New insights into the regulation of bile acids synthesis during the early stages of liver regeneration: A human and experimental study.

BACKGROUND AND AIMS: Liver regeneration is essential for the preservation of homeostasis and survival. Bile acids (BAs)-mediated signaling is necessary for liver regeneration, but BAs levels need to be carefully controlled to avoid hepatotoxicity. We studied the early response of the BAs-fibroblast growth factor 19 (FGF19) axis in healthy individuals undergoing hepatectomy for living donor liver transplant. We also evaluated BAs synthesis in mice upon partial hepatectomy (PH) and acute inflammation, focusing on the regulation of cytochrome-7A1 (CYP7A1), a key enzyme in BAs synthesis from cholesterol. METHODS: Serum was obtained from twelve human liver donors. Mice underwent 2/3-PH or sham-operation. Acute inflammation was induced with bacterial lipopolysaccharide (LPS) in mice fed control or antoxidant-supplemented diets. BAs and 7α-hydroxy-4-cholesten-3-one (C4) levels were measured by HPLC-MS/MS; serum FGF19 by ELISA. Gene expression and protein levels were analyzed by RT-qPCR and western-blot. RESULTS: Serum BAs levels increased after PH. In patients with more pronounced hypercholanemia, FGF19 concentrations transiently rose, while C4 levels (a readout of CYP7A1 activity) dropped 2 h post-resection in all cases. Serum BAs and C4 followed the same pattern in mice 1 h after PH, but C4 levels also dropped in sham-operated and LPS-treated animals, without marked changes in CYP7A1 protein levels. LPS-induced serum C4 decline was attenuated in mice fed an antioxidant-supplemented diet. CONCLUSIONS: In human liver regeneration FGF19 upregulation may constitute a protective response from BAs excess during liver regeneration. Our findings suggest the existence of post-translational mechanisms regulating CYP7A1 activity, and therefore BAs synthesis, independent from CYP7A1/Cyp7a1 gene transcription.

Time since liver transplant and immunosuppression withdrawal outcomes: Systematic review and individual patient data meta-analysis.

BACKGROUND & AIMS: Successful immunosuppression withdrawal (ISW) is possible for a subfraction of liver transplant (LT) recipients but the factors that define the risk of ISW failure are largely unknown. One candidate prognostic factor for ISW success or operational tolerance (OT) is longer time between LT and ISW which we term "pre-withdrawal time". To clarify the impact of pre-withdrawal time span on subsequent ISW success or failure, we conducted a systematic review with meta-analysis. METHODS: We systematically interrogated the literature for LT recipient ISW studies reporting pre-withdrawal time. Eligible articles from Embase, Medline, and the Cochrane Central Register of Controlled Trials were used for backward and forward citation searching. Pre-withdrawal time individual patient data (IPD) was requested from authors. Pooled mean differences and time-response curves were calculated using random-effects meta-analyses. RESULTS: We included 17 studies with 691 patients, 15 of which (620 patients) with IPD. Study-level risk of bias was heterogeneous. Mean pre-withdrawal time was greater by 427 days [95% confidence interval (CI) 67-788] in OT compared to non-OT patients. This increase was potentiated to 799 days (95% CI 369-1229) or 1074 days (95% CI 685-1463) when restricting analysis to adult or European study participants. In time-response meta-analysis for adult or European ISW candidates, likelihood of OT increased by 7% (95% CI 4-10%) per year after LT (GRADE low- and moderate-certainty of evidence, respectively). CONCLUSIONS: Our data support the impact of pre-withdrawal time in ISW decision-making for adult and European LT recipients. PROSPERO REGISTRATION: CRD42021272995.

The Impact of Portal Hypertension Assessment Method on the Outcomes of Hepatocellular Carcinoma Resection: A Meta-Analysis of Matched Cohort and Prospective Studies.

OBJECTIVE: Examine portal hypertension (PHT) impact on postoperative and survival outcomes in hepatocellular carcinoma (HCC) patients after liver resection (LR), specifically exploring distinctions between indirect signs and invasive measurements of PHT. BACKGROUND: PHT has historically discouraged LR in individuals with HCC due to the elevated risk of morbidity, including liver decompensation (LD). METHODS: A systematic review was conducted using 3 databases to identify prospective-controlled and matched cohort studies until December 28, 2022. Focus on comparing postoperative outcomes (mortality, morbidity, and liver-related complications) and overall survival in HCC patients with and without PHT undergoing LR. Three meta-analysis models were utilized: for aggregated data (fixed-effects inverse variance model), for patient-level survival data (one-stage frequentist meta-analysis with gamma-shared frailty Cox proportional hazards model), and for pooled data (Freeman-Tukey exact and double arcsine method). RESULTS: Nine studies involving 1124 patients were analyzed. Indirect signs of PHT were not significantly associated with higher mortality, overall complications, PHLF or LD. However, LR in patients with hepatic venous pressure gradient (HVPG) ≥10 mm Hg significantly increased the risk of overall complications, PHLF, and LD. Despite elevated risks, the procedure resulted in a 5-year overall survival rate of 55.2%. Open LR significantly increased the risk of overall complications, PHLF, and LD. Conversely, PHT did not show a significant association with worse postoperative outcomes in minimally invasive LR. CONCLUSIONS: LR in the presence of indirect signs of PHT poses no increased risk of complications. Yet, in HVPG ≥10 mm Hg patients, LR increases overall morbidity and liver-related complications risk. Transjugular HVPG assessment is crucial for LR decisions. Minimally invasive approach seems to be vital for favorable outcomes, especially in HVPG ≥10 mm Hg patients.

Prognosis of cardiogenic shock secondary to culprit left main coronary artery lesion-related myocardial infarction.

AIMS: This study aimed to assess, in patients with cardiogenic shock secondary to unprotected left main coronary artery-related myocardial infarction (ULMCA-related AMICS), the incidence and predictors of no recovery of left ventricular function during the admission. METHODS AND RESULTS: This was an observational study conducted at two tertiary care centres (2012-20). The main outcome measured was death or requirement for heart transplantation (HT) or left ventricular assist devices (LVAD) during the admission. A total of 70 patients were included. Percutaneous coronary intervention (PCI) was successful in 53/70 patients (75.7%). The combined endpoint of death or requirement of HT or LVAD during the admission occurred in 41/70 patients (58.6%). The highest incidence of the primary endpoint was observed among patients with profound shock and occluded left main coronary artery (LMCA) (20/23, 87%, P < 0.001). Although a successful PCI reduced the incidence of the event in the whole cohort (51.9% vs. 82.4% in failed PCI, P = 0.026), this association was not observed among this last group of complex patients (86.7% vs. 87.5% in failed PCI, P = 0.731). The predictive model included left ventricular ejection fraction, baseline ULMCA Thrombolysis In Myocardial Infarction flow, and severity of shock and showed an optimal ability for predicting death or requirements for HT or LVAD during the admission (area under the curve 0.865, P < 0.001). CONCLUSIONS: ULMCA-related AMICS was associated with a high in-hospital mortality or need for HT or LVAD. Prognosis was especially poor among patients with profound shock and baseline occluded LMCA, with a low probability of recovery regardless of successful PCI.

Is Instrumental Compression Equally Effective and Comfortable for Physiotherapists and Physiotherapy Students than Manual Compression? A Comparative Cross-Sectional Study.

The objective of this work is to compare the homogeneity of instrumental and manual compression during the simulation of a pressure release technique, measured with a dynamometer, as well as to evaluate the comparative degree of comfort by physiotherapists and physiotherapy students when performing this technique. METHODS: A comparative cross-sectional study was carried out with physiotherapists (lecturers with clinical experience) and 4th year students of the Physiotherapy Degree at Universidad San Jorge. The amount of pressure performed and how it was maintained during 80 s with both techniques was analysed using a digital dynamometer. The degree of comfort was evaluated using a modified numeric rating scale, with higher values representing a higher degree of discomfort. RESULTS: A total of 30 subjects participated. Significant differences were found between the techniques in terms of maintaining a constant pressure level for 80 s (p = 0.043). A statistically significant difference was found between both techniques in the period from 45 to 80 s. Regarding the degree of discomfort, the value obtained from the students' responses was 4.67 (1.35) for the manual technique and 1.93 (0.88) for the instrumental technique. In the case of physiotherapists, the comfort was 4.87 (2.13) for the manual technique and 3.33 (1.54) for the instrumental technique. CONCLUSION: The sustained manual compression necessary in manual pressure release techniques in the treatment of myofascial trigger points can be performed with assistive tools that guarantee a uniform compression maintained throughout the development of the technique and are more comfortable for physiotherapists.

Totally Laparoscopic Right Hepatectomy for Living Donor Liver Transplantation: Analysis of a Preliminary Experience on 5 Consecutive Cases.

BACKGROUND: The pure laparoscopic approach in right hepatectomy (LRH) for living donor liver transplantation (LDLT) is a controversial issue. Some authors have reported the procedure to be feasible but surgical outcomes and impact on short and long-term morbidity rates are yet to be determined. The aim of this study is to present the results of a preliminary 5 consecutive cases series of LRH for LDLT and to compare it with a successive cohort of open right hepatectomies (ORH) for LDLT. METHODS: From May 2013 to October 2015, 5 consecutive donors underwent LRH for LDLT in our center. The previous last 10 ORH for LDLT were selected for comparison. Special care was taken to include all adverse events. Each patient's complications were graded with the Clavien-Dindo Classification and scored with the Comprehensive Complication Index. RESULTS: All 5 consecutive donors completed a pure laparoscopic procedure. All allografts (open and laparoscopically procured) were successfully transplanted with no primary graft failures. Only 2 Clavien-Dindo Grade-I complications occurred in the LRH donors, while ORH donors had 10 Grade I, 2 Grade II and 1 Grade IIIa complications in the short term (<3 months). In the long term (6-12 months follow-up), LRH donors had a significant lower incidence of complications (Comprehensive Complication Index: 1.74; SD, 3891 vs 15.2 SD; 8.618; P = 0.006). CONCLUSIONS: In our experience, LRH for LDLT is a feasible procedure. Further comparative series may support our preliminary findings of reduced incidence and severity of complications as compared with the open approach.

First-line use of rituximab correlates with increased overall survival in late post-transplant lymphoproliferative disorders: retrospective, single-centre study.

This retrospective study evaluates the impact of rituximab on PTLD response and survival in a single-centre cohort. PTLD cases between 1984 and 2009, including heart, kidney, liver and lung transplant recipients, were included. Survival was analysed taking into account the type of PTLD (monomorphic vs. polymorphic), EBV infection status, IPI score, Ann Arbor stage and use of rituximab. Among 1335 transplanted patients, 24 developed PTLD. Median age was 54 yr (range 29-69), median time to diagnosis 50 months (range 0-100). PTLD type was predominantly late/monomorphic (79% and 75%), mostly diffuse large B-cell type. Overall response rate (ORR) was 62% (66% rituximab vs. 50% non-rituximab; P = 0.5). R-CHOP-like regimens were used most frequently (72% of patients treated with rituximab). Median overall survival was 64 months (CI 95% 31-96). OS was significantly increased in patients treated with rituximab (P = 0.01; CI 95% rituximab 58-79 months; non-rituximab 1-30 months). Post-transplant immunosuppression regimen had no effect on survival or time to PTLD, except for cyclosporine A (CyA), which associated with increased time to PTLD (P = 0.02). Rituximab was associated with increased survival in our single-centre series, and it should be considered as first-line therapy for PTLD patients. The possible protective effect of CyA for development of PTLD should be prospectively evaluated.

Controlling Diabetes After Liver Transplantation: Room for Improvement.

BACKGROUND: Diabetes mellitus is a chronic illness with great impact on long-term outcome after liver transplantation (LT). Despite this, the current level of glycemic control and quality of screening strategies for diabetes-associated conditions that are being provided to liver transplant recipients with diabetes have not yet been assessed. METHODS: We performed a cross-sectional, multicenter study that included 344 liver transplant recipients and examined the level of glycemic control and its associated factors, as well as the quality of screening strategies for diabetes-associated conditions. RESULTS: Seventy-five patients (21.8%) suffered from diabetes before transplantation, and 82 (23.8%) developed diabetes mellitus after transplantation. Adequate glycemic control (HbA1c < 7%) was achieved in 66.7% of the patients. Forty-eight percent of patients underwent regular screening for retinopathy, 47.1% for nephropathy, 4.5% for neuropathy, and 5.7% for foot ulcers. Diabetes was associated with higher frequency of cardiovascular disease and dyslipidemia both before and after LT. Multivariate analysis revealed association between poor glycemic control and arterial hypertension, presence of diabetes before transplantation, elevated GGT, and insulin use. CONCLUSIONS: Glycemic control was inadequate in 33.3% of LT recipients with diabetes, and screening protocols for diabetes-associated conditions did not meet the standards for medical care set by the American Diabetes Association in any of the participating centers. Consequently, this study reveals a clear deficiency in the quality of diabetes care provided to patients after LT and, hence, we predict that future progress in this area will have a significant impact on medium-term to long-term outcome of these patients.

Role of mTOR inhibitors for the control of viral infection in solid organ transplant recipients.

Appropriate post-transplant immunosuppressive regimens that avoid acute rejection, while reducing risk of viral reactivation, have been sought, but remain a chimera. Recent evidence suggesting potential regulatory and antiviral effects of mammalian target of rapamycin inhibitors (mTORi) is of great interest. Although the concept of an immunosuppressive drug with antiviral properties is not new, little effort has been made to put the evidence together to assess the management of immunosuppressive therapy in the presence of a viral infection. This review was developed to gather the evidence on antiviral activity of the mTORi against the viruses that most commonly reactivate in adult solid organ recipients: cytomegalovirus (CMV), polyomavirus, Epstein-Barr virus (EBV), human herpesvirus 8 (HHV8), and hepatitis C virus (HCV). A rapid review methodology and evaluation of quality and consistency of evidence based on the GRADE system was used. The existing literature was variable in nature, although indicating a potential advantage of mTORi in CMV, polyomavirus, and HHV8 infection, and a most doubtful relation with EBV and HCV infection. Several recommendations about the management of these infections are presented that can change certain current patterns of immunosuppression and help to improve the prognosis of the direct and indirect effects of viral infection in solid organ recipients.

Impact of Cytomegalovirus Infection on Severe Hepatitis C Recurrence in Patients Undergoing Liver Transplantation.

BACKGROUND: The influence of cytomegalovirus (CMV) on recurrent hepatitis C virus (HCV) in liver grafts is controversial. Our aim was to investigate the association between CMV infection and disease and severe HCV recurrence (composite variable of presence of stage 3 to 4 fibrosis, need for retransplantation or death due to liver disease) in the first year after transplantation. METHODS: An observational, prospective, multicenter study was performed. The CMV replication was monitored by determining CMV viral load weekly during hospitalization after transplantation, twice monthly in the first 3 months after discharge, and at each follow-up visit until month 12. Liver fibrosis was assessed histologically by liver biopsy or transient elastometry. Pretransplant, intraoperative, and posttransplant variables were recorded. Multiple logistic regression was performed to study the impact of CMV on severe HCV recurrence. RESULTS: Ninety-eight patients were included. The CMV infection was detected in 48 patients (49%) in the first year posttransplant, of which 11 patients (22.9%) had CMV disease. Twenty-three patients (23.5%) had severe HCV recurrence. Of these, 17 (73.9%) developed stage 3 to 4 fibrosis, 4 (17.4%) died, and 2 (8.7%) underwent retransplantation. Only 7 of 12 (58.3%) seronegative recipients of a seropositive donor (positive donor/negative recipient [D+/R-]) received universal prophylaxis, and 10 of 12 (83.3%) D+/R- patients developed CMV replication. In the multivariate analysis, the presence of CMV D+/R- serodiscordance (odds ratio, 6.87; 95% confidence interval, 1.89-24.99; P = 0.003), and detection of a higher peak HCV viral load (odds ratio, 3.85; 95% confidence interval, 1.49-9.94; P = 0.005) were associated with severe HCV recurrence. CONCLUSIONS: Our results support an association between CMV D+/R- serodiscordance and severe HCV recurrence in patients undergoing liver transplantation for HCV liver disease.

Factors related to increased resting energy expenditure in men with liver cirrhosis.

OBJECTIVE: Hypermetabolism in cirrhosis is associated with a high risk of complications and mortality. However, studies about underlying mechanisms are usually focussed on isolated potential determinants and specific etiologies, with contradictory results. We aimed at investigating differences in nutrition, metabolic hormones, and hepatic function between hypermetabolic and nonhypermetabolic men with cirrhosis of the liver. PATIENTS AND METHODS: We prospectively enrolled 48 male cirrhotic inpatients. We evaluated their resting energy expenditure (REE) and substrate utilization by indirect calorimetry, body composition by dual-energy X-ray absorptiometry, liver function, and levels of major hormones involved in energy metabolism by serum sample tests. Patients with ascites, specific metabolic disturbances, and hepatocellular carcinoma were excluded. RESULTS: REE and REE adjusted per fat-free mass (FFM) were significantly increased in cirrhotic patients. Overall, 58.3% of cirrhotic patients were classified as hypermetabolic. Groups did not differ significantly in age, etiology of cirrhosis, liver function, presence of ascites, use of diuretics, ß-blockers, or presence of transjugular intrahepatic portosystemic shunts. Hypermetabolic cirrhotic patients had lower weight, BMI (P<0.05), nonprotein respiratory quotient (P<0.01), leptin (P<0.05), and leptin adjusted per fat mass (FM) (P<0.05), but higher FFM% (P<0.05) and insulin resistance [homeostatic model assessment-insulin resistance (HOMA-IR)] (P<0.05). Only HOMA-IR, leptin/FM, and FFM% were independently related to the presence of hypermetabolism. CONCLUSION: Hypermetabolic cirrhotic men are characterized by lower weight, higher FFM%, insulin resistance, and lower leptin/FM when compared with nonhypermetabolic men. HOMA-IR, FFM%, and leptin/FM were independently associated with hypermetabolism, and may serve as easily detectable markers of this condition in daily clinical practice.

Renal function improvement in liver transplant recipients after early everolimus conversion: A clinical practice cohort study in Spain.

A national, multicenter, retrospective study was conducted to assess the results obtained for liver transplant recipients with conversion to everolimus in daily practice. The study included 477 recipients (481 transplantations). Indications for conversion to everolimus were renal dysfunction (32.6% of cases), hepatocellular carcinoma (HCC; 30.2%; prophylactic treatment for 68.9%), and de novo malignancy (29.7%). The median time from transplantation to conversion to everolimus was 68.7 months for de novo malignancy, 23.8 months for renal dysfunction, and 7.1 months for HCC and other indications. During the first year of treatment, mean everolimus trough levels were 5.4 (standard deviation [SD], 2.7) ng/mL and doses remained stable (1.5 mg/day) from the first month after conversion. An everolimus monotherapy regimen was followed by 28.5% of patients at 12 months. Patients with renal dysfunction showed a glomerular filtration rate (4-variable Modification of Diet in Renal Disease) increase of 10.9 mL (baseline mean, 45.8 [SD, 25.3] versus 57.6 [SD, 27.6] mL/minute/1.73 m(2) ) at 3 months after everolimus initiation (P < 0.001), and 6.8 mL at 12 months. Improvement in renal function was higher in patients with early conversion (<1 year). Adverse events were the primary reason for discontinuation in 11.2% of cases. The probability of survival at 3 years after conversion to everolimus was 83.0%, 71.1%, and 59.5% for the renal dysfunction, de novo malignancy, and HCC groups, respectively. Everolimus is a viable option for the treatment of renal dysfunction, and earlier conversion is associated with better recovery of renal function. Prospective studies are needed to confirm advantages in patients with malignancy.

Trasplante ortotópico de hígado en la poliquistosis hepática / Orthotopic liver transplantation in polycystic liver disease

Introducción A día de hoy no existe una terapia médica eficaz para la poliquistosis hepática (PQH), considerándose tratamientos paliativos la punción quística con escleroterapia, la fenestración o la hepatectomía parcial. El trasplante ortotópico de hígado (TOH) es el tratamiento de elección para la PQH terminal, estando indicado en pacientes con síntomas limitantes no susceptibles de recibir tratamiento médico. Con la aplicación del sistema Model for End-Stage Liver Disease (MELD) es difícil determinar la prioridad en la lista de espera.MétodosAnálisis retrospectivo de los TOH por PQH realizados consecutivamente en nuestro centro. Los criterios de inclusión para TOH en pacientes con síntomas limitantes fueron la presencia de poliquistosis bilateral (Gigot tipo iii ) y la hepatomegalia masiva con un hígado remanente insuficiente que imposibilitara una hepatectomía. Se realizó de donante cadáver con técnica piggy-back sin by-pass veno-venoso.ResultadosEntre abril de 1992 y abril de 2010 se realizaron 6 TOH, uno de ellos combinando trasplante hepatorrenal. La media de transfusión fue 3,25 concentrados de hematíes y 1.200 cc de plasma fresco congelado. El tiempo quirúrgico medio fue 299 min y 498 min en el hepatorrenal. No hubo mortalidad perioperatoria. La media de hospitalización fue 6,5 días, permaneciendo sanos todos los pacientes tras una media de seguimiento de 71 meses.ConclusiónEl TOH ofrece una excelente supervivencia global. Los resultados son mejores cuando el trasplante se realiza de una manera precoz, por lo que estos pacientes deberían recibir una puntuación adicional para poder emplear el MELD como una escala válida (AU)

Introduction There is currently no effective medical therapy for polycystic liver (PCL). Cyst puncture and sclerotherapy, cyst fenestration, or partial hepatic resections have been used as palliative treatments. Orthotopic liver transplantation (OLT) has become the treatment of choice for terminal PCL, being indicated in patients with limiting symptoms not susceptible to any other medical treatment. It is also difficult to determine the priority on the waiting list using the Model for End-Stage Liver Disease (MELD).MethodsA retrospective analysis of OLT for PCL was conducted in our centre. Inclusion criteria were patients with limiting symptoms, bilateral cysts liver, and insufficient remaining liver. In all cases a deceased donor liver transplantation with piggy-back technique without veno-venous bypass was performed.ResultsSix patients underwent liver transplantation for PCL between April 1992 and April 2010, one of them a combined liver-kidney transplantation. The mean intraoperative packed red blood cell transfusion was 3.25 L and fresh frozen plasma was 1.200 cc. Mean operation time was 299 min, and 498 min in the liver-kidney transplantation. There was no peri-operative mortality. The mean hospital stay was 6.5 days. All patients are healthy after a mean follow-up of 71 months.ConclusionOLT offers an excellent overall survival. Results are better when OLT is performed early; thus these patients should receive additional points to be able to use the MELD score as a valid prioritisation system for waiting lists (AU)

[Orthotopic liver transplantation in polycystic liver disease]. / Trasplante ortotópico de hígado en la poliquistosis hepática.

INTRODUCTION: There is currently no effective medical therapy for polycystic liver (PCL). Cyst puncture and sclerotherapy, cyst fenestration, or partial hepatic resections have been used as palliative treatments. Orthotopic liver transplantation (OLT) has become the treatment of choice for terminal PCL, being indicated in patients with limiting symptoms not susceptible to any other medical treatment. It is also difficult to determine the priority on the waiting list using the Model for End-Stage Liver Disease (MELD). METHODS: A retrospective analysis of OLT for PCL was conducted in our centre. Inclusion criteria were patients with limiting symptoms, bilateral cysts liver, and insufficient remaining liver. In all cases a deceased donor liver transplantation with piggy-back technique without veno-venous bypass was performed. RESULTS: Six patients underwent liver transplantation for PCL between April 1992 and April 2010, one of them a combined liver-kidney transplantation. The mean intraoperative packed red blood cell transfusion was 3.25 L and fresh frozen plasma was 1.200 cc. Mean operation time was 299 min, and 498 min in the liver-kidney transplantation. There was no peri-operative mortality. The mean hospital stay was 6.5 days. All patients are healthy after a mean follow-up of 71 months. CONCLUSION: OLT offers an excellent overall survival. Results are better when OLT is performed early; thus these patients should receive additional points to be able to use the MELD score as a valid prioritisation system for waiting lists.

Zolmitriptan: a novel portal hypotensive agent which synergizes with propranolol in lowering portal pressure.

OBJECTIVE: Only a limited proportion of patients needing pharmacological control of portal hypertension are hemodynamic responders to propranolol. Here we analyzed the effects of zolmitriptan on portal pressure and its potential interaction with propranolol. METHODS: ZOLMITRIPTAN, PROPRANOLOL OR BOTH WERE TESTED IN TWO RAT MODELS OF PORTAL HYPERTENSION: common bile duct ligation (CBDL) and CCl4-induced cirrhosis. In these animals we measured different hemodynamic parameters including portal venous pressure, arterial renal flow, portal blood flow and cardiac output. We also studied the changes in superior mesenteric artery perfusion pressure and in arterial wall cAMP levels induced by zolmitriptan, propranolol or both. Moreover, we determined the effect of splanchnic sympathectomy on the response of PVP to zolmitriptan. RESULTS: In both models of portal hypertension zolmitriptan induced a dose-dependent transient descent of portal pressure accompanied by reduction of portal flow with only slight decrease in renal flow. In cirrhotic rats, splanchnic sympathectomy intensified and prolonged zolmitriptan-induced portal pressure descent. Also, propranolol caused more intense and durable portal pressure fall when combined with zolmitriptan. Mesenteric artery perfusion pressure peaked for about 1 min upon zolmitriptan administration but showed no change with propranolol. However propranolol enhanced and prolonged the elevation in mesenteric artery perfusion pressure induced by zolmitriptan. In vitro studies showed that propranolol prevented the inhibitory effects of ß2-agonists on zolmitriptan-induced vasoconstriction and the combination of propranolol and zolmitriptan significantly reduced the elevation of cAMP caused by ß2-agonists. CONCLUSION: Zolmitriptan reduces portal hypertension and non-selective beta-blockers can improve this effect. Combination therapy deserves consideration for patients with portal hypertension failing to respond to non-selective beta-blockers.

Case-based reasoning emulation of persons for wheelchair navigation.

OBJECTIVE: Testing is a key stage in system development, particularly in systems such as a wheelchair, in which the final user is typically a disabled person. These systems have stringent safety requirements, requiring major testing with many different individuals. The best would be to have the wheelchair tested by many different end users, as each disability affects driving skills in a different way. Unfortunately, from a practical point of view it is difficult to engage end users as beta testers. Hence, testing often relies on simulations. Naturally, these simulations need to be as realistic as possible to make the system robust and safe before real tests can be accomplished. This work presents a tool to automatically test wheelchairs through realistic emulation of different wheelchair users. METHODS AND MATERIALS: Our approach is based on extracting meaningful data from real users driving a power wheelchair autonomously. This data is then used to train a case-based reasoning (CBR) system that captures the specifics of the driver via learning. The resulting case-base is then used to emulate the driving behavior of that specific person in more complex situations or when a new assistive algorithm needs to be tested. CBR returns user's motion commands appropriate for each specific situation to add the human component to shared control systems. RESULTS: The proposed system has been used to emulate several power wheelchair users presenting different disabilities. Data to create this emulation was obtained from previous wheelchair navigation experiments with 35 volunteer in-patients presenting different degrees of disability. CBR was trained with a limited number of scenarios for each volunteer. Results proved that: (i) emulated and real users returned similar paths in the same scenario (maximum and mean path deviations are equal to 23 and 10cm, respectively) and similar efficiency; (ii) we established the generality of our approach taking a new path not present in the training traces; (iii) the emulated user is more realistic - path and efficiency are less homogeneous and smooth - than potential field approaches; and (iv) the system adequately emulates in-patients - maximum and mean path deviations are equal to 19 and 8.3cm approximately and efficiencies are similar - with specific disabilities (apraxia and dementia) obtaining different behaviors during emulation for each of the in-patients, as expected. CONCLUSIONS: The proposed system adequately emulates the driving behavior of people with different disabilities in indoor scenarios. This approach is suitable to emulate real users' driving behaviors for early testing stages of assistive navigation systems.

Efficacy and safety of sorafenib in combination with mammalian target of rapamycin inhibitors for recurrent hepatocellular carcinoma after liver transplantation.

There is currently no consensus on the most suitable treatment for the recurrence of hepatocellular carcinoma (HCC) after liver transplantation. This open, multicenter, retrospective, uncontrolled cohort study was designed to evaluate the safety and preliminary efficacy of the combined use of a mammalian target of rapamycin (mTOR) inhibitor and sorafenib in this setting. In 31 patients who suffered from HCC recurrence after liver transplantation, the immunosuppressive therapy was changed to mTOR inhibitors, and systemic treatment with sorafenib was initiated. This combination was maintained until symptomatic tumor progression, death, hepatic decompensation, or unacceptable toxicity occurred. Primary treatment efficacy was determined by overall survival and progression-free survival, and secondary efficacy was determined by the overall response rate. Toxicity parameters associated with the use of sorafenib and mTOR inhibitors were also analyzed. The overall response rate according to the Response Evaluation Criteria in Solid Tumors was 3.8% (1/26), and there was sustained stabilization of the disease in 13 additional cases (50.0%). The median overall survival was 19.3 months [95% confidence interval (CI) = 13.4-25.1 months], and the median time to progression was 6.77 months (95% CI = 2.3-11.1 months). Only 2 grade 3/4 cases of hyperglycemia and 1 case of grade 3/4 mucositis were reported, and they were possibly related to mTOR inhibitors. The most common severe adverse event probably related to sorafenib was diarrhea (12.9%). In conclusion, the coadministration of sorafenib and an mTOR inhibitor could be effective despite notable toxicity in patients with post-liver transplant HCC recurrence not suitable for radical therapy. The toxicity and efficacy need to be further evaluated in randomized controlled studies for this combination to be considered a valid option.

Differential in vitro and in vivo effect of barley cysteine and serine protease inhibitors on phytopathogenic microorganisms.

Protease inhibitors from plants have been involved in defence mechanisms against pests and pathogens. Phytocystatins and trypsin/α-amylase inhibitors are two of the best characterized protease inhibitor families in plants. In barley, thirteen cystatins (HvCPI-1 to 13) and the BTI-CMe trypsin inhibitor have been previously studied. Their capacity to inhibit pest digestive proteases, and the negative in vivo effect caused by plants expressing these inhibitors on pests support the defence function of these proteins. Barley cystatins are also able to inhibit in vitro fungal growth. However, the antifungal effect of these inhibitors in vivo had not been previously tested. Moreover, their in vitro and in vivo effect on plant pathogenous bacteria is still unknown. In order to obtain new insights on this feature, in vitro assays were made against different bacterial and fungal pathogens of plants using the trypsin inhibitor BTI-CMe and the thirteen barley cystatins. Most barley cystatins and the BTI-CMe inhibitor were able to inhibit mycelial growth but no bacterial growth. Transgenic Arabidopsis plants independently expressing the BTI-CMe inhibitor and the cystatin HvCPI-6 were tested against the same bacterial and fungal pathogens. Neither the HvCPI-6 expressing transgenic plants nor the BTI-CMe ones were more resistant to plant pathogen fungi and bacteria than control Arabidopsis plants. The differences observed between the in vitro and in planta assays against phytopathogenic fungi are discussed.

Treatment of murine fulminant hepatitis with genetically engineered endothelial progenitor cells.

BACKGROUND & AIMS: Cell therapy has been used to attenuate liver injury. Here we evaluated whether genetic engineering of either bone marrow-derived mononuclear cells (MNC) or endothelial progenitor cells (EPC) many enhance their hepatoprotective properties. METHODS: Mice with ConA-induced hepatitis or with lethal fulminant hepatitis resulting from administration of an adenovirus encoding CD40L (AdCD40L) received an intra-splenic injection of saline or 2 × 10(6) unmodified MNC or EPC or the same cells transduced ex vivo with an adenovirus expressing luciferase (MNCLUC and EPCLUC) or encoding the hepatoprotective cytokine cardiotrophin-1 (CT-1) (MNCCT-1 and EPCCT-1). We analyzed the extent of liver damage, the intensity of inflammatory reaction, and animal survival. RESULTS: Luciferase immunohistochemistry showed that after injection into the spleen, the engineered cells migrated efficiently to the damaged liver. In mice with ConA hepatitis EPCCT-1, but not other forms of cell therapy, significantly decreased serum transaminases and induced more intense histological improvement than other treatments. This superior therapeutic effect was associated with upregulation of cytoprotective molecules including IGF-I and EGF, lower expression of proinflammatory cytokines, IL-1b and TNFα, and decreased granzyme B levels. In AdCD40L-induced lethal fulminant hepatitis, EPCCT-1 also exceeded other cell therapies in attenuating the expression of proinflammatory mediators and hepatic injury enabling 35.7% survival while mortality was 100% in the other treatment groups. CONCLUSIONS: Genetic engineering of EPC to overexpress CT-1 enhances the hepatoprotective properties of EPC and constitutes a therapy that deserves consideration for acute liver failure.