Biomedical subjects
Publications and source records attributed to R F Bishop.
We discuss the application of an extended version of the coupled cluster method to systems exhibiting a quantum phase transition. We use the lattice O(4) nonlinear sigma model in (1+1) and (3+1) dimensions as an example. We show how simple predictions get modified, leading to the absence of a phase transition in (1+1) dimensions, and strong indications for a phase transition in (3+1) dimensions.
Rotavirus strains that caused severe diarrhea in 4,634 (2,533 male) children aged less than 5 years and admitted to major hospitals in eight centers throughout Australia from 1993 to 1996 were subject to antigenic and genetic analyses. The G serotypes of rotaviruses were identified in 81.9% (3,793 of 4,634) children. They included 67.8% (from 3,143 children) serotype G1 isolates (containing 46 electropherotypes), 11.5% (from 531 children) serotype G2 isolates (27 electropherotypes), 0.8% (from 39 children) serotype G3 isolates (8 electropherotypes), and 1.6% (from 76 children) serotype G4 isolates (9 electropherotypes). G6 (two strains) and G8 (two strains) isolates were identified during the same period. G1 serotypes were predominant in all centers, with intermittent epidemics of G2 serotypes and sporadic detection of G3 and G4 strains. With the exception of two strains (typed as G1P2A[6] and G2P2A[6]) all serotype G1, G3, and G4 strains were P1A[8] and all serotype G2 strains were P1B[4]. Two contrasting epidemiological patterns were identified. In all temperate climates rotavirus incidence peaked during the colder months. The genetic complexity of strains (as judged by electropherotype) was greatest in centers with large populations. Identical electropherotypes appeared each winter in more than one center, apparently indicating the spread of some strains both from west to east and from east to west. Centers caring for children in small aboriginal communities showed unpredictable rotavirus peaks unrelated to climate, with widespread dissemination of a few rotavirus strains over distances of more than 1,000 km. Data from continued comprehensive etiological studies of genetic and antigenic variations in rotaviruses that cause severe disease in young children will serve as baseline data for the study of the effect of vaccination on the incidence of severe rotavirus disease and on the emergence of new strains.
Reverse transcription-PCR and sequence analysis identified calciviruses in 32 of 60 stool specimens (negative for other enteric pathogens) obtained from children admitted to our hospital with acute gastroenteritis. The overall annual incidence rate for calcivirus was 9% (32 of 354 children). Molecular analysis identified 30 "Norwalk-like virus" genogroup II (predominantly Lordsdale cluster) and 2 "Sapporo-like virus" strains.
The incidence of astrovirus infection in children less than 5 years of age hospitalized with acute gastroenteritis in Melbourne, Australia, from 1995 to 1998 was determined. Astrovirus was detected in 40 of 449 specimens tested by Northern hybridization, and astrovirus infection was confirmed by reverse transcription-PCR with or without culture in CaCO-2 cells. This represented 3.0% (40 of 1, 327) of all children tested for enteric pathogens, including viral, bacterial, and parasitic pathogens, over the survey period. The incidences of astrovirus infection in each year were 4.4% (1995), 2. 2% (1996), 3.9% (1997), and 1.4% (1998). In 1995 and 1997, the incidences of astrovirus infection were greater than the incidence of infection with all individual bacterial pathogens and were either greater than or equal to the incidence of adenovirus infection. Astrovirus exhibited an unusual biennial winter peak of incidence that correlated with a greater incidence of serotype 1 virus and an increased rate of hospitalization of children aged 6 to 12 months. Uncommon (serotype 2 and 4) and rare (serotype 8) serotypes were detected during the survey period. Genetic analysis of ORF2 (which encodes the astrovirus capsid precursor) of Melbourne isolates showed nucleotide sequence variation from year to year. This was not accompanied by significant amino acid substitutions. However, geographical variation was apparent by comparison of Melbourne astrovirus isolates with prototype strains identified in the United Kingdom.
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An atypical human rotavirus strain, DG8, was isolated from a 13-month-old child hospitalised with acute gastro-enteritis in Australia. The virus could not be serotyped by enzyme immunoassay (EIA) using standard reagents specific for common Group A human rotavirus G serotypes. The deduced amino acid sequence of the outer capsid glycoprotein, VP7, indicated that this strain belonged to the uncommon human serotype G8. This was confirmed by EIA incorporating a G8-specific neutralising monoclonal antibody (NMAb). The VP4 genotype of DG8 was determined as P[14], equivalent to P serotype P3B, by sequence analysis and confirmed by EIA incorporating a P3B-specific NMAb. Electrophoretic analysis of DG8 genomic dsRNA indicated that the virus exhibited a "long" electropherotype. Northern hybridisation analysis (using a whole-genome probe derived from DG8) indicated that DG8 shared overall homology with the European serotype G8 strain, HAL1166 (11 of 11 genes). In contrast, only 9 of 11 genes of DG8 hybridised with the Asian serotype G8 strain, B37, and with the bovine G8 strain, A5. Hence, DG8 displayed features reminiscent of the human serotype G8 rotaviruses isolated in Europe in the mid-1980s rather than the geographically local G8 Asian strains isolated a decade earlier. It is possible that DG8 arose through reassortment between human and bovine rotaviruses.
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OBJECTIVE: Rotavirus gastroenteritis causes substantial morbidity, including hospital admission, in young children. In the context of recent vaccine developments, this study aimed to estimate the cost-effectiveness of a rotavirus vaccination program in Australia. METHOD: Standard methods of health economic evaluation were used to assess the total cost of rotavirus immunisation (as the difference between estimated vaccination program costs and the cost of disease that would be avoided by immunisation) and relate this to the number of cases of disease that would be prevented. Estimates were made from both societal and health care systems perspectives. RESULTS: Based on Australian data on disease incidence and cost of hospitalisation, the current annual cost of rotavirus disease is about $26.0 million. Using conservative vaccine efficacy estimates, current immunization uptake rates and a cost of $30 per dose of vaccine, rotavirus immunisation would incur a net societal cost of $2.9 million ($11 per child), at a gross program cost of $21.6 million. These estimates are sensitive to two sources of uncertainty in the estimation of program delivery costs: vaccine price and whether separate immunization visits would be required. CONCLUSION: A rotavirus immunisation program would be cost-neutral to Australian society at a vaccine price of $26 per dose (or $19 when health care system costs only are considered). IMPLICATIONS: Rotavirus immunization may be cost-effective in Australia, but considerable uncertainty remains. Policy decisions will depend heavily on pricing of the vaccine and may also need to consider intangible costs not accounted for in this analysis.
Worldwide trials of rotavirus vaccines are currently in progress, but the basis of cross-reactive immunity between rotavirus serotypes is yet to be elucidated. The involvement of the outer capsid proteins, VP7 and VP4, in the production of cross-reactive neutralizing antibody (N-Ab) is unclear, and may be important for the success of animal rotavirus-based candidate vaccines that lack a VP4 of human rotavirus origin. In this study, VP7- and VP4-specific N-Ab was assayed in sera from children experiencing primary (27 children) and/or secondary (14 children) rotavirus infections using human-animal reassortant strains. These reassortants contained genes encoding the major G- and P-types found in human infection, including G1, 2, 3, and 4; or P1A[8], 1B[4], and 2[6]. After primary infection, the N-Ab response to VP7 was generally serotype-specific, whereas the response to VP4 was heterotypic. After reinfection (with the same or different serotypes) there was a significant increase (P=0.0313) in the number of VP7 serotypes seroconverted against with no broadening of cross-reactivity to VP4. Increases in homotypic N-Ab titer, following both primary and secondary infection, were greater against VP7 than VP4, with the seroconversion against VP7 being significantly greater upon reinfection than following primary infection (P=0.0280). In summary, heterotypic N-Ab produced following primary infection appears to be primarily against VP4. However, upon reinfection, VP7 becomes increasingly immunodominant both in terms of cross-reactive N-Ab production and increases in N-Ab titer.
OBJECTIVE: To determine rates of hospitalisation of young children for acute gastroenteritis in Australia, and to estimate the proportion of these admissions caused by rotavirus infection. DESIGN: Analysis of hospital admission records, and parallel, prospectively collected data on rotavirus-positive admissions. SETTING: Hospitals admitting young children in all Australian States and Territories in 1993-1996. PATIENTS: All children under five years admitted to hospital for acute gastroenteritis (International Classification of Diseases, ninth revision principal diagnosis codes 003.0, 004.0-009.3 and 558.9). MAIN OUTCOME MEASURES: Rate of hospital admission per 1000 children per year by State, and the proportion of admissions caused by rotavirus infection. RESULTS: There were almost 20,000 hospital admissions annually in Australia for acute gastroenteritis in children under five years, at an average rate of 15/1000. An estimated 50% of these were attributable to rotavirus infection, implying a rate of hospitalisation for rotavirus-related gastroenteritis of 7.5/1000/year. Among children under two years this rate was 11.6/1000. Rotavirus incidence rates generally followed a typical seasonal pattern in temperate regions of the country, with sharp peaks in mid to late winter. Rates of hospitalisation varied markedly, even between States with apparently similar patterns of disease, while the incidence in the Northern Territory was 3-5 times higher than other States. CONCLUSIONS: Rotavirus-related gastroenteritis is a major cause of hospital admissions in young children, and large savings to the healthcare system are possible if it can be prevented at reasonable cost. Variation in treatment practices between States may be worth studying in greater detail as another source of potential savings.
BACKGROUND: During an epidemiological study on the incidence of astrovirus infection in children hospitalized with acute gastroenteritis, a Northern hybridization method was used to screen stool samples for astrovirus RNA. Positive results were confirmed using reverse transcriptase-polymerase chain reaction (RT-PCR), which showed surprisingly low sensitivity. The low sensitivity of the RT-PCR method was considered likely to be due to the presence of non-specific inhibitors. OBJECTIVE: To develop and use a simple culture method to improve the sensitivity of diagnosis of astrovirus in clinical stool samples using RT-PCR. STUDY DESIGN: Stool samples from children hospitalized with acute gastroenteritis were screened for astrovirus using Northern hybridization. The presence of astrovirus RNA was then confirmed using an astrovirus-specific RT-PCR. Hybridization positive samples that failed to generate an RT-PCR product were cultured in CaCO-2 cells for 48 h. RNA was isolated from cultures and re-tested using the same RT-PCR method. RESULTS: Using Northern hybridization, human astroviruses were detected in the stools of 31 patients and confirmed by RT-PCR in 16 samples. RNA extracted directly from 15 faecal specimens could not be amplified by RT-PCR. After culture for 48 h in CaCO-2 cells, RNA extracted from these samples could be amplified and confirmed the presence of astrovirus in all 15 specimens. CONCLUSIONS: Development of a simplified culture method for astrovirus positive faecal specimens improved the sensitivity of astrovirus-specific RT-PCR from 52 to 100%. The technique should be of value as a confirmatory test in surveys of human astrovirus infection.
Acute infectious diarrhea is common in children. Control requires knowledge of causes. Few comprehensive long-term studies of etiology have been undertaken in developed countries. This report is of a 13-year survey of 4,637 children from 0 to 14 years of age, admitted to a large children's hospital for treatment of gastroenteritis, in which viruses, bacteria, and parasites were sought. A recognized enteric pathogen was identified in 56.6% of children. Group A rotaviruses occurred in 39.6% of children overall and in 55% of children 12 to 23 months of age. They were a frequent cause (18.7%) of acute gastroenteritis in children under 6 months and in those aged 5 to 13 years (16%). Rotaviruses were almost entirely responsible for winter admission peaks. Enteric adenovirus types 40 and 41 (6% overall) were more frequent in children under 12 months (9.4%). Salmonella spp. (5.8%) and Campylobacter jejuni (3.4%) were more common in children over 5 years (13.1% and 6.7%, respectively). The 43.5% of cases (60% in children under 6 months) where no enteric pathogen was identified are cause for concern. The involvement of small viruses (including caliciviruses and astroviruses) may be clarified when molecular biology techniques are utilized to address this gap in our knowledge. This comprehensive 13-year study of the cause of acute infectious diarrhea in children in developed countries reinforces the importance of rotavirus and highlights a large group for whom the etiology remains unknown, an issue of particular concern with babies under 6 months of age. New techniques have the potential to identify old and new pathogens causing disease in these vulnerable infants.
We recently established a rotavirus strain surveillance system in the United States to monitor the prevalent G serotypes before and after the anticipated implementation of a vaccination program against rotavirus and to identify the emergence of uncommon strains. In this study, we examined 348 rotavirus strains obtained in 1996 to 1997 from children with diarrhea in 10 U.S. cities. Strains were characterized for P and G types, subgroups, and electropherotypes by using a combination of monoclonal antibody immunoassay, reverse transcription-PCR, and hybridization. The four strains most commonly found worldwide comprised 83% of the isolates (P[8]G1, 66.4%; P[4]G2, 8.3%; P[8]G3, 6.9%; P[8]G4, 1.4%), but 9.2% were unusual strains (P[6]G9, 5.5%; P[8]G9, 1.7%; P[6]G1, 1.4%; and P[4]G1 and P[8]G2, 0. 3% each). Strains not typeable for P or G type accounted for 5.5% of the total, while 2.3% of the strains had more than one G type (mixed infections). All P[6]G9 strains tested had short electropherotypes and subgroup I specificity and were detected in 4 of 10 cities, while P[8]G9 strains had long electropherotypes and subgroup II VP6 antigens. Both sequence analysis of the VP7 open reading frame (about 94 to 95% amino acid identity with the VP7 gene of G9 prototype strain WI61) and binding to a G9-specific monoclonal antibody strongly suggest that U.S. G9 strains belong to serotype G9. The high detection rates of unusual rotaviruses with G9 (7.2%) or P[6] (6.9%) specificity in multiple U.S. cities suggest the emergence of new strains or inadequate diagnosis in the past. The epidemiologic importance of these strains remains to be determined.
Studies with human neonatal rotaviruses RV-3 and S12/85 and their reassortants showed that VP4 is a determinant of rotavirus attachment to and growth in Caco-2 cells. The binding of these viruses to MA104 and Caco-2 cells correlated with their growth ability. Virus sensitivity to trypsin and the VP4 fusion region may be implicated in these processes.
An atypical human rotavirus strain Z10262, isolated from a chronically infected immunodeficient child, displayed an unusual genomic RNA electrophoretic pattern. Besides, Northern blot analysis indicated that this strain contained an abnormally migrating gene 11 equivalent. Sequencing of this gene showed that it was derived from a genetic rearrangement which involved a partial duplication of the open reading frame (ORF) encoding the non-structural protein NSP5. However, the duplicated region contained a deletion and several point mutations relative to the first copy of the ORF. Phylogenetic analysis of human and animal NSP5 amino acid sequences including Z10262 revealed two groups of human proteins related to different animal proteins. The isolation and analysis of Z10262 strain provides further evidence for the genetic complexity of naturally occurring human rotaviruses.
OBJECTIVE: To assess the impact of rotavirus gastroenteritis on young children attending a paediatric hospital, their families and the health care system. DESIGN: Cross-sectional descriptive survey. SETTING: New Children's Hospital (Royal Alexandra Hospital for Children), Sydney, New South Wales, 15 July to 4 October 1996. PARTICIPANTS: Children aged under three years attending the Emergency Department with acute diarrhoea as the presenting symptom. OUTCOME MEASURES: Cases of rotavirus infection confirmed by enzyme-linked immunosorbent assay by age; rotavirus serotype; gastroenteritis severity score; estimated costs to parents (lost pay or leave, travel, medication and other expenses) and to the health care system (visits to Emergency Department and other health care workers, hospital admissions). RESULTS: 280 children were recruited (73% of 384 children who met the inclusion criteria and 27% of the 1037 aged under three years with acute gastroenteritis). Rotavirus was detected in 188 of the 280 (67%); most isolates were serotype G1 (86% of the 174 serotyped). Of the 188 children with confirmed rotavirus infection 78% were aged 7-24 months and 82% visited at least one other health care worker, usually a general practitioner. Seventy (37% of the 188) were admitted to hospital; 33 of these (47%) were aged 13-24 months. Estimated mean total cost per episode of rotavirus gastroenteritis was $1744 for children admitted to hospital and $441 for children not admitted. The mean cost to families was $493 for children admitted to hospital and $228 for children not admitted. CONCLUSIONS: Rotavirus gastroenteritis has a significant impact on young children, their families and the health care system. Prevention of severe disease through routine infant vaccination would be potentially cost-effective.
The major advance in knowledge about rotavirus infection and prevention has been in vaccine development. Several large studies of tetravalent rhesis rotavirus vaccine have had encouraging results, and a first-generation vaccine is likely to be licensed by the 25th anniversary of the discovery of rotavirus (in 1973). Epidemiologic studies have highlighted a diversity of less common G types and non-group A strains, observations to be taken into account in further vaccine development. Disconcerting anecdotal reports of central nervous system involvement need to be cautiously interpreted. New information on pathophysiology raises the intriguing concept of viral toxin involvement. Oral immunoglobulin has been used for prophylaxis and also for treatment during active infection.
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