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GOALS The aim of this study was to examine the impact of immunosuppressive therapy on the morbidity of intestinal surgery in patients with Crohn's disease. BACKGROUND An increasing number of immunomodulating agents are being used in the treatment of Crohn's disease. The effect of these medications on surgical morbidity is controversial. STUDY We performed a retrospective review of our prospectively maintained database of patients with Crohn's disease who underwent intestinal surgery between June 1999 and May 2010. The effect of perioperative immunomodulation on postoperative outcomes, specifically anastomotic complications, was evaluated. Predictors of postoperative morbidity among demographic and surgical variables were identified. Length of hospitalization and rate of hospital readmission were compared between groups. Comparisons were made using Student t test and Fisher exact test. RESULTS One hundred ninety-six intestinal procedures were performed. One hundred twenty-seven (64.8%) of these were performed among patients who received perioperative immunomodulation. Forty-six (23.5%) procedures were in patients who received >1 immunomodulating medication perioperatively. Complications occurred in 45 (23.0%) cases. There were 20 (10.2%) anastomotic complications, including 8 (4.1%) intra-abdominal abscesses, 8 (4.1%) anastomotic leaks, and 4 (2%) enterocutaneous fistulas. Preoperative treatment with steroids (P=0.21), 6-MP (P=0.10), and anti-tumor necrosis factor biologics (P=1.0) was not associated with increased postoperative anastomotic complications. Combination immunosuppressive therapy also did not increase morbidity (P=0.39). CONCLUSIONS In our series, single agent and combination immunosuppressive therapy given around the time of intestinal surgery did not increase the incidence of surgical complications in patients with Crohn's disease.

Background: The myrisolated alanine rich C-kinase substrate (MARCKS) is over expressed in animal models of intimal hyperplasia (IH) and in several human neoplasms. Further it has been demonstrated that MARCKS knock-down in vivo arrests vascular smooth muscle cell (VSMC) proliferation. We hypothesize that MARCKS arrests VSMC proliferation through a p27 dependent mechanism. Materials and Methods: Human coronary artery VSMC (Lonza) were grown in culture. Cell proliferation was determined by the AlamarBlue assay. Protein expression was determined by Western Blot analysis. MARCKS signaling was stimulated by treatment with the phorbol ester PMA, and MARCKS signaling was inhibited by either siRNA mediated knock-down or with one of two peptides that act as selective competitive antagonists. Results: Stimulation of VSMC in culture with PMA for 30 minutes resulted in and increased fraction of phosphor-MARCKS and complete knock-down of p27 protein. Treatment of VSMC in culture with siRNA resulted in arrest of cell proliferation, an increase in p27 expression with no change in p21 expression. Similarly, the peptide designed to specifically inhibit the functions of the N-terminal domain also resulted in similar effects in proliferation, p27, and p21 expression. The same results were noted when a separate peptide designed to inhibit the functions of the C-terminus domain was used to treat VSMC in culture. Conclusion: MARCKS signaling results in decreased p27 expression, which possibly explains proliferative VSMC phenotype observed in animal models of IH. Blockade of MARCKS signaling by siRNA mediated knock-down results in decreased cell proliferation and increased p27 protein expression. Antagonists to either the N- and C-terminus domains yield similar results in proliferation and p27 expression. VSMC proliferation requires both functional domains of MARCKS.

The monoterpene derivative, 2-methylisoborneol (MIB), is produced by many blue-green algae and often is responsible for the “musty” taste/odor in aquaculturally raised finfish and potable water supplies. Although previous researchers have suggested that taste/odor metabolites are partitioned among cell constituents and that coregulation with pigment biosynthesis occurs, no structural evidence for these hypotheses exists. MIB was localized in cells of Oscillatoria limosa (Roth) Agardh at the ultrastructural level using standard gold-labeled antibody techniques. There was no apparent relationship between age of the cells and MIB synthesis; cells that were and were not undergoing active division had similar amounts of MIB label. There was no consistent partitioning of MIB label within cells. However, occasionally, specific label was observed along photosynthetic lamellae, suggesting a potential linkage of MIB synthesis and/or binding to the pigment systems.

Thoracic aortic wall disruptions may occur secondary to trauma, surgical interventions, infection, or autoimmune or idiopathic inflammatory disorders. Such vessel wall disruption can lead to aortic dissections, aneurysm development, or more commonly, pseudoaneurysm (PSA) formation. Although aortic wall infections as an antecedent to mycotic aneurysms have been recognized since the 17th century, there has been a temporal evolution in the development of this disease. Prior to the antibiotic era they were commonly associated with endocarditis or syphilis. More recently, however, they are associated with infection of a damaged atherosclerotic area of the aorta and secondary hematogenous or contiguous seeding. We report the first case of the rapid development of a pseudoaneurysm in the descending thoracic aorta attributable to an infection of a contiguous esophageal duplication cyst by a diagnostic esophageal ultrasound (EUS) fine-needle aspiration. A literature review of mycotic thoracic aortic aneurysms and pseudoaneurysms is also presented.

Breast cancer is the most common cancer in women and the second leading cause of cancer-related death. In 2005, approximately 211,000 American women were diagnosed with invasive breast cancer and 40,000 died from the disease. 11,000 of these diagnoses were made in women under the age of 40 (American Cancer Society). BRCA1 and BRCA2 are tumor suppressor genes that are involved in multiple cellular processes including DNA repair and transcriptional regulation in response to DNA damage, chromosomal stability and cellcycle regulation (Kiyotsugu and Yoshio, 2004). Unlike classical tumor suppressor genes; however, mutations in BRCA1 and BRCA2 are almost never seen in sporadic breast cancers.

The standard of care in the management of the axilla for a woman with breast cancer was traditionally a level I and II axillary lymph node dissection (ALND). Since the pivotal studies in the mid-1990s, sentinel lymph node biopsy (SLNB) in breast carcinoma has come to replace ALND in women with clinically negative axillas. With the increased use of SLNB in women who present with breast carcinoma, the role of completion ALND for a positive sentinel lymph node has been challenged. We review the literature available and discuss future directions in identifying a subgroup who may avoid an ALND.

Although leukocytes of the innate immune system, including eosinophils, contain within their granules preformed stores of cytokines available for selective and rapid release, little is known about the mechanisms governing the mobilization and secretion of these cytokines. Here we show that a cytokine receptor, the IL-4 receptor α chain, mediates eotaxin-stimulated mobilization of preformed IL-4 from eosinophil granules into secretory vesicles. Eosinophils contain substantial intracellular quantities of several granule- and vesicle-associated cytokine receptors, including IL-4, IL-6, and IL-13 receptors as well as CCR3. Both IL-4 and IL-4 receptor α chain colocalized in eosinophil granules; and after eotaxin-stimulation, IL-4 receptor α chain, bearing bound IL-4, was mobilized into secretory vesicles. These findings indicate that intracellular cytokine receptors within secretory vesicles transport their cognate cytokines requisite for the secretion of cytokines preformed in innate immune leukocytes.

Background Survivin (SVV) is a unique inhibitor of apoptosis protein (IAP) that regulates both apoptosis and mitosis. Recent work suggests that SVV plays a critical role in the vascular injury response, but the molecular pathways remain unclear. Methods We examined the expression of SVV and the transcription factor, KLF5, in human venous smooth muscle cells (VSMC) by semi-quantitative reverse transcriptase polymerase chain reaction (RT-PCR) and Western blot analysis after treatment with angiotensin II (Ang II) or tumor necrosis factor-α (TNF-α). An adenoviral construct expressing SVV or GFP was also employed to assess effects on KLF5 expression. A rabbit carotid interposition vein graft model was used to assess the relevance of KLF5 to bypass graft healing. Results Stimulation of VSMC with Ang II and TNF-α led to a rapid upregulation of KLF5 expression, and a later increase in SVV, which was cell-cycle independent. Overexpression of SVV in VSMC led to an early and persistent induction of KLF5. KLF5 was upregulated in rabbit vein grafts early (1 day) after grafting. Conclusions We speculate that SVV is a central point of convergence of multiple signaling pathways in vascular injury, and that it regulates the local amplification of these pathways in the vessel wall.

Electric Energy Inc.’s Joppa generating station has six 181 MW coal-fired units located on the bank of the Ohio river in Massac county, Illinois. The original GE turbine-generators were installed in the early 1950’s without any fire protection for the bearings. In 1998, Securiplex watermist systems were installed on units 5 & 6 to protect the bearing areas of those turbine-generators from fires. The fire detection was done using VESDA air sampling technology. In subsequent years, Securiplex watermist – VESDA systems were installed on the remaining four units to protect the bearing areas of those turbine-generators. This paper explains the factors that went into the decision to install this type of fire suppression technology as opposed to conventional sprinkler or deluge systems. Operating and maintenance experience with the Securiplex watermist systems and the VESDA fire detection systems will be discussed with reference made to real life events.Copyright © 2006 by ASME

Sorting nexin (SNX) 1 and SNX2 are mammalian orthologs of Vps5p, a yeast protein that is a subunit of a large multimeric complex, termed the retromer complex, involved in retrograde transport of proteins from endosomes to the trans-Golgi network. We report the cloning and characterization of human orthologs of three additional components of the complex: Vps26p, Vps29p, and Vps35p. The close structural similarity between the yeast and human proteins suggests a similarity in function. We used both yeast two-hybrid assays and expression in mammalian cells to define the binding interactions among these proteins. The data suggest a model in which hVps35 serves as the core of a multimeric complex by binding directly to hVps26, hVps29, and SNX1. Deletional analyses of hVps35 demonstrate that amino acid residues 1–53 and 307–796 of hVps35 bind to the coiled coil-containing domain of SNX1. In contrast, hVps26 binds to amino acid residues 1–172 of hVps35, whereas hVps29 binds to amino acid residues 307–796 of hVps35. Furthermore, hVps35, hVps29, and hVps26 have been found in membrane-associated and cytosolic compartments. Gel filtration chromatography of COS7 cell cytosol showed that both recombinant and endogenous hVps35, hVps29, and hVps26 coelute as a large complex (∼220–440 kDa). In the absence of hVps35, neither hVps26 nor hVps29 is found in the large complex. These data provide the first insights into the binding interactions among subunits of a putative mammalian retromer complex.

The intraerythrocytic location of the malaria parasite necessitates modification of the host cell. These alterations are mediated either directly or indirectly by parasite proteins exported to specific compartments within the host cell. However, little is known about how the parasite specifically targets proteins to locations beyond its plasma membrane. Mark Wiser, Norbert Lanners and Richard Bafford here propose an alternative secretory pathway for the export of parasite proteins into the host erythrocyte. The first step of this pathway is probably an endoplasmic reticulum (ER)-like organelle that is distinct from the normal ER. Possible mechanisms of protein trafficking in the infected erythrocyte are also discussed. The proposed ER-like organelle and alternative secretory pathway raise many questions about the cell biology of protein export and trafficking in Plasmodium.

The malarial parasite dramatically alters its host cell by exporting and targeting proteins to specific locations within the erythrocyte. Little is known about the mechanisms by which the parasite is able to carry out this extraparasite transport. The fungal metabolite brefeldin A (BFA) has been used to study the secretory pathway in eukaryotes. BFA treatment of infected erythrocytes inhibits protein export and results in the accumulation of exported Plasmodium proteins into a compartment that is at the parasite periphery. Parasite proteins that are normally localized to the erythrocyte membrane, to nonmembrane bound inclusions in the erythrocyte cytoplasm, or to the parasitophorous vacuolar membrane accumulate in this BFA-induced compartment. A single BFA-induced compartment is detected per parasite and the various exported proteins colocalize to this compartment regardless of their final destinations. Parasite membrane proteins do not accumulate in this novel compartment, but accumulate in the endoplasmic reticulum (ER), suggesting that the parasite has two secretory pathways. This alternate secretory pathway is established immediately after merozoite invasion and at least some dense granule proteins also use the alternate pathway. The BFA-induced compartment exhibits properties that are similar to the ER, but it is clearly distinct from the ER. We propose to call this new organelle the secondary ER of apicomplexa. This ER-like organelle is an early, if not the first, step in the export of Plasmodium proteins into the host erythrocyte.

BackgroundMajor amputation is often selected over infrainguinal bypass in patients with severe systemic comorbidities because it is assumed to have lower perioperative risks, yet this assumption is unproven and largely unexamined.MethodsThe 2005 to 2008 National Surgical Quality Improvement Project (NSQIP) database was used to identify all patients undergoing either infrainguinal bypass or major amputation using procedural codes. Patients with systemic or local infections were excluded. A subset of high-risk patients were then defined as American Society of Anesthesiologists (ASA) class 4 or 5, or ASA class 3 with renal failure, dyspnea at rest, ventilator dependence, recent congestive heart failure, or recent myocardial infarct. Propensity score matching was used to obtain two high-risk patient groups matched for preoperative characteristics.ResultsNo significant differences in demographic, preoperative, or anesthetic variables were found between the matched, high-risk amputation or bypass groups (792 and 780 patients, respectively). Bypass was associated with a lower 30-day postoperative mortality than amputation (6.54% vs 9.97%; P = .0147). Amputation was associated with higher rates of pulmonary embolism (0.9% vs 0% for amputation vs bypass groups, respectively; P = .009) and urinary tract infection (5.2% vs 2.7%; P = .01), while bypass was associated with higher rates of return to the operating room (14.1% vs 27.6%; P < .001) and a trend toward higher postoperative transfusion requirements (0.9% vs 2.1%; P = .054). The postoperative time to discharge did not differ between the two groups.ConclusionThe decision to perform an infrainguinal bypass or amputation should depend on well-established predictors of graft patency and functional success rather than presumptions about different perioperative risks between the two procedures.