Postmortem Analyses Unveil the Poor Efficacy of Decontamination, Anti-Inflammatory and Immunosuppressive Therapies in Paraquat Human Intoxications

studies resulting from human PQ poisonings have assessed the relationship of these therapeutic measures with PQ toxicokinetics and related histopathological lesions, these being the aims of the present study.For that purpose, during 2008, we collected human fluids and tissues from five forensic autopsies following fatal PQ poisonings. PQ levels were measured by gas chromatography-ion trap mass spectrometry. Structural inflammatory lesions were evaluated by histological and immunohistochemistry analysis. The samples of cardiac blood, urine, gastric and duodenal wall, liver, lung, kidney, heart and diaphragm, showed quantifiable levels of PQ even at 6 days post-intoxication. Structural analysis showed diffused necrotic areas, intense macrophage activation and leukocyte infiltration in all analyzed tissues. By immunohistochemistry it was possible to observe a strong nuclear factor kappa-B (NF-κB) activation and excessive collagen deposition.Considering the observed PQ levels in all analyzed tissues and the expressive inflammatory reaction that ultimately leads to fibrosis, we conclude that the therapeutic protocol usually performed needs to be reviewed, in order to increase the efficacy of PQ elimination from the body as well as to diminish the inflammatory process

Complete response for advanced liver cancer during sorafenib therapy: Case Report

<p>Abstract</p> <p>Background</p> <p>Hepatocellular carcinoma (HCC) is the fifth most common neoplasia in the world. In the past, treatment of advanced HCC with conventional antineoplastic drugs did not result in satisfactory outcomes: recently, in this patient population the oral multikinase inhibitor sorafenib has been able to induce a statistically significant improvement of overall survival. Similarly to other anti-angiogenic drugs employed in other tumour types, also sorafenib seldom induces the dimensional tumour shrinking usually observed with conventional cytotoxic drugs: data gathered from studies carried out with sorafenib and other competitors under development do not report any complete response in HCV-induced HCC.</p> <p>Case presentation</p> <p>An 84-year old man with a long-lasting history of chronic HCV hepatitis was referred to our Institution for an ultrasonography investigation of a focal hepatic lesion. To better characterize the liver disease and clearly define the diagnosis of the focal hepatic lesion, the patient was hospitalized in our department. Laboratory and instrumental investigations confirmed the clinical picture of HCV-related liver cirrhosis and identified a hepatic lesion of about 6 cm featuring infiltrating HCC with thrombosis of the portal trunk. Due to the advanced stage of the disease, therapy with sorafenib 400 mg bid was started. Right from one month after the treatment was started, a reduction of alpha-fetoprotein level was observed which, by the third month, turned down within the normal limits. In addition the CT scan showed 50% reduction of the neoplastic lesion along with canalization of the portal trunk. At the sixth month the normalization of the alpha-fetoprotein level at the lower limit of normality was confirmed and the MRI showed complete disappearance of the neoplasia. In addition a reduction of a metallo-proteinase serum level was obserdved. At the twelfth month a further MRI confirmed complete response had been maintained. At present the patient is in a follow-up program to evaluate the duration of the complete response.</p> <p>Conclusions</p> <p>This case is worth mentioning since, to the best of our knowledge, it represents the first evidence of complete response to sorafenib in an elderly patient with advanced HCV-related HCC.</p

Vascular clamping in liver surgery: physiology, indications and techniques

This article reviews the historical evolution of hepatic vascular clamping and their indications. The anatomic basis for partial and complete vascular clamping will be discussed, as will the rationales of continuous and intermittent vascular clamping

Ebf factors and MyoD cooperate to regulate muscle relaxation via Atp2a1

Jin, Saihong et al.Myogenic regulatory factors such as MyoD and Myf5 lie at the core of vertebrate muscle differentiation. However, E-boxes, the cognate binding sites for these transcription factors, are not restricted to the promoters/enhancers of muscle cell-specific genes. Thus, the specificity in myogenic transcription is poorly defined. Here we describe the transcription factor Ebf3 as a new determinant of muscle cell-specific transcription. In the absence of Ebf3 the lung does not unfold at birth, resulting in respiratory failure and perinatal death. This is due to a hypercontractile diaphragm with impaired Ca2+ efflux-related muscle functions. Expression of the Ca2+ pump Serca1 (Atp2a1) is downregulated in the absence of Ebf3, and its transgenic expression rescues this phenotype. Ebf3 binds directly to the promoter of Atp2a1 and synergises with MyoD in the induction of Atp2a1. In skeletal muscle, the homologous family member Ebf1 is strongly expressed and together with MyoD induces Atp2a1. Thus, Ebf3 is a new regulator of terminal muscle differentiation in the diaphragm, and Ebf factors cooperate with MyoD in the induction of muscle-specific genes. © 2014 Macmillan Publishers Limited.This work was supported by grants from the German Research Foundation (DFG, TRR54; FOR1586; FOR2033) and by a stipend of the Max Planck SocietyPeer Reviewe

Endoscopic and Percutaneous Preoperative Biliary Drainage in Patients with Suspected Hilar Cholangiocarcinoma

INTRODUCTION: Controversy exists over the preferred technique of preoperative biliary drainage (PBD) in patients with hilar cholangiocarcinoma (HCCA) requiring major liver resection. The current study compared outcomes of endoscopic biliary drainage (EBD) and percutaneous transhepatic biliary drainage (PTBD) in patients with resectable HCCA. METHODS: One hundred fifteen consecutive patients were explored for HCCA between 2001 and July 2008 and assigned by initial PBD procedure to either EBD or PTBD. RESULTS: Of these patients, 101 (88%) underwent PBD; 90 patients underwent EBD as primary procedure, and 11 PTBD. The technical success rate of initial drainage was 81% in the EBD versus 100% in the PTBD group (P = 0.20). Stent dislocation was similar in the EBD and PTBD groups (23% vs. 20%, P = 0.70). Infectious complications were significantly more common in the endoscopic group (48% vs. 9%, P < 0.05). Patients in the EBD group underwent more drainage procedures (2.8 vs. 1.4, P < 0.01) and had a significantly longer drainage period until laparotomy (mean 15 weeks vs. 11 weeks in the PTBD group; P < 0.05). In 30 patients, EBD was converted to PTBD due to failure of the endoscopic approach. CONCLUSIONS: Preoperative percutaneous drainage could outperform endoscopic stent placement in patients with resectable HCCA, showing fewer infectious complications, using less procedure

Abnormal pancreatic enzymes and their prognostic role after acute paraquat poisoning

Ingestion of paraquat causes multi-organ failure. Prognosis is best estimated through measurement of blood paraquat concentrations but this facility is not available in most hospitals. We studied the prognostic significance of abnormal pancreatic enzymes for survival. Patients with acute paraquat poisoning were recruited. An extensive series of blood tests including serum amylase were serially checked. Patients were sorted according to their serum amylase activity (normal [<220 U/L], mildly elevated [220 to 660 U/L], elevated [>660 U/L]), and survival compared between groups. 177 patients were enrolled to the study, of whom 67 died and 110 survived. 122 (70.62%), 27 (15.25%) and 25 (14.13%) patients were in the normal, mildly elevated and elevated amylase activity groups, respectively. The case fatality in the elevated group was 100% compared to 17% in the normal group (P < 0.001). We found four independent factors for paraquat death prediction: amylase, PaCO(2), leukocyte number, and neutrophil percentage. Models using pancreatic enzyme activity showed good prediction power. We have found that abnormal pancreatic enzymes are useful prognostic marker of death after acute paraquat poisoning. Including serum amylase activity into a prognostic model provides a good prognostication