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Biomedical subjects

Stephen D Lawn

Publications and source records attributed to Stephen D Lawn.

At least 37 records · Page 2Linked to original sources
PubMed2005

Electrocardiographic and biochemical adverse effects of sodium stibogluconate during treatment of cutaneous and mucosal leishmaniasis among returned travellers.

Use of parenteral pentavalent antimonials to treat leishmaniasis is associated with a range of cardiological, biochemical and haematological adverse effects. The most serious of these is the development of ventricular tachyarrhythmias associated with prolongation of the electrocardiographic rate-corrected QT interval (QTc). Whereas some studies have reported that serious cardiological and biochemical adverse effects are common and often require treatment interruption or discontinuation, others have reported the drugs to be well tolerated. We conducted a detailed retrospective analysis of adverse events among British returned travellers (n=65) with New World cutaneous or mucosal leishmaniasis who received i.v. sodium stibogluconate (SbV) for >or=21 days. The mean+/-SEM QTc progressively increased from 389+/-3.1 msec to 404+/-2.9 msec during 3 weeks of treatment and the QTc reached the threshold for potential cardiac toxicity among 6 (10%) patients during the third week of treatment. Marked QTc prolongation and ventricular tachyarrhythmias occurred in one elderly patient with hypokalaemia and pre-existing cardiovascular morbidity. Although increased serum concentrations of amylase and hepatic transaminases were observed among 67% and 85% of patients respectively, none developed clinical pancreatitis or hepatitis and treatment modification was not required. SbV can be used safely in this population with adequate monitoring and the need for treatment interruption is uncommon. Identification of factors before and during treatment that may increase the risk of QTc prolongation and arrhythmias is important.

Adolescent↗
PubMed2005

How effectively does HAART restore immune responses to Mycobacterium tuberculosis? Implications for tuberculosis control.

Use of highly active antiretroviral treatment (HAART) has had a major impact on HIV-associated morbidity and mortality in industrialized countries. Access to HAART is now expanding in low-income countries where tuberculosis (TB) is the most important opportunistic disease. The incidence of TB has been fueled by the HIV epidemic and in many countries with high HIV prevalence current TB control measures are failing. HAART reduces the incidence of TB in treated cohorts by approximately 80% and therefore potentially has an important role in TB control in such countries. However, despite the huge beneficial effect of HAART, rates of TB among treated patients nevertheless remain persistently higher than among HIV-negative individuals. This observation raises the important question as to whether immune responses to Mycobacterium tuberculosis (MTB) are completely or only partially restored during HAART. Current data suggest that full restoration of circulating CD4 cell numbers occurs only among a minority of patients and that, even among these, phenotypic abnormalities and functional defects in lymphocyte subsets often persist. Suboptimal restoration of MTB-specific immune responses may greatly reduce the extent to which HAART is able to contribute to TB control at the community level because patients receiving HAART live much longer and yet would maintain a chronically heightened risk of TB.

AIDS-Related Opportunistic Infections↗
PubMed2005

Immune reconstitution disease associated with mycobacterial infections in HIV-infected individuals receiving antiretrovirals.

Immune reconstitution disease (IRD) in HIV-infected patients is an adverse consequence of the restoration of pathogen-specific immune responses during the initial months of highly active antiretroviral treatment (HAART). Previously subclinical infections are "unmasked" or pre-existing opportunistic infections clinically deteriorate as host immunopathological inflammatory responses are "switched on". IRD is most frequently associated with mycobacterial infections. Our literature search identified 166 published cases of IRD associated with mycobacterial infections. We review the underlying immunological mechanisms, difficulties surrounding case definition and diagnosis, the wide diversity of clinical manifestations, and treatment. The importance of screening patients for mycobacterial disease before starting HAART and the critical impact of the timing of commencement of HAART in patients receiving treatment for tuberculosis are highlighted. We also discuss the problem of IRD associated with mycobacterial diseases in developing countries where tuberculosis prevalence is high and access to HAART is currently expanding.

AIDS-Related Opportunistic Infections↗
PubMed2004

Human cystic echinococcosis: evaluation of post-treatment serologic follow-up by IgG subclass antibody detection.

Assessment of post-treatment disease activity among patients with cystic echinococcosis (CE) is insensitive using detection of CE-specific total IgG antibody. This study investigated whether serum concentrations of CE-specific IgG subclasses 1-4 correlate better with disease activity than total IgG. We studied a cohort of patients (n = 28) with symptomatic CE treated with anthelminthic drugs and surgery and who were followed up clinically and radiologically for a mean of 5.6 years (range = 3-12 years). Serial archived sera collected during follow-up were retrospectively analyzed by enzyme-linked immunosorbent assays using crude horse hydatid cyst fluid as antigen. Changes in concentrations of antibodies were correlated with clinical and radiologic outcome. At diagnosis, concentrations of CE-specific total IgG, IgG1, and IgG2 antibodies were significantly elevated in a greater proportion of patients compared with IgG3 and IgG4 antibodies. During post-treatment follow up, the IgG2 antibody response provided the best correlate of disease activity.

Adult↗
PubMed2003

Soluble forms of Toll-like receptor (TLR)2 capable of modulating TLR2 signaling are present in human plasma and breast milk.

Dysregulation of the initial, innate immune response to bacterial infection may lead to septic shock and death. Toll-like receptors (TLRs) play a crucial role in this innate immune response, and yet the regulatory mechanisms controlling microbial-induced TLR triggering are still to be fully understood. We have therefore sought specific regulatory mechanisms that may modulate TLR signaling. In this study, we tested for the possible existence of a functionally active soluble form of TLR2. We demonstrated the existence of natural soluble forms of TLR2 (sTLR2), which we show to be capable of modulating cell activation. We found that blood monocytes released sTLR2 constitutively and that the kinetics of sTLR2 release increased upon cell activation. Analysis of cells expressing the human TLR2 cDNA or its c-myc-tagged version indicated that sTLR2 resulted from the posttranslational modification of the TLR2 protein in an intracellular compartment. Moreover, an intracellular pool of sTLR2 is maintained. sTLR2 was found naturally expressed in breast milk and plasma. Milk sTLR2 levels mirrored those of the TLR coreceptor soluble CD14. Depletion of sTLR2 from serum resulted in an increased cellular response to bacterial lipopeptide. Notably, serum sTLR2 was lower in tuberculosis patients. Coimmunoprecipitation experiments and computational molecular docking studies showed an interaction between sTLR2 and soluble CD14 in plasma and milk. These findings suggest the existence of a novel and specific innate immune mechanism regulating microbial-induced TLR triggering, and may lead to new therapeutics for the prevention and/or treatment of severe infectious diseases.

Amino Acid Sequence↗
PubMed2003

Dengue hemorrhagic fever with fulminant hepatic failure in an immigrant returning to Bangladesh.

An immigrant from Bangladesh living in the United Kingdom presented with a nonspecific febrile illness after visiting his homeland and subsequently developed fulminant hepatic failure accompanied by hypotension, ascites, a generalized coagulopathy, and thrombocytopenia. Serology and detection of dengue virus serotype 3 by PCR established a postmortem diagnosis of hepatic failure secondary to dengue hemorrhagic fever.

Ascites↗
PubMed2002

Postmalaria neurological syndrome: two cases from the Gambia.

We describe 2 patients with severe Plasmodium falciparum malaria whose convalescence was complicated by fever, with acute confusion and acalculia in one patient and a triad of myoclonus, tremor, and dysphasia in the other. Inflammatory changes were found in cerebrospinal fluid samples. Postmalaria neurological syndrome was diagnosed in each patient, and a therapeutic response to oral corticosteroids was seen in the second patient.

Adrenal Cortex Hormones↗
PubMed2002

Immune activation and induction of HIV-1 replication within CD14 macrophages during acute Plasmodium falciparum malaria coinfection.

OBJECTIVES: To determine the impact of Plasmodium falciparum malaria coinfection and its treatment on cellular reservoirs of viral replication in HIV-1-infected persons and to relate this to changes in systemic immune activation. METHODS: Plasma samples were obtained from HIV-1-infected individuals (n = 10) at diagnosis of acute malaria, 4 weeks after parasite clearance and from HIV-infected aparasitemic controls (n = 10). Immunomagnetic HIV-1 capture analysis was used to determine the cellular origin of cell-free virus particles present in all 30 plasma samples and indices of immune activation were measured using enzyme-linked immunosorbent assays. RESULTS: Compared with controls, the detectable proportion of HIV-1 particles derived from CD14 macrophages and CD26 lymphocytes was increased in persons with acute malaria coinfection and correlated with markedly increased plasma concentrations of both proinflammatory cytokines and soluble markers of macrophage and lymphocyte activation. Parasite clearance following treatment with antimalarial drugs resulted in decreased detection of HIV-1 particles derived from the CD14 macrophage cell subset and correlated with a marked diminution in systemic immune activation. CONCLUSIONS: Acute P. falciparum malaria coinfection impacts virus-host dynamics in HIV-1-infected persons at the cellular level, notably showing a reversible induction of HIV-1 replication in CD14 macrophages that is associated with changes in immune activation.

Animals↗
PubMed2002

Tuberculosis unleashed: the impact of human immunodeficiency virus infection on the host granulomatous response to Mycobacterium tuberculosis.

The granuloma plays a critical role in the host immune response to Mycobacterium tuberculosis, containing the organism and confining it in a latent state in most infected individuals. Indeed, approximately one-third of the world's population has latent M. tuberculosis infection. However, over the past decade, the human immunodeficiency virus type 1 (HIV-1) pandemic has profoundly affected the incidence and clinicopathological features of tuberculosis. This review examines the immunological mechanisms whereby HIV-1 impairs the establishment, maintenance and function of the tuberculous granuloma.

CD4-Positive T-Lymphocytes↗