Neurokinin-1 Receptor Deficiency Improves Survival in Murine Polymicrobial Sepsis Through Multiple Mechanisms in Aged Mice.

OBJECTIVE: Substance P (SP) is a neuropeptide that contributes to a proinflammatory state by binding to the neurokinin 1 receptor (NK-1R). Limiting this interaction has been shown to attenuate the acute inflammation. Our hypothesis was that NK-1R activation would contribute to the morbidity and mortality of sepsis in a model using mice genetically deficient in the NK-1R. METHODS: To investigate the role of the SP/NK-1R axis in a murine model of sepsis, cecal ligation and puncture (CLP) in NK-1R deficient and wild type (WT) aged mice was performed. Acute inflammation was assessed by measuring circulating cytokines and clinical parameters. RESULTS: Deletion of the NK-1R results in improved survival following CLP (NK-1R knockout mice survival = 100% vs. WT = 14%). A reduction in the inflammatory cytokines interleukin (IL) 6, macrophage inflammatory peptide 2, and IL-1 receptor antagonist, improved hemodynamic parameters, and increased neutrophilia were present in the NK-1R-deficient mice after CLP compared with WT mice. CONCLUSIONS: These data confirm the hypothesis that eliminating the SP/NK-1R interaction in a highly lethal murine model of sepsis leads to decreased morbidity and mortality through multiple mechanisms.

Cutaneous Breast Radiation-associated Angiosarcoma: Anterior Chest Wall Reconstruction Options Following Extra-radical Resection.

BACKGROUND: Radiation-associated angiosarcoma (RAAS) of the breast is a rare complication following breast irradiation with high rates of recurrence and death. To improve survival, we have advocated for an extra-radical resection where the entire irradiated skin and subcutaneous tissue is excised. This results in very large chest defects for which we describe our reconstructive experience. METHODS: We performed a retrospective review of patients diagnosed with RAAS and treated with extra-radical resection followed by immediate reconstruction between 1999 and 2017. We analyzed reconstructive options, complications rates, length of stay, and operative times. RESULTS: Extra-radical resections were performed in 35 patients. We reconstructed these large defects with abdominal advancement flaps with split-thickness skin grafting in 25 patients and added a pedicled latissimus dorsi or omental flap in the 10 other patients. Skin grafts took well over the irradiated pectoralis major muscle with a median take rate of over 90%. Average operative times were 150 minutes for those treated with an abdominal advancement flap and skin grafting with a median length of stay of 5 days for all patients. CONCLUSION: Large anterior chest soft-tissue defects caused by extra-radical resections leaves defects too large to be covered by traditional breast reconstruction flaps. Abdominal advancement, latissimus dorsi muscle, and omental flaps along with skin grafts can be safely performed while leaving other traditional options open for future breast reconstruction.

Antagonism of the Neurokinin-1 Receptor Improves Survival in a Mouse Model of Sepsis by Decreasing Inflammation and Increasing Early Cardiovascular Function.

OBJECTIVES: Sepsis remains a serious clinical problem despite intensive research efforts and numerous attempts to improve outcome by modifying the inflammatory response. Substance P, the principal ligand for the neurokinin-1 receptor, is a potent proinflammatory mediator that exacerbates inflammatory responses and cardiovascular variables in sepsis. DESIGN: The current study examined whether inhibition of the neurokinin-1 receptor with a specific antagonist (CJ-12,255) would improve survival in the cecal ligation and puncture model of sepsis in adult female outbred mice. SETTING: University basic science research laboratory. MEASUREMENTS AND MAIN RESULTS: Neurokinin-1 receptor treatment at the initiation of sepsis improved survival in cecal ligation and puncture sepsis (neurokinin-1 receptor antagonist survival = 79% vs vehicle = 54%). Delaying therapy for as little as 8 hours postcecal ligation and puncture failed to provide a survival benefit. Neurokinin-1 receptor antagonist treatment did not prevent the sepsis-induced decrease in circulating WBCs, augment the early (6 hr postcecal ligation and puncture) recruitment of inflammatory cells to the peritoneum, or improve phagocytic cell killing of pathogens. However, the neurokinin-1 receptor antagonist significantly reduced both circulating and peritoneal cytokine concentrations. In addition, the cardiovascular variable, pulse distension (a surrogate for stroke volume) was improved in the neurokinin-1 receptor antagonist group during the first 6 hours of sepsis, and there was a significant reduction in loss of fluid into the intestine. CONCLUSION: These data show that early activation of the neurokinin-1 receptor by substance P decreases sepsis survival through multiple mechanisms including depressing stroke volume, increasing fluid loss into the intestine, and increasing inflammatory cytokine production.

Acute-Phase Deaths from Murine Polymicrobial Sepsis Are Characterized by Innate Immune Suppression Rather Than Exhaustion.

Sepsis, a leading cause of death in the United States, has poorly understood mechanisms of mortality. To address this, our model of cecal ligation and puncture (CLP) induced sepsis stratifies mice as predicted to Live (Live-P) or Die (Die-P) based on plasma IL-6. Six hours post-CLP, both Live-P and Die-P groups have equivalent peritoneal bacterial colony forming units and recruitment of phagocytes. By 24 h, however, Die-P mice have increased bacterial burden, despite increased neutrophil recruitment, suggesting Die-P phagocytes have impaired bacterial killing. Peritoneal cells were used to study multiple bactericidal processes: bacterial killing, reactive oxygen species (ROS) generation, and phagocytosis. Total phagocytosis and intraphagosomal processes were determined with triple-labeled Escherichia coli, covalently labeled with ROS- and pH-sensitive probes, and an ROS/pH-insensitive probe for normalization. Although similar proportions of Live-P and Die-P phagocytes responded to exogenous stimuli, Die-P phagocytes showed marked deficits in all parameters measured, thus suggesting immunosuppression rather than exhaustion. This contradicts the prevailing sepsis paradigm that acute-phase sepsis deaths (<5 d) result from excessive inflammation, whereas chronic-phase deaths (>5 d) are characterized by insufficient inflammation and immunosuppression. These data suggest that suppression of cellular innate immunity in sepsis occurs within the first 6 h.

Pathophysiologic mechanisms in septic shock.

The systemic inflammatory response that occurs in the septic patient as a result of an infectious insult affects multiple organs and systems, causing numerous physiological derangements. Alterations in phagocytic, lymphocytic and endothelial cell function and immune regulation are evident, leading to heterogeneity in a host's response to a septic challenge. In addition, the normal hemostatic balance shifts toward a procoagulant state through alterations in tissue factor, antithrombin, protein C and the inhibition of fibinolysis, which can result in thrombus formation and paradoxical hemostatic failure. In an effort to diagnose sepsis and predict outcomes, biomarkers such as C-reactive protein, pro-calcitonin, pro- and anti-inflammatory cytokines have been investigated with varying results. Targeted therapies for sepsis, most notably Xigris (recombinant human activated protein C), have proven unsuccessful and treatment continues to remain reliant on source control, antibiotics and supportive interventions, specifically early goal-directed therapy. This brief review gives an overview of the immunopathologic and coagulopathic alterations that occur in sepsis, soluble inflammatory mediators as potential diagnostic and prognostic biomarkers, and the clinical management of the septic patient.

Roles of STAT3 in protein secretion pathways during the acute-phase response.

The acute-phase response is characteristic of perhaps all infections, including bacterial pneumonia. In conjunction with the acute-phase response, additional biological pathways are induced in the liver and are dependent on the transcription factors STAT3 and NF-κB, but these responses are poorly understood. Here, we demonstrate that pneumococcal pneumonia and other severe infections increase expression of multiple components of the cellular secretory machinery in the mouse liver, including the endoplasmic reticulum (ER) translocon complex, which mediates protein translation into the ER, and the coat protein complexes (COPI and COPII), which mediate vesicular transport of proteins to and from the ER. Hepatocyte-specific mutation of STAT3 prevented the induction of these secretory pathways during pneumonia, with similar results observed following pharmacological activation of ER stress by using tunicamycin. These findings implicate STAT3 in the unfolded protein response and suggest that STAT3-dependent optimization of secretion may apply broadly. Pneumonia also stimulated the binding of phosphorylated STAT3 to promoter regions of secretion-related genes in the liver, supporting a direct role for STAT3 in their transcription. Altogether, these results identify a novel function of STAT3 during the acute-phase response, namely, the induction of secretory machinery in hepatocytes. This may facilitate the processing and delivery of newly synthesized loads of acute-phase proteins, enhancing innate immunity and preventing liver injury during infection.

Chest X-ray after tracheostomy is not necessary unless clinically indicated.

BACKGROUND: Chest radiography is routinely used post-tracheostomy to evaluate for complications. Often, the chest X-ray findings do not change clinical management. The present study was conducted to evaluate the utility of post-tracheostomy X-rays. METHOD: This retrospective review of 255 patients was performed at a single-center, university, level I trauma center. All patients underwent tracheostomy and were evaluated for postprocedure complications. RESULTS: Of the 255 patients, 95.7% had no change in postprocedure chest X-ray findings. New significant chest X-ray findings were found in 4.3% of patients, including subcutaneous emphysema, pneumothorax, and new significant consolidation. Only three of these patients required change in clinical management, and all changes were based on clinical presentation alone. CONCLUSIONS: Routine chest X-ray following tracheostomy fails to provide additional information beyond clinical examination. Therefore radiographic examination should be performed only after technically difficult procedures or if the patient experiences clinical deterioration. Significant cost savings and minimization of radiation exposure can be achieved when chest radiography after tracheostomy is performed exclusively for clinical indications.

Puerto Rico experience with plugs in the treatment of anal fistulas.

BACKGROUND: Anorectal fistula is a common problem that affects quality of life. Main objective of therapy has been to eradicate the fistula tract while preserving fecal continence. Latest good results for anal fistula treatment have been an anal fistula plug. This study was undertaken to determine if these results could be reproduced in Puerto Rico. METHOD: From January 2003 to January 2008, two experienced colorectal surgeons performed this new operation in 23 consecutive patients. A multivariable analysis was undertaken including age, sex, location of the fistula, previous surgeries, Seton placement before the insertion of the plug, continence pre and post operation, as well as close follow up. No patient with inflammatory bowel disease was included. RESULTS: We had a good result or healing of the fistula in 14 of 23 patients for a success rate of 60%. We had a subgroup of patients who did slightly better and had a healing rate of 66% compared to the 60% of the whole group. It appears to be a trend in favor of the Seton group but is not statically significant. We had 9 failures of 23 patients or 39%. Suppuration was noticed in three patients and all three had failures of the plug with recurrences. CONCLUSIONS: This new operation is another alternative to add to our armamentarium but we need to search for an operation that decreases the incidence of recurrences we had in our study while maintaining function of the sphincters.

Hermansky Pudlak syndrome: an unusual form of procto-colitis.

Hermansky-Pudlak syndrome (HPS) is a rare autosomal recessive disorder consisting of oculocutaneous albinism, platelet dysfunction and systemic complications associated with lipofuscin deposition in the reticuloendothelial system. HPS has been associated with a granulomatous enterocolitis with pathologic features suggestive of Crohn's disease. It remains uncertain if HPS represents a truly distinct form of granulomatous enterocolitis. We report a series of two patients with HPS treated in Puerto Rico, and the results from medical and surgical intervention for gastrointestinal disease. Our experience with HPS patients has shown the difficult management of perineal disease similar in the management of Crohn's. However, complications from the bleeding diathesis necessitate caution during surgery and potential anesthesia complications. Furthermore, avoidance of a perineal wound is preferred, and when possible, ileostomies have fewer complications than colostomies as they do not involve the small bowel.