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Biomedical subjects

E A Jones

Publications and source records attributed to E A Jones.

At least 19 recordsLinked to original sources
PubMed2006

Personal view: a potential novel treatment for fatigue complicating chronic liver disease--how should its efficacy be evaluated?

Profound fatigue is a clinically significant complication of chronic liver disease. A mechanism of fatigue in experimental animals and male athletes appears to be increased serotoninergic neurotransmission in the brain. Recently, attempts have been made to assess the efficacy of a serotonin antagonist, specifically the 5-HT3 receptor subtype antagonist, ondansetron, in ameliorating fatigue in patients with chronic liver disease. However, the results of a randomized controlled trial of ondansetron for fatigue in patients with primary biliary cirrhosis did not indicate that ondansetron was either effective or ineffective. The reasons for the uncertain outcome of the randomized controlled trial are not clear. One contributing factor may have been the use of subjective indices of fatigue as primary efficacy endpoints. There is a need to develop objective quantitative primary efficacy endpoints for use in trials of therapy for fatigue. Another contributing factor may relate to the conduct of a randomized controlled trial not invariably being the optimal approach to resolve a specific clinical issue, particularly when the application of statistical methods yields equivocal findings. When the results of a randomized controlled trial are indecisive, findings based on clinical judgement, medicine's most important asset, should be carefully evaluated.

Fatigue↗
PubMed2005

Application of TOF-SIMS with chemometrics to discriminate between four different yeast strains from the species Candida glabrata and Saccharomyces cerevisiae.

We present a TOF-SIMS analysis of the cell surface differences between four yeast strains from two species, Candida glabrata and Saccharomyces cerevisiae (haploid strains BY4742 and BY4741 and the derived diploid BY4743). The study assesses the suitability of TOF-SIMS analysis in combination with statistical methods (principal component analysis, Fisher's discriminant analysis, and cluster analysis) for the discrimination between the four yeast strains. We demonstrate that a combination of these statistical methods identifies 34 ions, from a total data set of 1200, which can be used to distinguish between the four yeasts. The study discusses the assignments of surface cell membrane phospholipids for the identified ions and the resulting differences in the phospholipid pattern between the four yeasts, particularly in relation to ploidy and budding pattern. The method shows that fatty acids, phosphatidylglycerols, phosphatidylethanolamines, phosphatidylserines, and phosphatidylcholines, as well as cardiolipins, are of diagnostic importance.

Candida glabrata↗
PubMed2003

Review article: is there an optimal therapeutic regimen for antimitochondrial antibody-negative primary biliary cirrhosis (autoimmune cholangitis)?

Testing for antimitochondrial antibodies is the most useful laboratory procedure in the diagnosis of primary biliary cirrhosis; nevertheless, 5-10% of patients with typical features of primary biliary cirrhosis do not have detectable antimitochondrial antibodies, their condition being referred to as antimitochondrial antibody-negative primary biliary cirrhosis or "autoimmune cholangitis". Uncertainty exists whether antimitochondrial antibody-positive and -negative primary biliary cirrhosis represent distinct entities. We reviewed studies that compared: (i) the clinical, laboratory and histological characteristics of antimitochondrial antibody-positive and -negative primary biliary cirrhosis; (ii) the response to treatment of both conditions; and (iii) the response of autoimmune cholangitis to ursodeoxycholic acid and immunosuppressive therapy. Antimitochondrial antibody-positive and -negative primary biliary cirrhosis were characterized by similar clinical, laboratory and histological abnormalities, clinical course and survival. Antimitochondrial antibody status did not seem to affect the response to ursodeoxycholic acid. At present, the efficacy of therapies for autoimmune cholangitis has not been established in controlled trials. Of 52 patients with autoimmune cholangitis treated with ursodeoxycholic acid in 13 uncontrolled studies, 83% had serum biochemical improvement. Also, a favourable effect of immunosuppressive drugs occurred in 57% of 54 patients with autoimmune cholangitis in 17 uncontrolled studies. Each of these trials included very few patients and most evaluated the effects of treatment on surrogate markers of disease only. No marker that consistently distinguished patients who would respond favourably to ursodeoxycholic acid or immunosuppression was apparent. Consequently, treatment is, at present, empirical. However, ursodeoxycholic acid may be given when histology reveals bile duct lesions, whereas immunosuppressive therapy should probably be reserved for patients exhibiting interface hepatitis.

Antibodies↗
PubMed2003

Itch: scratching more than the surface.

In origin, itch can be cutaneous ("pruritoceptive", e.g. dermatitis), neuropathic (e.g. multiple sclerosis), neurogenic (e.g. cholestasis), mixed (e.g. uraemia) or psychogenic. Although itch of cutaneous origin shares a common neural pathway with pain, the afferent C-fibres subserving this type of itch are a functionally distinct subset: they respond to histamine, acetylcholine and other pruritogens, but are insensitive to mechanical stimuli. Histamine is the main mediator for itch in insect bite reactions and in most forms of urticaria, and in these circumstances the itch responds well to H(1)-antihistamines. However, in most dermatoses and in systemic disease, low-sedative H(1)-antihistamines are ineffective. Opioid antagonists relieve itch caused by spinal opioids, cholestasis and, possibly, uraemia. Ondansetron relieves itch caused by spinal opioids (but not cholestasis and uraemia). Other drug treatments for itch include rifampicin, colestyramine and 17-alpha alkyl androgens (cholestasis), thalidomide (uraemia), cimetidine and corticosteroids (Hodgkin's lymphoma), paroxetine (paraneoplastic itch), aspirin and paroxetine (polycythaemia vera) and indometacin (some HIV+ patients). If the remedies specified fail, paroxetine and mirtazapine should be considered. Ultraviolet B therapy, particularly narrow-band UVB, may be superior to drug treatment for itch in uraemia.

Analgesics, Opioid↗
PubMed2002

Xbra3 elicits the production of neural tissue by a non-BMP-dependent mechanism in Xenopus sp.

Ectoderm cells in animal caps from Xenopus embryos develop to form either epidermis or neural tissue depending upon their receipt of intercellular signals. To date, several secreted neural inducers have been identified which act through the local inhibition of bone morphogenetic protein (BMP) signaling, preventing differentiation to epidermis and resulting in adoption of neural fate. In this work, we have exploited an interspecies animal cap assay, which enables detection of the effects of signaling molecules produced by cells of one animal cap and influencing development in a second cap cultured in close apposition in a Holtfreter combination. We show that expression of the T-box protein, Xbra3, in one cap causes the production of a factor, which causes adoption of neural fate by cells of the other animal cap. The action of this factor is not inhibited by the over-expression of BMP in cells of the responding animal cap, or by the inhibition of Wnt signaling. These findings suggest the existence of a secreted signaling molecule that is able to induce ectodermal cells to adopt neural fate by a mechanism independent of the inhibition of the BMP or Wnt signaling pathways.

Animals↗
PubMed2002

Th1/Th2 cytokine expression and its relationship with tumor growth in B cell non-Hodgkin's lymphoma (NHL).

AT helper 1 (Th1) immune response is considered more effective than T helper 2 (Th2) for anti-tumor immunity, but either response could potentially stimulate tumor cell growth in lymphomas. Moreover, both IL-4 and IL-2/IL-12 are used in experimental treatment models for non-Hodgkin's lymphoma (NHL) despite their differing ability to elicit Th2 or Th1 responses, respectively. Here, we investigate which T helper cytokines (Th1 or Th2) predominate in B cell NHL tissue and determine whether cytokine expression correlates with tumor cell growth, cell death, and survival in a series of 44 NHL patients. Overall, we observed both Th1 and Th2 cytokine expression at the mRNA level, detecting high levels of IFN-gamma, IL6 and IL-10 expression in the majority of tumors. Transcripts for the IL-12 subunits p35 (38 of 38) and p 40 (23 of 38) were frequently detected in NHL tissue, and high p40 levels were common in patients with a good prognosis. Furthermore, high IL-4 levels correlated with greater survival duration (P < 0.0024) but nor overall survival. Cytokine expression of IL-2, IFNgamma and IL-4 was significantly reduced in the high grade tumor group. Interestingly, there was a strong correlation between high IL-4 levels and reduced levels of apoptosis (P < 0.006) or proliferation (P < 0.0001), which has also been reported in leukemic models. This has important implications for the success of IL-4 as a treatment for low and high grade tumors.

Adolescent↗
PubMed2002

Opiate antagonist therapy for the pruritus of cholestasis: the avoidance of opioid withdrawal-like reactions.

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.

Administration, Oral↗
PubMed2001

Transforming growth factor-beta and ciliary neurotrophic factor synergistically induce vasoactive intestinal peptide gene expression through the cooperation of Smad, STAT, and AP-1 sites.

The cytokine ciliary neurotrophic factor (CNTF) and transforming growth factor-beta (TGF-beta) both induce transcription of the vasoactive intestinal peptide (VIP) gene through a 180-base pair cytokine response element (CyRE) in the VIP promoter. While CNTF induces STAT and AP-1 proteins to bind to cognate sites in the VIP CyRE, the mechanism through which TGF-beta acts to induce VIP gene transcription is not known. Here we show that Smad3 and Smad4 proteins can bind to two distinct sites within the VIP CyRE. These sites are absolutely required for the induction of VIP CyRE transcription by TGF-beta. TGF-beta induces endogenous Smad-containing complexes to bind to these sites in human neuroblastoma cells. CNTF and TGF-beta synergize to induce VIP mRNA expression and transcription through the VIP CyRE. This synergy is dependent on the Smad, STAT, and AP-1 sites, suggesting that these two independent cytokine pathways synergize through the cooperation of pathway-specific transcription factors binding to distinct sites within the VIP CyRE.

Animals↗
PubMed2001

Preservation of venous endothelial function in the forearm venous capacitance bed of patients with chronic heart failure despite arterial endothelial dysfunction.

OBJECTIVES: The goal of this study was to assess whether endothelial dysfunction occurs in the forearm venous capacitance bed of patients with chronic heart failure (CHF) and to determine the role of nitric oxide (NO) in modulating venous tone. BACKGROUND: Control of venous tone is crucially important in CHF. More than 70% of blood volume lies in the venous capacitance beds. Therefore, small changes in venous tone may markedly affect cardiac filling pressures and cardiac output. METHODS: Venous tone was measured using radionuclide forearm venous plethysmography in 24 patients with CHF and 16 age-matched controls. The effect of basal NO activity on venous tone was assessed by infusing N-monomethyl-L-arginine 12 mg/min and stimulated NO using carbachol 15 microg/min. Brachial artery flow-mediated dilation was assessed by ultrasonic wall-tracking. RESULTS: Blockade of basal NO release caused a significant and similar venoconstriction in patients (9.6 +/- 1.8%, p < 0.01) and controls (6.6 +/- 1.7%, p < 0.01). Carbachol-induced venodilation was significant and similar in patients (36.8 +/- 3.9%, p < 0.001) and controls (40.7 +/- 3.9%, p < 0.001). Brachial artery flow-mediated dilation was impaired in patients compared with controls (2.0 +/- 0.6% vs. 7.5 +/- 2.5%, p < 0.01). CONCLUSIONS: Our data indicate that, despite marked impairment of the function of the arterial endothelium, there is preservation of both basal and stimulated NO release in the forearm venous capacitance bed. This may provide important insights into mechanisms of endothelial dysfunction in CHF and the potential for novel therapy.

Aged↗
PubMed2001

Intrastriatal GABA(A) receptor blockade does not alter dopamine D(1)/D(2) receptor interactions in the intact rat striatum.

The purpose of this study was to investigate the effects of intrastriatal blockade of GABA(A) receptors on dopamine D(1)/D(2) receptor interactions in the intact rat striatum. Muscarinic receptors mediate the ability of the D(2) receptor antagonist, eticlopride, to block an increase in striatonigral neuropeptide messenger RNA stimulated by the full D(1) agonist, SKF-82958. However, because D(2) receptor antagonists activate striatopallidal neurons, it is possible that increased GABA release from local medium spiny axon collaterals also contributes to the ability of eticlopride to block the effects of SKF-82958. This hypothesis was addressed by infusing the GABA(A) receptor antagonist, bicuculline, into the dorsal striatum in rats treated with eticlopride and SKF-82958. In contrast to the actions of the muscarinic antagonist, scopolamine, bicuculline did not affect the increase in behaviors induced by SKF-82958 or the ability of eticlopride to block them. Quantitative in situ hybridization demonstrated that bicuculline did not significantly affect basal preprodynorphin messenger RNA, nor did it affect the ability of eticlopride to decrease SKF-82958-induced preprodynorphin messenger RNA. However, the level of the preprodynorphin hybridization signal in bicuculline plus SKF-82958-treated rats was significantly lower than in saline plus SKF-82958-treated rats. In contrast, bicuculline, eticlopride or SKF-82958 by themselves increased basal preproenkephalin messenger RNA. However, there was no significant interaction among bicuculline, eticlopride and SKF-82958 on preproenkephalin messenger RNA levels.These data indicate that blockade of striatal GABA(A) receptors has only a subtle effect on acute dopamine agonist-induced changes in gene expression. These results are discussed in the context of local intrastriatal interactions.

Animals↗
PubMed2001

A gene trap integration provides an early in situ marker for hepatic specification of the foregut endoderm.

We report the characterization of a gene trap integration that provides an in situ marker for one of the earliest events in liver development. Expression of the reporter gene is observed at the nine-somite stage in the hepatic field of the foregut endoderm. At 10.5 days post-coitus expression is observed exclusively and at high levels in the majority of cells in the developing liver bud. As development proceeds the proportion of expressing cells decreases with expression in adult liver being restricted to a few sporadic cells. This therefore provides the earliest, most specific in situ marker of the hepatic lineage reported to date and will be useful in the further characterization of the inductive events involved in hepatic specification. Molecular characterization of the gene trap insertion suggests that the expression pattern is the result of alternative promoter use in the ankyrin repeat-containing gene, gtar.

Amino Acid Sequence↗
PubMed2001

Xenopus Enhancer of Zeste (XEZ); an anteriorly restricted polycomb gene with a role in neural patterning.

We have identified the Xenopus homologue of Drosophila Enhancer of Zeste using a differential display strategy designed to identify genes involved in early anterior neural differentiation. XEZ codes for a protein of 748 amino acids that is very highly conserved in evolution and is 96% identical to both human and mouse EZ(H)2. In common with most other Xenopus Pc-G genes and unlike mammalian Pc-G genes, XEZ is anteriorly restricted. Zygotic expression of XEZ commences during gastrulation, much earlier than other anteriorly localized Pc-G genes; expression is restricted to the anterior neural plate and is confined later to the forebrain, eyes and branchial arches. XEZ is induced in animal caps overexpressing noggin; up-regulation of XEZ therefore represents a response to inhibition of BMP signalling in ectodermal cells. We show that the midbrain/hindbrain junction marker En-2,and hindbrain marker Krox-20, are target genes of XEZ and that XEZ functions to repress these anteroposterior marker genes. Conversely, XEZ does not repress the forebrain marker Otx-2. XEZ overexpression results in a greatly thickened floor of the forebrain. These results implicate an important role for XEZ in the patterning of the nervous system.

Amino Acid Sequence↗
PubMed2001

Visual event-related potentials in cirrhotic patients without overt encephalopathy: the effects of flumazenil.

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.

Adult↗
PubMed2001

Immunopathogenesis of cholestatic autoimmune liver diseases.

Primary biliary cirrhosis and primary sclerosing cholangitis are well recognized chronic cholestatic liver diseases that are considered to have an autoimmune basis. Recent progress in the study of autoimmune liver diseases has improved the recognition and characterization of these conditions. An important component of this progress has been the identification of liver disease-associated autoantibodies and their respective target antigens, and the development of specific assays for these autoantibodies. In addition, some nonhumoral immunological findings imply an involvement of specific immunopathogenic mechanisms in the development of these conditions. Furthermore, immunogenetic factors associated with increased susceptibility to some of these diseases have been identified. This article reviews the most relevant information relating to the postulated autoimmune pathogenesis of these diseases, with special emphasis on their associated humoral and cellular immunological abnormalities and immunopathogenetic factors. Some of the remaining important unresolved issues relating to the pathogenesis of these diseases, that need to be addressed in further research, are highlighted.

Autoimmune Diseases↗
PubMed2001

Differences between human and mouse alpha-fetoprotein expression during early development.

Alpha-fetoprotein (AFP) is the major serum protein during development. AFP is one of the earliest proteins to be synthesised by the embryonic liver. The synthesis of AFP decreases dramatically after birth and only trace amounts are expressed in the adult liver. The tissue distribution of AFP in early human embryogenesis has not been defined. We have studied the expression pattern of AFP mRNA in human and mouse embryos by in situ hybridisation. In humans, AFP is expressed in the hepatic diverticulum at 26 d postovulation as it differentiates from the foregut endoderm (i.e. in the most primitive hepatocytes). It is also expressed in the endoderm of the gastrointestinal tract and in the yolk sac at this age. AFP is subsequently expressed in the mesonephros and transiently in the developing pancreas. In the mouse, no expression of AFP was observed in the mesonephros but other sites of expression were similar. Thus AFP has a distinct temporospatial expression pattern during the embryonic period and this differs between human and mouse species. It is interesting that AFP is expressed by tumours such as primitive gastrointestinal, renal cell and pancreatic tumours as well as those of hepatocyte origin. This distribution reflects the sites of AFP expression during development.

Animals↗
PubMed2001

Altered central serotoninergic neurotransmission: a potential mechanism for profound fatigue complicating chronic hepatitis C.

Altered central neurotransmission contributes to behavioural complications of chronic liver disease, such as pruritus and hepatic encephalopathy. Another behavioural complication of chronic liver disease, including chronic hepatitis C, is profound fatigue. Evidence that altered serotoninergic neurotransmission contributes to fatigue of central origin, and relief of profound fatigue in a patient with chronic hepatitis C associated with long-term ondansetron therapy, support the hypothesis that altered central serotoninergic neurotransmission contributes to fatigue complicating chronic hepatitis C. Drugs that specifically modulate serotoninergic neurotransmission may be effective in ameliorating fatigue in patients with chronic hepatitis C.

Fatigue↗