Myometrial-derived CXCL12 promotes lipopolysaccharide induced preterm labour by regulating macrophage migration, polarization and function in mice.

Preterm birth is a major contributor to neonatal mortality and morbidity. Infection results in elevation of inflammation-related cytokines followed by infiltration of immune cells into gestational tissue. CXCL12 levels are elevated in preterm birth indicating it may have a role in preterm labour (PTL); however, the pathophysiological correlations between CXCL12/CXCR4 signalling and premature labour are poorly understood. In this study, PTL was induced using lipopolysaccharide (LPS) in a murine model. LPS induced CXCL12 RNA and protein levels significantly and specifically in myometrium compared with controls (3-fold and 3.5-fold respectively). Highest levels were found just before the start of labour. LPS also enhanced the infiltration of neutrophils, macrophages and T cells, and induced macrophage M1 polarization. In vitro studies showed that condition medium from LPS-treated primary smooth muscle cells (SMC) induced macrophage migration, M1 polarization and upregulated inflammation-related cytokines such as interleukin (IL)-1, IL-6 and tumor necrosis factor alpha (TNF-α). AMD3100 treatment in pregnant mice led to a significant decrease in the rate of PTL (70%), prolonged pregnancy duration and suppressed macrophage infiltration into gestation tissue by 2.5-fold. Further, in-vitro treatment of SMC by AMD3100 suppressed the macrophage migration, decreased polarization and downregulated IL-1, IL-6 and TNF-α expression. LPS treatment in pregnant mice induced PTL by increasing myometrial CXCL12, which recruits immune cells that in turn produce inflammation-related cytokines. These effects stimulated by LPS were completely reversed by AMD3100 through blocking of CXCL12/CXCR4 signalling. Thus, the CXCL12/CXCR4 axis presents an excellent target for preventing infection and inflammation-related PTL.

Isolated port site recurrence of node-negative clinical stage IB1 cervical adenocarcinoma.

INTRODUCTION: Port site metastasis after laparoscopic surgery for cervical cancer is a rare phenomenon. METHODS: We present a case report of isolated port site recurrence 4 years following laparoscopic surgery in a patient with node-negative, clinical stage IB1 cervical adenocarcinoma. RESULTS: A 44 year-old woman presented with a necrotic cervical lesion. A biopsy of the mass revealed invasive endocervical adenocarcinoma. She underwent a robotic-assisted radical hysterectomy, bilateral salpingectomy, and pelvic lymph node dissection with bilateral oophoropexy. All lymph nodes were placed in an Endocatch bag prior to removal via the 12 mm assistant port. There was no clinical evidence of metastatic disease and final pathology revealed negative surgical margins and lymph nodes. Four years later, she re-presented with a soft tissue mass in her abdominal wall underlying the site of the prior laparoscopic assistant port. This was confirmed by transcutaneous biopsy to be metastatic adenocarcinoma of endocervical origin. Further work-up revealed no other evidence of metastatic disease. The recurrence was excised and all margins were negative. CONCLUSION: This is the first case report describing an isolated port site recurrence in a patient who underwent robotic-assisted laparoscopic surgery for early-stage cervical adenocarcinoma with negative margins and negative lymph nodes. The mechanism underlying this isolated recurrence remains unknown.

Staphylococcus aureus secretes coagulase and von Willebrand factor binding protein to modify the coagulation cascade and establish host infections.

Clinical isolates of Staphylococcus aureus secrete coagulases, polypeptides that bind to and activate prothrombin, thereby converting fibrinogen to fibrin and promoting the clotting of plasma or blood. Two staphylococcal products, the canonical coagulase (Coa) as well as the recently identified von Willebrand factor binding protein (vWbp), promote similar modifications of the coagulation cascade during host infection. Staphylococcal binding to fibrinogen or fibrin is an important attribute of disease pathogenesis, which leads to the formation of abscesses and bacterial persistence in host tissues and also enables the pathogen to cause lethal sepsis. Circumstantial evidence suggests that the product of coagulase activity, staphylococci captured within a fibrin meshwork, enable this pathogen to disseminate as thromboembolic lesions and to resist opsonophagocytic clearance by host immune cells. In addition, the coagulation products of staphylococci appear to display discrete differences when compared to those of thrombin-mediated coagulation, the latter representing a key innate defense mechanism against many invading pathogens. Preclinical evidence suggests that inactivation or neutralization of coagulases may prevent the pathogenesis of staphylococcal infections, a strategy that could be used to combat the current epidemic of hospital-acquired infections with drug-resistant S. aureus isolates.

Distribution of protein A on the surface of Staphylococcus aureus.

Surface proteins of Staphylococcus aureus fulfill many important roles during the pathogenesis of human infections and are anchored to the cell wall envelope by sortases. Although the chemical linkage of proteins to cell wall cross bridges is known, the mechanisms whereby polypeptides are distributed on the staphylococcal surface have not been revealed. We show here that protein A, the ligand of immunoglobulin, is unevenly distributed over the staphylococcal surface. Upon removal with trypsin, newly synthesized polypeptide is deposited at two to four discrete foci. During subsequent growth, protein A appears to be slowly distributed from these sites. When viewed through multiple focal planes by laser scanning microscopy, protein A foci are arranged in a circle surrounding the bacterial cell. This pattern of distribution requires the LPXTG sorting signal of protein A as well as sortase A, the transpeptidase that anchors polypeptides to cell wall cross bridges. A model is presented whereby protein A deposition at discrete sites coupled with cell wall synthesis enables distribution of protein A on the staphylococcal surface.