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Biomedical subjects

S J Oliver

Publications and source records attributed to S J Oliver.

16 recordsLinked to original sources
PubMed2000

Disruptive sexual selection for plumage coloration in a passerine bird.

The theory of sexual selection was developed to explain the evolution of highly exaggerated sexual ornaments. Now supported by vast empirical evidence, sexual selection is generally considered to favour individuals with the most extreme trait expression. Here we describe disruptive selection on a sexual ornament, plumage coloration, in yearling male lazuli buntings (Passerina amoena). In habitats with limited good-quality nesting cover, the dullest and the brightest yearlings were more successful in obtaining high-quality territories, pairing with females and siring offspring, than yearlings with intermediate plumage. This pattern reflects the way that territorial adult males vary levels of aggression to influence the structure of their social neighbourhood. Adult males showed less aggression towards dull yearlings than intermediate and bright ones, permitting the dull yearlings to settle on good territories nearby. Fitness comparisons based on paternity analyses showed that both the adults and dull yearlings benefited genetically from this arrangement, revealing a rare example of sexually selected male-male cooperation.

Animals↗
PubMed2000

Immune stimulation in scleroderma patients treated with thalidomide.

Scleroderma (SSc) is a fibrosing connective tissue disease that is poorly responsive to any treatment, including immune suppression. SSc shares many characteristics with chronic graft-versus-host disease (GVHD). Because the immunomodulatory drug thalidomide has proven beneficial in chronic GVHD, we studied the immune response and clinical effects of thalidomide in SSc patients. We treated 11 SSc patients with thalidomide in an open label, dose escalating, 12 week study. Histologic comparison of skin biopsies showed changes in skin fibrosis and an increase in epidermal and dermal infiltrating CD8(+) T cells with thalidomide treatment. In thalidomide-treated SSc patients, plasma levels of IL-12 and TNF-alpha increased, while plasma IL-5 and IL-10 levels remained unchanged. These changes were associated with clinical effects, including dry skin, dermal edema, transient rashes, decreased gastroesophageal reflux symptoms, and healing of digital ulcers. When SSc PBMCs activated by anti-CD3 mAb were exposed to thalidomide, increases in both production of IL-2, IL-3, GM-CSF, and IFN-gamma and T cell expression of CD40L were observed. Thalidomide therefore appears to induce immune stimulation in SSc patients in association with clinical changes. However, it remains to be shown whether long-term enhancement of immune responses in SSc patients is clinically beneficial.

Adjuvants, Immunologic↗
PubMed2000

The Th1/Th2 paradigm in the pathogenesis of scleroderma, and its modulation by thalidomide.

The immunity generated in response to an antigenic stimulus can result in at least two distinct subclasses of immune responses, commonly referred to as Th1 and Th2. This review describes Th1- and Th2-type immune responses in animal models and in human mediated disease. Evidence obtained from working within these models suggests that manipulating the Th1/Th2 balance in the immune response can alter disease processes. The possible application of this strategy in scleroderma is presented. The immune modulating effects of the drug thalidomide on Th1 and Th2 immunity are also described, along with the drug's potential application to disease processes like scleroderma.

Animals↗
PubMed2000

Modulation of hyperoxia-induced TNF-alpha expression in the newborn rat lung by thalidomide and dexamethasone.

The effect of high oxygen concentrations on lungs of neonatal rats was studied. In addition, some oxygen-exposed animals were treated with either dexamethasone or thalidomide. No gross histologic changes were noted in the lungs following exposure to 95% oxygen nor were there changes in the total number or the phenotypic distribution of BAL cells obtained from these lungs compared to lungs from air exposed (control) neonatal rats. The majority of the BAL cells were CD45+ leukocytes (macrophages). However, when BAL cells were exposed to LPS in vitro, TNF-alpha production was higher in cells from rats exposed to 95% oxygen compared to cells from rats exposed to ambient air. In addition, lung TNF-alpha and IL-6 mRNA levels were increased after exposure to 95% oxygen. In the lungs of animals treated with either dexamethasone or thalidomide, TNF-alpha mRNA levels were reduced, while only dexamethasone treatment also reduced IL-6 mRNA levels.

Animals↗
PubMed1999

Thalidomide analogue CC1069 inhibits development of rat adjuvant arthritis.

The cytokine tumour necrosis factor-alpha (TNF-alpha) has been implicated in the aetiology of rheumatoid arthritis in humans as well as of experimental arthritis in rodents. Thalidomide, and to a greater extent the new thalidomide analogue CC1069, inhibit monocyte TNF-alpha production both in vitro and in vivo. The aim of the present study is to establish whether these drugs block production of TNF-alpha as well as IL-2 by rat leucocytes and whether this inhibition affects the development of rat adjuvant arthritis (AA). Cultured splenocytes were stimulated with either lipopolysaccharide (LPS) or concanavalin A (Con A) in the presence of thalidomide, CC1069, or solvent, and the production of TNF-alpha and IL-2 were compared. Next, adjuvant was injected into the base of the tail of rats without or with daily intraperitoneal injections with 100-200 mg/kg per day thalidomide or 50-200 mg/kg per day CC1069. Disease activity, including ankle swelling, hind limb radiographic and histological changes, weight gain, and ankle joint cytokine mRNA levels, were monitored. CC1069, but not the parent drug thalidomide, inhibited in vitro production of TNF-alpha and IL-2 by stimulated splenocytes in a dose-dependent manner. In vivo, a dose-dependent suppression of AA disease activity occurred in the CC1069-treated animals. In contrast, thalidomide-treated rats experienced comparable arthritis severity to placebo-treated animals. There was also a reduction in TNF-alpha and IL-2 mRNA levels in the ankle joints of CC1069-treated rats compared with thalidomide- and placebo-treated arthritic rats. Early initiation of CC1069 treatment suppressed AA inflammation more efficiently than delayed treatment. We conclude that thalidomide, which did not suppress TNF-alpha or IL-2 production in vitro by Lewis rat cells, did not suppress development of rat AA. However, the development of rat AA can be blocked by the thalidomide analogue CC1069, which is an efficient inhibitor of TNF-alpha production and IL-2 in vitro.

Animals↗
PubMed1998

The effect of thalidomide and 2 analogs on collagen induced arthritis.

OBJECTIVE: Thalidomide has been described as an inhibitor of both angiogenesis (which may account for its teratogenic effects on limb bud formation) and tumor necrosis factor-alpha (TNF-alpha) production. We evaluated its therapeutic potential in collagen induced arthritis (CIA), a rat model of rheumatoid arthritis (RA). METHODS: Rats were administered orally 200 mg/kg/day thalidomide (n = 10) or either of 2 analogs, EM-12 (n = 9) or supidimide (n = 9). An additional group was given thalidomide (n = 10) at 200 mg/kg twice daily, and a control group (n = 13) was given vehicle only. At completion of the protocols, serum levels of TNF-alpha and vascular endothelial growth factor (VEGF) were measured. RESULTS: Suppression of inflammatory synovitis by clinical and radiographic criteria was significantly lower in all experimental protocols except the lower dose thalidomide group. The EM-12 analog was the most efficacious, and twice daily thalidomide was better than once daily. The incidence of arthritis onset was comparable among all groups. Strong cell mediated and humoral responses to type II collagen, measured by a radiometric delayed type hypersensitivity assay and anti-type II collagen IgG ELISA, respectively, were similar in the experimental and control groups. TNF-alpha and VEGF levels were increased in all rats immunized with collagen compared to naive controls. CONCLUSION: Thalidomide and its analogs can suppress the clinical severity of rat CIA, but the mechanism of action is not a result of TNF-alpha or VEGF downregulation.

Animals↗
PubMed1996

Combination therapy in rheumatoid arthritis: the animal model perspective.

Attempts to improve antirheumatic agent efficacy have resulted in exploration of treatment protocols with combinations of 2 or more agents. Hypothetically, an ideal combination therapy would have greater efficacy and less toxicity than any of its component agents used individually. However, even a limited number of available drugs can produce a daunting number of possible combination protocols, each requiring clinical evaluation. Intelligent selection of combination protocols, based on a firm understanding of each agent's specific mechanism(s) of action, may help identify potentially useful regimens. Autoimmune animal models of inflammatory synovitis provide a unique opportunity to study the etiology, pathophysiology, and treatment of rheumatoid arthritis (RA). Induction of chronic inflammatory synovitis in susceptible inbred strains can allow for in vivo study under reproducible controlled conditions, using experimental protocols not possible in humans. Although animal models can only approximate human rheumatic disease in its complete form, they are nonetheless important for developing new therapeutic strategies. We review the 3 most common animal models of RA, the streptococcal cell wall, adjuvant, and collagen arthritis rat models. Surprisingly, few published studies evaluate combination therapy in RA animal models. We discuss these investigations, which use interventions aimed at angiogenesis, microtubule function, and immune regulation, as examples of animal models to assess and develop effective therapeutic combinations of antirheumatic agents.

Animals↗
PubMed1995

Suppression of collagen-induced arthritis by an angiogenesis inhibitor, AGM-1470, in combination with cyclosporin: reduction of vascular endothelial growth factor (VEGF).

Pannus formation characterized by neovascularization is a prominent pathologic finding in both rheumatoid arthritis (RA) and rat collagen-induced arthritis (CIA). CIA is a T-cell-dependent process induced by immunization of inbred LOU rats with native type II collagen in incomplete Freund's adjuvant. AGM-1470 is a highly specific inhibitor of new blood vessel formation by its effects on endothelial cell migration, endothelial cell proliferation, and capillary tube formation. Cyclosporin A (CSA) is an immunomodulating agent that inhibits IL-2 and other cytokine production involved in early antigen activation of T-cells. In this study the effects of single and combination therapy with AGM-1470 (27 mg/kg alternate days) and low-dose CSA (4 mg/kg/day continuous infusion via osmotic pump) on established CIA (total n = 62) were examined. At Day 18 post arthritis onset, clinical arthritis was significantly reduced in rats treated with single-agent AGM-1470 (1.88 +/- 0.33) or combination therapy (1.13 +/- 0.32) (P < 0.00001 and 0.000001, respectively) versus control. Single-agent CSA-treated rats, even if given CSA beginning on the day of immunization, did not attenuate arthritis severity. THe longitudinal mean arthritis score of combination-treated rats was significantly lower than that of rats receiving AGM-1470 (P < 0.0001), reflecting a more moderate early disease course in combination-treated rats. Disease severity in rats treated with single-agent CSA was not significantly different from control rats. Mean WBC counts, differentials, and delayed-type hypersensitivity responses were similar in all groups. CII antibody levels were lower in AGM-1470 protocols compared to CSA or controls. Flow cytometry of peripheral blood, spleen, and lymph nodes demonstrated decreased levels of CD4+ cells in rats given CSA. TNF-alpha levels remained elevated, even in treated rats, while vascular endothelial growth factor levels were reduced in rats receiving AGM-1470 compared to both arthritic controls and naive rats. Both single-agent and combination therapies were well tolerated. This is the first study to examine the effects of AGM-1470 together with CSA. Combination therapy was more effective than single-agent therapy. The results suggest that the use of interventions with distinct mechanisms of action may be efficacious in the treatment of RA.

Animals↗
PubMed1994

Suppression of collagen-induced arthritis using an angiogenesis inhibitor, AGM-1470, and a microtubule stabilizer, taxol.

Collagen-induced arthritis (CIA) is a T-cell-dependent rat model of rheumatoid arthritis (RA) that is induced by injection of collagen type II in incomplete Freund's adjuvant. Neovascularization within the synovium is a prominent feature of CIA and RA. The novel angiogenesis inhibitor AGM-1470 and the microtubule-stabilizing agent Taxol represent two new classes of agents with specific mechanisms of action. AGM-1470 inhibits fibroblast growth factor-induced stimulation of endothelial cell migration, endothelial cell proliferation, and capillary tube formation, resulting in effective suppression of new blood vessel formation. By enhancing microtubule polymerization, Taxol interferes with normal microtubule function in cell mitosis, migration, chemotaxis, and intracellular transport. Using a suppression protocol in established CIA, the effects of AGM-1470 and Taxol as single agents and in combination were evaluated. Combination therapy significantly reduced clinical arthritis compared to control rats (P < 0.00001). The combination therapy group also experienced earlier and significantly greater reduction of clinical arthritis compared to either single agent-treated groups (P < 0.05). Blinded radiographic scores at the end of the study demonstrated less soft tissue swelling and joint destruction using combination therapy than either single agent. This is the first use of AGM-1470 and Taxol in combination therapy. Further study of agents with distinct mechanisms of action may lead to more effective treatment options in chronic inflammatory arthritis and to a better understanding of the pathophysiologic processes of pannus formation.

Animals↗
PubMed1992

Loss of the first permanent molar and caries experience of adjacent teeth.

The caries experience of the occlusal and distal surfaces of the second premolars and the occlusal and mesial surfaces of the second permanent molars was examined in four groups of subjects aged 19-20 years. Group 1 comprised subjects with first permanent molars present, Group 2 subjects with early loss of the first permanent molar (before the age of 11-12 years), Group 3 subjects with late loss of the first permanent molar (after 11-12 years but before 15-16 years) and Group 4 included a combination of Group 2 and Group 3. Loss of the first permanent molar was associated with increased caries or restorations in the occlusal surfaces of adjacent teeth, but reduced caries or restorations in the proximal surfaces of adjacent teeth. Early loss of the first molar was associated with significantly greater caries or restoration experience in proximal surfaces than late loss, but no difference was detected for occlusal surfaces.

Adolescent↗
PubMed1990

Factors influencing the initiation of carious lesions in specific tooth surfaces over a 4-year period in children between the ages of 11-12 years and 15-16 years.

An analysis of factors influencing the initiation of carious lesions on specific tooth surfaces over a 4-year period in children between the ages of 11-12 years and 15-16 years is presented. Approximately 1000 children, resident in the County of South Glamorgan, Wales, were assessed for caries status and oral cleanliness in 1980 when aged 11-12 years and again in 1984 when aged 15-16 years. On both occasions, the children completed detailed questionnaires on dental health-related topics. Surfaces which were sound when the children were 11-12 years were identified and subsequently awarded a score of zero if they remained sound at 15-16 years or a score of one if they had developed carious lesions or had been filled. For each child, a mean mouth caries initiation score was computed for specific groups of surfaces, namely pit and fissure surfaces in posterior teeth, approximal surfaces in posterior teeth, buccal and lingual smooth surfaces of all teeth and approximal surfaces of anterior teeth. One-way analysis of variance and multiple regression techniques revealed that a number of factors had a significant influence on the initiation of caries. The factors and their level of significance varied between the surfaces. However, relatively little (less than 6 per cent) of the total variance in caries initiation score could be explained by the identified factors. Overall, more lesions developed in pit and fissure surfaces in posterior teeth than in the other surfaces included in the analyses.

Adolescent↗
PubMed1990

Factors influencing the caries experience of a group of children at the ages of 11-12 and 15-16 years: results from an ongoing epidemiological survey.

An analysis of factors influencing the caries experience of adolescents in South Wales is presented. Approximately 1000 children were assessed for caries status and oral cleanliness in 1980 when aged 11-12 years and again in 1984 when aged 15-16 years. In addition, on both occasions, the children completed detailed questionnaires on dental health-related topics. When aged 11-12 years, the observed mean DMFT, DMFS and DFS scores of the children were 4.0, 6.7 and 5.5 respectively. The corresponding scores at age 15-16 years were 6.5, 11.8 and 10.2. A preliminary analysis using conventional multiple regression techniques revealed that a number of factors had a significant influence on the caries experience of the children. The significance of the factors depended on the sex of the population subgroup, the age of the children and the particular caries index studied. However, at both ages the factors of most significance were the number of erupted teeth, total mean plaque score and the reported amount of money spent on sweets per week. A further evaluation using analysis of covariance with the number of erupted teeth and surfaces as the covariates confirmed the significant influence of the total mean plaque score and amount of money spent on sweets. In addition, both analyses indicated that toothbrushing frequency and social class had a significant influence on the caries experience of boys.

Analysis of Variance↗