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Sample records for abnormal hepatic function

  1. Abnormal hepatic function and splenomegaly on the newly diagnosed acute leukemia patients.

    PubMed

    Sharma Poudel, B; Karki, L

    2007-01-01

    To evaluate the liver function, splenomegaly and related factors in the newly diagnosed acute leukemia patients. One hundred of fifty eight acute leukemia patients admitted in our hospital from March 2003 to April 2006 were studied. The related factors such as peripheral WBC count, bone marrow blasts, peripheral blasts, sex, age, AML, ALL affecting the liver function and splenomegaly were evaluated. Sixty two (39.24%) patients presented with splenomegaly. Twelve (7.59%) patients presented with hepatomegaly. Serum ALT was elevated in 54 (34.17%) patients. Similarly, serum AST, GGT, ALP, and Direct bilirubin were elevated in 26 (16.45%), 32 (20.25%), 20 (12.65%), and 22 (13.92%) patients, respectively. Low serum albumin was found in 40 (25.31%) patients. PT was prolonged in 62 (39.24%) patients. Statistical study shows that there is a relation between high WBC counts and elevated serum ALT (P<0.05) and high WBC counts and splenomegaly (P<0.05). Acute leukemia patients with leukocytosis are more prone to develop abnormal liver function and splenomegaly. PMID:18340367

  2. Chromosome abnormalities in chronic active hepatitis

    PubMed Central

    Stefanescu, D. T.; Moanga, M.; Teodorescu, M.; Brucher, J.

    1972-01-01

    An investigation on human peripheral blood lymphocyte chromosomes in chronic active hepatitis was carried out. A higher percentage of chromatid and chromosome lesions was recorded in all patients studied as compared with control groups—normal individuals, healthy subjects who had suffered from acute viral hepatitis, patients with alcoholic liver disease, and patients with mechanical jaundice due to cancer. The possible origin of these abnormalities is discussed. PMID:5076805

  3. Abnormality on Liver Function Test

    PubMed Central

    2013-01-01

    Children with abnormal liver function can often be seen in outpatient clinics or inpatients wards. Most of them have respiratory disease, or gastroenteritis by virus infection, accompanying fever. Occasionally, hepatitis by the viruses causing systemic infection may occur, and screening tests are required. In patients with jaundice, the tests for differential diagnosis and appropriate treatment are important. In the case of a child with hepatitis B virus infection vertically from a hepatitis B surface antigen positive mother, the importance of the recognition of immune clearance can't be overstressed, for the decision of time to begin treatment. Early diagnosis changes the fate of a child with Wilson disease. So, screening test for the disease should not be omitted. Non-alcoholic fatty liver disease, which is mainly discovered in obese children, is a new strong candidate triggering abnormal liver function. Muscular dystrophy is a representative disease mimicking liver dysfunction. Although muscular dystrophy is a progressive disorder, and early diagnosis can't change the fate of patients, it will be better to avoid parent's blame for delayed diagnosis. PMID:24511518

  4. Glucose abnormalities in hepatitis C virus infection.

    PubMed

    Huang, Jee-Fu; Yu, Ming-Lung; Dai, Chia-Yen; Chuang, Wan-Long

    2013-02-01

    Hepatitis C virus (HCV) infection is one of the most important causes of cirrhosis and hepatocellular carcinoma and has a tremendous impact on public health worldwide. HCV is both hepatotropic and lymphotropic. Replication of HCV in diseased extrahepatic organs and tissues may either trigger latent autoimmunity or induce autoimmune disorders. In addition to established liver injury, type 2 diabetes mellitus (T2DM) is an important feature of extrahepatic metabolic disorders which is attributed to HCV infection. It also has some impact on the disease activity, disease course, clinical outcomes, and treatment efficacy of antiviral therapy. Previous experimental and clinical findings have highly suggested that HCV per se is diabetogenic. The cause-effect interaction between a common endocrine disorder and an infectious disease is an important issue to elucidate. Although the precise mechanisms whereby HCV infection leads to insulin resistance (IR) and glucose abnormalities are not entirely clear, it differs from the usual pathogenesis of T2DM in those with non-HCV liver diseases. This review initially highlights epidemiological and pathophysiological studies addressing the mutual link between chronic HCV infection (CHC) and T2DM. The characteristics of glucose abnormalities in this special population are depicted from the current evidence. The mutual roles of IR and CHC with respect to the prediction of treatment efficacy, how treatment response affects IR, and the role of pancreatic beta cell function in the entire suite are discussed. With the rapid progression of antiviral therapy for CHC in the past decade, we have also listed some points of future perspective in this issue. PMID:23347806

  5. Hepatic perfusion abnormalities during CT angiography: Detection and interpretation

    SciTech Connect

    Freeny, P.C.; Marks, W.M.

    1986-06-01

    Twenty-seven perfusion abnormalities were detected in 17 of 50 patients who underwent computed tomographic angiography (CTA) of the liver. All but one of the perfusion abnormalities occurred in patients with primary or metastatic liver tumors. Perfusion abnormalities were lobar in nine cases, segmental in 11, and subsegmental in seven; 14 were hypoperfusion and 13 were hyperperfusion abnormalities. The causes for the abnormalities included nonperfusion of a replaced hepatic artery (n = 11), cirrhosis and nodular regeneration (n = 3), altered hepatic hemodynamics (e.g., siphoning, laminar flow) caused by tumor (n = 7), contrast media washout from a nonperfused vessel (n = 1), compression of adjacent hepatic parenchyma (n = 1), and unknown (n = 4). Differentiation of perfusion abnormalities from tumor usually can be made by comparing the morphology of the known tumor with the suspected perfusion abnormality, changes of each on delayed CTA scans, and review of initial angiograms and other imaging studies.

  6. The development of hepatic stellate cells in normal and abnormal human fetuses – an immunohistochemical study

    PubMed Central

    Loo, Christine K C; Pereira, Tamara N; Pozniak, Katarzyna N; Ramsing, Mette; Vogel, Ida; Ramm, Grant A

    2015-01-01

    The precise embryological origin and development of hepatic stellate cells is not established. Animal studies and observations on human fetuses suggest that they derive from posterior mesodermal cells that migrate via the septum transversum and developing diaphragm to form submesothelial cells beneath the liver capsule, which give rise to mesenchymal cells including hepatic stellate cells. However, it is unclear if these are similar to hepatic stellate cells in adults or if this is the only source of stellate cells. We have studied hepatic stellate cells by immunohistochemistry, in developing human liver from autopsies of fetuses with and without malformations and growth restriction, using cellular Retinol Binding Protein-1 (cRBP-1), Glial Fibrillary Acidic Protein (GFAP), and α-Smooth Muscle Actin (αSMA) antibodies, to identify factors that influence their development. We found that hepatic stellate cells expressing cRBP-1 are present from the end of the first trimester of gestation and reduce in density throughout gestation. They appear abnormally formed and variably reduced in number in fetuses with abnormal mesothelial Wilms Tumor 1 (WT1) function, diaphragmatic hernia and in ectopic liver nodules without mesothelium. Stellate cells showed similarities to intravascular cells and their presence in a fetus with diaphragm agenesis suggests they may be derived from circulating stem cells. Our observations suggest circulating stem cells as well as mesothelium can give rise to hepatic stellate cells, and that they require normal mesothelial function for their development. PMID:26265759

  7. Normal and abnormal human vestibular ocular function

    NASA Technical Reports Server (NTRS)

    Peterka, R. J.; Black, F. O.

    1986-01-01

    The major motivation of this research is to understand the role the vestibular system plays in sensorimotor interactions which result in spatial disorientation and motion sickness. A second goal was to explore the range of abnormality as it is reflected in quantitative measures of vestibular reflex responses. The results of a study of vestibular reflex measurements in normal subjects and preliminary results in abnormal subjects are presented in this report. Statistical methods were used to define the range of normal responses, and determine age related changes in function.

  8. Evaluation of abnormal liver function tests.

    PubMed

    Agrawal, Swastik; Dhiman, Radha K; Limdi, Jimmy K

    2016-04-01

    Incidentally detected abnormality in liver function tests is a common situation encountered by physicians across all disciplines. Many of these patients do not have primary liver disease as most of the commonly performed markers are not specific for the liver and are affected by myriad factors unrelated to liver disease. Also, many of these tests like liver enzyme levels do not measure the function of the liver, but are markers of liver injury, which is broadly of two types: hepatocellular and cholestatic. A combination of a careful history and clinical examination along with interpretation of pattern of liver test abnormalities can often identify type and aetiology of liver disease, allowing for a targeted investigation approach. Severity of liver injury is best assessed by composite scores like the Model for End Stage Liver Disease rather than any single parameter. In this review, we discuss the interpretation of the routinely performed liver tests along with the indications and utility of quantitative tests. PMID:26842972

  9. Perceived functional impact of abnormal facial appearance.

    PubMed

    Rankin, Marlene; Borah, Gregory L

    2003-06-01

    Functional facial deformities are usually described as those that impair respiration, eating, hearing, or speech. Yet facial scars and cutaneous deformities have a significant negative effect on social functionality that has been poorly documented in the scientific literature. Insurance companies are declining payments for reconstructive surgical procedures for facial deformities caused by congenital disabilities and after cancer or trauma operations that do not affect mechanical facial activity. The purpose of this study was to establish a large, sample-based evaluation of the perceived social functioning, interpersonal characteristics, and employability indices for a range of facial appearances (normal and abnormal). Adult volunteer evaluators (n = 210) provided their subjective perceptions based on facial physical appearance, and an analysis of the consequences of facial deformity on parameters of preferential treatment was performed. A two-group comparative research design rated the differences among 10 examples of digitally altered facial photographs of actual patients among various age and ethnic groups with "normal" and "abnormal" congenital deformities or posttrauma scars. Photographs of adult patients with observable congenital and posttraumatic deformities (abnormal) were digitally retouched to eliminate the stigmatic defects (normal). The normal and abnormal photographs of identical patients were evaluated by the large sample study group on nine parameters of social functioning, such as honesty, employability, attractiveness, and effectiveness, using a visual analogue rating scale. Patients with abnormal facial characteristics were rated as significantly less honest (p = 0.007), less employable (p = 0.001), less trustworthy (p = 0.01), less optimistic (p = 0.001), less effective (p = 0.02), less capable (p = 0.002), less intelligent (p = 0.03), less popular (p = 0.001), and less attractive (p = 0.001) than were the same patients with normal facial

  10. Abnormalities in Cu and Zn levels in acute hepatitis of different etiologies

    PubMed Central

    Papanikolopoulos, K; Alexopoulou, A; Dona, A; Hadziyanni, E; Vasilieva, L; Dourakis, S

    2014-01-01

    Background: Copper (Cu) and Zinc (Zn) are essential trace elements which play an important role in various biological processes. Zn deficiency is common in liver diseases while Cu deficiency is rarely reported. To determine whether serum Cu and Zn concentrations differed in acute hepatitis, compared to controls and investigate possible correlations of Cu and Zn values with etiology and severity of liver diseases. Methods: Serum Cu and Zn concentrations were determined by air acetylene flame atomic absorption spectrometer in 40 patients (acute hepatitis A, B, C, autoimmune and drug induced hepatitis) and 150 healthy controls. Results: Compared to healthy controls, significantly higher Zn levels were found in patients (106.5 μg/dl, P <0.01). Abnormal levels of either Cu and/or Zn were found in 48% of patients vs 23.3% of the controls (P =0.01). Ten patients had abnormal Zn and fourteen had abnormal Cu levels. There was a trend for the severe hepatitis cases to have abnormal Cu values and in this subgroup Cu and Zn were positively correlated with prothrombin time and alanine aminotransferase (ALT) levels, respectively. Cu and Zn levels did not differ statistically across groups of different etiologies. Conclusions: Abnormalities in Cu and Zn concentrations are common in acute hepatitis. Cu and Zn exhibited positive correlations with prothrombin time and ALT respectively, in severe cases. PMID:25336878

  11. Inhibiting monoacylglycerol acyltransferase 1 ameliorates hepatic metabolic abnormalities but not inflammation and injury in mice.

    PubMed

    Soufi, Nisreen; Hall, Angela M; Chen, Zhouji; Yoshino, Jun; Collier, Sara L; Mathews, James C; Brunt, Elizabeth M; Albert, Carolyn J; Graham, Mark J; Ford, David A; Finck, Brian N

    2014-10-24

    Abnormalities in hepatic lipid metabolism and insulin action are believed to play a critical role in the etiology of nonalcoholic steatohepatitis. Monoacylglycerol acyltransferase (MGAT) enzymes convert monoacylglycerol to diacylglycerol, which is the penultimate step in one pathway for triacylglycerol synthesis. Hepatic expression of Mogat1, which encodes an MGAT enzyme, is increased in the livers of mice with hepatic steatosis, and knocking down Mogat1 improves glucose metabolism and hepatic insulin signaling, but whether increased MGAT activity plays a role in the etiology of nonalcoholic steatohepatitis is unclear. To examine this issue, mice were placed on a diet containing high levels of trans fatty acids, fructose, and cholesterol (HTF-C diet) or a low fat control diet for 4 weeks. Mice were injected with antisense oligonucleotides (ASOs) to knockdown Mogat1 or a scrambled ASO control for 12 weeks while remaining on diet. The HTF-C diet caused glucose intolerance, hepatic steatosis, and induced hepatic gene expression markers of inflammation, macrophage infiltration, and stellate cell activation. Mogat1 ASO treatment, which suppressed Mogat1 expression in liver and adipose tissue, attenuated weight gain, improved glucose tolerance, improved hepatic insulin signaling, and decreased hepatic triacylglycerol content compared with control ASO-treated mice on HTF-C chow. However, Mogat1 ASO treatment did not reduce hepatic diacylglycerol, cholesterol, or free fatty acid content; improve histologic measures of liver injury; or reduce expression of markers of stellate cell activation, liver inflammation, and injury. In conclusion, inhibition of hepatic Mogat1 in HTF-C diet-fed mice improves hepatic metabolic abnormalities without attenuating liver inflammation and injury. PMID:25213859

  12. Inhibiting Monoacylglycerol Acyltransferase 1 Ameliorates Hepatic Metabolic Abnormalities but Not Inflammation and Injury in Mice*

    PubMed Central

    Soufi, Nisreen; Hall, Angela M.; Chen, Zhouji; Yoshino, Jun; Collier, Sara L.; Mathews, James C.; Brunt, Elizabeth M.; Albert, Carolyn J.; Graham, Mark J.; Ford, David A.; Finck, Brian N.

    2014-01-01

    Abnormalities in hepatic lipid metabolism and insulin action are believed to play a critical role in the etiology of nonalcoholic steatohepatitis. Monoacylglycerol acyltransferase (MGAT) enzymes convert monoacylglycerol to diacylglycerol, which is the penultimate step in one pathway for triacylglycerol synthesis. Hepatic expression of Mogat1, which encodes an MGAT enzyme, is increased in the livers of mice with hepatic steatosis, and knocking down Mogat1 improves glucose metabolism and hepatic insulin signaling, but whether increased MGAT activity plays a role in the etiology of nonalcoholic steatohepatitis is unclear. To examine this issue, mice were placed on a diet containing high levels of trans fatty acids, fructose, and cholesterol (HTF-C diet) or a low fat control diet for 4 weeks. Mice were injected with antisense oligonucleotides (ASOs) to knockdown Mogat1 or a scrambled ASO control for 12 weeks while remaining on diet. The HTF-C diet caused glucose intolerance, hepatic steatosis, and induced hepatic gene expression markers of inflammation, macrophage infiltration, and stellate cell activation. Mogat1 ASO treatment, which suppressed Mogat1 expression in liver and adipose tissue, attenuated weight gain, improved glucose tolerance, improved hepatic insulin signaling, and decreased hepatic triacylglycerol content compared with control ASO-treated mice on HTF-C chow. However, Mogat1 ASO treatment did not reduce hepatic diacylglycerol, cholesterol, or free fatty acid content; improve histologic measures of liver injury; or reduce expression of markers of stellate cell activation, liver inflammation, and injury. In conclusion, inhibition of hepatic Mogat1 in HTF-C diet-fed mice improves hepatic metabolic abnormalities without attenuating liver inflammation and injury. PMID:25213859

  13. Hepatic glycogen deposition in a patient with anorexia nervosa and persistently abnormal transaminase levels.

    PubMed

    Kransdorf, Lisa N; Millstine, Denise; Smith, Maxwell L; Aqel, Bashar A

    2016-04-01

    Anorexia nervosa and other eating disorders characterized by calorie restriction have been associated with a variety of hepatic abnormalities. Fatty steatosis has been described in eating disorder patients. We report the rare finding of glycogen accumulation in the liver in a patient with anorexia nervosa, which to our knowledge is only the second such case reported in the literature. This case highlights the importance of monitoring for liver abnormalities in patients with restrictive eating disorders. PMID:26066296

  14. Abnormal spontaneous brain activity in minimal hepatic encephalopathy: resting-state fMRI study

    PubMed Central

    Zhong, Wei-Jia; Zhou, Zhi-Ming; Zhao, Jian-Nong; Wu, Wei; Guo, Da-Jing

    2016-01-01

    PURPOSE We aimed to assess the abnormality of baseline spontaneous brain activity in minimal hepatic encephalopathy (MHE) by amplitude of low frequency fluctuation (ALFF) and fraction ALFF (fALFF). METHODS A total of 14 MHE patients and 14 healthy controls were included in our study. Both ALFF and fALFF of functional magnetic resonance imaging were calculated for statistical analysis. RESULTS Compared with healthy controls, patients with MHE had significantly decreased ALFF in the bilateral medial prefrontal cortex (MPFC), left superior frontal gyrus, right precentral gyrus, left opercular part of inferior frontal gyrus, left gyrus rectus, bilateral precuneus, and the posterior lobe of right cerebellum; and they had significantly decreased fALFF in the bilateral MPFC, right middle frontal gyrus, right superior temporal gyrus, and the posterior lobe of left cerebellum. CONCLUSION ALFF and fALFF changes in many brain regions demonstrate abnormality of the spontaneous neuronal activity in MHE. Especially the impairment of right precuneus and left MPFC may play a critical role in manifestation of MHE. Changes of ALFF and fALFF in the precuneus and the MPFC can be used as a potential marker for MHE. PMID:26742646

  15. Functional Neuroimaging Abnormalities in Psychosis Spectrum Youth

    PubMed Central

    Wolf, Daniel H.; Satterthwaite, Theodore D.; Calkins, Monica E.; Ruparel, Kosha; Elliott, Mark A.; Hopson, Ryan D.; Jackson, Chad; Prabhakaran, Karthik; Bilker, Warren B.; Hakonarson, Hakon; Gur, Ruben C.; Gur, Raquel E.

    2015-01-01

    Importance The continuum view of the psychosis spectrum (PS) implies that in population-based samples, PS symptoms should be associated with neural abnormalities similar to those found in help-seeking clinical-risk individuals and in schizophrenia. Functional neuroimaging has not previously been applied in large population-based PS samples, and can help understand the neural architecture of psychosis more broadly, and identify brain phenotypes beyond symptomatology that are associated with the extended psychosis phenotype. Objective To examine the categorical and dimensional relationships of PS symptoms to prefrontal hypoactivation during working memory and to amygdala hyperactivation during threat emotion processing. Design The Philadelphia Neurodevelopmental Cohort (PNC) is a genotyped prospectively accrued population-based sample of nearly 10,000 youths, who received a structured psychiatric evaluation and a computerized neurocognitive battery. A subsample of 1,445 subjects underwent neuroimaging including functional magnetic resonance imaging (fMRI) tasks examined here. Setting The PNC is a collaboration between The Children’s Hospital of Philadelphia and the Hospital of the University of Pennsylvania. Participants Youths ages 11–22 years identified through structured interview as having psychosis-spectrum features (PS, n=260), and typically developing comparison subjects without significant psychopathology (TD, n=220). Main Outcomes and Measures Two fMRI paradigms were utilized, a fractal n-back working memory task probing executive system function, and an emotion identification task probing amygdala responses to threatening faces. Results In the n-back task, PS showed reduced activation in executive control circuitry, which correlated with cognitive deficits. During emotion identification, PS demonstrated elevated amygdala responses to threatening facial expressions, which correlated with positive symptom severity. Conclusions and Relevance The pattern of

  16. Sulforaphane-rich broccoli sprout extract improves hepatic abnormalities in male subjects

    PubMed Central

    Kikuchi, Masahiro; Ushida, Yusuke; Shiozawa, Hirokazu; Umeda, Rumiko; Tsuruya, Kota; Aoki, Yudai; Suganuma, Hiroyuki; Nishizaki, Yasuhiro

    2015-01-01

    AIM: To evaluate effects of dietary supplementation of sulforaphane (SF)-rich broccoli sprout (BS) extract on hepatic abnormalities in Japanese male participants. METHODS: In a randomized, placebo-controlled, double blind trial, male participants with fatty liver received either BS capsules containing glucoraphanin [GR; a precursor of SF (n = 24)] or placebo (n = 28) for 2 mo. Liver function markers, serum levels of aspartate and alanine aminotransferases (AST and ALT, respectively) and γ-glutamyl transpeptidase (γ-GTP) and an oxidative stress marker, urinary levels of 8-hydroxydeoxyguanosine (8-OHdG), were measured and compared in participants before and after the trial period. In an animal model, chronic liver failure was induced in Sprague-Dawley rats by successive intraperitoneal injection with N-nitrosodimethylamine (NDMA) for 4 wk. Concomitantly, rats received AIN-76 diets supplemented with or without BS extract. Thereafter, rats were sacrificed, and their sera and livers were collected to measure serum liver function markers and hepatic levels of thiobarbituric acid reactive substances (TBARS) levels and hepatic glutathione S-transferase (GST) activity, a prototypical phase 2 antioxidant enzyme. RESULTS: Dietary supplementation with BS extract containing SF precursor GR for 2 mo significantly decreased serum levels of liver function markers, ALT [median (interquartile range), before: 54.0 (34.5-79.0) vs after supplementation: 48.5 (33.3-65.3) IU/L, P < 0.05] and γ-GTP [before: 51.5 (40.8-91.3) vs after: 50.0 (37.8-85.3) IU/L, P < 0.05], as well as the alkali phosphatase activity. Placebo showed no significant effects on the markers. The urinary level of 8-OHdG, an established oxidative stress marker, was significantly reduced in participants who had received BS capsules but not the placebo [before: 6.66 (5.51-9.03) vs after: 5.49 (4.89-6.66) ng/mg-creatinine, P < 0.05]. The reduction of urinary 8-OHdG was significantly correlated with decreased levels of

  17. Executive function abnormalities in pathological gamblers

    PubMed Central

    2008-01-01

    Background Pathological gambling (PG) is an impulse control disorder characterized by persistent and maladaptive gambling behaviors with disruptive consequences for familial, occupational and social functions. The pathophysiology of PG is still unclear, but it is hypothesized that it might include environmental factors coupled with a genetic vulnerability and dysfunctions of different neurotransmitters and selected brain areas. Our study aimed to evaluate a group of patients suffering from PG by means of some neuropsychological tests in order to explore the brain areas related to the disorder. Methods Twenty outpatients (15 men, 5 women), with a diagnosis of PG according to DSM-IV criteria, were included in the study and evaluated with a battery of neuropsychological tests: the Wisconsin Card Sorting Test (WCST), the Wechsler Memory Scale revised (WMS-R) and the Verbal Associative Fluency Test (FAS). The results obtained in the patients were compared with normative values of matched healthy control subjects. Results The PG patients showed alterations at the WCST only, in particular they had a great difficulty in finding alternative methods of problem-solving and showed a decrease, rather than an increase, in efficiency, as they progressed through the consecutive phases of the test. The mean scores of the other tests were within the normal range. Conclusion Our findings showed that patients affected by PG, in spite of normal intellectual, linguistic and visual-spatial abilities, had abnormalities emerging from the WCST, in particular they could not learn from their mistakes and look for alternative solutions. Our results would seem to confirm an altered functioning of the prefrontal areas which might provoke a sort of cognitive "rigidity" that might predispose to the development of impulsive and/or compulsive behaviors, such as those typical of PG. PMID:18371193

  18. Abnormalities in Hippocampal Functioning with Persistent Pain

    PubMed Central

    Mutso, Amelia A.; Radzicki, Daniel; Baliki, Marwan N.; Huang, Lejian; Banisadr, Ghazal; Centeno, Maria Virginia; Radulovic, Jelena; Martina, Marco; Miller, Richard J.; Apkarian, A. Vania

    2012-01-01

    Chronic pain patients exhibit increased anxiety, depression, and deficits in learning and memory. Yet how persistent pain affects the key brain area regulating these behaviors, the hippocampus, has remained minimally explored. In this study we investigated the impact of spared nerve injury (SNI) neuropathic pain in mice on hippocampal-dependent behavior and underlying cellular and molecular changes. In parallel, we measured the hippocampal volume of three groups of chronic pain patients. We found that SNI animals were unable to extinguish to contextual fear and showed increased anxiety-like behavior. Additionally, SNI mice in comparison to sham animals exhibited hippocampal 1) reduced extracellular signal-regulated kinase (ERK) expression and phosphorylation, 2) decreased neurogenesis and 3) altered short-term synaptic plasticity. In order to relate the observed hippocampal abnormalities with human chronic pain, we measured the volume of human hippocampus in chronic back pain (CBP), complex regional pain syndrome (CRPS), and osteoarthritis patients (OA). Compared to controls, CBP and CRPS, but not OA, had significantly less bilateral hippocampal volume. These results indicate that hippocampus-mediated behavior, synaptic plasticity and neurogenesis are abnormal in neuropathic rodents. The changes may be related to the reduction in hippocampal volume we see in chronic pain patients, and these abnormalities may underlie learning and emotional deficits commonly observed in such patients. PMID:22539837

  19. Myelodysplastic syndromes: pathogenesis, functional abnormalities, and clinical implications.

    PubMed Central

    Jacobs, A

    1985-01-01

    The myelodysplastic syndromes represent a preleukaemic state in which a clonal abnormality of haemopoietic stem cell is characterised by a variety of phenotypic manifestations with varying degrees of ineffective haemopoiesis. This state probably develops as a sequence of events in which the earliest stages may be difficult to detect by conventional pathological techniques. The process is characterised by genetic changes leading to abnormal control of cell proliferation and differentiation. Expansion of an abnormal clone may be related to independence from normal growth factors, insensitivity to normal inhibitory factors, suppression of normal clonal growth, or changes in the immunological or nutritional condition of the host. The haematological picture is of peripheral blood cytopenias: a cellular bone marrow, and functional abnormalities of erythroid, myeloid, and megakaryocytic cells. In most cases marrow cells have an abnormal DNA content, often with disturbances of the cell cycle: an abnormal karyotype is common in premalignant clones. Growth abnormalities of erythroid or granulocyte-macrophage progenitors are common in marrow cultures, and lineage specific surface membrane markers indicate aberrations of differentiation. Progression of the disorder may occur through clonal expansion or through clonal evolution with a greater degree of malignancy. Current attempts to influence abnormal growth and differentiation have had only limited success. Clinical recognition of the syndrome depends on an acute awareness of the signs combined with the identification of clonal and functional abnormalities. PMID:2999194

  20. The functional hepatic volume assessed by 99mTc-GSA hepatic scintigraphy.

    PubMed

    Wu, J; Ishikawa, N; Takeda, T; Tanaka, Y; Pan, X Q; Sato, M; Todoroki, T; Hatakeyama, R; Itai, Y

    1995-11-01

    The accuracy of measurement of the functional hepatic volume by single photon emission computed tomography (SPECT) with 99mTc-galactosyl serum albumin (99mTc-GAS) was evaluated. 99mTc-GSA planar scintigraphic images were obtained dynamically and the hepatic SPECT imaging was then performed in 25 patients with hepatobiliary tumors. The patients were divided into 4 groups with normal hepatic function, and mild, moderate and severe hepatic dysfunction. The functional hepatic volume determined by SPECT was compared with the morphological hepatic volume determined by compute tomography. The ratio of the hepatic volumes obtained by the two methods was calculated. The mean hepatic volume ratio was 96.6 +/- 2.3% in the normal hepatic function group and 95.9 +/- 2.2% in the mild dysfunction group (n.s.). In both the moderate and severe hepatic dysfunction groups, the hepatic volume ratio was smaller than that in the normal group (87.9 +/- 5.2%, p < 0.0001, and 71.9 +/- 7.6%, p < 0.0001, respectively). There was a linear correlation between the hepatic volume ration and various indices of reserve hepatic function, such as LHL15 (r = 0.83, p < 0.0001), HH15(r = 0.74, p < 0.0001), and ICG15 (r = 0.75, p < 0.0005). These results indicate that the hepatic volume ratio is proportional to the severity of hepatic dysfunction, and suggest that the functional hepatic volume measured with 99mTc-GSA faithfully reflects the functioning hepatocyte mass. 99mTc-GSA scintigraphy and hepatic SPECT therefore provide information regarding global and regional reserve hepatic function. PMID:8770291

  1. Diverticular Disease of the Colon: Neuromuscular Function Abnormalities.

    PubMed

    Bassotti, Gabrio; Villanacci, Vincenzo; Bernardini, Nunzia; Dore, Maria P

    2016-10-01

    Colonic diverticular disease is a frequent finding in daily clinical practice. However, its pathophysiological mechanisms are largely unknown. This condition is likely the result of several concomitant factors occurring together to cause anatomic and functional abnormalities, leading as a result to the outpouching of the colonic mucosa. A pivotal role seems to be played by an abnormal colonic neuromuscular function, as shown repeatedly in these patients, and by an altered visceral perception. There is recent evidence that these abnormalities might be related to the derangement of the enteric innervation, to an abnormal distribution of mucosal neuropeptides, and to low-grade mucosal inflammation. The latter might be responsible for the development of visceral hypersensitivity, often causing abdominal pain in a subset of these patients. PMID:27622368

  2. Abnormal Functional Connectivity in Autism Spectrum Disorders during Face Processing

    ERIC Educational Resources Information Center

    Kleinhans, Natalia M.; Richards, Todd; Sterling, Lindsey; Stegbauer, Keith C.; Mahurin, Roderick; Johnson, L. Clark; Greenson, Jessica; Dawson, Geraldine; Aylward, Elizabeth

    2008-01-01

    Abnormalities in the interactions between functionally linked brain regions have been suggested to be associated with the clinical impairments observed in autism spectrum disorders (ASD). We investigated functional connectivity within the limbic system during face identification; a primary component of social cognition, in 19 high-functioning…

  3. Brief Report: Brain Mechanisms in Autism: Functional and Structural Abnormalities.

    ERIC Educational Resources Information Center

    Minshew, Nancy J.

    1996-01-01

    This paper summarizes results of research on functional and structural abnormalities of the brain in autism. The current concept of causation is seen to involve multiple biologic levels. A consistent profile of brain function and dysfunction across methods has been found and specific neuropathologic findings have been found; but some research…

  4. Abnormalities of autonomic function in the Lambert Eaton myasthenic syndrome.

    PubMed Central

    Heath, J P; Ewing, D J; Cull, R E

    1988-01-01

    Two cases of Lambert Eaton syndrome unassociated with an underlying malignancy are described. Both had mild autonomic symptoms but markedly abnormal autonomic function tests. These results are suggestive of a widespread defect in cholinergic transmission in addition to that at the skeletal neuromuscular junction. Images PMID:3361337

  5. Connectivity and functional profiling of abnormal brain structures in pedophilia

    PubMed Central

    Poeppl, Timm B.; Eickhoff, Simon B.; Fox, Peter T.; Laird, Angela R.; Rupprecht, Rainer; Langguth, Berthold; Bzdok, Danilo

    2015-01-01

    Despite its 0.5–1% lifetime prevalence in men and its general societal relevance, neuroimaging investigations in pedophilia are scarce. Preliminary findings indicate abnormal brain structure and function. However, no study has yet linked structural alterations in pedophiles to both connectional and functional properties of the aberrant hotspots. The relationship between morphological alterations and brain function in pedophilia as well as their contribution to its psychopathology thus remain unclear. First, we assessed bimodal connectivity of structurally altered candidate regions using meta-analytic connectivity modeling (MACM) and resting-state correlations employing openly accessible data. We compared the ensuing connectivity maps to the activation likelihood estimation (ALE) maps of a recent quantitative meta-analysis of brain activity during processing of sexual stimuli. Second, we functionally characterized the structurally altered regions employing meta-data of a large-scale neuroimaging database. Candidate regions were functionally connected to key areas for processing of sexual stimuli. Moreover, we found that the functional role of structurally altered brain regions in pedophilia relates to nonsexual emotional as well as neurocognitive and executive functions, previously reported to be impaired in pedophiles. Our results suggest that structural brain alterations affect neural networks for sexual processing by way of disrupted functional connectivity, which may entail abnormal sexual arousal patterns. The findings moreover indicate that structural alterations account for common affective and neurocognitive impairments in pedophilia. The present multi-modal integration of brain structure and function analyses links sexual and nonsexual psychopathology in pedophilia. PMID:25733379

  6. Connectivity and functional profiling of abnormal brain structures in pedophilia.

    PubMed

    Poeppl, Timm B; Eickhoff, Simon B; Fox, Peter T; Laird, Angela R; Rupprecht, Rainer; Langguth, Berthold; Bzdok, Danilo

    2015-06-01

    Despite its 0.5-1% lifetime prevalence in men and its general societal relevance, neuroimaging investigations in pedophilia are scarce. Preliminary findings indicate abnormal brain structure and function. However, no study has yet linked structural alterations in pedophiles to both connectional and functional properties of the aberrant hotspots. The relationship between morphological alterations and brain function in pedophilia as well as their contribution to its psychopathology thus remain unclear. First, we assessed bimodal connectivity of structurally altered candidate regions using meta-analytic connectivity modeling (MACM) and resting-state correlations employing openly accessible data. We compared the ensuing connectivity maps to the activation likelihood estimation (ALE) maps of a recent quantitative meta-analysis of brain activity during processing of sexual stimuli. Second, we functionally characterized the structurally altered regions employing meta-data of a large-scale neuroimaging database. Candidate regions were functionally connected to key areas for processing of sexual stimuli. Moreover, we found that the functional role of structurally altered brain regions in pedophilia relates to nonsexual emotional as well as neurocognitive and executive functions, previously reported to be impaired in pedophiles. Our results suggest that structural brain alterations affect neural networks for sexual processing by way of disrupted functional connectivity, which may entail abnormal sexual arousal patterns. The findings moreover indicate that structural alterations account for common affective and neurocognitive impairments in pedophilia. The present multimodal integration of brain structure and function analyses links sexual and nonsexual psychopathology in pedophilia. PMID:25733379

  7. Abnormal fronto-striatal functional connectivity in Parkinson's disease.

    PubMed

    Xu, Jinping; Zhang, Jiuquan; Wang, Jiaojian; Li, Guanglin; Hu, Qingmao; Zhang, Yuanchao

    2016-02-01

    Parkinson's disease (PD) is characterized by the relatively selective depletion of dopamine in the striatum, which consequently leads to dysfunctions in cortico-striatal-thalamic-cortical circuitries. It has been shown that the most common cognitive deficits in PD patients are related to the fronto-striatal circuits. In PD, most previous functional connectivity studies have been performed using seed-based methods to identify the brain regions that are abnormally connected to one or more seeds, but these cannot be used to quantify the interactions between one region and all other regions in a particular network. Functional connectivity degree, which is a measurement that can be used to quantify the functional or structural connectivity of a complex brain network, was adopted in this study to assess the interactions of the fronto-striatal network. Compared to healthy controls, PD patients had significantly decreased total functional connectivity degree for the left putamen and the right globus pallidum in fronto-striatal networks. Additionally, negative correlations between the fronto-pallial functional connectivity degree (i.e., the right globus pallidum with the left middle frontal gyrus, and with the right triangular part of inferior frontal gyrus) and disease duration were observed in PD patients. The results of this study demonstrate that fronto-striatal functional connectivity is abnormal in patients with PD and indicate that these deficits might be the result of motor and cognitive dysfunctions in PD patients. PMID:26724369

  8. Abnormal thyroid function tests in children on ethionamide treatment.

    PubMed

    Thee, S; Zöllner, E W; Willemse, M; Hesseling, A C; Magdorf, K; Schaaf, H S

    2011-09-01

    Ethionamide (ETH) treatment may cause hypothyroidism. Clinical data, serum thyroid stimulating hormone (TSH) and free thyroxine (fT4) levels were retrospectively assessed in 137 children receiving anti-tuberculosis treatment including ETH. Abnormal thyroid function tests (TFTs) were recorded in 79 (58%) children: elevated serum TSH and suppressed fT4 (n = 30), isolated elevated serum TSH (n = 20), isolated low serum fT4 (n = 28) and isolated low TSH (n = 1). The risk for biochemical hypothyroidism was higher for children on regimens including para-aminosalicylic acid and in human immunodeficiency virus infected children. TFT abnormalities are frequent in children on ETH and are mainly due to primary hypothyroidism or euthyroid sick syndrome. PMID:21943844

  9. Associations between Kidney Function and Subclinical Cardiac Abnormalities in CKD

    PubMed Central

    Hsu, Chi-yuan; Li, Yongmei; Mishra, Rakesh K.; Keane, Martin; Rosas, Sylvia E.; Dries, Daniel; Xie, Dawei; Chen, Jing; He, Jiang; Anderson, Amanda; Go, Alan S.; Shlipak, Michael G.

    2012-01-01

    Heart failure is a common consequence of CKD, and it portends high risk for mortality. However, among patients without known heart failure, the associations of different stages of estimated GFR (eGFR) with changes in cardiac structure and function are not well described. Here, we performed a cross-sectional analysis to study these associations among 3487 participants of the Chronic Renal Insufficiency Cohort Study. We estimated GFR using cystatin C. The prevalence of left ventricular hypertrophy (LVH) assessed by echocardiography was 32%, 48%, 57%, and 75% for eGFR categories ≥60, 45–59, 30–44, and <30 ml/min per 1.73 m2, respectively. In fully adjusted multivariable analyses, subjects with eGFR levels of <30 ml/min per 1.73 m2 had twofold higher odds of LVH (OR=2.20, 95% CI=1.40–3.40; P<0.001) relative to subjects with eGFR≥60 ml/min per 1.73 m2. This reduction in kidney function also significantly associated with abnormal LV geometry but not diastolic or systolic dysfunction. An eGFR of 30–44 ml/min per 1.73 m2 also significantly associated with LVH and abnormal LV geometry compared with eGFR≥60 ml/min per 1.73 m2. In summary, in this large CKD cohort, reduced kidney function associated with abnormal cardiac structure. We did not detect significant associations between kidney function and systolic or diastolic function after adjusting for potential confounding variables. PMID:22935481

  10. Abnormal Functional Connectivity Density in Post-traumatic Stress Disorder.

    PubMed

    Zhang, Youxue; Xie, Bing; Chen, Heng; Li, Meiling; Liu, Feng; Chen, Huafu

    2016-05-01

    Post-traumatic stress disorder (PTSD) is a psychiatric disorder that occurs in individuals who have experienced life-threatening mental traumas. Previous neuroimaging studies have indicated that the pathology of PTSD may be associated with the abnormal functional integration among brain regions. In the current study, we used functional connectivity density (FCD) mapping, a novel voxel-wise data-driven approach based on graph theory, to explore aberrant FC through the resting-state functional magnetic resonance imaging of the PTSD. We calculated both short- and long-range FCD in PTSD patients and healthy controls (HCs). Compared with HCs, PTSD patients showed significantly increased long-range FCD in the left dorsolateral prefrontal cortex (DLPFC), but no abnormal short-range FCD was found in PTSD. Furthermore, seed-based FC analysis of the left DLPFC showed increased connectivity in the left superior parietal lobe and visual cortex of PTSD patients. The results suggested that PTSD patients experienced a disruption of intrinsic long-range functional connections in the fronto-parietal network and visual cortex, which are associated with attention control and visual information processing. PMID:26830769

  11. Abnormalities of vascular structure and function in pediatric hypertension.

    PubMed

    Urbina, Elaine M

    2016-07-01

    Hypertension is associated with adverse cardiovascular (CV) events in adults. Measures of vascular structure and function, including increased carotid intima-media thickness (cIMT) and elevated arterial stiffness predict hard CV events in adulthood. Newer data suggest that abnormalities in target organ damage are occurring in adolescents and young adults with high blood pressure. In this review, we discuss the techniques for measuring vascular dysfunction in young people and the evidence linking blood pressure levels to this type of target organ damage. PMID:26275663

  12. Abnormal subendocardial function in restrictive left ventricular disease.

    PubMed Central

    Henein, M Y; Gibson, D G

    1994-01-01

    OBJECTIVE--To study possible disturbances in left ventricular long axis function in patients with a restrictive filling pattern. DESIGN--Prospective examination of the left ventricular transverse and longitudinal axes, transmitral flow, and the apexcardiogram. SETTING--A tertiary referral centre for cardiac diseases. SUBJECTS--21 normal subjects, age (SD) 51(11); 30 patients of similar age with a restrictive left ventricular filling pattern, defined as short early diastolic deceleration time less than the lower 95% confidence limit of the normal value (120 ms). 20 patients had a normal and 10 had an increased left ventricular end diastolic cavity size. RESULTS--Mitral Doppler echocardiography: E wave velocity was high only in patients with a normal cavity size. A wave velocity was greatly reduced in the two groups (P < 0.001) so that the E/A ratio was abnormally high. The relative A wave amplitude on the apexcardiogram was greatly increased in the two groups: 46(15)% (mean (SD)) and 54(4)% v 15(5)%. Minor axis: Fractional shortening was reduced from 30(10)% to 17(7)% in patients with normal cavity size and to 13(4.2)% in those with a dilated cavity (P < 0.001), as was the posterior wall thickening fraction from 100(30)% to 42(20)% and 50(25)% respectively (P < 0.001). Total systolic epicardial motion was normal and isovolumic relaxation time was short in the two groups. Long axis: Left ventricular abnormalities included reduced total amplitude of motion and its component during atrial systole (P < 0.001 for the two groups at both sites). Peak long axis shortening and lengthening were decreased at both left ventricular sites (P < 0.001). The time intervals from q wave of the electrocardiogram and A2 (aortic valve closure) to the onset of shortening and lengthening respectively were increased (both P < 0.001). Right ventricular long axis function was similarly affected but to a lesser extent. CONCLUSION--Left ventricular long axis function is consistently abnormal in

  13. Anatomical and functional brain abnormalities in unmedicated major depressive disorder

    PubMed Central

    Yang, Xiao; Ma, Xiaojuan; Li, Mingli; Liu, Ye; Zhang, Jian; Huang, Bin; Zhao, Liansheng; Deng, Wei; Li, Tao; Ma, Xiaohong

    2015-01-01

    Background Using magnetic resonance imaging (MRI) and resting-state functional magnetic resonance imaging (rsfMRI) to explore the mechanism of brain structure and function in unmedicated patients with major depressive disorder (MDD). Patients and methods Fifty patients with MDD and 50 matched healthy control participants free of psychotropic medication underwent high-resolution structural and rsfMRI scanning. Optimized diffeomorphic anatomical registration through exponentiated lie algebra and the Data Processing Assistant for rsfMRI were used to find potential differences in gray-matter volume (GMV) and regional homogeneity (ReHo) between the two groups. A Pearson correlation model was used to analyze associations of morphometric and functional changes with clinical symptoms. Results Compared to healthy controls, patients with MDD showed significant GMV increase in the left posterior cingulate gyrus and GMV decrease in the left lingual gyrus (P<0.001, uncorrected). In ReHo analysis, values were significantly increased in the left precuneus and decreased in the left putamen (P<0.001, uncorrected) in patients with MDD compared to healthy controls. There was no overlap between anatomical and functional changes. Linear correlation suggested no significant correlation between mean GMV values within regions with anatomical abnormality and ReHo values in regions with functional abnormality in the patient group. These changes were not significantly correlated with symptom severity. Conclusion Our study suggests a dissociation pattern of brain regions with anatomical and functional alterations in unmedicated patients with MDD, especially with regard to GMV and ReHo. PMID:26425096

  14. Abnormal Default System Functioning in Depression: Implications for Emotion Regulation.

    PubMed

    Messina, Irene; Bianco, Francesca; Cusinato, Maria; Calvo, Vincenzo; Sambin, Marco

    2016-01-01

    Depression is widely seen as the result of difficulties in regulating emotions. Based on neuroimaging studies on voluntary emotion regulation, neurobiological models have focused on the concept of cognitive control, considering emotion regulation as a shift toward involving controlled processes associated with activation of the prefrontal and parietal executive areas, instead of responding automatically to emotional stimuli. According to such models, the weaker executive area activation observed in depressed patients is attributable to a lack of cognitive control over negative emotions. Going beyond the concept of cognitive control, psychodynamic models describe the development of individuals' capacity to regulate their emotional states in mother-infant interactions during childhood, through the construction of the representation of the self, others, and relationships. In this mini-review, we link these psychodynamic models with recent findings regarding the abnormal functioning of the default system in depression. Consistently with psychodynamic models, psychological functions associated with the default system include self-related processing, semantic processes, and implicit forms of emotion regulation. The abnormal activation of the default system observed in depression may explain the dysfunctional aspects of emotion regulation typical of the condition, such as an exaggerated negative self-focus and rumination on self-esteem issues. We also discuss the clinical implications of these findings with reference to the therapeutic relationship as a key tool for revisiting impaired or distorted representations of the self and relational objects. PMID:27375536

  15. Abnormal Default System Functioning in Depression: Implications for Emotion Regulation

    PubMed Central

    Messina, Irene; Bianco, Francesca; Cusinato, Maria; Calvo, Vincenzo; Sambin, Marco

    2016-01-01

    Depression is widely seen as the result of difficulties in regulating emotions. Based on neuroimaging studies on voluntary emotion regulation, neurobiological models have focused on the concept of cognitive control, considering emotion regulation as a shift toward involving controlled processes associated with activation of the prefrontal and parietal executive areas, instead of responding automatically to emotional stimuli. According to such models, the weaker executive area activation observed in depressed patients is attributable to a lack of cognitive control over negative emotions. Going beyond the concept of cognitive control, psychodynamic models describe the development of individuals’ capacity to regulate their emotional states in mother-infant interactions during childhood, through the construction of the representation of the self, others, and relationships. In this mini-review, we link these psychodynamic models with recent findings regarding the abnormal functioning of the default system in depression. Consistently with psychodynamic models, psychological functions associated with the default system include self-related processing, semantic processes, and implicit forms of emotion regulation. The abnormal activation of the default system observed in depression may explain the dysfunctional aspects of emotion regulation typical of the condition, such as an exaggerated negative self-focus and rumination on self-esteem issues. We also discuss the clinical implications of these findings with reference to the therapeutic relationship as a key tool for revisiting impaired or distorted representations of the self and relational objects. PMID:27375536

  16. Vescalagin from Pink Wax Apple [Syzygium samarangense (Blume) Merrill and Perry] Alleviates Hepatic Insulin Resistance and Ameliorates Glycemic Metabolism Abnormality in Rats Fed a High-Fructose Diet.

    PubMed

    Huang, Da-Wei; Chang, Wen-Chang; Wu, James Swi-Bea; Shih, Rui-Wen; Shen, Szu-Chuan

    2016-02-10

    This study investigates the ameliorative effect of vescalagin (VES) isolated from Pink wax apple fruit on hepatic insulin resistance and abnormal carbohydrate metabolism in high-fructose diet (HFD)-induced hyperglycemic rats. The results show that in HFD rats, VES significantly reduced the values of the area under the curve for glucose in an oral glucose tolerance test and the homeostasis model assessment of insulin resistance index. VES significantly enhanced the activity of hepatic antioxidant enzymes while reducing thiobarbituric acid-reactive substances in HFD rats. Western blot assay revealed that VES reduced hepatic protein expression involved in inflammation pathways while up-regulating expression of hepatic insulin signaling-related proteins. Moreover, VES up-regulated the expression of hepatic glycogen synthase and hepatic glycolysis-related proteins while down-regulating hepatic gluconeogenesis-related proteins in HFD rats. This study suggests some therapeutic potential of VES in preventing the progression of diabetes mellitus. PMID:26800576

  17. Benign nodular hepatocellular lesions caused by abnormal hepatic circulation: etiological analysis and introduction of a new concept.

    PubMed

    Kondo, F

    2001-12-01

    Problems in definitive diagnosis and etiology of various benign nodular hepatocellular lesions were evaluated. Of these lesions, focal nodular hyperplasia (FNH), nodular regenerative hyperplasia (NRH), nodular lesions associated with idiopathic portal hypertension (IPH), non-cirrhotic large regenerative nodules (LRN), hepatocellular adenoma (HA)-like hyperplastic nodules, and partial nodular transformation (PNT) have been suggested to be related to abnormal hepatic circulation. However, the following points are considered to need further clarification: (i) is the abnormal circulation caused by thrombosis, vasculitis, or congenital anomaly?; (ii) is thrombosis a cause or a result of congestion?; (iii) are impaired blood vessels primarily the portal veins or arteries?; (iv) how are these disorders related to various syndromes, immunological abnormalities and abnormal blood flow of other organs, which are reported to coexist with these lesions often?; and (v) how should non-typical cases, which differ from typical cases, be interpreted? In addition, a concept that may lead to solving these problems (anomalous portal tract syndrome; a hypothesis that congenital vascular anomaly is the origin of these benign nodular hepatocellular lesions) was introduced. PMID:11851827

  18. Effects of petroleum hydrocarbons on hepatic function in the duck

    USGS Publications Warehouse

    Patton, J.F.; Dieter, M.P.

    1980-01-01

    1. The indocyanine green dye clearance test for hepatic function was determined in mallard ducks before and during the chronic ingestion (7 months) of representative paraffinic or aromatic petroleum hydrocarbons (PH). 2. No mortality or visible symptoms of toxicity occured in any of the tests. Ingestion of 4000 ppm aromatic PH produced significant increases in liver (25%), plasma clearance of indocyanine green (33%) and hepatic blood flow (30%). 3. Although the aromatics elicited a greater hepatic stress response than the paraffins, the ducks tolerated high concentrations of PH for extended periods.

  19. Biochemical and functional abnormalities in hypercholesterolemic rabbit platelets

    SciTech Connect

    Dalal, K.B.; Ebbe, S.; Mazoyer, E.; Carpenter, D.; Yee, T. )

    1990-02-01

    This study was designed to elucidate changes in rabbit platelet lipids induced by a cholesterol rich diet and to explore the possible correlation of these lipid changes with platelet abnormalities. Pronounced biochemical alterations were observed when serum cholesterol levels of 700-1000 mg% were reached. Hypercholesterolemic (HC) platelets contained 37% more neutral lipids and 16% less phospholipids than the controls. Lysolecithin, cholesterol esters and phosphatidylinositol (PI) levels were increased in HC platelets, and the levels of phosphatidylcholine (PC) were decreased. The cholesterol/phospholipid molar ratio of lipidemic platelets increased from 0.55 +/- 0.011 to 0.89 +/- 0.016 (P less than 0.01) in eight weeks. HC platelets had 90% more arachidonic acid (AA) in the PI than normal platelets. No significant changes in AA of PC were observed. Platelet function was monitored by the uptake and release of (14C)serotonin in platelet rich plasma (PRP), using varying concentrations of collagen as an aggregating agent. The uptake of (14C)serotonin in HC and normal platelets ranged from 78-94%. The percent of (14C)serotonin released from normal and HC platelets was proportional to the concentration of collagen. However, lipidemic platelets were hyperreactive to low concentrations of collagen. Incorporation of 50 microM acetylsalicylic acid into the aggregating medium suppressed the release of (14C)serotonin in normal PRP by more than 90%, but had only a partial effect on lipidemic PRP.

  20. Hepatitis

    MedlinePlus

    ... Got Homework? Here's Help White House Lunch Recipes Hepatitis KidsHealth > For Kids > Hepatitis Print A A A ... an important digestive liquid called bile . What Is Hepatitis? Hepatitis is an inflammation (say: in-fluh-MAY- ...

  1. Abnormalities of endothelial function in patients with predialysis renal failure

    PubMed Central

    Thambyrajah, J; Landray, M; McGlynn, F; Jones, H; Wheeler, D; Townend, J

    2000-01-01

    BACKGROUND—Endothelial dysfunction plays an important role in the development of atherosclerotic vascular disease, which is the leading cause of mortality in patients with chronic renal failure.
OBJECTIVE—To examine the relation between predialysis renal failure and endothelial function.
DESIGN—Two groups were studied: 80 patients with non-diabetic chronic renal failure and 26 healthy controls, with similar age and sex distributions. Two indices of endothelial function were assessed: high resolution ultrasonography to measure flow mediated endothelium dependent dilatation of the brachial artery following reactive hyperaemia, and plasma concentration of von Willebrand factor. Endothelium independent dilatation was also assessed following sublingual glyceryl trinitrate. The patients were divided into those with and without overt atherosclerotic vascular disease.
RESULTS—Although patients with chronic renal failure had significantly impaired endothelium dependent dilatation compared with controls (median (interquartile range), 2.6% (0.7% to 4.8%) v 6.5% (4.8% to 8.3%); p < 0.001) and increased von Willebrand factor (254 (207 to 294) v 106 (87 to 138) iu/dl; p < 0.001), there was no difference between renal failure patients with and without atherosclerotic vascular disease. Within the chronic renal failure group, endothelium dependent dilatation and von Willebrand factor were similar in patients in the upper and lower quartiles of glomerular filtration rate (2.7% (0.7% to 6.7%) v 2.8% (1.1% to 5.0%); and 255 (205 to 291) v 254 (209 to 292) iu/dl, respectively). Endothelium independent dilatation did not differ between the renal failure or control groups and was also similar in patients with renal failure irrespective of the degree of renal failure or the presence of atherosclerotic vascular disease.
CONCLUSIONS—Endothelial function is abnormal in chronic renal failure, even in patients with mild renal insufficiency and those without

  2. Technetium-99m NGA functional hepatic imaging: preliminary clinical experience

    SciTech Connect

    Stadalnik, R.C.; Vera, D.R.; Woodle, E.S.; Trudeau, W.L.; Porter, B.A.; Ward, R.E.; Krohn, K.A.; O'Grady, L.F.

    1985-11-01

    Technetium-99m galactosyl-neoglycoalbumin ( (Tc)NGA) is a radiolabeled ligand to hepatic binding protein, a receptor which resides at the plasma membrane of hepatocytes. This receptor-binding radiopharmaceutical and its kinetic model provide a noninvasive method for the assessment of liver function. Eighteen patients were studied: seven with hepatoma, eight with liver metastases, four with cirrhosis, and one patient with acute fulminant non-A, non-B hepatitis. Technetium-99m NGA liver imaging provided anatomic information of diagnostic quality comparable to that obtained with other routine imaging modalities, including computed tomography, angiography, ultrasound, and (Tc)sulfur colloid scintigraphy. Kinetic modeling of dynamic (Tc)NGA data produced estimates of standardized hepatic blood flow, Q (hepatic blood flow divided by total blood volume), and hepatic binding protein concentration, (HBP). Significant rank correlation was obtained between (HBP) estimates and CTC scores. This correlation supports the hypothesis that (HBP) is a measure of functional hepatocyte mass. The combination of decreased Q and markedly reduced (HBP) may have prognostic significance; all three patients with this combination died of hepatic failure within 6 wk of imaging.

  3. Morphological and functional platelet abnormalities in Berkeley sickle cell mice.

    PubMed

    Shet, Arun S; Hoffmann, Thomas J; Jirouskova, Marketa; Janczak, Christin A; Stevens, Jacqueline R M; Adamson, Adewole; Mohandas, Narla; Manci, Elizabeth A; Cynober, Therese; Coller, Barry S

    2008-01-01

    Berkeley sickle cell mice are used as animal models of human sickle cell disease but there are no reports of platelet studies in this model. Since humans with sickle cell disease have platelet abnormalities, we studied platelet morphology and function in Berkeley mice (SS). We observed elevated mean platelet forward angle light scatter (FSC) values (an indirect measure of platelet volume) in SS compared to wild type (WT) (37+/-3.2 vs. 27+/-1.4, mean+/-SD; p<0.001), in association with moderate thrombocytopenia (505+/-49 x 10(3)/microl vs. 1151+/-162 x 10(3)/microl; p<0.001). Despite having marked splenomegaly, SS mice had elevated levels of Howell-Jolly bodies and "pocked" erythrocytes (p<0.001 for both) suggesting splenic dysfunction. SS mice also had elevated numbers of thiazole orange positive platelets (5+/-1% vs. 1+/-1%; p<0.001), normal to low plasma thrombopoietin levels, normal plasma glycocalicin levels, normal levels of platelet recovery, and near normal platelet life spans. Platelets from SS mice bound more fibrinogen and antibody to P-selectin following activation with a threshold concentration of a protease activated receptor (PAR)-4 peptide compared to WT mice. Enlarged platelets are associated with a predisposition to arterial thrombosis in humans and some humans with SCD have been reported to have large platelets. Thus, additional studies are needed to assess whether large platelets contribute either to pulmonary hypertension or the large vessel arterial occlusion that produces stroke in some children with sickle cell disease. PMID:18374611

  4. The Therapeutic Function of the Instructor in Abnormal Psychology.

    ERIC Educational Resources Information Center

    Halgin, Richard P.

    1982-01-01

    Describes three main types of therapeutic problems which college instructors of abnormal psychology courses may encounter with their students. Students may seek the instructor's assistance in helping a relative or acquaintance or for self-help. Often a student may not seek help but may display pathological behavior. (AM)

  5. Is Abnormal Urine Protein/Osmolality Ratio Associated with Abnormal Renal Function in Patients Receiving Tenofovir Disoproxil Fumarate?

    PubMed Central

    Marcelin, Jasmine R.; Berg, Melody L.; Tan, Eugene M.; Amer, Hatem; Cummins, Nathan W.; Rizza, Stacey A.

    2016-01-01

    Background Risk factors for and optimal surveillance of renal dysfunction in patients on tenofovir disoproxil fumarate (TDF) remain unclear. We investigated whether a urine protein-osmolality (P/O) ratio would be associated with renal dysfunction in HIV-infected persons on TDF. Methods This retrospective, single-center study investigated the relationship between parameters of renal function (estimated glomerular filtration rate (eGFR) and P/O-ratio) and risk factors for development of kidney dysfunction. Subjects were HIV-infected adults receiving TDF with at least one urinalysis and serum creatinine performed between 2010 and 2013. Regression analyses were used to analyze risk factors associated with abnormal P/O-ratio and abnormal eGFR during TDF therapy. Results Patients were predominately male (81%); (65%) were Caucasian. Mean age was 45.1(±11.8) years; median [IQR] TDF duration was 3.3 years. [1.5–7.6]. Median CD4+ T cell count and HIV viral load were 451 cells/μL [267.5–721.5] and 62 copies/mL [0–40,150], respectively. Abnormal P/O-ratio was not associated with low eGFR. 68% of subjects had an abnormal P/O-ratio and 9% had low eGFR. Duration of TDF use, age, diabetes and hypertension were associated with renal dysfunction in this study. After adjustment for age, subjects on TDF > 5 years had almost a four-fold increased likelihood of having an abnormal P/O-ratio than subjects on TDF for < 1yr (OR 3.9; 95% CI 1.2–14.0; p = 0.024). Conclusion Abnormal P/O-ratio is common in HIV-infected patients on TDF but was not significantly associated with low eGFR, suggesting that abnormal P/O-ratio may be a very early biomarker of decreased renal function in HIV infected patients. PMID:26872144

  6. Abnormal ventilation scans in middle-aged smokers. Comparison with tests of overall lung function

    SciTech Connect

    Barter, S.J.; Cunningham, D.A.; Lavender, J.P.; Gibellino, F.; Connellan, S.J.; Pride, N.B.

    1985-07-01

    The uniformity of regional ventilation during tidal breathing has been assessed using continuous inhalation of krypton-81m in 43 male, lifelong nonsmokers and 46 male, current cigarette smokers (mean daily consumption 24.1 cigarettes/day) between 44 and 61 yr of age and with mild or no respiratory symptoms. All subjects had normal chest radiographs. The results of the ventilation scans were compared with tests of overall lung function (spirometry, maximal expiratory flow-volume curves, and single-breath N2 test). Diffuse abnormalities of the ventilation scan were found in 19 (41%) of the 46 smokers but in none of the nonsmokers. Focal abnormalities were found in 7 smokers and 3 nonsmokers. Smokers showed the expected abnormalities in overall lung function (reduced FEV1 and VC, increased single-breath N2 slope, and closing volume), but in individual smokers there was only a weak relation between the severity of abnormality of overall lung function and an abnormal ventilation scan. Abnormal scans could be found when overall lung function was normal and were not invariably found when significant abnormalities in FEV1/VC or N2 slope were present. There was no relation between the presence of chronic expectoration and an abnormal scan. The prognostic significance of an abnormal ventilation scan in such smokers remains to be established.

  7. Functional brain network changes associated with clinical and biochemical measures of the severity of hepatic encephalopathy.

    PubMed

    Jao, Tun; Schröter, Manuel; Chen, Chao-Long; Cheng, Yu-Fan; Lo, Chun-Yi Zac; Chou, Kun-Hsien; Patel, Ameera X; Lin, Wei-Che; Lin, Ching-Po; Bullmore, Edward T

    2015-11-15

    Functional properties of the brain may be associated with changes in complex brain networks. However, little is known about how properties of large-scale functional brain networks may be altered stepwise in patients with disturbance of consciousness, e.g., an encephalopathy. We used resting-state fMRI data on patients suffering from various degrees of hepatic encephalopathy (HE) to explore how topological and spatial network properties of functional brain networks changed at different cognitive and consciousness states. Severity of HE was measured clinically and by neuropsychological tests. Fifty-eight non-alcoholic liver cirrhosis patients and 62 normal controls were studied. Patients were subdivided into liver cirrhosis with no outstanding HE (NoHE, n=23), minimal HE with cognitive impairment only detectable by neuropsychological tests (MHE, n=28), and clinically overt HE (OHE, n=7). From the earliest stage, the NoHE, functional brain networks were progressively more random, less clustered, and less modular. Since the intermediate stage (MHE), increased ammonia level was accompanied by concomitant exponential decay of mean connectivity strength, especially in the primary cortical areas and midline brain structures. Finally, at the OHE stage, there were radical reorganization of the topological centrality-i.e., the relative importance-of the hubs and reorientation of functional connections between nodes. In summary, this study illustrated progressively greater abnormalities in functional brain network organization in patients with clinical and biochemical evidence of more severe hepatic encephalopathy. The early-than-expected brain network dysfunction in cirrhotic patients suggests that brain functional connectivity and network analysis may provide useful and complementary biomarkers for more aggressive and earlier intervention of hepatic encephalopathy. Moreover, the stepwise deterioration of functional brain networks in HE patients may suggest that hierarchical

  8. Abnormal fusiform activation during emotional-face encoding assessed with functional magnetic resonance imaging.

    PubMed

    Adleman, Nancy E; Kayser, Reilly R; Olsavsky, Aviva K; Bones, Brian L; Muhrer, Eli J; Fromm, Stephen J; Pine, Daniel S; Zarate, Carlos; Leibenluft, Ellen; Brotman, Melissa A

    2013-05-30

    This functional magnetic resonance imaging study shows that children and adults with bipolar disorder (BD), compared with healthy subjects, exhibit impaired memory for emotional faces and abnormal fusiform activation during encoding. Fusiform activation abnormalities in BD were correlated with mania severity and may therefore represent a trait and state BD biomarker. PMID:23541333

  9. Differential Impact of Hyponatremia and Hepatic Encephalopathy on Health-Related Quality of Life and Brain Metabolite Abnormalities in Cirrhosis

    PubMed Central

    Ahluwalia, Vishwadeep; Wade, James B; Thacker, Leroy; Kraft, Kenneth A; Sterling, Richard K; Stravitz, R Todd; Fuchs, Michael; Bouneva, Iliana; Puri, Puneet; Luketic, Velimir; Sanyal, Arun J; Gilles, HoChong; Heuman, Douglas M; Bajaj, Jasmohan S

    2013-01-01

    Background Hyponatremia (HN) and hepatic encephalopathy (HE) together can impair health-related quality-of-life (HRQOL) and cognition in cirrhosis. Aim To study effect of hyponatremia on cognition, HRQOL and brain MR spectroscopy (MRS) independent of HE. Methods Four cirrhotic groups(no HE/HN, HE alone, HN alone (sodium<130mEq/L),HE+HN) underwent cognitive testing, HRQOL using Sickness Impact Profile (SIP: higher score is worse; has psycho-social and physical sub-scores) and brain MRS (myoinositol(mI) and glutamate+glutamine(Glx)), which were compared across groups. A subset underwent HRQOL testing before/after diuretic withdrawal. Results 82 cirrhotics (30 no HE/HN, 25 HE, 17 HE+HN and 10 HN, MELD 12, 63% Hepatitis C) were included. Cirrhotics with HN alone and without HE/HN had better cognition compared to HE groups (median abnormal tests no-HE/HN:3, HN:3.5, HE:6.5,HE+HN:7, p=0.008). Despite better cognition, HN only patients had worse HRQOL in total and psychosocial SIP while both HN groups (with/without HE) had a significantly worse physical SIP(p<0.0001, all comparisons). Brain MRS showed lowest Glx in HN and highest in HE groups (p<0.02). mI levels were comparably decreased in the three affected (HE,HE+HN and HN) groups compared to no HE/HN and were associated with poor HRQOL. Six HE+HN cirrhotics underwent diuretic withdrawal which improved serum sodium and total/psycho-social SIP scores. Conclusions Hyponatremic cirrhotics without HE have poor HRQOL despite better cognition than those with concomitant HE. Glx levels were lowest in HN without HE but mI was similar across affected groups. HRQOL improved after diuretic withdrawal. Hyponatremia has a complex, non-linear relationship with brain Glx and mI, cognition and HRQOL. PMID:23665182

  10. Resolution of hypophosphatemia is associated with recovery of hepatic function in children with fulminant hepatic failure.

    PubMed

    Quirós-Tejeira, Rubén E; Molina, Ricardo A; Katzir, Lirona; Lie, Angela; Vargas, Jorge H; Ament, Marvin E; McDiarmid, Sue V; Martín, Martín G

    2005-09-01

    Fulminant hepatic failure (FHF) is a rare but often fatal disease in children. Clinical and laboratory predictors of liver regeneration and recovery, however, have not been well established. We hypothesized that hypophosphatemia may indicate recovery of liver synthetic function in children with FHF. We retrospectively reviewed the medical records of children with FHF who were admitted to UCLA and recovered hepatic function either spontaneously or by liver transplantation (LTx). Serum phosphate (Ph) and prothrombin time or international normalized ratio (INR) were compared over the patient's clinical course. Records of 39 children who spontaneously recovered experienced profound hypophosphatemia that resolved as liver synthetic function improved. Similar patterns were seen in the 84 children who recovered after LTx. We found that hypophosphatemia precedes the recovery of liver synthetic function in children with FHF who recovered with or without transplantation, and that Ph levels return to normal as liver synthetic function improves. These data suggest that hypophosphatemia may be a useful laboratory indicator of recovering liver function in children with FHF. PMID:16101727

  11. Abnormal Liver Function Tests in an Anorexia Nervosa Patient and an Atypical Manifestation of Refeeding Syndrome

    PubMed Central

    Vootla, Vamshidhar R.; Daniel, Myrta

    2015-01-01

    Refeeding syndrome is defined as electrolyte and fluid abnormalities that occur in significantly malnourished patients when they are refed orally, enterally, or parenterally. The principal manifestations include hypophosphatemia, hypokalemia, vitamin deficiencies, volume overload and edema. This can affect multiple organ systems, such as the cardiovascular, pulmonary, or neurological systems, secondary to the above-mentioned abnormalities. Rarely, patients may develop gastrointestinal symptoms and show abnormal liver function test results. We report the case of a 52-year-old woman with anorexia nervosa who developed refeeding syndrome and simultaneous elevations of liver function test results, which normalized upon the resolution of the refeeding syndrome. PMID:26351414

  12. Hepatitis

    MedlinePlus

    ... has been associated with drinking contaminated water. Hepatitis Viruses Type Transmission Prognosis A Fecal-oral (stool to ... risk for severe disease. Others A variety of viruses can affect the liver Signs and Symptoms Hepatitis ...

  13. Hepatic ischemia

    MedlinePlus

    Hepatic ischemia is a condition in which the liver does not get enough blood or oxygen, causing injury to ... pressure from any condition can lead to hepatic ischemia. Such conditions may include: Abnormal heart rhythms Dehydration ...

  14. Liver Function Test Abnormalities in Depressed Patients Treated with Antidepressants: A Real-World Systematic Observational Study in Psychiatric Settings

    PubMed Central

    Verstuyft, Céline; Corruble, Emmanuelle; Perlemuter, Gabriel; Colle, Romain

    2016-01-01

    Background Concerning the risk of antidepressant induced liver injury, it is not clear whether psychiatrists perform a liver function test (LFT) and whether an increase in aminotransferase levels should contraindicate antidepressant treatment. Aim To evaluate LFT availability, the prevalence of LFT abnormalities and the probable cause of an altered LFT in patients with a major depressive episode (MDE) requiring an antidepressant drug. Methods We studied LFT evaluation in a real world psychiatric setting, in a sample of 321 consecutive patients with a current major depressive episode (MDE) requiring an antidepressant drug treatment, but without current alcohol or drug dependence or unstable medical disease. Results An LFT is performed in 36.1% (116/321) of depressed patients. One fifth of antidepressant-treated patients who had an LFT evaluation had abnormal results. The most frequent causes of LFT abnormalities were: NAFLD (nonalcoholic fatty liver disease) (7/321; 2.1%), acute alcohol consumption (4/321; 1.2%), antidepressant-induced liver injury (3/321; 0.9%), hepatitis C virus infection (2/321; 0.6%) and heart failure (1/321; 0.3%). The cause of LFT abnormalities was unknown in 32% of patients (8/25) due to the absence of etiological investigations. Conclusion These results demonstrate that an LFT is infrequently performed by psychiatrists in depressed patients requiring an antidepressant drug. Baseline LFT assessment and observations during the first six months of antidepressant treatment may be useful for detection of patients with pre-existing liver disease such as NAFLD, and early identification of cases of antidepressant-induced liver injury. An increase in aminotransferase levels may be related to an underlying liver disease, but does not contraindicate antidepressant treatment. PMID:27171561

  15. Hepatic functional scintigraphic imaging with 99mtechnetium galactosyl serum albumin.

    PubMed

    Kubota, Y; Kitagawa, S; Inoue, K; Ha-Kawa, S K; Kojima, M; Tanaka, Y

    1993-02-01

    99mTc-galactosyl serum albumin (GSA), a specific radiolabeled synthetic ligand for asialoglycoprotein receptors on hepatocytes, was used for functional liver imaging in 18 patients. Six patients had chronic hepatitis, and 12 had liver cirrhosis. Serial scintigraphic images were obtained for 60 minutes after intravenous administration of 1 mg of the ligand. High-quality images of the liver was obtained in all the patients. Dispersed accumulation in the liver in association with delayed clearance of the ligand from the heart was noted in cirrhotic patients. The activity of the entire liver (L) and that of the heart (H) were measured. The capacity of the liver in terms of elimination of the ligand was estimated by calculating [L/H+L] 15 and 30 minutes after the administration. [L/H+L] showed significant differences between patients with chronic hepatitis and those with liver cirrhosis, and also showed significant correlations with laboratory values such as indocyanine green clearance, prothrombin time, hepaplastin test, serum albumin level, and the Child-Turcotte classification score. 99mTc-GSA might be a useful radiopharmaceutical for obtaining hepatic functional images. PMID:8462925

  16. Pheochromocytoma with Markedly Abnormal Liver Function Tests and Severe Leukocytosis

    PubMed Central

    Eun, Chai Ryoung; Ahn, Jae Hee; Seo, Ji A

    2014-01-01

    Pheochromocytoma is a rare neuroendocrine tumor arising from the medulla of the adrenal glands, which causes an overproduction of catecholamines. The common symptoms are headache, palpitations, and sweating; however, various other clinical manifestations might also be present. Accurate diagnosis of pheochromocytoma is important because surgical treatment is usually successful, and associated clinical problems are reversible if treated early. A 49-year-old man with a history of uncontrolled hypertension and diabetes mellitus presented with chest pain, fever, and sweating. His liver function tests and white blood cell counts were markedly increased and his echocardiography results suggested stress-induced cardiomyopathy. His abdominal computed tomography showed a 5×5-cm-sized tumor in the left adrenal gland, and laboratory tests confirmed catecholamine overproduction. After surgical resection of the left adrenal gland, his liver function tests and white blood cell counts normalized, and echocardiography showed normal cardiac function. Moreover, his previous antihypertensive regimen was deescalated, and his previously uncontrolled blood glucose levels normalized without medication. PMID:24741459

  17. Abnormal systolic and diastolic myocardial function in obese asymptomatic adolescents.

    PubMed

    Batalli-Këpuska, Arbnora; Bajraktari, Gani; Zejnullahu, Murat; Azemi, Mehmedali; Shala, Mujë; Batalli, Arlind; Ibrahimi, Pranvera; Jashari, Fisnik; Henein, Michael Y

    2013-10-01

    Structural and functional cardiac changes are known in obese adults. We aimed to assess the relationship between body mass index (BMI) and cardiac function in overweight and obese asymptomatic adolescents. Ninety three healthy adolescents, aged 12.6 ± 1.2 years, received weight, height, BMI, waist, hips, waist/hips ratio assessment, hematology and biochemistry tests and an echocardiogram. Based on BMI, subjects were divided into: lean (L, n=32), overweight (Ov, n=33) and obese (Ob, n=32). Interventricular septal and LV posterior wall thickness were increased parallel to the BMI (L: 0.84 ± 0.1cm, Ov: 0.88 ± 0.1cm, Ob: 0.96 ± 0.1cm, p<0.001, and L: 0.78 ± 0.1cm, Ov: 0.8 ± 0.1cm, Ob: 0.94 ± 0.1cm, p<0.001, respectively) as were relative wall thickness (RWT) and mass index (LVMI) (L: 0.34 ± 0.05, Ov: 0.34 ± 0.05, Ob: 0.40 ± 0.04, p<0.001, and L: 47.7 ± 8.4 g/m(2), Ov: 51.9 ± 8.3g/m(2), Ob: 65.2 ± 13.3g/m(2), p=0<001, respectively). LV early diastolic (E') lateral and septal velocities (L: 15.3 ± 3.9 cm/s, Ov: 13.6 ± 4 cm/s, Ob: 10.5 ± 3.4 cm/s, p<0.001, and L: 12.2 ± 2.3 cm/s, Ov: 11.1 ± 2.4 cm/s, Ob: 9.8 ± 3.1cm/s, p=0.003, respectively), and systolic (S') velocities (L: 9.2 ± 1.4 cm/s, Ov: 9.3 ± 2.3 cm/s, Ob: 8.04 ± 1.5 cm/s, p=0.018, and L: 9.05 ± 2.3 cm/s, Ov: 9 ± 2.4 cm/s, Ob: 7.6 ± 1.1cm/s, p=0.014, respectively) were all reduced, only in obese adolescents. LV lateral E' (r=-0.44, p<0.001) and S' (r=-0.29, p=0.005) correlated with BMI. In asymptomatic adolescents, LV wall is thicker and diastolic function impaired and correlate with BMI. These findings demonstrate early cardiac functional disturbances which might explain the known obesity risk for cardiac disease. PMID:23416017

  18. HFE gene: Structure, function, mutations, and associated iron abnormalities.

    PubMed

    Barton, James C; Edwards, Corwin Q; Acton, Ronald T

    2015-12-15

    The hemochromatosis gene HFE was discovered in 1996, more than a century after clinical and pathologic manifestations of hemochromatosis were reported. Linked to the major histocompatibility complex (MHC) on chromosome 6p, HFE encodes the MHC class I-like protein HFE that binds beta-2 microglobulin. HFE influences iron absorption by modulating the expression of hepcidin, the main controller of iron metabolism. Common HFE mutations account for ~90% of hemochromatosis phenotypes in whites of western European descent. We review HFE mapping and cloning, structure, promoters and controllers, and coding region mutations, HFE protein structure, cell and tissue expression and function, mouse Hfe knockouts and knockins, and HFE mutations in other mammals with iron overload. We describe the pertinence of HFE and HFE to mechanisms of iron homeostasis, the origin and fixation of HFE polymorphisms in European and other populations, and the genetic and biochemical basis of HFE hemochromatosis and iron overload. PMID:26456104

  19. Abnormal tracheal smooth muscle function in the CF mouse

    PubMed Central

    Wallace, Helen L; Southern, Kevin W; Connell, Marilyn G; Wray, Susan; Burdyga, Theodor

    2013-01-01

    Increased airway smooth muscle (ASM) contractility is thought to underlie symptoms of airway hyperresponsiveness (AHR). In the cystic fibrosis (CF) airway, ASM anomalies have been reported, but have not been fully characterized and the underlying mechanisms are largely unknown. We examined ASM in an adult CF mouse tracheal ring preparation, and determined whether changes in contractility were associated with altered ASM morphology. We looked for inherent changes in the cellular pathways involved in contractility, and characterized trachea morphology in the adult trachea and in an embryonic lung culture model during development. Results showed that that there was a reduction in tracheal caliber in CF mice as indicated by a reduction in the number of cartilage rings; proximal cross-sectional areas of cftr−/− tracheas and luminal areas were significantly smaller, but there was no difference in the area or distribution of smooth muscle. Morphological differences observed in adult trachea were not evident in the embryonic lung at 11.5 days gestation or after 72 h in culture. Functional data showed a significant reduction in the amplitude and duration of contraction in response to carbachol (CCh) in Ca-free conditions. The reduction in contraction was agonist specific, and occurred throughout the length of the trachea. These data show that there is a loss in the contractile capacity of the CF mouse trachea due to downregulation of the pathway specific to acetylcholine (ACh) activation. This reduction in contraction is not associated with changes in the area or distribution of ASM. PMID:24400140

  20. Abnormal functional connectivity during visuospatial processing is associated with disrupted organisation of white matter in autism

    PubMed Central

    McGrath, Jane; Johnson, Katherine; O'Hanlon, Erik; Garavan, Hugh; Leemans, Alexander; Gallagher, Louise

    2013-01-01

    Disruption of structural and functional neural connectivity has been widely reported in Autism Spectrum Disorder (ASD) but there is a striking lack of research attempting to integrate analysis of functional and structural connectivity in the same study population, an approach that may provide key insights into the specific neurobiological underpinnings of altered functional connectivity in autism. The aims of this study were (1) to determine whether functional connectivity abnormalities were associated with structural abnormalities of white matter (WM) in ASD and (2) to examine the relationships between aberrant neural connectivity and behavior in ASD. Twenty-two individuals with ASD and 22 age, IQ-matched controls completed a high-angular-resolution diffusion MRI scan. Structural connectivity was analysed using constrained spherical deconvolution (CSD) based tractography. Regions for tractography were generated from the results of a previous study, in which 10 pairs of brain regions showed abnormal functional connectivity during visuospatial processing in ASD. WM tracts directly connected 5 of the 10 region pairs that showed abnormal functional connectivity; linking a region in the left occipital lobe (left BA19) and five paired regions: left caudate head, left caudate body, left uncus, left thalamus, and left cuneus. Measures of WM microstructural organization were extracted from these tracts. Fractional anisotropy (FA) reductions in the ASD group relative to controls were significant for WM connecting left BA19 to left caudate head and left BA19 to left thalamus. Using a multimodal imaging approach, this study has revealed aberrant WM microstructure in tracts that directly connect brain regions that are abnormally functionally connected in ASD. These results provide novel evidence to suggest that structural brain pathology may contribute (1) to abnormal functional connectivity and (2) to atypical visuospatial processing in ASD. PMID:24133425

  1. Hepatic encephalopathy: effects of liver failure on brain function.

    PubMed

    Felipo, Vicente

    2013-12-01

    Liver failure affects brain function, leading to neurological and psychiatric alterations; such alterations are referred to as hepatic encephalopathy (HE). Early diagnosis of minimal HE reveals an unexpectedly high incidence of mild cognitive impairment and psychomotor slowing in patients with liver cirrhosis - conditions that have serious health, social and economic consequences. The mechanisms responsible for the neurological alterations in HE are beginning to emerge. New therapeutic strategies acting on specific targets in the brain (phosphodiesterase 5, type A GABA receptors, cyclooxygenase and mitogen-activated protein kinase p38) have been shown to restore cognitive and motor function in animal models of chronic HE, and NMDA receptor antagonists have been shown to increase survival in acute liver failure. This article reviews the latest studies aimed at understanding how liver failure affects brain function and potential ways to ameliorate these effects. PMID:24149188

  2. Hepatitis

    MedlinePlus

    ... be serious. Some can lead to scarring, called cirrhosis, or to liver cancer. Sometimes hepatitis goes away by itself. If it does not, it can be treated with drugs. Sometimes hepatitis lasts a lifetime. Vaccines can help prevent some viral forms.

  3. Liver Function Test Abnormalities in Patients with Inflammatory Bowel Diseases: A Hospital-based Survey

    PubMed Central

    Cappello, Maria; Randazzo, Claudia; Bravatà, Ivana; Licata, Anna; Peralta, Sergio; Craxì, Antonio; Almasio, Piero Luigi

    2014-01-01

    BACKGROUND AND AIMS Inflammatory bowel diseases (IBD) are frequently associated with altered liver function tests (LFTs). The causal relationship between abnormal LFTs and IBD is unclear. The aim of our study was to evaluate the prevalence and etiology of LFTs abnormalities and their association with clinical variables in a cohort of IBD patients followed up in a single center. MATERIALS AND METHODS A retrospective review was undertaken of all consecutive IBD in- and outpatients routinely followed up at a single referral center. Clinical and demographic parameters were recorded. Subjects were excluded if they had a previous diagnosis of chronic liver disease. LFT abnormality was defined as an increase in aspartate aminotransferase, (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), gamma-glutamyl transpeptidase (GGT), or total bilirubin. RESULTS A cohort of 335 patients (179 males, mean age 46.0 ± 15.6 years) was analyzed. Abnormal LFTs were detected in 70 patients (20.9%). In most cases, the alterations were mild and spontaneously returned to normal values in about 60% of patients. Patients with abnormal LFTs were less frequently on treatment with aminosalicylates (22.8 vs. 36.6%, P = 0.04). The most frequent cause for transient abnormal LFTs was drug-induced cholestasis (34.1%), whereas fatty liver was the most frequent cause of persistent liver damage (65.4%). A cholestatic pattern was found in 60.0% of patients and was mainly related to older age, longer duration of disease, and hypertension. CONCLUSIONS The prevalence of LFT abnormalities is relatively high in IBD patients, but the development of severe liver injury is exceptional. Moreover, most alterations of LFTs are mild and spontaneously return to normal values. Drug-induced hepatotoxicity and fatty liver are the most relevant causes of abnormal LFTs in patients with IBD. PMID:24966712

  4. Reversible cold-induced abnormalities in myocardial perfusion and function in systemic sclerosis

    SciTech Connect

    Alexander, E.L.; Firestein, G.S.; Weiss, J.L.; Heuser, R.R.; Leitl, G.; Wagner, H.N. Jr.; Brinker, J.A.; Ciuffo, A.A.; Becker, L.C.

    1986-11-01

    The effects of peripheral cold exposure on myocardial perfusion and function were studied in 13 patients with scleroderma without clinically evident myocardial disease. Ten patients had at least one transient, cold-induced, myocardial perfusion defect visualized by thallium-201 scintigraphy, and 12 had reversible, cold-induced, segmental left ventricular hypokinesis by two-dimensional echocardiography. The 10 patients with transient perfusion defects all had anatomically corresponding ventricular wall motion abnormalities. No one in either of two control groups (9 normal volunteers and 7 patients with chest pain and normal coronary arteriograms) had cold-induced abnormalities. This study is the first to show the simultaneous occurrence of cold-induced abnormalities in myocardial perfusion and function in patients with scleroderma. The results suggest that cold exposure in such patients may elicit transient reflex coronary vasoconstriction resulting in reversible myocardial ischemia and dysfunction. Chronic recurrent episodes of coronary spasm may lead to focal myocardial fibrosis.

  5. Abnormal Parietal Brain Function in ADHD: Replication and Extension of Previous EEG Beta Asymmetry Findings

    PubMed Central

    Hale, T. Sigi; Kane, Andrea M.; Tung, Kelly L.; Kaminsky, Olivia; McGough, James J.; Hanada, Grant; Loo, Sandra K.

    2014-01-01

    Background: Abundant work indicates ADHD abnormal posterior brain structure and function, including abnormal structural and functional asymmetries and reduced corpus callosum size. However, this literature has attracted considerably less research interest than fronto-striatal findings. Objective: To help address this imbalance, the current study replicates and extends our previous work showing abnormal parietal brain function in ADHD adults during the Conner’s Continuous Performance Test (CPT). Method: Our previous study found that ADHD adults had increased rightward EEG beta (16–21 Hz) asymmetry in inferior parietal brain regions during the CPT (p = 0.00001), and that this metric exhibited a lack of normal correlation (i.e., observed in controls) with beta asymmetry at temporal–parietal regions. We re-tested these effects in a new ADHD sample and with both new and old samples combined. We additionally examined: (a) EEG asymmetry in multiple frequency bands, (b) unilateral effects for all asymmetry findings, and (c) the association between EEG asymmetry and a battery of cognitive tests. Results: We replicated our original findings by demonstrating abnormal rightward inferior parietal beta asymmetry in adults with ADHD during the CPT, and again this metric exhibited abnormal reduced correlation to temporal–parietal beta asymmetry. Novel analyses also demonstrated a broader pattern of rightward beta and theta asymmetry across inferior, superior, and temporal–parietal brain regions, and showed that rightward parietal asymmetry in ADHD was atypically associated with multiple cognitive tests. Conclusion: Abnormal increased rightward parietal EEG beta asymmetry is an important feature of ADHD. We speculate that this phenotype may occur with any form of impaired capacity for top-down task-directed control over sensory encoding functions, and that it may reflect associated increase of attentional shifting and compensatory sustained/selective attention. PMID

  6. Functional Brain Network Abnormalities during Verbal Working Memory Performance in Adolescents and Young Adults with Dyslexia

    ERIC Educational Resources Information Center

    Wolf, Robert Christian; Sambataro, Fabio; Lohr, Christina; Steinbrink, Claudia; Martin, Claudia; Vasic, Nenad

    2010-01-01

    Behavioral and functional neuroimaging studies indicate deficits in verbal working memory (WM) and frontoparietal dysfunction in individuals with dyslexia. Additionally, structural brain abnormalities in dyslexics suggest a dysconnectivity of brain regions associated with phonological processing. However, little is known about the functional…

  7. Co-localisation of abnormal brain structure and function in specific language impairment

    PubMed Central

    Badcock, Nicholas A.; Bishop, Dorothy V.M.; Hardiman, Mervyn J.; Barry, Johanna G.; Watkins, Kate E.

    2012-01-01

    We assessed the relationship between brain structure and function in 10 individuals with specific language impairment (SLI), compared to six unaffected siblings, and 16 unrelated control participants with typical language. Voxel-based morphometry indicated that grey matter in the SLI group, relative to controls, was increased in the left inferior frontal cortex and decreased in the right caudate nucleus and superior temporal cortex bilaterally. The unaffected siblings also showed reduced grey matter in the caudate nucleus relative to controls. In an auditory covert naming task, the SLI group showed reduced activation in the left inferior frontal cortex, right putamen, and in the superior temporal cortex bilaterally. Despite spatially coincident structural and functional abnormalities in frontal and temporal areas, the relationships between structure and function in these regions were different. These findings suggest multiple structural and functional abnormalities in SLI that are differently associated with receptive and expressive language processing. PMID:22137677

  8. Somatosensory cortex functional connectivity abnormalities in autism show opposite trends, depending on direction and spatial scale

    PubMed Central

    Khan, Sheraz; Michmizos, Konstantinos; Tommerdahl, Mark; Ganesan, Santosh; Kitzbichler, Manfred G.; Zetino, Manuel; Garel, Keri-Lee A.; Herbert, Martha R.; Hämäläinen, Matti S.

    2015-01-01

    Functional connectivity is abnormal in autism, but the nature of these abnormalities remains elusive. Different studies, mostly using functional magnetic resonance imaging, have found increased, decreased, or even mixed pattern functional connectivity abnormalities in autism, but no unifying framework has emerged to date. We measured functional connectivity in individuals with autism and in controls using magnetoencephalography, which allowed us to resolve both the directionality (feedforward versus feedback) and spatial scale (local or long-range) of functional connectivity. Specifically, we measured the cortical response and functional connectivity during a passive 25-Hz vibrotactile stimulation in the somatosensory cortex of 20 typically developing individuals and 15 individuals with autism, all males and right-handed, aged 8–18, and the mu-rhythm during resting state in a subset of these participants (12 per group, same age range). Two major significant group differences emerged in the response to the vibrotactile stimulus. First, the 50-Hz phase locking component of the cortical response, generated locally in the primary (S1) and secondary (S2) somatosensory cortex, was reduced in the autism group (P < 0.003, corrected). Second, feedforward functional connectivity between S1 and S2 was increased in the autism group (P < 0.004, corrected). During resting state, there was no group difference in the mu-α rhythm. In contrast, the mu-β rhythm, which has been associated with feedback connectivity, was significantly reduced in the autism group (P < 0.04, corrected). Furthermore, the strength of the mu-β was correlated to the relative strength of 50 Hz component of the response to the vibrotactile stimulus (r = 0.78, P < 0.00005), indicating a shared aetiology for these seemingly unrelated abnormalities. These magnetoencephalography-derived measures were correlated with two different behavioural sensory processing scores (P < 0.01 and P < 0.02 for the autism

  9. Abnormal hippocampal structure and function in clinical anxiety and comorbid depression.

    PubMed

    Cha, Jiook; Greenberg, Tsafrir; Song, Inkyung; Blair Simpson, Helen; Posner, Jonathan; Mujica-Parodi, Lilianne R

    2016-05-01

    Given the high prevalence rates of comorbidity of anxiety and depressive disorders, identifying a common neural pathway to both disorders is important not only for better diagnosis and treatment, but also for a more complete conceptualization of each disease. Hippocampal abnormalities have been implicated in anxiety and depression, separately; however, it remains unknown whether these abnormalities are also implicated in their comorbidity. Here we address this question by testing 32 adults with generalized anxiety disorder (15 GAD only and 17 comorbid MDD) and 25 healthy controls (HC) using multimodal MRI (structure, diffusion and functional) and automated hippocampal segmentation. We demonstrate that (i) abnormal microstructure of the CA1 and CA2-3 is associated with GAD/MDD comorbidity and (ii) decreased anterior hippocampal reactivity in response to repetition of the threat cue is associated with GAD (with or without MDD comorbidity). In addition, mediation-structural equation modeling (SEM) reveals that our hippocampal and dimensional symptom data are best explained by a model describing a significant influence of abnormal hippocampal microstructure on both anxiety and depression-mediated through its impact on abnormal hippocampal threat processing. Collectively, our findings show a strong association between changes in hippocampal microstructure and threat processing, which together may present a common neural pathway to comorbidity of anxiety and depression. © 2016 Wiley Periodicals, Inc. PMID:26743454

  10. Abnormal Vascular Function and Hypertension in Mice Deficient in Estrogen Receptor β

    NASA Astrophysics Data System (ADS)

    Zhu, Yan; Bian, Zhao; Lu, Ping; Karas, Richard H.; Bao, Lin; Cox, Daniel; Hodgin, Jeffrey; Shaul, Philip W.; Thorén, Peter; Smithies, Oliver; Gustafsson, Jan-Åke; Mendelsohn, Michael E.

    2002-01-01

    Blood vessels express estrogen receptors, but their role in cardiovascular physiology is not well understood. We show that vascular smooth muscle cells and blood vessels from estrogen receptor β (ERβ)-deficient mice exhibit multiple functional abnormalities. In wild-type mouse blood vessels, estrogen attenuates vasoconstriction by an ERβ-mediated increase in inducible nitric oxide synthase expression. In contrast, estrogen augments vasoconstriction in blood vessels from ERβ-deficient mice. Vascular smooth muscle cells isolated from ERβ-deficient mice show multiple abnormalities of ion channel function. Furthermore, ERβ-deficient mice develop sustained systolic and diastolic hypertension as they age. These data support an essential role for ERβ in the regulation of vascular function and blood pressure.

  11. Hepatitis B virus antigens impair NK cell function.

    PubMed

    Yang, Yinli; Han, Qiuju; Zhang, Cai; Xiao, Min; Zhang, Jian

    2016-09-01

    An inadequate immune response of the host is thought to be a critical factor causing chronic hepatitis B virus (CHB) infection. Natural killer (NK) cells, as one of the key players in the eradication and control of viral infections, were functionally impaired in CHB patients, which might contribute to viral persistence. Here, we reported that HBV antigens HBsAg and HBeAg directly inhibited NK cell function. HBsAg and/or HBeAg blocked NK cell activation, cytokine production and cytotoxic granule release in human NK cell-line NK-92 cells, which might be related to the downregulation of activating receptors and upregulation of inhibitory receptor. Furthermore, the underlying mechanisms likely involved the suppression of STAT1, NF-κB and p38 MAPK pathways. These findings implicated that HBV antigen-mediated inhibition of NK cells might be an efficient strategy for HBV evasion, targeting the early antiviral responses mediated by NK cells and resulting in the establishment of chronic virus infection. Therefore, this study revealed the relationship between viral antigens and human immune function, especially a potential important interaction between HBV and innate immune responses. PMID:27341035

  12. Abnormal interhemispheric resting state functional connectivity of the insula in heroin users under methadone maintenance treatment.

    PubMed

    Wang, Peng-Wei; Lin, Huang-Chi; Liu, Gin-Chung; Yang, Yi-Hsin Connie; Ko, Chih-Hung; Yen, Cheng-Fang

    2016-09-30

    Abnormal interhemispheric functional connectivity is attracting more and more attention in the field of substance use. This study aimed to examine 1) the differences in interhemispheric functional connections of the insula with the contralateral insula and other brain regions between heroin users under methadone maintenance treatment (MMT) and healthy controls, and 2) the association between heroin users' interhemispheric insular functional connectivity using resting functional magnetic resonance imaging (fMRI) and the results of urine heroin analysis. Sixty male right-handed persons, including 30 with heroin dependence under MMT and 30 healthy controls, were recruited to this study. Resting fMRI experiments and urine heroin analysis were performed. Compared with the controls, the heroin users had a significantly lower interhemispheric insular functional connectivity. They also exhibited lower functional connectivity between insula and contralateral inferior orbital frontal lobe. After controlling for age, educational level and methadone dosage, less deviation of the interhemispheric insula functional connectivity was significantly associated with a lower risk of a positive urine heroin analysis result. Our findings demonstrated that the heroin users under MMT had abnormal long-range and interhemispheric resting functional connections. Those with a less dysfunctional interhemispheric insula functional connectivity had a lower risk of a positive urine heroin test. PMID:27497215

  13. Structural and Functional Small Fiber Abnormalities in the Neuropathic Postural Tachycardia Syndrome

    PubMed Central

    Gibbons, Christopher H.; Bonyhay, Istvan; Benson, Adam; Wang, Ningshan; Freeman, Roy

    2013-01-01

    Objective To define the neuropathology, clinical phenotype, autonomic physiology and differentiating features in individuals with neuropathic and non-neuropathic postural tachycardia syndrome (POTS). Methods Twenty-four subjects with POTS and 10 healthy control subjects had skin biopsy analysis of intra-epidermal nerve fiber density (IENFD), quantitative sensory testing (QST) and autonomic testing. Subjects completed quality of life, fatigue and disability questionnaires. Subjects were divided into neuropathic and non-neuropathic POTS, defined by abnormal IENFD and abnormal small fiber and sudomotor function. Results Nine of 24 subjects had neuropathic POTS and had significantly lower resting and tilted heart rates; reduced parasympathetic function; and lower phase 4 valsalva maneuver overshoot compared with those with non-neuropathic POTS (P<0.05). Neuropathic POTS subjects also had less anxiety and depression and greater overall self-perceived health-related quality of life scores than non-neuropathic POTS subjects. A sub-group of POTS patients (cholinergic POTS) had abnormal proximal sudomotor function and symptoms that suggest gastrointestinal and genitourinary parasympathetic nervous system dysfunction. Conclusions and Relevance POTS subtypes may be distinguished using small fiber and autonomic structural and functional criteria. Patients with non-neuropathic POTS have greater anxiety, greater depression and lower health-related quality of life scores compared to those with neuropathic POTS. These findings suggest different pathophysiological processes underlie the postural tachycardia in neuropathic and non-neuropathic POTS patients. The findings have implications for the therapeutic interventions to treat this disorder. PMID:24386408

  14. Prevalence and Determinants of True Thyroid Dysfunction Among Pediatric Referrals for Abnormal Thyroid Function Tests

    PubMed Central

    Lahoti, Amit; Klein, Jason; Schumaker, Tiffany; Vuguin, Patricia; Frank, Graeme

    2016-01-01

    Background/Aims. Abnormalities in thyroid function tests (TFTs) are a common referral reason for pediatric endocrine evaluation. However, a sizable proportion of these laboratory abnormalities do not warrant therapy or endocrine follow-up. The objectives of this study were (a) to evaluate the prevalence of true thyroid dysfunction among pediatric endocrinology referrals for abnormal TFTs; (b) to identify the historical, clinical, and laboratory characteristics that predict decision to treat. Methods. This was a retrospective chart review of patients evaluated in pediatric endocrinology office during a weekly clinic designated for new referrals for abnormal TFTs in 2010. Results. A total of 230 patients were included in the study. Median age at referral was 12 years (range = 2-18); 56% were females. Routine screening was cited as the reason for performing TFTs by 33% patients. Majority was evaluated for hypothyroidism (n = 206). Elevated thyroid-stimulating hormone was the most common referral reason (n = 140). A total of 41 out of 206 patients were treated for hypothyroidism. Conclusions. Prevalence of hypothyroidism was 20%. Thyroid follow-up was not recommended for nearly one third of the patients. Among all the factors analyzed, an elevated thyroid-stimulating hormone level and antithyroglobulin antibodies strongly correlated with the decision to treat (P < .005). PMID:27336020

  15. Role of local and distant functional connectivity density in the development of minimal hepatic encephalopathy

    PubMed Central

    Qi, Rongfeng; Zhang, Long Jiang; Chen, Hui Juan; Zhong, Jianhui; Luo, Song; Ke, Jun; Xu, Qiang; Kong, Xiang; Liu, Chang; Lu, Guang Ming

    2015-01-01

    The progression of functional connectivity (FC) patterns from non-hepatic encephalopathy (non-HE) to minimal HE (MHE) is not well known. This resting-state functional magnetic resonance imaging (rs-fMRI) study investigated the evolution of intrinsic FC patterns from non-HE to MHE. A total of 103 cirrhotic patients (MHE, n = 34 and non-HE, n = 69) and 103 healthy controls underwent rs-fMRI scanning. Maps of distant and local FC density (dFCD and lFCD, respectively) were compared among MHE, non-HE, and healthy control groups. Decreased lFCD in anterior cingulate cortex, pre- and postcentral gyri, cuneus, lingual gyrus, and putamen was observed in both MHE and non-HE patients relative to controls. There was no difference in lFCD between MHE and non-HE groups. The latter showed decreased dFCD in inferior parietal lobule, cuneus, and medial frontal cortex relative to controls; however, MHE patients showed decreased dFCD in frontal and parietal cortices as well as increased dFCD in thalamus and caudate head relative to control and non-HE groups. Abnormal FCD values in some regions correlated with MHE patients’ neuropsychological performance. In conclusion, lFCD and dFCD were perturbed in MHE. Impaired dFCD in regions within the cortico-striato-thalamic circuit may be more closely associated with the development of MHE. PMID:26329994

  16. Microheterogeneity of antithrombin III: effect of single amino acid substitutions and relationship with functional abnormalities.

    PubMed

    De Stefano, V; Leone, G; Mastrangelo, S; Lane, D A; Girolami, A; de Moerloose, P; Sas, G; Abildgaard, U; Blajchman, M; Rodeghiero, F

    1994-02-01

    Microheterogeneity of antithrombin III (AT-III) was investigated by crossed immunoelectrofocusing (CIEF) on eleven molecular variants. A normal pattern was found in five variants while two different abnormal CIEF patterns were found in the other four and two variants, respectively. Point mutations causing a major pI change (exceeding 4.0) of the amino acid substituted lead to alterations in the overall microheterogeneity. The variants thus substituted share a first type of abnormal CIEF pattern with alterations throughout the pH range, regardless of the location of the mutation (reactive site and adjacent regions or heparin binding region). Minor amino acid pI changes in these regions do not alter the AT-III overall microheterogeneity, whatever the resulting functional defect. However, if the mutation is placed in the region around positions 404 or 429, then even minor changes of the amino acid pI seem able to alter the overall charge, leading to a second type of abnormal CIEF pattern with the main alteration at pH 4.8-4.6. Neuraminidase treatment leads to disappearance of microheterogeneity except for the variants with the Arg393 to Cys substitution. Addition of thrombin induces CIEF modifications specifically related to the functional defect. A normal formation of thrombin-antithrombin complexes induces a shift towards the more acid pH range, whereas in the variants substituted at the reactive site the CIEF pattern is substantially unaffected by thrombin; variants substituted at positions 382-384 show a maximal thrombin-induced increase of the isoforms at pI 4.8-4.6. Therefore mutant antithrombins with different functional abnormalities but sharing a common CIEF pattern were well distinguished.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:8180341

  17. Abnormalities in personal space and parietal-frontal function in schizophrenia.

    PubMed

    Holt, Daphne J; Boeke, Emily A; Coombs, Garth; DeCross, Stephanie N; Cassidy, Brittany S; Stufflebeam, Steven; Rauch, Scott L; Tootell, Roger B H

    2015-01-01

    Schizophrenia is associated with subtle abnormalities in day-to-day social behaviors, including a tendency in some patients to "keep their distance" from others in physical space. The neural basis of this abnormality, and related changes in social functioning, is unknown. Here we examined, in schizophrenic patients and healthy control subjects, the functioning of a parietal-frontal network involved in monitoring the space immediately surrounding the body ("personal space"). Using fMRI, we found that one region of this network, the dorsal intraparietal sulcus (DIPS), was hyper-responsive in schizophrenic patients to face stimuli appearing to move towards the subjects, intruding into personal space. This hyper-responsivity was predicted both by the size of personal space (which was abnormally elevated in the schizophrenia group) and the severity of negative symptoms. In contrast, in a second study, the activity of two lower-level visual areas that send information to DIPS (the fusiform face area and middle temporal area) was normal in schizophrenia. Together, these findings suggest that changes in parietal-frontal networks that support the sensory-guided initiation of behavior, including actions occurring in the space surrounding the body, contribute to social dysfunction and negative symptoms in schizophrenia. PMID:26484048

  18. Abnormalities in personal space and parietal–frontal function in schizophrenia

    PubMed Central

    Holt, Daphne J.; Boeke, Emily A.; Coombs, Garth; DeCross, Stephanie N.; Cassidy, Brittany S.; Stufflebeam, Steven; Rauch, Scott L.; Tootell, Roger B.H.

    2015-01-01

    Schizophrenia is associated with subtle abnormalities in day-to-day social behaviors, including a tendency in some patients to “keep their distance” from others in physical space. The neural basis of this abnormality, and related changes in social functioning, is unknown. Here we examined, in schizophrenic patients and healthy control subjects, the functioning of a parietal–frontal network involved in monitoring the space immediately surrounding the body (“personal space”). Using fMRI, we found that one region of this network, the dorsal intraparietal sulcus (DIPS), was hyper-responsive in schizophrenic patients to face stimuli appearing to move towards the subjects, intruding into personal space. This hyper-responsivity was predicted both by the size of personal space (which was abnormally elevated in the schizophrenia group) and the severity of negative symptoms. In contrast, in a second study, the activity of two lower-level visual areas that send information to DIPS (the fusiform face area and middle temporal area) was normal in schizophrenia. Together, these findings suggest that changes in parietal–frontal networks that support the sensory-guided initiation of behavior, including actions occurring in the space surrounding the body, contribute to social dysfunction and negative symptoms in schizophrenia. PMID:26484048

  19. Limbic Metabolic Abnormalities in Remote Traumatic Brain Injury and Correlation With Psychiatric Morbidity and Social Functioning

    PubMed Central

    Capizzano, Arístides A.; Jorge, Ricardo E.; Robinson, Robert G.

    2013-01-01

    The aim of this study was to investigate limbic metabolic abnormalities in remote traumatic brain injury (TBI) and their psychiatric correlates. Twenty patients and 13 age-matched comparison subjects received complete psychiatric evaluation and brain MRI and MR spectroscopy at 3 Tesla. Patients had reduced NAA to creatine ratio in the left hippocampus relative to comparison subjects (mean=1.3 [SD=0.21] compared with mean=1.55 [SD=0.21]; F=10.73, df=1, 30, p=0.003), which correlated with the Social Functioning Examination scores (rs=−0.502, p=0.034). Furthermore, patients with mood disorders had reduced NAA to creatine ratio in the left cingulate relative to patients without mood disorders (1.47 compared with 1.68; F=3.393, df=3, 19, p=0.044). Remote TBI displays limbic metabolic abnormalities, which correlate to social outcome and psychiatric status. PMID:21037120

  20. Hepatitis C virus RNA functionally sequesters miR-122

    PubMed Central

    Luna, Joseph M.; Scheel, Troels K. H.; Danino, Tal; Shaw, Katharina S.; Mele, Aldo; Fak, John J.; Nishiuchi, Eiko; Takacs, Constantin N.; Catanese, Maria Teresa; de Jong, Ype P.; Jacobson, Ira M.; Rice, Charles M.; Darnell, Robert B.

    2015-01-01

    Summary Hepatitis C virus uniquely requires the liver specific microRNA-122 for replication, yet global effects on endogenous miRNA targets during infection are unexplored. Here, high-throughput sequencing and crosslinking immunoprecipitation (HITS-CLIP) experiments of human Argonaute (Ago) during HCV infection showed robust Ago binding on the HCV 5′UTR, at known and predicted miR-122 sites. On the human transcriptome, we observed reduced Ago binding and functional mRNA de-repression of miR-122 targets during virus infection. This miR-122 “sponge” effect was relieved and redirected to miR-15 targets by swapping the miRNA tropism of the virus. Single-cell expression data from reporters containing miR-122 sites showed significant de-repression during HCV infection depending on expression level and site number. We describe a quantitative mathematical model of HCV induced miR-122 sequestration and propose that such miR-122 inhibition by HCV RNA may result in global de-repression of host miR-122 targets, providing an environment fertile for the long-term oncogenic potential of HCV. PMID:25768906

  1. Function and structure of rat hepatic coproporphyrinogen oxidase.

    PubMed

    Sorianello, E M; Mazzetti, M B

    2000-10-01

    Rat hepatic coproporphyrinogen oxidase, the sixth enzyme in the heme biosynthetic pathway, was purified 1340-fold with a yield of 39.7%. To obtain the soluble enzyme, different methods were applied to disrupt mitochondria, with sonication giving the highest yield (85%). The minimum catalytic form of enzyme was a dimer with a molecular mass of 77 +/- 4 kDa. The existence of aggregated forms was possible since in fractions of gel filtration elution activity was observed with higher molecular mass. We determined a Stokes radius of 36.3 A, a sedimentation coefficient (S20,w) of 5.06 S, and frictional ratio of 1.29, suggesting a nearly globular shape of the protein. Regardless of the type of salt, high ionic strength inhibits the enzyme, probably modifying its native structure. Experiments with amino acid modifiers showed that histidine, arginine, and tryptophan are involved in the catalytic process. Non-ionic detergents and phospholipids activated the enzyme, probably because they reproduce its natural hydrophobic environment. The present study describes a simple method for the purification of rat liver coproporphyrinogen oxidase, introducing for the first time data on the structure and function of the protein in a tissue often used as a laboratory model in biological studies, and contributing to the study of human hereditary coproporphyria. PMID:11079369

  2. Retrospective analysis of lung function abnormalities of Bhopal gas tragedy affected population

    PubMed Central

    De, Sajal

    2012-01-01

    Background & objectives: A large numbers of subjects were exposed to the aerosol of methyl isocyanate (MIC) during Bhopal gas disaster and lung was one of the most commonly affected organs. The aim of the present study was to analyze retrospectively the lung function abnormalities among the surviving MIC exposed population (gas victims) and to compare it with the non-MIC exposed (non gas exposed) population. Methods: The spirometry data of both gas victims and non gas exposed population who attended the Bhopal Memorial Hospital & Research Centre for evaluation of their respiratory complaints from August 2001 to December 2009, were retrospectively evaluated and compared. Results: A total 4782 gas victims and 1190 non gas exposed individuals performed spirometry during the study period. Among the gas victims, obstructive pattern was the commonest (50.8%) spirometric abnormality followed by restrictive pattern (13.3%). The increased relative risk of developing restrictive abnormality among gas victims was observed in 20-29 yr age group only (adjusted relative risk: 2.94, P<0.001). Male gas victims were more affected by severe airflow obstruction than females and the overall increased relative risk (1.33 to 1.45, P<0.001) of developing obstructive pattern among gas victims was observed. Interpretation & conclusions: The present study showed that the relative risk for pulmonary function abnormalities in gas victims was significantly more among those who were young at the time of disaster. Increased smoking habit among gas victims might have played an additive effect on predominance of obstructive pattern in spirometry. PMID:22446861

  3. Abnormalities in large scale functional networks in unmedicated patients with schizophrenia and effects of risperidone

    PubMed Central

    Kraguljac, Nina Vanessa; White, David Matthew; Hadley, Jennifer Ann; Visscher, Kristina; Knight, David; ver Hoef, Lawrence; Falola, Blessing; Lahti, Adrienne Carol

    2015-01-01

    Objective To describe abnormalities in large scale functional networks in unmedicated patients with schizophrenia and to examine effects of risperidone on networks. Material and methods 34 unmedicated patients with schizophrenia and 34 matched healthy controls were enrolled in this longitudinal study. We collected resting state functional MRI data with a 3T scanner at baseline and six weeks after they were started on risperidone. In addition, a group of 19 healthy controls were scanned twice six weeks apart. Four large scale networks, the dorsal attention network, executive control network, salience network, and default mode network were identified with seed based functional connectivity analyses. Group differences in connectivity, as well as changes in connectivity over time, were assessed on the group's participant level functional connectivity maps. Results In unmedicated patients with schizophrenia we found resting state connectivity to be increased in the dorsal attention network, executive control network, and salience network relative to control participants, but not the default mode network. Dysconnectivity was attenuated after six weeks of treatment only in the dorsal attention network. Baseline connectivity in this network was also related to clinical response at six weeks of treatment with risperidone. Conclusions Our results demonstrate abnormalities in large scale functional networks in patients with schizophrenia that are modulated by risperidone only to a certain extent, underscoring the dire need for development of novel antipsychotic medications that have the ability to alleviate symptoms through attenuation of dysconnectivity. PMID:26793436

  4. Abnormal function of the corpus luteum in some ewes with phyto-oestrogenic infertility.

    PubMed

    Adams, N R; Hearnshaw, H; Oldham, C M

    1981-01-01

    Ewes with permanent phyto-estrogenic infertility show oestrus less regularly than normal ewes, and the present study examines the extent to which this results from abnormal ovarian function. Forty-nine affected ewes and 53 controls were run with rams fitted with marking crayons and harnesses, and crayon marks were recorded and laparoscopy performed at weekly intervals for 3 weeks. Fewer affected ewes showed oestrus accompanied by ovulation (28 v. 49, P less than 0.001), and four of these affected ewes had a second ovulation during the experiment. More of the ovulations observed in affected ewes were unaccompanied by behavioural oestrus than in controls (8 out of 38 v. 2 out of 50; P less than 0.05). Six affected ewes had no corpus luteum or oestrus, and five of these had adhesions over the genitalia. Hydrops uteri in five other affected ewes was accompanied by prolonged maintenance of the corpus luteum. Some other abnormalities were also observed. In a second study, plasma progesterone concentrations were measured twice daily in 12 affected ewes which were run with rams. Five ewes had oestrous cycles of abnormal duration (two of more than 23 days, two of 21 days, and one of 11 days), and these were accompanied by plasma progesterone patterns different from those of the ewes with an oestrous cycle duration of 16-18 days. It is concluded that the irregular oestrous cycles in affected ewes are due mainly to abnormal life span and progesterone secretion by the corpus luteum, which in turn largely result from changes in the uterus. PMID:7196218

  5. Functional changes are associated with tracheal structural abnormalities in patients with acromegaly

    PubMed Central

    Camilo, Gustavo Bittencourt; Guimarães, Fernando Silva; Mogami, Roberto; Faria, Alvaro Camilo Dias; Melo, Pedro Lopes

    2016-01-01

    Introduction Although impaired pulmonary function and respiratory sleep disorders are described as responsible for increased mortality in acromegalic patients, little is known about the tracheal abnormalities in this group of patients. Thus, the objectives of this study were to describe the tracheal structural abnormalities and correlate these changes with the respiratory function and clinical data of acromegalic patients. Material and methods This is a cross-sectional study that was carried out at two university hospitals. Twenty acromegalic patients underwent spirometry, forced oscillation technique, and computed tomography (CT) assessments. Dyspnea and daytime sleepiness were assessed using the Modified Medical Research Council (MMRC) scale and the Epworth Sleepiness Scale (ESS), respectively. Forty matched subjects served as controls. Results The acromegalic patients exhibited larger median ratios between forced expiratory flow and forced inspiratory flow at 50% of the forced vital capacity (FEF50%/FIF50%) (2.05 vs. 1.06, p = 0.0001) compared with healthy volunteers. In the CT analysis, acromegalic patients exhibited larger median differences between their cervical and thoracic tracheal diameters (Δ tracheal diameters) (3 vs. 1 mm; p = 0.003). An association was found between FEF50%/FIF50% and the following variables: mean resistance (Rm), cervical tracheal diameter, and Δ tracheal diameters. Rm also exhibited a negative correlation with cervical tracheal diameter. Neither the MMRC scale nor the ESS exhibited any significant correlation with large airway obstruction (LAO) indices or with the measured tracheal diameters. Conclusions Acromegalic patients have tracheal structural abnormalities which are associated with functional indicators of LAO but not with clinical data. PMID:26925121

  6. Deficiency of Cardiolipin Synthase Causes Abnormal Mitochondrial Function and Morphology in Germ Cells of Caenorhabditis elegans*

    PubMed Central

    Sakamoto, Taro; Inoue, Takao; Otomo, Yukae; Yokomori, Nagaharu; Ohno, Motoki; Arai, Hiroyuki; Nakagawa, Yasuhito

    2012-01-01

    Cardiolipin (CL) is a major membrane phospholipid specifically localized in mitochondria. At the cellular level, CL has been shown to have a role in mitochondrial energy production, mitochondrial membrane dynamics, and the triggering of apoptosis. However, the in vivo role of CL in multicellular organisms is largely unknown. In this study, by analyzing deletion mutants of a CL synthase gene (crls-1) in Caenorhabditis elegans, we demonstrated that CL depletion selectively caused abnormal mitochondrial function and morphology in germ cells but not in somatic cell types such as muscle cells. crls-1 mutants reached adulthood but were sterile with reduced germ cell proliferation and impaired oogenesis. In the gonad of crls-1 mutants, mitochondrial membrane potential was significantly decreased, and the structure of the mitochondrial cristae was disrupted. Contrary to the abnormalities in the gonad, somatic tissues in crls-1 mutants appeared normal with respect to cell proliferation, mitochondrial function, and mitochondrial morphology. Increased susceptibility to CL depletion in germ cells was also observed in mutants of phosphatidylglycerophosphate synthase, an enzyme responsible for producing phosphatidylglycerol, a precursor phospholipid of CL. We propose that the contribution of CL to mitochondrial function and morphology is different among the cell types in C. elegans. PMID:22174409

  7. Hepatitis B virus X protein (HBx)-induced abnormalities of nucleic acid metabolism revealed by 1H-NMR-based metabonomics

    PubMed Central

    Dan Yue; Zhang, Yuwei; Cheng, Liuliu; Ma, Jinhu; Xi, Yufeng; Yang, Liping; Su, Chao; Shao, Bin; Huang, Anliang; Xiang, Rong; Cheng, Ping

    2016-01-01

    Hepatitis B virus X protein (HBx) plays an important role in HBV-related hepatocarcinogenesis; however, mechanisms underlying HBx-mediated carcinogenesis remain unclear. In this study, an NMR-based metabolomics approach was applied to systematically investigate the effects of HBx on cell metabolism. EdU incorporation assay was conducted to examine the effects of HBx on DNA synthesis, an important feature of nucleic acid metabolism. The results revealed that HBx disrupted metabolism of glucose, lipids, and amino acids, especially nucleic acids. To understand the potential mechanism of HBx-induced abnormalities of nucleic acid metabolism, gene expression profiles of HepG2 cells expressing HBx were investigated. The results showed that 29 genes involved in DNA damage and DNA repair were differentially expressed in HBx-expressing HepG2 cells. HBx-induced DNA damage was further demonstrated by karyotyping, comet assay, Western blotting, immunofluorescence and immunohistochemistry analyses. Many studies have previously reported that DNA damage can induce abnormalities of nucleic acid metabolism. Thus, our results implied that HBx initially induces DNA damage, and then disrupts nucleic acid metabolism, which in turn blocks DNA repair and induces the occurrence of hepatocellular carcinoma (HCC). These findings further contribute to our understanding of the occurrence of HCC. PMID:27075403

  8. Abnormalities of functional brain networks in pathological gambling: a graph-theoretical approach

    PubMed Central

    Tschernegg, Melanie; Crone, Julia S.; Eigenberger, Tina; Schwartenbeck, Philipp; Fauth-Bühler, Mira; Lemènager, Tagrid; Mann, Karl; Thon, Natasha; Wurst, Friedrich M.; Kronbichler, Martin

    2013-01-01

    Functional neuroimaging studies of pathological gambling (PG) demonstrate alterations in frontal and subcortical regions of the mesolimbic reward system. However, most investigations were performed using tasks involving reward processing or executive functions. Little is known about brain network abnormalities during task-free resting state in PG. In the present study, graph-theoretical methods were used to investigate network properties of resting state functional magnetic resonance imaging data in PG. We compared 19 patients with PG to 19 healthy controls (HCs) using the Graph Analysis Toolbox (GAT). None of the examined global metrics differed between groups. At the nodal level, pathological gambler showed a reduced clustering coefficient in the left paracingulate cortex and the left juxtapositional lobe (supplementary motor area, SMA), reduced local efficiency in the left SMA, as well as an increased node betweenness for the left and right paracingulate cortex and the left SMA. At an uncorrected threshold level, the node betweenness in the left inferior frontal gyrus was decreased and increased in the caudate. Additionally, increased functional connectivity between fronto-striatal regions and within frontal regions has also been found for the gambling patients. These findings suggest that regions associated with the reward system demonstrate reduced segregation but enhanced integration while regions associated with executive functions demonstrate reduced integration. The present study makes evident that PG is also associated with abnormalities in the topological network structure of the brain during rest. Since alterations in PG cannot be explained by direct effects of abused substances on the brain, these findings will be of relevance for understanding functional connectivity in other addictive disorders. PMID:24098282

  9. Hepatitis B virus large surface protein: function and fame

    PubMed Central

    Churin, Yuri; Roderfeld, Martin

    2015-01-01

    Chronic infection with hepatitis B virus (HBV) is the leading cause of liver cirrhosis and hepatocellular carcinoma worldwide. HBV life cycle begins with viral attachment to hepatocytes, mediated by the large HBV surface protein (LHBs). Identification of the sodium-taurocholate cotransporting polypeptide (NTCP) as a HBV receptor has revealed a suitable target for viral entry inhibition. Analysis of serum hepatitis B surface antigen (HBsAg) level is a non-invasive diagnostic parameter that improves HBV treatment opportunities. Furthermore, HBsAg plays an important role in manipulation of host immune response by HBV. However, observations in patients with chronic hepatitis B under conditions of immune suppression and in transgenic mouse models of HBV infection suggest, that in absence of adaptive immune responses cellular mechanisms induced by HBV may also lead to the development of liver diseases. Thus, the multifaceted pathological aspects of HBsAg predetermine the design of new therapeutical options modulating associated biological implications. PMID:25713800

  10. Hepatitis B virus large surface protein: function and fame.

    PubMed

    Churin, Yuri; Roderfeld, Martin; Roeb, Elke

    2015-02-01

    Chronic infection with hepatitis B virus (HBV) is the leading cause of liver cirrhosis and hepatocellular carcinoma worldwide. HBV life cycle begins with viral attachment to hepatocytes, mediated by the large HBV surface protein (LHBs). Identification of the sodium-taurocholate cotransporting polypeptide (NTCP) as a HBV receptor has revealed a suitable target for viral entry inhibition. Analysis of serum hepatitis B surface antigen (HBsAg) level is a non-invasive diagnostic parameter that improves HBV treatment opportunities. Furthermore, HBsAg plays an important role in manipulation of host immune response by HBV. However, observations in patients with chronic hepatitis B under conditions of immune suppression and in transgenic mouse models of HBV infection suggest, that in absence of adaptive immune responses cellular mechanisms induced by HBV may also lead to the development of liver diseases. Thus, the multifaceted pathological aspects of HBsAg predetermine the design of new therapeutical options modulating associated biological implications. PMID:25713800

  11. Hepatic Inflammation and Fibrosis: Functional Links and Key Pathways

    PubMed Central

    Seki, Ekihiro; Schwabe, Robert F.

    2014-01-01

    Inflammation is one of the most characteristic features of chronic liver disease of viral, alcoholic, fatty and autoimmune origin. Inflammation is typically present in all disease stages, and associated with the development of fibrosis, cirrhosis and hepatocellular carcinoma. In the past decade, numerous studies have contributed to improved understanding of the links between hepatic inflammation and fibrosis. Here, we review mechanisms that link inflammation with the development of liver fibrosis, focusing on the role of inflammatory mediators in hepatic stellate cell (HSC) activation and HSC survival during fibrogenesis and fibrosis regression. We will summarize the contributions of different inflammatory cells, including hepatic macrophages, T- and B-lymphocytes, NK cells and platelets, as well as key effectors such as cytokines, chemokines, and damage-associated molecular patterns. Furthermore, we will discuss the relevance of inflammatory signaling pathways for clinical liver disease and for the development of anti-fibrogenic strategies. PMID:25066777

  12. Structural and functional brain abnormalities place phenocopy frontotemporal dementia (FTD) in the FTD spectrum

    PubMed Central

    Steketee, Rebecca M.E.; Meijboom, Rozanna; Bron, Esther E.; Osse, Robert Jan; de Koning, Inge; Jiskoot, Lize C.; Klein, Stefan; de Jong, Frank Jan; van der Lugt, Aad; van Swieten, John C.; Smits, Marion

    2016-01-01

    Purpose ‘Phenocopy’ frontotemporal dementia (phFTD) patients may clinically mimic the behavioral variant of FTD (bvFTD), but do not show functional decline or abnormalities upon visual inspection of routine neuroimaging. We aimed to identify abnormalities in gray matter (GM) volume and perfusion in phFTD and to assess whether phFTD belongs to the FTD spectrum. We compared phFTD patients with both healthy controls and bvFTD patients. Materials & methods Seven phFTD and 11 bvFTD patients, and 20 age-matched controls underwent structural T1-weighted magnetic resonance imaging (MRI) and 3D pseudo-continuous arterial spin labeling (pCASL) at 3T. Normalized GM (nGM) volumes and perfusion, corrected for partial volume effects, were quantified regionally as well as in the entire supratentorial cortex, and compared between groups taking into account potential confounding effects of gender and scanner. Results PhFTD patients showed cortical atrophy, most prominently in the right temporal lobe. Apart from this regional atrophy, GM volume was generally not different from either controls or from bvFTD. BvFTD however showed extensive frontotemporal atrophy. Perfusion was increased in the left prefrontal cortex compared to bvFTD and to a lesser extent to controls. Conclusion PhFTD and bvFTD show overlapping cortical structural abnormalities indicating a continuum of changes especially in the frontotemporal regions. Together with functional changes suggestive of a compensatory response to incipient pathology in the left prefrontal regions, these findings are the first to support a possible neuropathological etiology of phFTD and suggest that phFTD may be a neurodegenerative disease on the FTD spectrum. PMID:27222795

  13. Functional evaluation of an inherited abnormal fibrinogen: fibrinogen “Baltimore”

    PubMed Central

    Beck, Eugene A.; Shainoff, John R.; Vogel, Alfred; Jackson, Dudley P.

    1971-01-01

    The rate of clotting and the rate of development and degree of turbidity after addition of thrombin to plasma or purified fibrinogen from a patient with fibrinogen Baltimore was delayed when compared with normal, especially in the presence of low concentrations of thrombin. Optimal coagulation and development of translucent, rather than opaque, clots occurred at a lower pH with the abnormal fibrinogen than with normal. Development of turbidity during clotting of the abnormal plasma or fibrinogen was less than normal at each pH tested, but was maximal in both at approximately pH 6.4. The physical quality of clots formed from fibrinogen Baltimore was abnormal, as demonstrated by a decreased amplitude on thromboelastography. The morphologic appearance of fibrin strands formed from fibrinogen Baltimore by thrombin at pH 7.4 was abnormal when examined by phase contrast or electron microscopy, but those formed by thrombin at pH 6.4 or by thrombin and calcium chloride were similar to, though less compact, than normal fibrin. The periodicity of fibrin formed from fibrinogen Baltimore was similar to normal and was 231-233 Å. A study of the release of the fibrinopeptides from the patient's fibrinogen and its chromatographic subfractions verified the existence of both a normally behaving and a defective form of fibrinogen in the patient's plasma. The defective form differed from normal in three functionally different ways: (a) the rate of release of fibrinopeptides A and AP was slower than normal; (b) no visible clot formation accompanied either partial or complete release of the fibrinopeptides from the defective form in 0.3 M NaCl at pH 7.4; and (c) the defective component possessed a high proportion of phosphorylated, relative to nonphosphorylated, fibrinopeptide A, while the coagulable component contained very little of the phosphorylated peptide (AP). The high phosphate content of the defective component did not appear to be the cause of the abnormality, but may be the

  14. Physiologic abnormalities of cardiac function in progressive systemic sclerosis with diffuse scleroderma

    SciTech Connect

    Follansbee, W.P.; Curtiss, E.I.; Medsger, T.A. Jr.; Steen, V.D.; Uretsky, B.F.; Owens, G.R.; Rodnan, G.P.

    1984-01-19

    To investigate cardiopulmonary function in progressive systemic sclerosis with diffuse scleroderma, we studied 26 patients with maximal exercise and redistribution thallium scans, rest and exercise radionuclide ventriculography, pulmonary-function testing, and chest roentgenography. Although only 6 patients had clinical evidence of cardiac involvement, 20 had abnormal thallium scans, including 10 with reversible exercise-induced defects and 18 with fixed defects (8 had both). Seven of the 10 patients who had exercise-induced defects and underwent cardiac catheterization had normal coronary angiograms. Mean resting left ventricular ejection fraction and mean resting right ventricular ejection fraction were lower in patients with post-exercise left ventricular thallium defect scores above the median (59 +/- 13 per cent vs. 69 +/- 6 per cent, and 36 +/- 12 per cent vs. 47 +/- 7 per cent, respectively). The authors conclude that in progressive systemic sclerosis with diffuse scleroderma, abnormalities of myocardial perfusion are common and appear to be due to a disturbance of the myocardial microcirculation. Both right and left ventricular dysfunction appear to be related to this circulatory disturbance, suggesting ischemically mediated injury.

  15. Lactulose enhances neuroplasticity to improve cognitive function in early hepatic encephalopathy

    PubMed Central

    Yang, Nan; Liu, He; Jiang, Yao; Zheng, Ji; Li, Dong-mei; Ji, Chao; Liu, Yan-yong; Zuo, Ping-ping

    2015-01-01

    Lactulose is known to improve cognitive function in patients with early hepatic encephalopathy; however, the underlying mechanism remains poorly understood. In the present study, we investigated the behavioral and neurochemical effects of lactulose in a rat model of early hepatic encephalopathy induced by carbon tetrachloride. Immunohistochemistry showed that lactulose treatment promoted neurogenesis and increased the number of neurons and astrocytes in the hippocampus. Moreover, lactulose-treated rats showed shorter escape latencies than model rats in the Morris water maze, indicating that lactulose improved the cognitive impairments caused by hepatic encephalopathy. The present findings suggest that lactulose effectively improves cognitive function by enhancing neuroplasticity in a rat model of early hepatic encephalopathy. PMID:26604907

  16. Global functional connectivity abnormalities in children with Fetal Alcohol Spectrum Disorders (FASD)

    PubMed Central

    Wozniak, Jeffrey R.; Mueller, Bryon A.; Bell, Christopher J.; Muetzel, Ryan L.; Hoecker, Heather L.; Boys, Christopher J.; Lim, Kelvin O.

    2012-01-01

    Background Previous studies, including those employing Diffusion Tensor Imaging (DTI), have revealed significant disturbances in the white matter of individuals with Fetal Alcohol Spectrum Disorders (FASD). Both macrostructural and microstructural abnormalities have been observed across levels of FASD severity. Emerging evidence suggests that these white matter abnormalities are associated with functional deficits. This study used resting-state fMRI to evaluate the status of network functional connectivity in children with FASD compared to control subjects. Methods Participants included 24 children with FASD, ages 10–17, and 31 matched controls. Neurocognitive tests were administered including Wechsler Intelligence Scales, California Verbal Learning Test, and Behavior Rating Inventory of Executive Functioning. High resolution anatomical MRI data and six-minute resting-state fMRI data were collected. The resting-state fMRI data were subjected to a graph theory analysis and four global measures of cortical network connectivity were computed: characteristic path length, mean clustering coefficient, local efficiency, and global efficiency. Results Results revealed significantly altered network connectivity in those with FASD. The characteristic path length was 3.1% higher (p=.04, Cohen’s d=.47) and global efficiency was 1.9% lower (p=.04, d=.63) in children with FASD compared to controls, suggesting decreased network capacity that may have implications for integrative cognitive functioning. Global efficiency was significantly positively correlated with cortical thickness in frontal (r=.38, p=.005), temporal (r=.28, p=.043), and parietal (r=.36, p=.008) regions. No relationship between facial dysmorphology and functional connectivity was observed. Exploratory correlations suggested that global efficiency and characteristic path length are associated with capacity for immediate verbal memory on the CVLT (r=.41, p=.05 and r=.41, p=.01 respectively) among those with

  17. Investigation of intestine function during acute viral hepatitis using combined sugar oral loads.

    PubMed Central

    Parrilli, G; Cuomo, R; Nardone, G; Maio, G; Izzo, C M; Budillon, G

    1987-01-01

    One fifth of all cases of A virus hepatitis (AVH) have symptoms of gastroenteritis at the onset. This study investigated the mediated intestinal absorption of D-xylose (D-xyl) and 3-o-methyl-D-glucose (3-omG) and the non-mediated permeation of lactulose (Lacl, mol wt 342) and L-rhamnose (L-rh, mol wt 164) during acute and remission phases of AVH. Ten patients with AVH were given an oral load containing these sugars (5 g D-xyl: 2.5 g 3-omG, 1 g L-rh, 5 g lacl in 250 ml water) once during the acute phase and again during remission. The same load was given once to a group of 22 healthy controls. The mean concentration of D-xyl in urine and the ratio of D-xyl to 3-omG in plasma and urine were normal in both the AVH phases, ruling out intestinal malabsorption even in the acute phase. This study showed a significant increase in non-mediated permeation to Lacl, but not to L-rh, during the acute phase. These data indicate that the barrier function of the intestine is compromised in AVH infection while the absorptive function is not. An abnormally low concentration of D-xyl and 3-omG in plasma at one hour was found in all patients during the acute phase. This finding cannot be explained by alterations in intestinal absorption, but could be accounted for by increased space distribution of the sugars because of increased diffusion into tissue cells and/or expansion of the extracellular space by fluid retention. PMID:3428669

  18. Engineering EMT using 3D micro-scaffold to promote hepatic functions for drug hepatotoxicity evaluation.

    PubMed

    Wang, Jingyu; Chen, Fengling; Liu, Longwei; Qi, Chunxiao; Wang, Bingjie; Yan, Xiaojun; Huang, Chenyu; Hou, Wei; Zhang, Michael Q; Chen, Yang; Du, Yanan

    2016-06-01

    Accompanied by decreased hepatic functions, epithelial-mesenchymal transition (EMT) was observed in two dimensional (2D) cultured hepatocytes with elongated morphology, loss of polarity and weakened cell-cell interaction, while upgrading to 3D culture has been considered as significant improvement of its 2D counterpart for hepatocyte maintenance. Here we hypothesize that 3D culture enhances hepatic functions through regulating the EMT status. Biomaterial-engineered EMT was achieved by culturing HepaRG as 3D spheroids (SP-3D) or 3D stretched cells (ST-3D) in non-adherent and adherent micro-scaffold respectively. In SP-3D, constrained EMT of HepaRG, a hepatic stem cell line, as represented by increased epithelial markers and decreased mesenchymal markers, was echoed by improved hepatic functions. To investigate the relationship between EMT status and hepatic functions, time-series RNA-Seq and gene network analysis were used for comparing different cell culture models, which identified histone deacetylases (HDACs) as key mediating factors. Protein analysis confirmed that high HDAC activity was correlated with high expression of Cadherin-1 (CDH1) and hepatic function genes, which were decreased upon HDAC inhibitor treatment in SP-3D, suggesting HDACs may play positive role in regulating EMT and hepatic functions. To illustrate the application of 3D micro-scaffold culture in drug safety evaluation, hepatotoxicity and metabolism assays of two hepatotoxins (i.e. N-acetyl-p-aminophenol and Doxorubicin) were performed and SP-3D showed more biomimetic toxicity response, indicating regulation of EMT as a vital consideration in designing 3D hepatocyte culture configuration. PMID:26994875

  19. Functional and Structural Abnormalities in Deferoxamine Retinopathy: A Review of the Literature

    PubMed Central

    Di Nicola, Maura; Barteselli, Giulio; Dell'Arti, Laura; Ratiglia, Roberto; Viola, Francesco

    2015-01-01

    Deferoxamine mesylate (DFO) is the most commonly used iron-chelating agent to treat transfusion-related hemosiderosis. Despite the clear advantages for the use of DFO, numerous DFO-related systemic toxicities have been reported in the literature, as well as sight-threatening ocular toxicity involving the retinal pigment epithelium (RPE). The damage to the RPE can lead to visual field defects, color-vision defects, abnormal electrophysiological tests, and permanent visual deterioration. The purpose of this review is to provide an updated summary of the ocular findings, including both functional and structural abnormalities, in DFO-treated patients. In particular, we pay particular attention to analyzing results of multimodal technologies for retinal imaging, which help ophthalmologists in the early diagnosis and correct management of DFO retinopathy. Fundus autofluorescence, for example, is not only useful for screening patients at high-risk of DFO retinopathy, but is also a prerequisite for identify specific high-risk patterns of RPE changes that are relevant for the prognosis of the disease. In addition, optical coherence tomography may have a clinical usefulness in detecting extent and location of different retinal changes in DFO retinopathy. Finally, this review wants to underline the need for universally approved guidelines for screening and followup of this particular disease. PMID:26167477

  20. Abnormal Compartmentalization of Cartilage Matrix Components in Mice Lacking Collagen X: Implications for Function

    PubMed Central

    Kwan, Kin Ming; Pang, Michael K.M.; Zhou, Sheila; Cowan, Soot Keng; Kong, Richard Y.C.; Pfordte, Tim; Olsen, Bjorn R.; Sillence, David O.; Tam, Patrick P.L.; Cheah, Kathryn S.E.

    1997-01-01

    There are conflicting views on whether collagen X is a purely structural molecule, or regulates bone mineralization during endochondral ossification. Mutations in the human collagen α1(X) gene (COL10A1) in Schmid metaphyseal chondrodysplasia (SMCD) suggest a supportive role. But mouse collagen α1(X) gene (Col10a1) null mutants were previously reported to show no obvious phenotypic change. We have generated collagen X deficient mice, which shows that deficiency does have phenotypic consequences which partly resemble SMCD, such as abnormal trabecular bone architecture. In particular, the mutant mice develop coxa vara, a phenotypic change common in human SMCD. Other consequences of the mutation are reduction in thickness of growth plate resting zone and articular cartilage, altered bone content, and atypical distribution of matrix components within growth plate cartilage. We propose that collagen X plays a role in the normal distribution of matrix vesicles and proteoglycans within the growth plate matrix. Collagen X deficiency impacts on the supporting properties of the growth plate and the mineralization process, resulting in abnormal trabecular bone. This hypothesis would accommodate the previously conflicting views of the function of collagen X and of the molecular pathogenesis of SMCD. PMID:9015315

  1. Left-Hemispheric Microstructural Abnormalities in Children With High Functioning Autism Spectrum Disorder

    PubMed Central

    Peterson, Daniel; Mahajan, Rajneesh; Crocetti, Deana; Mejia, Amanda; Mostofsky, Stewart

    2014-01-01

    Current theories of the neurobiological basis of Autism Spectrum Disorder (ASD) posit an altered pattern of connectivity in large-scale brain networks. Here we used Diffusion Tensor Imaging to investigate the microstructural properties of the white matter that mediates inter-regional connectivity in 36 high-functioning children with ASD (HF-ASD), as compared to 37 controls. By employing an atlas-based analysis using LDDMM registration, a widespread, but left-lateralized pattern of abnormalities was revealed. The Mean Diffusivity (MD) of water in the white matter of HF-ASD children was significantly elevated throughout the left hemisphere, particularly in the outer-zone cortical white matter. Across diagnostic groups there was a significant effect of age on left hemisphere MD, with a similar reduction in MD during childhood in both TD and HF-ASD children. The increased MD in children with HF-ASD suggests hypomyelination, and may reflect increased short-range cortico-cortical connections subsequent to early white matter overgrowth. These findings also highlight left hemispheric connectivity as relevant to the pathophysiology of ASD, and indicate that the spatial distribution of microstructural abnormalities in HF-ASD is widespread, and left-lateralized. This altered left-hemispheric connectivity may contribute to deficits in communication and praxis observed in ASD. PMID:25256103

  2. Positron Emission Tomography Reveals Abnormal Topological Organization in Functional Brain Network in Diabetic Patients

    PubMed Central

    Qiu, Xiangzhe; Zhang, Yanjun; Feng, Hongbo; Jiang, Donglang

    2016-01-01

    Recent studies have demonstrated alterations in the topological organization of structural brain networks in diabetes mellitus (DM). However, the DM-related changes in the topological properties in functional brain networks are unexplored so far. We therefore used fluoro-D-glucose positron emission tomography (FDG-PET) data to construct functional brain networks of 73 DM patients and 91 sex- and age-matched normal controls (NCs), followed by a graph theoretical analysis. We found that both DM patients and NCs had a small-world topology in functional brain network. In comparison to the NC group, the DM group was found to have significantly lower small-world index, lower normalized clustering coefficients and higher normalized characteristic path length. Moreover, for diabetic patients, the nodal centrality was significantly reduced in the right rectus, the right cuneus, the left middle occipital gyrus, and the left postcentral gyrus, and it was significantly increased in the orbitofrontal region of the left middle frontal gyrus, the left olfactory region, and the right paracentral lobule. Our results demonstrated that the diabetic brain was associated with disrupted topological organization in the functional PET network, thus providing functional evidence for the abnormalities of brain networks in DM. PMID:27303259

  3. Neurological Gait Abnormalities Moderate the Functional Brain Signature of the Posture First Hypothesis.

    PubMed

    Holtzer, Roee; Verghese, Joe; Allali, Gilles; Izzetoglu, Meltem; Wang, Cuiling; Mahoney, Jeannette R

    2016-03-01

    The posture first hypothesis suggests that under dual-task walking conditions older adults prioritize gait over cognitive task performance. Functional neural confirmation of this hypothesis, however, is lacking. Herein, we determined the functional neural correlates of the posture first hypothesis and hypothesized that the presence of neurological gait abnormalities (NGA) would moderate associations between brain activations, gait and cognitive performance. Using functional near-infrared spectroscopy we assessed changes in oxygenated hemoglobin levels in the pre-frontal cortex (PFC) during normal walk and walk while talk (WWT) conditions in a large cohort of non-demented older adults (n = 236; age = 75.5 ± 6.49 years; female = 51.7 %). NGA were defined as central (due to brain diseases) or peripheral (neuropathic gait) following a standardized neurological examination protocol. Double dissociations between brain activations and behavior emerged as a function of NGA. Higher oxygenation levels during WWT were related to better cognitive performance (estimate = 0.145; p < 0.001) but slower gait velocity (estimate = -6.336, p < 0.05) among normals. In contrast, higher oxygenation levels during WWT among individuals with peripheral NGA were associated with worse cognitive performance (estimate = -0.355; p < 0.001) but faster gait velocity (estimate = 14.855; p < 0.05). Increased activation in the PFC during locomotion may have a compensatory function that is designed to support gait among individuals with peripheral NGA. PMID:26613725

  4. Cognitive, neurophysiological, and functional correlates of proverb interpretation abnormalities in schizophrenia.

    PubMed

    Kiang, Michael; Light, Gregory A; Prugh, Jocelyn; Coulson, Seana; Braff, David L; Kutas, Marta

    2007-07-01

    A hallmark of schizophrenia is impaired proverb interpretation, which could be due to: (1) aberrant activation of disorganized semantic associations, or (2) working memory (WM) deficits. We assessed 18 schizophrenia patients and 18 normal control participants on proverb interpretation, and evaluated these two hypotheses by examining within patients the correlations of proverb interpretation with disorganized symptoms and auditory WM, respectively. Secondarily, we also explored the relationships between proverb interpretation and a spectrum of cognitive functions including auditory sensory-memory encoding (as indexed by the mismatch negativity (MMN) event-related brain potential (ERP)); executive function; and social/occupational function. As expected, schizophrenia patients produced less accurate and less abstract descriptions of proverbs than did controls. These proverb interpretation difficulties in patients were not significantly correlated with disorganization or other symptom factors, but were significantly correlated (p < .05) with WM impairment, as well as with impairments in sensory-memory encoding, executive function, and social/occupational function. These results offer no support for disorganized associations in abnormal proverb interpretation in schizophrenia, but implicate WM deficits, perhaps as a part of a syndrome related to generalized frontal cortical dysfunction. PMID:17521483

  5. Positron Emission Tomography Reveals Abnormal Topological Organization in Functional Brain Network in Diabetic Patients.

    PubMed

    Qiu, Xiangzhe; Zhang, Yanjun; Feng, Hongbo; Jiang, Donglang

    2016-01-01

    Recent studies have demonstrated alterations in the topological organization of structural brain networks in diabetes mellitus (DM). However, the DM-related changes in the topological properties in functional brain networks are unexplored so far. We therefore used fluoro-D-glucose positron emission tomography (FDG-PET) data to construct functional brain networks of 73 DM patients and 91 sex- and age-matched normal controls (NCs), followed by a graph theoretical analysis. We found that both DM patients and NCs had a small-world topology in functional brain network. In comparison to the NC group, the DM group was found to have significantly lower small-world index, lower normalized clustering coefficients and higher normalized characteristic path length. Moreover, for diabetic patients, the nodal centrality was significantly reduced in the right rectus, the right cuneus, the left middle occipital gyrus, and the left postcentral gyrus, and it was significantly increased in the orbitofrontal region of the left middle frontal gyrus, the left olfactory region, and the right paracentral lobule. Our results demonstrated that the diabetic brain was associated with disrupted topological organization in the functional PET network, thus providing functional evidence for the abnormalities of brain networks in DM. PMID:27303259

  6. Abnormal prefrontal cortex resting state functional connectivity and severity of internet gaming disorder.

    PubMed

    Jin, Chenwang; Zhang, Ting; Cai, Chenxi; Bi, Yanzhi; Li, Yangding; Yu, Dahua; Zhang, Ming; Yuan, Kai

    2016-09-01

    Internet Gaming Disorder (IGD) among adolescents has become an important public concern and gained more and more attention internationally. Recent studies focused on IGD and revealed brain abnormalities in the IGD group, especially the prefrontal cortex (PFC). However, the role of PFC-striatal circuits in pathology of IGD remains unknown. Twenty-five adolescents with IGD and 21 age- and gender-matched healthy controls were recruited in our study. Voxel-based morphometric (VBM) and functional connectivity analysis were employed to investigate the abnormal structural and resting-state properties of several frontal regions in individuals with online gaming addiction. Relative to healthy comparison subjects, IGD subjects showed significant decreased gray matter volume in PFC regions including the bilateral dorsolateral prefrontal cortex (DLPFC), orbitofrontal cortex (OFC), anterior cingulate cortex (ACC) and the right supplementary motor area (SMA) after controlling for age and gender effects. We chose these regions as the seeding areas for the resting-state analysis and found that IGD subjects showed decreased functional connectivity between several cortical regions and our seeds, including the insula, and temporal and occipital cortices. Moreover, significant decreased functional connectivity between some important subcortical regions, i.e., dorsal striatum, pallidum, and thalamus, and our seeds were found in the IGD group and some of those changes were associated with the severity of IGD. Our results revealed the involvement of several PFC regions and related PFC-striatal circuits in the process of IGD and suggested IGD may share similar neural mechanisms with substance dependence at the circuit level. PMID:26311395

  7. Abnormal Functional Connectivity of Amygdala in Late-Onset Depression Was Associated with Cognitive Deficits

    PubMed Central

    Yue, Yingying; Yuan, Yonggui; Hou, Zhenghua; Jiang, Wenhao; Bai, Feng; Zhang, Zhijun

    2013-01-01

    Background Major depressive disorder (MDD) is associated with decreased function of cortico-limbic circuits, which play important roles in the pathogenesis of MDD. Abnormal functional connectivity (FC) with the amygdala, which is involved in cortico-limbic circuits, has also been observed in MDD. However, little is known about connectivity alterations in late-onset depression (LOD) or whether disrupted connectivity is correlated with cognitive impairment in LOD. Methods and Results A total of twenty-two LOD patients and twenty-two matched healthy controls (HC) underwent neuropsychological tests and resting state functional magnetic resonance imaging (rs-fMRI). Regional homogeneity (ReHo) and FC with bilateral amygdala seeds were used to analyze blood oxygen level-dependent fMRI data between two groups. Compared with HC, LOD patients showed decreased ReHo in the right middle frontal gyrus and left superior frontal gyrus. In the LOD group, the left amygdala had decreased FC with the right middle frontal gyrus and the left superior frontal gyrus in the amygdala positive network, and it had increased FC with the right post-central gyrus in the amygdala negative network. However, significantly reduced FC with the right amygdala was observed in the right middle occipital gyrus in the amygdala negative network. Further correlative analyses revealed that decreased FC between the amygdala and the right middle occipital gyrus was negatively correlated with the verbal fluency test (VFT, r = −0.485, P = 0.022) and the digit span test (DST, r = −0.561, P = 0.007). Conclusions Our findings of reduced activity of the prefrontal gyrus and abnormal FC with the bilateral amygdala may be key markers of cognitive dysfunction in LOD patients. PMID:24040385

  8. Abnormal GABAergic function and face processing in schizophrenia: A pharmacologic-fMRI study.

    PubMed

    Tso, Ivy F; Fang, Yu; Phan, K Luan; Welsh, Robert C; Taylor, Stephan F

    2015-10-01

    The involvement of the gamma-aminobutyric acid (GABA) system in schizophrenia is suggested by postmortem studies and the common use of GABA receptor-potentiating agents in treatment. In a recent study, we used a benzodiazepine challenge to demonstrate abnormal GABAergic function during processing of negative visual stimuli in schizophrenia. This study extended this investigation by mapping GABAergic mechanisms associated with face processing and social appraisal in schizophrenia using a benzodiazepine challenge. Fourteen stable, medicated schizophrenia/schizoaffective patients (SZ) and 13 healthy controls (HC) underwent functional MRI using the blood oxygenation level-dependent (BOLD) technique while they performed the Socio-emotional Preference Task (SePT) on emotional face stimuli ("Do you like this face?"). Participants received single-blinded intravenous saline and lorazepam (LRZ) in two separate sessions separated by 1-3weeks. Both SZ and HC recruited medial prefrontal cortex/anterior cingulate during the SePT, relative to gender identification. A significant drug by group interaction was observed in the medial occipital cortex, such that SZ showed increased BOLD signal to LRZ challenge, while HC showed an expected decrease of signal; the interaction did not vary by task. The altered BOLD response to LRZ challenge in SZ was significantly correlated with increased negative affect across multiple measures. The altered response to LRZ challenge suggests that abnormal face processing and negative affect in SZ are associated with altered GABAergic function in the visual cortex, underscoring the role of impaired visual processing in socio-emotional deficits in schizophrenia. PMID:26363970

  9. Abnormal functional architecture of amygdala-centered networks in adolescent posttraumatic stress disorder.

    PubMed

    Aghajani, Moji; Veer, Ilya M; van Hoof, Marie-José; Rombouts, Serge A R B; van der Wee, Nic J; Vermeiren, Robert R J M

    2016-03-01

    Posttraumatic stress disorder (PTSD) is a prevalent, debilitating, and difficult to treat psychiatric disorder. Very little is known of how PTSD affects neuroplasticity in the developing adolescent brain. Whereas multiple lines of research implicate amygdala-centered network dysfunction in the pathophysiology of adult PTSD, no study has yet examined the functional architecture of amygdala subregional networks in adolescent PTSD. Using intrinsic functional connectivity analysis, we investigated functional connectivity of the basolateral (BLA) and centromedial (CMA) amygdala in 19 sexually abused adolescents with PTSD relative to 23 matched controls. Additionally, we examined whether altered amygdala subregional connectivity coincides with abnormal grey matter volume of the amygdaloid complex. Our analysis revealed abnormal amygdalar connectivity and morphology in adolescent PTSD patients. More specifically, PTSD patients showed diminished right BLA connectivity with a cluster including dorsal and ventral portions of the anterior cingulate and medial prefrontal cortices (p < 0.05, corrected). In contrast, PTSD patients showed increased left CMA connectivity with a cluster including the orbitofrontal and subcallosal cortices (p < 0.05, corrected). Critically, these connectivity changes coincided with diminished grey matter volume within BLA and CMA subnuclei (p < 0.05, corrected), with CMA connectivity shifts additionally relating to more severe symptoms of PTSD. These findings provide unique insights into how perturbations in major amygdalar circuits could hamper fear regulation and drive excessive acquisition and expression of fear in PTSD. As such, they represent an important step toward characterizing the neurocircuitry of adolescent PTSD, thereby informing the development of reliable biomarkers and potential therapeutic targets. PMID:26859310

  10. Abnormal transient rise in hepatic glucose production after oral glucose in non-insulin-dependent diabetic subjects.

    PubMed

    Thorburn, A; Litchfield, A; Fabris, S; Proietto, J

    1995-05-01

    A transient rise in hepatic glucose production (HGP) after an oral glucosa load has been reported in some insulin-resistant states such as in obese fa/fa Zucker rats. The aim of this study was to determine whether this rise in HGP also occurs in subjects with established non-insulin-dependent diabetes mellitus (NIDDM). Glucose kinetics were measured basally and during a double-label oral glucose tolerance test (OGTT) in 12 NIDDM subjects and 12 non-diabetic 'control' subjects. Twenty minutes after the glucose load, HGP had increased 73% above basal in the NIDDM subjects (7.29 +/- 0.52 to 12.58 +/- 1.86 mumol/kg/min, P < 0.02). A transient rise in glucagon (12 pg/ml above basal, P < 0.004) occurred at a similar time. In contrast, the control subjects showed no rise in HGP or plasma glucagon. HGP began to suppress 40-50 min after the OGTT in both the NIDDM and control subjects. A 27% increase in the rate of gut-derived glucose absorption was also observed in the NIDDM group, which could be the result of increased gut glucose absorption or decreased first pass extraction of glucose by the liver. Therefore, in agreement with data in animal models of NIDDM, a transient rise in HGP partly contributes to the hyperglycemia observed after an oral glucose load in NIDDM subjects. PMID:7587920

  11. Resting state functional MRI reveals abnormal network connectivity in neurofibromatosis 1.

    PubMed

    Tomson, Steffie N; Schreiner, Matthew J; Narayan, Manjari; Rosser, Tena; Enrique, Nicole; Silva, Alcino J; Allen, Genevera I; Bookheimer, Susan Y; Bearden, Carrie E

    2015-11-01

    Neurofibromatosis type I (NF1) is a genetic disorder caused by mutations in the neurofibromin 1 gene at locus 17q11.2. Individuals with NF1 have an increased incidence of learning disabilities, attention deficits, and autism spectrum disorders. As a single-gene disorder, NF1 represents a valuable model for understanding gene-brain-behavior relationships. While mouse models have elucidated molecular and cellular mechanisms underlying learning deficits associated with this mutation, little is known about functional brain architecture in human subjects with NF1. To address this question, we used resting state functional connectivity magnetic resonance imaging (rs-fcMRI) to elucidate the intrinsic network structure of 30 NF1 participants compared with 30 healthy demographically matched controls during an eyes-open rs-fcMRI scan. Novel statistical methods were employed to quantify differences in local connectivity (edge strength) and modularity structure, in combination with traditional global graph theory applications. Our findings suggest that individuals with NF1 have reduced anterior-posterior connectivity, weaker bilateral edges, and altered modularity clustering relative to healthy controls. Further, edge strength and modular clustering indices were correlated with IQ and internalizing symptoms. These findings suggest that Ras signaling disruption may lead to abnormal functional brain connectivity; further investigation into the functional consequences of these alterations in both humans and in animal models is warranted. PMID:26304096

  12. Abnormal striatal resting-state functional connectivity in adolescents with obsessive-compulsive disorder.

    PubMed

    Bernstein, Gail A; Mueller, Bryon A; Schreiner, Melinda Westlund; Campbell, Sarah M; Regan, Emily K; Nelson, Peter M; Houri, Alaa K; Lee, Susanne S; Zagoloff, Alexandra D; Lim, Kelvin O; Yacoub, Essa S; Cullen, Kathryn R

    2016-01-30

    Neuroimaging research has implicated abnormalities in cortico-striatal-thalamic-cortical (CSTC) circuitry in pediatric obsessive-compulsive disorder (OCD). In this study, resting-state functional magnetic resonance imaging (R-fMRI) was used to investigate functional connectivity in the CSTC circuitry in adolescents with OCD. Imaging was obtained with the Human Connectome Project (HCP) scanner using newly developed pulse sequences which allow for higher spatial and temporal resolution. Fifteen adolescents with OCD and 13 age- and gender-matched healthy controls (ages 12-19) underwent R-fMRI on the 3T HCP scanner. Twenty-four minutes of resting-state scans (two consecutive 12-min scans) were acquired. We investigated functional connectivity of the striatum using a seed-based, whole brain approach with anatomically-defined seeds placed in the bilateral caudate, putamen, and nucleus accumbens. Adolescents with OCD compared with controls exhibited significantly lower functional connectivity between the left putamen and a single cluster of right-sided cortical areas including parts of the orbitofrontal cortex, inferior frontal gyrus, insula, and operculum. Preliminary findings suggest that impaired striatal connectivity in adolescents with OCD in part falls within the predicted CSTC network, and also involves impaired connections between a key CSTC network region (i.e., putamen) and key regions in the salience network (i.e., insula/operculum). The relevance of impaired putamen-insula/operculum connectivity in OCD is discussed. PMID:26674413

  13. Hepatic SirT1-Dependent Gain-of-Function of Stearoyl-CoA Desaturase-1 Conveys Dysmetabolic and Tumor Progression Functions

    PubMed Central

    Qiang, Li; Kon, Ning; Zhao, Wenhui; Jiang, Le; Knight, Colette M.; Welch, Carrie; Pajvani, Utpal

    2015-01-01

    SUMMARY Obesity is associated with higher incidence of cancer but the predisposing mechanisms remain poorly understood. The NAD+–dependent deacetylase SirT1 orchestrates metabolism, cellular survival, and growth. To date, there is no unifying mechanism to explain the metabolic and tumor-related effects of SirT1. In this work, we demonstrate that genetic ablation of the endogenous inhibitor of SirT1, Deleted-in-Breast-Cancer-1 (Dbc1), unexpectedly results in obesity and insulin-resistance. Dbc1 deficiency promoted SirT1-dependent gain-of-function of stearoyl-coenzyme A desaturase 1 (Scd1), increasing plasma and tissue levels of unsaturated fatty acids. The metabolic abnormalities in Dbc1−/− mice were reversed by ablation of hepatic SirT1 or by inhibition of Scd1 activity. Furthermore, loss of Dbc1 impaired master tumor suppressor p53 activation and treatment of Scd1 inhibitor extended survival of tumorigenic TP53−/− mice by decreasing tumor-related death. Together, our findings illustrate a shared mechanism of obesity and tumor progression through hepatic SirT1 gain-of-function in a metabolic control step, with potential therapeutic implications. PMID:26074075

  14. Quinine allergy causing acute severe systemic illness: report of 4 patients manifesting multiple hematologic, renal, and hepatic abnormalities

    PubMed Central

    2003-01-01

    Quinine is widely used for the common symptom of leg cramps. Quinine tablets require a prescription, but quinine and the product from which it is derived, cinchona, are also available without prescription. They are components of over-the-counter remedies for many common symptoms, of nutrition products, and of beverages such as tonic water and bitter lemon. Although quinine has been used for centuries, initially as an extract from the bark of the cinchona tree, allergic reactions to quinine can be severe and can affect multiple organs. These allergic reactions can cause thrombocytopenia, neutropenia, anemia, disseminated intravascular coagulation, acute renal failure, liver toxicity, and neurological abnormalities. Because quinine use is often intermittent, defining quinine as a cause of an acute disorder may be difficult. Moreover, since quinine use is often self-regulated, patients may not mention it in response to direct questions about medication use, adding to diagnostic difficulty. The diversity and severity of quinine-associated disorders and the difficulties of diagnosis are illustrated by the presentation of 4 case histories. Awareness of the variety of potential quinine-associated reactions is important for accurate diagnosis and critical for prevention of recurrent illness. PMID:16278718

  15. Gray Matter Abnormalities in Temporal Lobe Epilepsy: Relationships with Resting-State Functional Connectivity and Episodic Memory Performance

    PubMed Central

    Doucet, Gaelle E.; He, Xiaosong; Sperling, Michael; Sharan, Ashwini; Tracy, Joseph I.

    2016-01-01

    Temporal lobe epilepsy (TLE) affects multiple brain regions through evidence from both structural (gray matter; GM) and functional connectivity (FC) studies. We tested whether these structural abnormalities were associated with FC abnormalities, and assessed the ability of these measures to explain episodic memory impairments in this population. A resting-state and T1 sequences were acquired on 94 (45 with mesial temporal pathology) TLE patients and 50 controls, using magnetic resonance imaging (MRI) technique. A voxel-based morphometry analysis was computed to determine the GM volume differences between groups (right, left TLE, controls). Resting-state FC between the abnormal GM volume regions was computed, and compared between groups. Finally, we investigated the relation between EM, GM and FC findings. Patients with and without temporal pathology were analyzed separately. The results revealed reduced GM volume in multiple regions in the patients relative to the controls. Using FC, we found the abnormal GM regions did not display abnormal functional connectivity. Lastly, we found in left TLE patients, verbal episodic memory was associated with abnormal left posterior hippocampus volume, while in right TLE, non-verbal episodic memory was better predicted by resting-state FC measures. This study investigated TLE abnormalities using a multi-modal approach combining GM, FC and neurocognitive measures. We did not find that the GM abnormalities were functionally or abnormally connected during an inter-ictal resting state, which may reflect a weak sensitivity of functional connectivity to the epileptic network. We provided evidence that verbal and non-verbal episodic memory in left and right TLE patients may have distinct relationships with structural and functional measures. Lastly, we provide data suggesting that in the setting of occult, non-lesional right TLE pathology, a coupling of structural and functional abnormalities in extra-temporal/non-ictal regions is

  16. Gray Matter Abnormalities in Temporal Lobe Epilepsy: Relationships with Resting-State Functional Connectivity and Episodic Memory Performance.

    PubMed

    Doucet, Gaelle E; He, Xiaosong; Sperling, Michael; Sharan, Ashwini; Tracy, Joseph I

    2016-01-01

    Temporal lobe epilepsy (TLE) affects multiple brain regions through evidence from both structural (gray matter; GM) and functional connectivity (FC) studies. We tested whether these structural abnormalities were associated with FC abnormalities, and assessed the ability of these measures to explain episodic memory impairments in this population. A resting-state and T1 sequences were acquired on 94 (45 with mesial temporal pathology) TLE patients and 50 controls, using magnetic resonance imaging (MRI) technique. A voxel-based morphometry analysis was computed to determine the GM volume differences between groups (right, left TLE, controls). Resting-state FC between the abnormal GM volume regions was computed, and compared between groups. Finally, we investigated the relation between EM, GM and FC findings. Patients with and without temporal pathology were analyzed separately. The results revealed reduced GM volume in multiple regions in the patients relative to the controls. Using FC, we found the abnormal GM regions did not display abnormal functional connectivity. Lastly, we found in left TLE patients, verbal episodic memory was associated with abnormal left posterior hippocampus volume, while in right TLE, non-verbal episodic memory was better predicted by resting-state FC measures. This study investigated TLE abnormalities using a multi-modal approach combining GM, FC and neurocognitive measures. We did not find that the GM abnormalities were functionally or abnormally connected during an inter-ictal resting state, which may reflect a weak sensitivity of functional connectivity to the epileptic network. We provided evidence that verbal and non-verbal episodic memory in left and right TLE patients may have distinct relationships with structural and functional measures. Lastly, we provide data suggesting that in the setting of occult, non-lesional right TLE pathology, a coupling of structural and functional abnormalities in extra-temporal/non-ictal regions is

  17. 1-deoxynojirimycin isolated from Bacillus subtilis improves hepatic lipid metabolism and mitochondrial function in high-fat-fed mice.

    PubMed

    Do, Hyun Ju; Chung, Ji Hyung; Hwang, Ji Won; Kim, Oh Yoen; Lee, Jae-Yeon; Shin, Min-Jeong

    2015-01-01

    The aim of this study was to determine whether 1-deoxynojirimycin (DNJ) isolated from Bacillus subtilis MORI beneficially influences lipid metabolism and mitochondrial function in the liver of mice fed a high-fat diet in addition to the anti-obesity properties of DNJ. Male C57BL/6 mice (n = 29; 5 weeks old) were randomly assigned to three groups: normal control diet (CTL, n = 10), high-fat diet (HF, n = 10), and high-fat diet supplemented with DNJ (DNJ, n = 9). After 12 weeks, the HF group exhibited higher overall weight gain, of the liver, and of various fat pads than the CTL and DNJ groups did. The HF group also showed greater expression of C/EBPα and CD36 mRNA in the liver than that in the CTL and/or DNJ groups. In addition, mRNA expressions of AAC and FAS were lower, while mRNA expression of PGC-1β was higher in the liver of the DNJ group than that of the HF group. The hepatic expression of p-AMPK/AMPK was higher in the DNJ group than in the HF group. This study provides novel insight into the protective effect of DNJ supplementation against obesity-induced hepatic lipid abnormalities and mitochondrial dysfunction. PMID:25445511

  18. White matter microstructure abnormalities and executive function in adolescents with prenatal cocaine exposure

    PubMed Central

    Lebel, Catherine; Warner, Tamara; Colby, John; Soderberg, Lindsay; Roussotte, Florence; Behnke, Marylou; Davis Eyler, Fonda; Sowell, Elizabeth R.

    2013-01-01

    Children with prenatal exposure to cocaine are at higher risk for negative behavioral function and attention difficulties, and have demonstrated brain diffusion abnormalities in frontal white matter regions. However, brain regions beyond frontal and callosal areas have not been investigated using diffusion tensor imaging (DTI). DTI data were collected on 42 youth aged 14–16 years; subjects were divided into three groups based on detailed exposure histories: those with prenatal exposure to cocaine but not alcohol (PCE, n=12), prenatal exposure to cocaine and alcohol (CAE, n=17), and controls (n=13). Tractography was performed and along-tract diffusion parameters were examined for group differences and correlations with executive function measures. In the right arcuate fasciculus and cingulum, the CAE group had higher fractional anisotropy (FA) and/or lower mean diffusivity (MD) than the other two groups. The PCE group demonstrated lower FA in the right arcuate and higher MD in the splenium of the corpus callosum than controls. Diffusion parameters in tracts with group differences correlated with measures of executive function. In conclusion, these diffusion differences in adolescents with prenatal cocaine exposure suggest localized, long-term structural brain alterations that may underlie attention and response inhibition difficulties. PMID:23769420

  19. Neonatal Dexamethasone Treatment Leads to Alterations in Cell Signaling Cascades Controlling Hepatic and Cardiac Function in Adulthood

    PubMed Central

    Adigun, Abayomi A.; Wrench, Nicola; Seidler, Frederic J.; Slotkin, Theodore A.

    2009-01-01

    Increasing evidence indicates that early-life glucocorticoid exposure, either involving stress or the therapy of preterm labor, contributes to metabolic and cardiovascular disorders in adulthood. We investigated cellular mechanisms underlying these effects by administering dexamethasone (DEX) to neonatal rats on postnatal (PN) days 1–3 or 7–9, using doses spanning the threshold for somatic growth impairment: 0.05, 0.2 and 0.8 mg/kg. In adulthood, we assessed the effects on hepatic and cardiac cell function mediated through the adenylyl cyclase (AC) signaling cascade, which controls neuronal and hormonal inputs that regulate hepatic glucose metabolism and cardiac contractility. Treatment on PN1-3 produced heterologous sensitization of hepatic signaling, with upregulation of AC itself leading to parallel increases in the responses to β-adrenergic or glucagon receptor stimulation, or to activation of G-proteins by fluoride. The effects were seen at the lowest dose but increasing DEX past the point of somatic growth impairment led to loss of the effect in females. Nonmonotonic effects were also present in the heart, where males showed AC sensitization at the lowest dose, with decreasing effects as the dose was raised; females showed progressive deficits of cardiac AC activity. Shifting the exposure to PN7-9 still elicited AC sensitization but with a greater offsetting contribution at the higher doses. Our findings show that, in contrast to growth restriction, the glucocorticoids associated with stress or the therapy of preterm labor are more sensitive and more important contributors to the cellular abnormalities underlying subsequent metabolic and cardiovascular dysfunction. PMID:19853034

  20. Hepatic Steatosis and Thyroid Function Tests in Overweight and Obese Children

    PubMed Central

    Pacifico, L.; Bonci, E.; Ferraro, F.; Andreoli, G.; Bascetta, S.; Chiesa, C.

    2013-01-01

    Objectives. Associations between thyroid function and nonalcoholic fatty liver disease (NAFLD) are unknown in childhood. Thus, the aim of the present study was to investigate in 402 consecutive overweight/obese children the association between thyroid function tests and hepatic steatosis as well as metabolic variables. Methods. Hepatic steatosis was diagnosed by ultrasound after exclusion of infectious and metabolic disorders. Fasting serum samples were taken for determination of thyroid function (TSH, FT4, and FT3), along with alanine aminotransferase (ALT), lipid profile, glucose, insulin, and insulin resistance (IR). Results. Eighty-eight children (21.9%) had TSH above the normal range (>4.0 mIU/L). FT3 and FT4 were within the reference intervals in all subjects. Elevated TSH was associated with increased odds of having hepatic steatosis (OR 2.10 (95% CI, 1.22–3.60)), hepatic steatosis with elevated ALT (2.42 (95% CI, 1.29–4.51)), hypertriglyceridemia, elevated total cholesterol, and IR as well as metabolic syndrome (considered as a single clinical entity), after adjustment for age, gender, pubertal status, and body mass index-SD score (or waist circumference). Conclusions. In overweight/obese children, elevated TSH concentration is a significant predictor of hepatic steatosis and lipid and glucose dysmetabolism, independently of the degree of total and visceral obesity. PMID:23431294

  1. Diastolic abnormalities in systemic sclerosis: evidence for associated defective cardiac functional reserve.

    PubMed Central

    Valentini, G; Vitale, D F; Giunta, A; Maione, S; Gerundo, G; Arnese, M; Tirri, E; Pelaggi, N; Giacummo, A; Tirri, G; Condorelli, M

    1996-01-01

    OBJECTIVE: To investigate the pattern of diastolic abnormalities in patients with systemic sclerosis (SSc) and the relationship between impaired ventricular filling and systolic function. METHODS: Twenty four patients with SSc underwent M-mode and two dimensional echocardiography using echo-Doppler and gated blood pool cardiac angiography, both at rest and after exercise. RESULTS: An impaired diastolic relaxation of the left ventricle was detected in 10 of the 24 patients with SSc. Left ventricular ejection fraction at rest in these 10 patients with impaired ventricular filling did not differ from that in the remaining 14 patients, but eight of the 10 failed to increase their ejection fraction during exercise, compared with two of the 14 with normal ventricular filling (p = 0.003). CONCLUSION: Impaired relaxation of the left ventricle is a recently described feature of scleroderma heart disease. Diastolic dysfunction in SSc could depend on myocardial fibrosis or myocardial ischaemia, or both. It was found to be associated with a defective cardiac functional reserve. However, its prognostic significance remains to be clarified. PMID:8774164

  2. Kinesin family 17 (osmotic avoidance abnormal-3) is dispensable for photoreceptor morphology and function.

    PubMed

    Jiang, Li; Tam, Beatrice M; Ying, Guoxing; Wu, Sen; Hauswirth, William W; Frederick, Jeanne M; Moritz, Orson L; Baehr, Wolfgang

    2015-12-01

    In Caenorhabditis elegans, homodimeric [kinesin family (KIF) 17, osmotic avoidance abnormal-3 (OSM-3)] and heterotrimeric (KIF3) kinesin-2 motors are required to establish sensory cilia by intraflagellar transport (IFT) where KIF3 and KIF17 cooperate to build the axoneme core and KIF17 builds the distal segments. However, the function of KIF17 in vertebrates is unresolved. We expressed full-length and motorless KIF17 constructs in mouse rod photoreceptors using adeno-associated virus in Xenopus laevis rod photoreceptors using a transgene and in ciliated IMCD3 cells. We found that tagged KIF17 localized along the rod outer segment axoneme when expressed in mouse and X. laevis photoreceptors, whereas KIF3A was restricted to the proximal axoneme. Motorless KIF3A and KIF17 mutants caused photoreceptor degeneration, likely through dominant negative effects on IFT. KIF17 mutant lacking the motor domain translocated to nuclei after exposure of a C-terminal nuclear localization signal. Germ-line deletion of Kif17 in mouse did not affect photoreceptor function. A rod-specific Kif3/Kif17 double knockout mouse demonstrated that KIF17 and KIF3 do not act synergistically and did not prevent rhodopsin trafficking to rod outer segments. In summary, the nematode model of KIF3/KIF17 cooperation apparently does not apply to mouse photoreceptors in which the photosensory cilium is built exclusively by KIF3. PMID:26229057

  3. Cytoarchitectural and functional abnormalities of the inferior colliculus in sudden unexplained perinatal death.

    PubMed

    Lavezzi, Anna M; Pusiol, Teresa; Matturri, Luigi

    2015-02-01

    The inferior colliculus is a mesencephalic structure endowed with serotonergic fibers that plays an important role in the processing of acoustic information. The implication of the neuromodulator serotonin also in the aetiology of sudden unexplained fetal and infant death syndromes and the demonstration in these pathologies of developmental alterations of the superior olivary complex (SOC), a group of pontine nuclei likewise involved in hearing, prompted us to investigate whether the inferior colliculus may somehow contribute to the pathogenetic mechanism of unexplained perinatal death. Therefore, we performed in a wide set of fetuses and infants, aged from 33 gestational weeks to 7 postnatal months and died of both known and unknown cause, an in-depth anatomopathological analysis of the brainstem, particularly of the midbrain. Peculiar neuroanatomical and functional abnormalities of the inferior colliculus, such as hypoplasia/structural disarrangement and immunonegativity or poor positivity of serotonin, were exclusively found in sudden death victims, and not in controls. In addition, these alterations were frequently related to dysgenesis of connected structures, precisely the raphé nuclei and the superior olivary complex, and to nicotine absorption in pregnancy. We propose, on the basis of these results, the involvement of the inferior colliculus in more important functions than those related to hearing, as breathing and, more extensively, all the vital activities, and then in pathological conditions underlying a sudden death in vulnerable periods of the autonomic nervous system development, particularly associated to harmful risk factors as cigarette smoking. PMID:25674737

  4. Abnormal functional specialization within medial prefrontal cortex in high-functioning autism: a multi-voxel similarity analysis

    PubMed Central

    Meuwese, Julia D.I.; Towgood, Karren J.; Frith, Christopher D.; Burgess, Paul W.

    2009-01-01

    Multi-voxel pattern analyses have proved successful in ‘decoding’ mental states from fMRI data, but have not been used to examine brain differences associated with atypical populations. We investigated a group of 16 (14 males) high-functioning participants with autism spectrum disorder (ASD) and 16 non-autistic control participants (12 males) performing two tasks (spatial/verbal) previously shown to activate medial rostral prefrontal cortex (mrPFC). Each task manipulated: (i) attention towards perceptual versus self-generated information and (ii) reflection on another person's mental state (‘mentalizing'versus ‘non-mentalizing’) in a 2 × 2 design. Behavioral performance and group-level fMRI results were similar between groups. However, multi-voxel similarity analyses revealed strong differences. In control participants, the spatial distribution of activity generalized significantly between task contexts (spatial/verbal) when examining the same function (attention/mentalizing) but not when comparing different functions. This pattern was disrupted in the ASD group, indicating abnormal functional specialization within mrPFC, and demonstrating the applicability of multi-voxel pattern analysis to investigations of atypical populations. PMID:19174370

  5. Abnormal functional specialization within medial prefrontal cortex in high-functioning autism: a multi-voxel similarity analysis.

    PubMed

    Gilbert, Sam J; Meuwese, Julia D I; Towgood, Karren J; Frith, Christopher D; Burgess, Paul W

    2009-04-01

    Multi-voxel pattern analyses have proved successful in 'decoding' mental states from fMRI data, but have not been used to examine brain differences associated with atypical populations. We investigated a group of 16 (14 males) high-functioning participants with autism spectrum disorder (ASD) and 16 non-autistic control participants (12 males) performing two tasks (spatial/verbal) previously shown to activate medial rostral prefrontal cortex (mrPFC). Each task manipulated: (i) attention towards perceptual versus self-generated information and (ii) reflection on another person's mental state ('mentalizing'versus 'non-mentalizing') in a 2 x 2 design. Behavioral performance and group-level fMRI results were similar between groups. However, multi-voxel similarity analyses revealed strong differences. In control participants, the spatial distribution of activity generalized significantly between task contexts (spatial/verbal) when examining the same function (attention/mentalizing) but not when comparing different functions. This pattern was disrupted in the ASD group, indicating abnormal functional specialization within mrPFC, and demonstrating the applicability of multi-voxel pattern analysis to investigations of atypical populations. PMID:19174370

  6. Surface expression and cytolytic function of natural killer cell receptors is altered in chronic hepatitis C

    PubMed Central

    Nattermann, J; Feldmann, G; Ahlenstiel, G; Langhans, B; Sauerbruch, T; Spengler, U

    2006-01-01

    Introduction Impaired activity of natural killer (NK) cells has been proposed as a mechanism contributing to viral persistence in hepatitis C virus (HCV) infection. As the function of NK cells is primarily regulated by NK cell receptors (NKR), we analysed whether decreased NK cell function in hepatitis C may be related to dysregulated NKR expression. Patients and methods Expression of NK cell was analysed by flow cytometry on lymphocytes from HCV(+) subjects (n = 30), patients who became HCV(−) after antiviral therapy (n = 10), healthy individuals (n = 10), and hepatitis B virus (HBV) infected patients (n = 9). Cytolytic function of lymphocytes was studied in a redirected lysis assay and in a standard 51chromium release cytotoxicity assay, respectively. Results In patients with chronic hepatitis C, we found a significantly reduced proportion of NKp46 and NKp30 expressing NK cells compared with healthy and HBV infected subjects. Low expression of natural cytotoxicity receptor (NCR) was also confirmed in in vitro activated NK cell populations derived from HCV patients compared with uninfected donors. In contrast, patients who cleared HCV under antiviral therapy showed normal expression of NKp44, NKp30, and NKp46. Reduced NCR expression in chronic hepatitis C was associated with a parallel decrease in NCR mediated target cell killing. Furthermore, we found a significantly increased proportion of NKG2A expressing NK cells and CD8+ T cells in HCV positive patients, resulting in a reduced cytolytic activity against cells incubated with the HLA‐E stabilising peptide HCV core35–44. Conclusion The present study indicates that defective expression of NKR represents a novel mechanism contributing to impaired function of NK cells and CD8+ T cells in chronic hepatitis C. PMID:16322112

  7. Physiologic assessment before video thoracoscopic resection for lung cancer in patients with abnormal pulmonary function

    PubMed Central

    Benattia, Amira; Debeaumont, David; Guyader, Vincent; Tardif, Catherine; Peillon, Christophe; Cuvelier, Antoine

    2016-01-01

    Background Impaired respiratory function may prevent curative surgery for patients with non-small cell lung cancer (NSCLC). Video-assisted thoracoscopic surgery (VATS) reduces postoperative morbility-mortality and could change preoperative assessment practices and therapeutic decisions. We evaluated the relation between preoperative pulmonary function tests and the occurrence of postoperative complications after VATS pulmonary resection in patients with abnormal pulmonary function. Methods We included 106 consecutive patients with ≤80% predicted value of presurgical expiratory volume in one second (FEV1) and/or diffusing capacity of carbon monoxide (DLCO) and who underwent VATS pulmonary resection for NSCLC from a prospective surgical database. Results Patients (64±9.5 years) had lobectomy (n=91), segmentectomy (n=7), bilobectomy (n=4), or pneumonectomy (n=4). FEV1 and DLCO preoperative averages were 68%±21% and 60%±18%. Operative mortality was 1.89%. Only FEV1 was predictive of postoperative complications [odds ratio (OR), 0.96; 95% confidence interval (CI), 0.926–0.991, P=0.016], but there was no determinable threshold. Twenty-five patients underwent incremental exercise testing. Desaturations during exercise (OR, 0.462; 95% CI, 0.191–0.878, P=0.039) and heart rate (HR) response (OR, 0.953; 95% CI, 0.895–0.993, P=0.05) were associated with postoperative complications. Conclusions FEV1 but not DLCO was a significant predictor of pulmonary complications after VATS pulmonary resection despite a low rate of severe morbidity. Incremental exercise testing seems more discriminating. Further investigation is required in a larger patient population to change current pre-operative threshold in a new era of minimally invasive surgery. PMID:27293834

  8. Adolescent Intermittent Alcohol Exposure: Persistence of Structural and Functional Hippocampal Abnormalities into Adulthood

    PubMed Central

    Risher, Mary-Louise; Fleming, Rebekah L.; Risher, Christopher; Miller, K. M.; Klein, Rebecca C.; Wills, Tiffany; Acheson, Shawn K.; Moore, Scott D.; Wilson, Wilkie A.; Eroglu, Cagla; Swartzwelder, H. S.

    2015-01-01

    Background Human adolescence is a crucial stage of neurological development during which ethanol (EtOH) consumption is often at its highest. Alcohol abuse during adolescence may render individuals at heightened risk for subsequent alcohol abuse disorders, cognitive dysfunction, or other neurological impairments by irreversibly altering long-term brain function. To test this possibility, we modeled adolescent alcohol abuse (i.e., intermittent EtOH exposure during adolescence [AIE]) in rats to determine whether adolescent exposure to alcohol leads to long-term structural and functional changes that are manifested in adult neuronal circuitry. Methods We specifically focused on hippocampal area CA1, a brain region associated with learning and memory. Using electrophysiological, immunohistochemical, and neuroanatomical approaches, we measured post-AIE changes in synaptic plasticity, dendritic spine morphology, and synaptic structure in adulthood. Results We found that AIE-pretreated adult rats manifest robust long-term potentiation, induced at stimulus intensities lower than those required in controls, suggesting a state of enhanced synaptic plasticity. Moreover, AIE resulted in an increased number of dendritic spines with characteristics typical of immaturity. Immunohistochemistry-based analysis of synaptic structures indicated a significant decrease in the number of co-localized pre- and postsynaptic puncta. This decrease is driven by an overall decrease in 2 postsynaptic density proteins, PSD-95 and SAP102. Conclusions Taken together, these findings reveal that repeated alcohol exposure during adolescence results in enduring structural and functional abnormalities in the hippocampus. These synaptic changes in the hippocampal circuits may help to explain learning-related behavioral changes in adult animals preexposed to AIE. PMID:25916839

  9. Shared alterations in NK cell frequency, phenotype, and function in chronic human immunodeficiency virus and hepatitis C virus infections.

    PubMed

    Meier, Ute-Christiane; Owen, Rachel E; Taylor, Elizabeth; Worth, Andrew; Naoumov, Nikolai; Willberg, Christian; Tang, Kwok; Newton, Phillipa; Pellegrino, Pierre; Williams, Ian; Klenerman, Paul; Borrow, Persephone

    2005-10-01

    Human immunodeficiency virus (HIV) and hepatitis C virus (HCV) cause clinically important persistent infections. The effects of virus persistence on innate immunity, including NK cell responses, and the underlying mechanisms are not fully understood. We examined the frequency, phenotype, and function of peripheral blood CD3- CD56+ NK subsets in HIV+ and HCV+ patients and identified significantly reduced numbers of total NK cells and a striking shift in NK subsets, with a marked decrease in the CD56(dim) cell fraction compared to CD56(bright) cells, in both infections. This shift influenced the phenotype and functional capacity (gamma interferon production, killing) of the total NK pool. In addition, abnormalities in the functional capacity of the CD56(dim) NK subset were observed in HIV+ patients. The shared NK alterations were found to be associated with a significant reduction in serum levels of the innate cytokine interleukin 15 (IL-15). In vitro stimulation with IL-15 rescued NK cells of HIV+ and HCV+ patients from apoptosis and enhanced proliferation and functional activity. We hypothesize that the reduced levels of IL-15 present in the serum during HIV and HCV infections might impact NK cell homeostasis, contributing to the common alterations of the NK pool observed in these unrelated infections. PMID:16160163

  10. Claudin-16 Deficiency Impairs Tight Junction Function in Ameloblasts, Leading to Abnormal Enamel Formation.

    PubMed

    Bardet, Claire; Courson, Frédéric; Wu, Yong; Khaddam, Mayssam; Salmon, Benjamin; Ribes, Sandy; Thumfart, Julia; Yamaguti, Paulo M; Rochefort, Gael Y; Figueres, Marie-Lucile; Breiderhoff, Tilman; Garcia-Castaño, Alejandro; Vallée, Benoit; Le Denmat, Dominique; Baroukh, Brigitte; Guilbert, Thomas; Schmitt, Alain; Massé, Jean-Marc; Bazin, Dominique; Lorenz, Georg; Morawietz, Maria; Hou, Jianghui; Carvalho-Lobato, Patricia; Manzanares, Maria Cristina; Fricain, Jean-Christophe; Talmud, Deborah; Demontis, Renato; Neves, Francisco; Zenaty, Delphine; Berdal, Ariane; Kiesow, Andreas; Petzold, Matthias; Menashi, Suzanne; Linglart, Agnes; Acevedo, Ana Carolina; Vargas-Poussou, Rosa; Müller, Dominik; Houillier, Pascal; Chaussain, Catherine

    2016-03-01

    Claudin-16 protein (CLDN16) is a component of tight junctions (TJ) with a restrictive distribution so far demonstrated mainly in the kidney. Here, we demonstrate the expression of CLDN16 also in the tooth germ and show that claudin-16 gene (CLDN16) mutations result in amelogenesis imperfecta (AI) in the 5 studied patients with familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC). To investigate the role of CLDN16 in tooth formation, we studied a murine model of FHHNC and showed that CLDN16 deficiency led to altered secretory ameloblast TJ structure, lowering of extracellular pH in the forming enamel matrix, and abnormal enamel matrix protein processing, resulting in an enamel phenotype closely resembling human AI. This study unravels an association of FHHNC owing to CLDN16 mutations with AI, which is directly related to the loss of function of CLDN16 during amelogenesis. Overall, this study indicates for the first time the importance of a TJ protein in tooth formation and underlines the need to establish a specific dental follow-up for these patients. PMID:26426912

  11. Abnormal cleavage of APP impairs its functions in cell adhesion and migration.

    PubMed

    Sheng, Baiyang; Song, Bo; Zheng, Zhenhuan; Zhou, Fangfang; Lu, Guangyuan; Zhao, Nanming; Zhang, Xiufang; Gong, Yandao

    2009-02-01

    Amyloid precursor protein (APP) is expressed ubiquitously but its wrong cleavage only occurs in central nervous system. In this research, overexpression of wild type human APP695 was found to stimulate the adhesion and migration of N2a cells. In the cells co-transfected by familial Alzheimer's disease (FAD)-linked Swedish mutant of APP695 gene plus big up tri, openE9 deleted presenilin1 gene (N2a/Swe. big up tri, open9), however, this stimulating function was impaired compared to that in the cells co-transfected by Swedish mutant of APP695 gene plus dominant negative mutant of presenilin1 D385A gene (N2a/Swe.385). Furthermore, it was also found that the phosphorylation of FAK Tyr-861 and GSK-3beta Ser-9 was reduced in N2a/Swe.Delta9 cells, which can be possibly taken as a reasonable explanation for the underlying mechanism. Our results suggest that impaired cell adhesion and migration induced by abnormal cleavage of APP could contribute to the pathological effects in FAD brain. PMID:19056463

  12. Serotonin transporter variant drives preventable gastrointestinal abnormalities in development and function.

    PubMed

    Margolis, Kara Gross; Li, Zhishan; Stevanovic, Korey; Saurman, Virginia; Israelyan, Narek; Anderson, George M; Snyder, Isaac; Veenstra-VanderWeele, Jeremy; Blakely, Randy D; Gershon, Michael D

    2016-06-01

    Autism spectrum disorder (ASD) is an increasingly common behavioral condition that frequently presents with gastrointestinal (GI) disturbances. It is not clear, however, how gut dysfunction relates to core ASD features. Multiple, rare hyperfunctional coding variants of the serotonin (5-HT) transporter (SERT, encoded by SLC6A4) have been identified in ASD. Expression of the most common SERT variant (Ala56) in mice increases 5-HT clearance and causes ASD-like behaviors. Here, we demonstrated that Ala56-expressing mice display GI defects that resemble those seen in mice lacking neuronal 5-HT. These defects included enteric nervous system hypoplasia, slow GI transit, diminished peristaltic reflex activity, and proliferation of crypt epithelial cells. An opposite phenotype was seen in SERT-deficient mice and in progeny of WT dams given the SERT antagonist fluoxetine. The reciprocal phenotypes that resulted from increased or decreased SERT activity support the idea that 5-HT signaling regulates enteric neuronal development and can, when disturbed, cause long-lasting abnormalities of GI function. Administration of a 5-HT4 agonist to Ala56 mice during development prevented Ala56-associated GI perturbations, suggesting that excessive SERT activity leads to inadequate 5-HT4-mediated neurogenesis. We propose that deficient 5-HT signaling during development may contribute to GI and behavioral features of ASD. The consequences of therapies targeting SERT during pregnancy warrant further evaluation. PMID:27111230

  13. Serotonin transporter variant drives preventable gastrointestinal abnormalities in development and function

    PubMed Central

    Margolis, Kara Gross; Li, Zhishan; Stevanovic, Korey; Saurman, Virginia; Anderson, George M.; Snyder, Isaac; Blakely, Randy D.; Gershon, Michael D.

    2016-01-01

    Autism spectrum disorder (ASD) is an increasingly common behavioral condition that frequently presents with gastrointestinal (GI) disturbances. It is not clear, however, how gut dysfunction relates to core ASD features. Multiple, rare hyperfunctional coding variants of the serotonin (5-HT) transporter (SERT, encoded by SLC6A4) have been identified in ASD. Expression of the most common SERT variant (Ala56) in mice increases 5-HT clearance and causes ASD-like behaviors. Here, we demonstrated that Ala56-expressing mice display GI defects that resemble those seen in mice lacking neuronal 5-HT. These defects included enteric nervous system hypoplasia, slow GI transit, diminished peristaltic reflex activity, and proliferation of crypt epithelial cells. An opposite phenotype was seen in SERT-deficient mice and in progeny of WT dams given the SERT antagonist fluoxetine. The reciprocal phenotypes that resulted from increased or decreased SERT activity support the idea that 5-HT signaling regulates enteric neuronal development and can, when disturbed, cause long-lasting abnormalities of GI function. Administration of a 5-HT4 agonist to Ala56 mice during development prevented Ala56-associated GI perturbations, suggesting that excessive SERT activity leads to inadequate 5-HT4–mediated neurogenesis. We propose that deficient 5-HT signaling during development may contribute to GI and behavioral features of ASD. The consequences of therapies targeting SERT during pregnancy warrant further evaluation. PMID:27111230

  14. Abnormal functional global and local brain connectivity in female patients with anorexia nervosa

    PubMed Central

    Geisler, Daniel; Borchardt, Viola; Lord, Anton R.; Boehm, Ilka; Ritschel, Franziska; Zwipp, Johannes; Clas, Sabine; King, Joseph A.; Wolff-Stephan, Silvia; Roessner, Veit; Walter, Martin; Ehrlich, Stefan

    2016-01-01

    Background Previous resting-state functional connectivity studies in patients with anorexia nervosa used independent component analysis or seed-based connectivity analysis to probe specific brain networks. Instead, modelling the entire brain as a complex network allows determination of graph-theoretical metrics, which describe global and local properties of how brain networks are organized and how they interact. Methods To determine differences in network properties between female patients with acute anorexia nervosa and pairwise matched healthy controls, we used resting-state fMRI and computed well-established global and local graph metrics across a range of network densities. Results Our analyses included 35 patients and 35 controls. We found that the global functional network structure in patients with anorexia nervosa is characterized by increases in both characteristic path length (longer average routes between nodes) and assortativity (more nodes with a similar connectedness link together). Accordingly, we found locally decreased connectivity strength and increased path length in the posterior insula and thalamus. Limitations The present results may be limited to the methods applied during preprocessing and network construction. Conclusion We demonstrated anorexia nervosa–related changes in the network configuration for, to our knowledge, the first time using resting-state fMRI and graph-theoretical measures. Our findings revealed an altered global brain network architecture accompanied by local degradations indicating wide-scale disturbance in information flow across brain networks in patients with acute anorexia nervosa. Reduced local network efficiency in the thalamus and posterior insula may reflect a mechanism that helps explain the impaired integration of visuospatial and homeostatic signals in patients with this disorder, which is thought to be linked to abnormal representations of body size and hunger. PMID:26252451

  15. Prefrontal Dopaminergic Receptor Abnormalities and Executive Functions in Parkinson’s Disease

    PubMed Central

    Ko, Ji Hyun; Antonelli, Francesca; Monchi, Oury; Ray, Nicola; Rusjan, Pablo; Houle, Sylvain; Lang, Anthony E.; Christopher, Leigh; Strafella, Antonio P.

    2012-01-01

    The main pattern of cognitive impairments seen in early to moderate stages of Parkinson’s disease (PD) includes deficits of executive functions. These nonmotor complications have a significant impact on the quality of life and day-to-day activities of PD patients and are not effectively managed by current therapies, a problem which is almost certainly due to the fact that the disease extends beyond the nigrostriatal system. To investigate the role of extrastriatal dopamine in executive function in PD, PD patients and a control group were studied with positron-emission-tomography using a high-affinity dopamine D2/D3 receptor tracer, [11C]FLB-457. All participants were scanned twice while performing an executive task and a control task. Patients were off medication for at least 12 h. The imaging analysis revealed that parkinsonian patients had lower [11C]FLB-457 binding than control group independently of task conditions across different brain regions. Cognitive assessment measures were positively correlated with [11C]FLB-457 binding in the bilateral dorsolateral prefrontal cortex and anterior cingulate cortex only in control group, but not in PD patients. Within the control group, during the executive task (as compared to control task), there was evidence of reduced [11C]FLB-457 binding (indicative of increased dopamine release) in the right orbitofrontal cortex. In contrast, PD patients did not show any reduction in binding during the executive task (as compared with control task). These findings suggest that PD patients present significant abnormalities in extrastriatal dopamine associated with executive processing. These observations provide important insights on the pathophysiology of cognitive dysfunction in PD. PMID:22331665

  16. Graves' disease, Celiac disease and liver function abnormalities in a patient--clinical manifestation and diagnostic difficulties.

    PubMed

    Góra-Gębka, Magdalena; Woźniak, Małgorzata; Cielecka-Kuszyk, Joanna; Korpal-Szczyrska, Maria; Sznurkowska, Katarzyna; Zagierski, Maciej; Jankowska, Irena; Plata-Nazar, Katarzyna; Kamińska, Barbara; Liberek, Anna

    2014-01-01

    Autoimmune diseases due to probable common pathogenesis tend to coexist in some patients. Complex clinical presentation with diverse timing of particular symptoms and sophisticated treatment with numerous side effects, may cause diagnostic difficulties, especially in children. The paper presents diagnostic difficulties and pitfalls in a child with Graves' disease, celiac disease and liver function abnormalities. PMID:24904927

  17. Hepatic function in hypothermically stored porcine livers: comparison of hypothermic machine perfusion vs cold storage.

    PubMed

    Jain, S; Lee, C Y; Baicu, S; Duncan, H; Xu, H; Jones, J W; Clemens, M G; Brassil, J; Taylor, M J; Brockbank, K G M

    2005-01-01

    Hypothermic machine perfusion (HMP) has a potential to relieve the current donor liver crisis by providing an improved and extended preservation method. This study examined the effect of HMP on hepatocellular functions, using a prototype liver transporter capable of preserving livers for 24 hours. Livers obtained from adult farm pigs (28 to 32 kg body weight) were divided into three groups: fresh control, HMP, and simple cold storage (n = 4 each). A 4-hour normothermic reperfusion of livers was conducted to assess hepato-metabolic and cellular functions. The hepatic transport function, as indicated by canalicular excretion of indocyanine green, was improved in the HMP group than in the SCS group. The overall tissue viability, as indicated by oxygen consumption levels, was notably improved in HMP and control livers as compared to the SCS group. Higher bile production in both the preserved groups as compared to the fresh control livers could be a result of biliary edema and leakage of plasma into the canaliculus. The hepato-cellular injury, measured by ALT, release was significantly greater in the SCS group as compared to the HMP and control groups. These findings suggest that HMP could be a better method to preserve hepatic function and overall tissue viability as compared to SCS. Improved hepatic functions are indirect indicators of superior microcirculation and sinusoidal endothelial cell functions. Further studies in progress will evaluate these functions to confirm the significance of these observations. PMID:15808637

  18. Association of high viral load and abnormal liver function with high aflatoxin B1–albumin adduct levels in HIV-positive Ghanaians: preliminary observations

    PubMed Central

    Jolly, P.E.; Shuaib, F.M.; Jiang, Y.; Preko, P.; Baidoo, J.; Stiles, J.K.; Wang, J.-S.; Phillips, T.D.; Williams, J.H.

    2012-01-01

    We examined the association between certain clinical factors and aflatoxin B1–albumin adduct (AF-ALB) levels in HIV-positive people. Plasma samples collected from 314 (155 HIV-positive and 159 HIV-negative) people were tested for AF-ALB levels, viral load, CD4+ T-cell count, liver function profile, malaria parasitaemia, and hepatitis B and C virus infections. HIV-positive participants were divided into high and low groups based on their median AF-ALB of 0.93 pmol mg−1 albumin and multivariable logistic and linear regression methods used to assess relationships between clinical conditions and AF-ALB levels. Multivariable logistic regression showed statistically significant increased odds of having higher HIV viral loads (OR=2.84; 95% CI=1.17–7.78) and higher direct bilirubin levels (OR=5.47; 95% CI=1.03–22.85) among HIV-positive participants in the high AF-ALB group. There were also higher levels of total bilirubin and lower levels of albumin in association with high AF-ALB. Thus, aflatoxin exposure may contribute to high viral loads and abnormal liver function in HIV-positive people and so promote disease progression. PMID:21749228

  19. Abnormal barrier function in the pathogenesis of ichthyosis: Therapeutic implications for lipid metabolic disorders☆

    PubMed Central

    Elias, Peter M.; Williams, Mary L.; Feingold, Kenneth R.

    2013-01-01

    Ichthyoses, including inherited disorders of lipid metabolism, display a permeability barrier abnormality in which the severity of the clinical phenotype parallels the prominence of the barrier defect. The pathogenesis of the cutaneous phenotype represents the consequences of the mutation for epidermal function, coupled with a “best attempt” by affected epidermis to generate a competent barrier in a terrestrial environment. A compromised barrier in normal epidermis triggers a vigorous set of metabolic responses that rapidly normalizes function, but ichthyotic epidermis, which is inherently compromised, only partially succeeds in this effort. Unraveling mechanisms that account for barrier dysfunction in the ichthyoses has identified multiple, subcellular, and biochemical processes that contribute to the clinical phenotype. Current treatment of the ichthyoses remains largely symptomatic: directed toward reducing scale or corrective gene therapy. Reducing scale is often minimally effective. Gene therapy is impeded by multiple pitfalls, including difficulties in transcutaneous drug delivery, high costs, and discomfort of injections. We have begun to use information about disease pathogenesis to identify novel, pathogenesis-based therapeutic strategies for the ichthyoses. The clinical phenotype often reflects not only a deficiency of pathway end product due to reduced-function mutations in key synthetic enzymes but often also accumulation of proximal, potentially toxic metabolites. As a result, depending upon the identified pathomechanism(s) for each disorder, the accompanying ichthyosis can be treated by topical provision of pathway product (eg, cholesterol), with or without a proximal enzyme inhibitor (eg, simvastatin), to block metabolite production. Among the disorders of distal cholesterol metabolism, the cutaneous phenotype in Congenital Hemidysplasia with Ichthyosiform Erythroderma and Limb Defects (CHILD syndrome) and X-linked ichthyosis reflect metabolite

  20. Abnormal Mitochondrial Function and Impaired Granulosa Cell Differentiation in Androgen Receptor Knockout Mice

    PubMed Central

    Wang, Ruey-Sheng; Chang, Heng-Yu; Kao, Shu-Huei; Kao, Cheng-Heng; Wu, Yi-Chen; Yeh, Shuyuan; Tzeng, Chii-Reuy; Chang, Chawnshang

    2015-01-01

    In the ovary, the paracrine interactions between the oocyte and surrounded granulosa cells are critical for optimal oocyte quality and embryonic development. Mice lacking the androgen receptor (AR−/−) were noted to have reduced fertility with abnormal ovarian function that might involve the promotion of preantral follicle growth and prevention of follicular atresia. However, the detailed mechanism of how AR in granulosa cells exerts its effects on oocyte quality is poorly understood. Comparing in vitro maturation rate of oocytes, we found oocytes collected from AR−/− mice have a significantly poor maturating rate with 60% reached metaphase II and 30% remained in germinal vesicle breakdown stage, whereas 95% of wild-type AR (AR+/+) oocytes had reached metaphase II. Interestingly, we found these AR−/− female mice also had an increased frequency of morphological alterations in the mitochondria of granulosa cells with reduced ATP generation (0.18 ± 0.02 vs. 0.29 ± 0.02 µM/mg protein; p < 0.05) and aberrant mitochondrial biogenesis. Mechanism dissection found loss of AR led to a significant decrease in the expression of peroxisome proliferator-activated receptor γ (PPARγ) co-activator 1-β (PGC1-β) and its sequential downstream genes, nuclear respiratory factor 1 (NRF1) and mitochondrial transcription factor A (TFAM), in controlling mitochondrial biogenesis. These results indicate that AR may contribute to maintain oocyte quality and fertility via controlling the signals of PGC1-β-mediated mitochondrial biogenesis in granulosa cells. PMID:25941928

  1. Abnormalities of motor function, transcription and cerebellar structure in mouse models of THAP1 dystonia.

    PubMed

    Ruiz, Marta; Perez-Garcia, Georgina; Ortiz-Virumbrales, Maitane; Méneret, Aurelie; Morant, Andrika; Kottwitz, Jessica; Fuchs, Tania; Bonet, Justine; Gonzalez-Alegre, Pedro; Hof, Patrick R; Ozelius, Laurie J; Ehrlich, Michelle E

    2015-12-20

    DYT6 dystonia is caused by mutations in THAP1 [Thanatos-associated (THAP) domain-containing apoptosis-associated protein] and is autosomal dominant and partially penetrant. Like other genetic primary dystonias, DYT6 patients have no characteristic neuropathology, and mechanisms by which mutations in THAP1 cause dystonia are unknown. Thap1 is a zinc-finger transcription factor, and most pathogenic THAP1 mutations are missense and are located in the DNA-binding domain. There are also nonsense mutations, which act as the equivalent of a null allele because they result in the generation of small mRNA species that are likely rapidly degraded via nonsense-mediated decay. The function of Thap1 in neurons is unknown, but there is a unique, neuronal 50-kDa Thap1 species, and Thap1 levels are auto-regulated on the mRNA level. Herein, we present the first characterization of two mouse models of DYT6, including a pathogenic knockin mutation, C54Y and a null mutation. Alterations in motor behaviors, transcription and brain structure are demonstrated. The projection neurons of the deep cerebellar nuclei are especially altered. Abnormalities vary according to genotype, sex, age and/or brain region, but importantly, overlap with those of other dystonia mouse models. These data highlight the similarities and differences in age- and cell-specific effects of a Thap1 mutation, indicating that the pathophysiology of THAP1 mutations should be assayed at multiple ages and neuronal types and support the notion of final common pathways in the pathophysiology of dystonia arising from disparate mutations. PMID:26376866

  2. Cryo-chemical decellularization of the whole liver for mesenchymal stem cells-based functional hepatic tissue engineering

    PubMed Central

    Jiang, Wei-Cheng; Cheng, Yu-Hao; Yen, Meng-Hua; Chang, Yin; Yang, Vincent W.; Lee, Oscar K.

    2015-01-01

    Liver transplantation is the ultimate treatment for severe hepatic failure to date. However, the limited supply of donor organs has severely hampered this treatment. So far, great potentials of using mesenchymal stem cells (MSCs) to replenish the hepatic cell population have been shown; nevertheless, there still is a lack of an optimal three-dimensional scaffold for generation of well-transplantable hepatic tissues. In this study, we utilized a cryo-chemical decellularization method which combines physical and chemical approach to generate acellular liver scaffolds (ALS) from the whole liver. The produced ALS provides a biomimetic three-dimensional environment to support hepatic differentiation of MSCs, evidenced by expression of hepatic-associated genes and marker protein, glycogen storage, albumin secretion, and urea production. It is also found that hepatic differentiation of MSCs within the ALS is much more efficient than two-dimensional culture in vitro. Importantly, the hepatic-like tissues (HLT) generated by repopulating ALS with MSCs are able to act as functional grafts and rescue lethal hepatic failure after transplantation in vivo. In summary, the cryo-chemical method used in this study is suitable for decellularization of liver and create acellular scaffolds that can support hepatic differentiation of MSCs and be used to fabricate functional tissue-engineered liver constructs. PMID:24462361

  3. Disruption of Ah Receptor Signaling during Mouse Development Leads to Abnormal Cardiac Structure and Function in the Adult.

    PubMed

    Carreira, Vinicius S; Fan, Yunxia; Kurita, Hisaka; Wang, Qin; Ko, Chia-I; Naticchioni, Mindi; Jiang, Min; Koch, Sheryl; Zhang, Xiang; Biesiada, Jacek; Medvedovic, Mario; Xia, Ying; Rubinstein, Jack; Puga, Alvaro

    2015-01-01

    The Developmental Origins of Health and Disease (DOHaD) Theory proposes that the environment encountered during fetal life and infancy permanently shapes tissue physiology and homeostasis such that damage resulting from maternal stress, poor nutrition or exposure to environmental agents may be at the heart of adult onset disease. Interference with endogenous developmental functions of the aryl hydrocarbon receptor (AHR), either by gene ablation or by exposure in utero to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a potent AHR ligand, causes structural, molecular and functional cardiac abnormalities and altered heart physiology in mouse embryos. To test if embryonic effects progress into an adult phenotype, we investigated whether Ahr ablation or TCDD exposure in utero resulted in cardiac abnormalities in adult mice long after removal of the agent. Ten-months old adult Ahr-/- and in utero TCDD-exposed Ahr+/+ mice showed sexually dimorphic abnormal cardiovascular phenotypes characterized by echocardiographic findings of hypertrophy, ventricular dilation and increased heart weight, resting heart rate and systolic and mean blood pressure, and decreased exercise tolerance. Underlying these effects, genes in signaling networks related to cardiac hypertrophy and mitochondrial function were differentially expressed. Cardiac dysfunction in mouse embryos resulting from AHR signaling disruption seems to progress into abnormal cardiac structure and function that predispose adults to cardiac disease, but while embryonic dysfunction is equally robust in males and females, the adult abnormalities are more prevalent in females, with the highest severity in Ahr-/- females. The findings reported here underscore the conclusion that AHR signaling in the developing heart is one potential target of environmental factors associated with cardiovascular disease. PMID:26555816

  4. Disruption of Ah Receptor Signaling during Mouse Development Leads to Abnormal Cardiac Structure and Function in the Adult

    PubMed Central

    Carreira, Vinicius S.; Fan, Yunxia; Kurita, Hisaka; Wang, Qin; Ko, Chia-I; Naticchioni, Mindi; Jiang, Min; Koch, Sheryl; Zhang, Xiang; Biesiada, Jacek; Medvedovic, Mario; Xia, Ying; Rubinstein, Jack; Puga, Alvaro

    2015-01-01

    The Developmental Origins of Health and Disease (DOHaD) Theory proposes that the environment encountered during fetal life and infancy permanently shapes tissue physiology and homeostasis such that damage resulting from maternal stress, poor nutrition or exposure to environmental agents may be at the heart of adult onset disease. Interference with endogenous developmental functions of the aryl hydrocarbon receptor (AHR), either by gene ablation or by exposure in utero to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a potent AHR ligand, causes structural, molecular and functional cardiac abnormalities and altered heart physiology in mouse embryos. To test if embryonic effects progress into an adult phenotype, we investigated whether Ahr ablation or TCDD exposure in utero resulted in cardiac abnormalities in adult mice long after removal of the agent. Ten-months old adult Ahr-/- and in utero TCDD-exposed Ahr+/+ mice showed sexually dimorphic abnormal cardiovascular phenotypes characterized by echocardiographic findings of hypertrophy, ventricular dilation and increased heart weight, resting heart rate and systolic and mean blood pressure, and decreased exercise tolerance. Underlying these effects, genes in signaling networks related to cardiac hypertrophy and mitochondrial function were differentially expressed. Cardiac dysfunction in mouse embryos resulting from AHR signaling disruption seems to progress into abnormal cardiac structure and function that predispose adults to cardiac disease, but while embryonic dysfunction is equally robust in males and females, the adult abnormalities are more prevalent in females, with the highest severity in Ahr-/- females. The findings reported here underscore the conclusion that AHR signaling in the developing heart is one potential target of environmental factors associated with cardiovascular disease. PMID:26555816

  5. Pulmonary function abnormalities in adult patients with acute exacerbation of bronchiectasis: A retrospective risk factor analysis.

    PubMed

    Ma, Yanliang; Niu, Yuqian; Tian, Guizhen; Wei, Jingan; Gao, Zhancheng

    2015-08-01

    Lung function impairments, especially airflow obstruction, are important features during acute exacerbation in patients with bronchiectasis. Recognition of the risk factors associated with airflow obstruction is important in the management of these exacerbations. The medical records of adult patients admitted to the Peking University People's Hospital, Beijing, China, from 2004 to 2011 with a diagnosis of bronchiectasis were reviewed retrospectively. Univariate and multivariate analyses were used to evaluate the risk factors associated with airflow obstruction. Airflow obstruction was found in 55.6% of 156 patients hospitalized with acute exacerbation of bronchiectasis, and the risk factors associated with airflow obstruction included young age (≤14 years old) at diagnosis (odds ratio (OR) = 3.454, 95% confidence interval (CI) 1.709-6.982, p = 0.001) as well as the presence of chronic obstructive pulmonary disease (COPD; OR = 14.677, 95% CI 5.696-37.819, p = 0.001), asthma (OR = 3.063, 95% CI 1.403-6.690, p = 0.005), and wheezing on auscultation (OR = 3.279, 95% CI 1.495-7.194, p = 0.003). The C-reactive protein (13.9 mg/dl vs. 6.89 mg/dl, p = 0.005), partial pressure of arterial oxygen (66.7 ± 8.57 mmHg vs. 89.56 ± 12.80 mmHg, p < 0.001), and partial pressure of arterial carbon dioxide (40.52 ± 2.77 mmHg vs. 42.87 ± 5.39 mmHg, p = 0.02) profiles were different between patients with or without airflow obstruction. In addition, patients colonized with potential pathogenic microorganisms had a decreased diffusing capacity (56.0% vs. 64.7%, p = 0.04). Abnormal pulmonary function was common in hospitalized patients with bronchiectasis exacerbations. Airflow obstruction was correlated with the patient's age at diagnosis, as well as the presence of combined COPD and asthma, and wheezing on auscultation, which also resulted in more severe systemic inflammation and hypoxemia. PMID:25882894

  6. Aberrant Resting-State Functional Connectivity Density in Patients with Hepatitis B Virus-Related Cirrhosis

    PubMed Central

    Lv, Xiao-Fei; Wu, Hua-Wang; Tian, Li; Han, Lu-Jun; Li, Jing; Qiu, Ying-Wei; Jiang, Gui-Hua; Zhang, Xue-Lin; Zhang, Rong; Xie, Chuan-Miao

    2016-01-01

    There is increasing evidence that cirrhosis may affect functional connectivity among various brain regions in patients prior to onset of overt hepatic encephalopathy (HE). However, most investigators have focused mainly on alterations in functional connectivity strengths, and the changes in functional connectivity density (FCD) are largely unknown. Here, we investigated alterations in resting-state FCD in patients with hepatitis B virus-related cirrhosis (HBV-RC) without overt HE. Totally, 31 patients with HBV-RC without overt HE and 30 age- and sex-matched healthy controls underwent resting-state functional MRI examinations. FCD mapping was employed to compute local and global FCD maps. Then, short-range and long-range FCD values were calculated and voxel-based comparisons were performed between the two groups. The HBV-RC group showed significant decreases in FCD, including decreased short-range FCDs in the bilateral middle cingulum gyrus/precuneus, the bilateral cuneus, and the left lingual gyrus/inferior occipital gyrus and decreased long-range FCD in the bilateral cuneus/precuneus. In addition, the decreased long-range FCD in the bilateral cuneus/precuneus in the HBV-RC group was related to performance on the psychometric hepatic encephalopathy score (PHES) test. These findings suggest aberrant functional connectivity density in cirrhotic patients prior to overt HE onset, which may provide better insight into understanding the pathophysiological mechanisms underlying the cirrhotic-related cognitive impairment. PMID:27403426

  7. Pathogenesis of Hepatic Encephalopathy

    PubMed Central

    Ciećko-Michalska, Irena; Szczepanek, Małgorzata; Słowik, Agnieszka; Mach, Tomasz

    2012-01-01

    Hepatic encephalopathy can be a serious complication of acute liver failure and chronic liver diseases, predominantly liver cirrhosis. Hyperammonemia plays the most important role in the pathogenesis of hepatic encephalopathy. The brain-blood barrier disturbances, changes in neurotransmission, neuroinflammation, oxidative stress, GABA-ergic or benzodiazepine pathway abnormalities, manganese neurotoxicity, brain energetic disturbances, and brain blood flow abnormalities are considered to be involved in the development of hepatic encephalopathy. The influence of small intestine bacterial overgrowth (SIBO) on the induction of minimal hepatic encephalopathy is recently emphasized. The aim of this paper is to present the current views on the pathogenesis of hepatic encephalopathy. PMID:23316223

  8. Elevated copper impairs hepatic nuclear receptor function in Wilson’s disease

    PubMed Central

    Wooton-Kee, Clavia Ruth; Jain, Ajay K.; Wagner, Martin; Grusak, Michael A.; Finegold, Milton J.; Lutsenko, Svetlana; Moore, David D.

    2015-01-01

    Wilson’s disease (WD) is an autosomal recessive disorder that results in accumulation of copper in the liver as a consequence of mutations in the gene encoding the copper-transporting P-type ATPase (ATP7B). WD is a chronic liver disorder, and individuals with the disease present with a variety of complications, including steatosis, cholestasis, cirrhosis, and liver failure. Similar to patients with WD, Atp7b–/– mice have markedly elevated levels of hepatic copper and liver pathology. Previous studies have demonstrated that replacement of zinc in the DNA-binding domain of the estrogen receptor (ER) with copper disrupts specific binding to DNA response elements. Here, we found decreased binding of the nuclear receptors FXR, RXR, HNF4α, and LRH-1 to promoter response elements and decreased mRNA expression of nuclear receptor target genes in Atp7b–/– mice, as well as in adult and pediatric WD patients. Excessive hepatic copper has been described in progressive familial cholestasis (PFIC), and we found that similar to individuals with WD, patients with PFIC2 or PFIC3 who have clinically elevated hepatic copper levels exhibit impaired nuclear receptor activity. Together, these data demonstrate that copper-mediated nuclear receptor dysfunction disrupts liver function in WD and potentially in other disorders associated with increased hepatic copper levels. PMID:26241054

  9. Abnormal resting-state functional connectivity of the nucleus accumbens in multi-year abstinent heroin addicts.

    PubMed

    Zou, Feng; Wu, Xinhuai; Zhai, Tianye; Lei, Yu; Shao, Yongcong; Jin, Xiao; Tan, Shuwen; Wu, Bing; Wang, Lubin; Yang, Zheng

    2015-11-01

    Functional neuroimaging studies suggest that abnormal brain functional connectivity may be the neural underpinning of addiction to illicit drugs and of relapse after successful cessation therapy. Aberrant brain networks have been demonstrated in addicted patients and in newly abstinent addicts. However, it is not known whether abnormal brain connectivity patterns persist after prolonged abstinence. In this cross-sectional study, whole-brain resting-state functional magnetic resonance images (8 min) were collected from 30 heroin-addicted individuals after a long period of abstinence (more than 3 years) and from 30 healthy controls. We first examined the group differences in the resting-state functional connectivity of the nucleus accumbens (NAc), a brain region implicated in relapse-related processes, including craving and reactivity to stress following acute and protracted withdrawal from heroin. We then examined the relation between the duration of abstinence and the altered NAc functional connectivity in the heroin group. We found that, compared with controls, heroin-dependent participants exhibited significantly greater functional connectivity between the right ventromedial prefrontal cortex and the NAc and weaker functional connectivity between the NAc and the left putamen, left precuneus, and supplementary motor area. However, with longer abstinence time, the strength of NAc functional connectivity with the left putamen increased. These results indicate that dysfunction of the NAc functional network is still present in long-term-abstinent heroin-dependent individuals. PMID:26280556

  10. Inductive effects of rifapentine on mice hepatic mixed function oxidase system.

    PubMed

    Liu, D Y; Wang, Y S

    1990-03-01

    Rifapentine (R773, DL473) is a long-acting antituberculous drug used in China. In our experiments we have found some manifestations of induction of hepatic mixed function oxidase system in mice following pretreatment with rifapentine or phenobarbital. Both rifapentine and phenobarbital significantly increased the rate of antipyrine and pentobarbital metabolism in vivo. They also increased liver weight, the content of liver microsomal protein and cytochrome P-450, the activity of NADPH-cytochrome C reductase and NADPH oxidase. SDS-polyacylamide gel electrophoresis showed that the relative proportions of some polypeptide bands in mice microsomal fraction were significantly changed following rifapentine or phenobarbital pretreatment. The results indicate that rifapentine, like phenobarbital, is a potent inducer of hepatic mixed function oxidase system in mice and that it should be used carefully in clinical therapy, when combined with other drugs. PMID:2319833

  11. Effect of hepatic function on the EC50 of midazolam and the BIS50 at the time of loss of consciousness*

    PubMed Central

    Li, Yu-hong; He, Rui; Ruan, Jin-guang

    2014-01-01

    Objective: To explore the effect of hepatic function on loss of consciousness (LOC) and bispectral index (BIS) during sedation with midazolam (MDZ). Methods: Forty-five patients were assigned to three groups according to their liver function. Thirty of these patients with diagnoses of cholelithiasis were scheduled laparoscopic cholecystectomy, including 15 patients with normal liver function (normal group), and 15 patients with moderately abnormal liver function based on the results of ultrasonic diagnosis of a moderately fatty liver and elevated alanine transaminase levels of less than three times normal (moderate group). The other 15 patients with end-stage liver disease (severe group) underwent liver transplantation. Each patient was administered MDZ by way of target-controlled infusion to increase the concentration gradually. At the time of LOC, the BIS was recorded and a blood sample was withdrawn for measurement of the concentration of MDZ. The concentration of MDZ (EC50) and the BIS value (BIS50) at which 50% of patients lose consciousness were calculated using logistic regression. Results: At the time of LOC, the EC50 of MDZ and the BIS50 were similar in the normal and moderate groups (P>0.05). LOC occurred at a lower EC50 of MDZ and at a higher BIS50 in the severe group, compared with the normal and moderate groups (P<0.01). Conclusions: Patients with end-stage liver disease were more sensitive to MDZ and this affected the prediction of their time of LOC following MDZ administration. There were no changes in response in patients with moderately abnormal hepatic function. PMID:25091993

  12. FUNCTIONAL CONSEQUENCES OF PRENATAL METHYLMERCURY EXPOSURE: EFFECTS ON RENAL AND HEPATIC RESPONSES TO TROPHIC STIMULI AND ON RENAL EXCRETORY MECHANISMS

    EPA Science Inventory

    The effects of prenatal exposure to methylmercury on the functional development of renal and hepatic response systems was examined in the developing rat. Methylmercury produced an elevation of basal activity of renal ornithine decarboxylase (ODC, an enzyme involved in regulation ...

  13. Experimental nonalcoholic steatohepatitis compromises ureagenesis, an essential hepatic metabolic function.

    PubMed

    Thomsen, Karen Louise; Grønbæk, Henning; Glavind, Emilie; Hebbard, Lionel; Jessen, Niels; Clouston, Andrew; George, Jacob; Vilstrup, Hendrik

    2014-08-01

    Nonalcoholic steatohepatitis (NASH) is increasing in prevalence, yet its consequences for liver function are unknown. We studied ureagenesis, an essential metabolic liver function of importance for whole body nitrogen homeostasis, in a rodent model of diet-induced NASH. Rats were fed a high-fat, high-cholesterol diet for 4 and 16 wk, resulting in early and advanced experimental NASH, respectively. We examined the urea cycle enzyme mRNAs in liver tissue, the hepatocyte urea cycle enzyme proteins, and the in vivo capacity of urea-nitrogen synthesis (CUNS). Early NASH decreased all of the urea cycle mRNAs to an average of 60% and the ornithine transcarbamylase protein to 10%, whereas the CUNS remained unchanged. Advanced NASH further decreased the carbamoyl phosphate synthetase protein to 63% and, in addition, decreased the CUNS by 20% [from 5.65 ± 0.23 to 4.58 ± 0.30 μmol × (min × 100 g)(-1); P = 0.01]. Early NASH compromised the genes and enzyme proteins involved in ureagenesis, whereas advanced NASH resulted in a functional reduction in the capacity for ureagenesis. The pattern of urea cycle perturbations suggests a prevailing mitochondrial impairment by NASH. The decrease in CUNS has consequences for the ability of the body to adjust to changes in the requirements for nitrogen homeostasis e.g., at stressful events. NASH, thus, in terms of metabolic consequences, is not an innocuous lesion, and the manifestations of the damage seem to be a continuum with increasing disease severity. PMID:24924745

  14. Functional abnormalities in the cortical processing of sound complexity and musical consonance in schizophrenia: evidence from an evoked potential study

    PubMed Central

    2013-01-01

    Background Previous studies have demonstrated functional and structural temporal lobe abnormalities located close to the auditory cortical regions in schizophrenia. The goal of this study was to determine whether functional abnormalities exist in the cortical processing of musical sound in schizophrenia. Methods Twelve schizophrenic patients and twelve age- and sex-matched healthy controls were recruited, and participants listened to a random sequence of two kinds of sonic entities, intervals (tritones and perfect fifths) and chords (atonal chords, diminished chords, and major triads), of varying degrees of complexity and consonance. The perception of musical sound was investigated by the auditory evoked potentials technique. Results Our results showed that schizophrenic patients exhibited significant reductions in the amplitudes of the N1 and P2 components elicited by musical stimuli, to which consonant sounds contributed more significantly than dissonant sounds. Schizophrenic patients could not perceive the dissimilarity between interval and chord stimuli based on the evoked potentials responses as compared with the healthy controls. Conclusion This study provided electrophysiological evidence of functional abnormalities in the cortical processing of sound complexity and music consonance in schizophrenia. The preliminary findings warrant further investigations for the underlying mechanisms. PMID:23721126

  15. Associations Between Abnormal Rod-Mediated Dark Adaptation and Health and Functioning in Older Adults With Normal Macular Health

    PubMed Central

    Owsley, Cynthia; Huisingh, Carrie; Jackson, Gregory R.; Curcio, Christine A.; Szalai, Alexander J.; Dashti, Nassrin; Clark, Mark; Rookard, Kia; McCrory, Mark A.; Wright, Tyler T.; Callahan, Michael A.; Kline, Lanning B.; Witherspoon, C. Douglas; McGwin, Gerald

    2014-01-01

    Purpose. Delayed rod-mediated dark adaptation (DA) is characteristic of early age-related macular degeneration (AMD) and also can be observed in some older adults in normal macular health. We examine cross-sectional associations between rod-mediated DA and risk factors for AMD in older adults in normal macular health. Methods. The sample consisted of adults aged ≥60 years old in normal macular health per grading of fundus photos using an established disease classification system. Rod-mediated DA was measured psychophysically following a photobleach using a computer-automated dark adaptometer with targets centered at 5° on the inferior vertical meridian. The speed of DA was characterized by the rod-intercept value, with abnormal DA defined as rod-intercept ≥ 12.3 minutes. We assessed several health and functional characteristics that the literature has suggested increase AMD risk (e.g., smoking, alcohol use, inflammatory markers, apolipoproteins, low luminance visual acuity, chronic medical conditions, body mass, family history). Results. Among 381 participants (mean age, 68.5 years; SD, 5.5), 78% had normal and 22% had abnormal DA, with the prevalence of abnormal DA increasing with age. After age-adjustment, abnormal DA was associated with increased odds of elevated C-reactive protein (CRP), heavy use of or abstention from alcohol, high blood pressure, and drop in visual acuity under mesopic conditions. Conclusions. Despite having normal macular health according to accepted definitions of AMD presence, approximately one-quarter of older adults recruited from primary eye care clinics had abnormal DA, which was associated with known risk factors for AMD, including elevated CRP. PMID:24854857

  16. Association of increased rate of condemnation of broiler carcasses due to hepatic abnormalities with immunosuppressive diseases in the broiler chicken industry in Saskatchewan.

    PubMed

    Amini, Keyvan; Zachar, Tara; Popowich, Shelly; Knezacek, Tennille; Goodhope, Bob; Willson, Philip; Gomis, Susantha

    2015-10-01

    The objective of this study was to identify the causative agents of hepatitis observed in broiler chickens at processing. Livers of chickens from 16 broiler farms in Saskatchewan with gross lesions of hepatitis were collected at processing. In addition to routine bacterial isolation and histopathological examination, serologic studies for infectious bursal disease virus (IBDV) and Chicken anaemia virus (CAV), calculation of the ratio of the weight of the bursa of Fabricius (BF) to body weight (BBW), and histopathological examination of the BF were done. Of the 264 livers with gross lesions, 83% had multifocal to coalescing necrotizing hepatitis, 16% had perihepatitis, and 1% had hemorrhages. No definitive causative microorganisms were isolated from the hepatic lesions; however, no significant bacterial isolations were made. Bursal atrophy, low BBW ratio, and high titer of antibody against IBDV each correlated with the rate of total condemnations (P = 0.0188, P = 0.0001, and P = 0.0073, respectively). Nucleotide sequencing of IBDV isolated from the BF identified the variant strains Delaware-E and 586. Condemnation because of hepatic lesions was correlated with titer of antibody against IBDV and BBW (P = 0.016 and P = 0.027). The results of this study demonstrate that hepatic lesions in Saskatchewan chickens are not currently caused by a primary bacterial pathogen but are associated with indicators of immunosuppression that is likely due to variant IBDV. PMID:26424905

  17. Association of increased rate of condemnation of broiler carcasses due to hepatic abnormalities with immunosuppressive diseases in the broiler chicken industry in Saskatchewan

    PubMed Central

    Amini, Keyvan; Zachar, Tara; Popowich, Shelly; Knezacek, Tennille; Goodhope, Bob; Willson, Philip; Gomis, Susantha

    2015-01-01

    The objective of this study was to identify the causative agents of hepatitis observed in broiler chickens at processing. Livers of chickens from 16 broiler farms in Saskatchewan with gross lesions of hepatitis were collected at processing. In addition to routine bacterial isolation and histopathological examination, serologic studies for infectious bursal disease virus (IBDV) and Chicken anaemia virus (CAV), calculation of the ratio of the weight of the bursa of Fabricius (BF) to body weight (BBW), and histopathological examination of the BF were done. Of the 264 livers with gross lesions, 83% had multifocal to coalescing necrotizing hepatitis, 16% had perihepatitis, and 1% had hemorrhages. No definitive causative microorganisms were isolated from the hepatic lesions; however, no significant bacterial isolations were made. Bursal atrophy, low BBW ratio, and high titer of antibody against IBDV each correlated with the rate of total condemnations (P = 0.0188, P = 0.0001, and P = 0.0073, respectively). Nucleotide sequencing of IBDV isolated from the BF identified the variant strains Delaware-E and 586. Condemnation because of hepatic lesions was correlated with titer of antibody against IBDV and BBW (P = 0.016 and P = 0.027). The results of this study demonstrate that hepatic lesions in Saskatchewan chickens are not currently caused by a primary bacterial pathogen but are associated with indicators of immunosuppression that is likely due to variant IBDV. PMID:26424905

  18. Liver function in acute viral hepatitis as determined by a hepatocyte-specific ligand: 99mTc-galactosyl-neoglycoalbumin.

    PubMed

    Virgolini, I; Müller, C; Höbart, J; Scheithauer, W; Angelberger, P; Bergmann, H; O'Grady, J; Sinzinger, H

    1992-04-01

    Twelve patients with recently diagnosed acute viral hepatitis underwent serial 99mTc-galactosyl neoglycoalbumin scanning of the liver (for up to 8 mo). Injection of 99mTc-galactosyl neoglycoalbumin (150 mBq) at a rate of 3.5 mg (50 nmol; 1 ml) revealed that the liver is the exclusive site of tracer uptake. Simulation of 99mTc-galactosyl neoglycoalbumin kinetics allowed quantification of galactosyl neoglycoalbumin binding to human hepatic binding protein. Return of liver function test scores to normal values was associated in two patients with hepatitis A, in four patients with hepatitis B and in two patients with non-A, non-B hepatitis virus infection, with increases in hepatic binding protein concentration (up to three times the initial concentration), binding rate constant and hepatic blood flow. In the other four patients (three patients with hepatitis B and one patient with cytomegalovirus infection) a prolonged course of disease was monitored. In the mean, hepatic binding protein increased from 0.41 +/- 0.11 mumol/L after onset of acute hepatitis (n = 12) to 0.78 +/- 0.21 mumol/L after 6 mo of follow-up (n = 10) (p less than 0.001). During this period, binding rate constant (72.4 +/- 12.6 vs. 82 +/- 11.5 mumol/L/sec; p less than 0.05) and hepatic blood flow (0.027 +/- 0.0051 vs. 0.031 +/- 0.0083 L/sec; p less than 0.05) increased. Hepatic binding protein concentration correlated highly with actual laboratory test results for liver function (r = 0.98; p = 0.0001). We conclude that scintigraphic evaluation of functional liver cell mass using the new receptor-tracer 99mTc-galactosyl neoglycoalbumin could provide an in vivo diagnostic means of quantifying liver function and assessing liver morphology. In addition, our findings suggest that changes in hepatic binding protein-receptor concentration are likely to occur in vivo. PMID:1551636

  19. Expression and function of renal and hepatic organic anion transporters in extrahepatic cholestasis

    PubMed Central

    Brandoni, Anabel; Hazelhoff, María Herminia; Bulacio, Romina Paula; Torres, Adriana Mónica

    2012-01-01

    Obstructive jaundice occurs in patients suffering from cholelithiasis and from neoplasms affecting the pancreas and the common bile duct. The absorption, distribution and elimination of drugs are impaired during this pathology. Prolonged cholestasis may alter both liver and kidney function. Lactam antibiotics, diuretics, non-steroidal anti-inflammatory drugs, several antiviral drugs as well as endogenous compounds are classified as organic anions. The hepatic and renal organic anion transport pathways play a key role in the pharmacokinetics of these compounds. It has been demonstrated that acute extrahepatic cholestasis is associated with increased renal elimination of organic anions. The present work describes the molecular mechanisms involved in the regulation of the expression and function of the renal and hepatic organic anion transporters in extrahepatic cholestasis, such as multidrug resistance-associated protein 2, organic anion transporting polypeptide 1, organic anion transporter 3, bilitranslocase, bromosulfophthalein/bilirubin binding protein, organic anion transporter 1 and sodium dependent bile salt transporter. The modulation in the expression of renal organic anion transporters constitutes a compensatory mechanism to overcome the hepatic dysfunction in the elimination of organic anions. PMID:23197884

  20. Erythropoietin ameliorates the motor and cognitive function impairments in a rat model of hepatic cirrhosis.

    PubMed

    Aghaei, Iraj; Nazeri, Masoud; Shabani, Mohammad; Mossavinasab, Marziehsadat; Mirhosseini, Fatemeh Khaleghi; Nayebpour, Mohsen; Dalili, Afshin

    2015-02-01

    Hepatic encephalopathy (HE) is a serious consequence of hepatic cirrhosis (HC). Previous studies have demonstrated cognitive impairments in both clinical and animal experiments of HC. Some potential therapeutic agents have been used to alleviate the cognitive symptoms in the animal models of HC. In the current study, the possible effect of erythropoietin (ERY) as a potent neuroprotective agent on motor and cognitive impairments induced by HC has been studied. Male Wistar rats (180-200 g) underwent bile duct ligation (BDL) or sham surgery. Administration of ERY (5,000 IU/kg, i.p., daily for three days) was initiated 2 weeks after surgery and lasted for the next 28 days. Open field, rotarod, Morris water maze and passive avoidance learning was used to evaluate the motor and cognitive function of the animals. ANOVA and repeated measures ANOVA were used to analyze the data. p < 0.05 was considered statistically significant. BDL rats had an increased level of hepatic enzymes and bilirubin. Impairment of balance function by BDL was reversed by ERY. Spatial and passive avoidance learning impairments observed in BDL rats were also reversed by chronic administration of ERY. ERY can be offered as a potential neuroprotective agent in the treatment of patients with HC that manifest mental dysfunctions. Though further studies are needed to clarify the exact mechanisms, the neuroprotective properties of ERY against BDL impairments were demonstrated in the current study. PMID:25115607

  1. Pediatric Patients with Vitiligo in Eastern China: Abnormalities in 145 Cases Based on Thyroid Function Tests and Immunological Findings

    PubMed Central

    Xianfeng, Cheng; Yuegen, Jiang; Zhiyu, Yin; Yan, Yang; Xuesi, Zeng; Fenglai, Wang; Ansheng, Li; Wei, Wang

    2015-01-01

    Background The aim of this study was to evaluate abnormalities in thyroid function according to tests and the humoral immune systems of patients from Eastern China with pediatric vitiligo. Material/Methods A total of 145 pediatric patients with vitiligo were investigated in this study, along with 59 children without autoimmune diseases as controls. Laboratory tests of thyroid function were conducted, and these tests examined free triiodothyronine (FT3), free thyroxine (FT4), thyroid stimulating hormone (TSH), thyroglobulin antibody (TG-Ab), thyroid peroxidase antibody (TPO-Ab), antinuclear antibodies (ANAs), immunoglobulins (IgA, IgM, and IgG), and complements (C3 and C4). Results A total of 63 patients (43.4%), including 39 boys (44.3%) and 24 girls (42.1%), displayed abnormalities in thyroid function according to the tests. This finding indicated that patients with vitiligo differed significantly from those in the control group (P<0.001), particularly in terms of FT3 and TSH abnormalities (P<0.05). However, these groups did not deviate significantly with respect to FT4, Tg-Ab, and TPO-Ab abnormalities (P>0.05). Thirteen patients (8.9%) and 1 (1.7%) control were positive for ANA. All 12 specific antibodies were detected in 8 patients. Anti-SSA/Ro-60 and anti-SSA/Ro-52 were the most prevalent antibodies, followed by anti-dsDNA and then by anti-SmD1 and CENB-P. The serum levels of IgA and IgG decreased more significantly in the vitiligo group than in the control group (P<0.001). However, no significant difference was observed in terms of IgM levels (P>0.05). C4 serum levels also decreased more significantly in the vitiligo group than in the control group (P=0.035). Conclusions Results suggest that the incidence of abnormalities in the thyroid functions of children and adolescents is significantly higher in those with vitiligo than that in those in the control group. In addition, immunological dysfunction is common in the vitiligo group. PMID:26496247

  2. Abnormal gray matter volume and resting-state functional connectivity in former heroin-dependent individuals abstinent for multiple years.

    PubMed

    Wang, Lubin; Zou, Feng; Zhai, Tianye; Lei, Yu; Tan, Shuwen; Jin, Xiao; Ye, Enmao; Shao, Yongcong; Yang, Yihong; Yang, Zheng

    2016-05-01

    Previous studies have suggested that heroin addiction is associated with structural and functional brain abnormalities. However, it is largely unknown whether these characteristics of brain abnormalities would be persistent or restored after long periods of abstinence. Considering the very high rates of relapse, we hypothesized that there may exist some latent neural vulnerabilities in abstinent heroin users. In this study, structural and resting-state functional magnetic resonance imaging data were collected from 30 former heroin-dependent (FHD) subjects who were drug free for more than 3 years and 30 non-addicted control (CN) volunteers. Voxel-based morphometry was used to identify possible gray matter volume differences between the FHD and CN groups. Alterations in resting-state functional connectivity in FHD were examined using brain areas with gray matter deficits as seed regions. Significantly reduced gray matter volume was observed in FHD in an area surrounding the parieto-occipital sulcus, which included the precuneus and cuneus. Functional connectivity analyses revealed that the FHD subjects showed reduced positive correlation within the default mode network and visual network and decreased negative correlation between the default mode network, visual network and task positive network. Moreover, the altered functional connectivity was correlated with self-reported impulsivity scores in the FHD subjects. Our findings suggest that disruption of large-scale brain systems is present in former heroin users even after multi-year abstinence, which could serve as system-level neural underpinnings for behavioral dysfunctions associated with addiction. PMID:25727574

  3. Estimating Functional Liver Reserve Following Hepatic Irradiation: Adaptive Normal Tissue Response Models

    PubMed Central

    Stenmark, Matthew H.; Cao, Yue; Wang, Hesheng; Jackson, Andrew; Ben-Josef, Edgar; Ten Haken, Randall K.; Lawrence, Theodore S.; Feng, Mary

    2014-01-01

    Purpose To estimate the limit of functional liver reserve for safe application of hepatic irradiation using changes in indocyanine green, an established assay of liver function. Materials and Methods From 2005–2011, 60 patients undergoing hepatic irradiation were enrolled in a prospective study assessing the plasma retention fraction of indocyanine green at 15-min (ICG-R15) prior to, during (at 60% of planned dose), and after radiotherapy (RT). The limit of functional liver reserve was estimated from the damage fraction of functional liver (DFL) post-RT [1−(ICG-R15pre-RT/ICG-R15post-RT)] where no toxicity was observed using a beta distribution function. Results Of 48 evaluable patients, 3 (6%) developed RILD, all within 2.5 months of completing RT. The mean ICG-R15 for non-RILD patients pre-RT, during-RT and 1-month post-RT was 20.3%(SE 2.6), 22.0%(3.0), and 27.5%(2.8), and for RILD patients was 6.3%(4.3), 10.8%(2.7), and 47.6%(8.8). RILD was observed at post-RT damage fractions of ≥78%. Both DFL assessed by during-RT ICG and MLD predicted for DFL post-RT (p<0.0001). Limiting the post-RT DFL to 50%, predicted a 99% probability of a true complication rate <15%. Conclusion The DFL as assessed by changes in ICG during treatment serves as an early indicator of a patient’s tolerance to hepatic irradiation. PMID:24813090

  4. Somatosensory Amplification, Anxiety, and Depression in Patients With Hepatitis B: Impact on Functionality

    PubMed Central

    Yilmaz, Ahmet; Ucmak, Feyzullah; Dönmezdil, Süleyman; Kaya, Mehmet Cemal; Tekin, Recep; Günes, Mehmet; Arslan, Necmi; Bulut, Mahmut

    2016-01-01

    Abstract In the present study, we aimed to determine the differences in body image along with anxiety and depression levels, and also to evaluate their impact on disability parameters in patients with hepatitis B. Our study comprised 77 patients with hepatitis B (n = 41, chronic active patients; n = 36, patients with inactive hepatitis B) and 53 healthy individuals (control group). Enrolled patients responded to several questionnaires, including a sociodemographic form, Sheehan Disability Scale (SDS), Hospital Anxiety and Depression Scale (HADS), and Somatosensory Amplification Scale. Patients with chronic active hepatitis B (CAHB) had higher levels of somatosensory perception than patients with inactive hepatitis B (IHB) and control group (P < 0.001, P = 0.001, respectively). Patients with CAHB had high scores on all the 3 domains of SDS (work/school, P < 0.001; social life, P < 0.001; and family life, P < 0.001). Also, patients with CAHB had a significantly higher HADS total score, HADS anxiety score, and HADS depression score than control group (P < 0.001, P < 0.001, P < 0.001, respectively). No significant difference was noted between patients with CAHB and patients with IHB with regard to HADS depression score; however, HADS anxiety and HADS total scores were significantly higher in the CAHB group (NS, P = 0.027, P = 0.035, respectively). Moreover, the IHB group exhibited higher scores for the work/school and social life domains of SDS than those of the control group (P = 0.008, P = 0.047). Although patients with CAHB may present with somatosensory amplification, anxiety, and depression, patients with IHB do not exhibit such symptoms. However, functionality is affected in both carrier and active patient groups. We believe that routine health checks of patients with hepatitis B should include psychiatric evaluation, psychiatric examination, and follow-up. PMID:27227947

  5. Somatosensory Amplification, Anxiety, and Depression in Patients With Hepatitis B: Impact on Functionality.

    PubMed

    Yilmaz, Ahmet; Ucmak, Feyzullah; Dönmezdil, Süleyman; Kaya, Mehmet Cemal; Tekin, Recep; Günes, Mehmet; Arslan, Necmi; Bulut, Mahmut

    2016-05-01

    In the present study, we aimed to determine the differences in body image along with anxiety and depression levels, and also to evaluate their impact on disability parameters in patients with hepatitis B.Our study comprised 77 patients with hepatitis B (n = 41, chronic active patients; n = 36, patients with inactive hepatitis B) and 53 healthy individuals (control group). Enrolled patients responded to several questionnaires, including a sociodemographic form, Sheehan Disability Scale (SDS), Hospital Anxiety and Depression Scale (HADS), and Somatosensory Amplification Scale.Patients with chronic active hepatitis B (CAHB) had higher levels of somatosensory perception than patients with inactive hepatitis B (IHB) and control group (P < 0.001, P = 0.001, respectively). Patients with CAHB had high scores on all the 3 domains of SDS (work/school, P < 0.001; social life, P < 0.001; and family life, P < 0.001). Also, patients with CAHB had a significantly higher HADS total score, HADS anxiety score, and HADS depression score than control group (P < 0.001, P < 0.001, P < 0.001, respectively). No significant difference was noted between patients with CAHB and patients with IHB with regard to HADS depression score; however, HADS anxiety and HADS total scores were significantly higher in the CAHB group (NS, P = 0.027, P = 0.035, respectively). Moreover, the IHB group exhibited higher scores for the work/school and social life domains of SDS than those of the control group (P = 0.008, P = 0.047).Although patients with CAHB may present with somatosensory amplification, anxiety, and depression, patients with IHB do not exhibit such symptoms. However, functionality is affected in both carrier and active patient groups. We believe that routine health checks of patients with hepatitis B should include psychiatric evaluation, psychiatric examination, and follow-up. PMID:27227947

  6. Abnormal passive chloride absorption in cystic fibrosis jejunum functionally opposes the classic chloride secretory defect

    PubMed Central

    Russo, Michael A.; Högenauer, Christoph; Coates, Stephen W.; Santa Ana, Carol A.; Porter, Jack L.; Rosenblatt, Randall L.; Emmett, Michael; Fordtran, John S.

    2003-01-01

    Due to genetic defects in apical membrane chloride channels, the cystic fibrosis (CF) intestine does not secrete chloride normally. Depressed chloride secretion leaves CF intestinal absorptive processes unopposed, which results in net fluid hyperabsorption, dehydration of intestinal contents, and a propensity to inspissated intestinal obstruction. This theory is based primarily on in vitro studies of jejunal mucosa. To determine if CF patients actually hyperabsorb fluid in vivo, we measured electrolyte and water absorption during steady-state perfusion of the jejunum. As expected, chloride secretion was abnormally low in CF, but surprisingly, there was no net hyperabsorption of sodium or water during perfusion of a balanced electrolyte solution. This suggested that fluid absorption processes are reduced in CF jejunum, and further studies revealed that this was due to a marked depression of passive chloride absorption. Although Na+-glucose cotransport was normal in the CF jejunum, absence of passive chloride absorption completely blocked glucose-stimulated net sodium absorption and reduced glucose-stimulated water absorption 66%. This chloride absorptive abnormality acts in physiological opposition to the classic chloride secretory defect in the CF intestine. By increasing the fluidity of intraluminal contents, absence of passive chloride absorption may reduce the incidence and severity of intestinal disease in patients with CF. PMID:12840066

  7. Altered effector functions of NK cells in chronic hepatitis C are associated with IFNL3 polymorphism.

    PubMed

    Rogalska-Taranta, Magdalena; Markova, Antoaneta A; Taranta, Andrzej; Lunemann, Sebastian; Schlaphoff, Verena; Flisiak, Robert; Manns, Michael P; Cornberg, Markus; Kraft, Anke R M; Wedemeyer, Heiner

    2015-08-01

    Interferon α-mediated effector functions of NK cells may contribute to the control of HCV replication and the pathogenesis of liver disease. The single-nucleotide polymorphism rs12979860 near IFNL3 (previously known as IL28B) is important in response to IFN-α treatment and in spontaneous resolution of acute hepatitis C. The role of the IFNL3 polymorphism in NK cell function is unclear. Thus, we investigated the role of IFNL3 polymorphism in type I IFN-dependent regulation of NK cell functions in patients with cHC and healthy control subjects. We demonstrated a marked polarization of NK cells toward cytotoxicity in response to IFN-α stimulation in patients with hepatitis C. That TRAIL up-regulation was present, particularly in patients with the IFNL3-TT allele, was supported by a shift in the pSTAT-1:pSTAT-4 ratios toward pSTAT-1. In patients bearing the IFNL3-TT allele, NK cell effector function correlated with liver disease activity. In contrast, higher cytokine production of NK cells was observed in healthy individuals with the IFNL3-CC genotype, which may support spontaneous HCV clearance in acute infection. Overall, these findings show that the role of NK cells may differ in chronic infection vs. early antiviral defense and that the IFNL3 genotype differentially influences NK cell function. PMID:26034208

  8. Molecular changes in hepatic metabolism and transport in cirrhosis and their functional importance

    PubMed Central

    Dietrich, Christoph G; Götze, Oliver; Geier, Andreas

    2016-01-01

    Liver cirrhosis is the common endpoint of many hepatic diseases and represents a relevant risk for liver failure and hepatocellular carcinoma. The progress of liver fibrosis and cirrhosis is accompanied by deteriorating liver function. This review summarizes the regulatory and functional changes in phase I and phase II metabolic enzymes as well as transport proteins and provides an overview regarding lipid and glucose metabolism in cirrhotic patients. Interestingly, phase I enzymes are generally downregulated transcriptionally, while phase II enzymes are mostly preserved transcriptionally but are reduced in their function. Transport proteins are regulated in a specific way that resembles the molecular changes observed in obstructive cholestasis. Lipid and glucose metabolism are characterized by insulin resistance and catabolism, leading to the disturbance of energy expenditure and wasting. Possible non-invasive tests, especially breath tests, for components of liver metabolism are discussed. The heterogeneity and complexity of changes in hepatic metabolism complicate the assessment of liver function in individual patients. Additionally, studies in humans are rare, and species differences preclude the transferability of data from rodents to humans. In clinical practice, some established global scores or criteria form the basis for the functional evaluation of patients with liver cirrhosis, but difficult treatment decisions such as selection for transplantation or resection require further research regarding the application of existing non-invasive tests and the development of more specific tests. PMID:26755861

  9. Functional foods effective for hepatitis C: Identification of oligomeric proanthocyanidin and its action mechanism

    PubMed Central

    Ishida, Yo-ichi; Takeshita, Masahiko; Kataoka, Hiroaki

    2014-01-01

    Hepatitis C virus (HCV) is a major cause of viral hepatitis and currently infects approximately 170 million people worldwide. An infection by HCV causes high rates of chronic hepatitis (> 75%) and progresses to liver cirrhosis and hepatocellular carcinoma ultimately. HCV can be eliminated by a combination of pegylated α-interferon and the broad-spectrum antiviral drug ribavirin; however, this treatment is still associated with poor efficacy and tolerability and is often accompanied by serious side-effects. While some novel direct-acting antivirals against HCV have been developed recently, high medical costs limit the access to the therapy in cost-sensitive countries. To search for new natural anti-HCV agents, we screened local agricultural products for their suppressive activities against HCV replication using the HCV replicon cell system in vitro. We found a potent inhibitor of HCV RNA expression in the extracts of blueberry leaves and then identified oligomeric proanthocyanidin as the active ingredient. Further investigations into the action mechanism of oligomeric proanthocyanidin suggested that it is an inhibitor of heterogeneous nuclear ribonucleoproteins (hnRNPs) such as hnRNP A2/B1. In this review, we presented an overview of functional foods and ingredients efficient for HCV infection, the chemical structural characteristics of oligomeric proanthocyanidin, and its action mechanism. PMID:25544874

  10. Catechin averts experimental diabetes mellitus-induced vascular endothelial structural and functional abnormalities.

    PubMed

    Bhardwaj, Pooja; Khanna, Deepa; Balakumar, Pitchai

    2014-03-01

    Diabetes mellitus is associated with an induction of vascular endothelial dysfunction (VED), an initial event that could lead to the pathogenesis of atherosclerosis and hypertension. Previous studies showed that catechin, a key component of green tea, possesses vascular beneficial effects. We investigated the effect of catechin hydrate in diabetes mellitus-induced experimental vascular endothelial abnormalities (VEA). Streptozotocin (50 mg/kg, i.p., once) administration to rats produced diabetes mellitus, which subsequently induced VEA in 8 weeks by markedly attenuating acetylcholine-induced endothelium-dependent relaxation in the isolated aortic ring preparation, decreasing aortic and serum nitrite/nitrate concentrations and impairing aortic endothelial integrity. These abnormalities in diabetic rats were accompanied with elevated aortic superoxide anion generation and serum lipid peroxidation in addition to hyperglycemia. Catechin hydrate treatment (50 mg/kg/day p.o., 3 weeks) markedly prevented diabetes mellitus-induced VEA and vascular oxidative stress. Intriguingly, in vitro incubation of L-NAME (100 μM), an inhibitor of nitric oxide synthase, or Wortmannin (100 nM), a selective inhibitor of phosphatidylinositol 3-kinase (PI3K), markedly prevented catechin hydrate-induced improvement in acetylcholine-provoked endothelium-dependent relaxation in the diabetic rat aorta. Moreover, catechin hydrate treatment considerably reduced the elevated level of serum glucose in diabetic rats. In conclusion, catechin hydrate treatment prevents diabetes mellitus-induced VED through the activation of endothelial PI3K signal and subsequent activation of eNOS and generation of nitric oxide. In addition, reduction in high glucose, vascular oxidative stress, and lipid peroxidation might additionally contribute to catechin hydrate-associated prevention of diabetic VEA. PMID:24048981

  11. Sex ratio of congenital abnormalities in the function of maternal age: a population-based study.

    PubMed

    Csermely, Gyula; Urbán, Robert; Czeizel, Andrew E; Veszprémi, Béla

    2015-05-01

    Maternal age effect is well-known in the origin of numerical chromosomal aberrations and some isolated congenital abnormalities (CAs). The sex ratio (SR), i.e. number of males divided by the number of males and females together, of most CAs deviates from the SR of newborn population (0.51). The objective of this analysis was to evaluate the possible association of maternal age with the SR of isolated CAs in a population-based large dataset of the Hungarian Case-Control Surveillance of Congenital Abnormalities, 1980-1996. First, SR of 24 CA entities/groups was estimated in 21,494 patients with isolated CA. In the next step SR of different maternal age groups was compared to the mean SR of the given CA-groups. The SR of four CA-groups showed some deviation in certain maternal age groups. Cases with anencephaly had female excess in young mothers (<25 years). Cases with skull's CAs particularly craniosynostosis had a male excess in cases born to women over 30 years. Two other CA groups (cleft lip ± palate and valvar pulmonic stenosis within the group of right-sided obstructive defect of heart) had significant deviation in SR of certain maternal age groups from the mean SR, but these deviations were not harmonized with joining age groups and thus were considered as a chance effect due to multiple testing. In conclusion, our study did not suggest that in general SR of isolated CAs might be modified by certain maternal age groups with some exception such as anencephaly and craniosynostosis. PMID:25354028

  12. [The effect of altan on the functional activity of the liver mitochondria and microsomes from rats with toxic hepatitis].

    PubMed

    Gordienko, A D; Iakovleva, L V

    1999-01-01

    In in vitro experiments althan had no effect on the respiration of intact mitochondria in state 4 according to Chance and produced a high antioxidant effect in fermentative and ascorbate-dependent lipid peroxidation in intact microsomes isolated from the rat liver. In ethanol-induced toxic hepatitis althan restored the functional activity of mitochondria to the level of that in intact animals and increased microsome hydroxylase activity in CCl4-hepatitis. PMID:10513340

  13. Age-Related Changes in Hepatic Function: An Update on Implications for Drug Therapy.

    PubMed

    Tan, Joseph L; Eastment, Jacques G; Poudel, Arjun; Hubbard, Ruth E

    2015-12-01

    The accumulation of deficits with increasing age results in a decline in the functional capacity of multiple organs and systems. These changes can have a significant influence on the pharmacokinetics and pharmacodynamics of prescribed drugs. Although alterations in body composition and worsening renal clearance are important considerations, for most drugs the liver has the greatest effect on metabolism. Age-related change in hepatic function thereby causes much of the variability in older people's responses to medication. In this review, we propose that a decline in the ability of the liver to inactivate toxins may contribute to a proinflammatory state in which frailty can develop. Since inflammation also downregulates drug metabolism, medication prescribed to frail older people in accordance with disease-specific guidelines may undergo reduced systemic clearance, leading to adverse drug reactions, further functional decline and increasing polypharmacy, exacerbating rather than ameliorating frailty status. We also describe how increasing chronological age and frailty status impact liver size, blood flow and protein binding and enzymes of drug metabolism. This is used to contextualise our discussion of appropriate prescribing practices. For example, while the general axiom of 'start low, go slow' should underpin the initiation of medication (titrating to a defined therapeutic goal), it is important to consider whether drug clearance is flow or capacity-limited. By summarising the effect of age-related changes in hepatic function on medications commonly used in older people, we aim to provide a guide that will have high clinical utility for practising geriatricians. PMID:26547855

  14. Abnormal Functional Lateralization and Activity of Language Brain Areas in Typical Specific Language Impairment (Developmental Dysphasia)

    ERIC Educational Resources Information Center

    de Guibert, Clement; Maumet, Camille; Jannin, Pierre; Ferre, Jean-Christophe; Treguier, Catherine; Barillot, Christian; Le Rumeur, Elisabeth; Allaire, Catherine; Biraben, Arnaud

    2011-01-01

    Atypical functional lateralization and specialization for language have been proposed to account for developmental language disorders, yet results from functional neuroimaging studies are sparse and inconsistent. This functional magnetic resonance imaging study compared children with a specific subtype of specific language impairment affecting…

  15. Preserved local but disrupted contextual figure-ground influences in an individual with abnormal function of intermediate visual areas

    PubMed Central

    Brooks, Joseph L.; Gilaie-Dotan, Sharon; Rees, Geraint; Bentin, Shlomo; Driver, Jon

    2012-01-01

    Visual perception depends not only on local stimulus features but also on their relationship to the surrounding stimulus context, as evident in both local and contextual influences on figure-ground segmentation. Intermediate visual areas may play a role in such contextual influences, as we tested here by examining LG, a rare case of developmental visual agnosia. LG has no evident abnormality of brain structure and functional neuroimaging showed relatively normal V1 function, but his intermediate visual areas (V2/V3) function abnormally. We found that contextual influences on figure-ground organization were selectively disrupted in LG, while local sources of figure-ground influences were preserved. Effects of object knowledge and familiarity on figure-ground organization were also significantly diminished. Our results suggest that the mechanisms mediating contextual and familiarity influences on figure-ground organization are dissociable from those mediating local influences on figure-ground assignment. The disruption of contextual processing in intermediate visual areas may play a role in the substantial object recognition difficulties experienced by LG. PMID:22947116

  16. Thioacetamide-induced cirrhosis in selenium-adequate mice displays rapid and persistent abnormity of hepatic selenoenzymes which are mute to selenium supplementation

    SciTech Connect

    Zhang Jinsong Wang Huali; Yu Hanqing

    2007-10-01

    Selenium reduction in cirrhosis is frequently reported. The known beneficial effect of selenium supplementation on cirrhosis is probably obtained from nutritionally selenium-deficient subjects. Whether selenium supplementation truly improves cirrhosis in general needs additional experimental investigation. Thioacetamide was used to induce cirrhosis in selenium-adequate and -deficient mice. Selenoenzyme activity and selenium content were measured and the influence of selenium supplementation was evaluated. In Se-adequate mice, thioacetamide-mediated rapid onset of hepatic oxidative stress resulted in an increase in thioredoxin reductase activity and a decrease in both glutathione peroxidase activity and selenium content. The inverse activity of selenoenzymes (i.e. TrxR activity goes up and GPx activity goes down) was persistent and mute to selenium supplementation during the progress of cirrhosis; accordingly, cirrhosis was not improved by selenium supplementation in any period. On the other hand, selenium supplementation to selenium-deficient mice always more efficiently increased hepatic glutathione peroxidase activity and selenium content compared with those treated with thioacetamide, indicating that thioacetamide impairs the liver bioavailability of selenium. Although thioacetamide profoundly affects hepatic selenium status in selenium-adequate mice, selenium supplementation does not modify the changes. Selenium supplementation to cirrhotic subjects with a background of nutritional selenium deficiency can improve selenium status but cannot restore hepatic glutathione peroxidase and selenium to normal levels.

  17. Abnormalities in Cardiac Structure and Function in Adults with Sickle Cell Disease are not Associated with Pulmonary Hypertension

    PubMed Central

    Knight-Perry, Jessica E.; de las Fuentes, Lisa; Waggoner, Alan D.; Hoffmann, Raymond G.; Blinder, Morey A.; Dávila-Román, Victor G.; Field, Joshua J.

    2011-01-01

    Background In sickle cell disease (SCD), pulmonary hypertension (assessed by tricuspid regurgitant jet [TRJ] velocity ≥ 2.5 m/s) is associated with increased mortality. The relationships between TRJ velocity, left ventricular (LV) and right ventricular (RV) systolic and diastolic function (i.e., relaxation and compliance) have not been well characterized in SCD. Design and Methods Prospective study of 53 ambulatory SCD adults (age, mean: 34 years; range 21-65 years) and 33 African American controls to define the relationship between LV and RV function and TRJ velocity by use of echocardiography. Results SCD subjects had larger left and right atrial volumes and increased LV mass compared to controls. When SCD cases were compared to controls, LV and RV relaxation (i.e., E’) were similar. Among SCD subjects, pulmonary hypertension (TRJ ≥ 2.5 m/s) was present in 40% of cases. Higher TRJ velocity was correlated with larger LA volumes and areas in SCD cases. Additionally, some measures of LV (peak A, lateral and septal annulus E/E’) and RV compliance (TV E/E’) were correlated with TRJ velocity. No other measures of LV/RV systolic function or LV diastolic function (i.e., relaxation and compliance) were associated with TRJ velocity. Conclusions Ambulatory adults with SCD exhibited structural (i.e., LV and RV chamber enlargement) and functional (i.e., higher surrogate measures of LV and RV filling pressure) abnormalities compared to the control group. In SCD subjects, few abnormalities of LV and RV structure/function were associated with TRJ velocity. PMID:21873028

  18. Experiment K-6-14. Hepatic function in rats after spaceflight

    NASA Technical Reports Server (NTRS)

    Merrill, A., Jr.; Hoel, M.; Wang, E.; Jones, D.; Hargrove, J.; Mullins, R.; Popova, I.

    1990-01-01

    To determine the possible biochemical consequences of prolonged weightlessness on liver function, tissue samples from rats that had flown aboard Cosmos 1887 were analyzed for hepatic protein, glycogen and lipids as well as the activities of a number of key enzymes involved in metabolism of these compounds and xenobiotics. Among the parameters measured, the major differences were elevations in the hepatic glycogen content and HMG-CoA reductase activities of the rats flown on Cosmos 1887, and a decrease in the amount of microsomal cytochrome P sub 450 and the activity of aniline hydroxylase, a cytochrome P sub 450-dependent enzyme. Decreases in these two indices of the microsomal mixed-function oxidase system indicated that spaceflight may compromise the ability of liver to metabolize drugs and toxins. The higher HMG-CoA reductase correlated with elevated levels of serum cholestrol. Other changes included somewhat higher blood glucose, creatinine, SGOT, and much greater alkaline phosphatase and BUN. These results generally support the earlier observation of changes in these parameters (Merrill et al., Am. J. Physiol. 252:R22-R226, 1987). The importance of these alterations in liver function is not known; however, they have the potential to complicate long-term spaceflight.

  19. [Structuro-functional changes in dog liver and regional lymph node lysosomes in toxic hepatitis].

    PubMed

    Borodin, Iu I; Korolenko, T A; Malygin, A E; Pupyshev, A B; Sharaĭkina, E O

    1978-10-01

    Structural and functional changes in the dog liver and regional lymph nodes lysosomes were studied during toxic hepatitis induced by CCl4 administration (single and repeated). Total activity of lysosomal enzymes (acid RNA-ase and beta-galactosidase) was higher in the regional lymph nodes than in the liver, reflecting the barrier, protective function of the organ. During acute toxic hepatitis the specific activities of acid RNA-ase and cathepsin D displayed a sharp rise. No normalization of the indices under study occurred during the observation period (from 8 to 30 days). At the same time there was a rise of the regional lymph node weight and an elevation of the relative macrophage and neutrophil content in the sinuses. The increased activity of the lysosome enzymes in the regional lymph nodes in injury of the liver was connected with greater functional load on the lymph nodes effecting hydrolysis of biopolymeres which penetrated into the regional lymphatic node with the lymph. PMID:708870

  20. Dyslexic brain activation abnormalities in deep and shallow orthographies: A meta-analysis of 28 functional neuroimaging studies.

    PubMed

    Martin, Anna; Kronbichler, Martin; Richlan, Fabio

    2016-07-01

    We used coordinate-based meta-analysis to objectively quantify commonalities and differences of dyslexic functional brain abnormalities between alphabetic languages differing in orthographic depth. Specifically, we compared foci of under- and overactivation in dyslexic readers relative to nonimpaired readers reported in 14 studies in deep orthographies (DO: English) and in 14 studies in shallow orthographies (SO: Dutch, German, Italian, Swedish). The separate meta-analyses of the two sets of studies showed universal reading-related dyslexic underactivation in the left occipitotemporal cortex (including the visual word form area (VWFA)). The direct statistical comparison revealed higher convergence of underactivation for DO compared with SO in bilateral inferior parietal regions, but this abnormality disappeared when foci resulting from stronger dyslexic task-negative activation (i.e., deactivation relative to baseline) were excluded. Higher convergence of underactivation for DO compared with SO was further identified in the left inferior frontal gyrus (IFG) pars triangularis, left precuneus, and right superior temporal gyrus, together with higher convergence of overactivation in the left anterior insula. Higher convergence of underactivation for SO compared with DO was found in the left fusiform gyrus, left temporoparietal cortex, left IFG pars orbitalis, and left frontal operculum, together with higher convergence of overactivation in the left precentral gyrus. Taken together, the findings support the notion of a biological unity of dyslexia, with additional orthography-specific abnormalities and presumably different compensatory mechanisms. The results are discussed in relation to current functional neuroanatomical models of developmental dyslexia. Hum Brain Mapp 37:2676-2699, 2016. © 2016 The Authors Human Brain Mapping Published by Wiley Periodicals, Inc. PMID:27061464

  1. Abnormal resting-state functional connectivity of the left caudate nucleus in obsessive-compulsive disorder.

    PubMed

    Chen, Yunhui; Juhás, Michal; Greenshaw, Andrew J; Hu, Qiang; Meng, Xin; Cui, Hongsheng; Ding, Yongzhuo; Kang, Lu; Zhang, Yubo; Wang, Yuhua; Cui, Guangcheng; Li, Ping

    2016-06-01

    Altered brain activities in the cortico-striato-thalamocortical (CSTC) circuitry are implicated in the pathophysiology of obsessive-compulsive disorder (OCD). However, whether the underlying changes occur only within this circuitry or in large-scale networks is still not thoroughly understood. This study performed voxel-based functional connectivity analysis on resting-state functional magnetic resonance imaging (fMRI) data from thirty OCD patients and thirty healthy controls to investigate whole-brain intrinsic functional connectivity patterns in OCD. Relative to the healthy controls, OCD patients showed decreased functional connectivity within the CSTC circuitry but increased functional connectivity in other brain regions. Furthermore, decreased left caudate nucleus-thalamus connectivity within the CSTC circuitry was positively correlated with the illness duration of OCD. This study provides additional evidence that CSTC circuitry may play an essential role and alteration of large-scale brain networks may be involved in the pathophysiology of OCD. PMID:27143323

  2. Degranulation and abnormal bactericidal function of granulocytes procured by reversible adhesion to nylon wool.

    PubMed

    Klock, J C; Bainton, D F

    1976-07-01

    Granylocyte bactericidal capacity, chemotaxis, hexose monophosphate shung activity (before and after phagocytic stimulus), and quantitative nitroblue tetrazolium reduction and enzyme content were examined in cells obtained by filtration leukaphresis (FL) and continuous-flow centrifugation (CFC). A decrease in the bactericidal efficiency of FL-produced cells compared to that of both normal and CFC-procured granulocytes was found; the decrease was 17% with a cell-to-bacteria ratio of 5:1, and 55% with a 1:1 ratio. Moreover, FL-acquired cells were often vacuolated and consistently contained less acid phosphatase and beta-glucuronidase than did normal granulocytes. When normal cells were incubated for 1-2 hr with nylon wool, 30% of the total acid phosphatase and beta-glucuronidase was released, with no evidence of cell death, thus suggesting degranulation. Similar results were obtained with glass, cotton, or polysulfone plastic fibers. Electron microscopic and peroxidase cytochemical studies of the adherence of normal granulocytes to nylon fibers were also carried out. After 30 min of incubation, cell-to-fiber attachment and cellular aggregation had occurred, although the cells per se appeared normal. After 60 and 120 min, other changes became apparent: (1) a decrease in the amount of cytoplasmic granules; (2) large, intracytoplasmic vaculoles; and (3) extracellular peroxidase on fiber surfaces. We conclude that granulocytes obtained by adherence to nylon fibers show both morphological and biochemical evidence of degranulation and diminished bactericidal capacity, and that these abnormalities may be causally related to decreased granulocyte survival in transfusion recipients. PMID:947403

  3. Increasing or stabilizing renal epoxyeicosatrienoic acid production attenuates abnormal renal function and hypertension in obese rats.

    PubMed

    Huang, Hui; Morisseau, Christophe; Wang, JingFeng; Yang, Tianxin; Falck, John R; Hammock, Bruce D; Wang, Mong-Heng

    2007-07-01

    Since epoxyeicosatrienoic acids (EETs) affect sodium reabsorption in renal tubules and dilate the renal vasculature, we have examined their effects on renal hemodynamics and sodium balance in male rats fed a high-fat (HF) diet by fenofibrate, a peroxisome proliferator-activated receptor-alpha (PPAR-alpha) agonist and an inducer of cytochrome P-450 (CYP) epoxygenases; by N-methanesulfonyl-6-(2-proparyloxyphenyl)hexanamide (MSPPOH), a selective EET biosynthesis inhibitor; and by 12-(3-adamantane-1-yl-ureido)dodecanoic acid (AUDA), a selective inhibitor of soluble epoxide hydrolase. In rats treated with fenofibrate (30 mg.kg(-1).day(-1) ig) or AUDA (50 mg/l in drinking water) for 2 wk, mean arterial pressure, renal vascular resistance, and glomerular filtration rate were lower but renal blood flow was higher than in vehicle-treated control rats. In addition, fenofibrate and AUDA decreased cumulative sodium balance in the HF rats. Treatment with MSPPOH (20 mg.kg(-1).day(-1) iv) + fenofibrate for 2 wk reversed renal hemodynamics and sodium balance to the levels in control HF rats. Moreover, fenofibrate caused a threefold increase in renal cortical CYP epoxygenase activity, whereas the fenofibrate-induced elevation of this activity was attenuated by MSPPOH. Western blot analysis showed that fenofibrate induced the expression of CYP epoxygenases in renal cortex and microvessels and that the induction effect of fenofibrate was blocked by MSPPOH. These results demonstrate that the fenofibrate-induced increase of CYP epoxygenase expression and the AUDA-induced stabilization of EET production in the kidneys cause renal vascular dilation and reduce sodium retention, contributing to the improvement of abnormal renal hemodynamics and hypertension in HF rats. PMID:17442729

  4. Modification of the association of bisphenol A with abnormal liver function by polymorphisms of oxidative stress-related genes.

    PubMed

    Kim, Jin Hee; Lee, Mee-Ri; Hong, Yun-Chul

    2016-05-01

    Some studies suggested oxidative stress as a possible mechanism for the relation between exposure to bisphenol A (BPA) and liver damage. Therefore, we evaluated modification of genetic polymorphisms of cyclooxygenase 2 (COX2 or PTGS2), epoxide hydrolase 1 (EPHX1), catalase (CAT), and superoxide dismutase 2 (SOD2 or MnSOD), which are oxidative stress-related genes, on the relation between exposure to BPA and liver function in the elderly. We assessed the association of visit-to-visit variations in BPA exposure with abnormal liver function by each genotype or haplotype after controlling for age, sex, BMI, alcohol consumption, exercise, urinary cotinine levels, and low density lipoprotein cholesterol using a GLIMMIX model. A significant association of BPA with abnormal liver function was observed only in participants with COX2 GG genotype at rs5277 (odds ratio (OR)=3.04 and p=0.0231), CAT genotype at rs769218 (OR=4.16 and p=0.0356), CAT CT genotype at rs769217 (OR=4.19 and p=0.0348), SOD2 TT genotype at rs4880 (OR=2.59 and p=0.0438), or SOD2 GG genotype at rs2758331 (OR=2.57 and p=0.0457). Moreover, we also found higher OR values in participants with a pair of G-G haplotypes for COX2 (OR=2.81 and p=0.0384), G-C-A haplotype for EPHX1 (OR=4.63 and p=0.0654), A-T haplotype for CAT (OR=4.48 and p=0.0245), or T-G-A haplotype for SOD2 (OR=2.91 and p=0.0491) compared with those with the other pair of haplotypes for each gene. Furthermore, the risk score composed of 4 risky pair of haplotypes showed interactive effect with BPA on abnormal liver function (p=0.0057). Our study results suggest that genetic polymorphisms of COX2, EPHX1, CAT, and SOD2 modify the association of BPA with liver function. PMID:26922413

  5. Alterations in lipid profile, oxidative stress and hepatic function in rat fed with saccharin and methyl-salicylates

    PubMed Central

    Amin, Kamal Adel; AlMuzafar, Hessah Mohammed

    2015-01-01

    Background: Food additives attract consumers, improve foods quality, control weight, and replace sugar in foods, while it may affect seriously children and adults health. Aim: To investigate the adverse effects of saccharin and methylsalicyltaes on lipid profile, blood glucose, renal, hepatic function, and oxidative stress/antioxidant (lipid peroxidation, Catalase and reduced glutathione (GSH) in liver tissues). Methods: 46 young male albino rats were used. Saccharin and methylsalicylate were giving orally as low and high dose for 30 days. Rats were divided into 5 groups, 1st control group, 2nd and 3rd low and high saccharin-treated groups and 4th and 5th low and high methylsalicylate-treated group. Results: Serum total cholesterol, triglyceride, glucose levels and body weight gain were decreased in saccharin high dose compared to control. Rats ingested high dose of saccharin presented a significant reduction in serum triglycerides, cholesterol and LDL levels. Low and high doses of saccharin exhibited a significant increase in liver function marker of ALT, AST, ALP activity, total proteins and albumin levels and renal function test (urea and creatinine levels) in comparison with control group. Saccharin high dose induce a significant decline in hepatic GSH levels, catalase and SOD activities while increased in hepatic MDA level. Conclusion: It could be concluded that, saccharin affects harmfully and alters biochemical markers in hepatic and renal tissues not only at greater doses but also at low doses. Whereas uses of metylsalicylates would not pose a risk for renal function and hepatic oxidative markers. PMID:26131217

  6. P53 functional abnormality in mesenchymal stem cells promotes osteosarcoma development

    PubMed Central

    Velletri, T; Xie, N; Wang, Y; Huang, Y; Yang, Q; Chen, X; Chen, Q; Shou, P; Gan, Y; Cao, G; Melino, G; Shi, Y

    2016-01-01

    It has been shown that p53 has a critical role in the differentiation and functionality of various multipotent progenitor cells. P53 mutations can lead to genome instability and subsequent functional alterations and aberrant transformation of mesenchymal stem cells (MSCs). The significance of p53 in safeguarding our body from developing osteosarcoma (OS) is well recognized. During bone remodeling, p53 has a key role in negatively regulating key factors orchestrating the early stages of osteogenic differentiation of MSCs. Interestingly, changes in the p53 status can compromise bone homeostasis and affect the tumor microenvironment. This review aims to provide a unique opportunity to study the p53 function in MSCs and OS. In the context of loss of function of p53, we provide a model for two sources of OS: MSCs as progenitor cells of osteoblasts and bone tumor microenvironment components. Standing at the bone remodeling point of view, in this review we will first explain the determinant function of p53 in OS development. We will then summarize the role of p53 in monitoring MSC fidelity and in regulating MSC differentiation programs during osteogenesis. Finally, we will discuss the importance of loss of p53 function in tissue microenvironment. We expect that the information provided herein could lead to better understanding and treatment of OS. PMID:26775693

  7. Abnormal degree centrality in Alzheimer's disease patients with depression: A resting-state functional magnetic resonance imaging study.

    PubMed

    Guo, Zhongwei; Liu, Xiaozheng; Hou, Hongtao; Wei, Fuquan; Liu, Jian; Chen, Xingli

    2016-06-15

    Depression is common in Alzheimer's disease (AD) and occurs in AD patients with a prevalence of up to 40%. It reduces cognitive function and increases the burden on caregivers. Currently, there are very few medications that are useful for treating depression in AD patients. Therefore, understanding the brain abnormalities in AD patients with depression (D-AD) is crucial for developing effective interventions. The aim of this study was to investigate the intrinsic dysconnectivity pattern of whole-brain functional networks at the voxel level in D-AD patients based on degree centrality (DC) as measured by resting-state functional magnetic resonance imaging (R-fMRI). Our study included 32 AD patients. All patients were evaluated using the Neuropsychiatric Inventory and Hamilton Depression Rating Scale and further divided into two groups: 15 D-AD patients and 17 non-depressed AD (nD-AD) patients. R-fMRI datasets were acquired from these D-AD and nD-AD patients. First, we performed a DC analysis to identify voxels that showed altered whole brain functional connectivity (FC) with other voxels. We then further investigated FC using the abnormal DC regions to examine in more detail the connectivity patterns of the identified DC changes. D-AD patients had lower DC values in the right middle frontal, precentral, and postcentral gyrus than nD-AD patients. Seed-based analysis revealed decreased connectivity between the precentral and postcentral gyrus to the supplementary motor area and middle cingulum. FC also decreased in the right middle frontal, precentral, and postcentral gyrus. Thus, AD patients with depression fit a 'network dysfunction model' distinct from major depressive disorder and AD. PMID:27079332

  8. Abnormal spontaneous regional brain activity in primary insomnia: a resting-state functional magnetic resonance imaging study

    PubMed Central

    Li, Chao; Ma, Xiaofen; Dong, Mengshi; Yin, Yi; Hua, Kelei; Li, Meng; Li, Changhong; Zhan, Wenfeng; Li, Cheng; Jiang, Guihua

    2016-01-01

    Objective Investigating functional specialization is crucial for a complete understanding of the neural mechanisms of primary insomnia (PI). Resting-state functional magnetic resonance imaging (fMRI) is a useful tool to explore the functional specialization of PI. However, only a few studies have focused on the functional specialization of PI using resting-state fMRI and results of these studies were far from consistent. Thus, the current study aimed to investigate functional specialization of PI using resting-state fMRI with amplitude of low frequency fluctuations (ALFFs) algorithm. Methods In this study, 55 PI patients and 44 healthy controls were included. ALFF values were compared between the two groups using two-sample t-test. The relationship of abnormal ALFF values with clinical characteristics and duration of insomnia was investigated using Pearson’s correlation analysis. Results PI patients showed lower ALFF values in the left orbitofrontal cortex/inferior frontal gyrus, right middle frontal gyrus, left inferior parietal lobule, and bilateral cerebellum posterior lobes, while higher ALFF values in the right middle/inferior temporal that extended to the right occipital lobe. In addition, we found that the duration of PI negatively correlated with ALFF values in the left orbitofrontal cortex/inferior frontal gyrus, and the Pittsburgh Sleep Quality Index score negatively correlated with ALFF values in the left inferior parietal lobule. Conclusion The present study added information to limited studies on functional specialization and provided evidence for hyperarousal hypothesis in PI. PMID:27366068

  9. Cognitive function and endogenous cytokine levels in children with chronic hepatitis C.

    PubMed

    Abu Faddan, N H; Shehata, G A; Abd Elhafeez, H A; Mohamed, A O; Hassan, H S; Abd El Sameea, F

    2015-08-01

    Little is known about how hepatitis C (HCV) infection affects cognitive function in children. The aim of the study was to assess the impact of HCV infection on cognitive function of children with normal liver functions and their relationships to endogenous IFN-α, IL-6 and TNF-α. IFN-α, IL-6 and TNF-α were measured and the Arabic version of the Stanford-Binet test used to assess cognitive functions in 35 children with HCV infection and 23 controls. Serum levels of IL-6 and IFN-α were significantly higher in patients compared to controls. There was a significant effect on vocabulary, comprehension, and abstract visual reasoning, quantitative reasoning and bead memory tests, as well as total short-term memory and intelligence quotient in patients compared to controls. There was a significant positive correlation between IFN-α and IL-6. Also there were significant negative correlations between IFN-α and Abstract visual reasoning test, Quantitative reasoning test, Bead memory test, Total short-term memory and Intelligence quotient; and between IL-6 and Abstract visual reasoning test, Quantitative reasoning test and Intelligence quotient. There was no significant correlation between TNF-α and any of the cognitive functions. Cytokine levels were not related to demographic characteristics of the patients or viral load (PCR). Children with chronic hepatitis C infection in its early stages showed signs of cognitive impairment, with the memory tasks being mostly affected. There was a significant correlation between endogenous cytokines and cognitive impairment in these children. Further studies are needed to define the effect of successful antiviral treatment. PMID:25496114

  10. Docosahexaenoic acid reduces ER stress and abnormal protein accumulation and improves neuronal function following traumatic brain injury.

    PubMed

    Begum, Gulnaz; Yan, Hong Q; Li, Liaoliao; Singh, Amneet; Dixon, C Edward; Sun, Dandan

    2014-03-01

    In this study, we investigated the development of endoplasmic reticulum (ER) stress after traumatic brain injury (TBI) and the efficacy of post-TBI administration of docosahexaenoic acid (DHA) in reducing ER stress. TBI was induced by cortical contusion injury in Sprague-Dawley rats. Either DHA (16 mg/kg in DMSO) or vehicle DMSO (1 ml/kg) was administered intraperitoneally at 5 min after TBI, followed by a daily dose for 3-21 d. TBI triggered sustained expression of the ER stress marker proteins including phosphorylated eukaryotic initiation factor-2α, activating transcription factor 4, inositol requiring kinase 1, and C/EBP homologous protein in the ipsilateral cortex at 3-21 d after TBI. The prolonged ER stress was accompanied with an accumulation of abnormal ubiquitin aggregates and increased expression of amyloid precursor protein (APP) and phosphorylated tau (p-Tau) in the frontal cortex after TBI. The ER stress marker proteins were colocalized with APP accumulation in the soma. Interestingly, administration of DHA attenuated all ER stress marker proteins and reduced the accumulation of both ubiquitinated proteins and APP/p-Tau proteins. In addition, the DHA-treated animals exhibited early recovery of their sensorimotor function after TBI. In summary, our study demonstrated that TBI induces a prolonged ER stress, which is positively correlated with abnormal APP accumulation. The sustained ER stress may play a role in chronic neuronal damage after TBI. Our findings illustrate that post-TBI administration of DHA has therapeutic potentials in reducing ER stress, abnormal protein accumulation, and neurological deficits. PMID:24599472

  11. Abnormal functional connectivity density in patients with ischemic white matter lesions: An observational study.

    PubMed

    Ding, Ju-Rong; Ding, Xin; Hua, Bo; Xiong, Xingzhong; Wang, Qingsong; Chen, Huafu

    2016-09-01

    White matter lesions (WMLs) are frequently detected in elderly people. Previous structural and functional studies have demonstrated that WMLs are associated with cognitive and motor decline. However, the underlying mechanism of how WMLs lead to cognitive decline and motor disturbance remains unclear. We used functional connectivity density mapping (FCDM) to investigate changes in brain functional connectivity in 16 patients with ischemic WMLs and 13 controls. Both short- and long-range FCD maps were computed, and group comparisons were performed between the 2 groups. A correlation analysis was further performed between regions with altered FCD and cognitive test scores (Mini-Mental State Examination [MMSE] and Montreal Cognitive Assessment [MoCA]) in the patient group. We found that patients with ischemic WMLs showed reduced short-range FCD in the temporal cortex, primary motor cortex, and subcortical region, which may account for inadequate top-down attention, impaired motor, memory, and executive function associated with WMLs. The positive correlation between primary motor cortex and MoCA scores may provide evidence for the influences of cognitive function on behavioral performance. The inferior parietal cortex exhibited increased short-range FCD, reflecting a hyper bottom-up attention to compensate for the inadequate top-down attention for language comprehension and information retrieval in patients with WMLs. Moreover, the prefrontal and primary motor cortex showed increased long-range FCD and the former positively correlated with MoCA scores, which may suggest a strategy of cortical functional reorganization to compensate for motor and executive deficits. Our findings provide new insights into how WMLs cause cognitive and motor decline from cortical functional connectivity perspective. PMID:27603353

  12. Spatially resolved assessment of hepatic function using 99mTc-IDA SPECT

    SciTech Connect

    Wang, Hesheng; Cao, Yue

    2013-09-15

    Purpose: 99mTc-iminodiacetic acid (IDA) hepatobiliary imaging is usually quantified for hepatic function on the entire liver or regions of interest (ROIs) in the liver. The authors presented a method to estimate the hepatic extraction fraction (HEF) voxel-by-voxel from single-photon emission computed tomography (SPECT)/CT with a 99mTc-labeled IDA agent of mebrofenin and evaluated the spatially resolved HEF measurements with an independent physiological measurement.Methods: Fourteen patients with intrahepatic cancers were treated with radiation therapy (RT) and imaged by 99mTc-mebrofenin SPECT before and 1 month after RT. The dynamic SPECT volumes were with a resolution of 3.9 × 3.9 × 2.5 mm{sup 3}. Throughout the whole liver with approximate 50 000 voxels, voxelwise HEF quantifications were estimated and compared between using arterial input function (AIF) from the heart and using vascular input function (VIF) from the spleen. The correlation between mean of the HEFs over the nontumor liver tissue and the overall liver function measured by Indocyanine green clearance half-time (T1/2) was assessed. Variation of the voxelwise estimation was evaluated in ROIs drawn in relatively homogeneous regions of the livers. The authors also examined effects of the time range parameter on the voxelwise HEF quantification.Results: Mean of the HEFs over the liver estimated using AIF significantly correlated with the physiological measurement T1/2 (r= 0.52, p= 0.0004), and the correlation was greatly improved by using VIF (r= 0.79, p < 0.0001). The parameter of time range for the retention phase did not lead to a significant difference in the means of the HEFs in the ROIs. Using VIF and a retention phase time range of 7–30 min, the relative variation of the voxelwise HEF in the ROIs was 10%± 6% of respective mean HEF.Conclusions: The voxelwise HEF derived from 99mTc-IDA SPECT by the deconvolution analysis is feasible to assess the spatial distribution of hepatic function in the

  13. From DCPD to NTCP: The long journey towards identifying a functional hepatitis B virus receptor

    PubMed Central

    2015-01-01

    Hepatitis B virus (HBV) is the prototype of hepatotropic DNA viruses (hepadnaviruses) infecting a wide range of human and non-human hosts. Previous studies with duck hepatitis B virus (DHBV) identified duck carboxypeptidase D (dCPD) as a host specific binding partner for full-length large envelope protein, and p120 as a binding partner for several truncated versions of the large envelope protein. p120 is the P protein of duck glycine decarboxylase (dGLDC) with restricted expression in DHBV infectible tissues. Several lines of evidence suggest the importance of dCPD, and especially p120, in productive DHBV infection, although neither dCPD nor p120 cDNA could confer susceptibility to DHBV infection in any cell line. Recently, sodium taurocholate cotransporting polypeptide (NTCP) has been identified as a binding partner for the N-terminus of HBV large envelope protein. Importantly, knock down and reconstitution experiments unequivocally demonstrated that NTCP is both necessary and sufficient for in vitro infection by HBV and hepatitis delta virus (HDV), an RNA virus using HBV envelope proteins for its transmission. What remains unclear is whether NTCP is the major HBV receptor in vivo. The fact that some HBV patients are homozygous with an NTCP mutation known to abolish its receptor function suggests the existence of NTCP-independent pathways of HBV entry. Also, NTCP very likely mediates just one step of the HBV entry process, with additional co-factors for productive HBV infection still to be discovered. NTCP offers a novel therapeutic target for the control of chronic HBV infection. PMID:26523264

  14. Oculomotor executive function abnormalities with increased tic severity in Tourette syndrome

    PubMed Central

    Jeter, Cameron B.; Patel, Saumil S.; Morris, Jeffrey S.; Chuang, Alice Z.; Butler, Ian J.; Sereno, Anne B.

    2014-01-01

    Background Reports conflict as to whether Tourette Syndrome (TS) confers deficits in executive function. This study's aim was to evaluate executive function in youths with TS using oculomotor tasks while controlling for confounds of tic severity, age, medication and severity of comorbid disorders. Method Four saccade tasks requiring the executive functions of response generation, response inhibition, and working memory (prosaccade, antisaccade, 0-back and 1-back) were administered. Twenty youths with TS and low tic severity (TS-low), nineteen with TS and moderate tic severity (TS-moderate), and twenty-nine typically developing control subjects (Controls) completed the oculomotor tasks. Results There were small differences across groups in the prosaccade task. Controlling for any small sensorimotor differences, TS-moderate subjects had significantly higher error rates than Controls and TS-low subjects in the 0-back and 1-back tasks. In the 1-back task, these patients also took longer to respond than Controls or TS-low subjects. Conclusions In a highly controlled design, the findings demonstrate for the first time that increased tic severity in TS is associated with impaired response inhibition and impaired working memory and that these executive function deficits cannot be accounted for by differences in age, medication or comorbid symptom severity. PMID:25040172

  15. Post mTBI fatigue is associated with abnormal brain functional connectivity

    PubMed Central

    Nordin, Love Engström; Möller, Marika Christina; Julin, Per; Bartfai, Aniko; Hashim, Farouk; Li, Tie-Qiang

    2016-01-01

    This study set out to investigate the behavioral correlates of changes in resting-state functional connectivity before and after performing a 20 minute continuous psychomotor vigilance task (PVT) for patients with chronic post-concussion syndrome. Ten patients in chronic phase after mild traumatic brain injury (mTBI) with persisting symptoms of fatigue and ten matched healthy controls participated in the study. We assessed the participants’ fatigue levels and conducted resting-state fMRI before and after a sustained PVT. We evaluated the changes in brain functional connectivity indices in relation to the subject’s fatigue behavior using a quantitative data-driven analysis approach. We found that the PVT invoked significant mental fatigue and specific functional connectivity changes in mTBI patients. Furthermore, we found a significant linear correlation between self-reported fatigue and functional connectivity in the thalamus and middle frontal cortex. Our findings indicate that resting-state fMRI measurements may be a useful indicator of performance potential and a marker of fatigue level in the neural attentional system. PMID:26878885

  16. Co-Localisation of Abnormal Brain Structure and Function in Specific Language Impairment

    ERIC Educational Resources Information Center

    Badcock, Nicholas A.; Bishop, Dorothy V. M.; Hardiman, Mervyn J.; Barry, Johanna G.; Watkins, Kate E.

    2012-01-01

    We assessed the relationship between brain structure and function in 10 individuals with specific language impairment (SLI), compared to six unaffected siblings, and 16 unrelated control participants with typical language. Voxel-based morphometry indicated that grey matter in the SLI group, relative to controls, was increased in the left inferior…

  17. Abnormal Functional MRI BOLD Contrast in the Vegetative State after Severe Traumatic Brain Injury

    ERIC Educational Resources Information Center

    Heelmann, Volker

    2010-01-01

    For the rehabilitation process, the treatment of patients surviving brain injury in a vegetative state is still a serious challenge. The aim of this study was to investigate patients exhibiting severely disturbed consciousness using functional magnetic resonance imaging. Five cases of posttraumatic vegetative state and one with minimal…

  18. Distinct Patterns of Grey Matter Abnormality in High-Functioning Autism and Asperger's Syndrome

    ERIC Educational Resources Information Center

    McAlonan, Grainne M.; Suckling, John; Wong, Naikei; Cheung, Vinci; Lienenkaemper, Nina; Cheung, Charlton; Chua, Siew E.

    2008-01-01

    Background: Autism exists across a wide spectrum and there is considerable debate as to whether children with Asperger's syndrome, who have normal language milestones, should be considered to comprise a subgroup distinct other from high-functioning children with autism (HFA), who have a history of delayed language development. Magnetic resonance…

  19. Post mTBI fatigue is associated with abnormal brain functional connectivity.

    PubMed

    Nordin, Love Engström; Möller, Marika Christina; Julin, Per; Bartfai, Aniko; Hashim, Farouk; Li, Tie-Qiang

    2016-01-01

    This study set out to investigate the behavioral correlates of changes in resting-state functional connectivity before and after performing a 20 minute continuous psychomotor vigilance task (PVT) for patients with chronic post-concussion syndrome. Ten patients in chronic phase after mild traumatic brain injury (mTBI) with persisting symptoms of fatigue and ten matched healthy controls participated in the study. We assessed the participants' fatigue levels and conducted resting-state fMRI before and after a sustained PVT. We evaluated the changes in brain functional connectivity indices in relation to the subject's fatigue behavior using a quantitative data-driven analysis approach. We found that the PVT invoked significant mental fatigue and specific functional connectivity changes in mTBI patients. Furthermore, we found a significant linear correlation between self-reported fatigue and functional connectivity in the thalamus and middle frontal cortex. Our findings indicate that resting-state fMRI measurements may be a useful indicator of performance potential and a marker of fatigue level in the neural attentional system. PMID:26878885

  20. Resting state functional MRI reveals abnormal network connectivity in orthostatic tremor.

    PubMed

    Benito-León, Julián; Louis, Elan D; Manzanedo, Eva; Hernández-Tamames, Juan Antonio; Álvarez-Linera, Juan; Molina-Arjona, José Antonio; Matarazzo, Michele; Romero, Juan Pablo; Domínguez-González, Cristina; Domingo-Santos, Ángela; Sánchez-Ferro, Álvaro

    2016-07-01

    Very little is known about the pathogenesis of orthostatic tremor (OT). We have observed that OT patients might have deficits in specific aspects of neuropsychological function, particularly those thought to rely on the integrity of the prefrontal cortex, which suggests a possible involvement of frontocerebellar circuits. We examined whether resting-state functional magnetic resonance imaging (fMRI) might provide further insights into the pathogenesis on OT. Resting-state fMRI data in 13 OT patients (11 women and 2 men) and 13 matched healthy controls were analyzed using independent component analysis, in combination with a "dual-regression" technique, to identify group differences in several resting-state networks (RSNs). All participants also underwent neuropsychological testing during the same session. Relative to healthy controls, OT patients showed increased connectivity in RSNs involved in cognitive processes (default mode network [DMN] and frontoparietal networks), and decreased connectivity in the cerebellum and sensorimotor networks. Changes in network integrity were associated not only with duration (DMN and medial visual network), but also with cognitive function. Moreover, in at least 2 networks (DMN and medial visual network), increased connectivity was associated with worse performance on different cognitive domains (attention, executive function, visuospatial ability, visual memory, and language). In this exploratory study, we observed selective impairments of RSNs in OT patients. This and other future resting-state fMRI studies might provide a novel method to understand the pathophysiological mechanisms of motor and nonmotor features of OT. PMID:27442678

  1. Epidermal barrier abnormalities in exfoliative ichthyosis with a novel homozygous loss-of-function mutation in CSTA.

    PubMed

    Moosbrugger-Martinz, V; Jalili, A; Schossig, A S; Jahn-Bassler, K; Zschocke, J; Schmuth, M; Stingl, G; Eckl, K M; Hennies, H C; Gruber, R

    2015-06-01

    Autosomal recessive exfoliative ichthyosis (AREI) results from mutations in CSTA, encoding cysteine protease inhibitor A (cystatin A). We present a 25-year-old man from Iran with consanguineous parents, who presented with congenital erythroderma, hyperhidrosis and diffuse hyperkeratosis with coarse palmoplantar peeling of the skin, aggravated by exposure to water and by occlusion. Candidate gene analysis revealed a previously unknown homozygous loss-of-function mutation c.172C>T (p.Arg58Ter) in CSTA, and immunostaining showed absence of epidermal cystatin A, confirming the diagnosis of AREI. Ultrastructural analysis by transmission electron microscopy showed normal degradation of corneodesmosomes, mild intercellular oedema in the spinous layer but not in the basal layer, normal-appearing desmosomes, and prominent keratin filaments within basal keratinocytes. Thickness of cornified envelopes was reduced, lamellar lipid bilayers were disturbed, lamellar body secretion occurred prematurely and processing of secreted lamellar body contents was delayed. These barrier abnormalities were reminiscent of (albeit less severe than in) Netherton syndrome, which results from a deficiency of the serine protease inhibitor LEKTI. This work describes ultrastructural findings with evidence of epidermal barrier abnormalities in AREI. PMID:25400170

  2. Identification of abnormal motor cortex activation patterns in children with cerebral palsy by functional near-infrared spectroscopy

    NASA Astrophysics Data System (ADS)

    Khan, Bilal; Tian, Fenghua; Behbehani, Khosrow; Romero, Mario I.; Delgado, Mauricio R.; Clegg, Nancy J.; Smith, Linsley; Reid, Dahlia; Liu, Hanli; Alexandrakis, George

    2010-05-01

    We demonstrate the utility of functional near-infrared spectroscopy (fNIRS) as a tool for physicians to study cortical plasticity in children with cerebral palsy (CP). Motor cortex activation patterns were studied in five healthy children and five children with CP (8.4+/-2.3 years old in both groups) performing a finger-tapping protocol. Spatial (distance from center and area difference) and temporal (duration and time-to-peak) image metrics are proposed as potential biomarkers for differentiating abnormal cortical activation in children with CP from healthy pediatric controls. In addition, a similarity image-analysis concept is presented that unveils areas that have similar activation patterns as that of the maximum activation area, but are not discernible by visual inspection of standard activation images. Metrics derived from the images presenting areas of similarity are shown to be sensitive identifiers of abnormal activation patterns in children with CP. Importantly, the proposed similarity concept and related metrics may be applicable to other studies for the identification of cortical activation patterns by fNIRS.

  3. Developmental Abnormalities of Neuronal Structure and Function in Prenatal Mice Lacking the Prader-Willi Syndrome Gene Necdin

    PubMed Central

    Pagliardini, Silvia; Ren, Jun; Wevrick, Rachel; Greer, John J.

    2005-01-01

    Necdin (Ndn) is one of a cluster of genes deleted in the neurodevelopmental disorder Prader-Willi syndrome (PWS). Ndntm2Stw mutant mice die shortly after birth because of abnormal respiratory rhythmogenesis generated by a key medullary nucleus, the pre-Bötzinger complex (preBötC). Here, we address two fundamental issues relevant to its pathogenesis. First, we performed a detailed anatomical study of the developing medulla to determine whether there were defects within the preBötC or synaptic inputs that regulate respiratory rhythmogenesis. Second, in vitro studies determined if the unstable respiratory rhythm in Ndntm2Stw mice could be normalized by neuromodulators. Anatomical defects in Ndntm2Stw mice included defasciculation and irregular projections of axonal tracts, aberrant neuronal migration, and a major defect in the cytoarchitecture of the cuneate/gracile nuclei, including dystrophic axons. Exogenous application of neuromodulators alleviated the long periods of slow respiratory rhythms and apnea, but some instability of rhythmogenesis persisted. We conclude that deficiencies in the neuromodulatory drive necessary for preBötC function contribute to respiratory dysfunction of Ndntm2Stw mice. These abnormalities are part of a more widespread deficit in neuronal migration and the extension, arborization, and fasciculation of axons during early stages of central nervous system development that may account for respiratory, sensory, motor, and behavioral problems associated with PWS. PMID:15972963

  4. Identification of abnormal motor cortex activation patterns in children with cerebral palsy by functional near-infrared spectroscopy

    PubMed Central

    Khan, Bilal; Tian, Fenghua; Behbehani, Khosrow; Romero, Mario I.; Delgado, Mauricio R.; Clegg, Nancy J.; Smith, Linsley; Reid, Dahlia; Liu, Hanli; Alexandrakis, George

    2010-01-01

    We demonstrate the utility of functional near-infrared spectroscopy (fNIRS) as a tool for physicians to study cortical plasticity in children with cerebral palsy (CP). Motor cortex activation patterns were studied in five healthy children and five children with CP (8.4±2.3years old in both groups) performing a finger-tapping protocol. Spatial (distance from center and area difference) and temporal (duration and time-to-peak) image metrics are proposed as potential biomarkers for differentiating abnormal cortical activation in children with CP from healthy pediatric controls. In addition, a similarity image-analysis concept is presented that unveils areas that have similar activation patterns as that of the maximum activation area, but are not discernible by visual inspection of standard activation images. Metrics derived from the images presenting areas of similarity are shown to be sensitive identifiers of abnormal activation patterns in children with CP. Importantly, the proposed similarity concept and related metrics may be applicable to other studies for the identification of cortical activation patterns by fNIRS. PMID:20615010

  5. Hepatic encephalopathy.

    PubMed

    Córdoba, Juan; Mínguez, Beatriz

    2008-02-01

    Hepatic encephalopathy is a severe complication of cirrhosis that is related to the effects of ammonia. Analysis of interorgan ammonia trafficking has identified an important role of skeletal muscle in ammonia removal and has highlighted the importance of the nutritional status. Ammonia causes neurotransmitter abnormalities and induces injury to astrocytes that is partially mediated by oxidative stress. These disturbances lead to astrocyte swelling and brain edema, which appear to be involved in the pathogenesis of neurological manifestations. Inflammatory mediators worsen brain disturbances. New methods for assessing hepatic encephalopathy include clinical scales, neuropsychological tests, imaging of portal-systemic circulation, and magnetic resonance of the brain. Reappraisal of current therapy indicates the need for performing placebo-controlled trials and the lack of evidence for administering diets with restricted protein content. Liver transplant should be considered in selected patients with hepatic encephalopathy. Future prospects include new drugs that decrease plasma ammonia, measures to reduce brain edema, and liver-support devices. PMID:18293278

  6. A lack of functional NK1 receptors explains most, but not all, abnormal behaviours of NK1R-/- mice1

    PubMed Central

    Porter, A J; Pillidge, K; Tsai, Y C; Dudley, J A; Hunt, S P; Peirson, S N; Brown, L A; Stanford, S C

    2015-01-01

    Mice lacking functional neurokinin-1 receptors (NK1R-/-) display abnormal behaviours seen in Attention Deficit Hyperactivity Disorder (hyperactivity, impulsivity and inattentiveness). These abnormalities were evident when comparing the behaviour of separate (inbred: ‘Hom’) wildtype and NK1R-/- mouse strains. Here, we investigated whether the inbreeding protocol could influence their phenotype by comparing the behaviour of these mice with that of wildtype (NK1R+/+) and NK1R-/- progeny of heterozygous parents (‘Het’, derived from the same inbred strains). First, we recorded the spontaneous motor activity of the two colonies/genotypes, over 7 days. This continuous monitoring also enabled us to investigate whether the diurnal rhythm in motor activity differs in the two colonies/genotypes. NK1R-/- mice from both colonies were hyperactive compared with their wildtypes and their diurnal rhythm was also disrupted. Next, we evaluated the performance of the four groups of mice in the 5-Choice Serial Reaction-Time Task (5-CSRTT). During training, NK1R-/- mice from both colonies expressed more impulsive and perseverative behaviour than their wildtypes. During testing, only NK1R-/- mice from the Hom colony were more impulsive than their wildtypes, but NK1R-/- mice from both colonies were more perseverative. There were no colony differences in inattentiveness. Moreover, a genotype difference in this measure depended on time of day. We conclude that the hyperactivity, perseveration and, possibly, inattentiveness of NK1R-/- mice is a direct consequence of a lack of functional NK1R. However, the greater impulsivity of NK1R-/- mice depended on an interaction between a functional deficit of NK1R and other (possibly environmental and/or epigenetic) factors. PMID:25558794

  7. Static and Functional Hemodynamic Profiles of Women with Abnormal Uterine Artery Doppler at 22–24 Weeks of Gestation

    PubMed Central

    Widnes, Christian

    2016-01-01

    Objective To compare cardiac function, systemic hemodynamics and preload reserve of women with increased (cases) and normal (controls) uterine artery (UtA) pulsatility index (PI) at 22–24 weeks of gestation. Materials and Methods A prospective cross-sectional study of 620 pregnant women. UtA blood flow velocities were measured using Doppler ultrasonography, and PI was calculated. Mean UtA PI ≥ 1.16 (90th percentile) was considered abnormal. Maternal hemodynamics was investigated at baseline and during passive leg raising (PLR) using impedance cardiography (ICG). Preload reserve was defined as percent increase in stroke volume (SV) 90 seconds after passive leg raising compared to baseline. Results Mean UtA PI was 1.49 among cases (n = 63) and 0.76 among controls (n = 557) (p < 0.0001). Eighteen (28.6%) cases and 53 (9.5%) controls developed pregnancy complications (p <0.0001). The mean arterial pressure and systemic vascular resistance were 83 mmHg and 1098.89±293.87 dyne s/cm5 among cases and 79 mmHg and 1023.95±213.83 dyne s/cm5 among controls (p = 0.007 and p = 0.012, respectively). Heart rate, SV and cardiac output were not different between the groups. Both cases and controls responded with a small (4–5%) increase in SV in response to PLR, but the cardiac output remained unchanged. The preload reserve was not significantly different between two groups. Conclusion Pregnant women with abnormal UtA PI had higher blood pressure and systemic vascular resistance, but similar functional hemodynamic profile at 22–24 weeks compared to controls. Further studies are needed to clarify whether functional hemodynamic assessment using ICG can be useful in predicting pregnancy complications. PMID:27308858

  8. Analysis of renal function during telaprevir-based triple therapy for chronic hepatitis C

    PubMed Central

    KOHJIMA, MOTOYUKI; KUROKAWA, MIHO; ENJOJI, MUNECHIKA; YOSHIMOTO, TSUYOSHI; NAKAMURA, TSUKASA; OHASHI, TOMOKO; FUKUIZUMI, KUNITAKA; HARADA, NAOHIKO; MURATA, YUSUKE; MATSUNAGA, KAZUHISA; KATO, MASAKI; KOTOH, KAZUHIRO; NAKAMUTA, MAKOTO

    2016-01-01

    Telaprevir (TVR) is used for the treatment of chronic hepatitis C in a combination therapy with pegylated-interferon and ribavirin. Although renal dysfunction is one of the critical adverse outcomes of this treatment, little is known regarding the mechanism of its onset. The present study assessed the association of renal function with TVR dose and viral response. Hematological, biochemical, urinary and virological parameters of renal function were examined during the TVR-based triple therapy of patients infected with hepatitis C virus (HCV) genotype 1b. Serum creatinine levels were increased and the estimated glomerular filtration rate (eGFR) was decreased in every patient during TVR administration, but these values recovered to normal levels following cessation of TVR. Fractional excretion of sodium was <1% at days 3 and 7, appearing similar regardless of baseline renal function. Urinary β2-microglobulin levels were elevated and were significantly higher in patients with renal dysfunction, as compared with those not exhibiting renal dysfunction (P<0.05). The reduction in renal function was milder in patients treated with a reduced TVR dose, and these patients had a significantly lower risk of developing renal dysfunction (P<0.05). Using a multivariate analysis, TVR dose and eGFR at the initiation of treatment were identified as significant contributory factors in the development of renal dysfunction. Reduction in TVR dose did not lead to a significant increase in the viral kinetics of HCV or detrimental effects on the sustained viral response (SVR) rate. It is hypothesized that renal dysfunction during TVR treatment is caused by damage of the renal tubule, in addition to pre-renal dysfunction, and that reduction in TVR dose reduces the rate of renal dysfunction without causing a significant decrease in the SVR rate. PMID:27168803

  9. Genetic Variations in the Promoter of the APE1 Gene Are Associated with DMF-Induced Abnormal Liver Function: A Case-Control Study in a Chinese Population.

    PubMed

    Tong, Zhimin; Shen, Huanxi; Yang, Dandan; Zhang, Feng; Bai, Ying; Li, Qian; Shi, Jian; Zhang, Hengdong; Zhu, Baoli

    2016-01-01

    Acute or long-term exposure to N,N-dimethylformamide (DMF) can induce abnormal liver function. It is well known that DMF is mainly metabolized in the liver and thereby produces reactive oxygen species (ROS). The base excision repair (BER) pathway is regarded as a very important pathway involved in repairing ROS-induced DNA damage. Several studies have explored the associations between GSTM1, GSTT1, CYP2E1 polymorphisms and DMF-induced abnormal liver function; however, little is known about how common hOGG1, XRCC1 and APE1 polymorphisms and DMF induce abnormal liver function. The purpose of this study was to investigate whether the polymorphisms in the hOGG1 (rs159153 and rs2072668), XRCC1 (rs25487, rs25489, and rs1799782), APE1 (rs1130409 and 1760944) genes in the human BER pathway were associated with the susceptibility to DMF-induced abnormal liver function in a Chinese population. These polymorphisms were genotyped in 123 workers with DMF-induced abnormal liver function and 123 workers with normal liver function. We found that workers with the APE1 rs1760944 TG/GG genotypes had a reduced risk of abnormal liver function, which was more pronounced in the subgroups that were exposed to DMF for <10 years, exposed to ≥10 mg/m³ DMF, never smoked and never drank. In summary, our study supported the hypothesis that the APE1 rs1760944 T > G polymorphism may be associated with DMF-induced abnormal liver function in the Chinese Han population. PMID:27463724

  10. Genetic Variations in the Promoter of the APE1 Gene Are Associated with DMF-Induced Abnormal Liver Function: A Case-Control Study in a Chinese Population

    PubMed Central

    Tong, Zhimin; Shen, Huanxi; Yang, Dandan; Zhang, Feng; Bai, Ying; Li, Qian; Shi, Jian; Zhang, Hengdong; Zhu, Baoli

    2016-01-01

    Acute or long-term exposure to N,N-dimethylformamide (DMF) can induce abnormal liver function. It is well known that DMF is mainly metabolized in the liver and thereby produces reactive oxygen species (ROS). The base excision repair (BER) pathway is regarded as a very important pathway involved in repairing ROS-induced DNA damage. Several studies have explored the associations between GSTM1, GSTT1, CYP2E1 polymorphisms and DMF-induced abnormal liver function; however, little is known about how common hOGG1, XRCC1 and APE1 polymorphisms and DMF induce abnormal liver function. The purpose of this study was to investigate whether the polymorphisms in the hOGG1 (rs159153 and rs2072668), XRCC1 (rs25487, rs25489, and rs1799782), APE1 (rs1130409 and 1760944) genes in the human BER pathway were associated with the susceptibility to DMF-induced abnormal liver function in a Chinese population. These polymorphisms were genotyped in 123 workers with DMF-induced abnormal liver function and 123 workers with normal liver function. We found that workers with the APE1 rs1760944 TG/GG genotypes had a reduced risk of abnormal liver function, which was more pronounced in the subgroups that were exposed to DMF for <10 years, exposed to ≥10 mg/m3 DMF, never smoked and never drank. In summary, our study supported the hypothesis that the APE1 rs1760944 T > G polymorphism may be associated with DMF-induced abnormal liver function in the Chinese Han population. PMID:27463724

  11. Rat hepatic glutaminase: identification of the full coding sequence and characterization of a functional promoter.

    PubMed Central

    Chung-Bok, M I; Vincent, N; Jhala, U; Watford, M

    1997-01-01

    Glutamine catabolism in mammalian liver is catalysed by a unique isoenzyme of phosphate-activated glutaminase. The full coding and 5' untranslated sequence for rat hepatic glutaminase was isolated by screening lambda ZAP cDNA libraries and a Charon 4a rat genomic library. The sequence produces a mRNA 2225 nt in length, encoding a polypeptide of 535 amino acid residues with a calculated molecular mass of 59.2 kDa. The deduced amino acid sequence of rat liver glutaminase shows 86% similarity to that of rat kidney glutaminase and 65% similarity to a putative glutaminase from Caenorhabditis elegans. A genomic clone to rat liver glutaminase was isolated that contains 3.5 kb of the gene and 7.5 kb of the 5' flanking region. The 1 kb immediately upstream of the hepatic glutaminase gene (from -1022 to +48) showed functional promoter activity in HepG2 hepatoma cells. This promoter region did not respond to treatment with cAMP, but was highly responsive (10-fold stimulation) to the synthetic glucocorticoid dexamethasone. Subsequent 5' deletion analysis indicated that the promoter region between -103 and +48 was sufficient for basal promoter activity. This region does not contain an identifiable TATA element, indicating that transcription of the glutaminase gene is driven by a TATA-less promoter. The region responsive to glucocorticoids was mapped to -252 to -103 relative to the transcription start site. PMID:9164856

  12. History, heterogeneity, developmental biology, and functions of quiescent hepatic stellate cells.

    PubMed

    Geerts, A

    2001-08-01

    In 1876, von Kupffer described liver Sternzellen (star-shaped cells). The functions of these cells remained enigmatic for 75 years until Ito observed lipid-containing perisinusoidal cells in human liver. In 1971, Wake demonstrated that the Sternzellen of von Kupffer and the fat-storing cells described by Ito were identical. Wake also established that these cells were important sites of vitamin A storage. Soon thereafter, Kent and Popper demonstrated that the stellate cells were intimately linked to the pathogenesis of hepatic fibrosis. Since then, these cells have been studied in detail. Quiescent stellate cells represent 5-8% of the total number of liver cells. They play a cardinal role in storage and controlled release of retinoids. They control extracellular matrix (ECM) turnover in the space of Disse by secreting the correct amounts of a limited number of ECM molecules, and by releasing matrix metalloproteinases and their inhibitors. By virtue of their long cytoplasmic processes, quiescent stellate cells presumably contribute to the control of blood flow through the sinusoidal capillaries. They are important sources of paracrine, autocrine, juxtacrine, and chemoattractant factors that maintain homeostasis in the microenvironment of the hepatic sinusoid. PMID:11586463

  13. Sodium taurocholate cotransporting polypeptide is a functional receptor for human hepatitis B and D virus.

    PubMed

    Yan, Huan; Zhong, Guocai; Xu, Guangwei; He, Wenhui; Jing, Zhiyi; Gao, Zhenchao; Huang, Yi; Qi, Yonghe; Peng, Bo; Wang, Haimin; Fu, Liran; Song, Mei; Chen, Pan; Gao, Wenqing; Ren, Bijie; Sun, Yinyan; Cai, Tao; Feng, Xiaofeng; Sui, Jianhua; Li, Wenhui

    2014-01-01

    Human hepatitis B virus (HBV) infection and HBV-related diseases remain a major public health problem. Individuals coinfected with its satellite hepatitis D virus (HDV) have more severe disease. Cellular entry of both viruses is mediated by HBV envelope proteins. The pre-S1 domain of the large envelope protein is a key determinant for receptor(s) binding. However, the identity of the receptor(s) is unknown. Here, by using near zero distance photo-cross-linking and tandem affinity purification, we revealed that the receptor-binding region of pre-S1 specifically interacts with sodium taurocholate cotransporting polypeptide (NTCP), a multiple transmembrane transporter predominantly expressed in the liver. Silencing NTCP inhibited HBV and HDV infection, while exogenous NTCP expression rendered nonsusceptible hepatocarcinoma cells susceptible to these viral infections. Moreover, replacing amino acids 157-165 of nonfunctional monkey NTCP with the human counterpart conferred its ability in supporting both viral infections. Our results demonstrate that NTCP is a functional receptor for HBV and HDV. PMID:25409679

  14. Sodium taurocholate cotransporting polypeptide is a functional receptor for human hepatitis B and D virus.

    PubMed

    Yan, Huan; Zhong, Guocai; Xu, Guangwei; He, Wenhui; Jing, Zhiyi; Gao, Zhenchao; Huang, Yi; Qi, Yonghe; Peng, Bo; Wang, Haimin; Fu, Liran; Song, Mei; Chen, Pan; Gao, Wenqing; Ren, Bijie; Sun, Yinyan; Cai, Tao; Feng, Xiaofeng; Sui, Jianhua; Li, Wenhui

    2012-01-01

    Human hepatitis B virus (HBV) infection and HBV-related diseases remain a major public health problem. Individuals coinfected with its satellite hepatitis D virus (HDV) have more severe disease. Cellular entry of both viruses is mediated by HBV envelope proteins. The pre-S1 domain of the large envelope protein is a key determinant for receptor(s) binding. However, the identity of the receptor(s) is unknown. Here, by using near zero distance photo-cross-linking and tandem affinity purification, we revealed that the receptor-binding region of pre-S1 specifically interacts with sodium taurocholate cotransporting polypeptide (NTCP), a multiple transmembrane transporter predominantly expressed in the liver. Silencing NTCP inhibited HBV and HDV infection, while exogenous NTCP expression rendered nonsusceptible hepatocarcinoma cells susceptible to these viral infections. Moreover, replacing amino acids 157-165 of nonfunctional monkey NTCP with the human counterpart conferred its ability in supporting both viral infections. Our results demonstrate that NTCP is a functional receptor for HBV and HDV.DOI:http://dx.doi.org/10.7554/eLife.00049.001. PMID:23150796

  15. Tenoxicam-associated hepatic injury: a case report and review.

    PubMed

    Katsinelos, P; Katsos, I; Patsiaoura, K; Xiarchos, P; Goulis, I; Eugenidis, N

    1997-04-01

    A 51-year-old woman developed jaundice while taking tenoxicam. A full evaluation, including ultrasound, computed tomography, endoscopic cholangiography and liver biopsy, confirmed the diagnosis of mixed hepatic injury. The patient's jaundice and all other liver function abnormalities normalized 1 month after she discontinued taking tenoxicam. This is the first case report of mixed hepatic injury, confirmed with biopsy, associated with tenoxicam. Tenoxicam should be considered as a potential cause of hepatic injury when other more common aetiologies have been excluded. PMID:9160206

  16. Adenosine Kinase Deficiency Disrupts the Methionine Cycle and Causes Hypermethioninemia, Encephalopathy, and Abnormal Liver Function

    PubMed Central

    Bjursell, Magnus K.; Blom, Henk J.; Cayuela, Jordi Asin; Engvall, Martin L.; Lesko, Nicole; Balasubramaniam, Shanti; Brandberg, Göran; Halldin, Maria; Falkenberg, Maria; Jakobs, Cornelis; Smith, Desiree; Struys, Eduard; von Döbeln, Ulrika; Gustafsson, Claes M.; Lundeberg, Joakim; Wedell, Anna

    2011-01-01

    Four inborn errors of metabolism (IEMs) are known to cause hypermethioninemia by directly interfering with the methionine cycle. Hypermethioninemia is occasionally discovered incidentally, but it is often disregarded as an unspecific finding, particularly if liver disease is involved. In many individuals the hypermethioninemia resolves without further deterioration, but it can also represent an early sign of a severe, progressive neurodevelopmental disorder. Further investigation of unclear hypermethioninemia is therefore important. We studied two siblings affected by severe developmental delay and liver dysfunction. Biochemical analysis revealed increased plasma levels of methionine, S-adenosylmethionine (AdoMet), and S-adenosylhomocysteine (AdoHcy) but normal or mildly elevated homocysteine (Hcy) levels, indicating a block in the methionine cycle. We excluded S-adenosylhomocysteine hydrolase (SAHH) deficiency, which causes a similar biochemical phenotype, by using genetic and biochemical techniques and hypothesized that there was a functional block in the SAHH enzyme as a result of a recessive mutation in a different gene. Using exome sequencing, we identified a homozygous c.902C>A (p.Ala301Glu) missense mutation in the adenosine kinase gene (ADK), the function of which fits perfectly with this hypothesis. Increased urinary adenosine excretion confirmed ADK deficiency in the siblings. Four additional individuals from two unrelated families with a similar presentation were identified and shown to have a homozygous c.653A>C (p.Asp218Ala) and c.38G>A (p.Gly13Glu) mutation, respectively, in the same gene. All three missense mutations were deleterious, as shown by activity measurements on recombinant enzymes. ADK deficiency is a previously undescribed, severe IEM shedding light on a functional link between the methionine cycle and adenosine metabolism. PMID:21963049

  17. Abnormal functional integration of thalamic low frequency oscillation in the BOLD signal after acute heroin treatment.

    PubMed

    Denier, Niklaus; Schmidt, André; Gerber, Hana; Vogel, Marc; Huber, Christian G; Lang, Undine E; Riecher-Rossler, Anita; Wiesbeck, Gerhard A; Radue, Ernst-Wilhelm; Walter, Marc; Borgwardt, Stefan

    2015-12-01

    Heroin addiction is a severe relapsing brain disorder associated with impaired cognitive control, including deficits in attention allocation. The thalamus has a high density of opiate receptors and is critically involved in orchestrating cortical activity during cognitive control. However, there have been no studies on how acute heroin treatment modulates thalamic activity. In a cross-over, double-blind, vehicle-controlled study, 29 heroin-maintained outpatients were studied after heroin and placebo administration, while 20 healthy controls were included for the placebo condition only. Resting-state functional magnetic resonance imaging was used to analyze functional integration of the thalamus by three different resting state analysis techniques. Thalamocortical functional connectivity (FC) was analyzed by seed-based correlation, while intrinsic thalamic oscillation was assessed by analysis of regional homogeneity (ReHo) and the fractional amplitude of low frequency fluctuations (fALFF). Relative to the placebo treatment and healthy controls, acute heroin administration reduced thalamocortical FC to cortical regions, including the frontal cortex, while the reductions in FC to the mediofrontal cortex, orbitofrontal cortex, and frontal pole were positively correlated with the plasma level of morphine, the main psychoactive metabolite of heroin. Furthermore, heroin treatment was associated with increased thalamic ReHo and fALFF values, whereas fALFF following heroin exposure correlated negatively with scores of attentional control. The heroin-associated increase in fALFF was mainly dominated by slow-4 (0.027-0.073 Hz) oscillations. Our findings show that there are acute effects of heroin within the thalamocortical system and may shed new light on the role of the thalamus in cognitive control in heroin addiction. Future research is needed to determine the underlying physiological mechanisms and their role in heroin addiction. PMID:26441146

  18. Detecting abnormalities in left ventricular function during exercise by respiratory measurement

    SciTech Connect

    Koike, A.; Itoh, H.; Taniguchi, K.; Hiroe, M. )

    1989-12-01

    The degree of exercise-induced cardiac dysfunction and its relation to the anaerobic threshold were evaluated in 23 patients with chronic heart disease. A symptom-limited exercise test was performed with a cycle ergometer with work rate increased by 1 W every 6 seconds. Left ventricular function, as reflected by ejection fraction, was continuously monitored with a computerized cadmium telluride detector after the intravenous injection of technetium-labeled red blood cells. The anaerobic threshold (mean, 727 {plus minus} 166 ml/min) was determined by the noninvasive measurement of respiratory gas exchange. As work rate rose, the left ventricular ejection fraction increased but reached a peak value at the anaerobic threshold and then fell below resting levels. Ejection fraction at rest, anaerobic threshold, and peak exercise were 41.4 {plus minus} 11.3%, 46.5 {plus minus} 12.0%, and 37.2 {plus minus} 11.0%, respectively. Stroke volume also increased from rest (54.6 {plus minus} 17.0 ml/beat) to the point of the anaerobic threshold (65.0 {plus minus} 21.2 ml/beat) and then decreased at peak exercise (52.4 {plus minus} 18.7 ml/beat). The slope of the plot of cardiac output versus work rate decreased above the anaerobic threshold. The anaerobic threshold occurred at the work rate above which left ventricular function decreased during exercise. Accurate determination of the anaerobic threshold provides an objective, noninvasive measure of the oxygen uptake above which exercise-induced deterioration in left ventricular function occurs in patients with chronic heart disease.

  19. The Effect of Chronic Hepatitis B Virus Infection on BDCA3+ Dendritic Cell Frequency and Function

    PubMed Central

    van der Aa, Evelyn; Buschow, Sonja I.; Biesta, Paula J.; Janssen, Harry L. A.; Woltman, Andrea M.

    2016-01-01

    Chronic hepatitis B virus (HBV) infection results from inadequate HBV-specific immunity. BDCA3+ dendritic cells (DCs) are professional antigen presenting cells considered to be important for antiviral responses because of specific characteristics, including high interferon-λ production. BDCA3+ DCs may thus also have a role in the immune response against HBV, and immunotherapeutic strategies aiming to activate DCs, including BDCA3+ DCs, in patient livers may represent an interesting treatment option for chronic HBV. However, neither the effect of chronic hepatitis B (CHB) infection on the frequency and function of BDCA3+ DCs in liver and blood, nor the effect of the viral surface protein (HBsAg) that is abundantly present in blood of infected individuals are known. Here, we provide an overview of BDCA3+ DC frequency and functional capacity in CHB patients. We find that intrahepatic BDCA3+ DC numbers are increased in CHB patients. BDCA3+ DCs from patient blood are not more mature at steady state, but display an impaired capacity to mature and to produce interferon-λ upon polyI:C stimulation. Furthermore, in vitro experiments exposing blood and intrahepatic BDCA3+ DCs to the viral envelope protein HBsAg demonstrate that HBsAg does not directly induce phenotypical maturation of BDCA3+ DCs, but may reduce IFN-λ production via an indirect unknown mechanism. These results suggest that BDCA3+ DCs are available in the blood and on site in HBV infected livers, but measures may need to be taken to revive their function for DC-targeted therapy. PMID:27529176

  20. Microstructural abnormalities of uncinate fasciculus as a function of impaired cognition in schizophrenia: A DTI study.

    PubMed

    Singh, Sadhana; Singh, Kavita; Trivedi, Richa; Goyal, Satnam; Kaur, Prabhjot; Singh, Namita; Bhatia, Triptish; Deshpande, Smita N; Khushu, Subash

    2016-09-01

    Neuropsychological studies have reported that attention, memory, language, motor and emotion processing are impaired in schizophrenia. It is known that schizophrenia involves structural alterations in the white matter of brain that contribute to the pathophysiology of the disorder. Uncinate fasciculus (UNC), a bundle of white matter fibres, plays an important role in the pathology of this disorder and involved in cognitive functions such as memory, language and emotion processing. Therefore, the present study aimed to investigate microstructural changes in UNC fibre in schizophrenia patients relative to controls and its correlation with neuropsychological scores. Diffusion tensor imaging (DTI) and Hindi version of Penn Computerised Neuropsychological Battery test was performed in 14 schizophrenia patients and 14 controls. DTI measures [fractional anisotropy (FA) and mean diffusivity (MD)] from UNC fibre were calculated and a comparison was made between patients and controls. Pearson's correlation was performed between neuropsychological scores and DTI measures.Schizophrenia patients showed significantly reduced FA values in UNC fibre compared to controls. In schizophrenia patients, a positive correlation of attention, spatial memory, sensorimotor dexterity and emotion with FA was observed. These findings suggest that microstructural changes in UNC fibre may contribute to underlying dysfunction in the cognitive functions associated with schizophrenia. PMID:27581933

  1. Abnormal Functional Connectivity in Children with Attention-Deficit/Hyperactivity Disorder

    PubMed Central

    Tomasi, Dardo; Volkow, Nora D.

    2012-01-01

    Background Attention-deficit/hyperactivity disorder (ADHD) is typically characterized by symptoms of inattention and hyperactivity/impulsivity, but there is increased recognition of a motivation deficit too. This neuropathology may reflect dysfunction of both attention and reward-motivation networks. Methods To test this hypothesis, we compared the functional connectivity density between 247 ADHD and 304 typically developing control children from a public magnetic resonance imaging database. We quantified short- and long-range functional connectivity density in the brain using an ultrafast data-driven approach. Results Children with ADHD had lower connectivity (short- and long-range) in regions of the dorsal attention (superior parietal cortex) and default-mode (precuneus) networks and in cerebellum and higher connectivity (short-range) in reward-motivation regions (ventral striatum and orbitofrontal cortex) than control subjects. In ADHD children, the orbitofrontal cortex (region involved in salience attribution) had higher connectivity with reward-motivation regions (striatum and anterior cingulate) and lower connectivity with superior parietal cortex (region involved in attention processing). Conclusions The enhanced connectivity within reward-motivation regions and their decreased connectivity with regions from the default-mode and dorsal attention networks suggest impaired interactions between control and reward pathways in ADHD that might underlie attention and motivation deficits in ADHD. PMID:22153589

  2. Abnormal EEG Complexity and Functional Connectivity of Brain in Patients with Acute Thalamic Ischemic Stroke

    PubMed Central

    Liu, Shuang; Guo, Jie; Meng, Jiayuan; Wang, Zhijun; Yao, Yang; Yang, Jiajia; Qi, Hongzhi; Ming, Dong

    2016-01-01

    Ischemic thalamus stroke has become a serious cardiovascular and cerebral disease in recent years. To date the existing researches mostly concentrated on the power spectral density (PSD) in several frequency bands. In this paper, we investigated the nonlinear features of EEG and brain functional connectivity in patients with acute thalamic ischemic stroke and healthy subjects. Electroencephalography (EEG) in resting condition with eyes closed was recorded for 12 stroke patients and 11 healthy subjects as control group. Lempel-Ziv complexity (LZC), Sample Entropy (SampEn), and brain network using partial directed coherence (PDC) were calculated for feature extraction. Results showed that patients had increased mean LZC and SampEn than the controls, which implied the stroke group has higher EEG complexity. For the brain network, the stroke group displayed a trend of weaker cortical connectivity, which suggests a functional impairment of information transmission in cortical connections in stroke patients. These findings suggest that nonlinear analysis and brain network could provide essential information for better understanding the brain dysfunction in the stroke and assisting monitoring or prognostication of stroke evolution. PMID:27403202

  3. Altered Striatal Synaptic Function and Abnormal Behaviour in Shank3 Exon4-9 Deletion Mouse Model of Autism.

    PubMed

    Jaramillo, Thomas C; Speed, Haley E; Xuan, Zhong; Reimers, Jeremy M; Liu, Shunan; Powell, Craig M

    2016-03-01

    Shank3 is a multi-domain, synaptic scaffolding protein that organizes proteins in the postsynaptic density of excitatory synapses. Clinical studies suggest that ∼ 0.5% of autism spectrum disorder (ASD) cases may involve SHANK3 mutation/deletion. Patients with SHANK3 mutations exhibit deficits in cognition along with delayed/impaired speech/language and repetitive and obsessive/compulsive-like (OCD-like) behaviors. To examine how mutation/deletion of SHANK3 might alter brain function leading to ASD, we have independently created mice with deletion of Shank3 exons 4-9, a region implicated in ASD patients. We find that homozygous deletion of exons 4-9 (Shank3(e4-9) KO) results in loss of the two highest molecular weight isoforms of Shank3 and a significant reduction in other isoforms. Behaviorally, both Shank3(e4-9) heterozygous (HET) and Shank3(e4-9) KO mice display increased repetitive grooming, deficits in novel and spatial object recognition learning and memory, and abnormal ultrasonic vocalizations. Shank3(e4-9) KO mice also display abnormal social interaction when paired with one another. Analysis of synaptosome fractions from striata of Shank3(e4-9) KO mice reveals decreased Homer1b/c, GluA2, and GluA3 expression. Both Shank3(e4-9) HET and KO demonstrated a significant reduction in NMDA/AMPA ratio at excitatory synapses onto striatal medium spiny neurons. Furthermore, Shank3(e4-9) KO mice displayed reduced hippocampal LTP despite normal baseline synaptic transmission. Collectively these behavioral, biochemical and physiological changes suggest Shank3 isoforms have region-specific roles in regulation of AMPAR subunit localization and NMDAR function in the Shank3(e4-9) mutant mouse model of autism. PMID:26559786

  4. Abnormal Resting-State Functional Connectivity in Patients with Chronic Fatigue Syndrome: Results of Seed and Data-Driven Analyses.

    PubMed

    Gay, Charles W; Robinson, Michael E; Lai, Song; O'Shea, Andrew; Craggs, Jason G; Price, Donald D; Staud, Roland

    2016-02-01

    Although altered resting-state functional connectivity (FC) is a characteristic of many chronic pain conditions, it has not yet been evaluated in patients with chronic fatigue. Our objective was to investigate the association between fatigue and altered resting-state FC in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Thirty-six female subjects, 19 ME/CFS and 17 healthy controls, completed a fatigue inventory before undergoing functional magnetic resonance imaging. Two methods, (1) data driven and (2) model based, were used to estimate and compare the intraregional FC between both groups during the resting state (RS). The first approach using independent component analysis was applied to investigate five RS networks: the default mode network, salience network (SN), left frontoparietal networks (LFPN) and right frontoparietal networks, and the sensory motor network (SMN). The second approach used a priori selected seed regions demonstrating abnormal regional cerebral blood flow (rCBF) in ME/CFS patients at rest. In ME/CFS patients, Method-1 identified decreased intrinsic connectivity among regions within the LFPN. Furthermore, the FC of the left anterior midcingulate with the SMN and the connectivity of the left posterior cingulate cortex with the SN were significantly decreased. For Method-2, five distinct clusters within the right parahippocampus and occipital lobes, demonstrating significant rCBF reductions in ME/CFS patients, were used as seeds. The parahippocampal seed and three occipital lobe seeds showed altered FC with other brain regions. The degree of abnormal connectivity correlated with the level of self-reported fatigue. Our results confirm altered RS FC in patients with ME/CFS, which was significantly correlated with the severity of their chronic fatigue. PMID:26449441

  5. Abnormal resting-state functional connectivity within the default mode network subregions in male patients with obstructive sleep apnea

    PubMed Central

    Li, Hai-Jun; Nie, Xiao; Gong, Hong-Han; Zhang, Wei; Nie, Si; Peng, De-Chang

    2016-01-01

    Background and objective Abnormal resting-state functional connectivity (rs-FC) between the central executive network and the default mode network (DMN) in patients with obstructive sleep apnea (OSA) has been reported. However, the effect of OSA on rs-FC within the DMN subregions remains uncertain. This study was designed to investigate whether the rs-FC within the DMN subregions was disrupted and determine its relationship with clinical symptoms in patients with OSA. Methods Forty male patients newly diagnosed with severe OSA and 40 male education- and age-matched good sleepers (GSs) underwent functional magnetic resonance imaging (fMRI) examinations and clinical and neuropsychologic assessments. Seed-based region of interest rs-FC method was used to analyze the connectivity between each pair of subregions within the DMN, including the medial prefrontal cortex (MPFC), posterior cingulate cortex (PCC), hippocampus formation (HF), inferior parietal cortices (IPC), and medial temporal lobe (MTL). The abnormal rs-FC strength within the DMN subregions was correlated with clinical and neuropsychologic assessments using Pearson correlation analysis in patients with OSA. Results Compared with GSs, patients with OSA had significantly decreased rs-FC between the right HF and the PCC, MPFC, and left MTL. However, patients with OSA had significantly increased rs-FC between the MPFC and left and right IPC, and between the left IPC and right IPC. The rs-FC between the right HF and left MTL was positively correlated with rapid eye movement (r=0.335, P=0.035). The rs-FC between the PCC and right HF was negatively correlated with delayed memory (r=-0.338, P=0.033). Conclusion OSA selectively impairs the rs-FC between right HF and PCC, MPFC, and left MTL within the DMN subregions, and provides an imaging indicator for assessment of cognitive dysfunction in OSA patients. PMID:26855576

  6. [An effective case of hepatic arterial infusion chemotherapy based on biochemical modulation for hepatic recurrence of non-functioning islet cell carcinoma of the pancreas].

    PubMed

    Nishijima, K; Ohta, T; Elnemr, A; Yi, S; Ninomiya, I; Kitagawa, H; Fushida, S; Nishimura, G; Fujimura, T; Kayahara, M; Shimizu, K; Miwa, K

    2000-10-01

    A 55-year-old man had a metastasis in segment 3 of the liver 5 months after surgery for non-functioning islet cell carcinoma of the pancreas. The metastatic lesion increased in size in a short period, and other liver micro-metastases that could not be detected by imaging may exist, so hepatic arterial infusion chemotherapy was scheduled for 3 months. The patient underwent hepatic arterial infusion chemotherapy of 5-fluorouracil (250 mg/day/body for 5 days/week) and adriamycin (10 mg/day/body for 2 days/week) and cisplatin (10 mg/day/body for 5 days/week) and he was put on Leucovorin 30 mg/day as a biochemical modulator of 5-FU and tamoxifen 40 mg/day as a biochemical modulator of ADM. A total 6,000 mg of 5-FU, 100 mg of ADM and 240 mg of CDDP had been administered, until hepatic arterial infusion chemotherapy was discontinued because of complicated gastric ulcer. Three months later, the size of the metastatic liver tumor was reduced remarkably and no other metastasis was detected on CT scan, so he underwent partial hepatectomy of the metastatic lesion. No recurrence was found and he has survived in good physical condition during the follow-up period of 5 months after the second operation. PMID:11086447

  7. Abnormal functional connectivity of default mode sub-networks in autism spectrum disorder patients.

    PubMed

    Assaf, Michal; Jagannathan, Kanchana; Calhoun, Vince D; Miller, Laura; Stevens, Michael C; Sahl, Robert; O'Boyle, Jacqueline G; Schultz, Robert T; Pearlson, Godfrey D

    2010-10-15

    Autism spectrum disorders (ASDs) are characterized by deficits in social and communication processes. Recent data suggest that altered functional connectivity (FC), i.e. synchronous brain activity, might contribute to these deficits. Of specific interest is the FC integrity of the default mode network (DMN), a network active during passive resting states and cognitive processes related to social deficits seen in ASD, e.g. Theory of Mind. We investigated the role of altered FC of default mode sub-networks (DM-SNs) in 16 patients with high-functioning ASD compared to 16 matched healthy controls of short resting fMRI scans using independent component analysis (ICA). ICA is a multivariate data-driven approach that identifies temporally coherent networks, providing a natural measure of FC. Results show that compared to controls, patients showed decreased FC between the precuneus and medial prefrontal cortex/anterior cingulate cortex, DMN core areas, and other DM-SNs areas. FC magnitude in these regions inversely correlated with the severity of patients' social and communication deficits as measured by the Autism Diagnostic Observational Schedule and the Social Responsiveness Scale. Importantly, supplemental analyses suggest that these results were independent of treatment status. These results support the hypothesis that DM-SNs under-connectivity contributes to the core deficits seen in ASD. Moreover, these data provide further support for the use of data-driven analysis with resting-state data for illuminating neural systems that differ between groups. This approach seems especially well suited for populations where compliance with and performance of active tasks might be a challenge, as it requires minimal cooperation. PMID:20621638

  8. Abnormalities of follicular helper T-cell number and function in Wiskott-Aldrich syndrome.

    PubMed

    Zhang, Xuan; Dai, Rongxin; Li, Wenyan; Zhao, Hongyi; Zhang, Yongjie; Zhou, Lina; Du, Hongqiang; Luo, Guangjin; Wu, Junfeng; Niu, Linlin; An, Yunfei; Zhang, Zhiyong; Ding, Yuan; Song, Wenxia; Liu, Chaohong; Zhao, Xiaodong

    2016-06-23

    Wiskott-Aldrich syndrome protein (WASp) is a hematopoietic-specific regulator of actin nucleation. Wiskott-Aldrich syndrome (WAS) patients show immunodeficiencies, most of which have been attributed to defective T-cell functions. T follicular helper (Tfh) cells are the major CD4(+) T-cell subset with specialized B-cell helper capabilities. Aberrant Tfh cells activities are involved in immunopathologies such as autoimmunity, immunodeficiencies, and lymphomas. We found that in WAS patients, the number of circulating Tfh cells was significantly reduced due to reduced proliferation and increased apoptosis, and Tfh cells were Th2 and Th17 polarized. The expression of inducible costimulator (ICOS) in circulating Tfh cells was higher in WAS patients than in controls. BCL6 expression was decreased in total CD4(+) T and Tfh cells of WAS patients. Mirroring the results in patients, the frequency of Tfh cells in WAS knockout (KO) mice was decreased, as was the frequency of BCL6(+) Tfh cells, but the frequency of ICOS(+) Tfh cells was increased. Using WAS chimera mice, we found that the number of ICOS(+) Tfh cells was decreased in WAS chimera mice, indicating that the increase in ICOS(+) Tfh cells in WAS KO mice was cell extrinsic. The data from in vivo CD4(+) naive T-cell adoptive transfer mice as well as in vitro coculture of naive B and Tfh cells showed that the defective function of WASp-deficient Tfh cells was T-cell intrinsic. Consistent findings in both WAS patients and WAS KO mice suggested an essential role for WASp in the development and memory response of Tfh cells and that WASp deficiency causes a deficient differentiation defect in Tfh cells by downregulating the transcription level of BCL6. PMID:27170596

  9. Abnormalities of follicular helper T-cell number and function in Wiskott-Aldrich syndrome

    PubMed Central

    Zhang, Xuan; Dai, Rongxin; Li, Wenyan; Zhao, Hongyi; Zhang, Yongjie; Zhou, Lina; Du, Hongqiang; Luo, Guangjin; Wu, Junfeng; Niu, Linlin; An, Yunfei; Zhang, Zhiyong; Ding, Yuan; Song, Wenxia; Liu, Chaohong

    2016-01-01

    Wiskott-Aldrich syndrome protein (WASp) is a hematopoietic-specific regulator of actin nucleation. Wiskott-Aldrich syndrome (WAS) patients show immunodeficiencies, most of which have been attributed to defective T-cell functions. T follicular helper (Tfh) cells are the major CD4+ T-cell subset with specialized B-cell helper capabilities. Aberrant Tfh cells activities are involved in immunopathologies such as autoimmunity, immunodeficiencies, and lymphomas. We found that in WAS patients, the number of circulating Tfh cells was significantly reduced due to reduced proliferation and increased apoptosis, and Tfh cells were Th2 and Th17 polarized. The expression of inducible costimulator (ICOS) in circulating Tfh cells was higher in WAS patients than in controls. BCL6 expression was decreased in total CD4+ T and Tfh cells of WAS patients. Mirroring the results in patients, the frequency of Tfh cells in WAS knockout (KO) mice was decreased, as was the frequency of BCL6+ Tfh cells, but the frequency of ICOS+ Tfh cells was increased. Using WAS chimera mice, we found that the number of ICOS+ Tfh cells was decreased in WAS chimera mice, indicating that the increase in ICOS+ Tfh cells in WAS KO mice was cell extrinsic. The data from in vivo CD4+ naive T-cell adoptive transfer mice as well as in vitro coculture of naive B and Tfh cells showed that the defective function of WASp-deficient Tfh cells was T-cell intrinsic. Consistent findings in both WAS patients and WAS KO mice suggested an essential role for WASp in the development and memory response of Tfh cells and that WASp deficiency causes a deficient differentiation defect in Tfh cells by downregulating the transcription level of BCL6. PMID:27170596

  10. Abnormal functional connectivity of default mode sub-networks in autism spectrum disorder patients

    PubMed Central

    Assaf, Michal; Jagannathan, Kanchana; Calhoun, Vince D.; Miller, Laura; Stevens, Michael C.; Sahl, Robert; O'Boyle, Jacqueline G.; Schultz, Robert T.; Pearlson, Godfrey D.

    2011-01-01

    Autism spectrum disorders (ASDs) are characterized by deficits in social and communication processes. Recent data suggest that altered functional connectivity (FC), i.e. synchronous brain activity, might contribute to these deficits. Of specific interest is the FC integrity of the default mode network (DMN), a network active during passive resting states and cognitive processes related to social deficits seen in ASD, e.g. Theory of Mind. We investigated the role of altered FC of default mode sub-networks (DM-SNs) in 16 patients with high-functioning ASD compared to 16 matched healthy controls of short resting fMRI scans using independent component analysis (ICA). ICA is a multivariate data-driven approach that identifies temporally coherent networks, providing a natural measure of FC. Results show that compared to controls, patients showed decreased FC between the precuneus and medial prefrontal cortex/anterior cingulate cortex, DMN core areas, and other DM-SNs areas. FC magnitude in these regions inversely correlated with the severity of patients' social and communication deficits as measured by the Autism Diagnostic Observational Schedule and the Social Responsiveness Scale. Importantly, supplemental analyses suggest that these results were independent of treatment status. These results support the hypothesis that DM-SNs under-connectivity contributes to the core deficits seen in ASD. Moreover, these data provide further support for the use of data-driven analysis with resting-state data for illuminating neural systems that differ between groups. This approach seems especially well suited for populations where compliance with and performance of active tasks might be a challenge, as it requires minimal cooperation. PMID:20621638

  11. Acid sphingomyelinase (aSMase) deficiency leads to abnormal microglia behavior and disturbed retinal function

    SciTech Connect

    Dannhausen, Katharina; Karlstetter, Marcus; Caramoy, Albert; Volz, Cornelia; Jägle, Herbert; Liebisch, Gerhard; Utermöhlen, Olaf; Langmann, Thomas

    2015-08-21

    Mutations in the acid sphingomyelinase (aSMase) coding gene sphingomyelin phosphodiesterase 1 (SMPD1) cause Niemann-Pick disease (NPD) type A and B. Sphingomyelin storage in cells of the mononuclear phagocyte system cause hepatosplenomegaly and severe neurodegeneration in the brain of NPD patients. However, the effects of aSMase deficiency on retinal structure and microglial behavior have not been addressed in detail yet. Here, we demonstrate that retinas of aSMase{sup −/−} mice did not display overt neuronal degeneration but showed significantly reduced scotopic and photopic responses in electroretinography. In vivo fundus imaging of aSMase{sup −/−} mice showed many hyperreflective spots and staining for the retinal microglia marker Iba1 revealed massive proliferation of retinal microglia that had significantly enlarged somata. Nile red staining detected prominent phospholipid inclusions in microglia and lipid analysis showed significantly increased sphingomyelin levels in retinas of aSMase{sup −/−} mice. In conclusion, the aSMase-deficient mouse is the first example in which microglial lipid inclusions are directly related to a loss of retinal function. - Highlights: • aSMase-deficient mice show impaired retinal function and reactive microgliosis. • aSMase-deficient microglia express pro-inflammatory transcripts. • aSMase-deficient microglia proliferate and have increased cell body size. • In vivo imaging shows hyperreflective spots in the fundus of aSMase-deficient mice. • aSMase-deficient microglia accumulate sphingolipid-rich intracellular deposits.

  12. Characterization of neuromuscular synapse function abnormalities in multiple Duchenne muscular dystrophy mouse models.

    PubMed

    van der Pijl, Elizabeth M; van Putten, Maaike; Niks, Erik H; Verschuuren, Jan J G M; Aartsma-Rus, Annemieke; Plomp, Jaap J

    2016-06-01

    Duchenne muscular dystrophy (DMD) is an X-linked myopathy caused by dystrophin deficiency. Dystrophin is present intracellularly at the sarcolemma, connecting actin to the dystrophin-associated glycoprotein complex. Interestingly, it is enriched postsynaptically at the neuromuscular junction (NMJ), but its synaptic function is largely unknown. Utrophin, a dystrophin homologue, is also concentrated at the NMJ, and upregulated in DMD. It is possible that the absence of dystrophin at NMJs in DMD causes neuromuscular transmission defects that aggravate muscle weakness. We studied NMJ function in mdx mice (lacking dystrophin) and wild type mice. In addition, mdx/utrn(+/-) and mdx/utrn(-/-) mice (lacking utrophin) were used to investigate influences of utrophin levels. The three Duchenne mouse models showed muscle weakness when comparatively tested in vivo, with mdx/utrn(-/-) mice being weakest. Ex vivo muscle contraction and electrophysiological studies showed a reduced safety factor of neuromuscular transmission in all models. NMJs had ~ 40% smaller miniature endplate potential amplitudes compared with wild type, indicating postsynaptic sensitivity loss for the neurotransmitter acetylcholine. However, nerve stimulation-evoked endplate potential amplitudes were unchanged. Consequently, quantal content (i.e. the number of acetylcholine quanta released per nerve impulse) was considerably increased. Such a homeostatic compensatory increase in neurotransmitter release is also found at NMJs in myasthenia gravis, where autoantibodies reduce acetylcholine receptors. However, high-rate nerve stimulation induced exaggerated endplate potential rundown. Study of NMJ morphology showed that fragmentation of acetylcholine receptor clusters occurred in all models, being most severe in mdx/utrn(-/-) mice. Overall, we showed mild 'myasthenia-like' neuromuscular synaptic dysfunction in several Duchenne mouse models, which possibly affects muscle weakness and degeneration. PMID:27037492

  13. Genetic and functional analyses demonstrate a role for abnormal glycinergic signaling in autism.

    PubMed

    Pilorge, M; Fassier, C; Le Corronc, H; Potey, A; Bai, J; De Gois, S; Delaby, E; Assouline, B; Guinchat, V; Devillard, F; Delorme, R; Nygren, G; Råstam, M; Meier, J C; Otani, S; Cheval, H; James, V M; Topf, M; Dear, T N; Gillberg, C; Leboyer, M; Giros, B; Gautron, S; Hazan, J; Harvey, R J; Legendre, P; Betancur, C

    2016-07-01

    Autism spectrum disorder (ASD) is a common neurodevelopmental condition characterized by marked genetic heterogeneity. Recent studies of rare structural and sequence variants have identified hundreds of loci involved in ASD, but our knowledge of the overall genetic architecture and the underlying pathophysiological mechanisms remains incomplete. Glycine receptors (GlyRs) are ligand-gated chloride channels that mediate inhibitory neurotransmission in the adult nervous system but exert an excitatory action in immature neurons. GlyRs containing the α2 subunit are highly expressed in the embryonic brain, where they promote cortical interneuron migration and the generation of excitatory projection neurons. We previously identified a rare microdeletion of the X-linked gene GLRA2, encoding the GlyR α2 subunit, in a boy with autism. The microdeletion removes the terminal exons of the gene (GLRA2(Δex8-9)). Here, we sequenced 400 males with ASD and identified one de novo missense mutation, p.R153Q, absent from controls. In vitro functional analysis demonstrated that the GLRA2(Δex8)(-)(9) protein failed to localize to the cell membrane, while the R153Q mutation impaired surface expression and markedly reduced sensitivity to glycine. Very recently, an additional de novo missense mutation (p.N136S) was reported in a boy with ASD, and we show that this mutation also reduced cell-surface expression and glycine sensitivity. Targeted glra2 knockdown in zebrafish induced severe axon-branching defects, rescued by injection of wild type but not GLRA2(Δex8-9) or R153Q transcripts, providing further evidence for their loss-of-function effect. Glra2 knockout mice exhibited deficits in object recognition memory and impaired long-term potentiation in the prefrontal cortex. Taken together, these results implicate GLRA2 in non-syndromic ASD, unveil a novel role for GLRA2 in synaptic plasticity and learning and memory, and link altered glycinergic signaling to social and cognitive

  14. Development of a decision support tool to facilitate primary care management of patients with abnormal liver function tests without clinically apparent liver disease [HTA03/38/02]. Abnormal Liver Function Investigations Evaluation (ALFIE)

    PubMed Central

    Donnan, Peter T; McLernon, David; Steinke, Douglas; Ryder, Stephen; Roderick, Paul; Sullivan, Frank M; Rosenberg, William; Dillon, John F

    2007-01-01

    Background Liver function tests (LFTs) are routinely performed in primary care, and are often the gateway to further invasive and/or expensive investigations. Little is known of the consequences in people with an initial abnormal liver function (ALF) test in primary care and with no obvious liver disease. Further investigations may be dangerous for the patient and expensive for Health Services. The aims of this study are to determine the natural history of abnormalities in LFTs before overt liver disease presents in the population and identify those who require minimal further investigations with the potential for reduction in NHS costs. Methods/Design A population-based retrospective cohort study will follow up all those who have had an incident liver function test (LFT) in primary care to subsequent liver disease or mortality over a period of 15 years (approx. 2.3 million tests in 99,000 people). The study is set in Primary Care in the region of Tayside, Scotland (pop approx. 429,000) between 1989 and 2003. The target population consists of patients with no recorded clinical signs or symptoms of liver disease and registered with a GP. The health technologies being assessed are LFTs, viral and auto-antibody tests, ultrasound, CT, MRI and liver biopsy. The study will utilise the Epidemiology of Liver Disease In Tayside (ELDIT) database to determine the outcomes of liver disease. These are based on hospital admission data (Scottish Morbidity Record 1), dispensed medication records, death certificates, and examination of medical records from Tayside hospitals. A sample of patients (n = 150) with recent initial ALF tests or invitation to biopsy will complete questionnaires to obtain quality of life data and anxiety measures. Cost-effectiveness and cost utility Markov model analyses will be performed from health service and patient perspectives using standard NHS costs. The findings will also be used to develop a computerised clinical decision support tool. Discussion

  15. [Functional assessment of the hepatic arterial blood flow by pharmacoradiography (author's transl)].

    PubMed

    Stellamor, K; Hruby, W; Peschl, L

    1981-12-01

    By means of celiacography it was possible to demonstrate that parenteral medication with parathormone creates a selective dilatation of the liver vessels in man, provided that they are dilatable. This hemodynamic hormone effect could not be traced in the other mesenteric vessels. The increase of portal hypertension resulting from cirrhosis leads to a loss of the dilating ability of liver vessels. This regressive reaction is well demonstrated on the parathormon-celiaco-gram. Thus a functional assessment of the hepatic blood flow is possible. The extent of the dilatability of the liver artery seems to be of great importance for the prognosis and indication of the porto-systemic shunt-operation. Moreover we could show that an increase in the liver perfusion demonstrates pathologic liver processes in a better way. PMID:7323629

  16. Low-dose propranolol for multiple hepatic and cutaneous hemangiomas with deranged liver function.

    PubMed

    Tan, Swee Thong; Itinteang, Tinte; Leadbitter, Philip

    2011-03-01

    We report here the case of an infant with multiple hepatic and cutaneous infantile hemangiomas (IHs) associated with deranged liver function who was treated successfully with low-dose propranolol. We also discuss our recent data that show that IH is a developmental anomaly of hemogenic endothelium derived from primitive mesoderm with a neural crest-cell phenotype. We previously presented evidence that this hemogenic endothelium is governed by the renin-angiotensin system, which we propose can account for both the action of propranolol and the process of spontaneous involution of IH. We further speculate on the possibility of using inhibitors of angiotensin-converting enzyme and that of angiotensin II receptor 2 as potential alternative therapies. PMID:21357335

  17. Motor Network Plasticity and Low-Frequency Oscillations Abnormalities in Patients with Brain Gliomas: A Functional MRI Study

    PubMed Central

    Niu, Chen; Zhang, Ming; Min, Zhigang; Rana, Netra; Zhang, Qiuli; Liu, Xin; Li, Min; Lin, Pan

    2014-01-01

    Brain plasticity is often associated with the process of slow-growing tumor formation, which remodels neural organization and optimizes brain network function. In this study, we aimed to investigate whether motor function plasticity would display deficits in patients with slow-growing brain tumors located in or near motor areas, but who were without motor neurological deficits. We used resting-state functional magnetic resonance imaging to probe motor networks in 15 patients with histopathologically confirmed brain gliomas and 15 age-matched healthy controls. All subjects performed a motor task to help identify individual motor activity in the bilateral primary motor cortex (PMC) and supplementary motor area (SMA). Frequency-based analysis at three different frequencies was then used to investigate possible alterations in the power spectral density (PSD) of low-frequency oscillations. For each group, the average PSD was determined for each brain region and a nonparametric test was performed to determine the difference in power between the two groups. Significantly reduced inter-hemispheric functional connectivity between the left and right PMC was observed in patients compared with controls (P<0.05). We also found significantly decreased PSD in patients compared to that in controls, in all three frequency bands (low: 0.01–0.02 Hz; middle: 0.02–0.06 Hz; and high: 0.06–0.1 Hz), at three key motor regions. These findings suggest that in asymptomatic patients with brain tumors located in eloquent regions, inter-hemispheric connection may be more vulnerable. A comparison of the two approaches indicated that power spectral analysis is more sensitive than functional connectivity analysis for identifying the neurological abnormalities underlying motor function plasticity induced by slow-growing tumors. PMID:24806463

  18. Tspyl2 Loss-of-Function Causes Neurodevelopmental Brain and Behavior Abnormalities in Mice.

    PubMed

    Li, Qi; Chan, Siu Yuen; Wong, Kwun K; Wei, Ran; Leung, Yu On; Ding, Abby Y; Hui, Tomy C K; Cheung, Charlton; Chua, Siew E; Sham, Pak C; Wu, Ed X; McAlonan, Grainne M

    2016-07-01

    Testis specific protein, Y-encoded-like 2 (TSPYL2) regulates the expression of genes encoding glutamate receptors. Glutamate pathology is implicated in neurodevelopmental conditions such as autism spectrum disorder, attention deficit hyperactivity disorder (ADHD) and schizophrenia. In line with this, a microduplication incorporating the TSPYL2 locus has been reported in people with ADHD. However, the role of Tspyl2 remains unclear. Therefore here we used a Tspyl2 loss-of-function mouse model to directly examine how this gene impacts upon behavior and brain anatomy. We hypothesized that Tspyl2 knockout (KO) would precipitate a phenotype relevant to neurodevelopmental conditions. In line with this prediction, we found that Tspyl2 KO mice were marginally more active, had significantly impaired prepulse inhibition, and were significantly more 'sensitive' to the dopamine agonist amphetamine. In addition, the lateral ventricles were significantly smaller in KO mice. These findings suggest that disrupting Tspyl2 gene expression leads to behavioral and brain morphological alterations that mirror a number of neurodevelopmental psychiatric traits. PMID:26826030

  19. Abnormal pituitary-gonadal axis may be responsible for rat decreased testicular function under simulated microgravity

    NASA Astrophysics Data System (ADS)

    Zhou, Yi; Tan, Xin; Zhu, Bao-an; Qi, Meng-di; Ding, Su-ling

    Space flight and simulated microgravity lead to suppression of mammalian spermatogenesis and decreased plasma testosterone level. In order to explain the mechanism behind the depression, we used rat tail-suspended model to simulate weightless conditions. To prevent cryptorchidism caused by tail-suspension, some experimental animals received inguinal canal ligation. The results showed that mass of testis decreased significantly and seminiferous tubules became atrophied in rats after tail-suspension. The levels of plasma testosterone (T), luteinizing hormone (LH), and follicle-stimulating hormone (FSH) in tail-suspended rats with or without inguinal canal ligation decreased significantly compared with controls, and an increased level of plasma estradiol (E) was revealed in tail-suspended rats. The results indicate that besides the direct influence of fluid shift upon testis under short-term simulated microgravity, the pituitary function is also disturbed as a result of either immobilization stress or weight loss during tail-suspension treatment, which is responsible to some extent for the decreased testosterone secretion level and the atrophia of testis. The conversion of testosterone into E under simulated microgravity is another possible cause for the decline of plasma testosterone.

  20. Immunoregulation in onchocerciasis. Functional and phenotypic abnormalities of lymphocyte subsets and changes with therapy.

    PubMed Central

    Freedman, D O; Lujan-Trangay, A; Steel, C; Gonzalez-Peralta, C; Nutman, T B

    1991-01-01

    To help define the immunoregulatory defects in patients with onchocerciasis, flow cytometric analysis of circulating lymphocyte subpopulations was performed in parallel with functional assays. No significant differences in CD4/CD8 ratios were seen when microfilariae-positive individuals from Guatemala were compared with Guatemalan controls. However, the infected individuals had significantly increased numbers of circulating CD4+CD45RA+ lymphocytes (mean 38.3%) when compared with controls (mean 16.0%). Coexpression of the activation marker HLA-DR was significantly increased on CD4+ cells from infected individuals. In contrast, no up-regulation of HLA-DR was seen on CD8+ or CD19+ cells. At 1 year after initiation of treatment with semiannual doses of the microfilaricide ivermectin, there were significant increases (P less than 0.05) in the percentage of CD4+CD45RA- cells, the percentage of CD4+HLA-DR+ cells, and mitogen-induced lymphokine production (IL-2, IL-4). Despite these changes, parasite-specific IL-2 and IL-4 production which had been undetectable before treatment did not manifest itself even by the 2-yr follow-up. Defects in the T-cell activation pathway in Onchocerca volvulus-infected individuals may thus exist at several independent points; a state of parasite antigen-specific tolerance appears to remain even after the relative reversal of other generalized immunoregulatory defects. PMID:1829096

  1. Abnormal affective decision making revealed in adolescent binge drinkers using a functional magnetic resonance imaging study.

    PubMed

    Xiao, Lin; Bechara, Antoine; Gong, Qiyong; Huang, Xiaoqi; Li, Xiangrui; Xue, Gui; Wong, Savio; Lu, Zhong-Lin; Palmer, Paula; Wei, Yonglan; Jia, Yong; Johnson, C Anderson

    2013-06-01

    The goal of this study was to investigate the neural correlates of affective decision making, as measured by the Iowa Gambling Task (IGT), which are associated with adolescent binge drinking. Fourteen adolescent binge drinkers (16-18 years of age) and 14 age-matched adolescents who had never consumed alcohol--never drinkers--were recruited from local high schools in Chengdu, China. Questionnaires were used to assess academic performance, drinking experience, and urgency. Brain regions activated by the IGT performance were identified with functional magnetic resonance imaging. Results showed that, compared to never drinkers, binge drinkers performed worse on the IGT and showed higher activity in the subcomponents of the decision-making neural circuitry implicated in the execution of emotional and incentive-related behaviors, namely, the left amygdala and insula bilaterally. Moreover, measures of the severity of drinking problems in real life, as well as high urgency scores, were associated with increased activity within the insula, combined with decreased activity within the orbitofrontal cortex. These results suggest that hyperreactivity of a neural system implicated in the execution of emotional and incentive-related behaviors can be associated with socially undesirable behaviors, such as binge drinking, among adolescents. These findings have social implications because they potentially reveal underlying neural mechanisms for making poor decisions, which may increase an individual's risk and vulnerability for alcoholism. PMID:22486330

  2. Functional and structural abnormalities associated with empathy in patients with schizophrenia: An fMRI and VBM study.

    PubMed

    Singh, Sadhana; Modi, Shilpi; Goyal, Satnam; Kaur, Prabhjot; Singh, Namita; Bhatia, Triptish; Deshpande, Smita N; Khushu, Subash

    2015-06-01

    Empathy deficit is a core feature of schizophrenia which may lead to social dysfunction. The present study was carried out to investigate functional and structural abnormalities associated with empathy in patients with schizophrenia using functional magnetic resonance imaging (fMRI) and voxel-based morphometry (VBM). A sample of 14 schizophrenia patients and 14 healthy control subjects matched for age, sex and education were examined with structural highresolution T1-weighted MRI; fMRI images were obtained during empathy task in the same session. The analysis was carried out using SPM8 software. On behavioural assessment, schizophrenic patients (83.00+-29.04) showed less scores for sadness compared to healthy controls (128.70+-22.26) (p less than 0.001). fMRI results also showed reduced clusters of activation in the bilateral fusiform gyrus, left lingual gyrus, left middle and inferior occipital gyrus in schizophrenic subjects as compared to controls during empathy task. In the same brain areas, VBM results also showed reduced grey and white matter volumes. The present study provides an evidence for an association between structural alterations and disturbed functional brain activation during empathy task in persons affected with schizophrenia. These findings suggest a biological basis for social cognition deficits in schizophrenics. PMID:25963262

  3. Prevalence of Abnormalities in Vestibular Function and Balance among HIV-Seropositive and HIV-Seronegative Women and Men

    PubMed Central

    Cohen, Helen S.; Cox, Christopher; Springer, Gayle; Hoffman, Howard J.; Young, Mary A.; Margolick, Joseph B.; Plankey, Michael W.

    2012-01-01

    Background Most HIV-seropositive subjects in western countries receive highly active antiretroviral therapy (HAART). Although many aspects of their health have been studied, little is known about their vestibular and balance function. The goals of this study were to determine the prevalences of vestibular and balance impairments among HIV-seropositive and comparable seronegative men and women and to determine if those groups differed. Methods Standard screening tests of vestibular and balance function, including head thrusts, Dix-Hallpike maneuvers, and Romberg balance tests on compliant foam were performed during semiannual study visits of participants who were enrolled in the Baltimore and Washington, D. C. sites of the Multicenter AIDS Cohort Study and the Women's Interagency HIV Study. Results No significant differences by HIV status were found on most tests, but HIV-seropositive subjects who were using HAART had a lower frequency of abnormal Dix-Hallpike nystagmus than HIV-seronegative subjects. A significant number of nonclassical Dix-Hallpike responses were found. Age was associated with Romberg scores on foam with eyes closed. Sex was not associated with any of the test scores. Conclusion These findings suggest that HAART-treated HIV infection has no harmful association with vestibular function in community-dwelling, ambulatory men and women. The association with age was expected, but the lack of association with sex was unexpected. The presence of nonclassical Dix-Hallpike responses might be consistent with central nervous system lesions. PMID:22675462

  4. Fyn kinase genetic ablation causes structural abnormalities in mature retina and defective Müller cell function.

    PubMed

    Chavez-Solano, Marbella; Ibarra-Sanchez, Alfredo; Treviño, Mario; Gonzalez-Espinosa, Claudia; Lamas, Monica

    2016-04-01

    Fyn kinase is widely expressed in neuronal and glial cells of the brain, where it exerts multiple functional roles that affect fundamental physiological processes. The aim of our study was to investigate the, so far unknown, functional role of Fyn in the retina. We report that Fyn is expressed, in vivo, in a subpopulation of Müller glia. We used a mouse model of Fyn genetic ablation and Müller-enriched primary cultures to demonstrate that Fyn deficiency induces morphological alterations in the mature retina, a reduction in the thickness of the outer and inner nuclear layers and alterations in postnatal Müller cell physiology. These include shortening of Müller cell processes, a decrease in cell proliferation, inactivation of the Akt signal transduction pathway, a reduced number of focal adhesions points and decreased adhesion of these cells to the ECM. As abnormalities in Müller cell physiology have been previously associated to a compromised retinal function we evaluated behavioral responses to visual stimulation. Our results associate Fyn deficiency with impaired visual optokinetic responses under scotopic and photopic light conditions. Our study reveals novel roles for Fyn kinase in retinal morphology and Müller cell physiology and suggests that Fyn is required for optimal visual processing. PMID:26808221

  5. Prospective Randomized Trial Comparing Hepatic Venous Outflow and Renal Function after Conventional versus Piggyback Liver Transplantation

    PubMed Central

    Brescia, Marília D’Elboux Guimarães; Massarollo, Paulo Celso Bosco; Imakuma, Ernesto Sasaki; Mies, Sérgio

    2015-01-01

    Background This randomized prospective clinical trial compared the hepatic venous outflow drainage and renal function after conventional with venovenous bypass (n = 15) or piggyback (n = 17) liver transplantation. Methods Free hepatic vein pressure (FHVP) and central venous pressure (CVP) measurements were performed after graft reperfusion. Postoperative serum creatinine (Cr) was measured daily on the first week and on the 14th, 21st and 28th postoperative days (PO). The prevalence of acute renal failure (ARF) up to the 28th PO was analyzed by RIFLE-AKIN criteria. A Generalized Estimating Equation (GEE) approach was used for comparison of longitudinal measurements of renal function. Results FHVP-CVP gradient > 3 mm Hg was observed in 26.7% (4/15) of the patients in the conventional group and in 17.6% (3/17) in the piggyback group (p = 0.68). Median FHVP-CVP gradient was 2 mm Hg (0–8 mmHg) vs. 3 mm Hg (0–7 mm Hg) in conventional and piggyback groups, respectively (p = 0.73). There is no statistically significant difference between the conventional (1/15) and the piggyback (2/17) groups regarding massive ascites development (p = 1.00). GEE estimated marginal mean for Cr was significantly higher in conventional than in piggyback group (2.14 ± 0.26 vs. 1.47 ± 0.15 mg/dL; p = 0.02). The conventional method presented a higher prevalence of severe ARF during the first 28 PO days (OR = 3.207; 95% CI, 1.010 to 10.179; p = 0.048). Conclusion Patients submitted to liver transplantation using conventional or piggyback methods present similar results regarding venous outflow drainage of the graft. Conventional with venovenous bypass technique significantly increases the harm of postoperative renal dysfunction. Trial Registration ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT01707810 PMID:26115520

  6. Unique functional abnormalities in youth with combined marijuana use and depression: an FMRI study.

    PubMed

    Ford, Kristen A; Wammes, Michael; Neufeld, Richard W; Mitchell, Derek; Théberge, Jean; Williamson, Peter; Osuch, Elizabeth A

    2014-01-01

    Prior research has shown a relationship between early onset marijuana (MJ) use and depression; however, this relationship is complex and poorly understood. Here, we utilized passive music listening and fMRI to examine functional brain activation to a rewarding stimulus in 75 participants [healthy controls (HC), patients with major depressive disorder (MDD), frequent MJ users, and the combination of MDD and MJ (MDD + MJ)]. For each participant, a preferred and neutral piece of instrumental music was determined (utilizing ratings on a standardized scale), and each completed two 6-min fMRI scans of a passive music listening task. Data underwent pre-processing and 61 participants were carried forward for analysis (17 HC, 15 MDD, 15 MJ, 14 MDD + MJ). Two statistical analyses were performed using SPM8, an analysis of covariance with two factors (group × music type) and a whole brain, multiple regression analysis incorporating two predictors of interest [MJ use in past 28 days; and Beck Depression Inventory (BDI) score]. We identified a significant group × music type interaction. Post hoc comparisons showed that the preferred music had significantly greater activation in the MDD + MJ group in areas including the right middle and inferior frontal gyri extending into the claustrum and putamen and the anterior cingulate. No significant differences were identified in MDD, MJ, or HC groups. Multiple regression analysis showed that activation in medial frontal cortex was positively correlated with amount of MJ use, and activation in areas including the insula was negatively correlated with BDI score. Results showed modulation in brain activation during passive music listening specific to MDD, frequent MJ users. This supports the suggestion that frequent MJ use, when combined with MDD, is associated with changes in neurocircuitry involved in reward processing in ways that are absent with either frequent MJ use or MDD alone. This could help inform

  7. Abnormalities of endocrine function in patients with clinically "silent" adrenal masses.

    PubMed

    Ambrosi, B; Peverelli, S; Passini, E; Re, T; Ferrario, R; Colombo, P; Sartorio, A; Faglia, G

    1995-04-01

    Because, in recent years, patients with incidentally discovered adrenal masses have been encountered increasingly, their endocrine function was investigated in basal conditions and after dynamic tests. Thirty-two patients (23 women and 9 men, aged 28-74 years) were studied. Lesion diameter, as documented by computed tomography and/or nuclear magnetic resonance imaging, ranged between 5 and 65 mm; the tumors were localized on the right in 22 patients, on the left in 5 and bilaterally in 5 cases. In basal conditions, urinary free cortisol (UFC) excretion, plasma adrenocorticotropin (ACTH) and cortisol levels were normal, except for 4 patients who showed high UFC and ACTH levels in the low-normal range. Ovine corticotropin-releasing hormone (CRH, 1 microgram/kg iv) was given to 18 patients, inducing normal ACTH and cortisol responses in 12, blunted responses in 4 and no response in 2 cases. No reduction in ACTH and cortisol levels after suppression tests was observed in 4 of 29 patients after dexamethasone (1 mg overnight) or in 6 of 29 after loperamide. The 4 patients who were unresponsive to both tests did not show any further inhibition after high-dose dexamethasone administration, had low plasma ACTH levels and showed impaired or absent responses to the CRH test: they were diagnosed as affected with preclinical Cushing's syndrome. An exogenous ACTH test performed in 30 patients caused a normal cortisol rise. Basal mean 17-hydroxy-progesterone (17-OHP) levels were not different from those in normal subjects.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:7711879

  8. Loss of Rab27 function results in abnormal lung epithelium structure in mice

    PubMed Central

    Bolasco, Giulia; Tracey-White, Dhani C.; Tolmachova, Tanya; Thorley, Andrew J.; Tetley, Teresa D.; Seabra, Miguel C.

    2011-01-01

    Rab27 small GTPases regulate secretion and movement of lysosome-related organelles such as T cell cytolytic granules and platelet-dense granules. Previous studies indicated that Rab27a and Rab27b are expressed in the murine lung suggesting that they regulate secretory processes in the lung. Consistent with those studies, we found that Rab27a and Rab27b are expressed in cell types that contain secretory granules: alveolar epithelial type II (AEII) and Clara cells. We then used Rab27a/Rab27b double knockout (DKO) mice to examine the functional consequence of loss of Rab27 proteins in the murine lung. Light and electron microscopy revealed a number of morphological changes in lungs from DKO mice when compared with those in control animals. In aged DKO mice we observed atrophy of the bronchiolar and alveolar epithelium with reduction of cells numbers, thinning of the bronchiolar epithelium and alveolar walls, and enlargement of alveolar airspaces. In these samples we also observed increased numbers of activated foamy alveolar macrophages and granulocyte containing infiltrates together with reduction in the numbers of Clara cells and AEII cells compared with control. At the ultrastructural level we observed accumulation of cytoplasmic membranes and vesicles in Clara cells. Meanwhile, AEII cells in DKO accumulated large mature lamellar bodies and lacked immature/precursor lamellar bodies. We hypothesize that the morphological changes observed at the ultrastructural level in DKO samples result from secretory defects in AEII and Clara cells and that over time these defects lead to atrophy of the epithelium. PMID:21160031

  9. Unique Functional Abnormalities in Youth with Combined Marijuana Use and Depression: An fMRI Study

    PubMed Central

    Ford, Kristen A.; Wammes, Michael; Neufeld, Richard W.; Mitchell, Derek; Théberge, Jean; Williamson, Peter; Osuch, Elizabeth A.

    2014-01-01

    Prior research has shown a relationship between early onset marijuana (MJ) use and depression; however, this relationship is complex and poorly understood. Here, we utilized passive music listening and fMRI to examine functional brain activation to a rewarding stimulus in 75 participants [healthy controls (HC), patients with major depressive disorder (MDD), frequent MJ users, and the combination of MDD and MJ (MDD + MJ)]. For each participant, a preferred and neutral piece of instrumental music was determined (utilizing ratings on a standardized scale), and each completed two 6-min fMRI scans of a passive music listening task. Data underwent pre-processing and 61 participants were carried forward for analysis (17 HC, 15 MDD, 15 MJ, 14 MDD + MJ). Two statistical analyses were performed using SPM8, an analysis of covariance with two factors (group × music type) and a whole brain, multiple regression analysis incorporating two predictors of interest [MJ use in past 28 days; and Beck Depression Inventory (BDI) score]. We identified a significant group × music type interaction. Post hoc comparisons showed that the preferred music had significantly greater activation in the MDD + MJ group in areas including the right middle and inferior frontal gyri extending into the claustrum and putamen and the anterior cingulate. No significant differences were identified in MDD, MJ, or HC groups. Multiple regression analysis showed that activation in medial frontal cortex was positively correlated with amount of MJ use, and activation in areas including the insula was negatively correlated with BDI score. Results showed modulation in brain activation during passive music listening specific to MDD, frequent MJ users. This supports the suggestion that frequent MJ use, when combined with MDD, is associated with changes in neurocircuitry involved in reward processing in ways that are absent with either frequent MJ use or MDD alone. This could help inform

  10. Abnormal Functional Specialization within Medial Prefrontal Cortex in High-Functioning Autism: A Multi-Voxel Similarity Analysis

    ERIC Educational Resources Information Center

    Gilbert, Sam J.; Meuwese, Julia D. I.; Towgood, Karren J.; Frith, Christopher D.; Burgess, Paul W.

    2009-01-01

    Multi-voxel pattern analyses have proved successful in "decoding" mental states from fMRI data, but have not been used to examine brain differences associated with atypical populations. We investigated a group of 16 (14 males) high-functioning participants with autism spectrum disorder (ASD) and 16 non-autistic control participants (12 males)…

  11. Clinical investigation: thyroid function test abnormalities in cardiac arrest associated with acute coronary syndrome

    PubMed Central

    Iltumur, Kenan; Olmez, Gonul; Arıturk, Zuhal; Taskesen, Tuncay; Toprak, Nizamettin

    2005-01-01

    Introduction It is known that thyroid homeostasis is altered during the acute phase of cardiac arrest. However, it is not clear under what conditions, how and for how long these alterations occur. In the present study we examined thyroid function tests (TFTs) in the acute phase of cardiac arrest caused by acute coronary syndrome (ACS) and at the end of the first 2 months after the event. Method Fifty patients with cardiac arrest induced by ACS and 31 patients with acute myocardial infarction (AMI) who did not require cardioversion or cardiopulmonary resuscitation were enrolled in the study, as were 40 healthy volunteers. The patients were divided into three groups based on duration of cardiac arrest (<5 min, 5–10 min and >10 min). Blood samples were collected for thyroid-stimulating hormone (TSH), tri-iodothyronine (T3), free T3, thyroxine (T4), free T4, troponin-I and creatine kinase-MB measurements. The blood samples for TFTs were taken at 72 hours and at 2 months after the acute event in the cardiac arrest and AMI groups, but only once in the control group. Results The T3 and free T3 levels at 72 hours in the cardiac arrest group were significantly lower than in both the AMI and control groups (P < 0.0001). On the other hand, there were no significant differences between T4, free T4 and TSH levels between the three groups (P > 0.05). At the 2-month evaluation, a dramatic improvement was observed in T3 and free T3 levels in the cardiac arrest group (P < 0.0001). In those patients whose cardiac arrest duration was in excess of 10 min, levels of T3, free T3, T4 and TSH were significantly lower than those in patients whose cardiac arrest duration was under 5 min (P < 0.001, P < 0.001, P < 0.005 and P < 0.05, respectively). Conclusion TFTs are significantly altered in cardiac arrest induced by ACS. Changes in TFTs are even more pronounced in patients with longer periods of resuscitation. The changes in the surviving patients were characterized by euthyroid sick

  12. Abnormal development of sensory-motor, visual temporal and parahippocampal cortex in children with learning disabilities and borderline intellectual functioning

    PubMed Central

    Baglio, Francesca; Cabinio, Monia; Ricci, Cristian; Baglio, Gisella; Lipari, Susanna; Griffanti, Ludovica; Preti, Maria G.; Nemni, Raffaello; Clerici, Mario; Zanette, Michela; Blasi, Valeria

    2014-01-01

    Borderline intellectual functioning (BIF) is a condition characterized by an intelligence quotient (IQ) between 70 and 85. BIF children present with cognitive, motor, social, and adaptive limitations that result in learning disabilities and are more likely to develop psychiatric disorders later in life. The aim of this study was to investigate brain morphometry and its relation to IQ level in BIF children. Thirteen children with BIF and 14 age- and sex-matched typically developing (TD) children were enrolled. All children underwent a full IQ assessment (WISC-III scale) and a magnetic resonance (MR) examination including conventional sequences to assess brain structural abnormalities and high resolution 3D images for voxel-based morphometry analysis. To investigate to what extent the group influenced gray matter (GM) volumes, both univariate and multivariate generalized linear model analysis of variance were used, and the varimax factor analysis was used to explore variable correlations and clusters among subjects. Results showed that BIF children, compared to controls have increased regional GM volume in bilateral sensorimotor and right posterior temporal cortices and decreased GM volume in the right parahippocampal gyrus. GM volumes were highly correlated with IQ indices. The present work is a case study of a group of BIF children showing that BIF is associated with abnormal cortical development in brain areas that have a pivotal role in motor, learning, and behavioral processes. Our findings, although allowing for little generalization to the general population, contribute to the very limited knowledge in this field. Future longitudinal MR studies will be useful in verifying whether cortical features can be modified over time even in association with rehabilitative intervention. PMID:25360097

  13. Meiotic abnormalities

    SciTech Connect

    1993-12-31

    Chapter 19, describes meiotic abnormalities. These include nondisjunction of autosomes and sex chromosomes, genetic and environmental causes of nondisjunction, misdivision of the centromere, chromosomally abnormal human sperm, male infertility, parental age, and origin of diploid gametes. 57 refs., 2 figs., 1 tab.

  14. Pharmacokinetics and safety of olodaterol administered with the Respimat Soft Mist inhaler in subjects with impaired hepatic or renal function

    PubMed Central

    Kunz, Christina; Luedtke, Doreen; Unseld, Anna; Hamilton, Alan; Halabi, Atef; Wein, Martina; Formella, Stephan

    2016-01-01

    Purpose In two trials, the influences of hepatic and renal impairment on the pharmacokinetics of olodaterol, a novel long-acting inhaled β2-agonist for treatment of COPD, were investigated. Subjects and methods The first trial included eight subjects with mild hepatic function impairment (Child–Pugh A), eight subjects with moderate impairment (Child–Pugh B), and 16 matched healthy subjects with normal hepatic function. The second trial included eight subjects with severe renal impairment (creatinine clearance <30 mL·min−1) and 14 matched healthy subjects with normal renal function. Subjects received single doses of 20 or 30 μg olodaterol administered with the Respimat Soft Mist inhaler. Results Olodaterol was well tolerated in all subjects. The geometric mean ratios and 90% confidence intervals of dose-normalized area under the plasma concentration-time curve from time zero to 4 hours (AUC0–4) for subjects with mild and moderate hepatic impairment compared to healthy subjects were 97% (75%–125%) and 105% (79%–140%), respectively. Corresponding values for dose-normalized maximum concentration (Cmax) were 112% (84%–151%) (mild impairment) and 99% (73%–135%) (moderate impairment). The geometric mean ratio (90% confidence interval) of AUC0–4 for subjects with severe renal impairment compared to healthy subjects was 135% (94%–195%), and for Cmax was 137% (84%–222%). There was no significant relationship between creatinine clearance and AUC0–4 or Cmax. Renal clearance of olodaterol was reduced to 20% of normal in severe renal impairment. Conclusion Mild to moderate hepatic function impairment or severe renal function impairment did not result in a clinically relevant increase of olodaterol systemic exposure after a single inhaled dose. PMID:27051282

  15. EVALUATION OF HEPATIC FUNCTION AMONG PATIENTS UNDERGOING TOTAL HIP ARTHROPLASTY USING ENOXAPARIN

    PubMed Central

    Wink, Felipe Vitiello; Schwartsmann, Carlos Roberto

    2015-01-01

    Objective: To evaluate hepatic changes resulting from the use of enoxaparin for prophylaxis of deep vein thrombosis among patients undergoing total hip arthroplasty. Methods: Thirty-two patients underwent elective total hip arthroplasty, using enoxaparin, and were followed up for 65 days with serial hepatic enzyme assays. Results: Changes in laboratory parameters were found in up to 75% of the patients during the study, but the parameters normalized after suspension of the treatment. No clinical evidence of hepatic lesions was found. Conclusion: The hepatic enzyme levels increase in most patients using enoxaparin, but without clinical correlation, and the levels normalize after suspension of the treatment. PMID:27022533

  16. Assessment of Structural and Functional Abnormalities of the Myocardium and the Ascending Aorta in Fetus with Hypoplastic Left Heart Syndrome

    PubMed Central

    Jiang, Yan; Xu, Yali; Tang, Jinliang; Xia, Hongmei

    2016-01-01

    Aims. To detect anatomical and intrinsic histopathological features of the ascending aorta and left ventricular (LV) myocardium and evaluate right ventricular (RV) function in fetuses with hypoplastic left heart syndrome (HLHS). Methods. Twenty-five fetuses diagnosed with HLHS were followed up in the antenatal and postpartum periods. 12 necropsy heart specimens were analyzed for morphological and histological changes. Results. Prenatal echocardiography and pathologic anatomy displayed the typical characteristics of HLHS as a severe underdevelopment of the LV in the form of mitral stenosis or atresia or as aortic atresia or stenosis, with a decreased ratio of aortic diameter to pulmonary artery diameter (median of 0.49 with a range of 0.24 to 0.69, p ≤ 0.001) and a higher ratio of RV diameter to LV diameter (median of 2.44 with a range of 1.33 to 6.25, p ≤ 0.001). The RV volume, stroke volume, and cardiac output in HLHS fetuses were increased compared with the gestational age-matched normal controls (p < 0.01). Histological changes in the 12 HLHS specimens included LV myocardial fibrosis, aortic elastic fragmentation, and fibrosis. Conclusions. In addition to severe anatomical deformity, distinct histological abnormalities in the LV myocardium and aortic wall were identified in the fetuses with HLHS. RV function damage may be potentially exists. PMID:26981527

  17. Abnormal immune system development and function in schizophrenia helps reconcile diverse findings and suggests new treatment and prevention strategies.

    PubMed

    Anders, Sherry; Kinney, Dennis K

    2015-08-18

    Extensive research implicates disturbed immune function and development in the etiology and pathology of schizophrenia. In addition to reviewing evidence for immunological factors in schizophrenia, this paper discusses how an emerging model of atypical immune function and development helps explain a wide variety of well-established - but puzzling - findings about schizophrenia. A number of theorists have presented hypotheses that early immune system programming, disrupted by pre- and perinatal adversity, often combines with abnormal brain development to produce schizophrenia. The present paper focuses on the hypothesis that disruption of early immune system development produces a latent immune vulnerability that manifests more fully after puberty, when changes in immune function and the thymus leave individuals more susceptible to infections and immune dysfunctions that contribute to schizophrenia. Complementing neurodevelopmental models, this hypothesis integrates findings on many contributing factors to schizophrenia, including prenatal adversity, genes, climate, migration, infections, and stress, among others. It helps explain, for example, why (a) schizophrenia onset is typically delayed until years after prenatal adversity, (b) individual risk factors alone often do not lead to schizophrenia, and (c) schizophrenia prevalence rates actually tend to be higher in economically advantaged countries. Here we discuss how the hypothesis explains 10 key findings, and suggests new, potentially highly cost-effective, strategies for treatment and prevention of schizophrenia. Moreover, while most human research linking immune factors to schizophrenia has been correlational, these strategies provide ethical ways to experimentally test in humans theories about immune function and schizophrenia. This article is part of a Special Issue entitled SI: Neuroimmunology in Health And Disease. PMID:25736181

  18. The aged epidermal permeability barrier. Structural, functional, and lipid biochemical abnormalities in humans and a senescent murine model.

    PubMed Central

    Ghadially, R; Brown, B E; Sequeira-Martin, S M; Feingold, K R; Elias, P M

    1995-01-01

    Aged epidermis displays altered drug permeability, increased susceptibility to irritant contact dermatitis, and often severe xerosis, suggesting compromise of the aged epidermal barrier. To delineate the functional, structural, and lipid biochemical basis of epidermal aging, we compared barrier function in young (20-30 yr) vs aged (> 80 yr) human subjects, and in a murine model. Baseline transepidermal water loss in both aged humans and senescent mice was subnormal. However, the aged barrier was perturbed more readily with either acetone or tape stripping (18 +/- 2 strippings vs 31 +/- 5 strippings in aged vs young human subjects, respectively). Moreover, after either acetone treatment or tape stripping, the barrier recovered more slowly in aged than in young human subjects (50 and 80% recovery at 24 and 72 h, respectively, in young subjects vs 15% recovery at 24 h in aged subjects), followed by a further delay over the next 6 d. Similar differences in barrier recovery were seen in senescent vs young mice. Although the total lipid content was decreased in the stratum corneum of aged mice (approximately 30%), the distribution of ceramides (including ceramide 1), cholesterol, and free fatty acids was unchanged. Moreover, a normal complement of esterified, very long-chain fatty acids was present. Finally, stratum corneum lamellar bilayers displayed normal substructure and dimensions, but were focally decreased in number, with decreased secretion of lamellar body contents. Thus, assessment of barrier function in aged epidermis under basal conditions is misleading, since both barrier integrity and barrier repair are markedly abnormal. These functional changes can be attributed to a global deficiency in all key stratum corneum lipids, resulting in decreased lamellar bilayers in the stratum corneum interstices. This constellation of findings may explain the increased susceptibility of intrinsically aged skin to exogenous and environmental insults. Images PMID:7738193

  19. Pancreatic abnormalities and AIDS related sclerosing cholangitis.

    PubMed Central

    Teare, J P; Daly, C A; Rodgers, C; Padley, S P; Coker, R J; Main, J; Harris, J R; Scullion, D; Bray, G P; Summerfield, J A

    1997-01-01

    OBJECTIVES: Biliary tract abnormalities are well recognised in AIDS, most frequently related to opportunistic infection with Cryptosporidium, Microsporidium, and cytomegalovirus. We noted a high frequency of pancreatic abnormalities associated with biliary tract disease. To define these further we reviewed the clinical and radiological features in these patients. METHODS: Notes and radiographs were available from two centres for 83 HIV positive patients who had undergone endoscopic retrograde cholangiopancreatography for the investigation of cholestatic liver function tests or abdominal pain. RESULTS: 56 patients had AIDS related sclerosing cholangitis (ARSC); 86% of these patients had epigastric or right upper quadrant pain and 52% had hepatomegaly. Of the patients with ARSC, 10 had papillary stenosis alone, 11 had intra- and extrahepatic sclerosing cholangitis alone, and 35 had a combination of the two. Ampullary biopsies performed in 24 patients confirmed an opportunistic infection in 16. In 15 patients, intraluminal polyps were noted on the cholangiogram. Pancreatograms were available in 34 of the 45 patients with papillary stenosis, in which 29 (81%) had associated pancreatic duct dilatation, often with associated features of chronic pancreatitis. In the remaining 27 patients, final diagnoses included drug induced liver disease, acalculous cholecystitis, gall bladder empyema, chronic B virus hepatitis, and alcoholic liver disease. CONCLUSION: Pancreatic abnormalities are commonly seen with ARSC and may be responsible for some of the pain not relieved by biliary sphincterotomy. The most frequent radiographic biliary abnormality is papillary stenosis combined with ductal sclerosis. Images PMID:9389948

  20. Triple Therapy with First Generation Protease Inhibitors for Hepatitis C Markedly Impairs Function of Neutrophil Granulocytes.

    PubMed

    Spindelboeck, Walter; Horvath, Angela; Tawdrous, Monika; Schmerböck, Bianca; Zettel, Gabriele; Posch, Andreas; Streit, Andrea; Jurse, Petra; Lemesch, Sandra; Horn, Martin; Wuensch, Gerit; Stiegler, Philipp; Stauber, Rudolf E; Leber, Bettina; Stadlbauer, Vanessa

    2016-01-01

    First-generation HCV protease inhibitors represent a milestone in antiviral therapy for chronic hepatitis C infection (CHC), but substantially increased rates of viral clearance are offset by increased rates of infection and infection-associated deaths, especially of patients with advanced liver disease. We aimed to assess whether first generation protease inhibitors interfere with neutrophil function. We included 108 consecutive, retrospective CHC patients and 44 consecutive, prospective CHC patients who were treated with peginterferon and ribavirin with or without protease inhibitors according to the guidelines in the period of November 2012 to June 2015. 33 healthy volunteers served as controls. Infection data were evaluated in all patients. Neutrophil phagocytosis, oxidative burst, elastase and diamine oxidase levels during 12 weeks of triple (n = 23) or dual therapy (n = 21) were studied in the prospective part. In the retro- and prospective cohorts patients experiencing clinically relevant infections were significantly more frequent during protease inhibitor therapy (31% and 26%) than during therapy with peginterferon and ribavirin (13% and 0%). Neutrophil phagocytosis decreased to 40% of baseline with addition of protease inhibitors to P/R but recovered 6 months after end of treatment. Protease inhibitors also seemed to reduce serum elastase levels but did not impact on gut permeability. Impaired neutrophil function during triple therapy with first generation HCV protease inhibitors may explain the high infection rate associated to these treatments and be of relevance for treatment success and patient survival. PMID:26938078

  1. A Bayesian Nonparametric Approach for Functional Data Classification with Application to Hepatic Tissue Characterization

    PubMed Central

    Fronczyk, Kassandra M.; Guindani, Michele; Hobbs, Brian P.; Ng, Chaan S.; Vannucci, Marina

    2015-01-01

    Computed tomography perfusion (CTp) is an emerging functional imaging technology that provides a quantitative assessment of the passage of fluid through blood vessels. Tissue perfusion plays a critical role in oncology due to the proliferation of networks of new blood vessels typical of cancer angiogenesis, which triggers modifications to the vasculature of the surrounding host tissue. In this article, we consider a Bayesian semiparametric model for the analysis of functional data. This method is applied to a study of four interdependent hepatic perfusion CT characteristics that were acquired under the administration of contrast using a sequence of repeated scans over a period of 590 seconds. More specifically, our modeling framework facilitates borrowing of information across patients and tissues. Additionally, the approach enables flexible estimation of temporal correlation structures exhibited by mappings of the correlated perfusion biomarkers and thus accounts for the heteroskedasticity typically observed in those measurements, by incorporating change-points in the covariance estimation. This method is applied to measurements obtained from regions of liver surrounding malignant and benign tissues, for each perfusion biomarker. We demonstrate how to cluster the liver regions on the basis of their CTp profiles, which can be used in a prediction context to classify regions of interest provided by future patients, and thereby assist in discriminating malignant from healthy tissue regions in diagnostic settings. PMID:27279730

  2. Triple Therapy with First Generation Protease Inhibitors for Hepatitis C Markedly Impairs Function of Neutrophil Granulocytes

    PubMed Central

    Tawdrous, Monika; Schmerböck, Bianca; Zettel, Gabriele; Posch, Andreas; Streit, Andrea; Jurse, Petra; Lemesch, Sandra; Horn, Martin; Wuensch, Gerit; Stiegler, Philipp; Stauber, Rudolf E.; Leber, Bettina; Stadlbauer, Vanessa

    2016-01-01

    First-generation HCV protease inhibitors represent a milestone in antiviral therapy for chronic hepatitis C infection (CHC), but substantially increased rates of viral clearance are offset by increased rates of infection and infection-associated deaths, especially of patients with advanced liver disease. We aimed to assess whether first generation protease inhibitors interfere with neutrophil function. We included 108 consecutive, retrospective CHC patients and 44 consecutive, prospective CHC patients who were treated with peginterferon and ribavirin with or without protease inhibitors according to the guidelines in the period of November 2012 to June 2015. 33 healthy volunteers served as controls. Infection data were evaluated in all patients. Neutrophil phagocytosis, oxidative burst, elastase and diamine oxidase levels during 12 weeks of triple (n = 23) or dual therapy (n = 21) were studied in the prospective part. In the retro- and prospective cohorts patients experiencing clinically relevant infections were significantly more frequent during protease inhibitor therapy (31% and 26%) than during therapy with peginterferon and ribavirin (13% and 0%). Neutrophil phagocytosis decreased to 40% of baseline with addition of protease inhibitors to P/R but recovered 6 months after end of treatment. Protease inhibitors also seemed to reduce serum elastase levels but did not impact on gut permeability. Impaired neutrophil function during triple therapy with first generation HCV protease inhibitors may explain the high infection rate associated to these treatments and be of relevance for treatment success and patient survival. Trial Registration ClinicalTrials.gov NCT02545400 ClinicalTrials.gov NCT02545335 PMID:26938078

  3. Functional Characterization of Core Genes From Patients With Acute Hepatitis C

    PubMed Central

    Tang, Xi; Wagoner, Jessica; Negash, Amina; Austin, Michael; McLauchlan, John; Hahn, Young S.; Rosen, Hugo R.; Polyak, Stephen J.

    2009-01-01

    The HCV core protein is implicated in diverse aspects of HCV-induced pathogenesis. There is a paucity of information on core in acute hepatitis C infection. We analyzed core gene sequences and protein functions from 13 patients acutely infected with HCV genotype 1. While core isolates differed slightly between patients, core quasispecies were relatively homogeneous within a patient. In 2 of 4 patients studied temporally, core quasispecies did not change over time. Comparison with more than 2700 published core isolates indicated that amino acid changes from a prototype reference strain found in acute core isolates were present in chronically infected persons at low frequency (6.4%, range 0-32%). Core isolates associated with lipid droplets (LDs) to similar degrees in Huh7 cells. Core diffusion in cells was not affected by non-conservative changes F130L and G161S in the lipid targeting domain of core. Core isolates inhibited ISRE- and NF-κB-dependent transcription, and TNF-α- induced nuclear translocation of NF-κB and were also secreted from Huh7 cells. The data suggest that upon transmission, core quasispecies undergo genetic homogenization associated with amino acid changes that are rarely found in chronic infection, and that despite genetic variation, acute core isolates retain similar functions in vitro. PMID:20170366

  4. Abnormal reward functioning across substance use disorders and major depressive disorder: Considering reward as a transdiagnostic mechanism.

    PubMed

    Baskin-Sommers, Arielle R; Foti, Dan

    2015-11-01

    A common criticism of the Diagnostic and Statistical Manual of Mental Disorders (American Psychiatric Association, 2013) is that its criteria are based more on behavioral descriptions than on underlying biological mechanisms. Increasingly, calls have intensified for a more biologically-based approach to conceptualizing, studying, and treating psychological disorders, as exemplified by the Research Domain Criteria Project (RDoC). Among the most well-studied neurobiological mechanisms is reward processing. Moreover, individual differences in reward sensitivity are related to risk for substance abuse and depression. The current review synthesizes the available preclinical, electrophysiological, and neuroimaging literature on reward processing from a transdiagnostic, multidimensional perspective. Findings are organized with respect to key reward constructs within the Positive Valence Systems domain of the RDoC matrix, including initial responsiveness to reward (physiological 'liking'), approach motivation (physiological 'wanting'), and reward learning/habit formation. In the current review, we (a) describe the neural basis of reward, (b) elucidate differences in reward activity in substance abuse and depression, and (c) suggest a framework for integrating these disparate literatures and discuss the utility of shifting focus from diagnosis to process for understanding liability and co-morbidity. Ultimately, we believe that an integrative focus on abnormal reward functioning across the full continuum of clinically heterogeneous samples, rather than within circumscribed diagnostic categories, might actually help to refine the phenotypes and improve the prediction of onset and recovery of these disorders. PMID:25655926

  5. Congenital Abnormalities

    MedlinePlus

    ... serious health problems (e.g. Down syndrome ). Single-Gene Abnormalities Sometimes the chromosomes are normal in number, ... blood flow to the fetus impair fetal growth. Alcohol consumption and certain drugs during pregnancy significantly increase ...

  6. Craniofacial Abnormalities

    MedlinePlus

    ... of the skull and face. Craniofacial abnormalities are birth defects of the face or head. Some, like cleft ... palate, are among the most common of all birth defects. Others are very rare. Most of them affect ...

  7. Walking abnormalities

    MedlinePlus

    ... include: Arthritis of the leg or foot joints Conversion disorder (a psychological disorder) Foot problems (such as a ... injuries. For an abnormal gait that occurs with conversion disorder, counseling and support from family members are strongly ...

  8. Chromosome Abnormalities

    MedlinePlus

    ... decade, newer techniques have been developed that allow scientists and doctors to screen for chromosomal abnormalities without using a microscope. These newer methods compare the patient's DNA to a normal DNA ...

  9. Nail abnormalities

    MedlinePlus

    Nail abnormalities are problems with the color, shape, texture, or thickness of the fingernails or toenails. ... Fungus or yeast cause changes in the color, texture, and shape of the nails. Bacterial infection may ...

  10. Insulin Protects against Hepatic Damage Postburn

    PubMed Central

    Jeschke, Marc G; Kraft, Robert; Song, Juquan; Gauglitz, Gerd G; Cox, Robert A; Brooks, Natasha C; Finnerty, Celeste C; Kulp, Gabriela A; Herndon, David N; Boehning, Darren

    2011-01-01

    Burn injury causes hepatic dysfunction associated with endoplasmic reticulum (ER) stress and induction of the unfolded protein response (UPR). ER stress/UPR leads to hepatic apoptosis and activation of the Jun-N-terminal kinase (JNK) signaling pathway, leading to vast metabolic alterations. Insulin has been shown to attenuate hepatic damage and to improve liver function. We therefore hypothesized that insulin administration exerts its effects by attenuating postburn hepatic ER stress and subsequent apoptosis. Male Sprague Dawley rats received a 60% total body surface area (TBSA) burn injury. Animals were randomized to receive saline (controls) or insulin (2.5 IU/kg q. 24 h) and euthanized at 24 and 48 h postburn. Burn injury induced dramatic changes in liver structure and function, including induction of the ER stress response, mitochondrial dysfunction, hepatocyte apoptosis, and up-regulation of inflammatory mediators. Insulin decreased hepatocyte caspase-3 activation and apoptosis significantly at 24 and 48 h postburn. Furthermore, insulin administration decreased ER stress significantly and reversed structural and functional changes in hepatocyte mitochondria. Finally, insulin attenuated the expression of inflammatory mediators IL-6, MCP-1, and CINC-1. Insulin alleviates burn-induced ER stress, hepatocyte apoptosis, mitochondrial abnormalities, and inflammation leading to improved hepatic structure and function significantly. These results support the use of insulin therapy after traumatic injury to improve patient outcomes. PMID:21267509

  11. Left Atrial Volumes and Reservoir Function Are Associated With Subclinical Cerebrovascular Disease: The Cardiovascular Abnormalities and Brain Lesions (CABL) Study

    PubMed Central

    Russo, Cesare; Jin, Zhezhen; Liu, Rui; Iwata, Shinichi; Tugcu, Aylin; Yoshita, Mitsuhiro; Homma, Shunichi; Elkind, Mitchell S.V.; Rundek, Tatjana; DeCarli, Charles; Wright, Clinton B.; Sacco, Ralph L.; Di Tullio, Marco R.

    2013-01-01

    Objectives To assess the relationship of left atrial (LA) phasic volumes and LA reservoir function with subclinical cerebrovascular disease in a stroke-free community-based cohort. Background An increase in LA size is associated with cardiovascular events including stroke. However, it is not known whether LA phasic volumes and reservoir function are associated with subclinical cerebrovascular disease. Methods LA minimum (LAVmin) and maximum (LAVmax) volumes, and LA reservoir function, measured as total emptying volume (LAEV) and total emptying fraction (LAEF), were assessed by real-time three-dimensional echocardiography in 455 stroke-free participants from the community-based Cardiovascular Abnormalities and Brain Lesions (CABL) study. Subclinical cerebrovascular disease was assessed as silent brain infarcts (SBI) and white matter hyperintensity volume (WMHV) by brain magnetic resonance imaging (MRI). Results SBI prevalence was 15.4%; mean WMHV was 0.66±0.92%. Participants with SBI showed greater LAVmin (17.1±9.3 vs. 12.5±5.6 ml/m2, p<0.01) and LAVmax (26.6±8.8 vs. 23.3±7.0 ml/m2, p<0.01) compared to those without SBI. LAEV (9.5±3.4 vs. 10.8±3.9 ml/m2, p<0.01) and LAEF (38.7±14.7% vs. 47.0±11.9%, p<0.01) were also reduced in participants with SBI. In univariate analyses, greater LA volumes and smaller reservoir function were significantly associated with greater WMHV. In multivariate analyses, LAVmin remained significantly associated with SBI [adjusted odds ratio (OR) per SD increase: 1.37, 95% confidence intervals (CI) 1.04–1.80, p<0.05] and with WMHV (β=0.12, p<0.01), whereas LAVmax was not independently associated with either. Smaller LAEF was independently associated with SBI (adjusted OR=0.67, 95% CI 0.50–0.90, p<0.01) and WMHV (β=−0.09, p<0.05). Conclusions Greater LA volumes and reduced LA reservoir function are associated with subclinical cerebrovascular disease detected by brain MRI in subjects without history of stroke. LAVmin and LAEF

  12. Blockade of immunosuppressive cytokines restores NK cell antiviral function in chronic hepatitis B virus infection.

    PubMed

    Peppa, Dimitra; Micco, Lorenzo; Javaid, Alia; Kennedy, Patrick T F; Schurich, Anna; Dunn, Claire; Pallant, Celeste; Ellis, Gidon; Khanna, Pooja; Dusheiko, Geoffrey; Gilson, Richard J; Maini, Mala K

    2010-01-01

    NK cells are enriched in the liver, constituting around a third of intrahepatic lymphocytes. We have previously demonstrated that they upregulate the death ligand TRAIL in patients with chronic hepatitis B virus infection (CHB), allowing them to kill hepatocytes bearing TRAIL receptors. In this study we investigated whether, in addition to their pathogenic role, NK cells have antiviral potential in CHB. We characterised NK cell subsets and effector function in 64 patients with CHB compared to 31 healthy controls. We found that, in contrast to their upregulated TRAIL expression and maintenance of cytolytic function, NK cells had a markedly impaired capacity to produce IFN-γ in CHB. This functional dichotomy of NK cells could be recapitulated in vitro by exposure to the immunosuppressive cytokine IL-10, which was induced in patients with active CHB. IL-10 selectively suppressed NK cell IFN-γ production without altering cytotoxicity or death ligand expression. Potent antiviral therapy reduced TRAIL-expressing CD56(bright) NK cells, consistent with the reduction in liver inflammation it induced; however, it was not able to normalise IL-10 levels or the capacity of NK cells to produce the antiviral cytokine IFN-γ. Blockade of IL-10 +/- TGF-β restored the capacity of NK cells from both the periphery and liver of patients with CHB to produce IFN-γ, thereby enhancing their non-cytolytic antiviral capacity. In conclusion, NK cells may be driven to a state of partial functional tolerance by the immunosuppressive cytokine environment in CHB. Their defective capacity to produce the antiviral cytokine IFN-γ persists in patients on antiviral therapy but can be corrected in vitro by IL-10+/- TGF-β blockade. PMID:21187913

  13. True versus mild hyperthermia during isolated hepatic perfusion: effects on melphalan pharmacokinetics and liver function.

    PubMed

    Pilati, Pierluigi; Mocellin, Simone; Rossi, Carlo R; Ori, Carlo; Innocente, Federico; Scalerta, Romano; Ceccherini, Mauro; Da Pian, Pier Paolo; Nitti, Donato; Lise, Mario

    2004-08-01

    Hyperthermic antiblastic isolated hepatic perfusion (IHP) with melphalan has been recently proposed as an alternative therapeutic option for patients with unresectable liver tumors. Although melphalan-heat antiblastic synergism is at a maximum at temperatures higher than 41 degrees C, IHP has so far been performed in humans at lower temperatures. In this experimental work, we compared IHP under mild versus true hyperthermic conditions in terms of drug pharmacokinetics and liver function. Ten pigs were submitted to IHP with melphalan 1.5 mg/kg at a mean temperature of 40 degrees C (group A, n = 5) or 42 degrees C (group B, n = 5). After a 60-minute perfusion, a 15-minute washout was performed. Perfusate-to-plasma leakage was monitored using scintigraphy. Throughout perfusion, samples from the systemic blood, perfusate, and liver parenchyma were obtained to measure melphalan concentrations. Liver function was assessed using standard blood tests and the indocyanine green-based test. No deaths related to the IHP procedure were recorded. All animals had transient liver function impairment, with all liver function test results returning to normal within the observation period. At histologic examination, liver damage was similar under both hyperthermic conditions. Melphalan levels in the perfusate were not significantly different in the two study groups (the mean perfusate/plasma area under the curve from 0 to 60 minutes ratios were 463 and 501, respectively). These results correlated well with those obtained using the scintigraphic method. Liver drug concentrations remained unchanged after true hyperthermia IHP. Under true hyperthermic conditions, neither an increase in liver parenchyma toxicity nor changes in melphalan pharmacokinetics were observed. These findings support the use of true hyperthermia in the clinical setting to exploit fully the antitumor synergism between melphalan and heat. PMID:15457357

  14. Integrative Functional Genomics of Hepatitis C Virus Infection Identifies Host Dependencies in Complete Viral Replication Cycle

    PubMed Central

    Li, Qisheng; Zhang, Yong-Yuan; Chiu, Stephan; Hu, Zongyi; Lan, Keng-Hsin; Cha, Helen; Sodroski, Catherine; Zhang, Fang; Hsu, Ching-Sheng; Thomas, Emmanuel; Liang, T. Jake

    2014-01-01

    Recent functional genomics studies including genome-wide small interfering RNA (siRNA) screens demonstrated that hepatitis C virus (HCV) exploits an extensive network of host factors for productive infection and propagation. How these co-opted host functions interact with various steps of HCV replication cycle and exert pro- or antiviral effects on HCV infection remains largely undefined. Here we present an unbiased and systematic strategy to functionally interrogate HCV host dependencies uncovered from our previous infectious HCV (HCVcc) siRNA screen. Applying functional genomics approaches and various in vitro HCV model systems, including HCV pseudoparticles (HCVpp), single-cycle infectious particles (HCVsc), subgenomic replicons, and HCV cell culture systems (HCVcc), we identified and characterized novel host factors or pathways required for each individual step of the HCV replication cycle. Particularly, we uncovered multiple HCV entry factors, including E-cadherin, choline kinase α, NADPH oxidase CYBA, Rho GTPase RAC1 and SMAD family member 6. We also demonstrated that guanine nucleotide binding protein GNB2L1, E2 ubiquitin-conjugating enzyme UBE2J1, and 39 other host factors are required for HCV RNA replication, while the deubiquitinating enzyme USP11 and multiple other cellular genes are specifically involved in HCV IRES-mediated translation. Families of antiviral factors that target HCV replication or translation were also identified. In addition, various virologic assays validated that 66 host factors are involved in HCV assembly or secretion. These genes included insulin-degrading enzyme (IDE), a proviral factor, and N-Myc down regulated Gene 1 (NDRG1), an antiviral factor. Bioinformatics meta-analyses of our results integrated with literature mining of previously published HCV host factors allows the construction of an extensive roadmap of cellular networks and pathways involved in the complete HCV replication cycle. This comprehensive study of HCV host

  15. Successful Interferon-Free Therapy of Chronic Hepatitis C Virus Infection Normalizes Natural Killer Cell Function

    PubMed Central

    Serti, Elisavet; Chepa-Lotrea, Xenia; Kim, Yun Ju; Keane, Meghan; Fryzek, Nancy; Liang, T. Jake; Ghany, Marc; Rehermann, Barbara

    2015-01-01

    BACKGROUND & AIMS Chronic hepatitis C virus infection activates an intrahepatic immune response, leading to increased expression of interferon (IFN)-stimulated genes and activation of natural killer (NK) cells—the most prevalent innate immune cell in the liver. We investigated whether the elimination of HCV with direct-acting antiviral agents normalizes expression of IFN-stimulated genes and NK cell function. METHODS We used multicolor flow cytometry to analyze NK cells from liver and blood of 13 HCV-infected patients who did not respond to treatment with pegylated interferon and ribavirin. Samples were collected before and during IFN-free treatment with daclatasvir and asunaprevir therapy and compared with those from blood of 13 healthy individuals (controls). Serum levels of CXCL10 and CXCL11 were measured by ELISA. RESULTS Before treatment, all patients had increased levels of CXCL10 or CXCL11 and a different NK cell phenotype from controls, characterized by increased expression of HLA-DR, NKp46, NKG2A, CD85j, pSTAT1, STAT1, and TNF-related apoptosis-inducing ligand (TRAIL). NK cells from patients also had increased degranulation and decreased production of IFNγ and TNFα compared with NK cells from controls. Nine patients had an end-of-treatment response (undetectable virus) and 4 had virologic breakthrough between weeks 4 and 12 of therapy. A rapid decrease in viremia and level of inflammatory cytokines in all patients was associated with decreased activation of intrahepatic and blood NK cells; it was followed by restoration of a normal NK cell phenotype and function by week 8 in patients with undetectable viremia. This normalized NK cell phenotype was maintained until week 24 (EOT). CONCLUSIONS DAA-mediated clearance of HCV is associated with loss of intrahepatic immune activation by IFNα, indicated by decreased levels of CXCL10 and CXCL11 and normalization of NK cell phenotype and function. PMID:25754160

  16. Scintigraphic evaluation of functional hepatic mass in patients with advanced breast cancer.

    PubMed

    Virgolini, I; Kornek, G; Höbart, J; Li, S R; Raolerer, M; Bergmann, H; Scheithauer, W; Pantev, T; Angelberger, P; Sinzinger, H

    1993-09-01

    Recent studies suggest a high specificity of 99mTc-galactosyl neoglycoalbumin (99mTc-NGA) receptor scanning in vivo by providing both morphological and functional diagnosis of liver disease. In 22 patients with advanced breast cancer 99mTc-NGA (150 MBq; 50 nmol) was exclusively trapped by the liver, the images showing 'cold spots' in areas of liver metastases formation. A two-tailed analysis was performed: the time activity curves recorded for the liver and precordial area were subjected to a kinetic receptor-calculating model allowing an estimation of the NGA-receptor concentration of the liver (i.e. hepatic binding protein, HBP) as well as calculation of the residual functional liver volume (RFLV) via the S.P.E.C.T.-study. In breast cancer patients with liver metastases a significantly (P < 0.01) lower HBP-concentration was estimated (0.65 +/- 0.16 vs 0.82 +/- 0.17 mumol l-1) as evidenced by a lower 99mTc-NGA-accumulation in the liver resulting also in a significantly (P < 0.001) lower RFLV (739 +/- 348 vs 1336 +/- 184 ml). In four amonafide-treated patients (800 mg m-2 intravenous infusion over 3 h) approximately one week after one chemotherapy cycle a significant (P < 0.05) increase in HBP-concentration (0.56 +/- 0.10 vs 0.72 +/- 0.06 mumol l-1) of the liver was found corresponding with an increase in RVLF (546 +/- 297 vs 670 +/- 265 ml). These regulatory mechanisms at the HBP level measured in vivo provide further evidence that 99mTc-NGA should have promise as a clinically useful receptor radiopharmaceutical for both quantification of liver function and assessment of liver morphology. PMID:8353045

  17. Smooth Muscle α Actin (Acta2) and Myofibroblast Function during Hepatic Wound Healing

    PubMed Central

    Rockey, Don C.; Weymouth, Nate; Shi, Zengdun

    2013-01-01

    Smooth muscle α actin (Acta2) expression is largely restricted to smooth muscle cells, pericytes and specialized fibroblasts, known as myofibroblasts. Liver injury, associated with cirrhosis, induces transformation of resident hepatic stellate cells into liver specific myofibroblasts, also known as activated cells. Here, we have used in vitro and in vivo wound healing models to explore the functional role of Acta2 in this transformation. Acta2 was abundant in activated cells isolated from injured livers but was undetectable in quiescent cells isolated from normal livers. Both cellular motility and contraction were dramatically increased in injured liver cells, paralleled by an increase in Acta2 expression, when compared with quiescent cells. Inhibition of Acta2 using several different techniques had no effect on cytoplasmic actin isoform expression, but led to reduced cellular motility and contraction. Additionally, Acta2 knockdown was associated with a significant reduction in Erk1/2 phosphorylation compared to control cells. The data indicate that Acta2 is important specifically in myofibroblast cell motility and contraction and raise the possibility that the Acta2 cytoskeleton, beyond its structural importance in the cell, could be important in regulating signaling processes during wound healing in vivo. PMID:24204762

  18. Altered function of monocytes/macrophages in patients with autoimmune hepatitis

    PubMed Central

    LIN, RUI; ZHANG, JIE; ZHOU, LU; WANG, BANGMAO

    2016-01-01

    The pathogenesis of autoimmune hepatitis (AIH) involves the intervention of the innate and adaptive immune responses. In the current study, the alterations in monocytes/Kupffer cells (KCs) were investigated in patients with AIH. A total of 21 patients with AIH at different stages of the disease, and 7 controls with non-alcoholic fatty liver disease were selected. The abundance of VAV1 and p21-activated kinase 1 (PAK1) in the liver and KCs was analyzed. In addition, the expression levels of HLA-DR and CD80 in the peripheral blood monocytes (PBMs) were measured, and phagocytosis of PBMs was assessed. KCs of AIH patients exhibited higher expression levels of VAV1 and PAK1. This upregulated expression was associated with disease progression. A reduced expression of HLA-DR and CD80, and reduced capacity of E. coli phagocytosis in PBMs was observed for patients with AIH. This downregulated expression was associated with disease progression. The results of the current study indicated that defective function of KCs and PBMs may be involved in the pathogenesis of AIH. PMID:26986756

  19. Immunogenicity and functional characterization of Leishmania-derived hepatitis C virus envelope glycoprotein complex.

    PubMed

    Grzyb, Katarzyna; Czarnota, Anna; Brzozowska, Agnieszka; Cieślik, Anna; Rąbalski, Łukasz; Tyborowska, Jolanta; Bieńkowska-Szewczyk, Krystyna

    2016-01-01

    Hepatitis C virus (HCV) envelope glycoproteins E1 and E2 are the main inducers of a cross-neutralizing antibody response which plays an important role in the early phase of viral infection. Correctly folded and immunologically active E1E2 complex can be expressed in mammalian cells, though the production process might still prove restrictive, even if the immunological response of a vaccine candidate is positive. Here, we report a characterization and immunogenicity study of a full-length (fE1E2) and soluble version of the E1E2 complex (tE1E2) from genotype 1a, successfully expressed in the cells of Leishmania tarentolae. In a functional study, we confirmed the binding of both Leishmania-derived E1E2 complexes to the CD-81 receptor and the presence of the major epitopes participating in a neutralizing antibody response. Both complexes were proved to be highly immunogenic in mice and elicited neutralizing antibody response. Moreover, cross-reactivity of the mouse sera was detected for all tested HCV genotypes with the highest signal intensity observed for genotypes 1a, 1b, 5 and 6. Since the development of a prophylactic vaccine against HCV is still needed to control the global infection, our Leishmania-derived E1E2 glycoproteins could be considered a potential cost-effective vaccine candidate. PMID:27481352

  20. Immunogenicity and functional characterization of Leishmania-derived hepatitis C virus envelope glycoprotein complex

    PubMed Central

    Grzyb, Katarzyna; Czarnota, Anna; Brzozowska, Agnieszka; Cieślik, Anna; Rąbalski, Łukasz; Tyborowska, Jolanta; Bieńkowska-Szewczyk, Krystyna

    2016-01-01

    Hepatitis C virus (HCV) envelope glycoproteins E1 and E2 are the main inducers of a cross-neutralizing antibody response which plays an important role in the early phase of viral infection. Correctly folded and immunologically active E1E2 complex can be expressed in mammalian cells, though the production process might still prove restrictive, even if the immunological response of a vaccine candidate is positive. Here, we report a characterization and immunogenicity study of a full-length (fE1E2) and soluble version of the E1E2 complex (tE1E2) from genotype 1a, successfully expressed in the cells of Leishmania tarentolae. In a functional study, we confirmed the binding of both Leishmania-derived E1E2 complexes to the CD-81 receptor and the presence of the major epitopes participating in a neutralizing antibody response. Both complexes were proved to be highly immunogenic in mice and elicited neutralizing antibody response. Moreover, cross-reactivity of the mouse sera was detected for all tested HCV genotypes with the highest signal intensity observed for genotypes 1a, 1b, 5 and 6. Since the development of a prophylactic vaccine against HCV is still needed to control the global infection, our Leishmania-derived E1E2 glycoproteins could be considered a potential cost-effective vaccine candidate. PMID:27481352

  1. 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

  2. Systematic analysis of the regulatory functions of microRNAs in chicken hepatic lipid metabolism

    PubMed Central

    Li, Hong; Ma, Zheng; Jia, Lijuan; Li, Yanmin; Xu, Chunlin; Wang, Taian; Han, Ruili; Jiang, Ruirui; Li, Zhuanjian; Sun, Guirong; Kang, Xiangtao; Liu, Xiaojun

    2016-01-01

    Laying performance is an important economic trait in hens, and this physiological process is largely influenced by the liver function. The livers of hens at 20- and 30-week-old stages were investigated using the next generation sequencing to identify the differences of microRNA expression profiles. Compared with the 20-week-old hens, 67 down- and 13 up-regulated microRNAs were verified to be significant differentially expressed (false discovery rate, FDR ≤ 0.05) (SDE) in the 30-week-old. We also identified 13 down- and 6 up-regulated novel differentially expressed (DE) microRNAs. miR-22-3p and miR-146b-5p, which exhibit critical roles in mammalian lipid metabolism, showed the most abundant expression and the highest fold-change, respectively. A total of 648 potential target genes of the SDE microRNAs were identified through an integrated analysis of microRNAs and the DE genes obtained in previous RNA-sequencing, including FADS1, FADS2, ELOVL6 and ACSL5, which are critical lipid metabolism-related regulators. Bioinformatic analyses revealed that target genes were mainly enriched in lipid-related metabolism processes. This work provides the first study of the expression patterns of hepatic microRNAs between 20- and 30-week old hens. The findings may serve as a fundamental resource for understanding the detailed functions of microRNAs in the molecular regulatory systems of lipid metabolism. PMID:27535581

  3. Systematic analysis of the regulatory functions of microRNAs in chicken hepatic lipid metabolism.

    PubMed

    Li, Hong; Ma, Zheng; Jia, Lijuan; Li, Yanmin; Xu, Chunlin; Wang, Taian; Han, Ruili; Jiang, Ruirui; Li, Zhuanjian; Sun, Guirong; Kang, Xiangtao; Liu, Xiaojun

    2016-01-01

    Laying performance is an important economic trait in hens, and this physiological process is largely influenced by the liver function. The livers of hens at 20- and 30-week-old stages were investigated using the next generation sequencing to identify the differences of microRNA expression profiles. Compared with the 20-week-old hens, 67 down- and 13 up-regulated microRNAs were verified to be significant differentially expressed (false discovery rate, FDR ≤ 0.05) (SDE) in the 30-week-old. We also identified 13 down- and 6 up-regulated novel differentially expressed (DE) microRNAs. miR-22-3p and miR-146b-5p, which exhibit critical roles in mammalian lipid metabolism, showed the most abundant expression and the highest fold-change, respectively. A total of 648 potential target genes of the SDE microRNAs were identified through an integrated analysis of microRNAs and the DE genes obtained in previous RNA-sequencing, including FADS1, FADS2, ELOVL6 and ACSL5, which are critical lipid metabolism-related regulators. Bioinformatic analyses revealed that target genes were mainly enriched in lipid-related metabolism processes. This work provides the first study of the expression patterns of hepatic microRNAs between 20- and 30-week old hens. The findings may serve as a fundamental resource for understanding the detailed functions of microRNAs in the molecular regulatory systems of lipid metabolism. PMID:27535581

  4. Trans-activation function of a 3 prime truncated X gene-cell fusion product from integrated hepatitis B virus DNA in chronic hepatitis tissues

    SciTech Connect

    Takada, Shinako; Koike, Katsuro )

    1990-08-01

    To investigate the expression and transactivation function of the X gene in integrated hepatitis B virus (HBV) DNA from chronic hepatitis tissues, a series of transfectants containing cloned integrated HBV DNAs was made and analyzed for X mRNA expression and trans-activation activity by using a chloramphenicol acetyltransferase assay. Most of the integrated HBV DNAs expressed X mRNA and encoded a product with trans-activation activity in spite of the loss of the 3{prime} end region of the X gene due to integration. From cDNA cloning and sequence analysis of X mRNA transcribed from native or integrated HBV DNA, the X protein was found to be translated from the X open reading frame without splicing. For integrated HBV DNA, transcription was extended to a cellular flanking DNA and an X gene-cell fusion transcript was terminated by using a cellular poly(A) signal. The amino acid sequence deduced from an X-cell fusion transcript indicated truncation of the carboxyl-terminal five amino acids, but the upstream region of seven amino acids conserved among hepadnaviruses was retained in the integrated HBV DNA, suggesting that this conserved region is essential for the transactivation function of the X protein. These findings support the following explanation for hepatocarcinogenesis by HBV DNA integration: the expression of a cellular oncogene(s) is transactivated at the time of chronic infection by the increasing amounts of the integrated HBV gene product(s), such as the X-cell fusion product.

  5. Effects of melatonin on liver function and lipid peroxidation in a rat model of hepatic ischemia/reperfusion injury

    PubMed Central

    DENG, WEN-SHENG; XU, QING; LIU, YE; JIANG, CHUN-HUI; ZHOU, HONG; GU, LEI

    2016-01-01

    The present study aimed to investigate the effects of melatonin (MT) on liver function and lipid peroxidation following hepatic ischemia-reperfusion injury (IRI). A total of 66 male Sprague-Dawley rats were randomly assigned into three groups: Normal control (N) group, ischemia-reperfusion (IR) group and the MT-treated group. A hepatic IRI model was developed by blocking the first porta hepatis, and subsequently restoring hepatic blood inflow after 35 min. Following reperfusion, changes in the levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), lactate dehydrogenase (LDH), malondialdehyde (MDA), superoxide dismutase (SOD) and glutathione (GSH) were detected by a chemical method at various time points. In the MT group, the MDA levels were significantly reduced (P<0.05) at all time points, as compared with the IR group. Furthermore, SOD activity was significantly increased (P<0.05) in the MT group, as compared with the IR group at all time points; and the levels of GSH in the MT group were significantly higher (P<0.05) than those of the IR group at 2, 4, and 8 h post-reperfusion. The levels of ALT, AST and LDH were significantly reduced in the MT group at each time point, as compared with that of the IR group (P<0.05). In conclusion, MT exhibits potent antioxidant properties that may create favorable conditions for the recovery of liver function following IRI. PMID:27168834

  6. Relationship among blood indicators of lipomobilization and hepatic function during early lactation in high-yielding dairy cows

    PubMed Central

    Muiño, Rodrigo; Pereira, Víctor; Campos, Rómulo; Benedito, José Luis

    2011-01-01

    Blood indicators are used as a tool to diagnose metabolic disorders. The present work was conducted to study the relationships among blood indicators of lipomobilization and hepatic function in high-yielding dairy cows. Two groups of Holstein cows were studied: 27 early lactation cows and 14 mid lactation cows from four different herds with similar husbandry characteristics in Galicia, Spain. Blood samples were obtained to measure beta-hydroxybutyrate (BHB), non-esterified fatty acids (NEFA), triglycerides (TG), and the activity of aspartate transaminase (AST) and gamma-glutamyl transferase. Cows in early lactation had higher levels of BHB and NEFA than mid lactation cows. High lipomobilization (NEFA > 400 µmol/L) was detected in 67% and 7% of early lactation and mid lactation cows, respectively, while subclinical ketosis (BHB > 1.2 mmol/L) was detected in 41% and 28% of the early lactation and lactation cows, respectively. TG concentrations were low in all cows suffering subclinical ketosis and in 61% of the cows with high lipomobilization. During early lactation, 30% of cows suffered hepatic lipidosis as detected by levels of AST. Compromised hepatic function was observed in early lactation cows as shown by lower concentrations of glucose, total protein, and urea. PMID:21897097

  7. Influence of black cohosh (Cimicifuga racemosa) use by postmenopausal women on total hepatic perfusion and liver functions.

    PubMed

    Nasr, Ahmed; Nafeh, Hanan

    2009-11-01

    In this prospective longitudinal clinical trial, 87 postmenopausal women receiving for 12 consecutive months a daily dose of 40 mg of a dry extract preparation of Cimicifuga racemosa (Klimadynon) for relief of vasomotor symptoms were followed up by evaluation of total hepatic blood flow, assessed by color Doppler ultrasound, as well as prothrombin time and concentration, serum albumin, bilirubin, gamma-glutamyltransferase, alkaline phosphatase, alanine aminotransferase, and aspartate aminotransferase. Because no significant changes in total hepatic blood flow or any of the liver functions tested were reported, we concluded that use of C. racemosa for 1 year by healthy postmenopausal women without evidence of liver disease does not seem to influence the liver. PMID:19539907

  8. Identification of a Functional, CRM-1-Dependent Nuclear Export Signal in Hepatitis C Virus Core Protein

    PubMed Central

    Cerutti, Andrea; Maillard, Patrick; Minisini, Rosalba; Vidalain, Pierre-Olivier; Roohvand, Farzin; Pecheur, Eve-Isabelle; Pirisi, Mario; Budkowska, Agata

    2011-01-01

    Hepatitis C virus (HCV) infection is a major cause of chronic liver disease worldwide. HCV core protein is involved in nucleocapsid formation, but it also interacts with multiple cytoplasmic and nuclear molecules and plays a crucial role in the development of liver disease and hepatocarcinogenesis. The core protein is found mostly in the cytoplasm during HCV infection, but also in the nucleus in patients with hepatocarcinoma and in core-transgenic mice. HCV core contains nuclear localization signals (NLS), but no nuclear export signal (NES) has yet been identified. We show here that the aa(109–133) region directs the translocation of core from the nucleus to the cytoplasm by the CRM-1-mediated nuclear export pathway. Mutagenesis of the three hydrophobic residues (L119, I123 and L126) in the identified NES or in the sequence encoding the mature core aa(1–173) significantly enhanced the nuclear localisation of the corresponding proteins in transfected Huh7 cells. Both the NES and the adjacent hydrophobic sequence in domain II of core were required to maintain the core protein or its fragments in the cytoplasmic compartment. Electron microscopy studies of the JFH1 replication model demonstrated that core was translocated into the nucleus a few minutes after the virus entered the cell. The blockade of nucleocytoplasmic export by leptomycin B treatment early in infection led to the detection of core protein in the nucleus by confocal microscopy and coincided with a decrease in virus replication. Our data suggest that the functional NLS and NES direct HCV core protein shuttling between the cytoplasmic and nuclear compartments, with at least some core protein transported to the nucleus. These new properties of HCV core may be essential for virus multiplication and interaction with nuclear molecules, influence cell signaling and the pathogenesis of HCV infection. PMID:22039426

  9. Connective tissue growth factor hammerhead ribozyme attenuates human hepatic stellate cell function

    PubMed Central

    Gao, Run-Ping; Brigstock, David R

    2009-01-01

    AIM: To determine the effect of hammerhead ribozyme targeting connective tissue growth factor (CCN2) on human hepatic stellate cell (HSC) function. METHODS: CCN2 hammerhead ribozyme cDNA plus two self-cleaving sequences were inserted into pTriEx2 to produce pTriCCN2-Rz. Each vector was individually transfected into cultured LX-2 human HSCs, which were then stimulated by addition of transforming growth factor (TGF)-β1 to the culture medium. Semi-quantitative RT-PCR was used to determine mRNA levels for CCN2 or collagen I, while protein levels of each molecule in cell lysates and conditioned medium were measured by ELISA. Cell-cycle progression of the transfected cells was assessed by flow cytometry. RESULTS: In pTriEx2-transfected LX-2 cells, TGF-β1 treatment caused an increase in the mRNA level for CCN2 or collagen I, and an increase in produced and secreted CCN2 or extracellular collagen I protein levels. pTriCCN2-Rz-transfected LX-2 cells showed decreased basal CCN2 or collagen mRNA levels, as well as produced and secreted CCN2 or collagen I protein. Furthermore, the TGF-β1-induced increase in mRNA or protein for CCN2 or collagen I was inhibited partially in pTriCCN2-Rz-transfected LX-2 cells. Inhibition of CCN2 using hammerhead ribozyme cDNA resulted in fewer of the cells transitioning into S phase. CONCLUSION: Endogenous CCN2 is a mediator of basal or TGF-β1-induced collagen I production in human HSCs and regulates entry of the cells into S phase. PMID:19673024

  10. Hepatic stellate cells undermine the allostimulatory function of liver myeloid dendritic cells via STAT3-dependent induction of IDO

    PubMed Central

    Sumpter, Tina L.; Dangi, Anil; Matta, Benjamin M.; Huang, Chao; Stolz, Donna B.; Vodovotz, Yoram; Thomson, Angus W.; Gandhi, Chandrashekhar R.

    2012-01-01

    Hepatic stellate cells (HSCs) are critical for hepatic wound repair and tissue remodeling. They also produce cytokines and chemokines that may contribute to the maintenance of hepatic immune homeostasis and the inherent tolerogenicity of the liver. The functional relationship between HSCs and the professional migratory APCs in the liver, i.e. dendritic cells (DCs), has not been evaluated. Here, we report that murine liver DCs co-localize with HSCs in vivo under normal, steady-state conditions, and cluster with HSCs in vitro. In vitro, HSCs secrete high levels of DC chemoattractants, such as MIP1α and MCP-1, as well as cytokines that modulate DC activation, including TNFα, IL-6 and IL-1β. Culture of HSCs with conventional liver myeloid (m) DCs resulted in increased IL-6 and IL-10 secretion compared to that of either cell population alone. Co-culture also resulted in enhanced expression of co-stimulatory (CD80, CD86) and co-inhibitory (B7-H1) molecules on mDCs. HSC-induced mDC maturation required cell-cell contact and could be blocked, in part, by neutralizing MIP1α or MCP-1. HSC-induced mDC maturation was dependent on activation of STAT3 in mDCs and in part on HSC-secreted IL-6. Despite up-regulation of co-stimulatory molecules, mDCs conditioned by HSCs demonstrated impaired ability to induce allogeneic T cell proliferation, which was independent of B7-H1, but dependent upon HSC-induced STAT3 activation and subsequent up-regulation of IDO. In conclusion, by promoting IDO expression, HSCs may act as potent regulators of liver mDCs and function to maintain hepatic homeostasis and tolerogenicity. PMID:22962681

  11. Epididymal Hypo-Osmolality Induces Abnormal Sperm Morphology and Function in the Estrogen Receptor Alpha Knockout Mouse1

    PubMed Central

    Joseph, Avenel; Shur, Barry D.; Ko, CheMyong; Chambon, Pierre; Hess, Rex A.

    2010-01-01

    Estrogen receptor-alpha (ESR1) is highly expressed in the efferent ductules of all species studied as well as in the epididymal epithelium in mice and other select species. Male mice lacking ESR1 (Esr1KO) are infertile, but transplantation studies demonstrated that Esr1KO germ cells are capable of fertilization when placed in a wild-type reproductive tract. These results suggest that extratesticular regions, such as the efferent ductules and epididymis, are the major source of pathological changes in Esr1KO males. Previous studies have shown alterations in ion and fluid transporters in the efferent duct and epididymal epithelia of Esr1KO males, leading to misregulation of luminal fluid pH. To determine the effect of an altered epididymal milieu on Esr1KO sperm, we assayed sperm morphology in the different regions of the epididymis. Sperm recovered from the epididymis exhibited abnormal flagellar coiling and increased incidence of spontaneous acrosome reactions, both of which are consistent with exposure to abnormal epididymal fluid. Analysis of the epididymal fluid revealed that the osmolality of the Esr1KO fluid was reduced relative to wild type, consistent with prior reports of inappropriate fluid absorption from the efferent ductules. This, along with the finding that morphological defects increased with transit through the epididymal duct, suggests that the anomalies in sperm are a consequence of the abnormal luminal environment. Consistent with this, incubating Esr1KO sperm in a more wild-type-like osmotic environment significantly rescued the abnormal flagellar coiling. This work demonstrates that Esr1KO mice exhibit an abnormal fluid environment in the lumen of the efferent ducts and epididymis, precluding normal sperm maturation and instead resulting in progressive deterioration of sperm that contributes to infertility. PMID:20130266

  12. Hepatitis a virus infection-associated hemophagocytic lymphohistiocytosis in two children.

    PubMed

    Navamani, Kirubakaran; Natarajan, Manivachagan Muthappa; Lionel, Arul Premanand; Kumar, Sathish

    2014-09-01

    Hemophagocytic lymphohistiocytosis (HLH) is a syndrome characterized by high fever, maculopapular rash, neurological symptoms, abnormal liver functions and coagulopathy. Primary HLH is due to an underlying genetic abnormality. Secondary HLH are due to an underlying infection, autoimmune disease or malignancy. Secondary HLH due to viral infections are commonly due to the herpes group commonest of which is the Ebstein Barr virus (EBV). We describe two children with virus associated hemophagocytic lymphohistiocytosis (VAHLH) secondary to hepatitis A infection. PMID:25332588

  13. Small mine size is associated with lung function abnormality and pneumoconiosis among underground coal miners in Kentucky, Virginia and West Virginia

    PubMed Central

    Blackley, David J; Halldin, Cara N; Wang, Mei Lin; Laney, A Scott

    2015-01-01

    Objectives To describe the prevalence of lung function abnormality and coal workers’ pneumoconiosis (CWP) by mine size among underground coal miners in Kentucky, Virginia and West Virginia. Methods During 2005–2012, 4491 miners completed spirometry and chest radiography as part of a health surveillance programme. Spirometry was interpreted according to American Thoracic Society and European Respiratory Society guidelines, and radiography per International Labour Office standards. Prevalence ratios (PR) were calculated for abnormal spirometry (obstructive, restrictive or mixed pattern using lower limits of normal derived from National Health and Nutrition Examination Survey (NHANES) III) and CWP among workers from small mines (≤50 miners) compared with those from large mines. Results Among 3771 eligible miners, those from small mines were more likely to have abnormal spirometry (18.5% vs 13.8%, p<0.01), CWP (10.8% vs 5.2%, p<0.01) and progressive massive fibrosis (2.4% vs 1.1%, p<0.01). In regression analysis, working in a small mine was associated with 37% higher prevalence of abnormal spirometry (PR 1.37, 95% CI 1.16 to 1.61) and 2.1 times higher prevalence of CWP (95% CI 1.68 to 2.70). Conclusions More than one in four of these miners had evidence of CWP, abnormal lung function or both. Although 96% of miners in the study have worked exclusively under dust regulations implemented following the 1969 Federal Coal Mine Safety and Health Act, we observed high rates of respiratory disease including severe cases. The current approach to dust control and provision of safe work conditions for central Appalachian underground coal miners is not adequate to protect them from adverse respiratory health effects. PMID:25052085

  14. Cellular and molecular functions of hepatic stellate cells in inflammatory responses and liver immunology

    PubMed Central

    2014-01-01

    The liver is a central immunological organ. Liver resident macrophages, Kupffer cells (KC), but also sinusoidal endothelial cells, dendritic cells (DC) and other immune cells are involved in balancing immunity and tolerance against pathogens, commensals or food antigens. Hepatic stellate cells (HSCs) have been primarily characterized as the main effector cells in liver fibrosis, due to their capacity to transdifferentiate into collagen-producing myofibroblasts (MFB). More recent studies elucidated the fundamental role of HSC in liver immunology. HSC are not only the major storage site for dietary vitamin A (Vit A) (retinol, retinoic acid), which is essential for proper function of the immune system. This pericyte further represents a versatile source of many soluble immunological active factors including cytokines [e.g., interleukin 17 (IL-17)] and chemokines [C-C motif chemokine (ligand) 2 (CCL2)], may act as an antigen presenting cell (APC), and has autophagy activity. Additionally, it responds to many immunological triggers via toll-like receptors (TLR) (e.g., TLR4, TLR9) and transduces signals through pathways and mediators traditionally found in immune cells, including the Hedgehog (Hh) pathway or inflammasome activation. Overall, HSC promote rather immune-suppressive responses in homeostasis, like induction of regulatory T cells (Treg), T cell apoptosis (via B7-H1, PDL-1) or inhibition of cytotoxic CD8 T cells. In conditions of liver injury, HSC are important sensors of altered tissue integrity and initiators of innate immune cell activation. Vice versa, several immune cell subtypes interact directly or via soluble mediators with HSC. Such interactions include the mutual activation of HSC (towards MFB) and macrophages or pro-apoptotic signals from natural killer (NK), natural killer T (NKT) and gamma-delta T cells (γδ T-cells) on activated HSC. Current directions of research investigate the immune-modulating functions of HSC in the environment of liver

  15. Age and sensory processing abnormalities predict declines in encoding and recall of temporally manipulated speech in high-functioning adults with ASD.

    PubMed

    Mayer, Jennifer L; Heaton, Pamela F

    2014-02-01

    While temporal and perceptual processing abnormalities, identified in a number of electrophysiological and brain imaging studies of individuals with (ASD), are likely to impact on speech perception, surprisingly little is known about the behavioral outcomes of such abnormalities. It has been hypothesized that rapid temporal processing deficits may be linked to impaired language development through interference with acoustic information during speech perception. The present study aimed to investigate the impact of temporal changes on encoding and recall of speech, and the associated cognitive, clinical, and behavioral correlates in adults with ASD. Research carried out with typically developing (TD) adults has shown that word recall diminishes as the speed of speech increases, and it was predicted that the magnitude of this effect would be far greater in those with ASD because of a preexisting rapid temporal processing deficit. Nineteen high-functioning adults with ASD, and age- and intelligence-matched TD controls performed verbatim recall of temporally manipulated sentences. Reduced levels of word recall in response to increases in presentation speed were observed, and this effect was greater in the older participants in the ASD group than in the control group. This is the first study to show that both sensory abnormalities and aging impact on speech encoding in ASD. Auditory processing deficits in ASD may be indicative of an association with the sensory abnormalities and social and communication impairments characterizing the disorder. PMID:24106132

  16. [Hepatic encephalopathy].

    PubMed

    Córdoba, Juan; Mur, Rafael Esteban

    2014-07-01

    Hepatic encephalopathy (EH) is a severe complication of hepatic cirrhosis that is characterized by multiple neuropsychiatric manifestations. EH is usually triggered by a precipitating factor and occurs in patients with severely impaired hepatic function. Minimal EH is characterized by minor cognitive impairments that are difficult to specify but represent a risk for the patients. The primary pathophysiological mechanism of EH is considered to be an increase in blood ammonia with an impairment in the patency of the blood-brainbarrier and its metabolism to glutamine in astrocytes. The diagnosis is clinical and neuroimaging techniques can be complementary. The diagnosis of minimal EH requires specific neurocognitive tests. The clinical evaluation should be directed towards identifying the trigger. Nonabsorbable disaccharides and rifaximin constitute the treatment of choice, along with prophylaxis for new episodes. PMID:25087716

  17. Viral Hepatitis

    MedlinePlus

    ... Public Home » For Veterans and the Public Viral Hepatitis Menu Menu Viral Hepatitis Viral Hepatitis Home For ... the Public Veterans and Public Home How is Hepatitis C Treated? Find the facts about the newest ...

  18. [The influence to the function of cellular immunity after being infected by HBV in the PBMC in chronic hepatitis B].

    PubMed

    Xuan, S Y; Sun, Y; Zhang, J

    1997-04-01

    In this study, HBV DNA was detected by PCR from PBMC of chronic hepatitis B. A total number of 54 cases were positive and 71 cases were negative. When detecting the competence of NK cells, the subgroup of T cells the ratio of CD4/CD8, the concentration of sIL-2R in three groups, and between the two CHB groups and a normal control group, the differences between HBV DNA positive group and HBV DNA negative group and between HBVDNA positive group and the normal control group were all dramatically significant (P < 0.01). We also found that a lineal correlation of the competence of NK cells, the ratio of CD4/CD8 and the concentration of sIL-2R(P < 0.01) in the positive group, whereas in the negative group only the ratio of CD4/CD8 was consistent with the concentration of sIL-2R(P < 0.01), and the competence of NK cells did not decrease obviously. The results indicated that it was the infection of HBV in PBMC which caused the disorder of the function of cellular immunity. This finding helped us to explain the pathogenesis of hepatitis B. It could also lay a theoretical ground for the prevention and the treatment of hepatitis B. PMID:9812503

  19. Molecular and Functional Analysis of the Human Prothrombinase Gene (HFGL2) and Its Role in Viral Hepatitis

    PubMed Central

    Levy, Gary A.; Liu, Mingfeng; Ding, Jinwen; Yuwaraj, Shankary; Leibowitz, Julian; Marsden, Philip A.; Ning, Qin; Kovalinka, Ana; Phillips, M. James

    2000-01-01

    In the present studies, we report the cloning and structural characterization of the HFGL2 gene and its functional role in human fulminant hepatitis. The HFGL2 gene is approximately 7 kb in length with 2 exons. The putative promoter contains cis element consensus sequences that strongly suggest the inducibility of its expression. From the nucleotide sequence of the human gene, a 439-amino acid long protein is predicted. The overall identity between the murine fgl2 and hfgl2 coded proteins is over 70%. About 225 amino acids at the carboxyl end of these molecules are almost 90% identical, and correspond to a well-conserved fibrinogen-related domain. Both HFGL2 and FGL2 encode a type II transmembrane protein with a predicted catalytic domain toward the amino terminus of the protein. Transient transfection of Chinese hamster ovary (CHO) cells with a full-length cDNA of HFGL2 coding region resulted in high levels of prothrombinase activity. Livers from 8 patients transplanted for fulminant viral hepatitis were examined for extent of necrosis, inflammation, fibrin deposition, and HFGL2 induction. In situ hybridization showed positive staining of macrophages in areas of active hepatocellular necrosis. Fibrin stained positively in these areas and was confirmed by electron microscopy. These studies define a unique prothrombinase gene (HFGL2) and implicate its importance in the pathogenesis of fulminant viral hepatitis. PMID:10751347

  20. Conserved functional domains and a novel tertiary interaction near the pseudoknot drive translational activity of hepatitis C virus and hepatitis C virus-like internal ribosome entry sites

    PubMed Central

    Easton, Laura E.; Locker, Nicolas; Lukavsky, Peter J.

    2009-01-01

    The translational activity of the hepatitis C virus (HCV) internal ribosome entry site (IRES) and other HCV-like IRES RNAs depends on structured RNA elements in domains II and III, which serve to recruit the ribosomal 40S subunit, eukaryotic initiation factor (eIF) 3 and the ternary eIF2/Met-tRNAiMet/GTP complex and subsequently domain II assists subunit joining. Porcine teschovirus-1 talfan (PTV-1) is a member of the Picornaviridae family, with a predicted HCV-like secondary structure, but only stem-loops IIId and IIIe in the 40S-binding domain display significant sequence conservation with the HCV IRES. Here, we use chemical probing to show that interaction sites with the 40S subunit and eIF3 are conserved between HCV and HCV-like IRESs. In addition, we reveal the functional role of a strictly conserved co-variation between a purine–purine mismatch near the pseudoknot (A–A/G) and the loop sequence of domain IIIe (GAU/CA). These nucleotides are involved in a tertiary interaction, which serves to stabilize the pseudoknot structure and correlates with translational efficiency in both the PTV-1 and HCV IRES. Our data demonstrate conservation of functional domains in HCV and HCV-like IRESs including a more complex structure surrounding the pseudoknot than previously assumed. PMID:19596815

  1. 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

  2. Fenofibrate, a peroxisome proliferator-activated receptor α ligand, prevents abnormal liver function induced by a fasting–refeeding process

    SciTech Connect

    Lee, Joon No; Dutta, Raghbendra Kumar; Kim, Seul-Gi; Lim, Jae-Young; Kim, Se-Jin; Choe, Seong-Kyu; Yoo, Kyeong-Won; Song, Seung Ryel; Park, Do-Sim; So, Hong-Seob; Park, Raekil

    2013-12-06

    Highlights: •A fasting–refeeding high fat diet (HDF) model mimics irregular eating habit. •A fasting–refeeding HFD induces liver ballooning injury. •A fasting–refeeding HDF process elicits hepatic triglyceride accumulation. •Fenofibrate, PPARα ligand, prevents liver damage induced by refeeding HFD. -- Abstract: Fenofibrate, a peroxisome proliferator-activated receptor α (PPARα) agonist, is an anti-hyperlipidemic agent that has been widely used in the treatment of dyslipidemia. In this study, we examined the effect of fenofibrate on liver damage caused by refeeding a high-fat diet (HFD) in mice after 24 h fasting. Here, we showed that refeeding HFD after fasting causes liver damage in mice determined by liver morphology and liver cell death. A detailed analysis revealed that hepatic lipid droplet formation is enhanced and triglyceride levels in liver are increased by refeeding HFD after starvation for 24 h. Also, NF-κB is activated and consequently induces the expression of TNF-α, IL1-β, COX-2, and NOS2. However, treating with fenofibrate attenuates the liver damage and triglyceride accumulation caused by the fasting–refeeding HFD process. Fenofibrate reduces the expression of NF-κB target genes but induces genes for peroxisomal fatty acid oxidation, peroxisome biogenesis and mitochondrial fatty acid oxidation. These results strongly suggest that the treatment of fenofibrate ameliorates the liver damage induced by fasting–refeeding HFD, possibly through the activation of fatty acid oxidation.

  3. 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

  4. Evaluation of hepatobiliary scintigraphy as an indicator of hepatic function in domestic pigeons (Columba livia) before and after exposure to ethylene glycol.

    PubMed

    Hadley, Tarah L; Daniel, Gregory B; Rotstein, David S; Avenell, James S; Zagaya, Nancy; Jones, Michael P

    2007-01-01

    This study investigated the use of quantitative hepatobiliary scintigraphy to assess liver function in 14 white Carneaux pigeons (Columba livia). Liver scintigraphy using 99mTc-mebrofenin was performed and liver function was quantified using deconvolutional analysis and the area under the normalized heart time-activity curve as previously described in the dog and horse. Liver biopsies were performed in all birds before and after toxin-induced liver damage with ethylene glycol. Before the induction of liver disease, all biopsy specimens showed varying degrees of granulomatous inflammation. After ethylene glycol administration, hepatic lesions were scored and compared with scintigraphic findings. Scintigraphic results showed a significant decrease (P = 0.04) in hepatic function using the area under the normalized time-activity curve. There was good correlation between the overall histologic score posttoxin exposure and scintigraphic measures of liver function (P < 0.03). Based upon these preliminary results, the area under the heart time-activity curve can determine hepatic extraction as a measure of hepatic parenchymal cell function. The results also showed that worsening hepatic cellular function correlated with increased histologic damage to the liver. The use of hepatobiliary scintigraphy using 99mTc-mebrofenin to determine liver function in pigeons has not been previously reported. Additional studies are warranted to evaluate the application of this technique in clinical patients and to establish the sensitivity of this technique. PMID:17385376

  5. Viral Hepatitis

    MedlinePlus

    ... with hepatitis? How does a pregnant woman pass hepatitis B virus to her baby? If I have hepatitis B, what does my baby need so that she ... Can I breastfeed my baby if I have hepatitis B? More information on viral hepatitis What is hepatitis? ...

  6. 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

  7. Preserved Function of Circulating Invariant Natural Killer T Cells in Patients With Chronic Hepatitis B Virus Infection

    PubMed Central

    Zhu, Haoxiang; Zhang, Yongmei; Liu, Hongyan; Zhang, Yijun; Kang, Yaoyue; Mao, Richeng; Yang, Feifei; Zhou, Dapeng; Zhang, Jiming

    2015-01-01

    Abstract To date, the role of invariant natural killer T (iNKT) cells in chronic hepatitis B virus (HBV) infection is not fully understood. In previous reports, iNKT cells were identified by indirect methods. However, discrepancies regarding the prevalence and function of iNKT cells during HBV infection were observed. In this study, we have devised a direct, highly specific CD1d tetramer-based methodology to test whether patients with HBV infection have associated iNKT-cell defects. In our study, a total of 93 chronic HBV-infected patients and 30 healthy individuals (as control) were enrolled. The prevalence of iNKT cells, their cytokine producing capacity, and in vitro expansion were determined by flow cytometric analysis with CD1d tetramer staining. Our observation demonstrated that there was no significant difference in circulating CD1d-tetramer positive iNKT cell numbers between HBV-infected patients and healthy controls. The capacity of iNKT cells to produce IFN-γ or IL-4 as well as their in vitro expansion was also comparable between these 2 groups. However, among chronic HBV-infected patients, a decrease in iNKT cell-number was observed in chronic hepatitis B (CHB) and cirrhosis patients in comparison to that in immune tolerant (IT) patients. These results indicated that patients with chronic HBV infection may have normal prevalence and preserved function of circulating iNKT cells. And antiviral therapy with nucleot(s)ide analogue does not alter the frequency and function of circulating iNKT cells in chronic Hepatitis B patients.

  8. CCAAT/enhancer binding protein {beta} deletion increases mitochondrial function and protects mice from LXR-induced hepatic steatosis

    SciTech Connect

    Rahman, Shaikh M.; Choudhury, Mahua; Janssen, Rachel C.; Baquero, Karalee C.; Miyazaki, Makoto; Friedman, Jacob E.

    2013-01-04

    Highlights: Black-Right-Pointing-Pointer LXR agonist activation increases liver TG accumulation by increasing lipogenesis. Black-Right-Pointing-Pointer C/EBP{beta}{sup -/-} mouse prevents LXR activation-mediated induction of hepatic lipogenesis. Black-Right-Pointing-Pointer C/EBP{beta} deletion increases mitochondrial transport chain function. Black-Right-Pointing-Pointer Beneficial effects of LXR activation on liver cholesterol metabolism did not change. Black-Right-Pointing-Pointer C/EBP{beta} inhibition might have important therapeutic potential. -- Abstract: Drugs designed specifically to activate liver X receptors (LXRs) have beneficial effects on lowering cholesterol metabolism and inflammation but unfortunately lead to severe hepatic steatosis. The transcription factor CCAAT/enhancer binding protein beta (C/EBP{beta}) is an important regulator of liver gene expression but little is known about its involvement in LXR-based steatosis and cholesterol metabolism. The present study investigated the role of C/EBP{beta} expression in LXR agonist (T0901317)-mediated alteration of hepatic triglyceride (TG) and lipogenesis in mice. C/EBP{beta} deletion in mice prevented LXR agonist-mediated induction of lipogenic gene expression in liver in conjunction with significant reduction of liver TG accumulation. Surprisingly, C/EBP{beta}{sup -/-} mice showed a major increase in liver mitochondrial electron chain function compared to WT mice. Furthermore, LXR activation in C/EBP{beta}{sup -/-} mice increased the expression of liver ATP-binding cassette transporter ABCG1, a gene implicated in cholesterol efflux and reducing blood levels of total and LDL-cholesterol. Together, these findings establish a central role for C/EBP{beta} in the LXR-mediated steatosis and mitochondrial function, without impairing the influence of LXR activation on lowering LDL and increasing HDL-cholesterol. Inactivation of C/EBP{beta} might therefore be an important therapeutic strategy to prevent LXR

  9. Functional abnormalities of heparan sulfate in mucopolysaccharidosis-I are associated with defective biologic activity of FGF-2 on human multipotent progenitor cells.

    PubMed

    Pan, Chendong; Nelson, Matthew S; Reyes, Morayma; Koodie, Lisa; Brazil, Joseph J; Stephenson, Elliot J; Zhao, Robert C; Peters, Charles; Selleck, Scott B; Stringer, Sally E; Gupta, Pankaj

    2005-09-15

    In mucopolysaccharidosis-I (MPS-I), alpha-L-iduronidase deficiency leads to progressive heparan sulfate (HS) and dermatan sulfate (DS) glycosaminoglycan (GAG) accumulation. The functional consequences of these accumulated molecules are unknown. HS critically influences tissue morphogenesis by binding to and modulating the activity of several cytokines (eg, fibroblast growth factors [FGFs]) involved in developmental patterning. We recently isolated a multipotent progenitor cell from postnatal human bone marrow, which differentiates into cells of all 3 embryonic lineages. The availability of multipotent progenitor cells from healthy volunteers and patients with MPS-I (Hurler syndrome) provides a unique opportunity to directly examine the functional effects of abnormal HS on cytokine-mediated stem-cell proliferation and survival. We demonstrate here that abnormally sulfated HS in Hurler multipotent progenitor cells perturb critical FGF-2-FGFR1-HS interactions, resulting in defective FGF-2-induced proliferation and survival of Hurler multipotent progenitor cells. Both the mitogenic and survival-promoting activities of FGF-2 were restored by substitution of Hurler HS by normal HS. This perturbation of critical HS-cytokine receptor interactions may represent a mechanism by which accumulated HS contributes to the developmental pathophysiology of Hurler syndrome. Similar mechanisms may operate in the pathogenesis of other diseases where structurally abnormal GAGs accumulate. PMID:15947088

  10. Suppression of intralysosomal proteolysis aggravates structural damage and functional impairment of liver lysosomes in rats with toxic hepatitis

    SciTech Connect

    Korolenko, T.A.; Gavrilova, N.I.; Kurysheva, N.G.; Malygin, A.E.; Pupyshev, A.B.

    1986-01-01

    This paper estimates the effect of lowering protein catabolism in the lysosomes on structural and functional properties of the latter during liver damage. For comparison, polyvinylpyrrolidone (PVP), which is inert relative to intralysosomal proteolysis, and which also accumulates largely in lysosomes of the kupffer cells of the liver, was used. The uptake of labeled bovine serum albuman (C 14-BSA) by the liver is shown and the rate of intralysosomal proteolysis is given 24 hours after administration of suramin an CCl/sub 4/ to rats. It is suggested that it is risky to use drugs which inhibit intralysosomal proteolysis in the treatment of patients with acute hepatitis.

  11. Hepatic immunophenotyping for streptozotocin-induced hyperglycemia in mice

    PubMed Central

    Lee, Young-Sun; Eun, Hyuk Soo; Kim, So Yeon; Jeong, Jong-Min; Seo, Wonhyo; Byun, Jin-Seok; Jeong, Won-Il; Yi, Hyon-Seung

    2016-01-01

    Emerging evidence revealed that diabetes induces abnormal immune responses that result in serious complications in organs. However, the effect of hyperglycemia on hepatic immunity remains obscure. We evaluated the population and function of hepatic immune cells in streptozotocin (STZ)-induced hyperglycemic mice. CC chemokine receptor 2 (CCR2)-knockout mice and mice with a depletion of regulatory T cells (DEREG) were used to investigate the migration and role of regulatory T cells (Tregs) in hyperglycemic mice. The inflammatory cytokines and hepatic transaminase levels were significantly increased in the hyperglycemic mice. The population and number of infiltrating monocytes, granulocytes, and Tregs were enhanced in the livers of the hyperglycemic mice. Hepatic monocytes other than macrophages showed the increased expression of inflammatory cytokines and chemokines in the hyperglycemic mice. The CCR2 knockout and DEREG chimeric mice exhibited increased populations of activated T cells and neutrophils compared to the WT chimeric mice, which promoted hepatic inflammation in the hyperglycemic mice. The migration of CCR2 knockout Tregs into the liver was significantly reduced compared to the WT Tregs. We demonstrated that hyperglycemia contributes to increase in infiltrating monocytes and Tregs, which are associated with hepatic immune dysfunction in mice. CCR2-mediated migration of Tregs regulates hyperglycemia-induced hepatic inflammation. PMID:27464894

  12. Hepatic immunophenotyping for streptozotocin-induced hyperglycemia in mice.

    PubMed

    Lee, Young-Sun; Eun, Hyuk Soo; Kim, So Yeon; Jeong, Jong-Min; Seo, Wonhyo; Byun, Jin-Seok; Jeong, Won-Il; Yi, Hyon-Seung

    2016-01-01

    Emerging evidence revealed that diabetes induces abnormal immune responses that result in serious complications in organs. However, the effect of hyperglycemia on hepatic immunity remains obscure. We evaluated the population and function of hepatic immune cells in streptozotocin (STZ)-induced hyperglycemic mice. CC chemokine receptor 2 (CCR2)-knockout mice and mice with a depletion of regulatory T cells (DEREG) were used to investigate the migration and role of regulatory T cells (Tregs) in hyperglycemic mice. The inflammatory cytokines and hepatic transaminase levels were significantly increased in the hyperglycemic mice. The population and number of infiltrating monocytes, granulocytes, and Tregs were enhanced in the livers of the hyperglycemic mice. Hepatic monocytes other than macrophages showed the increased expression of inflammatory cytokines and chemokines in the hyperglycemic mice. The CCR2 knockout and DEREG chimeric mice exhibited increased populations of activated T cells and neutrophils compared to the WT chimeric mice, which promoted hepatic inflammation in the hyperglycemic mice. The migration of CCR2 knockout Tregs into the liver was significantly reduced compared to the WT Tregs. We demonstrated that hyperglycemia contributes to increase in infiltrating monocytes and Tregs, which are associated with hepatic immune dysfunction in mice. CCR2-mediated migration of Tregs regulates hyperglycemia-induced hepatic inflammation. PMID:27464894

  13. Hepatic fibrosis in Kabuki syndrome.

    PubMed

    Nobili, Valerio; Marcellini, Matilde; Devito, Rita; Capolino, Rossella; Viola, Laura; Digilio, M Cristina

    2004-01-15

    Kabuki (Niikawa-Kuroki) syndrome (KS) is characterized by a distinctive face, mental retardation, growth deficiency, skeletal anomalies, dermatoglyphic abnormalities, palatal anomalies, congenital heart defects, and urogenital malformations. Congenital hepatic abnormalities have been sporadically described in patients with KS from the literature, consisting of extrahepatic biliary atresia, neonatal sclerosing cholangitis, and severe neonatal jaundice. We report here on an additional patient with a congenital abnormality of the liver consisting of hepatic fibrosis. To our knowledge, idiopathic congenital hepatic fibrosis has not been reported in KS. Thus, our observation expands the spectrum of liver malformations found in KS with the inclusion of hepatic fibrosis and supports the evidence that hepatic abnormalities may not be uncommon in KS. Clinician should be advised to search for the specific facial anomalies of KS in patients with syndromic congenital hepatic diseases, and KS should be added to the list of previously recognized multiple congenital anomaly syndromes with hepatic involvement. Due to the frequent association with congenital heart malformations, KS should be considered in the evaluation of patients with neonatal liver disease and cardiac malformation. Due to the expression patterns of Notch genes, involvement of the Notch signaling pathway in the development of heart and liver anomalies in KS should be considered. PMID:14699623

  14. Midgut of the diplopod Urostreptus atrobrunneus: structure, function, and redefinition of hepatic cells.

    PubMed

    Moreira-de-Sousa, C; Iamonte, M; Fontanetti, C S

    2016-07-11

    Diplopods are considered important macroarthropods the soil as part of its maintenance and balance. These animals usually do not occur in high densities, but population explosions caused by environmental disturbances, climate changes, and use of pesticides that eliminate possible competitors, have been reported. The millipede Urostreptus atrobrunneus Pierozzi and Fontanetti, 2006 have become a nuisance to humans in infestation sites in urban centers of the state of Sao Paulo, Brazil. As a contribution to the understanding of this potential pest, this study describes the histology, histochemistry, and ultrastructure of the U. atrobrunneus midgut, and presents the redefinition of hepatic cells somewhat controversial in the literature. The region of the midgut is characterized by the absence of a cuticular intima, and composed of a pseudostratified epithelium on a thick basal membrane, followed by a muscle layer, a layer of hepatic cells, lined by an external membrane. The morphology observed in U. atrobrunneus is similar to that reported for other species of diplopods. The hepatic cells have been previously described as randomly without forming a layer, however, the present results clearly demonstrate that these cells form a continuous layer over the whole midgut. PMID:27409229

  15. Antigenic determinants and functional domains in core antigen and e antigen from hepatitis B virus

    SciTech Connect

    Salfeld, J.; Pfaff, E.; Noah, M.; Schaller, H.

    1989-02-01

    The precore/core gene of hepatitis B virus directs the synthesis of two polypeptides, the 21-kilodalton subunit (p21c) forming the viral nucleocapsid (serologically defined as core antigen (HBcAg)) and a secreted processed protein (p17e, serologically defined as HBe antigen (HBeAg)). Although most of their primary amino acid sequences are identical, HBcAg and HBeAg display different antigenic properties that are widely used in hepatitis B virus diagnosis. To locate and to characterize the corresponding determinants, segments of the core gene were expressed in Escherichia coli and probed with a panel of polyclonal or monoclonal antibodies in radioimmunoassays or enzyme-linked immunosorbent assays, Western blots, and competition assays. Three distinct major determinants were characterized. It is postulated that HBcAg and HBeAg share common basic three-dimensional structure exposing the common linear determinant HBe1 but that they differ in the presentation of two conformational determinants that are either introduced (HBc) or masked (HBe2) in the assembled core. The simultaneous presentation of HBe1 and HBc, two distinctly different antigenic determinants with overlapping amino acid sequences, is interpreted to indicate the presence of slightly differently folded, stable conformational states of p21c in the hepatitis virus nucleocapsid.

  16. Alcohol alters hepatic FoxO1, p53, and mitochondrial SIRT5 deacetylation function

    SciTech Connect

    Lieber, Charles S. Leo, Maria Anna; Wang, Xiaolei; DeCarli, Leonore M.

    2008-08-22

    Chronic alcohol consumption affects the gene expression of a NAD-dependent deacetylase Sirtuis 1 (SIRT1) and the peroxisome proliferator-activated receptor-{gamma} coactivator1{alpha} (PGC-1{alpha}). Our aim was to verify that it also alters the forkhead (FoxO1) and p53 transcription factor proteins, critical in the hepatic response to oxidative stress and regulated by SIRT1 through its deacetylating capacity. Accordingly, rats were pair-fed the Lieber-DeCarli alcohol-containing liquid diets for 28 days. Alcohol increased hepatic mRNA expression of FoxO1 (p = 0.003) and p53 (p = 0.001) while corresponding protein levels remained unchanged. However phospho-FoxO1 and phospho-Akt (protein kinase) were both decreased by alcohol consumption (p = 0.04 and p = 0.02, respectively) while hepatic p53 was found hyperacetylated (p = 0.017). Furthermore, mitochondrial SIRT5 was reduced (p = 0.0025), and PGC-1{alpha} hyperacetylated (p = 0.027), establishing their role in protein modification. Thus, alcohol consumption disrupts nuclear-mitochondrial interactions by post-translation protein modifications, which contribute to alteration of mitochondrial biogenesis through the newly discovered reduction of SIRT5.

  17. Holoprosencephaly in RSH/Smith-Lemli-Opitz syndrome: Does abnormal cholesterol metabolism affect the function of sonic hedgehog?

    SciTech Connect

    Kelley, R.I.; Roessler, E.; Muenke, M.

    1996-12-30

    The RAH/Smith-Lemli-Opitz syndrome (RAH/SLOS) is an autosomal recessive malformation syndrome associated with increased levels of 7-dehydrocholesterol (7-DHC) and a defect of cholesterol biosynthesis at the level of 3{beta}-hydroxy-steroid-{Delta}{sup 7}-reductase (7-DHC reductase). Because rats exposed to inhibitors of 7-DHC reductase during development have a high frequency of holoprosencephaly (HPE), we have undertaken a search for biochemical evidence of RSH/SLOS and other possible defects of sterol metabolism among patients with various forms of HPE. We describe 4 patients, one with semilobar HPE and three others with less complete forms of the HPE sequence, in whom we have made a biochemical diagnosis of RAH/SLOS. The clinical and biochemical spectrum of these and other patients with RAH/SLOS suggests a role of abnormal sterol metabolism in the pathogenesis of their malformations. The association of HPE and RAH/SLOS is discussed in light of the recent discoveries that mutations in the embryonic patterning gene, Sonic Hedgehog (SHH), can cause HPE in humans and that the sonic hedgehog protein product undergoes autoproteolysis to form a cholesterol-modified active product. These clinical, biochemical, and molecular studies suggest that HPE and other malformations in SLOS may be caused by incomplete or abnormal modification of the sonic hedgehog protein and, possibly, other patterning proteins of the hedgehog class, a hypothesis testable in somatic cell systems. 37 refs., 1 fig.

  18. The relationship between serology of hepatitis E virus with liver and kidney function in kidney transplant patients

    PubMed Central

    Zeraati, Abbas Ali; Nazemian, Fatemeh; Takalloo, Ladan; Sahebkar, Amirhossein; Heidari, Elahe; Yaghoubi, Mohammad Ali

    2016-01-01

    Although hepatitis E virus (HEV) is well known to cause acute hepatitis, there are reports showing that HEV may also be responsible for progression of acute to chronic hepatitis and liver cirrhosis in patients receiving organ transplantation. In this study, we aimed to evaluate the prevalence of HEV in patients with kidney transplantation. In this study, 110 patients with kidney transplantation were recruited, and anti-HEV IgG, creatinine, alanine transaminase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), and estimated glomerular filtration rate (eGFR) in the first, third and sixth months after renal transplantation were measured. The mean serum anti-HEV IgG titers in the study participants was 1.36 (range 0.23 to 6.3). Twenty-three patients were found to be seropositive for HEV Ab defined as anti-HEV IgG titer > 1.1. The difference in liver and renal function tests (creatinine, eGFR, AST, ALT and ALP) at different intervals was not significant between patients with HEV Ab titers higher and lower than 1.1 (p > 0.05). However, an inverse correlation was observed between HEV Ab and eGFR values in the first (p = 0.047, r = -0.21), third (p = 0.04, r = -0.20) and sixth (p = 0.04, r = -0.22) months after renal transplantation in patients with HEV Ab < 1.1 but not in the subgroup with HEV Ab > 1.1. Also, a significant correlation between age and HEV Ab levels was found in the entire study population (p = 0.001, r = 0.33). Our findings showed a high prevalence of seropositivity for anti-HEV IgG in patients receiving renal transplants. However, liver and renal functions were not found to be significantly different seropositive and seronegative patients by up to 6 months post-transplantation. PMID:27366144

  19. The relationship between serology of hepatitis E virus with liver and kidney function in kidney transplant patients.

    PubMed

    Zeraati, Abbas Ali; Nazemian, Fatemeh; Takalloo, Ladan; Sahebkar, Amirhossein; Heidari, Elahe; Yaghoubi, Mohammad Ali

    2016-01-01

    Although hepatitis E virus (HEV) is well known to cause acute hepatitis, there are reports showing that HEV may also be responsible for progression of acute to chronic hepatitis and liver cirrhosis in patients receiving organ transplantation. In this study, we aimed to evaluate the prevalence of HEV in patients with kidney transplantation. In this study, 110 patients with kidney transplantation were recruited, and anti-HEV IgG, creatinine, alanine transaminase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), and estimated glomerular filtration rate (eGFR) in the first, third and sixth months after renal transplantation were measured. The mean serum anti-HEV IgG titers in the study participants was 1.36 (range 0.23 to 6.3). Twenty-three patients were found to be seropositive for HEV Ab defined as anti-HEV IgG titer > 1.1. The difference in liver and renal function tests (creatinine, eGFR, AST, ALT and ALP) at different intervals was not significant between patients with HEV Ab titers higher and lower than 1.1 (p > 0.05). However, an inverse correlation was observed between HEV Ab and eGFR values in the first (p = 0.047, r = -0.21), third (p = 0.04, r = -0.20) and sixth (p = 0.04, r = -0.22) months after renal transplantation in patients with HEV Ab < 1.1 but not in the subgroup with HEV Ab > 1.1. Also, a significant correlation between age and HEV Ab levels was found in the entire study population (p = 0.001, r = 0.33). Our findings showed a high prevalence of seropositivity for anti-HEV IgG in patients receiving renal transplants. However, liver and renal functions were not found to be significantly different seropositive and seronegative patients by up to 6 months post-transplantation. PMID:27366144

  20. Erythropoietic and hepatic porphyrias.

    PubMed

    Gross, U; Hoffmann, G F; Doss, M O

    2000-11-01

    Porphyrias are divided into erythropoietic and hepatic manifestations. Erythropoietic porphyrias are characterized by cutaneous symptoms and appear in early childhood. Erythropoietic protoporphyria is complicated by cholestatic liver cirrhosis and progressive hepatic failure in 10%, of patients. Acute hepatic porphyrias (delta-aminolaevulinic acid dehydratase deficiency porphyria, acute intermittent porphyria, hereditary coproporphyria and variegate porphyria) are characterized by variable extrahepatic gastrointestinal, neurological-psychiatric and cardiovascular manifestations requiring early diagnosis to avoid life-threatening complications. Acute hepatic porphyrias are pharmacogenetic and molecular regulatory diseases (without porphyrin accumulation) mainly induced by drugs, sex hormones, fasting or alcohol. The disease process depends on the derepression of hepatic delta-aminolaevulinic acid synthase following haem depletion. In contrast to the acute porphyrias, nonacute, chronic hepatic porphyrias such as porphyria cutanea tarda are porphyrin accumulation disorders leading to cutaneous symptoms associated with liver disease, especially caused by alcohol or viral hepatitis. Alcohol, oestrogens, haemodialysis, hepatitis C and AIDS are triggering factors. Porphyria cutanea tarda is the most common porphyria, followed by acute intermittent porphyria and erythropoietic protoporphyria. The molecular genetics of the porphyrias is very heterogenous. Nearly every family has its own mutation. The mutations identified account for the corresponding enzymatic deficiencies, which may remain clinically silent throughout life. Thus, the recognition of the overt disorder with extrahepatic manifestations depends on the demonstration of biochemical abnormalities due to these primary defects and compensatory hepatic overexpression of hepatic delta-aminolaevulinic acid synthase in the acute porphyrias. Consequently, haem precursors are synthesized in excess. The increased

  1. Highly efficient differentiation of hESCs to functional hepatic endoderm requires ActivinA and Wnt3a signaling

    PubMed Central

    Hay, David C.; Fletcher, Judy; Payne, Catherine; Terrace, John D.; Gallagher, Ronald C. J.; Snoeys, Jan; Black, James R.; Wojtacha, Davina; Samuel, Kay; Hannoun, Zara; Pryde, Anne; Filippi, Celine; Currie, Ian S.; Forbes, Stuart J.; Ross, James A.; Newsome, Philip N.; Iredale, John P.

    2008-01-01

    Human embryonic stem cells (hESCs) are a valuable source of pluripotential primary cells. To date, however, their homogeneous cellular differentiation to specific cell types in vitro has proven difficult. Wnt signaling has been shown to play important roles in coordinating development, and we demonstrate that Wnt3a is differentially expressed at critical stages of human liver development in vivo. The essential role of Wnt3a in hepatocyte differentiation from hESCs is paralleled by our in vitro model, demonstrating the importance of a physiologic approach to cellular differentiation. Our studies provide compelling evidence that Wnt3a signaling is important for coordinated hepatocellular function in vitro and in vivo. In addition, we demonstrate that Wnt3a facilitates clonal plating of hESCs exhibiting functional hepatic differentiation. These studies represent an important step toward the use of hESC-derived hepatocytes in high-throughput metabolic analysis of human liver function. PMID:18719101

  2. Cocaine addiction related reproducible brain regions of abnormal default-mode network functional connectivity: a group ICA study with different model orders.

    PubMed

    Ding, Xiaoyu; Lee, Seong-Whan

    2013-08-26

    Model order selection in group independent component analysis (ICA) has a significant effect on the obtained components. This study investigated the reproducible brain regions of abnormal default-mode network (DMN) functional connectivity related with cocaine addiction through different model order settings in group ICA. Resting-state fMRI data from 24 cocaine addicts and 24 healthy controls were temporally concatenated and processed by group ICA using model orders of 10, 20, 30, 40, and 50, respectively. For each model order, the group ICA approach was repeated 100 times using the ICASSO toolbox and after clustering the obtained components, centrotype-based anterior and posterior DMN components were selected for further analysis. Individual DMN components were obtained through back-reconstruction and converted to z-score maps. A whole brain mixed effects factorial ANOVA was performed to explore the differences in resting-state DMN functional connectivity between cocaine addicts and healthy controls. The hippocampus, which showed decreased functional connectivity in cocaine addicts for all the tested model orders, might be considered as a reproducible abnormal region in DMN associated with cocaine addiction. This finding suggests that using group ICA to examine the functional connectivity of the hippocampus in the resting-state DMN may provide an additional insight potentially relevant for cocaine-related diagnoses and treatments. PMID:23707901

  3. An unusual occurrence of hepatic granulomas and secondary sitosterolemia in turner syndrome.

    PubMed

    Chintanaboina, JayaKrishna; Shah, Pragnesh R; Riley, Thomas R

    2015-01-01

    Although abnormal liver function tests occur in 50-80% of cases with Turner syndrome, there are no previous reports of overt hepatic disease or hepatic granulomas associated with Turner's syndrome. We report three cases of Turner syndrome associated with hepatic granulomas with a wide range of liver dysfunction. Of the three patients, first patient underwent liver transplantation; second patient remained stable on immunosuppressants; and third patient died from complications of decompensated liver cirrhosis as she declined liver transplantation due to multiple comorbidities. One patient had sitosterolemia, a rare inherited autosomal recessive disorder of cholesterol metabolism, after she ingested β-sitosterol supplement and had worsening liver function tests and lipid panel. She had remarkably abnormal lipid panel that responded to ezetimibe and by stopping the β-sitosterol supplement. PMID:25705228

  4. Abnormal calcium homeostasis in heart failure with preserved ejection fraction is related to both reduced contractile function and incomplete relaxation: an electromechanically detailed biophysical modeling study

    PubMed Central

    Adeniran, Ismail; MacIver, David H.; Hancox, Jules C.; Zhang, Henggui

    2015-01-01

    Heart failure with preserved ejection fraction (HFpEF) accounts for about 50% of heart failure cases. It has features of incomplete relaxation and increased stiffness of the left ventricle. Studies from clinical electrophysiology and animal experiments have found that HFpEF is associated with impaired calcium homeostasis, ion channel remodeling and concentric left ventricle hypertrophy (LVH). However, it is still unclear how the abnormal calcium homeostasis, ion channel and structural remodeling affect the electro-mechanical dynamics of the ventricles. In this study we have developed multiscale models of the human left ventricle from single cells to the 3D organ, which take into consideration HFpEF-induced changes in calcium handling, ion channel remodeling and concentric LVH. Our simulation results suggest that at the cellular level, HFpEF reduces the systolic calcium level resulting in a reduced systolic contractile force, but elevates the diastolic calcium level resulting in an abnormal residual diastolic force. In our simulations, these abnormal electro-mechanical features of the ventricular cells became more pronounced with the increase of the heart rate. However, at the 3D organ level, the ejection fraction of the left ventricle was maintained due to the concentric LVH. The simulation results of this study mirror clinically observed features of HFpEF and provide new insights toward the understanding of the cellular bases of impaired cardiac electromechanical functions in heart failure. PMID:25852567

  5. Expression and function of lysophosphatidic acid receptors (LPARs) 1 and 3 in human hepatic cancer progenitor cells

    PubMed Central

    Swet, Jacob H.; Ahrens, William A.; Showlater, Victor; Iannitti, David A.; Mckillop, Iain H.

    2016-01-01

    Hepatocellular carcinoma (HCC) is the most common primary cancer of the liver and is characterized by rapid tumor expansion and metastasis. Lysophosphatidic acid (LPA) signaling, via LPA receptors 1–6 (LPARs1–6), regulates diverse cell functions including motility, migration, and proliferation, yet the role of LPARs in hepatic tumor pathology is poorly understood. We sought to determine the expression and function of endothelial differentiation gene (EDG) LPARs (LPAR1–3) in human HCC and complimentary in vitro models. Human HCC were characterized by significantly elevated LPAR1/LPAR3 expression in the microenvironment between the tumor and non-tumor liver (NTL), a finding mirrored in human SKHep1 cells. Analysis of human tissue and human hepatic tumor cells in vitro revealed cells that express LPAR3 (HCC-NTL margin in vivo and SKHep1 in vitro) also express cancer stem cell markers in the absence of hepatocyte markers. Treatment of SKHep1 cells with exogenous LPA led to significantly increased cell motility but not proliferation. Using pharmacological agents and cells transfected to knock-down LPAR1 or LPAR3 demonstrated LPA-dependent cell migration occurs via an LPAR3-Gi-ERK-pathway independent of LPAR1. These data suggest cells that stain positive for both LPAR3 and cancer stem cell markers are distinct from the tumor mass per se, and may mediate tumor invasiveness/expansion via LPA-LPAR3 signaling. PMID:26701886

  6. Loss of Cystic Fibrosis Transmembrane Conductance Regulator Function Produces Abnormalities in Tracheal Development in Neonatal Pigs and Young Children

    PubMed Central

    Meyerholz, David K.; Stoltz, David A.; Namati, Eman; Ramachandran, Shyam; Pezzulo, Alejandro A.; Smith, Amanda R.; Rector, Michael V.; Suter, Melissa J.; Kao, Simon; McLennan, Geoffrey; Tearney, Guillermo J.; Zabner, Joseph; McCray, Paul B.; Welsh, Michael J.

    2010-01-01

    Rationale: Although airway abnormalities are common in patients with cystic fibrosis (CF), it is unknown whether they are all secondary to postnatal infection and inflammation, which characterize the disease. Objectives: To learn whether loss of the cystic fibrosis transmembrane conductance regulator (CFTR) might affect major airways early in life, before the onset of inflammation and infection. Methods: We studied newborn CFTR−/− pig trachea, using computed tomography (CT) scans, pathology, and morphometry. We retrospectively analyzed trachea CT scans in young children with CF and also previously published data of infants with CF. Measurements and Main Results: We discovered three abnormalities in the porcine CF trachea. First, the trachea and mainstem bronchi had a uniformly small caliber and cross-sections of trachea were less circular than in controls. Second, trachealis smooth muscle had an altered bundle orientation and increased transcripts in a smooth muscle gene set. Third, submucosal gland units occurred with similar frequency in the mucosa of CF and control airways, but CF submucosal glands were hypoplastic and had global reductions in tissue-specific transcripts. To learn whether any of these changes occurred in young patients with CF, we examined CT scans from children 2 years of age and younger, and found that CF tracheas were less circular in cross-section, but lacked differences in lumen area. However, analysis of previously published morphometric data showed reduced tracheal lumen area in neonates with CF. Conclusions: Our findings in newborn CF pigs and young patients with CF suggest that airway changes begin during fetal life and may contribute to CF pathogenesis and clinical disease during postnatal life. PMID:20622026

  7. Role of scintigraphy in focally abnormal sonograms of fatty livers

    SciTech Connect

    Lisbona, R.; Mishkin, S.; Derbekyan, V.; Novales-Diaz, J.A.; Roy, A.; Sanders, L.

    1988-06-01

    Fatty infiltration of the liver may cause a range of focal abnormalities on hepatic sonography which may simulate hepatic nodular lesions. Discrete deposits of fat or islands of normal tissue which are uninvolved by fatty infiltration may stand out as potential space-occupying lesions on the sonograms. Twelve patients with such focally abnormal ultrasound images were referred for liver scintigraphy with /sup 133/Xe and /sup 99m/Tc colloidal SPECT studies to clarify the issue. These examinations helped identify, in nine of 12 patients, the innocent nature of the sonographic abnormalities which were simply related to the fat deposition process. Further, (/sup 99m/Tc)RBC scans defined the additional pathologic process in three patients in whom actual space-occupying lesions were indeed present in the liver. Scintigraphy has an important role to play in the understanding of focal hepatic ultrasound abnormalities particularly in unsuspected hepatic steatosis.

  8. [Hepatic encephalopathy].

    PubMed

    Festi, Davide; Marasco, Giovanni; Ravaioli, Federico; Colecchia, Antonio

    2016-07-01

    Hepatic encephalopathy (HE) is a common complication of liver cirrhosis and it can manifest with a broad spectrum of neuropsychiatric abnormalities of varying severity, acuity and time course with important clinical implications. According to recent guidelines, HE has been classified into different types, depending on the severity of hepatic dysfunction, the presence of porto-systemic shunts and the number of previous episodes or persistent manifestations. From a clinical point of view, HE can be recognized as unimpaired, covert (that deals with minimal and grade 1 according to the grading of mental state), and overt (that is categorized from grade 2 to grade 4). Different and only partially known pathogenic mechanisms have been identified, comprising ammonia, inflammatory cytokines, benzodiazepine-like compounds and manganese deposition. Different therapeutic strategies are available for treating HE, in particular the overt HE, since covert HE needs to be managed case by case. Recognition and treatment of precipitating factors represent fundamental part of the management. The more effective treatments, which can be performed separately or combined, are represented by non-absorbable disaccharides (lactulose and lactitol) and the topic antibiotic rifaximin; other possible therapies, mainly used in patients non responders to previous treatments, are represented by branched chain amino acids and metabolic ammonia scavengers. PMID:27571468

  9. Abnormal brain function of the rat neonate in a prenatal 5-bromo-2'-deoxyuridine (BrdU)-induced developmental disorder model.

    PubMed

    Ogawa, Tetsuo; Kuwagata, Makiko; Muneoka, Katsumasa; Wakai, Chizu; Senuma, Mika; Kubo, Hiroko; Shioda, Seiji

    2012-10-01

    Neonatal brain function was investigated in a prenatal BrdU-induced developmental disorder model, which has been reported to exhibit behavioral abnormalities such as locomotor hyperactivity, impaired learning and memory, and lower anxiety in offspring. After 1h home cage deprivation we observed an increase in the number of c-Fos (neuronal activity marker) immunoreactive cells in several brain regions of the olfactory and stress-related areas in normal neonates at 11 days. Next, pregnant rats were exposed to 50mg/kg of BrdU from gestation days 9-15, and their offspring at 11 days were home-cage deprived. Compared to vehicle control, the number of c-Fos immunoreactive cells in BrdU group was found to be decreased in the piriform cortex and locus coeruleus, which are known to play an important role in neonatal learning and memory. We also analyzed Pearson product-moment correlation coefficient of the number of c-Fos immunoreactive cells, focusing on the piriform cortex and locus coeruleus versus numerous other brain areas (11 areas including amygdala). Numerous significant correlations were observed in the vehicle control group, however, correlations of the locus coeruleus disappeared in the BrdU group. By observing c-Fos immunoreactivity after home cage deprivation our study uncovers abnormal brain functions as early as postnatal day 11 in this disorder model. Based on these results, we propose a new histological approach for functional characterization of developmental disorder models. PMID:22609825

  10. Relationships (II) of International Classification of High-resolution Computed Tomography for Occupational and Environmental Respiratory Diseases with ventilatory functions indices for parenchymal abnormalities

    PubMed Central

    TAMURA, Taro; SUGANUMA, Narufumi; HERING, Kurt G.; VEHMAS, Tapio; ITOH, Harumi; AKIRA, Masanori; TAKASHIMA, Yoshihiro; HIRANO, Harukazu; KUSAKA, Yukinori

    2015-01-01

    The International Classification of High-Resolution Computed Tomography (HRCT) for Occupational and Environmental Respiratory Diseases (ICOERD) is used to screen and diagnose respiratory illnesses. Using univariate and multivariate analysis, we investigated the relationship between subject characteristics and parenchymal abnormalities according to ICOERD, and the results of ventilatory function tests (VFT). Thirty-five patients with and 27 controls without mineral-dust exposure underwent VFT and HRCT. We recorded all subjects’ occupational history for mineral dust exposure and smoking history. Experts independently assessed HRCT using the ICOERD parenchymal abnormalities (Items) grades for well-defined rounded opacities (RO), linear and/or irregular opacities (IR), and emphysema (EM). High-resolution computed tomography showed that 11 patients had RO; 15 patients, IR; and 19 patients, EM. According to the multiple regression model, age and height had significant associations with many indices ventilatory functions such as vital capacity, forced vital capacity, and forced expiratory volume in 1 s (FEV1). The EM summed grades on the upper, middle, and lower zones of the right and left lungs also had significant associations with FEV1 and the maximum mid-expiratory flow rate. The results suggest the ICOERD notation is adequate based on the good and significant multiple regression modeling of ventilatory function with the EM summed grades. PMID:25810443

  11. PEG-IFN Alpha but Not Ribavirin Alters NK Cell Phenotype and Function in Patients with Chronic Hepatitis C

    PubMed Central

    Markova, Antoaneta A.; Mihm, Ulrike; Schlaphoff, Verena; Lunemann, Sebastian; Filmann, Natalie; Bremer, Birgit; Berg, Thomas; Sarrazin, Christoph; Zeuzem, Stefan; Manns, Michael P.; Cornberg, Markus; Herrmann, Eva; Wedemeyer, Heiner

    2014-01-01

    Background Ribavirin (RBV) remains part of several interferon-free treatment strategies even though its mechanisms of action are still not fully understood. One hypothesis is that RBV increases responsiveness to type I interferons. Pegylated Interferon alpha (PEG-IFNa) has recently been shown to alter natural killer (NK) cell function possibly contributing to control of hepatitis C virus (HCV) infection. However, the effects of ribavirin alone or in combination with IFNa on NK cells are unknown. Methods Extensive ex vivo phenotyping and functional analysis of NK cells from hepatitis C patients was performed during antiviral therapy. Patients were treated for 6 weeks with RBV monotherapy (n = 11), placebo (n = 13) or PEG-IFNa-2a alone (n = 6) followed by PEG-IFNa/RBV combination therapy. The effects of RBV and PEG-IFNa-2a on NK cells were also studied in vitro after co-culture with K562 or Huh7.5 cells. Results Ribavirin monotherapy had no obvious effects on NK cell phenotype or function, neither ex vivo in patients nor in vitro. In contrast, PEG-IFNa-2a therapy was associated with an increase of CD56bright cells and distinct changes in expression profiles leading to an activated NK cell phenotype, increased functionality and decline of terminally differentiated NK cells. Ribavirin combination therapy reduced some of the IFN effects. An activated NK cell phenotype during therapy was inversely correlated with HCV viral load. Conclusions PEG-IFNa activates NK cells possibly contributing to virological responses independently of RBV. The role of NK cells during future IFN-free combination therapies including RBV remains to be determined. PMID:24751903

  12. Variants in Genes Controlling Oxidative Metabolism Contribute to Lower Hepatic ATP Independent of Liver Fat Content in Type 1 Diabetes.

    PubMed

    Gancheva, Sofiya; Bierwagen, Alessandra; Kaul, Kirti; Herder, Christian; Nowotny, Peter; Kahl, Sabine; Giani, Guido; Klueppelholz, Birgit; Knebel, Birgit; Begovatz, Paul; Strassburger, Klaus; Al-Hasani, Hadi; Lundbom, Jesper; Szendroedi, Julia; Roden, Michael

    2016-07-01

    Type 1 diabetes has been recently linked to nonalcoholic fatty liver disease (NAFLD), which is known to associate with insulin resistance, obesity, and type 2 diabetes. However, the role of insulin resistance and hyperglycemia for hepatic energy metabolism is yet unclear. To analyze early abnormalities in hepatic energy metabolism, we examined 55 patients with recently diagnosed type 1 diabetes. They underwent hyperinsulinemic-normoglycemic clamps with [6,6-(2)H2]glucose to assess whole-body and hepatic insulin sensitivity. Hepatic γATP, inorganic phosphate (Pi), and triglyceride concentrations (hepatocellular lipid content [HCL]) were measured with multinuclei magnetic resonance spectroscopy ((31)P/(1)H-MRS). Glucose-tolerant humans served as control (CON) (n = 57). Whole-body insulin sensitivity was 44% lower in patients than in age- and BMI-matched CON. Hepatic γATP was 15% reduced (2.3 ± 0.6 vs. 2.7 ± 0.6 mmol/L, P < 0.001), whereas hepatic Pi and HCL were similar in patients when compared with CON. Across all participants, hepatic γATP correlated negatively with glycemia and oxidized LDL. Carriers of the PPARG G allele (rs1801282) and noncarriers of PPARGC1A A allele (rs8192678) had 21 and 13% lower hepatic ATP concentrations. Variations in genes controlling oxidative metabolism contribute to a reduction in hepatic ATP in the absence of NAFLD, suggesting that alterations in hepatic mitochondrial function may precede diabetes-related liver diseases. PMID:27207512

  13. The Role of Cea and Liver Function Tests in the Detection of Hepatic Metastases From Colo-Rectal Cancer

    PubMed Central

    Bombelli, Luigia; Bozzetti, F.; Doci, R.; Gennari, L.; Koukouras, D.

    1990-01-01

    Carcinoembryonic antigen and some liver function tests (alkaline phosphatase, gamma-glutamyl-transpeptidase, lactic dehydrogenase and cholinesterase) were evaluated in patients with primary colorectal cancer in order to define their role in the pre-operative detection of liver metastases. The records of 278 consecutive patients admitted to the Istituto Nazionale Tumori of Milan between January 1982 and December 1983 who were suffering from primary invasive colo-rectal cancer and who underwent laparotomy were retrospectively analyzed. At laparotomy, liver metastases were found in 38 pts (13.7%). Considering single tests, CEA was the most sensitive (71%); no single test was found to be reliably predictive, when the result was abnormal. On the contrary, the normal value of each test was associated with a good prediction. When we considered all the five tests together in the single patient their predictive value, when abnormal, proved to be quite good only if four or five results were abnormal. On the other hand, liver metastases in the presence of all normal tests were found only in two patients, so giving a negative predictive value of about 97%. So we conclude that, in the lack of an infallable imaging technique for liver evaluation, in the presence of all normal tests any other investigation on the liver could be avoided. However, when liver tests are pathologic, some other imaging technique should be performed in order to supply the surgeon with information about the extent and the spread of the metastases. PMID:2090187

  14. Hyperammonemia in gene-targeted mice lacking functional hepatic glutamine synthetase

    PubMed Central

    Qvartskhava, Natalia; Lang, Philipp A.; Görg, Boris; Pozdeev, Vitaly I.; Ortiz, Marina Pascual; Lang, Karl S.; Bidmon, Hans J.; Lang, Elisabeth; Leibrock, Christina B.; Herebian, Diran; Bode, Johannes G.; Lang, Florian; Häussinger, Dieter

    2015-01-01

    Urea cycle defects and acute or chronic liver failure are linked to systemic hyperammonemia and often result in cerebral dysfunction and encephalopathy. Although an important role of the liver in ammonia metabolism is widely accepted, the role of ammonia metabolizing pathways in the liver for maintenance of whole-body ammonia homeostasis in vivo remains ill-defined. Here, we show by generation of liver-specific Gln synthetase (GS)-deficient mice that GS in the liver is critically involved in systemic ammonia homeostasis in vivo. Hepatic deletion of GS triggered systemic hyperammonemia, which was associated with cerebral oxidative stress as indicated by increased levels of oxidized RNA and enhanced protein Tyr nitration. Liver-specific GS-deficient mice showed increased locomotion, impaired fear memory, and a slightly reduced life span. In conclusion, the present observations highlight the importance of hepatic GS for maintenance of ammonia homeostasis and establish the liver-specific GS KO mouse as a model with which to study effects of chronic hyperammonemia. PMID:25870278

  15. Fatty liver and hepatic function for residents with markedly high serum PCDD/Fs levels in Taiwan.

    PubMed

    Lee, Ching-Chang; Yao, Yei-Jen; Chen, Hsiu-Ling; Guo, Yue-Liang; Su, Huey-Jen

    2006-03-01

    This study was designed to examine the associations between serum polychtorinated dibenzo-p-dioxins and dibenzofurans (PCDD/Fs) levels and adverse hepatic-related health outcomes. Residents living in the vicinity of a closed pentachlorophenol (PCP) manufacturing factory (exposure area) and other areas nearby (control area) were identified from prior investigation of serum PCDD/Fs measurements. A total of 85 subjects were recruited for the study, 52 from exposure area and 33 from control, respectively. Average level of serum PCDD/Fs was 80.1 6 50.9 pg WHO-TEQ/g lipid for those residing in exposure area, and 25.5 6 18.2 in control area. Statistically higher odds ratio (ORs) for fatty liver and gamma-glutamyltransferase (GGT) activity was found in subjects with higher serum PCDD/Fs levels and high body mass index (BMI) as compared to those with lower PCDD/Fs levels and less BMI. Data suggest that dioxin exposure and high lipid content affect the prevalence of fatty liver in exposed subjects. Future study should be directed to prevent continuous exposure to environmental PCDD/Fs from the defunct PCP factory, and to characterize prospectively, with a larger study sample size, the potential long-term consequences on hepatic function associated with contaminant exposure. PMID:16455615

  16. Success of antiviral therapy in chronic hepatitis C infection relates to functional status of myeloid dendritic cells

    PubMed Central

    Rana, Deepa; Chawla, Yogesh; Arora, Sunil K.

    2013-01-01

    Chronic hepatitis C infection poses a major global health predicament and appears to be potent threat to mankind. The treatment in wide use is interferon/ribavirin combination therapy which is generally effective in about 60-70 per cent of patients carrying genotype 3 and causes significant morbidity. The response to therapy is largely guided by limited number of factors such as genotype of virus, rapid virological response, ethnicity, pre-therapy viral load, etc. While involvement of host genetic factors has been a major focus of research in playing an important role in the outcome of disease, the role of immune system cannot be marginalized. Poor cellular trafficking and suboptimal T cell responses in liver, the hall marks of chronic hepatitis C virus infection, might be attributed to defective antigen presentation. Various immunological factors, both innate and adaptive, play role in the pathogenesis of the disease and become dysfunctional in active disease. Recent reports suggest the major impact of functional and numerical status of dendritic cells in deciding the fate of antiviral therapy. In this review we take a look at the involvement of dendritic cells in playing an important role in the response to therapy. PMID:24434330

  17. MCT8 Deficiency in Male Mice Mitigates the Phenotypic Abnormalities Associated With the Absence of a Functional Type 3 Deiodinase.

    PubMed

    Stohn, J Patrizia; Martinez, M Elena; Matoin, Kassey; Morte, Beatriz; Bernal, Juan; Galton, Valerie Anne; St Germain, Donald; Hernandez, Arturo

    2016-08-01

    Mice deficient in the type 3 deiodinase (D3KO mice) manifest impaired clearance of thyroid hormone (TH), leading to elevated levels of TH action during development. This alteration causes reduced neonatal viability, growth retardation, and central hypothyroidism. Here we examined how these phenotypes are affected by a deficiency in the monocarboxylate transporter 8 (MCT8), which is a major contributor to the transport of the active thyroid hormone, T3, into the cell. MCT8 deficiency eliminated the neonatal lethality of type 3 deiodinase (D3)-deficient mice and significantly ameliorated their growth retardation. Double-mutant newborn mice exhibited similar peripheral thyrotoxicosis and increased brain expression of T3-dependent genes as mice with D3 deficiency only. Later in neonatal life and adulthood, double-mutant mice manifested central and peripheral TH status similar to mice with single MCT8 deficiency, with low serum T4, elevated serum TSH and T3, and decreased T3-dependent gene expression in the hypothalamus. In double-mutant adult mice, both thyroid gland size and the hypothyroidism-induced rise in TSH were greater than those in mice with single D3 deficiency but less than those in mice with MCT8 deficiency alone. Our results demonstrate that the marked phenotypic abnormalities observed in the D3-deficient mouse, including perinatal mortality, growth retardation, and central hypothyroidism in adult animals, require expression of MCT8, confirming the interdependent relationship between the TH transport into cells and the deiodination processes. PMID:27254003

  18. Risk factors for damaged liver function after chemotherapy in hepatitis B virus carriers with non-Hodgkin lymphoma.

    PubMed

    Li, X; Fan, X W; Liu, W; Guo, L; Li, Y; Hu, X; Liang, X; Ma, X P; Yang, S E

    2015-01-01

    The goal of this study was to investigate damaged liver function after chemotherapy in hepatitis B virus (HBV) carriers with non-Hodgkin lymphoma (NHL) and to evaluate risk factors associated with a high risk of damaged liver function. Clinical histories of 134 HBV carriers with NHL who were treated with chemotherapy were obtained and analyzed for the occurrence of damaged liver function and other related high-risk factors. Analysis showed that 76 patients (56.7%) had damaged liver function after chemotherapy: 6 patients (7.9%) had I degree, 17 patients (22.4%) had II degree, 20 patients (26.3%) had III degree, and 33 patients (43.4%) had IV degree damage. After treatment, 18 patients (23.7%) continued to receive chemotherapy according to their original schedule, 39 patients (51.3%) delayed chemotherapy, 16 patients (21.1%) stopped chemotherapy, and 3 patients (3.9%) died. Analysis of a binary multivariate logistic regression model showed that administration of steroids was a high-risk factor for damaged liver function after chemotherapy in NHL patients. The incidence of damaged liver function after chemotherapy is high among HBV carriers with NHL; therefore, administration of steroid chemotherapy is a high-risk factor. PMID:25867413

  19. Functional and physical molecular size of the chicken hepatic lectin determined by radiation inactivation and sedimentation equilibrium analysis

    SciTech Connect

    Steer, C.J.; Osborne, J.C. Jr.; Kempner, E.S. )

    1990-03-05

    Radiation inactivation and sedimentation equilibrium analysis were used to determine the functional and physical size of the chicken hepatic membrane receptor that binds N-acetylglucosamine-terminated glycoproteins. Purified plasma membranes from chicken liver were irradiated with high energy electrons and assayed for 125I-agalactoorosomucoid binding. Increasing the dose of ionizing radiation resulted in a monoexponential decay in binding activity due to a progressive loss of binding sites. The molecular mass of the chicken lectin, determined in situ by target analysis, was 69,000 +/- 9,000 Da. When the same irradiated membranes were solubilized in Brij 58 and assayed, the binding protein exhibited a target size of 62,000 +/- 4,000 Da; in Triton X-100, the functional size of the receptor was 85,000 +/- 10,000 Da. Sedimentation equilibrium measurements of the purified binding protein yielded a lower limit molecular weight of 79,000 +/- 7,000. However, the solubilized lectin was detected as a heterogeneous population of oligomers with molecular weights as high as 450,000. Addition of calcium or calcium plus N-acetylglucosamine decreased the higher molecular weight species, but the lower limit molecular weights remained invariant. Similar results were determined when the chicken lectin was solubilized in Brij 58, C12E9, or 3-((3-cholamidopropyl)dimethylammonio)-1-propane-sulfonic acid (CHAPS). Results from the present study suggest that in the plasma membrane, the functional species of the chicken hepatic lectin exists as a trimer. However, in detergent solution, the purified receptor forms a heterogeneous population of irreversible oligomers that exhibit binding activity proportional to size.

  20. Functional interaction of nuclear factors EF-C, HNF-4, and RXR alpha with hepatitis B virus enhancer I.

    PubMed Central

    Garcia, A D; Ostapchuk, P; Hearing, P

    1993-01-01

    Hepatitis B virus (HBV) enhancer I contains cis-acting elements that are both sufficient and essential for liver-specific enhancer function. The EF-C binding site was previously shown to be a key element in enhancer I. EF-C binding activity is evident in hepatic and nonhepatic cells. Although the EF-C binding site is required for efficient HBV enhancer I function, the EF-C site does not possess intrinsic enhancer activity when assayed in the absence of flanking elements. We have defined a novel region in HBV enhancer I, termed the GB element, that is adjacent to and functions in conjunction with the EF-C binding site. The GB element and EF-C site confer interdependent liver-specific enhancer activity in the absence of flanking HBV enhancer sequences. The nucleotide sequence of the GB element is similar to sequences of the DNA binding sites for members of the steroid receptor superfamily. Among these proteins, we demonstrate that HNF-4, RXR (retinoid X receptor), and COUP-TF bind to the GB element in vitro. HNF-4 transactivates a promoter linked to a multimerized GB/EF-C domain via the GB element in vivo in a manner that is dependent on the integrity of the adjacent EF-C binding site. RXR alpha also transactivates promoter expression via the GB element in vivo in response to retinoic acid but in a largely EF-C-independent manner. Finally, we show that COUP-TF antagonizes the activity of the GB element in human liver cells. Images PMID:8389913

  1. Abnormal Resting-State Functional Connectivity Strength in Mild Cognitive Impairment and Its Conversion to Alzheimer's Disease

    PubMed Central

    Li, Yuxia; Wang, Xiaoni; Li, Yongqiu; Sun, Yu; Sheng, Can; Li, Hongyan; Li, Xuanyu; Yu, Yang; Chen, Guanqun; Hu, Xiaochen; Jing, Bin; Wang, Defeng; Li, Kuncheng; Jessen, Frank; Han, Ying

    2016-01-01

    Individuals diagnosed with mild cognitive impairment (MCI) are at high risk of transition to Alzheimer's disease (AD). However, little is known about functional characteristics of the conversion from MCI to AD. Resting-state functional magnetic resonance imaging was performed in 25 AD patients, 31 MCI patients, and 42 well-matched normal controls at baseline. Twenty-one of the 31 MCI patients converted to AD at approximately 24 months of follow-up. Functional connectivity strength (FCS) and seed-based functional connectivity analyses were used to assess the functional differences among the groups. Compared to controls, subjects with MCI and AD showed decreased FCS in the default-mode network and the occipital cortex. Importantly, the FCS of the left angular gyrus and middle occipital gyrus was significantly lower in MCI-converters as compared with MCI-nonconverters. Significantly decreased functional connectivity was found in MCI-converters compared to nonconverters between the left angular gyrus and bilateral inferior parietal lobules, dorsolateral prefrontal and lateral temporal cortices, and the left middle occipital gyrus and right middle occipital gyri. We demonstrated gradual but progressive functional changes during a median 2-year interval in patients converting from MCI to AD, which might serve as early indicators for the dysfunction and progression in the early stage of AD. PMID:26843991

  2. Abnormalities in intracellular calcium regulation and contractile function in myocardium from dogs with pacing-induced heart failure.

    PubMed Central

    Perreault, C L; Shannon, R P; Komamura, K; Vatner, S F; Morgan, J P

    1992-01-01

    24 d of rapid ventricular pacing induced dilated cardiomyopathy with both systolic and diastolic dysfunction in conscious, chronically instrumented dogs. We studied mechanical properties and intracellular calcium (Ca2+i) transients of trabeculae carneae isolated from 15 control dogs (n = 32) and 11 dogs with pacing-induced cardiac failure (n = 26). Muscles were stretched to maximum length at 30 degrees C and stimulated at 0.33 Hz; a subset (n = 17 control, n = 17 myopathic) was loaded with the [Ca2+]i indicator aequorin. Peak tension was depressed in the myopathic muscles, even in the presence of maximally effective (i.e., 16 mM) [Ca2+] in the perfusate. However, peak [Ca2+]i was similar (0.80 +/- 0.13 vs. 0.71 +/- 0.05 microM; [Ca2+]o = 2.5 mM), suggesting that a decrease in Cai2+ availability was not responsible for the decreased contractility. The time for decline from the peak of the Cai2+ transient was prolonged in the myopathic group, which correlated with prolongation of isometric contraction and relaxation. However, similar end-diastolic [Ca2+]i was achieved in both groups (0.29 +/- 0.05 vs. 0.31 +/- 0.02 microM), indicating that Cai2+ homeostasis can be maintained in myopathic hearts. The inotropic response of the myopathic muscles to milrinone was depressed compared with the controls. However, when cAMP production was stimulated by pretreatment with forskolin, the response of the myopathic muscles to milrinone was improved. Our findings provide direct evidence that abnormal [Ca2+]i handling is an important cause of contractile dysfunction in dogs with pacing-induced heart failure and suggest that deficient production of cAMP may be an important cause of these changes in excitation-contraction coupling. PMID:1311723

  3. Abnormalities in intracellular calcium regulation and contractile function in myocardium from dogs with pacing-induced heart failure

    NASA Technical Reports Server (NTRS)

    Perreault, C. L.; Shannon, R. P.; Komamura, K.; Vatner, S. F.; Morgan, J. P.

    1992-01-01

    24 d of rapid ventricular pacing induced dilated cardiomyopathy with both systolic and diastolic dysfunction in conscious, chronically instrumented dogs. We studied mechanical properties and intracellular calcium (Ca2+i) transients of trabeculae carneae isolated from 15 control dogs (n = 32) and 11 dogs with pacing-induced cardiac failure (n = 26). Muscles were stretched to maximum length at 30 degrees C and stimulated at 0.33 Hz; a subset (n = 17 control, n = 17 myopathic) was loaded with the [Ca2+]i indicator aequorin. Peak tension was depressed in the myopathic muscles, even in the presence of maximally effective (i.e., 16 mM) [Ca2+] in the perfusate. However, peak [Ca2+]i was similar (0.80 +/- 0.13 vs. 0.71 +/- 0.05 microM; [Ca2+]o = 2.5 mM), suggesting that a decrease in Cai2+ availability was not responsible for the decreased contractility. The time for decline from the peak of the Cai2+ transient was prolonged in the myopathic group, which correlated with prolongation of isometric contraction and relaxation. However, similar end-diastolic [Ca2+]i was achieved in both groups (0.29 +/- 0.05 vs. 0.31 +/- 0.02 microM), indicating that Cai2+ homeostasis can be maintained in myopathic hearts. The inotropic response of the myopathic muscles to milrinone was depressed compared with the controls. However, when cAMP production was stimulated by pretreatment with forskolin, the response of the myopathic muscles to milrinone was improved. Our findings provide direct evidence that abnormal [Ca2+]i handling is an important cause of contractile dysfunction in dogs with pacing-induced heart failure and suggest that deficient production of cAMP may be an important cause of these changes in excitation-contraction coupling.

  4. Hepatitis E Virus Superinfection and Clinical Progression in Hepatitis B Patients

    PubMed Central

    Hoan, Nghiem Xuan; Tong, Hoang Van; Hecht, Nicole; Sy, Bui Tien; Marcinek, Patrick; Meyer, Christian G.; Song, Le Huu; Toan, Nguyen Linh; Kurreck, Jens; Kremsner, Peter G.; Bock, C-Thomas; Velavan, Thirumalaisamy P.

    2015-01-01

    Hepatitis E virus (HEV) infection may cause acute hepatitis and lead to hepatic failure in developing and developed countries. We studied HEV seroprevalences in patients with hepatitis B virus (HBV) infection to understand the consequences of HEV superinfection in a Vietnamese population. This cross-sectional study was conducted from 2012 to 2013 and included 1318 Vietnamese patients with HBV-related liver diseases and 340 healthy controls. The case group included patients with acute (n = 26) and chronic hepatitis B (n = 744), liver cirrhosis (n = 160), hepatocellular carcinoma (n = 166) and patients with both liver cirrhosis and hepatocellular carcinoma (n = 222). Anti-HEV IgG and IgM antibodies were assessed in patients and controls by ELISA. HEV-RNA was identified by PCR assays and sequencing. Seroprevalences of anti-HEV IgG among hepatitis B patients and controls were 45% and 31%, respectively (adjusted P = 0.034). Anti-HEV IgM seroprevalences were 11.6% and 4.7% in patients and controls, respectively (adjusted P = 0.005). Seroprevalences were higher among the elder individuals. When stratifying for patient groups, those with liver cirrhosis had the highest anti-HEV IgG (52%) and anti-HEV IgM (19%) seroprevalences. Hepatitis B patients with current HEV infection had abnormal liver function tests compared to patients with past or without HEV infection. One HEV isolate was retrieved from a patient with both liver cirrhosis and hepatocellular carcinoma and identified as HEV genotype 3. This study indicates high prevalences of HEV infection in Vietnamese HBV patients and among healthy individuals and shows that HEV superinfection may influence the outcome and progression of HBV-related liver disease. PMID:26844288

  5. Structures of hepatitis C virus nonstructural proteins required for replicase assembly and function

    PubMed Central

    Gu, Meigang; Rice, Charles M.

    2013-01-01

    Approximately 3% of the world population is infected with hepatitis C virus (HCV), causing a serious public health burden. Like other positive-strand RNA viruses, HCV assembles replicase complexes in association with cellular membranes and produces progeny RNA genomes through negative-strand intermediates. The viral proteins required for RNA replication are nonstructural (NS) proteins NS3 to NS5B. Owing to many obstacles and limitations in structural characterization of proteins and complexes with multiple transmembrane segments, attempts to understand the assembly and action of the HCV replicase complex have been challenging. Nevertheless, great progress has been made in obtaining structural information for several replicase components, providing insights into some aspects of the viral genome replication machinery. PMID:23601958

  6. Alcohol-induced defects in hepatic transcytosis may be explained by impaired dynein function

    PubMed Central

    Groebner, Jennifer L.; Fernandez, David J.; Tuma, Dean J.; Tuma, Pamela L.

    2016-01-01

    Alcoholic liver disease has been clinically well described, but the molecular mechanisms leading to hepatotoxicity have not been fully elucidated. Previously, we determined that microtubules are hyperacetylated and more stable in ethanol-treated WIF-B cells, VL-17A cells, liver slices, and in livers from ethanol-fed rats. From our recent studies, we believe that these modifications can explain alcohol-induced defects in microtubule motor-dependent protein trafficking including nuclear translocation of a subset of transcription factors. Since cytoplasmic dynein/dynactin is known to mediate both microtubule-dependent translocation and basolateral to apical/canalicular transcytosis, we predicted that transcytosis is impaired in ethanol-treated hepatic cells. We monitored transcytosis of three classes of newly synthesized canalicular proteins in polarized, hepatic WIF-B cells, an emerging model system for the study of liver disease. As predicted, canalicular delivery of all proteins tested was impaired in ethanol-treated cells. Unlike in control cells, transcytosing proteins were observed in discrete sub-canalicular puncta en route to the canalicular surface that aligned along acetylated microtubules. We further determined that the stalled transcytosing proteins colocalized with dynein/dynactin in treated cells. No changes in vesicle association were observed for either dynein or dynactin in ethanol-treated cells, but significantly enhanced dynein binding to micro-tubules was observed. From these results, we propose that enhanced dynein binding to microtubules in ethanol-treated cells leads to decreased motor processivity resulting in vesicle stalling and in impaired canalicular delivery. Our studies also importantly indicate that modulating cellular acetylation levels with clinically tolerated deacetylase agonists may be a novel therapeutic strategy for treating alcoholic liver disease. PMID:25148871

  7. Hepatitis B Virus Impairs TLR9 Expression and Function in Plasmacytoid Dendritic Cells

    PubMed Central

    Lucifora, Julie; Norder, Helene; Protzer, Ulrike; Hainaut, Pierre; Zoulim, Fabien; Tommasino, Massimo; Trépo, Christian; Hasan, Uzma; Chemin, Isabelle

    2011-01-01

    Plasmacytoid dendritic cells (pDCs) play a key role in detecting pathogens by producing large amounts of type I interferon (IFN) by sensing the presence of viral infections through the Toll-Like Receptor (TLR) pathway. TLR9 is a sensor of viral and bacterial DNA motifs and activates the IRF7 transcription factor which leads to type I IFN secretion by pDCs. However, during chronic hepatitis B virus (HBV) infection, pDCs display an impaired ability to secrete IFN-α following ex vivo stimulation with TLR9 ligands. Here we highlight several strategies used by HBV to block IFN-α production through a specific impairment of the TLR9 signaling. Our results show that HBV particle internalisation could inhibit TLR9- but not TLR7-mediated secretion of IFN-α by pDCs. We observed that HBV down-regulated TLR9 transcriptional activity in pDCs and B cells in which TLR9 mRNA and protein levels were reduced. HBV can interfere with TLR9 activity by blocking the MyD88-IRAK4 axis and Sendai virus targeting IRF7 to block IFN-α production. Neutralising CpG motif sequences were identified within HBV DNA genome of genotypes A to H which displayed a suppressive effect on TLR9-immune activation. Moreover, TLR9 mRNA and protein were downregulated in PBMCs from patients with HBV-associated chronic hepatitis and hepatocellular carcinoma. Thus HBV has developed several escape mechanisms to avoid TLR9 activation in both pDCs and B lymphocytes, which may in turn contribute to the establishment and/or persistence of chronic infection. PMID:22046272

  8. Alcohol-induced defects in hepatic transcytosis may be explained by impaired dynein function.

    PubMed

    Groebner, Jennifer L; Fernandez, David J; Tuma, Dean J; Tuma, Pamela L

    2014-12-01

    Alcoholic liver disease has been clinically well described, but the molecular mechanisms leading to hepatotoxicity have not been fully elucidated. Previously, we determined that microtubules are hyperacetylated and more stable in ethanol-treated WIF-B cells, VL-17A cells, liver slices, and in livers from ethanol-fed rats. From our recent studies, we believe that these modifications can explain alcohol-induced defects in microtubule motor-dependent protein trafficking including nuclear translocation of a subset of transcription factors. Since cytoplasmic dynein/dynactin is known to mediate both microtubule-dependent translocation and basolateral to apical/canalicular transcytosis, we predicted that transcytosis is impaired in ethanol-treated hepatic cells. We monitored transcytosis of three classes of newly synthesized canalicular proteins in polarized, hepatic WIF-B cells, an emerging model system for the study of liver disease. As predicted, canalicular delivery of all proteins tested was impaired in ethanol-treated cells. Unlike in control cells, transcytosing proteins were observed in discrete sub-canalicular puncta en route to the canalicular surface that aligned along acetylated microtubules. We further determined that the stalled transcytosing proteins colocalized with dynein/dynactin in treated cells. No changes in vesicle association were observed for either dynein or dynactin in ethanol-treated cells, but significantly enhanced dynein binding to microtubules was observed. From these results, we propose that enhanced dynein binding to microtubules in ethanol-treated cells leads to decreased motor processivity resulting in vesicle stalling and in impaired canalicular delivery. Our studies also importantly indicate that modulating cellular acetylation levels with clinically tolerated deacetylase agonists may be a novel therapeutic strategy for treating alcoholic liver disease. PMID:25148871

  9. Large hepatic adenoma in a 21-year-old male

    PubMed Central

    Martinez-Mier, Gustavo; Enriquez De los Santos, Horacio; Grube-Pagola, Peter

    2013-01-01

    Hepatic adenoma is an uncommon benign lesion of the liver that occurs more frequently in women in their third and fourth decades. The female/male ratio is up to 11:1. Hepatic adenomas may be single or multiple occasionally reaching sizes up to 20 cm. They are non-cancerous lesions, however they can become malignant. We present a 21-year-old male patient with no medical history who presented with abdominal pain, a palpable abdominal mass, abnormal liver function tests and a 14 kg weight loss in a 2-year period. A CT scan was performed with a 17 cm tumour compressing intrahepatic bile ducts. The patient underwent a right hepatectomy with no complications. Histopathological analysis of the tumour revealed a hepatic adenoma with central necrosis. The patient is asymptomatic at 1-year follow-up. PMID:24306431

  10. The glucocorticoid receptor controls hepatic dyslipidemia through Hes1.

    PubMed

    Lemke, Ulrike; Krones-Herzig, Anja; Berriel Diaz, Mauricio; Narvekar, Prachiti; Ziegler, Anja; Vegiopoulos, Alexandros; Cato, Andrew C B; Bohl, Sebastian; Klingmüller, Ursula; Screaton, Robert A; Müller-Decker, Karin; Kersten, Sander; Herzig, Stephan

    2008-09-01

    Aberrant accumulation of lipids in the liver ("fatty liver" or hepatic steatosis) represents a hallmark of the metabolic syndrome and is tightly associated with obesity, type II diabetes, starvation, or glucocorticoid (GC) therapy. While fatty liver has been connected with numerous abnormalities of liver function, the molecular mechanisms of fatty liver development remain largely enigmatic. Here we show that liver-specific disruption of glucocorticoid receptor (GR) action improves the steatotic phenotype in fatty liver mouse models and leads to the induction of transcriptional repressor hairy enhancer of split 1 (Hes1) gene expression. The GR directly interferes with Hes1 promoter activity, triggering the recruitment of histone deacetylase (HDAC) activities to the Hes1 gene. Genetic restoration of hepatic Hes1 levels in steatotic animals normalizes hepatic triglyceride (TG) levels. As glucocorticoid action is increased during starvation, myotonic dystrophy, and Cushing's syndrome, the inhibition of Hes1 through the GR might explain the fatty liver phenotype in these subjects. PMID:18762022

  11. Abnormal Functional Connectivity of the Amygdala-Based Network in Resting-State fMRI in Adolescents with Generalized Anxiety Disorder

    PubMed Central

    Liu, Wen-jing; Yin, Da-zhi; Cheng, Wen-hong; Fan, Ming-xia; You, Mei-na; Men, Wei-wei; Zang, Li-li; Shi, Dian-hong; Zhang, Fang

    2015-01-01

    Background We aimed to investigate the disruptions of functional connectivity of amygdala-based networks in adolescents with untreated generalized anxiety disorder (GAD). Material/Methods A total of 26 adolescents with first-episode GAD and 20 normal age-matched volunteers underwent resting-state and T1 functional magnetic resonance imaging (fMRI). We analyzed the correlation of fMRI signal fluctuation between the amygdala and other brain regions. The variation of amygdala-based functional connectivity and its correlation with anxiety severity were investigated. Results Decreased functional connectivity was found between the left amygdala and left dorsolateral prefrontal cortex. An increased right amygdala functional connectivity with right posterior and anterior lobes of the cerebellum, insula, superior temporal gyrus, putamen, and right amygdala were found in our study. Negative correlations between GAD scores and functional connectivity of the right amygdala with the cerebellum were also observed in the GAD adolescents. Conclusions Adolescents with GAD have abnormalities in brain regions associated with the emotional processing pathways. PMID:25673008

  12. Genome-wide differences in hepatitis C- vs alcoholism-associated hepatocellular carcinoma

    PubMed Central

    Derambure, Céline; Coulouarn, Cédric; Caillot, Frédérique; Daveau, Romain; Hiron, Martine; Scotte, Michel; François, Arnaud; Duclos, Celia; Goria, Odile; Gueudin, Marie; Cavard, Catherine; Terris, Benoit; Daveau, Maryvonne; Salier, Jean-Philippe

    2008-01-01

    AIM: To look at a comprehensive picture of etiology-dependent gene abnormalities in hepatocellular carcinoma in Western Europe. METHODS: With a liver-oriented microarray, transcript levels were compared in nodules and cirrhosis from a training set of patients with hepatocellular carcinoma (alcoholism, 12; hepatitis C, 10) and 5 controls. Loose or tight selection of informative transcripts with an abnormal abundance was statistically valid and the tightly selected transcripts were next quantified by qRTPCR in the nodules from our training set (12 + 10) and a test set (6 + 7). RESULTS: A selection of 475 transcripts pointed to significant gene over-representation on chromosome 8 (alcoholism) or -2 (hepatitis C) and ontology indicated a predominant inflammatory response (alcoholism) or changes in cell cycle regulation, transcription factors and interferon responsiveness (hepatitis C). A stringent selection of 23 transcripts whose differences between etiologies were significant in nodules but not in cirrhotic tissue indicated that the above dysregulations take place in tumor but not in the surrounding cirrhosis. These 23 transcripts separated our test set according to etiologies. The inflammation-associated transcripts pointed to limited alterations of free iron metabolism in alcoholic vs hepatitis C tumors. CONCLUSION: Etiology-specific abnormalities (chromosome preference; differences in transcriptomes and related functions) have been identified in hepatocellular carcinoma driven by alcoholism or hepatitis C. This may open novel avenues for differential therapies in this disease. PMID:18350606

  13. Protective Effects of Higher Cognitive Reserve for Neuropsychological and Daily Functioning Among Individuals Infected with Hepatitis C

    PubMed Central

    Sakamoto, Maiko; Woods, Steven Paul; Kolessar, Michael; Kriz, Daniel; Anderson, J. Renee; Olavarria, Hannah; Sasaki, Anna W.; Chang, Michael; Flora, Kenneth D.; Loftis, Jennifer M.; Huckans, Marilyn

    2013-01-01

    Higher levels of cognitive reserve (CR) can be protective against the neuropsychological manifestation of neural injury across a variety of clinical disorders. However, the role of CR in the expression of neurocognitive deficits among persons infected with the hepatitis C virus (HCV) is not well understood. Thirty-nine HCV-infected participants were classified as having either high (n=19) or low (n=20) CR based on educational attainment, oral word reading, and IQ scores. A sample of 40 demographically comparable healthy adults (HA) was also included. All participants completed the Neuropsychological Assessment Battery (NAB), Delis-Kaplan Executive Function System (D-KEFS), and Behavioral Rating Inventory of Executive Function, Adult Version (BRIEF-A). Linear regression analyses, controlling for gender, depression and lifetime substance use disorders, found significant effects of HCV/CR group on verbal fluency, executive functions, and daily functioning T-scores, but not in learning or the BRIEF-A. Pairwise comparisons revealed that the HCV group with low CR performed significantly below the HCV high CR and HA cohorts, who did not differ from one another. Findings indicate that higher levels of CR may be a protective factor in the neurocognitive and real-world manifestation of neural injury commonly associated with HCV infection. PMID:24018902

  14. Functional consequences of prenatal methylmercury exposure: effects on renal and hepatic responses to trophic stimuli and on renal excretory mechanisms

    SciTech Connect

    Slotkin, T.A.; Kavlock, R.J.; Cowdery, T.; Orband, L.; Bartolome, M.

    1986-01-01

    The effects of prenatal exposure to methylmercury on the functional development of renal and hepatic response systems was examined in the developing rat. Methylmercury produced an elevation of basal activity of renal ornithine decarboxylase (ODC, an enzyme involved in regulation of cellular maturation) and an eventual relative hypertrophy; liver ODC was reduced and hypertrophy was not evident. In contrast, the reactivity of liver ODC to trophic stimulants (vasopressin, isoproterenol) was markedly enhanced by prenatal methylmercury exposure, whereas renal ODC responses were much less affected (vasopressin) or actually reduced (isoproterenol). Targeted actions of methylmercury on renal excretory function were also prominent, with increased fractional excretions urea and electrolytes and an eventual reduction in glomerular filtration as assessed by creatinine clearance. These studies show that doses of methylmercury ordinarily associated with selective actions on development of neurobehavioral patterns also influence the functional ontogeny of other organ systems; furthermore, the fact that the target tissues are different for prenatal vs postnatal methylmercury exposure, indicates that the functional teratology of methylmercury exhibits critical periods of sensitivity.

  15. IL-10 Gene Polymorphisms Are Associated with Post-Bronchiolitis Lung Function Abnormalities at Six Years of Age

    PubMed Central

    Lauhkonen, Eero; Koponen, Petri; Teräsjärvi, Johanna; Gröndahl-Yli-Hannuksela, Kirsi; Vuononvirta, Juho; Nuolivirta, Kirsi; Toikka, Jyri O.; Helminen, Merja; He, Qiushui; Korppi, Matti

    2015-01-01

    Aim Interleukin-10 (IL-10) has been associated with wheezing and asthma in children and the genetic variation of the IL-10 cytokine production may be linked to post-bronchiolitis lung function. We used impulse oscillometry (IOS) to evaluate the associations of IL10 polymorphisms with lung function at a median age of 6.3 years in children hospitalised for bronchiolitis before six months of age. Methods We performed baseline and post-exercise IOS on 103 former bronchiolitis patients. Data on single nucleotide polymorphisms (SNP) of IL10 rs1800896 (–1082G/A), rs1800871 (–819C/T), rs1800872 (–592C/A) were available for 99 children and of IL10 rs1800890 (–3575T/A) for 98 children. Results IL10 rs1800896, rs1800871 and rs1800872 combined genotype AA+CT+CA and carriage of haplotype ATA, respectively, were associated with higher resistance and lower reactance in baseline IOS in adjusted analyses. At IL10 rs1800890, the A/A-genotype and carriers of A-allele were associated with lower reactance in baseline IOS. There were no significant associations between the studied SNPs and airway hyper-reactivity to exercise. Conclusion Low-IL-10-producing polymorphisms in the IL-10 encoding gene were associated with obstructive lung function parameters, suggesting an important role for IL-10 in development of lung function deficit in early bronchiolitis patients. PMID:26473365

  16. Longxuetongluo Capsule Improves Erythrocyte Function against Lipid Peroxidation and Abnormal Hemorheological Parameters in High Fat Diet-Induced ApoE−/− Mice

    PubMed Central

    Zheng, Jiao; Liu, Binglin; Lun, Qixing; Yao, Weijuan; Zhao, Yunfang; Xiao, Wei; Huang, Wenzhe; Wang, Yonghua; Li, Jun; Tu, Pengfei

    2016-01-01

    Chinese dragon's blood, the red resin of Dracaena cochinchinensis, one of the renowned traditional medicines, has been used to facilitate blood circulation and disperse blood stasis for thousands of years. Phenolic compounds are considered to be responsible for its main biological activities. In this study, total phenolic compounds of Chinese dragon's blood were made into capsule (Longxuetongluo Capsule, LTC) and their effects on the abnormal hemorheological properties were examined by high fat diet (HFD) induced ApoE−/− mice. Compared to the model group, LTC recovered the abnormal hemorheological parameters in HFD-induced ApoE−/− mice by reducing whole blood viscosity (WBV) at high rate and improving erythrocyte function. In conclusion, LTC could ameliorate erythrocyte deformability and osmotic fragility through the reduction of lipid peroxidation on plasma and erythrocyte membranes in HFD-induced ApoE−/− mice, which supported the traditional uses of Chinese dragon's blood as an effective agent for improving blood microcirculation in hypercholesterolemia. PMID:26649134

  17. Disorder-specific functional abnormalities during temporal discounting in youth with Attention Deficit Hyperactivity Disorder (ADHD), Autism and comorbid ADHD and Autism.

    PubMed

    Chantiluke, Kaylita; Christakou, Anastasia; Murphy, Clodagh M; Giampietro, Vincent; Daly, Eileen M; Ecker, Christina; Brammer, Michael; Murphy, Declan G; Rubia, Katya

    2014-08-30

    Attention Deficit Hyperactivity Disorder (ADHD) and Autism Spectrum Disorder (ASD) are often comorbid and share cognitive abnormalities in temporal foresight. A key question is whether shared cognitive phenotypes are based on common or different underlying pathophysiologies and whether comorbid patients have additive neurofunctional deficits, resemble one of the disorders or have a different pathophysiology. We compared age- and IQ-matched boys with non-comorbid ADHD (18), non-comorbid ASD (15), comorbid ADHD and ASD (13) and healthy controls (18) using functional magnetic resonance imaging (fMRI) during a temporal discounting task. Only the ASD and the comorbid groups discounted delayed rewards more steeply. The fMRI data showed both shared and disorder-specific abnormalities in the three groups relative to controls in their brain-behaviour associations. The comorbid group showed both unique and more severe brain-discounting associations than controls and the non-comorbid patient groups in temporal discounting areas of ventromedial and lateral prefrontal cortex, ventral striatum and anterior cingulate, suggesting that comorbidity is neither an endophenocopy of the two pure disorders nor an additive pathology. PMID:24929553

  18. High incidence of functional ion-channel abnormalities in a consecutive Long QT cohort with novel missense genetic variants of unknown significance

    PubMed Central

    Steffensen, Annette Buur; Refaat, Marwan M.; David, Jens-Peter; Mujezinovic, Amer; Calloe, Kirstine; Wojciak, Julianne; Nussbaum, Robert L.; Scheinman, Melvin M.; Schmitt, Nicole

    2015-01-01

    The Long QT syndrome (LQTS) is a disorder characterized by a prolongation of the QT interval and a propensity to ventricular tachyarrhythmias, which may lead to syncope, cardiac arrest, or sudden death. Our objective was to (1) determine the incidence of variants with unknown significance (VUS) in a cohort of consecutive LQTS patients and (2) to determine the percentage of those with novel missense VUS that have demonstrable functional channel abnormalities from a single referral center. We performed genetic screening of candidate genes in 39 probands with a diagnosis of LQTS to identify mutations and variants. Seven variants of unknown significance were identified, six were missense variants and one was a splice site variant. We investigated the six novel missense VUS in five patients; three missense variants in KCNQ1 (L236R, W379R, Y522S) and three missense variants in KCNH2 (R35W, S620G, V491I). We employed two-electrode voltage-clamp experiments in Xenopus laevis oocytes and confocal imaging to characterize the novel missense mutations functionally. We revealed electrophysiological and trafficking loss-of-function phenotypes. This report emphasizes the frequency of adverse channel function in patients with LQTS and the importance of heterologous studies to define channel function. PMID:26066609

  19. Hepatitis virus panel

    MedlinePlus

    Hepatitis A antibody test; Hepatitis B antibody test; Hepatitis C antibody test; Hepatitis D antibody test ... or past infection, or immunity to hepatitis A Hepatitis B tests: Hepatitis B surface antigen (HBsAg), you have ...

  20. Hepatitis C and HIV

    MedlinePlus

    ... Problems : Hepatitis C Subscribe Translate Text Size Print Hepatitis C What is Hepatitis? Hepatitis means inflammation of the liver. This condition ... our related pages, Hepatitis A and Hepatitis B . Hepatitis C and HIV About 25% of people living ...

  1. Hepatitis B and HIV

    MedlinePlus

    ... Problems : Hepatitis B Subscribe Translate Text Size Print Hepatitis B What is Hepatitis? Hepatitis means inflammation of the liver. This condition ... our related pages, Hepatitis A and Hepatitis C . Hepatitis B and HIV About 10% of people living ...

  2. Quality of Life and Social Functioning during Treatment of Recent Hepatitis C Infection: A Multi-Centre Prospective Cohort

    PubMed Central

    Doyle, Joseph S.; Grebely, Jason; Spelman, Tim; Alavi, Maryam; Matthews, Gail V.; Thompson, Alexander J.; Dore, Gregory J.; Hellard, Margaret E.

    2016-01-01

    Aim Despite effective treatment for recent hepatitis C (HCV) infection, side-effects and adherence concerns limit its use among people who inject drugs (PWID). This study evaluated health-related quality of life (HRQoL) and social functioning following infection and during recent HCV treatment. Methods The Australian Trial of Acute Hepatitis C studied the natural history and treatment of recent HCV infection. HRQoL (SF-12v2) and social functioning (Opiate Treatment Index score) were measured over 48 weeks and their impact on treatment uptake, adherence and virological response were assessed. Results Of 163 participants, 111 received treatment (HCV n = 74, SVR 55%; HCV/HIV n = 37, SVR 74%). 116 (71%) were male, 124 (76%) ever injected drugs, with 55 (36%) injecting recently and 28/55 (51%) reported needle/syringe sharing. At baseline, median physical and mental HRQoL was 54 units (IQR 46–58) and 46 (35–54) (reference median: 50), respectively, and median social functioning score was 11 units (7–17). Higher social function (<10 vs ≥15) predicted increased treatment uptake (AOR 3.43, 95%CI 1.01–11.6, p = 0.048) and higher SVR (AOR 5.11, 95%CI 1.30–20.15, p = 0.020). After adjustment, treated participants had lower physical (-4.90 units, 95%CI -6.33 to -3.48, p<0.001) and mental HRQoL (-3.7 units, 95%CI -5.55 to -1.86, p<0.001) at on-treatment visits, but HRQoL returned to baseline levels during follow-up. Conclusions Social functioning can predict recent HCV treatment uptake and SVR. Efforts to maximise social stability may improve treatment response. Pegylated-interferon treatment is associated with reduced HRQoL on-treatment in an already vulnerable population of PWID that would be better served by interferon-free regimens particularly in treated target at PWID to prevent transmission. Trial Registration ClinicalTrials.gov NCT00192569 PMID:27355323

  3. Hepatitis Testing

    MedlinePlus

    ... caused by viruses. They include hepatitis A, hepatitis B, and hepatitis C. To diagnose hepatitis, your health care provider will ask you about your medical history and symptoms, do a physical exam, and order blood tests. There are blood tests for each type of ...

  4. Is the mind a cauliflower or an onion? British insights into cognitive organization from the study of abnormal function.

    PubMed

    McCarthy, R A

    2001-02-01

    Clinical and normal psychology have had a long tradition of close interaction in British psychology. The roots of this interplay may predate the development of the British Psychological Society, but the Society has encouraged and supported this line of research since its inception. One fundamental British insight has been to consider the evidence from pathology as a potential constraint on theories of normal function. In turn, theories of normal function have been used to understand and illuminate cognitive pathology. This review discusses some of the areas in which clinical contributions to cognitive theory have been most substantial. As with other contributions to this volume, attempts are also made to read the runes and anticipate future developments. PMID:11256762

  5. Is the mind a cauliflower or an onion? British insights into cognitive organization from the study of abnormal function.

    PubMed

    McCarthy, Rosaleen A.

    2001-02-01

    Clinical and normal psychology have had a long tradition of close interaction in British psychology. The roots of this interplay may predate the development of the British Psychological Society, but the Society has encouraged and supported this line of research since its inception. One fundamental British insight has been to consider the evidence from pathology as a potential constraint on theories of normal function. In turn, theories of normal function have been used to understand and illuminate cognitive pathology. This review discusses some of the areas in which clinical contributions to cognitive theory have been most substantial. As with other contributions to this volume, attempts are also made to read the runes and anticipate future developments. PMID:11802869

  6. Detecting Visual Function Abnormality with a Contrast-Dependent Visual Test in Patients with Type 2 Diabetes.

    PubMed

    Tsai, Li-Ting; Liao, Kuo-Meng; Jang, Yuh; Hu, Fu-Chang; Wu, Wei-Chi

    2016-01-01

    In addition to diabetic retinopathy, diabetes also causes early retinal neurodegeneration and other eye problems, which cause various types of visual deficits. This study used a computer-based visual test (Macular Multi-Function Assessment (MMFA)) to assess contrast-dependent macular visual function in patients with type 2 diabetes to collect more visual information than possible with only the visual acuity test. Because the MMFA is a newly developed test, this study first compared the agreement and discriminative ability of the MMFA and the Early Treatment Diabetic Retinopathy Study (ETDRS) contrast acuity charts. Then symbol discrimination performances of diabetic patients and controls were evaluated at 4 contrast levels using the MMFA. Seventy-seven patients and 45 controls participated. The agreement between MMFA and ETDRS scores was examined by fitting three-level linear mixed-effect models to estimate the intraclass correlation coefficients (ICCs). The estimated areas under the receiver operating characteristic (ROC) curve were used to compare the discriminative ability of diseased versus non-diseased participants between the two tests. The MMFA scores of patients and controls were compared with multiple linear regression analysis after adjusting the effects of age, sex, hypertension and cataract. Results showed that the scores of the MMFA and ETDRS tests displayed high levels of agreement and acceptable and similar discriminative ability. The MMFA performance was correlated with the severity of diabetic retinopathy. Most of the MMFA scores differed significantly between the diabetic patients and controls. In the low contrast condition, the MMFA scores were significantly lower for 006Eon-DR patients than for controls. The potential utility of the MMFA as an easy screening tool for contrast-dependent visual function and for detecting early functional visual change in patients with type 2 diabetes is discussed. PMID:27611680

  7. Abnormal functional connectivity density in first-episode, drug-naive adult patients with major depressive disorder.

    PubMed

    Zou, Ke; Gao, Qing; Long, Zhiliang; Xu, Fei; Sun, Xiao; Chen, Huafu; Sun, Xueli

    2016-04-01

    Previous studies have found evidence of brain functional connectivity (FC) changes with pre-selected region-of-interest (ROI) method in major depressive disorder (MDD). However, these studies could not completely exclude personal inequality when drawing ROIs manually and did not measure the total number of FC for each voxel. Here, we firstly applied functional connectivity density (FCD) mapping, a voxel-based analysis to locate the hubs with amount changes of FC between 22 first-episode, drug-naive adult MDD patients and 22 healthy control (HC) subjects. Both short-range (local) FCD and long-range (distal) FCD were measured. The relationships of FCD changes with Hamilton Depression Rating Scale (HAMD) scores and illness duration were also explored. Compared with the HC group, MDD patients showed significantly decreased short-range FCD in the left superior temporal gyrus (STG), the right orbital frontal cortex (OFC) and bilateral precuneus, while significantly decreased long-range FCD was found in bilateral middle occipital gyrus (MOG), superior occipital gyrus (SOG) and right calcarine. These results firstly demonstrated both local and distal alterations of connection amount at voxel level, and highlighted that the OFC, the precuneus, the STG and the visual cortex were important brain network hubs for first-episode, drug-naive adult MDD patients. Our findings were complementary for previous structural and functional studies in MDD patients, and provided new evidence of the dysfunction of connection hubs in the pathophysiology of MDD at voxel level. PMID:26826535

  8. Improvement of white matter and functional connectivity abnormalities by repetitive transcranial magnetic stimulation in crossed aphasia in dextral

    PubMed Central

    Lu, Haitao; Wu, Haiyan; Cheng, Hewei; Wei, Dongjie; Wang, Xiaoyan; Fan, Yong; Zhang, Hao; Zhang, Tong

    2014-01-01

    As a special aphasia, the occurrence of crossed aphasia in dextral (CAD) is unusual. This study aims to improve the language ability by applying 1 Hz repetitive transcranial magnetic stimulation (rTMS). We studied multiple modality imaging of structural connectivity (diffusion tensor imaging), functional connectivity (resting fMRI), PET, and neurolinguistic analysis on a patient with CAD. Furthermore, we applied rTMS of 1 Hz for 40 times and observed the language function improvement. The results indicated that a significantly reduced structural and function connectivity was found in DTI and fMRI data compared with the control. The PET imaging showed hypo-metabolism in right hemisphere and left cerebellum. In conclusion, one of the mechanisms of CAD is that right hemisphere is the language dominance. Stimulating left Wernicke area could improve auditory comprehension, stimulating left Broca’s area could enhance expression, and the results outlasted 6 months by 1 Hz rTMS balancing the excitability inter-hemisphere in CAD. PMID:25419415

  9. In vitro differentiation of unrestricted somatic stem cells into functional hepatic-like cells displaying a hepatocyte-like glucose metabolism.

    PubMed

    Waclawczyk, Simon; Buchheiser, Anja; Flögel, Ulrich; Radke, Teja F; Kögler, Gesine

    2010-11-01

    The hepatic-like phenotype resulting from in vitro differentiation of unrestricted somatic stem cells (USSC) derived from human umbilical cord blood (CB) was analyzed with regard to functional and metabolic aspects. USSC can be differentiated into cells of all three germ layers in vitro and in vivo and, although they share many features with mesenchymal stroma cells (MSC), can be distinguished from these by their expression of DLK1 as well as a restricted adipogenic differentiation potential. For the differentiation procedure described herein, a novel three-stage differentiation protocol resembling embryonic developmental processes of hepatic endoderm was applied. Hepatic pre-induction was performed by activinA and FGF4 resulting in enhanced SOX17 and FOXA2 expression. Further differentiation was achieved sequentially by retinoic acid, FGF4, HGF, EGF, and OSM resulting in a hepatic endodermal identity, characterized by the expression of AFP and HNF1alpha. Thereafter, expression of G6PC, ARG1, FBP1, and HNF4alpha was observed, thus indicating progressive differentiation. Functional studies concerning albumin secretion, urea formation, and cytochrome-p450-3A4 (CYP3A4) enzyme activity confirmed the hepatic-like phenotype. In order to characterize the differentiated cells at a metabolic level, USSC were incubated with [1-(13)C]glucose. By tracing the fate of the molecule's label via isotopomer analysis using (13)C NMR spectroscopy, formation of both glycogen and some gluconeogenetic activity could be observed providing evidence of a hepatocyte-like glucose metabolism in differentiated USSC. In conclusion, the results of the present study indicate that USSC represent a stem cell source with a substantial hepatic differentiation capacity which hold the potential for clinical applications. PMID:20458755

  10. Polymorphisms in MDA-5 link protein function to clearance of hepatitis C virus

    PubMed Central

    Hoffmann, Franziska; Schmidt, Andreas; Chevillotte, Meike Dittmann; Wisskirchen, Christian; Hellmuth, Johannes C.; Willms, Simone; Gilmore, Rachel H.; Glas, Jürgen; Folwaczny, Matthias; Müller, Tobias; Berg, Thomas; Spengler, Ulrich; Fitzmaurice, Karen; Kelleher, Dermot; Reisch, Nicole; Rice, Charles M.; Endres, Stefan; Rothenfusser, Simon

    2015-01-01

    Among patients newly infected with hepatitis C virus (HCV), only 20–30 % clear the infection spontaneously. In the remaining 70 %, the infection persists causing chronic liver inflammation and disease. It is well established that polymorphisms in host genes, especially in components of the innate immune response, contribute to the phenomenon of spontaneous HCV clearance. RIG-I-like helicases such as MDA-5 are cytoplasmic sensors of viral RNA that are critical for triggering innate immune responses after infection with RNA viruses. We analysed 14 non-synonymous single-nucleotide polymorphisms in RIG-I-like helicase-pathway-genes comparing European patients that spontaneously cleared HCV (n = 285) or had persistent infection (n = 509). We find that polymorphic haplotypes in the MDA-5 gene IFIH1 encoding histidine at position 843 and threonine at position 946 strongly correlate with the resolution of HCV infection (OR: 16.23 (95 % CI: 3.67 – 71.87); p = 1.1 × 10−6). Overexpression of MDA-5 genetic variants in HEK 293 cells and in a tissue culture model of HCV infection revealed that the histidine 843/threonine 946 variant leads to increased baseline and ligand-induced expression of interferon-induced genes and confers an increased ability to suppress HCV replication. Conclusion These data suggest that MDA-5 plays a significant role in the defense against HCV and that polymorphisms in MDA-5 can influence the outcome of HCV infection. PMID:25130193

  11. Functional incorporation of green fluorescent protein into hepatitis B virus envelope particles

    SciTech Connect

    Lambert, Carsten; Thome, Nicole; Kluck, Christoph J.; Prange, Reinhild . E-mail: prange@mail.uni-mainz.de

    2004-12-05

    The envelope of hepatitis B virus (HBV), containing the L, M, and S proteins, is essential for virus entry and maturation. For direct visualization of HBV, we determined whether envelope assembly could accommodate the green fluorescent protein (GFP). While the C-terminal addition of GFP to S trans-dominant negatively inhibited empty envelope particle secretion, the N-terminal GFP fusion to S (GFP.S) was co-integrated into the envelope, giving rise to fluorescent particles. Microscopy and topogenesis analyses demonstrated that the proper intracellular distribution and folding of GFP.S, required for particle export were rescued by interprotein interactions with wild-type S. Thereby, a dual location of GFP, inside and outside the envelope, was observed. GFP.S was also efficiently packaged into the viral envelope, and these GFP-tagged virions retained the capacity for attachment to HBV receptor-positive cells in vitro. Together, GFP-tagged virions should be suitable to monitor HBV uptake and egress in live hepatocytes.

  12. Evaluation of left atrial mechanical function and atrial conduction abnormalities in Maras powder (smokeless tobacco) users and smokers

    PubMed Central

    Akcay, Ahmet; Naci Aydin, M; Acar, Gurkan; Akgungor, Mehmet; Cabioglu, Eren; Ardic, İdris; Mese, Bulent; Bozoglan, Orhan; Çetin, Mustafa; Çakıcı, Musa

    2015-01-01

    Summary Objective In Turkey, a type of smokeless tobacco called Maras powder (MP) is widely used in the south-eastern region. Smokeless tobacco is found in preparations for chewing and for absorption by the nasal and oral mucosae. The purpose of this study was to investigate whether MP damages intra- and inter-atrial conduction delay and left atrial (LA) mechanical function as much as cigarette smoking. Method A total of 150 chronic MP users (50 males, 32.5 ± 5.4 years), smokers (50 males, 32.1 ± 6.0 years) and controls (50 males, 30.1 ± 5.8 years) were included in the study. LA volumes were measured echocardiographically according to the biplane area–length method. Atrial electromechanical coupling was measured with tissue Doppler imaging and LA mechanical function parameters were calculated. Results The LA passive emptying fraction was significantly decreased and LA active emptying volume (LAAEV) was significantly increased in the MP group (p = 0.012 and p = 0.024, respectively), and the LA active emptying fraction (LAAEF) was significantly increased in the smokers (p = 0.003). There was a positive correlation between the amount of MP used and smoking (pack years) with LAAEV and LAAEF (r = 0.26, p = 0.009 and r = 0.25, p = 0.013, respectively). Lateral atrial electromechanical intervals (PA) were significantly higher in MP users, and the septal mitral PA was statistically higher in the smokers (p = 0.05 and p = 0.04, respectively). Conclusion We suggest that atrial electromechanical coupling intervals were prolonged and LA mechanical function was impaired in MP users and smokers, but there was no significant difference between the MP users and smokers. These findings may be markers of subclinical cardiac involvement and tendency for atrial fibrillation. PMID:26592906

  13. Abnormal Degree Centrality of Bilateral Putamen and Left Superior Frontal Gyrus in Schizophrenia with Auditory Hallucinations: A Resting-state Functional Magnetic Resonance Imaging Study

    PubMed Central

    Chen, Cheng; Wang, Hui-Ling; Wu, Shi-Hao; Huang, Huan; Zou, Ji-Lin; Chen, Jun; Jiang, Tian-Zi; Zhou, Yuan; Wang, Gao-Hua

    2015-01-01

    Background: Dysconnectivity hypothesis of schizophrenia has been increasingly emphasized. Recent researches showed that this dysconnectivity might be related to occurrence of auditory hallucination (AH). However, there is still no consistent conclusion. This study aimed to explore intrinsic dysconnectivity pattern of whole-brain functional networks at voxel level in schizophrenic with AH. Methods: Auditory hallucinated patients group (n = 42 APG), no hallucinated patients group (n = 42 NPG) and normal controls (n = 84 NCs) were analyzed by resting-state functional magnetic resonance imaging. The functional connectivity metrics index (degree centrality [DC]) across the entire brain networks was calculated and evaluated among three groups. Results: DC decreased in the bilateral putamen and increased in the left superior frontal gyrus in all the patients. However, in APG, the changes of DC were more obvious compared with NPG. Symptomology scores were negatively correlated with the DC of bilateral putamen in all patients. AH score of APG positively correlated with the DC in left superior frontal gyrus but negatively correlated with the DC in bilateral putamen. Conclusion: Our findings corroborated that schizophrenia was characterized by functional dysconnectivity, and the abnormal DC in bilateral putamen and left superior frontal gyrus might be crucial in the occurrence of AH. PMID:26612293

  14. Structural and Functional Abnormalities of the Neuromuscular Junction in the Trembler-J Homozygote Mouse Model of Congenital Hypomyelinating Neuropathy.

    PubMed

    Scurry, Alexandra N; Heredia, Dante J; Feng, Cheng-Yuan; Gephart, Gregory B; Hennig, Grant W; Gould, Thomas W

    2016-04-01

    Mutations in peripheral myelin protein 22 (PMP22) result in the most common form of Charcot-Marie-Tooth (CMT) disease, CMT1A. This hereditary peripheral neuropathy is characterized by dysmyelination of peripheral nerves, reduced nerve conduction velocity, and muscle weakness. APMP22point mutation in L16P (leucine 16 to proline) underlies a form of human CMT1A as well as the Trembler-J mouse model of CMT1A. Homozygote Trembler-J mice (Tr(J)) die early postnatally, fail to make peripheral myelin, and, therefore, are more similar to patients with congenital hypomyelinating neuropathy than those with CMT1A. Because recent studies of inherited neuropathies in humans and mice have demonstrated that dysfunction and degeneration of neuromuscular synapses or junctions (NMJs) often precede impairments in axonal conduction, we examined the structure and function of NMJs inTr(J)mice. Although synapses appeared to be normally innervated even in end-stageTr(J)mice, the growth and maturation of the NMJs were altered. In addition, the amplitudes of nerve-evoked muscle endplate potentials were reduced and there was transmission failure during sustained nerve stimulation. These results suggest that the severe congenital hypomyelinating neuropathy that characterizesTr(J)mice results in structural and functional deficits of the developing NMJ. PMID:26921370

  15. Maintenance of Hepatic Functions in Primary Human Hepatocytes Cultured on Xeno-Free and Chemical Defined Human Recombinant Laminins.

    PubMed

    Watanabe, Masaaki; Zemack, Helen; Johansson, Helene; Hagbard, Louise; Jorns, Carl; Li, Meng; Ellis, Ewa

    2016-01-01

    Refined methods for maintaining specific functions of isolated hepatocytes under xeno-free and chemical defined conditions is of great importance for the development of hepatocyte research and regenerative therapy. Laminins, a large family of heterotrimeric basement membrane adhesion proteins, are highly cell and tissue type specific components of the extracellular matrix and strongly influence the behavior and function of associated cells and/or tissues. However, detailed biological functions of many laminin isoforms are still to be evaluated. In this study, we determined the distribution of laminin isoforms in human liver tissue and isolated primary human hepatocytes by western blot analysis, and investigated the efficacy of different human recombinant laminin isoforms on hepatic functions during culture. Protein expressions of laminin-chain α2, α3, α4, β1, β3, γ1, and γ2 were detected in both isolated human hepatocytes and liver tissue. No α1 and α5 expression could be detected in liver tissue or hepatocytes. Hepatocytes were isolated from five different individual livers, and cultured on human recombinant laminin isoforms -111, -211, -221, -332, -411, -421, -511, and -521 (Biolamina AB), matrigel (extracted from Engelbreth-Holm-Swarm sarcoma), or collagen type IV (Collagen). Hepatocytes cultured on laminin showed characteristic hexagonal shape in a flat cell monolayer. Viability, double stranded DNA concentration, and Ki67 expression for hepatocytes cultured for six days on laminin were comparable to those cultured on EHS and Collagen. Hepatocytes cultured on laminin also displayed production of human albumin, alpha-1-antitrypsin, bile acids, and gene expression of liver-enriched factors, such as hepatocyte nuclear factor 4 alpha, glucose-6-phosphate, cytochrome P450 3A4, and multidrug resistance-associated protein 2. We conclude that all forms of human recombinant laminin tested maintain cell viability and liver-specific functions of primary human

  16. Abnormal splicing in the N‐terminal variable region of cardiac troponin T impairs systolic function of the heart with preserved Frank‐Starling compensation

    PubMed Central

    Feng, Han‐Zhong; Chen, Guozhen; Nan, Changlong; Huang, Xupei; Jin, Jian‐Ping

    2014-01-01

    Abstract Abnormal splice‐out of the exon 7‐encoded segment in the N‐terminal variable region of cardiac troponin T (cTnT‐ΔE7) was found in turkeys and, together with the inclusion of embryonic exon (eTnT), in adult dogs with a correlation with dilated cardiomyopathy. Overexpression of these cTnT variants in transgenic mouse hearts significantly decreased cardiac function. To further investigate the functional effect of cTnT‐ΔE7 or ΔE7+eTnT in vivo under systemic regulation, echocardiography was carried out in single and double‐transgenic mice. No atrial enlargement, ventricular hypertrophy or dilation was detected in the hearts of 2‐month‐old cTnT‐ΔE7 and ΔE7+eTnT mice in comparison to wild‐type controls, indicating a compensated state. However, left ventricular fractional shortening and ejection fraction were decreased in ΔE7 and ΔE7+eTnT mice, and the response to isoproterenol was lower in ΔE7+eTnT mice. Left ventricular outflow tract velocity and gradient were decreased in the transgenic mouse hearts, indicating decreased systolic function. Ex vivo working heart function showed that high afterload or low preload resulted in more severe decreases in the systolic function and energetic efficiency of cTnT‐ΔE7 and ΔE7+eTnT hearts. On the other hand, increases in preload demonstrated preserved Frank‐Starling responses and minimized the loss of cardiac function and efficiency. The data demonstrate that the N‐terminal variable region of cardiac TnT regulates systolic function of the heart. PMID:25194024

  17. Thyroid function abnormalities associated with the chronic outpatient administration of recombinant interleukin-2 and recombinant interferon-alpha.

    PubMed

    Jacobs, E L; Clare-Salzler, M J; Chopra, I J; Figlin, R A

    1991-12-01

    We prospectively examined thyroid function during and following chronic, outpatient therapy with recombinant interleukin-2 (rIL-2) and Roferon-A (rIFN-alpha 2a). Twenty-two of 30 patients with advanced renal cell carcinoma treated on a phase II open pilot study of concomitant rIL-2 and rIFN-alpha 2a were included. Serum levels of thyroxine, triiodothyronine, free thyroxine index, thyrotropin, antithyroid antibodies, and thyrotropin (TSH) receptor binding antibodies were measured before therapy and after every other cycle. Selected patients underwent studies after every cycle and following completion of therapy. Twenty patients (91%) developed laboratory evidence of thyroid dysfunction, 11 (50%) developed hypothyroidism, five (23%) had a biphasic pattern, and four (18%) had hyperthyroidism. The incidence of thyroid dysfunction increased with increased number of treatment cycles. Transient hyperthyroidism was noted in six of the 11 patients studied after the first cycle and persisted after cycle three in only two patients. Hypothyroidism was not observed after cycle 1, but became increasingly frequent between cycles 2 (56%) and 6 (90%). Thyroid function normalized following therapy in nine of 12 patients tested. Antithyroid antibodies were identified pretherapy in five patients (23%) and de novo in none; TSH receptor binding antibodies were not detected. This study demonstrates a remarkably high frequency of reversible thyroid dysfunction in patients with advanced renal cell carcinoma treated with repeated cycles of rIL-2 plus rIFN-alpha 2a. We conclude that chronic therapy with rIL-2 and rIFN-alpha 2a produces thyroid dysfunction in virtually all patients most likely secondary to a nonspecific, nonautoimmune, toxic manifestation of prolonged treatment. IL-2 therapy may, therefore, produce thyroid dysfunction by more than one mechanism. PMID:1768679

  18. A Novel Strategy to Reveal the Latent Abnormalities in Human Embryonic Stages from a Large Embryo Collection.

    PubMed

    Kanahashi, Tohoru; Yamada, Shigehito; Tanaka, Mire; Hirose, Ayumi; Uwabe, Chigako; Kose, Katsumi; Yoneyama, Akio; Takeda, Tohoru; Takakuwa, Tetsuya

    2016-01-01

    The cause of spontaneous abortion of normal conceptuses remains unknown in most cases. The study was aimed to reveal the latent abnormalities by using a large collection of embryo images from a magnetic resonance imaging (MRI) database and novel phase-contrast radiographic computed tomography (PXCT). MRI from 1,156 embryos between Carnegie stage (CS) 14 and CS23 from the Kyoto Collection were screened by using the volume of the liver as the target organ. Embryos with liver volumes ≥2 SD above or below the mean for the stage of development were screened and examined precisely on MRI. Embryos with potentially abnormal livers were further analyzed by using PXCT. Liver abnormality was detected in all 7 embryos in the extra-small liver group and in 2 of 8 embryos in the extra-large liver group. The abnormalities in the extra-small liver group consisted of hepatic agenesis (2 embryos), hepatic hypogenesis (4), and liver lobe defect (1). Among the 7 extra-small liver group, 2 had only liver abnormalities and 5 exhibited complications in other organs. Of the 2 embryos in the extra-large liver group, one had only a single liver abnormality and the other had a morphologically abnormal liver with complications in other organs. Most of such liver abnormality cases are not survive, as liver function becomes essential. The prevalence of liver malformations in CS18 and CS21 in the intrauterine population of externally normal embryos is approximately 1.7%. The present study is the first step toward the elucidation of the latent abnormalities resulting in spontaneous abortion in externally normal embryos. PMID:26474800

  19. Mesenteric lymph from rats with trauma-hemorrhagic shock causes abnormal cardiac myocyte function and induces myocardial contractile dysfunction

    PubMed Central

    Sambol, Justin T.; Lee, Marlon A.; Jiang, Mingshan; Dosi, Garima; Dong, Wei; Deitch, Edwin A.

    2011-01-01

    Myocardial contractile dysfunction develops following trauma-hemorrhagic shock (T/HS). We have previously shown that, in a rat fixed pressure model of T/HS (mean arterial pressure of 30–35 mmHg for 90 min), mesenteric lymph duct ligation before T/HS prevented T/HS-induced myocardial contractile depression. To determine whether T/HS lymph directly alters myocardial contractility, we examined the functional effects of physiologically relevant concentrations of mesenteric lymph collected from rats undergoing trauma-sham shock (T/SS) or T/HS on both isolated cardiac myocytes and Langendorff-perfused whole hearts. Acute application of T/HS lymph (0.1–2%), but not T/SS lymph, induced dual inotropic effects on myocytes with an immediate increase in the amplitude of cell shortening (1.4 ± 0.1-fold) followed by a complete block of contraction. Similarly, T/HS lymph caused dual, positive and negative effects on cellular Ca2+ transients. These effects were associated with changes in the electrophysiological properties of cardiac myocytes; T/HS lymph initially prolonged the action potential duration (action potential duration at 90% repolarization, 3.3 ± 0.4-fold), and this was followed by a decrease in the plateau potential and membrane depolarization. Furthermore, intravenous infusion of T/HS lymph, but not T/SS lymph, caused myocardial contractile dysfunction at 24 h after injection, which mimicked actual T/HS-induced changes; left ventricular developed pressure (LVDP) and the maximal rate of LVDP rise and fall (±dP/dtmax) were decreased and inotropic response to Ca2+ was blunted. However, the contractile responsiveness to β-adrenergic receptor stimulation in the T/HS lymph-infused hearts remained unchanged. These results suggest that T/HS lymph directly causes negative inotropic effects on the myocardium and that T/HS lymph-induced changes in myocyte function are likely to contribute to the development of T/HS-induced myocardial dysfunction. PMID:21700891

  20. Hepatitis B - children

    MedlinePlus

    ... tests detect liver damage and the risk for liver cancer from chronic hepatitis B: Albumin level Liver function tests Prothrombin time Liver biopsy Abdominal ultrasound Liver cancer tumor markers such as alpha fetoprotein The provider ...

  1. A highly abnormal massive star mass function in the Orion Nebula cluster and the dynamical decay of trapezium systems

    NASA Astrophysics Data System (ADS)

    Pflamm-Altenburg, J.; Kroupa, P.

    2006-11-01

    The Orion Nebula cluster (ONC) appears to be unusual on two grounds: the observed constellation of the OB stars of the entire ONC and its Trapezium at its centre implies a time-scale problem given the age of the Trapezium, and an initial mass function (IMF) problem for the whole OB star population in the ONC. Given the estimated crossing time of the Trapezium, it ought to have totally dynamically decayed by now. Furthermore, by combining the lower limit of the ONC mass with a standard IMF it emerges that the ONC should have formed at least about 40 stars heavier than 5 Msolar while only 10 are observed. Using the N-body experiments we (i) confirm the expected instability of the Trapezium and (ii) show that beginning with a compact OB-star configuration of about 40 stars both the number of observed OB stars after 1 Myr within 1 pc radius and a compact trapezium configuration can be reproduced. These two empirical constraints thus support our estimate of 40 initial OB stars in the cluster. Interestingly, a more-evolved version of the ONC resembles the Upper Scorpius OB association. The N-body experiments are performed with the new C-code CATENA by integrating the equations of motion using the chain-multiple-regularization method. In addition, we present a new numerical formulation of the IMF.

  2. Abnormal degree centrality of functional hubs associated with negative coping in older Chinese adults who lost their only child.

    PubMed

    Liu, Wei; Liu, HuiJuan; Wei, Dongtao; Sun, Jiangzhou; Yang, Junyi; Meng, Jie; Wang, Lihong; Qiu, Jiang

    2015-12-01

    The loss of an only child is a negative life event and may potentially increase the risk of psychiatric disorders. However, the psychological consequences of the loss of an only child and the associated neural mechanisms remain largely unexplored. Degree centrality (DC), derived from resting-state functional magnetic resonance imaging (fMRI), was used to examine network communication in 22 older adults who lost their only child and 23 matched controls. The older adults who lost their only child exhibited an ineffective coping style. They also showed decreased distant and local DC in the precuneus and left inferior parietal lobule and decreased distant DC in the bilateral dorsolateral prefrontal cortex (DLPFC). Furthermore, the decreased local and distant DC of these regions and the decreased DLPFC-precuneus connectivity strength were negatively correlated with negative coping scores in the loss group but not in the controls. Overall, the results suggested a model that the impaired neural network communication of brain hubs within the default mode network (DMN) and central executive network (CEN) were associated with a negative coping style in older adults who lost their only child. The decreased connectivity of the hubs can be identified as a neural risk factor that is related to future psychopathology. PMID:26391339

  3. Abnormal functional resting-state networks in ADHD: graph theory and pattern recognition analysis of fMRI data.

    PubMed

    dos Santos Siqueira, Anderson; Biazoli Junior, Claudinei Eduardo; Comfort, William Edgar; Rohde, Luis Augusto; Sato, João Ricardo

    2014-01-01

    The framework of graph theory provides useful tools for investigating the neural substrates of neuropsychiatric disorders. Graph description measures may be useful as predictor variables in classification procedures. Here, we consider several centrality measures as predictor features in a classification algorithm to identify nodes of resting-state networks containing predictive information that can discriminate between typical developing children and patients with attention-deficit/hyperactivity disorder (ADHD). The prediction was based on a support vector machines classifier. The analyses were performed in a multisite and publicly available resting-state fMRI dataset of healthy children and ADHD patients: the ADHD-200 database. Network centrality measures contained little predictive information for the discrimination between ADHD patients and healthy subjects. However, the classification between inattentive and combined ADHD subtypes was more promising, achieving accuracies higher than 65% (balance between sensitivity and specificity) in some sites. Finally, brain regions were ranked according to the amount of discriminant information and the most relevant were mapped. As hypothesized, we found that brain regions in motor, frontoparietal, and default mode networks contained the most predictive information. We concluded that the functional connectivity estimations are strongly dependent on the sample characteristics. Thus different acquisition protocols and clinical heterogeneity decrease the predictive values of the graph descriptors. PMID:25309910

  4. Screening of inherited metabolic abnormalities in 56 children with intractable epilepsy

    PubMed Central

    LIU, XIAOMING; LI, RUI; CHEN, SHENGZHI; SANG, YAN; ZHAO, JIAQIANG

    2016-01-01

    Epilepsy is a common children's neural disease that is largely controlled by anti-epileptic drugs. Nevertheless, children experience repeated attacks that develop into intractable epilepsy (IE). The aim of the present study was to examine the inherited metabolic abnormalities in children with IE to provide early etiological and symptomatic treatment. Urine and blood samples of 56 children with IE served as the experimental group and 56 cases of children with IE, who were successfully treated served as the control group, and analyzed by gas chromatography-mass spectrometry and tandem mass spectrometry for the metabolic screening of amino, organic, and fatty acids. Urine routine, hepatic function, blood biochemistry, imageology of encephalon and brain stem-evoked potential (auditory and optical) were also examined. Of the 27 IE children confirmed as abnormal in urine and blood screening, there were 19 cases (70.3%) of hypoevolutism or retrogression of intelligence and motor function, 15 cases (55.5%) of brain stem-evoked potential and of encephalic computed tomography (CT) or magnetic resonance imaging (MRI) abnormality, 6 cases (22.2%) of abnormal family history and of abnormal blood biochemistry and blood gas analysis, and 5 cases (18.5%) with skin change and of abnormal hepatic function. Of the 27 cases, 11 cases (19.6%) were diagnosed with inherited metabolic diseases. Among the children in the control group, 3 cases showed abnormal urine test results, one of which had family history, one had hypoevolutism or retrogression of intelligence and motor function, one had brain stem-evoked potential and encephalic CT or MRI abnormality, while two of the 3 cases had inherited metabolic abnormalities. The correlation analysis revealed that abnormal urine test was significantly correlated with inherited metabolic abnormalities (P<0.05). Of the 56 IE patients, 25 cases (44.6%) were identified as abnormal under urine screening, and of the 25 cases, 6 cases had simple

  5. Mitochondria-targeted ROS scavenger improves post-ischemic recovery of cardiac function and attenuates mitochondrial abnormalities in aged rats

    PubMed Central

    Escobales, Nelson; Nuñez, Rebeca E.; Jang, Sehwan; Parodi-Rullan, Rebecca; Ayala-Peña, Sylvette; Sacher, Joshua R.; Skoda, Erin M.; Wipf, Peter; Frontera, Walter; Javadov, Sabzali

    2014-01-01

    Mitochondria-generated reactive oxygen species (ROS) play a crucial role in the pathogenesis of aging and age-associated diseases. In this study, we evaluated the effects of XJB-5-131 (XJB), a mitochondria-targeted ROS and electron scavenger, on cardiac resistance to ischemia-reperfusion (IR)-induced oxidative stress in aged rats. Male adult (5-month old, n=17) and aged (29-month old, n=19) Fischer Brown Norway (F344/BN) rats were randomly assigned to the following groups: adult (A), adult+XJB (AX), aged (O), and aged+XJB (OX). XJB was administered 3 times per week (3 mg/kg body weight, IP) for four weeks. At the end of the treatment period, cardiac function was continuously monitored in excised hearts using the Langendorff technique for 30 min, followed by 20-min of global ischemia, and 60-min reperfusion. XJB improved post-ischemic recovery of aged hearts, as evidenced by greater left ventricular developed-pressures and rate-pressure products than the untreated, aged-matched group. The state 3 respiration rates at complexes I, II and IV of mitochondria isolated from XJB-treated aged hearts were 57% (P<0.05), 25% (P<0.05) and 28% (P<0.05), respectively, higher than controls. Ca2+-induced swelling, an indicator of permeability transition pore opening, was reduced in mitochondria of XJB-treated aged rats. In addition, XJB significantly attenuated the H2O2-induced depolarization of the mitochondrial inner membrane as well as total and mitochondrial ROS levels in cultured cardiomyocytes. This study underlines the importance of mitochondrial ROS in aging-induced cardiac dysfunction and suggests that targeting mitochondrial ROS may be an effective therapeutic approach to protect the aged heart against IR injury. PMID:25451170

  6. Mitochondria-targeted ROS scavenger improves post-ischemic recovery of cardiac function and attenuates mitochondrial abnormalities in aged rats.

    PubMed

    Escobales, Nelson; Nuñez, Rebeca E; Jang, Sehwan; Parodi-Rullan, Rebecca; Ayala-Peña, Sylvette; Sacher, Joshua R; Skoda, Erin M; Wipf, Peter; Frontera, Walter; Javadov, Sabzali

    2014-12-01

    Mitochondria-generated reactive oxygen species (ROS) play a crucial role in the pathogenesis of aging and age-associated diseases. In this study, we evaluated the effects of XJB-5-131 (XJB), a mitochondria-targeted ROS and electron scavenger, on cardiac resistance to ischemia-reperfusion (IR)-induced oxidative stress in aged rats. Male adult (5-month old, n=17) and aged (29-month old, n=19) Fischer Brown Norway (F344/BN) rats were randomly assigned to the following groups: adult (A), adult+XJB (AX), aged (O), and aged+XJB (OX). XJB was administered 3 times per week (3mg/kg body weight, IP) for four weeks. At the end of the treatment period, cardiac function was continuously monitored in excised hearts using the Langendorff technique for 30 min, followed by 20 min of global ischemia, and 60-min reperfusion. XJB improved post-ischemic recovery of aged hearts, as evidenced by greater left ventricular developed-pressures and rate-pressure products than the untreated, aged-matched group. The state 3 respiration rates at complexes I, II and IV of mitochondria isolated from XJB-treated aged hearts were 57% (P<0.05), 25% (P<0.05) and 28% (P<0.05), respectively, higher than controls. Ca(2+)-induced swelling, an indicator of permeability transition pore opening, was reduced in the mitochondria of XJB-treated aged rats. In addition, XJB significantly attenuated the H2O2-induced depolarization of the mitochondrial inner membrane as well as the total and mitochondrial ROS levels in cultured cardiomyocytes. This study underlines the importance of mitochondrial ROS in aging-induced cardiac dysfunction and suggests that targeting mitochondrial ROS may be an effective therapeutic approach to protect the aged heart against IR injury. PMID:25451170

  7. Surface IgM expression and function are associated with clinical behavior, genetic abnormalities, and DNA methylation in CLL.

    PubMed

    D'Avola, Annalisa; Drennan, Samantha; Tracy, Ian; Henderson, Isla; Chiecchio, Laura; Larrayoz, Marta; Rose-Zerilli, Matthew; Strefford, Jonathan; Plass, Christoph; Johnson, Peter W; Steele, Andrew J; Packham, Graham; Stevenson, Freda K; Oakes, Christopher C; Forconi, Francesco

    2016-08-11

    Chronic lymphocytic leukemia (CLL) with unmutated (U-CLL) or mutated (M-CLL) immunoglobulin gene heavy-chain variable region (IGHV) displays different states of anergy, indicated by reduced surface immunoglobulin M (sIgM) levels and signaling, consequent to chronic (super)antigen exposure. The subsets also differ in the incidence of high-risk genetic aberrations and in DNA methylation profile, preserved from the maturational status of the original cell. We focused on sIgM expression and function, measured as intracellular Ca(2+) mobilization following stimulation, and probed correlations with clinical outcome. The relationship with genetic features and maturation status defined by DNA methylation of an 18-gene panel signature was then investigated. sIgM levels/signaling were higher and less variable in U-CLL than in M-CLL and correlated with disease progression between and within U-CLL and M-CLL. In U-CLL, increased levels/signaling associated with +12, del(17p) or NOTCH1 mutations. In M-CLL, there were fewer genetic lesions, although the methylation maturation status, generally higher than in U-CLL, varied and was increased in cases with lower sIgM levels/signaling. These features revealed heterogeneity in M-CLL and U-CLL with clear clinical correlations. Multivariate analyses with phenotype, genetic lesions, or DNA methylation maturation status identified high sIgM levels as a new potential independent factor for disease progression. Multiple influences on sIgM include the cell of origin, the clonal history of antigen encounter in vivo, and genetic damage. This simple marker compiles these different factors into an indicator worthy of further investigations for prediction of clinical behavior, particularly within the heterogeneous M-CLL subset. PMID:27301861

  8. Genetic Diversity Underlying the Envelope Glycoproteins of Hepatitis C Virus: Structural and Functional Consequences and the Implications for Vaccine Design

    PubMed Central

    Tarr, Alexander W.; Khera, Tanvi; Hueging, Kathrin; Sheldon, Julie; Steinmann, Eike; Pietschmann, Thomas; Brown, Richard J. P.

    2015-01-01

    In the 26 years since the discovery of Hepatitis C virus (HCV) a major global research effort has illuminated many aspects of the viral life cycle, facilitating the development of targeted antivirals. Recently, effective direct-acting antiviral (DAA) regimens with >90% cure rates have become available for treatment of chronic HCV infection in developed nations, representing a significant advance towards global eradication. However, the high cost of these treatments results in highly restricted access in developing nations, where the disease burden is greatest. Additionally, the largely asymptomatic nature of infection facilitates continued transmission in at risk groups and resource constrained settings due to limited surveillance. Consequently a prophylactic vaccine is much needed. The HCV envelope glycoproteins E1 and E2 are located on the surface of viral lipid envelope, facilitate viral entry and are the targets for host immunity, in addition to other functions. Unfortunately, the extreme global genetic and antigenic diversity exhibited by the HCV glycoproteins represents a significant obstacle to vaccine development. Here we review current knowledge of HCV envelope protein structure, integrating knowledge of genetic, antigenic and functional diversity to inform rational immunogen design. PMID:26193307

  9. Genetic Diversity Underlying the Envelope Glycoproteins of Hepatitis C Virus: Structural and Functional Consequences and the Implications for Vaccine Design.

    PubMed

    Tarr, Alexander W; Khera, Tanvi; Hueging, Kathrin; Sheldon, Julie; Steinmann, Eike; Pietschmann, Thomas; Brown, Richard J P

    2015-07-01

    In the 26 years since the discovery of Hepatitis C virus (HCV) a major global research effort has illuminated many aspects of the viral life cycle, facilitating the development of targeted antivirals. Recently, effective direct-acting antiviral (DAA) regimens with >90% cure rates have become available for treatment of chronic HCV infection in developed nations, representing a significant advance towards global eradication. However, the high cost of these treatments results in highly restricted access in developing nations, where the disease burden is greatest. Additionally, the largely asymptomatic nature of infection facilitates continued transmission in at risk groups and resource constrained settings due to limited surveillance. Consequently a prophylactic vaccine is much needed. The HCV envelope glycoproteins E1 and E2 are located on the surface of viral lipid envelope, facilitate viral entry and are the targets for host immunity, in addition to other functions. Unfortunately, the extreme global genetic and antigenic diversity exhibited by the HCV glycoproteins represents a significant obstacle to vaccine development. Here we review current knowledge of HCV envelope protein structure, integrating knowledge of genetic, antigenic and functional diversity to inform rational immunogen design. PMID:26193307

  10. Comparison of hepatic and renal function between inhalation anesthesia with sevoflurane and remifentanil and total intravenous anesthesia with propofol and remifentanil for thyroidectomy

    PubMed Central

    Kim, Ji Wook; Kim, Joo Duck; Yu, Soo Bong

    2013-01-01

    Background Inhalation anesthetics are an important factor for postoperative hepatic and renal dysfunction. In this regard, TIVA can reduce the risk of hepatic and renal dysfunction inherited to inhalation anesthetics. The present study was conducted to determine whether hepatic and renal functions differ after anesthesia with sevoflurane and propofol. Methods Two hundred patients, ASA physical status class I, II, scheduled for an elective thyroidectomy were randomly divided into two groups. Anesthesia was maintained with sevoflurane 1-2% and remifentanil in the sevoflurane group (Group S) and propofol 2-5 ug/ml and remifentanil 2-5 ng/ml at the effect site, using a target controlled infusion (TCI) pump in the TIVA group (Group T) to maintain BIS of 40-60. To evaluate the hepatic and renal function, aspartate aminotransferase (AST), alanine aminotransferase (ALT), blood urea nitrogen (BUN) and creatinine were tested at preoperation (baseline), postoperative 1 day and 3 days. Results AST was increased at postoperative 1 day and 3 days, compared with that of the preoperation in Group S, and postoperative 1 day in Group T, but the values were within its normal limit. ALT was not changed after anesthesia in both groups. BUN was increased at postoperative 1 day, compared with that of the preoperation in Group S, but the value was within its normal limit. Creatinine was not changed after anesthesia in both groups. Conclusions The changes of hepatic and renal function after inhalation anesthesia with sevoflurane and TIVA with propofol and remifentanil for thyroidectomy were clinically insignificant, and there was no difference between the two methods. PMID:23459368

  11. In vivo structure-function studies of human hepatic lipase: the catalytic function rescues the lean phenotype of HL-deficient (hl−/−) mice

    PubMed Central

    Chen, Jeffrey; Kaiyala, Karl J; Lam, Jennifer; Agrawal, Nalini; Nguyen, Lisa; Ogimoto, Kayoko; Spencer, Dean; Morton, Gregory J; Schwartz, Michael W; Dichek, Helén L

    2015-01-01

    The lean body weight phenotype of hepatic lipase (HL)–deficient mice (hl−/−) suggests that HL is required for normal weight gain, but the underlying mechanisms are unknown. HL plays a unique role in lipoprotein metabolism performing bridging as well as catalytic functions, either of which could participate in energy homeostasis. To determine if both the catalytic and bridging functions or the catalytic function alone are required for the effect of HL on body weight, we studied (hl−/−) mice that transgenically express physiologic levels of human (h)HL (with catalytic and bridging functions) or a catalytically-inactive (ci)HL variant (with bridging function only) in which the catalytic Serine 145 was mutated to Alanine. As expected, HL activity in postheparin plasma was restored to physiologic levels only in hHL-transgenic mice (hl−/−hHL). During high-fat diet feeding, hHL-transgenic mice exhibited increased body weight gain and body adiposity relative to hl−/−ciHL mice. A similar, albeit less robust effect was observed in female hHL-transgenic relative to hl−/−ciHL mice. To delineate the basis for this effect, we determined cumulative food intake and measured energy expenditure using calorimetry. Interestingly, in both genders, food intake was 5–10% higher in hl−/−hHL mice relative to hl−/−ciHL controls. Similarly, energy expenditure was ∼10% lower in HL-transgenic mice after adjusting for differences in total body weight. Our results demonstrate that (1) the catalytic function of HL is required to rescue the lean body weight phenotype of hl−/− mice; (2) this effect involves complementary changes in both sides of the energy balance equation; and (3) the bridging function alone is insufficient to rescue the lean phenotype of hl−/−ciHL mice. PMID:25862097

  12. Update on Alcoholic Hepatitis

    PubMed Central

    Torok, Natalie J.

    2015-01-01

    Alcoholic liver disease is one of the most prevalent liver diseases worldwide, and a major cause of morbidity and mortality. Alcoholic hepatitis is a severe form of liver injury in patients with alcohol abuse, can present as an acute on chronic liver failure associated with a rapid decline in liver synthetic function, and consequent increase in mortality. Despite therapy, about 30%–50% of patients with severe alcoholic hepatitis eventually die. The pathogenic pathways that lead to the development of alcoholic hepatitis are complex and involve oxidative stress, gut dysbiosis, and dysregulation of the innate and adaptive immune system with injury to the parenchymal cells and activation of hepatic stellate cells. As accepted treatment approaches are currently limited, a better understanding of the pathophysiology would be required to generate new approaches that improve outcomes. This review focuses on recent advances in the diagnosis, pathogenesis of alcoholic hepatitis and novel treatment strategies. PMID:26540078

  13. Lack of phenotypic and functional impairment in dendritic cells from chimpanzees chronically infected with hepatitis C virus.

    PubMed

    Larsson, Marie; Babcock, Ethan; Grakoui, Arash; Shoukry, Naglaa; Lauer, Georg; Rice, Charles; Walker, Christopher; Bhardwaj, Nina

    2004-06-01

    Dendritic cells (DCs), which are potent antigen-presenting cells (APCs), are used as adjuvants for the treatment of cancer and infectious diseases in human and nonhuman primates, with documented clinical efficacy. The hepatitis C virus (HCV)-chimpanzee model is the best available model for testing the immunotherapeutic effects of DCs in the setting of a chronic infection, as chimpanzees develop a persistent infection resembling that seen in humans. However, several reports have suggested that DCs derived from chronically infected individuals or nonhuman primates are functionally compromised. As a prelude to clinical studies, we evaluated whether functionally mature DCs could be generated in chimpanzee plasma by good manufacturing practice using CD14(+) mononuclear precursors from chronically infected chimpanzees. DCs generated in a medium with HCV-negative plasma and treated with a defined cocktail of cytokines or a CD40 ligand trimer matured fully, as measured by the induction of CD83 expression and the upregulation of costimulatory molecules. Furthermore, the expression of CCR7 was induced, suggesting an acquisition of migration capacity. Mature DCs were capable of stimulating allogeneic T cells, antigen-specific memory CD4(+) T cells, and HCV-specific CD8(+)-T-cell clones. In all cases, there was no evidence of HCV infection in DCs. Furthermore, these DCs maintained their phenotype and APC function after cryopreservation. Finally, no discernible differences were noted between DCs derived from HCV-infected and uninfected chimpanzees. In summary, precursor cells from HCV-infected chimpanzees are fully capable of differentiating into functional, mature DCs, which can now be reproducibly prepared for investigations of their immunotherapeutic potential in the setting of chronic HCV infection. PMID:15163708

  14. Hepatitis B and Hepatitis C in Pregnancy

    MedlinePlus

    ... infected with the hepatitis B virus, can I breastfeed? • If I am infected with the hepatitis B ... infected with the hepatitis C virus, can I breastfeed? • Glossary What are hepatitis B and hepatitis C ...

  15. Functionally reduced sensorimotor connections form with normal specificity despite abnormal muscle spindle development: the role of spindle-derived NT3

    PubMed Central

    Shneider, Neil A.; Mentis, George Z.; Schustak, Joshua; O’Donovan, Michael J.

    2009-01-01

    Summary The mechanisms controlling the formation of synaptic connections between muscle spindle afferents and spinal motor neurons are believed to be regulated by factors originating from muscle spindles. Here, we find that the connections form with appropriate specificity in mice with abnormal spindle development caused by the conditional elimination of the neuregulin1 receptor ErbB2 from muscle precursors. However, despite a modest (~30%) decrease in the number of afferent terminals on motor neuron somata, the amplitude of afferent-evoked synaptic potentials recorded in motor neurons was reduced by ~80%, suggesting that many of the connections that form are functionally silent. The selective elimination of neurotrophin 3 (NT3) from muscle spindles had no effect on the amplitude of afferent-evoked ventral root potentials until the second postnatal week, revealing a late role for spindle-derived NT3 in the functional maintenance of the connections. These findings indicate that spindle-derived factors regulate the strength of the connections, but not their initial formation or their specificity. PMID:19369542

  16. Functional and Biochemical Characterization of Hepatitis C Virus (HCV) Particles Produced in a Humanized Liver Mouse Model.

    PubMed

    Calattini, Sara; Fusil, Floriane; Mancip, Jimmy; Dao Thi, Viet Loan; Granier, Christelle; Gadot, Nicolas; Scoazec, Jean-Yves; Zeisel, Mirjam B; Baumert, Thomas F; Lavillette, Dimitri; Dreux, Marlène; Cosset, François-Loïc

    2015-09-18

    Lipoprotein components are crucial factors for hepatitis C virus (HCV) assembly and entry. As hepatoma cells producing cell culture-derived HCV (HCVcc) particles are impaired in some aspects of lipoprotein metabolism, it is of upmost interest to biochemically and functionally characterize the in vivo produced viral particles, particularly regarding how lipoprotein components modulate HCV entry by lipid transfer receptors such as scavenger receptor BI (SR-BI). Sera from HCVcc-infected liver humanized FRG mice were separated by density gradients. Viral subpopulations, termed HCVfrg particles, were characterized for their physical properties, apolipoprotein association, and infectivity. We demonstrate that, in contrast to the widely spread distribution of apolipoproteins across the different HCVcc subpopulations, the most infectious HCVfrg particles are highly enriched in apoE, suggesting that such apolipoprotein enrichment plays a role for entry of in vivo derived infectious particles likely via usage of apolipoprotein receptors. Consistent with this salient feature, we further reveal previously undefined functionalities of SR-BI in promoting entry of in vivo produced HCV. First, unlike HCVcc, SR-BI is a particularly limiting factor for entry of HCVfrg subpopulations of very low density. Second, HCVfrg entry involves SR-BI lipid transfer activity but not its capacity to bind to the viral glycoprotein E2. In conclusion, we demonstrate that composition and biophysical properties of the different subpopulations of in vivo produced HCVfrg particles modulate their levels of infectivity and receptor usage, hereby featuring divergences with in vitro produced HCVcc particles and highlighting the powerfulness of this in vivo model for the functional study of the interplay between HCV and liver components. PMID:26224633

  17. Hepatitis virus panel

    MedlinePlus

    Hepatitis A antibody test; Hepatitis B antibody test; Hepatitis C antibody test; Hepatitis D antibody test ... There are different tests for hepatitis A and B. A positive test is ... may mean: You currently have a hepatitis infection. This may ...

  18. Hepatitis C and Incarceration

    MedlinePlus

    HEPATITIS C & INCARCERATION What is hepatitis? “Hepatitis” means inflammation or swelling of the liver. The liver is an important ... viral hepatitis: Hepatitis A, Hepatitis B, and Hepatitis C. They are all different from each other and ...

  19. Hepatitis C: Treatment

    MedlinePlus

    ... Public Home » Hepatitis C » Hepatitis C Treatment Viral Hepatitis Menu Menu Viral Hepatitis Viral Hepatitis Home For ... Enter ZIP code here Enter ZIP code here Hepatitis C Treatment for Veterans and the Public Treatment ...

  20. Hepatic Encephalopathy

    MedlinePlus Videos and Cool Tools

    ... is Hepatic Encephalopathy? Hepatic Encephalopathy, sometimes referred to as portosystemic encephalopathy or PSE, is a condition that ... medical care is an important factor in staying as healthy as possible. The American Liver Foundation is ...

  1. Hepatitis D

    MedlinePlus

    ... if the hepatitis B virus is also present. Transmission Hepatitis D can be found in the blood, ... other body fluids of people who are infected. Transmission happens when infected body fluid enters another person’s ...

  2. Autoimmune hepatitis

    MedlinePlus

    Lupoid hepatitis; Chronic acute liver disease ... This form of hepatitis is an autoimmune disease . The body's immune system cannot tell the difference between healthy body tissue and harmful, outside ...

  3. Hepatitis C

    MedlinePlus

    ... 2014 Select a Language: Fact Sheet 507 Hepatitis C WHAT IS HEPATITIS C? HOW IS IT DIAGNOSED? ... treatment may be less likely to work. Hep C treatment is less effective for coinfected people. Cure ...

  4. Hepatitis A

    MedlinePlus

    ... an inflammation of the liver. One type, hepatitis A, is caused by the hepatitis A virus (HAV). The disease spreads through contact with ... washed in untreated water Putting into your mouth a finger or object that came into contact with ...

  5. Hepatitis B

    MedlinePlus

    ... this page: //medlineplus.gov/ency/article/000279.htm Hepatitis B To use the sharing features on this page, please enable JavaScript. Hepatitis B is irritation and swelling (inflammation) of the ...

  6. Controlled formation of heterotypic hepatic micro-organoids in anisotropic hydrogel microfibers for long-term preservation of liver-specific functions.

    PubMed

    Yamada, Masumi; Utoh, Rie; Ohashi, Kazuo; Tatsumi, Kohei; Yamato, Masayuki; Okano, Teruo; Seki, Minoru

    2012-11-01

    We have developed a hydrogel-based cell cultivation platform for forming 3D restiform hepatic micro-organoids consisting of primary rat hepatocytes and feeder cells (Swiss 3T3 cells). Sodium alginate solutions containing hepatocytes/3T3 cells were continuously introduced into a microfluidic channel to produce cell-incorporating anisotropic Ba-alginate hydrogel microfibers, where hepatocytes at the center were closely sandwiched by 3T3 cells. Hydrogel fiber-based cultivation under high oxygen tension enabled the formation of heterotypic micro-organoids with a length of up to 1 mm and a diameter of ∼50 μm, mimicking the hepatic cord structures found in the liver, while maintaining a high hepatocyte viability (∼80%) over 30 days. Long-term observation of up to 90 days revealed a significant enhancement of hepatic functions because of heterotypic and homotypic cell-cell interactions, including albumin secretion and urea synthesis as well as expression of hepatocyte-specific genes, compared with conventional monolayer culture and single cultivation in the hydrogel fibers. The encapsulated hepatic constructs were recovered as scaffold-free micro-organoids by enzymatically digesting the hydrogel matrices using alginate lyase. This technique for creating heterotypic micro-organoids with precisely ordered multiple cell types will be useful for the development of a new liver tissue engineering approach and may be applicable to the fabrication of extracorporeal bioartificial liver (BAL) devices and assessment tools for drug development and testing. PMID:22906609

  7. Impairments in fine-motor coordination and speed of information processing predict declines in everyday functioning in hepatitis C infection.

    PubMed

    Vigil, Ofilio; Posada, Carolina; Woods, Steven Paul; Atkinson, J Hampton; Heaton, Robert K; Perry, William; Hassanein, Tarek I; Grant, Igor; Letendre, Scott L

    2008-10-01

    Research increasingly supports the neurovirulence of chronic infection with the hepatitis C virus (HCV). For example, HCV infection has been associated with neuropsychological impairment in several ability areas, including psychomotor skills. This study aimed to examine whether HCV-associated neuropsychological impairment is predictive of declines in the independent performance of physical (PADLs) and instrumental (IADLs) activities of daily living. A total of 106 volunteers with HCV infection completed a comprehensive neuropsychological, medical, and psychiatric research evaluation. As compared to 30 HCV-seronegative comparison participants, the HCV-infected group reported significantly greater declines in both PADLs and IADLs. Within the HCV cohort, individuals with impaired speed of information processing reported significantly greater IADL declines, whereas impaired fine-motor coordination was associated with declines in both IADLs and PADLs. In a series of regression analyses, impaired speed of information processing and depressive symptoms (as measured by the Beck Depression Inventory) were the only independent predictors of IADL declines, whereas general affective distress (as measured by the Profile of Mood States), sex, and fine-motor coordination impairment were predictive of declines in PADLs. Although the clinical assessment of HCV typically emphasizes both affective (e.g., depression) and physical factors, findings from the present study suggest that cognitive impairment is an important contributor to everyday functioning in persons living with HCV infection and therefore warrants consideration in clinical and research evaluations. PMID:18608687

  8. Source and identity of compounds in a thermomechanical pulp mill effluent inducing hepatic mixed-function oxygenase activity in fish

    SciTech Connect

    Martel, P.H.; Kovacs, T.G.; O`Connor, B.I.; Voss, R.H.

    1997-11-01

    The source and identity of two mixed-function oxygenase (MFO)-inducing substances present in the primary-treated effluent of a thermomechanical pulp (TMP) mill producing newsprint was determined. The source was pinpointed by exposing rainbow trout (Oncorhynchus mykiss) to various process effluents sampled throughout the mill. Exposure concentrations were based on the flow of these process streams in relation to the final effluent flow. Contaminated TMP steam condensates were identified as the major process source of MFO-inducing substances. Using conventional extraction and fractionation procedures, an MFO-inducing fraction was isolated. The major gas chromatographic peaks in this fraction were identified by gas chromatography/mass spectrometry as juvabione, dehydrojuvabione, and manool, all naturally occurring extractives in balsam fix (Abies balsamea). These substances were extracted and isolated from balsam fir and TMP condensates. Trout exposed to juvabione and dehydrojuvabione responded by exhibiting significant hepatic MFO inductions. No MFO induction was observed for manool. Secondary treatment in an activated sludge system effectively eliminated the MFO-inducing potential of the combined mill effluent consistent with a corresponding 90% reduction of both juvabione and dehydrojuvabione.

  9. The RNA sensor RIG-I dually functions as an innate sensor and direct antiviral factor for hepatitis B virus.

    PubMed

    Sato, Seiichi; Li, Kai; Kameyama, Takeshi; Hayashi, Takaya; Ishida, Yuji; Murakami, Shuko; Watanabe, Tsunamasa; Iijima, Sayuki; Sakurai, Yu; Watashi, Koichi; Tsutsumi, Susumu; Sato, Yusuke; Akita, Hidetaka; Wakita, Takaji; Rice, Charles M; Harashima, Hideyoshi; Kohara, Michinori; Tanaka, Yasuhito; Takaoka, Akinori

    2015-01-20

    Host innate recognition triggers key immune responses for viral elimination. The sensing mechanism of hepatitis B virus (HBV), a DNA virus, and the subsequent downstream signaling events remain to be fully clarified. Here we found that type III but not type I interferons are predominantly induced in human primary hepatocytes in response to HBV infection, through retinoic acid-inducible gene-I (RIG-I)-mediated sensing of the 5'-ε region of HBV pregenomic RNA. In addition, RIG-I could also counteract the interaction of HBV polymerase (P protein) with the 5'-ε region in an RNA-binding dependent manner, which consistently suppressed viral replication. Liposome-mediated delivery and vector-based expression of this ε region-derived RNA in liver abolished the HBV replication in human hepatocyte-chimeric mice. These findings identify an innate-recognition mechanism by which RIG-I dually functions as an HBV sensor activating innate signaling and to counteract viral polymerase in human hepatocytes. PMID:25557055

  10. Acute acalculous cholecystitis caused by Hepatitis C: A rare case report

    PubMed Central

    Omar, Ahmed; Osman, Medhet; Bonnet, Gerard; Ghamri, Nafiz

    2015-01-01

    Introduction Acute acalculous cholecystitis (AAC) is rarely encountered in clinical practice and has a high morbidity and mortality. AAC caused by viral hepatitis, with hepatitis A, B and EBV infections are rare, but well documented in the literature. Hepatitis C virus has not been reported as cause of AAC. This case report documents the first case of AAC associated with Acute Hepatitis C. Presenting concerns We present a 40 years old female with abdominal pain. She has a history of previous HCV infection. Her liver function tests were markedly deranged with elevated inflammatory markers. USS scan showed rather a very unusual appearance of an inflamed gallbladder with no gallstones and associated acute hepatitis, confirmed by an abdominal CT scan. HCV RNA PCR confirms flair up of the virus. The patient was managed conservatively in the hospital with follow up USS scan and Liver function tests showed complete recovery. Follow up HCV RNA PCR also returned to an undetectable level. The patient recovered completely with no adverse outcomes. Conclusion This case report is to the first to document the association between acute HCV and AAC. Despite being uncommon in western countries, viral hepatitis should be suspected as a causative agent of AAC, particularly when there is abnormal liver function test and no biliary obstruction. PMID:26722714

  11. Absence of cytoglobin promotes multiple organ abnormalities in aged mice

    PubMed Central

    Thuy, Le Thi Thanh; Van Thuy, Tuong Thi; Matsumoto, Yoshinari; Hai, Hoang; Ikura, Yoshihiro; Yoshizato, Katsutoshi; Kawada, Norifumi

    2016-01-01

    Cytoglobin (Cygb) was identified in hepatic stellate cells (HSCs) and pericytes of all organs; however, the effects of Cygb on cellular functions remain unclear. Here, we report spontaneous and age-dependent malformations in multiple organs of Cygb−/− mice. Twenty-six percent of young Cygb−/− mice (<1 year old) showed heart hypertrophy, cystic disease in the kidney or ovary, loss of balance, liver fibrosis and lymphoma. Furthermore, 71.3% (82/115) of aged Cygb−/− mice (1–2 years old) exhibited abnormalities, such as heart hypertrophy and cancer development in multiple organs; by contrast, 5.8% (4/68) of aged wild-type (WT) mice had abnormalities (p < 0.0001). Interestingly, serum and urine analysis demonstrated that the concentration of nitric oxide metabolites increased significantly in Cygb−/− mice, resulting in an imbalance in the oxidative stress and antioxidant defence system that was reversed by NG-monomethyl-L-arginine treatment. A senescent phenotype and evidence of DNA damage were found in primary HSCs and the liver of aged Cygb−/− mice. Moreover, compared with HSC+/+, HSC−/− showed high expression of Il-6 and chemokine mRNA when cocultured with mouse Hepa 1–6 cells. Thus, the absence of Cygb in pericytes provokes organ abnormalities, possibly via derangement of the nitric oxide and antioxidant defence system and through accelerated cellular senescence. PMID:27146058

  12. Hepatitis A

    MedlinePlus

    ... is an inflammation of the liver. One type, hepatitis A, is caused by the hepatitis A virus (HAV). The disease spreads through contact with ... suggest medicines to help relieve your symptoms. The hepatitis A vaccine can prevent HAV. Good hygiene can also ...

  13. Hepatitis C

    MedlinePlus

    ... an inflammation of the liver. One type, hepatitis C, is caused by the hepatitis C virus (HCV). It usually spreads through contact with ... childbirth. Most people who are infected with hepatitis C don't have any symptoms for years. If ...

  14. Hepatitis A

    MedlinePlus

    ... Organizations ​​ (PDF, 341 KB)​​​​​ Alternate Language URL Español Hepatitis A Page Content On this page: What is ... Nutrition Points to Remember Clinical Trials What is hepatitis A? Hepatitis * A is a virus , or infection, ...

  15. Autoimmune Hepatitis

    MedlinePlus

    ... Organizations ​​ (PDF, 341 KB)​​​​​ Alternate Language URL Autoimmune Hepatitis Page Content On this page: What is autoimmune ... Points to Remember Clinical Trials What is autoimmune hepatitis? Autoimmune hepatitis is a chronic—or long lasting— ...

  16. Correlation of Tc-99m GSA hepatic studies with biopsies in patients with chronic active hepatitis.

    PubMed

    Tomiguchi, S; Kira, T; Oyama, Y; Nabeshima, M; Nakashima, R; Tsuji, A; Kojima, A; Takahashi, M; Yoshimatsu, S; Sagara, K

    1995-08-01

    To determine whether scintigraphic findings of Tc-99m DTPA-galactosyl-HSA (GSA) correspond to histopathologic findings, Tc-99m GSA hepatic scintigraphy and biopsy were compared in 65 patients with chronic active hepatitis. After injecting 185 MBq of Tc-99m GSA, anterior images were obtained at 5 minutes and 15 minutes. Scintigrams were classified into three grades according to the extent of visualization of the cardiac blood pool on 5 minute and 15 minute images. Biopsies were subjectively graded for findings of necrosis and fibrosis. Scintigraphic grades on 5 minute images were correlated with hepatic necrosis and fibrosis and those on 15-minute images with hepatic fibrosis. Scintigraphic abnormalities of Tc-99m GSA correlated well with histopathologic abnormalities, especially with hepatic fibrosis and necrosis in patients with chronic active hepatitis. PMID:7586877

  17. Hepatitis E: Epidemiology and prevention

    PubMed Central

    Teshale, Eyasu H; Hu, Dale J

    2011-01-01

    Hepatitis E is caused by the hepatitis E virus (HEV), the major etiologic agent of enterically transmitted non-A hepatitis worldwide. HEV is responsible for major outbreaks of acute hepatitis in developing countries, especially in many parts of Africa and Asia. The HEV is a spherical, non-enveloped, single-stranded, positive sense RNA virus that is approximately 32 nm to 34 nm in diameter and is the only member in the family Hepeviridae and genus Hepevirus. There are four distinct genotypes of HEV (genotypes 1-4). While genotype 1 is predominantly associated with large epidemics in developing countries, genotype 3 has recently emerged as a significant pathogen in developed countries. The clinical manifestations and the laboratory abnormalities of hepatitis E are not distinguishable from that caused by other hepatitis viruses. However, high mortality among pregnant women particularly during the third trimester distinguishes HEV from other causes of acute viral hepatitis. Specific etiologic diagnosis among infected cases can be made by serological testing or detection of viral nucleic acid by reverse transcription polymerase chain reaction. Although there are vaccine candidates that had been shown to be safe and efficacious in clinical trials, none are approved currently for use. There is no specific therapy for acute hepatitis E as treatment remains supportive. PMID:22216368

  18. The essential functions of endoplasmic reticulum chaperones in hepatic lipid metabolism.

    PubMed

    Zhang, LiChun; Wang, Hong-Hui

    2016-07-01

    The endoplasmic reticulum (ER) is an essential organelle for protein and lipid synthesis in hepatocytes. ER homeostasis is vital to maintain normal hepatocyte physiology. Perturbed ER functions causes ER stress associated with accumulation of unfolded protein in the ER that activates a series of adaptive signalling pathways, termed unfolded protein response (UPR). The UPR regulates ER chaperone levels to preserve ER protein-folding environment to protect the cell from ER stress. Recent findings reveal an array of ER chaperones that alter the protein-folding environment in the ER of hepatocytes and contribute to dysregulation of hepatocyte lipid metabolism and liver disease. In this review, we will discuss the specific functions of these chaperones in regulation of lipid metabolism, especially de novo lipogenesis and lipid transport and demonstrate their homeostatic role not only for ER-protein synthesis but also for lipid metabolism in hepatocyte. PMID:27133206

  19. Functional differences in hepatitis C virus nonstructural (NS) 3/4A- and 5A-specific T cell responses

    PubMed Central

    Holmström, Fredrik; Chen, Margaret; Balasiddaiah, Anangi; Sällberg, Matti; Ahlén, Gustaf; Frelin, Lars

    2016-01-01

    The hepatitis C virus nonstructural (NS) 3/4A and NS5A proteins are major targets for the new direct-acting antiviral compounds. Both viral proteins have been suggested as modulators of the response to the host cell. We have shown that NS3/4A- and NS5A-specific T cell receptors confer different effector functions, and that killing of NS3/4A-expressing hepatocytes is highly dependent on IFN-γ. We here characterize the functional differences in the T cell responses to NS3/4A and NS5A. NS3/4A- and NS5A-specific T cells could be induced at various frequencies in wild-type-, NS3/4A-, and NS5A-transgenic mice. Priming of NS5A-specific T cells required a high DNA dose, and was unlike NS3/4A dependent on both CD4+ and CD8+ T cells, but less influenced by CD25+/GITR+ regulatory T cells. The presence of IL-12 greatly improved specific CD8+ T cell priming by NS3/4A but not by NS5A, suggesting a less dependence of IFN-γ for NS5A. This notion was supported by the observation that NS5A-specific T cells could eliminate NS5A-expressing hepatocytes also in the absence of IFN-γ-receptor-2. This supports that NS3/4A- and NS5A-specific T cells become activated and eliminate antigen expressing, or infected hepatocytes, by distinct mechanisms, and that NS5A-specific T cells show an overall less dependence of IFN-γ. PMID:27141891

  20. Two Distinct Functional Patterns of Hepatitis C Virus (HCV)-Specific T Cell Responses in Seronegative, Aviremic Patients

    PubMed Central

    Nam, Seung Joo; Park, Jung Tak; Kim, Hyon-Suk; Choi, Kyu Hun; Kim, Beom Seok; Shin, Eui-Cheol

    2013-01-01

    In hepatitis C Virus (HCV) high-risk groups, HCV-specific T cell responses have been detected in seronegative, aviremic persons who have no evidence of HCV infection. Herein, we investigated functional profiles of HCV-specific T-cell responses in seronegative, aviremic patients of a HCV high-risk group. Seventy seven hemodialysis patients with chronic renal disease were analyzed by IFN-γ ELISpot assays, and eight of 71 (11.3%) seronegative, aviremic patients displayed HCV-specific T-cell responses. Their HCV-specific memory T cells were characterized by assessing cytokine polyfunctionality, known to provide antiviral protection. By intracellular staining of IFN-γ, TNF-α, IL-2 and MIP-1β, we identified two distinct populations in the seronegative, aviremic patients: polyfunctional responders and TNF-α-predominant responders. In further analysis, occult HCV infection was excluded as a cause of the HCV-specific T cell response via secondary nested RT-PCR of HCV RNA in peripheral blood mononuclear cell samples. HCV-specific T cells targeted multiple epitopes including non-structural proteins in a single patient, implying that their T cells might have been primed by HCV proteins synthesized within the host. We conclude that HCV-specific memory T cells of seronegative, aviremic patients arise from authentic HCV replication in the host, but not from current occult HCV infection. By functional pattern of HCV-specific T cells, there are two distinct populations in these patients: polyfunctional responders and TNF-α-predominant responders. PMID:23638039

  1. [Emotion Disorders and Abnormal Perspiration].

    PubMed

    Umeda, Satoshi

    2016-08-01

    This article reviewed the relationship between emotional disorders and abnormal perspiration. First, I focused on local brain areas related to emotional processing, and summarized the functions of the emotional network involving those local areas. Functional disorders followed by the damage in the amygdala, orbitofrontal cortex, and insular cortex were reviewed, including related abnormal perspiration. I then addressed the mechanisms of how autonomic disorders influence emotional processing. Finally, possible future directions for integrated understanding of the connection between neural activities and bodily reactions were discussed. PMID:27503817

  2. Neurological and behavioral abnormalities, ventricular dilatation, altered cellular functions, inflammation, and neuronal injury in brains of mice due to common, persistent, parasitic infection

    PubMed Central

    Hermes, Gretchen; Ajioka, James W; Kelly, Krystyna A; Mui, Ernest; Roberts, Fiona; Kasza, Kristen; Mayr, Thomas; Kirisits, Michael J; Wollmann, Robert; Ferguson, David JP; Roberts, Craig W; Hwang, Jong-Hee; Trendler, Toria; Kennan, Richard P; Suzuki, Yasuhiro; Reardon, Catherine; Hickey, William F; Chen, Lieping; McLeod, Rima

    2008-01-01

    Background Worldwide, approximately two billion people are chronically infected with Toxoplasma gondii with largely unknown consequences. Methods To better understand long-term effects and pathogenesis of this common, persistent brain infection, mice were infected at a time in human years equivalent to early to mid adulthood and studied 5–12 months later. Appearance, behavior, neurologic function and brain MRIs were studied. Additional analyses of pathogenesis included: correlation of brain weight and neurologic findings; histopathology focusing on brain regions; full genome microarrays; immunohistochemistry characterizing inflammatory cells; determination of presence of tachyzoites and bradyzoites; electron microscopy; and study of markers of inflammation in serum. Histopathology in genetically resistant mice and cytokine and NRAMP knockout mice, effects of inoculation of isolated parasites, and treatment with sulfadiazine or αPD1 ligand were studied. Results Twelve months after infection, a time equivalent to middle to early elderly ages, mice had behavioral and neurological deficits, and brain MRIs showed mild to moderate ventricular dilatation. Lower brain weight correlated with greater magnitude of neurologic abnormalities and inflammation. Full genome microarrays of brains reflected inflammation causing neuronal damage (Gfap), effects on host cell protein processing (ubiquitin ligase), synapse remodeling (Complement 1q), and also increased expression of PD-1L (a ligand that allows persistent LCMV brain infection) and CD 36 (a fatty acid translocase and oxidized LDL receptor that mediates innate immune response to beta amyloid which is associated with pro-inflammation in Alzheimer's disease). Immunostaining detected no inflammation around intra-neuronal cysts, practically no free tachyzoites, and only rare bradyzoites. Nonetheless, there were perivascular, leptomeningeal inflammatory cells, particularly contiguous to the aqueduct of Sylvius and hippocampus

  3. Progestins Upregulate FKBP51 Expression in Human Endometrial Stromal Cells to Induce Functional Progesterone and Glucocorticoid Withdrawal: Implications for Contraceptive- Associated Abnormal Uterine Bleeding.

    PubMed

    Guzeloglu Kayisli, Ozlem; Kayisli, Umit A; Basar, Murat; Semerci, Nihan; Schatz, Frederick; Lockwood, Charles J

    2015-01-01

    Use of long-acting progestin only contraceptives (LAPCs) offers a discrete and highly effective family planning method. Abnormal uterine bleeding (AUB) is the major side effect of, and cause for, discontinuation of LAPCs. The endometria of LAPC-treated women display abnormally enlarged, fragile blood vessels, decreased endometrial blood flow and oxidative stress. To understanding to mechanisms underlying AUB, we propose to identify LAPC-modulated unique gene cluster(s) in human endometrial stromal cells (HESCs). Protein and RNA isolated from cultured HESCs treated 7 days with estradiol (E2) or E2+ medroxyprogesterone acetate (MPA) or E2+ etonogestrel (ETO) or E2+ progesterone (P4) were analyzed by quantitative Real-time (q)-PCR and immunoblotting. HSCORES were determined for immunostained-paired endometria of pre-and 3 months post-Depot MPA (DMPA) treated women and ovariectomized guinea pigs (GPs) treated with placebo or E2 or MPA or E2+MPA for 21 days. In HESCs, whole genome analysis identified a 67 gene group regulated by all three progestins, whereas a 235 gene group was regulated by E2+ETO and E2+MPA, but not E2+P4. Ingenuity pathway analysis identified glucocorticoid receptor (GR) activation as one of upstream regulators of the 235 MPA and ETO-specific genes. Among these, microarray results demonstrated significant enhancement of FKBP51, a repressor of PR/GR transcriptional activity, by both MPA and ETO. q-PCR and immunoblot analysis confirmed the microarray results. In endometria of post-DMPA versus pre-DMPA administered women, FKBP51 expression was significantly increased in endometrial stromal and glandular cells. In GPs, E2+MPA or MPA significantly increased FKBP51 immunoreactivity in endometrial stromal and glandular cells versus placebo- and E2-administered groups. MPA or ETO administration activates GR signaling and increases endometrial FKBP51 expression, which could be one of the mechanisms causing AUB by inhibiting PR and GR-mediated transcription

  4. Progestins Upregulate FKBP51 Expression in Human Endometrial Stromal Cells to Induce Functional Progesterone and Glucocorticoid Withdrawal: Implications for Contraceptive- Associated Abnormal Uterine Bleeding

    PubMed Central

    Guzeloglu Kayisli, Ozlem; Kayisli, Umit A.; Basar, Murat; Semerci, Nihan; Schatz, Frederick; Lockwood, Charles J.

    2015-01-01

    Use of long-acting progestin only contraceptives (LAPCs) offers a discrete and highly effective family planning method. Abnormal uterine bleeding (AUB) is the major side effect of, and cause for, discontinuation of LAPCs. The endometria of LAPC-treated women display abnormally enlarged, fragile blood vessels, decreased endometrial blood flow and oxidative stress. To understanding to mechanisms underlying AUB, we propose to identify LAPC-modulated unique gene cluster(s) in human endometrial stromal cells (HESCs). Protein and RNA isolated from cultured HESCs treated 7 days with estradiol (E2) or E2+ medroxyprogesterone acetate (MPA) or E2+ etonogestrel (ETO) or E2+ progesterone (P4) were analyzed by quantitative Real-time (q)-PCR and immunoblotting. HSCORES were determined for immunostained-paired endometria of pre-and 3 months post-Depot MPA (DMPA) treated women and ovariectomized guinea pigs (GPs) treated with placebo or E2 or MPA or E2+MPA for 21 days. In HESCs, whole genome analysis identified a 67 gene group regulated by all three progestins, whereas a 235 gene group was regulated by E2+ETO and E2+MPA, but not E2+P4. Ingenuity pathway analysis identified glucocorticoid receptor (GR) activation as one of upstream regulators of the 235 MPA and ETO-specific genes. Among these, microarray results demonstrated significant enhancement of FKBP51, a repressor of PR/GR transcriptional activity, by both MPA and ETO. q-PCR and immunoblot analysis confirmed the microarray results. In endometria of post-DMPA versus pre-DMPA administered women, FKBP51 expression was significantly increased in endometrial stromal and glandular cells. In GPs, E2+MPA or MPA significantly increased FKBP51 immunoreactivity in endometrial stromal and glandular cells versus placebo- and E2-administered groups. MPA or ETO administration activates GR signaling and increases endometrial FKBP51 expression, which could be one of the mechanisms causing AUB by inhibiting PR and GR-mediated transcription

  5. Inhibition of late Na+ current, a novel target to improve diastolic function and electrical abnormalities in Dahl salt-sensitive rats.

    PubMed

    Chi, Liguo; Belardinelli, Luiz; Zeng, Aliya; Hirakawa, Ryoko; Rajamani, Sridharan; Ling, Haiyun; Dhalla, Arvinder K

    2016-05-15

    Late Na(+) current (INaL) is enhanced in myocytes of animals with chronic heart failure and patients with hypertrophic cardiomyopathy. To define the role of INaL in diastolic heart failure, the effects of GS-458967 (GS-967), a potent INaL inhibitor on mechanical and electrical abnormalities, were determined in an animal model of diastolic dysfunction. Dahl salt-sensitive (DSS) rats fed a high-salt (HS) diet for 8 wk, compared with a normal salt (NS) diet, had increased left ventricular (LV) mass (1,257 ± 96 vs. 891 ± 34 mg) and diastolic dysfunction [isovolumic relaxation time (IVRT): 26.8 ± 0.5 vs. 18.9 ± 0.2 ms; early transmitral flow velocity/early mitral annulus velocity (E/E') ratio: 25.5 ± 1.9 vs. 14.9 ± 0.9]. INaL in LV myocytes from HS rats was significantly increased to 0.41 ± 0.02 from 0.14 ± 0.02 pA/pF in NS rats. The action potential duration (APD) was prolonged to 136 ± 12 from 68 ± 9 ms in NS rats. QTc intervals were longer in HS vs. NS rats (267 ± 8 vs. 212 ± 2 ms). Acute and chronic treatment with GS-967 decreased the enhanced INaL to 0.24 ± 0.01 and 0.17 ± 0.02 pA/pF, respectively, vs. 0.41 ± 0.02 pA/pF in the HS group. Chronic treatment with GS-967 dose-dependently reduced LV mass, the increases in E/E' ratio, and the prolongation of IVRT by 27, 27, and 20%, respectively, at the 1.0 mg·kg(-1)·day(-1) dose without affecting blood pressure or LV systolic function. The prolonged APDs in myocytes and QTc of HS rats were significantly reduced with GS-967 treatment. These results indicate that INaL is a significant contributor to the LV diastolic dysfunction, hypertrophy, and repolarization abnormalities and thus, inhibition of this current is a promising therapeutic target for diastolic heart failure. PMID:26993228

  6. Structural and Functional Abnormalities of Retinal Ganglion Cells Measured In Vivo at the Onset of Optic Nerve Head Surface Change in Experimental Glaucoma

    PubMed Central

    Fortune, Brad; Burgoyne, Claude F.; Cull, Grant A.; Reynaud, Juan; Wang, Lin

    2012-01-01

    Purpose. To compare peripapillary retinal nerve fiber layer thickness (RNFLT), RNFL retardance, and retinal function at the onset of optic nerve head (ONH) surface topography change in experimental glaucoma (EG). Methods. Thirty-three rhesus macaques had three or more weekly baseline measurements in both eyes of ONH surface topography, peripapillary RNFLT, RNFL retardance, and multifocal electroretinography (mfERG). Laser photocoagulation was then applied to the trabecular meshwork of one eye to induce chronic elevation of IOP and weekly recordings continued alternating between ONH surface topography and RNFLT during one week and RNFL retardance and mfERG the next week. Data were pooled for the group at the onset of ONH surface topography change in each EG eye, which was defined as the first date when either the mean position of the disc (MPD) fell below the 95% confidence limit of each eye's individual baseline range and/or when the topographic change analysis (TCA) map was subjectively judged as having demonstrated change, whichever came first. Analysis of variance with post hoc tests corrected for multiple comparisons were used to assess parameter changes. Results. At onset of ONH surface topography change, there was no significant difference for RNFLT versus baseline or fellow control eyes. RNFL retardance and mfERG were significantly reduced in the recordings just prior (median of 9 days) to ONH onset (P < 0.01) and had progressed significantly (P < 0.001) an average of 17 days later (median of 7 days after ONH onset). RNFLT did not exhibit significant thinning until 15 days after onset of ONH surface topography change (P < 0.001). Conclusions. These results support the hypothesis that during the course of glaucomatous neurodegeneration, axonal cytoskeletal and retinal ganglion cell functional abnormalities exist before thinning of peripapillary RNFL axon bundles begins. PMID:22589428

  7. Altered Functionality of Anti-Bacterial Antibodies in Patients with Chronic Hepatitis C Virus Infection

    PubMed Central

    Lamontagne, Anne; Long, Ronald E.; Comunale, Mary Ann; Hafner, Julie; Rodemich-Betesh, Lucy; Wang, Mengjun; Marrero, Jorge; Di Bisceglie, Adrian M.; Block, Timothy; Mehta, Anand

    2013-01-01

    Background Using comparative glycoproteomics, we have previously identified a glycoprotein that is altered in both amount and glycosylation as a function of liver cirrhosis. The altered glycoprotein is an agalactosylated (G0) immunoglobulin G molecule (IgG) that recognizes the heterophilic alpha-gal epitope. Since the alpha gal epitope is found on gut enterobacteria, it has been hypothesized that anti-gal antibodies are generated as a result of increased bacterial exposure in patients with liver disease. Methods The N-linked glycosylation of anti-gal IgG molecules from patients with fibrosis and cirrhosis was determined and the effector function of anti-bacterial antibodies from over 100 patients examined. In addition, markers of microbial exposure were determined. Results Surprisingly, the subset of agalactosylated anti-gal antibodies described here, was impaired in their ability to mediate complement mediated lysis and inhibited the complement-mediated destruction of common gut bacteria. In an analysis of serum from more than 100 patients with liver disease, we have shown that those with increased levels of this modified anti-gal antibody had increased levels of markers of bacterial exposure. Conclusions Anti-gal antibodies in patients with liver cirrhosis were reduced in their ability to mediate complement mediated lysis of target cells. As bacterial infection is a major complication in patients with cirrhosis and bacterial products such as LPS are thought to play a major role in the development and progression of liver fibrosis, this finding has many clinical implications in the etiology, prognosis and treatment of liver disease. PMID:23750224

  8. Down regulation of hepatic PPARalpha function by AhR ligand.

    PubMed

    Shaban, Zein; El-Shazly, Samir; Abdelhady, Shawky; Fattouh, Ibrahim; Muzandu, Kaampwe; Ishizuka, Mayumi; Kimura, Kazuhiro; Kazusaka, Akio; Fujita, Shoichi

    2004-11-01

    Aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that mediates a spectrum of toxic and biological effects of 2,3,7,8-tetrachloro dibenzo-p-dioxin (TCDD) and related compounds. Peroxisome proliferator activated receptor alpha (PPARalpha) is a nuclear receptor involved in the maintenance of lipid and glucose homeostasis. In this study we hypothesized that one of the possible mechanisms for the effect of TCDD and its related chemicals on fat metabolism could be through down regulation of PPARalpha functions. We treated Wistar rats with an AhR ligand, Sudan III (S.III), and/or PPARalpha ligand, Clofibric Acid (CA), for 3 days. We analysed the expression of one of the PPARalpha-target gene products, CYP4A protein and its mRNA. We also tested HepG2 cells with the afore-mentioned treatments and evaluated their effects on PPARalpha and RXRalpha protein. Treatment of Wistar rats with S.III was found to down regulates CYP4A protein expression and reduced its induction with CA. It also decreased mRNA expressions of CYP4A1, CYP4A2, CYP4A3 and PPARalpha. In HepG2 cells, PPARalpha and RXRalpha protein expression was decreased by S.III treatment in a dose dependent manner. Our results suggest that AhR has an inhibitory effect on PPARalpha function and a new pathway by which AhR ligands could disturb lipid metabolism. PMID:15585952

  9. Abnormal Head Position

    MedlinePlus

    ... cause. Can a longstanding head turn lead to any permanent problems? Yes, a significant abnormal head posture could cause permanent ... occipitocervical synostosis and unilateral hearing loss. Are there any ... postures? Yes. Abnormal head postures can usually be improved depending ...

  10. Urine - abnormal color

    MedlinePlus

    ... straw-yellow. Abnormally colored urine may be cloudy, dark, or blood-colored. Causes Abnormal urine color may ... red blood cells, or mucus in the urine. Dark brown but clear urine is a sign of ...

  11. NHERF-1 Binds to Mrp2 and Regulates Hepatic Mrp2 Expression and Function*

    PubMed Central

    Li, Man; Wang, Wei; Soroka, Carol J.; Mennone, Albert; Harry, Kathy; Weinman, Edward J.; Boyer, James L.

    2010-01-01

    Multidrug resistance-associated protein 2 (Mrp2, Abcc2) is an ATP-binding cassette transporter localized at the canalicular membrane of hepatocytes that plays an important role in bile formation and detoxification. Prior in vitro studies suggest that Mrp2 can bind to Na+/H+ exchanger regulatory factor 1 (NHERF-1), a PDZ protein that cross-links membrane proteins to actin filaments. However the role of NHERF-1 in the expression and functional regulation of Mrp2 remains largely unknown. Here we examine the interaction of Mrp2 and NHERF-1 and its physiological significance in HEK293 cells and NHERF-1 knock-out mice. Mrp2 co-precipitated with NHERF-1 in co-transfected HEK293 cells, an interaction that required the PDZ-binding motif of Mrp2. In NHERF-1−/− mouse liver, Mrp2 mRNA was unchanged but Mrp2 protein was reduced in whole cell lysates and membrane-enriched fractions to ∼50% (p < 1 × 10−6) and ∼70% (p < 0.05), respectively, compared with wild-type mice, suggesting that the down-regulation of Mrp2 expression was caused by post-transcriptional events. Mrp2 remained localized at the apical/canalicular membrane of NHERF-1−/− mouse hepatocytes, although its immunofluorescent labeling was noticeably weaker. Bile flow in NHERF-1−/− mice was reduced to ∼70% (p < 0.001) in association with a 50% reduction in glutathione excretion (p < 0.05) and a 60% reduction in glutathione-methylfluorescein (GS-MF) excretion in isolated mouse hepatocyte (p < 0.01). Bile acid and bilirubin excretion remained unchanged compared with wild-type mice. These findings strongly suggest that NHERF-1 binds to Mrp2, and plays a critical role in the canalicular expression of Mrp2 and its function as a determinant of glutathione-dependent, bile acid-independent bile flow. PMID:20404332

  12. The role of rumen-protected choline in hepatic function and performance of transition dairy cows.

    PubMed

    Shahsavari, Arash; D'Occhio, Michael J; Al Jassim, Rafat

    2016-07-01

    High-producing dairy cows enter a period of negative energy balance during the first weeks of lactation. Energy intake is usually sufficient to cover the increase in energy requirements for fetal growth during the period before calving, but meeting the demand for energy is often difficult during the early stages of lactation. A catabolic state predominates during the transition period, leading to the mobilisation of energy reserves (NEFA and amino acids) that are utilised mainly by the liver and muscle. Increased uptake of mobilised NEFA by the liver, combined with the limited capacity of hepatocytes to either oxidise fatty acids for energy or to incorporate esterified fatty acids into VLDL results in fatty liver syndrome and ketosis. This metabolic disturbance can affect the general health, and it causes economic losses. Different nutritional strategies have been used to restrict negative effects associated with the energy challenge in transition cows. The provision of choline in the form of rumen-protected choline (RPC) can potentially improve liver function by increasing VLDL exportation from the liver. RPC increases gene expression of microsomal TAG transfer protein and APOB100 that are required for VLDL synthesis and secretion. Studies with RPC have looked at gene expression, metabolic hormones, metabolite profiles, milk production and postpartum reproduction. A reduction in liver fat and enhanced milk production has been observed with RPC supplementation. However, the effects of RPC on health and reproduction are equivocal, which could reflect the lack of sufficient dose-response studies. PMID:27138530

  13. A galactose-functionalized dendritic siRNA-nanovector to potentiate hepatitis C inhibition in liver cells

    NASA Astrophysics Data System (ADS)

    Lakshminarayanan, Abirami; Reddy, B. Uma; Raghav, Nallani; Ravi, Vijay Kumar; Kumar, Anuj; Maiti, Prabal K.; Sood, A. K.; Jayaraman, N.; Das, Saumitra

    2015-10-01

    A RNAi based antiviral strategy holds the promise to impede hepatitis C viral (HCV) infection overcoming the problem of emergence of drug resistant variants, usually encountered in the interferon free direct-acting antiviral therapy. Targeted delivery of siRNA helps minimize adverse `off-target' effects and maximize the efficacy of therapeutic response. Herein, we report the delivery of siRNA against the conserved 5'-untranslated region (UTR) of HCV RNA using a liver-targeted dendritic nano-vector functionalized with a galactopyranoside ligand (DG). Physico-chemical characterization revealed finer details of complexation of DG with siRNA, whereas molecular dynamic simulations demonstrated sugar moieties projecting ``out'' in the complex. Preferential delivery of siRNA to the liver was achieved through a highly specific ligand-receptor interaction between dendritic galactose and the asialoglycoprotein receptor. The siRNA-DG complex exhibited perinuclear localization in liver cells and co-localization with viral proteins. The histopathological studies showed the systemic tolerance and biocompatibility of DG. Further, whole body imaging and immunohistochemistry studies confirmed the preferential delivery of the nucleic acid to mice liver. Significant decrease in HCV RNA levels (up to 75%) was achieved in HCV subgenomic replicon and full length HCV-JFH1 infectious cell culture systems. The multidisciplinary approach provides the `proof of concept' for restricted delivery of therapeutic siRNAs using a target oriented dendritic nano-vector.A RNAi based antiviral strategy holds the promise to impede hepatitis C viral (HCV) infection overcoming the problem of emergence of drug resistant variants, usually encountered in the interferon free direct-acting antiviral therapy. Targeted delivery of siRNA helps minimize adverse `off-target' effects and maximize the efficacy of therapeutic response. Herein, we report the delivery of siRNA against the conserved 5'-untranslated

  14. Spirometric abnormalities among welders

    SciTech Connect

    Rastogi, S.K.; Gupta, B.N.; Husain, T.; Mathur, N.; Srivastava, S. )

    1991-10-01

    A group of manual welders age group 13-60 years having a mean exposure period of 12.4 {plus minus} 1.12 years were subjected to spirometry to evaluate the prevalence of spirometric abnormalities. The welders showed a significantly higher prevalence of respiratory impairment than that observed among the unexposed controls as a result of exposure to welding gases which comprised fine particles of lead, zinc, chromium, and manganese. This occurred despite the lower concentration of the pollutants at the work place. In the expose group, the smoking welders showed a prevalence of respiratory impairment significantly higher than that observed in the nonsmoking welders. The results of the pulmonary function tests showed a predominantly restrictive type of pulmonary impairment followed by a mixed ventilatory defect among the welders. The effect of age on pulmonary impairment was not discernible. Welders exposed for over 10 years showed a prevalence of respiratory abnormalities significantly higher than those exposed for less than 10 years. Smoking also had a contributory role.

  15. Identification of functionally important negatively charged residues in the carboxy end of mouse hepatitis coronavirus A59 nucleocapsid protein.

    PubMed

    Verma, Sandhya; Bednar, Valerie; Blount, Andrew; Hogue, Brenda G

    2006-05-01

    The coronavirus nucleocapsid (N) protein is a multifunctional viral gene product that encapsidates the RNA genome and also plays some as yet not fully defined role in viral RNA replication and/or transcription. A number of conserved negatively charged amino acids are located within domain III in the carboxy end of all coronavirus N proteins. Previous studies suggested that the negatively charged residues are involved in virus assembly by mediating interaction between the membrane (M) protein carboxy tail and nucleocapsids. To determine the importance of these negatively charged residues, a series of alanine and other charged-residue substitutions were introduced in place of those in the N gene within a mouse hepatitis coronavirus A59 infectious clone. Aspartic acid residues 440 and 441 were identified as functionally important. Viruses could not be isolated when both residues were replaced by positively charged amino acids. When either amino acid was replaced by a positively charged residue or both were changed to alanine, viruses were recovered that contained second-site changes within N, but not in the M or envelope protein. The compensatory role of the new changes was confirmed by the construction of new viruses. A few viruses were recovered that retained the D441-to-arginine change and no compensatory changes. These viruses exhibited a small-plaque phenotype and produced significantly less virus. Overall, results from our analysis of a large panel of plaque-purified recovered viruses indicate that the negatively charged residues at positions 440 and 441 are key residues that appear to be involved in virus assembly. PMID:16611893

  16. Functional characterization of nuclear localization and export signals in hepatitis C virus proteins and their role in the membranous web.

    PubMed

    Levin, Aviad; Neufeldt, Christopher J; Pang, Daniel; Wilson, Kristen; Loewen-Dobler, Darci; Joyce, Michael A; Wozniak, Richard W; Tyrrell, D Lorne J

    2014-01-01

    The hepatitis C virus (HCV) is a positive strand RNA virus of the Flavivirus family that replicates in the cytoplasm of infected hepatocytes. Previously, several nuclear localization signals (NLS) and nuclear export signals (NES) have been identified in HCV proteins, however, there is little evidence that these proteins travel into the nucleus during infection. We have recently shown that nuclear pore complex (NPC) proteins (termed nucleoporins or Nups) are present in the membranous web and are required during HCV infection. In this study, we identify a total of 11 NLS and NES sequences in various HCV proteins. We show direct interactions between HCV proteins and importin α5 (IPOA5/kapα1), importin β3 (IPO5/kap β3), and exportin 1 (XPO1/CRM1) both in-vitro and in cell culture. These interactions can be disrupted using peptides containing the specific NLS or NES sequences of HCV proteins. Moreover, using a synchronized infection system, we show that these peptides inhibit HCV infection during distinct phases of the HCV life cycle. The inhibitory effects of these peptides place them in two groups. The first group binds IPOA5 and inhibits infection during the replication stage of HCV life cycle. The second group binds IPO5 and is active during both early replication and early assembly. This work delineates the entire life cycle of HCV and the active involvement of NLS sequences during HCV replication and assembly. Given the abundance of NLS sequences within HCV proteins, our previous finding that Nups play a role in HCV infection, and the relocation of the NLS double-GFP reporter in HCV infected cells, this work supports our previous hypothesis that NPC-like structures and nuclear transport factors function in the membranous web to create an environment conducive to viral replication. PMID:25485706

  17. Effect of allyl alcohol on hepatic transporter expression: Zonal patterns of expression and role of Kupffer cell function

    PubMed Central

    Campion, Sarah N.; Tatis-Rios, Cristina; Augustine, Lisa M.; Goedken, Michael J.; van Rooijen, Nico; Cherrington, Nathan J.; Manautou, José E.

    2015-01-01

    During APAP toxicity, activation of Kupffer cells is critical for protection from hepatotoxicity and up-regulation of multidrug resistance-associated protein 4 (Mrp4) in centrilobular hepatocytes. The present study was performed to determine the expression profile of uptake and efflux transporters in mouse liver following treatment with allyl alcohol (AlOH), a periportal hepatotoxicant. This study also investigated the role of Kupffer cells in AlOH hepatotoxicity, and whether changes in transport protein expression by AlOH are dependent on the presence of Kupffer cells. C57BL/6J mice received 0.1 ml clodronate liposomes to deplete Kupffer cells or empty liposomes 48 h prior to dosing with 60 mg/kg AlOH, i.p. Hepatotoxicity was assessed by plasma ALT and histopathology. Hepatic transporter mRNA and protein expression were determined by branched DNA signal amplification assay and Western blotting, respectively. Depletion of Kupffer cells by liposomal clodronate treatment resulted in heightened susceptibility to AlOH toxicity. Exposure to AlOH increased mRNA levels of several Mrp genes, while decreasing organic anion transporting polypeptides (Oatps) mRNA expression. Protein analysis mirrored many of these mRNA changes. The presence of Kupffer cells was not required for the observed changes in uptake and efflux transporters induced by AlOH. Immunofluorescent analysis revealed enhanced Mrp4 staining exclusively in centrilobular hepatocytes of AlOH treated mice. These findings demonstrate that Kupffer cells are protective from AlOH toxicity and that induction of Mrp4 occurs in liver regions away from areas of AlOH damage independent of Kupffer cell function. These results suggest that Kupffer cell mediators do not play a role in mediating centrilobular Mrp4 induction in response to periportal damage by AlOH. PMID:19371622

  18. Functional Characterization of Nuclear Localization and Export Signals in Hepatitis C Virus Proteins and Their Role in the Membranous Web

    PubMed Central

    Levin, Aviad; Neufeldt, Christopher J.; Pang, Daniel; Wilson, Kristen; Loewen-Dobler, Darci; Joyce, Michael A.; Wozniak, Richard W.; Tyrrell, D. Lorne J

    2014-01-01

    The hepatitis C virus (HCV) is a positive strand RNA virus of the Flavivirus family that replicates in the cytoplasm of infected hepatocytes. Previously, several nuclear localization signals (NLS) and nuclear export signals (NES) have been identified in HCV proteins, however, there is little evidence that these proteins travel into the nucleus during infection. We have recently shown that nuclear pore complex (NPC) proteins (termed nucleoporins or Nups) are present in the membranous web and are required during HCV infection. In this study, we identify a total of 11 NLS and NES sequences in various HCV proteins. We show direct interactions between HCV proteins and importin α5 (IPOA5/kapα1), importin β3 (IPO5/kap β3), and exportin 1 (XPO1/CRM1) both in-vitro and in cell culture. These interactions can be disrupted using peptides containing the specific NLS or NES sequences of HCV proteins. Moreover, using a synchronized infection system, we show that these peptides inhibit HCV infection during distinct phases of the HCV life cycle. The inhibitory effects of these peptides place them in two groups. The first group binds IPOA5 and inhibits infection during the replication stage of HCV life cycle. The second group binds IPO5 and is active during both early replication and early assembly. This work delineates the entire life cycle of HCV and the active involvement of NLS sequences during HCV replication and assembly. Given the abundance of NLS sequences within HCV proteins, our previous finding that Nups play a role in HCV infection, and the relocation of the NLS double-GFP reporter in HCV infected cells, this work supports our previous hypothesis that NPC-like structures and nuclear transport factors function in the membranous web to create an environment conducive to viral replication. PMID:25485706

  19. Effect of allyl alcohol on hepatic transporter expression: Zonal patterns of expression and role of Kupffer cell function

    SciTech Connect

    Campion, Sarah N.; Tatis-Rios, Cristina; Augustine, Lisa M.; Goedken, Michael J.; Rooijen, Nico van; Cherrington, Nathan J.; Manautou, Jose E.

    2009-04-01

    During APAP toxicity, activation of Kupffer cells is critical for protection from hepatotoxicity and up-regulation of multidrug resistance-associated protein 4 (Mrp4) in centrilobular hepatocytes. The present study was performed to determine the expression profile of uptake and efflux transporters in mouse liver following treatment with allyl alcohol (AlOH), a periportal hepatotoxicant. This study also investigated the role of Kupffer cells in AlOH hepatotoxicity, and whether changes in transport protein expression by AlOH are dependent on the presence of Kupffer cells. C57BL/6J mice received 0.1 ml clodronate liposomes to deplete Kupffer cells or empty liposomes 48 h prior to dosing with 60 mg/kg AlOH, i.p. Hepatotoxicity was assessed by plasma ALT and histopathology. Hepatic transporter mRNA and protein expression were determined by branched DNA signal amplification assay and Western blotting, respectively. Depletion of Kupffer cells by liposomal clodronate treatment resulted in heightened susceptibility to AlOH toxicity. Exposure to AlOH increased mRNA levels of several Mrp genes, while decreasing organic anion transporting polypeptides (Oatps) mRNA expression. Protein analysis mirrored many of these mRNA changes. The presence of Kupffer cells was not required for the observed changes in uptake and efflux transporters induced by AlOH. Immunofluorescent analysis revealed enhanced Mrp4 staining exclusively in centrilobular hepatocytes of AlOH treated mice. These findings demonstrate that Kupffer cells are protective from AlOH toxicity and that induction of Mrp4 occurs in liver regions away from areas of AlOH damage independent of Kupffer cell function. These results suggest that Kupffer cell mediators do not play a role in mediating centrilobular Mrp4 induction in response to periportal damage by AlOH.

  20. Pericholecystic hepatic activity in cholescintigraphy

    SciTech Connect

    Smith, R.; Rosen, J.M.; Gallo, L.N.; Alderson, P.O.

    1985-09-01

    Gallbladder nonvisualization in cholescintigraphy has been shown to be a reliable finding in acute cholecystitis. In some cholescintigrams, the authors have observed faintly increased pericholecystic hepatic activity in conjunction with gallbladder nonvisualization. To determine the frequency and significance of the pericholecystic hepatic activity finding, they evaluated 334 consecutive adult patients who had cholescintigrams with technetium-99m diisopropylphenylcarboamoyl iminodiacetic acid. Pericholecystic hepatic activity was seen in 21% of the abnormal scans demonstrating gallbladder nonvisualization but in none of the other scans. Thirteen of these patients underwent surgery; 11 (85%) were found to have acute cholecystitis, and two (15%) had chronic cholecystitis. The pericholecystic hepatic activity sign is not specific for gangrenous cholecystitis or gallbladder perforation but does reliably indicate inflammatory gallbladder disease and is associated with a relatively high incidence of cholecystitis complicated by perforation.

  1. Calcium and ER stress mediate hepatic apoptosis after burn injury

    PubMed Central

    Gauglitz, Gerd G.; Song, Juquan; Kulp, Gabriela A.; Finnerty, Celeste C.; Cox, Robert A.; Barral, José M.; Herndon, David N.; Boehning, Darren

    2009-01-01

    Abstract A hallmark of the disease state following severe burn injury is decreased liver function, which results in gross metabolic derangements that compromise patient survival. The underlying mechanisms leading to hepatocyte dysfunction after burn are essentially unknown. The aim of the present study was to determine the underlying mechanisms leading to hepatocyte dysfunction and apoptosis after burn. Rats were randomized to either control (no burn) or burn (60% total body surface area burn) and sacrificed at various time‐points. Liver was either perfused to isolate primary rat hepatocytes, which were used for in vitro calcium imaging, or liver was harvested and processed for immunohistology, transmission electron microscopy, mitochondrial isolation, mass spectroscopy or Western blotting to determine the hepatic response to burn injury in vivo. We found that thermal injury leads to severely depleted endoplasmic reticulum (ER) calcium stores and consequent elevated cytosolic calcium concentrations in primary hepatocytes in vitro. Burn‐induced ER calcium depletion caused depressed hepatocyte responsiveness to signalling molecules that regulate hepatic homeostasis, such as vasopressin and the purinergic agonist ATP. In vivo, thermal injury resulted in activation of the ER stress response and major alterations in mitochondrial structure and function – effects which may be mediated by increased calcium release by inositol 1,4,5‐trisphosphate receptors. Our results reveal that thermal injury leads to dramatic hepatic disturbances in calcium homeostasis and resultant ER stress leading to mitochondrial abnormalities contributing to hepatic dysfunction and apoptosis after burn injury. PMID:20141609

  2. Effect of erythropoietin on hepatic cytochrome P450 expression and function in an adenine-fed rat model of chronic kidney disease

    PubMed Central

    Feere, D A; Velenosi, T J; Urquhart, B L

    2015-01-01

    BACKGROUND AND PURPOSE Erythropoietin (EPO) is used to treat anaemia associated with chronic kidney disease (CKD). Hypoxia is associated with anaemia and is known to cause a decrease in cytochrome P450 (P450) expression. As EPO production is regulated by hypoxia, we investigated the role of EPO on P450 expression and function. EXPERIMENTAL APPROACH Male Wistar rats were subjected to a 0.7% adenine diet for 4 weeks to induce CKD. The diet continued for an additional 2 weeks while rats received EPO by i.p. injection every other day. Following euthanasia, hepatic P450 mRNA and protein expression were determined. Hepatic enzyme activity of selected P450s was determined and chromatin immunoprecipitation was used to characterize binding of nuclear receptors involved in the transcriptional regulation of CYP2C and CYP3A. KEY RESULTS EPO administration decreased hepatic mRNA and protein expression of CYP3A2 (P < 0.05), but not CYP2C11. Similarly, EPO administration decreased CYP3A2 protein expression by 81% (P < 0.001). A 32% decrease (P < 0.05) in hepatic CYP3A enzymatic activity (Vmax) was observed for the formation of 6βOH-testosterone in the EPO-treated group. Decreases in RNA pol II recruitment (P < 0.01), hepatocyte nuclear factor 4α binding (P < 0.05) and pregnane X receptor binding (P < 0.01) to the promoter region of CYP3A were also observed in EPO-treated rats. CONCLUSIONS AND IMPLICATIONS Our data show that EPO decreases the expression and function of CYP3A, but not CYP2C in rat liver. PMID:25219905

  3. Hepatitis Vaccines

    PubMed Central

    Ogholikhan, Sina; Schwarz, Kathleen B.

    2016-01-01

    Viral hepatitis is a serious health problem all over the world. However, the reduction of the morbidity and mortality due to vaccinations against hepatitis A and hepatitis B has been a major component in the overall reduction in vaccine preventable diseases. We will discuss the epidemiology, vaccine development, and post-vaccination effects of the hepatitis A and B virus. In addition, we discuss attempts to provide hepatitis D vaccine for the 350 million individuals infected with hepatitis B globally. Given the lack of a hepatitis C vaccine, the many challenges facing the production of a hepatitis C vaccine will be shown, along with current and former vaccination trials. As there is no current FDA-approved hepatitis E vaccine, we will present vaccination data that is available in the rest of the world. Finally, we will discuss the existing challenges and questions facing future endeavors for each of the hepatitis viruses, with efforts continuing to focus on dramatically reducing the morbidity and mortality associated with these serious infections of the liver. PMID:26978406

  4. Hepatitis Vaccines.

    PubMed

    Ogholikhan, Sina; Schwarz, Kathleen B

    2016-01-01

    Viral hepatitis is a serious health problem all over the world. However, the reduction of the morbidity and mortality due to vaccinations against hepatitis A and hepatitis B has been a major component in the overall reduction in vaccine preventable diseases. We will discuss the epidemiology, vaccine development, and post-vaccination effects of the hepatitis A and B virus. In addition, we discuss attempts to provide hepatitis D vaccine for the 350 million individuals infected with hepatitis B globally. Given the lack of a hepatitis C vaccine, the many challenges facing the production of a hepatitis C vaccine will be shown, along with current and former vaccination trials. As there is no current FDA-approved hepatitis E vaccine, we will present vaccination data that is available in the rest of the world. Finally, we will discuss the existing challenges and questions facing future endeavors for each of the hepatitis viruses, with efforts continuing to focus on dramatically reducing the morbidity and mortality associated with these serious infections of the liver. PMID:26978406

  5. Variable patterns of programmed death-1 expression on fully functional memory T cells after spontaneous resolution of hepatitis C virus infection.

    PubMed

    Bowen, David G; Shoukry, Naglaa H; Grakoui, Arash; Fuller, Michael J; Cawthon, Andrew G; Dong, Christine; Hasselschwert, Dana L; Brasky, Kathleen M; Freeman, Gordon J; Seth, Nilufer P; Wucherpfennig, Kai W; Houghton, Michael; Walker, Christopher M

    2008-05-01

    The inhibitory receptor programmed death-1 (PD-1) is present on CD8(+) T cells in chronic hepatitis C virus (HCV), but expression patterns in spontaneously resolving infections are incompletely characterized. Here we report that PD-1 was usually absent on memory CD8(+) T cells from chimpanzees with resolved infections, but sustained low-level expression was sometimes observed in the absence of apparent virus replication. PD-1-positive memory T cells expanded and displayed antiviral activity upon reinfection with HCV, indicating conserved function. This animal model should facilitate studies of whether PD-1 differentially influences effector and memory T-cell function in resolved versus persistent human infections. PMID:18337576

  6. Functional polymorphisms in microRNA gene and hepatitis B risk among Asian population: a meta-analysis.

    PubMed

    Zhou, G Q; Meng, H; Wang, J R; Sun, F X; Wang, X J; Wang, R B; Wang, X B

    2015-01-01

    Genetic mutations in microRNA gene can alter expression, which may interact to increase the risk of developing various diseases, including hepatitis B. However, published results are inconclusive or ambiguous. The aim of this review and meta-analysis is to more precisely estimate the association between polymorphisms in microRNA genes and hepatitis B risk. A digital search was performed of the MEDLINE EMBASE, CNKI, and CBM databases to identify relevant articles published up to February 18, 2014. Ten case-control studies were included, with a total of 6042 patients with hepatitis B and 6834 healthy controls. Nine single-nucleotide polymorphisms in the miRNA gene were examined, including miR-34b/c [rs4938723 (T>C)], miR-196a-2 [rs11614913 (C>T)], miR-146a [rs2910164 (G>C)], miR-499 [rs3746444 (T>C)], miR-122 [rs3783553 (ins/del)], miR-149 [rs2292832 (C>T)], miR-106b-25 [rs999885 (A>G)], miR-let-7c [rs6147150 (ins/del)], and miR-218 [rs11134527 (A>G)]. The meta-analysis results indicated that the miR-196a-2*T, miR-122*del, miR-106b-25*A, and miR-let-7c*del alleles/carriers increase the risk of hepatitis B among the Asian population. However, the miR-146a, miR- 499, miR-149, miR-218, and miR-34b/c polymorphisms may not be linked with the risk of hepatitis B. Further investigations are warranted to determine the exact associations between microRNA mutations and hepatitis B susceptibility. PMID:25966251

  7. Four different mutations in codon 28 of alpha spectrin are associated with structurally and functionally abnormal spectrin alpha I/74 in hereditary elliptocytosis.

    PubMed Central

    Coetzer, T L; Sahr, K; Prchal, J; Blacklock, H; Peterson, L; Koler, R; Doyle, J; Manaster, J; Palek, J

    1991-01-01

    Hereditary elliptocytosis (HE) Sp alpha I/74 is a disorder associated with defective spectrin (Sp) heterodimer self-association and an abnormal tryptic cleavage of the 80-kD alpha I domain of Sp resulting in increased amounts of a 74-kD peptide. The molecular basis of this disorder is heterogeneous and mutations in codons 28, 46, 48, and 49 (codons 22, 40, 42, and 43 in the previous nomenclature which did not include the six NH2-terminal amino acids) have been reported. In this study we present data on seven unrelated HE Sp alpha I/74 kindred from diverse racial backgrounds in whom we identified four different mutations all occurring in exon 2 of alpha Sp at codon 28. Utilizing the polymerase chain reaction we established a CGT----CTT; Arg----Leu 28 mutation in one kindred of Arab/Druze origin. In two unrelated white kindred of English/European origin the substitution is CGT----AGT; Arg----Ser 28 and in two apparently unrelated white kindred from New Zealand, the mutation is CGT----TGT; Arg----Cys 28. Finally, in one American black kindred and in a black kindred from Ghana the mutation involves CGT----CAT; Arg----His 28. Allele specific oligonucleotide hybridization confirmed that the probands are heterozygous for the respective mutant alleles. All four point mutations abolished an Aha II restriction enzyme site which allowed verification of linkage of the mutation with HE Sp alpha I/74. Our results imply that codon 28 of alpha Sp is a "hot spot" for mutations and also indicate that Arg 28 is critical for the conformational stability and functional self association of Sp heterodimers. Images PMID:1679439

  8. Predictive Models for Regional Hepatic Function Based upon 99mTc-IDA SPECT and Local Radiation Dose for Physiological Adaptive RT

    PubMed Central

    Wang, Hesheng; Feng, Mary; Frey, Kirk A.; Ten Haken, Randall K.; Lawrence, Theodore S.; Cao, Yue

    2013-01-01

    Purpose High dose radiation therapy (RT) for intrahepatic cancer is limited by the development of liver injury. This study investigated whether regional hepatic function assessed prior to and during the course of RT using 99mTc-labeled immindodiacetic acid (IDA) SPECT could predict regional liver function reserve after RT. Methods and Materials Fourteen patients treated with RT for intrahepatic cancers underwent dynamic 99mTc-IDA SPECT scans prior to RT, during, and one month after completion of RT. Indocyanine green (ICG) tests (a measure of overall liver function) were performed within 1 day of each scan. 3D volumetric hepatic extraction fraction (HEF) images of the liver were estimated by deconvolution analysis. After co-registration of the CT/SPECT and the treatment planning CT, HEF dose-response functions during and post-RT were generated. The volumetric mean of the HEFs in the whole liver was correlated with ICG clearance time. Three models, Dose, Priori and Adaptive models, were developed using multivariate linear regression to assess whether the regional HEFs measured before and during RT helped predict regional hepatic function post-RT. Results The mean of the volumetric liver HEFs was significantly correlated with ICG clearance half-life time (r = −0.80, p<0.0001), for all time points. Linear correlations between local doses and regional HEFs one month post-RT were significant in 12 patients. In the priori model, regional HEF post-RT was predicted by the planned dose and regional HEF assessed prior to RT (R=0.71, p<0.0001). In the adaptive model, regional HEF post-RT was predicted by regional HEF re-assessed during RT and the remaining planned local dose (R=0.83, p<0.0001). Conclusions 99mTc-IDA SPECT obtained during RT could be used to assess regional hepatic function and helped predict post-RT regional liver function reserve. This could support individualized adaptive radiation treatment strategies to maximize tumor control and minimize the risk of

  9. Hepatobiliary scintigraphy in patients receiving hepatic artery infusion chemotherapy

    SciTech Connect

    Housholder, D.F.; Hynes, H.E.; Dakhil, S.R.; Marymont, J.V.

    1985-05-01

    Hepatic artery infusion chemotherapy is used in the treatment of certain selected hepatic tumors, especially metastatic adenocarcinoma of the colon. Chemical cholecystitis has been recognized recently as a complication of hepatic artery infusion chemotherapy. The authors performed hepatobiliary scans on ten patients receiving hepatic artery infusion chemotherapy. All ten patients had abnormal hepatobiliary scintigraphy. They present case reports of three patients with abnormal hepatobiliary scans who have required cholecystectomy for symptoms of chemical cholecystitis to illustrate the clinical, scintigraphic, and pathologic findings in these patients.

  10. Cardiac and other abnormalities in the sudden infant death syndrome.

    PubMed

    Naeye, R L; Whalen, P; Ryser, M; Fisher, R

    1976-01-01

    Many victims of the sudden infant death syndrome (SIDS) have abnormally heavy cardiac right ventricles. The degree of this abnormality is directly proportional to: a) the mass of muscle about small pulmonary arteries, b) the amount of brown fat retention about adrenal glands, and c) the presence of hepatic erythropoiesis. The pulmonary arterial abnormality is probably the result of chronic alveolar hypoventilation, while brown fat retention and hepatic erythropoiesis are likely consequences of chronic hypoxemia. These abnormalities are found in both SIDS victims who die with and those who die without mild respiratory tract infections. However, there are some differences between the two SIDS groups. Infected victims die at an older age and have smaller thymus glands and larger spleens; there is a greater proportion of males in the infected victims than in the noninfected victims. PMID:1247080

  11. Hepatitis B Vaccine

    MedlinePlus

    ... as a combination product containing Hepatitis A Vaccine, Hepatitis B Vaccine) ... What is hepatitis B?Hepatitis B is a serious infection that affects the liver. It is caused by the hepatitis B virus. ...

  12. Hepatitis A Vaccine

    MedlinePlus

    Twinrix® (as a combination product containing Hepatitis A Vaccine, Hepatitis B Vaccine) ... What is hepatitis A?Hepatitis A is a serious liver disease caused by the hepatitis A virus (HAV). HAV is found in ...

  13. Hepatitis C: Clinical Trials

    MedlinePlus

    ... and Public Home » Hepatitis C » Treatment Decisions Viral Hepatitis Menu Menu Viral Hepatitis Viral Hepatitis Home For ... can I find out about participating in a hepatitis C clinical trial? Many trials are being conducted ...

  14. Autoimmune hepatitis

    MedlinePlus

    ... diseases. These include: Graves disease Inflammatory bowel disease Rheumatoid arthritis Scleroderma Sjogren syndrome Systemic lupus erythematosus Thyroiditis Type 1 diabetes Ulcerative colitis Autoimmune hepatitis may occur in family ...

  15. Hepatitis B

    MedlinePlus

    ... A Hepatitis B HPV (Human Papillomavirus) Influenza (Flu) Measles Meningococcal Disease Mumps Pertussis (Whooping Cough) Pneumococcal Disease Rubella (German Measles) Shingles (Herpes Zoster) Tetanus (Lockjaw) Professional Resources Adult ...

  16. Euforia-induced acute hepatitis in a patient with scleroderma.

    PubMed

    Jiménez-Encarnación, Esther; Ríos, Grissel; Muñoz-Mirabal, Angel; Vilá, Luis M

    2012-01-01

    Euforia, a supplement containing a variety of natural ingredients, is widely used as an antioxidant and anti-inflammatory formula. It is not approved by the US Food and Drug Administration and its side effects are unknown. We report a 45-year-old woman with limited systemic sclerosis who presented with jaundice and marked elevation of serum transaminases. One month before, she started taking Euforia juice. A liver biopsy disclosed submassive hepatocellular necrosis with histopathological changes consistent with toxic hepatitis. The patient's symptoms resolved with cessation of Euforia. Six months later, she persisted with abnormal liver function tests, but these resolved 18 months after discontinuation of Euforia. The mechanism by which Euforia causes liver injury is unknown. Some ingredients contained in this supplement (green tea, Aloe vera, noni and goji) are linked to hepatic injury. To our knowledge, this is the first report of hepatotoxicity associated with Euforia. PMID:23257938

  17. Tamm-Horsfall protein in recurrent calcium kidney stone formers with positive family history: abnormalities in urinary excretion, molecular structure and function.

    PubMed

    Jaggi, Markus; Nakagawa, Yasushi; Zipperle, Ljerka; Hess, Bernhard

    2007-04-01

    Tamm-Horsfall protein (THP) powerfully inhibits calcium oxalate crystal aggregation, but structurally abnormal THPs from recurrent calcium stone formers may promote crystal aggregation. Therefore, increased urinary excretion of abnormal THP might be of relevance in nephrolithiasis. We studied 44 recurrent idiopathic calcium stone formers with a positive family history of stone disease (RCSF(fam)) and 34 age- and sex-matched healthy controls (C). Twenty-four-hour urinary THP excretion was measured by enzyme linked immunosorbent assay. Structural properties of individually purified THPs were obtained from analysis of elution patterns from a Sepharose 4B column. Sialic acid (SA) contents of native whole 24-h urines, crude salt precipitates of native urines and individually purified THPs were measured. THP function was studied by measuring inhibition of CaOx crystal aggregation in vitro (pH 5.7, 200 mM sodium chloride). Twenty-four-hour urine excretion of THP was higher in RCSF(fam) (44.0 +/- 4.0 mg/day) than in C (30.9 +/- 2.2 mg/day, P = 0.015). Upon salt precipitation and lyophilization, elution from a Sepharose 4B column revealed one major peak (peak A, cross-reacting with polyclonal anti-THP antibody) and a second minor peak (peak B, not cross-reacting). THPs from RCSF(fam) eluted later than those from C (P = 0.021), and maximum width of THP peaks was higher in RCSF(fam )than in C (P = 0.024). SA content was higher in specimens from RCSF(fam) than from C, in native 24-h urines (207.5 +/- 20.4 mg vs. 135.2 +/- 16.1 mg, P = 0.013) as well as in crude salt precipitates of 24-h urines (10.4 +/- 0.5 mg vs. 7.4 +/- 0.9 mg, P = 0.002) and in purified THPs (75.3 +/- 9.3 microg/mg vs. 48.8 +/- 9.8 microg/mg THP, P = 0.043). Finally, inhibition of calcium oxalate monohydrate crystal aggregation by 40 mg/L of THP was lower in RCSF(fam) (6.1 +/- 5.5%, range -62.0 to +84.2%) than in C (24.9 +/- 6.0%, range -39.8 to +82.7%), P = 0.022, and only 25 out of 44 (57%) THPs from RCSF

  18. Quantitative Liver Function Tests Improve the Prediction of Clinical Outcomes in Chronic Hepatitis C: Results from the HALT-C Trial

    PubMed Central

    Everson, Gregory T.; Shiffman, Mitchell L.; Hoefs, John C.; Morgan, Timothy R.; Sterling, Richard K.; Wagner, David A.; Lauriski, Shannon; Curto, Teresa M.; Stoddard, Anne; Wright, Elizabeth C.

    2011-01-01

    Risk for future clinical outcomes is proportional to the severity of liver disease in patients with chronic hepatitis C. We measured disease severity by quantitative liver function tests (QLFTs) to determine cutoffs for QLFTs that identified patients who were at low and high risk for a clinical outcome. Two hundred twenty seven participants in the Hepatitis C Antiviral Long-Term Treatment Against Cirrhosis (HALT-C) Trial underwent baseline QLFTs and were followed for a median of 5.5 years for clinical outcomes. QLFTs were repeated in 196 patients at month 24 and in 165 patients at month 48. Caffeine elimination rate (k), antipyrine (AP) clearance (Cl), MEGX concentration, methionine breath test (MBT), galactose elimination capacity (GEC), dual cholate (CA) clearances and shunt, and perfused hepatic mass (PHM) and liver and spleen volumes (SPECT) were measured. Baseline QLFTs were significantly worse (p=0.0017 to <0.0001) and spleen volumes larger (p<0.0001) in the 54 patients who subsequently experienced clinical outcomes. QLFT cutoffs that characterized patients as “low” and “high risk” for clinical outcome yielded hazard ratios ranging from 2.21 (95%CI 1.29–3.78) for GEC to 6.52 (95%CI 3.63–11.71) for CA Cloral. QLFTs independently predicted outcome in models with Ishak fibrosis score, platelet count, and standard laboratory tests. In serial studies, patients with “high risk” results for CA Cloral or PHM had a nearly 15-fold increase in risk for clinical outcome. Less than 5% of patients with “low risk” QLFTs experienced a clinical outcome. Conclusion QLFTs independently predict risk for future clinical outcomes. By improving risk assessment, QLFTs could enhance noninvasive monitoring, counseling, and management of patients with chronic hepatitis C. PMID:22030902

  19. Risk of hepatitis B transmission after amniocentesis in chronic hepatitis B carriers.

    PubMed Central

    Alexander, J M; Ramus, R; Jackson, G; Sercely, B; Wendel, G D

    1999-01-01

    OBJECTIVE: To measure the risk of perinatal transmission of HBV in chronic carriers who undergo amniocentesis. METHODS: This was a prospective, longitudinal study from 1990 to 1995 of women who were HBV carriers and underwent amniocentesis. The infants of these women were followed from birth to one year of age. Maternal data examined included HBV antigen and antibody status, liver function tests (LFTs) and the amniocentesis report. RESULTS: Twenty-eight women were identified. Two of 28 neonates were stillborn unrelated to hepatitis. Five infants were lost to follow-up leaving 21 mother-child pairs to evaluate. All 21 women were chronic HBV carriers at the time of amniocentesis for delivery. No mother had abnormal LFTs, and only one of 21 women was positive for hepatitis B e antigen (HBeAg). Thirteen amniocenteses were for advanced maternal age, and four were for abnormal maternal serum alphafetoprotein (MSAFP) screening. None of the amniocenteses were recorded as bloody, and the placenta was anterior in 6 of 21 procedures. None of the 21 infants (95% CI: 0-16.8%) were positive for HbsAg during the first month of life or at 12 months of age. All infants received HBV vaccine and HBIG immunoprophylaxis. CONCLUSION: The risk of transmission of HBV to the fetus after amniocentesis in women who are HBV carriers is low. Immunoprophylaxis in these infants was successful. PMID:10598917

  20. Hepatic (Liver) Function Panel

    MedlinePlus

    ... AST). This enzyme, which plays a role in processing proteins, is found in the liver, heart, muscles, ... doctor. © 1995- The Nemours Foundation. All rights reserved. Images provided by The Nemours Foundation, iStock, Getty Images, ...

  1. Function of a 5'-end genomic RNA mutation that evolves during persistent mouse hepatitis virus infection in vitro.

    PubMed Central

    Chen, W; Baric, R S

    1995-01-01

    Persistently infected cultures of DBT cells were established with mouse hepatitis virus strain A59 (MHV-A59), and the evolution of the MHV leader RNA and 5' end of the genome was studied through 119 days postinfection. Sequence analysis of independent clones demonstrated an overall mutation frequency approaching 1.2 x 10(-3) to 6.7 x 10(-3). The rate of fixation of mutations was about 1.2 x 10(-5) to 7.6 x 10(-5) per nucleotide (nt) per day. In contrast to finding in bovine coronavirus, the MHV leader RNA sequences were extremely stable and did not evolve significantly during persistent infection. Rather, a 5' untranslated region (UTR) A-to-G mutation at nt 77 in the genomic RNA emerged by day 56 and accumulated until 50 to 80% of the genome-length molecules retained the mutation by 119 days postinfection. Although other 5'-end mutations were noted, only the nt 77 mutation was significantly associated with viral persistence in vitro. Mutations were also found in the 5' end of the p28 coding region, but no specific alterations accumulated in genome-length molecules through 119 days postinfection. The 5' UTR nt 77 mutation resulted in an 18-amino-acid open reading frame (ORF) upstream of the ORF 1a AUG start site. By in vitro translation assays, the small ORF was not translated into detectable product but the mutation significantly enhanced translation of the downstream p28 ORF about 2.5-fold. Variant viruses, containing either the nt 77 A-to-G mutation (V16-ATG+) or wild-type sequences at this locus (V1-ATG-), were isolated at 119 days postinfection. The variant viruses replicated more efficiently than wild-type virus and were extremely cytolytic in DBT cells, suggesting that the A-to-G mutation did not encode a nonlytic or attenuated phenotype. Consistent with the in vitro translation results, a significant increase (approximately 3.5-fold) in p28 expression was also observed with the mutant virus (V16-ATG+) in DBT cells compared with that in wild-type controls

  2. Longitudinal Sequence and Functional Evolution within Glycoprotein E2 in Hepatitis C Virus Genotype 3a Infection

    PubMed Central

    Alhammad, Yousef M. O.; Maharajh, Sanvir; Butcher, Rebecca; Eden, John-Sebastian; White, Peter A.; Poumbourios, Pantelis; Drummer, Heidi E

    2015-01-01

    The E2 glycoprotein of Hepatitis C virus (HCV) is a major target of the neutralizing antibody (NAb) response with the majority of epitopes located within its receptor binding domain (RBD; 384–661). Within E2 are three variable regions located at the N-terminus (HVR1; 384–411), and internally at 460–480 (HVR2) and 570–580 [intergenotypic variable region (igVR)], all of which lie outside a conserved core domain that contains the CD81 binding site, essential for attachment of virions to host cells and a major target of NAbs. In this study, we examined the evolution of the E1 and E2 region in two patients infected with genotype 3a virus. Whereas one patient was able to clear the acute infection, the other developed a chronic infection. Mutations accumulated at multiple positions within the N-terminal HVR1 as well as within the igVR in both patients over time, whereas mutations in HVR2 were observed only in the chronically infected patient. Mutations within or adjacent to the CD81 contact site were observed in both patients but were less frequent and more conservative in the patient that cleared his/her infection. The evolution of CD81 binding function and antigenicity was examined with longitudinal E2 RBD sequences. The ability of the RBD to bind CD81 was completely lost by week 108 in the patient that developed chronic HCV. In the second patient, the ability of the week 36 RBD, just prior to viral clearance, to bind CD81 was reduced ~50% relative to RBD sequences obtained earlier. The binding of a NAb specific to a conserved epitope located within E2 residues 411–428 was significantly reduced by week 108 despite complete conservation of its epitope suggesting that E2 antigenicity is allosterically modulated. The exposure of non-neutralizing antibody epitopes was similarly explored and we observed that the epitope of 3 out of 4 non-NAbs were significantly more exposed in the RBDs representing the late timepoints in the chronic patient. By contrast, the

  3. The use of stable isotope-labeled glycerol and oleic acid to differentiate the hepatic functions of DGAT1 and -2

    PubMed Central

    Qi, Jenson; Lang, Wensheng; Geisler, John G.; Wang, Ping; Petrounia, Ioanna; Mai, Selyna; Smith, Charles; Askari, Hossein; Struble, Geoffrey T.; Williams, Robyn; Bhanot, Sanjay; Monia, Brett P.; Bayoumy, Shariff; Grant, Eugene; Caldwell, Gary W.; Todd, Matthew J.; Liang, Yin; Gaul, Micheal D.; Demarest, Keith T.; Connelly, Margery A.

    2012-01-01

    Diacylglycerol acyltransferase (DGAT) catalyzes the final step in triglyceride (TG) synthesis. There are two isoforms, DGAT1 and DGAT2, with distinct protein sequences and potentially different physiological functions. To date, the ability to determine clear functional differences between DGAT1 and DGAT2, especially with respect to hepatic TG synthesis, has been elusive. To dissect the roles of these two key enzymes, we pretreated HepG2 hepatoma cells with 13C3-D5-glycerol or 13C18-oleic acid, and profiled the major isotope-labeled TG species by liquid chromatography tandem mass spectrometry. Selective DGAT1 and DGAT2 inhibitors demonstrated that 13C3-D5-glycerol-incorporated TG synthesis was mediated by DGAT2, not DGAT1. Conversely, 13C18-oleoyl-incorporated TG synthesis was predominantly mediated by DGAT1. To trace hepatic TG synthesis and VLDL triglyceride (VLDL-TG) secretion in vivo, we administered D5-glycerol to mice and measured plasma levels of D5-glycerol-incorporated TG. Treatment with an antisense oligonucleotide (ASO) to DGAT2 led to a significant reduction in D5-glycerol incorporation into VLDL-TG. In contrast, the DGAT2 ASO had no effect on the incorporation of exogenously administered 13C18-oleic acid into VLDL-TG. Thus, our results indicate that DGAT1 and DGAT2 mediate distinct hepatic functions: DGAT2 is primarily responsible for incorporating endogenously synthesized FAs into TG, whereas DGAT1 plays a greater role in esterifying exogenous FAs to glycerol. PMID:22493088

  4. Dairy fat intake is associated with glucose tolerance, hepatic and systemic insulin sensitivity, and liver fat but not β-cell function in humans123

    PubMed Central

    Marcovina, Santica; Nelson, James E; Yeh, Matthew M; Kowdley, Kris V; Callahan, Holly S; Song, Xiaoling; Di, Chongzhi; Utzschneider, Kristina M

    2014-01-01

    Background: Plasma phospholipid concentrations of trans-palmitoleic acid (trans-16:1n−7), a biomarker of dairy fat intake, are inversely associated with incident type 2 diabetes in 2 US cohorts. Objective: The objective was to investigate whether the intake of trans-16:1n−7 in particular, or dairy fat in general, is associated with glucose tolerance and key factors determining glucose tolerance. Design: A cross-sectional investigation was undertaken in 17 men and women with nonalcoholic fatty liver disease and 15 body mass index (BMI)- and age-matched controls. The concentrations of trans-16:1n−7 and 2 other biomarkers of dairy fat intake, 15:0 and 17:0, were measured in plasma phospholipids and free fatty acids (FFAs). Liver fat was estimated by computed tomography–derived liver-spleen ratio. Intravenous-glucose-tolerance tests and oral-glucose-tolerance test (OGTT) and hyperinsulinemic-euglycemic clamps were performed to assess β-cell function and hepatic and systemic insulin sensitivity. Results: In multivariate analyses adjusted for age, sex, and BMI, phospholipid 17:0, phospholipid trans-16:1n−7, F