D. A. J. Tyrrell's research while affiliated with Salisbury NHS Foundation Trust and other places

Publications (340)

Article
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Chronic fatigue syndrome (CFS) is a multisystem disease, the pathogenesis of which remains undetermined. To test the hypothesis that there are reproducible abnormalities of gene expression in patients with CFS compared with normal healthy persons. To gain further insight into the pathogenesis of this disease, gene expression was analysed in periphe...
Article
Human parvovirus B19 infection has been associated with various clinical manifestations of a rheumatic nature such as arthritis, fatigue, and chronic fatigue syndrome (CFS), which can persist for years after the acute phase. The authors have demonstrated recently that acute B19 infection is accompanied by raised circulating levels of IL-1b, IL-6, T...
Article
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To determine the incidence of arthralgia and fatigue complicating B19 infection, along with associated B19 markers and autoantibodies. We studied patients with acute B19 infection (n = 51), patients followed from the time of acute B19 infection (mean 22.5 mo) (n = 39), and healthy controls (n = 50). Clinical details were collected using a questionn...
Data
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To investigate whether cytokine responses may have a bearing on the symptoms and outcome of parvovirus B19 infection, circulating cytokines were measured during acute infection (n l 51), follow-up of acute infection (n l 39) and in normal healthy controls (n l 50). At acute B19 virus infection (serum anti-B19 IgM-positive), patients ranged in age f...
Article
To investigate whether cytokine responses may have a bearing on the symptoms and outcome of parvovirus B19 infection, circulating cytokines were measured during acute infection (n=51), follow-up of acute infection (n=39) and in normal healthy controls (n=50). At acute B19 virus infection (serum anti-B19 IgM-positive), patients ranged in age from 4...
Article
Blood was collected from 684 healthy volunteers and examined for total and differential white blood cell (WBC) counts. A subgroup also was tested for numbers of T cells, B cells, and CD4 and CD8 subsets. Smoking status and alcohol consumption were determined by means of questionnaire, and smoking status was verified with serum cotinine concentratio...
Article
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Blood was collected from 684 healthy volunteers and examined for total and differential white blood cell (WBC) counts. A subgroup also was tested for numbers of T cells, B cells, and CD4 and CD8 subsets. Smoking status and alcohol consumption were determined by means of questionnaire, and smoking status was verified with serum cotinine concentratio...
Article
Experimental viral disease studies in volunteers have clarified many aspects of the pathogenesis of human viral disease. Recently, interest has focused on rhinovirus-associated asthma exacerbations, and new volunteer studies have suggested that airway responsiveness (AR) is enhanced during a cold. For scientific, ethical and safety reasons, it is i...
Article
We have shown that viruses are associated with 80 to 85% of asthma exacerbations in school-age children in the community. We hypothesize that viral infections are also associated with severe attacks of asthma precipitating hospital admissions. To investigate this, we conducted a time-trend analysis, comparing the seasonal patterns of respiratory in...
Chapter
Coronaviruses are found in avian and mammalian species. They resemble each other in morphology and chemical structure: for example, the coronaviruses of humans and cattle are antigenically related. There is no evidence, however, that human coronaviruses can be transmitted by animals. In animals, various coronaviruses invade many different tissues a...
Article
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To study the association between upper and lower respiratory viral infections and acute exacerbations of asthma in schoolchildren in the community. Community based 13 month longitudinal study using diary card respiratory symptom and peak expiratory flow monitoring to allow early sampling for viruses. 108 Children aged 9-11 years who had reported wh...
Article
This study was conducted to test the supposition that both smoking and consuming alcohol suppress host resistance to viral infections. The relations between smoking, alcohol consumption, and the incidence of documented clinical colds were prospectively studied among 391 subjects intentionally exposed to one of five respiratory viruses and 26 subjec...
Article
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The patterns of disease caused by five common viruses which infect the respiratory tract are described. The viruses were strains of rhinovirus types 2, 9, and 14, a strain of coronavirus type 229E and of respiratory syncytial virus. Volunteers were given nasal drops containing a low infectious dose of one of the viruses, quarantined from 2 days bef...
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After completing questionnaires assessing stressful life events, perceived stress, and negative affect, 394 healthy Ss were intentionally exposed to a common cold virus, quarantined, and monitored for the development of biologically verified++ clinical illness. Consistent with the hypothesis that psychological stress increases susceptibility to inf...
Article
The immunogenicity and pathogenicity of a strain of respiratory syncytial (RS) virus modified by sequential induction of three temperature-sensitive (ts) mutations have been evaluated by intranasal administration to 22 adult volunteers. This modified virus, a triple ts mutant designated ts1C, was derived from a double mutant ts1B evaluated in a pre...
Article
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Rhinoviruses and enteroviruses are the major members of the picornavirus genus that cause human disease. We compared the polymerase chain reaction and viral culture for the identification of picornaviruses in nasal aspirates from children during episodes of respiratory symptoms and when asymptomatic and from asymptomatic adults. One hundred eight c...
Article
I have been asked to stand back and describe in broad terms the view I have had of common colds--probably the most frequent of acute human diseases and a long-lasting scientific problem--and in particular our recent work on antivirals. I should be able to do this for two reasons. Like everyone else I have suffered from colds, but in addition I have...
Article
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SYNOPSIS Results from two studies involving challenge with respiratory syncytial viruses showed that volunteers who developed colds were more sensitive to a visually distracting pattern presented prior to virus challenge than were volunteers who did not get a cold. Volunteers with sub-clinical infections reported more illusions after virus challeng...
Article
The commonest adverse health effect from the indoor environment is a respi ratory tract infection, most often a common cold. Any one of a number of viruses can cause colds. The full process by which infections are contracted is poorly understood. However, there must be direct contact between the infect ing agent and the nasal or lower airway cells....
Article
We investigated the effects of rhinovirus (RV) infection on airways reactivity. Twenty seven normal volunteers (11 atopic) were inoculated with RV 2 or RV EL. The provocative concentrations of histamine and bradykinin required to produce a 15% fall in the forced expiratory volume in one second (FEV1) (PC15FEV1) were measured before, 7 and 21 days a...
Article
Mouse monoclonal antibodies (MAbs) against three distinct antigenic sites on rhinovirus type 2 have been obtained and the sites identified. We describe how these MAbs were used in a blocking test to detect antibodies in human sera directed against the same three defined sites. Sera from twelve volunteers were studied. All had been exposed to rhinov...
Article
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Richard R. Orlandi, Todd T. Kingdom, Peter H. Hwang, Timothy L. Smith, Jeremiah A. Alt, Fuad M. Baroody, Pete S. Batra, Manuel Bernal-Sprekelsen, Neil Bhattacharyya, Rakesh K. Chandra, Alexander Chiu, Martin J. Citardi, Noam A. Cohen, John DelGaudio, Martin Desrosiers, Hun-Jong Dhong, Richard Douglas, Berrylin Ferguson, Wytske J. Fokkens, Christos...
Article
The commonest adverse health effect from the indoor environment is a respiratory tract infection, most often a common cold. Any one of a number of viruses can cause colds. The full process by which infections are contracted is poorly understood. However, there must be direct contact between the infecting agent and the nasal or lower airway cells. S...
Chapter
Previous chapters have reviewed the cellular and molecular biology of a number of bacterial, viral and fungal diseases that represent the majority of the opportunistic infections occuring in HIV-positive patients. There is a great deal of interest in these agents and it is apparent that the techniques of modern biology provide an understanding of t...
Article
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BACKGROUND As respiratory virus infections often lead to exacerbations of chronic bronchitis and asthma an effective antiviral drug may be helpful in such patients. Alpha 2 interferon has been shown to give protection against rhinovirus infections in field studies. METHODS Patients with chronic respiratory disease exposed to close contacts with sym...
Article
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It is not known whether psychological stress suppresses host resistance to infection. To investigate this issue, we prospectively studied the relation between psychological stress and the frequency of documented clinical colds among subjects intentionally exposed to respiratory viruses. After completing questionnaires assessing degrees of psycholog...
Article
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The effects of three doses of interferon alpha (IFNα, 1.5 Mu, 0.5 Mu and 0.1 Mu) on performance, mood and physiological function were examined in a double-blind placebo controlled trial. The subjects given an injection of 1.5 Mu showed symptoms which closely resembled those seen in influenza, although most of the symptoms had gone by the next day....
Article
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Two studies are reported on the effects of drugs on the performance impairments induced by experimentally- produced colds. The first study examined the effects of zinc gluconate on choice reaction time, and showed that the zinc removed the cold-induced performance impairment. The second experiment used nedocromil sodium and, again, the drug was eff...
Article
Intranasal 7-thia-8-oxoguanosine (NARI 10146) compared with placebo had no influence on the course of experimental coronavirus 229E infections in human volunteers. Possible reasons are discussed for the failure to confirm successful rodent experiments in man.
Article
In a double-blind placebo controlled trial intranasal NPC 567, a bradykinin antagonist, failed to alleviate the symptoms of experimental rhinovirus colds. Indeed, there was evidence that the drug enhanced the symptoms although no irritant effect was detected on the uninfected nasal mucosa.
Article
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Four experiments were carried out to investigate the effects of experimentally-induced colds on various aspects of memory of 27, 47, 39, and 30 adults. Free recall, digit span, and retrieval from semantic memory were unaffected by having a cold. Immediate recognition of important information from a story was impaired in subjects with colds, which s...
Article
After preliminary trials, the detailed changes in the concentration of specific circulating and local antibodies were followed in 15 volunteers inoculated with coronavirus 229E. Ten of them, who had significantly lower concentrations of pre-existing antibody than the rest, became infected and eight of these developed colds. A limited investigation...
Article
The efficacy of the antiviral R 61837 in experimental colds in three previously reported volunteer trials and one new trial is reviewed here. It was dissolved in a new vehicle, hydroxy-β-cyclodextrin, and used as a nasal spray. A substantial reduction in illness occurred when given prophylactically and during the incubation period but not when used...
Article
In a double-blind, placebo-controlled study, self-administered intranasal interferon alpha-2a or placebo was given both before and after challenge with respiratory syncytial virus. The incidence of colds and the severity of signs and symptoms were reduced in those receiving interferon alpha-2a as compared with those given placebo. In a further doub...
Article
The virulence and immunogenicity of a wild-type respiratory syncytial (RS) virus together with four temperature sensitive (ts) mutants derived from this isolate were tested by intranasal inoculation into adult volunteers. Resistance to challenge correlated with neutralizing antibody titres in nasal secretions and to a lesser extent in serum. All ts...
Article
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Mutants of human rhinovirus type 2 (HRV-2) resistant to and dependent on the antirhinoviral compound chalcone Ro 09-0410 were selected in cell culture under clean laboratory conditions. A total of 42 volunteers were challenged with either the drug-resistant mutant [SR2-410(r)] (15 volunteers), the drug-dependent mutant [SR2-410(d)] (15 volunteers),...
Article
We have isolated a human rhinovirus type-2 (HRV-2) mutant that is resistant to the antiviral agent chalcone Ro 09-0410 (4′-ethoxy-2′-hydroxy-4, 6′-dimethoxychalcone). This Ro 09-0410-resistant HRV-2 mutant (SR2-0410) exhibited altered biological properties when compared with the parental wild-type (wt) HRV-2. It was unstable when exposed to acid an...
Article
An influenza B virus was passaged in man (virus A) and then in human embryo trachea (C) and into embryonated eggs (D) or directly into eggs (B). Virus A, B, and C had the same (cell-like) haemagglutinin phenotype on reaction with selected monoclonal antibodies while D had an "egg-like" phenotype. The viruses were administered at a dose of 1,000 TCD...
Article
Two studies involving double-blind group comparative trials in human volunteers compared the effects of intranasal nedocromil sodium (2.6 mg active drug per nostril, q.i.d.) with placebo on clinical symptoms and performance impairment associated with the common cold. In the first study volunteers were challenged with rhinoviruses (RV9 and RV14), an...
Article
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Article
The specific humoral immune response of 17 volunteers to infection with human rhinovirus type 2 (HRV-2) has been measured both by neutralization and by ELISA. Six volunteers who had HRV-2-specific antibodies in either serum or nasal secretions before HRV-2 inoculation were resistant to infection and illness. Of the remaining 11 volunteers who had l...
Article
This study describes the evaluation of a newly developed ELISA for the direct detection of rhinovirus antigens in nasal washings. Of 54 volunteers inoculated with 100 TCID50 of human rhinovirus type 2 (HRV-2), 50 (96.6%) and 32 (59%) excreted antigen and virus on at least 1 of 3 days investigated, respectively. Thirty-three (61%) had significant ri...
Article
A single dose of the immunomodulator CGP A (MTP-PE) given intranasally to human volunteers 24 h prior to challenge with influenza A2 virus failed to protect against infection or ameriolate any subsequent illness.
Article
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Synopsis In experiments designed to investigate transmission, cerebrospinal fluid (CSF) from patients with schizophrenia or neurological disease (Huntington's disease) which had been found to induce a cytopathic effect (CPE) in human embryonic fibroblast cell culture was injected intracerebrally into common marmosets. Behavioural observations were...
Article
To determine whether inhaling fully humidified air at 43 degrees C gave more benefit to cold sufferers than inhaling air at 30 degrees C. Randomised double blind trial. Setting--General practice and the common cold research unit. 87 Unselected patients with typical acute nasal and upper respiratory symptoms (general practice study), and 84 voluntee...
Article
This report describes double-blind placebo-controlled trials of a new synthetic antirhinovirus drug, R61837, which showed it to be effective in suppressing colds in human volunteers challenged with rhinovirus type 9. In one trial, R61837 was given by intranasal spray six times a day, commencing 28 h before virus challenge; treatment continued for 4...
Article
Twenty-four adult volunteers were inoculated with nasal drops containing a coronavirus of 229E serotype to determine the differences in the clinical and physiological reactions which occur between clinically infected, sub-clinically infected and non-infected individuals. Thirteen volunteers were clinically infected, 8 had sub-clinical infections an...
Article
Viruses were isolated from nasal washings of volunteers receiving experimental therapy for rhinovirus type 9 infection with intranasal sprays of a new synthetic antiviral R61837. On a screening test nine subjects yielded drug sensitive virus and four resistant virus. In four others the virus was sensitive at first but became resistant later, while...
Article
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Volunteers who develop a cold following virus challenge were significantly slower on choice reaction time tasks than those with no illness. This effect was still observed after the clinical symptoms had gone. In contrast to this, influenza illnesses only impaired performance in tasks in which subjects were uncertain where the target stimulus would...
Article
Current methods of detecting a human rhinovirus (HRV) infection are either based on isolation of virus in appropriate susceptible cell lines, which is time-consuming and requires considerable expertise, or are dependent on knowing the serotype. The existence of over 100 immunologically distinct serotypes makes serotype specific assays, such as ELIS...
Article
This study investigated the abilities of cDNA probes from the 5′ and 3′ ends of the genome of human rhinoviruses (HRV-) 14, 9, and 1B to detect RNA from 59 rhinovirus serotypes. The results show that probes from the 5′ end of the genomes of HRV-14, 9, and 1B detected a large number of serotypes but the detection rate was variable and depended on th...
Article
Marked synergy between the antirhinoviral effect of rHuIFN alpha and enviroxime has been observed in vitro but an attempt to demonstrate it in volunteers was unsuccessful. The sub-optimal intranasal dose of rHuIFN alpha (0.18 Mu four times daily for 4 1/4 days) used prophylactically in the trial did reduce the severity of colds induced by RV9 and 1...
Article
The first evaluation of intranasal (i.n.) recombinant human interferon-gamma (rHuIFN-gamma) as prophylaxis against experimental rhinovirus (RV) infection and illness in volunteers is reported. In two studies, 7 of 27 (26%) of the volunteers who received rHuIFN-gamma (2 Mu i.n. 3 x /day) had either blood stained nasal secretions or nose bleeding whi...
Article
Single temperature-sensitive (ts) mutants of a subgroup A strain of respiratory syncytial (RS) virus whose multiplication is restricted at 39°C in MRC-5 cells and double ts mutants that are restricted at 38°C, were obtained following mutagenesis using 5-fluorouracil and acridine-like compounds. Isolation and propagation of the parental RSS-2 strain...
Article
In an attempt to understand the relationship between viral upper respiratory tract infection and the underlying virological and immunological mechanisms, thirty-four volunteers were inoculated intranasally with coronavirus 229E; subsequent virus shedding and/or antibody rises, indicating active infection, were observed in twenty-nine. There was a g...
Article
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Synopsis Studies of experimentally induced respiratory infections and illnesses showed that influenza impaired performance on a visual search task but had no effect on a simple motor task, whereas colds impaired the motor task but not the search task. The effect of influenza on the search task was observed in both volunteers with significant clinic...
Article
Full-text available
The effects of three doses of interferon alpha (1.5 Mu, 0.5 Mu and 0.1 Mu) on performance were studied. The injection of 1.5 Mu IFN produced symptoms and performance changes which closely resembled those found in volunteers with influenza. Specifically, volunteers were slower at responding when they were uncertain when a target stimulus would appea...
Article
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The present research examined diurnal variation in the severity of symptoms of experimentally-induced colds and influenza. Nasal secretion was greatest in the morning, decreased over the day, and then showed a slight increase in the late evening. Colds did not change the average temperature, nor did they alter the temperature rhythm. Similar, negat...
Chapter
Disease: Common cold. Etiologic Agents: Rhinoviruses (over 115 serotypes. Source: Infected individuals excreting virus in nasal secretions; airborne transmission over short distances; enter via nasal epithelium or conjunctiva; transmission via contaminated fingers and fomites also possible. Clinical Manifestations: Rhinorrhea, nasal obstruction, so...
Article
Following a tolerance study, double-blind placebo controlled trials were conducted to determine the prophylactic effect of zinc gluconate lozenges on rhinovirus challenge and, in a third study, their therapeutic efficacy when given at the start of colds caused by virus inoculation was tested. In the prophylaxis study a total of 57 volunteers receiv...
Article
The antirhinovirus agent chalcone Ro 09–0410 was tested in double-blind place-controlled volunteer trials for its protective efficacy against experimental rhinovirus infection. Fifty volunteers received either drug (26 volunteers) or placebo (24 volunteers) both before and after challenge with 20–40 tissue culture infecting dose (TCID50) of human r...
Chapter
Considerable progress has been made in the development of some active antirhinovirus agents. Thus, various interferons (IFNs) including recombinant human IFN alpha and beta were found active and protected volunteers from experimental rhinovirus infections. However, clinical studies indicated that IFNs need to be given in large doses and over freque...
Article
A 'new' generation of synthetic antirhinovirus compounds has recently become available for in vitro evaluation. Thus a new group of compounds from Janssen was found to be 10-fold more active than enviroxime or 57-fold more active than dichloroflavan (DCF), against human rhinovirus 9 (HRV-9). In addition, they were also some 5- and 10-fold more pote...
Article
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Previous studies of boys at Christ's Hospital school have indicated that annual immunization with influenza virus vaccines did not significantly reduce the total incidence of influenza infection compared to unimmunized subjects. In view of the implications of this result, a similar study was conducted in ferrets to clarify these findings. Groups of...
Article
Conclusion The study of common colds, especially in volunteers, has occupied me for much of my scientific career and has constantly provided new and fascinating insights to someone like myself who is interested in human disease and how it is produced. But the study has also led me to investigate the biology of some fascinating organisms and to work...
Article
During studies of the antiviral activity of chalcone Ro-09-0410 on human rhinovirus type 9 (RV9) chalcone-resistant strains of RV9 were isolated and appeared with a frequency of about 10(-5) in chalcone sensitive stock. Chalcone-dependent viruses were found after further passage. Some characteristics of the resistant viruses were studied and compar...
Article
Infection of normal individuals with human parvovirus (B19) results in a mild disease (erythema infectiosum) but gives rise to aplastic crises in patients with chronic hemolytic anemias. The effects of this disease on hemopoiesis were investigated following intranasal inoculation of the virus into three volunteers. A typical disease ensued with a v...
Article
The study reported here examined the effects of experimentally induced minor illnesses (colds and influenza) on the efficiency of human performance. Influenza impaired the ability to detect and respond quickly to stimuli appearing at irregular intervals, but had no effect on a task requiring hand-eye coordination. In contrast to this, colds impaire...
Article
4',6-Dichloroflavan, a potent inhibitor of rhinovirus replication in tissue culture systems was tested in a double-blind, placebo-controlled volunteer trial for its protective efficacy against experimental rhinovirus infection. Dichloroflavan was administered intranasally as a 5 per cent w/v aqueous suspension (40 mg; 5 times per day) for 5 doses b...
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The safety and immunogenicity of two live influenza A virus vaccine strains, the CR 59 and 17/25/1 cold-adapted (ca) reassortants, were evaluated in 170 healthy young adult volunteers. The vaccines were produced by recombining A/Korea/1/82 (H3N2) wild-type virus with either A/Ann Arbor/6/60 (H2N2) or A/Leningrad/134/17/57 (H2N2) ca donors of attenu...
Article
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In two studies experimentally induced colds slowed the speed of response in a serial reaction task. Responding was also slower during the incubation period of the illness, which shows that performance on such a task may be used to predict subsequent illness. Volunteers who had no significant clinical illness, but who had a significant rise in IgG f...
Article
We describe here a cDNA:RNA hybridization system for the study of human rhinoviruses. We have constructed an M13 probe from the 5' end of the genome of rhinovirus 14 (HRV-14) and used this to detect directly viral RNA. Of the 56 human rhinoviruses so far investigated 54 or 96.4% gave clearly positive hybridization signals. However, the strength of...
Article
Intranasal sprays of interferons (IFNs) given one day before and for three days after virus challenge can protect human volunteers from infection with rhinoviruses, coronavirus, and influenza. Longer dosage of IFN gives rise to nasal symptoms and signs such as bloodstained nasal discharge. More effective IFNs and regimes are therefore needed. IFN b...
Article
An antibody dependent cellular cytotoxic (ADCC) reaction was elicited using human mixed lymphocyte cultures against coronavirus 229E-infected C-16 cells. The response was assayed in microtitre plates by radioactive chromium release. Optimal killing of target cells was achieved using cells