Chronic treatment with lisinopril decreases proliferative and apoptotic pathways in autosomal recessive polycystic kidney disease

Angiotensin converting enzyme (ACE) inhibition is a common therapeutic modality in the treatment of autosomal recessive polycystic kidney disease (ARPKD). This study was designed to investigate whether chronic inhibition of ACE would have a therapeutic effect in attenuating the progression of renal cystogenesis in an orthologous rat model of ARPKD, the polycystic kidney (PCK) rat. Lisinopril (3 mg/kg per day) was administered orally for a period of 12 weeks, beginning at post-natal week 4. Lisinopril treatment resulted in an ∼30% improvement in the collecting duct cystic indices (CT CI) of PCK animals. Activation of extracellular signal-regulated kinase 1 (ERK1) and 2 (ERK2), proliferative signaling markers, and proliferating cell nuclear antigen (PCNA), an end-point marker for proliferation, was reduced following chronic treatment with lisinopril compared to that in vehicle-treated PCK rats. To assess whether apoptotic pathways were altered due to chronic ACE inhibition, we examined p38 mitogen activated protein kinase (MAPK) and stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK), which are markers of apoptotic signaling cascades. p38 MAPK was significantly reduced (P < 0.0001) following chronic treatment with lisinopril, but no change in the activation of SAPK/JNK could be detected by immunoblot analysis. Lisinopril treatment resulted in a significant reduction (P < 0.01) in cleaved caspase-7 levels, but not caspase-3 activity, in PCK rat kidneys compared to the vehicle-treated PCK rat kidneys. Proteinuria was completely ameliorated in the presence of chronic ACE inhibition in the lisinopril-treated rats compared with the vehicle-treated PCK rats. In all, these findings demonstrated that chronic ACE inhibition can beneficially alter proliferative and apoptotic pathways to promote therapeutic reductions in renal cyst development in ARPKD.     

Preemptive Therapy in Adult Liver Transplant Recipients in CMV-Endemic Area

Cytomegalovirus (CMV) infection is not only a common complication after liver transplantation but also a significant contributing factor to morbidity and mortality. We investigated whether preemptive therapy can prevent CMV syndrome or tissue-invasive CMV disease in an endemic area. Preemptive therapy was initiated when more than 10 positive CMV pp65 antigen-positive cells per 400,000 white blood cells were detected, regardless of clinical manifestations. Intravenous ganciclovir as preemptive therapy was administered daily for 10 to 14 days until negative results were achieved. The incidence of initial CMV antigenemia and CMV syndrome during the posttransplantation period was 49.7% (353/710) and 5.2% (37/710), respectively. One hundred eight-two patients (51.6%) received ganciclovir as preemptive therapy. Patients with CMV antigenemia who received preemptive therapy had high Model for End-Stage Liver Disease score, repeat operation, renal dysfunction, infection, low hemoglobin concentration, low platelet count, low albumin concentration, high international normalized ratio, high total bilirubin value, high aspartate transaminase concentration, and high CMV peak titer. Cytomegalovirus syndrome and tissue-invasive CMV disease were more common in these patients. The survival curve in patients without CMV syndrome was better than that in those with CMV syndrome (P = .000). Patients with more than 10 pp65 antigen-positive cells per 400,000 white blood cells should be treated aggressively with an antiviral agent as preemptive therapy because CMV infection is common in CMV-endemic areas and patients with CMV syndrome demonstrate poor survival rates.     

Infection of Porcine Cells with Human Herpesviruses

Porcine organs are valuable candidate materials for xenotransplantation to humans. Long-term maintenance of well functioning transplants is a prerequisite for success. Transplanted organs may be damaged by immune reactions or by infectious agents in hosts. Human herpesviruses (HHVs) establish life-long latency in humans after a primary infection. They can be reactivated with various stimuli, including immunosuppression. This study was performed to verify the infectivity of some HHVs toward porcine cells. PK-15 cells infected with HHV-1 and HHV-2 showed cytopathology from 1 day after infection. Immunofluorescent (IF) staining of HHV-1- and HHV-2-infected PK-15 cells with respective antibodies demonstrated the expression of the respective viral antigens. Permissiveness of PK-15 to HHV-1 and -2 was confirmed by an infection test on Vero cells. Islet cells infected with HHV-5 showed no gross morphologic changes during the experimental course. A limited portion of islet cells reacted only to anti-IE1 and anti-IE2, but not to anti-UL44 or anti-gB antibody by IF staining, whereas a small portion of endothelial cells reacted to anti-IEs and anti-UL44, but not to anti-gB antibody. HHV-1 and -2 can permissively infect porcine cells, but HHV-5 infects a small proportion of cells with limited viral protein expression. HHV-4 could not transform peripheral blood mononuclear cells from miniature pigs. Collectively, because some HHVs can infect and damage porcine cells or impair their functions, HHVs should be cautiously monitored and controlled in humans when porcine cells or organs are transplanted to human beings.     

Timing of Resection for Synchronous Liver Metastases from Colorectal Cancer

Background  

This study aimed to compare the surgical outcome and long-term survival between simultaneous and delayed resection of liver metastases from colorectal cancer (LM), and to identify the factors influencing hepatic disease-free survival in patients with synchronous LM.     

Portal Hypertensive Gastropathy: Correlation with Portal Hypertension and Prognosis in Cirrhosis

Background

Portal hypertensive gastropathy (PHG) is a common endoscopic finding in patients with cirrhosis. However, the relationship between PHG and portal hypertension is controversial. Furthermore, nothing is known regarding the correlation between PHG and prognosis in patients with cirrhosis.

Methods

The hepatic venous pressure gradient (HVPG), endoscopic PHG grade, Child–Pugh score, and model for end-stage liver disease (MELD) score were assessed at baseline and were followed prospectively in 331 cirrhotic patients (284 males, 85.8%; mean age, 52.16 ± 9.05 years) from January 2001 to April 2009. The relationship between PHG with HVPG and survival was investigated.

Results

The HVPG was significantly higher in patients with severe PHG than in those with mild or no PHG (absent, 4.9 ± 1.7 mmHg; mild, 10.7 ± 4.1 mmHg; severe, 15.6 ± 4.6 mmHg; P < 0.001). During follow-up, 28 patients (8.5%) died from liver-related disease. In the Cox regression analysis, severe PHG (none and mild vs. severe) (hazard ratio 1.153, 95% confidence interval: 1.048–1.269) showed a significantly high relative risk of mortality, and in the Kaplan–Meier analysis, severe PHG showed a significantly shorter expected survival time than none or mild PHG (median survival time, 77.6 ± 9.6 months in severe PHG; log-rank test, P = 0.030).

Conclusions

PHG was associated with portal hypertension severity and prognosis in patients with cirrhosis.     

Early onset multiple myeloma in a patient with systemic lupus erythematosus: a case report and literature review

Patients with systemic lupus erythematosus (SLE) are at increased risk for various plasma cell dyscrasias, but the coexistence of SLE and multiple myeloma (MM) are rarely reported to date. Due to the rarity, the clinical features of MM associated with SLE have not been elucidated, and the pathogenesis under this association remains unclear. In this report, we investigate a 31-year-old woman with 5-year history of SLE, who is diagnosed as IgA λ-type MM with multiple lymph node involvement. We discuss the clinical features of MM in SLE by reviewing previous cases and possible mechanisms connecting the two conditions.