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Biomedical subjects

Roger Williams

Publications and source records attributed to Roger Williams.

At least 37 records · Page 2Linked to original sources
PubMed2005

Fulminant hepatic failure.

The rare but potentially devastating clinical syndrome of fulminant hepatic failure has as its components severe encephalopathy and finally cerebral edema, hemodynamic instability, renal failure, coagulopathy, profound metabolic disturbances and a particular susceptibility to bacterial and fungal infection. Despite advances in medical management, fulminant hepatic failure in its most severe form carries a high mortality rate unless urgent orthotopic liver transplantation is carried out. However, availability of cadaveric donor organs is limited and, due to the rapidly progressive clinical course in many cases, a substantial proportion of patients will die or develop contraindications to transplantation before the procedure can be performed. Consequently, recent interest has centred on living donor transplantation and the possibility of providing temporary liver support, either through auxiliary partial organ transplantation, extracorporeal perfusion or transplantation of hepatocytes, to allow time for either a liver graft to become available or native liver regeneration, on which spontaneous survival ultimately depends, to occur.

Journal Article↗
PubMed2005

Liver transplantation for hepatocellular carcinoma.

In patients with cirrhosis and hepatocellular carcinoma (HCC), orthotopic liver transplantation (OLT) offers hope for cure of both the complicating HCC and the underlying chronic liver disease. Excellent 5 year survival has been reported when the restrictive Milan criteria are used to select transplant candidates. Alternative recommendations have recently been proposed by groups at University of California San Francisco, University of Pittsburgh and Mount Sinai. We review current and evolving concepts regarding selection criteria for OLT in patients with HCC, along with strategies to reduce waiting times, such as the impact of the implementation of the model for end-stage liver disease (MELD) scoring system on organ distribution and the role of living donor OLT for this indication. The possible efficacy of adjuvant anti-tumour therapies in limiting HCC growth while waiting for OLT, along with factors influencing the risk of HCC recurrence post-OLT, the major cause of death in this setting, are also discussed.

Carcinoma, Hepatocellular↗
PubMed2005

Phosphoinositide 3-kinases as drug targets in cancer.

The past two years have seen phosphoinositide 3-kinases (PI3Ks) move from being seen as potential targets for chemotherapeutics, to one of them--PI3Kalpha--being generally accepted as validated. A huge amount of work indicated that there was an important role for PI3Ks in tumour progression and, particularly, in the control of proliferation, survival and regulation of the potential oncogene PKB. These links were further strengthened by studies showing that the tumour suppressor, PTEN, is an antagonist of PI3K signalling and that somatic mutations of p110alpha (PIK3CA) are present in a variety of cancers. We now know that three of the most frequent mutations in cancer constitutively activate PI3Kalpha and, when expressed in cells, they drive the oncogenic transformation and chronic activation of downstream signalling by molecules such as PKB, S6K and 4E bp1 that is commonly seen in cancer cells. A large body of research into the cellular roles of PI3Ks has also further validated them as potential foci for cancer chemotherapy, with several additional PI3K effectors controlling cell proliferation and apoptosis having been described. Furthermore, molecules important to the processes of metastasis, development of multi-drug resistance, the 'Warburg effect', angiogenesis and cell growth (i.e. distinct to proliferation) have been found to depend upon, or to be driven by, PI3K activity.

Animals↗
PubMed2005

Pharmacokinetics and efficacy of oral versus intravenous mixed-micellar phylloquinone (vitamin K1) in severe acute liver disease.

BACKGROUND/AIMS: In patients with severe acute liver dysfunction, i.v. phylloquinone (vitamin K1) may be given to exclude vitamin K deficiency, rather than impaired hepatic synthesis of coagulation factors alone, as the cause of the coagulopathy. However, there have been no studies of the pharmacokinetics or efficacy of i.v. or oral K1 in such patients. METHODS: 49 adults with severe acute liver disease were randomised double-blind to a single 10 mg dose of i.v. or oral mixed-micellar K(1), or placebo. Serum levels of phylloquinone and undercarboxylated prothrombin (PIVKA-II) were assessed before and after treatment. RESULTS: At admission, 13 patients (27%) had either low serum K1 levels or elevated PIVKA-II concentrations, indicative of subclinical vitamin K deficiency. In the 16 patients who received i.v. K1, there was one (6%) treatment failure (K1 rise <10 ng/ml above baseline), compared with 12 of the 15 (80%) who received oral K1 (P<0.0001). One patient in the placebo group developed overt vitamin K deficiency. CONCLUSIONS: A minority of patients with severe acute liver dysfunction have subclinical vitamin K deficiency at the time of presentation, which is corrected by a single dose of i.v. K1. The intestinal absorption of mixed-micellar K1 is unreliable in adults with severe acute liver dysfunction.

Acute Disease↗
PubMed2005

'Nipped in the Budd': hepatic venous outflow obstruction in evolution.

Hepatic venous thrombosis (Budd-Chiari) in evolution is a rare phenomenon and carries a high morbidity and mortality. We describe the case of a 39-year-old Bangladeshi lady who presented with severe abdominal pain secondary to a perforated duodenal ulcer and during her hospital admission developed an asymptomatic Budd-Chiari syndrome (BCS). Our report highlights the important role of an inflammatory focus, and how this process with an associated reactive thrombocytosis may act as a trigger for the development of BCS in an individual with predisposing risk factors. Our patient had been on the contraceptive pill, and was homozygous for the C677T mutation of 5,10-methylenetetrahydrofolate reductase, which results in hyperhomocysteinaemia. These pro-thrombotic risk factors were compounded by the thrombogenic potential of subsequent laparoscopic surgery, and resulted in an evolving thrombus that progressed into the inferior vena cava causing hepatic infarction. A particular feature of this case was the radiological demonstration of complete regression of the thrombus and the hepatic parenchymal changes, upon resolution of the inflammation and normalization of the platelet count. These changes occurred with oral anticoagulation as the only treatment modality, since our patient declined systemic thrombolysis. The demonstration of complete radiological resolution raises the question of how long one should continue oral anticoagulants and, indeed, whether in some instances a conservative approach may be the best management strategy for evolving BCS.

Adult↗
PubMed2005

Emerging indications for albumin dialysis.

The accumulation of albumin-bound toxins in liver failure is believed to be responsible for the development of associated end-organ dysfunctions (kidney, circulation, brain). Albumin dialysis utilizes the scavenging functions of albumin for the removal of toxins. The Molecular Adsorbents Recirculating System (MARS) is one such extracorporeal liver support device where blood is dialyzed across an albumin-impregnated membrane against 20% albumin. Charcoal and anion exchange resin columns in the circuit cleanse and regenerate the albumin dialysate. Clinical studies in the last decade have demonstrated proven reduction in hyperbilirubinemia, along with an improvement in encephalopathy in liver failure patients, as well as apparent improvement in survival. Some studies have also reported improvement of systemic hemodynamics and renal function in these patients. Amelioration of intractable pruritus and treatment of toxicities with albumin-bound substances are some of the newer indications emerging. However, the specific underlying pathophysiological mechanisms are still not clear. Two other systems based on the removal of albumin-bound toxins, the Prometheus (using the principle of fractionated plasma separation and adsorption [FPSA]), and the single pass albumin dialysis (SPAD) are also currently under development but available clinical data are limited.

Albumins↗
PubMed2005

Modulation of the CD8+-T-cell response by CD4+ CD25+ regulatory T cells in patients with hepatitis B virus infection.

CD4+ CD25+ regulatory T cells have been shown to maintain peripheral tolerance against self and foreign antigens. In this study we analyzed the effect of circulating CD4+ CD25+ T cells on CD8+-T-cell responses of patients with chronic and resolved hepatitis B virus (HBV) infection. We demonstrated that circulating CD4+ CD25+ T cells modulate the function and expansion of HBV-specific CD8+ cells ex vivo in all patients, regardless of whether they have chronic or resolved HBV infection. The possible role of CD4+ CD25+ T cells in the pathogenesis of chronic HBV infection is not supported by these data. However, these results might have implications for optimizing future immunotherapeutic approaches to HBV treatment.

Adult↗
PubMed2005

Variability in hepatic iron concentration in percutaneous needle biopsy specimens from patients with transfusional hemosiderosis.

In patients with sickle cell disease or beta-thalassemia receiving RBC transfusions for a long period, a precise knowledge of the liver iron concentration (LIC) is essential for treatment. Patients underwent LIC and liver pathology assessment by duplicate biopsies in 2 passes from the same local liver site. Fresh tissue cores in trace element-free containers and tissues from dissolved paraffin-embedded cores were analyzed. LIC measurements in each of 2 paraffin-embedded cores did not differ significantly (median, 12,455 vs 12,153 microg/g dry weight; n = 29). A significant difference was observed when 1 fresh tissue sample and 1 paraffin-embedded core were analyzed (median, 11,716 vs 12,864 microg/g dry weight; n = 16; P < .001) with a median disagreement between LIC measurements of 23.0%. We found high agreement in LICs between liver biopsy specimens processed by the paraffin-embedding technique but overestimation of LICs in comparison with desiccated fresh tissue samples.

Biopsy, Needle↗
PubMed2005

Rifaximin, a nonabsorbed oral antibiotic, in the treatment of hepatic encephalopathy: antimicrobial activity, efficacy, and safety.

The nonabsorbed (< 0.4%) oral antibiotic rifaximin, which has been available for enteric bacterial conditions for more than a decade in several countries outside the United States, was recently introduced in the United States for the treatment of travelers' diarrhea, and is being evaluated in clinical trials for possible introduction for hepatic encephalopathy and other conditions involving enteric bacteria. This article discusses the antimicrobial activity, efficacy, and safety of rifaximin in hepatic encephalopathy. Rifaximin is a nonsystemic antibiotic with antibacterial activity against enteric pathogens for gastrointestinal infections. In 15 studies, several of which were adequately powered to assess efficacy, rifaximin was at least as effective as lactulose/lactitol (the current mainstay of pharmacologic treatment for hepatic encephalopathy) and neomycin and paromomycin (the antibiotics most commonly prescribed for hepatic encephalopathy) in improving neurologic signs and symptoms and reducing blood ammonia levels. The results of studies employing small samples are similar to those of the larger studies. Finally, rifaximin has a good tolerability profile in patients with hepatic encephalopathy, and thus appears to constitute a promising new option for this disorder. The current database on rifaximin would be strengthened by results of placebo-controlled studies to quantify more precisely the benefits of therapy.

Anti-Infective Agents↗
PubMed2004

ARAP3 is a PI3K- and rap-regulated GAP for RhoA.

Rho and Arf family small GTPases are well-known regulators of cellular actin dynamics. We recently identified ARAP3, a member of the ARAP family of dual GTPase activating proteins (GAPs) for Arf and Rho family GTPases, in a screen for PtdIns(3,4,5)P(3) binding proteins. PtdIns(3,4,5)P(3) is the lipid product of class I phosphoinositide 3OH-kinases (PI3Ks) and is a signaling molecule used by growth factor receptors and integrins in the regulation of cell dynamics. We report here that as a Rho GAP, ARAP3 prefers RhoA as a substrate and that it can be activated in vitro by the direct binding of Rap proteins to a neighbouring Ras binding domain (RBD). This activation by Rap is GTP dependent and specific for Rap versus other Ras family members. We found no evidence for direct regulation of ARAP3's Rho GAP activity by PtdIns(3,4,5)P(3) in vitro, but PI3K activity was required for activation by Rap in a cellular context, suggesting that PtdIns(3,4,5)P(3)-dependent translocation of ARAP3 to the plasma membrane may be required for further activation by Rap. Our results indicate that ARAP3 is a Rap-effector that plays an important role in mediating PI3K-dependent crosstalk between Ras, Rho, and Arf family small GTPases.

Adaptor Proteins, Signal Transducing↗
PubMed2004

Alpha-fetoprotein impairs APC function and induces their apoptosis.

alpha-Fetoprotein (AFP) is a tumor-associated Ag, and its serum level is elevated in patients with hepatocellular carcinoma (HCC). In vitro, AFP induces functional impairment of dendritic cells (DCs). This was demonstrated by the down-regulation of CD40 and CD86 molecules and the impairment of allostimulatory function. Also, AFP was found to induce significant apoptosis of DCs, and AFP-treated DCs produced low levels of IL-12 and TNF-alpha, a cytokine pattern that could hamper an efficient antitumor immune response. Ex vivo, APCs of patients with HCC and high levels of AFP produced lower levels of TNF-alpha than that of healthy individuals. In conclusion, these results illustrate that AFP induces dysfunction and apoptosis of APCs, thereby offering a mechanism by which HCC escapes immunological control.

Antigen Presentation↗
PubMed2004

Albumin dialysis: a new therapeutic strategy for intoxication from protein-bound drugs.

OBJECTIVE: Although water-soluble drugs can be removed by haemofiltration/haemodialysis, morbidity and mortality from intoxication with protein-bound drugs remains high. The present study investigates whether albumin dialysis in the form of the Molecular Adsorbents Recirculating System (MARS) is effective in removal of protein-bound drugs. DESIGN: Prospective animal study. SETTING: Surgical research laboratory in a university hospital. SUBJECTS: Seven female Norwegian Landrace pigs. INTERVENTION: We studied whether midazolam (97% albumin-bound) and fentanyl (85% alpha-1-acid glycoprotein-bound), administered as anaesthetics to pigs with induced acute liver failure, could be removed by MARS dialysis lasting for 4 h. MEASUREMENTS: After 4 h of dialysis, total and free anaesthetic concentrations were measured in the blood and dialysate from different segments of the MARS circuit. MAIN RESULTS: Midazolam: total plasma concentrations fell by 47.1+/-2.1% (in 4 h) across the MARS filter ( p<0.01). The charcoal component of the system reduced the total dialysate drug concentration by 16.4+/-2.2% ( p<0.05). Free midazolam removal followed a similar pattern. Fentanyl: total plasma concentrations fell by 56.1+/-2.4% (in 4 h) across the MARS filter ( p<0.01). Clearance of fentanyl from the dialysate by the charcoal was 70+/-0.7% at 4 h ( p<0.001). CONCLUSIONS: The results of the study show that MARS can remove both albumin and other protein-bound drugs efficiently from the plasma, and it may have a place for the treatment of patients suffering from intoxication with this class of compounds.

Anesthetics, Intravenous↗
PubMed2004

Worsening of cerebral hyperemia by the administration of terlipressin in acute liver failure with severe encephalopathy.

There is increasing evidence that terlipressin is useful in patients with cirrhosis and hepatorenal syndrome, but there are no data of its use in patients with acute liver failure (ALF) in whom hepatorenal syndrome is common. Although terlipressin produces systemic vasoconstriction, it produces cerebral vasodilatation and may increase cerebral blood flow (CBF). Increased CBF contributes to intracranial hypertension in patients with ALF. The aim of this study was to evaluate the safety of terlipressin in patients with ALF with respect to cerebral hemodynamics. Six successive patients with ALF were ventilated electively for grade IV hepatic encephalopathy. Patients were monitored invasively and CBF was measured (Kety-Schmidt technique). Measurements were made before and at 1, 3, and 5 hours after intravenous (single bolus) administration of terlipressin (0.005 mg/kg), median, 0.25 mg (range, 0.2-0.3 mg). There was no significant change in heart rate, mean arterial pressure, or cardiac output. CBF and jugular venous oxygen saturation both increased significantly at 1 hour (P = 0.016). Intracranial pressure increased significantly at 1 hour (P = 0.031), returning back to baseline values at 2 hours. In conclusion, administration of terlipressin, at a dose that did not alter systemic hemodynamics, resulted in worsening of cerebral hyperemia and intracranial hypertension in patients with ALF and severe hepatic encephalopathy. These data suggest the need to exercise extreme caution in the use of terlipressin in these patients in view of its potentially deleterious consequences on cerebral hemodynamics.

Adult↗
PubMed2004

Direct evidence that naturally occurring mutations within hepatitis B core epitope alter CD4+ T-cell reactivity.

Exacerbations of chronic hepatitis B have been associated with accumulation of mutations in the HBV core gene, with amino acid (aa) substitutions clustering between aa 50 and 69. This region of the nucleocapsid protein is known as an immunodominant epitope for CD4+ T-lymphocytes, however the impact of these mutations on T-cell reactivity has not been investigated. For this purpose, we undertook fine mapping of the reactivity of peripheral blood lymphocytes, isolated from patients with acute (n = 8) or chronic hepatitis B (n = 10), against a panel of branched synthetic peptides. The peptide aa sequences corresponded to the wild type HBV (aa 50-69), or contained 1-3 aa changes derived on the basis of naturally occurring mutations. In four of eight patients with acute hepatitis B the wild type peptide 50-69, which corresponded to the core gene sequence of HBV present in these patients, induced a strong T-cell proliferative response. In the same cases, the T-cell response to the mutant peptides was altered at various degrees, depending on the number and the position of aa changes. The most pronounced inhibition of CD4+ T-cell response (between 44 and 92%) was caused by a peptide ligand with two aa substitutions at positions 64 and 67. These results demonstrate that mutations within immunodominant epitopes of the HBV nucleocapsid can affect the CD4+ T-lymphocyte reactivity, which may have a role for the accumulation of certain HBV strains after hepatitis flares during the course of chronic HBV infection.

Adolescent↗
PubMed2004

Pathophysiological effects of albumin dialysis in acute-on-chronic liver failure: a randomized controlled study.

The pathophysiological basis of acute-on-chronic liver failure (ACLF) is unclear but systemic inflammatory response is thought to be important. In patients with ACLF, the molecular adsorbents recirculating system (MARS) improves individual organ function, but the effect of MARS on the proposed mediators of systemic inflammatory response is unclear. The present study was designed to determine the effect of MARS on the cytokine profile, oxidative stress, nitric oxide, and ammonia. A total of 18 patients with alcohol-related ACLF due to inflammation-related precipitants were randomized to receive standard medical therapy (SMT) alone, or with MARS therapy over 7 days. Plasma cytokines, malondialdehyde (MDA), free radical production, nitrate / nitrite (NOx), and ammonia were measured. Encephalopathy improved significantly with MARS (P < .01), but not with SMT. Mean arterial pressure and renal function remained unchanged. No significant change of plasma cytokines and ammonia levels were observed in either group. Plasma MDA levels did not change either. There was a fall in NOx (P < .05) with MARS, but not with SMT. In conclusion, in inflammation-related ACLF patients, albumin dialysis using MARS results in improvement of encephalopathy, independent of changes of ammonia or cytokines, without improving blood pressure or renal function. These results should temper the liberal use of MARS until further data is available.

Adult↗
PubMed2004

Binding of bilirubin and bromosulphthalein to albumin: implications for understanding the pathophysiology of liver failure and its management.

The binding/transporting functions of albumin provide the rationale for using albumin dialysis (e.g., molecular adsorbents recirculating system [MARS]) in liver failure. This study investigates these properties in vitro, validating the findings in vivo. In vitro bromosulphthalein (BSP) and bilirubin-spiked plasma were dialyzed against albumin and sampled. In vivo serum biochemistry was analyzed in: 7 MARS-treated liver failure patients; 98 MARS-treated patients from the MARS Registry; and 8 patients receiving albumin infusion. In vitro BSP concentrations did not equilibrate, but the molar ratio of BSP to albumin (C(BSP)/C(alb)) did, with no subsequent transmembrane transport, suggesting that the C(BSP)/C(alb) gradient (rather than simple diffusion) drives BSP transport. Bilirubin was transported similarly. In vivo serum bilirubin reduction during MARS sessions (n = 26) correlated with pre-treatment bilirubin (r = 0.42), but better (r = 0.85) with pre-treatment molar ratio of bilirubin to albumin (C(bilirubin)/C(alb)). The strongest correlation was between C(bilirubin)/C(alb) reduction and pre-treatment C(bilirubin)/C(alb) (r = 0.9). A similar pattern was observed in the MARS Registry patients. After albumin infusion (n = 8), both serum albumin and bilirubin increased, while C(bilirubin)/C(alb) remained unchanged. C(bilirubin)/C(alb) appears to be important in albumin dialysis, and generally in liver disease patients, reinforcing the importance of the toxin-binding functions of albumin in liver disease.

Adsorption↗