Two mutations in the ORF1 of genotype 1 hepatitis E virus enhance virus replication and may associate with fulminant hepatic failure.

Hepatitis E virus (HEV) infection in pregnant women has a high incidence of developing fulminant hepatic failure (FHF) with significant mortality. Multiple amino acid changes in genotype 1 HEV (HEV-1) are reportedly linked to FHF clinical cases, but experimental confirmation of the roles of these changes in FHF is lacking. By utilizing the HEV-1 indicator replicon and infectious clone, we generated 11 HEV-1 single mutants, each with an individual mutation, and investigated the effect of these mutations on HEV replication and infection in human liver cells. We demonstrated that most of the mutations actually impaired HEV-1 replication efficiency compared with the wild type (WT), likely due to altered physicochemical properties and structural conformations. However, two mutations, A317T and V1120I, significantly increased HEV-1 replication. Notably, these two mutations simultaneously occurred in 100% of 21 HEV-1 variants from patients with FHF in Bangladesh. We further created an HEV-1 A317T/V1120I double mutant and found that it greatly enhanced HEV replication, which may explain the rapid viral replication and severe disease. Furthermore, we tested the effect of these FHF-associated mutations on genotype 3 HEV (HEV-3) replication and found that all the mutants had a reduced level of replication ability and infectivity, which is not unexpected due to distinct infection patterns between HEV-1 and HEV-3. Additionally, we demonstrated that these FHF-associated mutations do not appear to alter their sensitivity to ribavirin (RBV), suggesting that ribavirin remains a viable option for antiviral therapy for patients with FHF. The results have important implications for understanding the mechanism of HEV-1-associated FHF.

Outcomes of liver diseases in pregnant females: A study from a tertiary care medical center in Pakistan.

Objective: To determine the etiologies and outcomes of liver disease in pregnancy in a developing country. Method: A total of 336 consecutive pregnant women with liver disease were included in this prospective cohort study conducted at the Department of Gastroenterology, Jinnah Postgraduate Medical Center, Karachi from August 2019 to August 2021. Patients' baseline demographic, clinical, and laboratory data and outcomes were collected on a pre-designed questionnaire. Results: Among all the pregnant females, the most common liver disease was acute hepatitis E virus (HEV) infection (37.2%), followed by preeclampsia (PEC)/eclampsia (EC), hemolysis, elevated liver enzymes & low platelets (HELLP) syndrome, and hyperemesis gravidarum (HG). The most common maternal complications were fulminant hepatic failure (FHF) in 14.9% and placental abruption in 11.0%. Fetal complications included intrauterine death (IUD) in 20.8% and preterm birth in 8.6%. The maternal and neonatal mortality rates were 11.6% and 39.6%, respectively. Among the predictors, low maternal weight, low body mass index (BMI), and low hemoglobin (Hb) were associated with increased maternal mortality. Low fetal weight, height, maternal systolic blood pressure (SBP), and low maternal Hb were independent predictors of fetal mortality. Conclusion: In our cohort of pregnant females in a tertiary care medical center, acute HEV was the most common liver disease, followed by PEC/EC, HELLP, and HG. Maternal and fetal deaths were alarming in this group of patients and demanded careful management.

Role of Hepatitis C Infection in Acute Liver Injury/Acute Liver Failure in North America.

BACKGROUND: While hepatitis A and B are well-known causes of acute liver failure (ALF), few well-documented cases of hepatitis C virus (HCV) infection (absent preexisting liver disease or other liver insults) have been described that result in ALF. We reviewed the Acute Liver Failure Study Group registry for evidence of HCV as a primary or contributing cause to ALF. METHODS: From January 1998 to January 2017, 2,332 patients with ALF (INR ≥ 1.5, any degree of hepatic encephalopathy) and 667 with acute liver injury (ALI; INR ≥ 2.0, no hepatic encephalopathy) were enrolled. Anti-HCV testing was done routinely, with confirmatory RT-PCR testing for HCV RNA where necessary. RESULTS: A total of 136 patients were anti-HCV-antibody positive, as follows: 56 HCV RNA negative, 65 HCV RNA positive, and 8 with no result nor sera available for testing. Only three subjects with ALI/ALF were determined to represent acute HCV infection. Case 1: 47-year-old female with morbid obesity (BMI 52.4) developed ALF and recovered, experiencing anti-HCV seroconversion. Case 2: 37-year-old female using cocaine presented with ALI and fully recovered. Case 3: 54-year-old female developed ALF requiring transplantation and was anti-HCV negative but viremic prior to transplant experiencing anti-HCV seroconversion thereafter. Among 1636 APAP overdose patients, the 52 with concomitant chronic HCV had higher 3-week mortality than the 1584 without HCV (31% vs 17%, p = 0.01). CONCLUSIONS: ALI/ALF solely related to acute hepatitis C infection is very rare. Chronic HCV infection, found in at least 65 (2.2%) of ALI/ALF patients studied, contributed to more severe outcomes in APAP ALI/ALF; ClinicalTrials.gov number, NCT000518440. Trial Registration ClinicalTrials.gov number NCT000518440.

Scrub typus fulminating as liver failure: A rare report.

Scrub typhus is almost an endemic tropical mite-borne, zoonotic illness often cognate with the bacterium Orientia tsutsugamushi. After a typical incubation period of a fortnight, non-specific symptoms including fever, headache, and a specific skin 'eschar' is customary. If untreated after a symptomatic week, scrub typus may precipitate end-organ involvements spiraling into vivid complications. Nevertheless, crub typhus tends to display mild transaminitis, frank liver failure is hardly common in clinical practice. An instance of scrub typus triggering fulminant hepatic failure (FHF) in a middle-aged female is being reported here.

Pediatric Acute Liver Failure: A Clinicopathological Perspective.

Pediatric acute liver failure (PALF) is a life-threatening disorder characterized by acute hepatocellular injury occurring in children without recognized underlying liver disease. The clinicopathologic evaluation of PALF requires a different approach from that in adults. The diagnostic considerations differ depending on the age, personal and family history, geographical region, and clinical presentation. Distinct entities such as gestational alloimmune liver disease, herpes simplex virus infection, and metabolic disorders should be considered in neonates with acute liver failure, while acetaminophen toxicity and autoimmune hepatitis are more frequently seen in older children and adolescents. An identified cause for PALF despite a negative complete evaluation (indeterminate) is lacking in 30 to 50% of cases. Although not routinely performed in the setting of PALF, liver biopsy may be helpful in assessing the etiology, potential mechanisms of injury, determining the appropriateness of liver transplantation, and prognostication of the patients. In this article, we review the clinicopathologic characteristics of PALF with an emphasis on general approach of pathologic evaluation and histopathologic characteristic of selected entities.

MicroRNA Profile of Human Bone Marrow Mesenchymal Stem Cells during Hepatic Differentiation and Therapy.

Background and Aims: MicroRNAs (miRNAs) play important roles in hepatocyte differentiation from human bone marrow mesenchymal stem cells (hBMSCs) and the therapeutic application in vivo. However, the mechanisms of miRNA regulation are still unknown. This study aimed to profile the miRNA basis for improving the function of hBMSC-differentiated hepatocyte-like cells (hBMSC-Heps). Methods: Characteristic miRNAs of hBMSC-Heps were identified by transcriptome sequencing and validated by quantitative real-time polymerase chain reaction (qRT-PCR). An in vivo hBMSC transplantation model was used to assess the regulatory effects of miRNAs on liver regeneration during hBMSC therapy in pigs with fulminant hepatic failure (FHF). The biological functions of significant miRNA molecules were confirmed by transfection of miRNA activators or inhibitors into hBMSCs during hepatogenic differentiation. Results: The transcriptome of hBMSC-Heps showed characteristics distinct from those of undifferentiated hBMSCs. A total of 77 miRNAs were significantly differentially expressed in hBMSC-Heps at day 10 and day 20 after hBMSC differentiation that were directly related to the functions of hepatocytes. Among the top 10 significantly differentially expressed and the top 10 most abundant miRNAs, nine miRNAs that exhibited a pattern of gradual change were chosen for further analysis. The expression of nine miRNAs was confirmed by qRT-PCR in vitro and showed the same changing trends in vivo in an hBMSC transplantation model in pigs. Functional experiments with these miRNAs showed that activators of hsa-miR-26b-5p and hsa-miR-148a-3p and an inhibitor of hsa-miR-423-3p were sufficient to improve the differentiation of hBMSCs into hepatocyte-like cells. Conclusions: Transcriptome profiles of miRNA revealed the basis of the differentiation and development of hBMSC-Heps. Manipulation of three miRNAs (hsa-miR-26b-5p, hsa-miR-148a-3p and hsa-miR-423-3p) significantly improved hepatocyte generation and liver regeneration, indicating the potential of these miRNAs for future clinical applications.

Tropical Fever: Unveiling an Asymptomatic Case of Polycythemia Vera.

We report a case of fulminant hepatic failure due to the Budd-Chiari syndrome following preservation with a tropical fever. A young lady came with fever, altered mental status, jaundice, and renal failure. Following tropical workup, it was diagnosed as a case of leptospirosis (WHO Faine's criteria) with multi-organ dysfunction. Despite adequate antimicrobial cover, she progressed to hepatic coma (hyperammonemia) and was noted to have worsening conjugated hyperbilirubinemia. Following history review and evaluation for other causes of hepatic failure, hepatic vein thrombosis was detected in addition to the presence of antibodies against Leptospira antigen. Further studies into the causes of thrombosis and persistent hemoconcentration despite aggressive fluid resuscitation led to the diagnosis of polycythemia vera (cytometric analysis). During her stay, she further worsened despite aggressive organ support including dialysis but she succumbed to gram-negative sepsis that occurred during her stay in ICU. This is an interesting and rare case of leptospirosis that unveiled a case of previously asymptomatic polycythemia vera. How to cite this article: Naik BK, Sulakshana S, Gopaldas JA, Devvrat S. Tropical Fever: Unveiling an Asymptomatic Case of Polycythemia Vera. Indian J Crit Care Med 2022;26(3):387-389.

Impact of donation after circulatory death donor allografts on outcomes following liver transplantation for fulminant hepatic failure in the United States.

Limited data exist regarding the impact of donation after circulatory death (DCD) allografts on outcomes following liver transplantation in fulminant hepatic failure (FHF). Utilizing the Scientific Registry of Transplant Recipients (SRTR), we compared outcomes after DCD in FHF to donation after brain death (DBD) in FHF and DCD in non-FHF over a 15-year period. Primary outcome measures were graft and patient survival. A total of 117, 3437, and 4379 recipients underwent DCD-FHF, DBD-FHF and DCD-non-FHF, respectively. One-year graft survival in DCD-FHF was inferior to DBD-FHF (72.9% vs. 83.8%, p = .002), but comparable to DCD-non-FHF (72.9% vs. 82.7%, p = .23). However, 3- and 5-year graft survival in DCD-FHF were comparable to DBD-FHF (67.9 vs. 77.6%, p = .63; 57.8% vs. 73.2%, p = .27) and DCD-non-FHF (67.9% vs. 72.9%, p = .44; 57.8% vs. 66.6%, p = .06). One-, 3-, and 5-year patient survival were also comparable among the three groups. Graft and patient survival in DCD-FHF improved over the study period. Multivariable analysis identified recipient age, male gender, African American ethnicity, donor age, and cold ischemia time as predictors of graft and patient survival in FHF, while DCD status was only predictive of graft survival. Long-term graft survival and patient survival in DCD-FHF are comparable to DBD-FHF and DCD-non-FHF. Consideration of DCD in FHF could help expand the donor pool in this subset of critically ill patients.

Successful orthotopic liver transplantation in a patient with a positive SARS-CoV2 test and acute liver failure secondary to acetaminophen overdose.

SARS-CoV2, first described in December 2019, was declared a pandemic by the World Health Organization in March 2020. Various surgical and medical societies promptly published guidelines, based on expert opinion, on managing patients with COVID-19, with a consensus to postpone elective surgeries and procedures. We describe the case of an orthotopic liver transplantation (OLT) in a young female who presented with acute liver failure secondary to acetaminophen toxicity to manage abdominal pain and in the setting of a positive SARS-CoV2 test. Despite a positive test, she had no respiratory symptoms at time of presentation. The positive test was thought to be residual viral load. The patient had a very favorable outcome, likely related to multiple factors including her young age, lack of respiratory COVID-19 manifestations and plasma exchange peri-operatively. We recommend a full work-up for OLT in COVID-19 patients with uncomplicated disease according to standard of care, with careful interpretation of COVID-19 testing in patients presenting with conditions requiring urgent or emergent surgery as well as repeat testing even a few days after initial testing, as this could alter management.

Outcomes of status 1 liver transplantation for Budd-Chiari Syndrome with fulminant hepatic failure.

There is a paucity of data on the outcome of liver transplantation (LT) in Budd-Chiari Syndrome (BCS) patients who are listed as status 1. The objective of our study was to determine patient or graft survival following LT in status 1 BCS patients. We utilized United Network for Organ Sharing (UNOS) database to identify all adult patients (> 18 years of age) listed as status 1 with a primary diagnosis of BCS in the United States from 1998 to 2018, and analyzed their outcomes and compared it to non-status 1 BCS patients. Four hundred and forty-six patients with BCS underwent LT between 1998 and 2018, and of these 55 (12.3%) were listed as status 1. There was no difference in long-term post-liver transplant or "intention-to-treat" survival from the time of listing to death or the last day of follow-up between status 1 and non-status 1 groups. Graft and patient survival at 5 years for status 1 patients were 75% and 82%, respectively. Cox regression analysis showed that patients listed as status 1 (aHR: 0.45, p < .02) were associated with a better survival. BCS patients listed as status 1 have excellent survival following emergency LT.

Melatonin modulates mitophagy, innate immunity and circadian clocks in a model of viral-induced fulminant hepatic failure.

The haemorrhagic disease virus (RHDV) is a non-cultivable virus that promotes in rabbits an acute disease which accomplishes many characteristics of an animal model of fulminant hepatic failure (FHF). Beneficial effects of melatonin have been reported in RHDV-infected rabbits. This study investigated whether protection against viral-derived liver injury by melatonin is associated with modulation of mitophagy, innate immunity and clock signalling. Rabbits were experimentally infected with 2 × 104 haemagglutination units of a RHDV isolate and killed at 18, 24 and 30 hours after infection (hpi). Melatonin (20 mg/kg body weight ip) was administered at 0, 12 and 24 hpi. RHDV infection induced mitophagy, with the presence of a high number of mitophagosomes in hepatocytes and increased expression of mitophagy genes. Greater expression of main innate immune intermediaries and inflammasome components was also found in livers with RHDV-induced FHF. Both mitophagy and innate immunity activation was significantly hindered by melatonin. FHF induction also elicited an early dysregulation in clock signalling, and melatonin was able to prevent such circadian disruption. Our study discloses novel molecular routes contributing to RHDV-induced damage progression and supports the potential of melatonin as a promising therapeutic option in human FHF.

Up-regulation of microRNA-30b/30d cluster represses hepatocyte apoptosis in mice with fulminant hepatic failure by inhibiting CEACAM1.

Recently, impacts of microRNAs have been unraveled in human diseases, and we aimed to confirm the role of miR-30b/30d in fulminant hepatic failure (FHF). Expression of miR-30b/30d and CEACAM1 in serum of FHF patients and healthy people was measured by reverse transcription quantitative polymerase chain reaction (RT-qPCR) and Western blot analysis. Mice FHF models were established by injection of D-Galn and lipopolysaccharide, and were treated with miR-30b/30d mimics. Oxidative stress, liver injury, and inflammatory reaction in mouse liver tissues were measured using oxidative stress-related factor kits, hematoxylin-eosin staining and enzyme-linked immunosorbent assay, respectively. Moreover, cell cycle distribution and apoptosis of hepatocytes of mice were determined by flow cytometry, and the target relation between miR-30b/30d and CEACAM1 was confirmed by bioinformatic method and dual luciferase reporter gene assay. MiR-30b/30d expression was positively, and CEACAM1 expression was negatively related to prognosis of FHF patients. Up-regulation of miR-30b/30d attenuated oxidative stress, liver injury, and inflammatory reaction, and improved survival rate of FHF mice. Furthermore, elevated miR-30b/30d ameliorated apoptosis and cell cycle arrest of hepatocytes of FHF mice. CEACAM1 was a target gene of miR-30b/30d. This study highlights that up-regulated miR-30b/30d attenuates the progression of FHF by targeting CEACAM1, which may be helpful to FHF treatment.

Etiology, clinical presentation, and outcome of children with fulminant hepatic failure: Experience from a tertiary center in Pakistan.

OBJECTIVES: To determine etiologies, clinical presentations and outcomes of children with fulminant hepatic failure in the first liver transplant center of Pakistan. METHODS: It was a retrospective, observational study, conducted in Paediatric Gastroenterology Department of Shifa International Hospital. Patients between one month to 16 years were included who fulfilled the Pediatric Acute Liver Failure study group (PALFSG) definition of acute liver failure as biochemical evidence of liver injury with no known co-existing chronic liver disease, coagulopathy not corrected by vitamin K, an International Normalized Ratio (INR) greater than 1.5 if the patient has encephalopathy, or greater than 2.0 if the patient does not have encephalopathy. The data collected was recorded on a self-constructed proforma after IRB approval. RESULTS: There were 28 patients in the study which ncluded 17 males and 11 females with a mean age of 72.86±52.50 months. The most common etiologies were Hepatitis A (29%) in isolation or co-infection with Wilson Disease, typhoid fever. It was followed by seronegative hepatitis (29%). Majority (64%) had acute presentation (7 to 28 days), jaundice (82%) being the most common symptom. Severity of encephalopathy was significantly associated with outcome (p=0.02). There were 6 (21%) patients who succumbed to death. CONCLUSIONS: The study highlights infective diseases as the predominant etiology causing fulminant liver failure in children. Our study highlights lower mortality in children.

Geraniol protects against lipopolysaccharide and D-galactosamine-induced fulminant hepatic failure by activating PPARγ.

Geraniol (GOH), a natural component of plant essential oils, exhibits potent antioxidant and anti-inflammatory properties. The aim of this study was to assess the protective effects and mechanisms of GOH on lipopolysaccharide (LPS)/d-galactosamine (D-GalN)-induced fulminant hepatic failure (FHF). Mice were treated with GOH (12.5, 25, and 50 µg/kg) 1 h before challenging LPS (60 mg/kg) and D-GalN (800 mg/kg). 8 h later LPS/D-GlaN treatment, mice were sacrificed and the serum and the liver tissues were collected for testing. The liver pathological changes were assessed by H & E staining. MPO activity, MDA level in liver tissues, and AST, ALT levels in serum were detected by specific detection kits. The levels of TNF-α and IL-1ß were detected by ELISA. The expression of NF-κB and PPARγ were detected by western blot analysis and qRT-PCR. The results showed that GOH had a protective effect on LPS/D-GalN-induced FHF, as evidence by the attenuation of liver pathological injury, MPO activity, MDA level, and serum AST and ALT levels. GOH reduced liver TNF-α and IL-1ß levels through inhibiting NF-κB signaling pathway activation. Furthermore, GOH increased PPARγ expression in FHF induced by LPS/D-GalN. In conclusion, the present study proved that GOH protects against LPS/D-GalN-induced FHF through inhibiting inflammatory response and increasing PPARγ expression.

Liver transplantation in adults with acute liver failure: Outcomes from the Argentinean Transplant Registry.

INTRODUCTION AND AIM: Liver transplantation (LT) for acute liver failure (ALF) still has a high early mortality. We aimed to evaluate changes occurring in recent years and identify risk factors for poor outcomes. MATERIAL AND METHODS: Data were retrospectively obtained from the Argentinean Transplant Registry from two time periods (1998-2005 and 2006-2016). We used survival analysis to evaluate risk of death. RESULTS: A total of 561 patients were listed for LT (69% female, mean age 39.5±16.4 years). Between early and later periods there was a reduction in wait-list mortality from 27% to 19% (p<0.02) and 1-month post-LT survival rates improved from 70% to 82% (p<0.01). Overall, 61% of the patients underwent LT and 22% died on the waiting list. Among those undergoing LT, Cox regression analysis identified prolonged cold ischemia time (HR 1.18 [1.02-1.36] and serum creatinine (HR 1.31 [1.01-1.71]) as independent risk factors of death post-LT. Etiologies of ALF were only available in the later period (N=363) with indeterminate and autoimmune hepatitis accounting for 28% and 26% of the cases, respectively. After adjusting for age, gender, private/public hospital, INR, creatinine and bilirubin, and considering LT as the competing event, indeterminate etiology was significantly associated with death (SHR 1.63 [1.06-2.51] and autoimmune hepatitis presented a trend to improved survival (SHR 0.61 [0.36-1.05]). CONCLUSIONS: Survival of patients with ALF on the waiting list and after LT has significantly improved in recent years. Indeterminate cause and autoimmune hepatitis were the most frequent etiologies of ALF in Argentina and were associated with mortality.

Wilson disease.

Wilson disease (WD) is an inherited disorder of copper metabolism. The resultant defective handling of copper results in toxic effects on the hepatocytes and increased copper in the circulation. Copper accumulates in other organ sites especially the central nervous system. WD occurs worldwide, usually between 5 and 35 years; a wider age range is now recognized. Clinical presentations are diverse and include combinations of hepatic, neurological, ophthalmic and psychiatric manifestations. Biochemical abnormalities such as serum ceruloplasmin and 24-h urinary copper excretion are important for the diagnosis but are not always abnormal in WD. They can overlap with non-WD causes. Patients may present with hepatic or neurological disease or combinations thereof. Approx. 50% of WD patients present with liver disease. Liver presentation is variable: asymptomatic abnormal liver tests, chronic hepatitis picture, cirrhosis, and acute liver failure. Similarly, the histology has several different patterns: mild nonspecific changes, steatosis or steatohepatitis, chronic hepatitis, and acute hepatitis with submassive or massive necrosis. None of these are specific for WD. Aids to the histologic diagnosis include special stains for copper and copper associated protein, and copper concentration in liver tissue. The biopsy is performed in the context of the clinical algorithms for the diagnosis of WD put forth by the clinical hepatology organizations such as the European Association for the Study of Liver Disease and the American Association for the Study of Liver Disease. The discovery of the responsible gene ATP7B has made the molecular diagnosis feasible through genetic testing and sequencing of the gene.

Tectorigenin protects against experimental fulminant hepatic failure by regulating the TLR4/mitogen-activated protein kinase and TLR4/nuclear factor-κB pathways and autophagy.

Tectorigenin has received attention due to its antiproliferation, anti-inflammatory, and antioxidant activities. In this study, we investigated the effects of tectorigenin on lipopolysaccharide (LPS)/D-galactosamine(D-GalN)-induced fulminant hepatic failure (FHF) in mice and LPS-stimulated macrophages (RAW 264.7 cells). Pretreatment with tectorigenin significantly reduced the serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST), histological injury, apoptosis, and the mortality of FHF mice, by suppressing the production of inflammatory cytokines such as TNF-α and IL-6. Tectorigenin also suppressed the activation of the inflammatory response in LPS-stimulated RAW 264.7 cells. Tectorigenin-induced protection is mediated through its mitigation of TLR4 expression, inhibition of mitogen-activated protein kinase (MAPK) and nuclear factor-κB (NF-κB) pathway activation, and promotion of autophagy in FHF mice and LPS-stimulated RAW 264.7 cells. Therefore, tectorigenin has therapeutic potential for FHF in mice via the regulation of TLR4/MAPK and TLR4/NF-κB pathways and autophagy.

Interfering RNA against PKC-α inhibits TNF-α-induced IP3R1 expression and improves glomerular filtration rate in rats with fulminant hepatic failure.

We have reported that tumor necrosis factor-α (TNF-α) is critical for reduction of glomerular filtration rate (GFR) in rats with fulminant hepatic failure (FHF). The present study aims to evaluate the underlying mechanisms of decreased GFR during acute hepatic failure. Rats with FHF induced by d-galactosamine plus lipopolysaccharide (GalN/LPS) were injected intravenously with recombinant lentivirus harboring short hairpin RNA against the protein kinase C-α ( PKC-α) gene (Lenti-shRNA-PKC-α). GFR, serum levels of aminotransferases, creatinine, urea nitrogen, potassium, sodium, chloride, TNF-α, and endothelin-1 (ET-1), as well as type 1 inositol 1,4,5-trisphosphate receptor (IP3R1) expression in renal tissue were assessed. The effects of PKC-α silencing on TNF-α-induced IP3R1, specificity protein 1 (SP-1), and c-Jun NH2-terminal kinase (JNK) expression, as well as cytosolic calcium content were determined in glomerular mesangial cell (GMCs) with RNAi against PKC-α. Renal IP3R1 overexpression was abrogated by pre-treatment with Lenti-shRNA-PKC-α. The PKC-α silence significantly improved the compromised GFR, reduced Cr levels, and reversed the decrease in glomerular inulin space and the increase in glomerular calcium content in GalN/LPS-exposed rats. TNF-α treatment increased expression of PKC-α, IP3R1, specificity protein 1 (SP-1), JNK, and p-JNK in GMCs and increased Ca2 + release and binding activity of SP-1 to the IP3R1 promoter. These effects were blocked by transfection of siRNA against the PKC-α gene, and the PKC-α gene silence also restored cytosolic Ca2+ concentration. RNAi targeting PKC-α inhibited TNF-α-induced IP3R1 overexpression and in turn improved compromised GFR in the development of acute kidney injury during FHF in rats.

Consensus Report by the Pediatric Acute Lung Injury and Sepsis Investigators and Pediatric Blood and Marrow Transplantation Consortium Joint Working Committees on Supportive Care Guidelines for Management of Veno-Occlusive Disease in Children and Adolescents, Part 3: Focus on Cardiorespiratory Dysfunction, Infections, Liver Dysfunction, and Delirium.

Some patients with veno-occlusive disease (VOD) have multiorgan dysfunction, and multiple teams are involved in their daily care in the pediatric intensive care unit. Cardiorespiratory dysfunction is critical in these patients, requiring immediate action. The decision of whether to use a noninvasive or an invasive ventilation strategy may be difficult in the setting of mucositis or other comorbidities in patients with VOD. Similarly, monitoring of organ functions may be very challenging in these patients, who may have fulminant hepatic failure with or without hepatic encephalopathy complicated by delirium and/or infections. In this final guideline of our series on supportive care in patients with VOD, we address some of these questions and provide evidence-based recommendations on behalf of the Pediatric Acute Lung Injury and Sepsis Investigators and Pediatric Blood and Marrow Transplantation Consortium Joint Working Committees.