The antimicrobial activity of a carbon monoxide releasing molecule (EBOR-CORM-1) is shaped by intraspecific variation within3 Pseudomonas aeruginosa populations

Carbon monoxide releasing molecules (CORMs) have been suggested as a new synthetic class of antimicrobials to treat bacterial infections. Here we utilized a novel EBOR-CORM-1 ([NEt4][MnBr2(CO)4]) capable of water-triggered CO-release, and tested its efficacy against a collection of clinical Pseudomonas aeruginosa strains that differ in infection-related virulence traits. We found that while EBOR-CORM-1 was effective in clearing planktonic and biofilm cells of P. aeruginosa strain PAO1 in a concentration dependent manner, this effect was less clear and varied considerably between different P. aeruginosa cystic fibrosis (CF) lung isolates. While a reduction in cell growth was observed after 8 h of CORM application, either no effect or even a slight increase in cell densities and the amount of biofilm was observed after 24 h. This variation could be partly explained by differences in bacterial virulence traits: while CF isolates showed attenuated in vivo virulence and growth compared to strain PAO1, they formed much more biofilm, which could have potentially protected them from the CORM. Even though no clear therapeutic benefits against a subset of isolates was observed in an in vivo wax moth acute infection model, EBOR-CORM-1 was more efficient at reducing the growth of CF isolate co-culture populations harboring intraspecific variation, in comparison with efficacy against more uniform single isolate culture populations. Together these results suggest that CORMs could be effective at controlling genetically diverse P. aeruginosa populations typical for natural chronic CF infections and that the potential benefits of some antibiotics might not be observed if tested only against clonal bacterial populations

Handling and pathology reporting of circumcision and penectomy specimens

SCOPUS: re.jinfo:eu-repo/semantics/publishe

Handling and Reporting of Biopsy and Surgical Specimens of Testicular Cancer

This paper is the result of a meeting of the European Association of Pathologists, Uropathology Division in Florence 2003. The aims of this meeting were to establish: guidelines for specimen handling by urologists and minimum requirements for data accompanying testicular specimens submitted to pathologists; a consensus on techniques for processing specimens by pathologists; the essential information required from pathology reports; areas where our standard practice is traditional rather than evidence based and where further studies are required. The general aims of histopathology are to give or confirm a diagnosis; assess established prognostic markers; identify changes associated with treatment; provide information for audit (i.e. imaging, urology and pathology) and maintain a permanent record (slides/blocks). © 2003 Elsevier B.V. All rights reserved.SCOPUS: re.jinfo:eu-repo/semantics/publishe

Differential Diagnosis: Hepatic Complications in Inborn Errors of Immunity

Inborn errors of immunity (IEIs) are a heterogeneous group of diverse clinical and genetic phenotypes that have an estimated combined prevalence as high as 1/1000. Increased risk of frequent, severe, or opportunistic infections is a common feature of IEIs, but there are also diverse immune-mediated, non-infective complications that are associated with significant morbidity and mortality. As patient survival increases, these are becoming more apparent within the liver. Hepatic involvement of IEIs may not only manifest as infections, but also nodular regenerative hyperplasia, granulomatous disease, autoimmune hepatitis and malignancy. As therapeutic options for patients are expanding, with both pharmaceutical treatments as well as haematopoietic stem cell transplant (HSCT), iatrogenic liver injury is increasingly common and important to identify. This review article summarises the spectrum of hepatic complications seen in IEIs, and highlights the challenges of management within this patient cohort, where immunosuppression is poorly tolerated. Early recognition and prompt diagnosis of potential hepatic complications is therefore crucial in ensuring potentially reversible causes are treated, but significant uncertainty remains regarding best practice for many features of immune dysregulation with limited high-quality evidence

Immunosuppression in acutely decompensated cirrhosis is mediated by prostaglandin E2

Patients with advanced cirrhosis experience frequent infections leading to sepsis, which carries high mortality. While innate immune dysfunction underlies this vulnerability, the precise cause remains elusive. We found prostaglandin (PGE(2)) elevated in acutely decompensated (AD) patients at immunosuppressive levels. Plasma from AD and end-stage liver disease (ESLD) patients suppressed macrophage cytokine secretion and bacteria killing in a PGE(2) receptor-dependent manner, effects not seen in stable cirrhosis. Mouse models (bile duct ligation and CCL4-liver injury) also demonstrated elevated PGE(2), which when inhibited completely restored immune competence and survival following infection. Importantly, albumin binds/inactivates PGE(2) resulting in greater PGE(2) bioavailability. This results in enhanced immunosuppressive effects of AD plasma in patients with low albumin levels. Administering albumin to AD patients reversed immunosuppressive properties of their plasma; protective effects recapitulated in rodent survival studies. Thus, elevated PGE(2) combined with hypoalbuminemia mediates immunosuppression in AD and ESLD patients, which can be reversed with albumin

Impact of chemotherapy-associated liver injury on tumour regression grade and survival in patients with colorectal liver metastases

An inverse relation between chemotherapy-associated liver injury (CALI) and tumour response to chemotherapy has been reported. The aim was to validate these findings, and further investigate the impact of CALI on survival in patients who underwent partial hepatectomy for colorectal liver metastases (CRLM). Patients who received neoadjuvant chemotherapy and underwent partial hepatectomy for CRLM between 2008 and 2014 were included. Liver and tumour specimens were histologically examined for CALI (steatosis, steatohepatitis, sinusoidal dilatation [SD], nodular regeneration) and tumour regression grade (TRG). TRG 1-2 was defined as complete tumour response. 166 consecutive patients were included with a median survival of 30 and 44 months for recurrence-free and overall survival, respectively. Grade 2-3 SD was found in 44 (27%) and TRG 1-2 was observed in 33 (20%) patients. Of studied CALI, only grade 2-3 SD was associated with increased TRG 3-5 (odds ratio 3.99, 95% CI 1.17-13.65, p = 0.027). CALI was not significantly related to survival. TRG 1-2 was associated with prolonged recurrence-free (hazard ratio 0.47, 95% CI 0.25-0.89, p = 0.020) and overall survival (hazard ratio 0.35, 95% CI 0.18-0.68, p = 0.002). CALI was not directly related to survival. CALI was, however, associated with diminished complete tumour response, and diminished complete tumour response, in turn, was associated with decreased surviva