Post-Operative Superior Mesenteric Artery Syndrome Following Retroperitoneal Sarcoma Resection

Superior mesenteric artery (SMA) syndrome is an uncommon phenomenon caused by the compression of the third portion of the duodenum between the aorta and the SMA. Here, we present a previously healthy 15-year-old male who presented with early satiety and 20 kg weight loss. Computed tomography (CT) demonstrated a massive retroperitoneal liposarcoma displacing the entire small intestine into the right upper quadrant. Following resection of the large mass, the patient was intolerant of oral intake despite evidence of bowel function. Abdominal CT revealed a narrowing of the duodenum at the location of the SMA. A nasojejunal feeding tube was placed past this area, and enteral nutrition was initiated before slowly resuming oral intake. Post-operative SMA syndrome is an uncommon complication but should be considered in patients intolerant of oral intake following resection of large abdominal tumors associated with extensive retroperitoneal fat loss, even in the absence of concomitant major visceral resection

NMR Structure of the Myristylated Feline Immunodeficiency Virus Matrix Protein

Membrane targeting by the Gag proteins of the human immunodeficiency viruses (HIV types-1 and -2) is mediated by Gag’s N-terminally myristylated matrix (MA) domain and is dependent on cellular phosphatidylinositol-4,5-bisphosphate [PI(4,5)P2]. To determine if other lentiviruses employ a similar membrane targeting mechanism, we initiated studies of the feline immunodeficiency virus (FIV), a widespread feline pathogen with potential utility for development of human therapeutics. Bacterial co-translational myristylation was facilitated by mutation of two amino acids near the amino-terminus of the protein (Q5A/G6S; myrMAQ5A/G6S). These substitutions did not affect virus assembly or release from transfected cells. NMR studies revealed that the myristyl group is buried within a hydrophobic pocket in a manner that is structurally similar to that observed for the myristylated HIV-1 protein. Comparisons with a recent crystal structure of the unmyristylated FIV protein [myr(-)MA] indicate that only small changes in helix orientation are required to accommodate the sequestered myr group. Depletion of PI(4,5)P2 from the plasma membrane of FIV-infected CRFK cells inhibited production of FIV particles, indicating that, like HIV, FIV hijacks the PI(4,5)P2 cellular signaling system to direct intracellular Gag trafficking during virus assembly

Sequestration of Vascular Endothelial Growth Factor (VEGF) Induces Late Restrictive Lung Disease.

RATIONALE:Neonatal respiratory distress syndrome is a restrictive lung disease characterized by surfactant deficiency. Decreased vascular endothelial growth factor (VEGF), which demonstrates important roles in angiogenesis and vasculogenesis, has been implicated in the pathogenesis of restrictive lung diseases. Current animal models investigating VEGF in the etiology and outcomes of RDS require premature delivery, hypoxia, anatomically or temporally limited inhibition, or other supplemental interventions. Consequently, little is known about the isolated effects of chronic VEGF inhibition, started at birth, on subsequent developing lung structure and function. OBJECTIVES:To determine whether inducible, mesenchyme-specific VEGF inhibition in the neonatal mouse lung results in long-term modulation of AECII and whole lung function. METHODS:Triple transgenic mice expressing the soluble VEGF receptor sFlt-1 specifically in the mesenchyme (Dermo-1/rtTA/sFlt-1) were generated and compared to littermate controls at 3 months to determine the impact of neonatal downregulation of mesenchymal VEGF expression on lung structure, cell composition and function. Reduced tissue VEGF bioavailability has previously been demonstrated with this model. MEASUREMENTS AND MAIN RESULTS:Triple transgenic mice demonstrated restrictive lung pathology. No differences in gross vascular development or protein levels of vascular endothelial markers was noted, but there was a significant decrease in perivascular smooth muscle and type I collagen. Mutants had decreased expression levels of surfactant protein C and hypoxia inducible factor 1-alpha without a difference in number of type II pneumocytes. CONCLUSIONS:These data show that mesenchyme-specific inhibition of VEGF in neonatal mice results in late restrictive disease, making this transgenic mouse a novel model for future investigations on the consequences of neonatal RDS and potential interventions

Summary of effects of VEGF sequestration leading to restrictive lung disease phenotype.

<p>Summary of effects of VEGF sequestration leading to restrictive lung disease phenotype.</p

Reduced VEGF disrupts the parenchyma around airways and vasculature.

<p>(A, B) Representative images of immunofluorescent staining for α smooth muscle actin (αSMA) reveals fewer putative myofibroblasts surrounding the airways in mutant mice (B) compared to controls (A). (C) Quantification by Western blot confirms a statistically significant decrease in the relative abundance of αSMA in mutants. (D, E) Representative images of Sirius red stain for Type 1 collagen demonstrates decreased peri-vascular staining in mutants (E) compared to controls (D). (F) Mutant mice express significantly less collagen around pulmonary veins based on optical density quantification. <i>White and black arrows</i> point to magnified areas shown in insets. Scale bars represent 50 μm. Data are expressed as mean ± SD, *P< 0.05, **P< 0.01 versus control.</p

VEGF sequestration decreases PI3K-Akt and MAPK-ERK pathway signaling.

<p>Western blot data for (A) PI3K, (B) phosphorylated and total Akt, and (C) phosphorylated and total ERK1/2 demonstrate decreased activation of these signaling pathways in mutants. (D) Western blot data also show decreased relative production of HIF-1α in mutant mice. (E) Mutant mice also express decreased relative levels of activated EGFR, which could further decrease surfactant production through its synergistic effect on VEGF expression. Data are expressed as mean ± SD, *P<0.05 vs control.</p

Mesenchymal VEGF sequestration does not affect pulmonary angiogenesis but affects acinar air space morphogenesis.

<p>Western blot analyses of (A) total VEGFR-2 and phosphorylated VEGFR-2, and (B) endothelial markers PECAM-1 and VE-cad. No significant difference in expression between control and mutant mice was noted on either analysis. (C-D) Representative H&E images of peripheral lung sections from control and mutant mice demonstrate larger acinar air spaces in mutants. This was confirmed by mean linear intercept analysis. Images at 20x magnification, scale bars represent 100 μm.</p

Pulmonary function tests of mutant mice with reduced bioavailable VEGF indicate a restrictive lung disease.

<p>Plethysmography was performed at 12 weeks on anesthetized mutant mice and littermate controls. (A) Pressure volume curves of mutant mice were shifted downward compared to control mice. Data are expressed as mean ± SEM. (B, C) Mutant mice also demonstrated a 30% decrease in hysteresis and compliance. (D, E) They also showed a 1.5-fold increase in static elastance and a 2-fold increase in resistance, all indicative of a restrictive lung disease. All differences were statistically significant. Green bars represent mean values, **P<0.01, ***P<0.001, ****P<0.0001 compared to controls.</p