Autonomous Interfacial Assembly of Polymer Nanofilms via Surfactant-Regulated Marangoni Instability.

Interfacial polymerization (IP) provides a versatile platform for fabricating defect-free functional nanofilms for various applications, including molecular separation, energy, electronics, and biomedical materials. Unfortunately, coupled with complex natural instability phenomena, the IP mechanism and key parameters underlying the structural evolution of nanofilms, especially in the presence of surfactants as an interface regulator, remain puzzling. Here, we interfacially assembled polymer nanofilm membranes at the free water-oil interface in the presence of differently charged surfactants and comprehensively characterized their structure and properties. Combined with computational simulations, an in situ visualization of interfacial film formation discovered the critical role of Marangoni instability induced by the surfactants via various mechanisms in structurally regulating the nanofilms. Despite their different instability-triggering mechanisms, the delicate control of the surfactants enabled the fabrication of defect-free, ultra-permselective nanofilm membranes. Our study identifies critical IP parameters that allow us to rationally design nanofilms, coatings, and membranes for target applications.

Serum S100B Levels in Patients with Liver Cirrhosis and Hepatic Encephalopathy.

Hepatic encephalopathy (HE) is one of the main complications of liver cirrhosis (LC) and is classified into minimal hepatic encephalopathy (MHE) and overt hepatic encephalopathy (overt HE). S100B is expressed mainly in astrocytes and other glial cells, and S100B has been reported to be associated with various neurological disorders. The present study aimed to investigate the diagnostic ability of serum S100B to discriminate the grade of HE and the parameters correlated with serum S100B levels. Additionally, we investigated whether serum S100B levels can be used to predict 1-year mortality in cirrhotic patients. In total, 95 cirrhotic patients were consecutively enrolled and divided into the following three groups: (i) without any types of HEs; (ii) with MHE; and (iii) with overt HE. The diagnosis of MHE was made by the Mini-Mental State Examination (MMSE) and Psychometric Hepatic Encephalopathy Score (PHES). Among the three groups, there were no significant differences in serum S100B levels regardless of HE severity. The clinical parameters correlated with serum S100B levels were age, serum bilirubin, and creatinine levels. The Model for End-Stage Liver Disease (MELD) score showed a significant positive correlation with serum S100B levels. The relationship between serum S100B levels and MELD score was maintained in 48 patients without any type of HE. Additionally, hyperammonemia, low cholesterol levels, and the combination of serum S100B levels ≥ 35 pg/mL with MELD score ≥ 13 were factors for predicting 1- year mortality. In conclusion, serum S100B level was not useful for differentiating the severity of HE. However, we found that serum S100B levels can be affected by age, serum bilirubin, and creatinine in cirrhotic patients and are associated with MELD scores. Additionally, serum S100B levels showed the possibility of predicting 1-year mortality in cirrhotic patients. These findings suggest that serum S100B levels may reflect liver dysfunction and prognosis in liver disease.

Platelet-to-White Blood Cell Ratio: A Feasible Biomarker for Pyogenic Liver Abscess.

The platelet-to-white blood cell ratio (PWR) has been reported to predict the severity of patients with various diseases. However, no previous studies have assessed the use of the PWR as a prognostic marker for pyogenic liver abscesses (PLA). This observational retrospective study was performed between January 2008 and December 2017, including 833 patients with PLA from multiple centers. The enrolled patients, on average, had a PWR of 17.05, and 416 patients had a PWR lower than 17.05. A total of 260 patients (31.2%) with PLA showed complications of metastatic infection, pleural effusion and abscess rupture. A low PWR level was identified as a strong risk factor for metastatic infection and pleural effusion. The low PWR group also had a longer hospital stay. In the multivariate analysis, old age, anemia, albumin and CRP levels and unidentified pathogens were significant factors for low PWR levels. A low PWR, old age, male sex, abscess size, albumin, ALP and unidentified causative pathogens showed significant associations with a hospital stay longer than 28 days. As a result, PLA patients presenting with a low PWR were shown to have more complications and a poor prognosis. Considering its cost-effectiveness, PWR could be a novel biomarker used to predict a prognosis of PLA.

Primary Biliary Cholangitis and Primary Sclerosing Cholangitis: Current Knowledge of Pathogenesis and Therapeutics.

Cholangiopathies encompass various biliary diseases affecting the biliary epithelium, resulting in cholestasis, inflammation, fibrosis, and ultimately liver cirrhosis. Primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) are the most important progressive cholangiopathies in adults. Much research has broadened the scope of disease biology to genetic risk, epigenetic changes, dysregulated mucosal immunity, altered biliary epithelial cell function, and dysbiosis, all of which interact and arise in the context of ill-defined environmental triggers. An in-depth understanding of the molecular pathogenesis of these cholestatic diseases will help clinicians better prevent and treat diseases. In this review, we focus on the main underlying mechanisms of disease initiation and progression, and novel targeted therapeutics beyond currently approved treatments.

A Multicenter Retrospective Study on Clinical Characteristics and Outcome of Pyogenic Liver Abscess Focusing Multidrug-Resistant Organisms.

The emergence of multidrug-resistant organisms (MDROs) is a growing problem worldwide. However, little is known about the incidence, clinical features and outcomes of pyogenic liver abscesses (PLAs) caused by MDROs. A retrospective study of 833 patients with PLA admitted from 2008 to 2017 was performed. MDROs were found in 55 (6.6%) patients, and extended-spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae was the most common causative microorganism. To evaluate the clinical features of and risk factors for MDRO-induced PLAs, propensity score matching (PSM) was performed in a 1:3 ratio (55 patients with MDROs and 165 patients without MDROs). After PSM, previous hepatobiliary procedure, preadmission exposure to antibiotics and elevated alkaline phosphatase levels were independent risk factors for MDRO-induced PLA. Sixteen patients (7.3%) died during hospitalization. Admission to intensive care unit (ICU), inadequate initial antibiotic treatment and use of inotropic agents were factors predictive of mortality. Although the presence of MDROs was not associated with in-hospital mortality, inadequate initial antibiotic treatment was prescribed to a large portion of the patients with MDRO-induced PLAs. We conclude that initial empirical antibiotic therapy for PLA should be based on the possibility of infection with MDROs, and close monitoring is necessary for patients with risk factors for in-hospital mortality.

Plant-derived human recombinant growth factors and serum albumin maintain stemness of human-induced pluripotent stem cells.

Stem cells are an important therapeutic source for recovery and regeneration, as their ability of self-renewal and differentiation offers an unlimited supply of highly specialized cells for therapeutic transplantation. Growth factors and serum are essential for maintaining the characteristics of stem cells in culture and for inducing differentiation. Because growth factors are produced mainly in bacterial (Escherichia coli) or animal cells, the use of such growth factors raises safety concerns that need to be resolved for the commercialization of stem cell therapeutics. To overcome this problem, studies on proteins produced in plants have been conducted. Here, we describe the functions of plant-derived fibroblast growth factor 2 (FGF2) and human serum albumin in the maintenance and differentiation of human-induced pluripotent stem cells (hiPSCs). Plant-derived FGF2 and human epidermal growth factor EGF were able to differentiate hiPSCs into neural stem cells (NSCs). These NSCs could differentiate into neuronal and glial cells. Our results imply that culturing stem cells in animal-free culture medium, which is composed of plant-derived proteins, would facilitate stem cell application research, for example, for cell therapy, by reducing contamination risk.

Role of Microbiota-Derived Metabolites in Alcoholic and Non-Alcoholic Fatty Liver Diseases.

Chronic liver disease encompasses diseases that have various causes, such as alcoholic liver disease (ALD) and non-alcoholic fatty liver disease (NAFLD). Gut microbiota dysregulation plays a key role in the pathogenesis of ALD and NAFLD through the gut-liver axis. The gut microbiota consists of various microorganisms that play a role in maintaining the homeostasis of the host and release a wide number of metabolites, including short-chain fatty acids (SCFAs), peptides, and hormones, continually shaping the host's immunity and metabolism. The integrity of the intestinal mucosal and vascular barriers is crucial to protect liver cells from exposure to harmful metabolites and pathogen-associated molecular pattern molecules. Dysbiosis and increased intestinal permeability may allow the liver to be exposed to abundant harmful metabolites that promote liver inflammation and fibrosis. In this review, we introduce the metabolites and components derived from the gut microbiota and discuss their pathologic effect in the liver alongside recent advances in molecular-based therapeutics and novel mechanistic findings associated with the gut-liver axis in ALD and NAFLD.

Endovascular Treatments for Ruptured Intracranial Vertebral Artery Dissecting Aneurysms: Experience in 16 Patients.

OBJECTIVE: Intracranial vertebral artery dissecting aneurysms are rare lesions that are considered an important cause of spontaneous subarachnoid hemorrhage. We report our decade-long experience in treating ruptured intracranial vertebral artery dissecting aneurysms. MATERIALS AND METHODS: This retrospective single-center study included 21 consecutive patients between February 2005 and March 2015. Their clinical features included radiologic finding at the initial examination, treatment modality, functional outcome at the last follow-up, mortality, and radiologic outcome at more than 6 months after the initial treatment. RESULTS: All 16 aneurysms were treated endovascularly; aneurysm trapping was performed in 9 patients and vascular reconstruction was performed in 7 patients. For 6 aneurysms involving the posterior inferior cerebellar artery (PICA), the modalities of treatment were aneurysm trapping in 3 patients and vascular reconstruction in 3 patients. The mean duration of follow-up was 29 months (range, 6-70 months). Five patients expired, indicating a mortality rate of 31%. In surviving patients, the unfavorable outcome rate (modified Rankin Scale [mRS] > 2) was 36%. The overall mean mRS for survivors was 1.8. Angiographic follow-up in 11 survivors at 13 months, (range, 6-46 months) revealed recanalization of the aneurysm in one patient. CONCLUSIONS: Ruptured intracranial vertebral artery dissecting aneurysm is associated with poor functional outcome and high mortality. More immediate treatments are needed due to the high rebleeding rate in this disease condition. Endovascular treatment may be a useful option for ruptured intracranial vertebral artery dissecting aneurysms.

Genotypic shift of the hepatitis A virus and its clinical impact on acute hepatitis A in Korea: a nationwide multicenter study.

BACKGROUND: The genotypic shift of hepatitis A virus (HAV) and its correlation with clinical course has not been evaluated in acute hepatitis A (AHA). METHODS: From June 2007 to May 2009, we prospectively enrolled 546 AHA patients. We performed a nested reverse transcriptase polymerase chain reaction (RT-PCR) using the serum samples in addition to phylogenetic analysis, then we compared patient clinical features. RESULTS: Among 351 successfully genotyped patients, we found genotype IIIA in 178 patients (51%) and IA in 173 patients (49%). The sequences of genotype IA are identical to previously reported Korean genotype IA, and the new IIIA genotype is closely related to NOR24/Norway. We retrospectively analyzed 41 AHA samples collected from 2000 to 2006 and found that all of them were genotype IA. Patients with genotype IIIA showed significantly higher levels of aspartate aminotransferase, higher levels of alanine aminotransferase, and lower platelet counts than patients with genotype IA when comparing baseline laboratory data or peak/lowest laboratory data during the disease course. However, there were no differences in duration of hospital stay, incidence of cholestatic hepatitis, acute kidney injury, and acute liver failure, or mortality between them. CONCLUSIONS: A genotypic shift of the HAV was identified in Korean AHA subjects, and genotype IIIA HAV has become endemic. Although there were significant differences in the biochemical responses of AHA between genotype IA and genotype IIIA patients, we did not detect any differences in clinical outcomes such as complications or mortality.

Clevudine-induced viral response, associated with continued reduction of HBsAg titer, was durable after the withdrawal of therapy.

BACKGROUND: This study was conducted to evaluate the durability of clevudine-induced viral response after the withdrawal of treatment. METHODS: Patients who showed a complete response [alanine aminotransferase (ALT) normalization and hepatitis B virus (HBV) DNA <4,700 copies/mL for hepatitis B envelope antigen (HBeAg)-negative patients; ALT normalization, HBV DNA <4,700 copies/mL, and HBeAg seroconversion for HBeAg-positive patients] in the previous clevudine phase III trials were followed for an additional 96 weeks without any treatment for hepatitis B. RESULTS: Of the 63 patients in the study cohort, 73% and 35% of the patients had HBV DNA <141,500 and <4,700 copies/mL, respectively, and 75% of the patients had normal ALT at the end of follow-up. HBeAg seroconversion was maintained in 81% of the patients and hepatitis B surface antigen (HBsAg) loss occurred in 3 patients. Continued HBsAg titer decrease (-0.5 log IU/mL) was observed in the sustained viral responders, suggesting the reduction of covalently closed circular DNA in hepatocytes. CONCLUSIONS: The clevudine-induced viral response was durable in the majority of patients for 2 years after the withdrawal of treatment.

Helicobacter pylori infection and peptic ulcer disease in patients with liver cirrhosis.

BACKGROUND/AIMS: We investigated the prevalence and relationship of peptic ulcer disease and Helicobacter pylori infection to liver cirrhosis. METHODS: We examined 288 patients with liver cirrhosis, 322 patients with non-ulcer dyspepsia, and 339 patients with peptic ulcer disease. Rapid urease test and Wright-Giemsa staining were used for diagnosis of H. pylori infection. RESULTS: The prevalence of peptic ulcer disease in patients with cirrhosis was 24.3%. The prevalence of peptic ulcer disease in patients with cirrhosis divided into Child-Pugh classes A, B, and C was 22.3%, 21.0%, and 31.3%, respectively (p > 0.05). The prevalence of H. pylori infection in the patients with cirrhosis, non-ulcer dyspepsia, and peptic ulcer without chronic liver disease were 35.1%, 62.4%, and 73.7%, respectively (p < 0.001). The prevalence of H. pylori infection did not differ depending on whether there was peptic ulcer (35.6%) or not (34.9%) in patients with liver cirrhosis (p > 0.05). The prevalence of H. pylori infection in patients with hepatitis virus-related liver cirrhosis and in the patients with alcohol-related liver cirrhosis was 42.5% and 22.0%, respectively (p < 0.001). The prevalence of H. pylori infection in patients with Child-Pugh classes A, B, and C liver cirrhosis was 51.5%, 30.5%, and 20.0%, respectively (p < 0.001). CONCLUSIONS: Factors other than H. pylori may be involved in the pathogenesis of peptic ulcer disease in the setting of liver cirrhosis.

Clevudine is highly efficacious in hepatitis B e antigen-negative chronic hepatitis B with durable off-therapy viral suppression.

UNLABELLED: Clevudine is a pyrimidine analog with potent and sustained antiviral activity against HBV. In the present study, we evaluated the safety and efficacy of clevudine 30 mg daily for 24 weeks and assessed the durability of antiviral response for 24 weeks after cessation of dosing in hepatitis B e antigen (HBeAg)-negative chronic hepatitis B (e-CHB). We randomized a total of 86 patients (3:1) to receive clevudine 30 mg (n = 63) or placebo (n = 23) daily for 24 weeks. We followed patients for an additional 24 weeks after withdrawal of treatment. The median changes in HBV DNA from baseline were -4.25 and -0.48 log(10) copies/mL at week 24 in the clevudine and placebo groups, respectively (P < 0.0001). Viral suppression in the clevudine group was sustained after withdrawal of therapy, with 3.11 log(10) reduction at week 48. At week 24 and week 48, 92.1% and 16.4% of patients in the clevudine group had undetectable serum HBV DNA levels by Amplicor PCR assay (<300 copies/mL). The proportion of patients who achieved ALT normalization was 74.6% and 33.3% in the clevudine and placebo groups at week 24, respectively (P = 0.0006). ALT normalization in the clevudine group was well-maintained during the post-treatment follow-up period. The incidence of adverse events was similar in the 2 groups. No resistance to clevudine was detected during treatment. CONCLUSION: A 24-week clevudine therapy was well-tolerated and showed potent and sustained antiviral effect without evidence of viral resistance in e-CHB patients. However, treatment for longer than 24 weeks would be needed to achieve durable remission.

Twenty-four-week clevudine therapy showed potent and sustained antiviral activity in HBeAg-positive chronic hepatitis B.

UNLABELLED: Clevudine is a pyrimidine analogue with potent and sustained antiviral activity against HBV. The present study evaluated the safety and efficacy of 30 mg clevudine once daily for 24 weeks and assessed the durable antiviral response for 24 weeks after cessation of dosing. A total of 243 hepatitis B e antigen (HBeAg)-positive chronic hepatitis B patients were randomized (3:1) to receive clevudine 30 mg once daily (n=182) or placebo (n=61) for 24 weeks. Patients were followed for a further 24 weeks off therapy. Median serum HBV DNA reductions from baseline at week 24 were 5.10 and 0.27 log10 copies/mL in the clevudine and placebo groups, respectively (P<0.0001). Viral suppression in the clevudine group was sustained off therapy, with 3.73 log10 reduction at week 34 and 2.02 log10 reduction at week 48. At week 24, 59.0% of patients in the clevudine group had undetectable serum HBV DNA levels by Amplicor PCR assay (less than 300 copies/mL). The proportion of patients who achieved normalization of alanine aminotransferase (ALT) levels was 68.2% in the clevudine group and 17.5% in the placebo group at week 24 (P<0.0001). ALT normalization in the clevudine group was well maintained during post-treatment follow-up period. The incidence of adverse events (AEs) was similar between the clevudine group and the placebo group. No resistance to clevudine was detected with 24 weeks of administration of drug. CONCLUSION: A 24-week clevudine therapy was well tolerated and showed potent and sustained antiviral effect without evidence of viral resistance during treatment period in HBeAg-positive chronic hepatitis B.