Optimization of stress response through the nuclear receptor-mediated cortisol signalling network

It is an accepted paradigm that extended stress predisposes an individual to pathophysiology. However, the biological adaptations to minimize this risk are poorly understood. Using a computational model based upon realistic kinetic parameters we are able to reproduce the interaction of the stress hormone cortisol with its two nuclear receptors, the high-affinity glucocorticoid receptor and the low-affinity pregnane X-receptor. We demonstrate that regulatory signals between these two nuclear receptors are necessary to optimize the body’s response to stress episodes, attenuating both the magnitude and duration of the biological response. In addition, we predict that the activation of pregnane X-receptor by multiple, low-affinity endobiotic ligands is necessary for the significant pregnane X-receptor-mediated transcriptional response observed following stress episodes. This integration allows responses mediated through both the high and low-affinity nuclear receptors, which we predict is an important strategy to minimize the risk of disease from chronic stress

Dysregulation of Gene Expression in the Artificial Human Trisomy Cells of Chromosome 8 Associated with Transformed Cell Phenotypes

A change in chromosome number, known as aneuploidy, is a common characteristic of cancer. Aneuploidy disrupts gene expression in human cancer cells and immortalized human epithelial cells, but not in normal human cells. However, the relationship between aneuploidy and cancer remains unclear. To study the effects of aneuploidy in normal human cells, we generated artificial cells of human primary fibroblast having three chromosome 8 (trisomy 8 cells) by using microcell-mediated chromosome transfer technique. In addition to decreased proliferation, the trisomy 8 cells lost contact inhibition and reproliferated after exhibiting senescence-like characteristics that are typical of transformed cells. Furthermore, the trisomy 8 cells exhibited chromosome instability, and the overall gene expression profile based on microarray analyses was significantly different from that of diploid human primary fibroblasts. Our data suggest that aneuploidy, even a single chromosome gain, can be introduced into normal human cells and causes, in some cases, a partial cancer phenotype due to a disruption in overall gene expression

Clear cell carcinoid tumor of the distal common bile duct

BACKGROUND: Carcinoid tumors rarely arise in the extrahepatic bile duct and can be difficult to distinguish from carcinoma. There are no reports of clear cell carcinoid (CCC) tumors in the distal bile duct (DBD) to the best of our knowledge. Herein, we report a CCC tumor in the DBD and review the literature concerning extrahepatic bile duct carcinoid tumors. CASE PRESENTATION: A 73-old man presented with fever and occult obstructive jaundice. Ultrasonography, computed tomography (CT) and magnetic resonance cholangiopancreaticography (MRCP) demonstrated a nodular tumor projection in the DBD without regional lymph node swelling. Under suspicion of carcinoma, we resected the head of the pancreas along with 2(nd )portion duodenectomy and a lymph node dissection. The surgical specimen showed a golden yellow polypoid tumor in the DBD (0.8 × 0.6 × 0.5 cm in size). The lesion was composed of clear polygonal cells arranged in nests and a trabecular pattern. The tumor invaded through the wall into the fibromuscular layer. Immunohistochemical stains showed that neoplastic cells were positive for neuron-specific enolase (NSE), chromogranin A, synaptophysin, and pancreatic polypeptide and negative for inhibin, keratin, CD56, serotonin, gastrin and somatostatin. The postoperative course was uneventful and he is living well without relapse 12 months after surgery. CONCLUSION: Given the preoperative difficulty in differentiating carcinoid from carcinoma, the pancreaticoduodenectomy is an appropriate treatment choice for carcinoid tumors located within the intra-pancreatic bile duct

Delayed construction of the bilio-digestive anastomosis in right living donor liver transplantation

We describe a two-step procedure in the transplantation of a right lobe liver graft obtained from a living donor, in which the biliary anastomosis is delayed until the day after the actual implantation of the graft. The purpose of the two-step procedure is to minimize the factors that might contribute to biliary complications in living donor liver transplantation (LDLT). Three patients who received a graft with two hepatic ducts underwent Roux-en-Y hepatico-jejunostomies during a separate procedure the day after the implantation of the graft. Length of intubation, recovery of enteral alimentation, and hospital stay were similar to the patients who underwent one-step transplant. No biliary or infectious complications occurred. Delaying the hepatico-jejunostomy when two ducts are present and a bilio-digestive anastomosis is planned has no negative impact on the postoperative course of the patients but can ameliorate the conditions under which the anastomoses must be performed

Delayed Construction of the Bilio-Digestive Anastomosis in Right Living Donor Liver Transplantation

We describe a two-step procedure in the transplantation of a right lobe liver graft obtained from a living donor, in which the biliary anastomosis is delayed until the day after the actual implantation of the graft. The purpose of the two-step procedure is to minimize the factors that might contribute to biliary complications in living donor liver transplantation (LDLT). Three patients who received a graft with two hepatic ducts underwent Roux-en-Y hepatico-jejunostomies during a separate procedure the day after the implantation of the graft. Length of intubation, recovery of enteral alimentation, and hospital stay were similar to the patients who underwent one-step transplant. No biliary or infectious complications occurred. Delaying the hepatico-jejunostomy when two ducts are present and a bilio-digestive anastomosis is planned has no negative impact on the postoperative course of the patients but can ameliorate the conditions under which the anastomoses must be performed

Hepatic venous outflow reconstruction in adult living donor liver transplants without portal hypertension

Graft congestion is one of the causes of poor graft function in segmental liver transplantation. Three factors are implicated in segmental graft congestion: graft size, hepatic venous outflow and portal inflow. The graft size must be matched to the body weight, which is conventionally done by using graft to body weight ratio. Hepatic blood outflow must be optimized by hepatic vein reconstruction, which can be complicated. High portal blood flow has been shown to be detrimental to small-for-size grafts. These factors are strictly connected to each other. They can all contribute to graft congestion and poor function, while one factor can compensate for the others and decrease congestion. Ideally, all the accessory veins should be reconstructed, if possible, to maximize the outflow. In the absence of portal hypertension and with an adequate sized graft, complex venous reconstruction may not be necessary. We present a case report of an adult living donor liver transplant with the favorable conditions of normal portal pressure and a large sized graft, but complicated by the presence of several accessory hepatic veins. A simple hepatic vein anastomosis was sufficient for adequate outflow and prompt graft function

Successful rescue of refractory, severe antibody mediated rejection with splenectomy

Antibody-mediated rejection (AMR) commonly occurs after transplantation of ABO-incompatible and sensitized renal transplant. Treatment regimens commonly include a combination of plasmapheresis (PL) and intravenous immunoglobulin (IVIG). However, some cases of AMR remain refractory to treatment. We report a case series of four patients with AMR refractory to standard therapy (ST) who resolved after splenectomy. Four living donor kidney transplant recipients were diagnosed with AMR. Two patients were ABO incompatible, one was cross-match positive and one had no obvious predisposing factors. After failure of therapy with corticosteroids, PL, IVIG, Thymoglobulin, and Rituximab (three patients) or Campath (one patient), AMR was treated with laparoscopic splenectomy. After an average of I I days of ST, laparoscopic splenectomy was performed for rescue. The urinary output improved immediately in all patients, serum creatinine levels decreased within 48 hr, and ABO titers fell in the ABO-incompatible patient and the cross-match became negative in the two sensitized patients. Splenectomy may play a role in the treatment of AMR refractory to ST

Auto-islet transplantation after pancreatectomy

Chronic pancreatitis (CP) is an inflammatory disease that causes progressive and irreversible structural changes to the pancreas, resulting in permanent impairment of both endocrine and exocrine functions. In advanced cases of CP, pain can be relieved only with pancreatic resection. However, even partial resection of the pancreas in this setting may cause diabetes. Furthermore, postsurgical diabetes (PSD) always occurs after total or near-total pancreatectomy, which is commonly performed for CP Auto transplantation of pancreatic islets into the portal vein after pancreatic resection can prevent PSD. The results of this strategy, which are already encouraging, are likely to improve in the near future because of significant progress in the isolation and preservation of pancreatic islets. This review discusses the current status and future prospects for auto-islet transplantation after pancreatic resection forCP