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Biomedical subjects

D Kwiatkowski

Publications and source records attributed to D Kwiatkowski.

At least 109 records · Page 6Linked to original sources
PubMed1991

Periodic and chaotic host-parasite interactions in human malaria.

It has been recognized since ancient times that malaria fever is highly periodic but the mechanism has been poorly understood. Malaria fever is related to the parasite growth cycle in erythrocytes. After a fixed period of replication, a mature parasite (schizont) causes the infected erythrocyte to rupture, releasing progeny that quickly invade other erythrocytes. Simultaneous rupture of a large number of schizonts stimulates a host fever response. Febrile temperatures are damaging to Plasmodium falciparum, particularly in the second half of its 48-hr replicative cycle. Using a mathematical model, we show that these interactions naturally tend to generate periodic fever. The model predicts chaotic parasite population dynamics at high multiplication rates, consistent with the classical observation that P. falciparum causes less regular fever than other species of parasite.

Animals↗
PubMed1991

HLA class I typing by PCR: HLA-B27 and an African B27 subtype.

We describe a rapid method of HLA class I typing using the polymerase chain reaction and oligonucleotide hybridisation that eliminates the requirements for viable lymphocytes and allows subtypes to be defined. We have used this to demonstrate that the predominant subtype of HLA-B27 in the Gambia, West Africa, is HLA-B*2703, which is very rare or absent in other racial groups. This subtype differs from the common Caucasian HLA-B27 subtypes in its recognition by cytotoxic T cells. We propose that HLA*B-2703, unlike other HLA-B27 subtypes, may not be associated with ankylosing spondylitis, thus accounting in part for the rarity of this condition in black populations.

Adult↗
PubMed1991

Quantitative light and scanning electron microscopy of ferret sperm.

Sperm were obtained via electroejaculation from Domestic ferret, (Mustela putorius furo), Siberian ferret (M. eversmanni), Black-footed ferret (M. nigripes), and a hybrid between Siberian and Domestic, called the Fitch ferret (M. sp.). Comparisons of sperm were made by four different microscopy techniques to determine whether differences exist among species. First, Nomarski differential interference microscopy could be used to distinguish domestic ferret sperm from the others on the basis of the structure of the posterior part of the acrosome. Second, both silver staining, which demonstrates argentophilic protein distribution, and scanning electron microscopy (SEM), revealed differences among the morphology of sperm for each species; variation in the unique appearance of the acrosome in ferret sperm was detected especially well by SEM. To quantify differences in morphology, five sperm head parameters were measured using image analysis; light microscopy produced significantly larger values than did SEM (all parameters and all species but Fitch), and there were significant differences owing to species for all parameters but one. Generally, our data demonstrate the value of complementary techniques to distinguish among sperm of closely related species and more specifically may help establish evolutionary relationships among the ferret species studied. In addition, they provide baseline data important for the captive breeding of the endangered Black-footed ferret.

Acrosome↗
PubMed1991

Sequence analysis of HLA-Bw53, a common West African allele, suggests an origin by gene conversion of HLA-B35.

In the West African population of the Gambia the class I antigen HLA-Bw53 is found at high frequency. We used the polymerase chain reaction to amplify cDNA from an individual homozygous for this allele and determined the nucleotide sequence of the polymorphic alpha 1 and alpha 2 domains. The HLA-Bw53 sequence is identical to HLA-B35 except for a short sequence at the 3' end of exon 2 (encoding the alpha 1 domain) which specifies a Bw4 rather than a Bw6 motif. This suggests an origin for HLA-Bw53 involving a gene conversion of HLA-B35 by an allele containing this Bw4 sequence. The alpha 2 domain shared by HLA-Bw53, -B35, and -Bw58 is particularly common in sub-Saharan Africans.

Adult↗
PubMed1990

TNF concentration in fatal cerebral, non-fatal cerebral, and uncomplicated Plasmodium falciparum malaria.

Plasma levels of tumour necrosis factor (TNF) were significantly higher in 178 Gambian children with uncomplicated malaria due to Plasmodium falciparum than in 178 children with other illnesses. 110 children with cerebral malaria were studied shortly after admission to hospital; 28 subsequently died. Compared with the children with uncomplicated malaria, mean plasma TNF levels were twice as high in cerebral malaria survivors and ten times as high in the fatal cases. Although high TNF levels were associated with high parasitaemia and with hypoglycaemia, they predicted fatal outcome in cerebral malaria independently of parasitaemia and glucose concentrations. Concentrations of interleukin-1 alpha, but not interferon gamma, were also related to the severity of malaria. We conclude that increased TNF production is a normal host response to P falciparum infection, but that excessive levels of production may predispose to cerebral malaria and a fatal outcome.

Animals↗
PubMed1990

Neurological sequelae of cerebral malaria in children.

Out of 604 Gambian children admitted with falciparum malaria to one hospital between September and December, 1988, 308 had cerebral malaria and 203 were severely anaemic (haemoglobin less than 60 g/l). 14% of those with cerebral malaria died, as did 7.8% of those with severe anaemia. 32 (12%) of children surviving cerebral malaria had residual neurological deficit. 69 other children were admitted with clinical features strongly suggestive of cerebral malaria but with negative blood films; 16 of these died and 3 had residual neurological deficits. The commonest sequelae of cerebral malaria were hemiplegia (23 cases), cortical blindness (11), aphasia (9), and ataxia (6). Factors predisposing to sequelae included prolonged coma, protracted convulsions, severe anaemia, and a biphasic clinical course characterised by recovery of consciousness followed by recurrent convulsions and coma. At follow up 1-6 months later over half these children had made a full recovery, but a quarter were left with a major residual neurological deficit. Cerebral malaria in childhood may be an important cause of neurological handicap in the tropics.

Adolescent↗
PubMed1990

Tumour necrosis factor, fever and fatality in falciparum malaria.

In Gambian children with Plasmodium falciparum infection, uncomplicated malaria fever is associated with moderately elevated circulating tumour necrosis factor (TNF) levels. We review clinical and in vitro data suggesting that schizont rupture stimulates bursts of TNF production that mediate paroxysms of malaria fever, and that the fever could possibly be beneficial to the host. Mean plasma TNF levels are ten times higher in fatal cerebral malaria than in uncomplicated malaria, providing support for the hypothesis that excessive TNF production may contribute to the pathology of severe infection.

Animals↗
PubMed1990

Two soluble antigens of Plasmodium falciparum induce tumor necrosis factor release from macrophages.

The production of cytokines such as tumor necrosis factor (TNF) may contribute to the pathology of malaria. We showed previously that crude preparations of heat-stable exoantigens from parasite cultures induce the release of TNF in vitro and in vivo. When separated from the culture medium by affinity chromatography, in which immune immunoglobulin G was used as ligand, the mixture of exoantigens of Plasmodium falciparum retained the capacity to induce the secretion of TNF, both by human monocytes from Gambian children and by mouse macrophages. Two individual antigens, Ag1 and Ag7, further purified by affinity chromatography and identified by crossed immunoelectrophoresis, also stimulated TNF production by both types of cell but differed in other functional properties. Thus, the activity of Ag7, but not that of Ag1, was inhibited by polymyxin B, and antisera made against boiled exoantigens of the rodent parasite Plasmodium yoelii which blocked the ability of these antigens to induce the production of TNF also inhibited the activity of Ag7 without affecting Ag1. Since the prevalence of antibody against Ag7 in sera from children in endemic areas appears to correlate with the development of immunity against the manifestations of the disease, this antigen may be one cause of pathology, perhaps through its ability to induce the production of TNF. Its serological relationship with rodent exoantigens suggests that it might be a candidate for an anti-disease vaccine which has the advantage that its active moiety is not subject to significant antigen polymorphism.

Adult↗
PubMed1989

Open comparison of intramuscular chloroquine and quinine in children with severe chloroquine-sensitive falciparum malaria.

An open paired randomised comparison of intramuscular chloroquine (3.5 mg base/kg every 6 h) and intramuscular quinine (20 mg salt/kg followed by 10 mg/kg every 12 h) was carried out in 50 Gambian children with severe falciparum malaria. 8 children died, 6 from the quinine-treated and 2 from the chloroquine-treated group. Chloroquine reduced parasitaemia significantly more rapidly than did quinine, but other measures of the therapeutic response were similar in the two groups. Quinine injections were painful. These findings do not support the proposition that quinine is intrinsically superior to chloroquine in the treatment of severe drug-sensitive falciparum malaria.

Administration, Oral↗
PubMed1989

Febrile temperatures can synchronize the growth of Plasmodium falciparum in vitro.

To investigate the possibility that the host fever response in malaria may affect parasite development, we studied the effect of temperature on Plasmodium falciparum in erythrocytic culture in vitro. Growth was markedly suppressed at 40 degrees C compared with 37 degrees C, due to disruption of the second half of the 48-h erythrocytic cycle. However, young intraerythrocytic parasites, which are highly exposed to fever during natural infection, appeared to develop normally at 40 degrees C. Because of the differential temperature sensitivity within the erythrocytic cycle, asynchronous cultures could be synchronized by transient elevations of temperature. Pronounced synchronization was observed when cultures were exposed to periodic elevations of temperature that simulated the 48-h fever cycle of tertian malaria. These findings indicate that malaria fever might act to promote parasite synchronization in vivo.

Animals↗
PubMed1989

Why is malaria fever periodic? A hypothesis.

For poorly understood reasons, malaria parasites tend to develop in synchrony with each other in the asexual erythrocytic phase of infection, and this synchronization determines the periodic nature of malaria fever. There is evidence to suggest that fever might help to protect the host, while synchronization might provide counter-protection for the parasite. Dominic Kwiatkowski and Brian Greenwood propose that malaria fever may be of mutual benefit for parasite and host.

Journal Article↗
PubMed1989

Tumour necrosis factor production in Falciparum malaria and its association with schizont rupture.

To investigate the involvement of tumour necrosis factor (TNF) in human malaria, we studied TNF production in patients infected with Plasmodium falciparum, and in co-cultures of human mononuclear cells and malaria parasites in vitro. In the examined sample, plasma TNF levels of over 39 pg/ml were detected in the plasma of 59% of Gambian children with acute malaria, 17% of convalescents, 9% of children with mild infections other than malaria, and 7% of healthy Gambian adults. Mononuclear cells of acute malaria patients, when stimulated with endotoxin in vitro, secreted twice as much TNF as did those of convalescent individuals, and three times that of healthy adult controls. Erythrocytic cultures of P. falciparum stimulated increased TNF secretion by mononuclear cells from uninfected individuals, and a sharp rise in the rate of secretion occurred shortly after schizont rupture. We suggest that malaria fever is mediated, at least in part, through paroxysmal TNF release associated with schizont rupture.

Animals↗
PubMed1988

Interleukin-1 beta in human plasma: optimization of blood collection, plasma extraction, and radioimmunoassay methods.

Current immunoassays for interleukin-1 beta (IL-1 beta) are effective for analyzing fluids derived from cultured cells. However, IL-1 beta determinations in human plasma or serum samples are technically complicated by higher protein and lipid concentrations, physicochemical differences which exist between samples from healthy subjects and those experiencing acute phase responses, and by the fact that IL-1 beta can be produced and degraded in the blood collection tube after the sample is drawn. A simple chloroform extraction process has been developed which eliminates several of the interfering factors from plasma samples and increases the amount of IL-1 beta detected by radioimmunoassay and lymphocyte activation assay. In the radioimmunoassay, rabbit sera was found to influence the accuracy and variability of plasma measurements. Improvements in radioimmunoassay reagents and methods are reported which reduce this influence. Finally, different concentrations of IL-1 beta were measured depending on whether serum or plasma was tested. We propose that plasma samples collected with EDTA and aprotinin provide a better determination of free circulating IL-1 beta in vivo than serum samples, which may contain IL-1 beta secreted from blood leukocytes during the clotting process.

Acute-Phase Reaction↗
PubMed1976

A note on the effect of dithiothreitol (DTT) on the depolarization of isolated sympathetic ganglia by carbachol and bromo-acetylcholine.

The S-S reducing agent, dithiothreitol (DTT) altered the properties of nicotinic receptors in rat superior cervical ganglia such that (i) carbachol became less active as a depolarizing agent and (ii) bromo-acetylcholine produced an irreversible depolarization. The latter was temporarily annulled by hexamethonium (which retained antagonist properties), but returned when hexamethonium was removed. It is concluded that ganglionic nicotinic receptors might be quite similar to those for monoquaternary agonists in leech dorsal muscle.

Acetylcholine↗
PubMedDate not supplied

The pharmacokinetic properties of intramuscular quinine in Gambian children with severe falciparum malaria.

Plasma quinine concentrations were measured in 21 Gambian children with severe falciparum malaria after intramuscular administration of a 20 mg (salt) per kg loading dose of quinine dihydrochloride followed by 10 mg/kg at 12 h intervals. Quinine was well absorbed reaching mean peak concentrations of 15.6 (standard deviation [SD] 4.5) mg/litre in a median time of 3 h (range 1-6 h). A one compartment model was fitted to the plasma concentration-time profile. The mean estimated systemic clearance (Cl/F) was 0.89 (SD 0.81) ml/kg/min and the mean elimination half life was 18.8 (SD 8.0) h. Two patients, one of whom died, had low plasma quinine levels which remained below 10 mg/litre. Mean peak and trough plasma concentrations after subsequent intramuscular doses ranged between 11.1 and 15.1 mg/litre. In most cases this dose regimen provided a satisfactory profile of blood concentrations for the treatment of severe malaria in children.

Animals↗
PubMedDate not supplied

Lactic acidosis and hypoglycaemia in children with severe malaria: pathophysiological and prognostic significance.

Serial clinical and metabolic changes were monitored in 115 Gambian children (1.5-12 years old) with severe malaria. Fifty-three children (46%) had cerebral malaria (coma score < or = 2) and 21 (18%) died. Admission geometric mean venous blood lactate concentrations were almost twice as high in fatal cases as in survivors (7.1 mmol/L vs. 3.6 mmol/L; P < 0.001) and were correlated with levels of tumour necrosis factor (r = 0.42, n = 79; P < 0.0001) and interleukin 1-alpha (r = 0.6, n = 34; P < 0.0001). Admission blood venous glucose concentrations were lower in fatal cases than survivors (3.2 mmol/L, vs. 5.8 mmol/L; P < 0.0001). Treatment with quinine was associated with significantly more episodes of post-admission hypoglycaemia when compared with artemether or chloroquine. After treatment, lactate concentrations fell rapidly in survivors but fell only slightly, or rose, in fatal cases. Plasma cytokine levels fluctuated widely after admission. Sustained hyperlactataemia (raised lactate concentrations, 4 h after admission) proved to be the best overall prognostic indicator of outcome in this series. Lactic acidosis is an important cause of death in severe malaria.

Acidosis, Lactic↗