Biomedical subjects
Publications and source records attributed to E A Jones.
Structure-activity relationships were explored for some analogs of Brequinar having a linking atom between the 2-biphenyl substituent and the quinoline ring. Activities as inhibitors of dihydroorotate dehydrogenase and the mixed lymphocyte reaction were related to the overall shape and lipophilicity of the 2-substituent.
BACKGROUND: Hepatitis B surface antigen (HBsAg) and antibodies to hepatitis B e antigen (anti-HBe) commonly coexist, and laboratory tests are often requested to assess histological hepatitis activity. An optimum panel of tests has not been found and the usefulness of hepatitis B virus (HBV) DNA assays in this context has not been established. We assessed various blood tests to find which best predicted hepatitis activity. METHODS: Routine plasma biochemical liver tests and serum HBV DNA (hybridisation and PCR assays) were assessed prospectively in 123 patients positive for HBsAg and anti-HBe. We scored histological hepatitis activity (hepatitis activity index) and determined whether chronic active hepatitis (chronic hepatitis with portal and periportal lesions) was present. We analysed the relation between laboratory data and the hepatitis activity index or risk of chronic active hepatitis by multiple regression and multiple logistic regression, respectively. FINDINGS: The analyses provided models for predicting either the hepatitis activity index or the risk of chronic active hepatitis. Aspartate aminotransferase was the most important test in the two models. The contribution of HBV DNA and other assays, especially alanine-aminotransferase activity, were of no practical importance. INTERPRETATION: Because screening by aspartate-aminotransferase activity could not be improved by the addition of other assays or HBV DNA, patients positive for HBsAg and anti-HBe could be screened for chronic active hepatitis with a single assay and counselling of patients can be improved if proper reference values are used.
Three mitogen-activated protein kinase pathways are up-regulated during the activation of T lymphocytes, the extracellular signal-regulated kinase (ERK), Jun NH2-terminal kinase, and p38 mitogen-activated protein kinase pathways. To examine the effects of blocking the ERK pathway on T cell activation, we used the inhibitor U0126, which has been shown to specifically block mitogen-activated protein kinase/ERK kinase (MEK), the kinase upstream of ERK. This compound inhibited T cell proliferation in response to antigenic stimulation or cross-linked anti-CD3 plus anti-CD28 Abs, but had no effect on IL-2-induced proliferation. The block in T cell proliferation was mediated by down-regulating IL-2 mRNA levels. Blocking Ag-induced proliferation by inhibiting MEK did not induce anergy, unlike treatments that block entry into the cell cycle following antigenic stimulation. Surprisingly, induction of anergy in T cells exposed to TCR cross-linking in the absence of costimulation was also not affected by blocking MEK, unlike cyclosporin A treatment that blocks anergy induction. These results suggest that inhibition of MEK prevents T cell proliferation in the short term, but does not cause any long-term effects on either T cell activation or induction of anergy. These findings may help determine the viability of using mitogen-activated protein kinase inhibitors as immune suppressants.
The structure-activity relationships of some tetracyclic heterocycles related to Brequinar were explored. Activities as inhibitors of dihydroorotate dehydrogenase and the mixed lymphocyte reaction are related to ring system, heteroatom placement, and pendant ring substitution.
The aims of this study were to determine whether long-term oral administration of the opiate antagonist nalmefene is associated with any beneficial effects in patients with pruritus secondary to cholestatic liver disease and to assess the safety of long-term administration of this drug to these patients. Fourteen patients with unrelieved chronic pruritus of cholestasis were studied. Scratching activity, independent of limb movements, was recorded continuously for 24-hour periods before and during treatment with an initial ameliorating dose of nalmefene. Simultaneously, during these periods, visual analogue scores (VASs) of pruritus were recorded every 4 hours while patients were awake. The dose of nalmefene, which initially was 2 mg orally twice daily, was increased during the study, usually until a satisfactory clinical response was achieved. Five patients experienced a transient opioid withdrawal-like reaction that did not preclude continuing with nalmefene therapy. Serum biochemical indices of cholestasis did not change appreciably during treatment. Thirteen patients reported amelioration of the perception of pruritus on nalmefene. In 5 patients, exacerbations of pruritus occurred approximately 4 weeks after an initial ameliorating dose had been reached; these exacerbations were managed by increasing the dose. Baseline mean values for VAS and scratching activity were higher than corresponding means during nalmefene therapy in 13 (P = .002) and 12 (P = .013) patients, respectively. Possible tolerance to nalmefene occurred in 3 patients. Three patients experienced marked exacerbation of pruritus after nalmefene therapy was suddenly discontinued. Blood levels of nalmefene were consistent with normal pharmacokinetics of the drug. These results suggest that nalmefene may have a favorable risk-to-benefit ratio when it is administered orally long-term to patients with the pruritus of cholestasis.
Pruritus is an inherently subjective perception that cannot be quantified. However, in trials of new therapies for pruritus, it is necessary to base assessments of therapeutic efficacy on objective quantitative criteria. This can be achieved by measuring the behavioural consequence of pruritus, scratching activity, and using an index of scratching activity as an efficacy endpoint. A portable device to monitor scratching activity in patients with pruritus is described. The key feature of this device is a piezo-element attached to a fingernail. Vibrations of the fingernail in the act of scratching induce electrical impulses in the piezo-element. Electrical signals from the device are filtered and measured. The measurements, which are not absolute, have nevertheless been shown to provide an objective index of scratching activity that is independent of arm and hand movements. An advantage of the device is that recordings can be made while the patient is in a normal, non-hospital environment, thereby obviating effects of change of environment (e.g. hospitalisation) on the intensity of pruritus. Application of the device enables data on scratching activity during periods of treatment with a test drug and with a placebo to be compared in individual patients.
We have examined the timing of specification of the pronephric tubules and duct in Xenopus laevis by explanting the presumptive pronephric rudiments into blastula ectodermal wraps. We have established the time point of specification using the monoclonal antibody markers 3G8 and 4A6 which recognize antigens in pronephric tubule and duct, respectively. We show that, by experimental analysis in explants, kidney tubules are specified by stage 12.5 in the pronephric anlagen whereas pronephric duct is specified later between stages 13 and 14. Furthermore we show that signals involved in tubulogenesis of the pronephric tubules are normally received between stage 12.5 and 13. These experiments unambiguously pinpoint the timing of pronephros specification analyzed by explant experimentation to a developmental stage prior to that demonstrated for urodele amphibia, and provide an essential biological backdrop to a search for the molecular nature of pronephric inducers.
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.
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.
Although exacerbations of previously quiescent HBV infection, associated with chemotherapy, have been attributed to enhanced immunological responses to hepatocytes harboring reactivated HBV, the recommended treatment, prednisolone, is often unsuccessful. A young HBsAg-positive, anti-HBe-positive carrier, who received chemotherapy for choriocarcinoma, developed icteric hepatitis. The serum HBV DNA level was 34,000 x 10(6) genomic equivalents per milliliter serum. Treatment with prednisolone alone did not prevent progression to overt hepatic failure. By three days after initiating lamivudine therapy, however, there was reversal of stage III hepatic encephalopathy. With further lamivudine treatment, substantial further improvement in hepatocellular function occurred and HBV-DNA levels became undetectable. When an immunocompromised patient develops an exacerbation of hepatitis B associated with high HBV DNA levels, treatment with prednisolone seems inappropriate, as hepatocytotoxic HBV replication may be stimulated further. In this situation inhibition of HBV replication, eg, by administering lamivudine, may be life-saving.
Two natural neural inducing sources have been used, the notochord and the somites together with the growth factor bFGF, to investigate the anterior/posterior patterning of neural tissue in an animal cap explant model in Xenopus laevis. Notochord and somite tissue from stages 12.5/13 and 16, respectively, were manually isolated, and combined heterochronically with responding animal cap ectoderm aged to gastrula stages. Somite recombinants were also constructed with animal caps injected with noggin mRNA. The responses of the ectoderm were analyzed by reverse transcription polymerase chain reaction (RT-PCR) detection of marker gene expression, and in some cases by in situ hybridization. The requirement for FGF receptor function was analyzed using the dominant negative FGF receptor (XFD). The experiments showed that bFGF is capable of direct neural induction in caps aged to stage 10.5. It was also shown that notochords are capable of inducing anterior neural tissue in gastrula stage animal cap ectoderm, and this induction is sensitive to XFD in the responding tissue. Injection of noggin mRNA results in the induction of anterior neural differentiation, and it was demonstrated that this induction was insensitive to the expression of XFD in the responding tissue. It was also shown that somite tissue recombined with gastrula stage animal cap ectoderm, can induce both anterior and posterior nervous tissue and can also posteriorize noggin-induced anterior neural tissue when combined with noggin-injected animal cap ectoderm. This response is partially sensitive to XFD expression. The results shed light on the role of competence of animal cap ectoderm and the signals from postgastrulation axial and paraxial mesoderm in the patterning of the amphibian nervous system.
A 27-year-old woman with chronic renal failure, who had been treated with chronic ambulatory peritoneal dialysis and had developed sclerosing peritonitis, was admitted to the hospital with intra-abdominal sepsis. In spite of antibiotic therapy, sepsis recurred and was associated with intrahepatic cholestasis. In addition, over a period of about 4.5 weeks she developed hepatomegaly and portal hypertension unassociated with occlusion of the portal vein or one of its main extrahepatic branches. A wedge biopsy of the liver revealed extensive thick fibrosis of the liver capsule, intrahepatic cholestasis, diffuse swelling of hepatocytes, central veins that were difficult to visualize and small portal tracts. It is suggested that the sepsis was responsible for the intrahepatic cholestasis, swelling of hepatocytes and hepatomegaly. It is also suggested that the rigidity of the fibrotic liver capsule provided resistance to the development of hepatomegaly, with the result that intrahepatic pressure increased (compressing intrahepatic branches of the portal vein as well as portal tracts and central veins) and portal hypertension developed.
OBJECTIVE: The effect of blockade of the enzyme ornithine decarboxylase by difluoromethylornithine (DFMO) on hepatocellular necrosis and survival in rats treated with thioacetamide (TAA) was investigated. DESIGN: In one experiment, the effect of DFMO on survival of rats with TAA-induced acute hepatocellular necrosis was determined. In another experiment, blood and liver specimens were obtained from DFMO or saline-treated rats 24 h after the administration of TAA for determinations of serum alanine aminotransferase (ALT) and liver content of polyamines and microsomal cytochrome P-450 and for assessment of hepatic histology. METHODS: Liver polyamines were determined by reversed-phase HPLC and microsomal cytochrome P-450 content by dithionite-difference spectroscopy of CO-treated homogenates. The severity of hepatocellular necrosis was scored blindly. RESULTS: TAA-treated rats that received DFMO survived longer than saline-treated controls (P < 0.01). Serum ALT and liver putrescine concentrations were lower and the histological severity of acute hepatocellular necrosis was less in DFMO-treated rats with TAA-induced hepatocellular necrosis than in saline-treated controls (P < 0.05, P < 0.01 and P < 0.05, respectively). Total cytochrome P-450 levels were similar in DFMO and saline-treated rats with TAA-induced hepatocellular necrosis. CONCLUSIONS: DFMO increases survival in TAA-induced fulminant hepatic failure by decreasing the severity of acute hepatocellular necrosis. The beneficial effects of DFMO do not appear to be mediated by its effects on polyamine metabolism, but may be attributable to an effect of DFMO on thioacetamide metabolism or on an alternative pathway of ornithine metabolism.
Stimulation of T cells through the TCR leads to activation of the mitogen-activated protein kinase (MAPK) family members ERK (extracellular signal-regulated kinase) and JNK (jun NH2-terminal kinase). These kinases act in synergy to increase the activity of the transcription factor AP-1 which is involved in the transcriptional upregulation of IL-2. Recently a third MAPK member, p38, has been identified. The effects of T cell activation on this pathway have not yet been elucidated. Using two murine Th1 clones, we demonstrate that the p38 pathway is induced upon anti-CD3 plus anti-CD28 crosslinking or PMA plus ionomycin stimulation. p38 activity was induced fully by anti-CD3 or PMA alone and is not enhanced by costimulation even at low levels of TCR signaling. p38 activity peaked at 20 min and was significantly decreased by 2 hr. Anergic (tolerant) Th1 cells showed decreased p38 activity as well as decreased ERK and JNK activities even though levels of these proteins remained unchanged.
We have isolated a Xenopus laevis genomic sequence distinct from, but sharing high sequence similarity with N-cadherin. We present evidence that the gene represented by this sequence, named XNcad3, resides at a separate locus to the two previously isolated N-cadherin clones from this species. Extensive analysis could detect no expression of XNcad3 in embryonic or adult tissues. It seems likely that XNcad3 represents a non-expressed pseudogene, or perhaps a novel cadherin with a restricted expression pattern.
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