O-GlcNAcylation Mediates Glucose-Induced Alterations in Endothelial Cell Phenotype in Human Diabetes Mellitus.

Background Posttranslational protein modification with O-linked N-acetylglucosamine (O-GlcNAc) is linked to high glucose levels in type 2 diabetes mellitus (T2DM) and may alter cellular function. We sought to elucidate the involvement of O-GlcNAc modification in endothelial dysfunction in patients with T2DM. Methods and Results Freshly isolated endothelial cells obtained by J-wire biopsy from a forearm vein of patients with T2DM (n=18) was compared with controls (n=10). Endothelial O-GlcNAc levels were 1.8-ford higher in T2DM patients than in nondiabetic controls (P=0.003). Higher endothelial O-GlcNAc levels correlated with serum fasting blood glucose level (r=0.433, P=0.024) and hemoglobin A1c (r=0.418, P=0.042). In endothelial cells from patients with T2DM, normal glucose conditions (24 hours at 5 mmol/L) lowered O-GlcNAc levels and restored insulin-mediated activation of endothelial nitric oxide synthase, whereas high glucose conditions (30 mmol/L) maintained both O-GlcNAc levels and impaired insulin action. Treatment of endothelial cells with Thiamet G, an O-GlcNAcase inhibitor, increased O-GlcNAc levels and blunted the improvement of insulin-mediated endothelial nitric oxide synthase phosphorylation by glucose normalization. Conclusions Taken together, our findings indicate a role for O-GlcNAc modification in the dynamic, glucose-induced impairment of endothelial nitric oxide synthase activation in endothelial cells from patients with T2DM. O-GlcNAc protein modification may be a treatment target for vascular dysfunction in T2DM.

Tumor Lysis Syndrome After Bilobectomy for Typical Carcinoid Tumor of the Lung.

Tumor lysis syndrome is a life-threatening complication comprising hyperuricemia, hyperkalemia, hyperphosphatemia, and hypocalcemia attributed to release of intracellular contents. Although traditionally associated with leukemia and lymphoma after chemotherapy, it is known to occur in solid malignancies. We herein report a rare case of this syndrome after resection of bulky carcinoid tumor of the lung.

Routine Use of Ultrasound Guidance in Femoral Arterial Access for Peripheral Vascular Intervention Decreases Groin Hematoma Rates in High-Volume Surgeons.

BACKGROUND: There is a documented learning curve when adopting ultrasound guidance (UG) to aid vascular access. In the Vascular Study Group of New England (VSGNE), routine UG during percutaneous femoral artery access was shown to protect against the complication of groin hematoma. We sought to confirm this finding in the Vascular Quality Initiative (VQI), a data set with a larger sample size and broader geographic distribution, and to evaluate the effects of ultrasound usage and interventionalist volume on hematoma rates following peripheral vascular interventions (PVIs). METHODS: The VQI PVI database (2010-2014) was queried to identify the complication of groin hematoma after 43,947 PVIs performed via femoral artery access. Both procedure- and interventionalist-level analyses were performed. Multivariable logistic regression was used to assess factors associated with hematoma. Multivariable Poisson regression analyses were used to compare hematoma rates between routine (≥80% of PVIs) and selective (<80% of PVIs) users of UG in the adjusted overall sample and in subgroups based on interventionalist volume (low: <10 PVIs/year; medium: 10-50 PVIs/year; high: >50 PVIs/year). RESULTS: The overall groin hematoma rate was 3.2%, and lower hematoma rates correlated with increasing annual interventionalist volume (low vs. medium vs. high volume: 3.7% vs. 3.4% vs. 2.9%; P = 0.011). UG was associated with increased risk of hematoma (odds ratio [OR] 1.29, 95% confidence interval [CI] 1.13-1.47, P < 0.001), but this risk was isolated to patients treated by selective (OR 1.33, 95% CI 1.17-1.53, P < 0.001) rather than routine users of UG (OR 0.85, 95% CI 0.55-1.33, P = 0.484). In the overall interventionalist-level analysis, routine UG was not found to be protective against hematoma (rate ratio [RR] 0.97, 95% CI 0.85-1.11, P = 0.677), in contrast to what was previously reported from the VSGNE. However, subgroup analysis revealed that routine UG was further protective against hematoma among high-volume interventionalists (RR 0.73, 95% CI 0.54-0.97, P = 0.030). CONCLUSIONS: UG in percutaneous femoral artery access may decrease the complication rate of groin hematoma, especially as an interventionalist's volume increases and as selective use transforms into routine adoption. With repetition and practice, interventionalists likely overcome the learning curve associated with adoption of an unfamiliar technology and potentially improve patient outcomes.

Outcomes of Peripheral Vascular Interventions in Select Patients With Lower Extremity Acute Limb Ischemia.

BACKGROUND: Contemporary data on patients presenting with acute limb ischemia (ALI), who are selected for treatment with endovascular peripheral vascular interventions (PVI), are limited. Our study examined outcomes following endovascular PVI in patients with ALI by comparing with patients treated for chronic critical limb ischemia using a regional quality improvement registry. METHODS AND RESULTS: Of the 11 035 patients in the Vascular Study Group of New England PVI database (2010-2014), we identified 365 patients treated for lower extremity ALI who were 5:1 frequency matched (by procedure year and arterial segments treated) to 1808 patients treated for critical limb ischemia. ALI patients treated with PVI had high burden of atherosclerotic risk factors and were more likely to have had prior ipsilateral revascularizations. ALI patients were less likely to be treated with self-expanding stents and more likely to undergo thrombolysis than patients with critical limb ischemia. In multivariable analysis, ALI was associated with higher technical failure (odds ratio 1.7, 95% confidence interval, 1.1%-2.5%), increased rate of distal embolization (odds ratio 2.7, 95% confidence interval, 1.5%-4.9%), longer length of stay (means ratio 1.6, 95% confidence interval, 1.4%-1.8%), and higher in-hospital mortality (odds ratio 2.8, 95% confidence interval, 1.3%-5.9%). ALI was not associated with risk of major amputation or mortality at 1 year. CONCLUSIONS: In a multicenter cohort of patients treated with PVI, we found that ALI patients selected for treatment with endovascular techniques experienced greater short-term adverse events but similar long-term outcomes as their critical limb ischemia counterparts. Further studies are needed to refine the selection of ALI patients who are best served by PVI.

Role of language discordance in complication and readmission rate after infrainguinal bypass.

OBJECTIVE: Studies have shown that language discordance between treatment teams and patients leads to worse patient outcomes, including longer hospital stays, higher rates of readmission, impaired comprehension of discharge instructions, and lower treatment adherence. Yet, there is a paucity of data evaluating the effects of language discordance on postoperative outcomes among vascular surgery patients. This study compared 30-day postoperative complications and readmissions after nonemergent infrainguinal bypass between non-English-speaking (NES) and English-speaking (ES) patients. METHODS: Consecutive patients who underwent nonemergent infrainguinal bypass for claudication, ischemic rest pain, and tissue loss at an urban, academic medical center between 2007 and 2014 were identified. Patients were stratified into NES or ES groups by their self-identified primary language. Crude comparisons and multivariable analyses were performed to assess the association of primary language status with 30-day wound infections, adverse graft events (wound infections, graft thromboses, or hematomas), readmissions, and Emergency Department return visits. RESULTS: The study included 261 patients who underwent an infrainguinal bypass: 51 NES and 210 ES patients. The NES patients were older (67.4 ± 9.8 vs 63.1 ± 9.9 years; P = .005) and had a higher rate of diabetes (78.4% vs 58.6%; P = .009) and a lower rate of chronic obstructive pulmonary disease (5.9% vs 28.6%; P = .001). Other comorbidities were comparable between the two groups. The NES patients were more likely to be Medicaid beneficiaries (51.0% vs 21.4%; P < .001). Across all outcomes compared, crude analyses showed no significant difference between NES and ES patients. Adjusted analysis revealed that language discordance did not affect the odds of adverse outcomes of wound infections (odds ratio [OR], 1.87; 95% confidence interval [CI], 0.90-3.88; P = .095), adverse graft events (OR, 1.23; 95% CI, 0.62-2.45; P = .556), readmissions (OR, 1.51; 95% CI, 0.77-2.95; P = .478), or Emergency Department return visits (OR, 1.28; 95% CI, 0.58-2.83; P = .546). CONCLUSIONS: Our study suggests that language discordance does not affect 30-day complication and readmission rates after infrainguinal bypass.

Preoperative hypoalbuminemia is associated with poor clinical outcomes after open and endovascular abdominal aortic aneurysm repair.

OBJECTIVE: The effect of preoperative malnutrition on outcomes in patients undergoing major vascular surgery is unclear. We investigated the effects of preoperative hypoalbuminemia, a marker for malnutrition, on outcomes after open abdominal aortic aneurysm repair (OAR) and endovascular abdominal aortic aneurysm repair (EVAR). METHODS: Patients undergoing OAR or EVAR were identified in the 2005 to 2012 American College of Surgeons National Surgical Quality Improvement Program database and stratified into three groups: normal albumin (serum albumin >3.5 g/dL), moderate hypoalbuminemia (2.8-3.5 g/dL), and severe hypoalbuminemia (<2.8 g/dL). Multivariable analyses were performed to assess the association of preoperative hypoalbuminemia with 30-day morbidity and mortality. RESULTS: We identified 15,002 patients with a recorded preoperative serum albumin who underwent OAR (n = 4956) or EVAR (n = 10,046). Patients in both cohorts with hypoalbuminemia had a higher burden of comorbidity. In OAR patients, multivariable analyses demonstrated that moderate hypoalbuminemia was associated with an increased risk of 30-day mortality (odds ratio [OR], 1.32; 95% confidence interval [CI], 1.02-1.70) and postoperative length of stay (LOS; means ratio [MR], 1.10; 95% CI, 1.04-1.16), whereas severe hypoalbuminemia was associated with increased 30-day mortality (OR, 1.92; 95% CI, 1.37-2.70), reoperation ≤30 days (OR, 1.80; 95% CI, 1.32-2.48), pulmonary complications (OR, 1.40; 95% CI, 1.06-1.86), and postoperative LOS (MR, 1.33; 95% CI, 1.21-1.45). In EVAR patients, moderate hypoalbuminemia was associated with an increased risk of 30-day mortality (OR, 1.90; 95% CI, 1.38-2.62), pulmonary complications (OR, 1.61; 95% CI, 1.26-2.04), reoperation ≤30 days (OR, 1.39; 95% CI, 1.12-1.74), and postoperative LOS (MR, 1.23; 95% CI, 1.18-1.29), whereas severe hypoalbuminemia was associated with increased 30-day mortality (OR, 2.98; 95% CI, 1.96-4.53), pulmonary complications (OR, 1.88; 95% CI, 1.32-2.67), reoperation ≤30 days (OR, 1.54; 95% CI, 1.08-2.19), and postoperative LOS (MR, 1.52; 95% CI, 1.40-1.65). CONCLUSIONS: Preoperative hypoalbuminemia is associated with increased postoperative morbidity and mortality in a severity-dependent manner among patients undergoing OAR or EVAR. Evaluation and optimization of nutritional status should be performed preoperatively in this high-risk population.

Improving the retrieval rate of inferior vena cava filters with a multidisciplinary team approach.

OBJECTIVE: The option to retrieve inferior vena cava (IVC) filters has resulted in an increase in the utilization of these devices as stopgap measures in patients with relative contraindications to anticoagulation. These retrievable IVC filters, however, are often not retrieved and become permanent. Recent data from our institution confirmed a historically low retrieval rate. Therefore, we hypothesized that the implementation of a new IVC filter retrieval protocol would increase the retrieval rate of appropriate IVC filters at our institution. METHODS: All consecutive patients who underwent an IVC filter placement at our institution between September 2003 and July 2012 were retrospectively reviewed. In August 2012, a multidisciplinary task force was established, and a new IVC filter retrieval protocol was implemented. Prospective data were collected using a centralized interdepartmental IVC filter registry for all consecutive patients who underwent an IVC filter placement between August 2012 and September 2014. Patients were chronologically categorized into preimplementation (PRE) and postimplementation (POST) groups. Comparisons of outcome measures, including the retrieval rate of IVC filters along with rates of retrieval attempt and technical failure, were made between the two groups. RESULTS: In the PRE and POST groups, a total of 720 and 74 retrievable IVC filters were implanted, respectively. In the POST group, 40 of 74 filters (54%) were successfully retrieved compared with 82 of 720 filters (11%) in the PRE group (P < .001). Furthermore, a greater number of IVC filter retrievals were attempted in the POST group than in the PRE group (66% vs 14%; P < .001). No significant difference was observed between the PRE and POST groups for technical failure (17% vs 18%; P = .9). CONCLUSIONS: The retrieval rate of retrievable IVC filters at our institution was significantly increased with the implementation of a new IVC filter retrieval protocol with a multidisciplinary team approach. This improved retrieval rate is possible with minimal dedication of resources and can potentially lead to a decrease in IVC filter-related complications in the future.

Endothelial Dysfunction in Human Diabetes Is Mediated by Wnt5a-JNK Signaling.

OBJECTIVE: Endothelial dysfunction is linked to insulin resistance, inflammatory activation, and increased cardiovascular risk in diabetes mellitus; however, the mechanisms remain incompletely understood. Recent studies have identified proinflammatory signaling of wingless-type family member (Wnt) 5a through c-jun N-terminal kinase (JNK) as a regulator of metabolic dysfunction with potential relevance to vascular function. We sought to gain evidence that increased activation of Wnt5a-JNK signaling contributes to impaired endothelial function in patients with diabetes mellitus. APPROACH AND RESULTS: We measured flow-mediated dilation of the brachial artery and characterized freshly isolated endothelial cells by protein expression, eNOS activation, and nitric oxide production in 85 subjects with type 2 diabetes mellitus (n=42) and age- and sex-matched nondiabetic controls (n=43) and in human aortic endothelial cells treated with Wnt5a. Endothelial cells from patients with diabetes mellitus displayed 1.3-fold higher Wnt5a levels (P=0.01) along with 1.4-fold higher JNK activation (P<0.01) without a difference in total JNK levels. Higher JNK activation was associated with lower flow-mediated dilation, consistent with endothelial dysfunction (r=0.53, P=0.02). Inhibition of Wnt5a and JNK signaling restored insulin and A23187-mediated eNOS activation and improved nitric oxide production in endothelial cells from patients with diabetes mellitus. In endothelial cells from nondiabetic controls, rWnt5a treatment inhibited eNOS activation replicating the diabetic endothelial phenotype. In human aortic endothelial cells, Wnt5a-induced impairment of eNOS activation and nitric oxide production was reversed by Wnt5a and JNK inhibition. CONCLUSIONS: Our findings demonstrate that noncanonical Wnt5a signaling and JNK activity contribute to vascular insulin resistance and endothelial dysfunction and may represent a novel therapeutic opportunity to protect the vasculature in patients with diabetes mellitus.

Tolerance induction by hematopoietic cell transplantation: combined use of stem cells and progenitor cells.

BACKGROUND: Donor-specific hematopoietic cell transplantation (HCT) in the form of bone marrow transplantation has been long recognized experimentally as a means of inducing tolerance for subsequently transplanted organs. Clinical translation has been limited, however, due to HCT-associated complications. Unrelated myeloid progenitors (MP) can be administered simultaneously with hematopoietic stem cells (HSC). This reduces susceptibility to bacterial and fungal infections in neutropenic mice in laboratory studies. It is not known, however, if the addition of third-party MP interferes with tolerance induction. METHODS: BALB/c (H-2d) mice were irradiated and reconstituted with 4,000 AKR (H-2k) HSC or with 4,000 AKR HSC combined with 10(5) FVB (H-2q) MP. After 2 months, the mice received skin grafts from these three strains or from an unrelated strain, C57BL/6 (H-2b). Composition and origin of hematopoietic cells was analyzed using flow cytometry. RESULTS: Mice in both groups accepted all the host-type- and HSC-donor-matched grafts, and rejected unrelated grafts. Surprisingly, recipients of both HSC and MP also accepted MP-matched skin grafts (14 of 14), even with very low levels of MP-derived cells in circulation. The analysis revealed that, although most hematopoietic cells were derived from HSC donors, regulatory T cells were derived from both donors as well as the recipient. CONCLUSION: The addition of third-party MP cells does not interfere with HCT-induced tolerance induction and, surprisingly, induces MP-specific tolerance.