Predicting the need for vascular surgeons in Canada.

OBJECTIVE: With the introduction of direct entry (0+5) residency programs in addition to the traditional (5+2) programs, the number of vascular surgery graduates across Canada is expected to increase significantly during the next 5 to 10 years. Society's need for these newly qualified surgeons is unclear. This study evaluated the predicted requirement for vascular surgeons across Canada to 2021. A program director survey was also performed to evaluate program directors' perceptions of the 0+5 residency program, the expected number of new trainees, and faculty recruitment and retirement. METHODS: The estimated and projected Canadian population numbers for each year between 2013 and 2021 were determined by the Canadian Socio-economic Information and Management System (CANSIM), Statistics Canada's key socioeconomic database. The number of vascular surgery procedures performed from 2008 to 2012 stratified by age, gender, and province was obtained from the Canadian Institute for Health Information Discharge Abstract Database. The future need for vascular surgeons was calculated by two validated methods: (1) population analysis and (2) workload analysis. In addition, a 12-question survey was sent to each vascular surgery program director in Canada. RESULTS: The estimated Canadian population in 2013 was 35.15 million, and there were 212 vascular surgeons performing a total of 98,339 procedures. The projected Canadian population by 2021 is expected to be 38.41 million, a 9.2% increase from 2013; however, the expected growth rate in the age group 60+ years, who are more likely to require vascular procedures, is expected to be 30% vs 3.4% in the age group <60 years. Using population analysis modeling, there will be a surplus of 10 vascular surgeons in Canada by 2021; however, using workload analysis modeling (which accounts for the more rapid growth and larger proportion of procedures performed in the 60+ age group), there will be a deficit of 11 vascular surgeons by 2021. Program directors in Canada have a positive outlook on graduating 0+5 residents' skill, and the majority of programs will be recruiting at least one new vascular surgeon during the next 5 years. CONCLUSIONS: Although population analysis projects a potential surplus of surgeons, workload analysis predicts a deficit of surgeons because it accounts for the rapid growth in the 60+ age group in which the majority of procedures are performed, thus more accurately modeling future need for vascular surgeons. This study suggests that there will be a need for newly graduating vascular surgeons in the next 5 years, which could have an impact on resource allocation across training programs in Canada.

HIF-2α suppresses p53 to enhance the stemness and regenerative potential of human embryonic stem cells.

Human embryonic stem cells (hESCs) have been reported to exert cytoprotective activity in the area of tissue injury. However, hypoxia/oxidative stress prevailing in the area of injury could activate p53, leading to death and differentiation of hESCs. Here we report that when exposed to hypoxia/oxidative stress, a small fraction of hESCs, namely the SSEA3+/ABCG2+ fraction undergoes a transient state of reprogramming to a low p53 and high hypoxia inducible factor (HIF)-2α state of transcriptional activity. This state can be sustained for a period of 2 weeks and is associated with enhanced transcriptional activity of Oct-4 and Nanog, concomitant with high teratomagenic potential. Conditioned medium obtained from the post-hypoxia SSEA3+/ABCG2+ hESCs showed cytoprotection both in vitro and in vivo. We termed this phenotype as the "enhanced stemness" state. We then demonstrated that the underlying molecular mechanism of this transient phenotype of enhanced stemness involved high Bcl-2, fibroblast growth factor (FGF)-2, and MDM2 expression and an altered state of the p53/MDM2 oscillation system. Specific silencing of HIF-2α and p53 resisted the reprogramming of SSEA3+/ABCG2+ to the enhanced stemness phenotype. Thus, our studies have uncovered a unique transient reprogramming activity in hESCs, the enhanced stemness reprogramming where a highly cytoprotective and undifferentiated state is achieved by transiently suppressing p53 activity. We suggest that this transient reprogramming is a form of stem cell altruism that benefits the surrounding tissues during the process of tissue regeneration.

Wikipedia in Vascular Surgery Medical Education: Comparative Study.

BACKGROUND: Medical students commonly refer to Wikipedia as their preferred online resource for medical information. The quality and readability of articles about common vascular disorders on Wikipedia has not been evaluated or compared against a standard textbook of surgery. OBJECTIVE: The aims of this study were to (1) compare the quality of Wikipedia articles to that of equivalent chapters in a standard undergraduate medical textbook of surgery, (2) identify any errors of omission in either resource, and (3) compare the readability of both resources using validated ease-of-reading and grade-level tools. METHODS: Using the Medical Council of Canada Objectives for the Qualifying Examination, 8 fundamental topics of vascular surgery were chosen. The articles were found on Wikipedia using Wikipedia's native search engine. The equivalent chapters were identified in Schwartz Principles of Surgery (ninth edition). Medical learners (n=2) assessed each of the texts on their original platforms to independently evaluate readability, quality, and errors of omission. Readability was evaluated with Flesch Reading Ease scores and 5 grade-level scores (Flesch-Kincaid Grade Level, Gunning Fog Index, Coleman-Liau Index, Simple Measure of Gobbledygook Index, and Automated Readability Index), quality was evaluated using the DISCERN instrument, and errors of omission were evaluated using a standardized scoring system that was designed by the authors. RESULTS: Flesch Reading Ease scores suggested that Wikipedia (mean 30.5; SD 8.4) was significantly easier to read (P=.03) than Schwartz (mean 20.2; SD 9.0). The mean grade level (calculated using all grade-level indices) of the Wikipedia articles (mean 14.2; SD 1.3) was significantly different (P=.02) than the mean grade level of Schwartz (mean 15.9; SD 1.4). The quality of the text was also assessed using the DISCERN instrument and suggested that Schwartz (mean 71.4; SD 3.1) had a significantly higher quality (P=.002) compared to that of Wikipedia (mean 52.9; SD 11.4). Finally, the Wikipedia error of omission rate (mean 12.5; SD 6.8) was higher than that of Schwartz (mean 21.3; SD 1.9) indicating that there were significantly fewer errors of omission in the surgical textbook (P=.008). CONCLUSIONS: Online resources are increasingly easier to access but can vary in quality. Based on this comparison, the authors of this study recommend the use of vascular surgery textbooks as a primary source of learning material because the information within is more consistent in quality and has fewer errors of omission. Wikipedia can be a useful resource for quick reference, particularly because of its ease of reading, but its vascular surgery articles require further development.

Role of the exchange protein directly activated by cyclic adenosine 5'-monophosphate (Epac) pathway in regulating proglucagon gene expression in intestinal endocrine L cells.

Although proglucagon gene expression and the synthesis of proglucagon encoded peptide hormones could be activated by protein kinase A (PKA) activators such as forskolin/3-isobutyl-1-methylxanthine (IBMX) and cholera toxin, whether the activation is entirely attributed to PKA has not been previously examined. We found that forskolin/IBMX also activate ERK1/2 phosphorylation in intestinal and pancreatic proglucagon-producing cell lines. The MEK inhibitors PD98059 and U0126 were found to repress the expression of proglucagon promoter as well as endogenous proglucagon mRNA in two intestinal proglucagon-producing cell lines and to block the stimulatory effect of forskolin/IBMX on proglucagon mRNA expression. The repressive effect of the PKA-specific inhibitors H-89 and KT-5720, however, was either not observable or much less potent. Forskolin could activate ERK1/2 phosphorylation and proglucagon gene transcription on its own, whereas forskolin plus IBMX are required to effectively activate the PKA pathway in the proglucagon-producing cells. Exchange protein directly activated by cyclic AMP 2 (Epac2, or cAMP-binding guanine nucleotide exchange factor-2) was found to be expressed in gut and pancreatic proglucagon-producing cell lines, whereas the Epac-pathway-specific cAMP analog, 8-pMeOPT-2'O-Me-cAMP, effectively stimulated ERK1/2 phosphorylation as well as proglucagon mRNA expression. We therefore suggest that cAMP at least partially regulates proglucagon gene expression via the Epac-Ras/Rap-Raf-MEK-ERK signaling pathway.

Hybrid aortic arch repair.

Innovations in thoracic endovascular aortic repair techniques have enabled its incorporation in open procedures, resulting in a hybrid approach to aortic arch repair. The present study reported our experience with the hybrid technique in managing arch pathologies. Fifty-one patients underwent a hybrid repair of arch pathologies. 10 patients had urgent or emergency surgery, and 8 had previous abdominal aortic aneurysm repair; all were classified as high risk (ASA grade III or IV). Overall 30-day mortality was 9.8% (5/51). Hospital mortality was 30% (3/10) in urgent/emergent surgery and 4.90% (2/41) in elective cases. Ischemic stroke occurred in 11.8% (6/51) of patients, while 5.9% (3/51) experienced paraplegia. Endoleaks occurred in 8 patients, 6 of which were Type 1. Long-term patency rate was 96%. The hybrid technique is a safe, effective and less invasive alternative to open repair of arch pathologies, with comparable outcomes in high-risk patient groups. Patency rates and durability demonstrate the long-term potential of this technique.

Towards a more relevant hind limb model of muscle ischaemia.

Critical limb ischaemia is a severe manifestation of peripheral arterial disease characterised by intractable pain and tissue gangrene. Conventional treatments include percutaneous angioplasty and surgical bypass but up to one third of patients are not amenable to these interventions and will ultimately require amputation. Therapeutic neovascularisation has been proposed as an alternative treatment in these 'no option' patients and both cytokines and cells have shown impressive efficacy in the laboratory. Clinical trials in man, however, have had modest results. This discrepancy has put into question the relevance of the pre-clinical assays that are used to test potential agents. One of the most widely used of these assays is the hind limb ischaemia model that is often performed in young, healthy animals. This review critiques the techniques used to induce and assess ischaemia in this model and outlines the reasons why healthy rodents cannot fully recapitulate critical limb ischaemia in aged patients. Strategies that may produce a hind limb model that better simulates the human condition are proposed.

Occurrence and modulation of therapeutic targets of Aurora kinase inhibition in pediatric acute leukemia cells.

Acute lymphoblastic leukemia (ALL) is one of the most prevelant pediatric malignancies. Although cure rates have improved in recent decades, approximately one in five children relapse, and survival rates post-relapse remain low. Therefore, more effective and innovative therapeutic strategies are needed in order to improve the outcome in these children. Aurora kinases, a family of serine/threonine kinases essential for regulated mitosis, are overexpressed in many forms of cancer, and have been identified as potential targets for cancer therapeutics. Based on this premise, we evaluated the activity of the Aurora-A/B inhibitor AT9283 against pediatric leukemia cells. It was found that AT9283 significantly inhibited the growth and survival of cell lines derived from patients with pediatric leukemia. Specifically, AT9283 promoted Flt-3 dephosphorylation, inhibiting the activity of downstream effectors such as Erk and Mek. In addition, apoptotic markers were also identified, providing a panel of markers for biological correlative analysis for drug activity. Lastly, drug combination studies demonstrated the potential of several novel and conventional agents to synergize with AT9283, including apicidin, 17-allylamino-17-demethoxygeldanamycin (17-AAG) and doxorubicin. These data provide a rationale for further studies and the formulation of a clinical trial of AT9283 for the treatment of refractory pediatric ALL.

Squalene selectively protects mouse bone marrow progenitors against cisplatin and carboplatin-induced cytotoxicity in vivo without protecting tumor growth.

Squalene, an isoprenoid antioxidant is a potential cytoprotective agent against chemotherapy-induced toxicity. We have previously published that squalene protects light-density bone marrow cells against cis-diamminedichloroplatinum( II) (cisplatin)-induced toxicity without protecting tumor cells in vitro. Here, we developed an in vivo mouse model of cisplatin and cis-diammine (cyclobutane-1,1-dicarboxylato) platinum(II) (carboplatin)-induced toxicity to further investigate squalene-mediated LD-BM cytoprotection including the molecular mechanism behind selective cytoprotection. We found that squalene significantly reduced the body weight loss of cisplatin and carboplatin-treated mice. Light-density bone marrow cells from squalene-treated mice exhibited improved formation of hematopoietic colonies (colony-forming unit-granulocyte macrophage). Furthermore, squalene also protected mesenchymal stem cell colonies (colony-forming unit-fibroblast) from cisplatin and carboplatin-induced toxicity. Squalene-induced protection was associated with decreased reactive oxygen species and increased levels of glutathione and glutathione peroxidase/glutathione-S-transferase. Importantly, squalene did not protect neuroblastoma, small cell carcinoma, or medulloblastoma xenografts against cisplatin-induced toxicity. These results suggest that squalene is a potential candidate for future development as a cytoprotective agent against chemotherapeutic toxicity.