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Biomedical subjects

A J Ellis

Publications and source records attributed to A J Ellis.

At least 19 recordsLinked to original sources
PubMed2000

Retinoic acid combines with interleukin-1 to promote the degradation of collagen from bovine nasal cartilage: matrix metalloproteinases-1 and -13 are involved in cartilage collagen breakdown.

Retinoic acid (RetA) and interleukin-1alpha (IL-1) together can induce a reproducible release of proteoglycan fragments from bovine nasal cartilage in culture. However, release of collagen fragments with either agent alone is often variable. In this study over 70% of the total collagen was released from bovine nasal cartilage in culture by day 14 when RetA and IL-1 were combined. This release was accompanied by the appearance of collagenolytic activity in the culture medium that cleaved collagen specifically at the (1/4)/(3/4) position. Tissue inhibitor of metalloproteinases (TIMP) activity was present at day 7 but low or absent in media from resorbing tissue at day 14. The breakdown of cartilage collagen could be prevented by the addition of BB-94, a specific metalloproteinase inhibitor. These results suggest that RetA promotes the early release of TIMP from the tissue and that IL-1 stimulates pro-collagenase secretion which, when activated, exceeds the local concentration of TIMP. Thus in the later stages of culture collagen destruction occurs. Both MMP-1 and MMP-13 were detected and appear to be involved in IL-1 + RetA induced bovine cartilage destruction. However, for the first time, we also present evidence to suggest that MMP-13 is the predominant collagenase in this system.

Animals↗
PubMed2000

Subclinical seizure activity and prophylactic phenytoin infusion in acute liver failure: a controlled clinical trial.

Subclinical seizure activity in the patient with encephalopathy and on ventilation with acute liver failure (ALF) is a poorly recognized entity. Its importance lies in the likely exacerbation of cerebral hypoxia and the contribution of such seizure activity to the development of cerebral edema. The aim of the present study was to document the frequency of subclinical seizure activity in a cohort of patients with ALF by using a cerebral function and activity monitor that allows continuous recording of electroencephalogram activity at the bedside and to determine whether the prophylactic administration of the antiepileptic agent phenytoin would reduce its occurrence. Forty-two patients were enrolled in a controlled clinical trial: 20 patients were given phenytoin and 22 acted as controls. Subclinical seizure activity was recorded in 3 and 10 patients, respectively, of the treated and control groups. Pupillary abnormalities indicative of seizure activity and/or raised intracranial pressure (ICP) were also seen less frequently in the phenytoin-treated group compared with the controls (5 and 11 patients, respectively). Autopsy examinations available in 19 patients showed signs of cerebral edema in only 2 (22%) of the phenytoin-treated patients compared with 7 (70%) of the controls (P <.033). Based on these findings, we recommend that patients with ALF, on reaching the stage of grade III or IV encephalopathy, should be routinely monitored for subclinical seizure activity. In this study, prophylaxis with phenytoin reduced the frequency of such seizure activity and its effects, and proved to be safe with the regimen used.

Acute Disease↗
PubMed1999

Temporary extracorporeal liver support for severe acute alcoholic hepatitis using the BioLogic-DT.

Patients with severe acute alcoholic hepatitis develop multiple organ failure which is associated with production of inflammatory cytokines and a poor prognosis. The aim of the present pilot study was to evaluate the effects of the BioLogic-DT sorption-suspension dialyser in patients with severe acute alcoholic hepatitis. Ten patients with encephalopathy (grade II-IV) were entered into the study, 5 received treatment with the BioLogic-DT for 6 hours daily for 3 days and 5 received conventional treatment as controls. The system was biocompatible with no adverse effects on blood pressure or platelet counts, factor V, fibrinogen or antithrombin III. No bleeding episodes were observed even with the use of small doses of heparin. After 3 days, blood ammonia was lower in the BioLogic-DT treated patients than in the controls, although blood lactate was higher. There were slight increases in plasma TNF and IL-8 during treatment over and above the higher levels present initially, possibly as a result of activation of white cells in the extracorporeal circuit. The further development of the BioLogic-DT dialyser with the addition of a plasma treatment module capable of removing cytokines would be worth evaluating in acute alcoholic hepatitis.

Acute Disease↗
PubMed1998

Plasma cytokine levels and coagulation and complement activation during use of the extracorporeal liver assist device in acute liver failure.

Multiple organ failure frequently occurs in patients with acute liver failure, and this has been associated with increased cytokine production. Treatment by hemoperfusion with an extracorporeal liver assist device (ELAD) containing human liver-derived cells was performed in 12 patients with acute liver failure. Over the first 6 h, there were significant increases in plasma tumor necrosis factor alpha (TNFalpha; from 114+/-54 pg/ml [mean+/-SEM] to 236+/-161 pg/ml, p < 0.05) and interleukin (IL)-6 (260+/-121 pg/ml to 445+/-149 pg/ml, p < 0.05) but not in interferon gamma (IFNgamma). A similar pattern with a small peak increase was observed for complement C5b-9 complex. Plasma C-reactive protein (CRP) and thrombin antithrombin (TAT) III complex showed small peaks after 24 h of ELAD hemoperfusion. No such changes were seen in 12 control patients with acute liver failure who were treated with intensive care alone. These transitory effects, without changes in blood pressure, are likely to be due to the contact of the blood with the dialyzer membrane. There was no evidence of the clearance of cytokines by the ELAD.

Adolescent↗
PubMed1998

Sleep and psychological disturbance in nocturnal asthma.

Subjective and objective sleep disturbance was studied in children with nocturnal asthma. Relations between such disturbance and daytime psychological function were also explored, including possible changes in learning and behaviour associated with improvements in nocturnal asthma and sleep. Assessments included home polysomnography, parental questionnaires concerning sleep disturbance, behaviour, and mood and cognitive testing. Compared with matched controls, children with asthma had significantly more disturbed sleep, tended to have more psychological problems, and they performed less well on some tests of memory and concentration. In general, improvement of nocturnal asthma symptoms by changes in treatment was followed by improvement in sleep and psychological function in subsequent weeks. The effects of asthma on sleep and the possible psychological consequences are important aspects of overall care.

Adolescent↗
PubMed1997

Auxiliary partial orthotopic liver transplantation for acute liver failure.

BACKGROUND/AIMS: Auxiliary partial orthotopic liver transplantation holds potential advantages over conventional orthotopic liver transplantation, but experience with the technique in acute liver failure is limited. METHODS: We describe our initial experience in seven patients (4 men, 3 women; mean age 28, range 14-35 years) with acute liver failure (paracetamol 3, non A-E 2, autoimmune 1, Ecstasy 1) who fulfilled criteria for emergency transplantation. Preoperatively, the median international normalised ratio was seven (range 3.4-15), with a creatinine of 123 microM (51-389 microM) and bilirubin 320 microM (61-572 microM). The reasons for performing an auxiliary transplant were the patients' young age and stable preoperative condition (n = 5), or a significant psychiatric history precluding conventional transplantation (n = 2). RESULTS: All patients received blood group-matched left (n = 2) or right (n = 5) auxiliary grafts. Median duration of surgery was 8.5 h (7.3-10 h), with blood loss of 8.3 litres (4.6-14.6 litres). Post-transplant, the international normalised ratio and aspartate aminotransferase fell progressively in all patients, with median values at day 7 of 1.4 (1.0-2.4) and 108 IU/1 (78-910 IU/1). Three patients died from sepsis within the first postoperative month. At 2 weeks, four of six patients had partial regeneration of the native liver, which became complete in two of the survivors by 1 year. CONCLUSIONS: Although patient selection remains poorly defined, auxiliary partial orthotopic liver transplantation in acute liver failure is technically feasible and, in some patients, allows native liver regeneration and eventual immunosuppression withdrawal.

Acute Disease↗
PubMed1997

Use of extracorporeal liver assist device and auxiliary liver transplantation in fulminant hepatic failure.

The case history of a 14-year-old boy with fulminant hepatic failure secondary to non-A, non-B hepatitis who fulfilled selection criteria for orthotopic liver transplantation is described. Two forms of liver support were used (extracorporeal liver assist device and an auxiliary partial orthotopic liver transplantation) to provide additional time to allow spontaneous recovery to occur. During the 66 h of extracorporeal haemoperfusion through the device, haemodynamic stability was maintained along with improvements in serum bilirubin (555 to 381 mumol/l), and international normalized ratio (INR) (3.7 to 2.9). Deterioration in these parameters was observed following cessation of treatment and 10 h later, after a donor liver had become available, an auxiliary transplant was performed. Clinical recovery, though initially slow, was eventually complete, with histopathological and scintigraphic evidence of full liver regeneration at 3 months. Withdrawal of his immunosuppressive drugs began at 6 months and was complete by 14 months after auxiliary transplantation. He has since remained well with normal liver function tests. Temporary liver support may provide additional time for spontaneous recovery of the native liver to occur in selected cases of fulminant hepatic failure, even when criteria are fulfilled for orthotopic liver grafting.

Adolescent↗
PubMed1996

Interleukin-4 blocks the release of collagen fragments from bovine nasal cartilage treated with cytokines.

Interleukin-1 (IL-1) in combination with other cytokines can induce a reproducible release of collagen fragments from bovine nasal cartilage in culture. Over 70% of the total collagen is released by day 14 and this release is accompanied by the appearance of collagenolytic activity in the medium that cleaves collagen specifically at the one quarter/three quarter position. Interleukin-4 is able to prevent the release of collagen fragments from the tissue and this is accompanied by a reduced secretion and activation of collagenase (MMP-1) with an increase in tissue inhibitor of metalloproteinases-1 (TIMP-1). IL-4, especially in the presence of IL-1, increased TIMP secretion by bovine nasal cartilage in culture. These results suggest that IL-4 is able to specifically block cartilage collagen resorption by down-regulating the production of collagenase (MMP-1) and up-regulating TIMP-1 by chondrocytes within the cartilage.

Animals↗
PubMed1996

Coagulation factor V levels as a prognostic indicator in fulminant hepatic failure.

Data reported by Bernuau et al. have strongly supported the measurement of coagulation factor V as the best prognostic indicator in fulminant hepatic failure (FHF) and as the test on which selection for urgent liver transplantation should be made. In this study, we have measured plasma factor V in 110 patients with FHF, in grades I-IV coma, in 88 of whom the etiology was acetaminophen overdose. On admission, patients who did not survive had significantly lower factor V levels (median, 5%; range, 1-27; n = 49), compared with those who did (median, 10%; range, 2-70; P < .001). In the 81 patients with acetaminophen-induced FHF who did not receive a transplant, there was no cutoff level of factor V that clearly separated the patients. On statistical analysis, a positive predictive value (the mortality in patients predicted to have a poor prognosis) of 0.49 was calculated for factor V <20% and 0.57 for factor V < 10%. If the prognostic criteria included deep coma (grades III and IV) as well as factor V <20%, a positive predictive value of 0.73 was calculated. This compared with a value of 0.92 for the well-established King's prognostic criteria based on pH, and a combination of international normalized ratio (INR), renal failure, and coma. In the 17 mixed, nonacetaminophen group of patients who did not receive a liver graft, the positive predictive value was 0.85 for a factor V level <20% and 1.00 for factor V <10%, compared with 0.93 for the King's criteria for that etiologic group. This study demonstrates that the predictive accuracy of plasma factor V level is much less effective than the well-validated King's criteria in the selection of patients with acetaminophen-induced FHF needing liver grafting, although it may be useful in patients with FHF due to other causes.

Acetaminophen↗
PubMed1996

Pilot-controlled trial of the extracorporeal liver assist device in acute liver failure.

The objective of this pilot controlled study was to evaluate the extracorporeal liver assist device (ELAD) in patients with acute liver failure who were judged to still have a significant chance of survival (approximately 50%) and in those who had already fulfilled criteria for transplantation. Twenty-four patients were divided into two groups, 17 with a potentially recoverable lesion (group I) and 7 listed for transplantation (group II), and then randomly allocated to ELAD haemoperfusion or control. The median period of ELAD haemoperfusion was 72 hours (range 3-168 h). Biocompatibility of the device was good, with no acceleration in platelet consumption, and haemodynamic stability was maintained. Two patients were withdrawn from the study because of worsening of preexisting disseminated intravascular coagulation in one case and a hypersensitivity reaction in the other. Deterioration with respect to encephalopathy grade was more frequent in the control patients, 7 of 12 (58%), than in the ELAD-treated patients, 3 of 12 (25%). In group I where survival for the ELAD cases was 7 of 9 (78%), there was a higher than expected survival in the controls, 6 of 8 (75%). For group II cases, survival was 1 of 3 (33%) for the ELAD-treated patients, and 1 of 4 (25%) for the controls. Both of the survivors underwent transplantation. Assessment of additive function for the device revealed an improvement in galactose elimination capacity after 6 hours of haemoperfusion. Based on the results of this pilot-controlled trial, better indices of prognosis will be required, in addition to those used to select for transplantation, if patients at an earlier stage of clinical deterioration are to be included in future studies.

Adolescent↗
PubMed1996

Acute liver damage and ecstasy ingestion.

Eight cases of ecstasy related acute liver damage referred to a specialised liver unit are described. Two patients presented after collapse within six hours of ecstasy ingestion with hyperthermia, hypotension, fitting, and subsequently disseminated intravascular coagulation with rhabdomyolysis together with biochemical evidence of severe hepatic damage. One patient recovered and the other with evidence of hyperacute liver failure was transplanted but subsequently died, histological examination showing widespread microvesicular fatty change. Four patients presented with acute liver failure without hyperthermia. All four fulfilled criteria for transplantation, one died before a donor organ became available, and two died within one month post-transplantation of overwhelming sepsis. Histological examination showed submassive lobular collapse. Two patients presented with abdominal pain and jaundice and recovered over a period of three weeks; histological examination showed a lobular hepatitis with cholestasis. Patients developing jaundice or with evidence of hepatic failure particularly encephalopathy and prolongation of the international normalised ratio, or both, whether or not preceded by hyperthermia, should be referred to a specialised liver unit as liver transplantation probably provides the only chance of recovery.

Adolescent↗
PubMed1996

Effect of ELAD liver support on plasma HGF and TGF-beta 1 in acute liver failure.

The aim of this study was to investigate the effects of treatment with the extracorporeal liver assist device (ELAD) in patients with acute liver failure (ALF) on plasma hepatocyte growth factor (HGF), the most potent growth factor, and transforming growth factor-beta 1 (TGF-beta 1), an inhibitory factor for liver regeneration. Initial plasma HGF, measured by ELISA, was significantly increased in the ALF patients (7.86 +/- SEM 1.76 ng/ml) compared with normal subjects (0.10 +/- 0.02 ng/ml, p < 0.001). After 6 hours of ELAD haemoperfusion, plasma HGF increased further (30.5 +/- 6.19 ng/ml, p < 0.001), with a subsequent decrease towards the initial value by 48 hours. Initial plasma levels of TGF-beta 1 determined by ELISA were significantly increased in the ALF patients (43.4 +/- 5.9 ng/ml) compared with normal subjects (25.1 +/- 2.3 ng/ml, p < 0.01), but there was no change in plasma TGF-beta 1 during the study period in either the ELAD or control ALF group. As HGF is a heparin-binding growth factor and similar changes in HGF were observed during CVVHD, one possible explanation is that heparin administered as anticoagulant for extracorporeal circulation is involved in the effects observed on HGF.

Adolescent↗
PubMed1995

Interleukin-1 and oncostatin M in combination promote the release of collagen fragments from bovine nasal cartilage in culture.

Interleukin-1 (IL-1) and Oncostatin M (OM) induce a rapid and reproducible release of proteoglycan and collagen fragments from bovine nasal cartilage in culture. Over 90% of the total collagen was released by day 14 compared to a variable release with IL-1 alone. This release was accompanied by the appearance of collagenolytic activity in the medium that cleaved collagen specifically at the one quarter/three quarter position. Tissue inhibitor of metalloproteinases (TIMP-1) activity was low or absent in media from resorbing tissue. The breakdown of cartilage collagen could be prevented by the addition of BB94, a specific matrix metalloproteinase (MMP) inhibitor. These results suggest that T-cell/macrophage products within inflammed joints can interact with pro-inflammatory cytokines and lead to the rapid destruction of connective tissue collagen.

Animals↗
PubMed1995

Late-onset hepatic failure: clinical features, serology and outcome following transplantation.

A further series of 41 adult patients with late-onset hepatic failure was investigates with respect to aetiological factors, particularly hepatitis C and E, which have been identified since our earlier report of this condition. The increased use of transplantation and its impact on survival overall is assessed. Comparison is made with 64 patients admitted over the same period with fulminant hepatic failure of non-A, non-B aetiology. Screening for the hepatitis viruses revealed three cases of hepatitis A and one case of Epstein Barr virus hepatitis. There were no cases of hepatitis C or hepatitis E virus detected by enzyme immunoassay and reverse transcriptase/polymerase chain reaction techniques, although three patients had positivity for IgG anti-hepatitis E virus, demonstrating previous exposure. Serum autoantibodies in a titre greater than or equal to 1:40 were present in 29% of samples tested and in three cases, titres of SMA or ANF were greater than 1:320. In a further five cases, a potentially hepatotoxic agent had been given within 3 months of the onset of symptoms, leaving the majority of patients (29) with no identifiable cause for their disease. The frequency of symptoms, however, including nausea, abdominal discomfort with the subsequent development of ascites, encephalopathy and renal impairment suggest a similar disease process in these patients. Analysis of liver biopsy material showed similar patterns on all cases of map-like necrosis with nodular regeneration and without other additional features of aetiological significance. Differences in clinical and histological changes for the non-A, non-B fulminant hepatic failure comparison group reflect the tempo of disease process rather than the nature and cause of the liver damage. The introduction of transplantation has led to a marked improvement in survival (39% overall in the earlier series). In the 21 patients in whom transplantation was carried out, the 1-year actuarial survival is currently 55%. Treatment of late-onset hepatic failure with corticosteroids and the use of Prostaglandin E1 and interferon in individual cases has been disappointing, and the emphasis in management should be placed on teh early referral of such patients to a centre offering transplantation.

Adolescent↗
PubMed1994

The prevention of collagen breakdown in bovine nasal cartilage by TIMP, TIMP-2 and a low molecular weight synthetic inhibitor.

Interleukin-1 stimulated bovine nasal cartilage fragments were cultured in the presence and absence of various metalloproteinase inhibitors. Tissue inhibitor of metalloproteinases (TIMP) and tissue inhibitor of metalloproteinases-2 (TIMP-2) completely blocked the release of collagen from the cartilage but were unable to prevent the release of proteoglycan. Similarly, a low molecular weight synthetic inhibitor (BB87) inhibited collagen release in a dose dependent manner, but was unable to inhibit proteoglycan release at the same concentrations. Significantly greater concentrations of inhibitor than those required to block collagen release did, however, block proteoglycan release. These results indicate that the therapeutic use of naturally occurring or synthetic inhibitors may provide a means of modifying the destruction of connective tissue proteins occurring in the arthritides and other connective tissue pathologies.

Animals↗