E A Jones

Academisch Medisch Centrum Universiteit van Amsterdam, Amsterdam, North Holland, Netherlands

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Publications (121)997.03 Total impact

  • E A Jones, J Neuberger, N V Bergasa
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    ABSTRACT: Increased opioidergic neurotransmission in the brain appears to contribute to the pruritus that complicates cholestasis and certain non-cholestatic chronic liver diseases. Opiate antagonists have been shown to decrease scratching activity in patients with the pruritus of cholestasis. Initiation of oral administration of an orally bioavailable opiate antagonist may precipitate a florid opioid-withdrawal-like reaction in patients with pruritus complicating cholestasis. Such reactions can be minimized, or avoided completely, by cautiously infusing naloxone before giving small oral doses of an orally bioavailable opiate antagonist. The infusion rate of naloxone should initially be very low; it should be increased gradually and stopped when a rate known to be associated with opioid antagonist effects has been attained. Oral therapy with an opiate antagonist can then be initiated.
    QJM: monthly journal of the Association of Physicians 09/2002; 95(8):547-52. · 2.46 Impact Factor
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    ABSTRACT: The P300 complex was derived from the electroencephalogram (EEG) as subjects mentally counted infrequent large checkerboard visual stimuli, presented randomly among frequent small checkerboard stimuli. Use of low contrast (10%) stimuli and four midline scalp electrodes, facilitated separation of cognitive and sensory components and enabled the P300 complex to be resolved into three distinct components--N200, P3a, and P3b. In 20 healthy adult subjects normative data were established and the P3a and P3b components were shown to depend on cognitive function. In 19 age-matched cirrhotic patients without overt hepatic encephalopathy (HE) the EEG and visual evoked potentials (VEPs) were normal, but latencies of P3a and/or P3b were prolonged in 9. Prolonged latencies were not associated with an abnormal number connection test. Ten additional age-matched cirrhotic patients without overt HE, who were alcohol, drug, and caffeine free, were randomized to receive flumazenil (1 mg) and placebo intravenously, double-blind. After flumazenil or placebo, latencies of P3a and P3b and psychometric test results did not change significantly. These findings suggest that in cirrhotic patients without overt HE (i) impaired cognitive sensory function may occur in the absence of abnormalities of a standard psychometric test, the EEG, or VEPs, and (ii) increased latencies of P3a and P3b may constitute a component of subclinical HE, which is not mediated by increased brain levels of central benzodiazepine receptor agonist ligands.
    Metabolic Brain Disease 07/2001; 16(1-2):43-53. DOI:10.1023/A:1011662411913 · 2.40 Impact Factor
  • E A Jones, N V Bergasa
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    ABSTRACT: The site of the pathogenic events responsible for initiating the pruritus of cholestasis has been assumed to be the skin. This assumption cannot be excluded but is not supported by convincing data. Empirical therapies such as anion exchange resins and rifampicin often appear to be partially efficacious. Recent evidence suggests that altered neurotransmission in the brain may contribute to this form of pruritus. In particular, the hypothesis that increased central opioidergic tone is involved is supported by three observations: opiate agonists induce opioid receptor-mediated scratching activity of central origin, central opioidergic tone is increased in cholestasis and opiate antagonists reduce scratching activity in cholestatic patients. Apparent subjective ameliorations of pruritus following intravenous administration of ondansetron to cholestatic patients suggest that altered serotoninergic neurotransmission may also contribute to this form of pruritus.
    Canadian journal of gastroenterology = Journal canadien de gastroenterologie 02/2000; 14(1):33-40. · 1.97 Impact Factor
  • E A Jones, N V Bergasa
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    ABSTRACT: The pathogenesis of the pruritus that complicates cholestasis in patients with primary biliary cirrhosis (PBC) is uncertain. The limited and inconsistent efficacy of conventional empiric therapies, such as anion exchange resins and rifampicin, has led to inconclusive trials of invasive experimental therapies, such as plasmapheresis, charcoal haemoperfusion and partial external diversion of bile. However, some double-blind, placebo-controlled trials that used a subjective primary efficacy end-point (the perception of pruritus) have suggested that certain drugs that affect the metabolism of many compounds, for example rifampicin, may be efficacious. The potential mechanisms by which such drugs may mediate a beneficial effect have not been determined. There is a paucity of data to indicate whether peripheral events, such as the accumulation of bile acids in interstitial fluid of the skin, initiate the neural events which mediate this form of pruritus. Recent findings suggest that central events in the brain, specifically an increase in neurotransmission/ neuromodulation mediated by endogenous opioid agonists (increased opioidergic tone), may be implicated. This hypothesis is supported by three lines of evidence. (1) Opioid receptor ligands with agonist properties (e.g. morphine) mediate pruritus. (2) Endogenous opioid-mediated neurotransmission/neuromodulation in the central nervous system (CNS) is increased in cholestasis. (3) Controlled trials have shown that opiate antagonists induce ameliorations of the behavioural consequence of the pruritus of cholestasis (scratching activity). In such trials, measurements of scratching activity independent of limb movements constituted an objective quantitative primary efficacy end-point. Potent opiate antagonists, that are bioavailable when given by mouth, such as nalmefene and naltrexone, may have a place in the long-term management of pruritus in patients with PBC. Evidence that increased serotoninergic neurotransmission also contributes to the pruritus is at present less strong than that implicating an involvement of the opioid system, and further investigation is needed to determine whether specific serotonin receptor subtype ligands have a place in the treatment of pruritus in patients with PBC. There is some evidence which suggests that increased serotoninergic neurotransmission in the CNS contributes to fatigue of central origin, but whether there is a causal relationship between altered serotoninergic neurotransmission and the profound fatigue that occurs in many patients with PBC is currently uncertain.
    European Journal of Gastroenterology & Hepatology 07/1999; 11(6):623-31. · 2.15 Impact Factor
  • E A Jones, A S Basile
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    ABSTRACT: The ammonia and GABAergic neurotransmission hypotheses of the pathogenesis of hepatic encephalopathy (HE) have appeared to be unrelated and perhaps mutually exclusive. Observations in animal models of fulminant hepatic failure, that are consistent with increased GABAergic inhibitory neurotransmission contributing to the manifestations of HE, include: (i) abnormal visual evoked potential waveforms that resemble those induced by GABA(A)/benzodiazepine (BZ) receptor complex agonists; (ii) GABA(A)/BZ receptor complex antagonist-induced ameliorations of encephalopathy; (iii) increased resistance to drugs which decrease GABAergic tone; and (iv) hypersensitivity of CNS neurons to depression by GABA(A)/BZ receptor complex agonists. Mechanisms of increased GABAergic tone in HE may include the following: (i) increased brain concentrations of natural BZs; and (ii) increased GABA concentrations in synaptic clefts, possibly due to increased blood-brain-barrier permeability to GABA and a decrease in GABA(B) receptor density. Both neuroelectrophysiological and behavioral data indicate that ammonia concentrations in the range 0.75-2 mM induce increased excitatory neurotransmission. In contrast, recently, ammonia concentrations in the range 0.15-0.75 mM, i.e. concentrations that commonly occur in plasma in precoma HE, have been shown: (i) to increase GABA-induced chloride current in cultured neurons; and (ii) to enhance synergistically the binding of GABA(A)/BZ receptor agonists. In addition, increased ammonia concentrations enhance synthesis of neurosteroids in astrocytes, and some neurosteroids potently augment GABAergic neurotransmission. Thus, the modestly elevated concentrations of ammonia, that commonly occur in liver failure, may contribute to the manifestations of HE by enhancing GABAergic inhibitory neurotransmission. This concept appears to unify the ammonia and GABAergic neurotransmission hypotheses.
    Metabolic Brain Disease 01/1999; 13(4):351-60. DOI:10.1023/A:1020693026810 · 2.40 Impact Factor
  • N V Bergasa, E A Jones
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    ABSTRACT: Pruritus is a distressing symptom experienced by a large proportion of patients with cholestasis. The cause of this form of pruritus is unknown, and therapy tends to be empirical and unsatisfactory. This article discusses the emerging role of the brain and neurotransmitter systems in the pathogenesis of the pruritus of cholestasis and emphasizes the importance of the application of quantitative methodology in clinical trials of therapies for the pruritus of cholestasis.
    Clinics in Liver Disease 06/1998; 2(2):391-405, x. · 2.70 Impact Factor
  • E. A. Jones, N. V. Bergasa
  • N. V. Bergasa, E. A. Jones
  • N. V. Bergasa, E. A. Jones
  • Source
    A S Basile, EA Jones
    Hepatology 06/1997; 25(6):1303-5. DOI:10.1002/hep.510250636 · 11.19 Impact Factor
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    ABSTRACT: To assess the feasibility of developing a model of overt portal-systemic encephalopathy (PSE) in rats with a surgically constructed portacaval anastomosis (PCA). The ability of increasing the load of nitrogenous substances in the gastrointestinal tract and/or further decreasing hepatocellular function to induce overt encephalopathy in rats with a PCA was determined. The load of nitrogenous substances in the gastrointestinal tract was increased by feeding a pure horse-meat diet or by gavaging with blood. Partial hepatectomy and the induction of cirrhosis were used to decrease hepatocellular function further. The severity of encephalopathy was assessed using a neurobehavioural scale. Overt encephalopathy was not induced in rats by a PCA alone, by a PCA plus a horse-meat diet, by a PCA plus induction of cirrhosis, or by a PCA plus a 50% hepatectomy. Predominantly mild, but overt, encephalopathy was induced in rats with a PCA alone by gavaging with blood and a higher incidence of more severe overt encephalopathy was induced in rats with a PCA combined with either cirrhosis or partial hepatectomy by gavaging with blood. Although these models of PSE were associated in some instances with plasma ammonia concentrations about 25 times higher than normal, no seizures were observed. A syndrome that resembles overt PSE in humans can be induced in the rat with a PCA by further reducing hepatocellular function and also gavaging with blood. Although the rat with a PCA has been. extensively used as a model in studies relating to the pathogenesis of PSE, a syndrome resembling overt PSE in humans cannot readily be induced in rats with a PCA.
    European Journal of Gastroenterology & Hepatology 04/1997; 9(3):293-8. DOI:10.1097/00042737-199703000-00014 · 2.15 Impact Factor
  • Advances in Experimental Medicine and Biology 02/1997; 420:85-94. · 2.01 Impact Factor
  • E A Jones, A S Basile
    Advances in Experimental Medicine and Biology 02/1997; 420:75-83. · 2.01 Impact Factor
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    E A Jones, C Yurdaydin
    Hepatology 02/1997; 25(2):492-4. DOI:10.1002/hep.510250239 · 11.19 Impact Factor
  • K D Mullen, EA Jones
    Seminars in Liver Disease 09/1996; 16(3):255-64. DOI:10.1055/s-2007-1007238 · 5.12 Impact Factor
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    ABSTRACT: The expression of cytokine mRNA species was determined in liver biopsies from six normal subjects, 18 patients with PBC and 14 patients with hepatitis B e antigen (HBeAg)-positive CHB using a reverse transcriptase-polymerase chain reaction (RT-PCR) technique. cDNA, obtained by reverse transcription using oligo d(T) primers, was amplified by PCR using primers specific for the coding region of seven different cytokines (IL-1, IL-2, IL-4, IL-5, IL-6, interferon-gamma (IFN-gamma), tumour necrosis factor-alpha (TNF-alpha)). The abundance of some cytokines (IL-2, IL-4, IL-5 and IFN-gamma) was also estimated by semiquantitative RT-PCR, using as standards dilutions of synthetic cytokine mRNA transcripts, that could be distinguished electrophoretically from respective native cytokine mRNAs. Hepatic inflammation was assessed by a semiquantitative histologic score and by amplification of mRNA for T cell receptor (TCR)-alpha. mRNAs for IL-1 and IL-6 were detected in only one control liver. In CHB, mRNAs for IL-1, IL-2, IL-4, IL-5 and IFN-gamma were detected in 43%, 60%, 80%, 20%, and 54% of biopsies, respectively. mRNA for IFN-gamma and IL-4, but not IL-1, tended to be associated with severe inflammation. In five biopsies semiquantitative analyses revealed increased levels of mRNA for TCR-alpha and, when transcripts were detectable, high levels of mRNA for IFN-gamma and IL-4. In PBC, mRNA for IFN-gamma was detected in 60% of biopsies, but no mRNAs for IL-1, IL-2, IL-4, IL-5, or IL-6, or for TNF-alpha, were detected. Semiquantitative analyses revealed that absolute levels of mRNA for IFN-gamma tended to correlate with the severity of hepatic inflammation. The results suggest that: (i) there may be fundamental differences in the roles that cytokines play in the hepatic inflammatory processes of PBC and CHB; and (ii) while hepatic IFN-gamma mRNA expression is not specific for PBC, IFN-gamma may play a prominent role in the immunopathogenesis of PBC.
    Clinical & Experimental Immunology 09/1996; 105(2):254-9. DOI:10.1046/j.1365-2249.1996.d01-759.x · 3.28 Impact Factor
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    EA Jones, N V Bergasa
    Gut 06/1996; 38(5):644-5. DOI:10.1136/gut.38.5.644 · 13.32 Impact Factor
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    ABSTRACT: The p53 tumor suppressor gene is commonly mutated in human hepatocellular carcinoma (HCC). The most frequent mutation in HCC in populations exposed to a high dietary intake of aflatoxin B1 (AFB1) is an AGGarg-->AGTser missense mutation in codon 249 of the p53 gene. We analyzed HCCs from Monterrey, Mexico, for the codon 249ser hotspot mutation. We also analyzed the serum AFB1-albumin adduct levels of the donors and family members to measure the current AFB1 exposure in this population. Moreover, the presence of hepatitis B and/or C viral infection (HBV or HCV) was analyzed serologically in the patients. Tumor cells were microdissected from tissue sections and exon 7 p53 sequences were amplified by polymerase chain reaction from genomic DNA and sequenced directly. The serological tests for anti-p53 antibodies, HBV or HCV were done by ELISA. Immunohistochemical analysis of p53 protein was done using a polyclonal rabbit antiserum (CM-1). Eight of 21 cases were positive by p53 immunohistochemistry. Of the 16 cases sequenced for exon 7 of p53 three codon 249 AGGarg-->AGTser mutations were found. Serum antibodies recognizing p53 protein were found in one of 18 patients. Positive serology for HBV and/or HCV was found in 12 of 20 cases. The serum AFB1-albumin adduct levels in this population ranged from 0.54 to 4.64 pmol aflatoxin/mg albumin. These results indicate that dietary AFB1 and hepatitis viruses are etiological agents in the molecular pathogenesis of HCC in this geographic region of Mexico.
    Carcinogenesis 06/1996; 17(5):1007-12. DOI:10.1093/carcin/17.5.1007 · 5.27 Impact Factor
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    ABSTRACT: To determine whether endogenous opioids contribute to the pruritus of cholestasis by studying the effect of the opiate antagonist naloxone on the perception of pruritus and on scratching activity in patients with this form of pruritus. Double-blind, placebo-controlled, crossover trial with four periods. Clinical research referral center. 29 pruritic patients with liver diseases of various causes. Each patient received as many as two naloxone and two placebo solution infusions consecutively in random order. Each infusion lasted 24 hours. During the infusions, visual analog scores of pruritus were recorded every 4 hours while patients were awake; scratching activity independent of limb movements was recorded continuously. One patient had a mild reaction consistent with a naloxone-precipitated syndrome similar to opiate withdrawal. A significant 24-hour rhythm of scratching activity was seen in 7 of 11 patients for whom complete 96-hour data were collected. The mean of a visual analog score of the perception of pruritus (maximum, 10.0) recorded during naloxone infusions was 0.582 lower than that recorded during placebo infusions (95% CI, 0.176 to 0.988; P < 0.01). Furthermore, the ratio of the geometric mean hourly scratching activity during naloxone infusions to that during placebo infusions was 0.727 (CI, 0.612 to 0.842; P < 0.001) and was greater than 1.0 in only five patients. Naloxone administration is associated with amelioration of the perception of pruritus and reduction of scratching activity in cholestatic patients. Because of the opioid receptor specificity of the action of naloxone, these findings support the hypothesis that a mechanism underlying the pruritus of cholestasis is modulated by endogenous opioids and suggest that opiate antagonists may have a role in the management of this complication of cholestasis.
    Annals of internal medicine 09/1995; 123(3):161-7. · 16.10 Impact Factor
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    ABSTRACT: Although plasma levels of Met-enkephalin and beta-endorphin are elevated in patients suffering from liver failure, it is not known whether central nervous system (CNS) opioidergic neurotransmission is altered in these patients. Such changes may contribute to the motor dysfunction, psychiatric abnormalities and CNS depression observed in hepatic encephalopathy (HE). Therefore, Met- and Leu-enkephalin, dynorphin A and beta-endorphin levels were measured in discrete brain regions and plasma from thioacetamide-treated rats in Stages II to IV of HE. Pituitary and plasma beta-endorphin, Met- and Leu-enkephalin concentrations increased with the severity of HE by 50 to 290%. Pituitary and brainstem dynorphin A levels increased whereas plasma levels decreased in rats with thioacetamide-induced fulminant hepatic failure. Both striatal Met- and Leu-enkephalin levels increased and hypothalamic concentrations decreased in HE. Concurrent with the increase in striatal Met-enkephalin levels was a 26 to 48% decrease in the density of striatal and hypothalamic delta receptors. No change in either the density or affinity of radioligand binding to mu or delta receptors was observed in the CNS. Finally, administering (+/-)-naloxone (5 and 10 mg/kg) or (+/-)-naltrexone (5-15 mg/kg), but not (+)-naloxone (10 mg/kg), significantly increased the motor activity of rats with Stage III HE. Whereas elevated plasma levels of opioid peptides may play a role in the peripheral manifestations of hepatic failure (ascites and hypotension), increased CNS levels of these peptides may be involved in the neuropsychiatric abnormalities characteristic of HE. Thus, opioid antagonists may be effective in ameliorating some of the neurological manifestations of HE.
    Journal of Pharmacology and Experimental Therapeutics 05/1995; 273(1):185-92. · 3.86 Impact Factor

Publication Stats

4k Citations
997.03 Total Impact Points

Institutions

  • 1996–2002
    • Academisch Medisch Centrum Universiteit van Amsterdam
      • Academic Medical Center
      Amsterdam, North Holland, Netherlands
  • 1998
    • Beth Israel Medical Center
      • Division of Gastroenterology & Liver Disease
      New York City, New York, United States
  • 1972–1997
    • National Institutes of Health
      • • Laboratory of Neurosciences (LNS)
      • • Branch of Digestive Diseases (DDB)
      • • Branch of Metabolism
      Bethesda, MD, United States
  • 1987–1995
    • The National Institute of Diabetes and Digestive and Kidney Diseases
      Maryland, United States
  • 1994
    • Ankara University
      • Department of Gastroenterology
      Ankara, Ankara, Turkey
  • 1985–1994
    • The University of Calgary
      • • Gastrointestinal Research Group
      • • Department of Medicine
      Calgary, Alberta, Canada
  • 1990
    • National Heart, Lung, and Blood Institute
      Maryland, United States
  • 1988
    • Bethesda Neuroscience Clinic
      Maryland, United States