Path to a Profession: How a Physician Assistant Becomes a Physician Assistant.

This pilot study, through the application of phenomenological methodology, considered the physician assistant (PA) profession as a "lived experience" in an attempt to understand how these medical practitioners end up on the PA path and what keeps them there. Additionally, the researchers focused on understanding why specific individuals gravitate towards the PA education option. Major themes that developed during the interviews with eight PAs included personal unfamiliarity with the PA profession during the first two decades of life, the decision to pursue PA training while in undergraduate studies, assuming roles often considered MD/DO specific and the subsequent patient confusion with the difference between a PA and an MD/DO, and significant work satisfaction resulting in the lack of desire to change profession. These themes, especially personal unfamiliarity with the PA profession and patient confusion with the difference between a PA and an MD/DO, promotes an environment that perpetuates a lack of understanding about PAs, particularly in younger (e.g., pre-collegiate) individuals. Considering the consequences of this knowledge gap along with the equivocal validity of a pilot study and the potentially subjective nature of phenomenology, the researchers recommend further investigations, both quantitative and qualitative, to either confirm or repudiate these findings.

Chronic cardiac resynchronization therapy and reverse ventricular remodeling in a model of nonischemic cardiomyopathy.

While cardiac resynchronization therapy (CRT) has been shown to reduce morbidity and mortality in heart failure (HF) patients, the fundamental mechanisms for the efficacy of CRT are poorly understood. The lack of understanding of these basic mechanisms represents a significant barrier to our understanding of the pathogenesis of HF and potential recovery mechanisms. Our purpose was to determine cellular mechanisms for the observed improvement in chronic HF after CRT. We used a canine model of chronic nonischemic cardiomyopathy. After 15 months, dogs were randomized to continued RV tachypacing (untreated HF) or CRT for an additional 9 months. Six minute walk tests, echocardiograms, and electrocardiograms were done to assess the functional response to therapy. Left ventricular (LV) midmyocardial myocytes were isolated to study electrophysiology and intracellular calcium regulation. Compared to untreated HF, CRT improved HF-induced increases in LV volumes, diameters and mass (p<0.05). CRT reversed HF-induced prolongations in LV myocyte repolarization (p<0.05) and normalized HF-induced depolarization (p<0.03) of the resting membrane potential. CRT improved HF-induced reductions in calcium (p<0.05). CRT did not attenuate the HF-induced increases in LV interstitial fibrosis. Using a translational approach in a chronic HF model, CRT significantly improved LV structure; this was accompanied by improved LV myocyte electrophysiology and calcium regulation. The beneficial effects of CRT may be attributable, in part, to improved LV myocyte function.

Perlecan Domain V Inhibits Amyloid-ß Induced Activation of the α2ß1 Integrin-Mediated Neurotoxic Signaling Cascade.

Alzheimer's disease (AD) is characterized by neuronal death, neurofibrillary tangles, and senile plaques. Amyloid-beta (Aß) is the major component of plaques and consists of two prominent isoforms, Aß40 and Aß42. As many risk factors for AD are vascular in origin and blood vessel defects in clearing Aß from the brain are a potential key component of AD pathology, we have focused on the neuron-blood vessel interface, and in particular, the vascular basement membrane, which coats blood vessels and physically separates them from neurons. A prominent component of the vascular basement membrane is the extracellular matrix proteoglycan perlecan. Domain V (DV) is the C-terminal domain and is generated by perlecan proteolysis. DV interacts with the α2 integrin and Aß is a ligand for both α2ß1 and αvß1. Due to the known interaction of DV with α2ß1 and α2ß1's requirement for Aß deposition and neurotoxicity, we hypothesized that DV and/or its C-terminal domain, LG3, might alter neurotoxic signaling pathways by directly blocking or otherwise interfering with α2ß1 binding by Aß. Our study suggests that α2ß1 mediates Aß-induced activation of c-Jun and caspase-3, key components of the neurotoxic pathway, in primary cortical and hippocampal neurons. We further demonstrate that DV and/or LG3 may therapeutically modulate these α2ß1 mediated neurotoxic effects suggesting that they or other α2ß1 integrin modulators could represent a novel approach to treat AD. Finally, our results suggest different neurotoxicity susceptibilities between cortical and hippocampal neurons to Aß40 and Aß42 as further underscored by differing neuroprotective potencies of LG3 in each cell type.

Perlecan Domain V induces VEGf secretion in brain endothelial cells through integrin α5ß1 and ERK-dependent signaling pathways.

Perlecan Domain V (DV) promotes brain angiogenesis by inducing VEGF release from brain endothelial cells (BECs) following stroke. In this study, we define the specific mechanism of DV interaction with the α(5)ß(1) integrin, identify the downstream signal transduction pathway, and further investigate the functional significance of resultant VEGF release. Interestingly, we found that the LG3 portion of DV, which has been suggested to possess most of DV's angio-modulatory activity outside of the brain, binds poorly to α(5)ß(1) and induces less BEC proliferation compared to full length DV. Additionally, we implicate DV's DGR sequence as an important element for the interaction of DV with α(5)ß(1). Furthermore, we investigated the importance of AKT and ERK signaling in DV-induced VEGF expression and secretion. We show that DV increases the phosphorylation of ERK, which leads to subsequent activation and stabilization of eIF4E and HIF-1α. Inhibition of ERK activity by U0126 suppressed DV-induced expression and secretion of VEGR in BECs. While DV was capable of phosphorylating AKT we show that AKT phosphorylation does not play a role in DV's induction of VEGF expression or secretion using two separate inhibitors, LY294002 and Akt IV. Lastly, we demonstrate that VEGF activity is critical for DV increases in BEC proliferation, as well as angiogenesis in a BEC-neuronal co-culture system. Collectively, our findings expand our understanding of DV's mechanism of action on BECs, and further support its potential as a novel stroke therapy.

Perlecan domain V is neuroprotective and proangiogenic following ischemic stroke in rodents.

Stroke is the leading cause of long-term disability and the third leading cause of death in the United States. While most research thus far has focused on acute stroke treatment and neuroprotection, the exploitation of endogenous brain self-repair mechanisms may also yield therapeutic strategies. Here, we describe a distinct type of stroke treatment, the naturally occurring extracellular matrix fragment of perlecan, domain V, which we found had neuroprotective properties and enhanced post-stroke angiogenesis, a key component of brain repair, in rodent models of stroke. In both rat and mouse models, Western blot analysis revealed elevated levels of perlecan domain V. When systemically administered 24 hours after stroke, domain V was well tolerated, reached infarct and peri-infarct brain vasculature, and restored stroke-affected motor function to baseline pre-stroke levels in these multiple stroke models in both mice and rats. Post-stroke domain V administration increased VEGF levels via a mechanism involving brain endothelial cell α5ß1 integrin, and the subsequent neuroprotective and angiogenic actions of domain V were in turn mediated via VEGFR. These results suggest that perlecan domain V represents a promising approach for stroke treatment.