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Biomedical subjects

T O'Neill

Publications and source records attributed to T O'Neill.

At least 19 recordsLinked to original sources
PubMed1999

Phase I safety and antigenicity of TA-GW: a recombinant HPV6 L2E7 vaccine for the treatment of genital warts.

A phase I double-blind, randomized, placebo-controlled study was carried out in healthy subjects to assess the safety and immunogenicity of TA-GW, a recombinant HPV6 L2E7 fusion protein vaccine for the treatment of genital warts. Forty-two healthy male volunteers were randomised to receive three intramuscular injections of either 0, 3, 30 or 300 microg of recombinant L2E7 adsorbed onto Alhydrogel. Two vaccination schedules were compared: weeks 0, 1 and 4 (accelerated schedule) and weeks 0, 4 and 8 (classical schedule). Subjects were monitored for adverse events throughout. Immunogenicity was assessed by measuring L2E7 specific in vitro T cell proliferative responses, production of IFNgamma and IL-5 and serum antibodies. Dose-dependent and long-lived T and B cell immune responses were elicited by TA-GW with both vaccination schedules. In conclusion, TA-GW is both safe, well-tolerated and immunogenic. The results allow the selection of the 300-microg vaccine formulation and accelerated vaccination schedule for phase II trials in patients with genital warts.

Adult↗
PubMed1999

Phase IIa safety and immunogenicity of a therapeutic vaccine, TA-GW, in persons with genital warts.

A fusion protein vaccine consisting of human papillomavirus 6 L2E7 with Alhydrogel was developed for the treatment of genital warts. Twenty-seven subjects with genital warts received 3 immunizations over 4 weeks in an open-label study. The vaccine was well-tolerated, and all subjects made serum IgG antibodies, predominantly IgG1, against L2E7. Nineteen of 25 tested persons made antigen-specific T cell proliferative responses to L2E7, and peripheral blood mononuclear cells when cultured with L2E7 in vitro produced both interferon-gamma and interleukin (IL)-5, although IL-5 predominated after the final vaccination. Five subjects completely cleared warts within 8 weeks. Subjects whose warts were not cleared by 8 weeks were offered conventional therapy. Recurrence of warts was not seen in any of the 13 persons whose warts cleared by vaccine alone or with conventional therapy. While these preliminary results of the use of this therapeutic immunogen are encouraging, proof of efficacy will require randomized double-blind trials.

Adult↗
PubMed1998

Pathogenesis of neuroborreliosis--lessons from a monkey model.

The diagnosis of human LNB can be difficult, because its major clinical manifestations--meningitis, facial palsy, radiculitis, and neuritis--are non-specific and the characteristic skin lesion is usually absent at the time of neurological involvement. Thus, CSF assays are often used in diagnosis. Culture of CSF is rarely performed because it has a low yield and requires special culture medium. PCR of the CSF identified spirochetal DNA in clinical specimens with greater sensitivity, but it suffers from a number of disadvantages. Measurement of specific antibody in the CSF also has its limitations. The role of available assays for LNB has not been studied carefully in a comparative investigation. The recent development of the nonhumane primate (NHP) model of LNB allows us to address this need in a faithful model of human LNB. We compared PCR and culture in their ability to detect spirochetal presence in the CSF and brain tissue of infected NHPs, and related these measures of infection to the development of anti-B. burgdorferi antibody. We also tested a bioassay, the mouse infectivity test (MIT), in this model. Using these four assays (PCR, culture, MIT, and CSF Ab) at least one assay for spirochetal presence in CSFs from NHPs was positive in 87% of CSFs tested during early infection in the CNS. Detection of spirochetal presence by PCR, MIT, and culture in the CSF was inversely related to the concomitant presence of anti-B. burgdorferi antibody intrathecally. The performance of any particular test was associated with the strength of the host immune response. In early CNS infection, when anti-B. burgdorferi antibody had not yet appeared, or in immunocompromised hosts, the MIT compared favorably to culture and PCR in infected NHPs; antibody in the CSF was the most useful assay in immunocompetent NHPs. This is the first study demonstrating that a bioassay using inoculation of mice, the mouse infectivity test (MIT), has potential as a useful adjunct in the diagnosis of LNB. The MIT for LNB was modeled after the rabbit infectivity test or RIT, which is considered the "gold standard" for the diagnosis of the related CNS infection, neurosyphilis, and felt to be very sensitive and specific. The presence of specific anti-B. burgdorferi antibody in the CSF is the most widely used assay for Lyme neuroborreliosis. In the immunocompetent NHPs in our study it was a very successful assay for detection of CNS invasion. However, it is frequently false-negative, especially early in the course of the infection, or if there is transient immunosuppression. Transient suppression of the anti-B. burgdorferi immune response in the human could occur in instances of co-infection, i.e. simultaneous transmission via the tick of another pathogen other than B. burgdorferi. Thus, mild immunosuppression as accomplished in our NHPs with corticosteroids was designed to mimic conditions in the human host which allow B. burgdorferi in the natural state to gain a firm foothold in the central nervous system in the 10-15% of B. burgdorferi-infected patients who develop clinically symptomatic nervous system disease. This study is the first to compare utility of available diagnostic techniques in LNB in which necropsy proved presence of infection in the CNS. None of the assays was ideal for all conditions, and the utility of the assay was associated with the host immune status. The differences in the responses of immunocompromised and immunocompetent NHPs in this study were striking. In immunocompetent NHPs the window of opportunity for CNS invasion prior to the development of CSF antibody was brief, and the chance of detection of spirochete low by any of the three techniques used (i.e. culture, PCR, or MIT); in this group, measurement of CSF antibody was generally diagnostic. In immunocompromised NHPs, intrathecal antibody production was delayed, and this helpful diagnostic assay was false-negative; diagnosis required more labor-intensive assays such as PCR, culture, an

Animals↗
PubMed1998

Effects of menstrual history and use of medications on bone mineral density: the EVOS Study.

We have previously shown considerable between-center variation in bone mineral density (BMD) in the 13 EVOS centers that performed bone densitometry on their sex- and age-stratified population samples, after adjusting for weight and age. We have now investigated whether part of the between-center variability may be attributed to between-center variations in the use of medications. Information was collected from 2088 women and 1908 men at baseline on whether the subjects had ever been prescribed calcium, calcitonin, anabolic steroids, fluoride, vitamin D, or glucocorticoids and, for the women, whether they had ever used the oral contraceptive pill (OCP) or hormone replacement therapy (HRT). Each of these variables was fitted into a regression model adjusted for age, height, weight, and center. Only OCP and HRT significantly affected BMD. Those who had ever used OCPs had spinal BMD 0.029 g/cm2 greater than those who had never used them. Users of HRT had higher BMD than nonusers: 0. 037 g/cm2 at the spine, 0.018 g/cm2 at the trochanter, and 0.018 g/cm2 at the femoral neck. As expected, there was a great variation between centers in the use of OCP and HRT, but there were no significant correlations between mean BMD at any site in a given center and the prevalence of OCP or HRT use in that center. The between-center variance in BMD at all three sites remained highly significant after adjusting for treatment (P < 0.001). We conclude that HRT and OCP use are associated with moderate increases in BMD. The geographical variability of BMD in Europe was not explained by treatment with pharmaceuticals.

Absorptiometry, Photon↗
PubMed1998

Enhanced immunogenicity of a recombinant genital warts vaccine adjuvanted with monophosphoryl lipid A.

The regression of genital warts is believed to be a T-cell-mediated immune effect. We have sought to enhance the immunogenicity of a therapeutic vaccine for the treatment of genital warts with the use of the adjuvant monophosphoryl lipid A (MPL-immunostimulant), a detoxified form of the lipopolysaccharide (LPS) of Salmonella minnesota R595. The comparative immunogenicity and reactogenicity of a recombinant human papillomavirus type 6 (HPV6) L2E7 fusion protein in either aqueous, oil-in-water emulsions or Alhydrogel formulations containing MPL was evaluated. We conclude that the simple addition of MPL to the L2E7 fusion protein already adsorbed onto Alhydrogel preferentially enhances antigen specific in vitro T-cell proliferative responses, IFN gamma production and in vivo delayed type hypersensitivity responses without increasing its reactogenicity.

Adjuvants, Immunologic↗
PubMed1998

Detection of active infection in nonhuman primates with Lyme neuroborreliosis: comparison of PCR, culture, and a bioassay.

Ideally a diagnosis of infection of the central nervous system (CNS) is made by culture of the etiologic pathogen, but Borrelia burgdorferi, the causative agent of Lyme neuroborreliosis (LNB), is rarely cultured from the cerebrospinal fluid (CSF). PCR and measurement of specific antibody in the CSF also have their limitations. The role of available assays for LNB has not been studied carefully in a comparative investigation. There is a need to assess the reliability of assays and to increase the ability to document active infection in the CNS. The recent development of the nonhuman primate (NHP) model of LNB allowed us to address this need in a faithful model of human LNB. In this study we compared the abilities of PCR and culture to detect the presence of spirochetes in the CSF and brain tissue of infected NHPs and related these measures of infection to the development of anti-B. burgdorferi antibody. We also tested a bioassay, the mouse infectivity test (MIT), in this model. Fourteen of 16 CSFs from four NHPs were positive by at least one of these techniques. Detection of spirochetes in the CSF by PCR, the MIT, and culture was inversely related to the concomitant presence of anti-B. burgdorferi antibody intrathecally. The performance of any particular test was associated with the strength of the host immune response. In early CNS infection, when anti-B. burgdorferi antibody had not yet appeared, or in immunocompromised hosts, the MIT compared favorably to culture and PCR for infected NHPs; antibody in the CSF was the most useful assay for immunocompetent NHPs.

Animals↗
PubMed1997

Anthropometric measurements and vertebral deformities. European Vertebral Osteoporosis Study (EVOS) Group.

To investigate the association between anthropometric indices and morphometrically determined vertebral deformity, the authors carried out a cross-sectional study using data from the European Vertebral Osteoporosis Study (EVOS), a population-based study of vertebral osteoporosis in 36 European centers from 19 countries. A total of 16,047 EVOS subjects were included in this analysis, of whom 1,973 subjects (915 males, 1,058 females) (12.3%) aged 50 years or over had one or more vertebral deformities ("cases"). The cases were compared with the 14,074 subjects (6,539 males, 7,535 females) with morphometrically normal spines ("controls"). Data were collected on self-reported height at age 25 years and minimum weight after age 25 years, as well as on current measured height and weight. Body mass index (BMI) and height and weight change were calculated from these data. The relations between these variables and vertebral deformity were examined separately by sex with logistic regression adjusting for age, smoking, and physical activity. In females, there was a significant trend of decreasing risk with increasing quintile of current weight, current BMI, and weight gain since age 25 years. In males, subjects in the lightest quintile for these measures were at increased risk but there was no evidence of a trend. An ecologic analysis by country revealed a negative correlation between mean BMI and the prevalence of deformity in females but not in males. The authors conclude that low body weight is associated with presence of vertebral deformity.

Age Factors↗
PubMed1997

Can we prevent fractures?

The primary aim of any intervention in osteoporosis is the prevention of fractures in individuals who have not yet fractured or the prevention of the progression of the disease in individuals with fragility fractures. There is currently insufficient evidence to recommend either a population-based prevention strategy or a strategy based on general screening with treatment of those individuals identified at high risk. Identification of subjects with strong clinical risk factors for osteoporotic fractures with subsequent measurement or not of bone mineral density as well as those with fragility fractures constitute at present the most rational approach to fracture prevention. Current measures to prevent osteoporotic fractures aim mainly at influencing bone mass and bone turnover and reducing the risk and impact of falls. Interventions that can reduce effectively the frequency of osteoporotic fractures in subjects at risk are available and new or alternative interventions are being developed. Issues related to the impact of these interventions on public health and health economics need to be addressed and methods to calculate the clinical outcomes in a way allowing comparison with outcomes of interventions in other common diseases should be developed.

Accidental Falls↗
PubMed1997

Interleukin-6 is expressed at high levels in the CNS in Lyme neuroborreliosis.

In patients with Lyme neuroborreliosis, inflammation and symptoms of fatigue and malaise occur out of proportion to the relatively low number of spirochetes present. Previous studies have identified interleukin-6 (IL-6) as a candidate molecule for amplification of CNS inflammation in this disease. We pursued this possibility by measuring cytokine gene expression by reverse-transcriptase polymerase chain reaction (RT-PCR) in the brain of rhesus macaques actively infected with Borrelia burgdorferi. Samples of brain tissue were screened for IL-6 and interferon gamma using RT-PCR-ELISA, a technique that uses RT-PCR, subsequent hybridization of the PCR product with a biotinylated probe, and capture and ELISA readout of hybridization product. The number of copies in positive samples was then quantitated using qRT-PCR-ELISA, in which wild-type cytokine cDNA competes with recombinant competitor DNA in the PCR. Elevated levels of IL-6 cDNA and, to a lesser extent, interferon gamma were detected in three of three nonhuman primates with persistent infection with B burgdorferi, whereas the brains of three uninfected animals and undetectable levels of gene expression of these cytokines. These data support the hypothesis that cytokines such as IL-6 are important amplification molecules for CNS inflammation in Lyme neuroborreliosis.

Animals↗
PubMed1996

A sixth-century Irish headache cure and its use in a south German monastery.

Medieval headache treatment is largely unknown. Medieval incantations against headache enumerate bodily organs to be protected. One 8th-century Latin hymn from Lake Constance using this device is addressed to St. Aid "mechprech", who has been identified as Aed Mac Bricc, Bishop of Killare, 6th century. This Irish Saint inspired unusual legends by some rather unorthodox activities: He abducted a young girl as hostage while his inheritance was withheld, but at the same time was seen surrounded by angels. He prayed for a nun who was pregnant and made the pregnancy vanish by a miracle, and he replaced the severed heads of maids, men and horses, creating a new spring as a by-product of this operation. Already at his birth his head had hit a stone, leaving a hole in the stone which collected rainwater that cured all ailments. In our own time, such "bullaun stones" are still believed to cure headache in Ireland. According to the legends collected by Plummer and Colgan, St. Aed Mac Bricc was well known for his power to cure headaches. He relieved St. Brigid's headache when she was suffering many miles away, but his most impressive cure was in convincing a headache sufferer that the patient's headache could actually be transferred own head. The headache hymn or incantation is intended to repeat Aed's unique miracle.

Catholicism↗
PubMed1995

Neuroborreliosis in the nonhuman primate: Borrelia burgdorferi persists in the central nervous system.

Neurological involvement in Lyme disease is common, and is frequently difficult to diagnose and treat. Little is known about the fate of the causative spirochete Borrelia burgdorferi in the central nervous system (CNS). To determine the frequency of parenchymal infection and to determine localization of the organism, polymerase chain reaction/hybridization assays were performed in a newly described model of Lyme neuroborreliosis in nonhuman primates infected with B. burgdorferi. Polymerase chain reaction/hybridization of CNS tissues from 5 infected nonhuman primates was performed. Substantial amounts of B. burgdorferi DNA were detected in the CNS in all infected animals, with a predilection toward subtentorial structures. These data suggest that Lyme neuroborreliosis represents persistent infection with B. burgdorferi.

Animals↗
PubMed1995

Height and body mass index in Oslo, Norway, compared to other regions of Europe: do they explain differences in the incidence of hip fracture? European Vertebral Osteoporosis Study Group.

Lean body stature and tallness have both been identified as risk factors for hip fracture. In this study, height and weight data from a multinational multicenter study were used to compare Oslo, which has some of the highest incidence rates of hip fracture ever reported, to other regions of Europe, with respect to height and body mass index. More than 17,000 subjects in six age strata (50-54, 55-59, 60-64, 65-69, 70-74, 75+ years) from 36 centers in 19 European countries were enrolled in the European Vertebral Osteoporosis Study (EVOS), which included standardized height and weight measurements. We found that men in Oslo were 4.3 cm taller than men in western Europe, 5.0 cm taller than men in eastern Europe, and 8.6 cm taller than men in southern Europe. Oslo women were also taller, by 2.2 cm compared to women in western Europe, 2.7 cm compared to women in eastern Europe, and 5.2 cm compared to women in southern Europe. In all age groups, except women aged 55-59 years, mean body mass index (BMI) was lowest in Oslo. Nearly twice as many had a BMI less than 22.0 kg/m2 in Oslo compared to the other regions combined (11.1% vs. 6.6% in men and 19.2% vs. 9.9% in women). This study indicates that the people of Oslo are taller and leaner than people in other regions of Europe. This may in part explain the higher incidence of hip fracture in the population of Oslo.

Aged↗
PubMed1995

Inoculation of nonhuman primates with the N40 strain of Borrelia burgdorferi leads to a model of Lyme neuroborreliosis faithful to the human disease.

We injected rhesus macaques with a highly infective strain of Borrelia burgdorferi to assess whether experimentally inoculated nonhuman primates (NHPs) could serve as models of human Lyme neuroborreliosis (LNB). The animals developed biopsy-confirmed erythema migrans in the area of the inoculations. ELISA testing of sera revealed strong antibody reactivity to B burgdorferi antigens, and Western blotting showed that 16-, 22-, 31-, 34-, and 41-kd proteins of the spirochete were major antigens recognized by antibody. Culture and polymerase chain reaction (PCR) testing of serial CSF specimens revealed that chronic infection of the CNS occurred in all NHPs injected. CSF pleocytosis occurred concurrently with CNS infection. Brain MRI revealed intense meningeal inflammation in one NHP as manifested by gadolinium uptake by the dura at the base of the temporal lobes. All animals had measurable antibody in the CSF after invasion. These studies are the first to demonstrate that experimental LNB in NHPs is a reliable model faithful to the human disease, with spirochetal invasion of the subarachnoid space. This also is the first report of CSF samples positive by culture in experimental LNB. Inflammation in the CNS as manifested by CSF pleocytosis and MRI findings was also correlated with the presence of spirochetal DNA detected by PCR. These data support the hypothesis that the pathogenesis of LNB is associated with direct spirochetal invasion, and provide evidence that CNS involvement is more common than heretofore thought.

Animals↗
PubMed1994

Psoriatic arthritis. Historical background and epidemiology.

Psoriatic arthritis was first described in the early part of the nineteenth century. Over the past 50 years, concepts of the disease have evolved as a result of clinical, epidemiological, radiological and immunogenetic study. Epidemiological and clinical investigations suggest that the disease is a unique arthropathy rather than the coincident occurrence of two common diseases. There are no validated criteria for classification; this is partly because of the heterogeneous clinical features associated with the disease, and the relapsing and remitting nature of both psoriasis and arthritis. Clinical subgroups have been proposed and have proved useful in study of the disease; however, there are inconsistencies and overlaps in the published data. The population prevalence of psoriatic arthritis is in the range of 2-10 per 10,000 although this is probably an underestimate as those with sacroiliac involvement only are not included. There are currently no incidence figures from population samples. The disease is slightly more common in females than males, although there is variation in the sex ratio by disease subgroup. There is evidence that hormonal and environmental factors play a role in the occurrence of disease.

Age Distribution↗
PubMed1994

Measurement of shoulder related disability: results of a validation study.

OBJECTIVE: To develop and validate a questionnaire to quantify disability associated with shoulder symptoms. METHODS: A set of questions relevant to shoulder symptoms from a general disability interview was developed and the questionnaire applied to a cross-sectional population survey and a prospective study of general practice attenders. Subjects included adults who reported current shoulder pain in a population survey and patients from three general practices who attended with shoulder symptoms during a six month period. The main outcome measures were: frequency of problems with daily living related to shoulder symptoms, total score on 22-item disability questionnaire, and measures of shoulder movement. RESULTS: A higher proportion (80%) of patients attending their general practitioner with shoulder symptoms had five or more disabilities compared with subjects reporting shoulder pain in a community survey (34%). The ranked frequency with which each disability was reported was similar in the two groups, although sleep disturbance was the most common problem in consulters. Self-reported disability is correlated with measures of restricted shoulder movement. CONCLUSION: This disability questionnaire was simple to complete and should prove useful for both general practice and population-based studies of shoulder pain.

Activities of Daily Living↗
PubMed1993

The outbreak of equine influenza (H3N8) in the United Kingdom in 1989: diagnostic use of an antigen capture ELISA.

In July 1989 influenza A/equine-2 (H3N8) was isolated from a nasopharyngeal swab taken from a non-thoroughbred horse exhibiting acute clinical respiratory disease. This was the first isolation of equine influenza virus in the United Kingdom since 1981. Subsequent investigations of acute respiratory disease in horses indicated that the infection was dispersed throughout the UK. However, unlike the previous epidemic of 1979, the first horses from which the virus was isolated had been vaccinated. This outbreak of influenza provided an opportunity to evaluate an antigen capture ELISA, directed against the influenza virus nucleoprotein, as a rapid method for detecting virus in the nasopharyngeal secretions of naturally infected horses.

Animals↗
PubMed1993

Modulation of the serological response of specific pathogen-free (EHV-free) foals to EHV-1 by previous infection with EHV-4 or a TK-deletion mutant of EHV-1.

EHV-1 was inoculated into specific pathogen-free (SPF) foals in order to study uncomplicated primary responses. Infection resulted in a strong serological response recognizing EHV-1-specific antigens; this contrasts with a previous publication where a weak response was recorded in SPF animals. Antibodies to EHV-1 were readily detected by four techniques (virus neutralization, complement fixation, Western blots and immune precipitation), yet there was comparatively little cross-reaction to EHV-4 target antigen. Re-inoculation with the same virus strain stimulated antibodies to EHV-1 but no additional antigens were recognized and antibodies cross-reacting with EHV-4 antigens were not enhanced. Having characterized the uncomplicated primary response to EHV-1 in SPF foals, further animals were exposed to either EHV-4 or a thymidine kinase-deficient mutant of EHV-1 prior to challenge with w/t EHV-1 to investigate how these infections might modulate the immune responses to EHV-1 or 4. Primary inoculation with EHV-4 or with a thymidine kinase-deficient mutant of EHV-1 produced productive infections as evidenced by virus shedding and pyrexia. In both these cases, however, in contrast to that with w/t EHV-1, the serological response was very weak. Re-infection of foals primed with either EHV-4 or TK-deficient EHV-1 with w/t EHV-1 resulted in a strong response to EHV-1 antigens detected by all four methods. In addition, in the foals given a primary inoculation with EHV-4, superinfection with EHV-1 resulted in a strong cross-reactive response to EHV-4 target antigens. The relevance of these observations to the interpretation of previously reported serological responses to EHVs in SPF and naturally reared animals is discussed.

Animals↗