Stickler syndrome type 2 and linkage to the COL11A1 gene.
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Abnormalities, Multiple↗
Biomedical subjects
R Williams
Publications and source records attributed to R Williams.
Transforming growth factor-beta type-II receptor signalling: intrinsic/associated casein kinase activity, receptor interactions and functional effects of blocking antibodies.
The transforming growth factor beta (TGF-beta) family of growth factors control proliferation, extracellular matrix synthesis and/ or differentiation in a wide variety of cells. However, the molecular mechanisms governing ligand binding, receptor oligomerization and signal transduction remain incompletely understood. In this study, we utilized a set of antibodies selective for the extracellular and intracellular domains of the TGF-beta type-II receptor as probes to investigate the intrinsic kinase activity of this receptor and its physical association in multimeric complexes with type-I and type-III receptors. The type-II receptor immuno-precipitated from human osteosarcoma cells exhibited autophosphorylation and casein kinase activity that was markedly stimulated by polylysine yet was insensitive to heparin. Affinity cross-linking of 125I-TGF-beta 1 ligand to cellular receptors followed by specific immunoprecipitation demonstrated that type-II receptors form stable complexes with both type-I and type-III receptors expressed on the surfaces of both human osteosarcoma cells and rabbit chondrocytes. Pretreatment of the cultured cells with an antibody directed against a distinct extracellular segment of the type-II receptor (anti-TGF-beta-IIR-NT) effectively blocked the 125I-TGF-beta labelling of type-I receptors without preventing the affinity labelling of type-II or type-III receptors, indicating a selective disruption of the type-I/type-II hetero-oligomers. The anti-TGF-beta-IIR-NT antibodies also blocked the TGF-beta-dependent induction of the plasminogen activator inhibitor (PAI-1) promoter observed in mink lung epithelial cells. However, the same anti-TGF-beta-IIR-NT antibodies did not prevent the characteristic inhibition of cellular proliferation by TGF-beta 1, as determined by [3H]thymidine incorporation into DNA. The selective perturbation of PAI-1 promoter induction versus cell-cycle-negative regulation suggests that strategic disruption of TGF-beta type-I and -II receptor interactions can effectively alter specific cellular responses to TGF-beta signalling.
Amino Acid Sequence↗
Hepatic artery thrombosis after liver transplantation in children under 5 years of age.
The incidence of hepatic artery thrombosis (HAT) following orthotopic liver transplantation in children varies from 4% to 26% and represents a significant cause of graft loss. The purpose of this study was to analyze the risk factors for HAT following liver transplantation in children less than 5 years old. Seventy-three transplants were performed in 62 children under 5 years of age, including 16 for acute hepatic failure, 46 for chronic liver disease, and 11 retransplants. Twenty-four whole liver grafts (WLG) and 49 reduced size grafts (3 right lobes, 16 left lobes, and 30 left lateral segments) were transplanted. The recipient common hepatic artery was used to provide arterial inflow in 22 transplants and an infrarenal iliac conduit in 51 transplants. The overall incidence of HAT was 8 out of 73 transplants (11%). The cold ischemia time (14.3 +/- 3.03 hr) in this group was significantly longer than the cold ischemia time for those without HAT (11.7 +/- 3.94 hr) (P = 0.049). The incidence of HAT for whole and reduced grafts was 25% (6/24) and 4% (2/49), respectively (P = 0.01). HAT occurred in 6 of 22 grafts (27.3%) revascularized from the recipient common hepatic artery, compared with 2 of 51 grafts (3.9%) using an infrarenal arterial conduit (P = 0.008). The combination of recipient hepatic arterial inflow to a WLG resulted in HAT in 50% (6/12), whereas there were no cases of HAT with an iliac conduit to a WLG (P = 0.01). Of the eight patients with HAT, five are alive (median follow-up, 20 months; range, 7-27 months). Five patients were retransplanted, three within the first 2 weeks and two at 4 and 5 months for abnormal liver function in association with clinical and histological features of chronic rejection. Prolonged cold ischemia time and use of a whole graft with recipient hepatic arterial inflow are risk factors for developing HAT. The use of reduced size grafts and infrarenal iliac arterial conduits are associated with a low incidence of HAT.
Child, Preschool↗
Retrograde transport of neurotrophins from the eye to the brain in chick embryos: roles of the p75NTR and trkB receptors.
The receptors involved in retrograde transport of neurotrophins from the retina to the isthmo-optic nucleus (ION) of chick embryos were characterized using antibodies to the p75 neurotrophin receptor and trkB receptors. Survival of neurons in the ION has been shown previously to be regulated by target-derived trophic factors with survival promoted or inhibited by ocular injection of brain-derived neurotrophic factor (BDNF) or nerve growth factor (NGF), respectively. In the present paper, we show that during the period of target dependence, these neurons express trkB and p75 neurotrophin receptor but not trkA or trkC mRNAs. We also show that BDNF and NT-3 were transported efficiently at low doses, whereas NGF was transported significantly only at higher doses. The transport of BDNF and NT-3 was reduced by high concentrations of NGF or by antibodies to either trkB or the p75 neurotrophin receptor. Thus both receptors help mediate retrograde transport of these neurotrophins. Ocular injection of the comparatively specific trk inhibitor K252a did not reduce transport of exogenous BDNF, but did induce significant neuronal death in the ION, which could not be prevented by co-injection of BDNF. Thus, transport of BDNF alone does not generate a trophic signal at the cell body when axonal trkB is inactivated. In summary, our results indicate that both p75 neurotrophin and trkB receptors can mediate internalization and retrograde transport of BDNF, but activation of trkB seems to be essential for the survival-promoting actions of this neurotrophin.
Animals↗
Synthesis and targeted delivery of an azidothymidine homodinucleotide conferring protection to macrophages against retroviral infection.
The infectivity and replication of human (HIV-1), feline (FIV), and murine (LP-BM5) immunodeficiency viruses are all inhibited by several nucleoside analogues after intracellular conversion to their triphosphorylated derivatives. At the cellular level, the main problems in the use of these drugs concern their limited phosphorylation in some cells (e.g., macrophages) and the cytotoxic side effects of nucleoside analogue triphosphates. To overcome these limitations a new nucleoside analogue homodinucleotide, di(thymidine-3'-azido-2',3'-dideoxy-D-riboside)-5'-5'-p1-p2-pyrophosphat e (AZTp2AZT), was designed and synthesized. AZTp2AZT was a poor in vitro inhibitor of HIV reverse transcriptase, although it showed antiviral and cytotoxic activities comparable to those of the parent AZT when added to cultures of a HTLV-1 transformed cell line. AZTp2AZT encapsulated into erythrocytes was remarkably stable. Induction of erythrocyte-membrane protein clusterization and subsequent phagocytosis of AZTp2AZT-loaded cells allowed the targeted delivery of this impermeant drug to macrophages where its metabolic activation occurs. The addition of AZTp2AZT-loaded erythrocytes to human, feline, and murine macrophages afforded almost complete in vitro protection of these cells from infection by HIVBa-L, FIV, and LP-BM5, respectively. Therefore, AZTp2AZT, unlike the membrane-diffusing azidothymidine, acts as a very efficient antiretroviral prodrug following selective targeting to macrophages by means of loaded erythrocytes.
Animals↗
Long-term outcome of hepatitis C infection after liver transplantation.
BACKGROUND: End-stage cirrhosis related to hepatitic C virus (HCV) is a common reason for liver transplantation, although viremia ia known to persist in most cases. We investigated the impact of persistent HCV infection after liver transplantation on patient and graft survival and the effects of the HCV genotype and the degree of HLA matching between donor and recipient on the severity of recurrent hepatitis. METHODS: A group of 149 patients with HCV infection who received liver transplants between January 1982 and April 1994 were followed for a median of 36 months; 623 patients without HCV infection who underwent liver transplantation for end-stage chronic liver disease were used as a control group. A total of 528 liver-biopsy specimens from the HCV-infected recipients were reviewed, including 82 obtained one year after transplantation as scheduled and 39 obtained at five years as scheduled. In addition, biopsy specimens were obtained from 91 of the HCV-negative patients five years after transplantation. RESULTS: Cumulative survival rates for the 149 patients with HCV infection were 79 percent after one year, 74 percent after three years, and 70 percent after five years, as compared with rates of 75 percent, 71 percent, and 69 percent, respectively, in the HCV-negative transplant recipients (P=0.12). Of the 130 patients with hepatitis C infection who survived more than 6 months after transplantation, 15 (12 percent) had no evidence of chronic hepatitis on their most recent liver biopsy (median followup, 20 months), 70 (54 percent) had mild chronic hepatitis (median, 35 months), 35 (27 percent) had moderate chronic hepatitis (median, 35 months), and 10 (8 percent) had cirrhosis (median, 51 months). Graft loss occurred after a median of 303 days in 27 of the 149 patients, including 5 with HCV-related cirrhosis and 3 with HCV-related cholestatic hepatitis. Infection with HCV genotype 1b was associated with more severe graft injury, whereas the primary immunosuppressive regimen used and the extent of HLA mismatching between donors and recipients had no significant effect on this variable. CONCLUSIONS: After liver transplantation for HCV-related cirrhosis, persistent HCV infection can cause severe graft damage, and such damage is more frequent in patients infected with HCV genotype 1b than with other genotypes. After five years, the rates of graft and overall survival are similar between patients with and those without HCV infection.
Adult↗
Treating small hepatocellular carcinomas.
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Carcinoma, Hepatocellular↗
Anterograde transport of neurotrophins and axodendritic transfer in the developing visual system.
Neurotrophic factors support the differentiation and survival of neurons and influence properties of synaptic transmission. The neurotrophic hypothesis postulates a retrograde action of trophic factors: their production and release by target cells and their uptake by innervating axons. Besides the retrograde route of trophic messengers, the survival of neurons and the development of synapses is thought to be also regulated by anterograde, afferent trophic signals. We now show that exogenous neurotrophins are transported in the anterograde direction, from cell bodies to the axon terminals, and that the intact neurotrophin is released after anterograde transport, taken up and utilized by second-order visual neurons in the developing chick brain. These results suggest that anterogradely transported neurotrophins may play a role in synaptic plasticity and may have effects at more than one synapse beyond the initial release site.
Animals↗
Repeat HLA-B and -DR loci mismatching at second liver transplantation improves patient survival.
The role of HLA matching in liver transplantation remains uncertain, and the effect of HLA mismatches on the outcome of second transplants has not been studied. In renal transplantation, if HLA mismatches are repeated in the second graft there is a greatly increased risk of immunological graft failure. In the present study, 78 patients who had received second liver transplants were studied. HLA typing was performed using standard complement-dependent microcytotoxicity for class I (A and B) antigens, and a combination of restriction fragment length polymorphism and serology for HLA-DR. Patient survival at follow-up for those with a repeat B locus mismatch was improved (79% compared with 43%, P < 0.02), and a similar effect was noted for repeat DR mismatches (67% vs. 47%, P = 0.06). In the subgroup of patients who received a second transplant for graft rejection, 90% of patients with a repeat B mismatch were alive at follow-up compared with 46% without B mismatches (P = 0.02). This improvement in patient survival was evident during the first 2 months after the second transplant. In this study, repeat HLA-B and -DR mismatching improves survival after second transplantation.
Adolescent↗
Structure of a ribonuclease B+d(pA)4 complex.
The structure of a tetragonal crystal of bovine pancreatic RNase B complexed with d(pA)(4) was determined by molecular replacement and difference Fourier methods. This crystal belongs to space group P4(1)2(1)2 and has unit-cell dimensions a = b = 44.5, c = 156.5 A. The model consists of the enzyme and a tetranucleotide with fractional occupancies, suggesting multiple modes of oligonucleotide binding. It does not include any polysaccharide residues or solvent molecules. After refinement at 2.7 A, the R value was 0.163 with acceptable stereochemistry. The model illustrates a set of well defined interactions for substrate binding, particularly between the central dinucleotide and the enzyme.
Journal Article↗
A community prevalence study of antibodies to hepatitis A and E in inner-city London.
The seroprevalence of antibodies to hepatitis E virus (HEV) and hepatitis A virus (HAV) was determined in a community-based sample in innercity London where socioeconomic conditions were expected to result in a high prevalence of antibodies to HAV, and in which the presence of immigrants from the developing world pose a risk of imported infection of both HAV and HEV. The seroprevalence of anti-HAV was 45.1% in UK born subjects and 69.7% in non-UK born subjects and each group showed differing patterns of age-specific seroprevalence. The seroprevalence rates of anti-HEV was 3.9% in UK born subjects and 8.8% in non-UK born subjects. The age-specific seroprevalence of the UK born group is suggestive of a cohort effect. The data suggest a low circulation of HEV in inner-city London, remaining uncommon relative to HAV.
Adolescent↗
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↗
Impact of complete inhibition of viral replication on the cellular immune response in chronic hepatitis B virus infection.
Interferon alfa (IFN-alpha) treatment is effective in only a proportion of patients with chronic hepatitis B virus (HBV) infection. The mechanisms for therapeutic failure remain unknown but high levels of HBV replication are known to inhibit the immunopotentiating effects of IFN-alpha. In nine patients with chronic hepatitis B not responding to IFN-alpha monotherapy, we determined the virus-specific T-helper-cell responses during two consecutive therapeutic regimens: IFN-alpha alone and IFN-alpha in combination with a new potent inhibitor of HBV replication, lamivudine. By comparing the results obtained during the initial IFN-alpha monotherapy to those during the combination treatment, it was investigated whether complete inhibition of virus replication will enhance the interferon-induced immunoreactivity to HBV. Despite the rapid reduction to undetectable serum HBV DNA in all nine patients during the combination treatment, none sustained permanent hepatitis B e antigen (HBeAg) clearance during subsequent 12-month follow-up. HLA class II-restricted T-helper-cell responses to hepatitis B core antigen (HBcAg) showed no difference during IFN-alpha monotherapy and during the combination of lamivudine plus IFN-alpha. In contrast, a delayed T-cell activation occurred after a rebound in serum HBV DNA postcombination treatment, which lead to increased hepatocytolysis. These findings suggest that the profound inhibition of HBV replication by a nucleoside analogue does not restore the impaired virus-specific T-cell response in chronic HBV infection.
Adult↗
Prevalence of herpesviridae and hepatitis B virus DNA in the liver of patients with non-A, non-B fulminant hepatic failure.
Members of the herpes virus family and hepatitis B virus (HBV) have been implicated as etiologic agents in non-A, non-B (NANB) fulminant hepatic failure (FHF), but the frequency of infection with these agents has not been established using appropriate controls. To examine this issue, we studied 50 NANB FHF patients and 104 liver transplant recipients from North America and Europe. Hepatic DNA was analyzed by polymerase chain reaction (PCR) for evidence of Epstein-Barr virus (EBV), cytomegalovirus (CMV), herpes simplex virus I (HSV I) and II (HSV II), varicella-zoster virus (VZV), and human herpes virus-6 (HHV-6) nucleic acid sequences. The prevalence of HBV was assessed in North American subjects only. HSV I, HSV II, VZV, and HHV-6 viral sequences were not observed in any samples. Three of 50 FHF (6%) and 14 of 104 control patients (13%) were positive for CMV DNA. Two of 50 FHF (4%) and 10 of 104 control patients (10%) had EBV DNA, and HBV DNA was observed in 3 of 10 North American FHF patients (30%) and 3 of 59 controls (5%) without serum markers for HBV infection. The finding of HBV DNA in the liver of seronegative controls from North America but not Europe suggests that occult hepatitis B sequences in patients with NANB FHF may simply reflect geographic differences. The majority of cryptogenic FHF cases cannot be attributed to infection with herpes viruses or HBV.
Adolescent↗
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↗
Prospective study comparing the efficacy of prophylactic parenteral antimicrobials, with or without enteral decontamination, in patients with acute liver failure.
The efficacy of prophylactic parenteral antibacterials, with or without selective decontamination of the digestive tract, was compared in patients with acute liver failure (ALF) or severe acetaminophen hepatotoxicity. One hundred eight patients were randomized on admission to receive intravenous ceftazidime and flucloxacillin, plus either oral and enteral decontamination with colistin, tobramycin, and amphotericin B (group 1), or enteral amphotericin B alone (group 2). The two groups were comparable with respect to age, gender, etiology, coma grade on admission, international normalization ratio, presence of renal failure, Acute Physiology and Chronic Health Evaluation II score, and indicators of poor prognosis. Patients were monitored for clinical and microbiological evidence of infection. There were 15 episodes of infection in 10 of 47 patients (21%) in group 1 and 17 episodes in 12 of 61 patients (20%) in group 2. No differences in incidence, site, and causative organisms of infection were observed between the two groups. Overall, the incidence of infection was significantly higher in patients who developed encephalopathy than in those who did not. In patients who on arrival were not encephalopathic, the development of infection was associated with progression to coma. Duration of Liver Intensive Care Unit (LICU) stay was an independent risk factor for the development of infection. Parenteral antibiotics are effective at reducing the risk of infection in patients with ALF; enteral decontamination provided no additional benefit.
Adolescent↗
Prostaglandins in liver failure and transplantation: regeneration, immunomodulation, and cytoprotection. Prostaglandins in Liver Transplantation Research Group.
Prostaglandins (PG) are involved in the regulation of many physiological processes in the liver and play a major role in the pathophysiology and treatment of liver diseases. In addition to their effects of cell growth and immune function, PGs have shown cytoprotective effects on hepatocytes in various toxic, ischemic, and infectious models of liver injury. Although the mechanisms for these beneficial effects have not been precisely delineated, synthetic PG analogues have increasingly been used in patients with acute liver failure and chronic liver disease. There is also increasing evidence suggesting that PGs may reduce the early morbidity and mortality associated with liver transplantation, particularly in the context of primary graft nonfunction and renal dysfunction associated with cyclosporine and tacrolimus therapy. PG analogues have also been used for the treatment and control of recurrent hepatitis B virus infection in liver allograft recipients. The purpose of this review is to evaluate the role of PGs in hepatic physiology and disease and to review the use of synthetic PG analogues in the clinical settings of liver failure and transplantation.
Animals↗
Two-year data from the European multicentre tacrolimus (FK506) liver study.
To provide a more definitive assessment of the efficacy and safety of tacrolimus therapy in comparison with cyclosporin, the extended follow-up of the European multicentre study is reported. Two-year Kaplan-Meier estimates indicated significant reductions in acute (tacrolimus 45.4%, cyclosporin 55.8%; P = 0.006), refractory (1.2% versus 6.4%; P = 0.003) and chronic rejection (2.0% versus 6.9%; P = 0.015) despite significantly lower steroid usage in patients receiving tacrolimus therapy. Patient and graft survival rates (80.6% versus 74.8% and 74.5% versus 70.0%, respectively) were also superior, although these failed to reach statistical significance. Safety profiles were comparable for most major categories (including renal, neurological and glucose metabolic disorders) and in certain aspects were more favourable for tacrolimus. Hypertension (28.0% versus 39.6%, P < 0.01) and cytomegalovirus infection (14.8% versus 22.3%, P < 0.01), two events with important long-term clinical consequences, were reported significantly less frequently. Hirsutism (0.0% versus 8.7%, P < 0.01) and gum hyperplasia (0.0% versus 2.3%, P < 0.05) were absent in patients receiving tacrolimus. Tacrolimus appears to provide effective and safe long-term immunosuppression.
Adolescent↗