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Biomedical subjects

D H Dockrell

Publications and source records attributed to D H Dockrell.

At least 19 recordsLinked to original sources
PubMed2006

Invasive pneumococcal disease and the potential for prevention by vaccination in the United Kingdom.

OBJECTIVES: Invasive pneumococcal disease (IPD) is associated with a high mortality despite antimicrobial therapy, but may be preventable by pneumococcal vaccination. The extent of previous exposure to pneumococcal capsular polysaccharide vaccination prior to an episode of IPD in hospitalised adults in the United Kingdom is unclear. METHODS: We conducted a retrospective cohort study in adults with IPD admitted to either of two teaching hospitals in Sheffield, United Kingdom during 1992-2000. Receipt of pneumococcal vaccination, risk factors for IPD, death and disability were determined. RESULTS: The number of cases of IPD was 552 and 187/230 patient records from one site were reviewed. According to UK pneumococcal vaccination guidelines 59% of patients should have received the vaccine and 76% of patients if updated guidelines, which include age>65 years as an indication, are applied. In patients with known risk factors, excluding age, only 8% had been vaccinated. The mortality from IPD was 21% and an additional 6% suffered major complications. CONCLUSIONS: In patients hospitalised with IPD there is a high rate of pre-existing risk factors and a low rate of administration of pneumococcal vaccination. IPD incurs significant mortality, morbidity and economic cost and there is potential for reducing this by improved uptake of pneumococcal vaccination.

Adolescent↗
PubMed2003

Apoptosis in HIV-1 infection.

Apoptosis is a key event in biologic homeostasis with particular importance to the immune system. It is an active energy-dependent process that is tightly regulated and controlled by a variety of signal transduction pathways. Apoptosis modulation plays a part in the pathogenesis of many human diseases, including HIV infection. Although multiple mechanisms may contribute to the decline in CD4 T-lymphocyte numbers observed, apoptosis is a significant factor. Alterations in levels of apoptosis are observed in both directly infected and uninfected bystander cells and a variety of pathways of apoptosis induction have been implicated. Apoptosis induction is related to death receptor and mitochondrial-induced pathways in specific circumstances. These events have been linked to individual HIV proteins and have been demonstrated to be altered by antiretroviral therapy.

Apoptosis↗
PubMed2003

The multiple roles of Fas ligand in the pathogenesis of infectious diseases.

Fas ligand (FasL) is a type II transmembrane protein that plays a critical role in immune homeostasis by binding to its receptor Fas (CD95) and inducing apoptosis. Fas/FasL dysregulation contributes to infectious disease pathogenesis. Microorganisms may inhibit Fas signal transduction to prolong intracellular survival and prevent killing by immune effector cells. FasL may be upregulated in directly infected cells to enhance killing of responding immune cells and facilitate immune evasion. The host response to infection may aim to induce apoptosis in directly infected cells, but immune cells that target directly infected cells can induce Fas-mediated apoptosis of uninfected bystander cells. FasL also contributes to the generation and regulation of the inflammatory response in infection. The multiple roles of FasL in infectious disease pathogenesis are discussed in the context of viral, bacterial and parasitic infections.

Acquired Immunodeficiency Syndrome↗
PubMed2003

Human herpesvirus 6: molecular biology and clinical features.

Human herpesvirus 6 (HHV-6) exists as distinct variants HHV-6A and HHV-6B. The complete genomes of HHV-6A and HHV-6B have been sequenced. HHV-6B contains 97 unique genes. CD46 is the cell receptor for HHV-6, explaining its broad tissue tropism but its restricted host-species range. HHV-6 utilizes a number of strategies to down-regulate the host immune response, including molecular mimicry by production of a functional chemokine and chemokine receptors. Immunosuppression is enhanced by depletion of CD4 T lymphocytes via direct infection of intra-thymic progenitors and by apoptosis induction. Infection is widespread in infants between 6 months and 2 years of age. A minority of infants develop roseola infantum, but undifferentiated febrile illness is more common. Reactivation from latency occurs in immunocompromised hosts. Organ-specific clinical syndromes occasionally result, but indirect effects including interactions with other viruses such as human immunodeficiency virus type 1 and human cytomegalovirus or graft dysfunction in transplant recipients may be more significant complications in this population. Recent advances in quantitative PCR are providing additional insights into the natural history of infection in paediatric populations and immunocompromised hosts.

Gene Expression Regulation, Viral↗
PubMed2001

Immune-mediated phagocytosis and killing of Streptococcus pneumoniae are associated with direct and bystander macrophage apoptosis.

Apoptosis of macrophages may be a pathogen-directed mechanism of immune escape or may represent appropriate host response to infection. Human monocyte-derived macrophages (MDMs) from healthy donors (C-MDMs) exhibited low-level constitutive apoptosis, but culture of MDMs with opsonized serotype I Streptococcus pneumoniae (I-MDMs) for 20 h resulted in significantly increased apoptosis. I-MDM apoptosis was associated with phagocytosis of bacteria and intracellular killing that was blocked by the caspase inhibitor z-VAD-fmk but not by Fas-blocking antibody. Paraformaldehyde-fixed I-MDMs induced apoptosis in uninfected syngeneic monocytes at levels greater than those in monocytes incubated alone or incubated with fixed C-MDMs. Apoptosis of syngeneic monocytes was blocked by anti-Fas antibody. The immune response of macrophages to S. pneumoniae includes a novel form of apoptosis that is associated with successful phagocytosis and bacterial killing. This response in vivo may regulate the inflammatory response to infection during a successful host response against S. pneumoniae.

Amino Acid Chloromethyl Ketones↗
PubMed2001

Apoptotic cell death in the pathogenesis of infectious diseases.

Apoptosis is a physiological process critical for tissue homeostasis. It is essential for the regulation of immune responses. A series of molecules transduce apoptoic signals and induce the characteristic morphological appearances of apoptotic cells. Infectious diseases modulate apoptosis and this contributes to disease pathogenesis. Infection with HIV results in enhanced levels of CD4 T-lymphocyte apoptosis in both directly infected cells and in uninfected bystander cells. A variety of HIV proteins including gp120 contribute to this process. A number of different pathways induce HIV-associated CD4 T-lymphocyte apoptosis and apoptosis of uninfected bystander cells is particularly associated with increased susceptibility to Fas. Other viruses including hepatitis viruses and the human herpesviruses also modulate apoptosis. Bacterial infection induces apoptosis which is frequently mediated by the direct activation of caspases in the absence of death receptor ligation. Bacterial induction of apoptosis may either be due to bacterial factors such as the invasin IpaB of Shigella flexneri or be the result of host immune responses which control infection as demonstrated in infections due to Mycobacterium spp. Apoptosis may be modulated by therapeutic strategies, such as antiretroviral therapy, and an improved understanding of infection-associated apoptosis modulation will aid the design of novel therapeutic approaches to control infectious diseases.

Apoptosis↗
PubMed2001

Imiquimod and resiquimod as novel immunomodulators.

Augmenting the host's natural immune response to viruses by the administration of exogenous cytokines such as interferon-alpha (IFN-alpha) is a strategy increasingly employed in antiviral therapeutics. Enhancing the release of endogenous cytokines is, however, an alternative approach. The imidazoquinolinamines imiquimod and resiquimod have demonstrated potency as inducers of IFN-alpha and other cytokines both in vitro and in vivo. Cytokine gene activation is mediated via the signal transducer and activator of transcription 1 (STAT-1) and involves the transcription factors NFkappaB and alpha4F1. Antiviral activity has been demonstrated against a variety of viruses, and clinical efficacy has been demonstrated against genital warts, herpes genitalis and molluscum contagiosum. Imiquimod is administered as a 5% cream (Aldara) and has been licensed for the treatment of anogenital warts in immunocompetent patients. Complete clearance of warts has been observed in up to half of treated patients with only local side effects reported. Resiquimod can be administered topically but also exists as an oral formulation. The range of potential infections for which these agents may have clinical utility includes chronic hepatitis C virus infection and Kaposi's sarcoma. In addition, the imidazoquinolinamines may find roles in the therapy of cancers and as vaccine adjuvants.

Adjuvants, Immunologic↗
PubMed2000

Human beta-herpesvirus interactions in solid organ transplant recipients.

The replication of beta-herpesviruses-cytomegalovirus (CMV), human herpesvirus (HHV)-6, and HHV-7-and their association with CMV disease and response to antiviral therapy were prospectively investigated in 33 liver transplant recipients not given antiviral prophylaxis. CMV, HHV-6, and HHV-7 DNA were detected within 8 weeks after transplantation in 70%, 33%, and 42% of the patients, respectively. The univariate association between CMV disease and the 3 beta-herpesviruses was more significant by virus load quantitation than by qualitative detection of DNA. This association with high levels of CMV, HHV-6, and HHV-7 (P<.001,.022, and.001, respectively) occurred mainly in CMV-seronegative recipients of transplants from CMV-seropositive donors. Antiviral therapy with ganciclovir (Gcv) reduced the load of CMV and HHV-6 and HHV-7. These results suggest that CMV disease in transplant recipients is related to the unique interaction of the 3 beta-herpesviruses and is ultimately reduced after intravenous Gcv treatment.

Antibodies, Viral↗
PubMed2000

Mycophenolate mofetil increases cytomegalovirus invasive organ disease in renal transplant patients.

The impact of cytomegalovirus (CMV) infection post-transplantation is in part influenced by the degree of immunosuppression. While mycophenolate mofetil (MMF) does not increase the overall incidence of CMV infection, we have questioned whether or not it increases its severity. Using a case control study design in which 29 renal transplant patients developed CMV disease [17 (59%) of which received azathioprine (AZA) and 12 (41%) received MMF], increases in the frequency of organ involvement with CMV (58 vs. 18%; p = 0.03) and in the number of organs involved with CMV were noted in the MMF versus the AZA group (2.0 vs. 1.0; p = 0.015). These results indicate that the increased immunosuppressive activity of MMF impacts the morbidity of CMV infection, thus warranting the use of effective anti-CMV preventive regimens while patients are treated with MMF.

Acyclovir↗
PubMed1999

Activation-induced CD4+ T cell death in HIV-positive individuals correlates with Fas susceptibility, CD4+ T cell count, and HIV plasma viral copy number.

The relevance of activation-induced cell death (AICD) of CD4+ T cells to AIDS pathogenesis is unknown. The present study investigates the relationship of AICD to a defined molecular mechanism regulating peripheral T cell homeostasis, Fas-mediated apoptosis, and clinical correlates of the pathogenesis of AIDS. Increased pokeweed mitogen (PWM)-induced AICD (22.8 versus 4.4%, p = 0.006) and Fas-mediated apoptosis (27.7 versus 12.0%, p = 0.002) of CD4+ T cells were observed in HIV+ versus HIV- individuals. Similarly, increased PWM-mediated AICD (16.2 versus 2.2%, p < 0.001) and Fas-mediated apoptosis (25.8 versus 7.6%, p = 0.005) were noted in CD8+ T cells from HIV+ versus HIV- individuals. PWM-induced AICD of CD4+ T cells was blocked (83% median specific inhibition) by Fas-blocking antibodies, whereas PWM-induced AICD of CD8+ T cells was Fas independent. Comparison between PWM- and anti-CD3-mediated AICD of CD4+ T cells indicated that PWM- and not CD3-induced AICD is Fas dependent. HIV+ individuals with an HIV RNA copy number of <30,000 copies/ml had lower PWM-induced AICD of CD4+ T cells than did those with an HIV RNA copy number of >30,000 copies/ml (5.7 versus 22.1%, p = 0.034), and PWM-induced AICD inversely correlated with CD4+ T cell count (R = -0.567, p = 0.043). Initiation of HAART decreased PWM-induced CD4+ T cell AICD from 24.4 to 9.4% posttreatment (p = 0.035). These results demonstrate that PWM-induced AICD of CD4+ T cells from HIV+ individuals is mediated by Fas/FasL, parallels the in vivo susceptibility of the CD4+ T cell to Fas-mediated apoptosis, and correlates with clinical markers of AIDS pathogenesis and response to HAART.

Anti-HIV Agents↗
PubMed1999

Immunogenicity of three Haemophilus influenzae type b protein conjugate vaccines in HIV seropositive adults and analysis of predictors of vaccine response.

HIV-seropositive adults may be at increased risk of infection due to Haemophilus influenzae type b (Hib) as compared with HIV-seronegative adults. Protein conjugate vaccines have been demonstrated to induce protective levels of antibodies against Hib in immunocompetent infants and also in HIV-seropositive infants. In this study we determined the immunogenicity of three protein conjugate Hib vaccines (PRP-D, HbOC, HbNOMP) in 135 HIV-seropositive adults who received one dose of Hib vaccine. Anti-polyribosylribitol phosphate (PRP) antibodies were measured at 0, 1, 3 and 12 months postimmunization by the Farr method. We demonstrate that all three vaccines are highly immunogenic and result in protective (> 1.0 microg/ml) levels of antibody. Overall the anti-PRP antibody level was > 1.0 microg/ml in 26% of patients preimmunization, 91% at both 1 and 3 months, and 79% at 12 months postvaccination. Comparison of responses to the three vaccines over time demonstrated differences in the mean geometric anti-PRP antibody level at 1 month (p=0.03) and the 12 month time points (p=0.03) with lower geometric mean levels in the HbNOMP group, though baseline differences in groups limit the interpretation of these findings. In a univariate analysis of baseline characteristics which predicted poor vaccine response, low total IgG2 levels preimmunization predicted a poor antibody response at 1 month (p < 0.01) and at 12 months (p=0.05), while low CD4 T-cell count predicted poor response at 12 months (p < 0.01). We conclude that all three US licensed protein conjugate Hib vaccines are immunogenic in HIV-seropositive adults, and that baseline CD4 T-cell count and IgG2 levels predict the likelihood of antibody response to vaccine.

Adult↗
PubMed1999

Human herpesvirus 6 seronegativity before transplantation predicts the occurrence of fungal infection in liver transplant recipients.

BACKGROUND: Invasive fungal infection has a major impact on the morbidity and mortality of liver transplant recipients. Human herpesvirus (HHV)-6 infection after transplantation is associated with an immunosuppressive state and the development of cytomegalovirus disease. Because cytomegalovirus infection is a risk factor for invasive fungal infection after transplantation, we have examined whether HHV-6 and fungal infection are associated after transplantation. METHODS: Pretransplantation sera from 247 consecutive liver transplant recipients were analyzed for IgG to HHV-6. Thirty-three (13%) HHV-6-seronegative recipients were identified. Six of 33 (18%) seronegative recipients experienced fungal infection as compared with 15 of 214 (7%) seropositive recipients (P=0.034). RESULTS: In a univariate analysis of risk factors for fungal infection, pretransplantation seronegativity to HHV-6 (P=0.034), intraoperative cryoprecipitate requirements greater than the 75th percentile (P=0.035), reoperation (P=0.005), biliary stricturing postoperatively (P=0.046), and gastrointestinal or vascular complications postoperatively (P=0.030) were identified as significant risk factors. Moreover, in pairwise multivariate analysis, pretransplantation HHV-6 seronegativity remained a significant variable even in the presence of each of the other variables. CONCLUSIONS: These results suggest that HHV-6 seronegativity before transplantation is a valuable clinical marker that identifies patients at risk for developing fungal infection after transplantation.

Disease-Free Survival↗
PubMed1999

Human herpesvirus 6.

Human herpesvirus (HHV) 6 is a beta-herpes, DNA virus. This virus shows closest homology with cytomegalovirus and HHV-7. Infection usually occurs in infants 6 to 24 months of age, and primary infection may result in roseola. HHV-6 infection in infants is the commonest cause of fever-induced seizures. Infection in adults is seen primarily in immunocompromised hosts with solid organ transplants or in those with human immunodeficiency virus infection. The virus is capable of pronounced interaction in vitro with cytomegalovirus and human immunodeficiency virus and induces immunosuppression and apoptosis. The importance of these interactions in vivo necessitates further investigation. HHV-6 infection may contribute to the pathogenesis of multiple sclerosis. HHV-6 may be diagnosed by viral culture, serology, or polymerase chain reaction.

Herpesviridae Infections↗