20.5%) of men reported that they would be willing to have condomless anal intercourse with an opposite-status sexual partner when the HIV-positive partner was taking HIV treatments. Factors independently associated with such willingness were: HIV-positive serostatus, reporting any serodiscordant or serononconcordant condomless anal intercourse with a regular male partner in the previous six months, reporting any condomless anal intercourse with a casual male partner in the previous six months, and having greater beliefs in the effectiveness of TasP. This indicated that the men most willing to rely on TasP to prevent transmission were already engaging in higher risk practices. Biomedical HIV prevention represents a rapidly changing environment with new research as well as community and policy responses emerging at a fast pace. For men with serodiscordant sexual partners to successfully apply TasP to reducing transmission risk, more support and education is needed to enable better utilisation of TasP in specific relational and sexual contexts

Methodological challenges in collecting social and behavioural data regarding the HIV epidemic among gay and other men who have sex with men in Australia

©2014 Zablotska et al. Background: Behavioural surveillance and research among gay and other men who have sex with men (GMSM) commonly relies on non-random recruitment approaches. Methodological challenges limit their ability to accurately represent the population of adult GMSM. We compared the social and behavioural profiles of GMSM recruited via venue-based, online, and respondent-driven sampling (RDS) and discussed their utility for behavioural surveillance. Methods: Data from four studies were selected to reflect each recruitment method. We compared demographic characteristics and the prevalence of key indicators including sexual and HIV testing practices obtained from samples recruited through different methods, and population estimates from respondent-driven sampling partition analysis. Results: Overall, the socio-demographic profile of GMSM was similar across samples, with some differences observed in age and sexual identification. Men recruited through time-location sampling appeared more connected to the gay community, reported a greater number of sexual partners, but engaged in less unprotected anal intercourse with regular (UAIR) or casual partners (UAIC). The RDS sample overestimated the proportion of HIV-positive men and appeared to recruit men with an overall higher number of sexual partners. A single-website survey recruited a sample with characteristics which differed considerably from the population estimates with regards to age, ethnically diversity and behaviour. Data acquired through time-location sampling underestimated the rates of UAIR and UAIC, while RDS and online sampling both generated samples that underestimated UAIR. Simulated composite samples combining recruits from time-location and multi-website online sampling may produce characteristics more consistent with the population estimates, particularly with regards to sexual practices. Conclusion: Respondent-driven sampling produced the sample that was most consistent to population estimates, but this methodology is complex and logistically demanding. Time-location and online recruitment are more cost-effective and easier to implement; using these approaches in combination may offer the potential to recruit a more representative sample of GMSM