Michael C. Soult

Circulating bacterial membrane vesicles cause sepsis in rats.

ABSTRACT Gram-negative bacteria remain the leading cause of sepsis, a disease that is consistently in the top 10 causes of death internationally. Curing bacteremia alone does not necessarily end the disease process as other factors may cause inflammatory damage. Bacterial outer membrane vesicles (OMVs) are naturally produced blebs from the outer membrane of gram-negative bacteria, which contain various proteins and lipopolysaccharide (LPS). We hypothesize that these vesicles initiate an inflammatory response independent of the parent bacteria. Outer membrane vesicles were isolated from cultures of Escherichia coli, and the concentration of LPS in the OMVs was measured. Adult male Sprague-Dawley rats were separated into five treatment groups: OMV, 2xOMV, LPS, lactated Ringer’s, and sham. Our findings show that infused OMVs elicit physiological, histological, and molecular changes in rats that are consistent with sepsis. Hyperdynamic changes in heart rates and mean arterial pressures are observed as well as the elevation of the proinflammatory cytokines tumor necrosis factor &agr; and interleukin 6. Downstream events such as the recruitment of neutrophils into tissues due to the presentation of vascular adhesion molecules also occur in OMV-treated animals. Although soluble LPS elicits stronger responses than did OMVs, responses to the latter consistently exceeded those associated with lactated Ringer’s infusion. These results indicate OMVs, independent of the parent bacteria, do initiate an inflammatory response; however, further studies are required to better characterize the temporal biomolecular interactions involved.

Merkel cell carcinoma: high recurrence rate despite aggressive treatment.

BACKGROUND Merkel cell carcinoma (MCC) is a rare aggressive neuroendocrine cancer of the skin whose incidence has been increasing. The objective of the study was to evaluate current treatment modalities, including sentinel lymph node (SLN) biopsy and outcomes and identify prognostic factors in patients with MCC. METHODS A retrospective chart review of patients with MCC. Clinical, pathologic, treatment characteristics, disease status, and survival were collected. All slides were reviewed by a single pathologist, and additional pathologic elements were evaluated for prognosis. RESULTS Twenty-six patients were identified in the study period. All patients were Caucasian with an average age of 71.3 y. Twenty-one patients had tumors in sun-exposed locations, and 13 had a prior history of skin cancer. All nonmetastatic patients underwent wide excision. SLN biopsy was successful in 19 patients. The SLN was positive in 21% of patients. Radiation therapy was used in 13 patients. Average follow-up was 26 mo, and median survival was 29 mo. Recurrence occurred in eight patients: four locoregional, two distant, one combined, and one unknown. Recurrence occurred in five patients with stage I disease. Five patients with negative SLN later developed recurrence. The presence of metastasis to the nodes was significant for recurrence. No other pathologic factor was found to have prognostic significance. CONCLUSIONS Despite aggressive surgical and radiation treatment, MCC has a high rate of locoregional recurrence, even in early stage disease. SNLB is useful for the staging and management of patients. Further research is needed to identify better prognostic markers.

Outer membrane vesicles alter inflammation and coagulation mediators.

INTRODUCTION Outer membrane vesicles (OMVs) were previously shown to be capable of initiating the inflammatory response seen in the transition of an infection to sepsis. However, another tenet of sepsis is the development of a hypercoagulable state and the role of OMVs in the development of this hypercoagulability has not been evaluated. The objective of this study was to evaluate the ability of OMVs to elicit endothelial mediators of coagulation and inflammation and induce platelet activation. METHODS Human umbilical vein endothelial cells (HUVECs) were incubated with OMVs and were analyzed for the expression of tissue factor (TF), thrombomodulin, and the adhesion molecules P-selectin and E-selectin. Supernatants of OMV-treated HUVECs were mixed with whole blood and assessed for prothrombotic monocyte-platelet aggregates (MPA). RESULTS OMVs induce significantly increased expression of TF, E-selectin, and P-selectin, whereas, the expression of thrombomodulin by HUVECs is significantly decreased (P < 0.05). The lipopolysaccharide inhibitor clearly inhibited the expression of E-selectin following incubation with OMVs, although its impact on TF and thrombomodulin expression was nominal. Incubation of whole blood with supernatant from HUVECs exposed to OVMs resulted in increased MPAs. CONCLUSIONS This study demonstrates that, at the cellular level, OMVs from pathogenic bacteria play a complex role in endothelial activation. Although OMV-bound lipopolysaccharide modulates inflammatory proteins, including E-selectin, it has a negligible effect on the tested coagulation mediators. Additionally, endothelial activation by OMVs facilitates platelet activation as indicated by increased MPAs. By influencing the inflammatory and coagulation cascades, OMVs may contribute to the hypercoagulable response seen in sepsis.

Left subclavian artery revascularization in zone 2 thoracic endovascular aortic repair is associated with lower stroke risk across all aortic diseases

Background: The best management strategy for the left subclavian artery (LSA) in pathologic processes of the aorta requiring zone 2 thoracic endovascular aortic repair (TEVAR) remains controversial. We compared LSA coverage with or without revascularization as well as the different means of LSA revascularization. Methods: A retrospective chart review was conducted of patients with any aortic diseases who underwent zone 2 TEVAR deployment from 2007 to 2014. Primary end points included 30‐day stroke and 30‐day spinal cord injury (SCI). Secondary end points were 30‐day procedure‐related reintervention, freedom from aorta‐related reintervention, aorta‐related mortality, and all‐cause mortality. Results: We identified 96 patients with zone 2 TEVAR who met our inclusion criteria. The mean age of the patients was 62 years, with 61.5% male. Diseases included acute aortic dissections (n = 25), chronic aortic dissection with aneurysmal degeneration (n = 22), primary aortic aneurysms (n = 21), penetrating aortic ulcers/intramural hematomas (n = 17), and traumatic aortic injuries (n = 11). Strategies for the LSA included coverage with revascularization (n = 54) or without revascularization (n = 42). Methods of LSA revascularization included laser fenestration with stenting (n = 33) and surgical revascularization: transposition (n = 10) or bypass (n = 11). Of the 54 patients with LSA revascularization, 44 (81.5%) underwent LSA intervention at the time of TEVAR and 10 (18.5%) at a mean time of 33 days before TEVAR (range, 4‐63 days). For the entire cohort, the overall incidence of 30‐day stroke was 7.3%; of 30‐day SCI, 2.1%; and of procedure‐related reintervention, 5.2%. At a mean follow‐up of 24 months (range, 1‐79 months), aorta‐related reintervention was 15.6%, aorta‐related mortality was 12.5%, and all‐cause mortality was 29.2%. The 30‐day stroke rate was highest for LSA coverage without revascularization (6/42 [14.3%]) compared with any form of LSA revascularization (1/54 [1.9%]; P = .020), with no difference between LSA interventions done synchronously with TEVAR (1/44 [2.3%]) vs metachronously with TEVAR (0/10 [0%]; P = .63). There was no significant difference in 30‐day SCI in LSA coverage without revascularization (2/42 [4.8%]) vs with revascularization (0/54 [0%]; P = .11). There was no difference in aorta‐related reintervention, aorta‐related mortality, or all‐cause mortality in coverage without revascularization (5/42 [11.9%], 6/42 [14.3%], and 14/42 [33.3%]) vs with revascularization (10/54 [18.5%; P = .376], 6/54 [11.1%; P = .641], and 14/54 [25.9%; P = .43], respectively). After univariate and multivariable analysis, we identified LSA coverage without revascularization as associated with a higher rate of 30‐day stroke (hazard ratio, 17.2; 95% confidence interval, 1.3‐220.4; P = .029). Conclusions: Our study suggests that coverage of the LSA without revascularization increases the risk of stroke and possibly SCI.