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K Marsh

Publications and source records attributed to K Marsh.

At least 109 records · Page 6Linked to original sources
PubMed1997

Limited spatial clustering of individual Plasmodium falciparum alleles in field isolates from coastal Kenya.

We describe Plasmodium falciparum genetic diversity in coastal Kenya, typing S-antigen and the merozoite surface proteins 1 and 2 (MSP-1 and MSP-2) in field isolates by the polymerase chain reaction (PCR). Malaria in coastal Kenya is characterized by low seasonal transmission, and a relatively high incidence of severe disease, which tends to occur in time-space clusters. We chose the highly polymorphic S-antigen as a marker for localized parasite diversity because it has been shown to vary in serotype prevalence in time and space. A total of 261 children (up to nine years of age) in two neighboring locations with different transmission rates were sampled for blood-stage parasites in cross-sectional surveys before and after the main transmission period in 1991, and also in a concomitant one-year longitudinal survey tracing clinical infections. Six major sequence types of S-antigen were identified, which were subdivided into 70 alleles; however, only 50% of isolates were typeable. The S-antigen sequence types varied qualitatively between locations, over time, and between asymptomatic and clinical disease infections, but not between different age groups. The MSP-1 and MSP-2 sequence type prevalences, in contrast, did not differ in any of these comparisons. We describe the use of the Mantel test for assessing clustering of individual parasite alleles at the household level, and demonstrate low-level clustering of MSP-1 and MSP-2 alleles and S-antigen sequence types, at the end of a long period of low transmission.

Age Factors↗
PubMed1997

Receptor-specific adhesion and clinical disease in Plasmodium falciparum.

One important factor in the virulence of infections with Plasmodium falciparum is the adherence of infected erythrocytes to small vessel endothelium. In infections that lead to serious, life-threatening disease accumulation of large numbers of infected cells in particular organs is thought to lead to organ dysfunction or failure. This is of particular relevance when the affected organ is the brain, leading to the development of cerebral malaria. Many different endothelial receptors for infected red blood cells have been identified. Some receptors such as CD36 and thrombospondin are used by all parasite isolates, whereas others such as intercellular adhesion molecule-1 (ICAM-1) or vascular cell adhesion molecule (VCAM) are used by a subset of field and laboratory isolates. While it has been speculated that the ability to bind or affinity of binding to a particular endothelial receptor may be related to the pattern of disease, only studies with limited numbers of patients have been carried out to date and these have been in general inconclusive. Here we have taken parasite isolates from 150 patients with defined clinical syndromes as well as isolates from 50 healthy but parasitized community controls and quantitatively assessed their binding to purified endothelial receptors in vitro. Our results show that disregarding the level of adhesion, all parasites bind to CD36, most bind to ICAM-1, few bind to VCAM, and almost none bind to E-selectin. In assessing the degree of binding we show that 1) binding to all receptors was reduced in parasites taken from severely anemic patients; 2) binding to CD36 is identical in parasites from cerebral malaria patients and community controls but slightly elevated in parasites from nonsevere cases; and 3) binding to ICAM-1 is highest in cerebral malaria patients. Because rosette formation by uninfected cells has also been a phenotype associated with disease severity and one that may interfere in vitro with receptor binding, we also assessed rosette formation in all isolates. In this study the highest level of rosette-forming parasites was found in the anemic group and not the cerebral malaria group. Stratifying the data for the frequency of rosette formation showed that the above results were not significantly altered by this phenomenon. Our data are not consistent with a role for binding to CD36 in the development of severe disease but show an association between the degree of binding to ICAM-1 and clinical illness in nonanemic patients.

Anemia↗
PubMed1996

Synthesis and structure-activity relationships of 2-pyridones: a novel series of potent DNA gyrase inhibitors as antibacterial agents.

Two novel series of 2-pyridones were synthesized by transposition of the nitrogen of 4-quinolones to the bridgehead position. This subtle interchange of the nitrogen atom with a carbon atom yielded two novel heterocyclic nuclei, pyrido[1,2-alpha]pyrimidine and quinolizine, which had not previously been evaluated as antibacterial agents and were found to be potent inhibitors of DNA gyrase. Quinolizines with a methyl group at the 9-position such as (S)-45a (ABT-719) demonstrate exceptional broad spectrum antibacterial activity. Most notably, they are active against resistant bacteria such as methicillin-resistant Staphylococcus aureus, vancomycin-resistant strains of enterococci, and ciprofloxacin-resistant organisms. In addition, 2-pyridones also possess favorable physiochemical and pharmacokinetic properties. These 2-pyridones were synthesized from the commercially available starting materials by 10-17 linear transformations. The structure of an adduct yielded by this sequence, (S)-45a (ABT-719), was determined by X-ray crystallographic analysis.

Animals↗
PubMed1996

Chronic salicylate poisoning and severe malaria.

BACKGROUND Salicylates continue to be marketed and to be used in developing countries as over-the-counter (OTC) antipyretics in children, whereas in developed countries they are no longer used in children because of safety concerns. The presenting signs of salicylate poisoning, especially chronic (repeated administration of therapeutic or excessive doses for longer than 12 h), can include metabolic acidosis, hypoglycaemia, lethargy, and coma and fits. These signs are also common in severe malaria in African children. Admission of two probable cases of chronic salicylate poisoning prompted us to look for other cases among children presenting to our hospital in Kenya, apparently with severe malaria. METHODS All children admitted to Kilifi District Hospital between July and September, 1994, who had a positive blood film for Plasmodium falciparum, and one or more of coma, prostration, or respiratory distress were eligible. As well as routine tests for malaria and routine biochemistry, salicylate concentrations were measured. Management of children (aged 6 months to 10 years) in the community was assessed by a cross-sectional survey of 463 households and by interviews with mothers 2 days after they had bought OTC drugs for a child with fever. FINDINGS Data were available for 143 of 154 children with initial primary diagnoses of severe malaria. 129 (90 percent) had detectable (>l mg/dL) salicylate. Six of these had salicylate concentrations of 20 mg/dL or higher. All six had neurological impairment and metabolic acidosis and four were, or became, hypoglycaemic. OTC drugs were the first-line treatment in 188 (74 percent) of 254 fever episodes during the 2 weeks before the cross-sectional survey. Of 250 mothers who bought drugs for a febrile child, 236 (94 percent) bought a preparation containing salicylates and 50 (21 percent) gave a dose higher than the manufacturer's recommended maximum. INTERPRETATION These cases suggest that in some children salicylate poisoning may cause or contribute to the development of metabolic acidosis and hypoglycaemia, complications of severe malaria associated with high mortality.

Acidosis↗
PubMed1996

Identification of arginine 331 as an important active site residue in the class II fructose-1,6-bisphosphate aldolase of Escherichia coli.

Treatment of the Class II fructose-1,6-bisphosphate aldolase of Escherichia coli with the arginine-specific alpha-dicarbonyl reagents, butanedione or phenylglyoxal, results in inactivation of the enzyme. The enzyme is protected from inactivation by the substrate, fructose 1,6-bisphosphate, or by inorganic phosphate. Modification with [7-14C] phenylglyoxal in the absence of substrate demonstrates that enzyme activity is abolished by the incorporation of approximately 2 moles of reagent per mole of enzyme. Sequence alignment of the eight known Class II FBP-aldolases shows that only one arginine residue is conserved in all the known sequences. This residue, Arg-331, was mutated to either alanine or glutamic acid. The mutant enzymes were much less susceptible to inactivation by phenylglyoxal. Measurement of the steady-state kinetic parameters revealed that mutation of Arg-331 dramatically increased the K(m) for fructose 1,6-bisphosphate. Comparatively small differences in the inhibitor constant Ki for dihydroxyacetone phosphate or its analogue, 2-phosphoglycolate, were found between the wild-type and mutant enzymes. In contrast, the mutation caused large changes in the kinetic parameters when glyceraldehyde 3-phosphate was used as an inhibitor. Kinetic analysis of the oxidation of the carbanionic aldolase-substrate intermediate of the reaction by hexacyanoferrate (III) revealed that the K(m) for dihydroxyacetone phosphate was again unaffected, whereas that for fructose 1,6-bisphosphate was dramatically increased. Taken together, these results show that Arg-331 is critically involved in the binding of fructose bisphosphate by the enzyme and demonstrate that it interacts with the C-6 phosphate group of the substrate.

Amino Acid Sequence↗
PubMed1996

Perturbations of cerebral hemodynamics in Kenyans with cerebral malaria.

The mechanisms of death and neurologic sequelae in African children with cerebral malaria are undetermined. Because pathologic features are confined to the cerebral vasculature, perturbations in cerebral hemodynamics may be responsible. We compared the transcranial Doppler findings in 50 children with cerebral malaria with those of 115 conscious Kenyan children. In addition, 10 children with cerebral malaria were studied during intracranial pressure monitoring and nine children were studied during the agonal stages. In the children with cerebral malaria, cerebral blood flow velocity was increased in 30%, usually associated with seizures. Of the 11 children who developed neurologic sequelae, six had sonographic abnormalities associated with lateralizing deficits, including four children with hemiparesis (in two children the contralateral middle cerebral artery could not be insonated and two had transient increases in blood flow velocity associated with seizures). In the children with severe intracranial hypertension, there was a significant linear relationship between the cerebral perfusion pressure and blood flow velocity, suggesting that autoregulation was impaired. Sonographic features of progressive intracranial hypertension, were observed in three children with cerebral malaria who died. Perturbations of cerebral hemodynamics are associated with a poor outcome in Kenyan children with cerebral malaria.

Blood Flow Velocity↗
PubMed1996

The pathogenesis of severe malaria in African children.

The pathogenesis of severe, Plasmodium falciparum malaria in African children is considered in the context of its two major clinical syndromes: malaria with respiratory distress; and malaria with neurological disturbance. Respiratory distress is an important prognostic marker in children with P. falciparum infections. In the majority of cases it reflects an underlying metabolic acidosis, usually associated with lactic acidaemia. Hypovolaemia and anaemia are important underlying factors. The syndrome of malaria with neurological impairment is not a homogenous condition. Four distinct groups of children fulfilling the WHO definition of cerebral malaria may be distinguished: (1) prolonged post-ictal state; (2) covert status epilepticus; (3) severe metabolic derangement (particularly hypoglycaemia and metabolic acidosis); and (4) children with a primary neurological syndrome. These distinctions are important from a therapeutic point of view, as well as for their implications for studies on underlying pathogenic factors. A simple framework is presented to summarize how three major processes, anaemia, the acute phase response and sequestration of infected cells, may interact to lead to reduced tissue oxygenation as a unifying process in the pathogenesis of both major clinical syndromes of severe malaria.

Acute Disease↗
PubMed1996

Seizures and status epilepticus in childhood cerebral malaria.

Prolonged, multiple seizures complicate a high proportion of cases of childhood cerebral malaria, and several studies have shown an association between these and neurological sequelae. We prospectively studied 65 patients (38 female) admitted to Kilifi Hospital in 1994. Electroencephalographic recordings (EEGs) were made at 12-hourly intervals, with continuous recordings made on a cerebral function analysing monitor (CFAM). Survivors were seen one month after discharge. Cerebral computerized tomography was performed on children with neurological sequelae. Sixty-two percent of patients had seizures following admission, of whom half had an episode of status epilepticus. Fifty-two percent of seizures were partial motor, 34% generalized tonic-clonic, and 14% partial with secondary generalization. In 22%, coma appeared to be due to a prolonged postictal state. Ten children had subtle motor seizures. Posterior parieto-temporal discharges were the most common EEG finding. Seven children died, eight developed neurological sequelae, and 50 (77%) recovered fully. Status epilepticus was associated with the development of neurological sequelae. Prolonged, multiple seizures may play an important part in the pathogenesis of coma in childhood cerebral malaria, and are likely to contribute to both the morbidity and mortality of this disease.

Brain↗
PubMed1996

Insecticide-treated bednets reduce mortality and severe morbidity from malaria among children on the Kenyan coast.

New tools to prevent malaria morbidity and mortality are needed to improve child survival in sub-Saharan Africa. Insecticide treated bednets (ITBN) have been shown, in one setting (The Gambia, West Africa), to reduce childhood mortality. To assess the impact of ITBN on child survival under different epidemiological and cultural conditions we conducted a community randomized, controlled trial of permethrin treated bednets (0.5 g/m2) among a rural population on the Kenyan Coast. Between 1991 and 1993 continuous community-based demographic surveillance linked to hospital-based in-patient surveillance identified all mortality and severe malaria morbidity events during a 2-year period among a population of over 11000 children under 5 years of age. In July 1993, 28 randomly selected communities were issued ITBN, instructed in their use and the nets re-impregnated every 6 months. The remaining 28 communities served as contemporaneous controls for the following 2 years, during which continuous demographic and hospital surveillance was maintained until the end of July 1995. The introduction of ITBN led to significant reductions in childhood mortality (PE 33%, CI 7-51%) and severe, life-threatening malaria among children aged 1-59 months (PE 44%, CI 19-62). These findings confirm the value of ITBN in improving child survival and provide the first evidence of their specific role in reducing severe morbidity from malaria.

Bedding and Linens↗
PubMed1996

Hyponatraemia and dehydration in severe malaria.

The prevalence and likely cause of hyponatraemia in severe childhood malaria were investigated. One hundred and thirty two children, 47 of whom had cerebral malaria, were prospectively recruited and serial simple indices of fluid and electrolyte balance and renal function monitored during admission. In 55%, hyponatraemia (sodium < 135 mmol/l) was present on admission. Hyponatraemia was pronounced (sodium < or = 130 mmol/l) in 21%, and these children gained less weight during admission (mean weight gain 2.4% v 4.3%) than children with a normal sodium (135-145 mmol/l). Overall, 31% of survivors were at least moderately dehydrated on admission (5% weight gain by discharge). These children had higher plasma urea concentrations on admission (6.1 v 4.5 mmol/l) and were more acidotic (mean base excess -12.1 v -8.0) than children who were not dehydrated. There were changes in simple indices of renal function between admission and discharge in children who survived (creatinine 65.7 v 37.9 mumol/l and urea 5.5 v 1.9 mmol/l). The results suggest that dehydration is common in severe childhood malaria, that it may contribute to mild impairment in renal function, and that hyponatraemic children are less water depleted, showing appropriate rather than inappropriate secretion of antidiuretic hormone.

Child, Preschool↗
PubMed1996

Deep breathing in children with severe malaria: indicator of metabolic acidosis and poor outcome.

Despite the frequent association of respiratory symptoms and signs with malarial morbidity and mortality in sub-Saharan Africa, the value of individual symptoms and signs has rarely been assessed. We have prospectively examined the association of individual clinical findings with the summary diagnosis of respiratory distress, outcome, and the presence of metabolic acidosis in children admitted with severe malaria to a Kenyan district hospital. Respiratory distress was present in 119 of the 350 children included in the study and in 23 of the 30 deaths (relative risk = 6.5, 95% confidence interval = 2.8-14.4). The features of a history of dyspnea, nasal flaring, and indrawing or deep breathing (Kussmaul's respiration) were individually most closely associated with the summary diagnosis of respiratory distress. Of these, deep breathing, which was sensitive (91%) and specific (83%) for the presence of severe metabolic acidosis (base excess < or = -12), is the best candidate sign to represent the prognostically important syndrome of malarial respiratory distress. Therefore, it warrants further prospective evaluation in different clinical settings and areas of different malaria endemicity.

Acidosis↗
PubMed1996

Transfusion for respiratory distress in life-threatening childhood malaria.

We have prospectively collected information during resuscitation in 24 children with life-threatening malaria. All had clinical respiratory distress and 16 were severely anemic (hemoglobin < or = 5 g/dL) on admission. Central venous pressure (CVP) measurements were normal (< or = 5 cm of water) prior to treatment but all had a metabolic acidosis. The geometric mean lactate level was significantly higher in children admitted with severe anemia than in those without severe anemia (11.2 mmol/l versus 4.2 mmol/l; P = 0.009). Hypovolemia (a CVP on admission < 0 cm of water) was associated, although not significantly, with a higher admission plasma creatinine concentration (94 mumol/l versus 64 mumol/l; P = 0.06) and probably contributed to the severely reduced creatinine clearances (0-39 ml/min/1.73 ml2) found in 12 of the 13 children in whom this was assessed in the first 24 hr. Treatment resulted in a rapid decrease in blood lactate in 16 of the 13 children in whom this was assessed in the first 24 hr. Treatment resulted in a rapid decrease in blood lactate in 16 of the 20 children transfused, which was most dramatic in severely anemic children, who were rapidly resuscitated. In nonanemic children, early and rapid administration of normal saline usually resulted in both metabolic and clinical improvement. However, in three children, two of whom died, acidosis persisted despite resuscitation. Metabolic acidosis often accounts for respiratory distress in life-threatening childhood malaria. Severe anemia and hypovolemia appear to play major roles in its pathogenesis, are readily treatable, and there appears to be little risk of congestive cardiac failure even with an aggressive approach to fluid replacement.

Acidosis↗
PubMed1996

Infant parasite rates and immunoglobulin M seroprevalence as a measure of exposure to Plasmodium falciparum during a randomized controlled trial of insecticide-treated bed nets on the Kenyan coast.

Repeated cross-sectional surveys among infants sleeping under insecticide-treated bed nets (ITBN) and contemporary control infants were used to estimate changes in Plasmodium falciparum exposure due to ITBN use on the Kenyan coast. Presence of P. falciparum parasites or total P. falciparum Immunoglobulin M (IgM) seropositivity were used independently and in combination in a constant risk catalytic conversion model to estimate the force of infection in ITBN and control communities. Such studies during infancy avoid problems of early saturation of prevalence due to high forces of infection and persistence of infection, minimize problems of self-treatment, and can be conducted among large populations covering a wide geographic area. These contrast previous parasitologic studies of ITBN among older children and the traditional entomologic studies of transmission that are logistically demanding. Our investigations demonstrated that parasite prevalence, IgM seropositivity, and the force of transmission were all significantly reduced by 50%. In addition, more infants under ITBN entered their second year of life without previous exposure to P. falciparum than control infants. These effects upon delayed acquisition of effective immunity require careful monitoring during future vector control programs using ITBN.

Age Factors↗
PubMed1995

Indicators of life-threatening malaria in African children.

BACKGROUND: About 90 percent of the deaths from malaria are in African children, but criteria to guide the recognition and management of severe malaria have not been validated in them. METHODS: We conducted a prospective study of all children admitted to the pediatric ward of a Kenyan district hospital with a primary diagnosis of malaria. We calculated the frequency and mortality rate for each of the clinical and laboratory criteria in the current World Health Organization (WHO) definition of severe malaria, and then used logistic-regression analysis to identify the variables with the greatest prognostic value. RESULTS: We studied 1844 children (mean age, 26.4 months) with a primary diagnosis of malaria. Not included were 18 children who died on arrival and 4 who died of other causes. The mortality rate was 3.5 percent (95 percent confidence interval, 2.7 to 4.3 percent), and 84 percent of the deaths occurred within 24 hours of admission. Logistic-regression analysis identified four key prognostic indicators: impaired consciousness (relative risk, 3.3; 95 percent confidence interval, 1.6 to 7.0), respiratory distress (relative risk, 3.9; 95 percent confidence interval, 2.0 to 7.7), hypoglycemia (relative risk, 3.3; 95 percent confidence interval, 1.6 to 6.7), and jaundice (relative risk, 2.6; 95 percent confidence interval, 1.1 to 6.3). Of the 64 children who died, 54 were among those with impaired consciousness (n = 336; case fatality rate, 11.9 percent) or respiratory distress (n = 251; case fatality rate, 13.9 percent), or both. Hence, this simple bedside index identified 84.4 percent of the fatal cases, as compared with the 79.7 percent identified by the current WHO criteria. CONCLUSIONS: In African children with malaria, the presence of impaired consciousness or respiratory distress can identify those at high risk for death.

Anemia↗
PubMed1995

Synthesis of 4"-deoxy motilides: identification of a potent and orally active prokinetic drug candidate.

As an approach to discovering highly potent motilides with oral activity, novel 4"-deoxy derivatives of 8,9-anhydroerythromycin 6,9-hemiacetal were designed, synthesized, and evaluated for their gastrointestinal prokinetic activities. These compounds were orders of magnitude more potent than their 4"-hydroxy analogs in inducing smooth muscle contractions in an in vitro rabbit duodenal assay. Removal of the 12-hydroxy group, which was aimed at improving oral bioavailability, also afforded further potentiation in in vitro activity, leading to the identification of 8,9-anhydro-4"-deoxy-3'-N-desmethyl-3'-N-ethylerythromycin B 6,9-hemiacetal (ABT-229) as a potential prokinetic drug. ABT-229 was > 300,000 times more potent than erythromycin in vitro and had 39% oral bioavailability in dog compared to its 4",12-dihydroxy congener (EM-523), which was only 400 times more potent than erythromycin and had relatively low (1.4%) oral bioavailability.

Administration, Oral↗