Biomedical subjects
J F Mowbray
Publications and source records attributed to J F Mowbray.
Immunology of postviral fatigue syndrome.
Postviral fatigue syndrome is associated with persistent infection by a virus. The patient with the condition has failed to eliminate the virus in the usual time. There is little evidence of a deficient immune response by the patient as the explanation for the viral persistence, and it must be assumed that most of the explanation lies in down-regulation of virus expression in infected cells. The general symptomatology of postinfectious syndromes may be mediated by cytokines liberated as part of the infection. Part of the syndrome may also be due to local effects of virus infection in muscles or the central nervous system (CNS).
Familial recurrent spontaneous abortions.
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Persistence of hepatitis A virus in fulminant hepatitis and after liver transplantation.
A peroxidase-labelled, specific mouse monoclonal antibody to hepatitis A virus (HAV) and an in situ hybridization technique (streptavidin-biotin-horseradish peroxidase reaction) with an HAV-specific cDNA probe (recombinant plasmid pAWHA comprising 1.8 kb of the HAV-specific cDNA, located toward the 3' end of the genome) were used to detect HAV in liver tissues in two patients with fulminant viral hepatitis type A treated by liver transplantation after a protracted (day 40: case 1) and relapsing (day 60: case 2) clinical course. HAV antigens and HAV-specific genomic sequences were detected in the hepatectomy tissues and in serial biopsies of the liver grafts through to final follow-up at 2 months (case 2) or death at 7 months after re-grafting for chronic rejection (case 1). In the fulminant liver parenchyma, numerous degenerating and some surviving hepatocytes were positive and randomly scattered. The immunoperoxidase staining was predominantly cytoplasmic and often granular. The localization of the cDNA probe was predominantly nuclear/perinuclear but was occasionally cytoplasmic. High-titre IgM-anti-HAV antibodies persisted until death (case 1) or resolution (5 months) of an acute hepatitis (case 2), which occurred at 2 months, accompanied by HAV antigen (ELISA), in stool. Intact replicating virus particles must have been present in one or more sites in each case, including extrahepatic locations, with a viraemia as the most likely explanation for subsequent reinfection of the grafts.
Detection of enterovirus specific RNA sequences in muscle biopsy specimens from patients with adult onset myositis.
A subgenomic cDNA probe with broad specificity for a range of enteroviruses was used to test by an in situ hybridisation technique for the presence of enterovirus specific genomic sequences in muscle biopsy samples obtained from patients with chronic adult myositis. Virus specific RNA sequences were detected in 6/13 (46%) patients with idiopathic polymyositis or dermatomyositis. Control samples obtained from an equal number of patients suffering from other muscle disorders were negative. A monoclonal antibody specific for an enterovirus group was used to probe for viral antigens by indirect immunoperoxidase staining; all biopsy samples from test and control groups were negative.
Histologic and immunologic study of uterine biopsy tissue of women with incipient abortion.
Biopsy specimens taken from the region of the placental bed were examined for the presence of phloxinophilic granulated mononuclear cells in women with a history of recurrent miscarriage and who would eventually miscarry a current pregnancy. They were compared with biopsy specimens from women with intact pregnancies presenting for elective termination of pregnancy and those with "missed abortion." Cells with large cytoplasmic granules (greater than or equal to 1 micron) were abundant in the group of ongoing pregnancies whereas cells with smaller granules (less than 1 micron) that were similar to large granular lymphocytes were more abundant relative to cells with large granules in the biopsy specimens from failing pregnancies. Immunosuppressive activity was tested in the supernatants of cultured biopsy samples of each group and found to be significantly lower in the incipient miscarriage group. These findings could represent alterations associated with the process of miscarriage, such as inflammation, or there may be deficient suppressor cell activity at the fetomaternal interface as the reason for "rejection" of the early embryo.
Postviral syndrome--how can a diagnosis be made? A study of patients undergoing a Monospot test.
Eighty-nine of 150 patients having a Monospot test filled out a questionnaire about their illness, and the General Health Questionnaire. They completed a follow-up questionnaire 6 months later. Twelve (8%) had a positive Monospot. Twenty-eight of 83 serum samples tested (34%) were positive for VP1 enteroviral antigen. Forty of the patients had a self limiting illness, 13 had a definite diagnosis (excepting glandular fever), 14 had a possible postviral syndrome, 10 had recurrent sore throats/flu, and 12 had a chronic non-specific illness. Patients with a specific diagnosis were less likely to complain of aching muscles/joints, sore throat, tiredness or loss of concentration. Their GHQ scores were lower, although this just failed to reach significance (P = 0.08), and they scored significantly lower on the somatic symptoms subscale (P = 0.022). Overall 72% scored above the GHQ threshold for 'psychological caseness' which is higher than in other studies. Sixty-five per cent of the sample questioned at 6 months felt that their illness started with a viral infection. The methodological problems involved in making a diagnosis of postviral syndrome are discussed.
IgG on normal human placenta is bound both to antigen and Fc receptors.
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Chronic enterovirus infection in patients with postviral fatigue syndrome.
76 patients with the postviral fatigue syndrome (PVFS) and 30 matched controls were investigated. Virus isolation was attempted from concentrated faecal samples by direct culture and after acid dissociation of virus from antibody. Positive cultures of enteroviruses were obtained from 17 (22%) patients and 2 (7%) controls. An enterovirus-group-specific monoclonal antibody, 5-D8/1, directed against the VP1 polypeptide, was used to detect enteroviral antigen in the circulation, either free or complexed with antibody. VP1 antigen was detected in the serum of 44 (51%) of a further group of 87 PVFS patients. The number of patients positive for VP1 antigen was greater (42/44) when IgM complexes were detectable than when they were not (2/23). 1 year later, the 17 patients of the first group of 76 with positive cultures were again studied. The same virus was again isolated from 5 (29%), 13 (76%) had detectable IgM responses to enteroviruses, and 9 (53%) were positive for VP1 antigen in the serum. These results show that chronic infection with enteroviruses occurs in many PVFS patients and that detection of enterovirus antigen in the serum is a sensitive and satisfactory method for investigating infection in these patients.
Detection of enterovirus RNA in experimentally infected mice by molecular hybridisation: specificity of subgenomic probes in quantitative slot blot and in situ hybridisation.
Subgenomic cDNA clones representing defined regions of the genome of Coxsackie B3 virus were used as hybridisation probes to detect RNA of various enteroviruses in cell culture and mouse model systems. Radiolabelled probes were used in slot blots to quantitate the RNA in samples; biotinylated probes were used to localise virus RNA at the cellular level by in situ hybridisation with monolayers of infected cells or thin sections of tissue samples. Probes derived from the 5' or 3' terminal regions of Coxsackie virus RNA, which are highly conserved in the genus Enterovirus, detected RNA of various serotypes in infected cell cultures, but failed to hybridise with hepatitis A virus (HAV) RNA. Although HAV is clearly a Picornavirus, our data support the view that its taxonomic position within the enteroviruses should be reconsidered. The biotinylated probes were also used to detect in situ virus RNA in paraffin-embedded tissue samples from experimental mouse models of Coxsackie B3 virus-induced myocarditis or Coxsackie B1 virus-induced myositis. Since the integrity of the tissues was preserved during the process, and viral RNA was localised in the affected muscle fibres, this has enabled us unequivocally to relate the infecting virus to the underlying tissue injury.
Immunology of early pregnancy.
The results of immunization of women with recurrent spontaneous abortion with paternal lymphocytes are described. The women we have treated were those with more than two spontaneous abortions with the same partner, who did not have evidence of genetic or other causes of recurrent abortion. Only women with recurrent abortion and no more than one live child were considered suitable for treatment. The success of treatment before pregnancy was 77%, similar to that found in our original double-blind controlled trial of immunization. The failures of treatment were found to cluster in those women who did not make detectable cytotoxic antibody after treatment, and who did not become pregnant within 90 days. Those women who did develop antipaternal antibody after immunization showed a protective response with no significant drop in efficiency in the year after immunization. A further group of women are described who were treated in the early part of pregnancy. The success rate was very high when the treatment was given within 40 days of the last period, and was less effective the later in pregnancy it was given. Birthweight, gestational age and malformation rate of the babies born after treatment were not different from those found in the normal population.
Viruses and neuropsychiatric disorders.
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Immunisation with paternal lymphocytes in women with recurrent miscarriage.
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Derivation and biochemical characterization of an enterovirus group-specific monoclonal antibody.
This paper describes the derivation and characterization of monoclonal antibodies reactive with the group-specific epitopes of the VP1 peptide shared by enteroviruses. When tested against a wide range of the prototype strains of Coxsackie viruses A and B, polioviruses, and echoviruses, the monoclonal antibodies reacted with all of them in two or more assay systems. The virus of hepatitis A was the only enterovirus tested which was not recognized by these monoclonal antibodies. This finding is consistent with recent reports demonstrating genomic dissimilarity between this virus and the other enteroviruses. Although monoclonal antibodies have frequently been found to be assay specific, these particular antibodies were found to be equally effective in different immunochemical and biological assay systems. Biochemical characterization of one of these monoclonal antibodies is described and its potential usefulness for diagnosis is discussed.
Clinical and research application of an enterovirus group-reactive monoclonal antibody.
Diagnostic methods employed in enterovirus laboratories are generally laborious, slow and expensive. This is largely because type-specific neutralization tests still play the major role in identification and diagnostic serology. In the companion paper we describe the derivation of monoclonal antibodies against epitopes of the VPI peptide which are shared by all of the enteroviruses tested to date, with the exception of hepatitis A virus. This study describes the application of one of these monoclonal antibodies in several research and diagnostic procedures, illustrating a special utility in a wide variety of assay systems. This monoclonal antibody has proved particularly useful in the detection of enterovirus antigens in circulating immune complexes, and in identifying field isolates of this group of viruses. Immunohistochemistry, previously almost impossible in enterovirus diagnosis and research due to the large number of serotypes, is now shown to be practical and informative when this monoclonal antibody is used.
Genetic and immunological factors in human recurrent abortion.
The theoretical causes of recurrent spontaneous abortion may be several. Gill and others have suggested that the human disease may be mimicked by the rodent genetic diseases, as exemplified by the T locus in mice. He would suggest that there may be lethal recessive gene phenomena which may cause repeated abortion, or if the abortion is prevented by immunological means the birth of genetically defective individuals. The evidence presented here shows that prevention of abortion by immunological treatment, that is immunisation of the wife with paternal lymphocytes, is associated with a very high success rate, and the children born do not have more than the normal incidence of birth defects. Thus far, over the 7 years of study, the children also appear to develop normally. Probably the reason for this is that the methods of selection for treatment tend to exclude quite effectively those couples with pure genetic problems. In particular, the the exclusion of women who have had more than one live child removes a group of women who might have lethal recessive problems which would only affect 25-50% of the offspring. The interactive gene products that may produce abortion of all pregnancies, suggested as a theoretical concept by Gill, would be expected to show an incidence no more than the square root of the frequency of the recessive disease, and are probably too few to be seen even in the more than 1,500 couples we have studied.
Plasma fibronectin and complement activation in coronary bypass surgery.
In patients with severe sepsis, plasma fibronectin concentrations are reduced and complement is activated. It is not known whether complement activation interferes with plasma fibronectin. Cardiopulmonary bypass is known to activate complement. We have therefore used this operation to study the effect of complement activation on plasma fibronectin in the absence of sepsis. After 15 min of bypass the percentage changes of plasma fibronectin and haematocrit were similar (65.9 +/- s.e.m. 4.8 and 67.0 per cent +/- s.e.m. 2.3, respectively), but the changes in C3 and C5 (58.4 +/- s.e.m. 4.8 per cent and 52.5 per cent +/- s.e.m. 2.1) were significantly greater than those of the haematocrit, indicating complement consumption. During the first 60 min of bypass there was a significant increase in the neutrophil count which is compatible with complement activation. It is unlikely that complement activation alone, in the absence of sepsis, contributes to the reduction of plasma fibronectin concentrations.
Miscarriage or abortion.
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