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Biomedical subjects

R Williams

Publications and source records attributed to R Williams.

At least 433 records · Page 24Linked to original sources
PubMed1996

A longitudinal analysis of hepatitis C virus replication following liver transplantation.

BACKGROUND & AIMS: The pathogenesis of graft injury in liver transplant recipients with recurrent hepatitis C virus (HCV) infection remains poorly understood. In this study, the relationship between HCV replication, genotype, and the evolution of graft damage was investigated. METHODS: HCV RNA was quantified in 184 protocol sera from 25 patients transplanted for HCV cirrhosis. HCV isolates were genotyped, and hepatic expression of core and NS4 antigens was sought in protocol allograft biopsy specimens. RESULTS: Acute lobular hepatitis was accompanied by a steep increase in HCV RNA levels and the appearance of core and NS4 antigens in the graft. Methylprednisolone treatment for acute rejection led to a 4-100-fold increase in serum HCV RNA. At the end of follow-up, HCV RNA levels were 3-112 times pretransplant levels and were higher in patients with more severe hepatitis. Progressive liver damage developed in 7 of 14 patients with HCV genotype 1b and in 1 of 11 patients infected with other genotypes (P = 0.03). CONCLUSIONS: Peak viremia levels and the initial detection of HCV antigens in hepatocytes suggests increased viral replication at the time of acute HCV hepatitis in the graft. Genotype 1b and higher viremia levels were associated with more severe chronic graft damage.

Adult↗
PubMed1996

Hepatitis B virus variants with core gene deletions in the evolution of chronic hepatitis B infection.

BACKGROUND & AIMS: Genomic variants of the hepatitis B virus (HBV) with core gene deletions have been identified in patients with chronic active hepatitis B, but the significance of these mutations in the course of chronic HBV infection remains unknown. The aim of this study was to longitudinally analyze the changes of HBV core gene deletion variants under the enhanced immune pressure of interferon alfa treatment and hepatitis B e antigen (HBeAg) to antibody to hepatitis B e antigen (anti-HBe) seroconversion. METHODS: HBV precore/core gene was amplified in 358 serum samples from 67 chronic HBV carriers (all HBeAg-positive) followed up for a period of 2-11 years. The core gene deletions were analyzed by gel electrophoresis, cloning, and DNA sequencing. RESULTS: HBV mutants with core gene deletions (37-250 base pairs) were detected in patients with long-standing HBV replication and ongoing hepatic inflammation, always together with the wild-type strain. They were associated with a significantly lower level of viremia and a high rate of seroconversion to anti-HBe. Core gene deletion mutants were preferentially eliminated after seroconversion, in contrast to the accumulation of HBV strains with a precore stop codon. CONCLUSIONS: These data indicate that HBV variants with core gene deletions may inhibit HBV replication, do not persist in preference of the wild-type HBV under enhanced immune pressure, and do not confer resistance to interferon alfa treatment.

Adult↗
PubMed1996

Evidence of increased guanylate cyclase activation by acetylcysteine in fulminant hepatic failure.

Patients with fulminant hepatic failure (FHF) have a severe microcirculatory disturbance causing tissue hypoxia. Infusion of acetylcysteine improves survival and reduces the incidence of multiorgan failure by enhancing tissue oxygenation. Because the observed circulatory effects of acetylcysteine in FHF are similar to and synergistic with those produced by the microcirculatory vasodilator prostacyclin, we postulated that acetylcysteine might potentiate an endogenous vasodilator. Nitric oxide, a vasodilator that activates soluble guanylate cyclase, is a possible candidate as plasma cyclic 3',5'-guanosine monophosphate (cGMP) is raised in FHF, and in vitro acetylcysteine has been found to enhance soluble guanylate cyclase activity. To investigate this possible mechanism further, plasma cGMP was measured before and after acetylcysteine infusion in 24 patients with FHF and again in 6 patients after recovery from acute illness. cGMP levels were high in FHF during acute illness (median, 7.0 nmol/L [interquartile range, 2.6-10.0]) in comparison with levels taken after recovery (1.5 nmol/L [1.0-1.9]; P < .05). Levels rose further after acetylcysteine infusion in the FHF cases (mean increase, 204% [95% CI; 49 to +360]; P < .01) but not in the cases after recovery (38% [-7 to +84]). There were no significant changes in levels of plasma atrial natriuretic peptide (ANP) or cyclic adenosine monophosphate (cAMP) (mean increases, 8% [-6 to +22] and 17% [-9 to +43], respectively). The findings further support the hypothesis that the beneficial hemodynamic effects of acetylcysteine in FHF are mediated by enhancing the activity of the nitric oxide/soluble guanylate cyclase enzyme system.

Acetylcysteine↗
PubMed1996

Evidence that the HLA DQA1*03 allele confers protection from chronic HCV-infection in Northern European Caucasoids.

In the search for factors which may influence susceptibility to and outcome from chronic hepatitis C virus (HCV) infection, few studies have considered the influence of host genes. In the present investigation we have performed HLA DRB1, DQA1, DQB1, and DPB1 genotyping on 104 northern European patients with chronic HCV infection and 177 racially and geographically matched controls. Three HLA class II alleles, DRB1*0403, DQA1*03, and DQB1*0302 were present at a significantly lower frequency in patients compared with controls (4.9% vs. 13%, 20.7% vs. 41.2%, and 11.4% vs. 30.5%, respectively) though only two DQB1*0302 and DQA1*03 were significant after correction for multiple testing (pc = 0.038, and pc = 0.046, respectively). No further HLA associations with chronic HCV infection were observed and there was no correlation between stage of disease and HLA genotype. These data provide the first suggestion that susceptibility to chronic HCV infection may be influenced by the hosts' HLA DQ alleles.

Alleles↗
PubMed1996

Classification, etiology, and considerations of outcome in acute liver failure.

Clinical descriptions of fulminant hepatic failure as originally reported, along with the subgroups of subfulminant and late onset hepatic failure identified later, are considered in relation to the proposed new classification of hyperacute, acute, and subacute liver failure. This reflects different clinical patterns of illness, etiology, and most importantly, prognosis. In addition to the defining state of encephalopathy and other manifestations directly related to the severe derangement in function and structure of the liver, the constellation of clinical symptoms and signs in acute liver failure (ALF) includes, to varying degrees, those of multiorgan failure. The latter develops because of tissue hypoxia from microcirculatory changes consequent on endotoxemia, and activation of macrophages and release of cytokines as a result of secondary bacteria infection due to an early failure of host defenses to infection in ALF. Paracetamol overdose-the commonest cause of acute liver failure in the United Kingdom-is increasing in frequency in other Western countries, but fulminant viral hepatitis is the most frequent etiology worldwide. Marked geographical variations are seen in the frequency with which the viral types A to E are implicated. Whereas hepatitis C is the major cause of ALF in Japan and the Far East, fulminant hepatitis C is seen rarely in America and European countries where most series show that in about one third of cases of presumed viral ALF, no specific agent can be identified. Over the past 10 years, the survival of those with grade 3 to 4 encephalopathy has shown a steady rise as a result of improvements in medical care, quite apart from the introduction and now widespread availability of transplantation for the treatment of this condition. As shown by a number of groups, a variety of different hematologic, biochemical, and clinical features can be used as predictive indices of the likely outcome and in determining the approach to treatment.

Acetaminophen↗
PubMed1996

Bacterial and fungal infection in acute liver failure.

Patients with acute liver failure (ALF) have increased susceptibility to infections, principally as a result of impaired phagocytic function, reduced complement levels, and the need for invasive procedures. Bacteriologically proven infection is recorded in up to 80% of these patients and fungal infection (predominantly candidiasis) in 32%. Clinical signs such as high temperature and high WBC are absent in 30% of the cases. Pneumonia accounts for 50% of infective episodes, and bacteremia and urinary tract infection a further 20 to 25% each, at a median 5, 3, and 2 days, respectively, after the onset of ALF. Selective parenteral and enteral antisepsis regimens (SPEAR) were evaluated in prospective controlled studies, but early systemic antibiotics alone are as effective as SPEAR. With early antibiotics, the incidence of infective episodes is reduced to 20% and the overall mortality to 44%, with a reduction in progression to encephalopathy and an increased opportunity for transplantation.

Bacterial Infections↗
PubMed1996

The management of abnormalities of hemostasis in acute liver failure.

The liver is the primary site of synthesis of most coagulation and fibrinolytic proteins, and also plays a role in the clearance of hemostasis factors and their degradation products. In acute liver failure, these functions are severely disturbed, and the risk of hemorrhage is increased. Following a brief summary of the physiology of hemostasis, this review describes the nature and frequency of hemostatic abnormalities in acute liver failure. These abnormalities include quantitative and qualitative platelet defects, impaired synthesis and clearance of the coagulation factors and related inhibitory proteins, and enhanced fibrinolysis. Disseminated intravascular coagulation may also play a role, although this syndrome is difficult to distinguish from changes due to the failure of hepatic synthesis and clearance alone. At present, management options are limited to support with blood products, although pharmacological manipulation of the coagulation and fibrinolytic systems represent a potential area for future study.

Blood Coagulation Disorders↗
PubMed1996

Liver transplantation in Europe for patients with acute liver failure.

Approximately 11% of all liver transplants performed in Europe are for acute liver failure, with one-year patient survival rates ranging between 50% and 75%. This review summarizes the selection, perioperative management, and outcome of patients transplanted for acute liver failure, with particular reference to the experience at the Hôpital Paul Brousse in Paris and at King's College Hospital, London. In both centers, the decision to proceed to liver transplantation is based on criteria that predict a survival of less than 20% with medical management alone. Infectious complications and cerebral edema remain the most common causes of death, and highlight the importance of intensive monitoring and early treatment of perioperative complications. In selected patients, auxiliary partial orthotopic liver transplantation may be a therapeutic option, with the potential for native liver generation and eventual immunosuppression withdrawal in approximately two-thirds of patients.

Europe↗
PubMed1996

Use of bioartificial and artificial liver support devices.

With all the new work and current interest in extracorporeal liver support systems incorporating hepatocytes, the findings with earlier artificial systems need to be reconsidered, particularly as they may constitute a component of some bioartificial devices. Furthermore, new and more effective artificial systems are currently under development. Essential hepatic functions need to be replaced, including excretory (the capability of adsorbents and dialysis) and synthetic and biotransformatory function, but the relative importance of these three functions in terms of promoting recovery of the native liver is as yet unclear. Two bioartificial devices have already been used clinically in the treatment of acute liver failure (ALF): the bioartificial liver (BAL) based on pig hepatocytes attached to microcarriers, and the extracorporeal liver assist device (ELAD) which contains a human liver-derived tumor cell line. As with earlier completely artificial systems, the results so far obtained in man are less impressive than in animal models of ALF. An important question not yet answered relates to quantity of cells and specific function in the new hybrid bioreactor devices required for clinical benefit, as well as the duration of support needed. A better understanding of the effects of these devices on the metabolic function of the damaged liver and the recovery process will be essential in the further development and design of effective systems. Controlled clinical trials on a multicenter basis will be needed for proper evaluation of these new approaches to treatment of ALF. From our own initial experience, the design of these protocols and the selection of biochemical tests will be difficult.

Animals↗
PubMed1996

A family with Stickler syndrome type 2 has a mutation in the COL11A1 gene resulting in the substitution of glycine 97 by valine in alpha 1 (XI) collagen.

Stickler syndrome (hereditary arthro-ophthalmopathy) is the commonest inherited cause of retinal detachment and one of the commonest autosomal dominant connective tissue dysplasias. There is clinical and locus heterogeneity with about two thirds of families linked to the gene encoding type II procollagen (COL2A1). Families with Sticklers syndrome type 1 have a characteristic congenital vitreous anomaly and are linked without recombination to markers at the COL2A1 locus. In contrast families with the type 2 variety have a different vitreo-retinal phenotype and are not linked to the COL2A1 gene. Type XI collagen is a quantitatively minor fibrillar collagen related to type V collagen and associated with the more abundant type II collagen fibrils. A mutation in COL11A2, the gene for alpha 2 (XI) procollagen, has recently been found in a family described as having Stickler syndrome, although there was no ocular involvement. Here we show for the first time that a family with the full Type 2 Stickler syndrome including vitreous and retinal abnormalities is linked to the COL11A1 gene and characterise the mutation as a Glycine to Valine substitution at position 97 of the triple helical domain caused by a single base G-->T mutation. These results are the first to provide confirmation that type XI collagen is an important structural component of human vitreous. They also support previous work suggesting that mutations in the genes encoding collagen XI can give rise to some manifestations of Stickler syndrome, but of these, only mutations in COL11A1 will give the full syndrome including the vitreo-retinal features.

Collagen↗
PubMed1996

Part I of Membership of the Faculty of Public Health Medicine (MFPHM). Trends over time and factors associated with success in recent years.

BACKGROUND: The examination for Membership of the Faculty of Public Health Medicine (MFPHM) Part I, has been held for nearly 20 years. It aims 'to test the candidate's knowledge and understanding of the basic sciences of public health'. This paper presents simple statistics from the earliest years up to June 1995 and additional information on more recent sittings. METHOD: The number of people taking the examination and the proportion passing were obtained for every sitting from February 1978 to June 1995. Further data have been extracted for all sittings of the examination since the current regulations were introduced. The variables included were pass or fail as the outcome variable, date of birth, gender of candidate, postgraduate qualifications, present post of employer, and attendance at a formal academic course. RESULTS: The number of candidates has ranged from 12 to 115, the proportion passing from 42 per cent to 93 per cent. During the period from June 1992 to June 1995, 472 people applied to sit the examination. Of these 33 withdrew, leaving 439 person attempts. The overall proportion passing was 270/439 (61.5 per cent). Factors associated with success include being female, being a UK graduate, attending an academic course and having more experience in the specialty. CONCLUSION: Candidates and their tutors are reminded of the need for adequate preparation for the examination. The authors welcome comments on how monitoring should be carried out in the future.

Adult↗
PubMed1996

Imaging secondary neuroendocrine tumours of the liver: comparison of I123 metaiodobenzylguanidine (MIBG) and In111-labelled octreotide (Octreoscan).

Functional imaging of neuroendocrine tumours with Octreoscan and I123-metaiodobenzylguanidine (MIBG) is important for assessment prior to various therapies and assessing response. The two imaging methods have not been directly compared in hepatic neuroendocrine tumours. Patients (n = 18) were studied with both imaging techniques. The sensitivity of Octreoscan was 94%, and that of MIBG 39%. No previously occult primary sites were detected. Concurrent octreotide therapy did not reduce the sensitivity of Octreoscan. Widespread bone metastases were seen in two post-liver-transplant patients using Octreoscan. Octreoscan is a sensitive means of detecting hepatic neuroendocrine tumours, and the more specific technique. MIBG has poor sensitivity, reducing its clinical utility. Therapy with I131-MIBG is likely to be applicable to relatively few patients.

3-Iodobenzylguanidine↗
PubMed1996

Relationship between the humidity and temperature of inspired gas and the function of the airway mucosa.

OBJECTIVE: To review the available literature on the relationship between the humidity and temperature of inspired gas and airway mucosal function. DATA SOURCES: International computerized databases and published indices, experts in the field, conference proceedings, bibliographies. STUDY SELECTION/DATA EXTRACTION: Two hundred articles/texts on respiratory tract physiology and humidification were reviewed. Seventeen articles were selected from 40 articles for inclusion in the published data verification of the model. Selection was by independent reviewers. Extraction was by consensus, and was based on finding sufficient data. DATA SYNTHESIS: A relationship exists between inspired gas humidity and temperature, exposure time to a given humidity level, and mucosal function. This relationship can be modeled and represented as an inspired humidity magnitude vs. exposure time map. The model is predictive of mucosal function and can be partially verified by the available literature. It predicts that if inspired humidity deviates from an optimal level, a progressive mucosal dysfunction begins. The greater the humidity deviation, the faster the mucosal dysfunction progresses. CONCLUSIONS: A model for the relationship between airway mucosal dysfunction and the combination of the humidity of inspired gas and the duration over which the airway mucosa is exposed to that humidity is proposed. This model suggests that there is an optimal temperature and humidity above which, and below which, there is impaired mucosal function. This optimal level of temperature and humidity is core temperature and 100% relative humidity. However, existing data are only sufficient to test this model for gas conditions below core temperature and 100% relative humidity. These data concur with the model in that region. No studies have yet looked at this relationship beyond 24 hrs. Longer exposure times to any given level of inspired humidity and inspired gas temperatures and humidities above core temperature and 100% relative humidity need to be studied to fully verify the proposed model.

Animals↗
PubMed1996

Complications and effectiveness of gastrostomy feedings in pediatric cancer patients.

PURPOSE: The objective of this study was to assess the complications and efficacy of gastrostomy (GT) feedings in pediatric cancer patients. PATIENTS AND METHODS: We reviewed the medical records of 33 pediatric cancer patients who received enteral nutrition via a GT. RESULTS: Median age was 9.4 years (range, 1-19.8 years), and 28 of the 33 patients had solid tumors. Seventeen patients had a significant weight loss (median, 8.5%) and therapy-related weight loss was anticipated in 16 patients. The GT device was placed an average of 5.5 months after diagnosis. Twenty-five patients were fed via a tube and eight via a button device. The tube was placed surgically in 21 cases (including all eight button types) and endoscopically in 12. Nutritional support lasted a median of 9.5 months. One or more complications occurred in 30 patients and were categorized as (a) insertion site reactions (inflammation, 23; infection/colonization, 14; exuberant granulation tissue, 6); (b) mechanical problems (leaking, 3; obstruction, 2; breakage, 1; accidental dislodgement, 2); (c) insertion site bleeding, 8; and (d) feeding intolerance, 12. Only one insertion site cellulitis progressed to a systemic infection. All eight patients with a button GT experienced insertion site complications, with local infection occurring significantly more often in patients with the button than in those with the tube GT. There were no significant associations between insertion technique and type of complication. Twenty-seven patients (82%) achieved or maintained ideal body weight with this intervention. CONCLUSIONS: GT feeding was associated with minor complications, but permitted effective nutritional support for pediatric cancer patients.

Adolescent↗
PubMed1996

Chemoembolisation with lipiodol and doxorubicin: applicability in British patients with hepatocellular carcinoma.

Chemoembolisation has been extensively used as primary treatment for unresectable hepatocellular carcinoma (HCC). In this unit, 185 patients with a new diagnosis of HCC not amenable to surgery were seen between 1988 and 1991. Intended therapy for these patients was chemoembolisation with doxorubicin (60 mg/m2) and lipiodol, repeated at six week intervals until it was technically no longer possible or until complete tumour response had been obtained. Chemoembolisation was possible in 67 of the 185 (37%). Reasons for exclusion were portal vein occlusion (n = 36), decompensated cirrhosis (n = 44), distant metastases (n = 5), diffuse tumour or unsuitable anatomy (tumour or vasculature) (n = 11), patient refusal (n = 11), and other (n = 11). Patients excluded from treatment survived for a median of 10 weeks (range 3 days-19 months). In patients treated, 18 had small HCC (< 4 cm) and 49 had large or multifocal HCC. Chemoembolisation was carried out a median of two sessions for small and three sessions for large tumours. Ten of 18 patients with small HCC showed a 50% or greater reduction in tumour size. Five of 49 patients with large or multifocal tumours showed a response to treatment. Median overall survival for treated patients was 36 weeks (range 3 days-4 years). One patient has subsequently undergone liver transplantation with no recurrence and minimal residual disease at transplantation. Two other patients are alive three years after chemoembolisation, one with no evidence of recurrent disease. No patient was thought suitable for surgery after their response to chemoembolisation. Chemotherapy related complications were seen in 22%. Complications were significantly more common in patients with larger tumours and poor liver reserve. Five patients died as a result of chemotherapy related complications. In conclusion, only one third of UK patients with unresectable HCC are treatable by chemoembolisation. Results with small tumours are encouraging, with a high response rate and the possibility of surgical intervention in previously inoperable disease. Large tumours, however, show a poor response and a significant incidence of side effects, suggesting that this treatment offers little benefit in advanced disease.

Antineoplastic Agents↗