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Biomedical subjects

L Hviid

Publications and source records attributed to L Hviid.

At least 55 records · Page 3Linked to original sources
PubMed1997

Soluble haemoglobin is a marker of recent Plasmodium falciparum infections.

Monoclonal antibodies (Mab) were raised against haemoglobin (Hb) associated with Plasmodium falciparum protein and used to develop an ELISA, measuring circulating levels of released Hb. This assay was evaluated in different malaria patients in parallel with ELISA assays for C-reactive protein (CRP) and haptoglobin. Levels of Hb were negatively associated with levels of haptoglobin. Increased levels of serum Hb and CRP and decreased levels of haptoglobin were seen in Danish malaria patients. Consecutive studies showed that increased Hb levels were detectable 3-7 days after initiation of treatment probably because of drug induced destruction of infected erythrocytes. Increased levels of CRP were measured 0-3 days after initiation of treatment. The Hb assay was used in an epidemiological study of malaria in an area of Sudan with unstable malaria transmission. The proportion of Sudanese adults with detectable soluble Hb was higher in the rainy season with malaria transmission compared to the dry season. Hb levels in the rainy season were negatively associated with levels of haptoglobin. Most adults had increased levels of soluble Hb and decreased levels of haptoglobin 7 and 30 days after their treatment of P. falciparum malaria compared to the levels during acute disease. Thus, both soluble Hb and haptoglobin appear to be markers of recent P. falciparum infections. Very high levels of CRP protein were measured in some of the malaria patients at the day of treatment while lower levels were recorded 7 and 30 days after treatment. Soluble Hb levels were associated with malariometric parameters in a similar fashion to haptoglobin. The new Mab-based assay for measuring soluble Hb in the peripheral blood of malaria patients may be useful for future epidemiological studies of malaria.

Adult↗
PubMed1997

Reversible suppression of bone marrow response to erythropoietin in Plasmodium falciparum malaria.

To study the importance of bone marrow inhibition in the pathogenesis of malarial anaemia, haematological and parasitological parameters were followed in patients with acute malaria. Three patient categories were studied, severe malarial anaemia (SA), cerebral malaria (CM) and uncomplicated malaria (UM). Red cell distribution width (RDW) was used as a surrogate marker of release of young erythrocytes and reticulocytes. Initially RDW was low in all patients in spite of markedly increased concentrations of erythropoietin (EPO). 3 d after institution of treatment and coinciding with parasite clearance RDW increased dramatically, reaching the highest levels 1-2 weeks later. Although severe anaemia was corrected by blood transfusion during the first 3 d of treatment, the peak RDW correlated significantly with the initial EPO levels. This suggests that Plasmodium falciparum infection causes a rapidly reversible suppression of the bone marrow response to EPO. Furthermore, the inhibition of bone marrow response was a general finding irrespective of initial haemoglobin levels suggesting that the severity of anaemia depends upon the degree of peripheral erythrocyte destruction in patients with suppressed bone marrow response to EPO.

Antimalarials↗
PubMed1997

Antibody responses to Rhoptry-Associated Protein-1 (RAP-1) of Plasmodium falciparum parasites in humans from areas of different malaria endemicity.

Plasma IgM and IgG antibody reactivities against the recombinant Plasmodium falciparum protein, Rhoptry Associated Protein-1 (rRAP-1) were measured by ELISA in individuals from Sudan, Indonesia, Kenya and The Gambia living in areas of different malaria endemicity. IgG and IgM reactivities to rRAP-1 increased with malaria endemicity. IgG reactivities were associated with spleen rates in Indonesia with high malaria endemicity while IgM reactivities were associated with spleen rates in Kenya with low malaria endemicity. IgG and IgM reactivities to rRAP-1 increased during acute episodes of P. falciparum malaria in Sudanese adults and IgG reactivities remained high one month after treatment in all adults tested. Antibody reactivities to rRAP-1 in Gambian children in the dry season were higher in children with parasitaemia than in children without detectable parasitaemia. Antibody reactivities were not associated with protection against clinical episodes in the following rainy season but higher antibody reactivities were detectable at the end of the rainy season. There was no difference in antibody reactivity to rRAP-1 between Gambian children with mild or severe malaria.

Adolescent↗
PubMed1997

Interferon-gamma production by human T cells and natural killer cells in vitro in response to antigens from the two intracellular pathogens Mycobacterium tuberculosis and Leishmania major.

Acquired resistance to both mycobacteria and Leishmania is primarily mediated by interferon-gamma (IFN-gamma), which triggers mechanisms leading to the death of the microorganism in macrophages. In this study, cell activation and IFN-gamma production was investigated in human peripheral blood mononuclear cells (PBMC) from individuals previously sensitized to tuberculin and without known exposure to Leishmania parasites. Immune staining for intracellular IFN-gamma and surface markers allowed flow cytometric identification of the cellular sources of IFN-gamma in cell cultures incubated with purified protein derivative of tuberculin (PPD) and Leishmania antigens. It was found that IFN-gamma was produced in response to both PPD and Leishmania stimulant by T cells in the cultures. Activation of IFN-gamma producing natural killer (NK) cells was demonstrated only in some cultures, and only with concomitant T cell activation.

Adult↗
PubMed1997

Rapid reemergence of T cells into peripheral circulation following treatment of severe and uncomplicated Plasmodium falciparum malaria.

Frequencies and absolute numbers of peripheral T-cell subsets were monitored closely following acute Plasmodium falciparum malaria in 22 Ghanaian children from an area of hyperendemicity for seasonal malaria transmission. The children presented with cerebral or uncomplicated malaria (CM or UM, respectively) or with severe malarial anemia. For all patients the frequencies and absolute numbers of peripheral T cells were lower than normal during the acute stage of disease. This lowering was most pronounced in the CM group and least pronounced in the UM group. Of particular interest, the CM patients showed markedly reduced frequencies of CD4+ cells, the number of which also normalized slower than in the other clinical groups. In all patients, the T-cell frequencies gradually approached normal values after the initiation of therapy, whereas the absolute numbers rapidly reverted from lower than normal to higher than normal before returning to steady-state levels. Furthermore, the initially reduced T-cell surface density of the T-cell receptor/CD3 complex, which rapidly normalized, was a general finding for all three clinical groups, suggesting a state of peripheral T-cell hyporesponsiveness during acute malaria. The data presented suggest a rapid therapy-induced reemergence of T cells that had been temporarily removed from the peripheral circulation as a consequence of the malaria attack and that the degree of the disease-induced T-cell reallocation correlates with disease severity.

Anemia↗
PubMed1996

Antibody reactivities to glutamate-rich peptides of Plasmodium falciparum parasites in humans from areas of different malaria endemicity.

Synthetic P. falciparum peptides were evaluated as tools in epidemiological investigations of malaria. Plasma IgM and IgG antibody reactivities against synthetic peptides covering sequences of glutamate-rich protein (GLURP) and acidic-basic repeat antigen (ABRA) were measured by ELISA in individuals from malaria-endemic areas of Sudan, Indonesia and The Gambia to study antibody responses to these peptides in donors living in areas of different malaria endemicity. IgG and IgM reactivities to the peptides increased with malaria endemicity, although there were no differences in reactivities to the GLURP peptide between non-exposed donors and donors living in areas of low malaria endemicity. IgG reactivities to the GLURP peptide in Sudanese adults were high one month after treatment in all adults tested, while IgG reactivities to the ABRA peptide were infrequent. IgM responses to the peptides tested were shortlived in most patients. In Gambian children with malaria, IgM reactivities but not IgG antibody reactivities against the ABRA peptide were higher in those with mild malaria than in those with severe malaria. The peptides may be useful in future epidemiological studies, especially in areas of low malaria endemicity.

Adolescent↗
PubMed1996

The gamma/delta T-cell response to Plasmodium falciparum malaria in a population in which malaria is endemic.

Frequencies and absolute numbers of peripheral gamma/delta T cells have been reported to increase after episodes of Plasmodium falciparum malaria in adults with limited or no previous malaria exposure. In contrast, little is known about the gamma/delta T-cell response to malaria in children from areas where malaria is endemic, who bear the burden of malaria-related morbidity and mortality. We investigated the gamma/delta T-cell response in 19 Ghanaian children from an area of hyperendemic, seasonal malaria transmission. The children presented with cerebral malaria (n = 7), severe malarial anemia (n = 5), or uncomplicated malaria (n = 7) and were monitored from admission until 4 weeks later. We found no evidence of increased frequencies of gamma/delta T cells in any of the patient groups, whereas one adult expatriate studied in Ghana and three adults admitted to the hospital in Copenhagen, Denmark, all with uncomplicated, primary P. falciparum malaria, showed increased gamma/delta T-cell frequencies similar to those previously reported. All patients had lowered absolute numbers of peripheral gamma/delta T cells at admission, changing to increased numbers by days 7 to 14 and then returning to normal levels. The study raises questions regarding age and degree of previous exposure as determinants of malaria-induced gamma/delta T-cell responses.

Adult↗
PubMed1996

Detection of very low level Plasmodium falciparum infections using the nested polymerase chain reaction and a reassessment of the epidemiology of unstable malaria in Sudan.

We have used the nested polymerase chain reaction (PCR) to assay for low level Plasmodium falciparum infections that were below the threshold of detection of blood film examination. This revealed a substantial group of asymptomatic, submicroscopically patent infections within the population of a Sudanese village present throughout the year although clinical malaria episodes were almost entirely confined to the transmission season. In our September, January, April, and June surveys, the PCR-detected prevalences were 13%, 19%, 24%, and 19%, respectively. These figures reveal a much higher prevalence of dry season infection than previous microscopic surveys have indicated. Furthermore, 20% of a cohort of 79 individuals were healthy throughout the September to November transmission season but were PCR-positive for P. falciparum in a least one of a series of samples taken in the ensuing months. Levels of exposure to P. falciparum infection were therefore higher than was previously believed in this region, highlighting the fact that many individuals were infected but healthy for most of the year. The reservoir parasite population was thus larger and more stable than previously thought, a finding that is consistent with the high levels of genetic variation at polymorphic loci reported from analysis of P. falciparum parasites in this area.

Adolescent↗
PubMed1995

High proportion of subclinical Plasmodium falciparum infections in an area of seasonal and unstable malaria in Sudan.

In the present longitudinal study, a cohort (n = 98) of children and adults 5-30 years of age living in an area of highly seasonal and unstable malaria transmission were followed for malaria morbidity during several successive transmission seasons. Based on morbidity surveillance during 1993 and measurements of antibody titers to the Plasmodium falciparum ring-infected erythrocyte surface antigen (Pf155/RESA), the cohort was divided into three groups: those who had at least one episode of clinical malaria (Group 1, n = 31), those who did not suffer from clinical malaria but had (Group 2, n = 63) or had not (Group 3, n = 4) a significant increase in antibody titers against the Pf155/RESA antigen. This increase was defined as equal to or greater than a four-fold increase in antibody titer in samples from same individuals taken at the beginning and the end of the malaria transmission season. Such increases in specific antibody levels suggested that the donors had been exposed to a P. falciparum blood-stage infection. Measurements of antibody titers to a peptide derived from the glutamate-rich protein exoantigen gave data parallel to those for Pf155/RESA. A surprisingly high fraction of individuals in the study cohort (approximately 66%) showed evidence of infection without ensuing clinical disease (Group 2).

Adolescent↗
PubMed1994

The major surface glycoprotein (gp63) from Leishmania major and Leishmania donovani cleaves CD4 molecules on human T cells.

The effect of Leishmania major and L. donovani surface protease gp63 on surface markers on human T cells was studied using fluorescence-activated flow cytometry. Purified gp63 (63,000 m.w. glycoprotein) at concentrations above 10 micrograms/ml completely inhibited binding of six different anti-CD4 Abs to human T cells, whereas the binding of one Ab, OKT4, was not inhibited. Heat inactivation of the protease before the incubation with cells abolished the effect on binding of anti-CD4 Abs. Cells incubated for 2 h with the protease and subsequently washed free of the protease showed a gradual re-expression of CD4, reaching 50% of the initial level after 72 h of incubation in medium. Preincubation of cells with live promastigotes showed an inhibitory effect on CD4 comparable to that seen with purified gp63. The binding of Abs directed against other surface markers present on human T-cells--CD2, CD3, CD5, CD8, CD11A, CD25, CD45RO, CD45RA, CD58, TCR-alpha, TCR-gamma, and HLA DQ--was not inhibited by gp63. These data suggest that gp63, both in its purified form and in the form anchored to the parasite membrane, cleaves CD4 on human T cells. The cleavage of CD4 by the protease might play a role in interfering with the induction of the immune response and thus disease progression in Leishmania infections.

Animals↗
PubMed1994

Differential T-cell expression of LFA-1 in residents from Africa and Denmark. Description of the phenomenon and its possible basis.

All circulating T cells constitutively express the adhesion molecule leukocyte function-associated antigen 1 (LFA-1; CD11a/CD18) at either low or high surface density. In the present paper we have compared the expression of the LFA-1 alpha-chain CD11a on peripheral T cells obtained from indigenous Africans with permanent residence in Africa to T cells from indigenous Danes with permanent residence in Denmark. The Africans had a higher percentage of T cells with high CD11a expression than did Danish donors. The difference was evident in both the CD3-, CD4+, and CD8+ subsets. The difference did not appear to reflect a higher degree of peripheral T-cell activation in the African donors, as T-cell expression of the activation marker IL-2 receptor (CD25) was similar in the two groups. Furthermore, we observed no apparent correlation between CD3+ CD11a(hi) and CD3+ CD25+ values in individual donors. LFA-1 expression on T cells obtained from expatriate Africans with long-term residence in Denmark resembled that of Danish permanent residents more than that of Africans with permanent residence in Africa. In addition, T cells obtained from two expatriate Danes with long-term residence in rural Africa were phenotypically similar to those from African permanent residents. The data suggest that the observed difference is environmental rather than ethnic and may reflect the degree of exposure to infectious agents.

Africa↗
PubMed1994

Increased plasma levels of soluble IL-2R are associated with severe Plasmodium falciparum malaria.

Plasma samples from children with mild and severe Plasmodium falciparum malaria and from children with unrelated diseases were collected to investigate whether the clinical outcome of infection was associated with plasma factors which reflected the activity of different cells of the immune system. Children with severe P. falciparum malaria had significantly higher plasma levels of soluble IL-2R than children with mild malaria. Plasma levels of IL-2R and levels of parasitaemia were significantly correlated. Neither parasitaemia nor plasma levels of tumour necrosis factor-alpha (TNF-alpha), IL-6, lymphotoxin (LT), interferon-gamma (IFN-gamma), IL-4, soluble IL-4R or soluble CD8 differed significantly between the two groups of children with malaria. High plasma levels of soluble CD8 were associated with failure of lymphocytes to produce IFN-gamma in vitro following stimulation with P. falciparum antigen. We conclude that soluble IL-2R is a useful marker of disease severity independently of the association with levels of parasitaemia, and that functional regulation of different lymphocyte subsets occurs during acute malaria episodes.

CD8 Antigens↗
PubMed1994

Licochalcone A, a new antimalarial agent, inhibits in vitro growth of the human malaria parasite Plasmodium falciparum and protects mice from P. yoelii infection.

Licochalcone A, isolated from Chinese licorice roots, inhibited the in vitro growth of both chloroquine-susceptible (3D7) and chloroquine-resistant (Dd2) Plasmodium falciparum strains in a [3H]hypoxanthine uptake assay. The growth inhibition of the chloroquine-resistant strain by licochalcone A was similar to that of the chloroquine-susceptible strain. To examine the activity of licochalcone A on the different asexual blood stages of the parasite, licochalcone A was added to highly synchronized cultures containing rings, trophozoites, and schizonts. The growth of the parasites at all stages was inhibited by licochalcone A. The in vivo activity of licochalcone A was tested in a mouse model of infection with P. yoelii. Licochalcone A administered either intraperitoneally or orally for 3 to 6 days protected the mice from the otherwise lethal P. yoelii infection. These results demonstrate that licochalcone A exhibits potent antimalarial activity and might be developed into a new antimalarial drug.

Animals↗
PubMed1994

Evidence of endothelial inflammation, T cell activation, and T cell reallocation in uncomplicated Plasmodium falciparum malaria.

To explain the observation that acute Plasmodium falciparum malaria is associated with a transient inability of peripheral blood cells to respond to antigenic stimulation in vitro, we have postulated the disease-induced reallocation of peripheral lymphocytes, possibly by adhesion to inflamed endothelium. We measured plasma levels of soluble markers of endothelial inflammation and T cell activation in 32 patients suffering from acute, uncomplication P. falciparum malaria, as well as in 10 healthy, aparasitemic control donors. All donors were residents of a malaria-endemic area of Eastern State Sudan. In addition, we measured the T cell surface expression of the interleukin-2 receptor (CD25) and the lymphocyte function-associated antigen (LFA-1; CD11a/CD18). We found that the plasma levels of all inflammation and activation markers were significantly increased in the malaria patients compared with the control donors. In addition, we found a disease-induced depletion of T cells with high expression of the LFA-1 antigen, particularly in the CD4+ subset. The results obtained provide further support for the hypothesis of T cell reallocation to inflamed endothelium in acute P. falciparum malaria.

Adolescent↗
PubMed1994

Increased plasma concentrations of sICAM-1, sVCAM-1 and sELAM-1 in patients with Plasmodium falciparum or P. vivax malaria and association with disease severity.

Increased serum concentrations of soluble intercellular adhesion molecule-1 (sICAM-1), soluble endothelial leucocyte adhesion molecule-1 (sELAM-1) and soluble vascular cell adhesion molecule-1 (sVCAM-1) were detected in Danish malaria patients infected with sequestering Plasmodium falciparum or non-sequestering P. vivax parasites, as well as in patients with sepsis or meningitis. Levels of soluble adhesion molecules remained elevated in the P. falciparum patients for several weeks after initiation of treatment. Plasma concentrations of sICAM-1, sVCAM-1 and sELAM-1 were higher in Gambian children with severe P. falciparum malaria than in children with mild malaria. Plasma levels of sVCAM-1 and sELAM-1 were significantly correlated. Plasma levels of sELAM-1 and sVCAM-1 may reflect endothelial inflammatory reactions and these reactions may be harmful for humans infected with malaria parasites.

Adolescent↗
PubMed1993

A new portable device for automatic controlled-gradient cryopreservation of blood mononuclear cells.

Protection of the functional integrity of mononuclear cells stored in liquid N2 requires careful control of the freezing procedure. Consequently, optimal quality of cryopreserved cells is usually assured by freezing according to a specified time-temperature gradient generated by computer-controlled freezing devices. While such equipment offers large capacity and secures maximum survival and functional integrity of the lymphocytes upon thawing, it is quite costly and strictly stationary. We have previously developed and tested an alternative, manual device for controlled-gradient lymphocyte freezing, which has proved suitable for field conditions. We report here the development and testing of a similar micro-controller regulated device, allowing unattended and automatic controlled-gradient cell freezing. The equipment exploits the temperature gradient present between the liquid N2 surface and the neck in an ordinary liquid N2 refrigerator. The lymphocyte samples are placed in a small elevator, which is moved through the N2 gas phase by a stepper motor. Time and temperature are measured at regular intervals, and the position of the samples adjusted to ensure that the actual measurements closely match encoded ideal values. Results of assays of the functional integrity and phenotypic composition of human mononuclear cells frozen by the new system were comparable to those obtained when using cells frozen by a commercially available, stationary cell-freezing equipment, or fresh autologous cell samples tested in parallel. Furthermore, there was a good correlation between functional and phenotypic data obtained using frozen and autologous fresh samples of mononuclear cells. The equipment described is low weight and has low N2 consumption, and is thus suitable for the collection and cryopreservation of lymphocytes under field conditions. Furthermore, the technique provides an inexpensive alternative for researchers with a limited requirement for the simultaneous freezing of large quantities of cells.

Blood Preservation↗
PubMed1993

Increased plasma levels of soluble ICAM-1 and ELAM-1 (E-selectin) during acute Plasmodium falciparum malaria.

Acute P. falciparum malaria is associated with a loss of antigen-responsiveness of peripheral T cells, depletion of T cells characterized by high surface expression of the adhesion molecule LFA-1, and increased plasma levels of the T-cell activation marker soluble IL-2 receptor (sIL-2R). In the present study we show that clinical episodes of P. falciparum malaria produced an increase in plasma levels of soluble ICAM-1 (sICAM-1) and ELAM-1 (sELAM-1). The increase was transient and subsided slowly (sICAM-1) or rapidly (sELAM-1) following drug cure. The increases in plasma sICAM-1 and sELAM-1 were significantly correlated, and were furthermore associated with a concomitant increase in plasma levels of sIL-2R. Finally, plasma levels of sICAM-1, but not sELAM-1, were inversely correlated to the fraction of peripheral T cells having high surface expression of LFA-1, the receptor for T-cell adhesion to ICAM-1. Taken together, these observations suggest that acute P. falciparum malaria is characterized by a state of endothelial inflammation associated with the adherence of activated T cells.

Acute Disease↗