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G J Webster

Publications and source records attributed to G J Webster.

10 recordsLinked to original sources
PubMed2001

Kinetics of acute hepatitis B virus infection in humans.

Using patient data from a unique single source outbreak of hepatitis B virus (HBV) infection, we have characterized the kinetics of acute HBV infection by monitoring viral turnover in the serum during the late incubation and clinical phases of the disease in humans. HBV replicates rapidly with minimally estimated doubling times ranging between 2.2 and 5.8 d (mean 3.7 +/- 1.5 d). After a peak viral load in serum of nearly 10(10) HBV DNA copies/ml is attained, clearance of HBV DNA follows a two or three phase decay pattern with an initial rapid decline characterized by mean half-life (t(1/2)) of 3.7 +/- 1.2 d, similar to the t(1/2) observed in the noncytolytic clearance of covalently closed circular DNA for other hepadnaviruses. The final phase of virion clearance occurs at a variable rate (t(1/2) of 4.8 to 284 d) and may relate to the rate of loss of infected hepatocytes. Free virus has a mean t(1/2) of at most 1.2 +/- 0.6 d. We estimate a peak HBV production rate of at least 10(13) virions/day and a maximum production rate of an infected hepatocyte of 200-1,000 virions/day, on average. At this peak rate of virion production we estimate that every possible single and most double mutations would be created each day.

Acute Disease↗
PubMed2000

Molecular epidemiology of a large outbreak of hepatitis B linked to autohaemotherapy.

BACKGROUND: Unregulated skin-piercing procedures potentially facilitate the transmission of bloodborne pathogens. In February, 1998, a patient who had recently received autohaemotherapy at an alternative medicine clinic in the UK was diagnosed with acute hepatitis B. The autohaemotherapy procedure involved the drawing of 1 mL of the patient's blood, mixing with saline, and reinjection of the autologous blood mixture. We investigated the extent of hepatitis B virus (HBV) infection in patients and staff of the clinic. METHODS: Patients who had attended the clinic between January, 1997, and February, 1998, were tested for serological markers of HBV, and for HBV DNA by PCR. HBV DNA was sequenced to assess the relatedness of the virus identified in the cases. We analysed the number and dates of visits with regard to HBV status. FINDINGS: Serum samples were received from 352 patients and four staff members. Serological evidence of exposure to HBV was found in 57 (16%). Of the 33 patients and staff who were positive for hepatitis B surface antigen, 30 (91%) showed complete nucleotide identity in the DNA segments derived from the surface and core genes. Five patients with linked infection had markers of chronic hepatitis B, and one of these was regarded as the likely source of the outbreak. The attack rate was associated with the number of visits (p<0.0001) and the week of visit (p=0.011). Contaminated saline in a repeatedly used bottle was the probable vehicle of transmission. INTERPRETATION: We have described a large community-based outbreak of hepatitis B due to transmission by a single HBV variant. Our findings emphasise the continuing risk of transmission of bloodborne viruses in all health-care settings where skin-piercing procedures are used.

Adult↗
PubMed2000

T cell receptor usage of virus-specific CD8 cells and recognition of viral mutations during acute and persistent hepatitis B virus infection.

T cells specific for a single viral epitope, but using different T cell receptors, should have flexibility in their epitope recognition to protect the infected host against the emergence of viral escape mutants. Therefore, polyclonality of the hepatitis B virus (HBV)-specific cytotoxic T lymphocyte response has been hypothesized to be a major determinant in the control of infection. We analyzed the Vbeta chain composition of the core 18-27-specific CD8 cells in acute and persistently HBV-infected patients using HLA-A2 tetrameric complexes and a panel of Vbeta antibodies. Different T cell receptors were utilized by core 18-27-specific CD8 cells both in patients with acute and chronic infection. The functional ability of these epitope-specific T cells to respond to potential viral mutations was then tested. The polyclonal HBV-specific CD8 response present in patients with acute hepatitis displayed a limited efficiency to recognize mutations introduced within the epitope. The ability of core 18-27-specific CD8 to tolerate epitope mutations was found only during persistent HBV infection. The data suggest that although a clonally heterogeneous CD8 response can be largely inhibited by the occurrence of single epitope mutations in primary HBV infection, preferential selection of T cells able to counteract the emergence of viral mutations can occur during persistent infection.

Acute Disease↗
PubMed2000

Incubation phase of acute hepatitis B in man: dynamic of cellular immune mechanisms.

After hepatitis B virus (HBV) infection, liver injury and viral control have been thought to result from lysis of infected hepatocytes by virus-specific cytotoxic T cells. Patients are usually studied only after developing significant liver injury, and so the viral and immune events during the incubation phase of disease have not been defined. During a single-source outbreak of HBV infection, we identified patients before the onset of symptomatic hepatitis. The dynamics of HBV replication, liver injury, and HBV-specific CD8+ and CD4+ cell responses were investigated from incubation to recovery. Although a rise in alanine transaminase (ALT) levels was present at the time of the initial fall in HBV-DNA levels, maximal reduction in virus level occurred before significant liver injury. Direct ex vivo quantification of HBV-specific CD4+ and CD8+ cells, by using human leukocyte antigen (HLA) class I tetramers and intracellular cytokine staining, showed that adaptive immune mechanisms are present during the incubation phase, at least 4 weeks before symptoms. The results suggest that the pattern of reduction in HBV replication is not directly proportional to tissue injury during acute hepatitis B in humans. Furthermore, because virus-specific immune responses and significant reductions in viral replication are seen during the incubation phase, it is likely that the immune events central to viral control occur before symptomatic disease.

Acute Disease↗
PubMed1999

Infection and hemostasis in decompensated cirrhosis: a prospective study using thrombelastography.

Bacterial infections are common complications in decompensated cirrhosis, but their relationship with hemostasis has not been studied. We prospectively assessed whether infection affects hemostasis in cirrhosis using routine hemostasis tests and thrombelastography (TEG), a global test of hemostatic function. Eighty-four cirrhotic patients (Child-Pugh B: 26; C: 58) without overt bleeding or blood-product transfusion were prospectively evaluated with routine hemostasis tests and TEG on admission and/or the first day with signs of infection and 5 days later. There were 30 patients with infection; 15 had infection on admission, and 15 developed infection in hospital. In the patients who developed infection in hospital, there was a significant deterioration in all routine hemostasis tests except platelet count (PLT) and in all TEG parameters, on the first day of infection compared with 7 +/- 3 days previously. The same parameters significantly improved from the first day of infection to day 5 and after (P <.02) only in the 22 patients whose infection resolved, while the r, k, and alpha TEG parameters significantly worsened in the 8 patients with persistent infection. In those who developed infection in hospital and were cured (n = 11), the 5-day parameters did not differ from their preinfection values. In conclusion, bacterial infections frequently impair hemostasis in decompensated cirrhotic patients. Successful treatment of infection usually restores hemostasis parameters to preinfection levels in 5 days. Thus, infection may have a role in the bleeding diathesis of cirrhosis.

Adult↗
PubMed1999

Direct ex vivo analysis of hepatitis B virus-specific CD8(+) T cells associated with the control of infection.

BACKGROUND & AIMS: Cytotoxic T cells have been suggested to be responsible for lysis of hepatitis B virus (HBV)-infected hepatocytes and control of virus infection. The frequency, kinetics, phenotype, and capacity for clonal expansion of circulating HBV-specific CD8 cells were analyzed directly in patients with acute HBV infection to clarify their pathogenetic role. METHODS: Three HLA-A2 peptide tetramers able to visualize HBV core, envelope, and polymerase epitope-specific cytotoxic T lymphocytes were synthesized and used for flow cytometric analysis of antigen-specific populations. RESULTS: Tetramer-positive cells specific for the core 18-27 epitope were found at a higher frequency than those specific for polymerase 575-583 and envelope 335-343 epitopes in most patients with acute HBV. The number of HBV-specific CD8 cells was highest during the clinically acute stage of infection and decreased after recovery. These cells expressed an activated phenotype and had an impaired capacity to expand in vitro and to display cytolytic activity in response to peptide stimulation. Recovery of these functions was observed when the frequency of specific CD8 cells decreased, coincident with a progressive decrease in their expression of activation markers. CONCLUSIONS: This study provides the first ex vivo evidence that the highest frequency of circulating HBV-specific CD8 cells coincides with the clinically acute phase of hepatitis B. These cells exhibit an activated phenotype with limited further proliferative capacity that is restored during recovery.

Adult↗
PubMed1997

Drinking before endoscopy: milk or water?

BACKGROUND: The traditional fluid fast prior to endoscopy is unnecessary. We have previously shown that drinking water prior to endoscopy does not affect either the quality of mucosal views or residual gastric fluid volumes when compared to patients undergoing endoscopy after a standard fast. The present study was designed to establish whether milk, which may delay gastric emptying, could also be drunk prior to endoscopy without adverse effect. METHODS: Forty-eight patients (mean age 48 years, range 20 to 79) undergoing routine upper gastrointestinal endoscopy after overnight fast were randomized to drink 200 ml of either still mineral water or full fat milk. Endoscopy was performed 90 minutes later, when all residual gastric fluid was aspirated via the endoscope. Volume and pH of gastric aspirate were measured and the quality of the mucosal view at endoscopy recorded as poor, adequate, or excellent. RESULTS: No difference was shown between water (n = 27) and milk (n = 21) drinkers in residual gastric volume (mean +/- SEM, water vs milk) (16.0 ml +/- 1.5 vs 18.9 ml +/- 2.9) or pH (2.23 +/- 0.14 vs 2.48 +/- 0.14). Of those patients with poor, adequate, or excellent views, 4 of 4, 11 of 12, and 6 of 32 patients, respectively, were milk drinkers (chi-squared test for trend = 21.7, df = 1, p < 0.001), indicating significantly worse mucosal views in the group drinking milk. CONCLUSION: Drinking water up to 90 minutes prior to endoscopy is safe, but milk should be discouraged because of suboptimal mucosal views.

Animals↗
PubMed1996

Assessment of residual gastric volume and thirst in patients who drink before gastroscopy.

BACKGROUND: Before endoscopy patients undergo an uncomfortable fluid fast to reduce the risk of gastric acid aspiration and to ensure good endoscopic views are obtained. However, fluids rapidly leave the stomach and thus a long fluid fast before endoscopy may not be required. AIMS: The object of this study was to establish whether drinking before endoscopy is safe and relieves patients' symptoms of thirst. PATIENTS AND METHODS: 88 patients with American Society of Anaesthesiologists classification of physical status grades I and II were recruited in a controlled randomised single blind trial. The volume and pH of gastric aspirate obtained at gastroscopy was assessed in patients who drank 330 ml of water a minimum 90 minutes before their endoscopy and compared with values in patients who starved overnight. RESULTS: 44 patients who drank ('drinkers') 330 ml of water a mean 117 minutes before their morning gastroscopy had a similar volume and pH of gastric aspirate compared with 44 patients starved overnight ('starvers'); median volume 12.5 ml versus 10 ml, median pH 2.0 versus 2.0; 'drinkers' versus 'starvers' (NS). Before endoscopy patients were asked to score their thirst and hunger ratings as either none, mild, moderate or severe. Ratings for moderate and severe thirst were grouped together for analysis. The percentage of drinkers compared with starvers in each group with no thirst, mild thirst, and moderate severe thirst was 63%, 46%, and 37% respectively (chi 2 test for trend p < 0.05). Hunger ratings were similar in the two groups. CONCLUSIONS: It is safe for elective day cases to drink a significant volume of water two hours before endoscopy and this alleviates symptoms of thirst.

Adult↗
PubMed1991

Streptozotocin-induced diabetes in rats causes neuronal deficits in tyrosine hydroxylase and 5-hydroxytryptamine specific to mesenteric perivascular sympathetic nerves and without loss of nerve fibers.

The aim of this study was to investigate the possibility that inadequate venous return to the heart in diabetes is the result of a neuropathy which affects autonomic nerves supplying the splanchnic vasculature. Mesenteric veins from rats with streptozotocin-induced diabetes were markedly dilated in vivo compared to veins from control animals. Dilation appeared to be the result of loss of muscle tone rather than hypertrophy or hyperplasia of the vessel wall. Using quantification by image analysis and double-labeling immunohistochemistry on mesenteric veins, significant reductions in the density of nerve plexuses staining for 5-hydroxytryptamine (5-HT) and tyrosine hydroxylase (TH) were shown in vessels from diabetic rats compared to controls. No reductions were observed in the density of nerve plexuses stained for the neuronal marker, PGP 9.5, or for substance P (SP), a marker for afferent nerve fibers. These results indicate neurochemical deficits in experimentally induced diabetes which are specific to perivascular noradrenergic nerves and which, within the time-scale of our experiments, do not involve loss of nerve fibers. These deficits may contribute to an increase in venous pooling of blood in the splanchnic vasculature of diabetic rats and thus to inadequate venous return to the heart.

Animals↗