Contemporary management and natural history of aberrant right subclavian artery.

OBJECTIVE: An aberrant right subclavian artery (ARSA) is the most common congenital anomaly of the aortic arch. A paucity of reported studies is available regarding the treatment of these patients. The purpose of the present study was to evaluate the contemporary management strategies and natural history of ARSA in these patients. METHODS: A single-center retrospective review of patients with a diagnosis of ARSA from 2009 to 2019 was performed. Computed tomography scans were analyzed, and the aortic and ARSA diameters were measured at 10 different segments. The demographic data, comorbidities, and operative interventions were collected. The patients were categorized into those who had undergone intervention and those who had undergone expectant management. Linear mixed effect models were used to estimate the annual ARSA diameter changes. RESULTS: A total of 30 patients with ARSA were identified, 17 (57%) of whom were women. The average age for the cohort was 54.5 ± 14.6 years. Of the 30 patients, 20 (67%) had undergone operative repair at presentation and 10 (33%) were initially observed. The most common presenting symptom was dysphagia (30%). Of the 10 patients who had been initially treated expectantly, 4 had subsequently required intervention. Of the 24 operative interventions, 13 (54%) were hybrid procedures involving right carotid-subclavian bypass or transposition and thoracic endovascular aortic repair. The mean diameter of ARSA at its origin was 20.4 ± 5.7 mm, and the mean cross-sectional aortic diameter at the level of the ARSA was 31.8 ± 8.5 mm for the entire cohort. For the patients who had initially been observed and had subsequently required intervention, the largest change in the ARSA cross-sectional diameter was observed 1 cm distally to the vessel ostium at a rate of 3.05 mm annually (95% confidence interval, 1.54-4.56; P < .001). No statistically significant changes in the annual growth rate of the aortic segments were observed in the entire cohort or for those patients who had undergone intervention (P > .05). CONCLUSIONS: The decision to intervene on an ARSA should be individualized by the presence of symptoms (eg, dysphagia lusoria) or complications (eg, dissection, concomitant aortic aneurysmal disease, enlarging Kommerell diverticulum). Asymptomatic patients with nonaneurysmal ARSA might not require any intervention and can be safely observed. Measurement of the cross-sectional ARSA diameter 1 cm distally to the ostium of the vessel might aid in the surveillance of vessel diameter changes. Additional studies are required to determine the specific size criteria as an indication for operative repair of asymptomatic Kommerell diverticulum.

Standardizing Methods of Reading CT Maximum Aortic Diameters Amongst Experts Reduces Variations and Discordance, Improving Accuracy.

BACKGROUND: There is no consensus on the method of obtaining abdominal aortic aneurysm (AAA) maximum diameters based on computed tomographic angiography, and the reproducibility and accuracy of different methods have recently been debated due to advancements in imaging. This study compared the two most common methods based on orthogonal planes and centerline of flow to determine the discordances and accuracy amongst experiences readers. METHODS: The computed tomographic angiography max diameters of 148 AAAs were measured by three experienced observers, including a vascular surgeon, a radiologist and an imaging cardiologist. Observers used two different methods with standardized protocols: multiplanar reformations based on orthogonal planes, and a software using 3D aortic reconstructions to create centerline flow lumen providing diameters based on cross sections perpendicular to this lumen. Agreements and reliability of measurement methods were assessed by intra-class correlation coefficient and Bland - Altman analysis. Discordances between measurements of the methods and the original reported measurement, as well as outside hospitals were compared. RESULTS: The average age of the cohort was 75 years and aortic diameters ranged from 3.8 to 9.6 cm. For orthogonal readings, there were agreements within 3 mm between 86% and 92% of the time, while centerline - reading agreement was between 88% and 94%, which was not statistically significant. The intra-class correlation coefficient was high between method type and between readers. Within methods, agreement was between 0.96 and 0.97, while within - reader agreement measures was between 0.96 and 0.98. In comparison to the original and the outside hospital reports, 10% ≥ of the original and 20% ≥ of the outside hospital reported measurements were discordant between the readers. CONCLUSION: Maximal AAA measurements can have substantial variability leading to clinical significance and change in patient management and outcomes. Based on the results, orthogonal and centerline measurement methods have equally high agreements and concordance within 3 mm and low variations at a high volume center. However, when compared to the official read reports, there is high discordance rates that can significantly alter patient outcomes. A standardized method of measurement maximum diameter can reduce variations and discordances among different methods.

Decreased transfusion requirements with use of acute normovolemic hemodilution in open aortic aneurysm repair.

OBJECTIVE: Acute normovolemic hemodilution (ANH) is an operative blood conservation technique involving the removal and storage of patient blood after the induction of anesthesia, with maintenance of normovolemia by crystalloid and/or colloid replacement. Developed and used predominately in cardiac surgery, ANH has been applied to the vascular surgery population. However, data regarding the effects on transfusion requirements in this population are limited. The objective of the present study was to compare the transfusion requirements and coagulopathy for patients who had undergone open abdominal aortic aneurysm repair (oAAAR) using ANH to those for patients who had received only product replacements, as clinically indicated. METHODS: We performed a retrospective review of patients who had undergone elective oAAAR at a quaternary aortic referral center from 2017 to 2019. Those eligible for ANH, with no active cardiac ischemia, no valvular disease, normal left ventricular and right ventricular function, chronic kidney disease stage <3, hematocrit >38%, and a normal coagulation profile were included in the present study. Patient demographics and characteristics and operative variables, including aneurysm extent, clamp site, visceral and renal ischemia time, operative time, and transfusion requirements, were collected. Postoperative morbidity, mortality, and length of stay were analyzed. The patients with and without ANH were matched and compared. Continuous measures were analyzed using Wilcoxon rank sum tests and t tests. RESULTS: During the study period, 209 oAAARs had been performed. Of the 209 patients, 76 had met the inclusion criteria. Of these 76 patients, 27 had undergone ANH and 49 had not. The patients with ANH had required fewer PRBC transfusions intraoperatively (median, 0 U; interquartile range [IQR], 0-1 U; median, 1 U; IQR, 0-2 U; P = .02), at 24 hours (median, 0 U; IQR, 0-1 U; vs median, 1 U; IQR, 0-2 U; P = .008), at 48 hours (median, 0 U; IQR, 0-1 U; vs median, 1 U; IQR, 0-2; P = .007), and throughout the admission (median, 0 U; IQR, 0-1 U; vs median, 2 U; IQR, 0-2 U; P = .011). No difference was found in the number of intraoperative platelet or cryoprecipitate transfusions. At 48 hours, the ANH group had had significantly greater platelet counts (142 ± 35.8 × 103/µL vs 124 ± 37.6 × 103/µL; P = .044), lower partial thromboplastin time, and lower international normalized ratio. No difference in myocardial infarction, return to the operating room, or mortality (one death overall). The ANH patients had a shorter length of stay (7.0 ± 2.7 vs 8.8 ± 4.8 days; P = .041). CONCLUSIONS: The use of ANH during oAAAR resulted in fewer intraoperative and postoperative PRBC transfusions with improved coagulation parameters and a shorter hospital length of stay.

Spinal drainage complications after aortic surgery.

OBJECTIVE/BACKGROUND: Spinal drain (SD) placement is an adjunct used in open and endovascular aortic surgery to mitigate the risk of spinal cord injury. SD placement can lead to subdural hematoma and intracranial hemorrhage (SDH/ICH). Previous studies have highlighted a correlation between incidence of SDH/ICH and amount of cerebrospinal fluid (CSF) drained. We have two philosophies of SD management in our institution. One protocol allows fluid removal for pressure >10 cm H2O with no volume restriction. A second, similar protocol restricts CSF drainage to <25 mL/h. We examined SD complications and the influence of volume restriction. METHODS: Patients were identified according to the Current Procedure Terminology codes for SD placement, thoracic endovascular aortic repair, fenestrated/branched endovascular aortic repair, endovascular abdominal aortic repair, and open thoracic or thoracoabdominal aortic repair between January 1, 2012, and December 31, 2015. Patients' demographics included age, gender, race, body mass index, and comorbidities such as hypertension, chronic obstructive pulmonary disease, stroke, transient ischemic attack, diabetes mellitus, bleeding disorder, and connective tissue disorders. Management protocol was classified as volume independent (VI) or volume dependent (VD) by physician order. Postoperative complications related to the SD were noted. RESULTS: We identified 948 patients who had an SD placed during the study period; 473 were done before aortic surgeries. A total of 364 patients (77%) underwent endovascular aortic surgery. The mean age at the time of procedure was 67.2 years, and 66% of patients were male. Thirty-nine patients (8.3%) were noted to have connective tissue disorders. Bloody SD placement occurred in 14 patients (3.1%) requiring rescheduling of the operation. SDH/ICH occurred in 11 patients (2.3%), postoperative blood tinged SD output in 94 patients (19.9 %), and 22 patients (4.7 %) had a CSF leak after SD removal. The incidence of SDH/ICH was not affected by the management protocol (2.6% VI vs 2.0% VD, P = .66), whereas the incidence of postoperative blood tinged SD output was significantly higher in the VI group (25.1% VI vs 15.0% VD, P = .006). Perioperative low-dose aspirin (81 mg) and prophylactic subcutaneous heparin did not increase the incidence of SDH/ICH. Postoperative thrombocytopenia was found to be associated with higher incidence of SDH/ICH (median 86,000 vs 113,000, P = .002). CONCLUSIONS: Severe complications of SD placement (SDH/ICH) occur in 2.3% of SD patients undergoing aortic surgery, and the risk is higher in the setting of postoperative thrombocytopenia. SD volume limitation, blood tinged drainage, antiplatelet medication, and low-dose heparin do not affect the risk of SDH/ICH. The risks of spinal drains for aortic surgery should be balanced against potential benefits.

Thoracic outlet decompression for subclavian venous stenosis after ipsilateral hemodialysis access creation.

OBJECTIVE: Central venous stenosis is one of the most challenging complications in patients requiring hemodialysis. Venous thoracic outlet syndrome is an underappreciated cause of central venous stenosis in patients requiring dialysis that can result in failed percutaneous intervention and loss of a functioning dialysis access. Limited data exist about the safety and outcomes of first rib resection in patients requiring hemodialysis, and the results have been confounded by the various surgical approaches used. The purpose of the present study was to evaluate the safety, operative outcomes, and patency of the existing dialysis access after transaxillary thoracic outlet decompression. METHODS: A retrospective medical record review was performed from January 2008 to December 2019 of patients who had undergone thoracic outlet decompression for subclavian vein stenosis with ipsilateral upper extremity hemodialysis access. The baseline characteristics and comorbidities were reviewed. The operative and postoperative course were evaluated. The survival and patency rates were analyzed using the life-table method and Kaplan-Meier curve. RESULTS: A total of 18 extremities in 18 patients were identified. Their mean age was 59 ± 11 years, and 89% were men. A total of 13 fistulas and 5 grafts were included. All patients had undergone repair via a transaxillary approach. First rib resection, anterior scalenectomy, and circumferential venolysis were performed in all 18 patients. The mean operative time was 99 ± 19 minutes, with an estimated blood loss of 78 ± 66 mL. The median length of stay was 2 days. No patient had died at 30 days. The survival rate at 1 year was 83%. The primary, primary-assisted, and secondary patency at 1 year were 42%, 69%, and 93%, respectively. CONCLUSIONS: Thoracic outlet decompression via the transaxillary approach is a technically feasible and safe operation in patients with ipsilateral upper extremity hemodialysis access. Patients with threatened dialysis access due to subclavian vein stenosis should be carefully evaluated for possible extrinsic compression at the costoclavicular junction. These patients might benefit from transaxillary first rib resection, scalenectomy, and venolysis.

Impact of posthospital syndrome on outcomes of elective endovascular repair of abdominal aortic aneurysm.

OBJECTIVE: Posthospital syndrome (PHS) is an acquired, transient period of health vulnerability after a hospital admission for acute illness. It is characterized by physiologic deconditioning secondary to stressors from disruption in circadian rhythm, depletion of nutritional and physiologic reserve as well as the pain and discomfort associated with hospitalization. PHS is reported as an independent risk factor for readmission and adverse postoperative outcomes. The aim of this study is to investigate whether preoperative hospitalization affects outcomes of elective endovascular repair of abdominal aortic aneurysm (EVAR). METHODS: The Healthcare Cost and Utilization Project State Inpatient Database for California (2009-2011) were queried using International Classification of Disease Codes, Ninth Edition, codes of 441.4 (abdominal aneurysm without mention of rupture), 397.1 (EVAR with graft), and 397.8 (EVAR with branching or fenestrated graft). PHS exposure is defined as any inpatient admission 30 or fewer days before elective EVAR. Primary outcomes are all-cause mortality and overall complications. Secondary outcomes include length of stay (LOS), 30-day readmission, and hospital charge. RESULTS: A total of 6155 patients were identified. of which 327 patients (5.6%) had more than one episode of hospital admission 30 days or less before elective EVAR. In-hospital mortality was comparable after PHS exposure (P = .09). However, PHS exposure was associated with increased 30-day readmission (9.5% vs 18.4%; P < .001), LOS (3.0 vs 4.5 days; P < .001), and overall complications (14.8% vs 24.5%; P < .001). Risk adjustment was made based on age, sex, race, baseline comorbidities, and reason for preoperative admission. Multivariate logistic regression analysis demonstrated that PHS exposure was a predictor for longer LOS (odds ratio [OR], 2.5; 95% confidence interval [CI], 2.0-3.2; P < .001), higher incidence of 30-day readmission (OR, 2.0; 95% CI, 1.4-2.6; P < .001), and overall complications (OR, 1.7; 95% CI, 1.3-2.2; P < .001). Additional cost associated with increased 30-day readmission attributable to PHS exposure was estimated at $448,302 per 100 cases. CONCLUSIONS: PHS is an independent risk-adjusted predictor for increased LOS, 30-day readmission, and overall complications after elective EVAR. Recent hospital admission should be assessed carefully before elective EVAR. Medical optimization with an attempt to delay elective surgery by up to 30 days may help to improve surgical outcomes and decrease unnecessary health care expenditures.

Exploring perioperative complications of anterior lumber interbody fusion in patients with a history of prior abdominal surgery: A retrospective cohort study.

BACKGROUND CONTEXT: Anterior lumbar interbody fusion (ALIF) exposes the anterior aspect of the spine through a retroperitoneal approach. Access to the anterior spine requires mobilization of intra-abdominal viscera/vasculature, which can become complicated as scarring and/or adhesions develop from prior abdominal surgical interventions, increasing risk of intraoperative complications. The literature suggests that "significant prior abdominal surgery" is a relative contraindication of ALIF surgery; however, there is no consensus within the literature as to what defines "major/significant" abdominal surgeries. Additionally, the association between the number of prior abdominal surgeries and perioperative complications in ALIF surgery has not been explored within the literature. PURPOSE: This study seeks to explore the association between perioperative complications of ALIF surgery and the type (major and/or minor) and number of prior abdominal surgeries. DESIGN: A retrospective cohort study was performed to examine perioperative complications in ALIF patients with or without prior history of abdominal surgery. PATIENT SAMPLE: All consecutive patients undergoing ALIF with or without a history of prior abdominal surgery from 2008 to 2018 at a single tertiary center were evaluated. Patients under the age of 18, patients with spinal malignancy, or patients who had ALIF above L3 were excluded. OUTCOME MEASURES: Perioperative complications included intraoperative complications during ALIF surgery and postoperative complications within 90 days of ALIF surgery. Intraoperative complications include vascular injury, ureter injury, retroperitoneal hematoma, etc. Postoperative complications include urinary tract infection, revision of abdominal scar, ileus, deep vein thrombosis, pulmonary embolism, etc. Other outcome measures include readmission within 90 days, length of ALIF surgery, and length of hospital stay. METHODS: Electronic medical records of 660 patients who underwent ALIF between 2008 and 2018 were retrospectively reviewed. Patient demographics, Charleston Comorbidity Index (CCI), level of fusion, past abdominal surgical history, use of access surgeon during exposure, intraoperative, and postoperative complications were collected. Predictors of intraoperative and postoperative complications were analyzed using simple and multivariable logistic regression. Statistical analysis was performed using JMP 14.0 (SAS, Cary, NC, USA) software. RESULTS: After controlling for age, length of ALIF, gender, multilevel ALIF, and the use of an access surgeon, there was no significant association between the type of prior abdominal surgery (major and/or minor) and intraoperative complications on multivariable logistic regression analysis (Minor: odds ratio [OR]=1.68; 95% confidence interval [CI]: 0.58-4.86 & Major: OR=1.99; 95% CI: 0.80-4.91). On multivariable logistic regression, the odds of developing an intraoperative complication increases by 52% for each additional prior abdominal surgery after adjusting for age, length of ALIF, gender, multilevel ALIF, and the use of an access surgeon (OR=1.52, 95% CI: 1.10-2.11). Iliac vein laceration was the most common intraoperative complication (n=27, 4%). Neither the type (major and/or minor) nor the number of prior abdominal surgeries were significant predictors of postoperative complications (Minor: OR=1.29; 95% CI: .72-2.31, Major: OR=1.24; 95% CI: 0.77-2.00, & Number: OR=1.03; 95% CI: .84-1.26). CONCLUSION: With each additional prior abdominal surgery, accumulation of scarring and adhesions can likely obscure anatomical landmarks and increase the risk of developing an intraoperative complication. Therefore, the number of prior abdominal surgeries should be taken into consideration during planning and operative exposure of the anterior spine via a retroperitoneal approach.

The Majority of Patients Have Diagnostic Evaluation Prior to Major Lower Extremity Amputation.

BACKGROUND: Critical limb ischemia (CLI) patients who do not undergo revascularization are at great risk for major lower extremity (LE) amputation. It has been reported that less than half (49%) of a reference Medicare amputation population had any diagnostic vascular evaluation prior to a major LE amputation. We were surprised by these data so we reviewed the preoperative evaluation in all patients who had a major LE amputation. We propose that significantly more patients will have a vascular evaluation prior to major LE amputation at a tertiary care referral center when a vascular surgeon does the amputation. METHODS: A retrospective analysis of major LE amputations was performed. Patient demographics, comorbidities, type of amputation, reason for amputation, Rutherford classification, and type of preoperative vascular examination were evaluated. RESULTS: Over 4 years, 281 patients required major LE amputation. Above-knee amputation was performed in 39.1% of patients, whereas below-knee amputation was performed in 60.9%. Amputation was performed due to CLI in 92.9% of patients, whereas 7.1% of amputations were performed due to diabetes or other reasons. Preoperative vascular evaluation was performed in 100% of patients undergoing major LE amputation. Vascular surgeon pulse examination was most common (99.3%) followed by pulse volume recordings/ankle-brachial index (78.8%), angiography (54.8%), computed tomography angiography (29.3%), duplex ultrasonography (41.3%), and magnetic resonance angiography (0.4%). Amputations most commonly occurred due to Rutherford classification VI (63.3%) with 97.2% of patients having Rutherford IV-VI classification. CONCLUSIONS: Preoperative vascular evaluation prior to major LE amputation is achievable in the majority of patients, reported here in 100% of patients undergoing a major LE amputation. This allows us to evaluate the patient for revascularization options prior to amputation for possible limb salvage.

Celiac Plexus Block as a Predictor of Surgical Outcome for Sympathetically Mediated Abdominal Pain in a Case of Suspected Median Arcuate Ligament Syndrome: A Case Report.

Median arcuate ligament syndrome (MALS), also known as celiac artery compression syndrome, is an uncommon condition classically characterized by chronic abdominal pain, weight loss, and abdominal bruit. Chronic mesenteric ischemia caused by intermittent compression of the celiac artery by the MAL provokes upper abdominal pain that is sympathetically mediated via the celiac plexus. Because it is a diagnosis of exclusion, diagnosis of MALS in the clinical setting is typically challenging. We present an atypical case which highlights the utility of celiac plexus block as both an assistant diagnostic tool and a predictor of surgical outcomes for suspected MALS.

May-Thurner Syndrome: A Rare and Under-Appreciated Cause of Venous Thrombosis in a 18-Year-Old Healthy Female.

May-Thurner syndrome (MTS) is a rarely diagnosed vascular abnormality that typically presents in young adults. The anomaly arises from compression of the left common iliac vein between the right iliac artery anteriorly and the lumbar vertebral body posteriorly, resulting in lower extremity venous outflow obstruction and recurrent deep vein thromboses (DVTs). We report the case of a 24-year-old female with a long history of recurrent DVTs and pulmonary emboli (PE) despite full anticoagulation. A computed tomography (CT) scan revealed findings consistent with MTS, and a left common iliac vein stent was placed. However, the patient continued to have DVTs while trialing several anticoagulation therapies, including rivaroxaban, enoxaparin, and warfarin. Eventually, the patient developed arterial thrombi resulting in critical limb ischemia, necessitating a right below knee amputation (BKA). One month status-post BKA, the patient was admitted for severe BKA stump pain secondary to infection and necrosis. She underwent BKA revision, but continued to experience pain post-operatively and was found to have new right common iliac artery, external iliac artery, and common femoral artery thrombosis in the setting of continued inpatient anticoagulation therapy with enoxaparin and aspirin. The patient returned to the operating room for emergent Fogarty thrombectomy, however, this was complicated by rupture of the balloon catheter secondary to migration of the left common iliac vein stent into the right common iliac artery lumen. A stent was placed in the right common iliac artery to shift the rogue vein stent, but the patient continued to have poor distal circulation of the BKA stump and eventually underwent an above knee amputation. Dual anti-platelet therapy (DAPT) with aspirin and clopidogrel in combination with enoxaparin were used to prevent in-stent thrombosis and future formation of arterial and venous thrombi. After the initiation of DAPT and enoxaparin, her clinical course was free of any further thromboembolic events. Clinicians should consider MTS in the differential diagnosis of younger adults presenting with recurrent DVTs or other unprovoked thromboembolic events. A two-pronged strategy of DAPT and anticoagulation was employed for successful prevention of thrombotic events.

Inferior vena cava occlusion causing syncope during upper extremity exertion treated with iliocaval venous revascularization.

Inferior vena cava (IVC) thrombosis is rare, but its incidence is increased in those with IVC filters or inflammatory bowel disease. Once the IVC is thrombosed, venous return is via collateral channels on the torso and retroperitoneum. Limitations in this collateral venous return can result in symptoms, usually in the lower extremities. Syncope and dyspnea are rare. We report a patient with a 1-year history of worsening syncope when working with his upper extremities. Iliocaval venous occlusion with lack of accommodation of venous return at the thoracic outlet was diagnosed. Treatment with iliocaval stenting resolved his symptoms.

O-GlcNAcylation: a novel pathway contributing to the effects of endothelin in the vasculature.

Glycosylation with O-linked ß-N-acetylglucosamine (O-GlcNAc) or O-GlcNAcylation on serine and threonine residues of nuclear and cytoplasmic proteins is a posttranslational modification that alters the function of numerous proteins important in vascular function, including kinases, phosphatases, transcription factors, and cytoskeletal proteins. O-GlcNAcylation is an innovative way to think about vascular signaling events both in physiological conditions and in disease states. This posttranslational modification interferes with vascular processes, mainly vascular reactivity, in conditions where endothelin-1 (ET-1) levels are augmented (e.g. salt-sensitive hypertension, ischemia/reperfusion, and stroke). ET-1 plays a crucial role in the vascular function of most organ systems, both in physiological and pathophysiological conditions. Recognition of ET-1 by the ET(A) and ET(B) receptors activates intracellular signaling pathways and cascades that result in rapid and long-term alterations in vascular activity and function. Components of these ET-1-activated signaling pathways (e.g., mitogen-activated protein kinases, protein kinase C, RhoA/Rho kinase) are also targets for O-GlcNAcylation. Recent experimental evidence suggests that ET-1 directly activates O-GlcNAcylation, and this posttranslational modification mediates important vascular effects of the peptide. This review focuses on ET-1-activated signaling pathways that can be modified by O-GlcNAcylation. A brief description of the O-GlcNAcylation biology is presented, and its role on vascular function is addressed. ET-1-induced O-GlcNAcylation and its implications for vascular function are then discussed. Finally, the interplay between O-GlcNAcylation and O-phosphorylation is addressed.

O-GlcNAcylation: a novel post-translational mechanism to alter vascular cellular signaling in health and disease: focus on hypertension.

O-Linked attachment of beta-N-acetyl-glucosamine (O-GlcNAc) on serine and threonine residues of nuclear and cytoplasmic proteins is a highly dynamic posttranslational modification that plays a key role in signal transduction pathways. Preliminary data show that O-GlcNAcylation may represent a key regulatory mechanism in the vasculature, modulating contractile and relaxant responses. Proteins with an important role in vascular function, such as endothelial nitric oxide synthase, sarcoplasmic reticulum Ca(2+)-ATPase, protein kinase C, mitogen-activated protein kinases, and proteins involved in cytoskeleton regulation and microtubule assembly are targets for O-GlcNAcylation, indicating that this posttranslational modification may play an important role in vascular reactivity. Here, we will focus on a few specific pathways that contribute to vascular function and cardiovascular disease-associated vascular dysfunction, and the implications of their modification by O-GlcNAc. New chemical tools have been developed to detect and study O-GlcNAcylation, including inhibitors of O-GlcNAc enzymes, chemoenzymatic tagging methods, and quantitative proteomics strategies; these will also be briefly addressed. An exciting challenge in the future will be to better understand the cellular dynamics of this posttranslational modification, as well as the signaling pathways and mechanisms by which O-GlcNAc is regulated on specific proteins in the vasculature in health and disease.

Phospholipase d signaling and extracellular signal-regulated kinase-1 and -2 phosphorylation (activation) are required for maximal phorbol ester-induced transglutaminase activity, a marker of keratinocyte differentiation.

Protein kinase C (PKC)-activating 12-O-tetradecanoylphorbol 13-acetate (TPA) stimulates phospholipase D (PLD) activity in primary mouse epidermal keratinocytes. PLD catalyzes the hydrolysis of phosphatidylcholine to yield phosphatidic acid (PA), which can be dephosphorylated to produce PKC-activating diacylglycerol. In the presence of small amounts of a primary alcohol, PLD can instead produce novel phosphatidylalcohols at the expense of PA and diacylglycerol. Here, we have demonstrated that inhibiting PLD signal generation with 1-butanol reduced TPA-stimulated transglutaminase activity, a marker of keratinocyte differentiation. On the other hand, the structurally related tertiary alcohol tert-butanol, which cannot be used by PLD, had no effect on TPA-induced transglutaminase activity. Since TPA activates all conventional and novel PKC isoforms directly, yet cannot overcome 1-butanol-mediated inhibition, this result suggests that PLD mediates its effects on transglutaminase activity (and keratinocyte differentiation) through an effector enzyme system distinct from the conventional or novel PKC isoenzymes. Data in the literature suggest that PA can recruit Raf-1 to the membrane, where it can be activated and initiate the mitogen-activated protein kinase cascade that culminates in activation of extracellular signal-regulated kinase (ERK)-1 and -2. Indeed, we found that inhibition of ERK-1/2 phosphorylation (activation) inhibited TPA-induced transglutaminase activity. However, inhibition of PLD-mediated signal generation had only a small effect on TPA-elicited ERK-1/2 phosphorylation (activation), whereas inhibition of ERK-1/2 did not affect PLD activation, suggesting that these two pathways likely operate largely in parallel. Thus, our results suggest the independent involvement of the PLD and ERK-1/2 pathways in mediating transglutaminase activity and keratinocyte differentiation.

Detection of mercury and other undetermined materials in skin biopsies of endemic pemphigus foliaceus.

A novel variant of endemic pemphigus foliaceus (EPF) was described among individuals in an area surrounding El Bagre, Colombia, South America. The population in this rural mining community is exposed to high environmental levels of mercury, used for gold extraction, as well as other minerals, metalloids, and trace elements (e.g., quartz, rutile, granite, magnetite, and almenite) and ultraviolet radiation. Fifty control subjects and fifty EPF patients in the endemic area were examined for the presence of mercury in skin biopsies and hair, using autometallographic and mass spectroscopic analyses, respectively. Simultaneously, serum levels of IgE were measured, and cutaneous tests for hypersensitivity reactions were performed. Using autometallography, mercuric sulfides/selenides were detected in 14 of 51 skin biopsies distributed similarly in the control and patient groups. However, significantly higher serum IgE levels and mercury concentrations in hair, urine, and nails were found in patients compared with controls. Microscopic analysis revealed mercuric sulfides/selenides concentrated within and around the sweat gland epithelium, as well as in dendritic cells. Five skin biopsies from EPF patients and five from controls that tested positive for the presence of mercuric sulfides/selenides by autometallography were randomly selected for electron microscopic analysis. This analysis revealed a mixed electron-dense and electron-light material closely associated with desmosomes in patients. However, there were intracellular vesicles containing an amalgam of electron-dense and electron-light materials only in the EPF patients. Thus, EPF-affected individuals are exposed to high levels of environmental mercuric sulfides/selenides and other elements. This is the first study reporting mercuric sulfides/selenides in skin biopsies from people living in a focus of EPF, and these compounds may play a role in the pathogenesis of autoimmunity.