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Sample records for chronic liver impairment

  1. Impaired opsonization by serum from patients with chronic liver disease.

    PubMed Central

    Wyke, R J; Rajkovic, I A; Williams, R

    1983-01-01

    Serum opsonization of two organisms, E. coli and yeasts (S. cerivisiae), was examined in 68 patients with chronic liver disease (CLD). Impaired opsonization for yeasts was found in seven (29%) of 24 patients with chronic active hepatitis, six (27%) of 22 with alcoholic cirrhosis and five (23%) of 22 with primary biliary cirrhosis. Opsonization for E. coli was normal in patients with primary biliary cirrhosis but impaired in seven (29%) patients with chronic active hepatitis and three (14%) of those with alcoholic cirrhosis. The defect of opsonization in chronic active hepatitis was found mainly in patients with histological evidence of active disease. A deficiency, rather than antagonism or inhibition, of normal opsonization factors was responsible, but could not be related to reduced levels of serum complement factors of either the classical or the alternative pathway present in 45% of the patients with chronic active hepatitis, 71% with alcoholic cirrhosis and 18% of those with primary biliary cirrhosis. Serum from two of 11 patients with impaired opsonization antagonised the function of normal polymorphonuclear leucocytes, and polymorphonuclear leucocytes from six of seven patients had slightly reduced phagocytosis/killing of E. coli opsonized in normal serum. Defects of serum opsonization, complement activity and polymorphonuclear leucocyte function may be causes of the increased susceptibility to bacterial infection in patients with CLD. PMID:6339126

  2. Impaired Expression of Type I and Type II Interferon Receptors in HCV-Associated Chronic Liver Disease and Liver Cirrhosis

    PubMed Central

    Chandra, Partha K.; Gunduz, Feyza; Hazari, Sidhartha; Kurt, Ramazan; Panigrahi, Rajesh; Poat, Bret; Bruce, David; Cohen, Ari J.; Behorquez, Humberto E.; Carmody, Ian; Loss, George; Balart, Luis A.; Wu, Tong; Dash, Srikanta

    2014-01-01

    Purpose Chronic Hepatitis C Virus (HCV)-infected patients with liver cirrhosis (LC) respond poorly to interferon-alpha (IFN-α) and ribavirin (RBV) combination therapy, but the reason for this is unclear. We previously reported that HCV-infection induces endoplasmic reticulum (ER) stress and autophagy response that selectively down regulates the type I IFN-α receptor-1 (IFNAR1) and RBV transporters (CNT1 and ENT1), leading to IFN-α/RBV resistance. The goal of this study is to verify whether an increase in ER stress and autophagy response is also associated with the reduced expression of IFNAR1 and RBV transporters in chronic HCV-infected patients. Methods Primary human hepatocytes (PHH) were infected with cell culture grown HCV particles (JFH-ΔV3-Rluc). HCV replication was confirmed by the detection of viral RNA by RT-qPCR and HCV-core protein by Western blotting. The ER stress and autophagy response and expression of IFN receptors and RBV transporters in HCV infected PHH and liver tissues derived from patients were measured by Western blotting. Result HCV infection of PHH showed impaired expression of IFNAR1, IFNγR1 (Type II IFN receptor) and RBV transporters but not IL10Rβ (Type III IFN-λ receptor). ER stress markers (BiP, IRE1α and peIF2α) and autophagy response (LC3II, Beclin 1 and ATG5) were induced in HCV infected chronic liver disease (CLD) and LC patients. Liver biopsies (CLD) show a 50% reduced expression of IFNAR1 and RBV transporters. Furthermore, the expression of IFNAR1 and RBV transporters was impaired in almost all LC patients. Conclusion HCV infection induces ER stress and autophagy response in infected PHH and chronically infected liver tissues. The expression of IFNAR1, IFNγR1 and RBV transporters were significantly impaired in CLD and cirrhotic livers. Our study provides a potential explanation for the reduced response rate of IFN-α and RBV combination therapy in HCV infected patients with liver cirrhosis. PMID:25265476

  3. Renal Impairment with Sublethal Tubular Cell Injury in a Chronic Liver Disease Mouse Model

    PubMed Central

    Ishida, Tokiko; Kotani, Hirokazu; Miyao, Masashi; Kawai, Chihiro; Jemail, Leila; Abiru, Hitoshi; Tamaki, Keiji

    2016-01-01

    The pathogenesis of renal impairment in chronic liver diseases (CLDs) has been primarily studied in the advanced stages of hepatic injury. Meanwhile, the pathology of renal impairment in the early phase of CLDs is poorly understood, and animal models to elucidate its mechanisms are needed. Thus, we investigated whether an existing mouse model of CLD induced by 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) shows renal impairment in the early phase. Renal injury markers, renal histology (including immunohistochemistry for tubular injury markers and transmission electron microscopy), autophagy, and oxidative stress were studied longitudinally in DDC- and standard diet–fed BALB/c mice. Slight but significant renal dysfunction was evident in DDC-fed mice from the early phase. Meanwhile, histological examinations of the kidneys with routine light microscopy did not show definitive morphological findings, and electron microscopic analyses were required to detect limited injuries such as loss of brush border microvilli and mitochondrial deformities. Limited injuries have been recently designated as sublethal tubular cell injury. As humans with renal impairment, either with or without CLD, often show almost normal tubules, sublethal injury has been of particular interest. In this study, the injuries were associated with mitochondrial aberrations and oxidative stress, a possible mechanism for sublethal injury. Intriguingly, two defense mechanisms were associated with this injury that prevent it from progressing to apparent cell death: autophagy and single-cell extrusion with regeneration. Furthermore, the renal impairment of this model progressed to chronic kidney disease with interstitial fibrosis after long-term DDC feeding. These findings indicated that DDC induces renal impairment with sublethal tubular cell injury from the early phase, leading to chronic kidney disease. Importantly, this CLD mouse model could be useful for studying the pathophysiological mechanisms

  4. Generalized Liver- and Blood-Derived CD8+ T-Cell Impairment in Response to Cytokines in Chronic Hepatitis C Virus Infection

    PubMed Central

    Burke Schinkel, Stephanie C.; Carrasco-Medina, Lorna; Cooper, Curtis L.; Crawley, Angela M.

    2016-01-01

    Generalized CD8+ T-cell impairment in chronic hepatitis C virus (HCV) infection and the contribution of liver-infiltrating CD8+ T-cells to the immunopathogenesis of this infection remain poorly understood. It is hypothesized that this impairment is partially due to reduced CD8+ T-cell activity in response to cytokines such as IL-7, particularly within the liver. To investigate this, the phenotype and cytokine responsiveness of blood- and liver-derived CD8+ T-cells from healthy controls and individuals with HCV infection were compared. In blood, IL-7 receptor α (CD127) expression on bulk CD8+ T-cells in HCV infection was no different than controls yet was lower on central memory T-cells, and there were fewer naïve cells. IL-7-induced signalling through phosphorylated STAT5 was lower in HCV infection than in controls, and differed between CD8+ T-cell subsets. Production of Bcl-2 following IL-7 stimulation was also lower in HCV infection and inversely related to the degree of liver fibrosis. In liver-derived CD8+ T-cells, STAT5 activation could not be increased with cytokine stimulation and basal Bcl-2 levels of liver-derived CD8+ T-cells were lower than blood-derived counterparts in HCV infection. Therefore, generalized CD8+ T-cell impairment in HCV infection is characterized, in part, by impaired IL-7-mediated signalling and survival, independent of CD127 expression. This impairment is more pronounced in the liver and may be associated with an increased potential for apoptosis. This generalized CD8+ T-cell impairment represents an important immune dysfunction in chronic HCV infection that may alter patient health. PMID:27315061

  5. Glutamate-induced activation of nitric oxide synthase is impaired in cerebral cortex in vivo in rats with chronic liver failure.

    PubMed

    Rodrigo, Regina; Erceg, Slaven; Rodriguez-Diaz, Jesus; Saez-Valero, Javier; Piedrafita, Blanca; Suarez, Isabel; Felipo, Vicente

    2007-07-01

    It has been proposed that impairment of the glutamate-nitric oxide-cyclic guanosine monophosphate (cGMP) pathway in brain contributes to cognitive impairment in hepatic encephalopathy. The aims of this work were to assess whether the function of this pathway and of nitric oxide synthase (NOS) are altered in cerebral cortex in vivo in rats with chronic liver failure due to portacaval shunt (PCS) and whether these alterations are due to hyperammonemia. The glutamate-nitric oxide-cGMP pathway function and NOS activation by NMDA was analysed by in vivo microdialysis in cerebral cortex of PCS and control rats and in rats with hyperammonemia without liver failure. Similar studies were done in cortical slices from these rats and in cultured cortical neurons exposed to ammonia. Basal NOS activity, nitrites and cGMP are increased in cortex of rats with hyperammonemia or liver failure. These increases seem due to increased inducible nitric oxide synthase expression. NOS activation by NMDA is impaired in cerebral cortex in both animal models and in neurons exposed to ammonia. Chronic liver failure increases basal NOS activity, nitric oxide and cGMP but reduces activation of NOS induced by NMDA receptors activation. Hyperammonemia is responsible for both effects which will lead, independently, to alterations contributing to neurological alterations in hepatic encephalopathy. PMID:17286583

  6. Chronic Liver Disease and Hispanic Americans

    MedlinePlus

    ... Population Profiles > Hispanic/Latino > Chronic Liver Disease Chronic Liver Disease and Hispanic Americans Among the Hispanic/Latino population, chronic liver disease is a leading cause of death. While the ...

  7. Chronic Hyponatremia Causes Neurologic and Psychologic Impairments.

    PubMed

    Fujisawa, Haruki; Sugimura, Yoshihisa; Takagi, Hiroshi; Mizoguchi, Hiroyuki; Takeuchi, Hideyuki; Izumida, Hisakazu; Nakashima, Kohtaro; Ochiai, Hiroshi; Takeuchi, Seiji; Kiyota, Atsushi; Fukumoto, Kazuya; Iwama, Shintaro; Takagishi, Yoshiko; Hayashi, Yoshitaka; Arima, Hiroshi; Komatsu, Yukio; Murata, Yoshiharu; Oiso, Yutaka

    2016-03-01

    Hyponatremia is the most common clinical electrolyte disorder. Once thought to be asymptomatic in response to adaptation by the brain, recent evidence suggests that chronic hyponatremia may be linked to attention deficits, gait disturbances, risk of falls, and cognitive impairments. Such neurologic defects are associated with a reduction in quality of life and may be a significant cause of mortality. However, because underlying diseases such as adrenal insufficiency, heart failure, liver cirrhosis, and cancer may also affect brain function, the contribution of hyponatremia alone to neurologic manifestations and the underlying mechanisms remain unclear. Using a syndrome of inappropriate secretion of antidiuretic hormone rat model, we show here that sustained reduction of serum sodium ion concentration induced gait disturbances; facilitated the extinction of a contextual fear memory; caused cognitive impairment in a novel object recognition test; and impaired long-term potentiation at hippocampal CA3-CA1 synapses. In vivo microdialysis revealed an elevated extracellular glutamate concentration in the hippocampus of chronically hyponatremic rats. A sustained low extracellular sodium ion concentration also decreased glutamate uptake by primary astrocyte cultures, suggesting an underlying mechanism of impaired long-term potentiation. Furthermore, gait and memory performances of corrected hyponatremic rats were equivalent to those of control rats. Thus, these results suggest chronic hyponatremia in humans may cause gait disturbance and cognitive impairment, but these abnormalities are reversible and careful correction of this condition may improve quality of life and reduce mortality. PMID:26376860

  8. Autonomic dysfunction in chronic liver disease

    PubMed Central

    Frith, James; Newton, Julia L

    2011-01-01

    It is becoming increasingly clear that quality of life (QOL) is impaired in those with chronic liver disease (CLD). One of the most important contributors to impaired QOL is the symptomatic burden which can range from slight to debilitating. Autonomic dysfunction accounts for a significant proportion of these symptoms, which can be common, non-specific and challenging to treat. Investigating the autonomic nervous system can be straight forward and can assist the clinician to diagnose and treat specific symptoms. Evidence-based treatment options for autonomic symptoms, specifically in CLD, can be lacking and must be extrapolated from other studies and expert opinion. For those with severely impaired quality of life, liver transplantation may offer an improvement; however, more research is needed to confirm this. PMID:24367224

  9. Telomeres, NAFLD and Chronic Liver Disease

    PubMed Central

    Donati, Benedetta; Valenti, Luca

    2016-01-01

    Telomeres consist of repeat DNA sequences located at the terminal portion of chromosomes that shorten during mitosis, protecting the tips of chromosomes. During chronic degenerative conditions associated with high cell replication rate, progressive telomere attrition is accentuated, favoring senescence and genomic instability. Several lines of evidence suggest that this process is involved in liver disease progression: (a) telomere shortening and alterations in the expression of proteins protecting the telomere are associated with cirrhosis and hepatocellular carcinoma; (b) advanced liver damage is a feature of a spectrum of genetic diseases impairing telomere function, and inactivating germline mutations in the telomerase complex (including human Telomerase Reverse Transcriptase (hTERT) and human Telomerase RNA Component (hTERC)) are enriched in cirrhotic patients independently of the etiology; and (c) experimental models suggest that telomerase protects from liver fibrosis progression. Conversely, reactivation of telomerase occurs during hepatocarcinogenesis, allowing the immortalization of the neoplastic clone. The role of telomere attrition may be particularly relevant in the progression of nonalcoholic fatty liver, an emerging cause of advanced liver disease. Modulation of telomerase or shelterins may be exploited to prevent liver disease progression, and to define specific treatments for different stages of liver disease. PMID:26999107

  10. Telomeres, NAFLD and Chronic Liver Disease.

    PubMed

    Donati, Benedetta; Valenti, Luca

    2016-01-01

    Telomeres consist of repeat DNA sequences located at the terminal portion of chromosomes that shorten during mitosis, protecting the tips of chromosomes. During chronic degenerative conditions associated with high cell replication rate, progressive telomere attrition is accentuated, favoring senescence and genomic instability. Several lines of evidence suggest that this process is involved in liver disease progression: (a) telomere shortening and alterations in the expression of proteins protecting the telomere are associated with cirrhosis and hepatocellular carcinoma; (b) advanced liver damage is a feature of a spectrum of genetic diseases impairing telomere function, and inactivating germline mutations in the telomerase complex (including human Telomerase Reverse Transcriptase (hTERT) and human Telomerase RNA Component (hTERC)) are enriched in cirrhotic patients independently of the etiology; and (c) experimental models suggest that telomerase protects from liver fibrosis progression. Conversely, reactivation of telomerase occurs during hepatocarcinogenesis, allowing the immortalization of the neoplastic clone. The role of telomere attrition may be particularly relevant in the progression of nonalcoholic fatty liver, an emerging cause of advanced liver disease. Modulation of telomerase or shelterins may be exploited to prevent liver disease progression, and to define specific treatments for different stages of liver disease. PMID:26999107

  11. Osteoporosis across chronic liver disease.

    PubMed

    Guarino, M; Loperto, I; Camera, S; Cossiga, V; Di Somma, C; Colao, A; Caporaso, N; Morisco, F

    2016-06-01

    Osteoporosis is a complication of chronic liver disease, with impact on morbidity, quality of life, and survival. The progress of medicine and the new therapies stretched the disease's natural history and improved the survival of patients with liver disease. So, it is fundamental to make better the quality of life and to prevent complications. Metabolic bone disorders are common complications of chronic liver disease (CLD). Patients with CLD have an increased risk of bone fractures, with significant impact on morbidity, quality of life, and even on survival. Bone diseases, including osteomalacia, osteoporosis, and osteopenia, are frequently observed in many types of liver disease. The pathogenesis of damage and the mechanisms of bone loss are different in relation to the specific liver disease. The relevance of these conditions induced many authors to create a new nosographic entity known as "hepatic osteodystrophy", although this term is rarely used anymore and it is now commonly referred to as osteopenia or osteoporosis associated with chronic liver disease. This review is based on the personal experiences of the authors and upon research done of the available literature on this subject matter. The authors searched the PubMed database for publications containing the term "liver disease" in combination with "bone disease", "hepatic osteodistrophy", "osteoporosis", "osteopenia", "osteomalacia", and "fractures". They selected publications from the past 10 years but did not exclude older seminal publications, especially for colestatic liver diseases. This review of literature shows that osteoporosis crosses all CLD. It is important to underline that the progress of medicine and the new therapies stretched the disease's natural history and improved the survival of patients with CLD. It is fundamental to make better the quality of life and it is mandatory to prevent complications and in particular the osteoporotic ones, especially fractures. PMID:26846777

  12. Acute liver impairment after sodium valproate overdose

    PubMed Central

    Waring, William Stephen; Nixon, Andrew C

    2009-01-01

    Liver impairment is a recognised adverse effect of long-term sodium valproate treatment, but there are few reports concerning its occurrence after acute overdose. This report describes a 36-year-old woman who deliberately ingested 32 g of sodium valproate (Epilim). Serum valproate concentration was 4370 μmol/l (630 mg/l) at 4.3 h post-ingestion (therapeutic reference range: 300–600 μmol/l), and the elimination half-life was 14.1 h. Liver biochemistry tests were initially normal but gradually became impaired, and highest alanine aminotransferase (761 U/l) occurred 2.3 days after ingestion. Supportive measures alone were sufficient to allow recovery of liver function. This case indicates that sodium valproate overdose may cause acute hepatocellular injury, even in the absence of pre-existing liver disease. PMID:21686945

  13. Counseling the Chronically Health Impaired Student.

    ERIC Educational Resources Information Center

    Dale, Brian, Comp.; And Others

    The role of counselors in working with chronically health impaired students is examined, and illustrations of the Chronic Health Impaired/Sickle Cell Anemia Program in Baltimore (MD) are presented. The importance of setting goals with the student is underlined, as is the necessity for counselors to have proper flexibility and time to devote to…

  14. [Erythrocyte changes during alcoholism and chronic liver diseases].

    PubMed

    Triolo, L; Magris, D; Mian, G; D'Agnolo, B

    1978-01-01

    50 patients with chronic liver disease and/or alcoholism were studied. 28 cases of anemia were found and macrocytes (and target m.), spurr-cells, spherocytes and stomatocytes observed. For each of these abnormalities the authors report the observed incidence and discuss the literature's data about the pathogenesis. A personal research on the influence of the liver's impaired capability of protein synthesis was also carried out. The usefulness of a careful examination of the blood film is finally stressed, in patients with liver disease and to discover alcoholic subjects still "healthy". PMID:756712

  15. Chronic hepatitis C and liver fibrosis.

    PubMed

    Sebastiani, Giada; Gkouvatsos, Konstantinos; Pantopoulos, Kostas

    2014-08-28

    Chronic infection with hepatitis C virus (HCV) is a leading cause of liver-related morbidity and mortality worldwide and predisposes to liver fibrosis and end-stage liver complications. Liver fibrosis is the excessive accumulation of extracellular matrix proteins, including collagen, and is considered as a wound healing response to chronic liver injury. Its staging is critical for the management and prognosis of chronic hepatitis C (CHC) patients, whose number is expected to rise over the next decades, posing a major health care challenge. This review provides a brief update on HCV epidemiology, summarizes basic mechanistic concepts of HCV-dependent liver fibrogenesis, and discusses methods for assessment of liver fibrosis that are routinely used in clinical practice. Liver biopsy was until recently considered as the gold standard to diagnose and stage liver fibrosis. However, its invasiveness and drawbacks led to the development of non-invasive methods, which include serum biomarkers, transient elastography and combination algorithms. Clinical studies with CHC patients demonstrated that non-invasive methods are in most cases accurate for diagnosis and for monitoring liver disease complications. Moreover, they have a high prognostic value and are cost-effective. Non-invasive methods for assessment of liver fibrosis are gradually being incorporated into new guidelines and are becoming standard of care, which significantly reduces the need for liver biopsy. PMID:25170193

  16. Chronic hepatitis C and liver fibrosis

    PubMed Central

    Sebastiani, Giada; Gkouvatsos, Konstantinos; Pantopoulos, Kostas

    2014-01-01

    Chronic infection with hepatitis C virus (HCV) is a leading cause of liver-related morbidity and mortality worldwide and predisposes to liver fibrosis and end-stage liver complications. Liver fibrosis is the excessive accumulation of extracellular matrix proteins, including collagen, and is considered as a wound healing response to chronic liver injury. Its staging is critical for the management and prognosis of chronic hepatitis C (CHC) patients, whose number is expected to rise over the next decades, posing a major health care challenge. This review provides a brief update on HCV epidemiology, summarizes basic mechanistic concepts of HCV-dependent liver fibrogenesis, and discusses methods for assessment of liver fibrosis that are routinely used in clinical practice. Liver biopsy was until recently considered as the gold standard to diagnose and stage liver fibrosis. However, its invasiveness and drawbacks led to the development of non-invasive methods, which include serum biomarkers, transient elastography and combination algorithms. Clinical studies with CHC patients demonstrated that non-invasive methods are in most cases accurate for diagnosis and for monitoring liver disease complications. Moreover, they have a high prognostic value and are cost-effective. Non-invasive methods for assessment of liver fibrosis are gradually being incorporated into new guidelines and are becoming standard of care, which significantly reduces the need for liver biopsy. PMID:25170193

  17. Cognitive function in patients with alcoholic and nonalcoholic chronic liver disease.

    PubMed

    Brodersen, Carlos; Koen, Eduardo; Ponte, Alicia; Sánchez, Silvina; Segal, Eduardo; Chiapella, Alberto; Fernández, Maria; Torres, Maria; Tripodi, Valeria; Lemberg, Abraham

    2014-01-01

    The aim of the present study was to characterize the neurophysiological profile of cognitive impairment associated with patients with chronic alcoholic and nonalcoholic liver disease. The authors evaluated 43 patients with cirrhotic liver disease: 19 patients with chronic alcohol ingestion and 24 nonalcoholic patients who had been infected with hepatitis B or C virus. Eleven healthy subjects were included as control subjects. A battery of 12 psychological tests was used to investigate cognitive deficits in the patients with chronic liver disease. It was observed that alcoholic patients with chronic liver disease showed a more important cognitive deterioration than those affected by hepatitis B or C virus. PMID:25093764

  18. Chronic Liver Disease and Asian Americans/Pacific Islanders

    MedlinePlus

    ... Liver Disease Chronic Liver Disease and Asian Americans/Pacific Islanders Among Asian Americans, chronic liver disease is ... women. At a glance – Cancer Rates for Asian/Pacific Islanders (2008-2012) Cancer Incidence Rates per 100, ...

  19. Liver transplantation in acute-on-chronic liver failure: lessons learnt from acute liver failure setting.

    PubMed

    Reddy, Mettu Srinivas; Rajalingam, Rajesh; Rela, Mohamed

    2015-10-01

    Acute-on-chronic liver failure is a clinical entity with high risk of mortality. These patients can have severe liver dysfunction complicated with multiple organ failure. Liver transplantation is the definitive treatment for these patients. Literature regarding management of acute liver failure with special emphasis on liver transplantation was reviewed. Lessons learnt from the management of patients with acute liver failure which could be extrapolated to the management of patients with acute-on-chronic liver failure are discussed. Significant improvement in outcomes of acute liver failure has been reported across the world. Several aspects in transplantation for acute liver failure were found to be relevant to the management of acute-on-chronic liver failure. These include defining criteria to identify patients needing early liver transplantation, prioritizing patients with acute liver failure on the waiting list, defining when to abandon transplantation in acute liver failure, emphasis on graft quality and the need for a multi-disciplinary approach to manage multiple organ dysfunction. Useful lessons can be learnt from the progress made in the management of acute liver failure and these can be extrapolated to the management of patients with acute-on-chronic liver failure. PMID:25788191

  20. Animal models of chronic liver diseases.

    PubMed

    Liu, Yan; Meyer, Christoph; Xu, Chengfu; Weng, Honglei; Hellerbrand, Claus; ten Dijke, Peter; Dooley, Steven

    2013-03-01

    Chronic liver diseases are frequent and potentially life threatening for humans. The underlying etiologies are diverse, ranging from viral infections, autoimmune disorders, and intoxications (including alcohol abuse) to imbalanced diets. Although at early stages of disease the liver regenerates in the absence of the insult, advanced stages cannot be healed and may require organ transplantation. A better understanding of underlying mechanisms is mandatory for the design of new drugs to be used in clinic. Therefore, rodent models are being developed to mimic human liver disease. However, no model to date can completely recapitulate the "corresponding" human disorder. Limiting factors are the time frame required in humans to establish a certain liver disease and the fact that rodents possess a distinct immune system compared with humans and have different metabolic rates affecting liver homeostasis. These features account for the difficulties in developing adequate rodent models for studying disease progression and for testing new pharmaceuticals to be translated into the clinic. Nevertheless, traditional and new promising animal models that mimic certain attributes of chronic liver diseases are established and being used to deepen our understanding in the underlying mechanisms of distinct liver diseases. This review aims at providing a comprehensive overview of recent advances in animal models recapitulating different features and etiologies of human liver diseases. PMID:23275613

  1. Vitamin D deficiency in chronic liver disease

    PubMed Central

    Iruzubieta, Paula; Terán, Álvaro; Crespo, Javier; Fábrega, Emilio

    2014-01-01

    Vitamin D is an important secosteroid hormone with known effect on calcium homeostasis, but recently there is increasing recognition that vitamin D also is involved in cell proliferation and differentiation, has immunomodulatory and anti-inflammatory properties. Vitamin D deficiency has been frequently reported in many causes of chronic liver disease and has been associated with the development and evolution of non-alcoholic fatty liver disease (NAFLD) and chronic hepatitis C (CHC) virus infection. The role of vitamin D in the pathogenesis of NAFLD and CHC is not completely known, but it seems that the involvement of vitamin D in the activation and regulation of both innate and adaptive immune systems and its antiproliferative effect may explain its importance in these liver diseases. Published studies provide evidence for routine screening for hypovitaminosis D in patients with liver disease. Further prospectives studies demonstrating the impact of vitamin D replacement in NAFLD and CHC are required. PMID:25544877

  2. Impairment in episodic and chronic cluster headache.

    PubMed

    Jürgens, Tim P; Gaul, Charly; Lindwurm, Andrea; Dresler, Thomas; Paelecke-Habermann, Yvonne; Schmidt-Wilcke, Tobias; Lürding, Ralf; Henkel, Karsten; Leinisch, Elke

    2011-04-01

    Despite being an excruciating headache, little is known about the burden of cluster headache (CH) regarding its various subtypes. In a multicentre, prospective study, patients with chronic CH (n = 27), with episodic CH in the active (n = 26) and outside the active period (n = 22), migraine patients (n = 24) and healthy controls (n = 31) were included. Epidemiological data, the German version of the Headache Disability Inventory (HDI) and a screening for psychiatric complaints were applied. About 25% of chronic CH patients in our study received invalidity allowance due to CH. HDI scores (total and subscales emotion and function) indicated a severe headache-specific disability (one-way ANOVA: P < 0.01). Patients with chronic and active episodic CH were significantly more affected than patients with inactive CH and migraine. Healthy volunteers were significantly less affected than all headache patients. Symptoms suggestive of psychiatric co-morbidity were found predominantly in chronic CH: depressive symptoms (56%), signs of agoraphobia (33%) and suicidal tendencies (25%) were frequently reported. Patients with chronic and active episodic CH were severely impaired in non-economic and economic domains such as disability, working life and psychiatric complaints. Remarkably, psychiatric co-morbidity was highest in chronic CH. Thus, especially chronic CH warrants special medical and further supportive care. PMID:21123629

  3. Chronic Liver Disease and Native Hawaiian/Pacific Islanders

    MedlinePlus

    ... Liver Disease Chronic Liver Disease and Native Hawaiian/Pacific Islander Native Hawaiian/Pacific Islanders were seven times ... At a glance – Cancer Rates for Native Hawaiian/Pacific Islander Liver & IBD Cancer Incidence Rates per 100, ...

  4. Can paracetamol (acetaminophen) be administered to patients with liver impairment?

    PubMed

    Hayward, Kelly L; Powell, Elizabeth E; Irvine, Katharine M; Martin, Jennifer H

    2016-02-01

    Although 60 years have passed since it became widely available on the therapeutic market, paracetamol dosage in patients with liver disease remains a controversial subject. Fulminant hepatic failure has been a well documented consequence of paracetamol overdose since its introduction, while short and long term use have both been associated with elevation of liver transaminases, a surrogate marker for acute liver injury. From these reports it has been assumed that paracetamol use should be restricted or the dosage reduced in patients with chronic liver disease. We review the factors that have been purported to increase risk of hepatocellular injury from paracetamol and the pharmacokinetic alterations in different pathologies of chronic liver disease which may affect this risk. We postulate that inadvertent under-dosing may result in concentrations too low to enable efficacy. Specific research to improve the evidence base for prescribing paracetamol in patients with different aetiologies of chronic liver disease is needed. PMID:26460177

  5. The Impact of Liver Cell Injury on Health-Related Quality of Life in Patients with Chronic Liver Disease

    PubMed Central

    Alt, Yvonne; Grimm, Anna; Schlegel, Liesa; Grambihler, Annette; Kittner, Jens M.; Wiltink, Jörg; Galle, Peter R.; Wörns, Marcus A.; Schattenberg, Jörn M.

    2016-01-01

    Background Patients with chronic liver disease often suffer from unspecific symptoms and report severe impairment in the quality of life. The underlying mechanisms are multifactorial and include disease-specific but also liver related causes. The current analysis evaluated the association of hepatocellular apoptosis in non-viral chronic liver disease and health-related quality of life (HRQL). Furthermore we examined factors, which influence patient's physical and mental well-being. Methods A total of 150 patients with non-infectious chronic liver disease were included between January 2014 and June 2015. The German version of the Chronic Liver Disease Questionnaire (CLDQ-D), a liver disease specific instrument to assess HRQL, was employed. Hepatocellular apoptosis was determined by measuring Cytokeratin 18 (CK18, M30 Apoptosense ELISA). Results Female gender (5.24 vs. 5.54, p = 0.04), diabetes mellitus type II (4.75 vs. 5.46, p<0.001) and daily drug intake (5.24 vs. 6.01, p = 0.003) were associated with a significant impairment in HRQL. HRQL was not significantly different between the examined liver diseases. Levels of CK18 were the highest in patients with NASH compared to all other disease entities (p<0.001). Interestingly, CK18 exhibited significant correlations with obesity (p<0.001) and hyperlipidemia (p<0.001). In patients with cirrhosis levels of CK18 correlated with the MELD score (r = 0.18, p = 0.03) and were significantly higher compared to patients without existing cirrhosis (265.5 U/l vs. 186.9U/l, p = 0.047). Additionally, CK18 showed a significant correlation with the presence and the degree of hepatic fibrosis (p = 0.003) and inflammation (p<0.001) in liver histology. Finally, there was a small negative association between CLDQ and CK18 (r = -0.16, p = 0.048). Conclusion Different parameters are influencing HRQL and CK18 levels in chronic non-viral liver disease and the amount of hepatocellular apoptosis correlates with the impairment in HRQL in

  6. NADPH Oxidases in Chronic Liver Diseases

    PubMed Central

    Jiang, Joy X.; Török, Natalie J.

    2015-01-01

    Oxidative stress is a common feature observed in a wide spectrum of chronic liver diseases including viral hepatitis, alcoholic, and nonalcoholic steatohepatitis. The nicotinamide adenine dinucleotide phosphate (NADPH) oxidases (NOXs) are emerging as major sources of reactive oxygen species (ROS). Several major isoforms are expressed in the liver, including NOX1, NOX2, and NOX4. While the phagocytic NOX2 has been known to play an important role in Kupffer cell and neutrophil phagocytic activity and inflammation, the nonphagocytic NOX homologues are increasingly recognized as key enzymes in oxidative injury and wound healing. In this review, we will summarize the current advances in knowledge on the regulatory pathways of NOX activation, their cellular distribution, and their role in the modulation of redox signaling in liver diseases. PMID:26436133

  7. Acute-on-chronic and Decompensated Chronic Liver Failure: Definitions, Epidemiology, and Prognostication.

    PubMed

    Olson, Jody C

    2016-07-01

    Chronic liver disease is the fifth leading cause of death worldwide and represents a major burden for the health care community. Cirrhosis is a progressive disease resulting in end-stage liver failure, which in the absence of liver transplantation is fatal. Acute-on-chronic liver failure carries high short-term mortality but is potentially reversible. Viral hepatitis, alcohol, and nonalcoholic fatty liver disease remain the principal causes of liver disease. Though treatments exist for hepatitis B and C, they remain unavailable to many with these diseases. This article reviews the epidemiology of advanced liver disease and the concept of acute-on-chronic liver failure. PMID:27339672

  8. Impaired Hepatitis C Virus (HCV)-Specific Effector CD8+ T Cells Undergo Massive Apoptosis in the Peripheral Blood during Acute HCV Infection and in the Liver during the Chronic Phase of Infection▿

    PubMed Central

    Radziewicz, Henry; Ibegbu, Chris C.; Hon, Huiming; Osborn, Melissa K.; Obideen, Kamil; Wehbi, Mohammad; Freeman, Gordon J.; Lennox, Jeffrey L.; Workowski, Kimberly A.; Hanson, Holly L.; Grakoui, Arash

    2008-01-01

    A majority of patients infected with hepatitis C virus (HCV) do not sustain an effective T-cell response, and viremia persists. The mechanism leading to failure of the HCV-specific CD8+ T-cell response in patients developing chronic infection is unclear. We investigated apoptosis susceptibility of HCV-specific CD8+ T cells during the acute and chronic stages of infection. Although HCV-specific CD8+ T cells in the blood during the acute phase of infection and in the liver during the chronic phase were highly activated and expressed an effector phenotype, the majority was undergoing apoptosis. In contrast, peripheral blood HCV-specific CD8+ T cells during the chronic phase expressed a resting memory phenotype. Apoptosis susceptibility of HCV-specific CD8+ T cells was associated with very high levels of programmed death-1 (PD-1) and low CD127 expression and with significant functional T-cell deficits. Further evaluation of the “death phase” of HCV-specific CD8+ T cells during acute HCV infection showed that the majority of cells were dying by a process of cytokine withdrawal, mediated by activated caspase 9. Contraction during the acute phase occurred rapidly via this process despite the persistence of the virus. Remarkably, in the chronic phase of HCV infection, at the site of infection in the liver, a substantial frequency of caspase 9-mediated T-cell death was also present. This study highlights the importance of cytokine deprivation-mediated apoptosis with consequent down-modulation of the immune response to HCV during acute and chronic infections. PMID:18667503

  9. Fibroblast growth factor 15 deficiency impairs liver regeneration in mice

    PubMed Central

    Kong, Bo; Huang, Jiansheng; Zhu, Yan; Li, Guodong; Williams, Jessica; Shen, Steven; Aleksunes, Lauren M.; Richardson, Jason R.; Apte, Udayan; Rudnick, David A.

    2014-01-01

    Fibroblast growth factor (FGF) 15 (human homolog, FGF19) is an endocrine FGF highly expressed in the small intestine of mice. Emerging evidence suggests that FGF15 is critical for regulating hepatic functions; however, the role of FGF15 in liver regeneration is unclear. This study assessed whether liver regeneration is altered in FGF15 knockout (KO) mice following 2/3 partial hepatectomy (PHx). The results showed that FGF15 KO mice had marked mortality, with the survival rate influenced by genetic background. Compared with wild-type mice, the KO mice displayed extensive liver necrosis and marked elevation of serum bile acids and bilirubin. Furthermore, hepatocyte proliferation was reduced in the KO mice because of impaired cell cycle progression. After PHx, the KO mice had weaker activation of signaling pathways that are important for liver regeneration, including signal transducer and activator of transcription 3, nuclear factor-κB, and mitogen-activated protein kinase. Examination of the KO mice at early time points after PHx revealed a reduced and/or delayed induction of immediate-early response genes, including growth-control transcription factors that are critical for liver regeneration. In conclusion, the results suggest that FGF15 deficiency severely impairs liver regeneration in mice after PHx. The underlying mechanism is likely the result of disrupted bile acid homeostasis and impaired priming of hepatocyte proliferation. PMID:24699334

  10. Chronic Alcohol Ingestion in Rats Alters Lung Metabolism, Promotes Lipid Accumulation, and Impairs Alveolar Macrophage Functions

    PubMed Central

    Romero, Freddy; Shah, Dilip; Duong, Michelle; Stafstrom, William; Hoek, Jan B.; Kallen, Caleb B.; Lang, Charles H.

    2014-01-01

    Chronic alcoholism impairs pulmonary immune homeostasis and predisposes to inflammatory lung diseases, including infectious pneumonia and acute respiratory distress syndrome. Although alcoholism has been shown to alter hepatic metabolism, leading to lipid accumulation, hepatitis, and, eventually, cirrhosis, the effects of alcohol on pulmonary metabolism remain largely unknown. Because both the lung and the liver actively engage in lipid synthesis, we hypothesized that chronic alcoholism would impair pulmonary metabolic homeostasis in ways similar to its effects in the liver. We reasoned that perturbations in lipid metabolism might contribute to the impaired pulmonary immunity observed in people who chronically consume alcohol. We studied the metabolic consequences of chronic alcohol consumption in rat lungs in vivo and in alveolar epithelial type II cells and alveolar macrophages (AMs) in vitro. We found that chronic alcohol ingestion significantly alters lung metabolic homeostasis, inhibiting AMP-activated protein kinase, increasing lipid synthesis, and suppressing the expression of genes essential to metabolizing fatty acids (FAs). Furthermore, we show that these metabolic alterations promoted a lung phenotype that is reminiscent of alcoholic fatty liver and is characterized by marked accumulation of triglycerides and free FAs within distal airspaces, AMs, and, to a lesser extent, alveolar epithelial type II cells. We provide evidence that the metabolic alterations in alcohol-exposed rats are mechanistically linked to immune impairments in the alcoholic lung: the elevations in FAs alter AM phenotypes and suppress both phagocytic functions and agonist-induced inflammatory responses. In summary, our work demonstrates that chronic alcohol ingestion impairs lung metabolic homeostasis and promotes pulmonary immune dysfunction. These findings suggest that therapies aimed at reversing alcohol-related metabolic alterations might be effective for preventing and

  11. Liver steatosis associated with chronic hepatitis C.

    PubMed

    Irimia, Eugenia; Mogoantă, Laurentiu; Predescu, Ion Octavian; Efrem, Ion Cristian; Stănescu, Casiana; Streba, Letitia Adela Maria; Georgescu, Anca Meda

    2014-01-01

    Hepatic steatosis is a common histological finding in chronic liver diseases. One of the pathological entities in which hepatic steatosis has been found is chronic hepatitis C. The prevalence of steatosis in these patients ranges from 40% to 86%, with an average of 55%, which is two times higher than the steatosis seen in adults uninfected with hepatitis C. Many studies have shown that hepatic steatosis is a medical condition that may progress to steatohepatitis, progressive hepatic failure, hepatic cirrhosis, and is a risk factor for development of hepatocellular carcinoma. We have proposed to evaluate the severity of steatosis in patients with chronic hepatitis C and to correlate it with necroinflammatory processes and fibrosis. We included 259 patients diagnosed with chronic hepatitis C and proven histological steatosis. Age of patients with hepatic steatosis varied from 20 to 69 years. Most cases of steatosis associated with chronic hepatitis C (47.87%) were diagnosed in the age group 50-59 years. Of 259 patients, 141 (54.44%) were female and 118 (45.56%) male. Slight steatosis was identified in 130 cases (50.19%), moderate fatty changes were present in 54 (20.85%) patients and severe steatosis in 75 (28.96%) patients. The appearance of steatosis was macrovesicular and predominantly affected the third zone of the hepatic lobe. Most cases of hepatic steatosis were associated with necroinflammatory activity and low and moderate fibrosis. Cases of marked steatosis associated with intense activity accounted for about 10%, while marked steatosis was associated with severe fibrosis in less than 5% of cases. PMID:24969985

  12. Renal impairment with chronic hydrocarbon exposure.

    PubMed

    Yaqoob, M; Bell, G M; Stevenson, A; Mason, H; Percy, D F

    1993-03-01

    group 2 with at least one abnormal parameter, compared to only five individuals in internal controls. This difference between the two target groups and group 3 was highly significant (p < 0.001). Subjects with chronic paint exposure had renal impairment and tubular dysfunction. Tubular dysfunction was also prominent with petroleum oil exposure. We therefore conclude that chronic hydrocarbon exposure may be associated with clinical and sub-clinical renal dysfunction. We advocate careful monitoring of workers exposure to hydrocarbons and for more effective preventive measures. PMID:8483990

  13. Extracorporeal Liver Support and Liver Transplant for Patients with Acute-on-Chronic Liver Failure.

    PubMed

    Li, Han; Chen, Harvey Shi-Hsien; Nyberg, Scott L

    2016-05-01

    Recognition of acute-on-chronic liver failure (ACLF) as a unique entity is slowly evolving, as are therapies to improve survival of affected patients. Further investigation into its disease process and proper treatments with critical timing are important for improving patient survival. At this time, liver transplant is the only treatment known to improve survival in liver-failure patients. However, liver transplantation has its own disadvantages, such as organ shortage and the need for lifelong immunotherapy. Bridging therapies such as extracorporeal liver-support systems are attractive options to stabilize patients until transplantation or spontaneous recovery. The goals of these liver-support systems are to remove detoxification products, reduce systemic inflammation, and enhance regeneration of the injured liver. These devices have been under development for the past decade; a few are in clinical trials. At this time, there is no proven clearcut survival benefit in these devices, but they may improve the outcome of challenging cases and potentially avoid or postpone liver transplantation in some cases. PMID:27172357

  14. Chronic Liver Disease and American Indians/Alaska Natives

    MedlinePlus

    ... Disease Chronic Liver Disease and American Indians/Alaska Natives Among American Indians and Alaska Natives, chronic liver disease is ... 54. 1 At a glance – Cancer Rates for American Indian/Alaska Natives (2008-2012) Cancer Incidence Rates per 100,000 – ...

  15. Brain cholinergic impairment in liver failure.

    PubMed

    García-Ayllón, María-Salud; Cauli, Omar; Silveyra, María-Ximena; Rodrigo, Regina; Candela, Asunción; Compañ, Antonio; Jover, Rodrigo; Pérez-Mateo, Miguel; Martínez, Salvador; Felipo, Vicente; Sáez-Valero, Javier

    2008-11-01

    The cholinergic system is involved in specific behavioural responses and cognitive processes. Here, we examined potential alterations in the brain levels of key cholinergic enzymes in cirrhotic patients and animal models with liver failure. An increase (~30%) in the activity of the acetylcholine-hydrolyzing enzyme, acetylcholinesterase (AChE) is observed in the brain cortex from patients deceased from hepatic coma, while the activity of the acetylcholine-synthesizing enzyme, choline acetyltransferase, remains unaffected. In agreement with the human data, AChE activity in brain cortical extracts of bile duct ligated (BDL) rats was increased (~20%) compared to controls. A hyperammonemic diet did not result in any further increase of AChE levels in the BDL model, and no change was observed in hyperammonemic diet rats without liver disease. Portacaval shunted rats which display increased levels of cerebral ammonia did not show any brain cholinergic abnormalities, confirming that high ammonia levels do not play a role in brain AChE changes. A selective increase of tetrameric AChE, the major AChE species involved in hydrolysis of acetylcholine in the brain, was detected in both cirrhotic humans and BDL rats. Histological examination of BDL and non-ligated rat brains shows that the subcellular localization of both AChE and choline acetyltransferase, and thus the accessibility to their substrates, appears unaltered by the pathological condition. The BDL-induced increase in AChE activity was not parallelled by an increase in mRNA levels. Increased AChE in BDL cirrhotic rats leads to a pronounced decrease (~50-60%) in the levels of acetylcholine. Finally, we demonstrate that the AChE inhibitor rivastigmine is able to improve memory deficits in BDL rats. One week treatment with rivastigmine (0.6 mg/kg; once a day, orally, for a week) resulted in a 25% of inhibition in the enzymatic activity of AChE with no change in protein composition, as assessed by sucrose density gradient

  16. Brain cholinergic impairment in liver failure

    PubMed Central

    García-Ayllón, María-Salud; Cauli, Omar; Silveyra, María-Ximena; Rodrigo, Regina; Candela, Asunción; Compañ, Antonio; Jover, Rodrigo; Pérez-Mateo, Miguel; Martínez, Salvador; Felipo, Vicente

    2008-01-01

    The cholinergic system is involved in specific behavioural responses and cognitive processes. Here, we examined potential alterations in the brain levels of key cholinergic enzymes in cirrhotic patients and animal models with liver failure. An increase (∼30%) in the activity of the acetylcholine-hydrolyzing enzyme, acetylcholinesterase (AChE) is observed in the brain cortex from patients deceased from hepatic coma, while the activity of the acetylcholine-synthesizing enzyme, choline acetyltransferase, remains unaffected. In agreement with the human data, AChE activity in brain cortical extracts of bile duct ligated (BDL) rats was increased (∼20%) compared to controls. A hyperammonemic diet did not result in any further increase of AChE levels in the BDL model, and no change was observed in hyperammonemic diet rats without liver disease. Portacaval shunted rats which display increased levels of cerebral ammonia did not show any brain cholinergic abnormalities, confirming that high ammonia levels do not play a role in brain AChE changes. A selective increase of tetrameric AChE, the major AChE species involved in hydrolysis of acetylcholine in the brain, was detected in both cirrhotic humans and BDL rats. Histological examination of BDL and non-ligated rat brains shows that the subcellular localization of both AChE and choline acetyltransferase, and thus the accessibility to their substrates, appears unaltered by the pathological condition. The BDL-induced increase in AChE activity was not parallelled by an increase in mRNA levels. Increased AChE in BDL cirrhotic rats leads to a pronounced decrease (∼50–60%) in the levels of acetylcholine. Finally, we demonstrate that the AChE inhibitor rivastigmine is able to improve memory deficits in BDL rats. One week treatment with rivastigmine (0.6 mg/kg; once a day, orally, for a week) resulted in a 25% of inhibition in the enzymatic activity of AChE with no change in protein composition, as assessed by sucrose density

  17. The Effects of Alcohol on Other Chronic Liver Diseases.

    PubMed

    Hsu, Christine C; Kowdley, Kris V

    2016-08-01

    Alcohol consumption is often a comorbid condition in other chronic liver diseases. It has been shown to act in synergy to increase liver injury in viral hepatitis, hereditary hemochromatosis, and nonalcoholic fatty liver disease (NAFLD), leading to an increased risk of cirrhosis, hepatocellular carcinoma, and liver-related mortality. Data suggest that modest alcohol consumption may be inversely related to the risk of developing NAFLD and lower rates of progression of NAFLD to nonalcoholic steatohepatitis (NASH). This article reviews data on the relationship between alcohol consumption and other chronic liver diseases. PMID:27373618

  18. Cognitive Impairment in Chronic Obstructive Pulmonary Disease

    PubMed Central

    Crişan, Alexandru F.; Oancea, Cristian; Timar, Bogdan; Fira-Mladinescu, Ovidiu; Crişan, Alexandru; Tudorache, Voicu

    2014-01-01

    Background/Purpose Chronic obstructive pulmonary disease (COPD), especially in severe forms, is commonly associated with multiple cognitive problems. Montreal Cognitive Assessment test (MoCA) is used to detect cognitive impairment evaluating several areas: visuospatial, memory, attention and fluency. Our study aim was to evaluate the impact of stable COPD and exacerbation (AECOPD) phases on cognitive status using MoCA questionnaire. Methods We enrolled 39 patients (pts), smokers with COPD group D (30 stable and 9 in AECOPD) and 13 healthy subjects (control group), having similar level of education and no significant differences regarding the anthropometric measurements. We analyzed the differences in MoCA score between these three groups and also the correlation between this score and inflammatory markers. Results Patients with AECOPD had a significant (p<0.001) decreased MoCA score (14.6±3.4) compared to stable COPD (20.2±2.4) and controls (24.2±5.8). The differences between groups were more accentuated for the language abstraction and attention (p<0.001) and delayed recall and orientation (p<0.001) sub-topics. No significant variance of score was observed between groups regarding visuospatial and naming score (p = 0.095). The MoCA score was significantly correlated with forced expiratory volume (r = 0.28) and reverse correlated with C-reactive protein (CRP) (r = −0.57), fibrinogen (r = −0.58), erythrocyte sedimentation rate (ESR) (r = −0.55) and with the partial pressure of CO2 (r = −0.47). Conclusions According to this study, COPD significantly decreases the cognitive status in advanced and acute stages of the disease. PMID:25033379

  19. [Cytotoxic action of active forms of oxygen and mechanisms of development of a chronic process in the liver in liver disease].

    PubMed

    Loginov, A S; Matiushin, B N

    1996-01-01

    The paper deals with the damaging action of active oxygen forms (AOF) on the cell, which is associated with impairments of membranous structures and their functional properties. Based on the results of their own investigations, the authors forward a concept of the stereotypic pattern of changes in the enzyme mechanisms of AOF utilization in chronic hepatic diseases of viral etiology. It is suggested that impaired hepatocytic AOF formation and inactivation may be metabolic mechanisms mediating the status and development of a chronic process in the liver in its viral damage. Promising approaches to treating oxidative impairments are also discussed. PMID:9082318

  20. Diphenhydramine disposition in chronic liver disease.

    PubMed

    Meredith, C G; Christian, C D; Johnson, R F; Madhavan, S V; Schenker, S

    1984-04-01

    Diphenhydramine (DPHM) disposition was examined in nine patients with chronic alcohol-related liver disease and in eight normal subjects. Sleep of 1 to 2 hr duration was induced in all subjects by a 0.8 mg/kg iv dose without an apparent increase in cerebral sensitivity in the patients with cirrhosis. Protein binding as determined by equilibrium dialysis (3H-DPHM) revealed a 15% decrease in the cirrhotic patients, while recovery of unchanged DPHM in urine (2%) was of the same order in the two groups. Computerized biexponential curve analysis was used to compare the plasma profiles for five of the patients and six of the normal subjects. Monoexponential curve analysis of the terminal beta-phase, including all subjects, was also used to compare the two groups. The means of plasma clearance and apparent volume of distribution in cirrhotic patients were respectively less and greater than in normal subjects, but these differences were not significant. The t1/2 for the beta-phase (t1/2 beta), which reflects this reciprocal trend, was increased in the patients (15.2 +/- 1.5 and 9.3 +/- 0.9 hr). This correlated in part with severity of disease, with r = 0.723 between t1/2 beta and the serum bilirubin levels. In conclusion, a single intravenous dose of DPHM provided safe and effective sedation in patients with cirrhosis. PMID:6705445

  1. Tempol prevents chronic sleep-deprivation induced memory impairment.

    PubMed

    Alzoubi, Karem H; Khabour, Omar F; Albawaana, Amal S; Alhashimi, Farah H; Athamneh, Rabaa Y

    2016-01-01

    Sleep deprivation is associated with oxidative stress that causes learning and memory impairment. Tempol is a nitroxide compound that promotes the metabolism of many reactive oxygen species (ROS) and has antioxidant and neuroprotective effect. The current study investigated whether chronic administration of tempol can overcome oxidative stress and prevent learning and memory impairment induced by sleep deprivation. Sleep deprivation was induced in rats using multiple platform model. Tempol was administered to rats via oral gavages. Behavioral studies were conducted to test the spatial learning and memory using radial arm water maze. The hippocampus was dissected; antioxidant biomarkers (GSH, GSSG, GSH/GSSG ratio, GPx, SOD, and catalase) were assessed. The result of this project revealed that chronic sleep deprivation impaired both short and long term memory (P<0.05), while tempol treatment prevented such effect. Furthermore, tempol normalized chronic sleep deprivation induced reduction in the hippocampus activity of catalase, GPx, and SOD (P<0.05). Tempol also enhanced the ratio of GSH/GSSG in chronically sleep deprived rats treated with tempol as compared with only sleep deprived rats (P<0.05). In conclusion chronic sleep deprivation induced memory impairment, and treatment with tempol prevented this impairment probably through normalizing antioxidant mechanisms in the hippocampus. PMID:26616531

  2. Simulation of Chronic Liver Injury Due to Environmental Chemicals

    EPA Science Inventory

    US EPA Virtual Liver (v-Liver) is a cellular systems model of hepatic tissues to predict the effects of chronic exposure to chemicals. Tens of thousands of chemicals are currently in commerce and hundreds more are introduced every year. Few of these chemicals have been adequate...

  3. Patients with Chronically Diseased Livers Have Lower Incidence of Colorectal Liver Metastases: A Meta-Analysis

    PubMed Central

    Cai, Bin; Liao, Kai; Song, Xian-qing; Wei, Wei-yuan; Zhuang, Yuan; Zhang, Sen

    2014-01-01

    Background 70 years ago, it was put forward that the diseased liver was not a favorable soil for metastatic tumor cells. In addition, a few studies have demonstrated that rare occurrence of colorectal liver metastases among patients with fatty liver, cirrhosis or chronic hepatitis B and C virus infection. We performed a meta-analysis to verify the association between the incidences of colorectal liver metastases with chronically diseased livers. Methods Relevant studies were identified by a search of electronic database PubMed, Cochrane Library, OVID, Web of Science and CNKI (up to February 24, 2014). Pooled odds ratio (OR) with 95% confidence interval (CI) was calculated using random- or fixed-effect models when appropriate. Meta-analysis and publication bias (Bgger's test) was evaluated with STATA 12.0. Results A total of 10,349 colorectal cancer patients from 10 studies were included. The meta-analysis result showed there was a significant difference in the incidences of colorectal liver metastases between patients with normal and chronically diseased livers (OR = 0.32; 95% CI 95%: 0.26–0.38, P = 0.000 fixed-effects model). The result of Begg's test (Pr>|z| = 0.089; P>0.05) revealed no publication bias. Conclusions The results of this meta-analysis demonstrated that patients with chronically diseased livers had significantly lower incidences of colorectal liver metastases than those with normal livers. PMID:25265536

  4. Oxysterols induce mitochondrial impairment and hepatocellular toxicity in non-alcoholic fatty liver disease.

    PubMed

    Bellanti, Francesco; Mitarotonda, Domenica; Tamborra, Rosanna; Blonda, Maria; Iannelli, Giuseppina; Petrella, Antonio; Sanginario, Vittorio; Iuliano, Luigi; Vendemiale, Gianluigi; Serviddio, Gaetano

    2014-10-01

    Non-alcoholic fatty liver disease (NAFLD) is a chronic hepatic disorder affecting up to 25% of the general population. Several intracellular events leading to NAFLD and progression to non-alcoholic steatohepatitis (NASH) have been identified, including lipid accumulation, mitochondrial dysfunction and oxidative stress. Emerging evidence links both hepatic free fatty acids (FFAs) and cholesterol (FC) accumulation in NAFLD development; in particular oxysterols, the oxidative products of cholesterol, may contribute to liver injury. We performed a targeted lipidomic analysis of oxysterols in the liver of male Wistar rats fed a high-fat (HF), high-cholesterol (HC) or high-fat/high-cholesterol (HF/HC) diet. Both HF and HC diets caused liver steatosis, but the HF/HC diet resulted in steatohepatitis with associated mitochondrial dysfunction. Above all, the oxysterol cholestane-3beta,5alpha,6beta-triol (triol) was particularly increased in the liver of rats fed diets rich in cholesterol. To verify the molecular mechanism involved in mitochondrial dysfunction and hepatocellular toxicity, Huh7 and primary rat hepatocytes were exposed to palmitic acid (PA) and/or oleic acid (OA), with or without triol. This compound induced apoptosis in cells co-exposed to both PA and OA, and this was associated with impaired mitochondrial respiration as well as down-regulation of PGC1-alpha, mTFA and NRF1.In conclusion, our data show that hepatic free fatty acid or oxysterols accumulation per se induce low hepatocellular toxicity. On the contrary, hepatic accumulation of both fatty acids and toxic oxysterols such as triol are determinant in the impairment of mitochondrial function and biogenesis, contributing to liver pathology in NAFLD. PMID:26461297

  5. [Pathogenetic correction of metabolic disturbances in chronic liver affections].

    PubMed

    Romantsov, M G; Petrov, A Iu; Aleksandrova, L N; Sukhanov, D S; Kovalenko, A L

    2012-01-01

    The available drugs for the treatment of chronic liver affections (the adequate model is chronic hepatitis C) include agents of metabolic therapy, whose efficacy is not always enough, that required the search for original mitochondrial substrates on the basis of succinate. Such agents were composed as a pharmaceutical group named "Substrates of Energetic Metabolism" or "Substrate Antihypoxants". The review presents the description of the pharmacological effects of remaxole and cytoflavin, evident from lower levels of active metabolites of oxygen that increases the clinical efficacy of the therapy. Their role in the metabolic reactions in chronic liver affections is exclusive and rather actual. PMID:23700935

  6. [Anemic syndrome in chronic hepatitis and liver cirrhosis].

    PubMed

    Korolko, Iu R; Sarycheva, T G; Kotelńikov, V M; Kozinets, G I; Zherebtsov, L A

    1993-01-01

    Regularities in the development of anemia in patients with chronic hepatitis or hepato-cirrhosis were studied with regard to the pattern and stage of the affection of the liver. The impact of inefficient erythropoiesis on anemia development in patients with chronic diffuse diseases of the liver was demonstrated. Reasons of the red cells imperfection that caused their rapid hemolysis were indicated. In the bone marrow of chronically ill patients there were lower levels of early precursors of erythropoiesis with their proliferative activity reduced. On the basis of the data obtained the authors gave practical recommendations for anemia treatment. PMID:8301986

  7. Ito cells and fibrogenesis in chronic alcoholic liver disease.

    PubMed

    González-Reimers, C E; Brajín-Rodríguez, M M; Santolaria-Fernández, F; Diaz-Flores, L; Conde-Martel, A; Rodríguez-Rodríguez, E; Essardas-Daryanani, H

    1992-02-01

    The relationships between the number of Ito cells; serum N-terminal type III procollagen and laminin; clinical and biochemical parameters of liver function derangement; histomorphometrically assessed total amount of liver fibrosis; and daily ethanol intake were studied in 43 patients affected by chronic alcoholic liver disease (10 cirrhotics). Significant correlations were found between serum laminin and N-terminal type III procollagen and histological, clinical and biochemical data of liver function derangement, but no correlation was found between the aforementioned parameters and the percentage of Ito cells, which in turn seemed to be related to ethanol ingestion. PMID:1559427

  8. Hydrogen peroxide impairs autophagic flux in a cell model of nonalcoholic fatty liver disease

    SciTech Connect

    Jiang, Pengtao; Huang, Zhen; Zhao, Hong; Wei, Taotao

    2013-04-19

    Highlights: •Free fatty acids exposure induces elevated autophagy. •H{sub 2}O{sub 2} inhibits autophagic flux through impairing the fusion between autophagosomes and lysosomes. •Inhibition of autophagy potentiates H{sub 2}O{sub 2}-induced cell death. -- Abstract: Nonalcoholic fatty liver disease (NAFLD) has become the leading cause of chronic liver disease, but the pathogenesis of NAFLD is not fully clear. The aim of this study was to determine whether autophagy plays a role in the pathogenesis of NAFLD. We found that the levels of autophagy were elevated in hepatoma cells upon exposure to free fatty acids, as confirmed by the increase in the number of autophagosomes. However, exposure of hepatoma cells to H{sub 2}O{sub 2} and TNF-α, two typical “second hit” factors, increased the initiation of autophagy but inhibited the autophagic flux. The inhibition of autophagy sensitized cells to pro-apoptotic stimuli. Taken together, our results suggest that autophagy acts as a protective mechanism in the pathogenesis of NAFLD and that impairment of autophagy might induce more severe lesions of the liver. These findings will be a benefit to the understanding of the pathogenesis of NAFLD and might suggest a strategy for the prevention and cure of NAFLD.

  9. The pathophysiology of thrombocytopenia in chronic liver disease

    PubMed Central

    Mitchell, Oscar; Feldman, David M; Diakow, Marla; Sigal, Samuel H

    2016-01-01

    Thrombocytopenia is the most common hematological abnormality encountered in patients with chronic liver disease (CLD). In addition to being an indicator of advanced disease and poor prognosis, it frequently prevents crucial interventions. Historically, thrombocytopenia has been attributed to hypersplenism, which is the increased pooling of platelets in a spleen enlarged by congestive splenomegaly secondary to portal hypertension. Over the past decade, however, there have been significant advances in the understanding of thrombopoiesis, which, in turn, has led to an improved understanding of thrombocytopenia in cirrhosis. Multiple factors contribute to the development of thrombocytopenia and these can broadly be divided into those that cause decreased production, splenic sequestration, and increased destruction. Depressed thrombopoietin levels in CLD, together with direct bone marrow suppression, result in a reduced rate of platelet production. Thrombopoietin regulates both platelet production and maturation and is impaired in CLD. Bone marrow suppression can be caused by viruses, alcohol, iron overload, and medications. Splenic sequestration results from hypersplenism. The increased rate of platelet destruction in cirrhosis also occurs through a number of pathways: increased shear stress, increased fibrinolysis, bacterial translocation, and infection result in an increased rate of platelet aggregation, while autoimmune disease and raised titers of antiplatelet immunoglobulin result in the immunologic destruction of platelets. An in-depth understanding of the complex pathophysiology of the thrombocytopenia of CLD is crucial when considering treatment strategies. This review outlines the recent advances in our understanding of thrombocytopenia in cirrhosis and CLD. PMID:27186144

  10. The pathophysiology of thrombocytopenia in chronic liver disease.

    PubMed

    Mitchell, Oscar; Feldman, David M; Diakow, Marla; Sigal, Samuel H

    2016-01-01

    Thrombocytopenia is the most common hematological abnormality encountered in patients with chronic liver disease (CLD). In addition to being an indicator of advanced disease and poor prognosis, it frequently prevents crucial interventions. Historically, thrombocytopenia has been attributed to hypersplenism, which is the increased pooling of platelets in a spleen enlarged by congestive splenomegaly secondary to portal hypertension. Over the past decade, however, there have been significant advances in the understanding of thrombopoiesis, which, in turn, has led to an improved understanding of thrombocytopenia in cirrhosis. Multiple factors contribute to the development of thrombocytopenia and these can broadly be divided into those that cause decreased production, splenic sequestration, and increased destruction. Depressed thrombopoietin levels in CLD, together with direct bone marrow suppression, result in a reduced rate of platelet production. Thrombopoietin regulates both platelet production and maturation and is impaired in CLD. Bone marrow suppression can be caused by viruses, alcohol, iron overload, and medications. Splenic sequestration results from hypersplenism. The increased rate of platelet destruction in cirrhosis also occurs through a number of pathways: increased shear stress, increased fibrinolysis, bacterial translocation, and infection result in an increased rate of platelet aggregation, while autoimmune disease and raised titers of antiplatelet immunoglobulin result in the immunologic destruction of platelets. An in-depth understanding of the complex pathophysiology of the thrombocytopenia of CLD is crucial when considering treatment strategies. This review outlines the recent advances in our understanding of thrombocytopenia in cirrhosis and CLD. PMID:27186144

  11. Systematic review: unmet supportive care needs in people diagnosed with chronic liver disease

    PubMed Central

    Valery, Patricia C; Powell, Elizabeth; Moses, Neta; Volk, Michael L; McPhail, Steven M; Clark, Paul J; Martin, Jennifer

    2015-01-01

    Objective People with chronic liver disease, particularly those with decompensated cirrhosis, experience several potentially debilitating complications that can have a significant impact on activities of daily living and quality of life. These impairments combined with the associated complex treatment mean that they are faced with specific and high levels of supportive care needs. We aimed to review reported perspectives, experiences and concerns of people with chronic liver disease worldwide. This information is necessary to guide development of policies around supportive needs screening tools and to enable prioritisation of support services for these patients. Design Systematic searches of PubMed, MEDLINE, CINAHL and PsycINFO from the earliest records until 19 September 2014. Data were extracted using standardised forms. A qualitative, descriptive approach was utilised to analyse and synthesise data. Results The initial search yielded 2598 reports: 26 studies reporting supportive care needs among patients with chronic liver disease were included, but few of them were patient-reported needs, none used a validated liver disease-specific supportive care need assessment instrument, and only three included patients with cirrhosis. Five key domains of supportive care needs were identified: informational or educational (eg, educational material, educational sessions), practical (eg, daily living), physical (eg, controlling pruritus and fatigue), patient care and support (eg, support groups), and psychological (eg, anxiety, sadness). Conclusions While several key domains of supportive care needs were identified, most studies included hepatitis patients. There is a paucity of literature describing the supportive care needs of the chronic liver disease population likely to have the most needs—namely those with cirrhosis. Assessing the supportive care needs of people with chronic liver disease have potential utility in clinical practice for facilitating timely referrals

  12. Chronic liver disease: evaluation by magnetic resonance

    SciTech Connect

    Stark, D.D.; Goldberg, H.I.; Moss, A.A.; Bass, N.M.

    1984-01-01

    Magnetic resonance (MR) imaging distinguished hepatitis from fatty liver and cirrhosis in a woman with a history of alcohol abuse. Anatomic and physiologic manifestations of portal hypertension were also demonstrated by MR.

  13. Delayed Liver Function Impairment Secondary to Interferon β-1a Use in Multiple Sclerosis

    PubMed Central

    Liao, Ming-Feng; Yen, Su-Chen; Chun-Yen, Lin; Rong-Kuo, Lyu

    2013-01-01

    Interferon β-1a is a widely used immunomodulation treatment for multiple sclerosis. Liver function impairment is a common side effect and usually develops in the first 6 months after interferon use. Here, we describe 2 multiple sclerosis patients who developed delayed liver function impairment 5 years after receiving interferon β-1a treatment. Their liver function recovered after discontinuing interferon use, and further detailed hepatological evaluations excluded other etiologies of liver function impairment. Our case reports illustrate that liver function impairment induced by interferon β-1a can be delayed for 5 years after starting treatment and, probably, this is an idiosyncratic reaction. Regular liver function monitoring in multiple sclerosis patients who receive interferon β is necessary even after the first 6 months of treatment, especially in those patients with concomitant use of other liver-toxic medications. PMID:23904853

  14. Effect of chronic ethanol consumption on glycosylation processes in rat liver microsomes and Golgi apparatus.

    PubMed

    Cottalasso, D; Gazzo, P; Dapino, D; Domenicotti, C; Pronzato, M A; Traverso, N; Bellocchio, A; Nanni, G; Marinari, U M

    1996-01-01

    Previous studies have demonstrated that acute ethanol intoxication affects various steps of protein glycosylation at the level of rat liver endoplasmic reticulum and Golgi apparatus. The aim of this investigation was to demonstrate whether chronic ethanol intake can induce definitive changes of liver glycoprotein processing. Rats were given ethanol by liquid diet for 8 weeks. At the end of this period the triglyceride levels in liver homogenate and microsomes were significantly higher than in controls. Isolated hepatocytes prelabelled with [3H]Na palmitate and [14C]glucosamine showed a significant storage of the lipid and carbohydrate radioactivity in microsomes and Golgi apparatus and a significant impairment of labelled glycolipoprotein secretion. Changes of the glycosylation steps were observed both in endoplasmic reticulum and in Golgi apparatus: in the former the levels of dolichyl phosphate, which is rate-limiting for the synthesis of glycoprotein, showed a significant reduction; in the latter the activity of the main enzymes responsible for the terminal glycosylation process was significantly decreased. These data suggest that an impairment of glycoprotein maturation may be involved in the pathogenesis of liver injury induced by chronic ethanol intake. PMID:8672174

  15. [Various pathways leading to the progression of chronic liver diseases].

    PubMed

    Egresi, Anna; Lengyel, Gabriella; Somogyi, Anikó; Blázovics, Anna; Hagymási, Krisztina

    2016-02-21

    As the result of various effects (viruses, metabolic diseases, nutritional factors, toxic agents, autoimmune processes) abnormal liver function, liver steatosis and connective tissue remodeling may develop. Progression of this process is complex including various pathways and a number of factors. The authors summarize the factors involved in the progression of chronic liver disease. They describe the role of cells and the produced inflammatory mediators and cytokines, as well as the relationship between the disease and the intestinal flora. They emphasize the role of oxidative stress, mitochondrial dysfunction and cell death in disease progression. Insulin resistance and micro-elements (iron, copper) in relation to liver damage are also discussed, and genetic and epigenetic aspects underlying disease progression are summarized. Discovery of novel treatment options, assessment of the effectiveness of treatment, as well as the success and proper timing of liver transplantation may depend on a better understanding of the process of disease progression. PMID:26876265

  16. Critical comparison of elastography methods to assess chronic liver disease.

    PubMed

    Friedrich-Rust, Mireen; Poynard, Thierry; Castera, Laurent

    2016-07-01

    Staging of liver fibrosis and diagnosis, or exclusion, of early compensated liver cirrhosis are important in the treatment decisions and surveillance of patients with chronic liver disease. Good diagnostic accuracy, increased availability and the possibility to perform follow-up examinations led to the implementation of noninvasive methods into clinical practice. Noninvasive tests are increasingly included in national and international guidelines, leaving liver biopsy reserved for patients with unexplained discordance or suspected additional aetiologies of liver disease. In addition to staging of liver fibrosis, data on the prognostic value of these methods have increased in the past few years and are of great importance for patient care. This Review focuses on elastography methods for noninvasive assessment of liver fibrosis, disease severity and prognosis. Although liver elastography started with transient elastography, at present all large ultrasonography companies offer an elastography technique integrated in their machines. The goal of this Review is to summarize the methodological problems of noninvasive tests in general, in addition to providing an overview on currently available techniques and latest developments in liver elastography. PMID:27273167

  17. Chronic restraint stress reduces carbon tetrachloride-induced liver fibrosis

    PubMed Central

    LI, MENG; SUN, QUAN; LI, SHENGLI; ZHAI, YANAN; WANG, JINGJING; CHEN, BAIAN; LU, JING

    2016-01-01

    Stress as a cofactor has been reported to affect the progression and severity of liver diseases. The present study investigated the effect of chronic restraint stress on carbon tetrachloride (CCl4)-induced liver fibrosis. A total of 30 male BALB/c mice were randomly divided into three groups: Oil-treated control group; CCl4-treated group; and CCl4 + restraint-treated group. CCl4 was administrated via intraperitoneal injection once every 3 days over a period of 42 days. In the CCl4 + restraint-treated group, mice were immobilized using 50 ml centrifuge tubes for 0.5 h to inflict chronic restraint stress immediately after the injection of CCl4. On day 42, blood and liver tissue samples were collected for analysis. The effect of restraint on CCl4-induced liver fibrosis in mice was evaluated by analyzing the serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST). Histopathological examination of liver samples was performed using hematoxylin and eosin (HE), Masson's trichrome, 5-hydroxytryptamine 2B (5-HT2B) receptor and α-smooth muscle actin (α-SMA) immumohistochemical staining. ALT, AST, 5-HT2B receptor and α-SMA expression levels were significantly increased in mice exposed to CCl4 in comparison with those in the oil-treated control mice (P<0.01). However, these increases were significantly reduced by exposure to restraint (P<0.05). HE and Masson's trichrome staining revealed that restraint can alleviate CCl4-induced liver fibrosis. These results suggest that chronic restraint stress reduces the development of liver fibrosis by inhibiting the activation of hepatic stellate cells via 5-HT2B receptor. Therefore, restraint may be a useful therapeutic approach in the management of liver fibrosis. PMID:27284296

  18. Chronic Glucocorticoid-Rich Milieu and Liver Dysfunction.

    PubMed

    Villagarcía, Hernán Gonzalo; Sabugo, Vanesa; Castro, María Cecilia; Schinella, Guillermo; Castrogiovanni, Daniel; Spinedi, Eduardo; Massa, María Laura; Francini, Flavio

    2016-01-01

    We investigated the impact of chronic hypercorticosteronemia (due to neonatal monosodium L-glutamate, MSG, and treatment) on liver oxidative stress (OS), inflammation, and carbohydrate/lipid metabolism in adult male rats. We evaluated the peripheral concentrations of several metabolic and OS markers and insulin resistance indexes. In liver we assessed (a) OS (GSH and protein carbonyl groups) and inflammatory (IL-1b, TNFa, and PAI-1) biomarkers and (b) carbohydrate and lipid metabolisms. MSG rats displayed degenerated optic nerves, hypophagia, low body and liver weights, and enlarged adipose tissue mass; higher peripheral levels of glucose, triglycerides, insulin, uric acid, leptin, corticosterone, transaminases and TBARS, and peripheral and liver insulin resistance; elevated liver OS, inflammation markers, and glucokinase (mRNA/activity) and fructokinase (mRNA). Additionally, MSG liver phosphofructokinase-2, glucose-6-phosphatase (mRNA and activity) and glucose-6-phosphate dehydrogenase, Chrebp, Srebp1c, fatty acid synthase, and glycerol-3-phosphate (mRNAs) were increased. In conclusion adult MSG rats developed an insulin-resistant state and increased OS and serious hepatic dysfunction characterized by inflammation and metabolic signs suggesting increased lipogenesis. These features, shared by both metabolic and Cushing's syndrome human phenotypes, support that a chronic glucocorticoid-rich endogenous environment mainly impacts on hepatic glucose cycle, displacing local metabolism to lipogenesis. Whether correcting the glucocorticoid-rich environment ameliorates such dysfunctions requires further investigation. PMID:27597864

  19. Chronic Glucocorticoid-Rich Milieu and Liver Dysfunction

    PubMed Central

    Castro, María Cecilia

    2016-01-01

    We investigated the impact of chronic hypercorticosteronemia (due to neonatal monosodium L-glutamate, MSG, and treatment) on liver oxidative stress (OS), inflammation, and carbohydrate/lipid metabolism in adult male rats. We evaluated the peripheral concentrations of several metabolic and OS markers and insulin resistance indexes. In liver we assessed (a) OS (GSH and protein carbonyl groups) and inflammatory (IL-1b, TNFa, and PAI-1) biomarkers and (b) carbohydrate and lipid metabolisms. MSG rats displayed degenerated optic nerves, hypophagia, low body and liver weights, and enlarged adipose tissue mass; higher peripheral levels of glucose, triglycerides, insulin, uric acid, leptin, corticosterone, transaminases and TBARS, and peripheral and liver insulin resistance; elevated liver OS, inflammation markers, and glucokinase (mRNA/activity) and fructokinase (mRNA). Additionally, MSG liver phosphofructokinase-2, glucose-6-phosphatase (mRNA and activity) and glucose-6-phosphate dehydrogenase, Chrebp, Srebp1c, fatty acid synthase, and glycerol-3-phosphate (mRNAs) were increased. In conclusion adult MSG rats developed an insulin-resistant state and increased OS and serious hepatic dysfunction characterized by inflammation and metabolic signs suggesting increased lipogenesis. These features, shared by both metabolic and Cushing's syndrome human phenotypes, support that a chronic glucocorticoid-rich endogenous environment mainly impacts on hepatic glucose cycle, displacing local metabolism to lipogenesis. Whether correcting the glucocorticoid-rich environment ameliorates such dysfunctions requires further investigation. PMID:27597864

  20. Chronic Bickerstaff’s encephalitis with cognitive impairment, a reality?

    PubMed Central

    2014-01-01

    Background Bickerstaff’s encephalitis (BE) is an acute post-infectious demyelinating disease with albuminocytological dissociation. A chronic form has rarely been described previously. Case presentation A 44-year-old man was hospitalized for drowsiness, cognitive complaint limb weakness, ataxia and sensory disturbance after diarrhea. Neuropsychological evaluation showed slowing, memory and executive function impairment, while analysis of the CSF showed albuminocytological dissociation. Immunologic tests showed positive anti-ganglioside antibodies (anti-GM1 IgM, anti-GD1a IgG and anti-GD1b IgM). Brain MRI was normal but SPECT showed bilateral temporal and frontal hypoperfusion. Outcome under immunoglobulin treatment (IVIG) was favorable with an initial improvement but was marked by worsening after a few weeks. Consequently, the patient was treated with IVIG every 2 months due to the recurrence of symptoms after 6 weeks. Conclusion This case raises the question of the existence of a chronic form of BE with cognitive impairment, in the same way as chronic inflammatory demyelinating polyneuropathy is considered to be a chronic form of Guillain–Barré syndrome. PMID:24885623

  1. Management of chronic hepatitis B in severe liver disease

    PubMed Central

    Fung, James; Lai, Ching-Lung; Yuen, Man-Fung

    2014-01-01

    In the past few decades, chronic hepatitis B (CHB) has evolved from a disease that was untreatable and progressive, to one that can be easily controlled with antiviral therapy. However, patients with severe liver disease still remain difficult to treat despite the availability of highly potent nucleos(t)ide analogs. These include those with underlying cirrhosis, severe flares of CHB, hepatocellular carcinoma (HCC), and for those undergoing liver transplantation. For those with established cirrhosis, antiviral therapy should be considered for all, as unpredictable flares can still occur, which can be fatal for those with advanced chronic liver disease. However, even with effective viral suppression, the development of HCC can still occur. For patients with severe flares of CHB, although the use of antiviral can improve long term outcomes, a significant proportion may still die without liver transplantation. The short term prognosis of these patients is dependent on both the severity of flare and underlying pre-existing liver disease. In patients with decompensated cirrhosis, liver failure secondary to severe flares, or those with HCC, liver transplantation may be curative. After liver transplantation, long term antiviral therapy is required to prevent graft loss from recurrent hepatitis B infection. The use of hepatitis B immune globulin (HBIG) in combination with an oral antiviral agent has been the mainstay of post-transplant antiviral regimen for over a decade. With newer and more potent antiviral agents such as tenofovir and entecavir, use of these agents along with HBIG have demonstrated to be effective in preventing significant recurrence in the long term. PMID:25473157

  2. Liver dialysis in acute-on-chronic liver failure: current and future perspectives.

    PubMed

    Maiwall, Rakhi; Maras, Jaswinder Singh; Nayak, Suman Lata; Sarin, Shiv Kumar

    2014-09-01

    Patients with acute-on-chronic liver failure (ACLF) are known to have a very high mortality rate as the majority of these patients succumb to multiorgan failure. Liver transplant remains the only option for these patients; however, there are problems with its availability, cost and also the complications and side effects associated with immunosuppression. Unlike advanced decompensated liver disease, there is a potential for hepatic regeneration and recovery in patients with ACLF. A liver support system, cell or non-cell based, logically is likely to provide temporary functional support until the donor liver becomes available or the failing liver survives the onslaught of the acute insult and spontaneously regenerates. Understanding the pathogenesis of liver failure and regeneration is essential to define the needs for a support system. Removal of hepatotoxic metabolites and inhibitors of hepatic regeneration by liver dialysis, a non-cell-based hepatic support, could help to provide a suitable microenvironment and support the failing liver. The current systems, i.e., MARS and Prometheus, have failed to show survival benefits in patients with ACLF based on which newer devices with improved functionality are currently under development. However, larger randomized trials are needed to prove whether these devices can enable restoration of the complex dysregulated immune system and impact organ failure and mortality in these patients. PMID:26201332

  3. Assessment of adult patients with chronic liver failure for liver transplantation in 2015: who and when?

    PubMed

    McCaughan, G W; Crawford, M; Sandroussi, C; Koorey, D J; Bowen, D G; Shackel, N A; Strasser, S I

    2016-04-01

    In 2015, there are a few absolute contraindications to liver transplantation. In adult patients, survival post-liver transplant is excellent, with 1-year survival rate >90% and 5-year survival rates >80% and predicted median allograft survival beyond 20 years. Patients with a Child-Turcotte Pugh score ≥9 or a model for end-stage liver disease (MELD) score >15 should be referred for liver transplantation, with patients who have a MELD score >17 showing a 1-year survival benefit with liver transplantation. A careful selection of hepatocellular cancer patients results in excellent outcomes, while consideration of extra-hepatic disease (reversible vs irreversible) and social support structures are crucial to patient assessment. Alcoholic liver disease remains a challenge, and the potential to cure hepatitis C virus infection together with the emerging issue of non-alcoholic fatty liver disease-associated chronic liver failure will change the landscape of the who in the years ahead. The when will continue to be determined largely by the severity of liver disease based on the MELD score for the foreseeable future. PMID:27062203

  4. Role of Nrf2 in chronic liver disease

    PubMed Central

    Tang, Wei; Jiang, Yong-Fang; Ponnusamy, Murugavel; Diallo, Mamadou

    2014-01-01

    Nuclear erythroid 2-related factor 2 (Nrf2) is a central regulator of antioxidative response elements-mediated gene expression. It has a significant role in adaptive responses to oxidative stress by interacting with the antioxidant response element, which induces the expression of a variety of downstream targets aimed at cytoprotection. Previous studies suggested oxidative stress and associated damage could represent a common link between different forms of diseases. Oxidative stress has been implicated in various liver diseases, including viral hepatitis, nonalcoholic fatty liver disease/steatohepatitis, alcoholic liver disease and drug-induced liver injury. Nrf2 activation is initiated by oxidative or electrophilic stress, and aids in the detoxification and elimination of potentially harmful exogenous chemicals and their metabolites. The expression of Nrf2 has been observed throughout human tissue, with high expression in detoxification organs, especially the liver. Thus, Nrf2 may serve as a major regulator of several cellular defense associated pathways by which hepatic cells combat oxidative stress. We review the relevant literature concerning the crucial role of Nrf2 and its signaling pathways against oxidative stress to protect hepatic cell from oxidative damage during development of common chronic liver diseases. We also review the use of Nrf2 as a therapeutic target to prevent and treat liver diseases. PMID:25278702

  5. Chronic hepatitis C virus infection: Serum biomarkers in predicting liver damage

    PubMed Central

    Valva, Pamela; Ríos, Daniela A; De Matteo, Elena; Preciado, Maria V

    2016-01-01

    Currently, a major clinical challenge in the management of the increasing number of hepatitis C virus (HCV) infected patients is determining the best means for evaluating liver impairment. Prognosis and treatment of chronic hepatitis C (CHC) are partly dependent on the assessment of histological activity, namely cell necrosis and inflammation, and the degree of liver fibrosis. These parameters can be provided by liver biopsy; however, in addition to the risks related to an invasive procedure, liver biopsy has been associated with sampling error mostly due to suboptimal biopsy size. To avoid these pitfalls, several markers have been proposed as non-invasive alternatives for the diagnosis of liver damage. Distinct approaches among the currently available non-invasive methods are (1) the physical ones based on imaging techniques; and (2) the biological ones based on serum biomarkers. In this review, we discuss these approaches with special focus on currently available non-invasive serum markers. We will discuss: (1) class I serum biomarkers individually and as combined panels, particularly those that mirror the metabolism of liver extracellular matrix turnover and/or fibrogenic cell changes; (2) class II biomarkers that are indirect serum markers and are based on the evaluation of common functional alterations in the liver; and (3) biomarkers of liver cell death, since hepatocyte apoptosis plays a significant role in the pathogenesis of HCV infection. We highlight in this review the evidence behind the use of these markers and assess the diagnostic accuracy as well as advantages, limitations, and application in clinical practice of each test for predicting liver damage in CHC. PMID:26819506

  6. Telomere and telomerase in chronic liver disease and hepatocarcinoma.

    PubMed

    Carulli, Lucia; Anzivino, Claudia

    2014-05-28

    The pathogenesis of liver cirrhosis is not completely elucidated. Although in the majority of patients, the risk factors may be identified in B and C viral hepatitis, alcohol intake, drugs or fatty liver disease, there is a small percentage of patients with no apparent risk factors. In addition, the evolution of chronic liver disease is highly heterogeneous from one patient to another. Among patient with identical risk factors, some rapidly progress to cirrhosis and hepatocellular carcinoma (HCC) whereas others have a benign course. Therefore, a genetic predisposition may contribute to the development of cirrhosis and HCC. Evidence supporting the role of genetic factors as a risk for cirrhosis has been accumulating during the past years. In addition to the results from epidemiological studies, polymorphisms studies and data on twins, the concept of telomere shortening as a genetic risk factor for chronic liver disease and HCC has been proposed. Here we review the literature on telomerase mutations, telomere shortening and liver disease including hepatocellular carcinoma. PMID:24876749

  7. Cryoglobulins in acute and chronic liver diseases

    PubMed Central

    Florin-Christensen, A.; Roux, María E. B.; Arana, R. M.

    1974-01-01

    Cryoglobulins were detected in the sera of thirteen patients with acute viral hepatitis and of twelve with chronic hepatic diseases (active chronic hepatitis, primary biliary cirrhosis and cryptogenic cirrhosis). Their nature and antibody activity was studied. In both groups, most of them consisted of mixed cryoimmunoglobulins (IgM, IgG and/or IgA), but some were single-class immunoglobulins with one or both types of light chains. Unusual components were also found. α1-fetoprotein was present in four cryoprecipitates: in two as the single constituent and in two associated to immunoglobulins; hepatitis-associated antigen co-existed in one of the latter. Some cryoglobulins showed antibody activity against human IgG, smooth muscle and mitochondrial antigens. In one case, the IgM-kappa of the cryoprecipitate had antibody activity against α1-fetoprotein; this antigen was also present in the cryoprecipitate, suggesting immune-complex formation. Autoantibodies were also looked for in the sera of the twenty-five patients; apart from the most common ones, antibodies to α1-fetoprotein were found in two patients. PMID:4143195

  8. Hepatitis E and Acute-on-Chronic Liver Failure

    PubMed Central

    Kumar, Ashish; Saraswat, Vivek A.

    2013-01-01

    Hepatitis E virus (HEV) is the most common cause of acute viral hepatitis (AVH) globally. It causes large scale epidemics of AVH across the low- and middle income countries in Asia and Africa, and also causes sporadic cases of AVH in the same geographical region. AVH due to HEV is usually an acute, self-limiting illness, similar in clinical presentation to AVH caused by hepatitis A virus (HAV). When HEV causes AVH in patients of chronic liver disease it may worsen rapidly to a syndrome called acute-on-chronic liver failure (ACLF) leading to very high mortality. Acute deterioration of liver function in a patient with compensated chronic liver disease is the characteristic feature of ACLF. The typical disease course of patients with ACLF is the appearance of organ failure, which progresses to multi-organ failure and death. Many publications have reported HEV as one of the leading causes for ACLF from Asia and Africa, where HEV is endemic. The mortality rate of HEV-related ACLF (HEV-ACLF) ranges from 0% to 67% with a median being 34%. These patients require admission in the intensive care unit and they benefit from a team approach of clinicians with expertise in both hepatology and critical care. The goals of treatment are to prevent further deterioration in liver function, reverse precipitating factors, and support failing organs. Liver transplantation is required in selected patients to improve survival and quality of life. One preliminary report suggests that ribavirin may be an effective and safe drug for treatment of HEV-ACLF however this requires validation in large trials. PMID:25755504

  9. Characteristics and outcomes of chronic liver disease patients with acute deteriorated liver function by severity of underlying liver disease

    PubMed Central

    Hong, Yun Soo; Sinn, Dong Hyun; Gwak, Geum-Youn; Cho, Juhee; Kang, Danbee; Paik, Yong-Han; Choi, Moon Seok; Lee, Joon Hyeok; Koh, Kwang Cheol; Paik, Seung Woon

    2016-01-01

    AIM: To analyze characteristics and outcome of patients with acute-on-chronic liver failure (ACLF) according to the severity of underlying liver disease. METHODS: One hundred and sixty-seven adult patients with chronic liver disease and acute deteriorated liver function, defined by jaundice and coagulopathy, were analyzed. Predisposition, type of injury, response, organ failure, and survival were analyzed and compared between patients with non-cirrhosis (type A), cirrhosis (type B) and cirrhosis with previous decompensation (type C). RESULTS: The predisposition was mostly hepatitis B in type A, while it was alcoholic liver disease in types B and C. Injury was mostly hepatic in type A, but was non-hepatic in type C. Liver failure, defined by CLIF-SOFA, was more frequent in types A and B, and circulatory failure was more frequent in type C. The 30-d overall survival rate (85.3%, 81.1% and 83.7% for types A, B and C, respectively, P = 0.31) and the 30-d transplant-free survival rate (55.9%, 65.5% and 62.5% for types A, B and C, respectively P = 0.33) were not different by ACLF subtype, but 1-year overall survival rate were different (85.3%, 71.7% and 58.7% for types A, B and C, respectively, P = 0.02). CONCLUSION: There were clear differences in predisposition, type of injury, accompanying organ failure and long-term mortality according to spectrum of chronic liver disease, implying classifying subtype according to the severity of underlying liver disease is useful for defining, clarifying and comparing ACLF. PMID:27076763

  10. Endothelial Dysfunction Correlates with Liver Fibrosis in Chronic HCV Infection

    PubMed Central

    Barone, Michele; Viggiani, Maria Teresa; Amoruso, Annabianca; Schiraldi, Serafina; Devito, Fiorella; Brunetti, Natale; Di Leo, Alfredo; Ciccone, Marco Matteo

    2015-01-01

    Background. Hepatitis C virus (HCV) infection can exert proatherogenic activities due to its direct action on vessel walls and/or via the chronic inflammatory process involving the liver. Aims. To clarify the role of HCV in atherosclerosis development in monoinfected HCV patients at different degrees of liver fibrosis and with no risk factors for coronary artery disease. Methods. Forty-five patients were included. Clinical, serological, and anthropometric parameters, liver fibrosis (transient liver elastometry (fibroscan) and aspartate aminotransferase to platelet ratio index (APRI)), carotid intima-media thickness (c-IMT), and brachial artery flow-mediated vasodilatation (FMD) were assessed. Patients were divided into 3 tertiles according to fibroscan values. Results. Patients in the third tertile (fibroscan value >11.5 KPa) showed FMD values were significantly lower than second and first tertiles (4.7 ± 1.7% versus 7.1 ± 2.8%, p = 0.03). FMD values were inversely related to liver elastomeric values. c-IMT values were normal. The risk for endothelial dysfunction development in the third tertile (p = 0.02) was 6.9 higher than the first tertile. A fibroscan value >11.5 KPa had a positive predictive power equal to 79% for endothelial dysfunction. Conclusions. HCV advanced liver fibrosis promotes atherosclerosis by inducing endothelial dysfunction independently of common cardiovascular risk factors. PMID:26000012

  11. Endothelial dysfunction correlates with liver fibrosis in chronic HCV infection.

    PubMed

    Barone, Michele; Viggiani, Maria Teresa; Amoruso, Annabianca; Schiraldi, Serafina; Zito, Annapaola; Devito, Fiorella; Cortese, Francesca; Gesualdo, Michele; Brunetti, Natale; Di Leo, Alfredo; Scicchitano, Pietro; Ciccone, Marco Matteo

    2015-01-01

    Background. Hepatitis C virus (HCV) infection can exert proatherogenic activities due to its direct action on vessel walls and/or via the chronic inflammatory process involving the liver. Aims. To clarify the role of HCV in atherosclerosis development in monoinfected HCV patients at different degrees of liver fibrosis and with no risk factors for coronary artery disease. Methods. Forty-five patients were included. Clinical, serological, and anthropometric parameters, liver fibrosis (transient liver elastometry (fibroscan) and aspartate aminotransferase to platelet ratio index (APRI)), carotid intima-media thickness (c-IMT), and brachial artery flow-mediated vasodilatation (FMD) were assessed. Patients were divided into 3 tertiles according to fibroscan values. Results. Patients in the third tertile (fibroscan value >11.5 KPa) showed FMD values were significantly lower than second and first tertiles (4.7 ± 1.7% versus 7.1 ± 2.8%, p = 0.03). FMD values were inversely related to liver elastomeric values. c-IMT values were normal. The risk for endothelial dysfunction development in the third tertile (p = 0.02) was 6.9 higher than the first tertile. A fibroscan value >11.5 KPa had a positive predictive power equal to 79% for endothelial dysfunction. Conclusions. HCV advanced liver fibrosis promotes atherosclerosis by inducing endothelial dysfunction independently of common cardiovascular risk factors. PMID:26000012

  12. Insulin Resistance, Ceramide Accumulation, and Endoplasmic Reticulum Stress in Human Chronic Alcohol-Related Liver Disease

    PubMed Central

    Longato, Lisa; Ripp, Kelsey; Setshedi, Mashiko; Dostalek, Miroslav; Akhlaghi, Fatemeh; Branda, Mark; Wands, Jack R.; de la Monte, Suzanne M.

    2012-01-01

    Background. Chronic alcohol-related liver disease (ALD) is mediated by insulin resistance, mitochondrial dysfunction, inflammation, oxidative stress, and DNA damage. Recent studies suggest that dysregulated lipid metabolism with accumulation of ceramides, together with ER stress potentiate hepatic insulin resistance and may cause steatohepatitis to progress. Objective. We examined the degree to which hepatic insulin resistance in advanced human ALD is correlated with ER stress, dysregulated lipid metabolism, and ceramide accumulation. Methods. We assessed the integrity of insulin signaling through the Akt pathway and measured proceramide and ER stress gene expression, ER stress signaling proteins, and ceramide profiles in liver tissue. Results. Chronic ALD was associated with increased expression of insulin, IGF-1, and IGF-2 receptors, impaired signaling through IGF-1R and IRS1, increased expression of multiple proceramide and ER stress genes and proteins, and higher levels of the C14, C16, C18, and C20 ceramide species relative to control. Conclusions. In human chronic ALD, persistent hepatic insulin resistance is associated with dysregulated lipid metabolism, ceramide accumulation, and striking upregulation of multiple ER stress signaling molecules. Given the role of ceramides as mediators of ER stress and insulin resistance, treatment with ceramide enzyme inhibitors may help reverse or halt progression of chronic ALD. PMID:22577490

  13. Management of Acute-on-Chronic Liver Failure.

    PubMed

    Durand, Francois; Nadim, Mitra K

    2016-05-01

    Acute-on-chronic liver failure (ACLF) is defined by the occurrence of organ failure(s) other than the liver in patients with cirrhosis. Even though mortality rates are high, there should no longer be reluctance to admit patients with ACLF in the intensive care unit. The prevalence of multidrug-resistant bacteria is high and broad spectrum antibiotics should be initiated as soon as infection is suspected. In patients with circulatory failure, the assessment of circulatory status is challenging due to the hyperkinetic state and an imbalance between the splanchnic and systemic blood volume. Acute kidney injury is common in patients with ACLF. Acute tubular necrosis should be differentiated from hepatorenal syndrome, which justifies vasoconstrictive agents. Renal replacement therapy and mechanical ventilation should be decided on clinical grounds. Recent trials on extracorporeal liver support failed to demonstrate a survival benefit. Aggressive management may serve as a bridge to transplantation provided patients are likely to survive after transplantation. PMID:27172356

  14. Dipeptidyl peptidase-4: A key player in chronic liver disease

    PubMed Central

    Itou, Minoru; Kawaguchi, Takumi; Taniguchi, Eitaro; Sata, Michio

    2013-01-01

    Dipeptidyl peptidase-4 (DPP-4) is a membrane-associated peptidase, also known as CD26. DPP-4 has widespread organ distribution throughout the body and exerts pleiotropic effects via its peptidase activity. A representative target peptide is glucagon-like peptide-1, and inactivation of glucagon-like peptide-1 results in the development of glucose intolerance/diabetes mellitus and hepatic steatosis. In addition to its peptidase activity, DPP-4 is known to be associated with immune stimulation, binding to and degradation of extracellular matrix, resistance to anti-cancer agents, and lipid accumulation. The liver expresses DPP-4 to a high degree, and recent accumulating data suggest that DPP-4 is involved in the development of various chronic liver diseases such as hepatitis C virus infection, non-alcoholic fatty liver disease, and hepatocellular carcinoma. Furthermore, DPP-4 occurs in hepatic stem cells and plays a crucial role in hepatic regeneration. In this review, we described the tissue distribution and various biological effects of DPP-4. Then, we discussed the impact of DPP-4 in chronic liver disease and the possible therapeutic effects of a DPP-4 inhibitor. PMID:23613622

  15. Acute-on-chronic liver failure in cirrhosis.

    PubMed

    Arroyo, Vicente; Moreau, Richard; Kamath, Patrick S; Jalan, Rajiv; Ginès, Pere; Nevens, Frederik; Fernández, Javier; To, Uyen; García-Tsao, Guadalupe; Schnabl, Bernd

    2016-01-01

    The definition of acute-on-chronic liver failure (ACLF) remains contested. In Europe and North America, the term is generally applied according to the European Association for the Study of the Liver-Chronic Liver Failure (EASL-CLIF) Consortium guidelines, which defines this condition as a syndrome that develops in patients with cirrhosis and is characterized by acute decompensation, organ failure and high short-term mortality. One-third of patients who are hospitalized for acute decompensation present with ACLF at admission or develop the syndrome during hospitalization. ACLF frequently occurs in a closed temporal relationship to a precipitating event, such as bacterial infection or acute alcoholic, drug-induced or viral hepatitis. However, no precipitating event can be identified in approximately 40% of patients. The mechanisms of ACLF involve systemic inflammation due to infections, acute liver damage and, in cases without precipitating events, probably intestinal translocation of bacteria or bacterial products. ACLF is graded into three stages (ACLF grades 1-3) on the basis of the number of organ failures, with higher grades associated with increased mortality. Liver and renal failures are the most common organ failures, followed by coagulation, brain, circulatory and respiratory failure. The 28-day mortality rate associated with ACLF is 30%. Depending on the grade, ACLF can be reversed using standard therapy in only 16-51% of patients, leaving a considerable proportion of patients with ACLF that remains steady or progresses. Liver transplantation in selected patients with ACLF grade 2 and ACLF grade 3 increases the 6-month survival from 10% to 80%. PMID:27277335

  16. Role of hepatitis C virus in chronic liver disease occurring after orthotopic liver transplantation.

    PubMed Central

    Pastore, M; Willems, M; Cornu, C; Buts, J P; Reding, R; de Ville de Goyet, J; Rahier, J; Otte, J B; Yap, S H; Sokal, E M

    1995-01-01

    Paediatric orthotopic liver transplant recipients may develop chronic hepatitis after surgery. To investigate the role of hepatitis C virus in this pathology a cohort of 249 paediatric orthotopic liver transplant recipients was studied. Sixteen children (6.4%) were found to have chronic hepatitis C virus hepatitis after orthotopic liver transplantation. All but one of them had serum transaminase values which were persistently raised two to eight times the upper limit of normal. Thirteen were positive for both serology and serum hepatitis C virus RNA. Serum hepatitis C virus RNA detection occurred five to 33 months before hepatitis C virus antibodies. Liver tissue hepatitis C virus RNA and hepatitis C virus core antigen were detected in five. In one patient, tissue hepatitis C virus core antigen was detected when other tests for hepatitis C were negative. Two patients had positive human cytomegalovirus serum antibodies and RNA before transplantation. Although serum hepatitis C virus RNA was not detected after transplantation, serum enzyme immunosorbent assay and tissue core antigen were still detectable in both patients. In another child, serum hepatitis C virus RNA was positive and hepatitis C virus core antigen was found on a liver biopsy specimen but antihepatitis C virus antibodies were negative as well as liver hepatitis C virus RNA. No patient developed severe liver disease or cirrhosis during a follow up of up to 72 months. It is concluded that hepatitis C virus is a significant cause of morbidity after paediatric orthotopic liver transplantation. Diagnosis cannot rely on serological testing only. The patients remained stable on follow up, but longer prospective histological studies remain necessary to establish prognosis. PMID:7618905

  17. Chronic exercise increases insulin binding in muscles but not liver.

    PubMed

    Bonen, A; Clune, P A; Tan, M H

    1986-08-01

    It has been postulated that the improved glucose tolerance provoked by chronic exercise is primarily attributable to increased insulin binding in skeletal muscle. Therefore, we investigated the effects of progressively increased training (6 wk) on insulin binding by five hindlimb skeletal muscles and in liver. In the trained animals serum insulin levels at rest were lower either in a fed (P less than 0.05) or fasted (P less than 0.05) state and after an oral glucose tolerance test (n = 8) (P less than 0.05). Twenty-four hours after the last exercise bout sections of the liver, soleus (S), plantaris (P), extensor digitorum longus (EDL), and red (RG) and white gastrocnemius (WG) muscles were pooled from four to six rats. From control animals, killed at the same time of day, muscles and liver were also obtained. Insulin binding to plasma membranes increased in S, P, and EDL (P less than 0.05) but not in WG (P = 0.07), RG (P greater than 0.1), or in liver (P greater than 0.1). There were insulin binding differences among muscles (P less than 0.05). Comparison of rank orders of insulin binding data with published glucose transport data for the same muscles revealed that these parameters do not correspond well. In conclusion, insulin binding to muscle is shown to be heterogeneous and training can increase insulin binding to selected muscles but not liver. PMID:3526921

  18. Differences in Liver Impairment Between Adults and Children with Dengue Infection.

    PubMed

    Martínez Vega, Rosario; Phumratanaprapin, Weerapong; Phonrat, Benjaluck; Dhitavat, Jittima; Sutherat, Maleerat; Choovichian, Vorada

    2016-05-01

    Dengue infection (DI) is a major vector-borne disease in southeast Asia and an important cause of morbidity. The complications such as hepatic impairment are common, and because the physiology of the liver differs between children and adults, the DI-associated liver impairments might be expected to differ as well. This study aims to compare the differences in liver impairment between adults and children with DI. We retrospectively studied 158 adults and 79 children with serologically confirmed DI admitted to the Bangkok Hospital for Tropical Diseases from 2008 to 2012. In total, 93% of adults and 87% of children exhibited abnormal liver enzyme levels during hospitalization. Overall, 76 (42.4%) adults and 16 (20.3%) children had dengue hemorrhagic fever (DHF). Compared with children, adults with dengue fever (DF) presented a significantly higher incidence of liver function impairment (alanine transaminase [ALT] > 2 × upper limit of normal [ULN]) (47.1% versus 25.5%), hepatitis (ALT > 4 × ULN) (29.4% versus 12.8%), and severe hepatitis (aspartate transaminase [AST]/ALT > 10 × ULN) (16.5% versus 4.3%). Children with DHF showed a significantly higher incidence of liver function impairment due to AST derangement than did adults (100% versus 73%). There were no differences in the total bilirubin, albumin, or total protein levels between adults and children. Liver enzymes normalized significantly more slowly in adults, and AST recovery was faster than ALT. In conclusion, liver function impairment was more common among adults than children with DF. As the severity progressed to DHF, liver injury became more common in children. PMID:26976884

  19. Rat liver mitochondrial damage under acute or chronic carbon tetrachloride-induced intoxication: Protection by melatonin and cranberry flavonoids

    SciTech Connect

    Cheshchevik, V.T.; Lapshina, E.A.; Dremza, I.K.; Zabrodskaya, S.V.; Reiter, R.J.; Prokopchik, N.I.; Zavodnik, I.B.

    2012-06-15

    In current societies, the risk of toxic liver damage has markedly increased. The aim of the present work was to carry out further research into the mechanism(s) of liver mitochondrial damage induced by acute (0.8 g/kg body weight, single injection) or chronic (1.6 g/ kg body weight, 30 days, biweekly injections) carbon tetrachloride – induced intoxication and to evaluate the hepatoprotective potential of the antioxidant, melatonin, as well as succinate and cranberry flavonoids in rats. Acute intoxication resulted in considerable impairment of mitochondrial respiratory parameters in the liver. The activity of mitochondrial succinate dehydrogenase (complex II) decreased (by 25%, p < 0.05). Short-term melatonin treatment (10 mg/kg, three times) of rats did not reduce the degree of toxic mitochondrial dysfunction but decreased the enhanced NO production. After 30-day chronic intoxication, no significant change in the respiratory activity of liver mitochondria was observed, despite marked changes in the redox-balance of mitochondria. The activities of the mitochondrial enzymes, succinate dehydrogenase and glutathione peroxidase, as well as that of cytoplasmic catalase in liver cells were inhibited significantly. Mitochondria isolated from the livers of the rats chronically treated with CCl{sub 4} displayed obvious irreversible impairments. Long-term melatonin administration (10 mg/kg, 30 days, daily) to chronically intoxicated rats diminished the toxic effects of CCl{sub 4}, reducing elevated plasma activities of alanine aminotransferase and aspartate aminotransferase and bilirubin concentration, prevented accumulation of membrane lipid peroxidation products in rat liver and resulted in apparent preservation of the mitochondrial ultrastructure. The treatment of the animals by the complex of melatonin (10 mg/kg) plus succinate (50 mg/kg) plus cranberry flavonoids (7 mg/kg) was even more effective in prevention of toxic liver injury and liver mitochondria damage

  20. Biliary lipid secretion in chronic cholestatic liver disease.

    PubMed Central

    Kesäniemi, Y A; Salaspuro, M P; Vuoristo, M; Miettinen, T A

    1982-01-01

    Biliary lipid secretion rates, faecal steroids, and serum lipids were studied in patients with chronic cholestatic liver disease mainly primary biliary cirrhosis. The biliary secretion of cholesterol, bile acids, and phospholipids was markedly decreased as compared with those in the control group and in general correlated negatively with the serum cholesterol and triglyceride values. The molar percentage of cholesterol was increased in the hepatic bile. This suggests that, in cholestatic liver disease, in contrast with the normal state, the hapatic bile may be supersaturated postprandially. Faecal bile acids and neutral sterols of cholesterol origin were decreased proportionately to the corresponding biliary lipid secretion rates. In fact, both biliary and faecal steroid outputs were only about a half or less than those in the controls, indicating that the fractional absorption was not changed but absolute absorption and faecal steroid excretion were low in patients with chronic cholestatic liver disease. Thus, despite low cholesterol and bile acid absorption, cholesterol and bile acid synthesis is low. A negative correlation between faecal steroids and serum cholesterol suggests that the high serum cholesterol level contributed to regulation of cholesterol synthesis. PMID:7129204

  1. Quantification of liver fibrosis in chronic hepatitis B virus infection

    PubMed Central

    Jieanu, CF; Ungureanu, BS; Săndulescu, DL; Gheonea, IA; Tudorașcu, DR; Ciurea, ME; Purcărea, VL

    2015-01-01

    Chronic hepatitis B virus infection (HBV) is considered a global public issue with more than 78.000 people per year dying of its evolution. With liver transplantation as the only viable therapeutic option but only in end-stage disease, hepatitis B progression may generally be influenced by various factors. Assessing fibrosis stage plays an important part in future decisions on the patients’ wealth with available antiviral agents capable of preventing fibrosis passing to an end-stage liver disease. Several methods have been taken into consideration as an alternative for HBV quantification status, such as imaging techniques and serum based biomarkers. Magnetic resonance imaging, ultrasound, and elastography are considered non-invasive imaging techniques frequently used to quantify disease progression as well as patients future prognostic. Consequently, both direct and indirect biomarkers have been studied for differentiating between fibrosis stages. This paper reviews the current standings in HBV non-invasive liver fibrosis quantification, presenting the prognostic factors and available assessment procedures that might eventually replace liver biopsy. PMID:26351528

  2. Hepatic venous pressure gradient: clinical use in chronic liver disease

    PubMed Central

    2014-01-01

    Portal hypertension is a severe consequence of chronic liver diseases and is responsible for the main clinical complications of liver cirrhosis. Hepatic venous pressure gradient (HVPG) measurement is the best available method to evaluate the presence and severity of portal hypertension. Clinically significant portal hypertension is defined as an increase in HVPG to >10 mmHg. In this condition, the complications of portal hypertension might begin to appear. HVPG measurement is increasingly used in the clinical fields, and the HVPG is a robust surrogate marker in many clinical applications such as diagnosis, risk stratification, identification of patients with hepatocellular carcinoma who are candidates for liver resection, monitoring of the efficacy of medical treatment, and assessment of progression of portal hypertension. Patients who had a reduction in HVPG of ≥20% or to ≤12 mmHg in response to drug therapy are defined as responders. Responders have a markedly decreased risk of bleeding/rebleeding, ascites, and spontaneous bacterial peritonitis, which results in improved survival. This review provides clinical use of HVPG measurement in the field of liver disease. PMID:24757653

  3. Effect of Chronic Psychological Stress on Liver Metastasis of Colon Cancer in Mice

    PubMed Central

    Zhao, Lu; Xu, Jianhua; Liang, Fang; Li, Ao; Zhang, Yong; Sun, Jue

    2015-01-01

    Metastasis to the liver is a main factor in colorectal cancer mortality. Previous studies suggest that chronic psychological stress is important in cancer progression, but its effect on liver metastasis has not been investigated. To address this, we established a liver metastasis model in BALB/c nude mice to investigate the role of chronic stress in liver metastasis. Our data suggest that chronic stress elevates catecholamine levels and promotes liver metastasis. Chronic stress was also associated with increased tumor associated macrophages infiltration into the primary tumor and increased the expression of metastatic genes. Interestingly, β-blocker treatment reversed the effects of chronic stress on liver metastasis. Our results suggest the β-adrenergic signaling pathway is involved in regulating colorectal cancer progression and liver metastasis. Additionally, we submit that adjunctive therapy with a β-blocker may complement existing colorectal cancer therapies. PMID:26444281

  4. Prognosis and Biomarkers in Acute-on-Chronic Liver Failure.

    PubMed

    Mookerjee, Rajeshwar P

    2016-05-01

    As formal definitions of acute-on-chronic liver failure (ACLF) have now been established, and given an increased recognition of the dynamic nature of this condition, there is a growing clinical need to assess prognosis and response to interventions. Conventional scoring systems such as Model for End-Stage Liver Disease (MELD) fail to capture the two key prognostic elements in ACLF-namely, extrahepatic organ failure and measures of systemic inflammation-and as such are limited in their prognostic accuracy. Even the best available scoring systems such as the recently described CLIF (Chronic Liver Failure) Consortium ACLF (CLIF-C ACLF) score, are at best 75% accurate and need to be applicable to all etiologies of liver disease. Thus, in the absence of "gold standard" markers of prognosis that render one scoring system superior to another, there is a need to explore other markers of pathophysiology that may better define outcome. This review addresses the evidence for markers of oxidative stress, including those reflecting the inflammasome; elements of cell death such as cytokeratins M30 and M65; and indicators of immune dysfunction, innate immune failure and gut dysbiosis. Finally, evidence for relevance of markers of organ dysfunction, including hemodynamic response, are explored along with associated mediators such as copeptin, dimethylarginines, and renin. It is anticipated that further critique and validation of emerging and relevant biomarkers will facilitate a composite score which, either alone or in combination with existing scoring systems such as CLIF-C, will enable improved prognostication and targeting of therapy in ACLF. PMID:27172354

  5. Association between inherited monogenic liver disorders and chronic hepatitis C

    PubMed Central

    Piekuse, Linda; Kreile, Madara; Zarina, Agnese; Steinberga, Zane; Sondore, Valentina; Keiss, Jazeps; Lace, Baiba; Krumina, Astrida

    2014-01-01

    AIM: To determine the frequencies of mutations that cause inherited monogenic liver disorders in patients with chronic hepatitis C. METHODS: This study included 86 patients with chronic hepatitis C (55 men, 31 women; mean age at diagnosis, 38.36 ± 14.52 years) who had undergone antiviral therapy comprising pegylated interferon and ribavirin. Viral load, biochemical parameter changes, and liver biopsy morphological data were evaluated in all patients. The control group comprised 271 unrelated individuals representing the general population of Latvia for mutation frequency calculations. The most frequent mutations that cause inherited liver disorders [gene (mutation): ATP7B (H1069Q), HFE (C282Y, H63D), UGT1A1 (TA)7, and SERPINA1 (PiZ)] were detected by polymerase chain reaction (PCR), bidirectional PCR allele-specific amplification, restriction fragment length polymorphism analysis, and sequencing. RESULTS: The viral genotype was detected in 80 of the 86 patients. Viral genotypes 1, 2, and 3 were present in 61 (76%), 7 (9%), and 12 (15%) patients, respectively. Among all 86 patients, 50 (58%) reached an early viral response and 70 (81%) reached a sustained viral response. All 16 patients who did not reach a sustained viral response had viral genotype 1. Case-control analysis revealed a statistically significant difference in only the H1069Q mutation between patients and controls (patients, 0.057; controls, 0.012; odds ratio, 5.514; 95%CI: 1.119-29.827, P = 0.022). However, the H1069Q mutation was not associated with antiviral treatment outcomes or biochemical indices. The (TA) 7 mutation of the UGT1A1 gene was associated with decreased ferritin levels (beta regression coefficient = -295.7, P = 0.0087). CONCLUSION: Genetic mutations that cause inherited liver diseases in patients with hepatitis C should be studied in detail. PMID:24575168

  6. Chronic Melatonin Treatment Prevents Memory Impairment Induced by Chronic Sleep Deprivation.

    PubMed

    Alzoubi, Karem H; Mayyas, Fadia A; Khabour, Omar F; Bani Salama, Fatima M; Alhashimi, Farah H; Mhaidat, Nizar M

    2016-07-01

    Sleep deprivation (SD) has been associated with memory impairment through induction of oxidative stress. Melatonin, which promotes the metabolism of many reactive oxygen species (ROS), has antioxidant and neuroprotective properties. In this study, the effect of melatonin on memory impairment induced by 4 weeks of SD was investigated using rat animal model. Animals were sleep deprived using modified multiple platform model. Melatonin was administered via oral gavage (100 mg/kg/day). Spatial learning and memory were assessed using the radial arm water maze (RAWM). Changes in oxidative stress biomarkers in the hippocampus following treatments were measured using ELISA procedure. The result revealed that SD impaired both short- and long-term memory (P < 0.05). Use of melatonin prevented memory impairment induced by SD. Furthermore, melatonin normalized SD-induced reduction in the hippocampus activity of catalase, glutathione peroxidase (GPx), and superoxide dismutase (SOD). In addition, melatonin enhanced the ratio of reduced to oxidized glutathione GSH/GSSG in sleep-deprived rats (P < 0.05) without affecting thiobarbituric acid reactive substance (TBARS) levels (P > 0.05). In conclusion, SD induced memory impairment, which was prevented by melatonin. This was correlated with normalizing hippocampus antioxidant mechanisms during chronic SD. PMID:26084441

  7. Hypercalcemia of advanced chronic liver disease: a forgotten clinical entity!

    PubMed Central

    Kuchay, Mohammad Shafi; Mishra, Sunil Kumar; Farooqui, Khalid Jamal; Bansal, Beena; Wasir, Jasjeet Singh; Mithal, Ambrish

    2016-01-01

    Summary Hypercalcemia caused by advanced chronic liver disease (CLD) without hepatic neoplasia is uncommonly reported and poorly understood condition. We are reporting two cases of advanced CLD who developed hypercalcemia in the course of the disease. This diagnosis of exclusion was made only after meticulous ruling out of all causes of hypercalcemia. The unique feature of this type of hypercalcemia is its transient nature that may or may not require treatment. This clinical condition in patients with CLD should be kept in mind while evaluating the cause of hypercalcemia in them. PMID:27252737

  8. Overview on acute-on-chronic liver failure.

    PubMed

    Zhang, Jing; Gao, Shan; Duan, Zhongping; Hu, Ke-Qin

    2016-03-01

    Liver failure (LF) is defined as severe dysfunction in hepatic synthesis, detoxification, and metabolism induced by various etiologies. Clinical presentation of LF typically includes severe jaundice, coagulation disorder, hepatic encephalopathy, and ascites. LF can be classified into acute LF, acute-on-chronic LF (ACLF), and chronic LF. ACLF has been demonstrated as a distinct syndrome with unique clinical presentation and outcomes. The severity, curability, and reversibility of ACLF have attracted considerable attention. Remarkable developments in ACLF-related conception, diagnostic criteria, pathogenesis, and therapy have been achieved. However, this disease, especially its diagnostic criteria, remains controversial. In this paper, we systemically reviewed the current understanding of ACLF from its definition, etiology, pathophysiology, pathology, and clinical presentation to management by thoroughly comparing important findings between east and west countries, as well as those from other regions. We also discussed the controversies, challenges, and needs for future studies to promote the standardization and optimization of the diagnosis and treatment for ACLF. PMID:26976617

  9. [Impaired lung function in patients with moderate chronic obstructive bronchitis].

    PubMed

    Nefedov, V B; Popova, L A; Shergina, E A

    2004-01-01

    VC, FVC, FEV1, FEV1/VC%, PEF, MEF25, MEF50, MEF75, TLC, TGV, RV, Raw, Rin, Rex, DLCO-SS, paO2 and paCO2 were determined in 22 patients with moderate chronic obstructive bronchitis (FEV1, 79-50% of the normal value). All the patients were found to have impaired bronchial patency, 90.9% of the patients had lung volume and capacity changes; pulmonary gas exchange dysfunction was present in 72.7%. Bronchial patency impairments were manifested by a decrease in FEV1, FEV1/VC%, PEF, MEF25, MEF50, MEF75, and an increase in Raw, Rin, Rex. Changes in the lung volumes and capacities appeared as higher RV, TGV, TLC, lower VC and FVC. Pulmonary gas exchange dysfunction showed up as a reduction in pO2 and DLCO-SS a reduction and an increase in paCO2. The magnitude of the functional changes observed in most patients was low. Significant and pronounced disorders were seen in one third of the patients. PMID:15719666

  10. Chronic administration of isocarbophos induces vascular cognitive impairment in rats.

    PubMed

    Li, Peng; Yin, Ya-Ling; Zhu, Mo-Li; Pan, Guo-Pin; Zhao, Fan-Rong; Lu, Jun-Xiu; Liu, Zhan; Wang, Shuang-Xi; Hu, Chang-Ping

    2016-04-01

    Vascular dementia, being the most severe form of vascular cognitive impairment (VCI), is caused by cerebrovascular disease. Whether organophosphorus causes VCI remains unknown. Isocarbophos (0.5 mg/kg per 2 days) was intragastrically administrated to rats for 16 weeks. The structure and function of cerebral arteries were assayed. The learning and memory were evaluated by serial tests of step-down, step-through and morris water maze. Long-term administration of isocarbophos reduced the hippocampal acetylcholinesterase (AChE) activity and acetylcholine (ACh) content but did not alter the plasma AChE activity, and significantly damaged the functions of learning and memory. Moreover, isocarbophos remarkably induced endothelial dysfunction in the middle cerebral artery and the expressions of ICAM-1 and VCAM-1 in the posterior cerebral artery. Morphological analysis by light microscopy and electron microscopy indicated disruptions of the hippocampus and vascular wall in the cerebral arteries from isocarbophos-treated rats. Treatment of isocarbophos injured primary neuronal and astroglial cells isolated from rats. Correlation analysis demonstrated that there was a high correlation between vascular function of cerebral artery and hippocampal AChE activity or ACh content in rats. In conclusion, chronic administration of isocarbophos induces impairments of memory and learning, which is possibly related to cerebral vascular dysfunction. PMID:26818681

  11. Reproducibility of transient elastography in the evaluation of liver fibrosis in patients with chronic liver disease

    PubMed Central

    Fraquelli, Mirella; Rigamonti, Cristina; Casazza, Giovanni; Conte, Dario; Donato, Maria Francesca; Ronchi, Guido; Colombo, Massimo

    2007-01-01

    Objective Transient elastography (TE) is gaining popularity as a non‐invasive method for predicting liver fibrosis, but intraobserver and interobserver agreement and factors influencing TE reproducibility have not been adequately assessed. This study investigated these aspects. Setting Tertiary referral liver unit. Patients Over a 4‐month period, 200 patients with chronic liver disease (CLD) with varying aetiology consecutively underwent TE and liver biopsy. Interventions TE was performed twice by two different operators either concomitantly or within 3 days of the bioptic procedure (METAVIR classification). Main outcome measures Intraobserver and interobserver agreement were analysed using the intraclass correlation coefficient (ICC) and correlated with different patient‐related and liver disease‐related covariates. Results 800 TE examinations were performed, with an indeterminate result rate of 2.4%. The overall interobserver agreement ICC was 0.98 (95% CI 0.977 to 0.987). Increased body mass index (>25 kg/m2), steatosis, and low staging grades (fibrosis (F) stage <2) were significantly associated with reduced ICC (p<0.05). Intraobserver agreement ICC was 0.98 for both raters. Using receiver operating characteristic curves, three diagnostic TE thresholds were identified: >7.9 kPa for F⩾2, >10.3 for F⩾3 and >11.9 for F = 4. TE values assessed by the two raters fell within the same cut‐off of fibrosis in 88% of the cases for F⩾2, in 92% for F⩾3 and 91% for F = 4. Conclusions TE is a highly reproducible and user‐friendly technique for assessing liver fibrosis in patients with CLD. However, because TE reproducibility is significantly reduced (p<0.05) in patients with steatosis, increased BMI and lower degrees of hepatic fibrosis, caution is warranted in the clinical use of TE as a surrogate for liver biopsy. PMID:17255218

  12. Acute and chronic tramadol administration impair spatial memory in rat

    PubMed Central

    Hosseini-Sharifabad, Ali; Rabbani, Mohammad; Sharifzadeh, Mohammad; Bagheri, Narges

    2016-01-01

    Tramadol hydrochloride, a synthetic opioid, acts via a multiple mechanism of action. Tramadol can potentially change the behavioral phenomena. The present study evaluates the effect of tramadol after single or multiple dose/s on the spatial memory of rat using object recognition task (ORT). Tramadol, 20 mg/kg, was injected intraperitoneally (i.p) as a single dose or once a day for 21 successive days considered as acute or chronic treatment respectively. After treatment, animals underwent two trials in the ORT. In the first trial (T1), animals encountered with two identical objects for exploration in a five-minute period. After 1 h, in the T2 trial, the animals were exposed to a familiar and a nonfamiliar object. The exploration times and frequency of the exploration for any objects were recorded. The results showed that tramadol decreased the exploration times for the nonfamiliar object in the T2 trial when administered either as a single dose (P<0.001) or as the multiple dose (P<0.05) compared to the respective control groups. Both acute and chronic tramadol administration eliminated the different frequency of exploration between the familiar and nonfamiliar objects. Our findings revealed that tramadol impaired memory when administered acutely or chronically. Single dose administration of tramadol showed more destructive effect than multiple doses of tramadol on the memory. The observed data can be explained by the inhibitory effects of tramadol on the wide range of neurotransmitters and receptors including muscarinic, N-methyl D-aspartate, AMPA as well as some second messenger like cAMP and cGMP or its stimulatory effect on the opioid, gama amino butyric acid, dopamine or serotonin in the brain. PMID:27051432

  13. Herbal Products: Benefits, Limits, and Applications in Chronic Liver Disease

    PubMed Central

    Del Prete, Anna; Scalera, Antonella; Iadevaia, Maddalena Diana; Miranda, Agnese; Zulli, Claudio; Gaeta, Laura; Tuccillo, Concetta; Federico, Alessandro; Loguercio, Carmelina

    2012-01-01

    Complementary and alternative medicine soughts and encompasses a wide range of approaches; its use begun in ancient China at the time of Xia dynasty and in India during the Vedic period, but thanks to its long-lasting curative effect, easy availability, natural way of healing, and poor side-effects it is gaining importance throughout the world in clinical practice. We conducted a review describing the effects and the limits of using herbal products in chronic liver disease, focusing our attention on those most known, such as quercetin or curcumin. We tried to describe their pharmacokinetics, biological properties, and their beneficial effects (as antioxidant role) in metabolic, alcoholic, and viral hepatitis (considering that oxidative stress is the common pathway of chronic liver diseases of different etiology). The main limit of applicability of CAM comes from the lacking of randomized, placebo-controlled clinical trials giving a real proof of efficacy of those products, so that anecdotal success and personal experience are frequently the driving force for acceptance of CAM in the population. PMID:22991573

  14. Ciproxifan differentially modifies cognitive impairment evoked by chronic stress and chronic corticosterone administration in rats.

    PubMed

    Trofimiuk, Emil; Braszko, Jan J

    2015-04-15

    Despite the development of neuroscience and spectacular discoveries, the clear functions and the role of histamine are still not fully understood, especially in the context of the negative impact of prolonged stress exposure on the cognition. The purpose of this study was to evaluate the participation of hypercortisolemia in the detrimental effect of stress on cognitive function and their preclusion by affecting the histaminergic system with ciproxifan. Specifically, we attempted to characterize the preventive action of a single dose of ciproxifan (3mg/kg, i.p.) against an impairment caused by chronic restraint stress as well as parallel exogenous corticosterone (equivalent to that seen in chronically stressed rats), and show differences in the interaction on reference and working memories tested in both aversive (Morris water maze - MWM) and appetitive (Barnes maze-BM) incentives. We found that administration of ciproxifan potently prevented equally deleterious effects of chronic restraint stress (p<0.01) as well as prolonged administration of corticosterone (p<0.01), especially in the tests, which themselves generate high levels of stress. As it turns out, test provided in the less stressful conditions (BM) showed that administration of the H3 receptor antagonist to naïve rats resulted in even memory impairment (p<0.01, in some aspects of reference memory). These data support the idea that modulation of H3 receptors represents a novel and viable therapeutic strategy in the treatment but rather not for prevention of stress-evoked cognitive impairments. Even a single dose abolishes the effect of prolonged exposure to stress or steroids. PMID:25639546

  15. Peripheral neuropathy in chronic liver disease: clinical, electrodiagnostic, and nerve biopsy findings

    PubMed Central

    Knill-Jones, R. P.; Goodwill, C. J.; Dayan, A. D.; Williams, Roger

    1972-01-01

    In a prospective study of 70 unselected patients with chronic liver disease, clinical signs of a peripheral neuropathy were observed in 13 patients. Abnormal nerve conduction was demonstrated in nine of these and in one further patient who had no abnormal neurological signs. The occurrence of a neuropathy (in patients with cryptogenic cirrhosis, haemochromatosis, active chronic hepatitis as well as in alcoholic cirrhosis) could not be related to liver function, although it was associated with higher IgA and IgM values. Clinical diabetes was present in six of the 14 patients with neuropathy but there was no relation in the non-diabetic patients between neuropathy and minor impairment of carbohydrate tolerance. Those with neuropathy had a significantly higher incidence of oesophageal varices and there was also a relationship to a history of previous encephalopathy. Sural nerve biopsy was carried out on 14 patients, eight of whom had clinical or electrodiagnostic evidence of neuropathy. Single nerve fibres were examined by teasing and in all nerves histological evidence was found of an indolent process which had damaged whole Schwann cells and which resulted in demyelination and remyelination. Diabetic angiopathy was not seen and axonal degeneration, which was never severe, was found in all disease groups equally. Images PMID:4337271

  16. Ethanol-induced impairment of hepatic glycoprotein secretion in the isolated rat liver perfusion model

    SciTech Connect

    Volentine, G.D.; Ogden, K.A.; Tuma, D.J.; Sorrell, M.F.

    1987-05-01

    The authors have previously shown that acute administration of ethanol inhibits hepatic glycoprotein secretion in vivo. This ethanol-induced effect appears to be mediated by its reactive metabolite, acetaldehyde. Since hormonal influences and vascular changes can not be controlled in vivo during ethanol administration, they investigated the effect of ethanol in the isolated perfused liver model. Rat liver from fed animals was perfused with oxygenated KRB at 3 ml/min/g liver for 4 hrs. Since ethanol inhibits proteins synthesis in vitro, protein acceptor pool size was equalized in both ethanol and control perfused livers with 1 mM cycloheximide. /sup 3/H-glucosamine was used to label hepatic secretory glycoproteins in the perfusate. Colchicine, a known inhibitor of protein secretion, impaired the secretion of labeled glycoproteins with a concomitant retention of these export proteins in the liver; therefore, confirming the authors secretory model. Ethanol (50 mM) inhibited the appearance of glucosamine-labeled glycoproteins by 60% into the perfusate as compared to control livers. Pretreatment of animals with cyanamide (an aldehyde dehydrogenase inhibitor) further potentiated this effect of ethanol in the isolated perfused liver. These data suggest that ethanol inhibits hepatic glycoprotein secretion in the isolated liver perfusion model, and this ethanol-induced impairment appears to be mediated by acetaldehyde.

  17. Chronic obstructive pulmonary disease phenotypes and balance impairment

    PubMed Central

    Voica, Alina Sorina; Oancea, Cristian; Tudorache, Emanuela; Crisan, Alexandru F; Fira-Mladinescu, Ovidiu; Tudorache, Voicu; Timar, Bogdan

    2016-01-01

    Background/objective Chronic obstructive pulmonary disease (COPD) is a respiratory disease that results in airflow limitation and respiratory distress, also having many nonrespiratory manifestations that affect both function and mobility. Preliminary evidence suggests that balance deficits constitute an important secondary impairment in individuals with COPD. Our objective was to investigate balance performance in two groups of COPD patients with different body compositions and to observe which of these groups are more likely to experience falls in the future. Methods We included 27 stable COPD patients and 17 healthy individuals who performed a series of balance tests. The COPD patients were divided in two groups: emphysematous and bronchitic. Patients completed the activities balance confidence scale and the COPD assessment test questionnaire and afterward performed the Berg Balance Scale, timed up and go, single leg stance and 6-minute walking distance test. We analyzed the differences in the balance tests between the studied groups. Results Bronchitic COPD was associated with a decreased value when compared to emphysematous COPD for the following variables: single leg stance (8.7 vs 15.6; P<0.001) and activities balance confidence (53.2 vs 74.2; P=0.001). Bronchitic COPD patients had a significantly higher value of timed up and go test compared to patients with emphysematous COPD (14.7 vs 12.8; P=0.001). Conclusion Patients with COPD have a higher balance impairment than their healthy peers. Moreover, we observed that the bronchitic COPD phenotype is more likely to experience falls compared to the emphysematous phenotype. PMID:27199555

  18. Impaired sympathetic skin response in chronic obstructive pulmonary disease.

    PubMed

    Bir, Levent Sinan; Ozkurt, Sibel; Daloğlu, Güner; Kurt, Tülay

    2005-12-01

    The sympathetic skin response (SSR) is considered as one of the indexes of autonomic nervous system functions, especially related with the sudomotor function of unmyelinated sympathetic fibers. SSRs are recorded as the potentials with biphasic or multiphasic waveforms by conventional electromyography. SSRs are evaluated by measuring latency (time from the stimulus to the onset), amplitude, and area (the space under the curve of the waveform). Although dysautonomia is a feature of chronic obstructive pulmonary disease (COPD), as demonstrated by acetylcholine sweat-spot test, there are no data concerning SSR in COPD patients. In this study, we electrophysiologically investigated the sudomotor function of the sympathetic nervous system in patients with COPD. SSRs were recorded in 30 patients with COPD and 21 healthy volunteers. Normal responses were obtained from all subjects in the control group. No response was observed in three patients with COPD. The mean latency, amplitude and area values of the potentials recorded of the remaining 27 patients were compared to the control. The mean latency was longer (p<0.01) and the mean amplitude and area values were lower (p=0.012, p=0.021, respectively) in the patients compared to the control. We also demonstrated significant correlations between the latency, amplitude, or area values of the SSR and two parameters of pulmonary function tests forced expiratory volume one second/forced vital capacity (FEV1/FVC) and FEV1/FVC %. In conclusion, SSR is impaired in patients with COPD, which indicates the dysfunction of the sympathetic nervous system. Furthermore, the degree of impairment in SSR may reflect the severity of airway obstruction in patients with COPD. PMID:16272793

  19. [Respiratory functional impairment in patients with liver cirrhosis].

    PubMed

    Siemieniako, Andrzej; Łapiński, Tadeusz Wojciech; Flisiak, Robert

    2010-04-01

    Liver pathologies have negative influence on numerous organs including pulmonary system. Liver failure, which often results from cirrhosis, may lead to the hepatopulmonary syndrome and portopulmonary hypertension. The hepatopulmonary syndrome is characterized by increased alveolar-capillary oxygen gradient, presence of intrapulmonary leak and diminished retention of the carbon dioxide from arterial blood. Two types of the hepatopulmonary syndrome are distinguished: the type 1 connected with pre-capillary and capillaries extension, what shortens the time of the blood flow by the pulmonary vessels. The type 2 hepatopulmonary syndrome results from the formation of arteriovenous anastomoses and anatomical "shunt" connections. Most patients with hepatopulmonary syndrome demonstrate both types. Patients with liver failure may develop portopulmonary hypertension, independently from hepatopulmonary syndrome. If not treated, hypertension might lead to the death of 50 to 90% patients in the 5-year follow up. The patients with the serious damage of the liver have hiperdynamic circulation with the increased heart capacity and lowered systemic vascular resistance. The hepatopulmonary syndrome is characterized by the growth of the pulmonary artery pressure and the presence of portal hypertension. The mechanism how the portal hypertension leads to the pulmonary hypertension is not clear. PMID:20491346

  20. Liver-specific magnetic resonance contrast medium in the evaluation of chronic liver disease

    PubMed Central

    dos Reis, Marcio Augusto Correia Rodrigues; Baroni, Ronaldo Hueb

    2015-01-01

    ABSTRACT The hepatobiliary-specific contrast medium (gadoxetic acid – Primovist®) is primarily used to improve detection and characterization of focal hepatic lesions, such as in chronic liver disease patients with suspected hepatocellular carcinoma. Since the contrast medium is selectively taken up by functioning hepatocytes in the late hepatobiliary phase, it helps to detect typical hepatocellular carcinoma, which show low signal intensity on this phase. This imaging feature also assists in differentiating regenerative/dysplastic nodules from early hepatocellular carcinomas (with over 90% accuracy), as well as hypervascular hepatocellular carcinomas from arterial pseudo-enhancement foci. Future perspectives include its use in quantification of hepatic function and fibrosis. PMID:26154554

  1. Extracorporeal support for patients with acute and acute on chronic liver failure.

    PubMed

    Aron, Jonathan; Agarwal, Banwari; Davenport, Andrew

    2016-04-01

    The number of patients developing liver failure; acute on chronic liver failure and acute liver failure continues to increase, along with the demand for donor livers for transplantation. As such there is a clinical need to develop effective extracorporeal devices to support patients with acute liver failure or acute-on-chronic liver failure to allow time for hepatocyte regeneration, and so avoiding the need for liver transplantation, or to bridge the patient to liver transplantation, and also potentially to provide symptomatic relief for patients with cirrhosis not suitable for transplantation. Currently devices can be divided into those designed to remove toxins, including plasma exchange, high permeability dialyzers and adsorption columns or membranes, coupled with replacement of plasma proteins; albumin dialysis systems; and bioartificial devices which may provide some of the biological functions of the liver. In the future we expect combinations of these devices in clinical practice, due to the developments in bioartificial scaffolds. PMID:26894968

  2. Loss of p21 permits carcinogenesis from chronically damaged liver and kidney epithelial cells despite unchecked apoptosis.

    PubMed

    Willenbring, Holger; Sharma, Amar Deep; Vogel, Arndt; Lee, Andrew Y; Rothfuss, Andreas; Wang, Zhongya; Finegold, Milton; Grompe, Markus

    2008-07-01

    Accumulation of toxic metabolites in hereditary tyrosinemia type I (HT1) patients leads to chronic DNA damage and the highest risk for hepatocellular carcinomas (HCCs) of any human disease. Here we show that hepatocytes of HT1 mice exhibit a profound cell-cycle arrest that, despite concomitant apoptosis resistance, causes mortality from impaired liver regeneration. However, additional loss of p21 in HT1 mice restores the proliferative capabilities of hepatocytes and renal proximal tubular cells. This growth response compensates cell loss due to uninhibited apoptosis and enables animal survival but rapidly leads to HCCs, renal cysts, and renal carcinomas. Thus, p21's antiproliferative function is indispensable for the suppression of carcinogenesis from chronically injured liver and renal epithelial cells and cannot be compensated by apoptosis. PMID:18598944

  3. Chronic exposure to environmental levels of tribromophenol impairs zebrafish reproduction

    SciTech Connect

    Deng Jun; Liu Chunsheng; Yu Liqin; Zhou Bingsheng

    2010-02-15

    Tribromophenol (2,4,6-TBP) is ubiquitously found in aquatic environments and biota. In this study, we exposed zebrafish embryos (F{sub 0}; 2'''' days post-fertilization, dpf) to environmental concentration (0.3 mug/L) and a higher concentration (3.0 mug/L) of TBP and assessed the impact of chronic exposure (120 dpf) on reproduction. TBP exposure did not cause a significant increase in the malformation and reduction in the survival in the F{sub 0}-generation fish. After TBP exposure, the plasma testosterone and estradiol levels significantly increased in males and decreased in females. The transcription of steroidogenic genes (3beta-HSD, 17beta-HSD, CYP17, CYP19A, CYP19B) was significantly upregulated in the brain and testes in males and downregulated in the brain and ovary in females. TBP exposure significantly downregulated and upregulated the expression of VTG in the liver of female and male fish, respectively. Meanwhile, TBP exposure altered the sex ratio toward a male-dominant state. The F{sub 1}-generation larvae exhibited increased malformation, reduced survival, and retarded growth, suggesting that TBP in the aquatic environment has significant adverse effects on fish population.

  4. Impaired lipid accumulation in the liver of Tsc2-heterozygous mice during liver regeneration

    SciTech Connect

    Obayashi, Yoko; Campbell, Jean S.; Fausto, Nelson; Yeung, Raymond S.

    2013-07-19

    Highlights: •Tuberin phosphorylation correlated with mTOR activation in early liver regeneration. •Liver regeneration in the Tsc2+/− mice was not enhanced. •The Tsc2+/− livers failed to accumulate lipid bodies during liver regeneration. •Mortality rate increased in Tsc2+/− mice after partial hepatectomy. •Tuberin plays a critical role in hepatic lipid accumulation to support regeneration. -- Abstract: Tuberin is a negative regulator of mTOR pathway. To investigate the function of tuberin during liver regeneration, we performed 70% hepatectomy on wild-type and Tsc2+/− mice. We found the tuberin phosphorylation correlated with mTOR activation during early liver regeneration in wild-type mice. However, liver regeneration in the Tsc2+/− mice was not enhanced. Instead, the Tsc2+/− livers failed to accumulate lipid bodies, and this was accompanied by increased mortality. These findings suggest that tuberin plays a critical role in liver energy balance by regulating hepatocellular lipid accumulation during early liver regeneration. These effects may influence the role of mTORC1 on cell growth and proliferation.

  5. Chronic Inflammatory Liver Disease in Mice Expressing a CD28-specific Ligand

    PubMed Central

    Corse, Emily; Gottschalk, Rachel A.; Park, Joon Seok; Sepulveda, Manuel A.; Loke, P’ng; Sullivan, Timothy J.; Johnson, Linda K.; Allison, James P.

    2012-01-01

    Inflammation of the normally tolerant liver microenvironment precedes development of chronic liver disease. Study of the pathogenesis of autoimmune liver diseases such as autoimmune hepatitis (AIH) has been hampered by a lack of autochthonous chronic animal models. Through our studies of T cell costimulation, we generated transgenic mice expressing a ligand specific for the CD28 receptor, which normally shares ligands with the related inhibitory receptor CTLA-4. The mice spontaneously develop chronic inflammatory liver disease with several pathologies found in AIH including elevated serum aminotransferases in the context of normal alkaline phosphatase and bilirubin levels, lymphocytic inflammation, focal necrosis, oval cell hyperplasia, and fibrosis. The prevalence of IFN-γ-producing CD8+ T cells in the livers of transgenic mice suggests a role for autoimmune cytotoxicity in the chronic disease state. The CD28 ligand-specific transgenic mice will facilitate evaluation of CD8+ T cell function in liver disease pathologies found in AIH. PMID:23248264

  6. Hyaluronic acid as a biomarker of fibrosis in chronic liver diseases of different etiologies

    PubMed Central

    ORASAN, OLGA HILDA; CIULEI, GEORGE; COZMA, ANGELA; SAVA, MADALINA; DUMITRASCU, DAN LUCIAN

    2016-01-01

    Chronic liver diseases represent a significant public health problem worldwide. The degree of liver fibrosis secondary to these diseases is important, because it is the main predictor of their evolution and prognosis. Hyaluronic acid is studied as a non-invasive marker of liver fibrosis in chronic liver diseases, in an attempt to avoid the complications of liver puncture biopsy, considered the gold standard in the evaluation of fibrosis. We review the advantages and limitations of hyaluronc acid, a biomarker, used to manage patients with chronic viral hepatitis B or C infection, non-alcoholic fatty liver disease, HIV-HCV coinfection, alcoholic liver disease, primary biliary cirrhosis, biliary atresia, hereditary hemochromatosis and cystic fibrosis. PMID:27004022

  7. Knowledge, Attitudes, and Beliefs of Patients with Chronic Liver Disease

    PubMed Central

    Burnham, Brett; Wallington, Sherrie; Jillson, Irene A.; Trandafili, Holta; Shetty, Kirti; Wang, Judy; Loffredo, Christopher A.

    2015-01-01

    Objectives To explore knowledge, attitudes, behaviors, and barriers to care among patients with chronic liver disease (CLD). Methods Three separate, one-time-only, 60-minutes focus group sessions were audio-recorded, transcribed, and analyzed using an editing style of analysis. Results In total, 13 focus group participants provided 254 discrete comments. Emerging themes included: negative lifestyles/behaviors, lack of CLD knowledge, negative attitudes/emotions, stigma and negativity, health insurance, inaccessible/high cost medical care, drug/alcohol abuse, and discriminately sharing CLD diagnoses. Conclusions Participants felt lack of CLD knowledge was a key factor in how patients perceived prevention, risks, causes, and treatment. These findings contribute to the important, yet limited, base of knowledge about CLD and provide a benchmark for future, more extensive studies and interventions. PMID:24933143

  8. Up-regulated extracellular matrix components and inflammatory chemokines may impair the regeneration of cholestatic liver

    PubMed Central

    Zhang, Shuai; Li, Tao-Sheng; Soyama, Akihiko; Tanaka, Takayuki; Yan, Chen; Sakai, Yusuke; Hidaka, Masaaki; Kinoshita, Ayaka; Natsuda, Koji; Fujii, Mio; Kugiyama, Tota; Baimakhanov, Zhassulan; Kuroki, Tamotsu; Gu, Weili; Eguchi, Susumu

    2016-01-01

    Although the healthy liver is known to have high regenerative potential, poor liver regeneration under pathological conditions remains a substantial problem. We investigated the key molecules that impair the regeneration of cholestatic liver. C57BL/6 mice were randomly subjected to partial hepatectomy and bile duct ligation (PH+BDL group, n = 16), partial hepatectomy only (PH group, n = 16), or sham operation (Sham group, n = 16). The liver sizes and histological findings were similar in the PH and sham groups 14 days after operation. However, compared with those in the sham group, the livers in mice in the PH+BDL group had a smaller size, a lower cell proliferative activity, and more fibrotic tissue 14 days after the operation, suggesting the insufficient regeneration of the cholestatic liver. Pathway-focused array analysis showed that many genes were up- or down-regulated over 1.5-fold in both PH+BDL and PH groups at 1, 3, 7, and 14 days after treatment. Interestingly, more genes that were functionally related to the extracellular matrix and inflammatory chemokines were found in the PH+BDL group than in the PH group at 7 and 14 days after treatment. Our data suggest that up-regulated extracellular matrix components and inflammatory chemokines may impair the regeneration of cholestatic liver. PMID:27226149

  9. Up-regulated extracellular matrix components and inflammatory chemokines may impair the regeneration of cholestatic liver.

    PubMed

    Zhang, Shuai; Li, Tao-Sheng; Soyama, Akihiko; Tanaka, Takayuki; Yan, Chen; Sakai, Yusuke; Hidaka, Masaaki; Kinoshita, Ayaka; Natsuda, Koji; Fujii, Mio; Kugiyama, Tota; Baimakhanov, Zhassulan; Kuroki, Tamotsu; Gu, Weili; Eguchi, Susumu

    2016-01-01

    Although the healthy liver is known to have high regenerative potential, poor liver regeneration under pathological conditions remains a substantial problem. We investigated the key molecules that impair the regeneration of cholestatic liver. C57BL/6 mice were randomly subjected to partial hepatectomy and bile duct ligation (PH+BDL group, n = 16), partial hepatectomy only (PH group, n = 16), or sham operation (Sham group, n = 16). The liver sizes and histological findings were similar in the PH and sham groups 14 days after operation. However, compared with those in the sham group, the livers in mice in the PH+BDL group had a smaller size, a lower cell proliferative activity, and more fibrotic tissue 14 days after the operation, suggesting the insufficient regeneration of the cholestatic liver. Pathway-focused array analysis showed that many genes were up- or down-regulated over 1.5-fold in both PH+BDL and PH groups at 1, 3, 7, and 14 days after treatment. Interestingly, more genes that were functionally related to the extracellular matrix and inflammatory chemokines were found in the PH+BDL group than in the PH group at 7 and 14 days after treatment. Our data suggest that up-regulated extracellular matrix components and inflammatory chemokines may impair the regeneration of cholestatic liver. PMID:27226149

  10. A study of the awareness of chronic liver diseases among Korean adults

    PubMed Central

    Jun, Dae Won; Cho, Yong Kyun; Lee, Chang Hyeong; Kim, Seok Hyun; Eun, Jong Ryul

    2011-01-01

    Background/Aims Chronic liver disease is closely associated with lifestyle, and public enlightenment of the lifestyle factors is important in reducing prevalence of chronic liver disease. The KASL (Korean Association for the Study of the Liver) conducted a survey of basic information and epidemiological data regarding chronic liver diseases. Methods A survey of chronic liver disease involving a total of 2,794 respondents was conducted. The respondents included patients and their guardians, visitors for health check-ups, and online pollees who completed a questionnaire on the awareness of fatty liver or chronic liver disease. Results Of the entire cohort, 854 (39.7%) said they have had or still have fatty liver or an elevated transaminase level (>40 IU/L), but only 23.4% of the respondents had visited a hospital. It was found that 35% of healthy subjects and 45% of patients and their guardians misunderstood hepatitis B as the hereditary disesase. Furthermore, 26% of the subjects responded that patients with inactive hepatitis B do not require regular follow-up. While 17.9% answered that it is not too late to test for liver cancer when symptoms arise, 38.8% believed that liver transplant in liver cancer patients has a low success rate and is thus not recommended. Conclusions Despite the inundation of information and widespread media advertising, the awareness of chronic liver disease is unsatisfactory among Korean adults. Systematic nationwide studies are needed to obtain data and information regarding the prevalence of chronic liver disease and patterns of use of the health-care system. PMID:21757980

  11. Divergent Inflammatory, Fibrogenic, and Liver Progenitor Cell Dynamics in Two Common Mouse Models of Chronic Liver Injury.

    PubMed

    Köhn-Gaone, Julia; Dwyer, Benjamin J; Grzelak, Candice A; Miller, Gregory; Shackel, Nicholas A; Ramm, Grant A; McCaughan, Geoffrey W; Elsegood, Caryn L; Olynyk, John K; Tirnitz-Parker, Janina E E

    2016-07-01

    Complications of end-stage chronic liver disease signify a major cause of mortality worldwide. Irrespective of the underlying cause, most chronic liver diseases are characterized by hepatocellular necrosis, inflammation, fibrosis, and proliferation of liver progenitor cells or ductular reactions. Vast differences exist between experimental models that mimic these processes, and their identification is fundamental for translational research. We compared two common murine models of chronic liver disease: the choline-deficient, ethionine-supplemented (CDE) diet versus thioacetamide (TAA) supplementation. Markers of liver injury, including serum alanine transaminase levels, apoptosis, hepatic fat loading, and oxidative stress, as well as inflammatory, fibrogenic and liver progenitor cell responses, were assessed at days 3, 7, 14, 21, and 42. This study revealed remarkable differences between the models. It identified periportal injury and fibrosis with an early peak and slow normalization of all parameters in the CDE regimen, whereas TAA-treated mice had pericentral patterns of progressive injury and fibrosis, resulting in a more severe hepatic injury phenotype. This study is the first to resolve two different patterns of injury and fibrosis in the CDE and TAA model and to indisputably identify the fibrosis pattern in the TAA model as driven from the pericentral vein region. Our data provide a valuable foundation for future work using the CDE and TAA regimens to model a variety of human chronic liver diseases. PMID:27181403

  12. Chronic overeating impairs hepatic glucose uptake and disposition.

    PubMed

    Coate, Katie C; Kraft, Guillaume; Shiota, Masakazu; Smith, Marta S; Farmer, Ben; Neal, Doss W; Williams, Phil; Cherrington, Alan D; Moore, Mary Courtney

    2015-05-15

    Dogs consuming a hypercaloric high-fat and -fructose diet (52 and 17% of total energy, respectively) or a diet high in either fructose or fat for 4 wk exhibited blunted net hepatic glucose uptake (NHGU) and glycogen deposition in response to hyperinsulinemia, hyperglycemia, and portal glucose delivery. The effect of a hypercaloric diet containing neither fructose nor excessive fat has not been examined. Dogs with an initial weight of ≈25 kg consumed a chow and meat diet (31% protein, 44% carbohydrate, and 26% fat) in weight-maintaining (CTR; n = 6) or excessive (Hkcal; n = 7) amounts for 4 wk (cumulative weight gain 0.0 ± 0.3 and 1.5 ± 0.5 kg, respectively, P < 0.05). They then underwent clamp studies with infusions of somatostatin and intraportal insulin (4× basal) and glucagon (basal). The hepatic glucose load was doubled with peripheral (Pe) glucose infusion for 90 min (P1) and intraportal glucose at 4 mg·kg(-1)·min(-1) plus Pe glucose for the final 90 min (P2). NHGU was blunted (P < 0.05) in Hkcal during both periods (mg·kg(-1)·min(-1); P1: 1.7 ± 0.2 vs. 0.3 ± 0.4; P2: 3.6 ± 0.3 vs. 2.3 ± 0.4, CTR vs. Hkcal, respectively). Terminal hepatic glucokinase catalytic activity was reduced nearly 50% in Hkcal vs. CTR (P < 0.05), although glucokinase protein did not differ between groups. In Hkcal vs. CTR, liver glycogen was reduced 27% (P < 0.05), with a 91% increase in glycogen phosphorylase activity (P < 0.05) but no significant difference in glycogen synthase activity. Thus, Hkcal impaired NHGU and glycogen synthesis compared with CTR, indicating that excessive energy intake, even if the diet is balanced and nutritious, negatively impacts hepatic glucose metabolism. PMID:25783892

  13. TNFR1 determines progression of chronic liver injury in the IKKγ/Nemo genetic model

    PubMed Central

    Cubero, F J; Singh, A; Borkham-Kamphorst, E; Nevzorova, Y A; Al Masaoudi, M; Haas, U; Boekschoten, M V; Gassler, N; Weiskirchen, R; Muller, M; Liedtke, C; Trautwein, C

    2013-01-01

    Death receptor-mediated hepatocyte apoptosis is implicated in a wide range of liver diseases including viral and alcoholic hepatitis, ischemia/reperfusion injury, fulminant hepatic failure, cholestatic liver injury, as well as cancer. Deletion of NF-κB essential modulator in hepatocytes (IKKγ/Nemo) causes spontaneous progression of TNF-mediated chronic hepatitis to hepatocellular carcinoma (HCC). Thus, we analyzed the role of death receptors including TNFR1 and TRAIL in the regulation of cell death and the progression of liver injury in IKKγ/Nemo-deleted livers. We crossed hepatocyte-specific IKKγ/Nemo knockout mice (NemoΔhepa) with constitutive TNFR1−/− and TRAIL−/− mice. Deletion of TNFR1, but not TRAIL, decreased apoptotic cell death, compensatory proliferation, liver fibrogenesis, infiltration of immune cells as well as pro-inflammatory cytokines, and indicators of tumor growth during the progression of chronic liver injury. These events were associated with diminished JNK activation. In contrast, deletion of TNFR1 in bone-marrow-derived cells promoted chronic liver injury. Our data demonstrate that TNF- and not TRAIL signaling determines the progression of IKKγ/Nemo-dependent chronic hepatitis. Additionally, we show that TNFR1 in hepatocytes and immune cells have different roles in chronic liver injury–a finding that has direct implications for treating chronic liver disease. PMID:23933814

  14. Chronic liver inflammation modifies DNA methylation at the precancerous stage of murine hepatocarcinogenesis

    PubMed Central

    Stoyanov, Evgeniy; Ludwig, Guy; Mizrahi, Lina; Olam, Devorah; Schnitzer-Perlman, Temima; Tasika, Elena; Sass, Gabriele; Tiegs, Gisa; Jiang, Yong; Nie, Ting; Kohler, James; Schinazi, Raymond F.; Vertino, Paula M.; Cedar, Howard; Galun, Eithan; Goldenberg, Daniel

    2015-01-01

    Chronic liver inflammation precedes the majority of hepatocellular carcinomas (HCC). Here, we explore the connection between chronic inflammation and DNA methylation in the liver at the late precancerous stages of HCC development in Mdr2−/− (Mdr2/Abcb4-knockout) mice, a model of inflammation-mediated HCC. Using methylated DNA immunoprecipitation followed by hybridization with “CpG islands” (CGIs) microarrays, we found specific CGIs in 76 genes which were hypermethylated in the Mdr2−/− liver compared to age-matched healthy controls. The observed hypermethylation resulted mainly from an age-dependent decrease of methylation of the specific CGIs in control livers with no decrease in mutant mice. Chronic inflammation did not change global levels of DNA methylation in Mdr2−/− liver, but caused a 2-fold decrease of the global 5-hydroxymethylcytosine level in mutants compared to controls. Liver cell fractionation revealed, that the relative hypermethylation of specific CGIs in Mdr2−/− livers affected either hepatocyte, or non-hepatocyte, or both fractions without a correlation between changes of gene methylation and expression. Our findings demonstrate that chronic liver inflammation causes hypermethylation of specific CGIs, which may affect both hepatocytes and non-hepatocyte liver cells. These changes may serve as useful markers of an increased regenerative activity and of a late precancerous stage in the chronically inflamed liver. PMID:25918251

  15. The performance of acoustic radiation force impulse imaging in predicting liver fibrosis in chronic liver diseases.

    PubMed

    Lin, Yi-Hung; Yeh, Ming-Lun; Huang, Ching-I; Yang, Jeng-Fu; Liang, Po-Cheng; Huang, Chung-Feng; Dai, Chia-Yen; Lin, Zu-Yau; Chen, Shinn-Cherng; Huang, Jee-Fu; Yu, Ming-Lung; Chuang, Wan-Long

    2016-07-01

    Sonography-based noninvasive liver fibrosis assessment is promising in the prediction of treatment efficacy and prognosis in chronic liver disease (CLD) patients. Acoustic radiation force impulse imaging (ARFI) is a newly-developed transient elastography (TE) method integrated into a conventional ultrasound machine. The study aimed to assess the performance of ARFI imaging in the diagnosis of liver fibrosis in Taiwanese CLD patients. We also aimed to search for the optimal cut-off values in different fibrosis stages. A total of 60 CLD patients (40 males; mean age, 51.8±11 years) were consecutively included. They received standard ARFI measurement within 2 weeks at the time of liver biopsy. There were eight patients with Metavir fibrosis stage 0 (F0), 16 patients with F1, 20 patients with F2, eight patients with F3, and eight patients with F4, respectively. The mean values among patient with F0, F1, F2, F3, and F4 were 1.17±0.13, 1.30±0.17, 1.31±0.24, 2.01±0.45, and 2.69±0.91, respectively (p<0.001). The optimal cut-off ARFI value for significant fibrosis (F≥2) was 1.53 with the accuracy of 0.733, while it was 1.66 for advanced fibrosis (F≥3) with the accuracy of 0.957. Our study demonstrated that ARFI imaging is competent for fibrosis diagnosis, particularly in CLD patients with advanced fibrosis. PMID:27450025

  16. Relationship between 25-Hydroxyvitamin D Levels and Liver Fibrosis as Assessed by Transient Elastography in Patients with Chronic Liver Disease

    PubMed Central

    Ko, Bong Jin; Kim, Young Seok; Kim, Sang Gyune; Park, Jung Hwan; Lee, Sae Hwan; Jeong, Soung Won; Jang, Jae Young; Kim, Hong Soo; Kim, Boo Sung; Kim, Sun Mi; Kim, Young Don; Cheon, Gab Jin; Lee, Bo Ra

    2016-01-01

    Background/Aims Deficiencies of 25-hydroxyvitamin D (25(OH)D) are prevalent in patients with chronic liver disease (CLD). Liver fibrosis is the main determinant of CLD prognosis. The present study was performed to evaluate the correlation between 25(OH)D levels and liver fibrosis as assessed by transient elastography (TE) in patients with compensated CLD. Methods Serum 25(OH)D levels and liver stiffness were determined in a total of 207 patients who were subjected to the following exclusion criteria: patients with decompensated CLD; patients who had malignancies; patients who were taking medications; and patients who were pregnant. Results The most common etiology was chronic hepatitis B (53.1%). Advanced liver fibrosis (defined by TE [≥9.5 kPa]) was present in 75 patients (36.2%). There was a significant correlation between 25(OH)D deficiency and liver stiffness. Based on the multivariate analysis, the following factors were independently associated with advanced liver fibrosis: 25(OH)D deficiency (odds ratio [OR], 3.46; p=0.004), diabetes mellitus (OR, 3.04; p=0.041), and fibrosis-4 index (OR, 2.01; p<0.001). Conclusions Patients with compensated CLD exhibit a close correlation between vitamin D level and liver stiffness as assessed by TE. Vitamin D deficiency was independently associated with advanced liver fibrosis. PMID:27114415

  17. Role of chemokines and their receptors in viral persistence and liver damage during chronic hepatitis C virus infection.

    PubMed

    Larrubia, Juan R; Benito-Martínez, Selma; Calvino, Miryam; Sanz-de-Villalobos, Eduardo; Parra-Cid, Trinidad

    2008-12-21

    Chemokines produced in the liver during hepatitis C virus (HCV) infection induce migration of activated T cells from the periphery to infected parenchyma. The milieu of chemokines secreted by infected hepatocytes is predominantly associated with the T-helper cell/Tc1 T cell (Th1/Tc1) response. These chemokines consist of CCL3 (macrophage inflammatory protein-1 alpha; MIP-1 alpha), CCL4 (MIP-1 beta), CCL5 (regulated on activation normal T cell expressed and secreted; RANTES), CXCL10 (interferon-gamma-inducible protein-10; IP-10), CXCL11 (interferon-inducible T-cell alpha chemoattractant; I-TAC), and CXCL9 (monokine induced by interferon gamma; Mig) and they recruit T cells expressing either CCR5 or CXCR3 chemokine receptors. Intrahepatic and peripheral blood levels of these chemokines are increased during chronic hepatitis C. The interaction between chemokines and their receptors is essential in recruiting HCV-specific T cells to control the infection. When the adaptive immune response fails in this task, non-specific T cells without the capacity to control the infection are also recruited to the liver, and these are ultimately responsible for the persistent hepatic damage. The modulation of chemokine receptor expression and chemokine secretion could be a viral escape mechanism to avoid specific T cell migration to the liver during the early phase of infection, and to maintain liver viability during the chronic phase, by impairing non-specific T cell migration. Some chemokines and their receptors correlate with liver damage, and CXCL10 (IP-10) and CXCR3 levels have shown a clinical utility as predictors of treatment response outcome. The regulation of chemokines and their receptors could be a future potential therapeutic target to decrease liver inflammation and to increase specific T cell migration to the infected liver. PMID:19084927

  18. Non-invasive assessment of liver fibrosis in chronic liver diseases: Implementation in clinical practice and decisional algorithms

    PubMed Central

    Sebastiani, Giada

    2009-01-01

    Chronic hepatitis B and C together with alcoholic and non-alcoholic fatty liver diseases represent the major causes of progressive liver disease that can eventually evolve into cirrhosis and its end-stage complications, including decompensation, bleeding and liver cancer. Formation and accumulation of fibrosis in the liver is the common pathway that leads to an evolutive liver disease. Precise definition of liver fibrosis stage is essential for management of the patient in clinical practice since the presence of bridging fibrosis represents a strong indication for antiviral therapy for chronic viral hepatitis, while cirrhosis requires a specific follow-up including screening for esophageal varices and hepatocellular carcinoma. Liver biopsy has always represented the standard of reference for assessment of hepatic fibrosis but it has some limitations being invasive, costly and prone to sampling errors. Recently, blood markers and instrumental methods have been proposed for the non-invasive assessment of liver fibrosis. However, there are still some doubts as to their implementation in clinical practice and a real consensus on how and when to use them is not still available. This is due to an unsatisfactory accuracy for some of them, and to an incomplete validation for others. Some studies suggest that performance of non-invasive methods for liver fibrosis assessment may increase when they are combined. Combination algorithms of non-invasive methods for assessing liver fibrosis may represent a rational and reliable approach to implement non-invasive assessment of liver fibrosis in clinical practice and to reduce rather than abolish liver biopsies. PMID:19437558

  19. Chronic Acetaminophen Exposure in Pediatric Acute Liver Failure

    PubMed Central

    Alonso, Estella M.; Im, Kelly; Belle, Steven H.; Squires, Robert H.

    2013-01-01

    BACKGROUND: Acetaminophen (N-acetyl-p-aminophenol [APAP]) is a widely used medication that can cause hepatotoxicity. We examined characteristics and outcomes of children with chronic exposure (CE) to APAP in the multinational Pediatric Acute Liver Failure (PALF) Study. METHODS: A total of 895 children enrolled from 2002 to 2009 were grouped by APAP exposure history as: CE (received multiple doses \\x{2265}2 days; n = 83), single dose exposure (SE; n = 85), and no exposure (NE; n = 498). CE was the reference group for pairwise comparisons. Median values are shown. RESULTS: Patients with CE compared with those with SE were younger (3.5 vs 15.2 years, P < .0001), less likely to be female (46% vs 82%, P < .0001), and more likely to be Hispanic (25% vs 7%, P = .001), but they did not differ significantly from the NE group. At enrollment, total bilirubin was lower with CE than with NE (3.2 vs 13.1 mg/dL, P < .001). Alanine aminotransferase levels were higher with CE than with NE (2384 vs 855 IU/L, P < .0001), but lower than with SE (5140 IU/L, P < .0001). Survival without liver transplantation at 21 days was worse for CE than for SE (68% vs 92%, P = .0004) but better than for NE (49%, P = .008). CONCLUSIONS: Children in the PALF study with CE had lower bilirubin and higher alanine aminotransferase than those with NE. Outcomes with CE were worse than with SE but better than with NE. Potential reasons for this outcomes advantage over non–APAP-exposed subjects should be explored. PMID:23439908

  20. The Role of Iron and Iron Overload in Chronic Liver Disease.

    PubMed

    Milic, Sandra; Mikolasevic, Ivana; Orlic, Lidija; Devcic, Edita; Starcevic-Cizmarevic, Nada; Stimac, Davor; Kapovic, Miljenko; Ristic, Smiljana

    2016-01-01

    The liver plays a major role in iron homeostasis; thus, in patients with chronic liver disease, iron regulation may be disturbed. Higher iron levels are present not only in patients with hereditary hemochromatosis, but also in those with alcoholic liver disease, nonalcoholic fatty liver disease, and hepatitis C viral infection. Chronic liver disease decreases the synthetic functions of the liver, including the production of hepcidin, a key protein in iron metabolism. Lower levels of hepcidin result in iron overload, which leads to iron deposits in the liver and higher levels of non-transferrin-bound iron in the bloodstream. Iron combined with reactive oxygen species leads to an increase in hydroxyl radicals, which are responsible for phospholipid peroxidation, oxidation of amino acid side chains, DNA strain breaks, and protein fragmentation. Iron-induced cellular damage may be prevented by regulating the production of hepcidin or by administering hepcidin agonists. Both of these methods have yielded successful results in mouse models. PMID:27332079

  1. The Role of Iron and Iron Overload in Chronic Liver Disease

    PubMed Central

    Milic, Sandra; Mikolasevic, Ivana; Orlic, Lidija; Devcic, Edita; Starcevic-Cizmarevic, Nada; Stimac, Davor; Kapovic, Miljenko; Ristic, Smiljana

    2016-01-01

    The liver plays a major role in iron homeostasis; thus, in patients with chronic liver disease, iron regulation may be disturbed. Higher iron levels are present not only in patients with hereditary hemochromatosis, but also in those with alcoholic liver disease, nonalcoholic fatty liver disease, and hepatitis C viral infection. Chronic liver disease decreases the synthetic functions of the liver, including the production of hepcidin, a key protein in iron metabolism. Lower levels of hepcidin result in iron overload, which leads to iron deposits in the liver and higher levels of non-transferrin-bound iron in the bloodstream. Iron combined with reactive oxygen species leads to an increase in hydroxyl radicals, which are responsible for phospholipid peroxidation, oxidation of amino acid side chains, DNA strain breaks, and protein fragmentation. Iron-induced cellular damage may be prevented by regulating the production of hepcidin or by administering hepcidin agonists. Both of these methods have yielded successful results in mouse models. PMID:27332079

  2. [The role of immune complexes in chronic liver diseases and their dynamics during treatment].

    PubMed

    Iakhontova, O I; Dudanova, O P

    1992-01-01

    Chronic liver diseases are marked by a well-defined relationship between the intensity of the cytolytic syndrome and the level of circulating immune complexes (CIC). The highest damaging action on hepatocytes is produced by medium-sized CIC because of their penetrating and complement fixing effects. The level of thrombocytopenia and, to a less measure, of leukopenia also depends on the concentration and size of CIC in CAH and liver cirrhosis (LC), which may provide indirect evidence of the lytic action of CIC on hepatocytes, leading in turn to the impairment of microcirculation and aggravation of hepatocyte hypoxia. The data obtained attest to the role CIC of varying size play in the pathogenesis of CAH and LC. The changes in the properties of immune complexes induced by the derangement of cellular membranes also influence the course of immune responses, favouring an increase of antibody formation. As a result of an appreciable suppression of antibody and medium-sized CIC formation enhancing the cytolytic syndrome, the preference during glucocorticoid treatment should be given to the use of the medium doses of prednisolone which ensure less intensity and less duration of cytolysis as compared to the application of large drug doses. PMID:1509358

  3. Impaired Functional Connectivity in the Prefrontal Cortex: A Mechanism for Chronic Stress-Induced Neuropsychiatric Disorders

    PubMed Central

    Negrón-Oyarzo, Ignacio; Aboitiz, Francisco; Fuentealba, Pablo

    2016-01-01

    Chronic stress-related psychiatric diseases, such as major depression, posttraumatic stress disorder, and schizophrenia, are characterized by a maladaptive organization of behavioral responses that strongly affect the well-being of patients. Current evidence suggests that a functional impairment of the prefrontal cortex (PFC) is implicated in the pathophysiology of these diseases. Therefore, chronic stress may impair PFC functions required for the adaptive orchestration of behavioral responses. In the present review, we integrate evidence obtained from cognitive neuroscience with neurophysiological research with animal models, to put forward a hypothesis that addresses stress-induced behavioral dysfunctions observed in stress-related neuropsychiatric disorders. We propose that chronic stress impairs mechanisms involved in neuronal functional connectivity in the PFC that are required for the formation of adaptive representations for the execution of adaptive behavioral responses. These considerations could be particularly relevant for understanding the pathophysiology of chronic stress-related neuropsychiatric disorders. PMID:26904302

  4. Impaired Functional Connectivity in the Prefrontal Cortex: A Mechanism for Chronic Stress-Induced Neuropsychiatric Disorders.

    PubMed

    Negrón-Oyarzo, Ignacio; Aboitiz, Francisco; Fuentealba, Pablo

    2016-01-01

    Chronic stress-related psychiatric diseases, such as major depression, posttraumatic stress disorder, and schizophrenia, are characterized by a maladaptive organization of behavioral responses that strongly affect the well-being of patients. Current evidence suggests that a functional impairment of the prefrontal cortex (PFC) is implicated in the pathophysiology of these diseases. Therefore, chronic stress may impair PFC functions required for the adaptive orchestration of behavioral responses. In the present review, we integrate evidence obtained from cognitive neuroscience with neurophysiological research with animal models, to put forward a hypothesis that addresses stress-induced behavioral dysfunctions observed in stress-related neuropsychiatric disorders. We propose that chronic stress impairs mechanisms involved in neuronal functional connectivity in the PFC that are required for the formation of adaptive representations for the execution of adaptive behavioral responses. These considerations could be particularly relevant for understanding the pathophysiology of chronic stress-related neuropsychiatric disorders. PMID:26904302

  5. [The diagnostic value of the aminophenazone breath test in chronic liver diseases].

    PubMed

    Sensing, H; Treutler, J; Haustein, K O; Hüller, G

    1991-09-01

    In 230 patients (90 females, 140 males aged between 20 and 73 years, average age 47.8 years) with and without exception histologically and/or laparoscopically ascertained chronic liver diseases (degenerative damages of liver parenchyma in 45, fatty liver stage I in 28, fatty liver stage II in 36, cholangiohepatitis in 4, chronic persisting hepatitis in 31, chronic active hepatitis in 57 and liver cirrhosis in 59 cases) the incorporation of the aminophenazon breathing test in the so-called laboratory chemical liver spectrum was controlled. The restriction of the microsomal biotransformation established by means of the aminophenazon breathing test behaved parallel to the degree of severity of the disease. The aminophenazon breathing test was performed in the modification after Haustein and Schenker (1985). The largest delays in the decomposition were found in the complete cirrhotic transformation of the liver. The unequivocally pathologic result of the aminophenazon breathing test in severe irreversible damages of the liver parenchyma was confirmed by the formation of correlations with parameters of the conventional laboratory spectrum of the liver. Thus the restriction of the performance of the synthesis of the liver for coagulation factors and albumins was parallel to the loss of function of the mixed functional oxidases. In all patients with chronic liver diseases a connection between the value of the thromboplastin time (Quick's test) and result of the breathing test was found. Positive linear correlation between serum albumin and results of the breathing test could also be proved particularly in the group of the severe chronic inflammatory liver diseases. In chronic fibrosing liver diseases there were positive inverse correlations between gamma-globulin concentration in the serum and thymol turbidity test on the one hand as well as the aminophenazon breathing test on the other. There were no correlations between liver enzyme and aminophenazon breathing test. The

  6. Portal Chronic Inflammation in Nonalcoholic Fatty Liver Disease

    PubMed Central

    Brunt, Elizabeth M.; Kleiner, David E.; Wilson, Laura A.; Unalp, Aynur; Behling, Cynthia E.; Lavine, Joel E.; Neuschwander-Tetri, Brent A.

    2009-01-01

    Untreated adult nonalcoholic fatty liver disease (NAFLD) is characterized by absent or mild portal chronic inflammation (CI); in the portal-based pediatric pattern of NAFLD, portal CI may be a predominant component. This study was undertaken to correlate clinical features with portal CI in the subjects enrolled in the NASH CRN. Methods Histology from central grading and clinical parameters temporally related to the biopsy were evaluated from 728 adults and 205 children. Results Sixty percent of adult biopsies had mild, 23% had more than mild, and 16% had no portal CI. In children, 76% had mild, 14% were more than mild, and 10% had no portal CI. In neither group were autoantibodies, elevated ALT, or generic use of “any” medications associated with the presence or degree of portal CI. Clinical features associated with “more than mild” in adults were older age (51 y v 44 y) (p<0.0001), female gender (p=0.001), higher BMI (p<0.0001), elevated insulin levels (median 20 v 14uU/ml) (p=0.001), higher HOMA-IR (median 5 v 3) (p<0.0001), and medications used for NAFLD (p=0.0004), diabetes (p<0.0001), and hypertension (p<0.0001). The same comparisons for “more than mild” v “none” in the pediatric biopsies showed only an association with younger age (12 y v 14 y) (p=0.01), but there was a trend favoring boys. There was no association with BMI, insulin or HOMA-IR. In both groups, lobular and portal inflammation scores had no association, but there was an association with a definite steatohepatitis diagnosis (p<0.0001 for both). Features in the adult biopsies associated with “more than mild” were steatosis amount (p=0.01and location (p<0.0001), presence of ballooning (p<0.0001), and advanced fibrosis (p<0.0001). In the pediatric biopsies, “more than mild” compared with “none” was associated with steatosis location (p=0.0008), and fibrosis score (p<0.0001), specifically, the pediatric (zone 1 accentuation) pattern (p<0.001) and portal

  7. Acute stress does not affect the impairing effect of chronic stress on memory retrieval

    PubMed Central

    Ozbaki, Jamile; Goudarzi, Iran; Salmani, Mahmoud Elahdadi; Rashidy-Pour, Ali

    2016-01-01

    Objective(s): Due to the prevalence and pervasiveness of stress in modern life and exposure to both chronic and acute stresses, it is not clear whether prior exposure to chronic stress can influence the impairing effects of acute stress on memory retrieval. This issue was tested in this study. Materials and Methods: Adult male Wistar rats were randomly assigned to the following groups: control, acute, chronic, and chronic + acute stress groups. The rats were trained with six trials per day for 6 consecutive days in the water maze. Following training, the rats were either kept in control conditions or exposed to chronic stress in a restrainer 6 hr/day for 21 days. On day 22, a probe test was done to measure memory retention. Time spent in target and opposite areas, platform location latency, and proximity were used as indices of memory retention. To induce acute stress, 30 min before the probe test, animals received a mild footshock. Results: Stressed animals spent significantly less time in the target quadrant and more time in the opposite quadrant than control animals. Moreover, the stressed animals showed significantly increased platform location latency and proximity as compared with control animals. No significant differences were found in these measures among stress exposure groups. Finally, both chronic and acute stress significantly increased corticosterone levels. Conclusion: Our results indicate that both chronic and acute stress impair memory retrieval similarly. Additionally, the impairing effects of chronic stress on memory retrieval were not influenced by acute stress.

  8. Preventive strategies in chronic liver disease: part I. Alcohol, vaccines, toxic medications and supplements, diet and exercise.

    PubMed

    Riley, T R; Bhatti, A M

    2001-11-01

    Chronic liver disease is the 10th leading cause of death in the United States. Hepatitis C virus infection is the most frequent cause of chronic liver disease and the most common indication for liver transplantation. Preventive care can significantly reduce the progression of liver disease. Alcohol and hepatitis C virus are synergistic in hastening the development of cirrhosis; therefore, patients with hepatitis C infection should abstain from alcohol use. Because superinfection with hepatitis A or B virus can lead to liver failure, vaccination is recommended. Potentially hepatotoxic medications should be used with caution in patients with chronic liver disease. In general, nonsteroidal anti-inflammatory drugs should be avoided; acetaminophen in a dosage below 2 g per day is the safest choice. Many herbal remedies are potentially hepatotoxic, and only milk thistle can be used safely in patients who have chronic liver disease. Weight reduction and exercise can improve liver function in patients with fatty liver. PMID:11730310

  9. Molecular changes associated with chronic liver damage and neoplastic lesions in a murine model of hereditary tyrosinemia type 1.

    PubMed

    Angileri, Francesca; Roy, Vincent; Morrow, Geneviève; Scoazec, Jean Yves; Gadot, Nicolas; Orejuela, Diana; Tanguay, Robert M

    2015-12-01

    Hereditary tyrosinemia type 1 (HT1) is the most severe inherited metabolic disease of the tyrosine catabolic pathway, with a progressive hepatic and renal injury and a fatal outcome if untreated. Toxic metabolites accumulating in HT1 have been shown to elicit endoplasmic reticulum (ER) stress response, and to induce chromosomal instability, cell cycle arrest and apoptosis perturbation. Although many studies have concentrated on elucidating these events, the molecular pathways responsible for development of hepatocellular carcinoma (HCC) still remain unclear. In this study the fah knockout murine model (fah(-/-)) was used to investigate the cellular signaling implicated in the pathogenesis of HT1. Fah(-/-) mice were subjected to drug therapy discontinuation (Nitisinone withdrawal), and livers were analyzed at different stages of the disease. Monitoring of mice revealed an increasing degeneration of the overall physiological conditions following drug withdrawal. Histological analysis unveiled diffuse hepatocellular damage, steatosis, oval-like cells proliferation and development of liver cell adenomas. Immunoblotting results revealed a progressive and chronic activation of stress pathways related to cell survival and proliferation, including several stress regulators such as Nrf2, eIF2α, CHOP, HO-1, and some members of the MAPK signaling cascade. Impairment of stress defensive mechanisms was also shown by microarray analysis in fah(-/-) mice following prolonged therapy interruption. These results suggest that a sustained activation of stress pathways in the chronic HT1 progression might play a central role in exacerbating liver degeneration. PMID:26360553

  10. Chronic non-cholestatic liver disease is not associated with an increased fracture rate in children.

    PubMed

    Konstantynowicz, Jerzy; Lebensztejn, Dariusz M; Skiba, Elzbieta; Sobaniec-Lotowska, Maria E; Abramowicz, Pawel; Piotrowska-Jastrzebska, Janina; Kaczmarski, Maciej

    2011-05-01

    Chronic liver disease in adults is a risk factor of osteoporosis, but little is known about risk of fractures in children with non-cholestatic liver disease. The aim of this study was to investigate associations among the severity of liver fibrosis, bone mass and low-energy fractures in children. History of fractures, anthropometry, and bone mass and size were examined in 39 Caucasian children (25 boys, 14 girls) aged 7.1-18 years (mean 11.9 ± 3.1) with chronic hepatitis B and liver fibrosis evidenced by liver biopsy. Severity of liver fibrosis was based on histological classification according to the method of Batts and Ludwig (mild, 1-2 scores; advanced, 3 scores) and Ishak (1-3 and 4-5 scores, respectively). Bone mineral content (BMC), density (BMD) and body composition were determined in the total body and lumbar spine using dual energy X-ray absorptiometry. Seven subjects (4 girls, 3 boys; 18% of the sample) had low BMD in the total body and lumbar spine region (Z-scores below -2.0). No associations were found among BMC, BMD, bone size and the severity of liver fibrosis. Nine boys (36% of all boys) and one girl reported repeated fractures (forearm, wrist, tibia, ankle, humerus), showing trends similar to the prevalence in general population. Fractures were neither associated with lower BMD/BMC nor with scores of liver fibrosis. Deficits in BMD in children with chronic hepatitis B are not associated with the severity of liver fibrosis. This study suggests that non-cholestatic liver disease does not increase the risk of low-energy fractures during growth. From the practical perspective, however, children with chronic liver disease should be screened for history and clinical risk factors for fractures rather than referred to bone density testing. PMID:20838830

  11. Impact of hepatic function on serum procalcitonin for the diagnosis of bacterial infections in patients with chronic liver disease: A retrospective analysis of 324 cases.

    PubMed

    Qu, Junyan; Feng, Ping; Luo, Yan; Lü, Xiaoju

    2016-07-01

    Although procalcitonin (PCT) is a valid marker for early diagnosis of bacterial infections, it is unclear whether its accuracy in predicting bacterial infections is affected by impaired liver function. This study aimed to assess the impact of compromised liver function on the diagnostic value of PCT.This retrospective study was conducted between January 2013 and May 2015. A total of 324 patients with chronic liver disease were enrolled. Routine laboratory measurements and PCT were performed. Patients were divided into 3 groups according to clinical diagnosis: chronic hepatitis (group 1), decompensated cirrhosis (group 2), and acute-on-chronic liver failure/chronic liver failure (group 3). The correlation between PCT and liver function was analyzed. The area under the receiver operating characteristic (AUCROC) curve of PCT was analyzed according to infection status and liver function.PCT was more accurate than white blood cell count (P < 0.001) and percentage of neutrophils (P < 0.001) in detecting bacterial infections in patients with impaired liver function. In patients without infection, PCT had a moderate positive correlation with serum total bilirubin (TBIL) (r = 0.592), and a weak correlation with model for end-stage liver disease score (r = 0.483) and international normalized ratio (r = 0.389). The AUCROC and optimum thresholds of PCT and for predicting bacterial infections at different levels of TBIL were 0.907 (95% CI 0.828-0.958) and 0.38 ng/mL, respectively, for TBIL <5 mg/dL, 0.927 (95% CI 0.844-0.974) and 0.54 ng/mL (5 mg/dL ≤TBIL<10 mg/dL), 0.914 (95% CI 0.820-0.968) and 0.61 ng/mL (10 mg/dL ≤TBIL<20 mg/dL), 0.906 (95% CI 0.826-0.958) and 0.94 ng/mL (TBIL ≥20 mg/dL), respectively.This study demonstrated that PCT was a valuable marker of bacterial infection in patients with chronic liver diseases. TBIL affected PCT threshold, so different cut-offs should be used according to different TBIL values. PMID

  12. Serum γ-glutamyl Transferase Levels, Insulin Resistance and Liver Fibrosis in Patients with Chronic Liver Diseases

    PubMed Central

    Petta, Salvatore; Macaluso, Fabio Salvatore; Barcellona, Maria Rosa; Cammà, Calogero; Cabibi, Daniela; Di Marco, Vito; Craxì, Antonio

    2012-01-01

    Background and Aims Serum levels of γ-glutamyl-transpeptidase(γ-GT) were associated with liver disease severity and metabolic alterations, which in turn are able to affect hepatic damage. In patients with nonalcoholic fatty liver disease (NAFLD), genotype 1 chronic hepatitis C (G1CHC) and chronic hepatitis B (CHB), we assessed the link between liver fibrosis and γ-GT serum levels, and we evaluated if normal or high γ-GT serum levels affect the association between insulin resistance (IR) and severity of liver fibrosis. Methods 843 consecutive patients with chronic liver disease (CLD)(193 NAFLD, 481 G1CHC, 169 CHB) were evaluated by liver biopsy (Kleiner and Scheuer scores) and clinical and metabolic measurements. IR was diagnosed if HOMA>3. A serum γ-GT concentration of >36 IU/L in females and >61 IU/L in males was considered the threshold value for identifying high levels of γ-GT. Results By multivariate logistic regression analysis, abnormal γ-GT serum levels were independently linked to severe liver fibrosis in patients with NAFLD (OR2.711,CI1.120–6.564,p = 0.02), G1CHC (OR3.461,CI2.138–5.603,p<0.001) and CHB (OR2.778,CI1.042–7.414,p = 0.04), together with IR and liver necroinflammation, and with a negative predictive value>80%. Interestingly, among patients with high or normal γ-GT values, even if IR prevalence was significantly higher in patients with severe fibrosis compared to those without, IR remained significantly associated with severe fibrosis in patients with abnormal γ-GT values only (OR4.150,CI1.079–15.970,p = 0.03 for NAFLD; OR2.250,CI1.211–4.181,p = 0.01 for G1CHC; OR3.096,CI2.050–34.220,p = 0.01 for CHB). Conclusions In patients with CLD, IR is independently linked to liver fibrosis only in patients with abnormal γ-GT values, without differences according to liver disease etiology, and suggesting a role of γ-GT as a marker of metabolic-induced liver damage. These data could be useful for the clinical and

  13. Evaluation of Percutaneous Liver Biopsy Complications in Patients with Chronic Viral Hepatitis

    PubMed Central

    Kose, Sukran; Ersan, Gursel; Tatar, Bengu; Adar, Pelin; Sengel, Buket Erturk

    2015-01-01

    Objective: Liver biopsy is still the gold standard for the determination of liver fibrosis and necroinflammatory activity. It is an invasive method and may lead to severe complications. The aim of this study was to determine the evaluation of percutaneous liver biopsy complications in patients with chronic viral hepatitis. Materials and Methods: 1165 patients, who were followed with the diagnosis of chronic viral hepatitis and who were applied percutaneous liver biopsy between January 2000 and February 2013 at the out-patient clinic of Infectious Diseases and Clinical Microbiology, were included in the study. Results: Of 1165 patients who underwent liver biopsy, 196 (86 male, 110 female) were diagnosed with chronic hepatitis C, 969 (559 male, 410 female) were diagnosed with chronic hepatitis B. The mean age was 43.3 and 55.4% were male. 11% of the patients were diagnosed with chronic renal failure and underwent haemodialysis. Minor complication rate was about 20% (severe pain required usage of analgesic drugs in 19.8%, abdominal pain in 22.6%) whereas major complication rate was 1.15% (pneumothorax in 0.17%, heamobilia in 0.08%, hematoma in 0.9%). We did not observe severe complications such as fever, abscess, anaphylaxis, bacteraemia, organ perforations, sepsis or death. Conclusion: Despite being an invasive procedure, percutaneous liver biopsy can be considered a safe method because of the low rates of severe complications observed in our patients. PMID:26644763

  14. Multiparametric magnetic resonance imaging predicts clinical outcomes in patients with chronic liver disease

    PubMed Central

    Pavlides, Michael; Banerjee, Rajarshi; Sellwood, Joanne; Kelly, Catherine J.; Robson, Matthew D.; Booth, Jonathan C.; Collier, Jane; Neubauer, Stefan; Barnes, Eleanor

    2016-01-01

    Background & Aims Multiparametric magnetic resonance (MR) imaging has been demonstrated to quantify hepatic fibrosis, iron, and steatosis. The aim of this study was to determine if MR can be used to predict negative clinical outcomes in liver disease patients. Methods Patients with chronic liver disease (n = 112) were recruited for MR imaging and data on the development of liver related clinical events were collected by medical records review. The median follow-up was 27 months. MR data were analysed blinded for the Liver Inflammation and Fibrosis score (LIF; <1, 1–1.99, 2–2.99, and ⩾3 representing normal, mild, moderate, and severe liver disease, respectively), T2∗ for liver iron content and proportion of liver fat. Baseline liver biopsy was performed in 102 patients. Results Liver disease aetiologies included non-alcoholic fatty liver disease (35%) and chronic viral hepatitis (30%). Histologically, fibrosis was mild in 54 (48%), moderate in 17 (15%), and severe in 31 (28%) patients. Overall mortality was 5%. Ten patients (11%) developed at least one liver related clinical event. The negative predictive value of LIF <2 was 100%. Two patients with LIF 2–2.99 and eight with LIF ⩾3 had a clinical event. Patients with LIF ⩾3 had a higher cumulative risk for developing clinical events, compared to those with LIF <1 (p = 0.02) and LIF 1–1.99 (p = 0.03). Cox regression analysis including all 3 variables (fat, iron, LIF) resulted in an enhanced LIF predictive value. Conclusions Non-invasive standardised multiparametric MR technology may be used to predict clinical outcomes in patients with chronic liver disease. PMID:26471505

  15. Vitamin A deficiency in patients with hepatitis C virus-related chronic liver disease.

    PubMed

    Peres, W A F; Chaves, G V; Gonçalves, J C S; Ramalho, A; Coelho, H S M

    2011-12-01

    Hepatitis C virus (HCV) infection is associated with oxidative stress and vitamin A possesses antioxidant activity. The objective of the present study was to investigate vitamin A nutritional status in chronic hepatitis, liver cirrhosis and hepatocellular carcinoma (HCC), according to biochemical, functional and dietetic indicators correlating these findings with liver function, liver damage and death. Vitamin A nutritional status was analysed by serum retinol levels, dietetic indicators and functional indicators. A total of 140 patients with HCV-related liver disease were enrolled. Vitamin A deficiency was detected in 54·3 % of all patients, and there was a progressive drop in serum retinol levels from chronic hepatitis C patients towards cirrhosis and HCC patients. Increased total bilirubin, liver transaminases and prothrombin time, presence of hepatic encephalopathy and ascites were related to reduced serum retinol levels, and values ≤ 0·78 μmol/l of serum retinol were associated with liver-related death. A high prevalence of inadequate intake of vitamin A was observed in all stages of chronic liver disease. The functional indicator was not an adequate parameter for evaluating the vitamin A nutritional status. Therefore, serum retinol concentration is related to severity of the disease, liver complications and mortality. The effectiveness of nutritional counselling and measures of intervention in this group in improving vitamin A nutritional status should be examined further in a controlled study. PMID:21736776

  16. [Silymarin in the treatment of chronic liver diseases: past and future].

    PubMed

    Fehér, János; Lengyel, Gabriella

    2008-12-21

    In the treatment of chronic liver diseases adequate therapy can be chosen only in the knowledge of pathogenetic processes. In the liver diseases caused by oxidative stress (alcoholic and non-alcoholic fatty liver and steatohepatitis, drug and compound induced liver toxicity) the antioxidant drugs, like silymarin, in chronic hepatitis caused by hepatitis B and hepatitis C virus, combined peginterferon and nucleosid treatments are the primary therapy modalities to be selected. The main effects of silymarin are the membrane stabilising and antioxidant effects, it is able to help the liver cell regeneration, it can decrease the inflammatory reaction and inhibit the fibrogenesis in the liver. These results have been established by experimental and clinical trials. According to open studies, the long administration of silymarin significantly increased the survival time of patients with alcohol-induced liver cirrhosis. Recently it was demonstrated that high-dosage silibinin infusion treatment could significantly decrease the number of hepatitis C viruses after four-week application. On the basis of the results with the methods of molecular biology, silymarin is able to decrease significantly tumor cell proliferation, angiogenesis as well as insulin resistance. These results support the administration of silymarin preparations in the therapy of chronic liver diseases, especially in alcoholic and non-alcoholic steatohepatitis in current clinical practice, and as it can be awaited, also in the future. In some neoplastic diseases they could also be administered as adjuvant therapy. PMID:19073452

  17. Current Status of Herbal Medicines in Chronic Liver Disease Therapy: The Biological Effects, Molecular Targets and Future Prospects

    PubMed Central

    Hong, Ming; Li, Sha; Tan, Hor Yue; Wang, Ning; Tsao, Sai-Wah; Feng, Yibin

    2015-01-01

    Chronic liver dysfunction or injury is a serious health problem worldwide. Chronic liver disease involves a wide range of liver pathologies that include fatty liver, hepatitis, fibrosis, cirrhosis, and hepatocellular carcinoma. The efficiency of current synthetic agents in treating chronic liver disease is not satisfactory and they have undesirable side effects. Thereby, numerous medicinal herbs and phytochemicals have been investigated as complementary and alternative treatments for chronic liver diseases. Since some herbal products have already been used for the management of liver diseases in some countries or regions, a systematic review on these herbal medicines for chronic liver disease is urgently needed. Herein, we conducted a review describing the potential role, pharmacological studies and molecular mechanisms of several commonly used medicinal herbs and phytochemicals for chronic liver diseases treatment. Their potential toxicity and side effects were also discussed. Several herbal formulae and their biological effects in chronic liver disease treatment as well as the underlying molecular mechanisms are also summarized in this paper. This review article is a comprehensive and systematic analysis of our current knowledge of the conventional medicinal herbs and phytochemicals in treating chronic liver diseases and on the potential pitfalls which need to be addressed in future study. PMID:26633388

  18. Loss of Survivin influences liver regeneration and is associated with impaired Aurora B function

    PubMed Central

    Hagemann, S; Wohlschlaeger, J; Bertram, S; Levkau, B; Musacchio, A; Conway, E M; Moellmann, D; Kneiseler, G; Pless-Petig, G; Lorenz, K; Sitek, B; Baba, H A

    2013-01-01

    The chromosomal passenger complex (CPC) acts as a key regulator of mitosis, preventing asymmetric segregation of chromosomal material into daughter cells. The CPC is composed of three non-enzymatic components termed Survivin, the inner centromere protein (INCENP) and Borealin, and an enzymatic component, Aurora B kinase. Survivin is necessary for the appropriate separation of sister chromatids during mitosis and is involved in liver regeneration, but its role in regenerative processes is incompletely elucidated. Whether Survivin, which is classified as an inhibitor of apoptosis protein (IAP) based on domain composition, also has a role in apoptosis is controversial. The present study examined the in vivo effects of Survivin ablation in the liver and during liver regeneration after 70% hepatectomy in a hepatocyte-specific knockout mouse model. The absence of Survivin caused a reduction in the number of hepatocytes in the liver, together with an increase in cell volume, macronucleation and polyploidy, but no changes in apoptosis. During liver regeneration, mitosis of hepatocytes was associated with mislocalization of the members of the CPC, which were no longer detectable at the centromere despite an unchanged protein amount. Furthermore, the loss of survivin in regenerating hepatocytes was associated with reduced levels of phosphorylated Histone H3 at serine 28 and abolished phosphorylation of CENP-A and Hec1 at serine 55, which is a consequence of decreased Aurora B kinase activity. These data indicate that Survivin expression determines hepatocyte number during liver development and liver regeneration. Lack of Survivin causes mislocalization of the CPC members in combination with reduced Aurora B activity, leading to impaired phosphorylation of its centromeric target proteins and inappropriate cytokinesis. PMID:23519077

  19. Increased hepatic receptor interacting protein kinase 3 expression due to impaired proteasomal functions contributes to alcohol-induced steatosis and liver injury

    PubMed Central

    Wang, Shaogui; Ni, Hong-Min; Dorko, Kenneth; Kumer, Sean C.; Schmitt, Timothy M.; Nawabi, Atta; Komatsu, Masaaki; Huang, Heqing; Ding, Wen-Xing

    2016-01-01

    Chronic alcohol exposure increased hepatic receptor-interacting protein kinase (RIP) 3 expression and necroptosis in the liver but its mechanisms are unclear. In the present study, we demonstrated that chronic alcohol feeding plus binge (Gao-binge) increased RIP3 but not RIP1 protein levels in mouse livers. RIP3 knockout mice had decreased serum alanine amino transferase activity and hepatic steatosis but had no effect on hepatic neutrophil infiltration compared with wild type mice after Gao-binge alcohol treatment. The hepatic mRNA levels of RIP3 did not change between Gao-binge and control mice, suggesting that alcohol-induced hepatic RIP3 proteins are regulated at the posttranslational level. We found that Gao-binge treatment decreased the levels of proteasome subunit alpha type-2 (PSMA2) and proteasome 26S subunit, ATPase 1 (PSMC1) and impaired hepatic proteasome function. Pharmacological or genetic inhibition of proteasome resulted in the accumulation of RIP3 in mouse livers. More importantly, human alcoholics had decreased expression of PSMA2 and PSMC1 but increased protein levels of RIP3 compared with healthy human livers. Moreover, pharmacological inhibition of RIP1 decreased Gao-binge-induced hepatic inflammation, neutrophil infiltration and NF-κB subunit (p65) nuclear translocation but failed to protect against steatosis and liver injury induced by Gao-binge alcohol. In conclusion, results from this study suggest that impaired hepatic proteasome function by alcohol exposure may contribute to hepatic accumulation of RIP3 resulting in necroptosis and steatosis while RIP1 kinase activity is important for alcohol-induced inflammation. PMID:26769846

  20. Replicative senescence in normal liver, chronic hepatitis C, and hepatocellular carcinomas.

    PubMed

    Paradis, V; Youssef, N; Dargère, D; Bâ, N; Bonvoust, F; Deschatrette, J; Bedossa, P

    2001-03-01

    There is growing evidence that senescent cells accumulate in vivo and are associated with the aging process in parallel with the progressive erosion of telomeres. Because recent data show that telomere shortening is involved in the pathogenesis of liver cirrhosis, we looked for replicative senescence cells in normal livers, chronic hepatitis C, and hepatocellular carcinoma (HCC). Replicative senescent cells were detected on liver tissue cryosections using expression of a specific marker, senescence-associated beta-galactosidase, a cytoplasmic enzyme detected at pH 6. A total of 57 frozen liver samples (15 normal liver, 32 chronic hepatitis C, and 10 HCCs) were studied. Replicative senescence was graded as absent in 56% of cases (32 of 57) and present in 44% (25 of 57). Replicative senescence was considered present in 3 of 15 normal livers (20%), 16 of 32 chronic hepatitis cases (50%), and 6 of 10 HCCs (60%). In the group of nontumoral livers, the presence of senescent cells in liver was associated with older age (P =.03). In the group with chronic hepatitis C, fibrosis stage, but not activity grade, was significantly correlated with the accumulation of replicative senescent cells (P <.001). Finally, beta-Gal staining in nontumoral tissue was strongly correlated with the presence of HCC in the surrounding liver (P <.001). These results suggest that chronic hepatitis C represents a relevant model of accelerated replicative senescence and that accumulation of replicative senescent cells predispose to HCC development. Detection of replicative senescent cells may then serve as a predictive marker of a hepatocellular carcinoma in the surrounding tissue. HUM PATHOL 32:327-332. PMID:11274643

  1. Noninvasive models for assessment of liver fibrosis in patients with chronic hepatitis B virus infection.

    PubMed

    Zeng, Da-Wu; Dong, Jing; Liu, Yu-Rui; Jiang, Jia-Ji; Zhu, Yue-Yong

    2016-08-01

    There are approximately 240 million patients with chronic hepatitis B virus (HBV) infection worldwide. Up to 40% of HBV-infected patients can progress to liver cirrhosis, hepatocellular carcinoma or chronic end-stage liver disease during their lifetime. This, in turn, is responsible for around 650000 deaths annually worldwide. Repeated hepatitis flares may increase the progression of liver fibrosis, making the accurate diagnosis of the stage of liver fibrosis critical in order to make antiviral therapeutic decisions for HBV-infected patients. Liver biopsy remains the "gold standard" for diagnosing liver fibrosis. However, this technique has recently been challenged by the development of several novel noninvasive tests to evaluate liver fibrosis, including serum markers, combined models and imaging techniques. In addition, the cost and accessibility of imaging techniques have been suggested as additional limitations for invasive assessment of liver fibrosis in developing countries. Therefore, a noninvasive assessment model has been suggested to evaluate liver fibrosis, specifically in HBV-infected patients, owing to its high applicability, inter-laboratory reproducibility, wide availability for repeated assays and reasonable cost. The current review aims to present the status of knowledge in this new and exciting field, and to highlight the key points in HBV-infected patients for clinicians. PMID:27547009

  2. Noninvasive models for assessment of liver fibrosis in patients with chronic hepatitis B virus infection

    PubMed Central

    Zeng, Da-Wu; Dong, Jing; Liu, Yu-Rui; Jiang, Jia-Ji; Zhu, Yue-Yong

    2016-01-01

    There are approximately 240 million patients with chronic hepatitis B virus (HBV) infection worldwide. Up to 40% of HBV-infected patients can progress to liver cirrhosis, hepatocellular carcinoma or chronic end-stage liver disease during their lifetime. This, in turn, is responsible for around 650000 deaths annually worldwide. Repeated hepatitis flares may increase the progression of liver fibrosis, making the accurate diagnosis of the stage of liver fibrosis critical in order to make antiviral therapeutic decisions for HBV-infected patients. Liver biopsy remains the “gold standard” for diagnosing liver fibrosis. However, this technique has recently been challenged by the development of several novel noninvasive tests to evaluate liver fibrosis, including serum markers, combined models and imaging techniques. In addition, the cost and accessibility of imaging techniques have been suggested as additional limitations for invasive assessment of liver fibrosis in developing countries. Therefore, a noninvasive assessment model has been suggested to evaluate liver fibrosis, specifically in HBV-infected patients, owing to its high applicability, inter-laboratory reproducibility, wide availability for repeated assays and reasonable cost. The current review aims to present the status of knowledge in this new and exciting field, and to highlight the key points in HBV-infected patients for clinicians. PMID:27547009

  3. Impaired homocysteine metabolism in patients with alcoholic liver disease in Taiwan.

    PubMed

    Chien, Yi-Wen; Chen, Ya-Ling; Peng, Hsiang-Chi; Hu, Jui-Ting; Yang, Sien-Sing; Yang, Suh-Ching

    2016-08-01

    Impaired homocysteine metabolism plays an important role in alcoholic liver disease (ALD); however, there are limited data about its relationship with the risk and severity of patients with ALD in Taiwan. To understand plasma homocysteine and related vitamin concentrations in patients with ALD in Taiwan, we recruited 50 male patients with ALD from Cathay General Hospital, with 49 age-and gender-matched healthy adults as the control group. The Institutional Review Board for Human Studies approved the study, and informed consent was obtained from all patients prior to blood collection. Significantly higher plasma homocysteine concentrations but lower folate concentrations were obtained from patients with ALD. In addition, patients with ALD showed a significant lower erythrocyte reduced glutathione (GSH)/oxidized glutathione (GSSG) ratio but higher plasma thiobarbituric acid-reactive substance (TBARS) concentration, which indicated that oxidative stress was occurring in patients with ALD. A negative correlation between plasma folate and homocysteine was observed in all subjects. There was also a negative correlation between plasma homocysteine and the erythrocyte GSH/GSSG ratio which indicated impaired homocysteine metabolism may have disrupted the antioxidative status. In addition, patients in Child-Pugh Class B and C showed higher plasma vitamin B12 concentrations than did patients without cirrhosis and patients in Child-Pugh Class A. These findings show that impaired homocysteine metabolism was observed in patients with ALD in Taiwan. In addition, the plasma vitamin B12 concentration may reflect the degree of liver injury. PMID:27565754

  4. Associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) procedure for hepatocellular carcinoma with chronic liver disease: a case report and review of literature.

    PubMed

    Papamichail, Michail; Pizanias, Michail; Yip, Vincent; Prassas, Evangellos; Prachalias, Andreas; Quaglia, Alberto; Peddu, Praveen; Heaton, Nigel; Srinivasan, Parthi

    2016-05-01

    The incidence of complications after liver resection is closely related to functional future liver remnant (FLR). The standard approach to augment FLR is surgical or radiological occlusion of the artery or portal vein on the tumor side. Associated liver partition and portal vein ligation for staged hepatectomy (ALLPS) has been introduced as an alternative method to augment FLR. It offers rapid and effective hypertrophy for resecting liver metastases. However, data regarding its application in patients with hepatocellular carcinoma (HCC) with a background of chronic liver disease are limited. Here we describe the use of ALPPS procedure to manage a large solitary HCC with a background of chronic liver disease. The rising incidence of HCC has increased the number of surgical resections in patients with advanced stage liver disease not considered for liver transplantation. We reviewed reported experience of ALPPS in established chronic liver disease and current therapeutic modalities for HCC on a background of chronic liver disease in patients with potential liver insufficiency where tumor burden is beyond liver transplant criteria. PMID:27212995

  5. Associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) procedure for hepatocellular carcinoma with chronic liver disease: a case report and review of literature

    PubMed Central

    Pizanias, Michail; Yip, Vincent; Prassas, Evangellos; Prachalias, Andreas; Quaglia, Alberto; Peddu, Praveen; Heaton, Nigel; Srinivasan, Parthi

    2016-01-01

    The incidence of complications after liver resection is closely related to functional future liver remnant (FLR). The standard approach to augment FLR is surgical or radiological occlusion of the artery or portal vein on the tumor side. Associated liver partition and portal vein ligation for staged hepatectomy (ALLPS) has been introduced as an alternative method to augment FLR. It offers rapid and effective hypertrophy for resecting liver metastases. However, data regarding its application in patients with hepatocellular carcinoma (HCC) with a background of chronic liver disease are limited. Here we describe the use of ALPPS procedure to manage a large solitary HCC with a background of chronic liver disease. The rising incidence of HCC has increased the number of surgical resections in patients with advanced stage liver disease not considered for liver transplantation. We reviewed reported experience of ALPPS in established chronic liver disease and current therapeutic modalities for HCC on a background of chronic liver disease in patients with potential liver insufficiency where tumor burden is beyond liver transplant criteria. PMID:27212995

  6. Cardiac hemodynamics in alcoholic patients with chronic liver disease and a presystolic gallop

    PubMed Central

    Gould, Lawrence; Shariff, Mahmood; Zahir, Mohammad; Lieto, Mary Di

    1969-01-01

    10 male subjects with chronic liver disease and with normal cardiovascular findings, except for the presence of a presystolic gallop, underwent right and left heart catheterization. In general, all of the patients had a high resting cardiac output, narrow arteriovenous oxygen difference, a low peripheral vascular resistance, and normal left ventricular end-diastolic pressures and volumes. The plasma volume was increased in the seven patients in which it was determined. On exercise, all of the patients demonstrated a significant increase in the left ventricular end-diastolic pressure and mean pulmonary artery pressure, while the stroke index remained the same or fell in seven of the subjects. It appears logical to assume that the excessive intake of alcohol is associated with an impairment in the metabolic and contractile properties of the left ventricle and the resultant hemodynamic effects may not be readily discerned in the resting state. However, upon exercise these patients, with a congested circulation, can show abnormal cardiac dynamics. Images PMID:4180971

  7. Trace element analysis by PIXE in liver samples from dogs with chronic active hepatitis and liver cirrhosis

    NASA Astrophysics Data System (ADS)

    Andersson, Marianne; Ekholm, Ann-Kristin; Sevelius, Ewa

    1990-04-01

    Trace element levels of liver samples obtained from necropsied dogs suffering from hepatitis and/or liver cirrhosis were determined by PIXE. Two different techniques for preparation of the samples were compared: the pellet press method and wet digestion. Both methods gave similar results, but the pellet press method was chosen for the subsequent routine analyses because of its simplicity due to few preparation steps and little risk of contamination. Preliminary results indicate elevated levels of Cu in chronic hepatitis and cirrhosis. In hereditary copper-induced hepatitis (Bedlington hepatitis) Fe and Br levels were increased as well.

  8. Defining acute-on-chronic liver failure: East, West or Middle ground?

    PubMed

    Singh, Harneet; Pai, C Ganesh

    2015-11-01

    Acute-on-chronic liver failure (ACLF), a newly recognized clinical entity seen in hospitalized patients with chronic liver disease including cirrhosis, is associated with high short- and medium term morbidity and mortality. None of the definitions of ACLF proposed so far have been universally accepted, the two most commonly used being those proposed by the Asia-Pacific Association for the Study of Liver (APASL) and the European Association for the Study of Liver - Chronic Liver Failure (EASL-CLIF) consortium. On paper both definitions and diagnostic criteria appear to be different from each other, reflecting the differences in cut-off values for individual parameters used in diagnosis, the acute insult or precipitating event and the underlying chronic liver disease. Data directly comparing these two criteria are limited, and available studies reveal different outcomes when the two are applied to the same set of patients. However a review of the literature suggests that both definitions do not seem to identify the same set of patients. The definition given by the APASL consortium is easier to apply in day-to-day practice but the EASL-CLIF criteria appear to better predict mortality in ACLF. The World Gastroenterology Organization working party have proposed a working definition of ACLF which will identify patients from whom relevant data can be collected so that the similarities and the differences between the two regions, if any, can be clearly defined. PMID:26557949

  9. Fibroscan improves the diagnosis sensitivity of liver fibrosis in patients with chronic hepatitis B

    PubMed Central

    HUANG, RENGANG; JIANG, NAN; YANG, RENGUO; GENG, XIAOXIA; LIN, JIANMEI; XU, GANG; LIU, DANDAN; CHEN, JIDOG; ZHOU, GUO; WANG, SHUQIANG; LUO, TINGTING; WU, JIAZHEN; LIU, XIAOSHU; XU, KAIJU; YANG, XINGXIANG

    2016-01-01

    The aim of the present study was to investigate the diagnostic accuracy of Fibroscan for liver fibrosis in patients with chronic hepatitis B (CHB) with alanine aminotransferase (ALT) levels <2 times the upper normal limit. A total of 263 consecutive patients with CHB and ALT levels <2 times the upper normal limit were enrolled in the present study. Liver biopsies and liver stiffness measurements (LSM) were conducted. Receiver operating characteristic (ROC) analysis was used to determine the predictive ability of LSM for the development of liver fibrosis in patients with stage S1, S2 and S3 liver fibrosis. Bivariate Spearman rank correlation analysis was performed in order to determine the association between liver stiffness value, which was measured by Fibroscan, and liver fibrosis stage, which was measured by liver biopsy. The liver stiffness value was found to be positively correlated with the liver fibrosis stage (r=0.522, P<0.001) and necroinflammatory activity (r=0.461, P<0.001), which was measured by liver biopsy. The optimal cut-off value in the patients with stage S1, S2 and S3 liver fibrosis was 5.5, 8.0 and 10.95 kPa, respectively. The area under the ROC curve for the prediction of the development of liver fibrosis in these patients was 0.696, 0.911 and 0.923, respectively. The threshold of the optimal cut-off value exhibited a high sensitivity and specificity. The results of the present study suggested that Fibroscan may improve the sensitivity of the diagnosis of liver fibrosis in patients with CHB and ALT levels <2 times the upper normal limit, and that this sensitivity may increase with the progression of liver fibrosis. PMID:27168788

  10. Non invasive assessment of liver fibrosis in chronic hemodialysis patients with viral hepatitis C.

    PubMed

    Arrayhani, Mohamed; Sqalli, Tarik; Tazi, Nada; El Youbi, Randa; Chaouch, Safae; Aqodad, Nourdin; Ibrahimi, Sidi Adil

    2015-01-01

    The liver biopsy has long been the "gold standard" for assessing liver fibrosis in patients with hepatitis C. It's an invasive procedure which is associated with an elevated bleeding, especially in chronic hemodialysis patients. Main goal is to assess liver fibrosis in chronic hemodialysis with HCV by Fibroscan and by biological scores (APRI, Forns and Fib-4), and to measure the correlation between these tests. Cross-sectional study including all chronic hemodialysis patients with hepatitis C virus, in two public hemodialysis centers of Fez. All patients were evaluated for liver fibrosis using noninvasive methods (FibroScan and laboratory tests). Subsequently, the correlation between different tests has been measured. 95 chronic hemodialysis were studied, twenty nine patients (30.5%) with chronic hepatitis C. The average age was 52.38 ± 16.8 years. Nine liver fibrosis cases have been concluded by forns score. Fibroscan has objectified significant fibrosis in 6 cases. On the other side APRI has objectified sgnifivant fibrosis only in 3 cases. The Fib-4 showed severe fibrosis in five cases. The results have been most consistent between APRI and Fib-4, followed by Fibroscan and Forns, then APRI and FibroScan. PMID:26958136

  11. The role of lifestyle changes in the management of chronic liver disease

    PubMed Central

    2011-01-01

    The prevalence of obesity worldwide has dramatically increased during the last three decades. With obesity comes a variety of adverse health outcomes which are grouped under the umbrella of metabolic syndrome. The liver in particular seems to be significantly impacted by fat deposition in the presence of obesity. In this article we discuss several liver conditions which are directly affected by overweight and obese status, including non-alcoholic fatty liver disease, chronic infection with hepatitis C virus and post-liver transplant status. The deleterious effects of obesity on liver disease and overall health can be significantly impacted by a culture that fosters sustained nutritional improvement and regular physical activity. Here we summarize the current evidence supporting non-pharmacological, lifestyle interventions that lead to weight reduction, improved physical activity and better nutrition as part of the management and treatment of these liver conditions. PMID:21645344

  12. The role of lifestyle changes in the management of chronic liver disease.

    PubMed

    Nobili, Valerio; Carter-Kent, Christine; Feldstein, Ariel E

    2011-01-01

    The prevalence of obesity worldwide has dramatically increased during the last three decades. With obesity comes a variety of adverse health outcomes which are grouped under the umbrella of metabolic syndrome. The liver in particular seems to be significantly impacted by fat deposition in the presence of obesity. In this article we discuss several liver conditions which are directly affected by overweight and obese status, including non-alcoholic fatty liver disease, chronic infection with hepatitis C virus and post-liver transplant status. The deleterious effects of obesity on liver disease and overall health can be significantly impacted by a culture that fosters sustained nutritional improvement and regular physical activity. Here we summarize the current evidence supporting non-pharmacological, lifestyle interventions that lead to weight reduction, improved physical activity and better nutrition as part of the management and treatment of these liver conditions. PMID:21645344

  13. Non-invasive diagnosis of liver fibrosis in chronic hepatitis C

    PubMed Central

    Schiavon, Leonardo de Lucca; Narciso-Schiavon, Janaína Luz; de Carvalho-Filho, Roberto José

    2014-01-01

    Assessment of liver fibrosis in chronic hepatitis C virus (HCV) infection is considered a relevant part of patient care and key for decision making. Although liver biopsy has been considered the gold standard for staging liver fibrosis, it is an invasive technique and subject to sampling errors and significant intra- and inter-observer variability. Over the last decade, several noninvasive markers were proposed for liver fibrosis diagnosis in chronic HCV infection, with variable performance. Besides the clear advantage of being noninvasive, a more objective interpretation of test results may overcome the mentioned intra- and inter-observer variability of liver biopsy. In addition, these tests can theoretically offer a more accurate view of fibrogenic events occurring in the entire liver with the advantage of providing frequent fibrosis evaluation without additional risk. However, in general, these tests show low accuracy in discriminating between intermediate stages of fibrosis and may be influenced by several hepatic and extra-hepatic conditions. These methods are either serum markers (usually combined in a mathematical model) or imaging modalities that can be used separately or combined in algorithms to improve accuracy. In this review we will discuss the different noninvasive methods that are currently available for the evaluation of liver fibrosis in chronic hepatitis C, their advantages, limitations and application in clinical practice. PMID:24659877

  14. Chronic ethanol inhibits receptor-stimulated phosphoinositide hydrolysis in rat liver slices

    SciTech Connect

    Gonzales, R.A.; Crews, F.T. )

    1991-03-01

    The effects of chronic ethanol feeding on norepinephrine (NE)- and arginine-vasopressin (AVP)-stimulated phosphoinositide (PI) hydrolysis in rat liver slices was determined. The maximum NE-stimulated PI response was significantly reduced by 40% in liver slices from 8-month-old rats which had been treated for 5 months with a liquid diet containing ethanol compared to pair-fed controls. The maximum AVP-stimulated PI response was decreased by 39% in liver slices from the ethanol-fed rats compared to control. EC50 values for NE- and AVP-stimulated PI hydrolysis in liver slices were not affected by the chronic ethanol treatment. Similar reductions in the maximal NE- and AVP-stimulated PI hydrolysis (28% and 27%, respectively) were found in 22-month-old rats which had been maintained on an ethanol containing diet for 5 months compared to pair-fed controls. The binding of (3H)prazosin and (3H)AVP to liver plasma membranes from 8-month-old ethanol-fed rats was not significantly different from binding to liver membranes from sucrose-fed controls. Our data suggest that chronic ethanol ingestion may lead to a reduction in PI-linked signal transduction in liver.

  15. Non-invasive diagnosis of liver fibrosis in chronic hepatitis C.

    PubMed

    Schiavon, Leonardo de Lucca; Narciso-Schiavon, Janaína Luz; de Carvalho-Filho, Roberto José

    2014-03-21

    Assessment of liver fibrosis in chronic hepatitis C virus (HCV) infection is considered a relevant part of patient care and key for decision making. Although liver biopsy has been considered the gold standard for staging liver fibrosis, it is an invasive technique and subject to sampling errors and significant intra- and inter-observer variability. Over the last decade, several noninvasive markers were proposed for liver fibrosis diagnosis in chronic HCV infection, with variable performance. Besides the clear advantage of being noninvasive, a more objective interpretation of test results may overcome the mentioned intra- and inter-observer variability of liver biopsy. In addition, these tests can theoretically offer a more accurate view of fibrogenic events occurring in the entire liver with the advantage of providing frequent fibrosis evaluation without additional risk. However, in general, these tests show low accuracy in discriminating between intermediate stages of fibrosis and may be influenced by several hepatic and extra-hepatic conditions. These methods are either serum markers (usually combined in a mathematical model) or imaging modalities that can be used separately or combined in algorithms to improve accuracy. In this review we will discuss the different noninvasive methods that are currently available for the evaluation of liver fibrosis in chronic hepatitis C, their advantages, limitations and application in clinical practice. PMID:24659877

  16. Chlordecone potentiates hepatic fibrosis in chronic liver injury induced by carbon tetrachloride in mice.

    PubMed

    Tabet, Elise; Genet, Valentine; Tiaho, François; Lucas-Clerc, Catherine; Gelu-Simeon, Moana; Piquet-Pellorce, Claire; Samson, Michel

    2016-07-25

    Chronic liver damage due to viral or chemical agents leads to a repair process resulting in hepatic fibrosis. Fibrosis may lead to cirrhosis, which may progress to liver cancer or a loss of liver function, with an associated risk of liver failure and death. Chlordecone is a chlorinated pesticide used in the 1990s. It is not itself hepatotoxic, but its metabolism in the liver triggers hepatomegaly and potentiates hepatotoxic agents. Chlordecone is now banned, but it persists in soil and water, resulting in an ongoing public health problem in the Caribbean area. We assessed the probable impact of chlordecone on the progression of liver fibrosis in the population of contaminated areas, by developing a mouse model of chronic co-exposure to chlordecone and a hepatotoxic agent, carbon tetrachloride (CCl4). After repeated administrations of chlordecone and CCl4 by gavage over a 12-week period, we checked for liver damage in the exposed mice, by determining serum liver transaminase (AST, ALT) levels, histological examinations of the liver and measuring the expression of genes encoding extracellular matrix components. The co-exposure of mice to CCl4 and chlordecone resulted in significant increases in ALT and AST levels. Chlordecone also increased expression of the Col1A2, MMP-2, TIMP-1 and PAI-1 genes in CCl4-treated mice. Finally, we demonstrated, by quantifying areas of collagen deposition and alpha-SMA gene expression, that chlordecone potentiated the hepatic fibrosis induced by CCl4. In conclusion, our data suggest that chlordecone potentiates hepatic fibrosis in mice with CCl4-induced chronic liver injury. PMID:26853152

  17. Complete and rapid response to FOLFIRI plus bevacizumab in a patient presenting with impaired liver function and poor performance status from colon cancer liver metastases.

    PubMed

    Belda-Iniesta, Cristóbal; Sáenz, Enrique Casado; de Castro-Carpeño, Javier; Hernández, Elena; Barón, Manuel González

    2009-04-01

    Impaired liver function is a final complication of hepatic metastases from colon cancer. This disease status is of critical importance at first clinical presentation because of the tight therapeutic window for chemotherapy. A rapid response to treatment is required as other means of supportive care for hepatic function are limited. New targeted therapies including monoclonal antibodies directed against several proteins with key roles in colon cancer biology are now available, allowing new treatment options for this group of patients. Here, we present a patient with highly impaired liver function secondary to hepatic metastases from colon cancer that showed clinical and radiological improvement after systemic treatment including bevacizumab. PMID:19352108

  18. Metformin Eased Cognitive Impairment Induced by Chronic L-methionine Administration: Potential Role of Oxidative Stress

    PubMed Central

    Alzoubi, Karem. H; Khabour, Omar. F; Al-azzam, Sayer I; Tashtoush, Murad H; Mhaidat, Nizar M

    2014-01-01

    Chronic administration of L-methionine leads to memory impairment, which is attributed to increase in the level of oxidative stress in the brain. On the other hand, metformin is a commonly used antidiabetic drug with strong antioxidant properties. In the current study, we tested if chronic metformin administration prevents memory impairment induced by administration of L-methionine. In addition, a number of molecules related to the action of metformin on cognitive functions were examined. Both metformin and L-methionine were administered to animals by oral gavage. Testing of spatial learning and memory was carried out using radial arm water maze (RAWM). Additionally, hippocampal levels or activities of catalase, thiobarbituric acid reactive substances (TBARs), glutathione peroxidase (GPx), glutathione (GSH), oxidized glutathione (GSSG) and GSH/GSSG ratio were determined. Results showed that chronic L-methionine administration resulted in both short- and long- term memory impairment, whereas metformin treatment prevented such effect. Additionally, L-methionine treatment induced significant elevation in GSSG and TBARs, along with reduction in GSH/GSSG ratio and activities of catalase, and GPx. These effects were shown to be restored by metformin treatment. In conclusion, L-methionine induced memory impairment, and treatment with metformin prevented this impairment probably by normalizing oxidative stress in the hippocampus. PMID:24669211

  19. Cell-based therapy for acute and chronic liver failures: Distinct diseases, different choices

    PubMed Central

    Sun, Kai; Xie, Xuqin; Xie, Jing; Jiao, Shufan; Chen, Xiaojing; Zhao, Xue; Wang, Xin; Wei, Lixin

    2014-01-01

    Cell-based therapies (CBTs) are considered the effective approaches to treat liver failure. However, which cell type is the most suitable source of CBTs for acute liver failure (ALF) or chronic liver failure (CLF) remains unclear. To investigate this, mature hepatocytes in adult liver (adult HCs), fetal liver cells (FLCs), induced hepatic stem cells (iHepSCs) and bone marrow derived mesenchymal stromal cells (BMSCs) were used to CBTs for ConA-induced ALF and Fah-deficient induced CLF in mice. The results showed that only BMSCs remitted liver damage and rescued ALF in ConA-treated mice. In this process, BMSCs inhibited ConA-induced inflammatory response by decreasing the mRNA expressions of TNF-α, IFN-γ and FasL and increasing IL-10 mRNA expression. However, in the CLF model, not BMSCs but adult HCs transplantation lessened liver injury, recovered liver function and rescued the life of Fah-/- mice after NTBC withdrawal. Further study showed that adult HCs offered more effective liver regeneration compared to other cells in Fah-/- mice without NTBC. These results demonstrated that BMSCs and adult HCs are the optimal sources of CBTs for ConA-induced ALF and Fah-deficient induced CLF in mice, respectively. This finding deepens our understanding about how to select a proper CBT for different liver failure. PMID:25263068

  20. Association of serum α-tocopherol, β-carotene, and retinol with liver cancer incidence and chronic liver disease mortality

    PubMed Central

    Lai, G Y; Weinstein, S J; Albanes, D; Taylor, P R; Virtamo, J; McGlynn, K A; Freedman, N D

    2014-01-01

    Background: Micronutrients may influence the development or progression of liver cancer and liver disease. We evaluated the association of serum α-tocopherol, β-carotene, and retinol with incident liver cancer and chronic liver disease (CLD) mortality in a prospective cohort of middle-aged Finnish male smokers. Methods: Baseline and 3-year follow-up serum were available from 29 046 and 22 805 men, respectively. After 24 years of follow-up, 208 men were diagnosed with liver cancer and 237 died from CLD. Hazards ratios and 95% confidence intervals were calculated for highest vs lowest quartiles from multivariate proportional hazards models. Results: Higher β-carotene and retinol levels were associated with less liver cancer (β-carotene: 0.35, 0.22–0.55, P-trend <0.0001; retinol: 0.58, 0.39–0.85, P-trend=0.0009) and CLD mortality (β-carotene: 0.47, 0.30–0.75, P-trend=0.001; retinol: 0.55, 0.38–0.78, P-trend=0.0007). α-Tocopherol was associated with CLD mortality (0.63, 0.40–0.99, P-trend=0.06), but not with liver cancer (1.06, 0.64–1.74, P-trend=0.77). Participants with higher levels of β-carotene and retinol, but not α-tocopherol, at both baseline and year 3 had lower risk of each outcome than those with lower levels. Conclusions: Our findings suggest that higher concentrations of β-carotene and retinol are associated with incident liver cancer and CLD. However, such data do not indicate that supplementation should be considered for these diseases. PMID:25314058

  1. [THE MODERN CONCEPTS OF HEMOSTASIS SYSTEM UNDER CHRONIC DISEASES OF LIVER: THE PUBLICATIONS REVIEW].

    PubMed

    Batirova, A S; Bakanov, M I; Surkov, A N

    2015-08-01

    The disorder of system of hemostasis under chronic diseases of liver results in coagulation imbalance affecting both primary and secondary hemostasis. The shifting of hemostasis balance beyond the limits of physiological standards in such patients can result either in bleeding or thrombosis. For a long time already it is considered that in patients with chronic diseases of liver alterations in hemostasis system and occurrence of bleeding are very often interrelated. However results of such screening coagulation tests as prothrombin time and activated partial thromboplastin time poorly correlate with onset and duration of bleeding, for example after liver biopsy and also with occurrence of gastro-intestinal bleeding in patients with terminal stage of diseases of liver The foreign publications of last decade contest concept of cause and effect relationship between changes of indicators of screening coagulation tests and risk of development of bleeding in patients with chronic diseases of liver The publications also dispute both usefulness of the given tests in evaluation of hemorrhages and expediency of therapeutic strategies in the case of correction of anomalous results of mentioned tests. This issue in patients with rare diseases is factually unexplored. For example, there are single publications concerning patients with glycogenous disease type. The bleeding in such patients begin in early childhood They are related to dysfunction of thrombocytes and decreasing of particular oligomers of von Willebrand factor Hence, disorders in various chains of hemostasis system in patients with chronic diseases of liver are characterized by many unresolved issues that hinder furthering of development of diagnostic biomarkers. At that, diagnostic of coagulopathies and correction of pathological conditions in such patients the new tests are to be developed to monitor states of hemostasis system in patients with chronic diseases of liver, rare nosologic forms included. PMID

  2. Living with tics: reduced impairment and improved quality of life for youth with chronic tic disorders.

    PubMed

    McGuire, Joseph F; Arnold, Elysse; Park, Jennifer M; Nadeau, Joshua M; Lewin, Adam B; Murphy, Tanya K; Storch, Eric A

    2015-02-28

    Pharmacological and behavioral interventions have focused on reducing tic severity to alleviate tic-related impairment for youth with chronic tic disorders (CTDs), with no existing intervention focused on the adverse psychosocial consequences of tics. This study examined the preliminary efficacy of a modularized cognitive behavioral intervention ("Living with Tics", LWT) in reducing tic-related impairment and improving quality of life relative to a waitlist control of equal duration. Twenty-four youth (ages 7-17 years) with Tourette Disorder or Chronic Motor Tic Disorder and psychosocial impairment participated. A treatment-blind evaluator conducted all pre- and post-treatment clinician-rated measures. Youth were randomly assigned to receive the LWT intervention (n=12) or a 10-week waitlist (n=12). The LWT intervention consisted of up to 10 weekly sessions targeted at reducing tic-related impairment and developing skills to manage psychosocial consequences of tics. Youth in the LWT condition experienced significantly reduced clinician-rated tic-impairment, and improved child-rated quality of life. Ten youth (83%) in the LWT group were classified as treatment responders compared to four youth in the waitlist condition (33%). Treatment gains were maintained at one-month follow-up. Findings provide preliminary data that the LWT intervention reduces tic-related impairment and improves quality of life for youth with CTDs. PMID:25500348

  3. Chronic obstructive pulmonary disease and cognitive impairment in the Chinese elderly population: a large national survey

    PubMed Central

    Yin, Peng; Ma, Qingfeng; Wang, Limin; Lin, Peng; Zhang, Mei; Qi, Shige; Wang, Zhihui

    2016-01-01

    Background Previous studies suggested an association between chronic obstructive pulmonary disease (COPD) and cognitive impairment, mostly in developed countries. There is no evidence available on the association between these two common chronic disorders in the elderly people in People’s Republic of China where the population is aging rapidly. Methods The study population was randomly selected from a nationally representative Disease Surveillance Point System in People’s Republic of China. A standardized questionnaire was administered by trained interviewers during a face-to-face interview in the field survey conducted in 2010–2011. Cognitive function was assessed using the Mini-Mental State Examination. COPD was measured by self-report and the Medical Research Council respiratory questionnaire was used to assess respiratory symptoms. A multivariate logistic regression model was applied to examine the association between COPD and cognitive impairment with adjustment for potential confounding factors. Results A total of 16,629 subjects aged over 60 years were included in the study. The prevalence of cognitive impairment was 9.4% (95% confidence interval [CI] 7.7, 11.1). Chronic phlegm was associated with significantly higher prevalence of cognitive impairment in models adjusted for age, sex, marital status, geographic region, urban/rural, education, smoking status, alcohol drinking, and indoor air pollution (odds ratio [OR] 1.46, 95% CI 1.11, 1.93). Chronic respiratory symptoms and self-reported COPD were strongly related to cognitive impairment in urban areas. There were no significant effect modifications for sex, regions, educational level, smoking status, and alcohol drinking. Conclusion There was strong association between COPD and cognitive impairment in urban Chinese elderly population. PMID:26952279

  4. Current Evidence for Extracorporeal Liver Support Systems in Acute Liver Failure and Acute-on-Chronic Liver Failure.

    PubMed

    Karvellas, Constantine J; Subramanian, Ram M

    2016-07-01

    Artificial (nonbiological) extracorporeal liver support devices aim to remove albumin-bound and water-soluble toxins to restore and preserve hepatic function and mitigate or limit the progression of multiorgan failure while hepatic recovery or liver transplant occurs. The following beneficial effects have been documented: improvement of jaundice, amelioration of hemodynamic instability, reduction of portal hypertension, and improvement of hepatic encephalopathy. The only randomized prospective multicenter controlled trial to show an improvement in transplant-free survival was for high-volume plasmapheresis. Biological (cell-based) extracorporeal liver support systems aim to support the failing liver through detoxification and synthetic function and warrant further study for safety and benefit. PMID:27339682

  5. Epidemiology and Healthcare Burden of Acute-on-Chronic Liver Failure.

    PubMed

    Allen, Alina M; Kim, W Ray

    2016-05-01

    Chronic liver disease and cirrhosis, a common end result of viral hepatitis, alcohol abuse, and the emerging epidemic of nonalcoholic fatty liver disease are a significant source of morbidity and premature mortality globally. Acute clinical deterioration of chronic liver disease exemplifies the pinnacle of healthcare burden due to the intensive medical needs and high mortality risk. Although a uniformly accepted definition for epidemiological studies is lacking, acute-on-chronic liver failure (ACLF) is increasingly recognized as an important source of disease burden. At least in the United States, hospitalizations for ACLF have increased several fold in the last decade and have a high fatality rate. Acute-on-chronic liver failure incurs extremely high costs, exceeding the yearly costs of inpatient management of other common medical conditions. Although further epidemiological data are needed to better understand the true impact and future trends of ACLF, these data point to the urgency in the clinical investigation for ACLF and the deployment of healthcare resources for timely and effective interventions in affected patients. PMID:27172353

  6. Cyclooxygenase-2 Inhibitor Reduces Hepatic Stiffness in Pediatric Chronic Liver Disease Patients Following Kasai Portoenterostomy

    PubMed Central

    Chang, Hye Kyung; Chang, Eun Young; Ryu, Seonae

    2016-01-01

    Purpose The purpose of this study was to define the role of cyclooxygenase-2 inhibitors (COX-2i) in reducing hepatic fibrosis in pediatric patients with chronic liver disease. Materials and Methods From September 2009 to September 2010, patients over 2 years old who visited our outpatient clinic for follow-up to manage their chronic liver disease after Kasai portoenterostomy for biliary atresia, were included in this study. Volunteers were assigned to the study or control groups, according to their preference. A COX-2i was given to only the study group after obtaining consent. The degree of hepatic fibrosis (liver stiffness score, LSS) was prospectively measured using FibroScan, and liver function was examined using serum analysis before and after treatment. After 1 year, changes in LSSs and liver function were compared between the two groups. Results Twenty-five patients (18 females and 7 males) were enrolled in the study group. The control group included 44 patients (26 females and 18 males). After 1 year, the least square mean values for the LSSs were significantly decreased by 3.91±0.98 kPa (p=0.004) only in the study group. Serum total bilirubin did not decrease significantly in either group. Conclusion COX-2i treatment improved the LSS in patients with chronic liver disease after Kasai portoenterostomy for biliary atresia. PMID:27189282

  7. Vortioxetine restores reversal learning impaired by 5-HT depletion or chronic intermittent cold stress in rats.

    PubMed

    Wallace, Ashley; Pehrson, Alan L; Sánchez, Connie; Morilak, David A

    2014-10-01

    Current treatments for depression, including serotonin-specific reuptake inhibitors (SSRIs), are only partially effective, with a high incidence of residual symptoms, relapse, and treatment resistance. Loss of cognitive flexibility, a component of depression, is associated with dysregulation of the prefrontal cortex. Reversal learning, a form of cognitive flexibility, is impaired by chronic stress, a risk factor for depression, and the stress-induced impairment in reversal learning is sensitive to chronic SSRI treatment, and is mimicked by serotonin (5-HT) depletion. Vortioxetine, a novel, multimodal-acting antidepressant, is a 5-HT3, 5-HT7 and 5-HT1D receptor antagonist, a 5-HT1B receptor partial agonist, a 5-HT1A receptor agonist, and inhibits the 5-HT transporter. Using adult male rats, we first investigated the direct effects of vortioxetine, acting at post-synaptic 5-HT receptors, on reversal learning that was compromised by 5-HT depletion using 4-chloro-DL-phenylalanine methyl ester hydrochloride (PCPA), effectively eliminating any contribution of 5-HT reuptake blockade. PCPA induced a reversal learning impairment that was alleviated by acute or sub-chronic vortioxetine administration, suggesting that post-synaptic 5-HT receptor activation contributes to the effects of vortioxetine. We then investigated the effects of chronic dietary administration of vortioxetine on reversal learning that had been compromised in intact animals exposed to chronic intermittent cold (CIC) stress, to assess vortioxetine's total pharmacological effect. CIC stress impaired reversal learning, and chronic vortioxetine administration prevented the reversal-learning deficit. Together, these results suggest that the direct effect of vortioxetine at 5-HT receptors may contribute to positive effects on cognitive flexibility deficits, and may enhance the effect of 5-HT reuptake blockade. PMID:24852131

  8. Chronic high-carbohydrate, high-fat feeding in rats induces reversible metabolic, cardiovascular, and liver changes.

    PubMed

    Poudyal, Hemant; Panchal, Sunil K; Ward, Leigh C; Waanders, Jennifer; Brown, Lindsay

    2012-06-15

    Age-related physiological changes develop at the same time as the increase in metabolic syndrome in humans after young adulthood. There is a paucity of data in models mimicking chronic diet-induced changes in human middle age and interventions to reverse these changes. This study measured the changes during chronic consumption of a high-carbohydrate (as cornstarch), low-fat (C) diet and a high-carbohydrate (as fructose and sucrose), high-fat (H) diet in rats for 32 wk. C diet feeding induced changes without metabolic syndrome, such as disproportionate increases in total body lean and fat mass, reduced bone mineral content, cardiovascular remodeling with increased systolic blood pressure, left ventricular and arterial stiffness, and increased plasma markers of liver injury. H diet feeding induced visceral adiposity with reduced lean mass, increased lipid infiltration in the skeletal muscle, impaired glucose and insulin tolerance, cardiovascular remodeling, hepatic steatosis, and increased infiltration of inflammatory cells in the heart and the liver. Chia seed supplementation for 24 wk attenuated most structural and functional modifications induced by age or H diet, including increased whole body lean mass and lipid redistribution from the abdominal area, and normalized the chronic low-grade inflammation induced by H diet feeding; these effects may be mediated by increased metabolism of anti-inflammatory n-3 fatty acids from chia seed. These results suggest that chronic H diet feeding for 32 wk mimics the diet-induced cardiovascular and metabolic changes in middle age and that chia seed may serve as an alternative dietary strategy in the management of these changes. PMID:22436699

  9. Interactions between Myc and Mediators of Inflammation in Chronic Liver Diseases

    PubMed Central

    Liu, Ting; Zhou, Yu; Ko, Kwang Suk; Yang, Heping

    2015-01-01

    Most chronic liver diseases (CLDs) are characterized by inflammatory processes with aberrant expressions of various pro- and anti-inflammatory mediators in the liver. These mediators are the driving force of many inflammatory liver disorders, which often result in fibrosis, cirrhosis, and liver tumorigenesis. c-Myc is involved in many cellular events such as cell growth, proliferation, and differentiation. c-Myc upregulates IL-8, IL-10, TNF-α, and TGF-β, while IL-1, IL-2, IL-4, TNF-α, and TGF-β promote c-Myc expression. Their interactions play a central role in fibrosis, cirrhosis, and liver cancer. Molecular interference of their interactions offers possible therapeutic potential for CLDs. In this review, current knowledge of the molecular interactions between c-Myc and various well known inflammatory mediators is discussed. PMID:26508814

  10. Assessment of matrix metalloproteinase-1 for marking liver cirrhosis in chronic hepatitis C patients.

    PubMed

    Attallah, Abdelfattah M; Badr El-Din, Nariman K; Omran, Mohamed M; Farid, Khaled; El-Wahab, Ahmed H Abd; El-Bendary, Mohamed; El-Dosoky, Ibrahim

    2011-01-01

    Our objective in the present study was to observe the change in the serum MMP-1 concentration using ELISA in 129 chronic hepatitis C (CHC) (78 non-cirrhotic and 51 with cirrhotic liver) and 50 healthy controls. The values of MMP-1 concentration increased in patients with CHC according to the stage of liver fibrosis. An area under the ROC curves (AUC) of the MMP-1 was 0.98 for discriminating patients with cirrhotic liver from healthy individuals and was 0.78 for discriminating patients with cirrhotic liver from non cirrhotic patients. The diagnostic potential of MMP-1 for discriminating cirrhosis from healthy individuals was very high with 98% sensitivity and 97% efficiency. MMP-1 detected cirrhosis in CHC with 71% sensitivity and 73% efficiency. In Conclusion, measurement of serum MMP-1 is useful for diagnosing liver cirrhosis in CHC patients. PMID:23082478

  11. Chronic liver disease is triggered by taurine transporter knockout in the mouse.

    PubMed

    Warskulat, Ulrich; Borsch, Elena; Reinehr, Roland; Heller-Stilb, Birgit; Mönnighoff, Irmhild; Buchczyk, Darius; Donner, Markus; Flögel, Ulrich; Kappert, Günther; Soboll, Sibylle; Beer, Sandra; Pfeffer, Klaus; Marschall, Hanns-Ulrich; Gabrielsen, Marcus; Amiry-Moghaddam, Mahmood; Ottersen, Ole Petter; Dienes, Hans Peter; Häussinger, Dieter

    2006-03-01

    Taurine is an abundant organic osmolyte with antioxidant and immunomodulatory properties. Its role in the pathogenesis of chronic liver disease is unknown. The liver phenotype was studied in taurine transporter knockout (taut-/-) mice. Hepatic taurine levels were ~21, 15 and 6 mumol/g liver wet weight in adult wild-type, heterozygous (taut+/-) and homozygous (taut-/-) mice, respectively. Immunoelectronmicroscopy revealed an almost complete depletion of taurine in Kupffer and sinusoidal endothelial cells, but not in parenchymal cells of (taut-/-) mice. Compared with wild-type mice, (taut-/-) and (taut+/-) mice developed moderate unspecific hepatitis and liver fibrosis with increased frequency of neoplastic lesions beyond 1 year of age. Liver disease in (taut-/-) mice was characterized by hepatocyte apoptosis, activation of the CD95 system, elevated plasma TNF-alpha levels, hepatic stellate cell and oval cell proliferation, and severe mitochondrial abnormalities in liver parenchymal cells. Mitochondrial dysfunction was suggested by a significantly lower respiratory control ratio in isolated mitochondria from (taut-/-) mice. Taut knockout had no effect on taurine-conjugated bile acids in bile; however, the relative amount of cholate-conjugates acid was decreased at the expense of 7-keto-cholate-conjugates. In conclusion, taurine deficiency due to defective taurine transport triggers chronic liver disease, which may involve mitochondrial dysfunction. PMID:16421246

  12. A20 prevents chronic liver inflammation and cancer by protecting hepatocytes from death.

    PubMed

    Catrysse, L; Farhang Ghahremani, M; Vereecke, L; Youssef, S A; Mc Guire, C; Sze, M; Weber, A; Heikenwalder, M; de Bruin, A; Beyaert, R; van Loo, G

    2016-01-01

    An important regulator of inflammatory signalling is the ubiquitin-editing protein A20 that acts as a break on nuclear factor-κB (NF-κB) activation, but also exerts important cytoprotective functions. A20 knockout mice are cachectic and die prematurely due to excessive multi-organ inflammation. To establish the importance of A20 in liver homeostasis and pathology, we developed a novel mouse line lacking A20 specifically in liver parenchymal cells. These mice spontaneously develop chronic liver inflammation but no fibrosis or hepatocellular carcinomas, illustrating an important role for A20 in normal liver tissue homeostasis. Hepatocyte-specific A20 knockout mice show sustained NF-κB-dependent gene expression in the liver upon tumor necrosis factor (TNF) or lipopolysaccharide injection, as well as hepatocyte apoptosis and lethality upon challenge with sublethal doses of TNF, demonstrating an essential role for A20 in the protection of mice against acute liver failure. Finally, chronic liver inflammation and enhanced hepatocyte apoptosis in hepatocyte-specific A20 knockout mice was associated with increased susceptibility to chemically or high fat-diet-induced hepatocellular carcinoma development. Together, these studies establish A20 as a crucial hepatoprotective factor. PMID:27253414

  13. The role of macrophages in obesity-driven chronic liver disease.

    PubMed

    Devisscher, Lindsey; Verhelst, Xavier; Colle, Isabelle; Van Vlierberghe, Hans; Geerts, Anja

    2016-05-01

    Overnutrition and a sedentary lifestyle have resulted in the expansion of human obesity and associated metabolic complications. Nonalcoholic fatty liver disease has become the most common chronic liver disease in Western developed countries and can range from simple hepatic steatosis to a combination of steatosis, inflammation, and ballooning degeneration (nonalcoholic steatohepatitis). Obesity and its related liver disease are both risk factors for hepatocellular carcinoma, the incidence of which is expected to increase rapidly. The pathogenesis of nonalcoholic fatty liver disease and its progression to nonalcoholic steatohepatitis and hepatocellular carcinoma involve a deregulated lipid metabolism and a disruption of immune homeostasis and tissue integrity and are associated with a state of chronic inflammation. Macrophages are immune cells essential for maintenance of organ function and homeostasis but can also contribute to tissue damage and maintain a proinflammatory response. Their function depends on their origin, and tissue and can be converted based on local environmental cues. Resident liver macrophages, Kupffer cells, which function as sentinels, provide a first defense and are assisted by infiltrating monocytes in cases of hepatic insult. Until now, the contribution of tissue-residing and infiltrating macrophages to the onset and progression of nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, and hepatocellular carcinoma has been only partially unraveled. This review summarizes the current knowledge on the contribution of macrophage subsets to obesity-driven fatty liver disease and its complications and sheds light on still unexplored areas. PMID:26936934

  14. Effect of chronic carbon monoxide exposure on experimental alcoholic liver injury in rats

    SciTech Connect

    Nanji, A.A. ); Jui, L.T.; French, S.W. )

    1989-01-01

    Two groups of experimental animals with pair-fed controls were studied to evaluate the effect of chronic carbon monoxide (CO) exposure on progression of experimental alcoholic liver injury. Eight pairs of male Wistar rats were continuously infused liquid diet and ethanol or isocaloric dextrose for four months. Four pairs were also exposed to CO. Liver damage was followed monthly by serum ALT and morphologic assessment of liver biopsy. Serum levels of ALT were significantly higher in the CO-ethanol group compared to other groups. Electron microscopy revealed a greater degree of cell necrosis in the CO exposed group which explained the significantly higher ALT activity in these animals. Both experimental groups had significantly greater liver damage than controls. Carboxyhemoglobin levels were not different in the ethanol-fed and control group. Our results show that chronic CO exposure enhances liver cell necrosis in ethanol-fed rats thereby lending support to the hypothesis that ethanol and hypoxia enhance cellular disruption in the liver which could be important in the pathogenesis of alcoholic liver disease in rats.

  15. Magnetic Resonance Elastography and Other Magnetic Resonance Imaging Techniques in Chronic Liver Disease: Current Status and Future Directions.

    PubMed

    Tan, Cher Heng; Venkatesh, Sudhakar Kundapur

    2016-09-15

    Recent advances in the noninvasive imaging of chronic liver disease have led to improvements in diagnosis, particularly with magnetic resonance imaging (MRI). A comprehensive evaluation of the liver may be performed with the quantification of the degree of hepatic steatosis, liver iron concentration, and liver fibrosis. In addition, MRI of the liver may be used to identify complications of cirrhosis, including portal hypertension, ascites, and the development of hepatocellular carcinoma. In this review article, we discuss the state of the art techniques in liver MRI, namely, magnetic resonance elastography, hepatobiliary phase MRI, and liver fat and iron quantification MRI. The use of these advanced techniques in the management of chronic liver diseases, including nonalcoholic fatty liver disease, will be elaborated. PMID:27563019

  16. Magnetic Resonance Elastography and Other Magnetic Resonance Imaging Techniques in Chronic Liver Disease: Current Status and Future Directions

    PubMed Central

    Tan, Cher Heng; Venkatesh, Sudhakar Kundapur

    2016-01-01

    Recent advances in the noninvasive imaging of chronic liver disease have led to improvements in diagnosis, particularly with magnetic resonance imaging (MRI). A comprehensive evaluation of the liver may be performed with the quantification of the degree of hepatic steatosis, liver iron concentration, and liver fibrosis. In addition, MRI of the liver may be used to identify complications of cirrhosis, including portal hypertension, ascites, and the development of hepatocellular carcinoma. In this review article, we discuss the state of the art techniques in liver MRI, namely, magnetic resonance elastography, hepatobiliary phase MRI, and liver fat and iron quantification MRI. The use of these advanced techniques in the management of chronic liver diseases, including non-alcoholic fatty liver disease, will be elaborated. PMID:27563019

  17. Impaired methylation as a novel mechanism for proteasome suppression in liver cells

    SciTech Connect

    Osna, Natalia A.; White, Ronda L.; Donohue, Terrence M.; Beard, Michael R.; Tuma, Dean J.; Kharbanda, Kusum K.

    2010-01-08

    The proteasome is a multi-catalytic protein degradation enzyme that is regulated by ethanol-induced oxidative stress; such suppression is attributed to CYP2E1-generated metabolites. However, under certain conditions, it appears that in addition to oxidative stress, other mechanisms are also involved in proteasome regulation. This study investigated whether impaired protein methylation that occurs during exposure of liver cells to ethanol, may contribute to suppression of proteasome activity. We measured the chymotrypsin-like proteasome activity in Huh7CYP cells, hepatocytes, liver cytosols and nuclear extracts or purified 20S proteasome under conditions that maintain or prevent protein methylation. Reduction of proteasome activity of hepatoma cell and hepatocytes by ethanol or tubercidin was prevented by simultaneous treatment with S-adenosylmethionine (SAM). Moreover, the tubercidin-induced decline in proteasome activity occurred in both nuclear and cytosolic fractions. In vitro exposure of cell cytosolic fractions or highly purified 20S proteasome to low SAM:S-adenosylhomocysteine (SAH) ratios in the buffer also suppressed proteasome function, indicating that one or more methyltransferase(s) may be associated with proteasomal subunits. Immunoblotting a purified 20S rabbit red cell proteasome preparation using methyl lysine-specific antibodies revealed a 25 kDa proteasome subunit that showed positive reactivity with anti-methyl lysine. This reactivity was modified when 20S proteasome was exposed to differential SAM:SAH ratios. We conclude that impaired methylation of proteasome subunits suppressed proteasome activity in liver cells indicating an additional, yet novel mechanism of proteasome activity regulation by ethanol.

  18. MR Quantification of Total Liver Fat in Patients with Impaired Glucose Tolerance and Healthy Subjects

    PubMed Central

    Zhang, Zhongwei; Cai, Huasong; Li, Yanbing; Chan, Tao; Wu, Ling; Li, Zi-Ping; Feng, Shi-Ting

    2014-01-01

    Objective To explore the correlations between liver fat content and clinical index in patients with impaired glucose tolerance (IGT) and healthy subjects. Materials and Methods 56 subjects were enrolled and each of them underwent upper-abdominal MRI examination that involved a T1 VIBE Dixon sequence. 14 was clinically diagnosed with IGT (collectively as IGT group ) while 42 showed normal glucose tolerance,(collectively as NGT group). NGT group was further divided into NGTFat (BMI≥25, 18 subjects) and NGTLean (BMI<25, 24 subjects). The total liver fat contents was measured and compared with clinical findings and laboratory results in order to determine statistical correlations between these parameters. Differences among IGT, NGTFat and NGTLean groups were evaluated. Results For all the subjects, fat volume fractions (FVFs) ranged from 4.2% to 24.2%, positive correlations was observed with BMI, waist hip ratio(WHR), low density lipoprotein(LDL), fasting plasma insulin(FPI), homeostasis model assessment insulin resistance (HOMA-IR) and homeostasis model assessment β(HOMAβ). FVFs of IGT group (p = 0.004) and NGTFat group (p = 0.006) were significantly higher than those of NGTLean group. Conclusions People with higher BMI, WHR and LDL levels tend to have higher liver fat content. Patients with BMI≥25 are more likely to develop IGT. Patients with higher FVF showed higher resistance to insulin, thus obtained a higher risk of developing type 2 diabetes mellitus. PMID:25343445

  19. The Molecular Epidemiology of Chronic Aflatoxin Driven Impaired Child Growth

    PubMed Central

    Turner, Paul Craig

    2013-01-01

    Aflatoxins are toxic secondary fungal metabolites that contaminate dietary staples in tropical regions; chronic high levels of exposure are common for many of the poorest populations. Observations in animals indicate that growth and/or food utilization are adversely affected by aflatoxins. This review highlights the development of validated exposure biomarkers and their use here to assess the role of aflatoxins in early life growth retardation. Aflatoxin exposure occurs in utero and continues in early infancy as weaning foods are introduced. Using aflatoxin-albumin exposure biomarkers, five major studies clearly demonstrate strong dose response relationships between exposure in utero and/or early infancy and growth retardation, identified by reduced birth weight and/or low HAZ and WAZ scores. The epidemiological studies include cross-sectional and longitudinal surveys, though aflatoxin reduction intervention studies are now required to further support these data and guide sustainable options to reduce the burden of exposure. The use of aflatoxin exposure biomarkers was essential in understanding the observational data reviewed and will likely be a critical monitor of the effectiveness of interventions to restrict aflatoxin exposure. Given that an estimated 4.5 billion individuals live in regions at risk of dietary contamination the public health concern cannot be over stated. PMID:24455429

  20. Chronic Kidney Disease Impairs Bone Defect Healing in Rats

    PubMed Central

    Liu, Weiqing; Kang, Ning; Seriwatanachai, Dutmanee; Dong, Yuliang; Zhou, Liyan; Lin, Yunfeng; Ye, Ling; Liang, Xing; Yuan, Quan

    2016-01-01

    Chronic kidney disease (CKD) has been regarded as a risk for bone health. The aim of this study was to evaluate the effect of CKD on bone defect repair in rats. Uremia was induced by subtotal renal ablation, and serum levels of BUN and PTH were significantly elevated four weeks after the second renal surgery. Calvarial defects of 5-mm diameter were created and implanted with or without deproteinized bovine bone mineral (DBBM). Micro-CT and histological analyses consistently revealed a decreased newly regenerated bone volume for CKD rats after 4 and 8 weeks. In addition, 1.4-mm-diameter cortical bone defects were established in the distal end of femora and filled with gelatin sponge. CKD rats exhibited significantly lower values of regenerated bone and bone mineral density (BMD) within the cortical gap after 2 and 4 weeks. Moreover, histomorphometric analysis showed an increase in both osteoblast number (N.Ob/B.Pm) and osteoclast number (N.Oc/B.Pm) in CKD groups due to hyperparathyroidism. Notably, collagen maturation was delayed in CKD rats as verified by Masson’s Trichrome staining. These data indicate that declined renal function negatively affects bone regeneration in both calvarial and femoral defects. PMID:26955758

  1. Life expectancy of brain impaired, chronically ventilated children.

    PubMed

    Gale, Rena; Namestnic, Julia

    2013-04-01

    We present a 5-year survival profile of 42 children and adolescents between 1 to 21 years of age in an immobile minimally conscious state, chronically dependent on supportive ventilation. Data were collected from a 22-bed pediatric unit dedicated to this unique population, within a 350-bed geriatric hospital, between May 2006 and May 2011. The practice of ventilating children even in minimally conscious state stems from the unique cultural, religious, and ethnic background of the population in Israel. The 5-year survival probability was 48% (52% probability of death within 5 years, 26.5% within 2 years). No significant difference was found in the survival profile of patients admitted following hypoxic accidents (20 children) and those admitted with other problems such as genetic/metabolic diseases or brain anomalies (22). The mortality rate of male patients was higher than that of female patients, but the difference was not statistically significant. No difference in 5-year mortality rates was found between children of different ethnic backgrounds. PMID:23498560

  2. Micro-RNA-122 Levels in Acute Liver Failure and Chronic Hepatitis C

    PubMed Central

    Dubin, Perry H.; Yuan, Hejun; Devine, Robert K.; Hynan, Linda S.; Jain, Mamta K.; Lee, William M.

    2016-01-01

    MicroRNA-122 (miR-122) is the foremost liver-related micro-RNA, but its role in the hepatocyte is not fully understood. To evaluate whether circulating levels of miR-122 are elevated in chronic-HCV for a reason other than hepatic injury, we compared serum level in patients with chronic hepatitis C to other forms of liver injury including patients with acute liver failure and healthy controls. MiR-122 was quantitated using sera from 35 acute liver failure patients (20 acetaminophen-induced, 15 other etiologies), 39 chronic-HCV patients and 12 controls. In parallel, human genomic DNA (hgDNA) levels were measured to reflect quantitatively the extent of hepatic necrosis. Additionally, six HIV–HCV co-infected patients, who achieved viral clearance after undergoing therapy with interferon and ribavirin, had serial sera miR-122 and hgDNA levels measured before and throughout treatment. Serum miR-122 levels were elevated approximately 100-fold in both acute liver failure and chronic-HCV sera as compared to controls (P<0.001), whereas hgDNA levels were only elevated in acute liver failure patients as compared to both chronic-HCV and controls (P<0.001). Subgroup analysis showed that chronic-HCV sera with normal aminotransferase levels showed elevated miR-122 despite low levels of hepatocyte necrosis. All successfully treated HCV patients showed a significant Log10 decrease in miR-122 levels ranging from 0.16 to 1.46, after sustained viral response. Chronic-HCV patients have very elevated serum miR-122 levels in the range of most patients with severe hepatic injury leading to acute liver failure. Eradication of HCV was associated with decreased miR-122 but not hgDNA. An additional mechanism besides hepatic injury may be active in chronic-HCV to explain the exaggerated circulating levels of miR-122 observed. PMID:24895202

  3. Chronic pain patients are impaired on an emotional decision-making task.

    PubMed

    Apkarian, A Vania; Sosa, Yamaya; Krauss, Beth R; Thomas, P Sebastian; Fredrickson, Bruce E; Levy, Robert E; Harden, R Norman; Chialvo, Dante R

    2004-03-01

    Chronic pain can result in anxiety, depression and reduced quality of life. However, its effects on cognitive abilities have remained unclear although many studies attempted to psychologically profile chronic pain. We hypothesized that performance on an emotional decision-making task may be impaired in chronic pain since human brain imaging studies show that brain regions critical for this ability are also involved in chronic pain. Chronic back pain (CBP) patients, chronic complex regional pain syndrome (CRPS) patients, and normal volunteers (matched for age, sex, and education) were studied on the Iowa Gambling Task, a card game developed to study emotional decision-making. Outcomes on the gambling task were contrasted to performance on other cognitive tasks. The net number of choices made from advantageous decks after subtracting choices made from disadvantageous decks on average was 22.6 in normal subjects (n = 26), 13.4 in CBP patients (n = 26), and -9.5 in CRPS patients (n = 12), indicating poor performance in the patient groups as compared to the normal controls (P < 0.004). Only pain intensity assessed during the gambling task was correlated with task outcome and only in CBP patients (r = -0.75, P < 0.003). Other cognitive abilities, such as attention, short-term memory, and general intelligence tested normal in the chronic pain patients. Our evidence indicates that chronic pain is associated with a specific cognitive deficit, which may impact everyday behavior especially in risky, emotionally laden, situations. PMID:15109516

  4. Chronic Exposure to Low Frequency Noise at Moderate Levels Causes Impaired Balance in Mice

    PubMed Central

    Tamura, Haruka; Ohgami, Nobutaka; Yajima, Ichiro; Iida, Machiko; Ohgami, Kyoko; Fujii, Noriko; Itabe, Hiroyuki; Kusudo, Tastuya; Yamashita, Hitoshi; Kato, Masashi

    2012-01-01

    We are routinely exposed to low frequency noise (LFN; below 0.5 kHz) at moderate levels of 60–70 dB sound pressure level (SPL) generated from various sources in occupational and daily environments. LFN has been reported to affect balance in humans. However, there is limited information about the influence of chronic exposure to LFN at moderate levels for balance. In this study, we investigated whether chronic exposure to LFN at a moderate level of 70 dB SPL affects the vestibule, which is one of the organs responsible for balance in mice. Wild-type ICR mice were exposed for 1 month to LFN (0.1 kHz) and high frequency noise (HFN; 16 kHz) at 70 dB SPL at a distance of approximately 10–20 cm. Behavior analyses including rotarod, beam-crossing and footprint analyses showed impairments of balance in LFN-exposed mice but not in non-exposed mice or HFN-exposed mice. Immunohistochemical analysis showed a decreased number of vestibular hair cells and increased levels of oxidative stress in LFN-exposed mice compared to those in non-exposed mice. Our results suggest that chronic exposure to LFN at moderate levels causes impaired balance involving morphological impairments of the vestibule with enhanced levels of oxidative stress. Thus, the results of this study indicate the importance of considering the risk of chronic exposure to LFN at a moderate level for imbalance. PMID:22768129

  5. SPONTANEOUS REPOPULATION OF β-CATENIN NULL LIVERS WITH β-CATENIN POSITIVE HEPATOCYTES AFTER CHRONIC MURINE LIVER INJURY

    PubMed Central

    Thompson, Michael D.; Wickline, Emily D.; Bowen, William B.; Lu, Amy; Singh, Sucha; Misse, Amalea; Monga, Satdarshan P. S.

    2011-01-01

    Prolonged exposure of mice to diet containing 0.1% 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) results in hepatobiliary injury, atypical ductular proliferation, oval cell appearance and limited fibrosis. Previously, we reported that short-term ingestion of DDC diet by hepatocyte-specific β-catenin conditional knockout (KO) mice, led to fewer A6-positive oval cells than wild-type (WT) littermates. To examine the role of β-catenin in chronic hepatic injury and repair, we exposed WT and KO mice to DDC for 80 and 150 days. Paradoxically, long-term DDC exposure led to significantly more A6-positive cells indicating greater atypical ductular proliferation in KO, which coincided with increased fibrosis and cholestasis. Surprisingly, at 80 and 150 days in KO, we observed a significant amelioration of hepatocyte injury. This coincided with extensive repopulation of β-catenin null livers with β-catenin-positive hepatocytes at 150 days, which was preceded by appearance of β-catenin-positive hepatocyte clusters at 80 days and a few β-catenin-positive hepatocytes at earlier times. Intriguingly, occasional β-catenin-positive hepatocytes that were negative for progenitor markers were also observed at baseline in the KO livers suggesting spontaneous escape from cre-mediated recombination. These cells with hepatocyte morphology expressed mature hepatocyte markers but lacked markers of hepatic progenitors. The gradual repopulation of KO livers with β-catenin-positive hepatocytes occurred only following DDC injury and coincided with a progressive loss of hepatic cre-recombinase expression. A few β-catenin-positive cholangiocytes were observed albeit only after long-term DDC-exposure and trailed the appearance of β-catenin-positive hepatocytes. In conclusion, in a chronic liver injury model, β-catenin-positive hepatocytes exhibit growth and survival advantages and repopulate KO livers eventually limiting hepatic injury and dysfunction despite increased fibrosis and

  6. Impaired postprandial lipemic response in chronic kidney disease.

    PubMed

    Saland, Jeffrey M; Satlin, Lisa M; Zalsos-Johnson, Jeanna; Cremers, Serge; Ginsberg, Henry N

    2016-07-01

    Dyslipidemia in chronic kidney disease (CKD) is usually characterized by hypertriglyceridemia. Here we studied postprandial lipemia in children and young adults to determine whether an increasing degree of CKD results in a proportional increase in triglyceride and chylomicron concentration. Secondary goals were to determine whether subnephrotic proteinuria, apolipoprotein (apo)C-III and insulin resistance modify the CKD effect. Eighteen fasting participants (mean age of 15 years, mean glomerular filtration rate (GFR) of 50 ml/min/1.73 m(2)) underwent a postprandial challenge with a high fat milkshake. Triglycerides, apoB-48, insulin, and other markers were measured before and 2, 4, 6, and 8 hours afterward. Response was assessed by the incremental area under the curve of triglycerides and of apoB-48. The primary hypothesis was tested by correlation to estimated GFR. Significantly, for every 10 ml/min/1.73 m(2) lower estimated GFR, the incremental area under the curve of triglycerides was 17% greater while that of apoB-48 was 16% greater. Univariate analyses also showed that the incremental area under the curve of triglycerides and apoB-48 were significantly associated with subnephrotic proteinuria, apoC-III, and insulin resistance. In multivariate analysis, CKD and insulin resistance were independently associated with increased area under the curve and were each linked to increased levels of apoC-III. Thus, postprandial triglyceride and chylomicron plasma excursions are increased in direct proportion to the degree of CKD. Independent effects are associated with subclinical insulin resistance and increased apoC-III is linked to both CKD and insulin resistance. PMID:27162092

  7. Liver Stiffness Measurement-Based Scoring System for Significant Inflammation Related to Chronic Hepatitis B

    PubMed Central

    Hong, Mei-Zhu; Zhang, Ru-Mian; Chen, Guo-Liang; Huang, Wen-Qi; Min, Feng; Chen, Tian; Xu, Jin-Chao; Pan, Jin-Shui

    2014-01-01

    Objectives Liver biopsy is indispensable because liver stiffness measurement alone cannot provide information on intrahepatic inflammation. However, the presence of fibrosis highly correlates with inflammation. We constructed a noninvasive model to determine significant inflammation in chronic hepatitis B patients by using liver stiffness measurement and serum markers. Methods The training set included chronic hepatitis B patients (n = 327), and the validation set included 106 patients; liver biopsies were performed, liver histology was scored, and serum markers were investigated. All patients underwent liver stiffness measurement. Results An inflammation activity scoring system for significant inflammation was constructed. In the training set, the area under the curve, sensitivity, and specificity of the fibrosis-based activity score were 0.964, 91.9%, and 90.8% in the HBeAg(+) patients and 0.978, 85.0%, and 94.0% in the HBeAg(−) patients, respectively. In the validation set, the area under the curve, sensitivity, and specificity of the fibrosis-based activity score were 0.971, 90.5%, and 92.5% in the HBeAg(+) patients and 0.977, 95.2%, and 95.8% in the HBeAg(−) patients. The liver stiffness measurement-based activity score was comparable to that of the fibrosis-based activity score in both HBeAg(+) and HBeAg(−) patients for recognizing significant inflammation (G ≥3). Conclusions Significant inflammation can be accurately predicted by this novel method. The liver stiffness measurement-based scoring system can be used without the aid of computers and provides a noninvasive alternative for the prediction of chronic hepatitis B-related significant inflammation. PMID:25360742

  8. Carbamazepine suppresses calpain-mediated autophagy impairment after ischemia/reperfusion in mouse livers

    SciTech Connect

    Kim, Jae-Sung Wang, Jin-Hee Biel, Thomas G. Kim, Do-Sung Flores-Toro, Joseph A. Vijayvargiya, Richa Zendejas, Ivan Behrns, Kevin E.

    2013-12-15

    Onset of the mitochondrial permeability transition (MPT) plays a causative role in ischemia/reperfusion (I/R) injury. Current therapeutic strategies for reducing reperfusion injury remain disappointing. Autophagy is a lysosome-mediated, catabolic process that timely eliminates abnormal or damaged cellular constituents and organelles such as dysfunctional mitochondria. I/R induces calcium overloading and calpain activation, leading to degradation of key autophagy-related proteins (Atg). Carbamazepine (CBZ), an FDA-approved anticonvulsant drug, has recently been reported to increase autophagy. We investigated the effects of CBZ on hepatic I/R injury. Hepatocytes and livers from male C57BL/6 mice were subjected to simulated in vitro, as well as in vivo I/R, respectively. Cell death, intracellular calcium, calpain activity, changes in autophagy-related proteins (Atg), autophagic flux, MPT and mitochondrial membrane potential after I/R were analyzed in the presence and absence of 20 μM CBZ. CBZ significantly increased hepatocyte viability after reperfusion. Confocal microscopy revealed that CBZ prevented calcium overloading, the onset of the MPT and mitochondrial depolarization. Immunoblotting and fluorometric analysis showed that CBZ blocked calpain activation, depletion of Atg7 and Beclin-1 and loss of autophagic flux after reperfusion. Intravital multiphoton imaging of anesthetized mice demonstrated that CBZ substantially reversed autophagic defects and mitochondrial dysfunction after I/R in vivo. In conclusion, CBZ prevents calcium overloading and calpain activation, which, in turn, suppresses Atg7 and Beclin-1 depletion, defective autophagy, onset of the MPT and cell death after I/R. - Highlights: • A mechanism of carbamazepine (CBZ)-induced cytoprotection in livers is proposed. • Impaired autophagy is a key event contributing to lethal reperfusion injury. • The importance of autophagy is extended and confirmed in an in vivo model. • CBZ is a potential

  9. Chronic Intake of Japanese Sake Mediates Radiation-Induced Metabolic Alterations in Mouse Liver

    PubMed Central

    Nakajima, Tetsuo; Vares, Guillaume; Wang, Bing; Nenoi, Mitsuru

    2016-01-01

    Sake is a traditional Japanese alcoholic beverage that is gaining popularity worldwide. Although sake is reported to have beneficial health effects, it is not known whether chronic sake consumption modulates health risks due to radiation exposure or other factors. Here, the effects of chronic administration of sake on radiation-induced metabolic alterations in the livers of mice were evaluated. Sake (junmai-shu) was administered daily to female mice (C3H/He) for one month, and the mice were exposed to fractionated doses of X-rays (0.75 Gy/day) for the last four days of the sake administration period. For comparative analysis, a group of mice were administered 15% (v/v) ethanol in water instead of sake. Metabolites in the liver were analyzed by capillary electrophoresis-time-of-flight mass spectrometry one day following the last exposure to radiation. The metabolite profiles of mice chronically administered sake in combination with radiation showed marked changes in purine, pyrimidine, and glutathione (GSH) metabolism, which were only partially altered by radiation or sake administration alone. Notably, the changes in GSH metabolism were not observed in mice treated with radiation following chronic administration of 15% ethanol in water. Changes in several metabolites, including methionine and valine, were induced by radiation alone, but were not detected in the livers of mice who received chronic administration of sake. In addition, the chronic administration of sake increased the level of serum triglycerides, although radiation exposure suppressed this increase. Taken together, the present findings suggest that chronic sake consumption promotes GSH metabolism and anti-oxidative activities in the liver, and thereby may contribute to minimizing the adverse effects associated with radiation. PMID:26752639

  10. Nephrogenic Systemic Fibrosis Risk After Liver Magnetic Resonance Imaging With Gadoxetate Disodium in Patients With Moderate to Severe Renal Impairment

    PubMed Central

    Lauenstein, Thomas; Ramirez-Garrido, Francisco; Kim, Young Hoon; Rha, Sung Eun; Ricke, Jens; Phongkitkarun, Sith; Boettcher, Joachim; Gupta, Rajan T.; Korpraphong, Pornpim; Tanomkiat, Wiwatana; Furtner, Julia; Liu, Peter S.; Henry, Maren; Endrikat, Jan

    2015-01-01

    Objective The objective of this study was to assess the risk of gadoxetate disodium in liver imaging for the development of nephrogenic systemic fibrosis (NSF) in patients with moderate to severe renal impairment. Materials and Methods We performed a prospective, multicenter, nonrandomized, open-label phase 4 study in 35 centers from May 2009 to July 2013. The study population consisted of patients with moderate to severe renal impairment scheduled for liver imaging with gadoxetate disodium. All patients received a single intravenous bolus injection of 0.025-mmol/kg body weight of liver-specific gadoxetate disodium. The primary target variable was the number of patients who develop NSF within a 2-year follow-up period. Results A total of 357 patients were included, with 85 patients with severe and 193 patients with moderate renal impairment, which were the clinically most relevant groups. The mean time period from diagnosis of renal disease to liver magnetic resonance imaging (MRI) was 1.53 and 5.46 years in the moderate and severe renal impairment cohort, respectively. Overall, 101 patients (28%) underwent additional contrast-enhanced MRI with other gadolinium-based MRI contrast agents within 12 months before the start of the study or in the follow-up. No patient developed symptoms conclusive of NSF within the 2-year follow-up. Conclusions Gadoxetate disodium in patients with moderate to severe renal impairment did not raise any clinically significant safety concern. No NSF cases were observed. PMID:25756684

  11. Health-Related Quality of Life in Pediatric Liver Transplant Recipients Compared to Other Chronic Disease Groups

    PubMed Central

    Limbers, Christine A; Neighbors, Katie; Martz, Karen; Bucuvalas, John C; Webb, Thomas; Varni, James W; Alonso, Estella M

    2010-01-01

    This cross-sectional, multi-center cohort study compares the level of health-related quality of life (HRQOL) of pediatric liver transplant (LT) recipients to children with other chronic health conditions. Design and Methods LT sample included 873 children who survived at least 12 months following LT. Six chronic disease samples were compiled from numerous studies, including over 800 patients with Juvenile Rheumatoid Arthritis (JRA), type 1 diabetes, cancer in remission, cardiac disease, end-stage renal disease and inflammatory bowel disease. Generic HRQOL was measured from both the parental and patient perspective using the PedsQL™ 4.0 Generic Core Scales. Results Pediatric LT patients reported better physical health than children with JRA. According to parents, pediatric LT recipients had better HRQOL than children on renal dialysis on all domains except school functioning. Across all domains but emotional functioning, pediatric LT recipients reported significantly lower HRQOL than children with type 1 diabetes. Overall, pediatric LT patients reported comparable HRQOL to children who had undergone renal transplantation and patients with cancer in remission. Conclusions Pediatric LT patients manifested impaired HRQOL similar to children with chronic diseases and these data suggest they face ongoing challenges that warrant monitoring and indicate a need for interventions to improve their HRQOL. PMID:21199214

  12. Functional activity of sphingomyelin cycle in rat liver in chronic toxic hepatitis.

    PubMed

    Serebrov, V Yu; Kuzmenko, D I; Burov, P G; Novitsky, S V

    2008-12-01

    Activities of sphingomyelinase and ceramidase decreased in the liver in chronic toxic hepatitis and the balance between the levels of proapoptotic ceramide and antiapoptotic sphyngosine-1-phosphate shifts towards the latter substance. Pronounced changes in the qualitative and quantitative composition of fatty acids in the sphingomyelin cycle effector molecules were revealed. PMID:19513367

  13. Risk of liver injury after α-glucosidase inhibitor therapy in advanced chronic kidney disease patients

    PubMed Central

    Kao, Chih-Chin; Wu, Pei-Chen; Wu, Che-Hsiung; Chen, Li-kwang; Chen, Hsi-Hsien; Wu, Mai-Szu; Wu, Vin-Cent

    2016-01-01

    Although α-glucosidase inhibitors (AGIs) are commonly used for controlling postprandial blood glucose, AGIs-induced liver injuries have been reported. However, the relationship between AGIs and liver injuries in advanced chronic kidney disease (CKD) patients remains unexplored. In this nationwide case-control study, we recruited 1765 advanced diabetic CKD patients, who received AGIs therapy from January 1, 2000 to December 31, 2010 as the study sample and 5295 matched controls. Recent and former AGIs users were defined as patients who received the AGIs prescription for 30–60 d and 30–210 d before the event of liver injury. The risk of AGIs-induced liver injury was examined using time-dependent Cox proportional hazards model. Liver injury occurred in 3.9% of patients in the study group and 3.3% of patients in the control group. AGIs use did not increase the risk of liver injury in advanced CKD patients (P = 0.19). The stratified analysis indicated no increased risk of liver injury in all AGIs-using subgroups (all P > 0.05). The available evidence supports extending the use of AGIs without increasing the risk of liver injury in patients with advanced CKD. Additional randomized controlled trials are warranted to confirm our results. PMID:26751038

  14. Sarcopenia in Patients with Chronic Liver Disease: Can It Be Altered by Diet and Exercise?

    PubMed

    Kappus, Matthew R; Mendoza, Mardeli Saire; Nguyen, Douglas; Medici, Valentina; McClave, Stephen A

    2016-08-01

    Sarcopenia, a loss of muscle mass, is being increasingly recognized to have a deleterious effect on outcomes in patients with chronic liver disease. Factors related to diet and the inflammatory nature of chronic liver disease contribute to the occurrence of sarcopenia in these patients. Sarcopenia adversely influences quality of life, performance, morbidity, success of transplantation, and even mortality. Specific deficiencies in macronutrients (protein, polyunsaturated fatty acids) and micronutrients (vitamins C, D, and E, carotenoids, and selenium) have been linked to sarcopenia. Lessons learned from nutritional therapy in geriatric patient populations may provide strategies to manage sarcopenia in patients with liver disease. Combining diet modification and nutrient supplementation with an organized program of exercise may help ameliorate or even reverse the effects of sarcopenia on an already complex disease process. PMID:27372291

  15. Chronic hepatitis E virus infection after living donor liver transplantation via blood transfusion: a case report.

    PubMed

    Kurihara, Takeshi; Yoshizumi, Tomoharu; Itoh, Shinji; Harimoto, Norifumi; Harada, Noboru; Ikegami, Toru; Inagaki, Yuki; Oshiro, Yukio; Ohkohchi, Nobuhiro; Okamoto, Hiroaki; Maehara, Yoshihiko

    2016-12-01

    Although it occurs worldwide, hepatitis E virus (HEV) infection in developed countries is generally foodborne. HEV infection is subclinical in most individuals. Although fulminant liver failure may occur, progression to chronic hepatitis is rare. This study describes a 41-year-old man with liver cirrhosis caused by non-alcoholic steatohepatitis and hepatocellular carcinoma within the Milan criteria. His liver function was classified as Child-Pugh grade C. Living donor liver transplantation (LDLT) was performed, and he was discharged from the hospital on postoperative day (POD) 22. However, his alanine aminotransferase concentration began to increase on POD 60 and HEV infection was detected on POD 81. Retrospective assessments of stored blood samples showed that this patient became positive for HEV RNA on POD 3. The liver donor was negative for anti-HEV antibodies and HEV RNA. However, the platelet concentrate transfused into the liver recipient the day after LDLT was positive for HEV RNA. The patient remained positive for HEV infection for 10 months. Treatment with 800 mg/day ribavirin for 20 weeks reduced HEV RNA to an undetectable level. In conclusion, this report describes a patient infected with HEV through a blood transfusion after LDLT, who progressed to chronic hepatitis probably due to his immunosuppressed state and was treated well with ribavirin therapy. PMID:27059470

  16. The treatment of diabetes mellitus of patients with chronic liver disease.

    PubMed

    García-Compeán, Diego; González-González, José A; Lavalle-González, Fernando J; González-Moreno, Emmanuel I; Maldonado-Garza, Héctor J; Villarreal-Pérez, Jesús Zacarías

    2015-01-01

    About 80% of patients with liver cirrhosis may have glucose metabolism disorders, 30% show overt diabetes mellitus (DM). Prospective studies have demonstrated that DM is associated with an increased risk of hepatic complications and death in patients with liver cirrhosis. DM might contribute to liver damage by promoting inflammation and fibrosis through an increase in mitochondrial oxidative stress mediated by adipokines. Based on the above mentioned the effective control of hyperglycemia may have a favorable impact on the evolution of these patients. However, only few therapeutic studies have evaluated the effectiveness and safety of antidiabetic drugs and the impact of the treatment of DM on morbidity and mortality in patients with liver cirrhosis. In addition, oral hypoglycemic agents and insulin may produce hypoglycemia and lactic acidosis, as most of these agents are metabolized by the liver. This review discusses the clinical implications of DM in patients with chronic liver disease. In addition the effectiveness and safety of old, but particularly the new antidiabetic drugs will be described based on pharmacokinetic studies and chronic administration to patients. Recent reports regarding the use of the SGLT2 inhibitors as well as the new incretin-based therapies such as injectable glucagon-like peptide-1 (GLP-1) receptor agonists and oral inhibitors of dipeptidylpeptidase-4 (DPP-4) will be discussed. The establishment of clear guidelines for the management of diabetes in patients with CLD is strongly required. PMID:26436350

  17. Acute-on-chronic liver failure: Pathogenesis, prognostic factors and management

    PubMed Central

    Blasco-Algora, Sara; Masegosa-Ataz, José; Gutiérrez-García, María Luisa; Alonso-López, Sonia; Fernández-Rodríguez, Conrado M

    2015-01-01

    Acute-on-chronic liver failure (ACLF) is increasingly recognized as a complex syndrome that is reversible in many cases. It is characterized by an acute deterioration of liver function in the background of a pre-existing chronic liver disease often associated with a high short-term mortality rate. Organ failure (OF) is always associated, and plays a key role in determining the course, and the outcome of the disease. The definition of ACLF remains controversial due to its overall ambiguity, with several disparate criteria among various associations dedicated to the study of liver diseases. Although the precise pathogenesis needs to be clarified, it appears that an altered host response to injury might be a contributing factor caused by immune dysfunction, ultimately leading to a pro-inflammatory status, and eventually to OF. The PIRO concept (Predisposition, Insult, Response and Organ Failure) has been proposed to better approach the underlying mechanisms. It is accepted that ACLF is a different and specific form of liver failure, where a precipitating event is always involved, even though it cannot always be ascertained. According to several studies, infections and active alcoholism often trigger ACLF. Viral hepatitis, gastrointestinal haemorrhage, or drug induced liver injury, which can also provoke the syndrome. This review mainly focuses on the physiopathology and prognostic aspects. We believe these features are essential to further understanding and providing the rationale for improveddisease management strategies. PMID:26576097

  18. Impairment of contextual fear extinction by chronic nicotine and withdrawal from chronic nicotine is associated with hippocampal nAChR upregulation.

    PubMed

    Kutlu, Munir Gunes; Oliver, Chicora; Huang, Peng; Liu-Chen, Lee-Yuan; Gould, Thomas J

    2016-10-01

    Chronic nicotine and withdrawal from chronic nicotine have been shown to be major modulators of fear learning behavior. Moreover, recent studies from our laboratory have shown that acute nicotine impaired fear extinction and safety learning in mice. However, the effects of chronic nicotine and withdrawal on fear extinction are unknown. Therefore, the current experiments were conducted to investigate the effects of chronic nicotine as well as withdrawal from chronic nicotine on contextual fear extinction in mice. C57BL6/J mice were given contextual fear conditioning training and retention testing during chronic nicotine administration. Mice then received contextual fear extinction either during chronic nicotine or during withdrawal from chronic nicotine. Our results showed that contextual fear extinction was impaired both during chronic nicotine administration and subsequent withdrawal. However, it was also observed that the effects of prior chronic nicotine disappeared after 72 h in withdrawal, a timeline that closely matches with the timing of the chronic nicotine-induced upregulation of hippocampal nicotinic acetylcholine receptor (nAChR) density. Additional experiments found that 4 days, but not 1 day, of continuous nicotine administration upregulated hippocampal nAChRs and impaired contextual fear extinction. These effects disappeared following 72 h withdrawal. Overall, these experiments provide a potential link between nicotine-induced upregulation of hippocampal nAChRs and fear extinction deficits observed in patients with anxiety disorders, which may lead to advancements in the pharmacological treatment methods for this disorder. PMID:27378334

  19. Mental development and growth in children with chronic liver disease of early and late onset.

    PubMed

    Stewart, S M; Uauy, R; Kennard, B D; Waller, D A; Benser, M; Andrews, W S

    1988-08-01

    Comparison was made of the mental function and physical growth of 21 children in whom liver disease occurred in the first year of life with 15 patients with late (17 months of age to 12 years of age) manifestation of liver disease. Ages (mean +/- SD) at testing for the two groups was 8 +/- 3 years for the early group and 11 +/- 5 years for the late group. Wechsler verbal, performance, and full-scale IQ scores were lower for the early group (range of mean scores: early, 85 to 86 v late, 96 to 103). Growth measures were significantly different in the two groups. Means +/- SD (percentage of standard) were: length for early group, 92 +/- 9; for late, 99 +/- 7; and head circumference for early, 98 +/- 4; for late, 101 +/- 2. The groups were similar in severity of liver disease and acute nutritional status, however. Patients with intellectual impairment had a longer duration of illness, poor nutritional status, and vitamin E deficiency; 82% of impaired patients were in the early group. The data suggest that liver disease during early life has pernicious effects on intellectual function and linear growth. Careful monitoring of nutritional status of children with early-onset liver disease and aggressive nutritional support beginning at the time of diagnosis may help reduce delays in growth and mental development. PMID:3399290

  20. [A case of multiple liver abscesses associated with Streptococcus salivarius in a patient with chronic periodontitis].

    PubMed

    Kamachi, Saori; Otsuka, Taiga; Tsuji, Chika; Nakashita, Shunya; Ide, Yasushi; Mizuta, Toshihiko

    2014-08-01

    Streptococcus salivarius is an oral commensal bacterium that rarely causes disease in humans. Here, we report a case of liver abscess associated with S. salivarius in a 41-year-old woman who presented with continuous abdominal discomfort, fatigue, and fever. She was diagnosed with multiple liver abscesses; she underwent percutaneous transhepatic abscess drainage. Thereafter, S. salivarius was isolated in all bacterial cultures of the drained abscesses, and it was sensitive to penicillins. She made a good recovery after treatment. In the absence of an infective source other than chronic periodontitis, the cause of liver abscesses was attributed to oral S. salivarius. S. salivarius is a normal oral commensal, and oral commensals must be considered if the infective origin of liver abscess cannot be determined. PMID:25100350

  1. Simultaneous impairment of passive avoidance learning and nociception in rats following chronic swim stress

    PubMed Central

    Nazeri, Masoud; Shabani, Mohammad; Parsania, Shahrnaz; Golchin, Leila; Razavinasab, Moazamehosadat; Abareghi, Fatemeh; Kermani, Moein

    2016-01-01

    Background: Stress can alter response to nociception. Under certain circumstances stress enhances nociception, a phenomenon which is called stress-induced hyperalgesia (SIH). While nociception has been studied in this paradigm, possible alterations occurring in passive avoidance (PA) learning after exposing rats to this type of stress has not been studied before. Materials and Methods: In the current study, we evaluated the effect of chronic swim stress (FS) or sham swim (SS) on nociception in both spinal (tail-flick) and supraspinal (53.5°C hot-pate) levels. Furthermore, PA task was performed to see whether chronic swim stress changes PA learning or not. Mobility of rats and anxiety-like behavior were assessed using open-field test (OFT). Results: Supraspinal pain response was altered by swim stress (hot-plate test). PA learning was impaired by swim stress, rats in SS group did not show such impairments. Rats in the FS group showed increased mobility (rearing, velocity, total distant moved (TDM) and decreased anxiety-like behavior (time spent in center and grooming) compared to SS rats. Conclusions: This study demonstrated the simultaneous impairment of PA and nociception under chronic swim stress, whether this is simply a co-occurrence or not is of special interest. This finding may implicate a possible role for limbic structures, though this hypothesis should be studied by experimental lesions in different areas of rat brain to assess their possible role in the pathophysiology of SIH. PMID:27308265

  2. Chronic social stress during adolescence induces cognitive impairment in aged mice.

    PubMed

    Sterlemann, Vera; Rammes, Gerhard; Wolf, Miriam; Liebl, Claudia; Ganea, Karin; Müller, Marianne B; Schmidt, Mathias V

    2010-04-01

    Age-related cognitive decline is one of the major aspects that impede successful aging in humans. Environmental factors, such as chronic stress, can accelerate or aggravate cognitive deficits during aging. While there is abundant evidence that chronic stress directly affects cognitive performance, the lasting consequences of stress exposures during vulnerable developmental time windows are largely unknown. This is especially true for the adolescent period, which is critical in terms of physical, sexual, and behavioral maturation. Here we used chronic social stress during adolescence in male mice and investigated the consequences of this treatment on cognitive performance during aging. We observed a substantial impairment of spatial memory, but not other memory domains, 12 months after the end of the stress period. This hippocampus-dependent cognitive dysfunction was supported by concomitant impairment in LTP induction in CA1 neurons in 15-month-old animals. Further, we observed a decrease of hippocampal BDNF mRNA and synaptophysin immunoreactivity, suggesting plasticity and structural alterations in formerly stressed mice. Finally, we identified expression changes of specific neurotransmitter subunits critically involved in learning and memory, specifically the NMDA receptor subunit NR2B. Taken together, our results identify possible molecular mechanisms underlying cognitive impairment during aging, demonstrating the detrimental impact of stress during adolescence on hippocampus-dependent cognitive function in aged mice. PMID:19489003

  3. Small hepatocellular carcinomas in chronic liver disease: Detection with SPECT

    SciTech Connect

    Kudo, M.; Hirasa, M.; Takakuwa, H.; Ibuki, Y.; Fujimi, K.; Miyamura, M.; Tomita, S.; Komori, H.; Todo, A.; Kitaura, Y.

    1986-06-01

    Single-photon emission computed tomography (SPECT) performed using a rotating gamma camera was compared with ..cap alpha../sub 1/-fetoprotein (AFP) assay, conventional liver scintigraphy, ultrasound (US) imaging, computed tomography (CT), and selective celiac angiography in 40 patients with a total of 50 small hepatocellular carcinomas (HCCs;<5 cm). The detection rates of US and CT were determined on an initial screening study and on a second, more precisely focused study. The detection rate of small HCCs by the various modalities was as follows: AFP, 13%; liver scintigraphy, 36%; SPECT, 72%; initial screening US, 80%; second, more precise US studies, 94%; initial screening CT, 64%; second, more precise CT study, 82%; angiography, 88%. Although SPECT was inferior to the initial screening US examination in detecting HCCs less than 2 cm in size, its sensitivity was identical to that of the initial screening US study for detecting HCCs of 2-5 cm. The combination of SPECT and US was an excellent method for the early detection of HCCs, yielding a detection rate of 94%.

  4. BubR1 Insufficiency Impairs Liver Regeneration in Aged Mice after Hepatectomy through Intercalated Disc Abnormality.

    PubMed

    Ikawa-Yoshida, Ayae; Matsumoto, Takuya; Okano, Shinji; Aoyagi, Yukihiko; Matsubara, Yutaka; Furuyama, Tadashi; Nakatsu, Yoshimichi; Tsuzuki, Teruhisa; Onimaru, Mitsuho; Ohkusa, Tomoko; Nomura, Masatoshi; Maehara, Yoshihiko

    2016-01-01

    A delay in liver regeneration after partial hepatectomy (PHx) leads to acute liver injury, and such delays are frequently observed in aged patients. BubR1 (budding uninhibited by benzimidazole-related 1) controls chromosome mitotic segregation through the spindle assembly checkpoint, and BubR1 down-regulation promotes aging-associated phenotypes. In this study we investigated the effects of BubR1 insufficiency on liver regeneration in mice. Low-BubR1-expressing mutant (BubR1(L/L)) mice had a delayed recovery of the liver weight-to-body weight ratio and increased liver deviation enzyme levels after PHx. Microscopic observation of BubR1(L/L) mouse liver showed an increased number of necrotic hepatocytes and intercalated disc anomalies, resulting in widened inter-hepatocyte and perisinusoidal spaces, smaller hepatocytes and early-stage microvilli atrophy. Up-regulation of desmocollin-1 (DSC1) was observed in wild-type, but not BubR1(L/L), mice after PHx. In addition, knockdown of BubR1 expression caused down-regulation of DSC1 in a human keratinocyte cell line. BubR1 insufficiency results in the impaired liver regeneration through weakened microstructural adaptation against PHx, enhanced transient liver failure and delayed hepatocyte proliferation. Thus, our data suggest that a reduction in BubR1 levels causes failure of liver regeneration through the DSC1 abnormality. PMID:27561386

  5. BubR1 Insufficiency Impairs Liver Regeneration in Aged Mice after Hepatectomy through Intercalated Disc Abnormality

    PubMed Central

    Ikawa-Yoshida, Ayae; Matsumoto, Takuya; Okano, Shinji; Aoyagi, Yukihiko; Matsubara, Yutaka; Furuyama, Tadashi; Nakatsu, Yoshimichi; Tsuzuki, Teruhisa; Onimaru, Mitsuho; Ohkusa, Tomoko; Nomura, Masatoshi; Maehara, Yoshihiko

    2016-01-01

    A delay in liver regeneration after partial hepatectomy (PHx) leads to acute liver injury, and such delays are frequently observed in aged patients. BubR1 (budding uninhibited by benzimidazole-related 1) controls chromosome mitotic segregation through the spindle assembly checkpoint, and BubR1 down-regulation promotes aging-associated phenotypes. In this study we investigated the effects of BubR1 insufficiency on liver regeneration in mice. Low-BubR1-expressing mutant (BubR1L/L) mice had a delayed recovery of the liver weight-to-body weight ratio and increased liver deviation enzyme levels after PHx. Microscopic observation of BubR1L/L mouse liver showed an increased number of necrotic hepatocytes and intercalated disc anomalies, resulting in widened inter-hepatocyte and perisinusoidal spaces, smaller hepatocytes and early-stage microvilli atrophy. Up-regulation of desmocollin-1 (DSC1) was observed in wild-type, but not BubR1L/L, mice after PHx. In addition, knockdown of BubR1 expression caused down-regulation of DSC1 in a human keratinocyte cell line. BubR1 insufficiency results in the impaired liver regeneration through weakened microstructural adaptation against PHx, enhanced transient liver failure and delayed hepatocyte proliferation. Thus, our data suggest that a reduction in BubR1 levels causes failure of liver regeneration through the DSC1 abnormality. PMID:27561386

  6. Tributyltin chloride leads to adiposity and impairs metabolic functions in the rat liver and pancreas.

    PubMed

    Bertuloso, Bruno D; Podratz, Priscila L; Merlo, Eduardo; de Araújo, Julia F P; Lima, Leandro C F; de Miguel, Emilio C; de Souza, Leticia N; Gava, Agata L; de Oliveira, Miriane; Miranda-Alves, Leandro; Carneiro, Maria T W D; Nogueira, Celia R; Graceli, Jones B

    2015-05-19

    Tributyltin chloride (TBT) is an environmental contaminant used in antifouling paints of boats. Endocrine disruptor effects of TBT are well established in animal models. However, the adverse effects on metabolism are less well understood. The toxicity of TBT in the white adipose tissue (WAT), liver and pancreas of female rats were assessed. Animals were divided into control and TBT (0.1 μg/kg/day) groups. TBT induced an increase in the body weight of the rats by the 15th day of oral exposure. The weight gain was associated with high parametrial (PR) and retroperitoneal (RP) WAT weights. TBT-treatment increased the adiposity, inflammation and expression of ERα and PPARγ proteins in both RP and PR WAT. In 3T3-L1 cells, estrogen treatment reduced lipid droplets accumulation, however increased the ERα protein expression. In contrast, TBT-treatment increased the lipid accumulation and reduced the ERα expression. WAT metabolic changes led to hepatic inflammation, lipid accumulation, increase of PPARγ and reduction of ERα protein expression. Accordingly, there were increases in the glucose tolerance and insulin sensitivity tests with increases in the number of pancreatic islets and insulin levels. These findings suggest that TBT leads to adiposity in WAT specifically, impairing the metabolic functions of the liver and pancreas. PMID:25819109

  7. Transient elastography compared to liver biopsy and morphometry for predicting fibrosis in pediatric chronic liver disease: Does etiology matter?

    PubMed Central

    Behairy, Behairy El-Sayed; Sira, Mostafa Mohamed; Zalata, Khaled Refat; Salama, El-Sayed Ebrahem; Abd-Allah, Mohamed Ahmed

    2016-01-01

    AIM: To evaluate transient elastography (TE) as a noninvasive tool in staging liver fibrosis compared with liver biopsy and morphometry in children with different chronic liver diseases. METHODS: A total of 90 children [50 with chronic hepatitis C virus (HCV), 20 with autoimmune hepatitis (AIH) and 20 with Wilson disease] were included in the study and underwent liver stiffness measurement (LSM) using TE. Liver biopsies were evaluated for fibrosis, qualitatively, by Ishak score and quantitatively by fibrosis area fraction (FAF) using digital image analysis (morphometry). LSM was correlated with fibrosis and other studied variables using spearman correlation. A stepwise multiple regression analysis was also performed to examine independent factors associated with LSM. Different cut-off values of LSM were calculated for predicting individual fibrosis stages using receiver-operating characteristic curve. Cut-off values with optimal clinical performance (optimal sensitivity and specificity simultaneously) were selected. RESULTS: The majority of HCV group had minimal activity (80%) and no/mild fibrosis (72%). On the other hand, the majority of AIH group had mild to moderate activity (70%) and moderate to severe fibrosis (95%) and all Wilson disease group had mild to moderate activity (100%) and moderate to severe fibrosis (100%). LSM correlated significantly with both FAF and Ishak scores and the correlation appeared better with the latter (r = 0.839 vs 0.879, P < 0.0001 for both). LSM discriminated individual stages of fibrosis with high performance. Sensitivity ranged from 81.4% to 100% and specificity ranged from 75.0% to 97.2%. When we compared LSM values for the same stage of fibrosis, they varied according to the different etiologies. Higher values were in AIH (16.15 ± 7.23 kPa) compared to Wilson disease (8.30 ± 0.84 kPa) and HCV groups (7.43 ± 1.73 kPa). Multiple regression analysis revealed that Ishak fibrosis stage was the only independent variable

  8. Expression and function of the atypical cadherin FAT1 in chronic liver disease

    SciTech Connect

    Valletta, Daniela; Czech, Barbara; Thasler, Wolfgang E.; Mueller, Martina; Bosserhoff, Anja-Katrin; Hellerbrand, Claus

    2012-09-28

    Highlights: Black-Right-Pointing-Pointer The expression of the atypical cadherin FAT1 is increased in chronic liver disease. Black-Right-Pointing-Pointer FAT1 expression goes up during the activation of hepatic stellate cells (HSCs). Black-Right-Pointing-Pointer Activated HSCs are the cellular source of enhanced FAT1 expression in diseased livers. Black-Right-Pointing-Pointer FAT1 enhanced NFkB activity and resistance to apoptosis in activated HSCs. Black-Right-Pointing-Pointer FAT1 is a new therapeutic target for prevention and treatment of hepatic fibrosis. -- Abstract: Hepatic fibrosis can be considered as wound healing process in response to hepatocellular injury. Activation of hepatic stellate cells (HSCs) is a key event of hepatic fibrosis since activated HSCs are the cellular source of enhanced extracellular matrix deposition, and reversion of liver fibrosis is accompanied by clearance of activated HSCs by apoptosis. The atypical cadherin FAT1 has been shown to regulate diverse biological functions as cell proliferation and planar cell polarity, and also to affect wound healing. Here, we found increased FAT1 expression in different murine models of chronic liver injury and in cirrhotic livers of patients with different liver disease. Also in hepatic tissue of patients with non-alcoholic steatohepatitis FAT1 expression was significantly enhanced and correlated with collagen alpha I(1) expression. Immunohistochemistry revealed no significant differences in staining intensity between hepatocytes in normal and cirrhotic liver tissue but myofibroblast like cells in fibrotic septa of cirrhotic livers showed a prominent immunosignal. Furthermore, FAT1 mRNA and protein expression markedly increased during in vitro activation of primary human and murine HSCs. Together, these data indicated activated HSCs as cellular source of enhanced FAT1 expression in diseased livers. To gain insight into the functional role of FAT1 in activated HSCs we suppressed FAT1 in these

  9. Association of Chronic Diseases and Impairments with Disability in Older Adults: A Decade of Change?

    PubMed Central

    Hung, William W; Ross, Joseph S; Boockvar, Kenneth S; Siu, Albert L

    2012-01-01

    Background Little is known about how the relationship between chronic disease, impairment, and disability has changed over time among older adults. Objective To examine how the associations of chronic disease and impairment with specific disability have changed over time. Research Design Repeated cross-sectional analysis, followed by examining the collated sample using time interaction variables, of 3 recent waves of the Health and Retirement Study. Subjects 10390, 10621 and 10557 community dwelling adults aged 65+ in 1998, 2004, 2008 Measurements Survey-based history of chronic diseases including hypertension, heart disease, heart failure, stroke, diabetes, cancer, chronic lung disease and arthritis; impairments, including cognition, vision and hearing; and disability, including mobility, complex activities of daily living (ADL) and self-care ADL. Results Over time, the relationship of chronic diseases and impairments with disability were largely unchanged; however, the association between hypertension and complex ADL disability weakened from 1998, to 2004 and 2008 (OR=1.24, 99% CI, 1.06–1.46; OR=1.07, 99% CI, 0.90–1.27; OR=1.00, 99%CI, 0.83–1.19 respectively), as it did for hypertension and self-care disability (OR=1.32, 99%CI, 1.13–1.54; OR=0.97, 99% CI, 0.82–1.14; OR=0.99, 99%CI, 0.83–1.17). The association between diabetes and self-care disability strengthened from 1998 to 2004 and 2008 (OR=1.21, 99% CI, 1.01–1.46; OR=1.37, 99% CI, 1.15–1.64; OR=1.52, 99% CI, 1.29–1.79), as it also did for lung disease and self-care disability (OR=1.64, 99%CI, 1.33–2.03; OR=1.63, 99% CI, 1.32–2.01; OR=2.11, 99% CI, 1.73–2.57). Conclusions While relationships between diseases, impairments and disability were largely unchanged, disability became less associated with hypertension and more with diabetes and lung disease. PMID:22584885

  10. Invasive and non-invasive methods for the assessment of fibrosis and disease progression in chronic liver disease.

    PubMed

    Castera, Laurent

    2011-04-01

    Chronic liver diseases represent a major public health problem, accounting for significant morbidity and mortality worldwide. Their prognosis and management greatly depend on the amount and progression of liver fibrosis with the risk of developing cirrhosis. Liver biopsy, traditionally considered as the reference standard for staging of fibrosis, has been challenged over the past decade by the development of novel non invasive methodologies. These methods rely on two distinct but complementary approaches: i) a 'biological' approach based on the dosage of serum biomarkers of fibrosis; ii) a 'physical' approach based on the measurement of liver stiffness using transient elastography (TE). Non invasive methods have been initially studied and validated in chronic hepatitis C but are now increasingly used in other chronic liver diseases, resulting in a significant decrease in the need for liver biopsy. However, they will likely not completely abolish the need for liver biopsy and they should rather be employed as an integrated system with liver biopsy. This review is aimed at discussing the advantages and inconveniences of non invasive methods in comparison with liver biopsy for the management of patients with chronic liver diseases. PMID:21497746

  11. Early warning and clinical outcome prediction of acute-on-chronic hepatitis B liver failure

    PubMed Central

    Chen, En-Qiang; Zeng, Fan; Zhou, Ling-Yun; Tang, Hong

    2015-01-01

    Hepatitis B virus (HBV) associated acute-on-chronic liver failure (ACLF) is an increasingly recognized fatal liver disease encompassing a severe acute exacerbation of liver function in patients with chronic hepatitis B (CHB). Despite the introduction of an artificial liver support system and antiviral therapy, the short-term prognosis of HBV-ACLF is still extremely poor unless emergency liver transplantation is performed. In such a situation, stopping or slowing the progression of CHB to ACLF at an early stage is the most effective way of reducing the morbidity and mortality of HBV-ACLF. It is well-known that the occurrence and progression of HBV-ACLF is associated with many factors, and the outcomes of HBV-ACLF patients can be significantly improved if timely and appropriate interventions are provided. In this review, we highlight recent developments in early warning and clinical outcome prediction in patients with HBV-ACLF and provide an outlook for future research in this field. PMID:26576085

  12. Chronic overexpression of PNPLA3I148M in mouse liver causes hepatic steatosis

    PubMed Central

    Li, John Zhong; Huang, Yongcheng; Karaman, Ruchan; Ivanova, Pavlina T.; Brown, H. Alex; Roddy, Thomas; Castro-Perez, Jose; Cohen, Jonathan C.; Hobbs, Helen H.

    2012-01-01

    A genetic variant in PNPLA3 (PNPLA3I148M), a triacylglycerol (TAG) hydrolase, is a major risk factor for nonalcoholic fatty liver disease (NAFLD); however, the mechanism underlying this association is not known. To develop an animal model of PNPLA3-induced fatty liver disease, we generated transgenic mice that overexpress similar amounts of wild-type PNPLA3 (PNPLA3WT) or mutant PNPLA3 (PNPLA3I148M) either in liver or adipose tissue. Overexpression of the transgenes in adipose tissue did not affect liver fat content. Expression of PNPLA3I148M, but not PNPLA3WT, in liver recapitulated the fatty liver phenotype as well as other metabolic features associated with this allele in humans. Metabolic studies provided evidence for 3 distinct alterations in hepatic TAG metabolism in PNPLA3I148M transgenic mice: increased formation of fatty acids and TAG, impaired hydrolysis of TAG, and relative depletion of TAG long-chain polyunsaturated fatty acids. These findings suggest that PNPLA3 plays a role in remodeling TAG in lipid droplets, as they accumulate in response to food intake, and that the increase in hepatic TAG levels associated with the I148M substitution results from multiple changes in hepatic TAG metabolism. The development of an animal model that recapitulates the metabolic phenotype of the allele in humans provides a new platform in which to elucidate the role of PNLPA3I148M in NAFLD. PMID:23023705

  13. YKL-40 expression in CD14+ liver cells in acute and chronic injury

    PubMed Central

    Pizano-Martínez, Oscar; Yañez-Sánchez, Irinea; Alatorre-Carranza, Pilar; Miranda-Díaz, Alejandra; Ortiz-Lazareno, Pablo C; García-Iglesias, Trinidad; Daneri-Navarro, Adrian; Mercado, Mónica Vázquez-Del; Fafutis-Morris, Mary; Delgado-Rizo, Vidal

    2011-01-01

    AIM: To demonstrate that CD14+ cells are an important source of the growth factor YKL-40 in acute and chronic liver damage. METHODS: Rats were inoculated with one dose of CCl4 to induce acute damage. Liver biopsies were obtained at 0, 6, 12, 24, 48 and 72 h. For chronic damage, CCl4 was administered three days per week for 6 or 8 wk. Tissue samples were collected, and cellular populations were isolated by liver digestion and purified by cell sorting. YKL-40 mRNA and protein expression were evaluated by real-time polymerase chain reaction and western blot. RESULTS: Acute liver damage induced a rapid increase of YKL-40 mRNA beginning at 12 h. Expression peaked at 24 h, with a 26-fold increase over basal levels. By 72 h however, YKL-40 expression levels had nearly returned to control levels. On the other hand, chronic damage induced a sustained increase in YKL-40 expression, with 7- and 9-fold higher levels at 6 and 8 wk, respectively. The pattern of YKL-40 expression in different subpopulations showed that CD14+ cells, which include Kupffer cells, are a source of YKL-40 after acute damage at 72 h [0.09 relative expression units (REU)] as well as after chronic injury at 6 wk (0.11 REU). Hepatocytes, in turn, accounted for 0.06 and 0.01 REU after 72 h (acute) or 6 wk (chronic), respectively. The rest of the CD14- cells (including T lymphocytes, B lymphocytes, natural killer and natural killer T cells) yielded 0.07 and 0.15 REU at 72 h and 6 wk, respectively. YKL-40 protein expression in liver was detected at 72 h as well as 6 and 8 wk, with the highest expression relative to controls (11-fold; P ≤ 0.05) seen at 6 wk. Macrophages were stimulated by lipopolysaccharide. We demonstrate that under these conditions, these cells showed maximum expression of YKL-40 at 12 h, with P < 0.05 compared with controls. CONCLUSION: Hepatic CD14+ cells are an YKL-40 mRNA and protein source in acute and chronic liver injury, with expression patterns similar to growth factors implicated

  14. Risk factors and ultrasound can predict chronic hepatitis caused by nonalcoholic fatty liver disease.

    PubMed

    Riley, Thomas R; Kahn, Amin

    2006-01-01

    The diagnosis of nonalcoholic fatty liver disease (NAFLD) is under-recognized. The aim of this study was to develop a scoring system that separates NAFLD diagnosis as a cause of chronic hepatitis from controls by using clinical features and liver ultrasound. A retrospective review of consecutive NAFLD cases and other liver disease controls was undertaken selecting patients from an abnormal liver function test code. To qualify for analysis all patients had to have elevated liver injury tests for more then 6 months, a biopsy-confirmed diagnosis, and an ultrasound as part of the evaluation. There were 84 cases of NAFLD and 75 liver disease controls. The NAFLD group had a larger body mass index (BMI) (34.9 versus 26.1; P < or = 0.0001), a larger liver span (9.8 versus 8.1 cm; P < or = 0.0001), and higher triglycerides (252 versus 142.6; P < or = 0.0001). The ultrasound reports recorded features consistent with fatty infiltration in 65.5% of NAFLD cases, compared to 5.3% of other liver diseases (P < or = 0.0001). Diabetes mellitus was found in 35% of NAFLD and 6.7% of other cases (P < or = 0.0001). The BMI was >30 in 79.8% of NAFLD cases and 22.7% of other liver disease cases (P < or = 0.0001). The liver span was >8 cm in 78.6% of NAFLD cases and in only 16% of controls (P = 0.0001). On multivariate analysis using logistic regression, the odds ratio of having ultrasound report findings suggestive of fatty infiltration was 15.9 (CI, 4.1-60). The odds ratio was 9.4 (CI, 2.3-37.9) for diabetes, 5.0 (CI, 1.7-14.6) for BMI >30, and 2.3 for liver span >8 cm (CI, 1.36-3.90). A scoring system using clinical features and ultrasound was shown to reliably separate NAFLD from other cases of chronic hepatitis. PMID:16416209

  15. Interferon-λ rs12979860 genotype and liver fibrosis in viral and non-viral chronic liver disease.

    PubMed

    Eslam, Mohammed; Hashem, Ahmed M; Leung, Reynold; Romero-Gomez, Manuel; Berg, Thomas; Dore, Gregory J; Chan, Henry L K; Irving, William L; Sheridan, David; Abate, Maria L; Adams, Leon A; Mangia, Alessandra; Weltman, Martin; Bugianesi, Elisabetta; Spengler, Ulrich; Shaker, Olfat; Fischer, Janett; Mollison, Lindsay; Cheng, Wendy; Powell, Elizabeth; Nattermann, Jacob; Riordan, Stephen; McLeod, Duncan; Armstrong, Nicola J; Douglas, Mark W; Liddle, Christopher; Booth, David R; George, Jacob; Ahlenstiel, Golo

    2015-01-01

    Tissue fibrosis is a core pathologic process that contributes to mortality in ~45% of the population and is likely to be influenced by the host genetic architecture. Here we demonstrate, using liver disease as a model, that a single-nucleotide polymorphism (rs12979860) in the intronic region of interferon-λ4 (IFNL4) is a strong predictor of fibrosis in an aetiology-independent manner. In a cohort of 4,172 patients, including 3,129 with chronic hepatitis C (CHC), 555 with chronic hepatitis B (CHB) and 488 with non-alcoholic fatty liver disease (NAFLD), those with rs12979860CC have greater hepatic inflammation and fibrosis. In CHC, those with rs12979860CC also have greater stage-constant and stage-specific fibrosis progression rates (P<0.0001 for all). The impact of rs12979860 genotypes on fibrosis is maximal in young females, especially those with HCV genotype 3. These findings establish rs12979860 genotype as a strong aetiology-independent predictor of tissue inflammation and fibrosis. PMID:25740255

  16. Chronic Stress Impairs Prefrontal Cortex-Dependent Response Inhibition and Spatial Working Memory

    PubMed Central

    Mika, Agnieszka; Mazur, Gabriel J.; Hoffman, Ann N.; Talboom, Joshua S.; Bimonte-Nelson, Heather A.; Sanabria, Federico; Conrad, Cheryl D.

    2012-01-01

    Chronic stress leads to neurochemical and structural alterations in the prefrontal cortex (PFC) that correspond to deficits in PFC-mediated behaviors. The present study examined the effects of chronic restraint stress on response inhibition (using a response-withholding task, fixed-minimum interval schedule of reinforcement, or FMI), and working memory (using a radial arm water maze, RAWM). Adult male Sprague Dawley rats were first trained on the RAWM and subsequently trained on FMI. Following acquisition of FMI, rats were assigned to a restraint stress (6h/d/28d in wire mesh restrainers) or control condition. Immediately after chronic stress, rats were tested on FMI and subsequently on RAWM. FMI results suggest that chronic stress reduces response inhibition capacity and motivation to initiate the task on selective conditions when food reward was not obtained on the preceding trial. RAWM results suggest that chronic stress produces transient deficits in working memory without altering previously consolidated reference memory. Behavioral measures from FMI failed to correlate with metrics from RAWM except for one in which changes in FMI timing precision negatively correlated with changes in RAWM working memory errors for the controls, a finding that was not observed following chronic stress. Fisher’s r to z transformation revealed no significant differences between control and stress with correlation coefficients. These findings are the first to show that chronic stress impairs both response inhibition and working memory, two behaviors that have never been direct compared within the same animals following chronic stress, using FMI, an appetitive task, and RAWM, a non-appetitive task. PMID:22905921

  17. Relevance of chronic hepatitis E in liver transplant recipients: a real-life setting.

    PubMed

    Galante, A; Pischke, S; Polywka, S; Luetgehethmann, M; Suneetha, P V; Gisa, A; Hiller, J; Dienes, H P; Nashan, B; Lohse, A W; Sterneck, M

    2015-08-01

    The chronic course of hepatitis E virus (HEV) infections in orthotopic liver transplant (OLT) recipients has been described previously, but prospectively collected data are rare. We aimed to study the role of chronic hepatitis E in OLT in a real-life setting. Therefore, 287 adult OLT recipients (169 male [59%], median age 56 years) were prospectively tested by HEV polymerase chain reaction assay (lower level of detection = 10 IU/mL), irrespective of their level of liver enzymes. In 4 patients (1.4%), chronic HEV infection was diagnosed. All 4 patients were male, and their age (median 48.5 years), the time since transplantation (median 45.5 months), and bilirubin level (median 0.6 mg/dL) did not differ significantly from the total cohort. However, alanine transaminase and aspartame transaminase levels were significantly higher in HEV-infected patients (75-646 U/L, median 216 U/L and 68-317 U/L, median 108 U/L) than in non-infected patients (6-617 U/L, median 41 and 6-355 U/L, median 36; P = 0.004 and 0.040, Mann-Whitney test). In 3 patients, liver biopsy was performed and revealed signs of inflammation and chronic liver disease, as enlarged densely infiltrated portal tracts with mild-to-moderate interface hepatitis. All infected patients were treated with ribavirin with the starting dose adjusted to renal function (400-800 mg/day). In 2 patients, dose reduction was necessary. Transaminases normalized in all 4 patients, and all patients cleared their infection within 3 months of ribavirin treatment. However, 1 patient experienced viral relapse 12 weeks after discontinuation. Ribavirin medication was re-started and viral clearance occurred within 8 weeks and persisted. Sequence analysis of the HEV genome of this patient revealed that he was infected with an HEV variant, which recently has been shown to have a reduced response to ribavirin in cell culture. The risk of chronic HEV infections in OLT recipients in low-endemic countries should not be overestimated. No case

  18. High neutrophil-lymphocyte ratio indicates poor prognosis for acute-on-chronic liver failure after liver transplantation

    PubMed Central

    Lin, Bing-Yi; Zhou, Lin; Geng, Lei; Zheng, Zhi-Yun; Jia, Jun-Jun; Zhang, Jing; Yao, Jia; Zheng, Shu-Sen

    2015-01-01

    AIM: To investigate the significance of pre-transplant neutrophil-lymphocyte ratio (NLR) in determining the prognosis of liver transplant (LT) recipients with acute-on-chronic liver failure (ACLF). METHODS: Data were collected from the liver transplantation data bank. The NLR values and other conventional inflammatory markers were evaluated for their ability to predict the prognosis of 153 patients with ACLF after LT. The NLR cut-off value was based on a receiver operating characteristic curve analysis. A Kaplan-Meier curve analysis and univariate and multivariate Cox regression models were used to define the independent risk factors for poor outcomes. RESULTS: The optimal NLR cut-off value was 4.6. Out of 153 patients, 83 (54.2%) had an NLR ≥ 4.6. The 1-, 3-, and 5-year overall survival rates were 94.3%, 92.5% and 92.5%, respectively, in the normal NLR group and 74.7%, 71.8% and 69.8%, respectively, in patients with high NLRs (P < 0.001). Furthermore, there was a significant difference in infectious complications after LT between the high and normal NLR groups. There were no significant differences for other complications. In the multivariate Cox regression model, a high NLR was defined as a significant predictor of poor outcomes for LT. CONCLUSION: A high NLR is a convenient and available predictor for prognosis of LT patients and can potentially optimize the current criteria for LT in ACLF. PMID:25805939

  19. Impairment and Coping in Children and Adolescents with Chronic Fatigue Syndrome: A Comparative Study with Other Paediatric Disorders

    ERIC Educational Resources Information Center

    Garralda, M. Elena; Rangel, Luiza

    2004-01-01

    Background: Functional impairment is a key feature of chronic fatigue syndrome (CFS) of childhood. Aim: To compare impairment, illness attitudes and coping mechanisms in childhood CFS and in other paediatric disorders. Method: Participants were 28 children and adolescents with CFS, 30 with juvenile idiopathic arthritis (JIA) and 27 with emotional…

  20. Liver regeneration after partial hepatectomy in rat is more impaired in a steatotic liver induced by dietary fructose compared to dietary fat

    SciTech Connect

    Tanoue, Shirou; Uto, Hirofumi; Kumamoto, Ryo; Arima, Shiho; Hashimoto, Shinichi; Nasu, Yuichiro; Takami, Yoichiro; Moriuchi, Akihiro; Sakiyama, Toshio; Oketani, Makoto; Ido, Akio; Tsubouchi, Hirohito

    2011-04-01

    Highlights: {yields} Hepatic steatosis in rats fed a high fructose diet was less severe than that in rats fed a high fat diet. {yields} Liver regeneration was more impaired in rats fed a high fructose diet than in rats fed a high fat diet. {yields} Dysregulation of genes associated with metabolism may contribute to impairment of liver regeneration. {yields} Regulation of the TGF-{beta}1 level after partial hepatectomy may be impaired in rats fed a high fructose diet. -- Abstract: Hepatic steatosis (HS) has a negative effect on liver regeneration, but different pathophysiologies of HS may lead to different outcomes. Male Sprague-Dawley rats were fed a high fructose (66% fructose; H-fruc), high fat (54% fat; H-fat), or control chow diet for 4 weeks. Based on hepatic triglyceride content and oil red O staining, HS developed in the H-fruc group, but was less severe compared to the H-fat group. Hepatic mRNA expression levels of fatty acid synthase and fructokinase were increased and those of carnitine palmitoyltransferase-1 and peroxisome proliferator-activated receptor-{alpha} were decreased in the H-fruc group compared to the H-fat group. Liver regeneration after 70% partial hepatectomy (PHx) was evaluated by measuring the increase in postoperative liver mass and PCNA-positive hepatocytes, and was impaired in the H-fruc group compared to the H-fat and control groups on days 3 and 7. Serum levels of tumor necrosis factor-{alpha}, interleukin-6 and hepatocyte growth factor did not change significantly after PHx. In contrast, serum TGF-{beta}1 levels were slightly but significantly lower in the control group on day 1 and in the H-fat group on day 3 compared to the level in each group on day 0, and then gradually increased. However, the serum TGF-{beta}1 level did not change after PHx in the H-fruc group. These results indicate that impairment of liver regeneration after PHx in HS is related to the cause, rather than the degree, of steatosis. This difference may result

  1. Inverse Association of Plasma Level of Glutathione Peroxidase with Liver Fibrosis in Chronic Hepatitis B: Potential Role of Iron

    PubMed Central

    Moossavi, Shirin; Besharat, Sima; Sharafkhah, Maryam; Ghanbari, Reza; Sharifi, Amrollah; Rezanejad, Parisa; Pourshams, Akram; Poustchi, Hossein; Mohamadkhani, Ashraf

    2016-01-01

    BACKGROUND Oxidative stress has a major pathogenic role for liver damage following chronic hepatitis B. Glutathione peroxidase (Gpx) is necessary in oxidative state mechanism that is generally down-regulated by Hepatitis B virus (HBV) infection. On the other hand, disorders of iron homeostasis have been found out in HBV infected patients. Therefore, the objective of this study was to assess the interplay of Gpx and serum iron on clinical and virological features of patients with chronic HBV infection. METHODS One hundred and fifty adult, treatment-naïve, patients with chronic hepatitis B were randomly designated from an ongoing cohort of patients with HBV. Plasma Gpx1 concentration and HBV DNA quantity were measured. Liver stiffness was measured by transient elastography. RESULTS Serum iron had a positive association with HBV DNA count in the total population. Serum iron was not associated with liver stiffness. However, HBV DNA was significantly associated with liver stiffness only in male patients. Serum Gpx was inversely associated with liver stiffness. Serum iron and Gpx had indirect effects on liver stiffness via HBV DNA count. We observed dissimilar effects of serum iron on HBV DNA and Gpx on liver stiffness in male and female patients. CONCLUSION We identified interplay of serum iron and Gpx1 in relation to level of liver fibrosis in patients with chronic hepatitis B. Our results propose that oxidative stress and serum iron are differentially implicated in the progression of chronic hepatitis B in male and female patients. PMID:27252819

  2. A panoramic view of chronic liver diseases and natural remedies reported in Traditional Persian Medicine.

    PubMed

    Zarshenas, Mohammad M; Farrokhi, Ratin Ranjbar; Akhavein, Mahshad; Kiafar, Mohammad Reza

    2016-01-01

    Regarding limited effectiveness of many hepatic medical approaches, seeking for novel treatment strategies is crucial to improve outcomes. Hence, the current study aims to compile a concise but critical review over reported liver diseases and related medicinal plants from the Persian medicine perspectives. To this end, five main pharmaceutical manuscripts of Persian medicine from 9th-18th A.D. as well as the latest and largest medical textbook of Persian medicine were studied. By searching through databases such as PubMed and ScienceDirect, mechanisms or pharmacological activities of reported medicinal plants in the field of liver diseases were cited and discussed. In all, seventeen different liver diseases, mainly chronic, were cited in Persian medicine. Ninety three medicinal plants with liver tonic, hepatoprotective and related effectiveness belonging to 49 families were derived and authenticated from these studied manuscripts. More than 75% of the herbs showed related hepatoprotectivity and antioxidant activities. However, none of them have been examined clinically. Besides historical clarification, the current investigation compiled an evidence- based study on reported liver herbal remedies from the standpoints of Persian scholars. Conducting attributable clinical trials against the backdrops of proven in vitro and in vivo studies may result in new treatment discoveries for liver diseases. PMID:26581222

  3. [Interferon-alpha and liver fibrosis in patients with chronic damage due to hepatitis C virus].

    PubMed

    Gonzalez-Huezo, María Sarai; Gallegos-Orozco, Juan Fernando

    2003-01-01

    The present review focuses on the published information published regarding the effects of interferon alpha therapy on liver fibrosis in patients with chronic liver damage secondary to hepatitis C infection. Data reviewed included results of the in vitro effects of interferon on hepatic cell line cultures with regards to indirect markers of fibrosis, activation of hepatic stellate cells and oxidative stress response. In the clinical arena, there is current clear evidence of a favorable histological outcome in patients with sustained viral response to interferon therapy. For this reason, the current review focuses more on the histological outcomes regarding liver fibrosis in patients who have not attained viral response to therapy (non-responders) or who already have biopsy defined cirrhosis. Data in these patients were analyzed according to the results of objective testing of fibrosis through the assessment of liver biopsy and its change during time, specially because the morbidity and mortality of this disease is directly related to the complications of liver cirrhosis and not necessarily to the persistence of the hepatitis C virus. Lastly, it is concluded that the process of liver fibrosis/cirrhosis is a dynamic one and that there is some evidence to support the usefulness of interferon alpha therapy as a means to halt or retard the progression of hepatic fibrosis. The result of current clinical trials in which interferon therapy is being used to modify the progression of fibrosis in non-responders or cirrhotic patients is eagerly awaited. PMID:14702938

  4. Early treatment of minocycline alleviates white matter and cognitive impairments after chronic cerebral hypoperfusion

    PubMed Central

    Ma, Jing; Zhang, Jing; Hou, Wei Wei; Wu, Xiao Hua; Liao, Ru Jia; Chen, Ying; Wang, Zhe; Zhang, Xiang Nan; Zhang, Li San; Zhou, Yu Dong; Chen, Zhong; Hu, Wei Wei

    2015-01-01

    Subcortical ischemic vascular dementia (SIVD) caused by chronic cerebral hypoperfusion develops with progressive white matter and cognitive impairments, yet no effective therapy is available. We investigated the temporal effects of minocycline on an experimental SIVD exerted by right unilateral common carotid arteries occlusion (rUCCAO). Minocycline treated at the early stage (day 0–3), but not the late stage after rUCCAO (day 4–32) alleviated the white matter and cognitive impairments, and promoted remyelination. The actions of minocycline may not involve the inhibition of microglia activation, based on the effects after the application of a microglial activation inhibitor, macrophage migration inhibitory factor, and co-treatment with lipopolysaccharides. Furthermore, minocycline treatment at the early stage promoted the proliferation of oligodendrocyte progenitor cells (OPCs) in subventricular zone, increased OPC number and alleviated apoptosis of mature oligodendrocytes in white matter. In vitro, minocycline promoted OPC proliferation and increased the percentage of OPCs in S and G2/M phases. We provided direct evidence that early treatment is critical for minocycline to alleviate white matter and cognitive impairments after chronic cerebral hypoperfusion, which may be due to its robust effects on OPC proliferation and mature oligodendrocyte loss. So, early therapeutic time window may be crucial for its application in SIVD. PMID:26174710

  5. MDMA pretreatment leads to mild chronic unpredictable stress-induced impairments in spatial learning.

    PubMed

    Cunningham, Jacobi I; Raudensky, Jamie; Tonkiss, John; Yamamoto, Bryan K

    2009-10-01

    3,4-Methylenedioxymethamphetamine (MDMA) is a drug of abuse worldwide and a selective serotonin (5-HT) neurotoxin. An important factor in the risk of drug abuse and relapse is stress. Although multiple parallels exist between MDMA abuse and stress, including effects on 5-HTergic neurotransmission, few studies have investigated the consequences of combined exposure to MDMA and chronic stress. Therefore, rats were pretreated with MDMA and exposed 7 days later to 10 days of mild chronic unpredictable stress (CUS). MDMA pretreatment was hypothesized to enhance the effects of CUS leading to enhanced 5-HT transporter (SERT) depletion in the hippocampus and increased anxiety and cognitive impairment. Whereas MDMA alone increased anxiety-like behavior on the elevated plus maze, CUS alone or in combination with MDMA pretreatment did not increase anxiety-like behavior. In contrast, MDMA pretreatment led to CUS-induced learning impairment in the Morris water maze but not an enhanced depletion of hippocampal SERT protein. These results show that prior exposure to MDMA leads to stress-induced impairments in learning behavior that is not otherwise observed with stress alone and appear unrelated to an enhanced depletion of SERT. PMID:19824774

  6. Impairment of energy metabolism in intact residual myocardium of rat hearts with chronic myocardial infarction.

    PubMed Central

    Neubauer, S; Horn, M; Naumann, A; Tian, R; Hu, K; Laser, M; Friedrich, J; Gaudron, P; Schnackerz, K; Ingwall, J S

    1995-01-01

    The purpose of this study was to test the hypothesis that energy metabolism is impaired in residual intact myocardium of chronically infarcted rat heart, contributing to contractile dysfunction. Myocardial infarction (MI) was induced in rats by coronary artery ligation. Hearts were isolated 8 wk later and buffer-perfused isovolumically. MI hearts showed reduced left ventricular developed pressure, but oxygen consumption was unchanged. High-energy phosphate contents were measured chemically and by 31P-NMR spectroscopy. In residual intact left ventricular tissue, ATP was unchanged after MI, while creatine phosphate was reduced by 31%. Total creatine kinase (CK) activity was reduced by 17%, the fetal CK isoenzymes BB and MB increased, while the "adult" mitochondrial CK isoenzyme activity decreased by 44%. Total creatine content decreased by 35%. Phosphoryl exchange between ATP and creatine phosphate, measured by 31P-NMR magnetization transfer, fell by 50% in MI hearts. Thus, energy reserve is substantially impaired in residual intact myocardium of chronically infarcted rats. Because phosphoryl exchange was still five times higher than ATP synthesis rates calculated from oxygen consumption, phosphoryl transfer via CK may not limit baseline contractile performance 2 mo after MI. In contrast, when MI hearts were subjected to acute stress (hypoxia), mechanical recovery during reoxygenation was impaired, suggesting that reduced energy reserve contributes to increased susceptibility of MI hearts to acute metabolic stress. PMID:7883957

  7. Baboon alcohol dehydrogenase isozymes: phenotypic changes in liver following chronic consumption of alcohol.

    PubMed

    Holmes, R S; VandeBerg, J L

    1987-01-01

    According to the nomenclature of Vallee and Bazzone [1983] for mammalian alcohol dehydrogenase (ADH) isozymes, baboon ADHs comprise three major classes of activity, which were distinguished according to the following properties: Class I ADHs. These isozymes exhibited low-Km characteristics with ethanol as substrate, high isoelectric points (8.5-9.3), and sensitivity to 5 mM 4-methyl pyrazole inhibition, and were the major liver (ADH-2) and kidney (ADH-1) isozymes in the baboon. Class II ADHs. These isozymes showed high-Km values for ethanol, neutral isoelectric points (7.7 for the liver ADH-4 [pi-ADH] and 7.2 for the major stomach ADH [ADH-3], respectively), and were insensitive to inhibition with 5 mM 4-methyl pyrazole. Class III ADH. This enzyme was characterized by its inactivity with ethanol as substrate (up to 0.5 M), insensitivity to 4-methyl pyrazole inhibition, preference for medium-chain-length alcohols as substrate (trans-2-hexen-1-ol was routinely used in this study), and an isoelectric point (6.5) similar to that of the human liver chi-ADH (pI 6.4). Major activity variation of the liver pi-ADH (ADH-4) isozyme was observed among the 114 liver samples examined, with 34 percent exhibiting a null (or low-activity) phenotype. An electrophoretic variant phenotype for the major class II stomach isozyme (ADH-3) was also found in the population studied. The baboon was used as a model for studying alcohol-induced changes in liver ADH phenotype following chronic alcohol consumption. Prepuberal male baboons were pair-fed nutritionally adequate liquid diets containing ethanol (50 percent of calories) or isocaloric carbohydrates, and liver ADH isozyme patterns from biopsy samples were monitored for 20 weeks. Dramatic decreases in class II liver ADH activity (ADH-4, or pi-ADH) were observed within 4 weeks after the start of alcohol feeding, and a shift in liver class I isozymes was found during the later stages of alcohol consumption. These changes during chronic

  8. Tissue Localization of Australia Antigen Immune Complexes in Acute and Chronic Hepatitis and Liver Cirrhosis

    PubMed Central

    Nowosławski, Adam; Krawczyński, Krzysztof; Brzosko, Witold J.; Madaliński, Kazimierz

    1972-01-01

    In a significant percentage of examined cases of fulminant hepatitis, subacute hepatitis, chronic aggressive hepatitis, liver cirrhosis and chronic persistent hepatitis, Australia (hepatitis-associated) antigen (Au HAA) was identified in the liver and in extrahepatic locations. The several immunofluorescent patterns of Au HAA localization in hepatocytes strongly suggested various stages of Au HAA accumulation and release. Deposits of a mixture of immunoglobulins G and M and occasionally β1C-globulin were found in the cytoplasm of Au HAA containing hepatocytes, on their plasma membranes, on or in the nuclei, in the cytoplasm of Kupffer cells and, rarely, in the sinusoids. The accompanying tissue changes were hepatocellular degeneration and necrosis. These intra- and extracellular complexes of Au HAA and immunoglobulins displayed strong affinity for guinea pig complement in the immunohistochemical complement fixation reaction. When tested by immunodiffusion in agar, IgG dissociated from these complexes by potassium thiocyanate (KSCN) treatment showed anti-Au HAA specificity. In fulminant hepatitis neither Au HAA nor immunoglobulins and complement were found in the liver. In chronic aggressive hepatitis and subacute hepatitis the amount of the Au HAA immune complexes identified in the liver was approximately inversely proportional to the extent and severity of the parenchymal lesions. In liver cirrhosis and chronic persistent hepatitis there was a positive correlation between the amount of the Au HAA immune complexes found in the liver and the degree of hepatocellular damage. The deposits of Au HAA, identified in extrahepatic locations including germinal centers of lymph nodes and spleen, kidney glomeruli and blood vessel walls, were as a rule accompanied by deposits of IgG, IgM, β1C-globulin and fibrin. All these deposits showed strong affinity for guinea pig complement in the immunohistochemical reaction of complement fixation. Germinal center activation, chronic

  9. When to consider liver transplant during the management of chronic liver disease.

    PubMed

    Fox, Rena K

    2014-01-01

    The decision to perform liver transplantation for a particular patient is never the decision of one single individual, although a single individual could preclude transplant as an option if the opportunity for referral is missed. Every physician treating patients with cirrhosis, including primary care physicians and primary gastroenterologists, should watch for the essential turning points at which a patient may become eligible for a transplant referral. Timing of referral could be assessed according to either the type of liver disease or non–disease-specific measures of disease severity. Although the MELD score is an easily accessible and convenient tool it is not as well known as CTP classification, and many cirrhotic patients under long-term management may not be being allocated a MELD score regularly calculated by their primary physicians. Because a slow progression in MELD score may occur without a change in symptoms, reaching the MELD score acceptable for transplant referral may go unrecognized. As generalists face the rising prevalence of NAFLD and the rising prevalence of cirrhosis and HCC from HCV, there will be an increasing need for education in the management of liver disease. It will be necessary for specialists and health care systems to better inform primary care physicians about the recommendations on criteria for transplant referral and the critical windows of opportunity within which they can act. Although there is a recognized knowledge gap that needs to be addressed, once a patient is in medical care, inadequate physician knowledge should never be the cause for late timing or missing the opportunity for referral. PMID:24266919

  10. Cellular and humoral immune reactions in chronic active liver disease. II. Lymphocyte subsets and viral antigens in liver biopsies of patients with acute and chronic hepatitis B.

    PubMed Central

    Eggink, H F; Houthoff, H J; Huitema, S; Wolters, G; Poppema, S; Gips, C H

    1984-01-01

    The characteristics and distribution of the inflammatory infiltrate in liver biopsies of 25 patients with hepatitis B viral (HBV) infection were studied in relation to the distribution and expression of HBV antigens. Mononuclear subsets were characterized with monoclonal (OKT, OKM, Leu) antibodies to surface antigens. For the demonstration of viral antigens directly conjugated antibodies to surface (HBsAg), core (HBcAg) and 'e' (HBeAg) antigen were used. For the study of mutual relations all methods were performed on serial cut tissue sections. In chronic active hepatitis B (CAH-B, n = 12) OKT8+ lymphocytes of T cell origin were the only cell type present in areas with liver cell degeneration and T cell cytotoxicity appears to be the only immune mechanism. In chronic persistent hepatitis B (CPH-B, n = 7) the only conspicuous feature was the presence of many Leu 3+ lymphocytes of the helper/inducer population in the portal tracts. In acute hepatitis B (AHB, n = 6) OKT8+ cells of non-T origin (OKT1-,3-) and Leu 7+ cells of presumed natural killer (NK) potential predominated in the areas with liver cell necrosis, and non-T cell cytotoxicity appears to be the predominant immune mechanism. In none of these disease entities a positive spatial relation could be established between the cytotoxic cells and the demonstrable expression of HBV antigens in hepatocytes. It is concluded that differences in immunological reaction pattern may explain the different course in the three forms of HBV infection studied. Images Fig. 1 Fig. 2 PMID:6713726

  11. Dissociated sterol-based liver X receptor agonists as therapeutics for chronic inflammatory diseases.

    PubMed

    Yu, Shan; Li, Sijia; Henke, Adam; Muse, Evan D; Cheng, Bo; Welzel, Gustav; Chatterjee, Arnab K; Wang, Danling; Roland, Jason; Glass, Christopher K; Tremblay, Matthew

    2016-07-01

    Liver X receptor (LXR), a nuclear hormone receptor, is an essential regulator of immune responses. Activation of LXR-mediated transcription by synthetic agonists, such as T0901317 and GW3965, attenuates progression of inflammatory disease in animal models. However, the adverse effects of these conventional LXR agonists in elevating liver lipids have impeded exploitation of this intriguing mechanism for chronic therapy. Here, we explore the ability of a series of sterol-based LXR agonists to alleviate inflammatory conditions in mice without hepatotoxicity. We show that oral treatment with sterol-based LXR agonists in mice significantly reduces dextran sulfate sodium colitis-induced body weight loss, which is accompanied by reduced expression of inflammatory markers in the large intestine. The anti-inflammatory property of these agonists is recapitulated in vitro in mouse lamina propria mononuclear cells, human colonic epithelial cells, and human peripheral blood mononuclear cells. In addition, treatment with LXR agonists dramatically suppresses inflammatory cytokine expression in a model of traumatic brain injury. Importantly, in both disease models, the sterol-based agonists do not affect the liver, and the conventional agonist T0901317 results in significant liver lipid accumulation and injury. Overall, these results provide evidence for the development of sterol-based LXR agonists as novel therapeutics for chronic inflammatory diseases.-Yu, S., Li, S., Henke, A., Muse, E. D., Cheng, B., Welzel, G., Chatterjee, A. K., Wang, D., Roland, J., Glass, C. K., Tremblay, M. Dissociated sterol-based liver X receptor agonists as therapeutics for chronic inflammatory diseases. PMID:27025962

  12. Prognosis of acute-on-chronic liver failure patients treated with artificial liver support system

    PubMed Central

    Zhou, Pi-Qi; Zheng, Shao-Ping; Yu, Min; He, Sheng-Song; Weng, Zhi-Hong

    2015-01-01

    AIM: To establish a new model for predicting survival in acute-on-chronic liver failure (ACLF) patients treated with an artificial liver support system. METHODS: One hundred and eighty-one ACLF patients who were admitted to the hospital from January 1, 2012 to December 31, 2014 and were treated with an artificial liver support system were enrolled in this retrospective study, including a derivation cohort (n = 113) and a validation cohort (n = 68). Laboratory parameters at baseline were analyzed and correlated with clinical outcome. In addition to standard medical therapy, ACLF patients underwent plasma exchange (PE) or plasma bilirubin adsorption (PBA) combined with plasma exchange. For the derivation cohort, Kaplan-Meier methods were used to estimate survival curves, and Cox regression was used in survival analysis to generate a prognostic model. The performance of the new model was tested in the validation cohort using a receiver-operator curve. RESULTS: The mean overall survival for the derivation cohort was 441 d (95%CI: 379-504 d), and the 90- and 270-d survival probabilities were 70.3% and 58.3%, respectively. The mean survival times of patients treated with PBA plus PE and patients treated with PE were 531 d (95%CI: 455-605 d) and 343 d (95%CI: 254-432 d), respectively, which were significantly different (P = 0.012). When variables with bivariate significance were selected for inclusion into the multivariate Cox regression model, number of complications, age, scores of the model for end-stage liver disease (MELD) and type of artificial liver support system were defined as independent risk factors for survival in ACLF patients. This new prognostic model could accurately discriminate the outcome of patients with different scores in this cohort (P < 0.001). The model also had the ability to assign a predicted survival probability for individual patients. In the validation cohort, the new model remained better than the MELD. CONCLUSION: A novel model was

  13. Protective effect of Xingnaojia formulation on rats with brain and liver damage caused by chronic alcoholism

    PubMed Central

    LI, SHUANG; WANG, SU; GUO, ZHI-GANG; HUANG, NING; ZHAO, FAN-RONG; ZHU, MO-LI; MA, LI-JUAN; LIANG, JIN-YING; ZHANG, YU-LIN; HUANG, ZHONG-LIN; WAN, GUANG-RUI

    2015-01-01

    The aim of this study was to observe the effect of a formulation of traditional Chinese medicine extracts known as Xingnaojia (XNJ) on the liver function, learning ability and memory of rats with chronic alcoholism and to verify the mechanism by which it protects the brain and liver. A rat model of chronic alcoholism was used in the study. The spatial learning ability and memory of the rats were tested. The rats were then sacrificed and their brains and hepatic tissues were isolated. The activity of superoxide dismutase (SOD) and levels of glutamate (Glu), N-methyl D-aspartate receptor subtype 2B (NR2B), cyclin-dependent kinase 5 (CDK5) and cannabinoid receptor 1 (CB1) in the hippocampus were analyzed. The ultrastructure of the hepatic tissue was observed by electron microscopy. In addition, the activities of alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) in serum were tested and the levels of low-density lipoprotein (LDL), high-density lipoprotein (HDL), triglycerides (TG) and total cholesterol (TCHOL) were analyzed. XNJ enhanced the learning and memory of rats with chronic alcoholism. Treatment with XNJ increased the activity of SOD, and decreased the expression levels of NR2B mRNA and NR2B, CB1 and CDK5 proteins in the brain tissues compared with those in the model rats. It also increased the activity of ALDH in the serum and liver, decreased the serum levels of LDL, TG and TCHOL and increased the serum level of HDL. These results indicate that XNJ exhibited a protective effect against brain and liver damage in rats with chronic alcoholism. PMID:26640531

  14. Circulating and Hepatic Fas Expression in HCV-Induced Chronic Liver Disease and Hepatocellular Carcinoma

    PubMed Central

    El Bassiouny, Azza E. I.; El-Bassiouni, Nora E. I.; Nosseir, Mona M. F.; Zoheiry, Mona M.K.; El-Ahwany, Eman G.; Salah, Faten; Omran, Zeinab S.O.; Ibrahim, Raafat A.

    2008-01-01

    Apoptosis is central for control and elimination of viral infections. In chronic hepatitis C virus (HCV) infection, enhanced hepatocyte apoptosis and upregulation of the death-inducing ligands CD95/Fas occur. This study aimed to study the role of serum soluble Fas and hepatic Fas expression as early predictors of advancement of chronic hepatitis C disease. The current study included 50 cases of chronic hepatitis C (CHC) (and negative hepatitis B virus infection), 30 cases of liver cirrhosis (LC) and HCV, and 20 cases of hepatocellular carcinoma (HCC) and HCV admitted to Theodor Bilharz Research Institute, Giza, Egypt. Fifteen wedge liver biopsies, taken during laparoscopic cholecystectomy, were included in the study as normal controls. Assessment of serum soluble Fas level (sFas) and other laboratory investigations, including liver function tests, serologic markers for viral hepatitis, and serum alpha-fetoprotein level (alpha-FP), were determined for all cases. Histopathologic study and immunohistochemistry using monoclonal antibody for CD95 were also done. The sFas was significantly increased in CHC, LC, and HCC cases compared with normal controls (P < .01). The increase of sFas in HCC was also significantly higher than that of CHC (P < .01). However, positive hepatic expression of Fas antigen was higher in CHC than LC with no significant difference; meanwhile, it was significantly lower in HCC (P < .01) compared with CHC. In conclusion, circulating and hepatic Fas expression in chronic hepatitis C infection illustrate the mechanism of liver injury caused by death receptors throughout the multistep process of fibrosis/carcinogenesis. Not only the higher degree of hepatic fibrosis, but also the lower expression of Fas protein, are correlated with the increased incidence of HCC. PMID:18679533

  15. [PROTEIN CONTENT CHANGES IN RATS' LIVER AND BRAIN UNDER CHRONIC ALCOHOL INTOXICATION].

    PubMed

    Raksha, N G; Savchuk, A N; Kharchenko, O I; Galenova, T I; Ostapchenko, L I

    2015-01-01

    An electrophoretic investigation of quantitative protein content in rat's' tissyes under chronic alcoholic intoxication has been done. It was shown the significant increase of protein content with molecular mass 55, 48-50, 43-45, 39-41 KDa and the decrease-of protein fractions with molecular mass 46-48, 34-35, 27-30, 16-18 KDa accordingly in liver and brain homogenates of experimental animals. PMID:26827457

  16. Nutritional care in hospitalized patients with chronic liver disease

    PubMed Central

    Huynh, Dep K; Selvanderan, Shane P; Harley, Hugh AJ; Holloway, Richard H; Nguyen, Nam Q

    2015-01-01

    AIM: To evaluate the practice of nutritional assessment and management of hospitalised patients with cirrhosis and the impact of malnutrition on their clinical outcome. METHODS: This was a retrospective cohort study on patients with liver cirrhosis consecutively admitted to the Department of Gastroenterology and Hepatology at the Royal Adelaide Hospital over 24 mo. Details were gathered related to the patients’ demographics, disease severity, nutritional status and assessment, biochemistry and clinical outcomes. Nutritional status was assessed by a dietician and determined by subjective global assessment. Estimated energy and protein requirements were calculated by Simple Ratio Method. Intake was estimated from dietary history and/or food charts, and represented as a percentage of estimated daily requirements. Median duration of follow up was 14.9 (0-41.4) mo. RESULTS: Of the 231 cirrhotic patients (167 male, age: 56.3 ± 0.9 years, 9% Child-Pugh A, 42% Child-Pugh B and 49% Child-Pugh C), 131 (57%) had formal nutritional assessment during their admission and 74 (56%) were judged to have malnutrition. In-hospital caloric (15.6 ± 1.2 kcal/kg vs 23.7 ± 2.3 kcal/kg, P = 0.0003) and protein intake (0.65 ± 0.06 g/kg vs 1.01 ± 0.07 g/kg, P = 0.0003) was significantly reduced in patients with malnutrition. Of the malnourished cohort, 12 (16%) received enteral nutrition during hospitalisation and only 6 (8%) received ongoing dietetic review and assessment following discharge from hospital. The overall mortality was 51%, and was higher in patients with malnutrition compared to those without (HR = 5.29, 95%CI: 2.31-12.1; P < 0.001). CONCLUSION: Malnutrition is common in hospitalised patients with cirrhosis and is associated with higher mortality. Formal nutritional assessment, however, is inadequate. This highlights the need for meticulous nutritional evaluation and management in these patients. PMID:26668507

  17. Altered Peripheral Blood Monocyte Phenotype and Function in Chronic Liver Disease: Implications for Hepatic Recruitment and Systemic Inflammation

    PubMed Central

    Gadd, Victoria L.; Patel, Preya J.; Jose, Sara; Horsfall, Leigh

    2016-01-01

    Background and Aims Liver and systemic inflammatory factors influence monocyte phenotype and function, which has implications for hepatic recruitment and subsequent inflammatory and fibrogenic responses, as well as host defence. Methods Peripheral blood monocyte surface marker (CD14, CD16, CD163, CSF1R, CCR2, CCR4, CCR5, CXCR3, CXCR4, CX3CR1, HLA-DR, CD62L, SIGLEC-1) expression and capacity for phagocytosis, oxidative burst and LPS-stimulated TNF production were assessed in patients with hepatitis C (HCV) (n = 39) or non-alcoholic fatty liver disease (NAFLD) (n = 34) (classified as non-advanced disease, compensated cirrhosis and decompensated cirrhosis) and healthy controls (n = 11) by flow cytometry. Results The selected markers exhibited similar monocyte-subset-specific expression patterns between patients and controls. Monocyte phenotypic signatures differed between NAFLD and HCV patients, with an increased proportion of CD16+ non-classical monocytes in NAFLD, but increased expression of CXCR3 and CXCR4 in HCV. In both cohorts, monocyte CCR2 expression was reduced and CCR4 elevated over controls. CD62L expression was specifically elevated in patients with decompensated cirrhosis and positively correlated with the model-for-end-stage-liver-disease score. Functionally, monocytes from patients with decompensated cirrhosis had equal phagocytic capacity, but displayed features of dysfunction, characterised by lower HLA-DR expression and blunted oxidative responses. Lower monocyte TNF production in response to LPS stimulation correlated with time to death in 7 (46%) of the decompensated patients who died within 8 months of recruitment. Conclusions Chronic HCV and NAFLD differentially affect circulating monocyte phenotype, suggesting specific injury-induced signals may contribute to hepatic monocyte recruitment and systemic activation state. Monocyte function, however, was similarly impaired in patients with both HCV and NAFLD, particularly in advanced disease, which

  18. Novel bile acid therapeutics for the treatment of chronic liver diseases

    PubMed Central

    Hegade, Vinod S.; Speight, R. Alexander; Etherington, Rachel E.; Jones, David E. J.

    2016-01-01

    Recent developments in understanding the role of bile acids (BAs) as signalling molecules in human metabolism and inflammation have opened new avenues in the field of hepatology research. BAs are no longer considered as simple molecules helping in fat digestion but as agents with real therapeutic value in treating complex autoimmune and metabolic liver diseases. BAs and their receptors such as farnesoid X receptor, transmembrane G protein-coupled receptor 5 and peroxisome proliferator-activated receptor have been identified as novel targets for drug development. Some of these novel pharmaceuticals are already in clinical evaluation with the most advanced drugs having reached phase III trials. Chronic liver diseases such as primary biliary cholangitis, primary sclerosing cholangitis and nonalcoholic fatty liver disease, for which there is no or limited pharmacotherapy, are most likely to gain from these developments. In this review we discuss recent and the most relevant basic and clinical research findings related to BAs and their implications for novel therapy for chronic liver diseases. PMID:27134666

  19. Chronic Arsenic Exposure-Induced Oxidative Stress is Mediated by Decreased Mitochondrial Biogenesis in Rat Liver.

    PubMed

    Prakash, Chandra; Kumar, Vijay

    2016-09-01

    The present study was executed to study the effect of chronic arsenic exposure on generation of mitochondrial oxidative stress and biogenesis in rat liver. Chronic sodium arsenite treatment (25 ppm for 12 weeks) decreased mitochondrial complexes activity in rat liver. There was a decrease in mitochondrial superoxide dismutase (MnSOD) activity in arsenic-treated rats that might be responsible for increased protein and lipid oxidation as observed in our study. The messenger RNA (mRNA) expression of mitochondrial and nuclear-encoded subunits of complexes I (ND1 and ND2) and IV (COX I and COX IV) was downregulated in arsenic-treated rats only. The protein and mRNA expression of MnSOD was reduced suggesting increased mitochondrial oxidative damage after arsenic treatment. There was activation of Bax and caspase-3 followed by release of cytochrome c from mitochondria suggesting induction of apoptotic pathway under oxidative stress. The entire phenomenon was associated with decrease in mitochondrial biogenesis as evident by decreased protein and mRNA expression of nuclear respiratory factor 1 (NRF-1), nuclear respiratory factor 2 (NRF-2), peroxisome proliferator activator receptor gamma-coactivator 1α (PGC-1α), and mitochondrial transcription factor A (Tfam) in arsenic-treated rat liver. The results of the present study indicate that arsenic-induced mitochondrial oxidative stress is associated with decreased mitochondrial biogenesis in rat liver that may present one of the mechanisms for arsenic-induced hepatotoxicity. PMID:26767369

  20. LIVER BIOPSY: IMPORTANCE OF SPECIMEN SIZE IN THE DIAGNOSIS AND STAGING OF CHRONIC VIRAL HEPATITIS

    PubMed Central

    CORAL, Gabriela P.; ANTUNES, Aline Dal Pozzo; SERAFINI, Ana Paula Almeida; ARAUJO, Fernanda B.; de MATTOS, Angelo Alves

    2016-01-01

    Liver biopsy is the gold standard method for the grading and staging of chronic viral hepatitis, but optimal biopsy specimen size remains controversial. The aim of this study was to evaluate the quality of liver specimen (number of portal tracts) and to evaluate the impact of the number of portal tracts in the staging of chronic hepatitis. Material and Methods: 468 liver biopsies from consecutive patients with hepatitis C virus and hepatitis B virus infection from 2009 to 2010 were evaluated. Results: The length of fragment was less than 10 mm in 43 cases (9.3%), between 10 and 14 mm in 114 (24.3%), and ≥ 15 mm in 311 (64.4%); of these, in 39 (8.3%) cases were ≥ 20 mm. The mean representation of portal tracts was 17.6 ± 2.1 (5-40); in specimens ≥ 15 mm the mean portal tract was 13.5 ± 4.7 and in cases ≤ 15 mm was 11.4 ± 5.0 (p = 0.002). Cases with less than 11 portal tracts were associated with F3, and cases with 11 or more portal tracts with F2 (p = 0.001). Conclusion: this study demonstrated the good quality of liver biopsy and a relationship between the macroscopic size of the fragment and the number of portal tracts. PMID:26910447

  1. Liver biopsy in chronic hepatitis C: the experience of 15 Italian wards of infectious diseases.

    PubMed

    Sagnelli, Evangelista; Sagnelli, Caterina; Pisaturo, Maria Antonietta; Coppola, Nicola; Pasquale, Giuseppe; Piccinino, Felice

    2012-03-01

    To evaluate the impact of liver histology on the management of HCV-related chronic hepatitis, 281 patients with chronic HCV infection who consecutively underwent percutaneous liver biopsy (LB) at one of the 15 participating Italian Units of Infectious Diseases were investigated in 2005. Demographic, aetiological, laboratory and clinical data and information on methods applied to perform ultrasonography (US) and LB were recorded. Males predominated (61.6%), mean age was 47.5 years and the mean BMI 22.3. In each case LB was US-guided or US-assisted. An 18-gauge Menghini-type needle was used in 203 (72.2%) cases. The length of the specimen ranged between 1.5 and 5 cm in 279 (99.3%) cases, it was smaller in two cases, but the diagnosis was still possible. Haemoperitoneum was the only (0.4%) major unpredictable complication; minor complications were also infrequent (4%). Using both clinical and laboratory data and US examination the physician misdiagnosed liver histology in 25% of cases. After LB the physicians changed their opinion on whether to treat with PEG-INF plus ribavirin in 43 (15.5%) cases. Liver histology allows more accurate diagnosis and enables physicians to make the most appropriate choic. PMID:22475658

  2. Modulation of TGF-beta signaling during progression of chronic liver diseases.

    PubMed

    Matsuzaki, Koichi

    2009-01-01

    A large body of work has established roles for epithelial cells as important mediators of progressive fibrosis and carcinogenesis. Transforming growth factor-beta (TGF-beta) and pro-inflammatory cytokines are important inducers of fibro-carcinogenesis. TGF-beta signaling involves phosphorylation of Smad3 at middle linker and/or C-terminal regions. Reversible shifting of Smad3-dependent signaling between tumor-suppression and oncogenesis in hyperactive Ras-expressing epithelial cells indicates that Smad3 phosphorylated at the C-terminal region (pSmad3C) transmits a tumor-suppressive TGF-beta signal, while oncogenic activities such as cell proliferation and invasion are promoted by Smad3 phosphorylated at the linker region (pSmad3L). Notably, pSmad3L-mediated signaling promotes extracellular matrix deposition by activated mesenchymal cells. During progression of chronic liver diseases, hepatic epithelial hepatocytes undergo transition from the tumor-suppressive pSmad3C pathway to the fibrogenic/oncogenic pSmad3L pathway, accelerating liver fibrosis and increasing risk of hepatocellular carcinoma. c-Jun N-terminal kinase activated by pro-inflammatory cytokines is mediating this perturbed hepatocytic TGF-beta signaling. Thus, TGF-beta signaling of hepatocytes affected by chronic inflammation offers a general framework for understanding the molecular mechanisms of human fibro-carcinogenesis during progression of chronic liver diseases. PMID:19273245

  3. Talc in liver tissue of intravenous drug abusers with chronic hepatitis. A comparative study.

    PubMed

    Allaire, G S; Goodman, Z D; Ishak, K G; Rabin, L

    1989-11-01

    To determine the frequency of talc microcrystals in liver tissue of intravenous (IV) drug abusers and the significance of this finding, the authors reviewed, with light and polarizing microscopy, sections of liver tissue from 70 patients with chronic hepatitis and a history of active (45) or past (25) IV drug abuse. Birefringent crystalline particles consistent with talc were found in 44 cases (63%), 31 associated with active and 13 with past drug abuse. The microcrystals were situated predominantly in hypertrophied portal macrophages; there were no well-formed granulomas. Scanning electron microscopic and energy-dispersive spectrophotometry performed on eight of the positive cases showed the characteristic "flake-pastry" appearance and chemical composition (silicon and magnesium) of talc. For comparison, the authors similarly examined 70 cases of posttransfusion chronic hepatitis, all of which had negative findings for talc, and 70 cases of chronic hepatitis with no documented risk factors for viral hepatitis, of which two had positive findings for talc, even though IV drug abuse was denied by the two patients. The authors conclude that talc is frequently present in the liver of IV drug abusers and whenever encountered it strongly suggests IV drug abuse. Only two patients (1.4%) with a negative history also had talc. PMID:2816811

  4. Vascular pathobiology in chronic liver disease and cirrhosis – Current status and future directions

    PubMed Central

    Iwakiri, Yasuko; Shah, Vijay; Rockey, Don C.

    2015-01-01

    Summary Chronic liver disease is associated with remarkable alterations in the intra- and extrahepatic vasculature. Because of these changes, the fields of liver vasculature and portal hypertension have recently become closely integrated within the broader vascular biology discipline. As developments in vascular biology have evolved, a deeper understanding of vascular processes has led to a better understanding of the mechanisms of the dynamic vascular changes associated with portal hypertension and chronic liver disease. In this context, hepatic vascular cells, such as sinusoidal endothelial cells and pericyte-like hepatic stellate cells, are closely associated with one another, where they have paracrine and autocrine effects on each other and themselves. These cells play important roles in the pathogenesis of liver fibrosis/cirrhosis and portal hypertension. Further, a variety of signaling pathways have recently come to light. These include growth factor pathways involving cytokines such as transforming growth factor β, platelet derived growth factor, and others as well as a variety of vasoactive peptides and other molecules. An early and consistent feature of liver injury is the development of an increase in intra-hepatic resistance; this is associated with changes in hepatic vascular cells and their signaling pathway that cause portal hypertension. A critical concept is that this process aggregates signals to the extrahepatic circulation, causing derangement in this system’s cells and signaling pathways, which ultimately leads to the collateral vessel formation and arterial vasodilation in the splanchnic and systemic circulation, which by virtue of the hydraulic derivation of Ohm’s law (pressure = resistance × flow), worsens portal hypertension. This review provides a detailed review of the current status and future direction of the basic biology of portal hypertension with a focus on the physiology, pathophysiology, and signaling of cells within the

  5. Vascular pathobiology in chronic liver disease and cirrhosis - current status and future directions.

    PubMed

    Iwakiri, Yasuko; Shah, Vijay; Rockey, Don C

    2014-10-01

    Chronic liver disease is associated with remarkable alterations in the intra- and extrahepatic vasculature. Because of these changes, the fields of liver vasculature and portal hypertension have recently become closely integrated within the broader vascular biology discipline. As developments in vascular biology have evolved, a deeper understanding of vascular processes has led to a better understanding of the mechanisms of the dynamic vascular changes associated with portal hypertension and chronic liver disease. In this context, hepatic vascular cells, such as sinusoidal endothelial cells and pericyte-like hepatic stellate cells, are closely associated with one another, where they have paracrine and autocrine effects on each other and themselves. These cells play important roles in the pathogenesis of liver fibrosis/cirrhosis and portal hypertension. Further, a variety of signaling pathways have recently come to light. These include growth factor pathways involving cytokines such as transforming growth factor β, platelet derived growth factor, and others as well as a variety of vasoactive peptides and other molecules. An early and consistent feature of liver injury is the development of an increase in intra-hepatic resistance; this is associated with changes in hepatic vascular cells and their signaling pathway that cause portal hypertension. A critical concept is that this process aggregates signals to the extrahepatic circulation, causing derangement in this system's cells and signaling pathways, which ultimately leads to the collateral vessel formation and arterial vasodilation in the splanchnic and systemic circulation, which by virtue of the hydraulic derivation of Ohm's law (pressure = resistance × flow), worsens portal hypertension. This review provides a detailed review of the current status and future direction of the basic biology of portal hypertension with a focus on the physiology, pathophysiology, and signaling of cells within the liver, as well

  6. Significant impairment of health-related quality of life in mainland Chinese patients with chronic hepatitis B: a cross-sectional survey with pair-matched healthy controls

    PubMed Central

    2014-01-01

    Objective Few studies have evaluated health-related quality of life (HRQoL) of patients with chronic hepatitis B (CHB) in mainland China. We aimed at characterizing the impact of CHB on HRQoL in mainland Chinese and finding out factors associated with HRQoL. Methods 460 CHB patients (323 with CHB only, 54 with compensated cirrhosis and 83 with decompensated cirrhosis) and 460 pair-matched healthy controls were recruited in Xi’an city. They answered a structured questionnaire including the Short Form 36 version 2 (SF-36v2), the Chronic Liver Disease Questionnaire (CLDQ) (only for patients), and questions on socio-demographic and clinical characteristics. A blood sample was collected from each of patients for liver function tests. SF-36v2 scores were compared between patients and controls overall and by groups by paired-samples t-test, and CLDQ scores and paired differences of SF-36v2 scores were compared among three patient groups by one-way ANOVA or Kruskal-Wallis test. Multi-variable linear regression analyses were performed to identify determinants of HRQoL in patients. Results Patients, overall and by groups had significantly lower SF-36v2 scores than controls on all summaries and domains, with differences higher than the suggested minimally important difference values. Both the SF-36v2 and the CLDQ showed that HRQoL of patients with cirrhosis further deteriorated, but compensated and decompensated cirrhosis patients had similar total HRQoL impairments. The gradually increasing impairment with disease progression was confirmed only on physical components. Impaired liver function and currently taken anti-viral treatment were associated with lower HRQoL. Education attainment and annual per capita household income had a positive effect on HRQoL. Conclusions Mainland Chinese CHB patients suffered significant HRQoL impairment on all health dimensions, and the impairment reached a high level on mental health at initial stage of illness and increased gradually on

  7. Mechanisms of impaired arterial oxygenation in patients with liver cirrhosis and severe respiratory insufficiency. Effects of indomethacin.

    PubMed

    Andrivet, P; Cadranel, J; Housset, B; Herigault, R; Harf, A; Adnot, S

    1993-02-01

    The mechanisms of impaired arterial oxygenation that occur in certain patients with chronic liver cirrhosis are still debated. In the present study, we investigated nine cirrhotic patients with severe respiratory disability (mean PaO2, 64 +/- 5 mm Hg), using the inert gas elimination technique to assess the distribution of ventilation-perfusion (VA/Q) ratios. We also determined shunt fraction during pure oxygen breathing, both in supine and sitting positions. To test the hypothesis that vasodilating prostaglandins could contribute to alter gas exchange in such patients with cirrhosis, we examined the hemodynamic and gasometric responses to indomethacin, 50 mg IV, in six of them. During baseline conditions, patients had high cardiac index (CI, 4.9 +/- 0.2 L/min/m2), and low pulmonary (PVR, 1.78 +/- 0.37 mm Hg/L/min/m2) or systemic (SVR, 17.7 +/- 1.15 mm Hg/L/min/m2) vascular resistances. Large intrapulmonary shunt fraction was documented in each patient with a mean value of 19.6 +/- 2.7 percent. Small perfusion in low VA/Q areas was associated with shunt in only three patients (2.5 to 5.3 percent of blood flow). Arterial PO2 was negatively related to shunt (p < 0.01) and to the dispersion of blood flow distribution (p < 0.02). There was no difference between measured and predicted PaO2. Shunt estimates from the inert gas and the 100 percent O2 breathing techniques were, respectively, 19.6 +/- 2.7 percent and 21.7 +/- 3.0 percent. During 100 percent oxygen breathing, changing from supine to sitting position decreased PaO2 from 401 +/- 50 to 333 +/- 64 mm Hg (p < 0.02), while O2 shunt remained unchanged, arteriovenous difference widened, and mixed venous PO2 decreased, from 61 +/- 3 to 47 +/- 4 mm Hg (p < 0.001). Indomethacin did not improve gas exchange or VA/Q distribution and did not affect systemic or pulmonary hemodynamics. The results show that in cirrhotic patients with severe respiratory disability, intrapulmonary shunting is the main determinant of impaired

  8. Liver Expression of Sulphotransferase 2A1 Enzyme Is Impaired in Patients with Primary Sclerosing Cholangitis: Lack of the Response to Enhanced Expression of PXR

    PubMed Central

    Wunsch, Ewa; Klak, Marta; Wasik, Urszula; Milkiewicz, Malgorzata; Blatkiewicz, Malgorzata; Urasinska, Elzbieta; Barbier, Olivier; Bielicki, Dariusz; Bogdanos, Dimitrios P.; Elias, Elwyn; Milkiewicz, Piotr

    2015-01-01

    Background/Aim. Sulphotransferase 2A1 (SULT2A1) exerts hepatoprotective effects. Transcription of SULT2A1 gene is induced by pregnane-X-receptor (PXR) and can be repressed by miR-378a-5p. We studied the PXR/SULT2A1 axis in chronic cholestatic conditions: primary sclerosing cholangitis (PSC) and primary biliary cirrhosis (PBC). Materials/Methods. Western-blot/PCRs for SULT2A1/PXR were performed in PSC (n = 11), PBC (n = 19), and control liver tissues (n = 19). PXR and SULT2A1 mRNA was analyzed in intestinal tissues from 22 PSC patients. Genomic DNA was isolated from blood of PSC patients (n = 120) and an equal number of healthy volunteers. Liver miRNA expression was evaluated using Affymetrix-Gene-Chip miRNA4.0. Results. Increased PXR protein was observed in both PSC and PBC compared to controls and was accompanied by a significant increase of SULT2A1 in PBC but not in PSC. Decreased expression of SULT2A1 mRNA was also seen in ileum of patients with PSC. Unlike PBC, miRNA analysis in PSC has shown a substantial increase in liver miR-378a-5p. Conclusions. PSC is characterized by disease-specific impairment of SULT2A1 expression following PXR activation, a phenomenon which is not noted in PBC, and may account for the impaired hepatoprotection in PSC. miRNA analysis suggests that SULT2A1 expression in PSC may be regulated by miR-378a-5p, connoting its pathogenic role. PMID:26504856

  9. White matter changes in chronic alcoholic liver disease: Hypothesized association and putative biochemical mechanisms.

    PubMed

    Hathout, Leith; Huang, Jimmy; Zamani, Amir; Morioka, Craig; El-Saden, Suzie

    2015-12-01

    Advanced liver disease has long been associated with cerebral abnormalities. These abnormalities, termed acquired hepatocerebral degeneration, are typically visualized as T1 weighted hyperintensity on MRI in the deep gray matter of the basal ganglia. Recent reports, however, have demonstrated that a subset of patients with chronic alcoholic liver disease may also develop white matter abnormalities. Thus far, the morphology of these changes is not well characterized. Previous studies have described these changes as patchy, sporadic white matter abnormalities but have not posited localization of these changes to any particular white matter tracts. This paper hypothesizes that the white matter findings associated with advanced alcoholic liver disease localize to the corticocerebellar tracts. As an initial investigation of this hypothesis, 78 patients with a diagnosis of liver cirrhosis and an MRI showing clearly abnormal T1 weighted hyperintensity in the bilateral globus pallidus, characteristic of chronic liver disease, were examined for white matter signal abnormalities in the corticocerebellar tracts using FLAIR and T2 weighted images. The corticocerebellar tracts were subdivided into two regions: periventricular white matter (consisting of the sum of the centrum-semiovale and corona radiata), and lower white matter (consisting of the corona radiata, internal capsules, middle cerebral peduncles, middle cerebellar peduncles and cerebellum). As compared to matched controls, significantly greater signal abnormalities in both the periventricular white matter and lower white matter regions of the corticocerebellar tracts were observed in patients with known liver cirrhosis and abnormal T1 W hyperintensity in the globi pallidi. This difference was most pronounced in the lower white matter region of the corticocerebellar tract, with statistical significance of p<0.0005. Furthermore, the pathophysiologic mechanism underlying these changes remains unknown. This paper

  10. Pharmacokinetics, Efficacy, and Safety of Hepatitis C Virus Drugs in Patients with Liver and/or Renal Impairment.

    PubMed

    Smolders, Elise J; de Kanter, Clara T M M; van Hoek, Bart; Arends, Joop E; Drenth, Joost P H; Burger, David M

    2016-07-01

    Hepatitis C virus (HCV)-infected patients often suffer from liver cirrhosis, which can be complicated by renal impairment. Therefore, in this review we describe the treatment possibilities in HCV patients with hepatic and renal impairment. Cirrhosis alters the structure of the liver, which affects drug-metabolizing enzymes and drug transporters. These modifications influence the plasma concentration of substrates of drugs metabolized/transported by these enzymes. The direct-acting antivirals (DAAs) are substrates of, for example, cytochrome P450 enzymes in the liver. Most DAAs are not studied in HCV-infected individuals with decompensated cirrhosis, and therefore awareness is needed when these patients are treated. Most DAAs are contraindicated in cirrhotic patients; however, patients with a Child-Pugh score of B or C can be treated safely with a normal dose sofosbuvir plus ledipasvir or daclatasvir, in combination with ribavirin. Patients with renal impairment (glomerular filtration rate [GFR] <90 mL/min) or who are dependent on dialysis often tolerate ribavirin treatment poorly, even after dose adjustments. However, most DAAs can be used at the normal dose because DAAs are not renally excreted. To date, grazoprevir plus elbasvir is the preferred DAA regimen in patients with renal impairment as data are pending for sofosbuvir patients with GFR <30 mL/min (as for ledipasvir and velpatasvir). However, sofosbuvir has been used in a small number of patients with severe renal impairment and, based on these trials, we recommend sofosbuvir 400 mg every day when no other DAA regimen is available. Ledipasvir and velpatasvir are not recommended in patients with severe renal impairment. PMID:27098247

  11. Impaired Gallbladder Motility and Increased Gallbladder Wall Thickness in Patients with Nonalcoholic Fatty Liver Disease

    PubMed Central

    Colak, Yasar; Bozbey, Gulcin; Erim, Tolga; Caklili, Ozge Telci; Ulasoglu, Celal; Senates, Ebubekir; Mutlu, Hasan Huseyin; Mesci, Banu; Doğan, Mehmet Sait; Tasan, Guralp; Enc, Feruze Yilmaz; Tuncer, Ilyas

    2016-01-01

    Background/Aims Nonalcoholic fatty liver disease (NAFLD) is currently the most common chronic liver disease worldwide. Along with the increase in the incidence of NAFLD and associated obesity, an increase in gallbladder disease (GD) has been noted. This has led to the identification of a new disease entity called fatty GD. There is a gap in the literature on the dynamics of gallbladder function in patients with NAFLD. Methods An observational case-control study, a total of 50 patients with biopsy proven NAFLD without gallbladder stone/sludge and 38 healthy comparison subjects were enrolled. Fasting, postprandial gallbladder volumes (PGV), gallbladder ejection fraction (GEF), and fasting gallbladder wall thickness (FGWT) were measured by real-time 2-dimensional ultrasonography. Results Fasting gallbladder wall thickness, fasting gallbladder volumes and PGV were significantly higher in patients with NAFLD than control subjects (P < 0.001, P = 0.006, and P < 0.001, respectively). Gallbladder ejection fraction was significantly lower in the NAFLD group than the controls (P = 0.008). The presence of NAFLD was an independent predictor for GEF, PGV, and FGWT. Also, steatosis grade was an independent predictor for GEF, and GEF was significantly lower in the nonalcoholic steatohepatitis (NASH) subgroup than the controls. Conclusions Gallbladder dysfunction and increase in gallbladder wall thickness exists in asymptomatic (without stone/sludge and related symptoms) patients with NAFLD and are useful in identifying fatty GD. Measurement of these variables in NAFLD patients may be useful in identifying those at higher risk for GD. PMID:26932908

  12. Honey Bees' Behavior Is Impaired by Chronic Exposure to the Neonicotinoid Thiacloprid in the Field.

    PubMed

    Tison, Léa; Hahn, Marie-Luise; Holtz, Sophie; Rößner, Alexander; Greggers, Uwe; Bischoff, Gabriela; Menzel, Randolf

    2016-07-01

    The decline of pollinators worldwide is of growing concern and has been related to the use of plant-protecting chemicals. Most studies have focused on three neonicotinoid insecticides (clothianidin, imidacloprid, and thiamethoxam) currently subject to a moratorium in the EU. Here, we focus on thiacloprid, a widely used cyano-substituted neonicotinoid thought to be less toxic to honey bees and of which use has increased in the last years. Honey bees (Apis mellifera carnica) were exposed chronically to thiacloprid in the field for several weeks at a sublethal concentration. Foraging behavior, homing success, navigation performance, and social communication were impaired, and thiacloprid residue levels increased both in the foragers and the nest mates over time. The effects observed in the field were not due to a repellent taste of the substance. For the first time, we present the necessary data for the risk evaluation of thiacloprid taken up chronically by honey bees in field conditions. PMID:27268938

  13. [DIACYLGLYCEROL ACCUMULATION IMPAIRS SHORT-TERM ACTIVATION OF PHOSPHOLIPASE D BY THYROXINE IN THE LIVER CELLS].

    PubMed

    Hassouneh, Loay Kh M

    2015-01-01

    Thyroid hormones (TG) are known modulators of signal transduction. Phospholipase D (PLD) is one of the targets of TG in the stimulated cells. Response of cells to the short-term TG action significantly reduces at old age. Taking into account that diacylglycerol (DAG) accumulation induces the resistance of cells to some of regulatory factors in the target cells the aim of the present study was to determine if DAG content increase in hepatocytes impairs the L-thyroxine (L-T4) short-term action. The experiments were performed in either the [14C]palmitic acid- labeled hepatocytes or [14C]oleic acid-pre-labeled liver cells of 3- and 24-month-old rats. To study the short-term L-T4 action on cells the PLD activation was determined. The DAG production and content in hepatocytes significantly increased at old age and in the young cells pre-treated with palmitic acid. The reduction of DAG level in cells by means of DAG-kinase activator, alfa-tocoferol acetate, or long-term L-T4 treatment improved the short-term hormone action. The above data have indicated that DAG play important role in the L-T4 PLD regulation. The cross-talk between classic and non-genomic pathways of TG regulation of lipid metabolism has been determined. PMID:26387163

  14. Chronic Alcohol Consumption Impairs Visuo-Spatial Associative Memory in Periadolescent Rhesus Monkeys

    PubMed Central

    Crean, Rebecca D.; Vandewater, Sophia A.; Katner, Simon N.; Huitron-Resendiz, Salvador

    2010-01-01

    Alcohol abuse in the adult is often preceded by high alcohol consumption during adolescence. Profound changes in brain structure and function occur during this developmental period, therefore alcohol may impact essential cognitive skill development during the formal educational years. The objective of this study was to determine if chronic oral alcohol intake slows acquisition and performance of cognitive tasks in male adolescent rhesus monkeys. Treatment groups (Alcohol, N=4; Control, N=3) were evaluated on bimanual dexterity and tests of visuo-spatial memory and learning adapted from the Cambridge Neuropsychological Test Automated Battery. Animals were trained daily in 30 min sessions and had subsequent access to alcohol/Tang® solutions (Alcohol group) or Tang® only (Control group) Monday through Friday for 11 months. Recordings of brainstem auditory evoked potentials (BSAEP) were conducted periodically before and during the chronic drinking. Results Chronic alcohol drinking (ave of 1.78g/kg alcohol per session) impaired behavioral performance assessed ~22 hrs after the prior drinking session. The Alcohol group required more trials than the Control group to reach criterion on the visuo-spatial memory task and showed increased sensitivity to trial difficulty and retention interval. Alcohol animals also had slowed initial acquisition of the bimanual task. The latency of P4 and P5 BSAEP peaks were also delayed in the Alcohol group. Chronic alcohol consumption impaired the acquisition and performance of a spatial memory task and disrupted brainstem auditory processing, thus these results show that repeated alcohol exposure in adolescence interferes with a range of brain functions including complex visuo-spatial mnemonic processing. PMID:20951512

  15. Concomitant use of corticosteroid and antimicrobials for liver abscesses in patients with chronic granulomatous disease.

    PubMed

    Shin, Kyung-Sue; Lee, Mu Suk

    2016-04-01

    Chronic granulomatous disease (CGD) is a rare inherited disorder caused by defective nicotinamide adenine dinucleotide phosphate oxidase enzyme and characterized by recurrent bacterial and fungal infections. Although liver abscess is a common manifestation of CGD, its management in CGD patients is not well-defined. In addition, the generalized guidelines for treating liver abscesses do not necessarily apply to CGD patients. Corticosteroids are commonly used to control granulomatous complications, such as inflammatory gastrointestinal and genitourinary lesions, in patients with CGD, Corticosteroids have also been used in combination with antimicrobials to treat refractory infections in patients with CGD. Because corticosteroids are capable of suppressing symptomatic inflammation, all potential infections must be adequately controlled prior to corticosteroid initiation. We report 3 typical CGD cases with liver abscesses refractory to conventional treatments that were successfully treated with the concomitant use of corticosteroid and antimicrobials. It remains unclear whether corticosteroid therapy is required for liver abscesses in CGD refractory to conventional treatments. However, based on our observations, use of corticosteroids in combination with optimal antimicrobials should be considered for refractory liver abscesses in CGD. PMID:27186231

  16. Factors associated with significant liver necroinflammation in chronic hepatitis B patients with cirrhosis.

    PubMed

    Chen, Sheng-Sen; Yu, Kang-Kang; Ling, Qing-Xia; Huang, Chong; Li, Ning; Zheng, Jian-Ming; Bao, Su-Xia; Cheng, Qi; Zhu, Meng-Qi; Chen, Ming-Quan

    2016-01-01

    We determined the association between various clinical parameters and significant liver necroinflammation in patients with chronic hepatitis B (CHB) related cirrhosis. Two hundred patients with CHB related cirrhosis were recruited in the final analysis. Clinical laboratory values and characteristics were obtained from the medical record. We performed analyses of the relationships between independent variables and significant liver necroinflammation by using binary logistic regression analysis and discriminant analysis. Significant liver necroinflammation (grade≥2) was found in 58.0% (80/138) of antiviral therapy patients and 48.4% (30/62) of non antiviral therapy patients respectively. Also, there were some significant differences in serum hepatitis B surface antigen (HBsAg), serum hepatitis B e antigen (HBeAg) and serum hepatitis B virus (HBV) DNA between antiviral therapy and non antiviral therapy patients. After that, aspartate aminotransferase (AST), total bilirubin (TBIL), total bile acid (TBA), prothrombin time (PT), aspartate aminotransferase to platelet ratio index (APRI) and serum HBV DNA were confirmed as independent predictors of significant liver necroinflammation in CHB patients with cirrhosis by univariate analysis and multivariate analysis (p = 0.002, 0.044, 0.001, 0.014, 0.01 and 0.02 respectively). Finally, receiver operating characteristic (ROC) curve analysis and discriminant analysis validated that these six variables together have strong predictive power to evaluate significant liver necroinflammation. PMID:27615602

  17. Concomitant use of corticosteroid and antimicrobials for liver abscesses in patients with chronic granulomatous disease

    PubMed Central

    Lee, Mu Suk

    2016-01-01

    Chronic granulomatous disease (CGD) is a rare inherited disorder caused by defective nicotinamide adenine dinucleotide phosphate oxidase enzyme and characterized by recurrent bacterial and fungal infections. Although liver abscess is a common manifestation of CGD, its management in CGD patients is not well-defined. In addition, the generalized guidelines for treating liver abscesses do not necessarily apply to CGD patients. Corticosteroids are commonly used to control granulomatous complications, such as inflammatory gastrointestinal and genitourinary lesions, in patients with CGD, Corticosteroids have also been used in combination with antimicrobials to treat refractory infections in patients with CGD. Because corticosteroids are capable of suppressing symptomatic inflammation, all potential infections must be adequately controlled prior to corticosteroid initiation. We report 3 typical CGD cases with liver abscesses refractory to conventional treatments that were successfully treated with the concomitant use of corticosteroid and antimicrobials. It remains unclear whether corticosteroid therapy is required for liver abscesses in CGD refractory to conventional treatments. However, based on our observations, use of corticosteroids in combination with optimal antimicrobials should be considered for refractory liver abscesses in CGD. PMID:27186231

  18. Brainstem evoked response audiometry: an investigatory tool in detecting hepatic encephalopathy in decompensated chronic liver disease.

    PubMed

    Kabali, Balasubramanian; Velayutham, Gowri; Kapali, Suresh Chander

    2014-01-01

    It is estimated that globally there is a marked increase in liver disease with reports of rising morbidity and mortality, particularly in younger age groups. Brainstem auditory evoked potential (BAEP) was recorded in 60 decompensated chronic liver disease (DCLD) subjects who fulfilled the selection criteria and compared to 60 age and gender matched healthy subjects with normal liver functions. DCLD subjects were divided into two inter groups based on presence or absence of hepatic encephalopathy (HE). Group 1 comprises of 30 subjects of grade- I HE and Group 2 included 30 subjects without hepatic encephalopathy (NHE). Absolute and interpeak wave latencies were measured. Results were analysed by student independent t- test using SPSS software 11 version. Statistical significance was tested using P value. From the present study it can be concluded that the central nervous system is involved in liver cirrhosis evidenced by an abnormal BAEP latencies parameters. This shows that there may be progressive demyelination occurring along with axonal loss or dysfunction in liver cirrhosis HE. This study suggests that periodic evaluation of cirrhotic individuals to such test will help in monitoring the progress of encephalopathy. The prime goal of this study is early diagnosis and initiation of treatment before the onset of coma can reduce the fatality rate. PMID:25508308

  19. Brainstem evoked response audiometry: an investigatory tool in detecting hepatic encephalopathy in decompensated chronic liver disease.

    PubMed

    Kabali, Balasubramanian; Velayutham, Gowri; Kapali, Suresh Chander

    2014-01-01

    It is estimated that globally there is a marked increase in liver disease with reports of rising morbidity and mortality, particularly in younger age groups. Brainstem auditory evoked potential (BAEP) was recorded in 60 decompensated chronic liver disease (DCLD) subjects who fulfilled the selection criteria and compared to 60 age and gender matched healthy subjects with normal liver functions. DCLD subjects were divided into two inter groups based on presence or absence of hepatic encephalopathy (HE). Group 1 comprises of 30 subjects of grade- I HE and Group 2 included 30 subjects without hepatic encephalopathy (NHE). Absolute and interpeak wave latencies were measured. Results were analysed by student independent t- test using SPSS software 11 version. Statistical significance was tested using P value. From the present study it can be concluded that the central nervous system is involved in liver cirrhosis evidenced by an abnormal BAEP latencies parameters. This shows that there may be progressive demyelination occurring along with axonal loss or dysfunction in liver cirrhosis HE. This study suggests that periodic evaluation of cirrhotic individuals to such test will help in monitoring the progress of encephalopathy. The prime goal of this study is early diagnosis and initiation of treatment before the onset of coma can reduce the fatality rate. PMID:25464677

  20. Non-invasive assessment of liver fibrosis in chronic hepatitis B

    PubMed Central

    Branchi, Federica; Conti, Clara Benedetta; Baccarin, Alessandra; Lampertico, Pietro; Conte, Dario; Fraquelli, Mirella

    2014-01-01

    The goal of this review is to provide a comprehensive picture of the role, clinical applications and future perspectives of the most widely used non-invasive techniques for the evaluation of hepatitis B virus (HBV) infection. During the past decade many non-invasive methods have been developed to reduce the need for liver biopsy in staging fibrosis and to overcome whenever possible its limitations, mainly: invasiveness, costs, low reproducibility, poor acceptance by patients. Elastographic techniques conceived to assess liver stiffness, in particular transient elastography, and the most commonly used biological markers will be assessed against their respective role and limitations in staging hepatic fibrosis. Recent evidence highlights that both liver stiffness and some bio-chemical markers correlate with survival and major clinical end-points such as liver decompensation, development of hepatocellular carcinoma and portal hypertension. Thus the non-invasive techniques here discussed can play a major role in the management of patients with chronic HBV-related hepatitis. Given their prognostic value, transient elastography and some bio-chemical markers can be used to better categorize patients with advanced fibrosis and cirrhosis and assign them to different classes of risk for clinically relevant outcomes. Very recent data indicates that the combined measurements of liver and spleen stiffness enable the reliable prediction of portal hypertension and esophageal varices development. PMID:25356021

  1. Survival Benefits of Small Anatomical Resection of the Liver for Patients with Hepatocellular Carcinoma and Impaired Liver Function, Based on New-Era Imaging Studies

    PubMed Central

    Sakoda, Masahiko; Ueno, Shinichi; Iino, Satoshi; Hiwatashi, Kiyokazu; Minami, Koji; Kawasaki, Yota; Kurahara, Hiroshi; Mataki, Yuko; Maemura, Kosei; Shinchi, Hiroyuki; Natsugoe, Shoji

    2016-01-01

    Background: It has been reported that anatomical resection of the liver may be preferred for primary hepatocellular carcinoma (HCC), and is at least recommended for systematic removal of a segment confined by tumor-bearing portal tributaries. However, nonanatomical resection (NAR) is often selected because of the patient's background, impairment of liver function, and tumor factors. The aims of the present study were to retrospectively compare the recurrence-free survival (RFS) rates for cases of partial resection (PR) and for small anatomical resection (SAR), which is regarded as NAR for primary HCC with impaired liver function. Patients and Methods: So-called NAR was performed for a primary and solitary (≤ 5cm) HCC in 47 patients; the patients were classified into PR (n=25) and SAR (n=22) groups. Clinicopathological factors, survival data, and recurrence patterns were compared between groups. Results: There were no significant differences in the preoperative characteristics between the two groups. Operative time was significantly longer in the SAR group than in the PR group. There was no significant difference in the postoperative morbidity and tumor pathological characteristics between the two groups. The RFS of the SAR group was significantly better than those of the PR group. Although there was no significant difference in the pattern of recurrence between the two groups, the rate of intrahepatic recurrence in the same segment as the initial tumor tended to be higher in the PR group than in the SAR group. Multivariate analysis revealed that only the PR operative procedure was significant independent risk factor for poorer RFS. Conclusion: Compared with PR, SAR effectively improves the rate of RFS after surgery for a primary and solitary HCC with impaired liver function. PMID:27326244

  2. Adjunctive Memantine Therapy for Cognitive Impairment in Chronic Schizophrenia: A Placebo-Controlled Pilot Study

    PubMed Central

    Lee, Jung Goo; Lee, Sae Woom; Lee, Bong Ju; Park, Sung Woo; Kim, Gyung Mee

    2012-01-01

    Objective To investigate the effects of memantine, an N-methyl-d-aspartate (NMDA) receptor antagonist, on cognitive impairments in patients with chronic schizophrenia. Methods A 12-week, placebo-controlled trial was conducted to determine the effectiveness of memantine as an adjunctive treatment with conventional antipsychotic medications in 26 patients with chronic schizophrenia. The subjects were evaluated with the Korean version of the Mini-Mental State Examination (K-MMSE), the Positive and Negative Syndrome Scale (PANSS), the Hamilton Rating Scale for Depression (HAM-D), and a standard neuropsychological screening test. Results Memantine treatment was not associated with significantly improved cognitive test scores compared with the placebo control treatment. An improvement in the scores on the PANSS negative subscale was noted with memantine, but it was not significant. Conclusion Adjunctive memantine treatment did not improve cognitive functioning or affect psychopathology in patients with chronic schizophrenia in the present study. Memantine, however, was tolerated well and did not exacerbate positive symptoms in patients with chronic schizophrenia. PMID:22707968

  3. Serum Paraoxonase Levels are Correlated with Impaired Aortic Functions in Patients with Chronic Kidney Disease

    PubMed Central

    Efe, Tolga H; Ertem, Ahmet G; Altunoglu, Alpaslan; Koseoglu, Cemal; Erayman, Ali; Bilgin, Murat; Kurmuş, Özge; Aslan, Turgay; Bilge, Mehmet

    2016-01-01

    Background The correlation between aortic functions and paraoxonase levels has been previously demonstrated by several earlier studies. In this study, we aimed to investigate the correlation between serum paraoxonase levels and aortic functions among patients with chronic kidney disease. Methods Our study enrolled 46 chronic kidney disease patients and 45 healthy controls. From these patients, serum cholesterol, creatinine, hemoglobin, and paraoxonase-1 levels were analyzed. Results Paraoxonase-1 levels were significantly lower in patients with chronic kidney disease compared to the controls (p < 0.001). Additionally, the extent of aortic stiffness index (%) was significantly higher in chronic kidney disease patients, but aortic strain and aortic distensibility were significantly higher in healthy controls (p < 0.001, p < 0.001, and p < 0.001, respectively). We further found that paraoxonase-1 levels were correlated with aortic stiffness index, aortic strain, and aortic distensibility (p < 0.001, p < 0.001, and p < 0.001, respectively). Conclusions Our study demonstrated that serum paraoxonase-1 levels were significantly correlated with impaired aortic functions. The results of this study highlight the impact of serum paraoxonase-1 activity on atherosclerosis and cardiovascular adverse events. PMID:27122934

  4. Effect of interferon therapy on radionuclide imaging in chronic liver diseases due to HCV infection

    SciTech Connect

    Ghaffar, Y.; Dorgham, L.; Lotfy, N. |

    1995-09-01

    Interferon (alpha-IFN) exerts a modulating effect on the immune system. Kupffer cells of the liver play an important immunological role by their uptake of various agents and particles, including colloids. We sought to discover if alpha-IFN could enhance the colloid uptake function of the Kupffer cells. The effect of alpha-IFN therapy on radioisotope scans of the liver was studied in 20 patients with chronic liver disease due to hepatitic C virus (HCV) infection who received therapy at a dose of 3 million IU for 6 mo, in another patients who received the same therapy for 12 mo and in matched control groups (10 patients with HCV infection for each study group) who did not received alpha-IFN. A {sup 99m}Tc-sulfur colloid scan of the liver was obtained for each group before and after therapy and, for control subjects, at the start and end of the study periods. The liver-to-spleen geometric mean ratio of colloid uptake was assessed. In the first study group, the mean rate of improvement in the liver-to-spleen ratio was 48% in 70% of the patients, compared to 8% in 20% of controls (p<0.05). In the second study group, mean liver-to-spleen ratio was 88% in 85% of patients, compared to 12% in 40% of controls (p<0.001). Alpha-IFN therapy appears to enhance the colloidal uptake function of Kupffer cells, which adds a new dimension to the immunomodulatory effect of interferon. 13 refs., 2 tabs.

  5. Acute and chronic effects of IL-22 on acetaminophen-induced liver injury.

    PubMed

    Feng, Dechun; Wang, Yan; Wang, Hua; Weng, Honglei; Kong, Xiaoni; Martin-Murphy, Brittany V; Li, Yongmei; Park, Ogyi; Dooley, Steven; Ju, Cynthia; Gao, Bin

    2014-09-01

    Acetaminophen (APAP)-induced liver injury (AILI) accounts for half of the acute liver failure cases in the United States. A better understanding of the underlying mechanisms of AILI is necessary for the development of novel antidotes. We found that pretreatment with IL-22 protected mice from APAP-mediated hepatotoxicity. The protection was dependent on STAT3, as IL-22 failed to reduce APAP hepatotoxicity in liver-specific STAT3 knockout mice. In contrast to the acute exposure to IL-22, the endogenous chronic overexpression of IL-22 in IL-22 transgenic (TG) mice or IL-22 adenovirus treatment for 6 wk resulted in a markedly increased susceptibility to AILI. Furthermore, the hepatic expression levels of cytochrome 2E1 (Cyp2E1) and Cyp1A2 were much higher in IL-22TG mice. Ablation of Cyp2E1 but not hepatic STAT3 abolished AILI and protein-adduct formation in IL-22TG mice. Finally, hepatic expression of HNF-1α, a transcriptional factor that is known to control Cyp2E1 expression, was elevated in IL-22TG mice compared with wild-type mice. Upregulation of hepatic Cyp2E1 was only observed in mice with constitutive overexpression of IL-22 but not with short-term treatment with one dose of IL-22 or multiple doses of IL-22 for 2 wk. In conclusion, short-term acute IL-22 exposure protects mice against AILI through STAT3 activation; however, chronic constitutive overexpression of IL-22 exacerbates AILI by increasing Cyp2E1 and toxic reactive APAP metabolite production. These findings may not only enhance our understanding of the effects of chronic inflammation on AILI in patients with liver disease, but are also helpful to identify novel therapeutic targets for the treatment of AILI. PMID:25063867

  6. Characteristics of upper abdominal pain in those with chronic liver disease.

    PubMed

    Riley, Thomas R; Koch, Kenneth

    2003-10-01

    Chronic hepatitis has many causes. Symptoms include upper abdominal pain. To allow for a better understanding of this pain we compare HCV patients with other liver diseases and normal controls on their reporting of pain over one month and describe associations. A cross-sectional, case control study was performed. Three groups are studied: (1) normal individuals (NC) (N = 64), (2) patients with chronic liver diseases other than HCV (LD) (N = 53), and (3) HCV infection (N = 64). A dyspepsia questionnaire was utilized, which inquired about a one-month symptom presence of upper abdominal pain and associated symptoms. There was a one-month period prevalence of upper abdominal pain of 45.3% in the HCV group vs 32% in the LD and 20.3% in the NC groups (P = 0.01). The LD (22.6%) and HCV (26.6%) groups had markedly more pain that was worsened by eating compared with NC (1.6%) (P = .003). On univariate analysis, when comparing those with upper abdominal pain to those without, there was a lower age (41.3 vs 44.5), a higher BMI (30.3 vs 26), and more symptoms of fatigue, bloating, and pain worsened by eating and early satiety. On multivariate analysis, age < 50 (OR 5.1; CI 1.5-17), BMI > 30 (OR 4.1; CI 1.5-10.9), nausea (OR 4.1; CI 1.6-10.4), and pain with eating (OR 30: CI 6.7-133) predicted upper abdominal pain. In conclusion, upper abdominal pain is more commonly reported over one month in those with chronic liver diseases. That the abdominal pain worsened after meals in liver patients but not in the normal subjects was a surprise. Possible explanations for this finding are offered. PMID:14627332

  7. Prevalence and characteristics of hypoxic hepatitis in the largest single-centre cohort of avian influenza A(H7N9) virus-infected patients with severe liver impairment in the intensive care unit

    PubMed Central

    Zhang, YiMin; Liu, JiMin; Yu, Liang; Zhou, Ning; Ding, Wei; Zheng, ShuFa; Shi, Ding; Li, LanJuan

    2016-01-01

    Avian influenza A(H7N9) virus (A(H7N9)) emerged in February 2013. Liver impairment of unknown cause is present in 29% of patients with A(H7N9) infection, some of whom experience severe liver injury. Hypoxic hepatitis (HH) is a type of acute severe liver injury characterized by an abrupt, massive increase in serum aminotransferases resulting from anoxic centrilobular necrosis of liver cells. In the intensive care unit (ICU), the prevalence of HH is ∼1%–2%. Here, we report a 1.8% (2/112) incidence of HH in the largest single-centre cohort of ICU patients with A(H7N9) infection. Both HH patients presented with multiple organ failure (MOF) involving respiratory, cardiac, circulatory and renal failure and had a history of chronic heart disease. On admission, severe liver impairment was found. Peak alanine aminotransferase (ALT) and aspartate aminotransferase (AST) values were 937 and 1281 U/L, and 3117 and 3029 U/L, respectively, in the two patients. Unfortunately, both patients died due to deterioration of MOF. A post-mortem biopsy in case 1 confirmed the presence of centrilobular necrosis of the liver, and real-time reverse transcription polymerase chain reaction of A(H7N9)-specific genes was negative, which excluded A(H7N9)-related hepatitis. The incidence of HH in A(H7N9) patients is similar to that in ICU patients with other aetiologies. It seems that patients with A(H7N9) infection and a history of chronic heart disease with a low left ventricular ejection fraction on admission are susceptible to HH, which presents as a marked elevation in ALT at the time of admission. PMID:26733380

  8. Losartan may inhibit the progression of liver fibrosis in chronic HCV patients

    PubMed Central

    Salama, Zakaria A.; Sadek, Ahmed; Abdelhady, Ahmed M.; Morsy, Shereif Ahmed; Esmat, Gamal

    2016-01-01

    Background Abundant experimental evidence indicates overproduction of angiotensin II in the injured liver, and a role in stimulation of hepatic stellate cell (HSC) activation and fibrogenesis thereby, representing an attractive antifibrotic target. The aim of this study was to examine the antifibrotic effect of losartan on histopathologic level in chronic HCV patients. Methods A prospective study on fifty patients with chronic HCV and liver fibrosis proved by liver biopsy was conducted. They included patients who did not respond (n=36) or comply (n=2) or receive therapy due to established cirrhosis (n=10), or refused to receive (n=2) combined interferon and ribavirin therapy. They were divided randomly into 2 groups. The 1st group (n=25) was given losartan 50 mg OD for 1 year and the 2nd group (25 patients) was given silymarin, 140 mg t.i.d., (silymarin group). Liver biopsy was done at baseline and 1 year from the onset of treatment (end of study). Results In the second liver biopsy after 1 year, the decrease in fibrosis stage was significantly different between losartan group and silymarin group (a decrease of 1.88±0.96 (50.9%) vs. 0.45±0.93 (11.7%), respectively; P<0.01). In patients treated with losartan, regression in fibrosis stage was observed in 14/16 patients vs. 2/11 in silymarin group (P<0.01). No differences were observed in inflammation grades in both groups. A significant increase in albumin and prothrombin levels and a decrease in systolic blood pressure were found in losartan but not in silymarin group (P=0.009, 0.001 & 0.018 respectively and P=0.158, 0.603 & 0.288, respectively). Conclusions Histopathological scores showed that losartan had an inhibitory effect on progression and even led to regression of fibrosis stage but had no effect on the grade of inflammation. PMID:27275467

  9. Building an Evidence Base for the Co-Occurrence of Chronic Disease and Psychiatric Distress and Impairment

    PubMed Central

    Smith, Tyler C.

    2014-01-01

    Introduction Mental disorders and chronic diseases have been reported to independently affect half of the US population. The objective of this study was to evaluate the comorbid nature of these conditions. Methods We analyzed data from 39,954 participants from the 2009 California Health Interview Survey who reported both psychological distress and impairment, on the basis of the Kessler 6 and the Sheehan Disability Scale, and 1 or more of 4 chronic diseases (type 2 diabetes, high blood pressure, asthma, heart disease). Weighted and nonweighted multivariable logistic regression were used to investigate the association between psychological distress and impairment and chronic disease, after adjusting for sex, age, race, current smoking, binge drinking in the previous year, moderate physical activity, and body mass index. Results After controlling for covariates in the model, we found a significant dose–response relationship between reported chronic diseases and psychiatric distress and impairment that ranged from 1.50 for 1 reported chronic disease to 4.68 for 4 reported chronic diseases. Conclusion The growing chronic disease burden should be understood clinically in the context of mental health conditions. Further research is needed to identify ways to integrate mental health and chronic disease prevention in primary care. PMID:25340360

  10. Population-representative Incidence of Acute-On-Chronic Liver Failure

    PubMed Central

    Shao, Jian-Guo; Zhu, Yong-Chang; Xu, Ai-Dong; Yao, Jian-Hua; Wang, Xu-Lin; Qian, Yin-Kun; Wang, Hua-Yu; Shen, Yi; Lu, Peng; Wang, Lu-Jun

    2016-01-01

    Background: Acute-on-chronic liver failure (ACLF) is a major cause of hepatic death in the world, but no population-based studies have evaluated the incidence of ACLF. This study was conducted to determine the incidence and short-term outcomes of ACLF in a region of Eastern China. Methods: In this prospective cross-sectional study, we collected data from public hospitals in Nantong city between January 1, 2005, and December 31, 2014. All hospitals with admission potential for ACLF patients were included. The primary outcome was ACLF defined as severe jaundice and coagulopathy with underlying chronic liver disease, according to diagnostic and laboratory criteria suggested by Chinese Society for Hepatology (CSH). Results: During the 10-year period, a consecutive sample of 1934 ACLF patients was included in this study. The overall ACLF incidence rate over the 10-year period was 2.53 (95% confidence interval, 2.16-2.91) per 100,000 population per year, decreasing from 3.35 in 2005 to 2.06 in 2014. Chronic hepatitis B virus (HBV) infection was the leading cause of chronic liver disease and HBV reactivation was the most common cause of acute hepatic event. The 28-day mortality for the ACLF patients had a clear decline during the study period, form 50.39% in 2005 to 35.44% in 2014. Conclusions: In the Eastern China population, the incidence of ACLF is decreasing and the prognosis improving. Short-term mortality was associated with the presence of cirrhosis and growing age. While ACLF remains a life-threatening disorder, our findings suggest that nationwide and long-term cohorts should be conducted for the natural history of ACLF. PMID:27136963

  11. Noninvasive fat quantification of the liver and pancreas may provide potential biomarkers of impaired glucose tolerance and type 2 diabetes

    PubMed Central

    Dong, Zhi; Luo, Yanji; Cai, Huasong; Zhang, Zhongwei; Peng, Zhenpeng; Jiang, Mengjie; Li, Yanbing; Li, Chang; Li, Zi-Ping; Feng, Shi-Ting

    2016-01-01

    Abstract The aim of the study is to investigate if the fat content of the liver and pancreas may indicate impaired glucose tolerance (IGT) or type 2 diabetes mellitus (T2DM). A total of 83 subjects (34 men; aged 46.5 ± 13.5 years) were characterized as T2DM, IGT, or normal glucose tolerant (NGT). NGT individuals were stratified as <40 or ≥40 years. Standard laboratory tests were conducted for insulin resistance and β-cell dysfunction. The magnetic resonance imaging Dixon technique was used to determine fat distribution in the liver and pancreas. Correlations among liver and pancreatic fat volume fractions (LFVFs and PFVFs, respectively) and laboratory parameters were analyzed. Among the groups, fat distribution was consistent throughout sections of the liver and pancreas, and LFVFs closely correlated with PFVFs. LFVFs correlated more closely than PFVFs with insulin resistance and β-cell function. Both the LFVFs and PFVFs were the highest in the T2DM patients, less in the IGT, and least in the NGT; all differences were significant. The PFVFs of the NGT subjects ≥40 years were significantly higher than that of those <40 years. The fat content of the liver and pancreas, particularly the liver, may be a biomarker for IGT and T2DM. PMID:27281097

  12. High antigen levels induce an exhausted phenotype in a chronic infection without impairing T cell expansion and survival.

    PubMed

    Utzschneider, Daniel T; Alfei, Francesca; Roelli, Patrick; Barras, David; Chennupati, Vijaykumar; Darbre, Stephanie; Delorenzi, Mauro; Pinschewer, Daniel D; Zehn, Dietmar

    2016-08-22

    Chronic infections induce T cells showing impaired cytokine secretion and up-regulated expression of inhibitory receptors such as PD-1. What determines the acquisition of this chronic phenotype and how it impacts T cell function remain vaguely understood. Using newly generated recombinant antigen variant-expressing chronic lymphocytic choriomeningitis virus (LCMV) strains, we uncovered that T cell differentiation and acquisition of a chronic or exhausted phenotype depend critically on the frequency of T cell receptor (TCR) engagement and less significantly on the strength of TCR stimulation. In fact, we noted that low-level antigen exposure promotes the formation of T cells with an acute phenotype in chronic infections. Unexpectedly, we found that T cell populations with an acute or chronic phenotype are maintained equally well in chronic infections and undergo comparable primary and secondary expansion. Thus, our observations contrast with the view that T cells with a typical chronic infection phenotype are severely functionally impaired and rapidly transition into a terminal stage of differentiation. Instead, our data unravel that T cells primarily undergo a form of phenotypic and functional differentiation in the early phase of a chronic LCMV infection without inheriting a net survival or expansion deficit, and we demonstrate that the acquired chronic phenotype transitions into the memory T cell compartment. PMID:27455951

  13. Analysis of hepatic gene expression during fatty liver change due to chronic ethanol administration in mice

    SciTech Connect

    Yin, H.-Q.; Je, Young-Tae; Kim, Mingoo; Kim, Ju-Han; Kong, Gu; Kang, Kyung-Sun; Kim, Hyung-Lae; Yoon, Byung-IL; Lee, Mi-Ock; Lee, Byung-Hoon

    2009-03-15

    Chronic consumption of ethanol can cause cumulative liver damage that can ultimately lead to cirrhosis. To explore the mechanisms of alcoholic steatosis, we investigated the global intrahepatic gene expression profiles of livers from mice administered alcohol. Ethanol was administered by feeding the standard Lieber-DeCarli diet, of which 36% (high dose) and 3.6% (low dose) of the total calories were supplied from ethanol for 1, 2, or 4 weeks. Histopathological evaluation of the liver samples revealed fatty changes and punctate necrosis in the high-dose group and ballooning degeneration in the low-dose group. In total, 292 genes were identified as ethanol responsive, and several of these differed significantly in expression compared to those of control mice (two-way ANOVA; p < 0.05). Specifically, the expression levels of genes involved in hepatic lipid transport and metabolism were examined. An overall net increase in gene expression was observed for genes involved in (i) glucose transport and glycolysis, (ii) fatty acid influx and de novo synthesis, (iii) fatty acid esterification to triglycerides, and (iv) cholesterol transport, de novo cholesterol synthesis, and bile acid synthesis. Collectively, these data provide useful information concerning the global gene expression changes that occur due to alcohol intake and provide important insights into the comprehensive mechanisms of chronic alcoholic steatosis.

  14. From the prodrome to chronic schizophrenia: the neurobiology underlying psychotic symptoms and cognitive impairments

    PubMed Central

    Howes, OD; Fusar-Poli, P; Bloomfield, M; Selvaraj, S; McGuire, P

    2013-01-01

    Schizophrenia is a chronic psychotic disorder that remains a considerable cause of global disease burden. Cognitive impairments are common and contribute significantly to the morbidity of the disorder. Over the last two decades or so molecular imaging studies have refined understanding of the pathophysiology underlying the development of psychosis and cognitive impairments. Firstly they have consistently implicated presynaptic dopaminergic dysfunction in the disorder, finding that dopamine synthesis capacity, dopamine release and baseline dopamine levels are increased in the illness. Secondly recent findings show that dopamine synthesis capacity is elevated in those that go on to develop psychosis in the following year, but not in those that do not, and appears to increase further with the development of psychosis. Thirdly evidence links greater dopamine synthesis capacity to poorer cognitive performance and altered frontal cortical function measured using functional imaging during cognitive tasks. Finally they have provided data on the nature of other neurofunctional alterations in the disorder, in particular in the serotonergic system and neuroinflammation. We review these findings and discuss their implications for understanding the neurobiology of psychosis and cognitive impairments in schizophrenia. PMID:22239576

  15. Protective effect of l-theanine on chronic restraint stress-induced cognitive impairments in mice.

    PubMed

    Tian, Xia; Sun, Lingyan; Gou, Lingshan; Ling, Xin; Feng, Yan; Wang, Ling; Yin, Xiaoxing; Liu, Yi

    2013-03-29

    The present work was aimed to study the protective effect of l-theanine on chronic restraint stress (CRS)-induced cognitive impairments in mice. The stress was produced by restraining the animals in well-ventilated polypropylene tubes (3.2 cm in diameter ×10.5 cm in length) for 8h once daily for 21 consecutive days. L-theanine (2 and 4 mg/kg) was administered 30 min before the animals subjected to acute immobilized stress. At week 4, mice were subjected to Morris water maze and step-through tests to measure the cognitive function followed by oxidative parameters and corticosterone as well as catecholamines (norepinephrine and dopamine) subsequently. Our results showed that the cognitive performances in CRS group were markedly deteriorated, accompanied by noticeable alterations in oxidative parameters and catecholamine levels in the hippocampus and the cerebral cortex as well as corticosterone and catecholamine levels in the serum. However, not only did l-theanine treatment exhibit a reversal of the cognitive impairments and oxidative damage induced by CRS, but also reversed the abnormal level of corticosterone in the serum as well as the abnormal levels of catecholamines in the brain and the serum. This study indicated the protective effect of l-theanine against CRS-induced cognitive impairments in mice. PMID:23395732

  16. The interaction of acute and chronic stress impairs model-based behavioral control.

    PubMed

    Radenbach, Christoph; Reiter, Andrea M F; Engert, Veronika; Sjoerds, Zsuzsika; Villringer, Arno; Heinze, Hans-Jochen; Deserno, Lorenz; Schlagenhauf, Florian

    2015-03-01

    It is suggested that acute stress shifts behavioral control from goal-directed, model-based toward habitual, model-free strategies. Recent findings indicate that interindividual differences in the cortisol stress response influence model-based decision-making. Although not yet investigated in humans, animal studies show that chronic stress also shifts decision-making toward more habitual behavior. Here, we ask whether acute stress and individual vulnerability factors, such as stress reactivity and previous exposure to stressful life events, impact the balance between model-free and model-based control systems. To test this, 39 male participants (21-30 years old) were exposed to a potent psychosocial stressor (Trier Social Stress Test) and a control condition in a within-subjects design before they performed a sequential decision-making task which evaluates the balance between the two systems. Physiological and subjective stress reactivity was assessed before, during, and after acute stress exposure. By means of computational modeling, we demonstrate that interindividual variability in stress reactivity predicts impairments in model-based decision-making. Whereas acute psychosocial stress did not alter model-based behavioral control, we found chronic and acute stress to interact in their detrimental effect on decision-making: subjects with high but not low chronic stress levels as indicated by stressful life events exhibited reduced model-based control in response to acute psychosocial stress. These findings emphasize that stress reactivity and chronic stress play an important role in mediating the relationship between stress and decision-making. Our results might stimulate new insights into the interplay between chronic and acute stress, attenuated model-based control, and the pathogenesis of various psychiatric diseases. PMID:25662093

  17. Spatial cognition and sexually dimorphic synaptic plasticity balance impairment in rats with chronic prenatal ethanol exposure.

    PubMed

    An, Lei; Zhang, Tao

    2013-11-01

    Prenatal ethanol exposure can lead to long-lasting impairments in the ability of rats to process spatial information, as well as produce long-lasting deficits in long-term potentiation (LTP), a biological model of learning and memory processing. The present study aimed to examine the sexually dimorphic effects of chronic prenatal ethanol exposure (CPEE) on behavior cognition and synaptic plasticity balance (SPB), and tried to understand a possible mechanism by evaluating the alternation of SPB. The animal model was produced by ethanol exposure throughout gestational period with 4 g/kg bodyweight. Offspring of both male and female were selected and studied on postnatal days 36. Subsequently, the data showed that chronic ethanol exposure resulted in birth weight reduction, losing bodyweight gain, microcephaly and hippocampus weight retardation. In Morris water maze (MWM) test, escape latencies were significantly higher in CPEE-treated rats than that in control ones. They also spent much less time in the target quadrant compared to that of control animals in the probe phase. In addition, it was found that there was a more severe impairment in females than that in males after CPEE treatment. Electrophysiological studies showed that CPEE considerably inhibited hippocampal LTP and facilitated depotentiation in males, while significantly enhanced LTP and suppressed depotentiation in females. A novel index, developed by us, showed that the action of CPEE on SPB was more sensitive in females than that in males, suggesting that it might be an effective index to distinguish the difference of SPB impairment between males and females. PMID:24050890

  18. Effects of α-tocopherol and β-carotene supplementation on liver cancer incidence and chronic liver disease mortality in the ATBC study

    PubMed Central

    Lai, G Y; Weinstein, S J; Taylor, P R; McGlynn, K A; Virtamo, J; Gail, M H; Albanes, D; Freedman, N D

    2014-01-01

    Background: Recent data suggest the possible benefits of α-tocopherol and β-carotene supplementation on liver cancer and chronic liver disease (CLD), but the long-term trial data are limited. Methods: We evaluated the efficacy of supplemental 50 mg day−1 α-tocopherol and 20 mg day−1 β-carotene on incident liver cancer and CLD mortality in a randomised trial of 29 105 Finnish male smokers, who received supplementation for 5–8 years and were followed for 16 additional years for outcomes. Results: Supplemental α-tocopherol, β-carotene, or both, relative to placebo, did not reduce the risk of liver cancer or CLD, either overall, during the intervention or during the post-intervention period. Conclusions: Long-term supplemental α-tocopherol or β-carotene had no effect on liver cancer or CLD mortality over 24 years of follow-up. PMID:25314069

  19. Factors Associated With Protein-energy Malnutrition in Chronic Liver Disease

    PubMed Central

    Nishikawa, Hiroki; Yoh, Kazunori; Enomoto, Hirayuki; Iwata, Yoshinori; Kishino, Kyohei; Shimono, Yoshihiro; Hasegawa, Kunihiro; Nakano, Chikage; Takata, Ryo; Nishimura, Takashi; Aizawa, Nobuhiro; Sakai, Yoshiyuki; Ikeda, Naoto; Takashima, Tomoyuki; Ishii, Akio; Iijima, Hiroko; Nishiguchi, Shuhei

    2016-01-01

    Abstract We aimed to elucidate the incidence of protein–energy malnutrition (PEM) in patients with chronic liver disease and to identify factors linked to the presence of PEM. A total of 432 patients with chronic liver disease were analyzed in the current analysis. We defined patients with serum albumin level of ≤3.5 g/dL and nonprotein respiratory quotient (npRQ) value using indirect calorimetry less than 0.85 as those with PEM. We compared between patients with PEM and those without PEM in baseline characteristics and examined factors linked to the presence of PEM using univariate and multivariate analyses. There are 216 patients with chronic hepatitis, 123 with Child–Pugh A, 80 with Child–Pugh B, and 13 with Child–Pugh C. Six patients (2.8%) had PEM in patients with chronic hepatitis, 17 (13.8%) in patients with Child–Pugh A, 42 (52.5%) in patients with Child–Pugh B, and 10 (76.9%) in patients with Child–Pugh C (P < 0.001). Multivariate analysis revealed that Child–Pugh classification (P < 0.001), age ≥64 years (P = 0.0428), aspartate aminotransferase (AST) ≥40 IU/L (P = 0.0023), and branched-chain amino acid to tyrosine ratio (BTR) ≤5.2 (P = 0.0328) were independent predictors linked to the presence of PEM. On the basis of numbers of above risk factors (age, AST, and BTR), the proportions of patients with PEM were well stratified especially in patients with early chronic hepatitis or Child–Pugh A (n = 339, P < 0.0001), while the proportions of patients with PEM tended to be well stratified in patients with Child–Pugh B or C (n = 93, P = 0.0673). Age, AST, and BTR can be useful markers for identifying PEM especially in patients with early stage of chronic liver disease. PMID:26765430

  20. Clinical and prognostic value of serum procollagen levels in chronic alcoholic liver disease.

    PubMed

    González-Reimers, E; Brajin-Rodríguez, M M; Rodríguez-Moreno, F; Santolaria-Fernández, F; Batista-López, N; Alvarez-Argüelles, H; Milena, A; Rodríguez-Hernández, A

    1990-02-01

    Liver fibrogenesis involves the synthesis of collagen fibrils and proteoglycans by various types of liver cells, including Ito cells, transitional cells, myofibroblasts and hepatocytes. Synthesis of collagen fibrils follows a complex metabolic pathway with intermediate products such as type III procollagen (III-PC). Serum levels of III-PC may reflect the activity of the fibrogenetic process. We analysed the relationship between the serum levels of III-PC (N-terminal peptide) and diverse clinical, biochemical and histological parameters of 77 alcoholic patients (27 cirrhotics), comparing them with those of 15 age- and sex-matched controls. A highly significant difference was obtained between controls and patients (P less than 0.0001), but no differences were observed between cirrhotics and non-cirrhotics. Serum III-PC significantly correlated with clinical and biochemical data of liver function derangement (prothrombin activity, serum albumin, bilirubin, gynecomastia, ascites, encephalopathy, edema, splenomegaly); with the duration of ethanol addiction and with MCV. Sixty patients were followed up for a period ranging between 3 and 1056 days (mean = 356 days); 9 of them died. Patients with III-PC levels above 38 ng/ml had a significantly higher mortality (P = 0.006) than those with levels under 38 (log rank test). Thus, serum III-PC may be a useful tool in the clinical evaluation and prognostic assessment of patients with chronic alcoholic liver disease. PMID:2323314

  1. Functional Roles of Protein Nitration in Acute and Chronic Liver Diseases

    PubMed Central

    Abdelmegeed, Mohamed A.; Song, Byoung-Joon

    2014-01-01

    Nitric oxide, when combined with superoxide, produces peroxynitrite, which is known to be an important mediator for a number of diseases including various liver diseases. Peroxynitrite can modify tyrosine residue(s) of many proteins resulting in protein nitration, which may alter structure and function of each target protein. Various proteomics and immunological methods including mass spectrometry combined with both high pressure liquid chromatography and 2D PAGE have been employed to identify and characterize nitrated proteins from pathological tissue samples to determine their roles. However, these methods contain a few technical problems such as low efficiencies with the detection of a limited number of nitrated proteins and labor intensiveness. Therefore, a systematic approach to efficiently identify nitrated proteins and characterize their functional roles is likely to shed new insights into understanding of the mechanisms of hepatic disease pathophysiology and subsequent development of new therapeutics. The aims of this review are to briefly describe the mechanisms of hepatic diseases. In addition, we specifically describe a systematic approach to efficiently identify nitrated proteins to study their causal roles or functional consequences in promoting acute and chronic liver diseases including alcoholic and nonalcoholic fatty liver diseases. We finally discuss translational research applications by analyzing nitrated proteins in evaluating the efficacies of potentially beneficial agents to prevent or treat various diseases in the liver and other tissues. PMID:24876909

  2. Fibrosis assessment: impact on current management of chronic liver disease and application of quantitative invasive tools.

    PubMed

    Wang, Yan; Hou, Jin-Lin

    2016-05-01

    Fibrosis, a common pathogenic pathway of chronic liver disease (CLD), has long been indicated to be significantly and most importantly associated with severe prognosis. Nowadays, with remarkable advances in understanding and/or treatment of major CLDs such as hepatitis C, B, and nonalcoholic fatty liver disease, there is an unprecedented requirement for the diagnosis and assessment of liver fibrosis or cirrhosis in various clinical settings. Among the available approaches, liver biopsy remains the one which possibly provides the most direct and reliable information regarding fibrosis patterns and changes in the parenchyma at different clinical stages and with different etiologies. Thus, many endeavors have been undertaken for developing methodologies based on the strategy of quantitation for the invasive assessment. Here, we analyze the impact of fibrosis assessment on the CLD patient care based on the data of recent clinical studies. We discuss and update the current invasive tools regarding their technological features and potentials for the particular clinical applications. Furthermore, we propose the potential resolutions with application of quantitative invasive tools for some major issues in fibrosis assessment, which appear to be obstacles against the nowadays rapid progress in CLD medicine. PMID:26742762

  3. Management of chronic hepatitis B: Canadian Association for the Study of the Liver consensus guidelines

    PubMed Central

    Coffin, Carla S; Fung, Scott K; Ma, Mang M

    2012-01-01

    Chronic hepatitis B (CHB) is a dynamic disease that is influenced by host and virological factors. The management of CHB has become more complex with the increasing use of long-term oral nucleos/tide analogue antiviral therapies and the availability of novel diagnostic assays. Furthermore, there is often a lack of robust data to guide optimal management such as the selection of therapy, duration of treatment, potential antiviral side effects and the treatment of special populations. In November 2011, the Canadian Liver Foundation and the Canadian Association for the Study of the Liver convened a consensus conference to review the literature and analyze published data, including other international expert guidelines on CHB management. The proceedings of the consensus conference are summarized and provide updated clinical practice guidelines to assist Canadian health care providers in the prevention, diagnosis, assessment and treatment of CHB. PMID:23248795

  4. Transcriptional Dysregulation of Upstream Signaling of IFN Pathway in Chronic HCV Type 4 Induced Liver Fibrosis.

    PubMed

    Ibrahim, Marwa K; Salum, Ghada Maher; Bader El Din, Noha G; Dawood, Reham M; Barakat, Ahmed; Khairy, Ahmed; El Awady, Mostafa K

    2016-01-01

    IFN orchestrates the expression of various genes to halt hepatitis C virus (HCV) replication with the possibility of either reduced or increased liver fibrosis; due to controlled viral replication or overproduction of inflammatory mediators, repectively. In this study, we examined the transcriptional profiling of type I IFN related genes in HCV-chronically infected patients with varying degrees of liver fibrosis. PCR array was used to examine the expression of 84 type I IFN related genes in peripheral blood mononuclear cells (PBMCs) RNA from 12 treatment-naïve chronic HCV patients (5 F0-F1 and 7 F2-F4) and 5 healthy subjects. We further validated our results by quantitative real time PCR (qRT-PCR) in 103 treatment-naïve chronic HCV patients (43 F0-F1 and 60 F2-F4) and 15 controls. PCR array data revealed dysregulation in TLR7 pathway. The expression of TLR7 was decreased by 4 folds and MyD88 was increased by 3 folds in PBMCs of F2-F4 patients when compared to the healthy volunteers (p = 0.03 and 0.002, respectively). In addition, IRF7 and TLR7 showed dramatic downregulation (6 and 8 folds, respectively) in F2-F4 patients when compared to F0-F1 ones. qRT-PCR confirmed the altered expression patterns of TLR7 and MyD88 in F2-F4 patients when compared to either controls or F0-F1 patients. However, by qRT-PCR, IRF7 and NF-κB1 (TLR7 pathway transcription factors) exhibited similar mRNA abundance among F2-F4 and F0-F1 patients. These results suggest that TLR7 and MyD88 are possible candidates as biomarkers for the progression of HCV-induced liver fibrosis and/ or targets for therapeutic intervention. PMID:27135246

  5. Transcriptional Dysregulation of Upstream Signaling of IFN Pathway in Chronic HCV Type 4 Induced Liver Fibrosis

    PubMed Central

    Ibrahim, Marwa K.; Salum, Ghada Maher; Bader El Din, Noha G.; Dawood, Reham M.; Barakat, Ahmed; Khairy, Ahmed; El Awady, Mostafa K.

    2016-01-01

    IFN orchestrates the expression of various genes to halt hepatitis C virus (HCV) replication with the possibility of either reduced or increased liver fibrosis; due to controlled viral replication or overproduction of inflammatory mediators, repectively. In this study, we examined the transcriptional profiling of type I IFN related genes in HCV-chronically infected patients with varying degrees of liver fibrosis. PCR array was used to examine the expression of 84 type I IFN related genes in peripheral blood mononuclear cells (PBMCs) RNA from 12 treatment-naïve chronic HCV patients (5 F0-F1 and 7 F2-F4) and 5 healthy subjects. We further validated our results by quantitative real time PCR (qRT-PCR) in 103 treatment-naïve chronic HCV patients (43 F0-F1 and 60 F2-F4) and 15 controls. PCR array data revealed dysregulation in TLR7 pathway. The expression of TLR7 was decreased by 4 folds and MyD88 was increased by 3 folds in PBMCs of F2-F4 patients when compared to the healthy volunteers (p = 0.03 and 0.002, respectively). In addition, IRF7 and TLR7 showed dramatic downregulation (6 and 8 folds, respectively) in F2-F4 patients when compared to F0-F1 ones. qRT-PCR confirmed the altered expression patterns of TLR7 and MyD88 in F2-F4 patients when compared to either controls or F0-F1 patients. However, by qRT-PCR, IRF7 and NF-κB1 (TLR7 pathway transcription factors) exhibited similar mRNA abundance among F2-F4 and F0-F1 patients. These results suggest that TLR7 and MyD88 are possible candidates as biomarkers for the progression of HCV-induced liver fibrosis and/ or targets for therapeutic intervention. PMID:27135246

  6. Reliability and validity of the Chronic Liver Disease Questionnaire (CLDQ) in adults with non-alcoholic steatohepatitis (NASH)

    PubMed Central

    Chawla, Kashmira S; Talwalkar, Jayant A; Keach, Jill C; Malinchoc, Michael; Lindor, Keith D; Jorgensen, Roberta

    2016-01-01

    Introduction Significant impairments in health-related quality of life (HRQL) in patients with non-alcoholic fatty liver disease have been previously described. The disease-specific HRQL among patients with non-alcoholic steatohepatitis (NASH), however, remains unknown. Aim To determine the degree of construct validity of the Chronic Liver Disease Questionnaire (CLDQ) in adults with NASH. Methods Participants referred for the evaluation of histology-proven NASH at Mayo Clinic, Rochester, between 1996 and 2000, were evaluated. HRQL assessment by the Short-Form 36 (SF-36) Health Survey and CLD) was performed. The primary outcome was to determine the level of correlation between overall and subscale scores for the CLDQ and SF-36 instruments. Results Among 79 participants (70%) with NASH completing both questionnaires (mean age, 51.2 years with 64% female gender), excellent reliability was noted for the CLDQ instrument. Significant reductions in all SF-36 domains (p<0.05 for all) including PCS and MCS scores (p<0.02 for both) among participants with NASH compared with normative data from an age-matched and sex-matched US general population sample was observed. Highly significant correlations were observed between overall CLDQ score with SF-36 PCS (r=0.82, p<0.0001) and SF-36 MCS (r=0.67, p<0.0001) scores. Similar degrees of correlation were observed between relevant subscales of the CLDQ and SF-36 as well. Discussion The CLDQ has excellent reliability and validity of construct for HRQL assessment in adults with NASH when compared with the SF-36. Future investigations among participants with NASH require assessing the responsiveness of the CLDQ to medical therapies and disease progression. PMID:27110379

  7. Serum and liver HCV RNA levels in patients with chronic hepatitis C: correlation with clinical and histological features

    PubMed Central

    De Moliner, L; Pontisso, P; De Salvo, G L; Cavalletto, L; Chemello, L; Alberti, A

    1998-01-01

    Background—Liver disease in chronic hepatitis C virus (HCV) infection ranges from minimal lesions to liver cirrhosis, eventually evolving to hepatocellular carcinoma. Whether and how HCV determines the different clinical and histological manifestations of the disease is not fully understood. 
Aims—To verify whether the amount of virus in individual patients could be related to the severity of liver injury. 
Patients and methods—Levels of HCV RNA were measured in serum in 96 consecutive patients with chronic hepatitis type C using a signal amplification assay. The relation between viraemic values and the corresponding viral load in the liver was assessed in a subgroup of 21 patients in whom HCV RNA was measured in serum samples and liver specimens obtained at the same time. 
Results—A positive correlation was observed between the amount of viral nucleic acid in the two compartments, indicating that levels of viraemia reflect the amount of virus present in the liver. Viral load did not correlate with aminotransferase activities nor with histological diagnosis, and serum and liver levels of HCV RNA were not significantly different in patients infected by the various HCV genotypes. 
Conclusions—Measurement of HCV replication in serum is a mirror of viral replication in the liver. The extent of replicative activity of HCV does not seem to play a role in the modulation of the associated hepatic disease. 

 Keywords: HCV RNA; bDNA assay; liver disease activity PMID:9691926

  8. Salivary anti-Helicobacter pylori positivity among endoscopy patients with chronic liver disease.

    PubMed

    Feteih, R; Abdel-Salam, M; Jamjoom, H; Akbar, H

    2009-01-01

    In this study, endoscopy patients with and without chronic liver disease (CLD) were examined and tested for Helicobacter pylori infection by detecting the presence of serum and salivary anti-H. pylori antibody. The validity of these measures was compared with Campylobacter-like organism analysis (gold standard) performed on patients requiring gastric biopsy. Among 114 patients with CLD and 50 without, the commonest endoscopy diagnosis was gastritis (27.2%). Salivary H. pylori positivity was significantly associated with older age. Salivary anti-H. pylori antibody positivity showed low sensitivity (36.6%) and high specificity (75.8%) in CLD patients. PMID:20218127

  9. In Vivo Acute on Chronic Ethanol Effects in Liver: A Mouse Model Exhibiting Exacerbated Injury, Altered Metabolic and Epigenetic Responses

    PubMed Central

    Shukla, Shivendra D.; Aroor, Annayya R.; Restrepo, Ricardo; Kharbanda, Kusum K.; Ibdah, Jamal A.

    2015-01-01

    Chronic alcoholics who also binge drink (i.e., acute on chronic) are prone to an exacerbated liver injury but its mechanism is not understood. We therefore investigated the in vivo effects of chronic and binge ethanol ingestion and compared to chronic ethanol followed by three repeat binge ethanol on the liver of male C57/BL6 mice fed ethanol in liquid diet (4%) for four weeks followed by binge ethanol (intragastric administration, 3.5 g/kg body weight, three doses, 12h apart). Chronic followed by binge ethanol exacerbated fat accumulation, necrosis, decrease in hepatic SAM and SAM:SAH ratio, increase in adenosine levels, and elevated CYP2E1 levels. Histone H3 lysine acetylation (H3AcK9), dually modified phosphoacetylated histone H3 (H3AcK9/PS10), and phosphorylated H2AX increased after binge whereas phosphorylation of histone H3 ser 10 (H3S10) and H3 ser 28 (H3S28) increased after chronic ethanol-binge. Histone H3 lysine 4 and 9 dimethylation increased with a marked dimethylation in H3K9 in chronic ethanol binge group. Trimethylated histone H3 levels did not change. Nuclear levels of histone acetyl transferase GCN5 and histone deacetylase HDAC3 were elevated whereas phospho-CREB decreased in a distinctive manner. Taken together, acute on chronic ethanol ingestion caused amplification of liver injury and elicited characteristic profiles of histone modifications, metabolic alterations, and changes in nuclear protein levels. These findings demonstrate that chronic ethanol exposure renders liver more susceptible to repeat acute/binge ethanol induced acceleration of alcoholic liver disease. PMID:26610587

  10. [The algorithm for the medical maintenance of the aircraft personnel suffering from chronic sensorineural impairment of hearing].

    PubMed

    Pankova, V B; Skryabina, L Yu; Barkhatova, O A

    2016-01-01

    The present study was designed to systematize the causes underlying the development of chronic sensorineural impairment of hearing in the aircraft personnel engaged in commercial aviation of the Russian Federation. A detailed clinical and audiological picture of chronic sensorineural loss of hearing in the aircraft personnel is presented with special reference to the criteria accepted in the civil aviationfor the evaluation of professional suitability and occupational selection in terms of hearing conditions. The study has demonstrated the paramount importance of the aviation medical expertise for the flight safety control in civil aviation. We analyzed the results of the audiological examination of the aircraft personnel suffering from chronic sensorineural impairment of hearing and proposed the algorithm for the rehabilitation of such subjects taking into consideration the stage of the chronic process. PMID:27213653

  11. (14C)Aminopyrine breath test in chronic liver disease: preliminary diagnostic implications

    SciTech Connect

    Burnstein, A.V.; Galambos, J.T.

    1981-12-01

    The (14C)aminopyrine breath test (APBT) score, an estimate of hepatic mixed-oxidase function, was evaluated in 21 consecutive patients wih active nonalcoholic chronic liver diseases. Ten had primary biliary cirrhosis (PBC) and 11 had chronic active hepatitis (CAH). The APBT score was normal or elevated in patients with PBC (P less than 0.001), and lower than normal in CAH patients (P less than 0.01); 10.5 +/- 1.6 and 3.5 +/- 1.86, respectively, vs control 7.65 +/- 1.15 (mean +/- SD). The 11 patients with CAH included two middle-aged women who displayed ambiguous severe intrahepatic cholestasis. There was no overlap between the APBT scores of the 10 PBC and 11 CAH patients. These initial data suggest that the APBT may be helpful in the differentiation of PBC and CAH, including misleading cholestatic forms of CAH.

  12. A New Mouse Model That Spontaneously Develops Chronic Liver Inflammation and Fibrosis

    PubMed Central

    Fransén-Pettersson, Nina; Duarte, Nadia; Nilsson, Julia; Lundholm, Marie; Mayans, Sofia; Larefalk, Åsa; Hannibal, Tine D.; Hansen, Lisbeth; Schmidt-Christensen, Anja; Ivars, Fredrik; Cardell, Susanna; Palmqvist, Richard; Rozell, Björn

    2016-01-01

    Here we characterize a new animal model that spontaneously develops chronic inflammation and fibrosis in multiple organs, the non-obese diabetic inflammation and fibrosis (N-IF) mouse. In the liver, the N-IF mouse displays inflammation and fibrosis particularly evident around portal tracts and central veins and accompanied with evidence of abnormal intrahepatic bile ducts. The extensive cellular infiltration consists mainly of macrophages, granulocytes, particularly eosinophils, and mast cells. This inflammatory syndrome is mediated by a transgenic population of natural killer T cells (NKT) induced in an immunodeficient NOD genetic background. The disease is transferrable to immunodeficient recipients, while polyclonal T cells from unaffected syngeneic donors can inhibit the disease phenotype. Because of the fibrotic component, early on-set, spontaneous nature and reproducibility, this novel mouse model provides a unique tool to gain further insight into the underlying mechanisms mediating transformation of chronic inflammation into fibrosis and to evaluate intervention protocols for treating conditions of fibrotic disorders. PMID:27441847

  13. Role of liver progenitors in liver regeneration

    PubMed Central

    Best, Jan; Manka, Paul; Syn, Wing-Kin; Dollé, Laurent; van Grunsven, Leo A.

    2015-01-01

    During massive liver injury and hepatocyte loss, the intrinsic regenerative capacity of the liver by replication of resident hepatocytes is overwhelmed. Treatment of this condition depends on the cause of liver injury, though in many cases liver transplantation (LT) remains the only curative option. LT for end stage chronic and acute liver diseases is hampered by shortage of donor organs and requires immunosuppression. Hepatocyte transplantation is limited by yet unresolved technical difficulties. Since currently no treatment is available to facilitate liver regeneration directly, therapies involving the use of resident liver stem or progenitor cells (LPCs) or non-liver stem cells are coming to fore. LPCs are quiescent in the healthy liver, but may be activated under conditions where the regenerative capacity of mature hepatocytes is severely impaired. Non-liver stem cells include embryonic stem cells (ES cells) and mesenchymal stem cells (MSCs). In the first section, we aim to provide an overview of the role of putative cytokines, growth factors, mitogens and hormones in regulating LPC response and briefly discuss the prognostic value of the LPC response in clinical practice. In the latter section, we will highlight the role of other (non-liver) stem cells in transplantation and discuss advantages and disadvantages of ES cells, induced pluripotent stem cells (iPS), as well as MSCs. PMID:25713804

  14. Non-invasive prediction of development of hepatocellular carcinoma using transient elastography in patients with chronic liver disease.

    PubMed

    Park, Mi Sung; Han, Kwang-Hyub; Kim, Seung Up

    2014-07-01

    Prognosis of patients with chronic liver disease is determined by the extent and progression of liver fibrosis, which may ultimately lead to hepatocellular carcinoma (HCC). Liver biopsy (LB) is regarded as the gold standard to estimate the extent of liver fibrosis. However, because LB has several limitations, the foremost being its invasiveness, several non-invasive methods for assessing liver fibrosis have been proposed. Of these, transient elastography (TE) provides an accurate representation of the extent of liver fibrosis. Furthermore, recent studies have focused on the usefulness of TE for assessing the risk of HCC development and HCC recurrence after curative treatment, and developed novel models to calculate the risk of HCC development based on TE findings. These issues are discussed in this expert review. PMID:24939348

  15. The severity of liver fibrosis is associated with high leptin levels in chronic hepatitis C.

    PubMed

    Piche, T; Vandenbos, F; Abakar-Mahamat, A; Vanbiervliet, G; Barjoan, E M; Calle, G; Giudicelli, J; Ferrua, B; Laffont, C; Benzaken, S; Tran, A

    2004-01-01

    Recent attention has focused on the liver profibrogenic role of leptin in animal models. The purpose of this study was to evaluate the role of leptin and TNF-alpha in the severity of liver fibrosis in patients with chronic hepatitis C (CHC). We used a radioimmunoassay to determine serum leptin concentrations in 77 consecutive patients with CHC and 22 healthy controls. Leptin was correlated with liver histological (METAVIR) and metabolic indices. Sixty five patients had none to moderate liver fibrosis (F0-F2) and twelve severe fibrosis (F3-F4). Steatosis was observed in all but 27 patients. Leptin was significantly increased in patients compared with controls and was significantly more elevated in females both in patients and controls. The age, age at infection, prothrombin index, body mass index (BMI), triglycerides, glycaemia, ferritin, leptin and TNF-alpha, were associated with severe fibrosis. Steatosis was significantly more pronounced in patients with severe than those without or moderate fibrosis (P = 0.04). Only leptin was significantly and independently associated with severe fibrosis (OR = 1.2, CI 95%: 1.1-1.4, P = 0.03). Leptin was significantly associated with BMI (r = 0.64, P < 0.001) and glycaemia (r = 0.43, P < 0.001). Significant correlations were found between steatosis and BMI (r = 0.30, P < 0.01) and glycaemia (r = 0.30, P < 0.01). In patients with CHC and higher BMI and glycaemia levels, the severity of liver fibrosis is associated with serum leptin. TNF-alpha is a putative candidate involved in the mechanism. PMID:14738564

  16. Crepidiastrum denticulatum Extract Protects the Liver Against Chronic Alcohol-Induced Damage and Fat Accumulation in Rats

    PubMed Central

    Yoo, Ji-Hye; Kang, Kyungsu; Yun, Ji Ho; Kim, Mi Ae

    2014-01-01

    Abstract Alcohol is a severe hepatotoxicant that causes liver abnormalities such as steatosis, cirrhosis, and hepatocarcinoma. Crepidiastrum denticulatum (CD) is a well-known, traditionally consumed vegetable in Korea, which was recently reported to have bioactive compounds with detoxification and antioxidant properties. In this study, we report the hepatoprotective effect of CD extract against chronic alcohol-induced liver damage in vivo. The rats that were given CD extract exhibited decreased alanine aminotransferase, aspartate aminotransferase, and γ-glutamyl transpeptidase activities, which are liver damage markers that are typically elevated by alcohol consumption. The results were confirmed by histopathology with hematoxylin and eosin staining. Chronic alcohol consumption induced the formation of alcoholic fatty liver. However, treatment with CD extract dramatically decreased the hepatic lipid droplets. Treatment with CD extract also restored the antioxidative capacity and lipid peroxidation of the liver that had been changed by alcohol consumption. Furthermore, treatment with CD extract normalized the activities of the antioxidative enzymes superoxide dismutase, catalase, glutathione reductase, and glutathione peroxidase, which had been decreased by alcohol consumption. The results indicate that CD extract has protective effects against chronic alcohol hepatotoxicity in rats by increasing the liver's antioxidant capacity, and has potential as a dietary supplement intervention for patients with alcohol-induced liver damage. PMID:24650230

  17. The End-Organ Impairment in Liver Cirrhosis: Appointments for Critical Care

    PubMed Central

    Figueiredo, Antonio; Romero-Bermejo, Francisco; Perdigoto, Rui; Marcelino, Paulo

    2012-01-01

    Liver cirrhosis (LC) can lead to a clinical state of liver failure, which can exacerbate through the course of the disease. New therapies aimed to control the diverse etiologies are now more effective, although the disease may result in advanced stages of liver failure, where liver transplantation (LT) remains the most effective treatment. The extended lifespan of these patients and the extended possibilities of liver support devices make their admission to an intensive care unit (ICU) more probable. In this paper the LC is approached from the point of view of the pathophysiological alterations present in LC patients previous to ICU admission, particularly cardiovascular, but also renal, coagulopathic, and encephalopathic. Infections and available liver detoxifications devices also deserve mentioning. We intend to contribute towards ICU physician readiness to the care for this particular type of patients, possibly in dedicated ICUs. PMID:22666568

  18. Impaired bactericidal but not fungicidal activity of polymorphonuclear neutrophils in patients with chronic lymphocytic leukemia.

    PubMed

    Kontoyiannis, Dimitrios P; Georgiadou, Sarah P; Wierda, William G; Wright, Susan; Albert, Nathaniel D; Ferrajoli, Alessandra; Keating, Michael; Lewis, Russell E

    2013-08-01

    We examined the qualitative polymorphonuclear neutrophil (PMN)-associated immune impairment in patients with chronic lymphocytic leukemia (CLL) by characterizing phagocytic killing of key non-opsonized bacterial (Staphylococcus aureus and Pseudomonas aeruginosa) and fungal (Candida albicans and Aspergillus fumigatus) pathogens. Neutrophils were collected from 47 non-neutropenic patients with CLL (PMN count > 1000/mm(3)) and age-matched and young healthy controls (five each). A subset of patients (13%) had prior or subsequent infections. We found that the patients with CLL had diminished PMN microbicidal response against bacteria but not against fungi compared with the controls. Compared to patients with effective PMN responses, we did not identify differences of basal PMN pathogen-associated molecular pattern receptor gene expression, soluble pathogen-associated molecular pattern gene expression or inflammatory cytokine signatures in patients with impaired PMN responses when PMNs were analyzed in multiplex real-time polymerase chain reaction assays. However, differences in PMN microbicidal response against A. fumigatus in patients with CLL were associated with the degree of hypogammaglobulinemia. PMID:23163595

  19. Hepcidin as a Biomarker of Impaired Renal Function in Rat Models for Chronic Allograft Nephropathy.

    PubMed

    Xue, Dong; Zhou, Cuixing; Shi, Yunbo; Lu, Hao; He, Xiaozhou

    2016-01-01

    BACKGROUND To explore the use of hepcidin as a marker of impaired renal function in a rat model for chronic allograft nephropathy (CAN). MATERIAL AND METHODS Twenty-four models were developed and 20 models were included in this study, using Fisher (F344) rats (donors) and Lewis rats (recipients). Renal function tests were performed preoperatively and postoperatively. Hepcidin, interleukin-6 (IL-6), and erythropoietin levels in serum and urine were measured by enzyme-linked immunosorbent assay (ELISA). To observe pathological changes in the kidneys, 10 rats each were sacrificed at 2 months and 4 months after surgery. RESULTS After transplantation, the serum hepcidin and IL-6 levels increased, while urine hepcidin levels decreased. Erythropoietin levels showed a similar trend; all P<0.05. Serum creatinine (SCr) and blood urea nitrogen significantly increased post-operatively, with SCr positively correlating with serum hepcidin. Serum hepcidin positively correlated with IL-6 and negatively correlated with EPO. Histopathological results were consistent with CAN, after transplantation. CONCLUSIONS Hepcidin may be considered as a potential marker of impaired renal function. PMID:26907911

  20. Hepcidin as a Biomarker of Impaired Renal Function in Rat Models for Chronic Allograft Nephropathy

    PubMed Central

    Xue, Dong; Zhou, Cuixing; Shi, Yunbo; Lu, Hao; He, Xiaozhou

    2016-01-01

    Background To explore the use of hepcidin as a marker of impaired renal function in a rat model for chronic allograft nephropathy (CAN). Material/Methods Twenty-four models were developed and 20 models were included in this study, using Fisher (F344) rats (donors) and Lewis rats (recipients). Renal function tests were performed preoperatively and postoperatively. Hepcidin, interleukin-6 (IL-6), and erythropoietin levels in serum and urine were measured by enzyme-linked immunosorbent assay (ELISA). To observe pathological changes in the kidneys, 10 rats each were sacrificed at 2 months and 4 months after surgery. Results After transplantation, the serum hepcidin and IL-6 levels increased, while urine hepcidin levels decreased. Erythropoietin levels showed a similar trend; all P<0.05. Serum creatinine (SCr) and blood urea nitrogen significantly increased post-operatively, with SCr positively correlating with serum hepcidin. Serum hepcidin positively correlated with IL-6 and negatively correlated with EPO. Histopathological results were consistent with CAN, after transplantation. Conclusions Hepcidin may be considered as a potential marker of impaired renal function. PMID:26907911

  1. Robotic therapy for chronic stroke: general recovery of impairment or improved task-specific skill?

    PubMed Central

    Goldsmith, Jeff; Harran, Michelle; Kane, Leslie; Berard, Jessica; Huang, Sylvia; Ryan, Sophia L.; Mazzoni, Pietro; Krakauer, John W.; Huang, Vincent S.

    2015-01-01

    There is a great need to develop new approaches for rehabilitation of the upper limb after stroke. Robotic therapy is a promising form of neurorehabilitation that can be delivered in higher doses than conventional therapy. Here we sought to determine whether the reported effects of robotic therapy, which have been based on clinical measures of impairment and function, are accompanied by improved motor control. Patients with chronic hemiparesis were trained for 3 wk, 3 days a week, with titrated assistive robotic therapy in two and three dimensions. Motor control improvements (i.e., skill) in both arms were assessed with a separate untrained visually guided reaching task. We devised a novel PCA-based analysis of arm trajectories that is sensitive to changes in the quality of entire movement trajectories without needing to prespecify particular kinematic features. Robotic therapy led to skill improvements in the contralesional arm. These changes were not accompanied by changes in clinical measures of impairment or function. There are two possible interpretations of these results. One is that robotic therapy only leads to small task-specific improvements in motor control via normal skill-learning mechanisms. The other is that kinematic assays are more sensitive than clinical measures to a small general improvement in motor control. PMID:26180120

  2. Chronic ketamine exposure induces permanent impairment of brain functions in adolescent cynomolgus monkeys.

    PubMed

    Sun, Lin; Li, Qi; Li, Qing; Zhang, Yuzhe; Liu, Dexiang; Jiang, Hong; Pan, Fang; Yew, David T

    2014-03-01

    Ketamine, a non-competitive N-methyl-D-aspartic acid receptor antagonist, has emerged as an increasingly popular drug among young drug abusers worldwide. Available evidence suggests that ketamine produces acute impairments of working, episodic and semantic memory along with psychotogenic and dissociative effects when a single dose is given to healthy volunteers. However, understanding of the possible chronic effects of ketamine on behavior, cognitive anomalies and neurochemical homeostasis is still incomplete. Although previous human studies demonstrate that ketamine could impair a range of cognitive skills, investigation using non-human models would permit more precise exploration of the neurochemical mechanisms which may underlie the detrimental effects. The current study examined the abnormalities in behavior (move, walk, jump and climb) and apoptosis of the prefrontal cortex using terminal deoxynucleotidyl transferase-mediated biotinylated dUTP nick end labeling (TUNEL) and apoptotic markers, including Bax, Bcl-2 and caspase-3 in adolescent male cynomolgus monkeys (Macaca fascicularis) after 1 or 6 months of sub-anesthetic ketamine administration (1 mg/kg, i.v.). Results showed that ketamine decreased locomotor activity and increased cell death in the prefrontal cortex of monkeys with 6 months of ketamine treatment when compared with the control monkeys. Such decreases were not found in the 1-month ketamine-treated group. Our study suggested that ketamine administration of recreational dose in monkeys might produce permanent and irreversible deficits in brain functions due to neurotoxic effects, involving the activation of apoptotic pathways in the prefrontal cortex. PMID:23145560

  3. Anti-TGF-beta strategies for the treatment of chronic liver disease.

    PubMed

    Breitkopf, Katja; Haas, Stephan; Wiercinska, Eliza; Singer, Manfred V; Dooley, Steven

    2005-11-01

    Permanent alcohol abuse may lead to chronic liver injury with deleterious sequelae such as liver cirrhosis and hepatocellular carcinoma. Mechanisms of fibrogenesis encompass recruitment of inflammatory cells at the site of injury and cytokine mediated activation of hepatic stellate cells (HSC) with accumulation of interstitial collagens. HSC transdifferentiation and accompanying apoptosis result in destruction of liver architecture and are therefore key steps of disease progression. TGF-beta represents the main profibrogenic cytokine in liver fibrosis and other fibroproliferative disorders by inducing extracellular matrix deposition as part of the wound healing response. In parallel, TGF-beta triggers hepatocytes that are strongly responsive for this cytokine, to undergo apoptosis, thereby providing space for HSC proliferation and generation of a collagenous matrix. Anti TGF-beta approaches were established and successfully utilized for the treatment of experimental fibrogenesis. Dominant negative TGF-beta receptors (TbetaR), generated by fusing the Fc domain of human IgG and the N-terminal (extracellular) fragment of TbetaRII (Fc:TbetaRII) were applied to suppress fibrosis. Similarly TGF-beta binding proteins like decorin, antagonistic cytokines such as bone morphogenetic protein-7, hepatocyte growth factor, IL-10, or IFN-gamma were as efficient as camostat mesilate, a protease inhibitor that possibly abrogated proteolytic activation of TGF-beta. Further, our group recently overexpressed Smad7 in bile duct ligation induced liver fibrosis and achieved efficient inhibition of intracellular TGF-beta signaling, thereby counteracting profibrogenic effects in cultured HSC and in vivo. A direct link between the effect of alcohol and TGF-beta exists through reactive oxygen species that are generated in liver cells by alcohol metabolism and represent activators of TGF-beta signaling. Thus, soluble TbetaRII expression reduced experimental fibrogenesis in vitro and in vivo

  4. Is perception of vertical impaired in individuals with chronic stroke with a history of 'pushing'?

    PubMed

    Mansfield, Avril; Fraser, Lindsey; Rajachandrakumar, Roshanth; Danells, Cynthia J; Knorr, Svetlana; Campos, Jennifer

    2015-03-17

    Post-stroke 'pushing' behaviour appears to be caused by impaired perception of vertical in the roll plane. While pushing behaviour typically resolves with stroke recovery, it is not known if misperception of vertical persists. The purpose of this study was to determine if perception of vertical is impaired amongst stroke survivors with a history of pushing behaviour. Fourteen individuals with chronic stroke (7 with history of pushing) and 10 age-matched healthy controls participated. Participants sat upright on a chair surrounded by a curved projection screen in a laboratory mounted on a motion base. Subjective visual vertical (SVV) was assessed using a 30 trial, forced-choice protocol. For each trial participants viewed a line projected on the screen and indicated if the line was tilted to the right or the left. For the subjective postural vertical (SPV), participants wore a blindfold and the motion base was tilted to the left or right by 10-20°. Participants were asked to adjust the angular movements of the motion base until they felt upright. SPV was not different between groups. SVV was significantly more biased towards the contralesional side for participants with history of pushing (-3.6 ± 4.1°) than those without (-0.1 ± 1.4°). Two individuals with history of pushing had SVV or SPV outside the maximum for healthy controls. Impaired vertical perception may persist in some individuals with prior post-stroke pushing, despite resolution of pushing behaviours, which could have consequences for functional mobility and falls. PMID:25666890

  5. Association between Plasma Fibrinogen Levels and Mortality in Acute-on-Chronic Hepatitis B Liver Failure

    PubMed Central

    Shao, Zhexin; Zhao, Ying; Feng, Limin; Feng, Guofang; Zhang, Juanwen; Zhang, Jie

    2015-01-01

    Acute-on-chronic liver failure (AoCLF) is the most common type of liver failure and is associated with high mortality. Fibrinogen is critical in maintaining primary and secondary hemostasis. Therefore, we prospectively analyzed the association between fibrinogen and outcomes in AoCLF patients. Plasma fibrinogen was measured in 169 AoCLF, 173 chronic hepatitis B (CHB), and 171 healthy patients using a coagulation method. The predictive ability of fibrinogen for 3-month mortality in AoCLF patients was assessed using receiver operating characteristic (ROC) curve and multivariable logistic regression analyses. Plasma fibrinogen was significantly lower in nonsurvivor AoCLF patients compared with survivor AoCLF, CHB, and control patients. The sensitivity, specificity, and area under the ROC curve of 1/fibrinogen predicting mortality in AoCLF patients were 66.7%, 72.5%, and 0.746 (95% confidence interval (CI): 0.672–0.820, P < 0.001), and the fibrinogen cutoff value was 0.90 g/L. On multivariate logistic regression analysis, low fibrinogen was an independent factor predicting mortality (odds ratio: 0.304; 95% CI: 0.094–0.983; P = 0.047). Nonsurvivor AoCLF patients had significantly decreased fibrinogen levels, suggesting that low plasma fibrinogen may be a useful predictor of poor prognosis in AoCLF patients. PMID:25960593

  6. Biochemical assessment of oxidative status versus liver enzymes in patients with chronic fascioliasis.

    PubMed

    Kamel, Hanan H; Sarhan, Rania M; Saad, Ghada A

    2015-12-01

    The aim of this study was to examine the oxidative status in Egyptian patients suffering chronic fascioliasis. The relationship between serum malondialdehyde (MDA) levels, superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPX) activities was investigated in relation to the level of liver enzymes; ALT and AST compared to healthy controls. Twenty patients versus ten controls were included in the study. Among cases the MDA, CAT, AST and ALT were higher than controls, while SOD and GPX higher values were present among controls. There was a highly significant difference between cases and controls as regard MDA, CAT, SOD, GPX, and AST, and a significant difference regarding ALT. The findings of increased serum lipid peroxidation and decreased antioxidant enzymes in erythrocytes of chronic fascioliasis patients indicated the presence of persistent inflammation and oxidative stress which confirms the underlying pathogenesis and reflected the stage of infection providing a baseline data for comparison between normal and infected patients guided by the level of liver enzymes in relation to oxidative status. PMID:26688624

  7. Growth rate of early-stage hepatocellular carcinoma in patients with chronic liver disease

    PubMed Central

    An, Chansik; Choi, Youn Ah; Choi, Dongil; Paik, Yong Han; Ahn, Sang Hoon; Kim, Myeong-Jin; Paik, Seung Woon; Han, Kwang-Hyub

    2015-01-01

    Background/Aims The goal of this study was to estimate the growth rate of hepatocellular carcinoma (HCC) and identify the host factors that significantly affect this rate. Methods Patients with early-stage HCC (n=175) who underwent two or more serial dynamic imaging studies without any anticancer treatment at two tertiary care hospitals in Korea were identified. For each patient, the tumor volume doubling time (TVDT) of HCC was calculated by comparing tumor volumes between serial imaging studies. Clinical and laboratory data were obtained from the medical records of the patients. Results The median TVDT was 85.7 days, with a range of 11 to 851.2 days. Multiple linear regression revealed that the initial tumor diameter (a tumor factor) and the etiology of chronic liver disease (a host factor) were significantly associated with the TVDT. The TVDT was shorter when the initial tumor diameter was smaller, and was shorter in HCC related to hepatitis B virus (HBV) infection than in HCC related to hepatitis C virus (HCV) infection (median, 76.8 days vs. 137.2 days; P=0.0234). Conclusions The etiology of chronic liver disease is a host factor that may significantly affect the growth rate of early-stage HCC, since HBV-associated HCC grows faster than HCV-associated HCC. PMID:26523271

  8. Oxidative damage in the progression of chronic liver disease to hepatocellular carcinoma: an intricate pathway.

    PubMed

    Cardin, Romilda; Piciocchi, Marika; Bortolami, Marina; Kotsafti, Andromachi; Barzon, Luisa; Lavezzo, Enrico; Sinigaglia, Alessandro; Rodriguez-Castro, Kryssia Isabel; Rugge, Massimo; Farinati, Fabio

    2014-03-28

    The histo-pathologic and molecular mechanisms leading to initiation and progression of hepatocellular carcinoma (HCC) are still ill-defined; however, there is increasing evidence that the gradual accumulation of mutations, genetic and epigenetic changes which occur in preneoplastic hepatocytes results in the development of dysplastic foci, nodules, and finally, overt HCC. As well as many other neoplasias, liver cancer is considered an "inflammatory cancer", arising from a context of inflammation, and characterized by inflammation-related mechanisms that favor tumor cell survival, proliferation, and invasion. Molecular mechanisms that link inflammation and neoplasia have been widely investigated, and it has been well established that inflammatory cells recruited at these sites with ongoing inflammatory activity release chemokines that enhance the production of reactive oxygen species. The latter, in turn, probably have a major pathogenic role in the continuum starting from hepatitis followed by chronic inflammation, and ultimately leading to cancer. The relationship amongst chronic liver injury, free radical production, and development of HCC is explored in the present review, particularly in the light of the complex network that involves oxidative DNA damage, cytokine synthesis, telomere dysfunction, and microRNA regulation. PMID:24696595

  9. Chronic intermittent psychological stress promotes macrophage reverse cholesterol transport by impairing bile acid absorption in mice

    PubMed Central

    Silvennoinen, Reija; Quesada, Helena; Kareinen, Ilona; Julve, Josep; Kaipiainen, Leena; Gylling, Helena; Blanco-Vaca, Francisco; Escola-Gil, Joan Carles; Kovanen, Petri T; Lee-Rueckert, Miriam

    2015-01-01

    Psychological stress is a risk factor for atherosclerosis, yet the pathophysiological mechanisms involved remain elusive. The transfer of cholesterol from macrophage foam cells to liver and feces (the macrophage-specific reverse cholesterol transport, m-RCT) is an important antiatherogenic pathway. Because exposure of mice to physical restraint, a model of psychological stress, increases serum levels of corticosterone, and as bile acid homeostasis is disrupted in glucocorticoid-treated animals, we investigated if chronic intermittent restraint stress would modify m-RCT by altering the enterohepatic circulation of bile acids. C57Bl/6J mice exposed to intermittent stress for 5 days exhibited increased transit through the large intestine and enhanced fecal bile acid excretion. Of the transcription factors and transporters that regulate bile acid homeostasis, the mRNA expression levels of the hepatic farnesoid X receptor (FXR), the bile salt export pump (BSEP), and the intestinal fibroblast growth factor 15 (FGF15) were reduced, whereas those of the ileal apical sodium-dependent bile acid transporter (ASBT), responsible for active bile acid absorption, remained unchanged. Neither did the hepatic expression of cholesterol 7α-hydroxylase (CYP7A1), the key enzyme regulating bile acid synthesis, change in the stressed mice. Evaluation of the functionality of the m-RCT pathway revealed increased fecal excretion of bile acids that had been synthesized from macrophage-derived cholesterol. Overall, our study reveals that chronic intermittent stress in mice accelerates m-RCT specifically by increasing fecal excretion of bile acids. This novel mechanism of m-RCT induction could have antiatherogenic potential under conditions of chronic stress. PMID:25969465

  10. Chronic intermittent psychological stress promotes macrophage reverse cholesterol transport by impairing bile acid absorption in mice.

    PubMed

    Silvennoinen, Reija; Quesada, Helena; Kareinen, Ilona; Julve, Josep; Kaipiainen, Leena; Gylling, Helena; Blanco-Vaca, Francisco; Escola-Gil, Joan Carles; Kovanen, Petri T; Lee-Rueckert, Miriam

    2015-05-11

    Psychological stress is a risk factor for atherosclerosis, yet the pathophysiological mechanisms involved remain elusive. The transfer of cholesterol from macrophage foam cells to liver and feces (the macrophage-specific reverse cholesterol transport, m-RCT) is an important antiatherogenic pathway. Because exposure of mice to physical restraint, a model of psychological stress, increases serum levels of corticosterone, and as bile acid homeostasis is disrupted in glucocorticoid-treated animals, we investigated if chronic intermittent restraint stress would modify m-RCT by altering the enterohepatic circulation of bile acids. C57Bl/6J mice exposed to intermittent stress for 5 days exhibited increased transit through the large intestine and enhanced fecal bile acid excretion. Of the transcription factors and transporters that regulate bile acid homeostasis, the mRNA expression levels of the hepatic farnesoid X receptor (FXR), the bile salt export pump (BSEP), and the intestinal fibroblast growth factor 15 (FGF15) were reduced, whereas those of the ileal apical sodium-dependent bile acid transporter (ASBT), responsible for active bile acid absorption, remained unchanged. Neither did the hepatic expression of cholesterol 7α-hydroxylase (CYP7A1), the key enzyme regulating bile acid synthesis, change in the stressed mice. Evaluation of the functionality of the m-RCT pathway revealed increased fecal excretion of bile acids that had been synthesized from macrophage-derived cholesterol. Overall, our study reveals that chronic intermittent stress in mice accelerates m-RCT specifically by increasing fecal excretion of bile acids. This novel mechanism of m-RCT induction could have antiatherogenic potential under conditions of chronic stress. PMID:25969465

  11. Bumblebee learning and memory is impaired by chronic exposure to a neonicotinoid pesticide.

    PubMed

    Stanley, Dara A; Smith, Karen E; Raine, Nigel E

    2015-01-01

    Bumblebees are exposed to pesticides applied for crop protection while foraging on treated plants, with increasing evidence suggesting that this sublethal exposure has implications for pollinator declines. The challenges of navigating and learning to manipulate many different flowers underline the critical role learning plays for the foraging success and survival of bees. We assessed the impacts of both acute and chronic exposure to field-realistic levels of a widely applied neonicotinoid insecticide, thiamethoxam, on bumblebee odour learning and memory. Although bees exposed to acute doses showed conditioned responses less frequently than controls, we found no difference in the number of individuals able to learn at field-realistic exposure levels. However, following chronic pesticide exposure, bees exposed to field-realistic levels learnt more slowly and their short-term memory was significantly impaired following exposure to 2.4 ppb pesticide. These results indicate that field-realistic pesticide exposure can have appreciable impacts on learning and memory, with potential implications for essential individual behaviour and colony fitness. PMID:26568480

  12. Resveratrol prevents impaired cognition induced by chronic unpredictable mild stress in rats.

    PubMed

    Liu, Dexiang; Zhang, Qingrui; Gu, Jianhua; Wang, Xueer; Xie, Kai; Xian, Xiuying; Wang, Jianmei; Jiang, Hong; Wang, Zhen

    2014-03-01

    Depression is one of the most common neuropsychiatric disorders and has been associated with impaired cognition, as well as causing neuroendocrine systems and brain proteins alterations. Resveratrol is a natural polyphenol enriched in polygonum cuspidatum and has diverse biological activities, including potent antidepressant-like effects. The aim of this study was to determine whether resveratrol administration influences chronic unpredictable mild stress (CUMS)-induced cognitive deficits and explores underlying mechanisms. The results showed that CUMS (5weeks) was effective in producing cognitive deficits in rats as indicated by Morris water maze and novel object recognition task. Additionally, CUMS exposure significantly elevated serum corticosterone levels and decreased BDNF levels in the prefrontal cortex (PFC) and hippocampus, accompanied by decreased phosphorylation of extracellular signal-regulated kinase (pERK) and cAMP response element-binding protein (pCREB). Chronic administration of resveratrol (80mg/kg, i.p., 5weeks) significantly prevented all these CUMS-induced behavioral and biochemical alterations. In conclusion, our study shows that resveratrol may be an effective therapeutic agent for cognitive disturbances as was seen within the stress model and its neuroprotective effect was mediated in part by normalizing serum corticosterone levels, up-regulating of the BDNF, pCREB and pERK levels. PMID:24184538

  13. Work-related chronic neck impairment. Neck motion analysis in female traverse crane operators.

    PubMed

    Alund, M; Larsson, S E; Lewin, T

    1992-09-01

    Twenty-one female steel industry traverse crane operators with long-term sick-leave (3 (1-8) years) due to chronic neck disability underwent careful analysis of case history, physical status and electrogoniometric three-dimensional recordings of active neck motion. Results were compared with those from working female crane operators having identical work posture and tasks and, further, with a group of working female clerks. The sick-listed crane operators had previous frequent contacts with the primary health care because of complaints from the neck and back. In comparison with the reference groups, the sick-listed crane operators showed tenderness of the trapezius and levator scapulae muscles and a short neck stature in combination with impaired active neck motion range with reduced motion speed. The motion pattern was however unchanged. The findings are consistent with the clinical picture of chronic neck myalgia that persisted despite long-term absence from the previous exposure to high static work load upon the neck-shoulders. PMID:1411359

  14. Bumblebee learning and memory is impaired by chronic exposure to a neonicotinoid pesticide

    PubMed Central

    Stanley, Dara A.; Smith, Karen E.; Raine, Nigel E.

    2015-01-01

    Bumblebees are exposed to pesticides applied for crop protection while foraging on treated plants, with increasing evidence suggesting that this sublethal exposure has implications for pollinator declines. The challenges of navigating and learning to manipulate many different flowers underline the critical role learning plays for the foraging success and survival of bees. We assessed the impacts of both acute and chronic exposure to field-realistic levels of a widely applied neonicotinoid insecticide, thiamethoxam, on bumblebee odour learning and memory. Although bees exposed to acute doses showed conditioned responses less frequently than controls, we found no difference in the number of individuals able to learn at field-realistic exposure levels. However, following chronic pesticide exposure, bees exposed to field-realistic levels learnt more slowly and their short-term memory was significantly impaired following exposure to 2.4 ppb pesticide. These results indicate that field-realistic pesticide exposure can have appreciable impacts on learning and memory, with potential implications for essential individual behaviour and colony fitness. PMID:26568480

  15. Liver transplantation for chronic graft-versus-host disease: case report with 10-year follow-up.

    PubMed

    Orlando, Giuseppe; Ferrant, Augustin; Schots, Rik; Goffette, Pierre; Mathijs, Jules; Lemaire, Julien; Danse, Etienne; Talpe, Stéphanie; Latinne, Dominique; Lerut, Jan

    2005-01-01

    Graft-versus-host disease (GVHD) is a frequent complication of bone marrow transplantation (BMT). Chronic GVHD (cGVHD) may lead to irreversible liver failure. We report a case of successful liver transplantation (LT) for end-stage liver failure because of cGVHD that had developed 22 months after BMT in a 24-year-old male. Re-transplantation was necessary 6 months later because of intrahepatic ischaemic type biliary tract lesions. He is now in excellent condition 10 years after the first transplant. This experience and the review of literature indicate that LT can cure GVHD-related chronic liver failure. Recurrent GVHD in the allograft has not yet been reported. PMID:15612994

  16. Surveillance for hepatocellular carcinoma in chronic liver disease: Evidence and controversies

    PubMed Central

    van Meer, Suzanne; de Man, Robert A; Siersema, Peter D; van Erpecum, Karel J

    2013-01-01

    Primary liver cancer is the sixth most common cancer in the world and the third cause of cancer-related death. Hepatocellular carcinoma (HCC) represents more than 90% of primary liver cancers and generally occurs in patients with underlying chronic liver disease such as viral hepatitis, hemochromatosis, primary biliary cirrhosis and non-alcoholic steatohepatitis. Especially cirrhotic patients are at risk of HCC and regular surveillance could enable early detection and therapy, with potentially improved outcome. We here summarize existing evidence for surveillance including ultrasound, other radiological modalities and various serum biomarkers, and current international guideline recommendations for surveillance. Ultrasound and α-fetoprotein (alone or in combination) are most frequently used for surveillance, but their sensitivities and specificities are still far from perfect, and evidence for surveillance remains weak and controversial. Various other potential surveillance tools have been tested, including serum markers as des-carboxyprothrombin, lectin-bound α-fetoprotein, and (most recently) circulating TIE2-expressing monocytes, and radiological investigations such as computed tomography-scan or magnetic resonance imaging-scan. Although early results appear promising, these tools have generally been tested in diagnostic rather than surveillance setting, and in most cases, no detailed information is available on their cost-effectiveness. For the near future, it remains important to define those patients with highest risk of HCC and most benefit from surveillance, and to restrict surveillance to these categories. PMID:24187450

  17. Mitochondrial antibodies in chronic liver diseases and connective tissue disorders: further characterization of the autoantigens.

    PubMed Central

    Meek, F; Khoury, E L; Doniach, D; Baum, H

    1980-01-01

    The heterogeneity of mitochrondrial autoantibodies in a variety of diseases states has been critically re-examined by a combination of immunofluorescence staining (IFL) and complement fixation tests (CFT). The different mitochondrial IFL patterns described by other workers were confirmed and extra criteria using new substrates are presented for their differential recognition. Biochemically defined mitochondrial subfractions were used in the CFT to confirm and extend the IFL classifications. The 'M1' cardiolipin antibodies of syphilis did not react with the ATPase fraction but the antigen was present in all membrane preparations and found to be chemically resistant. The major antibody specificity of the 'M3' pattern associated with drug-induced pseudolupus syndrome is a firmly bound, outer membrane component; and a second, minor reactivity is apparently to a mercurial-insensitive antigen present in the chloroform-released ATPase preparation. The 'M5' antibody pattern correlates with a digitonin-sensitive outer membrane component. Although it was not possible to differentiate within the group of liver diseases between the 'M2' antibodies of primary biliary cirrhosis and the previously described 'M4' antibodies of other chronic liver diseases, several antibody specificities were demonstrated. All sera from liver disease patients contain the antibody directed against a mercurial-sensitive protein found in the chloroform-released ATPase preparation, and, in addition, varying titres of antibodies against two or more mercurial-resistant membrane components, of which at least one is on the inner membrane and one on the outer membrane. Images Fig. 3 PMID:6449333

  18. Mechanism of chronic dietary iron overload-induced liver damage in mice.

    PubMed

    Liu, Dan; He, Huan; Yin, Dong; Que, Ailing; Tang, Lei; Liao, Zhangping; Huang, Qiren; He, Ming

    2013-04-01

    Chronic iron overload may result in hepatic fibrosis and even neoplastic transformation due to a burst of reactive oxygen species (ROS). Mitochondria have been proposed to be important in the production of ROS. The purpose of this study was to investigate the role of the mitochondrial permeability transition pore (mPTP) in the burst of ROS, and to clarify the mechanism whereby ROS induced by iron overload results in hepatic damage. It has been demonstrated that when ferrocene-induced iron-overloaded mice were fed the cyclosporin A (CsA), a specific inhibitor of the mPTP, diet (10 mg/kg/day) for 50 days, liver-to-body weight ratio, serum levels of alanine transaminase (ALT) and aspartate transaminase (AST), ROS production, mitochondrial swelling, loss of mitochondrial membrane potential (Δψ) and hepatocyte apoptosis decreased. However, the total antioxidant status, including superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) and catalase activities, increased. The protective effect of CsA on the liver of iron-overloaded mice may be due to inhibition of the ROS burst and a successive antioxidant effect. To the best of our knowledge, these data provide the first support for the theory that ROS-induced ROS release (RIRR) may be involved in the burst of ROS in the liver and greatly contribute to the hepatic damage initiated by iron overload. PMID:23404080

  19. Relationship between serum and hepatic 7S fragments of type IV collagen in chronic liver disease.

    PubMed

    Suou, T; Yamada, S; Hosho, K; Yoshikawa, N; Kawasaki, H

    1996-05-01

    We evaluated the mechanism of increased serum concentrations of the 7S fragment of the N-terminal domain of type IV collagen (7S collagen) in chronic liver disease. We measured the concentrations of hepatic-free and deposited 7S collagens after extraction with Tris-HCl buffer and bacterial collagenase, then compared them with the serum levels in 8 normal controls and 48 patients with chronic liver disease. The hepatic 7S collagen levels extracted with Tris-HCl buffer and collagenase accounted for 7% and 93%, respectively, of the total 7S collagen levels in normal controls. Both hepatic 7S collagen levels as well as serum levels increased in accordance with the progress of liver disease. Serum levels of 7S collagen showed a closer correlation with the hepatic 7S collagen levels extracted with Tris-HCl buffer (r = .822), compared with those extracted with collagenase (r = .382). On the other hand, the histological degrees of liver fibrosis were highly correlated with the hepatic collagenase-extracted 7S collagen levels (r = .822), compared with serum and the hepatic Tris-HCl buffer-extracted levels (r = .478 and r = .537, respectively). Although there was no difference in serum and hepatic 7S collagen levels between B and C viral patients, the serum and hepatic Tris-HCl buffer-extracted 7S collagen levels were higher in patients with alcoholic cirrhosis than patients with viral cirrhosis. However, the hepatic collagenase-extracted levels were similar in both groups. Gel filtration demonstrated that the serum and hepatic Tris-HCl buffer-extracted 7S collagens were mainly eluted in the macromolecular 7S collagen-reactive fraction in cirrhosis, whereas the hepatic collagenase-extracted 7S collagen was eluted in the authentic 7S collagen-reactive fraction. The results suggest that serum 7S collagen levels are not a particularly reliable measure of hepatic fibrosis but reflect the enhanced metabolism, especially synthesis of type IV collagen in the liver. PMID:8621148

  20. Plasma and Liver Lipid Profiles in Rats Exposed to Chronic Hypobaric Hypoxia: Changes in Metabolic Pathways

    PubMed Central

    Brito, Julio; Naveas, Nelson; Pulido, Ruth; De la Cruz, Juan José; Mamani, Maribel; León-Velarde, Fabiola

    2014-01-01

    Abstract Siques, Patricia, Julio Brito, Nelson Naveas, Ruth Pulido, Juan José De la Cruz, Maribel Mamani, and Fabiola León-Velarde. Plasma and liver lipid profiles in rats exposed to chronic hypobaric hypoxia: Changes in metabolic pathways. High Alt Med Biol 15:388–395, 2014.—Lipid metabolism under chronic hypoxia (CH) has not received equal attention as intermittent hypoxia (IH). To determine the CH-induced changes in plasma and liver, as well as the mRNA and protein expression of two key enzymes in the triglyceride and cholesterol biosynthesis pathways, SREBP-1 (HMG-CoA reductase) and SREBP-2 (SCD-1), we exposed adult male Wistar rats to CH (4600 m; n=15) for 30 days compared to normoxic rats (n=15). The CH rats exhibited weight loss (p<0.001), higher hematocrit (%), and higher hemoglobin (g/dL) (p<0.01). In the plasma of CH rats, total cholesterol and LDL-cholesterol increased at day 15. VLDL-cholesterol and triglycerides (p<0.01) greatly increased (35%), while HDL-cholesterol decreased (p<0.01). Triglycerides and VLDL-cholesterol remained elevated by 28% at day 30 (p<0.01). Hepatic triglycerides increased two-fold, while total cholesterol increased by 51% (p<0.001; p<0.05). Upregulation of SCD-1 mRNA and protein was observed in the CH rats (p<0.01); however, no differences were observed in HMG-CoA reductase mRNA or protein expression in both groups. In conclusion, CH, like IH, alters lipid profiles by increasing triglycerides in the plasma and liver and upregulating triglyceride biosynthesis without affecting the cholesterol biosynthetic pathway. Additional involved mechanisms require further study because of the importance of lipids in cardiovascular risk. PMID:25185022

  1. Assessment of the "fish tumors or other deformities" beneficial use impairment in brown bullhead (Ameiurus nebulosus): II. Liver neoplasia

    USGS Publications Warehouse

    Blazer, V.S.; Rafferty, S.D.; Baumman, P.C.; Smith, S.B.; Obert, E.C.

    2009-01-01

    Liver pathology of fishes, including neoplastic and preneoplastic lesions, is widely used as an indicator of exposure to anthropogenic contaminants. By definition, the "fish tumor or other deformities" beneficial use impairment (BUI) at Great Lakes Areas of Concern (AOC) includes neoplastic and preneoplastic liver lesions in brown bullhead (Ameiurus nebulosus) or suckers. Unfortunately, adequate guidelines for defining neoplastic and preneoplastic liver lesions or determining rates at unimpacted control sites were not provided and different criteria have been used. In some cases, only neoplastic changes were used to calculate tumor prevalence, in some both neoplastic and preneoplastic changes and in some it is difficult to determine which changes were included. Using standardized criteria, the prevalence of liver neoplasia was compared at eight AOC during 1998-2000. The Cuyahoga River had the highest prevalence (25.0%), while the Maumee River had the lowest (3.9%). The Buffalo (4.8%), Detroit (5.9%), Ashtabula (6.8%), Niagara (7.5%) and Black (8.9%) rivers were intermediate, as was Presque Isle Bay (7.1%). From 2002 to 2007 the prevalence of liver neoplasia at Presque Isle Bay ranged from a low of 2.1% (2002) to a high of 12.0% (2007). Non-AOC sites, as potential reference sites, also were monitored during this time. By combining years and sites, the prevalence of liver neoplasia in bullhead (aged 2 to 12 years) at inland lakes was 0.7%, at bays/harbors was 1.6% and at tributary sites was 4.1%. This is the same trend (inland lakes < bays/harbors < tributaries < Presque Isle Bay) noted for orocutaneous neoplasms.

  2. Clinically significant chronic liver disease in people with Type 2 diabetes: the Edinburgh Type 2 Diabetes Study

    PubMed Central

    Fallowfield, J.A.; Guha, I.N.; Williamson, R.M.; Ali, M.; Glancy, S.; Strachan, M.W.J.; Price, J.F.

    2016-01-01

    Background: Type 2 diabetes is an independent risk factor for chronic liver disease, however disease burden estimates and knowledge of prognostic indicators are lacking in community populations. Aims: To describe the prevalence and incidence of clinically significant chronic liver disease amongst community-based older people with Type 2 diabetes and to determine risk factors which might assist in discriminating patients with unknown prevalent or incident disease. Design: Prospective cohort study. Methods: Nine hundred and thirty-nine participants in the Edinburgh Type 2 Diabetes Study underwent investigation including liver ultrasound and non-invasive measures of non-alcoholic steatohepatitis (NASH), hepatic fibrosis and systemic inflammation. Over 6-years, cases of cirrhosis and hepatocellular carcinoma were collated from multiple sources. Results: Eight patients had known prevalent disease with 13 further unknown cases identified (prevalence 2.2%) and 15 incident cases (IR 2.9/1000 person-years). Higher levels of systemic inflammation, NASH and hepatic fibrosis markers were associated with both unknown prevalent and incident clinically significant chronic liver disease (all P < 0.001). Conclusions: Our study investigations increased the known prevalence of clinically significant chronic liver disease by over 150%, confirming the suspicion of a large burden of undiagnosed disease. The disease incidence rate was lower than anticipated but still much higher than the general population rate. The ability to identify patients both with and at risk of developing clinically significant chronic liver disease allows for early intervention and clinical monitoring strategies. Ongoing work, with longer follow-up, including analysis of rates of liver function decline, will be used to define optimal risk prediction tools. PMID:26454513

  3. Isolated spinal cord contusion in rats induces chronic brain neuroinflammation, neurodegeneration, and cognitive impairment

    PubMed Central

    Wu, Junfang; Stoica, Bogdan A; Luo, Tao; Sabirzhanov, Boris; Zhao, Zaorui; Guanciale, Kelsey; Nayar, Suresh K; Foss, Catherine A; Pomper, Martin G; Faden, Alan I

    2014-01-01

    Cognitive dysfunction has been reported in patients with spinal cord injury (SCI), but it has been questioned whether such changes may reflect concurrent head injury, and the issue has not been addressed mechanistically or in a well-controlled experimental model. Our recent rodent studies examining SCI-induced hyperesthesia revealed neuroinflammatory changes not only in supratentorial pain-regulatory sites, but also in other brain regions, suggesting that additional brain functions may be impacted following SCI. Here we examined effects of isolated thoracic SCI in rats on cognition, brain inflammation, and neurodegeneration. We show for the first time that SCI causes widespread microglial activation in the brain, with increased expression of markers for activated microglia/macrophages, including translocator protein and chemokine ligand 21 (C–C motif). Stereological analysis demonstrated significant neuronal loss in the cortex, thalamus, and hippocampus. SCI caused chronic impairment in spatial, retention, contextual, and fear-related emotional memory—evidenced by poor performance in the Morris water maze, novel objective recognition, and passive avoidance tests. Based on our prior work implicating cell cycle activation (CCA) in chronic neuroinflammation after SCI or traumatic brain injury, we evaluated whether CCA contributed to the observed changes. Increased expression of cell cycle-related genes and proteins was found in hippocampus and cortex after SCI. Posttraumatic brain inflammation, neuronal loss, and cognitive changes were attenuated by systemic post-injury administration of a selective cyclin-dependent kinase inhibitor. These studies demonstrate that chronic brain neurodegeneration occurs after isolated SCI, likely related to sustained microglial activation mediated by cell cycle activation. PMID:25483194

  4. Conditional neuroligin-2 knockout in adult medial prefrontal cortex links chronic changes in synaptic inhibition to cognitive impairments.

    PubMed

    Liang, J; Xu, W; Hsu, Y-T; Yee, A X; Chen, L; Südhof, T C

    2015-07-01

    Abnormal activity in the medial prefrontal cortex (mPFC) is consistently observed in neuropsychiatric disorders, but the mechanisms involved remain unclear. Chronic aberrant excitation and/or inhibition of mPFC neurons were proposed to cause cognitive impairments. However, direct evidence for this hypothesis is lacking because it is technically challenging to control synaptic properties in a chronic and locally restricted, yet specific, manner. Here, we generated conditional knockout (cKO) mice of neuroligin-2 (Nlgn2), a postsynaptic cell-adhesion molecule of inhibitory synapses linked to neuropsychiatric disorders. cKO of Nlgn2 in adult mPFC rendered Nlgn2 protein undetectable after already 2-3 weeks, but induced major reductions in synaptic inhibition after only 6-7 weeks, and caused parallel impairments in anxiety, fear memory and social interaction behaviors. Moreover, cKO of Nlgn2 severely impaired behavioral stimulation of immediate-early gene expression in the mPFC, suggesting that chronic reduction in synaptic inhibition uncoupled the mPFC from experience-dependent inputs. Our results indicate that Nlgn2 is required for continuous maintenance of inhibitory synapses in the adult mPFC, and that chronic impairment of local inhibition disengages the mPFC from its cognitive functions by partially uncoupling the mPFC from experience-induced inputs. PMID:25824299

  5. Osseous and Nonosseous Bone Scan Findings in Liver Transplant Candidates with end-stage Chronic Liver Disease

    PubMed Central

    Erhamamcı, Seval; Aktaş, Ayşe; Bahçeci, Tatiana; Kavak, Kevser

    2013-01-01

    Objective: End-stage chronic liver disease (CLD) adversely affects the function of multiple organ systems including the skeletal system. The aim of this study was to assess osseous and nonosseous bone scintigraphy (BS) findings in liver transplant (LT) candidates with end-stage CLD. Methods: We retrospectively evaluated BS findings in 50 consecutive patients with end-stage CLD who were undergoing preoperative assessment for LT from January 2006 to December 2011. All the patients were analyzed with respect to clinical and laboratory parameters, and BS findings. Scintigrams were visually assessed for the presence of osseous and nonosseous abnormalities. Osseous abnormalities were classified as those indicating bone metabolism changes or metastatic bone disease. Typical scintigraphic findings denoting to changes in bone metabolism were the presence of decreased osseous uptake, increased periarticular uptake, asymmetrical or unusual uptake patterns. Nonosseous findings were classified according to the degree of soft-tissue uptake as mild and severe. Results: The group consisted of 46 adult and 4 adolescent patients. All adolescent patients had normal skeletal accumulation with growth plate uptake and one had mildly increased renal cortical activity. A total of 46 adult patients had one or more of the following osseous findings: generalized decrease in osseous uptake (n=4, 8.7%); bilateral decrease in lower extremity uptake (n=26, 56.5%); symmetrically increased periarticular uptake (n=26, 56.5%); bilateral cortical/periosteal increased uptake in the lower extremity indicating hepatic hypertrophic osteoarthropathy (HOA) (n=8, 17.4%); bilateral increased sacroiliac activity (n=16, 34.8%); sacral activity (n=10, 21.7%), coccygeal activity (n=2, 4.3%), focally increased uptake suggestive of metastases (n=5, 10.9%). Three rib metastases appeared to be linear. Nonosseous findings observed in adult patients were mild diffuse liver uptake (n=4, 8.7%) and bilateral diffuse mild

  6. Chronic Portal Vein Thrombosis After Liver Transplantation in a Child Treated by a Combined Minimally Invasive Approach

    SciTech Connect

    Carnevale, Francisco Cesar Santos, Aline Cristine Barbosa; Zurstrassen, Charles Edouard; Moreira, Airton Mota; Neto, Joao Seda; Filho, Eduardo Carone; Chapchap, Paulo

    2009-09-15

    Portal vein thrombosis (PVT) after orthotopic liver transplantation is an infrequent complication, and when it is present surgical treatment is considered for traditional management. Percutaneous transhepatic portal vein angioplasty has been described as an option to treat PVT with a lower morbidity than conventional surgical treatments. This article describes a case of chronic PVT in a child after a living donor liver transplantation managed by percutaneous transhepatic and surgical approaches.

  7. Mechanisms and consequences of the impaired trans-sulphuration pathway in liver disease: Part I. Biochemical implications.

    PubMed

    Mato, J M; Corrales, F; Martin-Duce, A; Ortiz, P; Pajares, M A; Cabrero, C

    1990-01-01

    The energy-dependent conversion of methionine to S-adenosyl-L-methionine (SAMe) is catalysed by S-adenosyl-L-methionine synthetase (SAMe-synthetase) in the liver. In the hepatocyte, an equilibrium exists between the high and low molecular weight forms of SAMe-synthetase, which consist of a tetramer and a dimer, respectively, of a 48.5 kilodalton subunit. The 2 enzymic forms differ in their affinity for methionine and sensitivity to inhibition by pyrophosphate; 2 of the sulfhydryl groups of SAMe-synthetase have been identified as essential for the normal functioning of the enzyme. In patients with liver cirrhosis, a marked reduction in the utilisation of the high molecular weight SAMe-synthetase and displacement of the equilibrium occur, the molecular mechanism of which has yet to be established. This loss of activity is associated with a delay in methionine clearance and impairment of the trans-sulphuration pathway, which normally eliminates excess methionine by oxidising homocysteine to sulphate anion. It is hypothesised that in normal liver function the essential sulfhydryl groups of SAMe-synthetase are protected from oxidation by glutathione, a by-product of the trans-sulphuration pathway. However, glutathione levels are reduced in liver cirrhosis, and this may result in increased oxidation of the essential sulfhydryl groups, and consequent inactivation of the enzyme. Thus, the trans-sulphuration pathway may play an important role in the maintenance of normal SAMe-synthetase activity. PMID:2081481

  8. Clinical profile of hepatitis B virus chronic infection in patients of Brazilian liver reference units

    PubMed Central

    Galizzi Fº, João; Teixeira, Rosângela; Fonseca, José C. F.

    2010-01-01

    Purpose To assess data about chronic forms of hepatitis B virus (HBV) infection in Brazilian reference units, the Brazilian Society of Hepatology (SBH) performed a survey, with its associates spread throughout the country. Methods SBH members were contacted by electronic mail. They were asked for data from their liver units regarding chronically infected HBV patients between January 2005 and September 2007. All subjects with HBV surface antigenemia lasting more than 6 months were eligible. Patients who died after January 2005 were also included. Results Data from 24 units of 17 cities (12 Brazilian states) were obtained. These corresponded to 3,913 patients. Mean age was 39 years, ranging from 1 to 84 years. The northern region had the lowest mean age (35 years) and the southern region the highest (43 years). Most of the sampled people were white; 1,448 of 3,614 patients had chronic hepatitis B. Most of them were HBeAg negative (1.4:1). There were 1,695 (46.9%) inactive carriers of 3,614 HBV-infected patients and other 69 (1.9%) were considered as having immune-tolerant status. Hepatitis D coinfection was common among the Amazonian sample (n = 369). Conclusions This large sample study shows important tendencies of chronic hepatitis B infection in Brazilian reference units, such as HBeAg-negative chronic hepatitis B cases overwhelming wild-type strains infected cases. Besides, hepatitis D occurs only among the Amazonian patients. PMID:20827409

  9. Accurate Prediction of Advanced Liver Fibrosis Using the Decision Tree Learning Algorithm in Chronic Hepatitis C Egyptian Patients

    PubMed Central

    Hashem, Somaya; Esmat, Gamal; Elakel, Wafaa; Habashy, Shahira; Abdel Raouf, Safaa; Darweesh, Samar; Soliman, Mohamad; Elhefnawi, Mohamed; El-Adawy, Mohamed; ElHefnawi, Mahmoud

    2016-01-01

    Background/Aim. Respectively with the prevalence of chronic hepatitis C in the world, using noninvasive methods as an alternative method in staging chronic liver diseases for avoiding the drawbacks of biopsy is significantly increasing. The aim of this study is to combine the serum biomarkers and clinical information to develop a classification model that can predict advanced liver fibrosis. Methods. 39,567 patients with chronic hepatitis C were included and randomly divided into two separate sets. Liver fibrosis was assessed via METAVIR score; patients were categorized as mild to moderate (F0–F2) or advanced (F3-F4) fibrosis stages. Two models were developed using alternating decision tree algorithm. Model 1 uses six parameters, while model 2 uses four, which are similar to FIB-4 features except alpha-fetoprotein instead of alanine aminotransferase. Sensitivity and receiver operating characteristic curve were performed to evaluate the performance of the proposed models. Results. The best model achieved 86.2% negative predictive value and 0.78 ROC with 84.8% accuracy which is better than FIB-4. Conclusions. The risk of advanced liver fibrosis, due to chronic hepatitis C, could be predicted with high accuracy using decision tree learning algorithm that could be used to reduce the need to assess the liver biopsy. PMID:26880886

  10. Accurate Prediction of Advanced Liver Fibrosis Using the Decision Tree Learning Algorithm in Chronic Hepatitis C Egyptian Patients.

    PubMed

    Hashem, Somaya; Esmat, Gamal; Elakel, Wafaa; Habashy, Shahira; Abdel Raouf, Safaa; Darweesh, Samar; Soliman, Mohamad; Elhefnawi, Mohamed; El-Adawy, Mohamed; ElHefnawi, Mahmoud

    2016-01-01

    Background/Aim. Respectively with the prevalence of chronic hepatitis C in the world, using noninvasive methods as an alternative method in staging chronic liver diseases for avoiding the drawbacks of biopsy is significantly increasing. The aim of this study is to combine the serum biomarkers and clinical information to develop a classification model that can predict advanced liver fibrosis. Methods. 39,567 patients with chronic hepatitis C were included and randomly divided into two separate sets. Liver fibrosis was assessed via METAVIR score; patients were categorized as mild to moderate (F0-F2) or advanced (F3-F4) fibrosis stages. Two models were developed using alternating decision tree algorithm. Model 1 uses six parameters, while model 2 uses four, which are similar to FIB-4 features except alpha-fetoprotein instead of alanine aminotransferase. Sensitivity and receiver operating characteristic curve were performed to evaluate the performance of the proposed models. Results. The best model achieved 86.2% negative predictive value and 0.78 ROC with 84.8% accuracy which is better than FIB-4. Conclusions. The risk of advanced liver fibrosis, due to chronic hepatitis C, could be predicted with high accuracy using decision tree learning algorithm that could be used to reduce the need to assess the liver biopsy. PMID:26880886

  11. Case report of acute-on-chronic liver failure secondary to diffuse large B-cell lymphoma

    PubMed Central

    Siba, Yahuza; Obiokoye, Kenechukwu; Ferstenberg, Richard; Robilotti, James; Culpepper-Morgan, Joan

    2014-01-01

    Acute liver failure is a rare presentation of hematologic malignancy. Acute on chronic liver failure (ACLF) is a newly recognized clinical entity that describes acute hepatic decompensation in persons with preexisting liver disease. Diffuse large B-cell lymphoma (DLBCL) is an aggressive non-Hodgkin’s lymphoma (NHL) with increasing incidence in older males, females and blacks. However, it has not yet been reported, to present with acute liver failure in patients with preexisting chronic liver disease due to human immunodeficiency virus (HIV)/hepatitis C virus (HCV) co-infection. We describe a case of ACLF as the presenting manifestation of DLBCL in an elderly black man with HIV/HCV co-infection and prior Hodgkin’s disease in remission for three years. The rapidly fatal outcome of this disease is highlighted as is the distinction of ACLF from decompensated cirrhosis. Due to the increased prevalence of HIV/HCV co-infection in the African American 1945 to 1965 birth cohort and the fact that both are risk factors for chronic liver disease and NHL we postulate that the incidence of NHL presenting as ACLF may increase. PMID:25469050

  12. Impaired Myocardial Oxygenation Response to Stress in Patients With Chronic Kidney Disease

    PubMed Central

    Parnham, Susie; Gleadle, Jonathan M; Bangalore, Sripal; Grover, Suchi; Perry, Rebecca; Woodman, Richard J; De Pasquale, Carmine G; Selvanayagam, Joseph B

    2015-01-01

    Background Coronary artery disease and left ventricular hypertrophy are prevalent in the chronic kidney disease (CKD) and renal transplant (RT) population. Advances in cardiovascular magnetic resonance (CMR) with blood oxygen level–dependent (BOLD) technique provides capability to assess myocardial oxygenation as a measure of ischemia. We hypothesized that the myocardial oxygenation response to stress would be impaired in CKD and RT patients. Methods and Results Fifty-three subjects (23 subjects with CKD, 10 RT recipients, 10 hypertensive (HT) controls, and 10 normal controls without known coronary artery disease) underwent CMR scanning. All groups had cine and BOLD CMR at 3 T. The RT and HT groups also had late gadolinium CMR to assess infarction/replacement fibrosis. The CKD group underwent 2-dimensional echocardiography strain to assess fibrosis. Myocardial oxygenation was measured at rest and under stress with adenosine (140 μg/kg per minute) using BOLD signal intensity. A total of 2898 myocardial segments (1200 segments in CKD patients, 552 segments in RT, 480 segments in HT, and 666 segments in normal controls) were compared using linear mixed modeling. Diabetes mellitus (P=0.47) and hypertension (P=0.57) were similar between CKD, RT, and HT groups. The mean BOLD signal intensity change was significantly lower in the CKD and RT groups compared to HT controls and normal controls (−0.89±10.63% in CKD versus 5.66±7.87% in RT versus 15.54±9.58% in HT controls versus 16.19±11.11% in normal controls, P<0.0001). BOLD signal intensity change was associated with estimated glomerular filtration rate (β=0.16, 95% CI=0.10 to 0.22, P<0.0001). Left ventricular mass index and left ventricular septal wall diameter were similar between the CKD predialysis, RT, and HT groups. None of the CKD patients had impaired global longitudinal strain and none of the RT group had late gadolinium hyperenhancement. Conclusions Myocardial oxygenation response to stress is

  13. Ligularia fischeri extract attenuates liver damage induced by chronic alcohol intake.

    PubMed

    Kim, Dongyeop; Kim, Gyeong-Woo; Lee, Seon-Ho; Han, Gi Dong

    2016-08-01

    Context Ligularia fischeri (Ledebour) Turcz. (Compositae) has been used as a leafy vegetable and in traditional medicine to treat hepatic disorder in East Asia. Objective The present study explores the antioxidant activity of LF aqueous extract on EtOH-induced oxidative stress accompanied by hepatotoxicity both in vitro and in vivo. Materials and methods In vitro study using the mouse liver NCTC-1469 cell line was conducted to estimate the cytotoxicity as well as the inhibitory effect of LF extract against alcohol-treated cell damage. In vivo study used an alcohol-fed Wister rat model orally administered EtOH (3.95 g/kg of body weight/d) with or without LF extract (100 or 200 mg/kg body weight) for 6 weeks. Serum and liver tissue were collected to evaluate hepatic injury and antioxidant-related enzyme activity. Results The EC50 value for the DPPH radical scavenging capacity of LF extract was 451.5 μg/mL, whereas the IC50 value of LF extract in terms of EtOH-induced reactive oxygen species (ROS) generation was 98.3 μg/mL without cell cytotoxicity. LF extract (200 mg/kg body weight) significantly reduced the triglyceride content of serum (33%) as well as hepatic lipid peroxidation (36%), whereas SOD activity was elevated three-fold. LF extract suppressed expression of CYP2E1 and TNF-α, and attenuated alcohol-induced abnormal morphological changes. Discussion and conclusion LF extract attenuated liver damage induced by alcoholic oxidative stress through inhibition of ROS generation, down-regulation of CYP2E1, and activation of hepatic antioxidative enzymes. Homeostasis of the antioxidative defence system in the liver by LF extract mitigated hepatic disorder following chronic alcohol intake. PMID:26799831

  14. Characteristics of highly impaired children with severe chronic pain: a 5-year retrospective study on 2249 pediatric pain patients

    PubMed Central

    2012-01-01

    Background Prevalence of pain as a recurrent symptom in children is known to be high, but little is known about children with high impairment from chronic pain seeking specialized treatment. The purpose of this study was the precise description of children with high impairment from chronic pain referred to the German Paediatric Pain Centre over a 5-year period. Methods Demographic variables, pain characteristics and psychometric measures were assessed at the first evaluation. Subgroup analysis for sex, age and pain location was conducted and multivariate logistic regression applied to identify parameters associated with extremely high impairment. Results The retrospective study consisted of 2249 children assessed at the first evaluation. Tension type headache (48%), migraine (43%) and functional abdominal pain (11%) were the most common diagnoses with a high rate of co-occurrence; 18% had some form of musculoskeletal pain disease. Irrespective of pain location, chronic pain disorder with somatic and psychological factors was diagnosed frequently (43%). 55% of the children suffered from more than one distinct pain diagnosis. Clinically significant depression and general anxiety scores were expressed by 24% and 19% of the patients, respectively. Girls over the age of 13 were more likely to seek tertiary treatment compared to boys. Nearly half of children suffered from daily or constant pain with a mean pain value of 6/10. Extremely high pain-related impairment, operationalized as a comprehensive measure of pain duration, frequency, intensity, pain-related school absence and disability, was associated with older age, multiple locations of pain, increased depression and prior hospital stays. 43% of the children taking analgesics had no indication for pharmacological treatment. Conclusion Children with chronic pain are a diagnostic and therapeutic challenge as they often have two or more different pain diagnoses, are prone to misuse of analgesics and are severely

  15. Chronic ethanol consumption in mice alters hepatocyte lipid droplet properties

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Background: Hepatosteatosis is a common pathological feature of impaired hepatic metabolism following chronic alcohol consumption. Although often benign and reversible, it is widely believed that steatosis is a risk factor for development of advanced liver pathologies, including steatohepatitis and ...

  16. Reversal of severe hepatopulmonary syndrome in chronic hepatic cirrhosis by living donor liver transplantation: report of two cases.

    PubMed

    Chen, Kefei; Li, Bo

    2011-03-01

    Severe hepatopulmonary syndrome (HPS) is a rare complication of decompensated liver cirrhosis and a relative contraindication for liver transplantation. This report describes the treatment of two cases with severe HPS resulting from chronic liver failure by living donor liver transplantation (LDLT). The clinical data of the two cases were reviewed. The parameters included the intrapulmonary shunt ratio as measured by (99m)Tc pulmonary scintigraphy, perioperative treatment and examination results, and the duration of post-transplant hypoxemia. Liver dysfunction was reversed in both patients 2-3 weeks after LDLT. Both patients experienced slightly increased intrapulmonary shunt ratios in the first postoperative month, followed by substantial decreases at postoperative days 90 and 361. These findings suggest severe HPS can be resolved by LDLT. Pulmonary infection requires proper treatment and may be anticipated during the early postoperative course. The differences in the intrapulmonary shunt ratio between these patients may contribute to the differences in the time required for rehabilitation. PMID:21365434

  17. Procollagen III peptide and fibronectin in alcohol-related chronic liver disease: correlations with morphological features and biochemical tests.

    PubMed

    Gabrielli, G B; Faccioli, G; Casaril, M; Capra, F; Bonazzi, L; Falezza, G; Tomba, A; Baracchino, F; Corrocher, R

    1989-02-22

    In order to clarify the significance of procollagen III peptide (PIIIP) and fibronectin (FN) blood concentration in alcohol related chronic liver disease (ALD), we have investigated their relationships with histological liver features and biochemical liver tests in 44 ALD patients. PIIIP was measured in serum by radioimmunoassay whereas FN was determined in plasma using an immunonephelometric method. In each liver biopsy, steatosis, portal infiltrate, lobular necro-inflammation, portal fibrosis and lobular fibrosis were semiquantitatively assessed by scoring from 0 to 3. A close correlation of PIIIP was found with morphological features of fibrosis (both of lobular and portal type), but not with necro-inflammation or steatosis. PIIIP was also positively correlated with ALP and GGT and exhibited a good diagnostic value in liver fibrosis. On the contrary, FN did not distinguish between normals and patients and was not correlated with any morphological liver feature or biochemical liver test. We also conclude that serum NP3P effectively reflects liver fibrosis, whereas plasma FN seems not related to any of the main histological aspects of liver damage in ALD. PMID:2714004

  18. Smad phosphoisoform signals in acute and chronic liver injury: similarities and differences between epithelial and mesenchymal cells.

    PubMed

    Matsuzaki, Koichi

    2012-01-01

    Hepatocellular carcinoma (HCC) usually arises from hepatic fibrosis caused by chronic inflammation. In chronic liver damage, hepatic stellate cells undergo progressive activation to myofibroblasts (MFB), which are important extracellular-matrix-producing mesenchymal cells. Concomitantly, perturbation of transforming growth factor (TGF)-β signaling by pro-inflammatory cytokines in the epithelial cells of the liver (hepatocytes) promotes both fibrogenesis and carcinogenesis (fibro-carcinogenesis). Insights into fibro-carcinogenic effects on chronically damaged hepatocytes have come from recent detailed analyses of the TGF-β signaling process. Smad proteins, which convey signals from TGF-β receptors to the nucleus, have intermediate linker regions between conserved Mad homology (MH) 1 and MH2 domains. TGF-β type I receptor and pro-inflammatory cytokine-activated kinases differentially phosphorylate Smad2 and Smad3 to create phosphoisoforms phosphorylated at the COOH-terminal, linker, or both (L/C) regions. After acute liver injury, TGF-β-mediated pSmad3C signaling terminates hepatocytic proliferation induced by the pro-inflammatory cytokine-mediated mitogenic pSmad3L pathway; TGF-β and pro-inflammatory cytokines synergistically enhance collagen synthesis by activated hepatic stellate cells via pSmad2L/C and pSmad3L/C pathways. During chronic liver disease progression, pre-neoplastic hepatocytes persistently affected by TGF-β together with pro-inflammatory cytokines come to exhibit the same carcinogenic (mitogenic) pSmad3L and fibrogenic pSmad2L/C signaling as do MFB, thereby accelerating liver fibrosis while increasing risk of HCC. This review of Smad phosphoisoform-mediated signals examines similarities and differences between epithelial and mesenchymal cells in acute and chronic liver injuries and considers Smad linker phosphorylation as a potential target for the chemoprevention of fibro-carcinogenesis. PMID:21626291

  19. Liver Governs Tendon: A Theory from Traditional Chinese Medicine—Evidence from a Population-Based Matched Cohort Study in Taiwan for the Association of Chronic Liver Disease and Common Diseases in the Chiropractic Office

    PubMed Central

    Lin, Lih-Hwa; Chen, Huey-Yi; Chiang, Jen-Huai; Chen, Wen-Chi

    2016-01-01

    In traditional Chinese medicine (TCM) theory, the liver governs the tendons. This retrospective cohort study investigated the relationship between chronic liver disease and common orthopedic conditions by utilizing the National Health Insurance Research Database of Taiwan. The populations included within this study were chronic liver disease patients (International Classification of Diseases/ICD-9 code: 571) and a comparison group composed of patients with nonchronic liver disease. The medical event that was evaluated was internal derangement of joints (ICD-9 codes: 717-718). In comparison with the control group, patients with chronic liver disease were 1.29 times more likely to develop internal derangement of joints when major trauma had also occurred. We did not find the association of viral hepatitis with internal derangement of joints. Patients with chronic liver disease as well as anemia were 3.01 times more likely to develop joint derangements. Our study shows that patients with anemia in addition to chronic liver disease are more prone to develop joint derangements. This is the first documented research study that endorses “the liver governs the tendons which gives the body the ability to move” theory of TCM. The incidence rate of internal derangement of knee joints was higher in patients with chronic liver disease. PMID:27437024

  20. Inhibition of phosphodiesterase 2 reverses impaired cognition and neuronal remodeling caused by chronic stress.

    PubMed

    Xu, Ying; Pan, Jianchun; Sun, Jiao; Ding, Lianshu; Ruan, Lina; Reed, Miranda; Yu, Xuefeng; Klabnik, Jonathan; Lin, Dan; Li, Jianxin; Chen, Ling; Zhang, Chong; Zhang, Hanting; O'Donnell, James M

    2015-02-01

    Chronic stress and neuronal vulnerability have recently been recognized as factors contributing to cognitive disorders. One way to modify neuronal vulnerability is through mediation of phosphodiesterase 2 (PDE2), an enzyme that exerts its action on cognitive processes via the control of intracellular second messengers, cGMP and, to a lesser extent, cAMP. This study explored the effects of a PDE2 inhibitor, Bay 60-7550, on stress-induced learning and memory dysfunction in terms of its ramification on behavioral, morphologic, and molecular changes. Bay 60-7550 reversed stress-induced cognitive impairment in the Morris water maze, novel object recognition, and location tasks (object recognition test and/or object location test), effects prevented by treatment with 7-NI, a selective inhibitor of neuronal nitric oxide synthase; MK801, a glutamate receptor (NMDAR) inhibitor; myr-AIP, a CaMKII inhibitor; and KT5823, a protein kinase G inhibitor. Bay 60-7550 also ameliorated stress-induced structural remodeling in the CA1 of the hippocampus, leading to increases in dendritic branching, length, and spine density. However, the neuroplasticity initiated by Bay 60-7550 was not seen in the presence of 7-NI, MK801, myr-AIP, or KT5823. PDE2 inhibition reduced stress-induced extracellular-regulated protein kinase activation and attenuated stress-induced decreases in transcription factors (e.g., Elk-1, TORC1, and CREB phosphorylation) and plasticity-related proteins (e.g., Egr-1 and brain-derived neurotrophic factor). Pretreatment with inhibitors of NMDA, CaMKII, neuronal nitric oxide synthase, and protein kinase G (or protein kinase A) blocked the effects of Bay 60-7550 on cGMP or cAMP signaling. These findings indicate that the effect of PDE2 inhibition on stress-induced memory impairment is potentially mediated via modulation of neuroplasticity-related NMDAR-CaMKII-cGMP/cAMP signaling. PMID:25442113

  1. Rat lung macrophage tumor cytotoxin production: impairment by chronic in vivo cigarette smoke exposure.

    PubMed

    Flick, D A; Gonzalez-Rothi, R J; Harris, J O; Gifford, G E

    1985-11-01

    Macrophages in the presence of bacteria-derived lipopolysaccharide (LPS) stimuli produce a soluble cytotoxin which is toxic to tumor cells. In this study, we examined various parameters of cytotoxin production from pulmonary lavage cells obtained from Fisher 344 cesarean-derived rats. Cultures of macrophages were derived from pulmonary lavage cells and stimulated in vitro with LPS. Cytotoxin production was assayed in vitro using an L-929 cell target assay. Pulmonary lavage preparations contained a relatively pure population of macrophages, and adherence studies revealed that nonadherent lavage cells contributed negligible amounts of cytotoxin, indicating that macrophages were responsible for cytotoxin production. After LPS stimulation, cytotoxin production became maximal within 10 h and thereafter plateaued. Doses of LPS above 0.1 microgram/ml were optimal for production, and in the absence of LPS, no cytotoxin was detected. Because cigarette smoke is the major etiological factor in the development of lung cancers and because smoking is known to profoundly alter the function of alveolar macrophages in humans and experimental animals, subsequent experiments examined the role of chronic cigarette smoke exposure on tumoricidal activity of lung macrophages. Rats were exposed in vivo for 8 wk to either cigarette smoke or air (sham-treated controls). When lavage cells were cultured and stimulated with LPS (1 microgram/ml), 5- to 10-fold less cytotoxin was produced by lavage cells from rats exposed to cigarette smoke. Similarly, using a direct cytotoxicity assay, lung macrophages of smoke-exposed animals also revealed marked impairment in cytotoxicity against L-929 cell targets, and this was noted over a wide range of macrophage:tumor target cell ratios. Another product of macrophages, interferon, was also decreased in rats exposed in vivo to cigarette smoke when compared to sham-treated controls. These results suggest that cigarette smoke exposure may impair pulmonary

  2. Increased fibrin formation and impaired fibrinolytic capacity in severe chronic kidney disease.

    PubMed

    Mörtberg, Josefin; Blombäck, Margareta; Wallén, Åkan; He, Shu; Jacobson, Stefan H; Spaak, Jonas

    2016-06-01

    Chronic kidney disease (CKD) is associated with a concurrent increased risk of thrombosis and bleeding. We aimed to investigate whether CKD is associated with increased fibrin formation, impaired fibrin degradation, or both. Twenty-one patients with CKD stage 4 (CKD 4), 15 haemodialysis patients, and 13 controls (C) without kidney disease were studied. We used a global assay to determine fibrin formation and degradation in plasma. Fibrin turbidity was measured over time to obtain a value of the coagulation activation profile (Cp) and the fibrinolysis activation profile (Fp), and the amount of fibrin formed, termed fibrin optical density sum (fibrin OD-sum). We used scanning electron microscopy (SEM) to visualize the fibrin network. Plasminogen activator inhibitor type-1 antigen, thrombin-activatable fibrinolysis inhibitor activity, fibrinogen, von Willebrand factor, antithrombin, albumin, and C-reactive protein were measured in plasma. Fibrin OD-sum was significantly elevated in haemodialysis patients [312 a.u.; 278-435 (median; interquartile range); P < 0.0013] and in CKD 4 (293 a.u.; 169-434; P = 0.0119) compared with controls (115 a.u.; 82-234). SEM showed a tight fibrin network in haemodialysis and CKD 4 patients. Fp was lower in the haemodialysis group than in controls (P = 0.030). Plasminogen activator inhibitor type-1 was lower in haemodialysis patients (P = 0.034). Thrombin-activatable fibrinolysis inhibitor activity, Cp, antithrombin, and C-reactive protein did not differ between groups. Fibrinogen was significantly elevated and albumin decreased in both haemodialysis and CKD 4 patients compared with controls. Von Willebrand factor was elevated in haemodialysis patients compared with controls (P = 0.010). The prothrombotic state in severe CKD is characterized by impaired fibrinolysis in association with increased fibrin formation despite normal levels of endogenous fibrinolysis inhibitors. PMID:26650459

  3. Sexual quality of life is impaired in patients with chronic hepatitis C.

    PubMed

    Vergniol, J; Duc, S; Hou, G; Hiriart, J B; Foucher, J; Chenus, F; Fabères, C; Chermak, F; Lafournière, A; Souakri, N; de Lédinghen, V

    2016-03-01

    Chronic hepatitis C (CHC) patients often have altered quality of life. Few data are available about sexual impairment (SI) in CHC. From 2011 to 2013, we included consecutive CHC outpatients. Exclusion criteria were: antiviral therapy, co-infection, age <18 or >75, transplantation, alcohol consumption, Eastern Cooperative Oncology Group >1. Non-CHC subjects were healthy blood donors. Sexual questionnaires for men and women were adapted from the International Index of Erectile Function and Female Sexual Function Index, respectively, and concerned the past 30 days. Two hundred eighty-one patients were compared with 1086 blood donors. SI was more frequent in CHC patients. Men with CHC had worse desire, confidence, erections, climax and satisfaction (P<0.001). Women with CHC had worse desire, arousal, climax, satisfaction, lubrication and comfort (P<0.001). In multivariate analysis, factors associated with SI in men were CHC (odds ratio (OR)=4.45, 95% confidence interval (CI) 2.46-8.06), age (OR=1.06, 95% CI 1.03-1.09), no intercourse (OR=8.74, 95% CI 4.65-16.04) and unemployment (OR=2.14, 95% CI 1.16-3.95). Factors associated with a worse global sexual life in women were CHC (OR=7.96, 95% CI 4.07-15.58) and no intercourse (OR=21.39, 95% CI 11.03-41.48). The study results were corroborated by propensity score-matching analysis. Sexual life is impaired in men and women with CHC. In clinical practice, sexual quality of life should be evaluated and treated. PMID:26865102

  4. Inhibition of phosphodiesterase 2 reverses impaired cognition and neuronal remodeling caused by chronic stress

    PubMed Central

    Xu, Ying; Pan, Jianchun; Sun, Jiao; Ding, Lianshu; Ruan, Lina; Reed, Miranda; Yu, Xuefeng; Klabni, Jonathan; Lin, Dan; Li, Jianxin; Chen, Ling; Zhang, Chong; Zhang, Hanting; O’Donnell, James M.

    2014-01-01

    Chronic stress and neuronal vulnerability have recently been recognized as factors contributing to cognitive disorders. One way to modify neuronal vulnerability is through mediation of phosphodiesterase 2 (PDE2), an enzyme that exerts its action on cognitive processes via the control of intracellular second messengers, cGMP and, to a lesser extent, cAMP. This study explored the effects of a PDE2 inhibitor, Bay 60-7550, on stress-induced learning and memory dysfunction in terms of its ramification on behavioral, morphological and molecular changes. Bay 60-7550 reversed stress-induced cognitive impairment in the Morris water maze (MWM), novel object recognition and location tasks (ORT/OLT), effects prevented by treatment with 7-NI, a selective inhibitor of neuronal nitric oxide synthase (nNOS); MK801, a glutamate receptor (NMDAR) inhibitor; myr-AIP, a CaMKII inhibitor; and KT5823, a PKG inhibitor. Bay 60-7550 also ameliorated stress-induced structural remodeling in the CA1 of the hippocampus, leading to increases in dendritic branching, length, and spine density. However, the neuroplasticity initiated by Bay 60-7550 was not seen in the presence of 7-NI, MK801, myr-AIP or KT5823. PDE2 inhibition reduced stress-induced ERK activation and attenuated stress-induced decreases in transcription factors (e.g., Elk-1, TORC1, and pCREB) and plasticity-related proteins (e.g, Egr-1 and BDNF). Pre-treatment with inhibitors of NMDA, CaMKII, nNOS, PKG (or PKA), blocked the effects of Bay 60-7550 on cGMP or cAMP signaling. These findings indicate that the effect of PDE2 inhibition on stress-induced memory impairment is potentially mediated via modulation of neuroplasticity-related, NMDAR-CaMKII-cGMP/cAMP signaling. PMID:25442113

  5. Impaired adaptation of gastrointestinal motility following chronic stress in maternally separated rats.

    PubMed

    Bülbül, Mehmet; Babygirija, Reji; Cerjak, Diana; Yoshimoto, Sazu; Ludwig, Kirk; Takahashi, Toku

    2012-04-01

    Exposure to early life stress causes increased stress responsiveness and permanent changes in the central nervous system. We recently showed that delayed gastric emptying (GE) and accelerated colonic transit (CT) in response to acute restraint stress (ARS) were completely restored following chronic homotypic stress (CHS) in rats via upregulation of hypothalamic oxytocin (OXT) expression. However, it is unknown whether early life stress affects hypothalamic OXT circuits and gastrointestinal motor function. Neonatal rats were subjected to maternal separation (MS) for 180 min/day for 2 wk. Anxiety-like behaviors were evaluated by the elevated-plus-maze test. GE and CT were measured under nonstressed (NS), ARS, and CHS conditions. Expression of corticotropin-releasing factor (CRF) and OXT in the paraventricular nucleus (PVN) of the hypothalamus was evaluated by real time RT-PCR and immunohistochemistry. MS increased anxiety-like behaviors. ARS delayed GE and accelerated CT in control and MS rats. After CHS, delayed GE and accelerated CT were restored in control, but not MS, rats. CRF mRNA expression was significantly increased in response to ARS in control and MS rats. Increased CRF mRNA expression was still observed following CHS in MS, but not control, rats. In response to CHS, OXT mRNA expression was significantly increased in control, but not MS, rats. The number of OXT-immunoreactive cells was increased following CHS in the magnocellular part of the PVN in control, but not MS, rats. MS impairs the adaptation response of gastrointestinal motility following CHS. The mechanism of the impaired adaptation involves downregulation of OXT and upregulation of CRF in the hypothalamus in MS rats. PMID:22241856

  6. Functional impairment in chronic fatigue syndrome, fibromyalgia, and multiple chemical sensitivity

    PubMed Central

    Lavergne, M. Ruth; Cole, Donald C.; Kerr, Kathleen; Marshall, Lynn M.

    2010-01-01

    ABSTRACT OBJECTIVE To characterize patients diagnosed with multiple chemical sensitivity (MCS), chronic fatigue syndrome (CFS), or fibromyalgia (FM), to compare their level of function with Canadian population average values, and to assess factors associated with function. DESIGN Chart review and abstraction of clinical information. SETTING The Environmental Health Clinic (EHC) at Women’s College Hospital in Toronto, Ont, which is a provincial referral centre for patients with illnesses with suspected environmental links, especially MCS, CFS, and FM. PARTICIPANTS A total of 128 consecutive patients diagnosed with 1 or more of MCS, CFS, or FM, seen between January 2005 and March 2006 at the EHC. MAIN OUTCOME MEASURES Demographic and socioeconomic characteristics, comorbid diagnoses, duration of illness, health services usage, life stresses, helpful therapeutic strategies, and functional impairment measured by the Short Form–36, compared with Canadian population average values. Factors significantly associated with function in bivariate analyses were included in multiple linear and logistic regression models. RESULTS The patient population was predominantly female (86.7%), with a mean age of 44.6 years. Seventy-eight patients had discrete diagnoses of 1 of MCS, CFS, or FM, while the remainder had 2 or 3 overlapping diagnoses. Most (68.8%) had stopped work, and on average this had occurred 3 years after symptom onset. On every Short Form–36 subscale, patients had markedly lower functional scores than population average values, more so when they had 2 or 3 of these diagnoses. Having FM, younger age at onset, and lower socioeconomic status were most consistently associated with poor function. CONCLUSION Patients seen at the EHC demonstrated marked functional impairment, consistent with their reported difficulties working and caring for their homes and families during what should be their peak productive years. Early comprehensive assessment, medical management

  7. Acute and chronic methyl mercury poisoning impairs rat adrenal and testicular function

    SciTech Connect

    Burton, G.V.; Meikle, A.W.

    1980-05-01

    Animals poisoned with methyl mercury (CH/sub 3/Hg) exhibit stress intolerance and decreased sexual activity, which suggest both adrenal and testicular dysfunction. Adrenal and testicular function was studied in male rats after treatment with CH/sub 3/Hg. In animals treated chronically, the adrenal glands were markedly hyperplastic with enlargement of the zona fasciculata. The mean basal serum levels of corticosterone were similar in experimental (17.8 ..mu..g/dl) and control (16.8 ..mu..g/dl) groups. However, with ether stress, experimental animals had a subnormal response, and the mean serum levels of corticosterone increased to only 23.9 ..mu../dl compared to 40.6 ..mu..g/dl in the controls. Exogenous ACTH stimulation produced a mean level of 19.0 ..mu..g/dl in the CH/sub 3/Hg-treated animals and 49.7 ..mu..g/dl in the controls. In vitro studies demonstrated a defect in the conversion of cholesterol to pregnenolone. A profound impairment in swimming was partially reversed with glucocorticoid therapy. In animals treated with CH/sub 3/Hg, serum testosterone was lower than normal in the basal state. Human chorionic gonadotropin stimulation increased the mean serum concentration of testosterone to 23.4 ng/ml in controls, but it was only 4.50 ng/ml in experimental animals. The data indicate that CH/sub 3/Hg poisoning impairs adrenal and testicular steroid hormone secretion, which accounts in part for the diminished stress tolerance and decreased sexual activity observed in CH/sub 3/Hg-intoxicated animals.

  8. A Mechanistic Assessment of the Discordance between Normal Serum Alanine Aminotransferase Levels and Altered Liver Histology in Chronic Hepatitis B

    PubMed Central

    Gong, Xianqiong; Yang, Jiaen; Tang, Jinmo; Gu, Chong; Huang, Lijian; Zheng, Ying; Liang, Huiqing; Wang, Min; Wu, Chuncheng; Chen, Yue; Zhang, Manying; Yu, Zhijian; Mao, Qianguo

    2015-01-01

    To understand the mechanisms underlying the discordance between normal serum alanine aminotransferase (ALT) levels and significant alterations in liver histology of chronic hepatitis B virus (HBV) infection with persistent normal ALT (PNALT) or minimally elevated ALT. A total of 300 treatment-naive chronic HBV-infected patients with PNALT (ALT ≤ upper limit of normal [ULN, 40 U/ml]) or minimally elevated ALT (1-2×ULN) were retrospectively enrolled. All patients underwent liver biopsy and histological changes were analyzed along with biochemical and HBV markers. Among 300 participants, 177 were HBeAg-positive and 123 HBeAg-negative. Significant histologic abnormalities were found in 42.9% (76/177) and 52.8% (65/123) of HBeAg-positive and HBeAg-negative patients, respectively. Significant fibrosis, which is a marker of prior injury, was more frequently detected than significant necroinflammation (suggesting active liver injury) in both HBeAg-positive and -negative groups, suggesting that liver injury occurred intermittently in our cohort. No significant differences were noticed in the percentage of patients with severe fibrosis between HBeAg-positive and negative phases or between ages 30 and 40 and over 40, suggesting that the fibrosis was possibly carried over from an early phase. Finally, lowering ALT ULN (30 U/L for men, 19 U/L for women) alone was not adequate to increase the sensitivity of ALT detection of liver injury. However, the study was limited to a small sample size of 13 HBeAg-positive patients with ALT in the revised normal range. We detected significant liver pathology in almost 50% of chronic HBV infected patients with PNALT (ALT ≤ 40 U/ml) or minimally elevated ALT. We postulated that small-scale intermittent liver injury was possibly responsible for the discordance between normal serum ALT and significant liver changes in our cohort. PMID:26230094

  9. Chronic dietary chlorpyrifos causes long-term spatial memory impairment and thigmotaxic behavior.

    PubMed

    López-Granero, Caridad; Ruiz-Muñoz, Ana M; Nieto-Escámez, Francisco A; Colomina, María T; Aschner, Michael; Sánchez-Santed, Fernando

    2016-03-01

    Little is known about the long-term effects of chronic exposure to low-level organophosphate (OP) pesticides, and the role of neurotransmitter systems, other than the cholinergic system, in mediating OP neurotoxicity. In this study, rats were administered 5mg/kg/day of chlorpyrifos (CPF) for 6 months commencing at 3-months-of-age. The animals were examined 7 months later (at 16-months-of-age) for spatial learning and memory in the Morris water maze (MWM) and locomotor activity. In addition, we assessed the chronic effects of CPF on glutamatergic and gamma-aminobutyric acid (GABAergic) function using pharmacological challenges with dizocilpine (MK801) and diazepam. Impaired performance related to altered search patterns, including thigmotaxis and long-term spatial memory was noted in the MWM in animals exposed to CPF, pointing to dietary CPF-induced behavioral disturbances, such as anxiety. Twenty-four hours after the 31st session of repeated acquisition task, 0.1mg/kg MK801, an N-methyl-d-aspartate (NMDA) antagonist was intraperitoneally (i.p.) injected for 4 consecutive days. Decreased latencies in the MWM in the control group were noted after two sessions with MK801 treatment. Once the MWM assessment was completed, animals were administered 0.1 or 0.2mg/kg of MK801 and 1 or 3mg/kg of diazepam i.p., and tested for locomotor activity. Both groups, the CPF dietary and control, displayed analogous performance in motor activity. In conclusion, our data point to a connection between the long-term spatial memory, thigmotaxic response and CPF long after the exposure ended. PMID:26748072

  10. [Activity of beta-N-acetylglucosaminidase in chronic alcoholic liver disease].

    PubMed

    Pinto, C; Galvão-Teles, A; Monteiro, E; Marques, C; Azevedo, M; Manso, C

    1990-01-01

    Serum N-acetyl-B-glucosaminidase (NAG) activity was determined in a control group of 76 normal people and in 23 patients with hepatic cirrhosis: 15 non-compensated patients and 8 with compensated chronic liver fibrosis. NAG is significantly increased in the non-compensated group--mean value of 931.67 units vs 637.71 units for the controls (p less than 0.001). There is no significant elevation regarding the compensated group. No significant correlations were observed between NAG activity and hepatic functional tests. In the follow-up of the non-compensated group, NAG activity returned to normal with the clinical improvement; in 7 cases where this goal was not achieved there was elevation of NAG activity, with higher values in photo-systemic encephalopathy. PMID:2349891

  11. [An establishment of theoretical structure of PRO questionnaire in treating chronic liver disease by Chinese medicine].

    PubMed

    Wang, Li; Zhang, Hua; Yuan, Wei-An; Wang, Yi-Xing; Tang, Jie; Cui, Chen; Zeng, Jin; Miao, Ping; Jiang, Jian

    2014-11-01

    By reviewing research contents of patient-reported outcome (PRO) and discussing Chinese medicine (CM) theories related to chronic liver disease (CLD), we have followed international PRO questionnaire development specification, combined CM theories such as uniformed spirit and body, correspondence between human and the universe, yin in property and yang in function of Gan, and seven emotions, and constructed theoretical structure of PRO questionnaire of treating CLD, including four major areas as physiology, psychology, independence, and society and nature. Of them, the physiological field contained six aspects such as blood deficiency, yin deficiency, bleeding, disorder of qi movement, improper transformation and transportation of Pi-Wei, and abnormal biliary excretion. The psychological field contained two aspects: Gan-related emotions and general disease related emotions. The independence field contained two aspects: daily life and study and work. The field of society and nature contains three aspects: social relations, social environment, and natural adaptability. PMID:25566635

  12. Novel forms of woodchuck hepatitis virus DNA isolated from chronically infected woodchuck liver nuclei.

    PubMed Central

    Rogler, C E; Summers, J

    1982-01-01

    We cloned several unique forms of woodchuck hepatitis virus, a DNA virus closely related to hepatitis B virus, from a chronically infected woodchuck liver. Each of the three clones contained more than two genome equivalents of viral sequences with extensive rearrangements and no detectable cellular sequences. From the frequency by which they were isolated from a library of recombinant clones, we estimate that they are present in approximately one copy per cell. Of a total of 11 sites at which rearrangements were mapped in the clones, 10 occurred between segments of opposite polarity, and 1 occurred between segments of the same polarity. The possible significance of these findings to the persistence of virus production in infected cells is discussed. Images PMID:6294334

  13. Acute-on-chronic liver failure: a new syndrome in cirrhosis

    PubMed Central

    Moreau, Richard

    2016-01-01

    Patients with cirrhosis who are hospitalized for an acute decompensation (AD) and also have organ failure(s) are at high risk of short-term death. These patients have a syndrome called Acute-on-Chronic Liver Failure (ACLF). ACLF is now considered as a new syndrome that it is distinct from “mere” AD not only because of the presence of organ failure(s) and high short-term mortality but also because of younger age, higher prevalence of alcoholic etiology of cirrhosis, higher prevalence of some precipitants (such as bacterial infections, active alcoholism), and more intense systemic inflammatory response. ACLF is a new syndrome also because severe sepsis or severe alcoholic hepatitis do not account for 100% of the observed cases; in fact, almost 50% of the cases are of “unknown” origin. In other words, severe sepsis, severe alcoholic hepatitis and ACLF of “unknown origin” are subcategories of the syndrome. PMID:27044760

  14. Acute-on-chronic liver failure: a new syndrome in cirrhosis.

    PubMed

    Moreau, Richard

    2016-03-01

    Patients with cirrhosis who are hospitalized for an acute decompensation (AD) and also have organ failure(s) are at high risk of short-term death. These patients have a syndrome called Acute-on-Chronic Liver Failure (ACLF). ACLF is now considered as a new syndrome that it is distinct from "mere" AD not only because of the presence of organ failure(s) and high short-term mortality but also because of younger age, higher prevalence of alcoholic etiology of cirrhosis, higher prevalence of some precipitants (such as bacterial infections, active alcoholism), and more intense systemic inflammatory response. ACLF is a new syndrome also because severe sepsis or severe alcoholic hepatitis do not account for 100% of the observed cases; in fact, almost 50% of the cases are of "unknown" origin. In other words, severe sepsis, severe alcoholic hepatitis and ACLF of "unknown origin" are subcategories of the syndrome. PMID:27044760

  15. Chronic neuroinflammation and cognitive impairment following transient global cerebral ischemia: role of fractalkine/CX3CR1 signaling

    PubMed Central

    2014-01-01

    Although neuroinflammation has been studied extensively in animal models of cerebral ischemia, their contrasting functions are still not completely understood. A major participant in neuroinflammation is microglia and microglial activation usually regulated by the chemokine CX3CL1 (fractalkine) and its receptor, CX3CR1. Here, we examined the involvement of CX3CR1 on ischemia-induced chronic neuroinflammation and cognitive function using small interfering RNA (siRNA). Forty adult male Wistar rats were included in the study and received either ischemia or sham surgery then were randomized to receive either CX3CR1 siRNA or scrambled RNA as control starting at 7 days after reperfusion. Behavioral testing commenced 28 days after siRNA delivery and all rats were euthanized after behavioral testing. Our data showed that: (i) transient global cerebral ischemia significantly decreased fractalkine/CX3CR1 signaling in the hippocampus; (ii) inhibition of CX3CR1 function exacerbated the ischemia-induced chronic increase in microglial activation and pro-inflammatory cytokine levels; (iii) inhibition of CX3CR1 function worsened ischemia-induced chronic cognitive impairment; (iv) inhibition of CX3CR1 function in sham rats resulted in increased IL-1β expression and impaired behavioral performance. However, no significant effect of CX3CR1 on ischemia-induced neurodegeneration was seen. The present study provides important insight to understanding the involvement of CX3CR1 in chronic neuroinflammation and cognitive impairment. PMID:24447880

  16. [A Case of Composite Hepatocellular Carcinoma and Neuroendocrine Carcinoma in a Patient with Liver Cirrhosis Caused by Chronic Hepatitis B].

    PubMed

    Yun, Eun Young; Kim, Tae Hyo; Lee, Sang Soo; Kim, Hong Jun; Kim, Hyun Jin; Jung, Woon Tae; Lee, Ok Jae; Song, Dae Hyun

    2016-08-25

    Primary hepatic neuroendocrine carcinoma (PHNEC) is rare and its origin is not clearly understood. The coexistence of PHNEC and hepaotcellular carcinoma has been reported in only a few cases. We report a rare case of combined PHNEC and hepaotcellular carcinoma in a patient with liver cirrhosis caused by chronic hepatitis B that resulted in aggressive behavior and poor prognosis. PMID:27554219

  17. Loss of α-catenin elicits a cholestatic response and impairs liver regeneration

    PubMed Central

    Herr, Keira Joann; Tsang, Ying-hung Nicole; Ong, Joanne Wei En; Li, Qiushi; Yap, Lai Lai; Yu, Weimiao; Yin, Hao; Bogorad, Roman L.; Dahlman, James E.; Chan, Yee Gek; Bay, Boon Huat; Singaraja, Roshni; Anderson, Daniel G.; Koteliansky, Victor; Viasnoff, Virgile; Thiery, Jean Paul

    2014-01-01

    The liver is unique in its capacity to regenerate after injury, during which hepatocytes actively divide and establish cell-cell contacts through cell adhesion complexes. Here, we demonstrate that the loss of α-catenin, a well-established adhesion component, dramatically disrupts liver regeneration. Using a partial hepatectomy model, we show that regenerated livers from α-catenin knockdown mice are grossly larger than control regenerated livers, with an increase in cell size and proliferation. This increased proliferation correlated with increased YAP activation, implicating α-catenin in the Hippo/YAP pathway. Additionally, α-catenin knockdown mice exhibited a phenotype reminiscent of clinical cholestasis, with drastically altered bile canaliculi, elevated levels of bile components and signs of jaundice and inflammation. The disrupted regenerative capacity is a result of actin cytoskeletal disorganisation, leading to a loss of apical microvilli, dilated lumens in the bile canaliculi, and leaky tight junctions. This study illuminates a novel, essential role for α-catenin in liver regeneration. PMID:25355493

  18. Usefulness of non-invasive serum markers for predicting liver fibrosis in Egyptian patients with chronic HCV infection.

    PubMed

    El Guesiry, Dalal; Moez, Pacinte; Hossam, Nermine; Kassem, Mohamed

    2011-01-01

    Accurate monitoring of liver fibrosis changes in patients with hepatitis C virus (HCV) infection would be helpful in defining the need to intervene, implement the appropriate response in treatment and to minimize the use of liver biopsy. We aimed to evaluate the diagnostic utility of the different serum markers and indices in detecting liver fibrosis in study patients. Initial liver biopsy, routine liver function tests, estimation of hyaluronic acid, MMP-1, and PIIINP levels was performed for 30 Egyptian patients with HCV and 15 controls. Marker algorithms based on common laboratory such APRI score, Fibrotest and Actitest. PIIINP and MMP-1 serum markers were combined and entered into a stepwise logistic regression analysis with formulation of a score equation for fibrosis staging. Combined PIIINP and MMP-1 yielded different cut off scores to estimate two clinically relevant fibrosis stages: "significant fibrosis" versus "extensive fibrosis. Apri score also showed AUC of 1.0 with 100 % sensitivity and specificity to exclude the presence of cirrhosis and was significantly correlated to Metavair fibrosis stage in early fibrosis. On the other hand, PIIINP, Fibrotest and acti test were significantly correlated to Metavair fibrosis stage in both early and late fibrosis. In conclusion, integrating PIIINP/MMP-1 score was able to provide reliable information about the degree of liver fibrosis in chronic hepatitis C patients using different cut-offs values. A combination of liver markers as well as its related indices is an emerging tool to differentiate early from advanced liver fibrosis in HCV patients. PMID:23082465

  19. Recent advances in managing chronic HCV infection: focus on therapy in patients with severe liver disease

    PubMed Central

    Maan, Raoel; van der Meer, Adriaan J.

    2016-01-01

    Chronic hepatitis C virus (HCV) infection still represents a major public health problem, as it is thought to be responsible for more than 350,000 deaths around the globe on a yearly basis. Fortunately, successful eradication of the virus has been associated with improved clinical outcome and reduced mortality rates. In the past few years, treatment has improved considerably by the implementation of direct-acting antivirals (DAAs). From 2014 onwards, sofosbuvir, simeprevir, daclatasvir, ledipasvir, paritaprevir, ombitasvir, and dasabuvir have been approved by the US Food and Drug Administration (FDA) and European Medicines Agency (EMA). Regimens with various combinations of these new drugs, without the use of interferon (IFN), proved to be very effective and well tolerated, even among patients with advanced liver disease. Moreover, treatment duration could be shortened to 12 weeks in the majority of patients. The high costs of these DAAs, however, limit the availability of IFN-free therapy worldwide. Even in wealthy countries, it is deemed necessary to prioritize DAA treatment in order to limit the immediate impact on the health budget. As patients with advanced liver disease are in most need of HCV clearance, many countries decided to treat those patients first. In the current review, we focus on the currently available IFN-free treatment options for patients with cirrhosis. We discuss the virological efficacy as well as the clinical relevance of these regimens among this specific patient population. PMID:27006761

  20. Current status of novel antifibrotic therapies in patients with chronic liver disease

    PubMed Central

    Cohen-Naftaly, Michal; Friedman, Scott L.

    2011-01-01

    Fibrosis accumulation is a dynamic process resulting from a wound-healing response to acute or chronic liver injury of all causes. The cascade starts with hepatocyte necrosis and apoptosis, which instigate inflammatory signaling by chemokines and cytokines, recruitment of immune cell populations, and activation of fibrogenic cells, culminating in the deposition of extracellular matrix. These key elements, along with pathways of transcriptional and epigenetic regulation, represent fertile therapeutic targets. New therapies include drugs specifically designed as antifibrotics, as well as drugs already available with well-established safety profiles, whose mechanism of action may also be antifibrotic. At the same time, the development of noninvasive fibrogenic markers, and techniques (e.g. fibroscan), as well as combined scoring systems incorporating serum and clinical features will allow improved assessment of therapy response. In aggregate, the advances in the elucidation of the biology of fibrosis, combined with improved technologies for assessment will provide a comprehensive framework for design of antifibrotics and their analysis in well-designed clinical trials. These efforts may ultimately yield success in halting the progression of, or reversing, liver fibrosis. PMID:22043231

  1. Recent advances in managing chronic HCV infection: focus on therapy in patients with severe liver disease.

    PubMed

    Maan, Raoel; van der Meer, Adriaan J

    2016-01-01

    Chronic hepatitis C virus (HCV) infection still represents a major public health problem, as it is thought to be responsible for more than 350,000 deaths around the globe on a yearly basis. Fortunately, successful eradication of the virus has been associated with improved clinical outcome and reduced mortality rates. In the past few years, treatment has improved considerably by the implementation of direct-acting antivirals (DAAs). From 2014 onwards, sofosbuvir, simeprevir, daclatasvir, ledipasvir, paritaprevir, ombitasvir, and dasabuvir have been approved by the US Food and Drug Administration (FDA) and European Medicines Agency (EMA). Regimens with various combinations of these new drugs, without the use of interferon (IFN), proved to be very effective and well tolerated, even among patients with advanced liver disease. Moreover, treatment duration could be shortened to 12 weeks in the majority of patients. The high costs of these DAAs, however, limit the availability of IFN-free therapy worldwide. Even in wealthy countries, it is deemed necessary to prioritize DAA treatment in order to limit the immediate impact on the health budget. As patients with advanced liver disease are in most need of HCV clearance, many countries decided to treat those patients first. In the current review, we focus on the currently available IFN-free treatment options for patients with cirrhosis. We discuss the virological efficacy as well as the clinical relevance of these regimens among this specific patient population. PMID:27006761

  2. Chronic Cold-Water-Induced Hypothermia Impairs Memory Retrieval and Nepeta menthoides as a Traditional "Hot" Herb Reverses the Impairment.

    PubMed

    Ahmadian-Attar, Mohammad Mahdi; Ahmadiani, Abolhassan; Kamalinejad, Mohammad; Dargahi, Leila; Mosaddegh, Mahmoud

    2014-01-01

    Iranian Traditional Medicine (ITM) describes a kind of dementia with similar signs and symptoms of Alzheimer's disease (AD). It explains the pathology of dementia with cold intemperament of the brain, which means that the brain is colder than its healthy form. ITM strategy for treatment of dementia is to heat the brain up by medical "hot" herbs. Nepeta menthoides (NM) is one of these "hot" herbs. To evaluate the veracity of ITM concept about dementia and its treatment, we first try to examine if coldness of brain can make memory impairment. If so, can NM reverse memory impairment? Rats in cold-water-induced hypothermic (CWH) groups were immersed up to the neck in 3.5 °C water, for 5 min during 14 consecutive days. As a control, rats were forced to swim in warm water at the same conditions. To eliminate the impact of forced swimming stress, a group of intact rats was also added. After last swimming in day 14, some groups received drug (100 or 500 mg/ Kg aqueous extract of NM) or vehicle via i.p. injection. Learning and memory were assessed by Morris water maze, and tau hyperphosphorylation was measured by western blotting. The results showed that CWH impairs learning and memory and induces tau hyperphosphorylation. 100 mg/Kg of NM reversed memory impairment as well as tau hyperphosphorylation. ITM theory about the relationship between brain hypothermia and dementia is in accordance with our findings. PMID:24711845

  3. PI3K-Akt1 expression and its significance in liver tissues with chronic fluorosis

    PubMed Central

    Fan, Bin; Yu, Yanni; Zhang, Ying

    2015-01-01

    This study was to explore the effect and significance of PI3K signal pathway on mechanism of liver injury in chronic fluorosis. We used 48 Sprague-Dawley rats which were randomly divided into 4 groups according to the body weight, 12 in each group, half of male and female. The control group was fed with the solid feed (the fluorine content was 1.5 mg/kg). The fluorosis animals were fed with the corn containing fluorine content of 17 mg/kg from the endemic fluorosis areas. Blocking agent LY294002 was injected in the blocking group and phosphate buffer solution was injected in the blocking control in the caudal vein with 10 mg/kg once every other day in the one week before the end of the experiment. The animals were drunk by tap water freely. The fluoride contents of urinary and skeletal were determined by the F-ion selective electrode method. The mRNA and protein expressions of PI3K, Akt1 in the liver tissues were determined by real-time polymerase chain reaction, and streptavidin-perosidase and Western blot, respectively. Results showed that fluoride contents of the urine and bone were increased in the fluorosis compared to those in the control. The expression of PI3K and Akt1 mRNA and proteins was significantly increased in fluorosis hepatocytes, and lower than that of the fluorosis in the blocking. The apoptosis and the intracellular calcium concentration were increased. Therefore, we conclude that PI3K-Akt signaling pathway may be one of the signaling pathways in the pathogenesis of liver injury caused by fluorosis. PMID:25973007

  4. PI3K-Akt1 expression and its significance in liver tissues with chronic fluorosis.

    PubMed

    Fan, Bin; Yu, Yanni; Zhang, Ying

    2015-01-01

    This study was to explore the effect and significance of PI3K signal pathway on mechanism of liver injury in chronic fluorosis. We used 48 Sprague-Dawley rats which were randomly divided into 4 groups according to the body weight, 12 in each group, half of male and female. The control group was fed with the solid feed (the fluorine content was 1.5 mg/kg). The fluorosis animals were fed with the corn containing fluorine content of 17 mg/kg from the endemic fluorosis areas. Blocking agent LY294002 was injected in the blocking group and phosphate buffer solution was injected in the blocking control in the caudal vein with 10 mg/kg once every other day in the one week before the end of the experiment. The animals were drunk by tap water freely. The fluoride contents of urinary and skeletal were determined by the F-ion selective electrode method. The mRNA and protein expressions of PI3K, Akt1 in the liver tissues were determined by real-time polymerase chain reaction, and streptavidin-perosidase and Western blot, respectively. Results showed that fluoride contents of the urine and bone were increased in the fluorosis compared to those in the control. The expression of PI3K and Akt1 mRNA and proteins was significantly increased in fluorosis hepatocytes, and lower than that of the fluorosis in the blocking. The apoptosis and the intracellular calcium concentration were increased. Therefore, we conclude that PI3K-Akt signaling pathway may be one of the signaling pathways in the pathogenesis of liver injury caused by fluorosis. PMID:25973007

  5. Chronic Liver Disease: Noninvasive Subharmonic Aided Pressure Estimation of Hepatic Venous Pressure Gradient

    PubMed Central

    Eisenbrey, John R.; Dave, Jaydev K.; Halldorsdottir, Valgerdur G.; Merton, Daniel A.; Miller, Cynthia; Gonzalez, José M.; Machado, Priscilla; Park, Suhyun; Dianis, Scott; Chalek, Carl L.; Kim, Christopher E.; Baliff, Jeffrey P.; Thomenius, Kai E.; Brown, Daniel B.; Navarro, Victor

    2013-01-01

    Purpose: To compare subharmonic aided pressure estimation (SHAPE) with pressure catheter–based measurements in human patients with chronic liver disease undergoing transjugular liver biopsy. Materials and Methods: This HIPAA-compliant study had U.S. Food and Drug Administration and institutional review board approval, and written informed consent was obtained from all participants. Forty-five patients completed this study between December 2010 and December 2011. A clinical ultrasonography (US) scanner was modified to obtain SHAPE data. After transjugular liver biopsy with pressure measurements as part of the standard of care, 45 patients received an infusion of a microbubble US contrast agent and saline. During infusion, SHAPE data were collected from a portal and hepatic vein and were compared with invasive measurements. Correlations between data sets were determined by using the Pearson correlation coefficient, and statistical significance between groups was determined by using the Student t test. Results:- The 45 study patients included 27 men and 18 women (age range, 19–71 years; average age, 55.8 years). The SHAPE gradient between the portal and hepatic veins was in good overall agreement with the hepatic venous pressure gradient (HVPG) (R = 0.82). Patients at increased risk for variceal hemorrhage (HVPG ≥ 12 mm Hg) had a significantly higher mean subharmonic gradient than patients with lower HVPGs (1.93 dB ± 0.61 [standard deviation] vs −1.47 dB ± 0.29, P < .001), with a sensitivity of 100% and a specificity of 81%, indicating that SHAPE may be a useful tool for the diagnosis of clinically important portal hypertension. Conclusion: Preliminary results show SHAPE to be an accurate noninvasive technique for estimating portal hypertension. © RSNA, 2013 Supplemental material: http://radiology.rsna.org/lookup/suppl/doi:10.1148/radiol.13121769/-/DC1 PMID:23525208

  6. Lipids changes in liver cancer*

    PubMed Central

    Jiang, Jing-ting; Xu, Ning; Zhang, Xiao-ying; Wu, Chang-ping

    2007-01-01

    Liver is one of the most important organs in energy metabolism. Most plasma apolipoproteins and endogenous lipids and lipoproteins are synthesized in the liver. It depends on the integrity of liver cellular function, which ensures homeostasis of lipid and lipoprotein metabolism. When liver cancer occurs, these processes are impaired and the plasma lipid and lipoprotein patterns may be changed. Liver cancer is the fifth common malignant tumor worldwide, and is closely related to the infections of hepatitis B virus (HBV) and hepatitis C virus (HCV). HBV and HCV infections are quite common in China and other Southeast Asian countries. In addition, liver cancer is often followed by a procession of chronic hepatitis or cirrhosis, so that hepatic function is damaged obviously on these bases, which may significantly influence lipid and lipoprotein metabolism in vivo. In this review we summarize the clinical significance of lipid and lipoprotein metabolism under liver cancer. PMID:17565510

  7. MR imaging and spectroscopy of the basal ganglia in chronic liver disease: correlation of T1-weighted contrast measurements with abnormalities in proton and phosphorus-31 MR spectra.

    PubMed

    Taylor-Robinson, S D; Sargentoni, J; Oatridge, A; Bryant, D J; Hajnal, J V; Marcus, C D; Seery, J P; Hodgson, H J; deSouza, N M

    1996-09-01

    The purpose of this study was to correlate the hyperintensity in the globus pallidus seen on T1-weighted magnetic resonance imaging (MRI) of the brain in chronic liver disease with changes in metabolite ratios measured from both proton and phosphorus-31 magnetic resonance spectroscopy (MRS) localised to the basal ganglia. T1-weighted spin echo (T1WSE) images were obtained in 21 patients with biopsy-proven cirrhosis (nine Child's grade A, eight Child's grade B and four Child's grade C). Four subjects showed no evidence of neuropsychiatric impairment on clinical, psychometric and electrophysiological testing, four showed evidence of subclinical hepatic encephalopathy and 13 had overt hepatic encephalopathy. Signal intensities of the globus pallidus and adjacent brain parenchyma were measured and contrast calculated, which correlated with the severity of the underlying liver disease, when graded according to the Pugh's score (p < 0.05). Proton MRS of the basal ganglia was performed in 12 patients and 14 healthy volunteers. Peak area ratios of choline (Cho), glutamine and glutamate (Glx) and N-acetylaspartate relative to creatine (Cr) were measured. Significant reductions in mean Cho/Cr and elevations in mean Glx/Cr ratios were observed in the patient population. Phosphorus-31 MRS of the basal ganglia was performed in the remaining nine patients and in 15 healthy volunteers. Peak area ratios of phosphomonoesters (PME), inorganic phosphate, phosphodiesters (PDE) and phosphocreatine relative to beta ATP (ATP) were then measured. Mean values of PME/ATP and PDE/ATP were significantly lower in the patient population. No correlation was found between the T1WSE MRI contrast measurements of the globus pallidus and the abnormalities in the metabolite ratios measured from either proton or phosphorus-31 MR spectra. Our results suggest that pallidal hyperintensity seen on T1WSE MR imaging of patients with chronic liver disease is not related to the functional abnormalities of the

  8. Combined prenatal and chronic postnatal vitamin D deficiency in rats impairs prepulse inhibition of acoustic startle.

    PubMed

    Burne, Thomas H J; Féron, François; Brown, Jillanne; Eyles, Darryl W; McGrath, John J; Mackay-Sim, Alan

    2004-06-01

    There is growing evidence that 1,25-dihydroxyvitamin D3 is involved in normal brain development. The aim of this study was to examine the impact of prenatal and postnatal hypovitaminosis D on prepulse inhibition (PPI) of acoustic startle in adult rats. We compared six groups of rats: control rats with normal vitamin D throughout life and normal litter size (Litter); control rats with normal vitamin D but with a reduced litter size of two (Control); offspring from reduced litters of vitamin D deplete mothers who were repleted at birth (Birth), repleted at weaning (Weaning) or remained on a deplete diet until 10 weeks of age (Life); or control rats that were placed on a vitamin D-deficient diet from 5 to 10 weeks of age (Adult). All rats were tested in acoustic startle chambers at 5 and 10 weeks of age for acoustic startle responses and for PPI. There were no significant group differences at 5 weeks of age on the acoustic startle response or on PPI. At 10 weeks of age, rats in the Life group only had impaired PPI despite having normal acoustic startle responses. We conclude that combined prenatal and chronic postnatal hypovitaminosis D, but not early life hypovitaminosis D, alters PPI. PMID:15178159

  9. Frontal Lobe Contusion in Mice Chronically Impairs Prefrontal-Dependent Behavior.

    PubMed

    Chou, Austin; Morganti, Josh M; Rosi, Susanna

    2016-01-01

    Traumatic brain injury (TBI) is a major cause of chronic disability in the world. Moderate to severe TBI often results in damage to the frontal lobe region and leads to cognitive, emotional, and social behavioral sequelae that negatively affect quality of life. More specifically, TBI patients often develop persistent deficits in social behavior, anxiety, and executive functions such as attention, mental flexibility, and task switching. These deficits are intrinsically associated with prefrontal cortex (PFC) functionality. Currently, there is a lack of analogous, behaviorally characterized TBI models for investigating frontal lobe injuries despite the prevalence of focal contusions to the frontal lobe in TBI patients. We used the controlled cortical impact (CCI) model in mice to generate a frontal lobe contusion and studied behavioral changes associated with PFC function. We found that unilateral frontal lobe contusion in mice produced long-term impairments to social recognition and reversal learning while having only a minor effect on anxiety and completely sparing rule shifting and hippocampal-dependent behavior. PMID:26964036

  10. Frontal Lobe Contusion in Mice Chronically Impairs Prefrontal-Dependent Behavior

    PubMed Central

    Rosi, Susanna

    2016-01-01

    Traumatic brain injury (TBI) is a major cause of chronic disability in the world. Moderate to severe TBI often results in damage to the frontal lobe region and leads to cognitive, emotional, and social behavioral sequelae that negatively affect quality of life. More specifically, TBI patients often develop persistent deficits in social behavior, anxiety, and executive functions such as attention, mental flexibility, and task switching. These deficits are intrinsically associated with prefrontal cortex (PFC) functionality. Currently, there is a lack of analogous, behaviorally characterized TBI models for investigating frontal lobe injuries despite the prevalence of focal contusions to the frontal lobe in TBI patients. We used the controlled cortical impact (CCI) model in mice to generate a frontal lobe contusion and studied behavioral changes associated with PFC function. We found that unilateral frontal lobe contusion in mice produced long-term impairments to social recognition and reversal learning while having only a minor effect on anxiety and completely sparing rule shifting and hippocampal-dependent behavior. PMID:26964036

  11. Rectification of impaired adipose tissue methylation status and lipolytic response contributes to hepatoprotective effect of betaine in a mouse model of alcoholic liver disease

    PubMed Central

    Dou, Xiaobing; Xia, Yongliang; Chen, Jing; Qian, Ying; Li, Songtao; Zhang, Ximei; Song, Zhenyuan

    2014-01-01

    Background and Purpose Overactive lipolysis in adipose tissue contributes to the pathogenesis of alcoholic liver disease (ALD); however, the mechanisms involved have not been elucidated. We previously reported that chronic alcohol consumption produces a hypomethylation state in adipose tissue. In this study we investigated the role of hypomethylation in adipose tissue in alcohol-induced lipolysis and whether its correction contributes to the well-established hepatoprotective effect of betaine in ALD. Experimental Approach Male C57BL/6 mice were divided into four groups and started on one of four treatments for 5 weeks: isocaloric pair-fed (PF), alcohol-fed (AF), PF supplemented with betaine (BT/AF) and AF supplemented with betaine (BT/AF). Betaine, 0.5% (w v−1), was added to the liquid diet. Both primary adipocytes and mature 3T3-L1 adipocytes were exposed to demethylation reagents and their lipolytic responses determined. Key Results Betaine alleviated alcohol-induced pathological changes in the liver and rectified the impaired methylation status in adipose tissue, concomitant with attenuating lipolysis. In adipocytes, inducing hypomethylation activated lipolysis through a mechanism involving suppression of protein phosphatase 2A (PP2A), due to hypomethylation of its catalytic subunit, leading to increased activation of hormone-sensitive lipase (HSL). In line with in vitro observations, reduced PP2A catalytic subunit methylation and activity, and enhanced HSL activation, were observed in adipose tissue of alcohol-fed mice. Betaine attenuated this alcohol-induced PP2A suppression and HSL activation. Conclusions and Implications In adipose tissue, a hypomethylation state contributes to its alcohol-induced dysfunction and an improvement in its function may contribute to the hepatoprotective effects of betaine in ALD. PMID:24819676

  12. 3'-Azido-3'-deoxythmidine uptake into isolated rat liver mitochondria and impairment of ADP/ATP translocator.

    PubMed

    Barile, M; Valenti, D; Passarella, S; Quagliariello, E

    1997-04-01

    To gain some insight into the mechanism by which 3'-azido-3'-deoxythymidine (AZT) impairs mitochondrial metabolism, [14C]AZT uptake by rat liver mitochondria (RLM) in vitro was investigated. AZT accumulated in mitochondria in a time-dependent manner and entered the mitochondrial matrix. The rate of AZT uptake into mitochondria showed a hyperbolic dependence on the drug concentration and was inhibited by mersalyl, a thiol reagent that cannot enter mitochondria, thus showing that a membrane protein is involved in AZT transport. Investigation into the capability of AZT to affect certain mitochondrial carriers demonstrated that AZT was able to impair the ADP/ATP translocator, but had no effect on Pi, dicarboxylate, tricarboxylate, or oxodicarboxylate carriers. AZT inhibited ADP/ATP antiport in either mitochondria or mitoplasts in a competitive manner with different sensitivity (Ki values were 18.3 +/- 2.9 and 70.2 +/- 5.8 microM, respectively). Consistent with this were isotopic measurements showing that AZT accumulates in the intermembrane space. AZT does not use ADP/ATP carrier to enter mitochondria, as shown by the failure of both carboxyatractyloside (CAT) to inhibit AZT transport into mitochondria and AZT to induce ATP efflux from ATP-loaded mitochondria. ADP/ATP translocator impairment by AZT as one of the biochemical processes responsible for the ATP deficiency syndrome is discussed. PMID:9174103

  13. The Developmental Potential of Oocytes is Impaired in Cattle with Liver Abnormalities

    PubMed Central

    SARENTONGLAGA, Borjigin; OGATA, Kazuko; TAGUCHI, Yoriko; KATO, Yoku; NAGAO, Yoshikazu

    2012-01-01

    Abstract Here, we investigated the effect of liver abnormality on the developmental potential of bovine oocytes. Good quality oocytes from healthy cows and from animals with a liver abnormality were matured and fertilized in vitro and then cultured to the blastocyst stage. On day 7 after fertilization, embryo cleavage and development were assessed. The concentrations of glucose, nonesterified fatty acid (NEFA), γ-glutamyl transpeptidase (γ-GTP), β-hydroxybutyrate (BHBA) and glutathione were measured in follicular fluids (FF). The proportion of good quality oocytes and the frequency of development to the blastocyst stage were lower in the liver anomaly group than those of the control group (P<0.05). The concentrations of γ-GTP and BHBA in the FF of the liver anomaly group were higher than those of the control group (P<0.05). The concentration of glutathione in the FF of the liver anomaly group was lower than that of the control group (P<0.05). Moreover, there was a negative correlation between these concentrations and the proportions of oocytes that developed to the blastocyst stage (P<0.05). Supplementation of the culture medium with γ-GTP or BHBA did not affect the rate of oocyte maturation but did cause a concentration-dependent reduction in the frequency of fertilized oocytes that developed to the blastocyst stage. Our findings indicate that the quality of oocytes and their potential for development are lower in cattle with liver disorders than those in healthy cattle; one possible cause may be the high concentration of γ-GTP and/or BHBA in their FF. PMID:23291712

  14. The developmental potential of oocytes is impaired in cattle with liver abnormalities.

    PubMed

    Sarentonglaga, Borjigin; Ogata, Kazuko; Taguchi, Yoriko; Kato, Yoku; Nagao, Yoshikazu

    2013-01-01

    Here, we investigated the effect of liver abnormality on the developmental potential of bovine oocytes. Good quality oocytes from healthy cows and from animals with a liver abnormality were matured and fertilized in vitro and then cultured to the blastocyst stage. On day 7 after fertilization, embryo cleavage and development were assessed. The concentrations of glucose, nonesterified fatty acid (NEFA), γ-glutamyl transpeptidase (γ-GTP), β-hydroxybutyrate (BHBA) and glutathione were measured in follicular fluids (FF). The proportion of good quality oocytes and the frequency of development to the blastocyst stage were lower in the liver anomaly group than those of the control group (P<0.05). The concentrations of γ-GTP and BHBA in the FF of the liver anomaly group were higher than those of the control group (P<0.05). The concentration of glutathione in the FF of the liver anomaly group was lower than that of the control group (P<0.05). Moreover, there was a negative correlation between these concentrations and the proportions of oocytes that developed to the blastocyst stage (P<0.05). Supplementation of the culture medium with γ-GTP or BHBA did not affect the rate of oocyte maturation but did cause a concentration-dependent reduction in the frequency of fertilized oocytes that developed to the blastocyst stage. Our findings indicate that the quality of oocytes and their potential for development are lower in cattle with liver disorders than those in healthy cattle; one possible cause may be the high concentration of γ-GTP and/or BHBA in their FF. PMID:23291712

  15. Impaired hepatic handling and processing of lysophosphatidylcholine in rats with liver cirrhosis

    SciTech Connect

    Angelico, M.; Alvaro, D.; Cantafora, A.; Masella, R.; Gaudio, E.; Gandin, C.; Ginanni Corradini, S.; Ariosto, F.; Riggio, O.; Capocaccia, L. )

    1991-07-01

    Lysophosphatidylcholine is a major metabolic product in the plasma and cellular turnover of phospholipids, with well-known membrane-toxic and proinflammatory properties. Because the liver plays a key role in plasma lysophosphatidylcholine removal and biotransformation and because virtually nothing is known of these processes in a diseased organ, the hepatobiliary metabolism of lysophosphatidylcholine was investigated in rats with carbon tetrachloride-induced liver cirrhosis. Twelve adult male Wistar rats with histologically confirmed cirrhosis and 8 control animals were fitted with jugular and biliary catheters and allowed to recover. The animals were kept under constant IV infusion of taurocholate (1 mumol/min). Two microcuries of sn-1{sup 14}Cpalmitoyl-lysophosphatidylcholine was administered as a single bolus. The fate of the injected radioactivity, including removal from plasma, uptake, and subcellular location in the liver and molecular and aggregative forms, was studied by combined chromatographic and radiochemical methods. Major findings were (a) that lysophosphatidylcholine has a prolonged permanence in plasma of cirrhotic rats, due both to decreased hepatic clearance and to depressed conversion into phosphatidylcholine; (b) that the rate of lysophosphatidylcholine acylation is much slower in the cirrhotic than in the normal liver, both at the microsomal and at the cytosolic level; (c) that cytosolic lysophosphatidylcholine in the cirrhotic liver, but not in the normal liver, is predominantly non-protein bound; (d) that the strict molecular selectivity of lysophosphatidylcholine acylation observed in controls is partially lost in cirrhosis; and (e) that a consistent fraction of lysophosphatidylcholine is converted into triacylglycerols in cirrhotics but not in controls.

  16. Genetic association of interleukin-6 polymorphism (-174 G/C) with chronic liver diseases and hepatocellular carcinoma.

    PubMed

    Giannitrapani, Lydia; Soresi, Maurizio; Balasus, Daniele; Licata, Anna; Montalto, Giuseppe

    2013-04-28

    Interleukin-6 (IL-6) is a pleiotropic cytokine which is expressed in many inflammatory cells in response to different types of stimuli, regulating a number of biological processes. The IL-6 gene is polymorphic in both the 5' and 3' flanking regions and more than 150 single nucleotide polymorphisms have been identified so far. Genetic polymorphisms of IL-6 may affect the outcomes of several diseases, where the presence of high levels of circulating IL-6 have been correlated to the stage and/or the progression of the disease itself. The -174 G/C polymorphism is a frequent polymorphism, that is located in the upstream regulatory region of the IL-6 gene and affects IL-6 production. However, the data in the literature on the genetic association between the -174 G/C polymorphism and some specific liver diseases characterized by different etiologies are still controversial. In particular, most of the studies are quite unanimous in describing a correlation between the presence of the high-producer genotype and a worse evolution of the chronic liver disease. This is valid for patients with hepatitis C virus (HCV)-related chronic hepatitis and liver cirrhosis and hepatocellular carcinoma (HCC) whatever the etiology. Studies in hepatitis B virus-related chronic liver diseases are not conclusive, while specific populations like non alcoholic fatty liver disease/non-alcoholic steatohepatitis, autoimmune and human immunodeficiency virus/HCV co-infected patients show a higher prevalence of the low-producer genotype, probably due to the complexity of these clinical pictures. In this direction, a systematic revision of these data should shed more light on the role of this polymorphism in chronic liver diseases and HCC. PMID:23674845

  17. Feasibility and safety of autologous bone marrow mononuclear cell transplantation in patients with advanced chronic liver disease

    PubMed Central

    Lyra, Andre Castro; Soares, Milena Botelho Pereira; da Silva, Luiz Flavio Maia; Fortes, Marcos Fraga; Silva, André Goyanna Pinheiro; Mota, Augusto César de Andrade; Oliveira, Sheilla A; Braga, Eduardo Lorens; de Carvalho, Wilson Andrade; Genser, Bernd; dos Santos, Ricardo Ribeiro; Lyra, Luiz Guilherme Costa

    2007-01-01

    AIM: To evaluate the safety and feasibility of bone marrow cell (BMC) transplantation in patients with chronic liver disease on the waiting list for liver transplantation. METHODS: Ten patients (eight males) with chronic liver disease were enrolled to receive infusion of autologous bone marrow-derived cells. Seven patients were classified as Child-Pugh B and three as Child-Pugh C. Baseline assessment included complete clinical and laboratory evaluation and abdominal MRI. Approximately 50 mL of bone marrow aspirate was prepared by centrifugation in a ficoll-hypaque gradient. At least of 100 millions of mononuclear-enriched BMCs were infused into the hepatic artery using the routine technique for arterial chemoembolization for liver tumors. Patients were followed up for adverse events up to 4 mo. RESULTS: The median age of the patients was 52 years (range 24-70 years). All patients were discharged 48 h after BMC infusion. Two patients complained of mild pain at the bone marrow needle puncture site. No other complications or specific side effects related to the procedure were observed. Bilirubin levels were lower at 1 (2.19 ± 0.9) and 4 mo (2.10 ± 1.0) after cell transplantation that baseline levels (2.78 ± 1.2). Albumin levels 4 mo after BMC infusion (3.73 ± 0.5) were higher than baseline levels (3.47 ± 0.5). International normalized ratio (INR) decreased from 1.48 (SD = 0.23) to 1.43 (SD = 0.23) one month after cell transplantation. CONCLUSION: BMC infusion into hepatic artery of patients with advanced chronic liver disease is safe and feasible. In addition, a decrease in mean serum bilirubin and INR levels and an increase in albumin levels are observed. Our data warrant further studies in order to evaluate the effect of BMC transplantation in patients with advanced chronic liver disease. PMID:17373741

  18. Comparison of collagen proportionate areas in liver fibrosis quantification between chronic hepatitis B and C.

    PubMed

    Chen, Sheng-Hung; Peng, Cheng-Yuan; Chiang, I-Ping; Lai, Hsueh-Chou; Lee, Chiung-Ju; Su, Wen-Pang; Kao, Jung-Ta; Chuang, Po-Heng

    2016-08-01

    Few studies have compared the distinct hepatic collagen morphometrics of chronic hepatitis B (CHB) and chronic hepatitis C (CHC). This study compared the discrepancies between CHB and CHC in liver fibrosis (F) quantification by using the collagen proportionate area (CPA) and liver stiffness (LS) measured with shear wave velocity (SWV).This study enrolled 274 eligible consecutive patients diagnosed with CHB (n = 137) or CHC (n = 137). Their ages ranged from 20 to 80 years (median = 50). In total, 154 patients (56.2%) were male. Participant LS was measured by using acoustic radiation force impulse elastography preceding an immediate percutaneous liver biopsy. The total proportion of the collagen stained with picrosirius red to the total tissue area was expressed as the CPA percentage, which was stratified into portal-bridging (PB) and perisinusoidal (PS) proportionate areas (PAs).Based on the METAVIR F staging system, 36 (26.3%), 36 (26.3%), 28 (20.4%), and 37 (27.0%) participants in the CHB group and 34 (24.8%), 45 (32.9%), 34 (24.8%), and 24 (17.5%) participants in the CHC group were staged as F1, F2, F3, and F4, respectively. Both the total CPAs and PBPAs were significantly (P < 0.05) higher in the CHC group than in the CHB group within all F-stratified subgroups. The SWVs were significantly (P < 0.05) higher in the CHC group than in the CHB group only within the F2, F3, and F4 subgroups. However, the PSPAs did not differ significantly between the CHC and CHB groups within all subgroups. Multiple regression analysis revealed that viral hepatitis etiology (P < 0.001), METAVIR F stages (P < 0.001), and platelet count (P = 0.007) were independent factors correlated with the CPA (R = 0.543, P < 0.001).In conclusion, both the F stage-stratified CPAs and SWVs tended to be higher in cases of CHC than in those of CHB. The type of viral hepatitis significantly affected both the CPA and SWV values. The PBPAs were more closely

  19. Comparison of collagen proportionate areas in liver fibrosis quantification between chronic hepatitis B and C

    PubMed Central

    Chen, Sheng-Hung; Peng, Cheng-Yuan; Chiang, I-Ping; Lai, Hsueh-Chou; Lee, Chiung-Ju; Su, Wen-Pang; Kao, Jung-Ta; Chuang, Po-Heng

    2016-01-01

    Abstract Few studies have compared the distinct hepatic collagen morphometrics of chronic hepatitis B (CHB) and chronic hepatitis C (CHC). This study compared the discrepancies between CHB and CHC in liver fibrosis (F) quantification by using the collagen proportionate area (CPA) and liver stiffness (LS) measured with shear wave velocity (SWV). This study enrolled 274 eligible consecutive patients diagnosed with CHB (n = 137) or CHC (n = 137). Their ages ranged from 20 to 80 years (median = 50). In total, 154 patients (56.2%) were male. Participant LS was measured by using acoustic radiation force impulse elastography preceding an immediate percutaneous liver biopsy. The total proportion of the collagen stained with picrosirius red to the total tissue area was expressed as the CPA percentage, which was stratified into portal–bridging (PB) and perisinusoidal (PS) proportionate areas (PAs). Based on the METAVIR F staging system, 36 (26.3%), 36 (26.3%), 28 (20.4%), and 37 (27.0%) participants in the CHB group and 34 (24.8%), 45 (32.9%), 34 (24.8%), and 24 (17.5%) participants in the CHC group were staged as F1, F2, F3, and F4, respectively. Both the total CPAs and PBPAs were significantly (P < 0.05) higher in the CHC group than in the CHB group within all F-stratified subgroups. The SWVs were significantly (P < 0.05) higher in the CHC group than in the CHB group only within the F2, F3, and F4 subgroups. However, the PSPAs did not differ significantly between the CHC and CHB groups within all subgroups. Multiple regression analysis revealed that viral hepatitis etiology (P < 0.001), METAVIR F stages (P < 0.001), and platelet count (P = 0.007) were independent factors correlated with the CPA (R2 = 0.543, P < 0.001). In conclusion, both the F stage-stratified CPAs and SWVs tended to be higher in cases of CHC than in those of CHB. The type of viral hepatitis significantly affected both the CPA and SWV values. The PBPAs were more

  20. Diethylcarbamazine Reduces Chronic Inflammation and Fibrosis in Carbon Tetrachloride- (CCl4-) Induced Liver Injury in Mice

    PubMed Central

    Rocha, Sura Wanessa Santos; de França, Maria Eduarda Rocha; Rodrigues, Gabriel Barros; Barbosa, Karla Patrícia Sousa; Nunes, Ana Karolina Santana; Pastor, André Filipe; Oliveira, Anne Gabrielle Vasconcelos; Oliveira, Wilma Helena; Luna, Rayana Leal Almeida; Peixoto, Christina Alves

    2014-01-01

    This study investigated the anti-inflammatory effects of DEC on the CCl4-induced hepatotoxicity in C57BL/6 mice. Chronic inflammation was induced by i.p. administration of CCl4 0.5 μL/g of body weight through two injections a week for 6 weeks. DEC (50 mg/kg) was administered by gavage for 12 days before finishing the CCl4 induction. Histological analyses of the DEC-treated group exhibited reduced inflammatory process and prevented liver necrosis and fibrosis. Immunohistochemical and immunofluorescence analyses of the DEC-treated group showed reduced COX-2, IL1β, MDA, TGF-β, and αSMA immunopositivity, besides exhibiting decreased IL1β, COX-2, NFκB, IFNγ, and TGFβ expressions in the western blot analysis. The DEC group enhanced significantly the IL-10 expression. The reduction of hepatic injury in the DEC-treated group was confirmed by the COX-2 and iNOS mRNA expression levels. Based on the results of the present study, DEC can be used as a potential anti-inflammatory drug for chronic hepatic inflammation. PMID:25374445

  1. N-acetylcysteine inhibits the upregulation of mitochondrial biogenesis genes in livers from rats fed ethanol chronically

    PubMed Central

    Caro, Andres A.; Bell, Matthew; Ejiofor, Shannon; Zurcher, Grant; Petersen, Dennis R.; Ronis, Martin J. J.

    2014-01-01

    Background Chronic ethanol administration to experimental animals induces hepatic oxidative stress and upregulates mitochondrial biogenesis. The mechanisms by which chronic ethanol upregulates mitochondrial biogenesis have not been fully explored. In this work, we hypothesized that oxidative stress is a factor that triggers mitochondrial biogenesis after chronic ethanol feeding. If our hypothesis is correct, co-administration of antioxidants should prevent upregulation of mitochondrial biogenesis genes. Methods Rats were fed an ethanol-containing diet intragastrically by total enteral nutrition for 150 days, in the absence or presence of the antioxidant N-acetylcysteine (NAC) at 1.7 g/kg/day; control rats were administered isocaloric diets where carbohydrates substituted for ethanol calories. Results Ethanol administration significantly increased hepatic oxidative stress, evidenced as decreased liver total glutathione and GSH/GSSG ratio. These effects were inhibited by co-administration of ethanol and NAC. Chronic ethanol increased the expression of mitochondrial biogenesis genes including peroxisome proliferator activated receptor gamma-coactivator-1 alpha and mitochondrial transcription factor A, and mitochondrial DNA; co-administration of ethanol and NAC prevented these effects. Chronic ethanol administration was associated with decreased mitochondrial mass, inactivation and depletion of mitochondrial complex I and complex IV, and increased hepatic mitochondrial oxidative damage, effects that were not prevented by NAC. Conclusions These results suggest that oxidative stress caused by chronic ethanol triggered the upregulation of mitochondrial biogenesis genes in rat liver, because an antioxidant such as NAC prevented both effects. Because NAC did not prevent liver mitochondrial oxidative damage, extra-mitochondrial effects of reactive oxygen species may regulate mitochondrial biogenesis. In spite of the induction of hepatic mitochondrial biogenesis genes by

  2. Deep Sequencing Reveals Novel Genetic Variants in Children with Acute Liver Failure and Tissue Evidence of Impaired Energy Metabolism

    PubMed Central

    Valencia, C. Alexander; Wang, Xinjian; Wang, Jin; Peters, Anna; Simmons, Julia R.; Moran, Molly C.; Mathur, Abhinav; Husami, Ammar; Qian, Yaping; Sheridan, Rachel; Bove, Kevin E.; Witte, David; Huang, Taosheng; Miethke, Alexander G.

    2016-01-01

    Background & Aims The etiology of acute liver failure (ALF) remains elusive in almost half of affected children. We hypothesized that inherited mitochondrial and fatty acid oxidation disorders were occult etiological factors in patients with idiopathic ALF and impaired energy metabolism. Methods Twelve patients with elevated blood molar lactate/pyruvate ratio and indeterminate etiology were selected from a retrospective cohort of 74 subjects with ALF because their fixed and frozen liver samples were available for histological, ultrastructural, molecular and biochemical analysis. Results A customized next-generation sequencing panel for 26 genes associated with mitochondrial and fatty acid oxidation defects revealed mutations and sequence variants in five subjects. Variants involved the genes ACAD9, POLG, POLG2, DGUOK, and RRM2B; the latter not previously reported in subjects with ALF. The explanted livers of the patients with heterozygous, truncating insertion mutations in RRM2B showed patchy micro- and macrovesicular steatosis, decreased mitochondrial DNA (mtDNA) content <30% of controls, and reduced respiratory chain complex activity; both patients had good post-transplant outcome. One infant with severe lactic acidosis was found to carry two heterozygous variants in ACAD9, which was associated with isolated complex I deficiency and diffuse hypergranular hepatocytes. The two subjects with heterozygous variants of unknown clinical significance in POLG and DGUOK developed ALF following drug exposure. Their hepatocytes displayed abnormal mitochondria by electron microscopy. Conclusion Targeted next generation sequencing and correlation with histological, ultrastructural and functional studies on liver tissue in children with elevated lactate/pyruvate ratio expand the spectrum of genes associated with pediatric ALF. PMID:27483465

  3. Value of the 8-oxodG/dG ratio in chronic liver inflammation of patients with hepatocellular carcinoma.

    PubMed

    Li, Pengcheng; Ramm, Grant A; Macdonald, Graeme A

    2016-08-01

    The aim of this study was to examine the role of oxidative DNA damage in chronic liver inflammation in the evolution of hepatocellular carcinoma. The accumulated data demonstrated that oxidative DNA damage and chronic liver inflammation are involved in the transformation of normal hepatocytes and their evolution towards hepatocellular carcinoma. However, the levels of 8-oxy-2'-deoxy-guanosine (8-oxodG), a biomarker of oxidative DNA damage, were overestimated and underestimated in previous reports due to various technical limitations. The current techniques are not suitable to analyze the 8-oxodG levels in the non-malignant liver tissues and tumors of hepatocellular carcinoma patients unless they are modified. Therefore, in this study, the protocols for extraction and hydrolysis of DNA were optimized using 54 samples from hepatocellular carcinoma patients with various risk factors, and the 8-oxodG and 2'-deoxyguanosine (dG) levels were measured. The patients enrolled in the study include 23 from The Princess Alexandra Hospital and The Royal Brisbane and Women's Hospitals, Brisbane, Australia, and 31 from South Africa. This study revealed that the 8-oxodG/dG ratios tended to be higher in most non-malignant liver tissues compared to hepatocellular carcinoma tissue (p=0.2887). It also appeared that the ratio was higher in non-malignant liver tissue from Southern African patients (p=0.0479), but there was no difference in the 8-oxodG/dG ratios between non-malignant liver tissues and tumors of Australian hepatocellular carcinoma patients (p=0.7722). Additionally, this study also revealed a trend for a higher 8-oxodG/dG ratio in non-malignant liver tissues compared to tumoural tissues of patients with HBV. Significant differences were not observed in the 8-oxodG/dG ratios between non-cirrhotic and cirrhotic non-malignant liver tissues. PMID:26890046

  4. Value of the 8-oxodG/dG ratio in chronic liver inflammation of patients with hepatocellular carcinoma

    PubMed Central

    Li, Pengcheng; Ramm, Grant A; Macdonald, Graeme A

    2016-01-01

    The aim of this study was to examine the role of oxidative DNA damage in chronic liver inflammation in the evolution of hepatocellular carcinoma. The accumulated data demonstrated that oxidative DNA damage and chronic liver inflammation are involved in the transformation of normal hepatocytes and their evolution towards hepatocellular carcinoma. However, the levels of 8-oxy-2′-deoxy-guanosine (8-oxodG), a biomarker of oxidative DNA damage, were overestimated and underestimated in previous reports due to various technical limitations. The current techniques are not suitable to analyze the 8-oxodG levels in the non-malignant liver tissues and tumors of hepatocellular carcinoma patients unless they are modified. Therefore, in this study, the protocols for extraction and hydrolysis of DNA were optimized using 54 samples from hepatocellular carcinoma patients with various risk factors, and the 8-oxodG and 2′-deoxyguanosine (dG) levels were measured. The patients enrolled in the study include 23 from The Princess Alexandra Hospital and The Royal Brisbane and Women's Hospitals, Brisbane, Australia, and 31 from South Africa. This study revealed that the 8-oxodG/dG ratios tended to be higher in most non-malignant liver tissues compared to hepatocellular carcinoma tissue (p=0.2887). It also appeared that the ratio was higher in non-malignant liver tissue from Southern African patients (p=0.0479), but there was no difference in the 8-oxodG/dG ratios between non-malignant liver tissues and tumors of Australian hepatocellular carcinoma patients (p=0.7722). Additionally, this study also revealed a trend for a higher 8-oxodG/dG ratio in non-malignant liver tissues compared to tumoural tissues of patients with HBV. Significant differences were not observed in the 8-oxodG/dG ratios between non-cirrhotic and cirrhotic non-malignant liver tissues. PMID:26890046

  5. Assessment of liver fibrosis with 2-D shear wave elastography in comparison to transient elastography and acoustic radiation force impulse imaging in patients with chronic liver disease.

    PubMed

    Gerber, Ludmila; Kasper, Daniela; Fitting, Daniel; Knop, Viola; Vermehren, Annika; Sprinzl, Kathrin; Hansmann, Martin L; Herrmann, Eva; Bojunga, Joerg; Albert, Joerg; Sarrazin, Christoph; Zeuzem, Stefan; Friedrich-Rust, Mireen

    2015-09-01

    Two-dimensional shear wave elastography (2-D SWE) is an ultrasound-based elastography method integrated into a conventional ultrasound machine. It can evaluate larger regions of interest and, therefore, might be better at determining the overall fibrosis distribution. The aim of this prospective study was to compare 2-D SWE with the two best evaluated liver elastography methods, transient elastography and acoustic radiation force impulse (point SWE using acoustic radiation force impulse) imaging, in the same population group. The study included 132 patients with chronic hepatopathies, in which liver stiffness was evaluated using transient elastography, acoustic radiation force impulse imaging and 2-D SWE. The reference methods were liver biopsy for the assessment of liver fibrosis (n = 101) and magnetic resonance imaging/computed tomography for the diagnosis of liver cirrhosis (n = 31). No significant difference in diagnostic accuracy, assessed as the area under the receiver operating characteristic curve (AUROC), was found between the three elastography methods (2-D SWE, transient elastography, acoustic radiation force impulse imaging) for the diagnosis of significant and advanced fibrosis and liver cirrhosis in the "per protocol" (AUROCs for fibrosis stages ≥2: 0.90, 0.95 and 0.91; for fibrosis stage [F] ≥3: 0.93, 0.95 and 0.94; for F = 4: 0.92, 0.96 and 0.92) and "intention to diagnose" cohort (AUROCs for F ≥2: 0.87, 0.92 and 0.91; for F ≥3: 0.91, 0.93 and 0.94; for F = 4: 0.88, 0.90 and 0.89). Therefore, 2-D SWE, ARFI imaging and transient elastography seem to be comparably good methods for non-invasive assessment of liver fibrosis. PMID:26116161

  6. The use of DWI to assess spleen and liver quantitative ADC changes in the detection of liver fibrosis stages in chronic viral hepatitis.

    PubMed

    Cece, Hasan; Ercan, Abdulbasit; Yıldız, Sema; Karakas, Ekrem; Karakas, Omer; Boyacı, Fatıma Nurefsan; Aydogan, Timucin; Karakas, Emel Yigit; Cullu, Nesat; Ulas, Turgay

    2013-08-01

    This study aimed to evaluate the changes in spleen and liver diffusion-weighted magnetic resonance imaging (DWI) in chronic viral hepatitis patients. The study comprised 47 patients and 30 healthy volunteers. DWIs were obtained. Apparent Diffusion Coefficient (ADC) measurements were made by transferring the images to the workstation. The measurements of value b 1000 were made from a total of five points of the liver and three points of the spleen. Liver biopsy was performed on the 47 patients. The fibrosis stages of the patients were defined according to the METAVIR scoring system. Student's t-test was used in the comparison of mean ages, liver and spleen ADC values between the patient and the control group. Kruskal-Wallis followed by Mann-Whitney U Test with Bonferroni adjustment was performed in the comparison of mean ADC values of the patients at different stages and the control group. A statistically significant difference was determined between the patient and control group in respect of liver and spleen mean ADC values (P<0.05). F3 group showed a significant difference compared to control and F1 and F4 group showed a significant difference compared to control, F1, F2 and F3 group in terms of the mean liver ADC value (P<0.01). F3 and F4 group showed a significant difference compared to control and F1 group in terms of the mean spleen ADC value (P<0.01). As a result we believe that the measurement of liver and spleen ADC values may be an indicator in the determination of the level of fibrosis. PMID:23518145

  7. Effect of chronic phenobarbitone administration on liver tumour formation in the C57BL/10J mouse.

    PubMed

    Jones, Huw B; Orton, Terry C; Lake, Brian G

    2009-06-01

    The hepatocarcinogenicity of sodium phenobarbitone (PB) was studied in male and female mice of the low spontaneous liver tumour incidence C57BL/10 J strain. Treatment with 200 and 1000 ppmPB for 1 month increased relative liver weight in both sexes, with 1000 ppmPB also producing a transient increase in replicative DNA synthesis. The treatment of male and female mice with 200 and 1000 ppm (the maximum tolerated dose) PB for 99 weeks resulted in centrilobular hypertrophy and a dose-dependent increase in relative liver weight. Altered hepatic foci were observed in both sexes given 1000 ppm PB. In male mice given 1000 ppm PB significant increases were observed in the incidence of hepatocellular adenoma and carcinoma, to 43% and 10% of the animals examined, respectively. No increase in liver tumours was observed in male mice given 200 ppm PB and in female mice given 200 and 1000 ppm PB. In summary, PB at a dose level which produces liver hypertrophy, a transient stimulation of replicative DNA synthesis and on chronic administration altered hepatic foci, three key events in the established mode of action for PB-induced rodent liver tumour formation, results in a significant increase in liver tumours in male C57BL/10 J mice. PMID:19298838

  8. Abnormal Localization of STK17A in Bile Canaliculi in Liver Allografts: An Early Sign of Chronic Rejection

    PubMed Central

    Aini, Wulamujiang; Tamaki, Keiji; Haga, Hironori; Miyagawa-Hayashino, Aya

    2015-01-01

    The biological significance of STK17A, a serine/threonine kinase, in the liver is not known. We analyzed STK17A expression in HepG2 cells and human liver tissue. Accordingly, we investigated whether STK17A could help in identifying earlier changes during the evolution of chronic rejection (CR) after liver transplantation. RT-PCR and immunofluorescence were used to analyze STK17A expression in HepG2 cells. Antibody microarray was performed using human liver samples from CR and healthy donors. Immunohistochemistry was used to verify the clinical utility of STK17A on sequential biopsies for the subsequent development of CR. A novel short isoform of STK17A was found in HepG2 cells. STK17A was localized in the nuclei and bile canaliculi in HepG2 cells and human livers. Microarray of STK17A revealed its decrease in failed liver allografts by CR. During the evolution of CR, the staining pattern of bile canalicular STK17A gradually changed from diffuse linear to focal intermittent. The focal intermittent staining pattern was observed before the definite diagnosis of CR. In conclusion, the present study was the first to find localization of STK17A in normal bile canaliculi. Abnormal expression and localization of STK17A were associated with CR of liver allografts since the early stage of the rejection process. PMID:26305096

  9. Impairment of intradimensional shift in an attentional set-shifting task in rats with chronic bilateral common carotid artery occlusion.

    PubMed

    Kim, Dong-Hee; Choi, Bo-Ryoung; Jeon, Won Kyung; Han, Jung-Soo

    2016-01-01

    Studies of rats with chronic bilateral common carotid artery occlusion (BCCAo), an animal model for vascular dementia (VaD), have reported hippocampus-dependent memory impairment and associated neuropathologies. Patients with VaD also experience attentional shifting dysfunction. However, animal models of VaD have not been used to study attentional function. Therefore, the present study examined attentional function in rats with BCCAo, using attentional set-shifting task (ASST) that required rats to choose a food-baited pot from 2 possible pots. ASST included 6 consecutive sessions including simple discrimination, compound discrimination, intradimensional shifting, extradimensional shifting, and reversals. The BCCAo rats were significantly slower at learning the intradimensional set-shifting task compared to control rats. Previous studies have demonstrated that the cingulate cortex and medial prefrontal cortex are critical to intradimensional and extradimensional set-shifting, respectively. Additionally, inflammatory responses and neuronal dysfunction were observed in rats with chronic BCCAo. In addition, OX-6 positive microglia significantly increased in the forceps minor white matter of BCCAo rats, and glutamate decarboxylase signals co-localized with NeuN were reduced in the anterior cingulate cortex of BCCAo rats, compared to control rats. Impaired neuronal and GABAergic neuronal integrity in the anterior cingulate cortex, damage to white matter, and attentional impairments observed in BCCAo rats suggest dysfunction of brain structures that are associated with attentional impairments observed in patients with VaD. PMID:26365458

  10. Chronic administration of R-flurbiprofen attenuates learning impairments in transgenic amyloid precursor protein mice

    PubMed Central

    Kukar, Thomas; Prescott, Sonya; Eriksen, Jason L; Holloway, Vallie; Murphy, M Paul; Koo, Edward H; Golde, Todd E; Nicolle, Michelle M

    2007-01-01

    Background Long-term use of non-steroidal anti-inflammatory drugs (NSAIDs) is associated with a reduced incidence of Alzheimer's disease (AD). We and others have shown that certain NSAIDs reduce secretion of Aβ42 in cell culture and animal models, and that the effect of NSAIDs on Aβ42 is independent of the inhibition of cyclooxygenase by these compounds. Since Aβ42 is hypothesized to be the initiating pathologic molecule in AD, the ability of these compounds to lower Aβ42 selectively may be associated with their protective effect. We have previously identified R-flurbiprofen (tarenflurbil) as a selective Aβ42 lowering agent with greatly reduced cyclooxygenase activity that shows promise for testing this hypothesis. In this study we report the effect of chronic R-flurbiprofen treatment on cognition and Aβ loads in Tg2576 APP mice. Results A four-month preventative treatment regimen with R-flurbiprofen (10 mg/kg/day) was administered to young Tg2576 mice prior to robust plaque or Aβ pathology. This treatment regimen improved spatial learning as assessed by the Morris water maze, indicated by an increased spatial bias during the third probe trial and an increased utilization of a place strategy to solve the water maze. These results are consistent with an improvement in hippocampal- and medial temporal lobe-dependent memory function. A modest, though not statistically significant, reduction in formic acid-soluble levels of Aβ was also observed. To determine if R-flurbiprofen could reverse cognitive deficits in Tg2576 mice where plaque pathology was already robust, a two-week therapeutic treatment was given to older Tg2576 mice with the same dose of R-flurbiprofen. This approach resulted in a significant decrease in Aβ plaque burden but no significant improvement in spatial learning. Conclusion We have found that chronic administration of R-flurbiprofen is able to attenuate spatial learning deficits if given prior to plaque deposition in Tg2576 mice. Given its

  11. Liver Gene Expression Profiles Correlate with Virus Infection and Response to Interferon Therapy in Chronic Hepatitis B Patients.

    PubMed

    Wu, Hui-Lin; Hsiao, Tzu-Hung; Chen, Pei-Jer; Wong, Siao-Han; Kao, Jia-Horng; Chen, Ding-Shinn; Lu, Jo-Yang; Lu, Tzu-Pin; Chen, Yidong; Chuang, Eric Y; Tu, Hui-Chu; Liu, Chun-Jen

    2016-01-01

    The natural course of chronic hepatitis B (CHB) infection and treatment response are determined mainly by the genomic characteristics of the individual. We investigated liver gene expression profiles to reveal the molecular basis associated with chronic hepatitis B and IFN-alpha (IFNα) treatment response in CHB patients. Expression profiles were compared between seven paired liver biopsy samples taken before and 6 months after successful IFNα treatment or between pretreatment biopsy samples of 11 IFNα responders and 11 non-responders. A total of 132 differentially up-regulated and 39 down-regulated genes were identified in the pretreated livers of CHB patients. The up-regulated genes were mainly related to cell proliferation and immune response, with IFNγ and B cell signatures significantly enriched. Lower intrahepatic HBV pregenomic RNA levels and 25 predictive genes were identified in IFNα responders. The predictive gene set in responders significantly overlapped with the up-regulated genes associated with the pretreated livers of CHB patients. The mechanisms responsible for IFNα treatment responses are different between HBV and HCV patients. HBV infection evokes significant immune responses even in chronic infection. The up-regulated genes are predictive of responsiveness to IFNα therapy, as are lower intrahepatic levels of HBV pregenomic RNA and pre-activated host immune responses. PMID:27546197

  12. Liver Gene Expression Profiles Correlate with Virus Infection and Response to Interferon Therapy in Chronic Hepatitis B Patients

    PubMed Central

    Wu, Hui-Lin; Hsiao, Tzu-Hung; Chen, Pei-Jer; Wong, Siao-Han; Kao, Jia-Horng; Chen, Ding-Shinn; Lu, Jo-Yang; Lu, Tzu-Pin; Chen, Yidong; Chuang, Eric Y.; Tu, Hui-Chu; Liu, Chun-Jen

    2016-01-01

    The natural course of chronic hepatitis B (CHB) infection and treatment response are determined mainly by the genomic characteristics of the individual. We investigated liver gene expression profiles to reveal the molecular basis associated with chronic hepatitis B and IFN-alpha (IFNα) treatment response in CHB patients. Expression profiles were compared between seven paired liver biopsy samples taken before and 6 months after successful IFNα treatment or between pretreatment biopsy samples of 11 IFNα responders and 11 non-responders. A total of 132 differentially up-regulated and 39 down-regulated genes were identified in the pretreated livers of CHB patients. The up-regulated genes were mainly related to cell proliferation and immune response, with IFNγ and B cell signatures significantly enriched. Lower intrahepatic HBV pregenomic RNA levels and 25 predictive genes were identified in IFNα responders. The predictive gene set in responders significantly overlapped with the up-regulated genes associated with the pretreated livers of CHB patients. The mechanisms responsible for IFNα treatment responses are different between HBV and HCV patients. HBV infection evokes significant immune responses even in chronic infection. The up-regulated genes are predictive of responsiveness to IFNα therapy, as are lower intrahepatic levels of HBV pregenomic RNA and pre-activated host immune responses. PMID:27546197

  13. BALB/c Mice Show Impaired Hepatic Tolerogenic Response Following AAV Gene Transfer to the Liver

    PubMed Central

    Breous, Ekaterina; Somanathan, Suryanarayan; Wilson, James M

    2010-01-01

    Following adeno-associated virus (AAV) gene transfer to the liver, both C57BL/6 and BALB/c mice show long-term expression of nonself transgene antigens along with the absence of a transgene-specific immune response. However, in this study, we report that despite the equal ability to induce T-cell tolerance to vector-encoded antigens, the underlying mechanisms are entirely different in these two strains. We have previously shown that in C57BL/6 mice, cytotoxic T lymphocyte (CTL) responses to systemic AAV-delivered antigens are suppressed by combined actions of hepatic regulatory T cells (Tregs), Kupffer cells, and hepatic suppressive cytokines. In stark contrast, our present findings reveal that such tolerogenic response is not induced in the liver of BALB/c mice systemically administered with AAV. As a result, these mice fail to suppress a transgene-specific CTL response induced by a strong immunogenic challenge and express dramatically reduced levels of AAV-encoded antigen. Interestingly, there was active B-cell tolerance to the transgene antigen, which was mediated by splenic Tregs. We conclude that lack of tolerance induction in the liver renders BALB/c mice susceptible to CTL-mediated clearance of transduced hepatocytes. PMID:20068550

  14. CHRONIC OBSTRUCTIVE PULMONARY DISEASE IS ASSOCIATED WITH MILD COGNITIVE IMPAIRMENT: THE MAYO CLINIC STUDY OF AGING

    PubMed Central

    Singh, Balwinder; Parsaik, Ajay K; Mielke, Michelle M.; Roberts, Rosebud O.; Scanlon, Paul D.; Geda, Yonas E.; Pankratz, V. Shane; Christianson, Teresa; Yawn, Barbara; Petersen, Ronald C.

    2013-01-01

    Objectives To investigate the association of chronic obstructive pulmonary disease (COPD) with mild cognitive impairment (MCI) and MCI sub-types, amnestic MCI (a-MCI) and non-amnestic MCI (na-MCI), in a population-based study of elderly. Patients and Methods Participants included 1,927 individuals, aged 70 to 89 years, enrolled in the population-based, Mayo Clinic Study of Aging. Participants were evaluated with a nurse assessment, neurological evaluation, and neuropsychological testing and the diagnosis of MCI was made according to the standardized criteria by a consensus panel. COPD was identified by the review of medical records. The study was conducted from October 1, 2004, through July 31, 2007. The associations of COPD, and disease duration with MCI, and its subtypes were evaluated using logistic regression models adjusted for potential covariates. Results Of 1,927 subjects, 288 had COPD (men vs women 17.9% vs 11.8%, p<0.001). As compared to subjects without COPD, the subjects with COPD had higher prevalence of MCI (27.1% vs 14.6%, p<0.001). The odds ratio (OR) of MCI was almost two times higher in subjects with COPD (OR =1.90, 95 %CI =1.35 – 2.65), with a similar effect in men and women. The OR for MCI increased from 1.67 (97% CI, 1.00 – 2.69) in subjects with COPD duration of ≤ 5 years to 2.08 (95% CI, 1.36 – 3.14) in subjects > 5 years. Conclusion This population-based study suggests that COPD is associated with increased odds of having MCI and its sub-types. There was a dose-response association with duration of COPD, after controlling for the potential covariates. PMID:24182702

  15. Impaired function of regulatory T-cells in patients with chronic obstructive pulmonary disease (COPD).

    PubMed

    Tan, Dino B A; Fernandez, Sonia; Price, Patricia; French, Martyn A; Thompson, Philip J; Moodley, Yuben P

    2014-12-01

    Anti-inflammatory pathways affecting chronic obstructive pulmonary disease (COPD) are poorly understood. Regulatory T-cells (Tregs) are important negative regulators of T-cell activity and hence were investigated in COPD patients in this study. We hypothesised that functional defects in Tregs may promote increased inflammation contributing to the pathogenesis of COPD. Peripheral blood mononuclear cells (PBMC) were isolated from patients with stable COPD and age-matched non-smoking controls. Treg-mediated suppression of memory non-Treg (Foxp3(-)CD45RO(+)) CD4(+) T-cell activation was analysed by comparing PBMC responses to staphylococcal enterotoxin-B (SEB) pre- and post-depletion of Tregs (CD25(+)CD127(low)CD4(+) T-cells) by fluorescence-activated cell sorting (FACS). Activation of T-cells was assessed by HLA-DR expression. Levels of secreted cytokines were measured by ELISA. Depletion of Tregs increased SEB-induced activation of Foxp3(-)CD45RO(+) CD4(+) T-cells in samples from 15/15 healthy controls (demonstrating Treg-mediated suppression) and 9/14 COPD patients (Fisher's test, p=0.017). A screen of clinical data associated a failure of Treg-mediated suppression in the remaining five COPD patients with a higher body mass index (BMI) (33-38 kg/m(2)) compared to patients with unimpaired Treg function (20-32 kg/m(2)). In conclusion, we demonstrate impaired Treg-mediated suppression of CD4(+) T-cell activation in a subset of COPD patients, all of whom had high BMI. Obesity and/or perturbed homeostasis of Treg subsets may explain this defect and therefore contribute to increased inflammation observed in COPD. PMID:25097153

  16. Chronic Stress During Adolescence Impairs and Improves Learning and Memory in Adulthood

    PubMed Central

    Chaby, Lauren E.; Cavigelli, Sonia A.; Hirrlinger, Amy M.; Lim, James; Warg, Kendall M.; Braithwaite, Victoria A.

    2015-01-01

    HIGHLIGHTS This study tested the effects of adolescent-stress on adult learning and memory.Adolescent-stressed rats had enhanced reversal learning compared to unstressed rats.Adolescent-stress exposure made working memory more vulnerable to disturbance.Adolescent-stress did not affect adult associative learning or reference memory. Exposure to acute stress can cause a myriad of cognitive impairments, but whether negative experiences continue to hinder individual as they age is not as well understood. We determined how chronic unpredictable stress during adolescence affects multiple learning and memory processes in adulthood. Using male Sprague Dawley rats, we measured learning (both associative and reversal) and memory (both reference and working) starting 110 days after completion of an adolescent-stress treatment. We found that adolescent-stress affected adult cognitive abilities in a context-dependent way. Compared to rats reared without stress, adolescent-stressed rats exhibited enhanced reversal learning, an indicator of behavioral flexibility, but showed no change in associative learning and reference memory abilities. Working memory, which in humans is thought to underpin reasoning, mathematical skills, and reading comprehension, may be enhanced by exposure to adolescent-stress. However, when adolescent-stressed animals were tested after a novel disturbance, they exhibited a 5-fold decrease in working memory performance while unstressed rats continued to exhibit a linear learning curve. These results emphasize the capacity for stress during adolescence to transform the cognitive abilities of adult animals, even after stress exposure has ceased and animals have resided in safe environments for the majority of their lifespans. PMID:26696849

  17. Impaired gastric myoelectricity in patients with chronic pancreatitis: Role of maldigestion

    PubMed Central

    Lu, Ching-Liang; Chen, Chih-Yen; Luo, Jiing-Chyuan; Chang, Full-Young; Lee, Shou-Dong; Wu, Han-Chang; Chen, JDZ

    2005-01-01

    AIM: To investigate whether gastric myoelectrical activity was impaired in patients with chronic pancreatitis (CP) and to explore the role of pancreatic enzyme in regulating gastric myoelectrical activity. METHODS: Twenty CP patients and 20 controls participated in the study. Gastric myoelectrical activity was recorded by a homemade electrogastrography (EGG) device. Two experiments were carried out. In experiment one, EGG was recorded in both controls and CP patients. While in experiment two, either pancreatic enzymes or placebo was given together with test meals. Spectral analysis was used to generate various EGG parameters. RESULTS: The control subjects, but not the CP patients, showed typically increased postprandial dominant frequency. The postprandial dominant power (DP) increment (2.24±1.13 vs 5.35±0.96 dB, P = 0.04) and the percentage of normal 2-4 cpm slow waves (63.0±3.8% vs 77.4 ±3.1%, P<0.05) were lower in CP patients when compared with the control. In the 20 CP patients, the DP increment (4.76±1.02 vs 2.53±1.20 dB, P<0.05) and the postprandial percentage of normal 2-4 cpm (74.4±2.8% vs 64.8 ±5.7%, P<0.05) were significantly higher with pancreatic enzyme replacement than the placebo. CONCLUSION: CP patients have an abnormal postprandial stomach myoelectricity showing poor response in dominant frequency/power and regularity, whereas these abnormalities are corrected after pancreatic enzyme replacement. Maldigestion is likely to be the factor leading to abnormal postprandial gastric myoelectricity of CP patients. PMID:15637747

  18. Chronic hypoxia impairs muscle function in the Drosophila model of Duchenne's muscular dystrophy (DMD).

    PubMed

    Mosqueira, Matias; Willmann, Gabriel; Ruohola-Baker, Hannele; Khurana, Tejvir S

    2010-01-01

    Duchenne's muscular dystrophy (DMD) is a severe progressive myopathy caused by mutations in the DMD gene leading to a deficiency of the dystrophin protein. Due to ongoing muscle necrosis in respiratory muscles late-stage DMD is associated with respiratory insufficiency and chronic hypoxia (CH). To understand the effects of CH on dystrophin-deficient muscle in vivo, we exposed the Drosophila model for DMD (dmDys) to CH during a 16-day ascent to the summit of Mount Denali/McKinley (6194 meters above sea level). Additionally, dmDys and wild type (WT) flies were also exposed to CH in laboratory simulations of high altitude hypoxia. Expression profiling was performed using Affymetrix GeneChips® and validated using qPCR. Hypoxic dmDys differentially expressed 1281 genes, whereas the hypoxic WT flies differentially expressed 56 genes. Interestingly, a number of genes (e.g. heat shock proteins) were discordantly regulated in response to CH between dmDys and WT. We tested the possibility that the disparate molecular responses of dystrophin-deficient tissues to CH could adversely affect muscle by performing functional assays in vivo. Normoxic and CH WT and dmDys flies were challenged with acute hypoxia and time-to-recover determined as well as subjected to climbing tests. Impaired performance was noted for CH-dmDys compared to normoxic dmDys or WT flies (rank order: Normoxic-WT ≈ CH-WT> Normoxic-dmDys> CH-dmDys). These data suggest that dystrophin-deficiency is associated with a disparate, pathological hypoxic stress response(s) and is more sensitive to hypoxia induced muscle dysfunction in vivo. We hypothesize that targeting/correcting the disparate molecular response(s) to hypoxia may offer a novel therapeutic strategy in DMD. PMID:20975992

  19. Chronic Hypoxia Impairs Muscle Function in the Drosophila Model of Duchenne's Muscular Dystrophy (DMD)

    PubMed Central

    Mosqueira, Matias; Willmann, Gabriel; Ruohola-Baker, Hannele; Khurana, Tejvir S.

    2010-01-01

    Duchenne's muscular dystrophy (DMD) is a severe progressive myopathy caused by mutations in the DMD gene leading to a deficiency of the dystrophin protein. Due to ongoing muscle necrosis in respiratory muscles late-stage DMD is associated with respiratory insufficiency and chronic hypoxia (CH). To understand the effects of CH on dystrophin-deficient muscle in vivo, we exposed the Drosophila model for DMD (dmDys) to CH during a 16-day ascent to the summit of Mount Denali/McKinley (6194 meters above sea level). Additionally, dmDys and wild type (WT) flies were also exposed to CH in laboratory simulations of high altitude hypoxia. Expression profiling was performed using Affymetrix GeneChips® and validated using qPCR. Hypoxic dmDys differentially expressed 1281 genes, whereas the hypoxic WT flies differentially expressed 56 genes. Interestingly, a number of genes (e.g. heat shock proteins) were discordantly regulated in response to CH between dmDys and WT. We tested the possibility that the disparate molecular responses of dystrophin-deficient tissues to CH could adversely affect muscle by performing functional assays in vivo. Normoxic and CH WT and dmDys flies were challenged with acute hypoxia and time-to-recover determined as well as subjected to climbing tests. Impaired performance was noted for CH-dmDys compared to normoxic dmDys or WT flies (rank order: Normoxic-WT ≈ CH-WT> Normoxic-dmDys> CH-dmDys). These data suggest that dystrophin-deficiency is associated with a disparate, pathological hypoxic stress response(s) and is more sensitive to hypoxia induced muscle dysfunction in vivo. We hypothesize that targeting/correcting the disparate molecular response(s) to hypoxia may offer a novel therapeutic strategy in DMD. PMID:20975992

  20. Chronic stress differentially affects antioxidant enzymes and modifies the acute stress response in liver of Wistar rats.

    PubMed

    Djordjevic, J; Djordjevic, A; Adzic, M; Niciforovic, A; Radojcic, M B

    2010-01-01

    Clinical reports suggest close interactions between stressors, particularly those of long duration, and liver diseases, such as hepatic inflammation, that is proposed to occur via reactive oxygen species. In the present study we have used 21-day social isolation of male Wistar rats as a model of chronic stress to investigate protein expression/activity of liver antioxidant enzymes: superoxide dismutases (SODs), catalase (CAT), glutathione peroxidase (GPx) and glutathione reductase (GLR), and protein expression of their upstream regulators: glucocorticoid receptor (GR) and nuclear factor kappa B (NFkB). We have also characterized these parameters in either naive or chronically stressed animals that were challenged by 30-min acute immobilization. We found that chronic isolation caused decrease in serum corticosterone (CORT) and blood glucose (GLU), increase in NFkB signaling, and disproportion between CuZnSOD, peroxidases (CAT, GPx) and GLR, thus promoting H2O2 accumulation and prooxidative state in liver. The overall results suggested that chronic stress exaggerated responsiveness to subsequent stressor at the level of CORT and GLU, and potentiated GLR response, but compromised the restoration of oxido-reductive balance due to irreversible alterations in MnSOD and GPx. PMID:20406049

  1. Is spleen circulation impaired in systemic sclerosis and what is the role of liver fibrosis?

    PubMed Central

    Tarantino, Giovanni; Spanò, Angelo; Loi, Gabriella; Parisi, Anna; Tarantino, Marianna; Brancaccio, Giuseppina; Gaeta, Giovanni Battista; Riccio, Antonio

    2011-01-01

    AIM: To investigate the spleen vascular involvement and the presence of liver fibrosis in a population of subjects with established systemic sclerosis (SSc). METHODS: In a cross-sectional fashion, 17 patients with SSc were compared with 18 patients suffering from hepatitis C virus (HCV)-related liver cirrhosis, grade A and B Child-Pugh classification. Eighteen non elderly subjects, apparently healthy, were used as the control group. Splenic artery resistivity index (SARI) at doppler ultraSound, transient elastography of liver and nailfold capillaroscopy were the main outcomes. RESULTS: Transient elastography values of SSc patients were similar to those of controls; 5.2 ± 1.1 vs 4.5 ± 1, (P = 0.07). Median Alanine amino transferase (ALT) concentrations of cirrhotic patients were greater than those of controls and SSc patients, i.e. 66.5 (36-89) U/L vs 29 (22-34) U/L and 31 (22-41) U/L, respectively, (P = 0.005). SARI determinations in cirrhotic patients, although significantly higher than those found in controls and SSc patients, showed some degree of overlap with SSc patients, i.e. 0.59 vs 0.52 and 0.57, respectively, (P = 0.04). Mean systolic blood pressure was significantly higher in SSc patients than in cirrhotics and controls, i.e. 142 mmHg vs 128.2 mmHg and 127 mmHg, respectively, (P = 0.005). Mean diastolic blood pressure behaved in a similar fashion, i.e. 84 mmHg vs 72.2 mmHg and 76.9 mmHg (P = 0.005). Nailfold Capillaroscopy grades and diastolic blood pressure values correlated well with SARI results. CONCLUSION: An enhanced resistivity of the splenic artery was found in patients suffering from SSc; they did not have evidence of splenomegaly as well as no liver fibrosis or any other form of liver damage. PMID:21472128

  2. [Psychometrics of the chronic liver disease questionnaire for patients with posthepatitic B cirrhosis].

    PubMed

    Hu, Xin-cai; Zhang, Hua; Lin, Yan; Zhou, Yang; Liu, Ping

    2012-08-01

    To report on the validity and reliability of the Chronic Liver Disease Questionnaire (CLDQ) for assessing subjects with posthepatitic B cirrhosis. The CLDQ was administered to 117 healthy volunteers and 297 patients with posthepatitic B cirrhosis. All posthepatic B cirrhosis patients were assessed for the Child-Pugh stage. The entire questionnaire and each individual item was analyzed for precision and reliability. Exploratory factor analysis, responsiveness, and discrimination validity were also assessed. No significant floor effects were detected, but a moderate ceiling effect (less than 30%) was found for the following subscales: abdominal symptoms (AS), activity (AC), and worry (WO). For most items, the ceiling effect was between 30% to 60%. The internal consistency (Cronbach's a) on total scale level was good (a = 0.905), and ranged from 0.442 to 0.848 for the different subscales. The correlation coefficients of the total scale with subscales were above 0.6 (P less than 0.01) for reliability. The CLDQ and subscale scores for healthy controls were higher than those for the patients (P less than 0.001), and were gradated from the patients with Child-Pugh A cirrhosis to those with Child-Pugh B or C cirrhosis. Increase in severity of liver disease was accompanied by lower scores by the CLDQ and 4 out 6 subscales. Exploratory factor analysis moderately reproduced the original factor structure. The CLDQ has good reliability, satisfactory content, responsiveness and discriminant validity, and moderate precision and construct validity. It is useful for effectively evaluating health-related quality of life and curative effect in patients with posthepatitic B cirrhosis. PMID:23207158

  3. A novel prognostic score for acute-on-chronic hepatitis B liver failure.

    PubMed

    Yi, Zhao-quan; Lu, Meng-hou; Xu, Xu-wen; Fu, Xiao-yu; Tan, De-ming

    2015-02-01

    Patients with acute-on-chronic hepatitis B liver failure (HBV-ACLF) show high morbidity and mortality. Independent prognostic predictors of short-term HBV-ACLF mortality include the Child-Turcotte-Pugh (CTP) score, the model for end-stage liver disease (MELD) score, other MELD-based indices and the dynamic changes in these indices. The aims of this study were to evaluate the existing prognostic scores in a large cohort of HBV-ACLF patients and create a new predictive model. We retrospectively reviewed 392 HBV-ACLF patients from December 2008 to November 2011 and evaluated their 3-month survival. The predictive accuracy of CTP, MELD and MELD-based indices and the dynamic changes in the MELD-related scores (Δ scoring systems) upon admission and after two weeks of treatment were compared using the area under the receiver operating characteristic (ROC) curve method. Life-threatening factors and a series of bio-clinical parameters were studied by univariate and multivariate analyses. Among the existing scores, MELD had the best predictive ability. However, our new regression model provided an area under the curve of 0.930 ± 0.0161 (95% CI: 0.869 to 0.943), which was significantly larger than that obtained with the MELD score at admission and after two weeks of treatment as well as with the dynamic changes of the MELD score (0.819, 0.921, and 0.826, respectively) (Z=3.542, P=0.0004). In a large cohort of patients retrospectively reviewed for this study, our prognostic model was superior to the MELD score and is, therefore, a promising predictor of short-term survival in patients with HBV-ACLF. PMID:25673199

  4. Lactobacillus rhamnosus GG reduces hepatic TNFα production and inflammation in chronic alcohol-induced liver injury.

    PubMed

    Wang, Yuhua; Liu, Yanlong; Kirpich, Irina; Ma, Zhenhua; Wang, Cuiling; Zhang, Min; Suttles, Jill; McClain, Craig; Feng, Wenke

    2013-09-01

    The therapeutic effects of probiotic treatment in alcoholic liver disease (ALD) have been studied in both patients and experimental animal models. Although the precise mechanisms of the pathogenesis of ALD are not fully understood, gut-derived endotoxin has been postulated to play a crucial role in hepatic inflammation. Previous studies have demonstrated that probiotic therapy reduces circulating endotoxin derived from intestinal gram-negative bacteria in ALD. In this study, we investigated the effects of probiotics on hepatic tumor necrosis factor-α (TNFα) production and inflammation in response to chronic alcohol ingestion. Mice were fed Lieber DeCarli liquid diet containing 5% alcohol for 8weeks, and Lactobacillus rhamnosus GG (LGG) was supplemented in the last 2 weeks. Eight-week alcohol feeding caused a significant increase in hepatic inflammation as shown by histological assessment and hepatic tissue myeloperoxidase activity assay. Two weeks of LGG supplementation reduced hepatic inflammation and liver injury and markedly reduced TNFα expression. Alcohol feeding increased hepatic mRNA expression of Toll-like receptors (TLRs) and CYP2E1 and decreased nuclear factor erythroid 2-related factor 2 expression. LGG supplementation attenuated these changes. Using human peripheral blood monocytes-derived macrophages, we also demonstrated that incubation with ethanol primes both lipopolysaccharide- and flagellin-induced TNFα production, and LGG culture supernatant reduced this induction in a dose-dependent manner. In addition, LGG treatment also significantly decreased alcohol-induced phosphorylation of p38 MAP kinase. In conclusion, probiotic LGG treatment reduced alcohol-induced hepatic inflammation by attenuation of TNFα production via inhibition of TLR4- and TLR5-mediated endotoxin activation. PMID:23618528

  5. [Drug-induced Cognitive Impairment].

    PubMed

    Shinohara, Moeko; Yamada, Masahito

    2016-04-01

    Elderly people are more likely than young people to develop cognitive impairments associated with medication use. One of the reasons for this is that renal and liver functions are often impaired in elderly people. Dementia and delirium (an acute confused state) are known to be associated with drug toxicity. Anticholinergic medications are common causes of both acute and chronic cognitive impairment. Psychoactive drugs, antidepressants and anticonvulsants can cause dementia and delirium. In addition, non-psychoactive drugs such as histamine H2 receptor antagonists, corticosteroids, NSAIDs (nonsteroidal anti-inflammatory agent), and cardiac medications, may cause acute or chronic cognitive impairment. Early diagnosis and withdrawal of the offending agent are essential for the prevention of drug-induced dementia and delirium. PMID:27056860

  6. Older Adults with Chronic Lung Disease Report Less Limitation Compared with Younger Adults with Similar Lung Function Impairment

    PubMed Central

    Han, Meilan K.; Thompson, Bruce; Limper, Andrew H.; Martinez, Fernando J.; Schwarz, Marvin I.; Sciurba, Frank C.; Criner, Gerald J.; Wise, Robert A.

    2015-01-01

    Rationale: Disability guidelines are often based on pulmonary function testing, but factors other than lung function influence how an individual experiences physiologic impairment. Age may impact the perception of impairment in adults with chronic lung disease. Objectives: To determine if self-report of physical functional impairment differs between older adults with chronic lung disease compared with younger adults with similar degrees of lung function impairment. Methods: The Lung Tissue Research Consortium provided data on 981 participants with chronic obstructive pulmonary disease and interstitial lung disease who were well characterized with clinical, radiological, and pathological diagnoses. We used multiple logistic regression to determine if responses to health status questions (from the Short Form-12 and St. George’s Respiratory Questionnaire) related to perception of impairment differed in older adults (age ≥ 65 yr, n = 427) compared with younger adults (age < 65 yr, n = 393). Measurements and Main Results: Pulmonary function was higher in older adults (median FEV1 %, 70) compared with younger adults (median FEV1 %, 62) (P < 0.001), whereas the median 6-minute-walk distance was similar between groups (372 m vs. 388 m, P = 0.21). After adjusting for potential confounders, older adults were less likely to report that their health limited them significantly in performing moderate activities (odds ratio [OR], 0.36; 95% confidence interval [CI], 0.22–0.58) or climbing several flights of stairs (OR, 0.51; 95% CI, 0.34–0.77). The odds of reporting that their physical health limited the kinds of activities they performed were reduced by 63% in older adults (OR, 0.37; 95% CI, 0.24–0.58), and, similarly, the odds of reporting that their health caused them to accomplish less than they would like were also lower in older adults (OR, 0.39; 95% CI, 0.25–0.60). The OR for reporting that their breathing problem stops them from doing most

  7. Liver.

    PubMed

    Kim, W R; Lake, J R; Smith, J M; Skeans, M A; Schladt, D P; Edwards, E B; Harper, A M; Wainright, J L; Snyder, J J; Israni, A K; Kasiske, B L

    2016-01-01

    The median waiting time for patients with MELD ≥ 35 decreased from 18 days in 2012 to 9 days in 2014, after implementation of the Share 35 policy in June 2013. Similarly, mortality among candidates listed with MELD ≥ 35 decreased from 366 per 100 waitlist years in 2012 to 315 in 2014. The number of new active candidates added to the pediatric liver transplant waiting list in 2014 was 655, down from a peak of 826 in 2005. The number of prevalent candidates (on the list on December 31 of the given year) continued to decline, 401 active and 173 inactive. The number of deceased donor pediatric liver transplants peaked at 542 in 2008 and was 478 in 2014. The number of living donor liver pediatric transplants was 52 in 2014; most were from donors closely related to the recipients. Graft survival continued to improve among pediatric recipients of deceased donor and living donor livers. PMID:26755264

  8. Chronic Stress Impairs α1-Adrenoceptor-Induced Endocannabinoid-Dependent Synaptic Plasticity in the Dorsal Raphe Nucleus

    PubMed Central

    Shen, Roh-Yu

    2014-01-01

    Alpha 1-adrenergic receptors (α1-ARs) control the activity of dorsal raphe nucleus (DRn) serotonin (5-HT) neurons and play crucial role in the regulation of arousal and stress homoeostasis. However, the precise role of these receptors in regulating glutamate synapses of rat DRn 5-HT neurons and whether chronic stress exposure alters such regulation remain unknown. In the present study, we examined the impact of chronic restraint stress on α1-AR-mediated regulation of glutamate synapses onto DRn 5-HT neurons. We found that, in the control condition, activation of α1-ARs induced an inward current and long-term depression (LTD) of glutamate synapses of DRn 5-HT neurons. The α1-AR LTD was initiated by postsynaptic α1-ARs but mediated by a decrease in glutamate release. The presynaptic expression of the α1-AR LTD was signaled by retrograde endocannabinoids (eCBs). Importantly, we found that chronic exposure to restraint stress profoundly reduced the magnitude of α1-AR LTD but had no effect on the amplitude of α1-AR-induced inward current. Chronic restraint stress also reduced the CB1 receptor-mediated inhibition of EPSC and the eCB-mediated depolarization-induced suppression of excitation. Collectively, these results indicate that chronic restraint stress impairs the α1-AR LTD by reducing the function of presynaptic CB1 receptors and reveal a novel mechanism by which noradrenaline controls synaptic strength and plasticity in the DRn. They also provide evidence that chronic stress impairs eCB signaling in the DRn, which may contribute, at least in part, to the dysregulation of the stress homeostasis. PMID:25355210

  9. The metabolism of menadione impairs the ability of rat liver mitochondria to take up and retain calcium.

    PubMed

    Bellomo, G; Jewell, S A; Orrenius, S

    1982-10-10

    The ability of mitochondria to take up and retain Ca2+, and thereby to effect the free intracellular concentration of this ion, is well established. More recently, it has been reported (Lehninger, A. L., Vercesi, A., and Bababunmi, E. A. (1978) Proc. Natl. Acad. Sci. U. S. A. 75, 1690-1696) that the redox state of pyridine nucleotides modulates mitochondrial Ca2+ balance, since the oxidation of mitochondrial NAD(P)H is associated with the release of Ca2+ from these organelles. The latter may be achieved by a variety of treatments including the incubation of Ca2+-loaded liver mitochondria with hydroperoxides, the metabolism of which by the glutathione peroxidase-glutathione reductase system results in NADPH consumption. The metabolism of menadione (2-methyl-1,4-naphthoquinone) by Ca2+-loaded rat liver mitochondria results in rapid oxidation and loss of pyridine nucleotides and a decrease in ATP level. It is also associated with Ca2+ release and an impaired ability of the mitochondria to take up and retain Ca2+. The effects of menadione on mitochondrial Ca2+ balance are more rapid and pronounced than those of t-butylhydroperoxide, and in contrast to those observed with the hydroperoxide, they are not abolished by pretreatment with a glutathione-depleting agent. The effects of menadione on Ca2+ homeostasis are probably initiated by NAD(P)H oxidation linked to the reduction of menadione by both NADH-ubiquinone oxidoreductase and NAD(P)H:(quinone-acceptor) oxidoreductase. PMID:7118897

  10. Serum Basal Paraoxonase 1 Activity as an Additional Liver Function Test for the Evaluation of Patients with Chronic Hepatitis

    PubMed Central

    Halappa, Chandrakanth K; Pyati, Sudharani A; Nagaraj; Wali, Vinod

    2015-01-01

    Background The diagnostic accuracy of currently available standard panel of liver function tests is not satisfactory for the reliable diagnosis of chronic liver disorders. Earlier studies have reported that serum basal paraoxonase 1 (PON1) activity measurement may add a significant contribution to the liver function tests. Aim To assess whether the measurement of serum basal paraoxonase 1 (PON1) activity would be useful as an index of liver function status in chronic hepatitis patients. Materials and Methods The study included 50 chronic hepatitis patients and 50 apparently healthy controls based on inclusion & exclusion criteria. In all the subjects, standard liver function tests were analysed by using standard methods. Basal PON1 activity was estimated using spectrophotometric method by the hydrolysis of p-nitrophenylacetate. Student t-test, Pearson’s correlation coefficient, diagnostic validity tests and ROC curve analysis were the methods used for the statistical analysis of the data. Results The serum basal PON1 activity was significantly decreased in chronic hepatitis cases when compared to controls (p< 0.001). Also basal PON1 activity was positively correlated with serum total protein and albumin, and negatively correlated with serum total bilirubin, alanine amino transferase (ALT), and alkaline phosphatase (ALP) (p< 0.001) in chronic hepatitis cases but not in healthy controls. Diagnostic validity tests showed, basal PON1 activity was a better discriminator of chronic hepatitis than total protein, albumin and ALP with sensitivity of 68%, specificity of 100%, positive predictive value of 100% and negative predictive value of 75%. ROC curve analysis demonstrated highest diagnostic accuracy for ALT (AUC = 0.999) followed by PON1 (AUC = 0.990), total bilirubin (AUC = 0.977), ALP (AUC = 0.904), total protein (AUC = 0.790) and albumin (AUC = 0.595). Conclusion Diagnostic accuracy of serum PON1 activity is better than total bilirubin, total protein, albumin and

  11. Automated morphometry provides accurate and reproducible virtual staging of liver fibrosis in chronic hepatitis C

    PubMed Central

    Calès, Paul; Chaigneau, Julien; Hunault, Gilles; Michalak, Sophie; Cavaro-Menard, Christine; Fasquel, Jean-Baptiste; Bertrais, Sandrine; Rousselet, Marie-Christine

    2015-01-01

    Background: Liver fibrosis staging provides prognostic value, although hampered by observer variability. We used digital analysis to develop diagnostic morphometric scores for significant fibrosis, cirrhosis and fibrosis staging in chronic hepatitis C. Materials and Methods: We automated the measurement of 44 classical and new morphometric descriptors. The reference was histological METAVIR fibrosis (F) staging (F0 to F4) on liver biopsies. The derivation population included 416 patients and liver biopsies ≥20 mm-length. Two validation population included 438 patients. Results: In the derivation population, the area under the receiver operating characteristic (AUROC) for clinically significant fibrosis (F stage ≥2) of a logistic score combining 5 new descriptors (stellar fibrosis area, edge linearity, bridge thickness, bridge number, nodularity) was 0.957. The AUROC for cirrhosis of 6 new descriptors (edge linearity, nodularity, portal stellar fibrosis area, portal distance, granularity, fragmentation) was 0.994. Predicted METAVIR F staging combining 8 morphometric descriptors agreed well with METAVIR F staging by pathologists: κ = 0.868. Morphometric score of clinically significant fibrosis had a higher correlation with porto-septal fibrosis area (rs = 0.835) than METAVIR F staging (rs = 0.756, P < 0.001) and the same correlations with fibrosis biomarkers, e.g., serum hyaluronate: rs = 0.484 versus rs = 0.476 for METAVIR F (P = 0.862). In the validation population, the AUROCs of clinically significant fibrosis and cirrhosis scores were, respectively: 0.893 and 0.993 in 153 patients (biopsy < 20 mm); 0.955 and 0.994 in 285 patients (biopsy ≥ 20 mm). The three morphometric diagnoses agreed with consensus expert reference as well as or better than diagnoses by first-line pathologists in 285 patients, respectively: significant fibrosis: 0.733 versus 0.733 (κ), cirrhosis: 0.900 versus 0.827, METAVIR F: 0.881 versus 0.865. Conclusion: The new automated

  12. The Synergistic Roles of the Chronic Prenatal and Offspring Stress Exposures in Impairing Offspring Learning and Memory.

    PubMed

    Tang, Wei; Cheng, Juan; Wang, Zheng-Yu; Chen, Ke-Yang; Han, Zhen-Min; Wang, Qi-Hong; Yao, Yu-You

    2016-04-23

    In Alzheimer's disease (AD), extensive experimental studies have demonstrated a negative impact of chronic stress during various stages of life (including prenatal phase) on some aspects of AD pathology. Nevertheless, presently, few studies have been involved in the learning and memory impairments, as well as neuropathology elicited by the chronic prenatal stress (CPS) and the chronic offspring stress (COS) exposures simultaneously, particularly for the adult male APPswe/PS1dE9 murine offspring. Therefore, the aim of the present study was to investigate the influence of CPS on learning and memory impairments induced by COS in 6-month-old male APPswe/PS1dE9 offspring mice and the related mechanism. Our study firstly demonstrates that 14-day exposure to CPS could exacerbate the learning and memory impairments, as well as neuropathological damages in the CA3 regions of the hippocampus and cortex neurons, which is induced by the 28-day exposure to COS in 6-month-old male APPswe/PS1dE9 offspring mice. In addition, CPS could potentiate the production of AβPP, Aβ42, and corticosterone in 6-month-old male APPswe/PS1dE9 offspring that also suffer COS. In conclusion, our novel findings strongly implicate the synergistic roles of the CPS and COS exposures in impairing offspring learning and memory. Moreover, CPS potentiating the production of Aβ42 might be mediated by glucocorticoids through increasing the expression of APP and BACE1 gene. PMID:27128656

  13. Real-time elastography as a noninvasive assessment of liver fibrosis in chronic hepatitis C Egyptian patients: a prospective study

    PubMed Central

    Mobarak, Lamiaa; Nabeel, Mohammed M.; Hassan, Ehsan; Omran, Dalia; Zakaria, Zeinab

    2016-01-01

    Background Hepatitis C virus is a worldwide problem. Noninvasive methods for liver fibrosis assessment as ultrasound-based approaches have emerged to replace liver biopsy. The aim of this study was to evaluate the diagnostic accuracy of real-time elastography (RTE) in the assessment of liver fibrosis in patients with chronic hepatitis C (CHC), compared with transient elastography and liver biopsy. Methods RTE, FibroScan and liver biopsy were performed in 50 CHC patients. In addition, aspartate aminotransferase to platelet ratio index (APRI) and routine laboratory values were included in the analysis. Results RTE was able to diagnose significant hepatic fibrosis (F ≥2) according to METAVIR scoring system at cut-off value of 2.49 with sensitivity 100%, specificity 66%, and area under the receiver-operating characteristics (AUROC) 0.8. FibroScan was able to predict significant fibrosis at cut-off value 7.5 KPa with sensitivity 88%, specificity 100%, and AUROC 0.94.APRI was able to predict significant hepatic fibrosis (F ≥2) with sensitivity 54%, specificity 80%, and AUROC 0.69. There was a significant positive correlation between the FibroScan score and RTE score (r=0.6, P=0.001). Conclusions Although FibroScan is superior in determining significant hepatic fibrosis, our data suggest that RTE may be a useful and promising noninvasive method for liver fibrosis assessment in CHC patients especially in cases with technical limitations for FibroScan. PMID:27366038

  14. Turnover Rates of Hepatic Collagen and Circulating Collagen-Associated Proteins in Humans with Chronic Liver Disease

    PubMed Central

    Li, Kelvin; Gatmaitan, Michelle; Luo, Flora; Cattin, Jerome; Nakamura, Corelle; Holmes, William E.; Angel, Thomas E.; Peters, Marion G.; Turner, Scott M.; Hellerstein, Marc K.

    2015-01-01

    Accumulation and degradation of scar tissue in fibrotic liver disease occur slowly, typically over many years. Direct measurement of fibrogenesis, the rate of scar tissue deposition, may provide valuable therapeutic and prognostic information. We describe here results from a pilot study utilizing in vivo metabolic labeling to measure the turnover rate of hepatic collagen and collagen-associated proteins in plasma for the first time in human subjects. Eight subjects with chronic liver disease were labeled with daily oral doses of 2H2O for up to 8 weeks prior to diagnostic liver biopsy and plasma collection. Tandem mass spectrometry was used to measure the abundance and fractional synthesis rate (FSR) of proteins in liver and blood. Relative protein abundance and FSR data in liver revealed marked differences among subjects. FSRs of hepatic type I and III collagen ranged from 0.2–0.6% per day (half-lives of 4 months to a year) and correlated significantly with worsening histologic fibrosis. Analysis of plasma protein turnover revealed two collagen-associated proteins, lumican and transforming growth factor beta-induced-protein (TGFBI), exhibiting FSRs that correlated significantly with FSRs of hepatic collagen. In summary, this is the first direct measurement of liver collagen turnover in vivo in humans and suggests a high rate of collagen remodeling in advanced fibrosis. In addition, the FSRs of collagen-associated proteins in plasma are measurable and may provide a novel strategy for monitoring hepatic fibrogenesis rates. PMID:25909381

  15. Cost-effectiveness of non-invasive methods for assessment and monitoring of liver fibrosis and cirrhosis in patients with chronic liver disease: systematic review and economic evaluation.

    PubMed Central

    Crossan, Catriona; Tsochatzis, Emmanuel A; Longworth, Louise; Gurusamy, Kurinchi; Davidson, Brian; Rodríguez-Perálvarez, Manuel; Mantzoukis, Konstantinos; O'Brien, Julia; Thalassinos, Evangelos; Papastergiou, Vassilios; Burroughs, Andrew

    2015-01-01

    BACKGROUND Liver biopsy is the reference standard for diagnosing the extent of fibrosis in chronic liver disease; however, it is invasive, with the potential for serious complications. Alternatives to biopsy include non-invasive liver tests (NILTs); however, the cost-effectiveness of these needs to be established. OBJECTIVE To assess the diagnostic accuracy and cost-effectiveness of NILTs in patients with chronic liver disease. DATA SOURCES We searched various databases from 1998 to April 2012, recent conference proceedings and reference lists. METHODS We included studies that assessed the diagnostic accuracy of NILTs using liver biopsy as the reference standard. Diagnostic studies were assessed using the Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) tool. Meta-analysis was conducted using the bivariate random-effects model with correlation between sensitivity and specificity (whenever possible). Decision models were used to evaluate the cost-effectiveness of the NILTs. Expected costs were estimated using a NHS perspective and health outcomes were measured as quality-adjusted life-years (QALYs). Markov models were developed to estimate long-term costs and QALYs following testing, and antiviral treatment where indicated, for chronic hepatitis B (HBV) and chronic hepatitis C (HCV). NILTs were compared with each other, sequential testing strategies, biopsy and strategies including no testing. For alcoholic liver disease (ALD), we assessed the cost-effectiveness of NILTs in the context of potentially increasing abstinence from alcohol. Owing to a lack of data and treatments specifically for fibrosis in patients with non-alcoholic fatty liver disease (NAFLD), the analysis was limited to an incremental cost per correct diagnosis. An analysis of NILTs to identify patients with cirrhosis for increased monitoring was also conducted. RESULTS Given a cost-effectiveness threshold of £20,000 per QALY, treating everyone with HCV without prior testing was cost

  16. Lack of mitochondrial topoisomerase I (TOP1mt) impairs liver regeneration

    PubMed Central

    Khiati, Salim; Baechler, Simone A.; Factor, Valentina M.; Zhang, Hongliang; Huang, Shar-yin N.; Dalla Rosa, Ilaria; Sourbier, Carole; Neckers, Leonard; Thorgeirsson, Snorri S.; Pommier, Yves

    2015-01-01

    The liver has an exceptional replicative capacity following partial hepatectomy or chemical injuries. Cellular proliferation requires increased production of energy and essential metabolites, which critically depend on the mitochondria. To determine whether Top1mt, the vertebrate mitochondrial topoisomerase, is involved in this process, we studied liver regeneration after carbon tetrachloride (CCl4) administration. TOP1mt knockout (KO) mice showed a marked reduction in regeneration and hepatocyte proliferation. The hepatic mitochondrial DNA (mtDNA) failed to increase during recovery from CCl4 exposure. Reduced glutathione was also depleted, indicating increased reactive oxygen species (ROS). Steady-state levels of ATP, O2 consumption, mtDNA, and mitochondrial mass were also reduced in primary hepatocytes from CCl4-treated KO mice. To further test whether Top1mt acted by enabling mtDNA regeneration, we tested TOP1mt KO fibroblasts and human colon carcinoma HCT116 cells and measured mtDNA after 3-d treatment with ethidium bromide. Both types of TOP1mt knockout cells showed defective mtDNA regeneration following mtDNA depletion. Our study demonstrates that Top1mt is required for normal mtDNA homeostasis and for linking mtDNA expansion with hepatocyte proliferation. PMID:26305952

  17. Serum metabolomic signatures discriminate early liver inflammation and fibrosis stages in patients with chronic hepatitis B.

    PubMed

    Huang, Haijun; Sun, Zeyu; Pan, Hongying; Chen, Meijuan; Tong, Yongxi; Zhang, Jiajie; Chen, Deying; Su, Xiaoling; Li, Lanjuan

    2016-01-01

    Chronic HBV (CHB) infected patients with intermediate necroinflammation and fibrosis are recommended to receive antiviral treatment. However, other than liver biopsy, there is a lack of sensitive and specific objective method to determine the necroinflammation and fibrosis stages in CHB patients. This study aims to identify unique serum metabolomic profile associated with histological progression in CHB patients and to develop novel metabolite biomarker panels for early CHB detection and stratification. A comprehensive metabolomic profiling method was established to compare serum samples collected from health donor (n = 67), patients with mild (G < 2 and S < 2, CHB1, n = 52) or intermediate (G ≥ 2 or S ≥ 2, CHB2, n = 36) necroinflammation and fibrosis. Multivariate models were developed to differentiate CHB1 and CHB2 from controls. A set of CHB-associated biomarkers was identified, including lysophosphatidylcholines, phosphatidylcholines, phosphatidylinositol, phosphatidylserine, and bile acid metabolism products. Stratification of CHB1 and CHB2 patients by a simple logistic index, the PIPSindex, based on phosphatidylinositol (PI) and phosphatidylserine (PS), was achieved with an AUC of 0.961, which outperformed all currently available markers. A panel of serum metabolites that differentiate health control, CHB1 and CHB2 patients has been identified. The proposed metabolomic biosignature has the potential to be used as indicator for antiviral treatment for CHB management. PMID:27498553

  18. Serum metabolomic signatures discriminate early liver inflammation and fibrosis stages in patients with chronic hepatitis B

    PubMed Central

    Huang, Haijun; Sun, Zeyu; Pan, Hongying; Chen, Meijuan; Tong, Yongxi; Zhang, Jiajie; Chen, Deying; Su, Xiaoling; Li, Lanjuan

    2016-01-01

    Chronic HBV (CHB) infected patients with intermediate necroinflammation and fibrosis are recommended to receive antiviral treatment. However, other than liver biopsy, there is a lack of sensitive and specific objective method to determine the necroinflammation and fibrosis stages in CHB patients. This study aims to identify unique serum metabolomic profile associated with histological progression in CHB patients and to develop novel metabolite biomarker panels for early CHB detection and stratification. A comprehensive metabolomic profiling method was established to compare serum samples collected from health donor (n = 67), patients with mild (G < 2 and S < 2, CHB1, n = 52) or intermediate (G ≥ 2 or S ≥ 2, CHB2, n = 36) necroinflammation and fibrosis. Multivariate models were developed to differentiate CHB1 and CHB2 from controls. A set of CHB-associated biomarkers was identified, including lysophosphatidylcholines, phosphatidylcholines, phosphatidylinositol, phosphatidylserine, and bile acid metabolism products. Stratification of CHB1 and CHB2 patients by a simple logistic index, the PIPSindex, based on phosphatidylinositol (PI) and phosphatidylserine (PS), was achieved with an AUC of 0.961, which outperformed all currently available markers. A panel of serum metabolites that differentiate health control, CHB1 and CHB2 patients has been identified. The proposed metabolomic biosignature has the potential to be used as indicator for antiviral treatment for CHB management. PMID:27498553

  19. New therapeutic aspect for carvedilol: Antifibrotic effects of carvedilol in chronic carbon tetrachloride-induced liver damage

    SciTech Connect

    Hamdy, Nadia; El-Demerdash, Ebtehal

    2012-06-15

    Portal hypertension is a common complication of chronic liver diseases associated with liver fibrosis and cirrhosis. At present, beta-blockers such as carvedilol remain the medical treatment of choice for protection against variceal bleeding and other complications. Since carvedilol has powerful antioxidant properties we assessed the potential antifibrotic effects of carvedilol and the underlying mechanisms that may add further benefits for its clinical usefulness using a chronic model of carbon tetrachloride (CCl4)-induced hepatotoxicity. Two weeks after CCl4 induction of chronic hepatotoxicity, rats were co-treated with carvedilol (10 mg/kg, orally) daily for 6 weeks. It was found that treatment of animals with carvedilol significantly counteracted the changes in liver function and histopathological lesions induced by CCl4. Also, carvedilol significantly counteracted lipid peroxidation, GSH depletion, and reduction in antioxidant enzyme activities; glutathione-S-transferase and catalase that was induced by CCl4. In addition, carvedilol ameliorated the inflammation induced by CCl4 as indicated by reducing the serum level of acute phase protein marker; alpha-2-macroglobulin and the liver expression of nuclear factor-kappa B (NF-κB). Finally, carvedilol significantly reduced liver fibrosis markers including hydroxyproline, collagen accumulation, and the expression of the hepatic stellate cell (HSC) activation marker; alpha smooth muscle actin. In conclusion, the present study provides evidences for the promising antifibrotic effects of carvedilol that can be explained by amelioration of oxidative stress through mainly, replenishment of GSH, restoration of antioxidant enzyme activities and reduction of lipid peroxides as well as amelioration of inflammation and fibrosis by decreasing collagen accumulation, acute phase protein level, NF-κB expression and finally HSC activation. -- Highlights: ► Carvedilol is a beta blocker with antioxidant and antifibrotic

  20. Interleukin-22 Promotes Proliferation of Liver Stem/Progenitor Cells in Mice and Patients with Chronic HBV Infection

    PubMed Central

    Feng, Dechun; Kong, Xiaoni; Weng, Honglei; Park, Ogyi; Wang, Hua; Dooley, Steven; Gershwin, M. Eric; Gao, Bin

    2012-01-01

    Background & Aims Proliferation of liver stem/progenitor cells (LPCs), which can differentiate into hepatocytes or biliary epithelial cells, is often observed in chronically inflamed regions of liver in patients. We investigated how inflammation might promote proliferation of LPCs. Methods We examined the role of interleukin (IL)-22, a survival factor for hepatocytes, on proliferation of LPCs in patients with chronic hepatitis B virus (HBV) infection and in mice. Proliferation of LPCs in mice was induced by feeding a diet that contained 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC). Results Hepatic expression of IL-22 was increased in patients with HBV and correlated with the grade of inflammation and proliferation of LPCs. Mice on the DDC diet that overexpressed an IL-22 transgene specifically in liver (IL-22TG), or that were infected with an IL-22–expressing adenovirus, had increased proliferation of LPCs. Signal transducer and activator of transcription (STAT) 3, a component of the IL-22 signaling pathway, was activated in LPCs isolated from DDC-fed IL-22TG mice. Deletion of STAT3 from livers of IL-22TG mice reduced proliferation of LPCs. Moreover, the receptors IL-22R1 and IL-10R2 were detected on EpCAM+CD45– LPCs isolated from DDC-fed wild-type mice. Culture of these cells with IL-22 activated STAT3 and led to cell proliferation, but IL-22 had no effect on proliferation of STAT3-deficient EpCAM+CD45– LPCs. IL-22 also activated STAT3 and promoted proliferation of cultured BMOL cells (a mouse LPC line). Conclusion In livers of mice and patients with chronic HBV infection, inflammatory cells produce IL-22, which promotes proliferation of LPCs via STAT3. These findings link inflammation with proliferation of LPCs in patients with HBV infection. PMID:22484119

  1. Differential Regulation of TGF-β/Smad Signaling in Hepatic Stellate Cells between Acute and Chronic Liver Injuries.

    PubMed

    Yoshida, Katsunori; Matsuzaki, Koichi

    2012-01-01

    Current evidence suggests that regulation of extracellular matrix (ECM) accumulation by fibrogenic transforming growth factor (TGF)-β and platelet-derived growth factor (PDGF) signals involves different mechanisms in acute and chronic liver injuries, even though hepatic stellate cells (HSC) are the principal effecter in both cases. As a result of chronic liver damage, HSC undergo progressive activation to become myofibroblasts (MFB)-like cells. Our current review will discuss the differential regulation of TGF-β signaling between HSC and MFB in vitro and in vivo. Smad proteins, which convey signals from TGF-β receptors to the nucleus, have intermediate linker regions between conserved Mad-homology (MH) 1 and MH2 domains. TGF-β type I receptor and Ras-associated kinases differentially phosphorylate Smad2 and Smad3 to create COOH-terminally (C), linker (L), or dually (L/C) phosphorylated (p) isoforms. After acute liver injury, TGF-β and PDGF synergistically promote collagen synthesis in the activated HSC via pSmad2L/C and pSmad3L/C pathways. To avoid unlimited ECM deposition, Smad7 induced by TGF-β negatively regulates the fibrogenic TGF-β signaling. In contrast, TGF-β and PDGF can transmit the fibrogenic pSmad2L/C and mitogenic pSmad3L signals in MFB throughout chronic liver injury, because Smad7 cannot be induced by the pSmad3L pathway. This lack of Smad7 induction might lead to constitutive fibrogenesis in MFB, which eventually develop into accelerated liver fibrosis. PMID:22457652

  2. Hepatocellular expression of a novel glycoprotein with sialylated difucosyl Lex activity in the active inflammatory lesions of chronic liver disease.

    PubMed Central

    Okada, Y.; Shimoe, T.; Muguruma, M.; Usumoto, R.; Tsuji, T.; Jinno, K.; Moriwaki, S.; Shin, S.; Hakomori, S.

    1988-01-01

    Hepatic expression of sialylated difucosyl Lex antigen (SDLex, NeuAc alpha 2-3Gal beta 1-4(Fuc alpha 1-3)GlcNAc beta 1-3Gal beta 1-4(Fuc alpha 1-3)GlcNAc beta 1-) was studied with monoclonal antibody FH6, which defines this structure. Hepatocytes in the severe form of chronic active hepatitis and liver cirrhosis strongly expressed SDLex. The antigen was only weakly and focally detected in chronic persistent hepatitis. The mild form of chronic active hepatitis showed intermediate expression. SDLex expressed along the liver cell membranes displayed a honeycomb pattern when extensively expressed in the severe form of chronic active hepatitis or in liver cirrhosis. Cytoplasmic expression was faint and focal. Preferential tissue distribution was at the periphery of the hepatic lobules where the distruction of the limiting plate was present. The antigen was also expressed in sinusoidal lining cells and polymorphonuclear cells but not in the biliary epithelia. Hepatocytes expressing SDLex did not express related carbohydrate antigens, ie, Type 2 chain N-acetyllactosamine, Lex, and sialylated Lea. On subcellular fractionation, the microsome fraction contained the majority of the antigen activity. SDS-PAGE and Western blot analysis revealed one major SDLex-active glycoprotein with an apparent molecular weight of 110 kilodaltons. This glycoprotein was different from SDLex-active glycoproteins found in the sera of cancer patients. No ganglioside showed FH6 reactivity. These results indicate that liver cells in active inflammatory lesion expressed a novel glycoprotein carrying SDLex antigen in honeycomblike membrane-associated pattern. Images Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 PMID:3341453

  3. Effect of chronic alcohol consumption on the development and progression of non-alcoholic fatty liver disease (NAFLD)

    PubMed Central

    Mueller, Sebastian; Hellerbrand, Claus; Liangpunsakul, Suthat

    2015-01-01

    A number of epidemiologic studies show a protective effect of light to moderate daily alcohol consumption on the development of non-alcoholic fatty liver disease (NAFLD). Although these small amounts of ethanol may prevent fatty liver, they may also be a risk factor for other diseases such as breast and colon cancer. Those individuals who have underlying hepatic steatosis or non-alcoholic steatohepatitis (NASH) should not use ethanol chronically since the data available at present do not support a beneficial effect of alcohol in this situation. Especially overweight and obese individuals may be more susceptible towards alcohol even at moderate doses. Animal experiments show a negative effect of ethanol on liver histology in either dietary or genetic NASH models. In addition, patients with NASH reveal a significant increased risk for hepatocellular cancer (HCC) even with social alcohol consumption. Thus, subjects with underlying NASH should abstain from alcohol at any amounts. PMID:26151054

  4. [Asymptomatic chronic intrahepatic cholestasis and multiple hypodense nodules in the liver and the spleen: manifestations of a case of sarcoidosis].

    PubMed

    Guilarte López-Mañas, J; Bellot García, V; Gallego Rojo, F J; Casado Caballero, F J; Ardoy Ibáñez, F M; Ortego Centeno, N; Caballero Plasencia, A M

    1996-01-01

    Sarcoidosis is a systemic granulomatous disease of unknown etiology which may present multiple clinical manifestations. Liver involvement is observed among 21-79% of the cases. Nonetheless, hepatic sarcoidosis is usually asymptomatic and the finding of cholestasis is an infrequent complication. In the last few years, the presence of multiple hypodense nodules in the liver and spleen has been described in 5-15% of these patients following the application of dynamic intravenous techniques in abdominal CT scan. Although the histopathologic study of these nodules suggests that their formation is due to the coalescence of the microscopic granulomas, the cause of this aggregation remains unknown. A case of hepatic sarcoidosis presenting chronic cholestasis and whose abdominal tomographic study with intravenous contrast demonstrated the existence of hypodense lesions in the liver and spleen suggesting malignant disseminated disease is reported. PMID:8963906

  5. Human peripheral blood CD34-positive cells enhance therapeutic regeneration of chronically injured liver in nude rats.

    PubMed

    Nakamura, Toru; Tsutsumi, Victor; Torimura, Takuji; Naitou, Masako; Iwamoto, Hideki; Masuda, Hiroshi; Hashimoto, Osamu; Koga, Hironori; Abe, Mitsuhiko; Ii, Masaaki; Kawamoto, Atsuhiko; Asahara, Takayuki; Ueno, Takato; Sata, Michio

    2012-04-01

    We investigated whether transplantation of purified human peripheral blood CD34(+) cells could reduce established liver fibrosis and up-regulate therapeutic regeneration. Human peripheral blood CD34(+) cells were isolated from total mononuclear cells of healthy volunteers by magnetic cell sorting. Recipient nude rats were injected intraperitoneally with carbon tetrachloride (CCl(4)) twice weekly for 3 weeks before single administration of CD34(+) cells. CCl(4) was then re-administered twice weekly for 3 more weeks, and the nude rats were sacrificed. Saline (control group), 1 × 10(5) (low-dose group), 5 × 10(5) (middle-dose group), or 2 × 10(6) (high-dose group) CD34(+) cells/kg body weight were intrasplenically transplanted after CCl(4) treatment for 3 weeks. Reverse transcriptase-polymerase chain reaction analysis of the freshly isolated CD34(+) cells revealed the expression of CD31, keratin19, α-smooth muscle actin (α-SMA), and epithelial growth factor, but not other liver related markers. The transplanted cells differentiated into vascular and sinusoidal endothelial cells, and vascular smooth muscle cells. CD34(+) cell transplantation reduced liver fibrosis in a dose-dependent fashion, with decreased collagen type-I and α-SMA-positive cells after 6 weeks of CCl(4) treatment by Mallory's Azan and immunohistochemical staining. Gelatin zymography showed that the expression levels of active matrix metalloproteinase-2 and -9 in CD34(+) cell transplanted livers were significantly stronger than those in saline-infused livers. In recipients of high-doses of CD34(+) cells, the number of PCNA-positive hepatocyte increased 6 weeks after CCl(4) treatment compared with saline-infused livers. We conclude that human peripheral blood CD34(+) cell transplantation halts established liver fibrosis and promotes hepatic regeneration in CCl(4)-induced chronic liver injury. PMID:21678408

  6. An empirical investigation of the 'Biopsychosocial Disease Consequence model': psychological impairment, disability and handicap in chronic pain patients.

    PubMed

    Talo, S; Rytökoski, U; Puukka, P; Alanen, E; Niitsuo, L; Hämäläinen, A; Vaara, M; Tuomaala, M

    1995-01-01

    The purpose of this study is to emphasize the meaningfulness of a global, functional rather than a narrow medical view in the efficacy evaluation of chronic pain treatment. Therefore, the 'Biopsychosocial Disease Consequence (BPSDC) model' to assess function more globally than before, is presented in this article. The model is based on two theories: (1) the biopsychosocial approach and (2) WHO's classification of impairments, disabilities and handicaps. In addition to the presentation of the conceptual model, the development of the hypothetical criteria and assessment models for psychological impairments, disabilities and handicaps, and the validity testing of the psychological assessment axis are described. Within each of the three classes, i.e. psychological impairments, disabilities and handicaps, the results supported the independence of the hypothetical criteria from each other. On the other hand, results suggested that some changes to the hypothetical assessment models for some of the criteria might be valuable. It was concluded that although the most adequate psychological assessment models for function, found in this study, can be considered as robust and recommendable as one set of tools for functional assessment, the main aim of this article is to encourage multidisciplinary team efforts to develop and systematize the assessment procedures of function in patients suffering from chronic diseases. PMID:7579478

  7. A Prospective Study of Chronic Obstructive Pulmonary Disease and Risk of Mild Cognitive Impairment

    PubMed Central

    Singh, Balwinder; Mielke, Michelle M.; Parsaik, Ajay K; Cha, Ruth H.; Roberts, Rosebud O.; Scanlon, Paul D.; Geda, Yonas E.; Christianson, Teresa J.; Pankratz, V. Shane; Petersen, Ronald C.

    2014-01-01

    BACKGROUND Previous studies suggest cross-sectional associations between a diagnosis of chronic obstructive pulmonary disease (COPD) and mild cognitive impairment (MCI). However, few studies have assessed whether COPD, a potentially modifiable factor, is associated with an increased risk of MCI and if the relation is specific to type of MCI. OBJECTIVE To investigate whether a diagnosis of COPD, and COPD duration, is associated with an increased risk of incident MCI, and MCI subtypes (amnestic MCI (a-MCI) and non-amnestic MCI (na-MCI)). DESIGN Mayo Clinic Study on Aging, a prospective population-based cohort study. SETTING Olmsted County, Minnesota. PARTICIPANTS The study included 1425 cognitively normal individuals aged 70–89 years, who were randomly selected from Olmsted County, MN, on October 1, 2004, using the medical records linkage system. METHODS At baseline and every 15 months thereafter, participants were assessed with a nurse interview, neurological examination, and neuropsychological testing. A diagnosis of COPD was confirmed via medical record chart review. A baseline diagnosis of COPD and disease duration were examined as risk factors for MCI and MCI-subtypes using Cox proportional hazards models and adjusting for demographic variables and medical comorbidities, using age as the time scale. MAIN OUTCOME MEASURES Incident MCI, amnestic MCI, non-amnestic MCI RESULTS Of 1425 cognitively normal subjects at baseline, 370 developed incident MCI. The median duration of follow-up was 5.1 years (Interquartile Range [IQR], 3.8–5.4 years). COPD significantly increased the risk of na-MCI by 83% (HR 1.83; 95% CI, 1.04–3.23), but not any MCI or a-MCI in multivariate analyses. There was a dose-response relationship such that individuals with COPD duration of 5 years or longer at baseline had the greatest risk of both MCI (HR 1.58, 95% CI:1.04, 2.40) and na-MCI (HR 2.58, 95% CI:1.32–5.06). CONCLUSIONS AND RELEVANCE COPD was associated with an increased risk of

  8. Impaired motor preparation and execution during standing reach in people with chronic stroke.

    PubMed

    McCombe Waller, Sandy; Yang, Chieh-Ling; Magder, Laurence; Yungher, Don; Gray, Vicki; Rogers, Mark W

    2016-09-01

    Movement preparation of both anticipatory postural adjustments (APAs) and goal directed movement during a standing reaching task in adults with chronic hemiparesis and healthy controls was investigated. Using a simple reaction time paradigm, while standing on two separate force platforms, subjects received a warning light cue to "get ready to reach" followed 2.5s later by an imperative light cue to "reach as quickly as possible" with the paretic arm (matched arm for controls) to touch a target in front of them for a total of 90 trials. In 30 of the reaching trials a loud acoustic stimulus (LAS) of 123 dB was randomly - -200, or 0ms relative to the "go" cue. APA (postural) responses were characterized by the onset and maximal posterior displacement of center of pressure (CoP) and onset/offset of electromyography (EMG) from tibialis anterior (TA), soleus (SOL), while reach was characterized by onset and maximal forward displacement of the reach hand and onset of the anterior (AD), biceps brachii (BB) and middle deltoid (MD). Subjects with stroke, demonstrated a marked reduction in the occurrence of the StartReact responses for both APA and forward reach at all LAS time points indicating movement preparation dysfunction. Movement execution during a cued reach showed significant delays in APA and reach onsets, significant reduction in the magnitude of APA (posterior CoP displacement) and reach excursion, and an increased latency between the APA and reach compared to controls. EMG activation patterns for the TA and SOL demonstrated co contraction compared to the temporally sequenced pattern of control subjects. When LAS was provided at the "go" there were earlier but not significant differences in APA onset latency compared to reaching without LAS and significant delays in reach onset latency when compared to control subjects with or without LAS. An early burst of EMG in biceps brachii muscles with a further delay of the reach onset compared to reaching without LAS may

  9. HIV Impairs Lung Epithelial Integrity and Enters the Epithelium to Promote Chronic Lung Inflammation

    PubMed Central

    Ferreira, Fernanda; Mandke, Pooja; Chau, Eric; Aggarwal, Neil R.; D’Alessio, Franco R.; Lambert, Allison A.; Kirk, Gregory; Blankson, Joel; Drummond, M. Bradley; Tsibris, Athe M.

    2016-01-01

    Several clinical studies show that individuals with HIV are at an increased risk for worsened lung function and for the development of COPD, although the mechanism underlying this increased susceptibility is poorly understood. The airway epithelium, situated at the interface between the external environment and the lung parenchyma, acts as a physical and immunological barrier that secretes mucins and cytokines in response to noxious stimuli which can contribute to the pathobiology of chronic obstructive pulmonary disease (COPD). We sought to determine the effects of HIV on the lung epithelium. We grew primary normal human bronchial epithelial (NHBE) cells and primary lung epithelial cells isolated from bronchial brushings of patients to confluence and allowed them to differentiate at an air- liquid interface (ALI) to assess the effects of HIV on the lung epithelium. We assessed changes in monolayer permeability as well as the expression of E-cadherin and inflammatory modulators to determine the effect of HIV on the lung epithelium. We measured E-cadherin protein abundance in patients with HIV compared to normal controls. Cell associated HIV RNA and DNA were quantified and the p24 viral antigen was measured in culture supernatant. Surprisingly, X4, not R5, tropic virus decreased expression of E-cadherin and increased monolayer permeability. While there was some transcriptional regulation of E-cadherin, there was significant increase in lysosome-mediated protein degradation in cells exposed to X4 tropic HIV. Interaction with CXCR4 and viral fusion with the epithelial cell were required to induce the epithelial changes. X4 tropic virus was able to enter the airway epithelial cells but not replicate in these cells, while R5 tropic viruses did not enter the epithelial cells. Significantly, X4 tropic HIV induced the expression of intercellular adhesion molecule-1 (ICAM-1) and activated extracellular signal-regulated kinase (ERK). We demonstrate that HIV can enter airway

  10. HIV Impairs Lung Epithelial Integrity and Enters the Epithelium to Promote Chronic Lung Inflammation.

    PubMed

    Brune, Kieran A; Ferreira, Fernanda; Mandke, Pooja; Chau, Eric; Aggarwal, Neil R; D'Alessio, Franco R; Lambert, Allison A; Kirk, Gregory; Blankson, Joel; Drummond, M Bradley; Tsibris, Athe M; Sidhaye, Venkataramana K

    2016-01-01

    Several clinical studies show that individuals with HIV are at an increased risk for worsened lung function and for the development of COPD, although the mechanism underlying this increased susceptibility is poorly understood. The airway epithelium, situated at the interface between the external environment and the lung parenchyma, acts as a physical and immunological barrier that secretes mucins and cytokines in response to noxious stimuli which can contribute to the pathobiology of chronic obstructive pulmonary disease (COPD). We sought to determine the effects of HIV on the lung epithelium. We grew primary normal human bronchial epithelial (NHBE) cells and primary lung epithelial cells isolated from bronchial brushings of patients to confluence and allowed them to differentiate at an air- liquid interface (ALI) to assess the effects of HIV on the lung epithelium. We assessed changes in monolayer permeability as well as the expression of E-cadherin and inflammatory modulators to determine the effect of HIV on the lung epithelium. We measured E-cadherin protein abundance in patients with HIV compared to normal controls. Cell associated HIV RNA and DNA were quantified and the p24 viral antigen was measured in culture supernatant. Surprisingly, X4, not R5, tropic virus decreased expression of E-cadherin and increased monolayer permeability. While there was some transcriptional regulation of E-cadherin, there was significant increase in lysosome-mediated protein degradation in cells exposed to X4 tropic HIV. Interaction with CXCR4 and viral fusion with the epithelial cell were required to induce the epithelial changes. X4 tropic virus was able to enter the airway epithelial cells but not replicate in these cells, while R5 tropic viruses did not enter the epithelial cells. Significantly, X4 tropic HIV induced the expression of intercellular adhesion molecule-1 (ICAM-1) and activated extracellular signal-regulated kinase (ERK). We demonstrate that HIV can enter airway

  11. Percutaneous Transsplenic Access to the Portal Vein for Management of Vascular Complication in Patients with Chronic Liver Disease

    SciTech Connect

    Chu, Hee Ho; Kim, Hyo-Cheol Jae, Hwan Jun; Yi, Nam-Joon; Lee, Kwang-Woong; Suh, Kyung-Suk; Chung, Jin Wook; Park, Jae Hyung

    2012-12-15

    Purpose: To evaluate the safety and feasibility of percutaneous transsplenic access to the portal vein for management of vascular complication in patients with chronic liver diseases. Methods: Between Sept 2009 and April 2011, percutaneous transsplenic access to the portal vein was attempted in nine patients with chronic liver disease. Splenic vein puncture was performed under ultrasonographic guidance with a Chiba needle, followed by introduction of a 4 to 9F sheath. Four patients with hematemesis or hematochezia underwent variceal embolization. Another two patients underwent portosystemic shunt embolization in order to improve portal venous blood flow. Portal vein recanalization was attempted in three patients with a transplanted liver. The percutaneous transsplenic access site was closed using coils and glue. Results: Percutaneous transsplenic splenic vein catheterization was performed successfully in all patients. Gastric or jejunal varix embolization with glue and lipiodol mixture was performed successfully in four patients. In two patients with a massive portosystemic shunt, embolization of the shunting vessel with a vascular plug, microcoils, glue, and lipiodol mixture was achieved successfully. Portal vein recanalization was attempted in three patients with a transplanted liver; however, only one patient was treated successfully. Complete closure of the percutaneous transsplenic tract was achieved using coils and glue without bleeding complication in all patients. Conclusion: Percutaneous transsplenic access to the portal vein can be an alternative route for portography and further endovascular management in patients for whom conventional approaches are difficult or impossible.

  12. Chronic Heat Stress Induces Immune Response, Oxidative Stress Response, and Apoptosis of Finishing Pig Liver: A Proteomic Approach

    PubMed Central

    Cui, Yanjun; Hao, Yue; Li, Jielei; Bao, Weiguang; Li, Gan; Gao, Yanli; Gu, Xianhong

    2016-01-01

    Heat stress (HS) negatively affects human health, animal welfare, and livestock production. We analyzed the hepatic proteomes of finishing pigs subjected to chronic heat stress (HS), thermal neutral (TN), and restricted feed intake conditions, identifying differences between direct and indirect (via reduced feed intake) HS. Twenty-four castrated male pigs were randomly allocated to three treatments for three weeks: (1) thermal neutral (TN) (22 °C) with ad libitum feeding; (2) chronic HS (30 °C) with ad libitum feeding; and (3) TN, pair-fed to HS intake (PF). Hepatic proteome analysis was conducted using two-dimensional gel electrophoresis and mass spectrometry. Both HS and PF significantly reduced liver weight (p < 0.05). Forty-five hepatic proteins were differentially abundant when comparing HS with TN (37), PF with TN (29), and HS with PF (16). These proteins are involved in heat shock response and immune defense, oxidative stress response, cellular apoptosis, metabolism, signal transduction, and cytoskeleton. We also observed increased abundance of proteins and enzymes associated with heat shock response and immune defense, reduced the redox state, enhanced multiple antioxidant abilities, and increased apoptosis in HS liver. Heat-load, independent of reduced feed intake, induced an innate immune response, while food restriction caused stress and cellular apoptosis. Our results provide novel insights into the effects of chronic HS on liver. PMID:27187351

  13. Evaluation of the antioxidant effects of Ziziphus mauritiana Lam. Leaf extracts against chronic ethanol-induced hepatotoxicity in rat liver.

    PubMed

    Dahiru, D; Obidoa, O

    2007-01-01

    Chronic alcohol ingestion is known to increase the generation of reactive oxygen species (ROS), thereby leading to liver damage. Antioxidant enzymes act individually or in combination to reduce or counter the effect of these ROS. Chronic administration of alcohol at (40% v/v, 1 ml/100 g), for 6 weeks showed a significant (p<0.05) elevated levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), and total bilirubin (TB). There was also a significant (p<0.05) decreased levels of catalase, glutathione peroxidase, glutathione reductase and superoxide dismutase compared to control rats. Pre-treatment of rats with 200, 400 mg/kg body weight of aqueous leaf extract of Ziziphus mauritiana or 100 mg/kg silymarin resulted in a significant (p<0.05) decreased levels of ALT, AST, ALP, and TB with levels of catalase, glutathione peroxidase, glutathione reductase and superoxide dismutase showing a significant (p<0.05) increase compared to group administered alcohol only. Histopathology of rat liver administered with alcohol only resulted in severe necrosis, mononuclear cell aggregation and fatty degeneration in the central and mid zonal areas which was a characteristic of a damaged liver. Pre-treatment with the aqueous extract of Ziziphus mauritiana or silymarin reduced the morphological changes that are associated with chronic alcohol administration. The presence of tannins, saponins and phenolic compounds observed in the plant extract could be responsible for the observed effects of decreasing the levels of injured tissue marker and lipid peroxidation. PMID:20162053

  14. Chronic Heat Stress Induces Immune Response, Oxidative Stress Response, and Apoptosis of Finishing Pig Liver: A Proteomic Approach.

    PubMed

    Cui, Yanjun; Hao, Yue; Li, Jielei; Bao, Weiguang; Li, Gan; Gao, Yanli; Gu, Xianhong

    2016-01-01

    Heat stress (HS) negatively affects human health, animal welfare, and livestock production. We analyzed the hepatic proteomes of finishing pigs subjected to chronic heat stress (HS), thermal neutral (TN), and restricted feed intake conditions, identifying differences between direct and indirect (via reduced feed intake) HS. Twenty-four castrated male pigs were randomly allocated to three treatments for three weeks: (1) thermal neutral (TN) (22 °C) with ad libitum feeding; (2) chronic HS (30 °C) with ad libitum feeding; and (3) TN, pair-fed to HS intake (PF). Hepatic proteome analysis was conducted using two-dimensional gel electrophoresis and mass spectrometry. Both HS and PF significantly reduced liver weight (p < 0.05). Forty-five hepatic proteins were differentially abundant when comparing HS with TN (37), PF with TN (29), and HS with PF (16). These proteins are involved in heat shock response and immune defense, oxidative stress response, cellular apoptosis, metabolism, signal transduction, and cytoskeleton. We also observed increased abundance of proteins and enzymes associated with heat shock response and immune defense, reduced the redox state, enhanced multiple antioxidant abilities, and increased apoptosis in HS liver. Heat-load, independent of reduced feed intake, induced an innate immune response, while food restriction caused stress and cellular apoptosis. Our results provide novel insights into the effects of chronic HS on liver. PMID:27187351

  15. Acute-on-chronic liver failure: consensus recommendations of the Asian Pacific Association for the Study of the Liver (APASL) 2014.

    PubMed

    Sarin, Shiv Kumar; Kedarisetty, Chandan Kumar; Abbas, Zaigham; Amarapurkar, Deepak; Bihari, Chhagan; Chan, Albert C; Chawla, Yogesh Kumar; Dokmeci, A Kadir; Garg, Hitendra; Ghazinyan, Hasmik; Hamid, Saeed; Kim, Dong Joon; Komolmit, Piyawat; Lata, Suman; Lee, Guan Huei; Lesmana, Laurentius A; Mahtab, Mamun; Maiwall, Rakhi; Moreau, Richard; Ning, Qin; Pamecha, Viniyendra; Payawal, Diana Alcantara; Rastogi, Archana; Rahman, Salimur; Rela, Mohamed; Saraya, Anoop; Samuel, Didier; Saraswat, Vivek; Shah, Samir; Shiha, Gamal; Sharma, Brajesh Chander; Sharma, Manoj Kumar; Sharma, Kapil; Butt, Amna Subhan; Tan, Soek Siam; Vashishtha, Chitranshu; Wani, Zeeshan Ahmed; Yuen, Man-Fung; Yokosuka, Osamu

    2014-10-01

    The first consensus report of the working party of the Asian Pacific Association for the Study of the Liver (APASL) set up in 2004 on acute-on-chronic liver failure (ACLF) was published in 2009. Due to the rapid advancements in the knowledge and available information, a consortium of members from countries across Asia Pacific, "APASL ACLF Research Consortium (AARC)," was formed in 2012. A large cohort of retrospective and prospective data of ACLF patients was collated and followed up in this data base. The current ACLF definition was reassessed based on the new AARC data base. These initiatives were concluded on a 2-day meeting in February 2014 at New Delhi and led to the development of the final AARC consensus. Only those statements which were based on the evidence and were unanimously recommended were accepted. These statements were circulated again to all the experts and subsequently presented at the annual conference of the APASL at Brisbane, on March 14, 2014. The suggestions from the delegates were analyzed by the expert panel, and the modifications in the consensus were made. The final consensus and guidelines document was prepared. After detailed deliberations and data analysis, the original proposed definition was found to withstand the test of time and identify a homogenous group of patients presenting with liver failure. Based on the AARC data, liver failure grading, and its impact on the "Golden therapeutic Window," extra-hepatic organ failure and development of sepsis were analyzed. New management options including the algorithms for the management of coagulation disorders, renal replacement therapy, sepsis, variceal bleed, antivirals, and criteria for liver transplantation for ACLF patients were proposed. The final consensus statements along with the relevant background information are presented here. PMID:26202751

  16. Chronic Iron Overload Results in Impaired Bacterial Killing of THP-1 Derived Macrophage through the Inhibition of Lysosomal Acidification

    PubMed Central

    Kao, Jun-Kai; Wang, Shih-Chung; Ho, Li-Wei; Huang, Shi-Wei; Chang, Shu-Hao; Yang, Rei-Cheng; Ke, Yu-Yuan; Wu, Chun-Ying; Wang, Jiu-Yao; Shieh, Jeng-Jer

    2016-01-01

    Iron is essential for living organisms and the disturbance of iron homeostasis is associated with altered immune function. Additionally, bacterial infections can cause major complications in instances of chronic iron overload, such as patients with transfusion-dependent thalassemia. Monocytes and macrophages play important roles in maintaining systemic iron homoeostasis and in defense against invading pathogens. However, the effect of iron overload on the function of monocytes and macrophages is unclear. We elucidated the effects of chronic iron overload on human monocytic cell line (THP-1) and THP-1 derived macrophages (TDM) by continuously exposing them to high levels of iron (100 μM) to create I-THP-1 and I-TDM, respectively. Our results show that iron overload did not affect morphology or granularity of I-THP-1, but increased the granularity of I-TDM. Bactericidal assays for non-pathogenic E. coli DH5α, JM109 and pathogenic P. aeruginosa all revealed decreased efficiency with increasing iron concentration in I-TDM. The impaired P. aeruginosa killing ability of human primary monocyte derived macrophages (hMDM) was also found when cells are cultured in iron contained medium. Further studies on the bactericidal activity of I-TDM revealed lysosomal dysfunction associated with the inhibition of lysosomal acidification resulting in increasing lysosomal pH, the impairment of post-translational processing of cathepsins (especially cathepsin D), and decreased autophagic flux. These findings may explain the impaired innate immunity of thalassemic patients with chronic iron overload, suggesting the manipulation of lysosomal function as a novel therapeutic approach. PMID:27244448

  17. The