Search PubMed⌕ Search

Biomedical subjects

S Britton

Publications and source records attributed to S Britton.

At least 55 records · Page 3Linked to original sources
PubMed1999

Clinical presentation of onchocerciasis among indigenous and migrant farmers in southwest Ethiopia.

OBJECTIVE: To show the magnitude of the problem and give a systematic account of the clinical manifestations of onchocerciasis in a rain forest ecology in southwest Ethiopia. DESIGN: A cross sectional clinico-epidemiological study. SETTING: Teppi Health Centre and Endris-Goji Clinic, Ethiopia. SUBJECTS: Four hundred and twenty one individuals aged ten years and above. RESULTS: Eighty four per cent of the examined people had a macrofilarial load ranging from one to 855 microfilariae per mg of skin snip. If the presence of any of skin microfilaria, nodule and/or leopard skin were taken as diagnostic criteria, the overall prevalence rate of onchocerciasis would be 88%. However, if we strictly followed stringent diagnostic criteria such as presence of unprompted itching, nodule(s), microfilaraedermia and skin dermatitis, the prevalence rate of onchocerciasis would be 23% (98/421). Hanging or pendular scrotum, which has been rarely reported in Africa but not until now in Ethiopia, was found in 19% (46/246) of the male patients. There was neither negative nor positive correlation between microfilarial load and severity of clinical manifestations of the disease. CONCLUSION: Onchocerciasis has been found to be one of the major health problems in this community and its diagnosis should not be based on selected signs and symptoms such as nodules and leopard skin alone that could undermine the magnitude of the problem.

Adolescent↗
PubMed1998

Decrease in thymidylate kinase activity in peripheral blood mononuclear cells from HIV-infected individuals.

Nucleosides and nucleoside analogs are anabolised to their triphosphates by intracellular kinases. The anti-HIV analogue zidovudine (AZT) is phosphorylated by cytosolic thymidine kinase 1 (TK1), thymidylate kinase (dTMPK), and nucleoside diphosphate kinase. It is known that dTMPK is one of the rate-limiting steps in the activation of zidovudine. The activities of TK1, dTMPK, and deoxycytidine kinase (dCK) were determined in extracts of in vitro activated peripheral blood mononuclear cells from HIV-infected patients and healthy noninfected individuals. dTMPK activity was 10-fold lower and TK1 activity was five-fold lower in extracts from infected as compared to uninfected persons. Deoxycytidine kinase activities in the extracts from both groups were very similar. Differences in in vitro activation, as determined by flow cytometry, of the peripheral lymphocytes were not responsible for the decreased TK1 and dTMPK activities. A reduced level of intracellular azido-dideoxythymidinetriphosphate in activated mononuclear cells from HIV-infected patients was also observed. The low levels of TK1 and dTMPK in lymphocytes from HIV-infected patients may be related to the anergy phenomenon observed as a result of HIV infection. This effect should also be considered in the development of new anti-HIV drugs.

Cell Cycle↗
PubMed1998

A gene related to Caenorhabditis elegans spermatogenesis factor fer-1 is mutated in limb-girdle muscular dystrophy type 2B.

The limb-girdle muscular dystrophies are a genetically heterogeneous group of inherited progressive muscle disorders that affect mainly the proximal musculature, with evidence for at least three autosomal dominant and eight autosomal recessive loci. The latter mostly involve mutations in genes encoding components of the dystrophin-associated complex; another form is caused by mutations in the gene for the muscle-specific protease calpain 3. Using a positional cloning approach, we have identified the gene for a form of limb-girdle muscular dystrophy that we previously mapped to chromosome 2p13 (LGMD2B). This gene shows no homology to any known mammalian gene, but its predicted product is related to the C. elegans spermatogenesis factor fer-1. We have identified two homozygous frameshift mutations in this gene, resulting in muscular dystrophy of either proximal or distal onset in nine families. The proposed name 'dysferlin' combines the role of the gene in producing muscular dystrophy with its C. elegans homology.

Adolescent↗
PubMed1998

Live and killed human immunodeficiency virus type-1 increases the intracellular growth of Leishmania donovani in monocyte-derived cells.

We coincubated killed or live human immunodeficiency virus type-1 (HIV-1) with human monocyte-derived cells infected with Leishmania donovani and examined the effect of the virus preparations on the intracellular growth of the parasite. We found that there was significant enhancement (by a mean of 53%, p < 0.001) of intracellular L. donovani growth in the human monocytic leukaemia THP-1 cell line coincubated with killed HIV-1. Infection of peripheral blood monocyte-derived macrophages with live HIV-1 initiated after L. donovani infection led to an increase in intracellular parasites by an overall mean of 2.8% vs 4.9% (p < 0.01) at 2 and 5 d after HIV infection in L. donovani and L. donovani plus HIV-1 infected, respectively, and by an overall mean of 5.0% vs 13.3% (p < 0.001) at 5, 12 and 15 d after HIV-1 infection in L. donovani and L. donovani + HIV-1 infected, respectively. Further, L. donovani infection 2 d after infection with HIV-1 led to enhanced parasite growth (34.5%, p < 0.001) compared with cells infected with L. donovani alone (5.5%), and those where HIV-1 was added after L. donovani (18.1%). In all cases, HIV-1 from live and killed virus preparations led to decreased anti-leishmanial activity of the macrophages as evidenced by decreased control of intracellular multiplication. The findings may suggest a mechanism not requiring live virus to explain how HIV-1 coinfection may impair the control of intracellular Leishmania growth in individuals with pre-existing asymptomatic infection leading to the reactivation of the parasite. Moreover, patients with HIV-1 infection might be at increased risk of developing Leishmania infection.

Animals↗
PubMed1997

Leishmania aethiopica derived from diffuse leishmaniasis patients preferentially induce mRNA for interleukin-10 while those from localized leishmaniasis patients induce interferon-gamma.

Exposure of peripheral blood mononuclear cells to promastigotes of Leishmania aethiopica derived from patients with the self-limiting, localized form of the disease (local cutaneous leishmaniasis; LCL) preferentially induced mRNA for interferon (IFN)-gamma but little for interleukin (IL)-10. In contrast, stimulation of the same cells with promastigotes derived from patients with the persistent, disseminated form of the disease (diffuse cutaneous leishmaniasis; DCL) stimulated the expression of IL-10 rather than IFN-gamma. In general, parasites derived from LCL patients induced more expression of other cytokines tested, including IL-4, IL-6, and transforming growth factor-beta, although tumor necrosis factor-alpha was equivalent in cultures stimulated with LCL or DCL promastigotes. The results suggest that the antigen-specific immunosuppression observed in DCL patients and the resulting clinical picture could in part be due to the properties of the infecting parasite to induce more IL-10 than IFN-gamma.

Animals↗
PubMed1997

Differences in humoral responses to the p24 antigen between Ethiopian and Swedish human immunodeficiency virus type 1-infected patients may suggest influences from a T-helper 2-like phenotype.

The levels of human immunodeficiency virus type 1 p24 antibodies and p24 antigen among 256 Ethiopians and Africans and 86 Swedes were compared. The elevated levels of total anti-p24 immunoglobulin G (IgG) and anti-p24 IgG4 among the Ethiopian and African patients suggest influences from T-helper-cell type 2-like responses.

Black People↗
PubMed1996

A novel ribozyme target site located in the HIV-1 nef open reading frame.

We have tested the sequence UUC CAG UCA GAC CU, at position 9016--9029 within the HIV-1(SF2) nef open reading frame, for accessibility to antisense and hammerhead ribozyme attack. The accessibility was first studied using a phosphorothioate-modified 14-nt DNA oligo (complementary to the nef9016--9029 site). A dose-dependent repression of HIV-1(SF2) growth was observed in human peripheral blood mononuclear cells after exogenous administration of the oligo to the cell culture medium. A hammerhead ribozyme with a 6+7-nt antisense specificity for the nef9016--9029 site (hhRz.nef9016--9029) was constructed and transfected into the human T-cell line HUT78. Again, a dose-dependent repression of virus growth was observed when different individual clones expressing hhRz.nef9016--9029 were infected with HIV-1(SF2). A complete abrogation of virus production was observed after infection with a low (0.5 TCID50) HIV-1 titer. Increasing doses (2.5 and 12.5 TCID50) of HIV-1 virus yielded a low production (10(3)-fold reduced) of virus particles in most cases; but a complete, or close to complete, abrogation was observed even in individual cultures infected with the highest dose. Presence of proviral pol and gag sequences in hhRz.nef9016--9029-expressing HUT78 clones was assayed, using PCR. Interestingly, since no pol and gag PCR products could be detected, the results strongly indicated that the hammerhead ribozyme was already acting on the infecting HIV RNA before its reverse transcription and integration as proviral DNA. In summary, the results obtained in this study support the nef9016--9029 site as a strong new candidate for ribozymal gene therapy against HIV-1 infection.

Base Sequence↗
PubMed1996

Ivermectin-induced immunopotentiation in onchocerciasis: recognition of selected antigens following a single dose of ivermectin.

Onchocerciasis is associated with blindness and gross skin changes, believed to be a consequence of the immune response to antigens released from the offspring of the female worm of Onchocerca volvulus, the microfilariae (mf). An effective microfilaricidal drug is now available which quickly reduces the mf burden without affecting the adult worm. There exist foci in onchocerciasis endemic areas where some of the patients have many mf in their skin but relatively few clinical symptoms. This state of hyposensitivity is believed to be due to immunosuppression. The aim of this study was to address the question of the basis of, and the effect of ivermectin treatment on this immunosuppression. Female adult worms of O. volvulus were used as whole or fractionated antigens to stimulate peripheral blood mononuclear cells. Microfilariae are found in the reproduction tract of the female worms, and thus an antigen preparation of the female adult O. volvulus contains both exclusive adult antigens as well as antigens from microfilariae. Cells were obtained from onchocerciasis patients, individuals of similar socio-economic status living in the same Ghanaian village, but who showed no parasitological or clinical evidence of onchocerciasis (exposed endemic controls), healthy Ghanaians living in areas where transmission of onchocerciasis does not seem to occur (non-exposed endemic controls) and unexposed healthy Swedish donors. As a group, cells from onchocerciasis patients proliferated to a lesser degree than cells from the exposed endemic control and the non-exposed endemic control groups to the whole worm antigen, whereas the phytohaemagglutinin (PHA) response was strongest in the patients. Proliferative responses of above 1000 ct/min to fractions of the worm extract were only evident in the cells from a few individuals in each of the various groups. However, 28 days following ivermectin treatment, cells from all onchocerciasis patients were able to mount significantly enhanced proliferation to a fraction of approximately 96 kD (fraction 3), while only four of nine of this group showed an increased response to the whole worm antigen. The proportional increase in the response to the whole organism in these individuals was of a much lower magnitude than the increased response to fraction 3. The O. volvulus antigen-specific immunosuppression observed in these onchocerciasis patients appears to be due to suppressive antigens which have the capacity to mask the potential response to selected antigens of O. volvulus, and ivermectin treatment possibly modulates the immune response, allowing for stepwise recognition of such antigens. Since ivermectin treatment kills only the microfilariae and not the adult worm, the putative suppressive antigens would be expected to be from the microfilariae.

Adolescent↗
PubMed1995

Decreased thymidine kinase levels in peripheral blood cells from HIV-seropositive individuals: implications for zidovudine metabolism.

Azidothymidine (zidovudine, AZT) used for treatment of HIV infection blocks the viral reverse transcriptase after phosphorylation by cellular enzymes. The first step in this reaction is the formation of AZT monophosphate, primarily catalyzed by host cytoplasmatic thymidine kinase (TK1). The activity of TK1 was determined in extracts of PHA-stimulated peripheral blood mononuclear cells (PBMCs) from 20 healthy volunteers and 49 HIV-infected patients at different stages of disease. In both groups we found a large intra- and interindividual variation of TK activity. Because TK1 expression is cell cycle regulated the proportion of stimulated cells was determined in the samples and the median thymidine kinase activity calculated. It was 3.0 pmol/mg/min x % S phase in the HIV-seronegative group and 1.1 pmol/mg/min x % S phase in HIV-infected individuals. The difference in thymidine kinase activity is statistically significant (p = 0.0001). The concentration of TK1 protein in the same extracts was also determined by immunoblotting. A positive correlation (r = 0.74) was observed between TK activity and amount of TK1 protein. The reason for this downregulation of TK is still unknown but may be related to the anergy observed in lymphocytes from HIV-infected persons. The reduced capacity for intracellular phosphorylation of AZT in HIV-infected individuals may be an important factor in the emergence of clinical AZT resistance and should also be accounted for in testing AZT resistance in vitro with PBMCs from healthy blood donors.

Antiviral Agents↗
PubMed1994

HIV-1 inhibits Leishmania-induced cell proliferation but not production of interleukin-6 and tumour necrosis factor alpha.

The immune response of normal human peripheral blood mononuclear cells (PBMC) after stimulation with human immunodeficiency virus-1 (HIV-1) antigens plus Leishmania donovani promastigotes in vitro was investigated. HIV-1-antigen stimulation of PBMC did not induce the intracellular accumulation of interleukin-6 (IL-6), tumour necrosis factor-alpha (TNF-alpha), or interferon-gamma (IFN-gamma). However, cells stimulated with L. donovani antigens exhibited the production of IL-6 and TNF-alpha, but not IFN-gamma. Furthermore, co-stimulation of PBMC with HIV-1 antigen plus L. donovani resulted in the intracellular accumulation of IL-6 and TNF-alpha comparable to that of cells that were activated with L. donovani antigen alone. Heat-inactivated HIV-1 antigen did not appear to induce or suppress cytokine production by PBMC. However, the same HIV antigens did suppress L. donovani-induced proliferation as well as PPD-induced proliferation in a dose-dependent fashion. Elevated levels of serum cytokines have been demonstrated in patients with HIV infection indicating their role in the pathogenesis of HIV-associated immunosuppression. The results may partially support the idea that the abnormally increased cytokine levels in the sera of HIV-infected subjects is due to the various opportunistic pathogens that these patients contract, rather than a response to HIV antigens. As cytokines have been shown to up-regulate HIV replication, the data suggest a role for opportunistic infections in cytokine-induced transactivation of HIV-1 and disease progression.

AIDS-Related Opportunistic Infections↗