Sirolimus: efficacy in liver transplant patients with nephrotoxicity and renal insufficiency.

Nephrotoxicity is a complication of patients undergoing orthotopic liver transplantation. Herein we present several factors that play an important role in this complication.

Production of 89Sr in solution reactor.

The new method for medical (89)Sr production in a reactor with solution fuel is proposed which is characterized by simplicity, high production efficiency and low buildup of radioactive waste. The main advantages of the new technology were validated by numerous experiments. The proposed new technology selectively extracts (89)Sr from a fuel of solution reactor and precludes penetration of (90)Sr into the final product. This method is based on the presence of gaseous radionuclide (89)Kr (T(1/2)=190.7s) in the decay chain (89)Se-->(89)Br-->(89)Kr-->(89)Rb-->(89)Sr. The performed experiments on taking the gas probes from internal volume of the solution 20 kW mini-reactor "Argus" have confirmed that the mechanism for (89)Sr delivery to the sorption volume of the reactor experimental loop is based on transport of gaseous (89)Sr predecessor-radionuclide (89)Kr. According to the measurements of radioactive impurities in a final (89)SrCl(2) solution, the filtration of the gas flow with cermet filters followed by cleaning of (89)Sr chloride solution in chromatographic columns with DOWEX-50 x 8 or Sr-Resin ensures reception of (89)Sr fully meeting the requirements for medical application. The experimental estimations have shown that the proposed new technology is multiply more productive than the traditional industrial methods of (89)Sr reception.

STRUCTURAL VIROLOGY. Conformational plasticity of a native retroviral capsid revealed by x-ray crystallography.

Retroviruses depend on self-assembly of their capsid proteins (core particle) to yield infectious mature virions. Despite the essential role of the retroviral core, its high polymorphism has hindered high-resolution structural analyses. Here, we report the x-ray structure of the native capsid (CA) protein from bovine leukemia virus. CA is organized as hexamers that deviate substantially from sixfold symmetry, yet adjust to make two-dimensional pseudohexagonal arrays that mimic mature retroviral cores. Intra- and interhexameric quasi-equivalent contacts are uncovered, with flexible trimeric lateral contacts among hexamers, yet preserving very similar dimeric interfaces making the lattice. The conformation of each capsid subunit in the hexamer is therefore dictated by long-range interactions, revealing how the hexamers can also assemble into closed core particles, a relevant feature of retrovirus biology.

[Intestinal failure and transplantation in microvillous inclusion disease]. / Fracaso intestinal y trasplante en la enfermedad por inclusiones microvellositarias.

INTRODUCTION: Microvillous inclusion disease is a rare autosomal recessive condition, characterized by severe secretory diarrhea that produces a permanent intestinal failure and dependency on parenteral nutrition. It usually begins in the neonatal period, and the only treatment at present is intestinal transplantation. PATIENTS AND METHODS: A retrospective review was conducted on 6 patients (three males and three females) diagnosed with microvillous inclusion disease between 1998 and 2013. RESULTS: All debuted in the first month of life, with a median age of three days (range, 3-30 days), and had secretory diarrhea dependent on parenteral nutrition, with fasting fecal volume of 150-200ml/kg/day. Light microscopy of duodenal biopsy samples showed varying degrees of villous atrophy without cryptic hyperplasia, accumulation of PAS positive material in the cytoplasm of enterocytes brush border, and anti-CD10 immunostaining was suggestive of intracytoplasmic inclusions. Diagnostic confirmation was performed with electron microscopy. Two of them had a genetic study, and showed mutations in MYO5B gene. Three died and three are alive; two of them with an intestinal transplantation and the third waiting for a multivisceral transplantation.

Incidentally discovered hepatocellular carcinoma in explanted liver: clinical, histopathologic features and outcome.

BACKGROUND: Incidental hepatocellular carcinomas (iHCCs) are tumors discovered on the explanted liver that were not present on imaging before transplantation. The natural history, histopathologic characteristics, and prognosis are not clearly defined. METHODS: We compared the characteristics of iHCC and previously known hepatocellular carcinoma (pkHCC) in patients who underwent liver transplantation from 1998 to 2012 in a retrospective study. RESULTS: During this period a total of 675 patients were transplanted; 56 patients (9%) had pkHCC and 12 (2%) had iHCC. The sex and age distributions were similar. The median Model for End-Stage Liver Disease score in iHCC patients was 17.0 versus 13.0 in patients with pkHCC (P = .001). Thirty-three percent of iHCC patients had multiple tumors, and 25% had bilobar involvement. The median cumulative tumor size in iHCC was 1.8 cm, and 5.5 cm in pkHCC (P = .005). Incidence of microvascular invasion was not different (16.7% vs 38.9%; P = .191). American Joint Committee on Cancer T1 stage was found in 58.3% of patients with iHCC and in 22.2% of pkHCC patients. Patients with iHCC had 1-, 3-, and 5-year survivals, respectively, of 100%, 83% and 64%, compared with 80%, 66%, and 38% for patients with pkHCC (P = .138). None of the patients with iHCC had recurrence of HCC, whereas incidence of recurrence in pkHCC patients was 12.5%. CONCLUSIONS: iHCC occurred in patients with more advanced liver disease. The cumulative tumor size of iHCC was smaller but one-third were multifocal. Survival was similar to patients with pkHCC, and recurrence was not noted in patients with iHCC.

Liver retransplantation in patients with acquired familial amyloid polyneuropathy: a Portuguese center experience.

In 1995 Furtado et al performed the first domino transplantation using a donor liver with familial amyloid polyneuropathy (FAP), thereby increasing the pool of donors. Our experience showed that the onset of FAP symptoms occurs earlier in some patients. Patients with FAP acquired by transplantation are candidates for liver retransplantation to minimize the progression of symptoms. Liver retransplantation is considered to be a high-risk procedure and has lower survival compared with the first transplantation. We evaluated the risk of liver retransplantation in patients with acquired FAP. We did a retrospective analysis of these patients based on the records of perioperative data. From 1995 to 2004 we carried out 81 domino transplantations, of which 10 were submitted to liver retransplantation because of acquired FAP. The better outcomes in this group lead us to think that the liver retransplantation in patients with acquired FAP is not associated with the same risks of liver retransplantation in candidates with graft failure.

Evaluation of operative risk in de novo familial amyloid polyneuropathy retransplantation.

Familial amyloid polyneuropathy (FAP) is the most common hereditary amyloidosis, characterized by progressive peripheral sensory and motor neuropathy. The livers of patients with FAP are used in domino liver transplantation in selected cases to increase the number of grafts available. In our department 10 patients underwent liver retransplantation (ReLTx) in the absence of liver dysfunction by de novo FAP after domino liver transplantation. Our aim was to compare the differences in the consumption of blood products and intraoperative hemodynamic support among patients with FAP undergoing liver transplantation (LTx) and patients with de novo FAP undergoing ReLTx in the same time frame. The anesthetic records of all patients who underwent LTx for FAP and ReLTx for de novo FAP were analyzed, from January 2009 to May 2014. Patients were divided into 2 groups: group 1 patients with FAP, and group 2 patients with de novo FAP. Statistical differences in the value of preoperative creatinine were found. Hemoglobin levels, preoperative international normalized ratio (INR), use of blood products, aminergic support, and surgical time showed no statistical difference. Major bleeding rates would be expected in patients undergoing ReLTx. Changes in renal function, chronic immunosuppressive therapy, and age may contribute to the increase in intraoperative complications. We did not find statistically significant differences, leading us to the conclusion that de novo FAP does not seem to be a predictor of perioperative risk.

Endoscopic injection therapy vs. multipolar electrocoagulation vs. laser vs. injection + octreotide vs. injection + omeprazole in the treatment of bleeding peptic ulcers. A prospective randomized study.

BACKGROUND/AIMS: A prospective randomized study was performed to assess the effectiveness and safety of 5 different methods of hemostasis in selected patients with high-risk bleeding peptic ulcers. METHODOLOGY: Two hundred and eight patients (n = 208; mean age: 61.6 yrs) with endoscopic stigmata of active hemorrhage, non-bleeding vessel or adherent fresh clot were randomized during emergency endoscopy to receive one of the following modalities of endoscopic therapy (with or without pharmacological therapy): I) injection of absolute alcohol (n = 44); II) multipolar electrocoagulation (BICAP; n = 42); III) Nd-YAG laser (n = 40); IV) injection of absolute ethanol + octreotide (n = 42); V) injection of absolute ethanol + omeprazole (n = 40). RESULTS: The 5 treatment groups were clinically and endoscopically comparable. The initial hemostatic success was > 90% in every group. No significant differences between groups were found in any of the following parameters assessed during hospitalization: incidence of rebleeding (I = 14.8% vs. II = 19.0% vs. III = 16.6% vs. IV = 18.1% vs. V = 20.0%; P > 0.05 mean = 17.7%); incidence of definitive hemostasis (I = 89.3% vs. II = 85.7% vs. III = 86.6% vs. IV = 84.0% vs. V = 86.6%; P > 0.05; mean = 86.5%); incidence of emergency surgery (I = 8.5% vs. II = 11.9% vs. III = 10.0% vs. IV = 6.8% vs. V = 11.1%; P > 0.05; mean = 9.6%); mortality rate (I = 4.2% vs. II = 4.7% vs. III = 3.3% vs. IV = 13.6% vs. V = 4.4%; P > 0.05; mean = 6.2%). Mean age of deceased patients was significantly higher than living patients (71.2 +/- 13.4 vs. 60.9 +/- 14.4; P < 0.05). Approximately 2/3 of the fatal cases were strongly weakened by coexistent medical diseases. The duration of hospital stay was similar for all groups. The BICAP group required less units of blood transfusion (1.9 +/- 1.8 vs. I = 3.0 +/- 2.6; III = 3.5 +/- 3.6; IV = 2.8 +/- 2.3; V = 3.1 +/- 2.5; P < 0.05), perhaps due to the higher mean value of hemoglobin of these patients at hospital admission, compared to all other groups. No significant complications were reported. CONCLUSIONS: This study provides good evidence that injection of absolute ethanol, multipolar electrocoagulation (BICAP) and Nd-YAG laser are equally safe and effective in the endoscopic therapy of acute bleeding peptic ulcers. In contrast, no additional hemostatic benefits arose from the association of pharmacological agents (octreotide or omeprazole) to sclerosis injection.

Octreotide in acute bleeding esophageal varices: a prospective randomized study.

BACKGROUND/AIMS: To assess the value of octreotide in the control of acute bleeding esophageal varices, in a prospective randomized study. METHODOLOGY: One hundred and ninety-seven patients admitted for variceal bleeding confirmed at endoscopy were recruited and divided into two groups: group I (n = 111) with endoscopic stigmata of recent bleeding; and group II (n = 86) with active bleeding at emergency endoscopy. Patients in group I were randomized to receive a continuous infusion of octreotide (n = 58) or emergency sclerotherapy (n = 53). Patients in group II were assigned to sclerotherapy (n = 42) or to sclerotherapy plus octreotide (n = 44). At the end of the period of study (48 hours), patients were submitted to sclerotherapy or band ligation until variceal obliteration was achieved. RESULTS: In group I, octreotide was found to be as effective as sclerotherapy regarding hemostasis at 48 hours and on day 7 after the index bleeding episode. Transfusion needs were not significantly different for the two treatment modalities. In group II, the association of octreotide with sclerotherapy was significantly better than sclerotherapy alone either in controlling acute active bleeding (P < 0.001) or in achieving hemostasis at 48 hours (P < 0.01). Transfusion needs were significantly fewer in patients treated with this therapeutic association as compared to sclerotherapy alone. CONCLUSIONS: These results suggest that octreotide infusion is effective in the treatment of variceal bleeding. In patients with recent bleeding, octreotide infusion is as effective as emergency sclerotherapy. In active variceal bleeding, it is a valuable adjuvant treatment in association with emergency sclerotherapy.

One year of Lamivudine therapy for portuguese patients with chronic hepatitis B.

OBJECTIVE: To assess the efficacy of lamivudine treatment on hepatitis B e antigen (HBeAg) and/or hepatitis B surface antigen (HBsAg) seroconversion, on other virological and serological markers of response including hepatitis B virus (HBV) DNA and serum aminotransferases, and the safety of lamivudine treatment in hepatitis B patients. PATIENTS: This phase III open-label study evaluated the virological and biochemical response to lamivudine in 70 Portuguese patients with HBeAg positive chronic hepatitis B. Patients were treated with lamivudine 100mg once daily for 12 months. METHODS: Antiviral activity was assessed by measuring alanine aminotransferase (ALT)/aspartate aminotransferase (AST) levels at all protocol visits, and hepatitis B serology and HBV DNA were performed at baseline and at month 12 visits. Evaluation of safety and tolerance was based on clinical adverse events and laboratory analyses. RESULTS: The primary endpoint was virological response at month 12, defined as loss of detectable HBeAg from serum with a reduction of HBV DNA to undetectable levels, and this was observed in 19/69 (27.5%) of patients. Almost half of the patients were HBV DNA negative by this time. Mean ALT values decreased steadily during treatment and by 12 months 61% of patients had values within the normal range. HBeAg seroconversion (HBeAg negative, HBeAb positive) was achieved in 27.9% of patients by 12 months, although all patients remained HBsAg positive. CONCLUSION: Lamivudine was well tolerated and the incidence of adverse events was similar to those reported in previous studies. Lamivudine treatment resulted in virological and biochemical improvements in HBeAg positive chronic hepatitis B patients, with HBeAg seroconversion in one-third of patients.

Haemodynamics during liver transplantation in familial amyloidotic polyneuropathy: study of the intraoperative cardiocirculatory data of 50 patients.

BACKGROUND: Circulatory instability frequently complicates liver transplantation for familial amyloidotic polyneuropathy (FAP) and may be a source of surgical morbidity and mortality. OBJECTIVE: To evaluate FAP intraoperative haemodynamic data and their relation to the duration of surgery, and need for anaesthetic drugs. RBC and sympathomimetic amines. SETTING: Clinical study during a four year period. PATIENTS (mean +/- SD): Group I included 50 consecutive FAP ATTR Met 30 recipients of first transplantation. Age was 35.3 +/- 7.1 years, neurological score 34.3 +/- 13 in 100 and time elapsed from first symptom 5.0 +/- 2.7 years. Group II (control), not different concerning age and sex, included 51 patients transplanted during the same period with other pathologies. METHOD: Anaesthetic protocol, monitoring and surgical techniques were similar in both groups. Data of the two groups were compared either by the Student's t-test or Fisher's exact test. RESULTS: Low values of systemic vascular resistance index were observed in both groups, with no differences between them. Systemic arterial pressures were usually lower in group I, because cardiac index and heart rate were also significantly lower, although within normal values. However, in group I, isoflurane (a vasodilator anaesthetic) was used during less time (p < 0.05) and in lower concentrations (p < 0.01) and phenylephrine was necessary in 26% of patients vs 0 patients in group II (p < 0.001). CONCLUSION: FAP patients presented a different intraoperative behaviour when compared to other patients submitted to liver transplantation. From a clinical point of view, the authors stress: 1--As a result of autonomic dysfunction, the administration of anaesthetic drugs to FAP patients always presents the risk of producing significant hypotension; even the use of ketamine does not prevent hypotension; 2--Safety is ensured by beat-to-beat surveillance of arterial pressures and the capacity to act immediately to support circulation; 3--These patients seem to be very sensitive to decreases in the pre-load; 4--Hypotension is also frequent with an adequate pre-load, usually as the result of low SVR; an infusion of a vasoconstrictor drug emerges as the most frequent treatment requested and our experience supports it as an effective one.

[Value of ascitic lipids and sero-ascitic gradient of albumin in the differential diagnosis of ascites]. / Valor dos lípidos ascíticos e do gradiente sero-ascítico de albumina no diagnóstico diferencial das ascites.

In order to compare its diagnostic value in the differentiation between malignant and hepatic ascites, we analysed the ascitic fluid concentrations of cholesterol (Ct) and triglycerides (Tg) and the serum-ascites albumin gradient (S-A alb grad) in 58 patients--forty one with chronic liver disease (CLD) and 17 with malignancy. In CLD group the mean values +/- SD for Ct (27.1 +/- 20.1 mg/dl), Tg (34.2 +/- 33.8 mg/dl) and S-A alb grad (1.9 +/- 0.6 g/dl) were significantly different from those obtained in malignant ascites (Ct 103.1 +/- 45.1 mg/dl; Tg 62.1 +/- 43.0 mg/dl; S-A alb grad 0.5 +/- 0.4 g/dl) (p less than 0.001 for all parameters). Application of the cutoff concentrations given in the literature revealed the following results: Ct-Sensitivity (Se) 82.4%, Specificity (Sp) 85.4%, Efficiency (E) 84.5%; Tg-Se 29.4%, Sp 95.1%, E 75.9%; S-A alb grad- Se 88.2%, Sp 97.6%, E 94.8%. The exclusion of the 4 patients with massive hepatic metastasis from malignant group by ultrasound or computer tomography gave an efficiency of 87.0% for Ct, 88.9% for Tg and 98.1% for S-A alb grad. We conclude that: 1) S-A alb grad is the best analysed parameter in the discrimination between malignant and hepatic ascites, 2) the combination with non-invasive imaging methods increases its diagnostic value.

Long-term outcome of the first 150 liver transplant recipients: a single-center experience.

INTRODUCTION: Liver transplantation modifies the natural history of end-stage liver diseases and stabilizes the course of familial amyloidotic polyneuropathy. An evaluation of its long-term results allows insight and awareness of factors that impact survival. PATIENTS AND METHODS: We included 150 consecutive patients who underwent liver transplantation between October 1992 and January 1998. The impact of disease, cold ischemic time, ABO compatibility, acute and chronic rejection episodes, and vascular, biliary and infectious complications on survival were compared. RESULTS: We included 65 patients (43.3%) with familial amyloidotic polyneuropathy, 41 (27.3%) with cirrhosis, 12 (8%) with hepatocellular carcinoma, and 11 (7.3%) with acute hepatic failure. The mean age was 39 years. The mean cold ischemic time was 493 ± 161 minutes. There were 115 (77.2%) ABO-identical transplants; 25 (16.8%) were ABO compatible, and 9 (6%) were ABO incompatible. Acute cellular rejection occurred in 88 recipients (58.7%); chronic rejection was diagnosed in 9 (6%). Complications included vascular (16.7% patients; n = 25) and biliary (38.7%; n = 58). Infections were bacterial in 92 (61.3%), fungal in 35 (23.3%), and cytomegalovirus in 9 (6%). The survival rates were 78% at 1 year, 68.7% at 5 years, and 58% at 10 years. Of the 150 patients, 82 survived until November 2011. Follow-up ranged from 13 to 19 years. In this study, only bacterial infections had a negative influence on patients' survival (P = .014). CONCLUSION: The high frequency of biliary and vascular complications was associated with increased morbidity but not mortality. Bacterial infections were related to an ominous outcome, being responsible for short- and long-term mortality.