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Biomedical subjects

S R Duncan

Publications and source records attributed to S R Duncan.

At least 19 recordsLinked to original sources
PubMed2000

Modelling the dynamics of scarlet fever epidemics in the 19th century.

Annual deaths from scarlet fever in Liverpool, UK during 1848-1900 have been used as a model system for studying the historical dynamics of the epidemics. Mathematical models are developed which include the growth of the population and the death rate from scarlet fever. Time-series analysis of the results shows that there were two distinct phases to the disease (i) 1848-1880: regular epidemics (wavelength = 3.7 years) consistent with the system being driven by an oscillation in the transmission coefficient (deltabeta) at its resonant frequency, probably associated with dry conditions in winter (ii) 1880-1900: an undriven SEIR system with a falling endemic level and decaying epidemics. This period was associated with improved nutritive levels. There is also evidence from time-series analysis that raised wheat prices in pregnancy caused increased susceptibility in the subsequent children. The pattern of epidemics and the demographic characteristics of the population can be replicated in the modelling which provides insights into the detailed epidemiology of scarlet fever in this community in the 19th century.

Adult↗
PubMed1999

Tumor-targeted IL-2 amplifies T cell-mediated immune response induced by gene therapy with single-chain IL-12.

Induction, maintenance, and amplification of tumor-protective immunity after cytokine gene therapy is essential for the clinical success of immunotherapeutic approaches. We investigated whether this could be achieved by single-chain IL-12 (scIL-12) gene therapy followed by tumor-targeted IL-2 using a fusion protein containing a tumor-specific recombinant anti-ganglioside GD(2) antibody and IL-2 (ch14.18-IL-2) in a poorly immunogenic murine neuroblastoma model. Herein, we demonstrate the absence of liver and bone marrow metastases after a lethal challenge with NXS2 wild-type cells only in mice (five of six animals) vaccinated with scIL-12-producing NXS2 cells and given a booster injection of low-dose ch14.18-IL-2 fusion protein. This tumor-protective immunity was effective 3 months after initial vaccination, in contrast to control animals treated with a nonspecific fusion protein or an equivalent mixture of antibody and IL-2. Only vaccinated mice receiving the tumor-specific ch14.18-IL-2 fusion protein revealed a reactivation of CD8(+) T cells and subsequent MHC class I-restricted tumor target cell lysis in vitro. The sequential increase in the usage of TCR chains Vbeta11 and -13 in mouse CD8(+) T cells after vaccination and amplification with ch14.18-IL-2 suggests that the initial polyclonal CD8(+) T cell response is effectively boosted by targeted IL-2. In conclusion, we demonstrate that a successful boost of a partially protective memory T cell immune response that is induced by scIL-12 gene therapy could be generated by tumor-specific targeting of IL-2 with a ch14.18-IL-2 fusion protein. This approach could increase success rates of clinical cancer vaccine trials.

Animals↗
PubMed1999

Clonal characteristics of T cell infiltrates in skin and synovium of patients with psoriatic arthritis.

Psoriasis is a chronic inflammatory skin disease that is often complicated by an inflammatory arthritis. Considerable evidence implicates cellular immune responses in psoriatic skin lesions, but the pathogenesis of the associated arthritis has not been elucidated. We analyzed T cell antigen receptor beta chain variable (TCRbetaV) gene repertoires among peripheral blood lymphocytes, skin and synovium of nine patients with psoriatic arthritis. RNase protection assays were used to quantitate the expression levels of 25 TCRbetaV genes, and CDR3 region sequencing was used to further characterize selected expansions. All patients exhibited significant TCRbetaV biases in the peripheral blood and moreover, all had expansions common to both skin and synovium. CDR3 sequencing demonstrated these expansions frequently consisted of oligo- or monoclonal populations. Although no ubiquitous CDR3 nucleotide sequences were identified, two patients shared identical sequences and several highly homologous amino acid motifs were present in skin and synovium among and between individual patients. Findings of common TCRbetaV expansions in diverse inflammatory sites, among multiple afflicted individuals, suggest that these T cell proliferations are driven by engagements with a limited set of conventional antigens. These findings demonstrate an important role for cognate T cell responses in the pathogenesis of psoriatic arthritis, and further suggest the inciting antigen(s) is identical or homologous between afflicted skin and synovium.

Adult↗
PubMed1998

The interacting effects of prices and weather on population cycles in a preindustrial community.

The exogenous cycles and population dynamics of the community at Penrith, Cumbria, England, have been studied (1557-1812) using aggregative analysis, family reconstitution and time series analysis. This community was living under marginal conditions for the first 200 years and the evidence presented is of a homeostatic regime where famine, malnutrition and epidemic disease acted to regulate the balance between resources and population size. This provides an ideal historic population for an investigation of the direct and indirect effects of malnutrition. Throughout the period studied, a short wavelength oscillation in grain prices was apparently the major external factor that drove exogenous cycles in mortality, birth rate, and migration. In particular, the different responses of children to variations in food supply are emphasised; fluctuations in poor nutrition correlated significantly with the variations in mortality rates for infants (probably indirectly during pregnancy and directly during the first year of life) and for young children (via susceptibility to lethal infectious diseases). Migratory movements contributed to the maintenance of homeostasis in the population dynamics. A medium wavelength cycle in low winter temperatures was associated with a rise in adult mortality which, in turn, promoted an influx of migrants into this saturated habitat. A model incorporating these interacting associations between vital events and exogenous cycles is presented: grain prices were an important density-dependent factor and constituted the major component of the negative feedback of this population and drove the exogenous, short wavelength mortality cycles. Cycles of births and immigration provide a positive feedback for the build-up of susceptibles and the initiation of smallpox epidemics and increased population size.

Commerce↗
PubMed1998

The effects of population density and malnutrition on the dynamics of whooping cough.

Liverpool, a seaport in NW England, suffered severely from lethal infectious diseases in the second half of the 19th century: the population was densely crowded and malnourished and life expectancy was low. Time-series analysis shows that the epidemics of whooping cough (i) had an interepidemic interval of 2.9 years, 1863-85, which lengthened to 3.4 years, 1885-1900 (ii) were strongly coherent with wheat prices (P < 0.001) and (iii) also correlated with cycles of seasonal weather conditions. It is suggested from mathematical modelling that the epidemics in this compromised population were maintained (i.e. the system was driven) by an oscillation of malnutrition and by seasonal weather conditions. A model that incorporates both the dynamics of whooping cough and the demographic characteristics of the population is presented. It has been shown to replicate the dynamics of the epidemics and has been used to predict the changes with time of (i) the force of the infection and (ii) the proportion of those infected with whooping cough who died.

Disease Outbreaks↗
PubMed1997

Autoimmunity caused by disruption of central T cell tolerance. A murine model of drug-induced lupus.

A side effect of therapy with procainamide and numerous other medications is a lupus-like syndrome characterized by autoantibodies directed against denatured DNA and the (H2A-H2B)-DNA subunit of chromatin. We tested the possibility that an effect of lupus-inducing drugs on central T cell tolerance underlies these phenomena. Two intrathymic injections of procainamide-hydroxylamine (PAHA), a reactive metabolite of procainamide, resulted in prompt production of IgM antidenatured DNA antibodies in C57BL/6xDBA/2 F1 mice. Subsequently, IgG antichromatin antibodies began to appear in the serum 3 wk after the second injection and were sustained for several months. Specificity, inhibition and blocking studies demonstrated that the PAHA-induced antibodies showed remarkable specificity to the (H2A-H2B)-DNA complex. No evidence for polyclonal B cell activation could be detected based on enumeration of Ig-secreting B cells and serum Ig levels, suggesting that a clonally restricted autoimmune response was induced by intrathymic PAHA. The IgG isotype of the antichromatin antibodies indicated involvement of T cell help, and proliferative responses of splenocytes to oligonucleosomes increased up to 100-fold. As little as 5 microM PAHA led to a 10-fold T cell proliferative response to chromatin in short term organ culture of neonatal thymi. We suggest that PAHA interferes with self-tolerance mechanisms accompanying T cell maturation in the thymus, resulting in the emergence of chromatin-reactive T cells followed by humoral autoimmunity.

Adoptive Transfer↗
PubMed1997

The dynamics of measles epidemics.

The interepidemic interval (T) of measles in London from 1647 to 1837 evolved progressively from 5-yearly to 2-yearly by 1800. Measles mortality was significantly ( p<0.001) cross-correlated with the annual wheat prices, a good index of nutrition although at a 2-year lag. Epidemics correlated with low autumn temperatures (p<0. 001). A linearised model of the dynamics of epidemics shows that T is determined by the product of population (N) and susceptibility (beta) and that the system will settle at its steady state unless the epidemics are driven. It is suggested that (i) the progressive change in T was caused by a rise in population size (N) and an increased susceptibility (beta) related to malnutrition and (ii) epidemics were driven by oscillations in low autumn temperature (p<0. 001) and by cycles of susceptible young children produced by malnutrition during pregnancy.

Child↗
PubMed1997

T-cell receptor biases and clonal proliferations in blood and pleural effusions of patients with lung cancer.

We sought evidence that pulmonary carcinomas mediate a cellular immunologic response by analyzing T-cell antigen receptor beta-chain variable gene (TCRBV) repertoires of lymphocytes from peripheral blood (PBL) and malignant pleural effusions (PEL) of five lung cancer patients. Expression levels of 27 TCRBV were quantitated by multiprobe RNase protection assay (RPA), and clonal expansions were identified by sequence enrichment nuclease assay (SENA) and junctional region sequencing. Abnormal TCRBV expansions were identified in all subjects by RPA (mean 6.9 +/- 1.7/patient), and their number closely correlated with elapsed time since initial diagnosis (r = 0.97). SENA, performed in specimens from three patients, confirmed the presence of mono or oligoclonality in 48% of abnormal RPA expansions, and further identified T-cell clones among TCRBV with normal expression levels. The majority of clonal expansions were among PEL, and were nearly equally divided between CD4 and CD8. These data show that T-cell repertoires of lung cancer patients are characterized by marked abnormalities and frequent clonal expansions, most likely representing responses to unique, tumor-specific antigens (TSA). Moreover, this process appears exaggerated among PEL, further suggesting that malignant effusions include local proliferations of tumor reactive T cells. These findings imply the presence of lung cancer TSA capable of eliciting cellular immune responses and raise the possibility that selective immunotherapies can ultimately be developed.

Aged↗
PubMed1997

T cell receptor (TCR) BV gene repertoires and clonal expansions of CD4 cells in patients with HIV infections.

Despite extensive investigation, the pathogenesis of T cell depletions that characterize AIDS has not been elucidated. To study this process further, we evaluated T cell antigen receptor beta-chain variable gene (TCRBV) repertoires in peripheral blood lymphocytes (PBL) of 23 HIV-infected patients. Expression levels of 28 TCRBV were determined by multiprobe RNase protection assay after polymerase chain reaction (PCR) amplifications. Abnormal expansions (> 2 s.d. from mean normal values) were frequent in HIV CD4, accounting for 26% of total measured TCRBV in this population. The number and magnitude of abnormalities among individuals were inversely proportional to their CD4 counts (P < 0.012 and P < 0.01, respectively). While abnormalities were not randomly distributed among TCRBV subfamilies, no particular genes were expanded or contracted among all patients. Only 14% of CD8 TCRBV were proportionally expanded (P < 0.01 compared with CD4), and there were limited concordances between paired CD8 and CD4 repertoires among individuals. CDR3 length analyses and TCRBV sequencing showed that most CD4 expansions comprised clonal or oligoclonal populations. Thus, T cell responses in HIV patients are characterized by severe TCRBV biases and clonal expansions among CD4 subsets, and these processes are exaggerated with disease progression. The heterogeneity and oligoclonality of the TCRBV expansions are consistent with responses to HIV-encoded or other conventional antigens rather than superantigenic effects. The presence of CD4 clonal proliferations in these patients may be important in the pathogenesis of HIV, and the absence or reduction of many T cell specificities due to oligoclonal expansions may increase susceptibility to opportunistic infections.

Acquired Immunodeficiency Syndrome↗
PubMed1997

Dexamethasone inhibits lung epithelial cell apoptosis induced by IFN-gamma and Fas.

Lung epithelium plays a central role in modulation of the inflammatory response and in lung repair. Airway epithelial cells are targets in asthma, viral infection, acute lung injury, and fibrotic lung disease. Activated T lymphocytes release cytokines such as interferon-gamma (IFN-gamma) that can cooperate with apoptotic signaling pathways such as the Fas-APO-1 pathway to induce apoptosis of damaged epithelial cells. We report that IFN-gamma alone and in combination with activation of the Fas pathway induced apoptosis in A549 lung epithelial cells. Interestingly, the corticosteroid dexamethasone was the most potent inhibitor of IFN-gamma- and IFN-gamma plus anti-Fas-induced apoptosis. IFN-gamma induced expression of an effector of apoptosis, the cysteine protease interleukin-1 beta-converting enzyme, in A549 cells. Dexamethasone, in contrast, induced expression of an inhibitor of apoptosis, human inhibitor of apoptosis (hIAP-1), also known as cIAP2. We suggest that the inhibition of epithelial cell apoptosis by corticosteroids may be one mechanism by which they suppress the inflammatory response.

Antibodies↗
PubMed1996

Oscillatory dynamics of smallpox and the impact of vaccination.

The evolution of smallpox epidemics in London, 1647-1893, was studied by time series analysis of deaths from the disease in the Bills of Mortality. The interepidemic interval (T) evolved progressively from 4 years to 2 years at 1800. The dynamics of epidemics during 1647-1800 are explicable in terms of the transmission of viral diseases which shows that (i) T is determined by the product of population size (N) and susceptibility (beta), (ii) T determines the mean age of catching the disease, (iii) the system will settle at its steady-state, endemic level unless the epidemics are driven. It is suggested that (i) the progressive change in T was initially caused by a rise in N and later by an increased beta related to malnutrition and (ii) the epidemics were driven by an oscillation in delta beta associated with seasonal dry conditions. The effects of variolation and vaccination became apparent after 1800: the endemic level fell progressively, the epidemics were reduced in amplitude and they were not driven. The dynamics of the disease can now be described by an SEIR model: severe outbreaks of smallpox are followed by decaying epidemics. Endemic smallpox mortality also interacts with the dynamics of the population so that a long wavelength oscillation (associated with recovery after the plague) and a 5/6 year (associated with immigration) oscillation are generated.

Disease Outbreaks↗
PubMed1996

T cell receptor biases and clonal proliferations among lung transplant recipients with obliterative bronchiolitis.

Obliterative bronchiolitis (OB) is the most serious late complication of lung transplantation, but the pathogenesis of this disorder has not been elucidated. We sought evidence that OB is mediated by a cellular immunologic response by characterizing T cell antigen receptor beta-chain variable gene (TCRBV) repertoires in lung allograft recipients. Expression levels of 27 TCRBV among recipients were determined by multiprobe RNase protection assay after PCR amplification. In comparison to recipients with no evidence of rejection (n = 9), the PBL TCRBV repertoires of OB subjects (n = 16) exhibited more frequent expansions (16 vs. 9% of all measured TCRBV, P < 0.02), and the magnitudes of these abnormalities were greater (8.2 +/- 0.8 vs. 4.5 +/- 0.3 SD from mean normal values, P < 0.01). TCRBV sequencing showed these expansions were composed of clonal or oligoclonal populations. Thus, T cell responses in the recipients are marked by highly selective clonal expansions, presumably driven by indirect recognition of a limited number of immunodominant alloantigens. These processes are exaggerated among allograft recipients with OB, implying that cognate immune mechanisms are important in the pathogenesis of the disorder. Furthermore, the prominence of finite, distinct TCR phenotypes raise possibilities for development of novel diagnostic modalities and targeted immunotherapies for OB and other manifestations of chronic allograft rejection.

Adult↗
PubMed1996

Whooping cough epidemics in London, 1701-1812: infection dynamics, seasonal forcing and the effects of malnutrition.

Time series analysis of the London Bills of Mortality, 1701-1812, reveals that whooping cough appeared as a lethal endemic disease after 1700 with epidemics of progressively increasing amplitude after 1720. The interepidemic period changed from 5 years (1720-1750) to 3 years (1750-1785) before returning to 5 years during 1785-1812. The epidemiology of whooping cough can be described by the mathematics of linearized dynamic systems and the interepidemic interval is determined by population size and susceptibility. The latter was governed by fluctuating levels of malnutrition, which were directly associated with oscillations in the wheat prices. It is suggested that the epidemics were driven in 1720-1785 by fluctuating seasonal temperatures which interacted with oscillations in wheat prices to produce an oscillation in susceptibility, but after 1785 the dynamics escaped from the pattern predicted by mathematical theory and the epidemics were apparently driven only by the wheat prices which generated a regular oscillation in susceptibility. The results emphasize the importance of an adequate nutritive level in combating whooping cough in the Third World today where it remains a lethal disease in children because of immunodeficiency linked to fluctuating and severe malnutrition which is often a consequence of crop cycles.

Agriculture↗
PubMed1996

Intrathymic injection of polynucleosomes delays autoantibody production in BXSB mice.

T-cell dependent autoimmunization with nucleosomes appears to be an early event in the induction of lupus anti-chromatin antibodies. We investigated this phenomenon by injecting H1-stripped chromatin polynucleosomes into the thymuses of BXSB male lupus-prone mice. In comparison to uninjected controls, the production of IgG antichromatin, anti-native DNA, and anti-denatured DNA were significantly reduced among the injected animals for a period of 8 to 10 weeks. Peripheral T-cells from intrathymic (i.t.)-treated animals showed decreased proliferative responses to polynucleosomes compared to those from uninjected controls. Treatment did not affect T-cell antigen receptor V beta profiles, excluding the possibility that results were due to superantigen-imposed deletions. In situ staining using the TUNEL method demonstrated that generation and phagocytosis of apoptotic material in thymuses of unmanipulated BXSB mice were similar to normal controls. These findings show that polynucleosomes likely comprise the antigens for helper T-cell engagement and induction of lupus-associated anti-chromatin antibodies. Bypassing the underlying defect of T-cell tolerance for polynucleosomal antigens among BXSB mice, by i.t. administration of exogenous polynucleosomes, results in abrogation of autoantibody production.

Animals↗
PubMed1996

The dynamics of scarlet fever epidemics in England and Wales in the 19th century.

There was a marked rise in scarlet fever mortality in England and Wales in the mid-nineteenth century and spectral analysis of the registration details, 1847-80, shows that the interepidemic interval was 5-6 years, but after 1880 the endemic level fell and the fatal epidemics disappeared. The dynamics of the scarlet fever epidemics can be represented by a linearized mathematical model and because the system is lightly damped, it could be driven by an oscillation in susceptibility. Epidemics were significantly correlated with dry conditions in spring/summer (P < 0.001), suggesting that these produced a low amplitude oscillation in susceptibility which drove the system. Epidemics also correlated (P < 0.001) with an oscillation in wheat prices but at a lag of 3 years, suggesting that malnutrition during pregnancy caused increased susceptibility in the subsequent children which interacted synergistically with seasonal dry conditions. Scarlet fever mortality was sharply reduced after 1880 in parallel with falling wheat prices suggesting that the remarkable period of high scarlet fever mortality (1840-80) was dependent on poor nutritive levels during that time.

Disease Outbreaks↗
PubMed1996

Aerosolized cyclosporine in lung recipients with refractory chronic rejection.

This study evaluated aerosolized cyclosporine as rescue therapy for lung transplant recipients with unremitting chronic rejection. Nine patients with histologic active obliterative bronchiolitis and progressively worsening airway obstruction refractory to conventional immune suppression received aerosolized cyclosporine. Improvement in rejection histology was seen in seven of nine patients. We compared the changes in the FVC and FEV1 over time using linear regression analysis in these seven histologic responders and nine historical control patients. During the pretreatment period for both the experimental and control groups, the FVC and FEV1 declined at comparable rates. After aerosolized cyclosporine there was stabilization of pulmonary function, whereas in the controls there was continued decline. Cyclosporine blood levels were less than 50 ng/ml 24 h after an aerosolized dose of 300 mg in five patients receiving oral tacrolimus. Nephrotoxicity, hepatotoxicity, and a greater than expected rate of infection was not observed. This study suggests that aerosolized cyclosporine is safe and may be effective therapy for refractory chronic rejection in lung transplant recipients.

Adult↗
PubMed1996

Pulmonary capillaritis and alveolar hemorrhage. Update on diagnosis and management.

Pulmonary vascular inflammatory disorders may involve all components of the pulmonary vasculature, including capillaries. The principal histopathologic features of pulmonary capillaritis include capillary wall necrosis with infiltration by neutrophils, interstitial erythrocytes, and/or hemosiderin, and interalveolar septal capillary occlusion by fibrin thrombi. Immune complex deposition is variably present. Patients often present clinically with diffuse alveolar hemorrhage, which is characterized by dyspnea and hemoptysis; diffuse, bilateral, alveolar infiltrates on chest radiograph; and anemia. Pulmonary capillaritis has been reported with variable frequency and severity as a manifestation of Wegener's granulomatosis, microscopic polyarteritis, systemic lupus erythematosus, Goodpasture's syndrome, idiopathic pulmonary renal syndrome, Behçet's syndrome, Henoch-Schönlein purpura, IgA nephropathy, antiphospholipid syndrome, progressive systemic sclerosis, and diphenylhydantoin use. In addition to history, physical examination, and routine laboratory studies, certain ancillary laboratory tests, such as antineutrophil cytoplasmic antibodies, antinuclear antibodies, and antiglomerular basement membrane antibodies, may help diagnose an underlying disease. Diagnosis of pulmonary capillaritis can be made by fiberoptic bronchoscopy with transbronchial biopsy, but thoracoscopic biopsy is often employed. Since many disorders can result in pulmonary capillaritis with diffuse alveolar hemorrhage, it is crucial for clinicians and pathologists to work together when attempting to identify an underlying disease. Therapy depends on the disorder that gave rise to the pulmonary capillaritis and usually includes corticosteroids and cyclophosphamide or azathioprine. Since most diseases that result in pulmonary capillaritis are treated with immunosuppression, infection must be excluded aggressively.

Anemia↗