Soybean polyenylphosphatidylcholine (PPC) is beneficial in liver and extrahepatic tissue injury: An update in experimental research.

Polyenylphosphatidylcholine (PPC) is a purified polyunsaturated phosphatidylcholine extract of soybeans. This article updates PPC's beneficial effects on various forms of liver cell injury and other tissues in experimental research. PPC downregulates hepatocyte CYP2E1 expression and associated hepatotoxicity, as well as attenuates oxidative stress, apoptosis, lipoprotein oxidation and steatosis in alcoholic and nonalcoholic liver injury. PPC inhibits pro-inflammatory cytokine production, while stimulating anti-inflammatory cytokine secretion in ethanol or lipopolysaccharide-stimulated Kupffer cells/macrophages. It promotes M2-type macrophage polarization and metabolic reprogramming of glucose and lipid metabolism. PPC mitigates steatosis in NAFLD through inhibiting polarization of pro-inflammatory M1-type Kupffer cells, alleviating metabolic inflammation, remodeling hepatic lipid metabolism, correcting imbalances between lipogenesis and lipolysis and enhancing lipoprotein secretion from hepatocytes. PPC is antifibrotic by preventing progression of alcoholic hepatic fibrosis in baboons and also prevents CCl4-induced fibrosis in rats. PPC supplementation replenishes the phosphatidylcholine content of damaged cell membranes, resulting in increased membrane fluidity and functioning. Phosphatidylcholine repletion prevents increased membrane curvature of the endoplasmic reticulum and Golgi and decreases sterol regulatory element binding protein-1-mediated lipogenesis, reducing steatosis. PPC remodels gut microbiota and affects hepatic lipid metabolism via the gut-hepatic-axis and also alleviates brain inflammatory responses and cognitive impairment via the gut-brain-axis. Additionally, PPC protects extrahepatic tissues from injury caused by various toxic compounds by reducing oxidative stress, inflammation, and membrane damage. It also stimulates liver regeneration, enhances sensitivity of cancer cells to radiotherapy/chemotherapy, and inhibits experimental hepatocarcinogenesis. PPC's beneficial effects justify it as a supportive treatment of liver disease.

A review of hepatic fibrosis-associated histopathology in aged cadavers.

This article reviews hepatic fibrosis-associated histopathology of aged cadavers (mean age 82 years). A study of 68 livers identified steatosis in 35.5%, central vein fibrosis in 49.2%, perisinusoidal fibrosis in 63.2%, portal tract fibrosis in 47.7%, septa formation in 44.1%, bridging fibrosis in 30.8%, and cirrhosis in 4.4% of the samples as well as one hepatocellular carcinoma and six metastatic tumors. Other studies have revealed that collagens I, III, IV, V, and VI and fibronectin constitute the matrices of fibrous central veins, perisinusoidal space, portal tracts, and septa. Elastin is rich in portal tracts and fibrous septa but absent from the perisinusoidal space. Hepatic stellate cells are ubiquitous in the liver parenchyma while myofibroblasts localize in fibrotic foci. Factor VIII-related antigen expression signals sinusoidal to systemic vascular endothelium transformation while collagen IV and laminin codistribution indicates formation of perisinusoidal membranes. Their coincidence reflects focalized capillarization of sinusoids in the aged liver. In response to fibrogenesis, hepatic progenitor cells residing in the canal of Hering in the periportal parenchyma undergo expansion and migration deep into the lobule. Concomitantly, intermediate hepatocyte-like cells increase in advanced fibrosis stages, which is possibly related to hepatic regeneration. Metabolic zonation of glutamine synthetase expands from the perivenous to non-perivenous parenchyma in fibrosis progression but its expression is lost in cirrhosis, while cytochrome P-4502E1 expression is maintained in centrilobular and midlobular zones in fibrosis progression and expressed in cirrhosis. Hence, cadaveric livers provide a platform for further investigation of hepatic histopathologies associated with the aging liver.

Lipid droplets, the Holy Grail of hepatic stellate cells: In health and hepatic fibrosis.

Lipid droplets (LDs) are distinct morphological markers of hepatic stellate cells (HSCs). They are composed of a core of predominantly retinyl esters and triacylglycerols surrounded by a phospholipid layer; the latter harbors perilipins 2, 3, and 5, which help control LD lipolysis. Electron microscopy distinguishes between Types I and II LDs. Type I LDs are surrounded by acid phosphatase-positive lysosomes, which likely digest LDs. LD count and retinoid concentration are modulated by vitamin A intake. Alcohol consumption depletes hepatic retinoids and HSC LDs, with concomitant transformation of HSCs to fibrogenic myofibroblast-like cells. LD loss and accompanying HSC activation occur in HSC cell culture models. Loss of LDs is a consequence of and not a prerequisite for HSC activation. LDs are endowed with enzymes for synthesizing retinyl esters and triacylglycerols as well as neutral lipases and lysosomal acid lipase for breaking down LDs. HSCs have two distinct metabolic LD pools: an "original" pool in quiescent HSCs and a "new" pool emerging in HSC activation; this two-pool model provides a platform for analyzing LD dynamics in HSC activation. Besides lipolysis, LDs are degraded by lipophagy; however, the coordination between and relative contributions of these two pathways to LD removal are unclear. While induction of autophagy accelerates LD loss in quiescent HSCs and promotes HSC activation, blocking autophagy impairs LD degradation and inhibits HSC activation and fibrosis. This article is a critique of five decades of investigations into the morphology, molecular structure, synthesis, and degradation of LDs associated with HSC activation and fibrosis.

Alcohol-associated capillarization of sinusoids: A critique since the discovery by Schaffner and Popper in 1963.

This article reviews the literature on capillarization of hepatic sinusoids since its discovery in 1963. Liver sinusoidal endothelial cells are uniquely fenestrated and lack an underlying basement membrane. In chronic liver disease, the sinusoids capillarize and transform into systemic capillaries, a process termed capillarization of sinusoids. The histopathology is marked by defenestration, basement membrane formation, and space of Disse fibrogenesis. Capillarized sinusoids compromise the bidirectional exchange of materials between sinusoids and hepatocytes, leading to hepatocellular dysfunction. Sinusoidal capillarization was first described in active cirrhosis of alcoholics in 1963. Since then, it has been found in early and progressive stages of alcoholic hepatic fibrosis before the onset of cirrhosis. The sinusoidal structure is not altered in alcoholic steatosis without fibrosis. Defenestration impairs the ability of the endothelium to filter chylomicron remnants from sinusoids into the Disse's space, contributing to alcohol-induced postprandial hyperlipidemia and possibly atherosclerosis. Ethanol also modulates the fenestration dynamics in animals. In baboons, chronic alcohol consumption diminishes endothelial porosity in concomitance with hepatic fibrogenesis and in rats defenestrates the endothelium in the absence of fibrosis, and sometimes capillarizes the sinusoids. Acute ethanol ingestion enlarges fenestrations in rats and contracts fenestrations in rabbits. In sinusoidal endothelial cell culture, ethanol elicits fenestration dilation, which is likely related to its interaction with fenestration-associated cytoskeleton. Ethanol potentiates sinusoidal injury caused by cocaine, acetaminophen or lipopolysaccharide in mice and rats. Understanding ethanol's mechanisms on pathogenesis of sinusoidal capillarization and fenestration dynamics will lead to development of methods to prevent risks for atherosclerosis in alcoholism.

Perceived friend support buffers against symptoms of depression in peer victimized adolescents: Evidence from a population-based cohort in South Korea.

BACKGROUND: Peer victimization is associated with an increased risk for depression, but there is less evidence on how certain factors such as friend support can buffer this association. This study investigated the associations between friend support and depressive symptoms among victimized and non-victimized adolescent girls and boys from South Korea. METHODS: Participants includes 2258 students from the Korean Children and Youth Panel Survey, a nationally representative sample of middle school students in South Korea. Self-reported perceived friend support, depressive symptoms and peer victimization were measured using validated scales during middle school year 3 (mean age= 15.7 years). RESULTS: The association between peer victimization and depressive symptoms varied by sex (p for sex by peer victimization interaction<0.05). Peer victimization was more strongly associated with same year depressive symptoms in girls (ß=0.55) than boys (ß=0.24). After controlling for key confounders, including prior year mental health symptoms, higher levels of friend support were found to attenuate the association between peer victimization and depressive symptoms (p for friend support by peer victimization interaction <0.05). Peer victimization was associated with more depressive symptoms for adolescents with low and moderate friend support, but not those with high friend support. LIMITATIONS: Peer victimization, depressive symptoms, and friend support, were self-reported and measured the same year. CONCLUSIONS: Friend support protects victimized South Korean adolescents from the negative effect of peer victimization on depressive symptoms, hence contributes to closing the gap in depression between victimized and non-victimized adolescents.

Hepatic sinusoids versus central veins: Structures, markers, angiocrines, and roles in liver regeneration and homeostasis.

The blood circulates through the hepatic sinusoids delivering nutrients and oxygen to the liver parenchyma and drains into the hepatic central vein, yet the structures and phenotypes of these vessels are distinctively different. Sinusoidal endothelial cells are uniquely fenestrated, lack basal lamina and possess organelles involved in endocytosis, pinocytosis, degradation, synthesis and secretion. Hepatic central veins are nonfenestrated but are also active in synthesis and secretion. Endothelial cells of sinusoids and central veins secrete angiocrines that play respective roles in hepatic regeneration and metabolic homeostasis. The list of markers for identifying sinusoidal endothelial cells is long and their terminologies are complex. Further, their uses vary in different investigations and, in some instances, could be confusing. Central vein markers are fewer but more distinctive. Here we analyze and categorize the molecular pathways/modules associated with the sinusoid-mediated liver regeneration in response to partial hepatectomy and chemical-induced acute or chronic injury. Similarly, we highlight the findings that central vein-derived angiocrines interact with Wnt/ß-catenin in perivenous hepatocytes to direct gene expression and maintain pericentral metabolic zonation. The proposal that perivenous hepatocytes behave as stem/progenitor cells to provoke hepatic homeostatic cell renewal is reevaluated and newer concepts of broad zonal distribution of hepatocyte proliferation in liver homeostasis and regeneration are updated. Thus, this review integrates the structures, biology and physiology of liver sinusoids and central veins in mediating hepatic regeneration and metabolic homeostasis.

Comparison of Electromechanical Delay during Ventricular Tachycardia and Fibrillation under Different Conductivity Conditions Using Computational Modeling.

Electromechanical delay (EMD) is the time interval between local myocyte depolarization and the onset of myofiber shortening. Previously, researchers measured EMD during sinus rhythm and ectopic pacing in normal and heart failure conditions. However, to our knowledge, there are no reports regarding EMD during another type of rhythms or arrhythmia. The goal of this study was to quantify EMD during sinus rhythm, tachycardia, and ventricular fibrillation conditions. We hypothesized that EMD under sinus rhythm is longer due to isovolumetric contraction which is imprecise during arrhythmia. We used a realistic model of 3D electromechanical ventricles. During sinus rhythm, EMD was measured in the last cycle of cardiac systole under steady conditions. EMD under tachycardia and fibrillation conditions was measured during the entire simulation, resulting in multiple EMD values. We assessed EMD for the following 3 conduction velocities (CVs): 31 cm/s, 51 cm/s, and 69 cm/s. The average EMD during fibrillation condition was the shortest corresponding to 53.45 ms, 55.07 ms, and 50.77 ms, for the CVs of 31 cm/s, 51 cm/s, and 69 cm/s, respectively. The average EMD during tachycardia was 58.61 ms, 58.33 ms, and 52.50 ms for the three CVs. Under sinus rhythm with action potential duration restitution (APDR) slope 0.7, the average EMD was 66.35 ms, 66.41 ms, and 66.60 ms in line with the three CVs. This result supports our hypothesis that EMD under sinus rhythm is longer than that under tachyarrhythmia conditions. In conclusion, this study observed and quantified EMD under tachycardia and ventricular fibrillation conditions. This simulation study has widened our understanding of EMD in 3D ventricles under chaotic conditions.

The Hepatic Central Vein: Structure, Fibrosis, and Role in Liver Biology.

The hepatic central vein is a primary source of Wnt2, Wnt9b, and R-spondin3. These angiocrines activate ß-catenin signaling to regulate hepatic metabolic zonation and perivenous gene expression in mice. Little is known about the central vein ultrastructure. Here, we describe the morphological-functional correlates of the central vein and its draining and branching patterns. Central vein fibrosis occurs in liver disease and is often accompanied by perivenous perisinusoidal fibrosis, which may affect perivenous gene expression. We review the biological properties of perivenous hepatocytes and glutamine synthetase that serve as a biomarker of perivenous hepatocytes. Glutamine synthetase and P4502E1 are indicators of ß-catenin activity in centrilobular liver injury and regeneration. The Wnt/ß-catenin pathway is the master regulator of hepatic metabolic zonation and perivenous gene expression and is modulated by the R-spondin-LGR4/5-ZNRF3/RNF43 module. We examined the structures of the molecules of these pathways and their involvements in liver biology. Central vein-derived Wnts and R-spondin3 participate in the cellular-molecular circuitry of the Wnt/ß-catenin and R-spondin-LGR4/5-ZNRF3/RNF43 module. The transport and secretion of lipidated Wnts in Wnt-producing cells require Wntless protein. Secreted Wnts are carried on exosomes in the extracellular matrix to responder cells. The modes of release of Wnts and R-spondin3 from central veins and their transit in the venular wall toward perivenous hepatocytes are unknown. We hypothesize that central vein fibrosis may impact perivenous gene expression. The proposal that the central vein constitutes an anatomical niche of perivenous stem cells that subserve homeostatic hepatic renewal still needs studies using additional mouse models for validation. Anat Rec, 2019. © 2019 American Association for Anatomy Anat Rec, 303:1747-1767, 2020. © 2019 American Association for Anatomy.

Influence of age at seizure onset on the acquisition of neurodevelopmental skills in an SCN8A cohort.

OBJECTIVE: To characterize a cohort of patients with SCN8A-related epilepsy and to perform analyses to identify correlations involving the acquisition of neurodevelopmental skills. METHODS: We analyzed patient data (n = 91) submitted to an online registry tailored to characteristics of children with SCN8A variants. Participants provided information on the history of their child's seizures, medications, comorbidities, and developmental skills based on the Denver II items. Spearman rank tests were utilized to test for correlations among a variety of aspects of seizures, medications, and neurodevelopmental progression. RESULTS: The 91 participants carried 71 missense variants (41 newly reported) and three truncating variants. Ages at seizure onset ranged from birth to >12 months of age (mean ± SD = 5 months 21 days ± 7 months 14 days). Multiple seizure types with multimodal onset times and developmental delay were observed as general features of this cohort. We found a positive correlation between a developmental score based upon percentage of acquired skills and the age at seizure onset, current seizure freedom, and initial febrile seizures. Analyses of cohort subgroups revealed clear distinctions between patients who had a single reported variant in SCN8A and those with an additional variant reported in a gene other than SCN8A, as well as between patients with different patterns of regression before and at seizure onset. SIGNIFICANCE: This is the first study of an SCN8A patient cohort of this size and for which correlations between age at seizure onset and neurodevelopment were investigated. Our correlation studies suggest that variants of uncertain significance should be considered in assessing children with SCN8A-related disorders. This study substantially improves the characterization of this patient population and our understanding of the neurodevelopmental effects associated with seizures for SCN8A patients, and provides a clinical context at initial presentation that may be prognostic for developmental outcome.

Computational Prediction of the Combined Effect of CRT and LVAD on Cardiac Electromechanical Delay in LBBB and RBBB.

Two case reports showed that the combination of CRT and LVAD benefits the end-stage heart failure patients with prolonged QRS interval significantly. In one of the reports, the patient had the LVAD removed due to the recovery of the heart function. However, the quantification of the combined devices has yet to be conducted. This study aimed at computationally predicting the effects of CRT-only or combined with LVAD on electromechanical behaviour in the failing ventricle with left bundle branch blocked (LBBB) and right bundle branch blocked (RBBB) conditions. The subjects are normal sinus rhythm, LBBB, RBBB, LBBB with CRT-only, RBBB with CRT-only, LBBB with CRT + LVAD, and RBBB with CRT + LVAD. The results showed that the CRT-only shortened the total electrical activation time (EAT) in the LBBB and RBBB conditions by 20.2% and 17.1%, respectively. The CRT-only reduced the total mechanical activation time (MAT) and electromechanical delay (EMD) of the ventricle under LBBB by 21.3% and 10.1%, respectively. Furthermore, the CRT-only reduced the contractile adenosine triphosphate (ATP) consumption by 5%, increased left ventricular (LV) pressure by 6%, and enhanced cardiac output (CO) by 0.2 L/min under LBBB condition. However, CRT-only barely affects the ventricle under RBBB condition. Under the LBBB condition, CRT + LVAD increased LV pressure and CO by 10.5% and by 0.9 L/min, respectively. CRT + LVAD reduced ATP consumption by 15%, shortened the MAT by 23.4%, and shortened the EMD by 15.2%. In conclusion, we computationally predicted and quantified that the CRT + LVAD implementation is superior to CRT-only implementation particularly in HF with LBBB condition.

High reproduction number of Middle East respiratory syndrome coronavirus in nosocomial outbreaks: mathematical modelling in Saudi Arabia and South Korea.

BACKGROUND: Effective countermeasures against emerging infectious diseases require an understanding of transmission rate and basic reproduction number (R0). R0 for severe acute respiratory syndrome is generally considered to be >1, whereas that for Middle East respiratory syndrome (MERS) is considered to be <1. However, this does not explain the large-scale outbreaks of MERS that occurred in Kingdom of Saudi Arabia (KSA) and South Korean hospitals. AIM: To estimate R0 in nosocomial outbreaks of MERS. METHODS: R0 was estimated using the incidence decay with an exponential adjustment model. The KSA and Korean outbreaks were compared using a line listing of MERS cases compiled using publicly available sources. Serial intervals to estimate R0 were assumed to be six to eight days. Study parameters [R0 and countermeasures (d)] were estimated by fitting a model to the cumulative incidence epidemic curves using Matlab. FINDINGS: The estimated R0 in Korea was 3.9 in the best-fit model, with a serial interval of six days. The first outbreak cluster in a hospital in Pyeongtaek had an R0 of 4.04, and the largest outbreak cluster in a hospital in Samsung had an R0 of 5.0. Assuming a six-day serial interval, the KSA outbreaks in Jeddah and Riyadh had R0 values of 3.9 and 1.9, respectively. CONCLUSION: R0 for the nosocomial MERS outbreaks in KSA and South Korea was estimated to be in the range of 2-5, which is significantly higher than the previous estimate of <1. Therefore, more comprehensive countermeasures are needed to address these infections.

Risk of diabetes in viral hepatitis B or C patients compared to that in noninfected individuals in Korea, 2002-2013: A population-based cohort study.

While the association between hepatitis C virus (HCV) infection and diabetes has been established, the relationship between hepatitis B virus (HBV) infection and diabetes remains unclear. Therefore, we compared the association between diabetes development in HBV, HCV and co-infected (HBV/HCV) patients to that in noninfected participants using population-based cohort data. We used the National Health Insurance Service-National Sample Cohort, which consists of 514 791 randomly selected persons among those who underwent health check-ups from 2002 to 2003 aged 40-79 years. Adults found to have HBV or HCV infection from 2002 to 2003, without a prior history of diabetes, were selected as subjects. Competing risk regression models were used to estimate cumulative incidence and hazards ratios (HRs) of diabetes development. The cumulative incidences, incidence densities and HRs of diabetes were highest in the co-infected group, followed by those in the HCV-, HBV- and noninfected groups. The 12-year cumulative incidences were as follows: 42.0% in HBV/HCV-, 32.9% in HCV-, 23.9% in HBV- and 18.3% in the noninfected groups. The incidence density per 1000 person-years was 55.0, 51.5, 38.2 and 28.2 for the HBV/HCV-, HCV-, HBV- and noninfected groups, respectively. The adjusted HRs for diabetes were 1.90, 1.68 and 1.41 for the HBV/HCV-, HCV- and HBV-infected groups, respectively. Our findings suggest that both HCV and HBV infections are associated with the development of diabetes; therefore, prevention of, screening for, and treatment of both may reduce the risk of diabetes in these patients.

Wnt/ß-catenin and ERK pathway activation: A possible mechanism of photobiomodulation therapy with light-emitting diodes that regulate the proliferation of human outer root sheath cells.

BACKGROUND: Outer root sheath cells (ORSCs) play important roles in maintaining hair follicle structure and provide support for the bulge area. The hair growth promoting effects of photobiomodulation therapy (PBMT) have been reported, but the mechanisms for this in human ORCs (hORSCs) have rarely been studied. OBJECTIVE: The aim of this study was to investigate the effect of various wavelengths of light-emitting diode (LED) irradiation on human ORSCs (hORSCs). METHODS: LED irradiation effects on hORSC proliferation and migration were examined with MTT assay, BrdU incorporation assay and migration assays. hORSCs were irradiated using four LED wavelengths (415, 525, 660, and 830 nm) with different low energy levels. LED irradiation effects on the expression of molecules associated with the Wnt/ß-catenin signaling and ERK pathway, hair stem cell markers, and various growth factors and cytokines in hORSCs were examined with real-time PCR and Western blot assay. The effect of the LED-irradiated hORSCs on cell proliferation of human dermal papilla cells (hDPCs) was examined with co-culture and MTT assay. RESULTS: PBMT with LED light variably promoted hORSC proliferation and suppressed cell apoptosis depending on energy level. LED irradiation induced Wnt5a, Axin2, and Lef1 mRNA expression and ß-catenin protein expression in hORSCs. Phosphorylation of ERK, c-Jun, and p38 in hORSCs was observed after LED light irradiation, and ERK inhibitor treatment before irradiation reduced ERK and c-Jun phosphorylation. Red light-treated hORSCs showed substantial increase in IL-6, IL-8, TNF-a, IGF-1, TGF-ß1, and VEGF mRNA. Light irradiation at 660 and 830 nm projected onto hORSCs accelerated in vitro migration. LED-irradiated hORSCs increased hDPCs proliferation when they were co-cultured. The conditioned medium from LED-irradiated hORSCs was sufficient to stimulate hDPCs proliferation. CONCLUSION: These results demonstrate that LED light irradiation induced hORSC proliferation and migration and inhibited apoptosis in vitro. The growth-promoting effects of LEDs on hORSCs appear to be associated with direct stimulation of the Wnt5a/ß-catenin and ERK signaling pathway. Lasers Surg. Med. 49:940-947, 2017. © 2017 Wiley Periodicals, Inc.

Basement Membrane Type IV Collagen and Laminin: An Overview of Their Biology and Value as Fibrosis Biomarkers of Liver Disease.

Basement membranes provide structural support to epithelium, endothelium, muscles, fat cells, Schwann cells, and axons. Basement membranes are multifunctional: they modulate cellular behavior, regulate organogenesis, promote tissue repair, form a barrier to filtration and tumor metastasis, bind growth factors, and mediate angiogenesis. All basement membranes contain type IV collagen (Col IV), laminin, nidogen, and perlecan. Col IV and laminin self-assemble into two independent supramolecular networks that are linked to nidogen and perlecan to form a morphological discernable basement membrane/basal lamina. The triple helical region, 7S domain and NCI domain of Col IV, laminin and laminin fragment P1 have been evaluated as noninvasive fibrosis biomarkers of alcoholic liver disease, viral hepatitis, and nonalcoholic fatty liver disease. Elevated serum Col IV and laminin are related to degrees of fibrosis and severity of hepatitis, and may reflect hepatic basement membrane metabolism. But the serum assays have not been linked to disclosing the anatomical sites and lobular distribution of perisinusoidal basement membrane formation in the liver. Hepatic sinusoids normally lack a basement membrane, although Col IV is a normal matrix component of the space of Disse. In liver disease, laminin deposits in the space of Disse and codistributes with Col IV, forming a perisinusoidal basement membrane. Concomitantly, the sinusoidal endothelium loses its fenestrae and is transformed into vascular type endothelium. These changes lead to capillarization of hepatic sinusoids, a significant pathology that impairs hepatic function. Accordingly, codistribution of Col IV and laminin serves as histochemical marker of perisinusoidal basement membrane formation in liver disease. Anat Rec, 300:1371-1390, 2017. © 2017 Wiley Periodicals, Inc.

Type V Collagen in Health, Disease, and Fibrosis.

Type V collagen (COLV) is a regulatory fibril-forming collagen. It has at least three different molecular isoforms-α1(V)2 α2(V), α1(V)3, and α1(V)α2(V)α3(V)-formed by combinations of three different polypeptide α chains-α1(V), α2(V), and α3(V). COL V is a relatively minor collagen of the extracellular matrix (ECM). Morphologically, COLV occurs as heterotypic fibrils with type I collagen (COLI), microfilaments, or 12-nm-thick fibrils. COLV is synthesized in various mesenchymal cells and its gene expression is modulated by TGF-ß and growth factors. While resistant to digestion by interstitial collagenases, native and denatured COLV are degraded by metalloproteinases and gelatinases, thereby promoting ECM remodeling. COLV interacts with matrix collagens and structural proteins, conferring structural integrity to tissue scaffolds. It binds matrix macromolecules, modulating cellular behavior, and functions. COLV co-assembles with COLI into heterotypic fibrils in the cornea and skin dermis, acting as a dominant regulator of collagen fibrillogenesis. COLV deficiency is associated with loss of corneal transparency and classic Ehlers-Danlos syndrome, while COLV overexpression is found in cancer, granulation tissue, inflammation, atherosclerosis, and fibrosis of lungs, skin, kidneys, adipose tissue, and liver. COLV isoform containing the α3(V) chain is involved in mediating pancreatic islet cell functions. In the liver, COLV is a minor but regular component of the ECM. Increases in COLV are associated with both early and advanced hepatic fibrosis. The neoepitopes of COLV have been shown to be a useful noninvasive serum biomarker for assessing fibrotic progression and resolution in experimental hepatic fibrosis. COLV is multifunctional in health, disease, and fibrosis.

Population-based epidemiology of primary biliary cirrhosis in South Korea.

BACKGROUND: As a rare disease, only a few population-based epidemiology studies of primary biliary cirrhosis (PBC) have been reported. AIMS: To elucidate the nationwide prevalence, incidence, complications, fatality and direct medical costs of PBC in South Korea. METHODS: The nationwide Health Insurance Review and Assessment Service claims data and Rare Intractable Disease registration data on PBC, identified with the International Classification of Diseases (ICD) 10 code of K74.3, were obtained from 2009 to 2013. Age- and gender-specific prevalence and incidence rates of PBC were calculated, and data on complications, comorbidities, prescribed drugs, therapeutic procedures and direct medical costs were analysed. RESULTS: A total of 2824 patients over 20 years old with PBC were identified in 2009-2013 (female-to-male ratio 6.2, median age 57 years old). The average age- and sex-adjusted incidence from 2011 to 2013 was 8.57 per million per year, and the average age- and sex-adjusted prevalence from 2009 to 2013 was 47.50 per million population. About 10% of patients presented with complications such as ascites (10.3%), variceal bleeding (5.8%) and/or hepatocellular carcinoma (HCC) (1.3%). Liver transplantation was undertaken in 71 patients (2.5%) for 5 years. Case fatality was 2.2% and the transplantation-free survival was 95.4% for 5 years. CONCLUSIONS: This is the first report on the nationwide epidemiology of primary biliary cirrhosis in South Korea, demonstrating lower incidence and prevalence rates than those of Western countries, but a considerable disease burden, representing at least 10% were complicated with decompensated cirrhosis or hepatocellular carcinoma requiring liver transplantation.

Clinical characteristics predicting early clinical failure after 72 h of antibiotic treatment in women with community-onset acute pyelonephritis: a prospective multicentre study.

In patients with community-onset acute pyelonephritis (CO-APN), assessing the risk factors for poor clinical response after 72 h of antibiotic treatment (early clinical failure) is important. The objectives of this study were to define those risk factors, and to assess whether early clinical failure influences mortality and treatment outcomes. We prospectively collected the clinical and microbiological data of women with CO-APN in South Korea from March 2010 to February 2012. The numbers of cases in the early clinical success and early clinical failure groups were 840 (79.1%) and 222 (20.9%), respectively. Final clinical failure and mortality were higher in the early clinical failure group than in the early clinical success group (14.9% vs 2.3%, p <0.001; 6.8% vs 0.1%, p 0.001, respectively). In a multiple logistic regression model, the risk factors for early clinical failure among the total 1062 patients were diabetes mellitus (OR 1.5; 95% CI 1.1-2.1), chronic liver diseases (OR 3.3; 95% CI 1.6-6.7), malignancy (OR 2.2; 95% CI 1.1-4.4), Pitt score ≥2 (OR 2.5; 95% CI 1.6-3.8), presence of azotaemia (OR 1.8; 95% CI 1.2-2.7), white blood cell count ≥20 000/mm(3) (OR 2.5; 95% CI 1.6-4.0), serum C-reactive protein level ≥20 mg/dL (OR 1.7; 95% CI 1.2-2.4), and history of antibiotic usage within the previous year (OR 1.5; 95% CI 1.1-2.2). Analysing the subgroup of 743 patients with CO-APN due to Enterobacteriaceae, fluoroquinolone resistance of the uropathogen was another factor associated with early clinical failure (OR 1.7; 95% CI 1.1-2.5). Simple variables of underlying diseases, previous antibiotic usage and initial laboratory test outcomes can be used to decide on the direction of treatment in CO-APN.

Factor VIII-Related Antigen Detects Phenotypic Change of Sinusoidal to Vascular Endothelium in Hepatic Fibrosis of Elderly Cadavers.

In advanced stages of hepatic fibrosis, the liver sinusoidal endothelium transforms to vascular endothelium with accompanying expression of factor VIII-related antigen (FVIIIRAg), a phenotypic marker of vascular endothelial cells. Liver fibrosis has been shown to be associated with aging and was found to be prevalent in elderly cadavers. Using immunohistochemistry, we studied FVIIIRAg expression in the livers of elderly cadavers with progressive stages of fibrosis. The vascular endothelium of portal tracts and central veins was stained for FVIIIRAg, providing an internal positive control. The incidence of FVIIIRAg expression was low in the sinusoids of livers that showed minimal fibrosis or perisinusoidal fibrosis but was increased in livers with advanced fibrosis (i.e., septa formation, bridging fibrosis, and cirrhosis). FVIIIRAg positive sinusoidal endothelial cells were distributed in loose aggregates in the periportal, periseptal, and midlobular parenchyma and were found less frequently in the centrilobular area. FVIIIRAg immune deposits appeared patchy and discontinuous along the sinusoidal lining, likely representing focalized transformation of sinusoidal to vascular endothelium. There was a discrete localization of FVIIIRAg immunoreactivity in the foci of severe parenchymal fibrosis. Conclusion. FVIIIRAg is a reliable marker for detecting the transformation of sinusoidal to vascular endothelium in advanced liver fibrosis in elderly cadavers.

Human antibodies targeting the C-type lectin-like domain of the tumor endothelial cell marker clec14a regulate angiogenic properties in vitro.

It has been suggested that clec14a may be involved in tumor angiogenesis. However, a molecular mechanism has not been clearly identified. In this study, we show for the first time that C-type lectin-like domain (CTLD) of clec14a may be important for regulating cell migration and filopodia formation. Using phage display technology, recombinant human antibodies specific to the CTLDs of human and mouse clec14a (clec14a-CTLD (immunoglobulin G) IgG) were selected. Functional assays using the antibodies showed that clec14a-CTLD IgGs specifically blocked endothelial cell migration and tube formation without affecting cell viability or activation. Further, clec14a-CTLD IgGs inhibited clec14a-mediated cell-cell contact by blocking interaction between CTLDs. Finally, clec14a cross-linking by the clec14a-CTLD IgGs significantly downregulated clec14a expression on the surface of endothelial cells. These results strongly suggest that the clec14a-CTLD may be a key domain in angiogenesis, and that clec14a-CTLD IgGs specifically inhibit angiogenesis by modulating CTLD-mediated cell interactions and clec14a expression on the surface of endothelial cells.

Codistribution of collagen type IV and laminin in liver fibrosis of elderly cadavers: immunohistochemical marker of perisinusoidal basement membrane formation.

Liver sinusoids are lined by a fenestrated endothelium that lacks a basement membrane. Formation of perisinusoidal basement membranes beneath the endothelium is an integral feature of capillarization of sinusoids that is a significant pathology found in advanced fibrosis. Liver fibrosis is prevalent in elderly cadavers; however, basement membrane formation in these liver samples has yet to be studied. Collagen type IV and laminin are major basement membrane proteins and their codistribution around sinusoids provides an immunohistochemical marker of basement membrane formation. Here, we examined the intralobular sites of perisinusoidal basement membrane formation in elderly cadaveric livers having various stages of fibrosis. Collagen IV and laminin codistributed in basement membranes of portal and septal ductular and vascular structures, providing a positive control. In the parenchyma, collagen IV immunostaining of sinusoids was panlobular in all stages of fibrosis, and the stain was continuous along the sinusoids. In contrast, laminin was not detected in livers, showing minimal fibrotic change. It was rarely seen in perisinusoidal/pericellular fibrosis, but frequently in septa formation, bridging fibrosis, and cirrhosis. The laminin stain was patchy, occurring principally in sinusoids of periportal and periseptal areas, less commonly in mid-lobular and rarely in centrilobular areas. Consecutive sections revealed that laminin codistributed with collagen IV in these sinusoidal locations, thus marking the sites of perisinusoidal basement membrane formation in aged fibrotic livers. This development is presumably related to aging of the liver and exacerbated by liver injury caused by advanced liver fibrosis, possibly resulting in sinusoidal capillarization.