Calmodulin antagonists inhibit and phorbol esters enhance transferrin endocytosis and iron uptake by immature erythroid cells

Seven antagonists of the calcium-binding protein calmodulin were found to inhibit iron and transferrin uptake by reticulocytes. This inhibition could be completely accounted for by inhibition of the endocytosis and exocytosis of transferrin. When four of the antagonists were tested with the nucleated erythroid cells from the liver of the fetal rat, inhibition of iron uptake was also observed but at higher concentrations than required for the same degree of inhibition with reticulocytes. The tumor promoters phorbol 12-myristate 13-acetate (PMA) and phorbol 12,13-dibutyrate (PDB) were shown to increase the rates of iron and transferrin uptake by reticulocytes and fetal liver erythroid cells by accelerating the rates of transferrin endocytosis and exocytosis. Since these substances are known to stimulate the calcium-activated enzyme protein kinase C while calmodulin antagonists are inhibitory, it is concluded that this enzyme plays an important role in the endocytosis and intracellular cycling of transferrin, and iron uptake by immature erythroid cells. However, the possibilities that calmodulin is also involved or that the inhibitory effects of the calmodulin antagonists are due to nonspecific actions on the cell membrane cannot be excluded.     

Low clinical stage renal cell carcinoma: relevance of microvascular tumor invasion as a prognostic parameter

PURPOSE: Renal cell carcinoma is a tumor with unpredictable behavior and defining reliable prognostic factors would be extremely valuable in the clinical setting. Tumor stage, nuclear grade and tumor cell type are the main prognostic clinical parameters available. In this study we evaluated the role of microvascular involvement in the primary lesion for predicting tumor behavior in patients with low stage clinical disease. MATERIALS AND METHODS: A total of 95 patients with clinically localized renal cell carcinoma (stages T1-T2 Nx M0) underwent radical nephrectomy and/or nephron sparing surgery, and were followed for a median of 45 months. The impact of microvascular tumor invasion on disease progression and its correlation with known pathological outcomes (tumor size, nuclear grade and cell type) were studied. RESULTS: Microvascular tumor invasion was observed in 24 patients (25%), of whom 50% had disease recurrence. Of the 71 patients without microvascular invasion only 4 (6%) showed tumor recurrence. When microvascular invasion was correlated with other histological parameters, a significant statistical association was noted with tumor diameter, perirenal fat invasion, macroscopic extension to the renal vein, nuclear grade, lymph node metastasis and sarcomatous elements in the tumor. Multivariate analysis showed that microvascular invasion and the involvement of regional lymph nodes were independent predictors of disease recurrence. Concerning cancer specific survival, microvascular invasion and perirenal fat infiltration were the only factors related to death. CONCLUSIONS: Microvascular invasion is an independent and relevant clinical prognostic parameter for low clinical stage renal cell carcinoma.     

Biliary Complications in Orthotopic Liver Transplantation Using Choledochocholedochostomy with a T-tube

Despite significant advances in orthotopic liver transplantation (OLT), biliary tract reconstruction is still a major source of complications. Choledochocholedochostomy with a T-tube used to be the standard procedure for biliary reconstruction after OLT. However, many centers currently avoid use of the T-tube because of the high incidence of complications. Our aim was to study the biliary complications occurring at our center when end-to-end choledochocholedochostomy (EE-CC) over a T-tube was used as the standard procedure for biliary reconstruction. A retrospective review was conducted of all patients who underwent liver transplantation from February 1, 1996, to April 30, 2010. Only patients requiring any therapy to treat biliary complications were considered, whereas those with concomitant hepatic artery complications were excluded. The study cohort consisted of 743 patients who had EE-CC with a T-tube.Of these, 73 patients (9.8%) experienced any biliary complication. Anastomotic strictures occurred in 17 patients (2.3%), and non-anastomotic strictures in 2 (0.3%). Fifteen patients with anastomotic strictures were successfully treated by dilatation and stenting. Bile leakage was diagnosed in 39 patients (5.2%). Leakage occurred at the anastomosis in 15 patients (2%), and at the exit site of the T-tube in 24 patients (3.2%). Tube opening was the only treatment used in 30 patients with bile leakage (76.9%). Seven patients experienced leaks after elective T-tube removal (1%). Overall, repeat surgery to manage biliary complications was needed in 9 patients (1.2%). The mortality rate from biliary complications was 0.13%. In conclusion, EE-CC with a T-tube was followed by a low incidence of biliary complications. The complication rate after elective T-tube removal and the repeat surgery rate were extremely low. These results might challenge the current trend to avoid T-tube stenting in OLT.     

Adult patients with sporadic polycystic kidney disease: the importance of screening for mutations in the PKD1 and PKD2 genes

Background

ADPKD is one of the most common inherited disorders, with high risk for end-stage renal disease. Numerous patients, however, have no relatives in whom this disorder is known and are unsure whether they may transmit the disease to their offsprings. The aim of this study was to evaluate whether germline mutation analysis adds substantial information to clinical symptoms for diagnosis of ADPKD in these patients.

Methods

Clinical data included renal function and presence of liver or pancreas cysts, heart valve insufficiency, intracranial aneurysms, colonic diverticles, and abdominal hernias. Family history was evaluated regarding ADPKD. Germline mutation screening of the PKD1 and PKD2 genes was performed for intragenic mutations and for large deletions.

Results

A total of 324 adult patients with ADPKD including 30 patients without a family history of ADPKD (sporadic cases) were included. PKD1 mutations were found in 24/30 and PKD2 mutations in 6 patients. Liver cysts were present in 14 patients and intracranial aneurysms in 2 patients. Fourteen patients (45%) had no extrarenal involvement. Compared to the 294 patients with familial ADPKD, the clinical characteristics and the age at the start of dialysis were similar in those with sporadic ADPKD.

Conclusion

The clinical characteristics of patients with sporadic and familial ADPKD are similar, but sporadic ADPKD is often overlooked because of the absence of a family history. Molecular genetic screening for germline mutations in both PKD1 and PKD2 genes is essential for the definitive diagnosis of ADPKD.     

Renal Vein Extension Using Gonadal Vein: A Useful Strategy for Right Kidney Living Donor Harvested Using Laparoscopy

Introduction

Vascular management of the right renal vein during laparoscopic living donor nephrectomy is still an unsolved problem. This short vessel has limited the use of right kidneys. However, the right kidney should be harvested in some instances. Based on experience in open donor nephrectomy, our unit has used the donor gonadal vein to obtain a longer renal vein in this setting.

Methods

Four consecutive living related donors with the indication for laparoscopic right nephrectomy underwent this procedure. Three donors were females and the overall average age was 48.5 years. The renal vein was controlled with a 30-mm stapler and we included 5-6 cm of the ipsilateral gonadal vein during the harvest. The donor kidney was perfused and renal vessels prepared under cold conditions. The gonadal vein was opened longitudinally and sutured to the donor right renal vein as a wide tube in 3 cases and as a spiral tube in 1 case with 6-0 monofilament suture.

Results

This procedure extended the bench work between 25 to 40 minutes permitting an 2.5- to 3.5-cm extension of the donor vein. The transplantations were performed in the usual mode and the vein enlargement enormously facilitated the implantation surgery. All recipients displayed immediate graft function; no complications were observed with this strategy.

Conclusions

Vein extension with the gonadal vein was a simple, safe method to enlarge the renal vein among right living donor kidneys procured using laparoscopy.