Paediatrics and Child Health

Permanent URI for this community

http://41.93.62.172:4000/handle/123456789/142

Browse

Now showing 1 - 20 of 31

Acute diarrhea in children less than five years of age: epidemiology of bacterial pathogens
(Journal of Microbiology and Infectious Diseases, 2020-12-15) Kalabamu, Florence S.; Mwaikambo, Esther D.
Objectives: Acute diarrhea is among the leading causes of mortality and morbidity worldwide. Bacteria tend to cause more fatal illnesses and complications such as septicemia and persistent diarrhea. This study aimed to determine the causes of acute diarrhea, laboratory and clinical predictors of bacterial causes, and antimicrobial resistance pattern among the isolates among children in Dar es salaam, Tanzania. Methods: A cross-sectional hospital-based study was conducted in Dar es salaam Hospitals from April 2015 to March 2016 among children below five years of age who presented with acute diarrhea. Demographic characteristics and results from stool specimen analysis, complete blood count,C-reactive protein and antimicrobial resistance results were recorded using a pre-structured clinical research form. Results: Among 200 children enrolled, viruses were identified in 149 (74.5%) of the cases. Bacterial pathogens were found in 15 (7.5%) cases only. Elevated stool red blood cell count, stool white blood cell count, and fever were highly associated with enteric bacterial pathogens (p<0.001, p=0.002 and p=0.04 respectively). Most of the bacterial isolates were resistant to Cotrimoxazole and erythromycin but highly sensitive to ciprofloxacin and Ceftriaxone. Conclusion: Fever, elevated stool leukocyte and elevated stool red blood cells are significant predictors of bacterial enteric pathogens in children with acute diarrhea. These parameters may guide clinicians in resource-limited settings in the diagnosis and management of acute diarrhea. Further studies should be conducted to determine local antimicrobial resistance patterns. J Microbiol Infect Dis 2020; 10(3):208-214. Keywords:Acute diarrhea, causes, predictors, antimicrobial resistance, children
Age-related susceptibility to severe malaria associated with galectin-2 in highland Papuans
(The Journal of infectious diseases, 2010) Mwaikambo, Esther D.
Background. Age and host genetics are important determinants of malaria severity. Lymphotoxin-α (LTα) has been associated with the development of cerebral malaria (CM) and other severe malaria (SM) syndromes. Mutations in genes regulating LTα production contribute to other acute vascular diseases and may contribute to malaria pathogenesis. Methods. We tested the association between rs7291467, a single-nucleotide polymorphism (SNP) in the LTαrelated gene encoding galectin-2 (LGALS2), disease severity, and function in a case-control study of ethnic Highland Papuan adults and children with SM (n=380) and asymptomatic malaria-exposed controls (n=356) originating from a non-malaria-endemic region but residing in a lowland malaria-endemic area of Papua, Indonesia. Results. The LGALS2 SNP showed a significant association with susceptibility to SM (including CM), in children (odds ratio, 2.02 [95% confidence interval, 1.14–3.57]) but not in adults. In SM, the C allele at rs7291467 was associated with enhanced galectin-2 transcript levels. In a separate group of Tanzanian children originating from a malaria-endemic region, we found preservation of the major ancestral LGALS2 allele and no association with susceptibility to CM. Conclusions. Results suggest differences in the inflammatory contribution to the development of SM between children and adults in the same population and potential differences between individuals originating from malariaendemic and non-malaria-endemic areas.
Arginine, nitric oxide, carbon monoxide, and endothelial function in severe malaria
(Current opinion in infectious diseases, 2008) Mwaikambo, Esther D.
Purpose of review Parasiticidal therapy of severe falciparum malaria improves outcome, but up to 30% of these patients die despite best therapy. Nitric oxide is protective against severe disease, and both nitric oxide and arginine (the substrate for nitric oxide synthase) are low in clinical malaria. Parasitized red blood cell interactions with endothelium are important in the pathophysiology of malaria. This review describes new information regarding nitric oxide, arginine, carbon monoxide, and endothelial function in malaria. Recent findings Low arginine, low nitric oxide production, and endothelial dysfunction are common in severe malaria. The degree of hypoargininemia and endothelial dysfunction (measured by reactive hyperemia peripheral artery tonometry) is proportional to parasite burden and severity of illness. Plasma arginase (an enzyme that catabolizes arginine) is elevated in severe malaria. Administering arginine intravenously reverses hypoargininemia and endothelial dysfunction. The cause(s) of hypoargininemia in malaria is unknown. Carbon monoxide (which shares certain functional properties with nitric oxide) protects against cerebral malaria in mice. Summary Replenishment of arginine and restoration of nitric oxide production in clinical malaria should diminish parasitized red blood cells adherence to endothelium and reduce the sequelae of these interactions (e.g., cerebral malaria). Arginine therapy given in addition to conventional antimalaria treatment may prove to be beneficial in severe malaria.
Cerebrospinal fluid pterins, pterin-dependent neurotransmitters, and mortality in pediatric cerebral malaria
(The Journal of Infectious Diseases, 2021-02-22) Kalabamu, Florence S.; Mwaikambo, Esther D.
Background Cerebral malaria (CM) pathogenesis remains incompletely understood. Having shownlow systemic levels of tetrahydrobiopterin (BH4), an enzymatic cofactor forneurotransmitter synthesis, we hypothesized that BH4and BH4-dependentneurotransmitters would likewise be low in cerebrospinal fluid (CSF) in CM. Methods We prospectively enrolled Tanzanian children with CM and children with nonmalariacentral nervous system conditions (NMCs). We measured CSF levels of BH4, neopterin,and BH4-dependent neurotransmittermetabolites, 3-O-methyldopa, homovanillic acid,and 5-hydroxyindoleacetate, and we derived age-adjusted z-scores using publishedreference ranges. Results Cerebrospinal fluid BH4was elevated in CM (n=49) compared with NMC (n=51) (z-score 0.75 vs−0.08;P<.001). Neopterin was increased in CM (z-score 4.05 vs 0.09;P<.001), and a cutoff at the upper limit of normal (60 nmol/L) was 100% sensitive forCM. Neurotransmitter metabolite levels were overall preserved. A higher CSFBH4/BH2ratio was associated with increased odds of survival (odds ratio, 2.94; 95%confidence interval, 1.03–8.33;P=.043). Conclusion Despite low systemic BH4, CSF BH4was elevated and associated with increased odds ofsurvival in CM. Coma in malaria is not explained by deficiency of BH4-dependentneurotransmitters. Elevated CSF neopterin was 100% sensitive for CM diagnosis andwarrants further assessment of its clinical utility for ruling out CM in malaria-endemicareas. Keywords: cerebralmalaria, neopterin, neurotransmitter, Palciparum, tetrahydrobiopterin
Clinical realities and moral dilemmas: Contrasting perspective from academic medicine in Kenya, Tanzania and America
(Daedalus, 1999) Mwaikambo, Esther D.
Physians in university hospitals in Africa face a funda mental moral crisis: hospitals are overwhelmed by pa tients dying from AIDS, and physicians have few re sources to respond. In such settings, not only do physicians face very specific moral dilemmas?how to ration scarce resources and acquire costly medications, how to inform families that a child is HIV positive?but the very moral foundations of medi cine as a scientific and caring profession are called into ques tion. Practicing medicine and training new physicians in such settings produce profound ethical dilemmas. On the surface, the situation in teaching hospitals in North America could hardly be more different. Resources for high technology medical practice are abundant, though not unlim ited. Physicians and medical students see a wide range of dis ease conditions and manage patients with diverse prognoses.Ethical dilemmas about when to provide or withhold care and how to involve patients in decision making are present, but at a different level.
Decreased Microvascular Function in Tanzanian Children With Severe and Uncomplicated Falciparum Malaria
(Open Forum Infectious Diseases, 2017) Kalabamu, Florence S.; Kalingonji, Ayam R.; Mwaikambo, Esther D.
Microvascular function and oxygen consumption affect oxygen homeostasis but have not been assessed in African children with malaria. Microvascular function in Tanzanian children with severe malaria (SM) or uncomplicated malaria were 39% and 72%, respectively, of controls (P < .001). Uncomplicated malaria (P = .04), not SM (P = .06), children had increased oxygen consumption compared with controls. A major pathogenic mechanism in severe falciparum malaria is microcirculatory obstruction due to parasite sequestration [1]. However, several studies suggest that sequestration alone may not impair microcirculatory flow in malaria [1–3]. The normal microvasculature matches oxygen delivery and demand, with a major mediator being nitric oxide (NO) [2, 4]. In malaria, NO pathway dysregulation impairs host NO production and bioavailability [5–8]. In Indonesian children, vascular NO and microvascular function was decreased in severe and uncomplicated falciparum malaria [3]. Oxygen demand may exacerbate tissue hypoxia and was increased in Indonesian adults and children with malaria [2, 3]. However, microvascular function and oxygen demand have not been assessed in African children, the group with the highest burden of malaria. We assessed skeletal muscle microvascular function and oxygen consumption in Tanzanian children with severe malaria (SM) or uncomplicated malaria (UM) and compared these to controls.
Decreased systemic tetrahydrobiopterin bioavailability and increased oxidized biopterins in children with cerebral malaria
(Nitric Oxide-Biology and Chemistry, 2014) Kalabamu, Florence S.; Mwaikambo, Esther D.
Background: Falciparum malaria causes over 600,000 deaths worldwide each year. Despite advances in anti-parasitic drug therapies, 10–20% of children treated for severe malaria die. We have previously documented that NO protects against development of severe malaria, and that NO levels are low in malaria patients. Tetrahydrobiopterin (BH4) is an enzyme cofactor required for NO synthase that converts L-arginine to NO. Low or absent BH4 results in superoxide (instead of NO) production by NOS, with a consequent increase in “oxidative stress.” Hypothesis: Systemic levels of BH4 are decreased in children with cerebral malaria, contributing to low NO bioavailability and increased severity of malaria. Objective: Determine systemic levels of BH4 in children with malaria. Methods: In an observational study in Tanzania, we measured urine levels of biopterin in its various redox states [fully reduced biopterin (BH4), and the oxidized metabolites dihydrobiopterin (BH2) and biopterin (B0)] in children with uncomplicated malaria (UM, n = 55), cerebral malaria (CM, n = 46), as well as control children with non-malaria central nervous system conditions (NMC, n = 48) and healthy control children (HC, n = 111). Urine was collected into dithioerythritol and diethylene triamine penta-acetic acid (DETAPAC). Pterins were measured by high-performance liquid chromatography using sequential electrochemical and fluorescence detection. Results: Urine BH4 concentrations [µmol/mmol creatinine; median (IQR)] in CM were significantly lower compared to those in children in each of the other three groups. Oxidized biopterins were increased, and the BH4:BH2 ratio was markedly reduced in CM. Blood mononuclear cell guanosine triphosphate cyclohydrolase I mRNA was not low in any of the groups compared to the HC children. In a multivariate logistic regression model, each unit decrease in urine BH4 was independently associated with a 3.85 (95% CI: 1.89–7.69) fold increase in odds of CM (p < 0.001). Conclusions: Low systemic BH4 levels and increased oxidized biopterins likely contribute to the low NO bioavailability observed in cerebral malaria. Adjunctive interventions to increase BH4 may reduce occurrence of severe falciparum malaria in children.
Effects of age and Parasitemia on Nitric Oxide production/ Leoukocyte Nitric Oxide Synthase type 2 expression in asymptomatic Malaria-exposed children
(The American journal of tropical medicine and hygiene, 1999) Mwaikambo, Esther D.
Age appears to influence not only the acquisition of clinical immunity to malaria but also the susceptibility to and clinical manifestations of severe malaria. Asymptomatic malaria-exposed Tanzanian children have high production of nitric oxide (NO) and universal expression of leukocyte NO synthase type 2 (NOS2), which may protect against disease. To determine the effects of age and parasitemia on NO production, we measured urine and plasma NO metabolites and leukocyte NOS2 expression in 45 fasting, asymptomatic, malaria-exposed children of different ages, stratifying parasitemia by thick film and polymerase chain reaction (PCR) analysis. Although NO production was significantly higher in thick film-positive children than in thick film-negative children, after adjusting for age and gender, we were unable to detect a difference in NO production in thick film-negative children between those who were PCR positive and PCR negative. The relationship between age and NO production was determined using a generalized additive model adjusted for the effects of gender and parasitemia. Production of NO using all three measures was highest in infancy, decreasing after the first year of life, and then increasing again after 5 years of age. This pattern of age-related NO production is the reverse of the pattern of age-related morbidity from cerebral malaria in coastal Tanzanian children. Elevated production of NO in both infants and older children may be related to age per se and malaria infection respectively, and may be one of the mediators of the anti-disease immunity found most commonly in these two age groups.
Elevated levels of methaemoglobin in Tanzanian children with severe and uncomplicated malaria
(Transactions of the Royal Society of Tropical Medicine and Hygiene, 1996) Mwaikambo, Esther D.
Elevated levels of methaemoglobin, the ferric form of haemoglobin incapable of oxygen transport, have been previously found during Plasmodium vivax infections and in acidotic infants. We measured methaemoglobin in the following 5 groups of children with P. falciparum malaria admitted to Muhimbili Medical Centre, Dar es Salaam, Tanzania, (i) Cerebral malaria (CM) with unrousable coma (n = 50), including 32 with complete recovery (CMCR) and 18 with death or neurological sequelae (CMDS); (ii) malaria with severe anaemia but without severe respiratory distress (SA; n = 6); (iii) uncomplicated malaria (UM; n = 37); (iv) asymptomatic parasitaemia (AP; n = 5); and (v) healthy controls (HC; n = 34). Mean methaemoglobin levels were elevated in all groups with malaria, forming up to 16·4% of circulating haemoglobin. The degree of methaemoglobinaemia correlated with disease severity and severity of anaemia. Mean methaemoglobin levels in children with AP, UM, SA, CMCR and CMDS were 3·3%, 4·1%, 5·6%, 4·7% and 5·8% respectively; the mean levels in those with clinical disease were significantly higher than those in healthy controls (2·0%). Methaemoglobinaemia >10% was found in 5·4%, 16·7%, 12·5% and 22·2% of those with UM, SA, CMCR and CMDS, respectively. In the presence of parasite sequestration, impaired tissue perfusion, and a reduction in oxygen carrying capacity of blood due to anaemia, a further reduction in oxygen carrying capacity from even a modest concentration of methaemoglobin is likely to exacerbate tissue hypoxia, perhaps critically so in a minority of anaemic and acidotic patients with severe falciparum malaria.
Elevated Plasma Phenylalanine in Severe Malaria and Implications for Pathophysiology of Neurological Complications
(Infection and Immunity, 2006) Mwaikambo, Esther D.
Cerebral malaria is associated with decreased production of nitric oxide and decreased levels of its precursor, l-arginine. Abnormal amino acid metabolism may thus be an important factor in malaria pathogenesis. We sought to determine if other amino acid abnormalities are associated with disease severity in falciparum malaria. Subjects were enrolled in Dar es Salaam, Tanzania (children) (n = 126), and Papua, Indonesia (adults) (n = 156), in two separate studies. Plasma samples were collected from subjects with WHO-defined cerebral malaria (children), all forms of severe malaria (adults), and uncomplicated malaria (children and adults). Healthy children and adults without fever or illness served as controls. Plasma amino acids were measured using reverse-phase high-performance liquid chromatography with fluorescence detection. Several plasma amino acids were significantly lower in the clinical malaria groups than in healthy controls. Despite the differences, phenylalanine was the only amino acid with mean levels outside the normal range (40 to 84 μM) and was markedly elevated in children with cerebral malaria (median [95% confidence interval], 163 [134 to 193] μM; P < 0.0001) and adults with all forms of severe malaria (median [95% confidence interval], 129 [111 to 155] μM; P < 0.0001). In adults who survived severe malaria, phenylalanine levels returned to normal, with clinical improvement (P = 0.0002). Maintenance of plasma phenylalanine homeostasis is disrupted in severe malaria, leading to significant hyperphenylalaninemia. This is likely a result of an acquired abnormality in the function of the liver enzyme phenylalanine hydroxylase. Determination of the mechanism of this abnormality may contribute to the understanding of neurological complications in malaria.
Evidence of Degradation of Endothelial Glycocalyx in African Children with Falciparum Malaria
(The FASEB Journal, 2020-04-19) Mwaikambo, Esther D.; Kalingonji, Ayam R.; Kalabamu, Florence S.
Abstract The microvasculature and endothelium play a pivotal role in pathophysiology of malaria. The endothelial glycocalyx (eGC) is a layer on the luminal side of vascular endothelial cells with involvement in homeostatic functions including regulation of vascular permeability, cellular adhesion and blood flow‐mediated nitric oxide formation. Breakdown products of eGC degradation include glycosaminoglycans (GAG) and syndecan‐1, a core protein. The objective of this study was to evaluate a possible role of eGC breakdown in the pathogenesis of malaria. We prospectively evaluated measures of endothelial glycocalyx integrity in children with severe and moderately severe malaria and healthy controls, and determined the relationship between glycocalyx integrity and markers of malaria severity, microvascular reactivity, and endothelial activation. At the Hubert Kairuki Medical Center in Dar es Salaam, Tanzania we studied 146 subjects, aged 2–11 years, including 60 healthy controls (HC), 49 patients with moderately severe malaria (MSM) and 37 patients meeting WHO criteria for severe malaria (SM). Ethics committee approvals were obtained prior to study initiation. We assessed eGC integrity biochemically by measuring plasma syndecan‐1 (ELISA) and total urinary glycosaminoglycan (GAG) breakdown products (dimethylmethylene blue assay). Angiopoietin‐2 has been reported to cause breakdown of eGC and was measured by ELISA. Quantitative measures of eGC were assessed using non‐invasive, side‐stream dark field (SDF) microscopy of the pinna and axilla. Levels of urinary GAG were increased in malaria patients compared with HC (mean±SEM 4.3±0.4 g/mol creatinine); MSM (12.4±1.0); SM (13.4±1.0); p<0.0001. Plasma levels of angiopoietin‐2 and syndecan‐1 were also elevated in MSM and SM compared with HC (p<0.0001), and significantly correlated with each other. For HC compared with MSM, imaging results showed eGC degradation [an increase in the perfused boundary region (mean±SEM 1.55±0.04 microns vs.1.68±0.05; p<0.05)], increased microvascular density (549± 34 μm/mm2 vs. 649 ±38; p<0.05)], and a decrease in the extent of RBC filling (79.1± 0.98% vs. 74.9±1.02%; p<0.01). In conclusion, these results provide evidence for degradation of the eGC that could contribute to pathogenesis of vascular dysfunction in malaria. Decreased nitric oxide formation, endothelial activation and increased adhesion of infected RBC are potential consequences of the eGC degradation and vascular dysfunction. Administration of an agent that prevents or repairs eGC degradation may be helpful as adjunctive therapy for malaria. Support or Funding Information National Institutes of Health (R01 HL130783)
An expanded histatin gene polymorphism and test of a possible disease resistant phenotype
(Human mutation, 1997) Mwaikambo, Esther D.
Abstract Histatins are small molecular weight salivary proteins that are important in the non‐immune host defense system. Two frequent cis‐linked coding‐change mutations were previously described in exon 5 of the HIS2 gene of Blacks. The polymorphic mutant allele was termed HIS22 and the wild‐type allele HIS21. We here describe two new non‐coding change polymorphisms of the HIS2 gene: a deletion in intron 5 (7183‐7198 del) and a C⇒T mutation in exon 5 [C⇒T (7104)] that characterize two new HIS2 alleles, HIS23 and HIS24 respectively. Both mutations occur on a HIS21 background. The HIS23 allele occurred only in Afro‐Americans, but not in 67 Japanese, 51 Chinese and 50 Whites. Among 66 random DNA samples from Afro‐Americans, frequencies of HIS21, HIS22, HIS23 and HIS24 were 0.67, 0.22, 0.05 and 0.07 respectively, with a heterozygosity of 0.45. The frequencies of the HIS24 allele in 50 Whites and 50 Chinese were 0.06, and 0.1 respectively. In a comparison of 60 matched saliva and DNA samples from the Afro‐American population, the DNA‐based mutation analysis reliably identified salivary histatin phenotypes. The salivary histatin polymorphism (inferred from PCR analysis) was used to test a biologically plausible hypothesis, that the mutant histatin phenotype (coded by the HIS22 allele) confers relative resistance to severe and fatal malaria. In a study of 185 Black Tanzanian subjects, there were no significant differences in HIS22 allelic frequencies between the various test groups: for 86 cerebral malaria subjects, 54 uncomplicated malaria subjects, and 45 combined asymptomatic parasitemia and health controls, HIS22 frequencies were 0.16, 0.17 and 0.17 respectively. Thus, there was no support for the hypothesis in this population. Hum. Mutat. 10:58–64, 1997. © 1997 Wiley‐Liss, Inc.
Glycocalyx breakdown is increased in African children with cerebral and uncomplicated falciparum malaria
(The FASEB Journal, 2019) Mwaikambo, Esther D.
Abstract Cerebral malaria (CM) from Plasmodium falciparum infection is associated with endothelial dysfunction and parasite sequestration. The glycocalyx (GCX), a carbohydrate‐rich layer lining the endothelium, is crucial in vascular homeostasis. To evaluate the role of its loss in the pathogenesis of pediatric CM, we measured GCX degradation in Tanzanian children with World Health Organization‐defined CM (n = 55), uncomplicated malaria (UM; n = 20), and healthy controls (HCs; n = 25). Urine GCX breakdown products [glycosaminoglycans (GAGs)] were quantified using dimethylmethylene blue (DMMB) and liquid chromatography‐tandem mass spectrometry assays. DMMB‐GAG and mass spectrometry (MS)‐GAG (g/mol creatinine) were increased in CM and UM compared with HCs (P < 0.001), with no differences in DMMB‐GAG and MS‐GAG between CM and UM children or between those with and without a fatal outcome. In CM survivors, urinary GCX DMMB‐GAG normalized by d 3. After adjusting for disease severity, DMMB‐GAG was significantly associated with parasitemia [partial correlation coefficient (P corr ) = 0.34; P = 0.01] and plasma TNF (P corr = 0.26; P = 0.04) and inversely with plasma and urine NO oxidation products [P corr = ‐0.31 (P = 0.01) and P corr = ‐0.26 (P = 0.03), respectively]. GCX breakdown is increased in children with falciparum malaria, with similar elevations in CM and UM. Endothelial GCX degradation may impair endothelial NO production, exacerbate adhesion‐molecule expression, exposure, and parasite sequestration, and contribute to malaria pathogenesis
HIV, disease plague, demoralization and “burnout”: resident experience of the medical profession in Nairobi, Kenya
(Culture, Medicine and Psychiatry,, 2002) Mwaikambo, Esther D.
This paper describes the experiencesof physicians-in-training at a public hospitalin Nairobi, Kenya, where medical professionalspractice in an environment characterized byboth significant lack of resources andpatients with HIV/AIDS in historicallyunprecedented numbers. The data reported hereare part of a larger study examining ethicaldilemmas in medical education and practiceamong physicians in East Africa. Aquestionnaire and semi-structured interviewwere completed by fifty residents in fourmedical specialties, examining social andemotional supports, personal and professionalsources of stress, emotional numbing anddisengagement from patients and peers, andsymptoms of post-traumatic stress anddepression. The factors affecting residentwell-being are found in this study to be morecomplex than previous interviews suggested. This study highlights the fact that as a resultof working in an environment characterized by poor communication among hospital staff aswell as a lack of resources and high numbersof patients with HIV/AIDS, residents'perceptions of themselves – their technicalproficiency, their ability to care and feel forothers and themselves, and for some theirentire sense of self – are significantlyaffected. Also affected are the patients theywork to treat.
Impaired Systemic Production of Prostaglandin E2 in Children with Cerebral Malaria
(The Journal of infectious diseases., 2005) Mwaikambo, Esther D.
Prostaglandins (PGs) are important mediators of macrophage activity, vascular permeability, fever, erythropoiesis, and proinflammatory responses to infection. Our recent studies have shown that plasma levels of bicyclo-PGE2 (a stable end product of PGE2 metabolism) and leukocyte cyclooxygenase (COX)–2 gene expression are suppressed in children with malarial anemia. Since the role of PGs as immunomodulators of human cerebral malaria (CM) has not been examined, we investigated urinary levels of bicyclo-PGE2/creatinine in children with varying clinical outcomes of CM. Among parasitemic children, those with asymptomatic parasitemia had the highest levels of bicyclo-PGE2/creatinine, whereas those with CM had significantly lower levels of bicyclo-PGE2. Systemic levels of bicyclo-PGE2/creatinine were not significantly associated with parasitemia, hemoglobin levels, or levels of the PG-regulatory cytokine tumor necrosis factor–α but were positively correlated with levels of interleukin-10. The results presented here show that impaired systemic production of PGE2 is associated with adverse outcomes of CM, whereas elevated levels of PGE2 in asymptomatic parasitemia suggest a potential role for PGs in protective immunity.
Impaired Systemic Tetrahydrobiopterin Bioavailability and Increased Oxidized Biopterins in Pediatric Falciparum Malaria: Association with Disease Severity
(PLoS pathogens, 2015) Mwaikambo, Esther D.
Decreased bioavailability of nitric oxide (NO) is a major contributor to the pathophysiology of severe falciparum malaria. Tetrahydrobiopterin (BH4) is an enzyme cofactor required for NO synthesis from L-arginine. We hypothesized that systemic levels of BH4 would be decreased in children with cerebral malaria, contributing to low NO bioavailability. In an observational study in Tanzania, we measured urine levels of biopterin in its various redox states (fully reduced [BH4] and the oxidized metabolites, dihydrobiopterin [BH2] and biopterin [B0]) in children with uncomplicated malaria (UM, n = 55), cerebral malaria (CM, n = 45), non-malaria central nervous system conditions (NMC, n = 48), and in 111 healthy controls (HC). Median urine BH4 concentration in CM (1.10 [IQR:0.55–2.18] μmol/mmol creatinine) was significantly lower compared to each of the other three groups — UM (2.10 [IQR:1.32–3.14]; p<0.001), NMC (1.52 [IQR:1.01–2.71];p = 0.002), and HC (1.60 [IQR:1.15–2.23];p = 0.005). Oxidized biopterins were increased, and the BH4:BH2 ratio markedly decreased in CM. In a multivariate logistic regression model, each Log10-unit decrease in urine BH4 was independently associated with a 3.85-fold (95% CI:1.89–7.61) increase in odds of CM (p<0.001). Low systemic BH4 levels and increased oxidized biopterins contribute to the low NO bioavailability observed in CM. Adjunctive therapy to regenerate BH4 may have a role in improving NO bioavailability and microvascular perfusion in severe falciparum malaria.
Kinetic and Cross-Sectional Studies on the Genesis of Hypoargininemia in Severe Pediatric Plasmodium falciparum Malaria
(Infection and immunity, 2019) Kalabamu, Florence S.; Kalingonji, Ayam R.; Mwaikambo, Esther D.
The low bioavailability of nitric oxide (NO) and its precursor, arginine, contributes to the microvascular pathophysiology of severe falciparum malaria. To better characterize the mechanisms underlying hypoargininemia in severe malaria, we measured the plasma concentrations of amino acids involved in de novo arginine synthesis in children with uncomplicated falciparum malaria (UM; n = 61), children with cerebral falciparum malaria (CM; n = 45), and healthy children (HC; n = 109). We also administered primed infusions of l-arginine uniformly labeled with 13C6 and 15N4 to 8 children with severe falciparum malaria (SM; age range, 4 to 9 years) and 7 healthy children (HC; age range, 4 to 8 years) to measure the metabolic flux of arginine, hypothesizing that arginine flux is increased in SM. Using two different tandem mass spectrometric methods, we measured the isotopic enrichment of arginine in plasma obtained at 0, 60, 90, 120, 150, and 180 min during the infusion. The plasma concentrations of glutamine, glutamate, proline, ornithine, citrulline, and arginine were significantly lower in UM and CM than in HC (P ≤ 0.04 for all pairwise comparisons). Of these, glutamine concentrations were the most markedly decreased: median, 457 μM (interquartile range [IQR], 400 to 508 μM) in HC, 300 μM (IQR, 256 to 365 μM) in UM, and 257 μM (IQR, 195 to 320 μM) in CM. Arginine flux during steady state was not significantly different in SM than in HC by the respective mass spectrometric methods: 93.2 μmol/h/kg of body weight (IQR, 84.4 to 129.3 μmol/h/kg) versus 88.0 μmol/h/kg (IQR, 73.0 to 102.2 μmol/h/kg) (P = 0.247) by the two mass spectrometric methods in SM and 93.7 μmol/h/kg (IQR, 79.1 to 117.8 μmol/h/kg) versus 81.0 μmol/h/kg (IQR, 75.9 to 88.6 μmol/h/kg) (P = 0.165) by the two mass spectrometric methods in HC. A limited supply of amino acid precursors for arginine synthesis likely contributes to the hypoargininemia and NO insufficiency in falciparum malaria in children.
Low plasma arginine concentrations in children with cerebral malaria and decreased nitric oxide production
(The Lancet, 2003) Mwaikambo, Esther D.
Nitric oxide (NO) production and mononuclear cell NO synthase 2 (NOS2) expression are high in healthy Tanzanian children but low in those with cerebral malaria. Factors that downregulate NOS2 also diminish factors involved in cellular uptake and biosynthesis of L-arginine, the substrate for NO synthesis. We therefore postulated that L-arginine concentrations would be low in individuals with cerebral malaria. We measured concentrations of L-arginine in cryopreserved plasma samples from Tanzanian children with and without malaria. L-arginine concentrations were low in individuals with cerebral malaria (mean 46 μmol/L, SD 14), intermediate in those with uncomplicated malaria (70 μmol/L, 20), and within the normal range in healthy controls (122 μmol/L, 22; p<0·0001). Analysis by logistic regression showed that hypoargininaemia was significantly associated with cerebral malaria case-fatality. Hypoargininaemia may contribute to limited NO production in children with cerebral malaria and to severe disease.
Malaria severity and human nitric oxide synthase type 2 (NOS2) promoter haplotypes.
(Human genetics., 2009) Mwaikambo, Esther D.; Mutabingwa, Theonest K.
Nitric oxide (NO) mediates host resistance to severe malaria and other infectious diseases. NO production and mononuclear cell expression of the NO producing enzyme-inducible nitric oxide synthase (NOS2) have been associated with protection from severe falciparum malaria. The purpose of this study was to identify single nucleotide polymorphisms (SNPs) and haplotypes in the NOS2 promoter, to identify associations of these haplotypes with malaria severity and to test the effects of these polymorphisms on promoter activity. We identified 34 SNPs in the proximal 7.3 kb region of the NOS2 promoter and inferred NOS2 promoter haplotypes based on genotyping 24 of these SNPs in a population of Tanzanian children with and without cerebral malaria. We identified 71 haplotypes; 24 of these haplotypes comprised 82% of the alleles. We determined whether NOS2 promoter haplotypes were associated with malaria severity in two groups of subjects from Dar es Salaam (N = 185 and N = 250) and in an inception cohort of children from Muheza-Tanga, Tanzania (N = 883). We did not find consistent associations of NOS2 promoter haplotypes with malaria severity or malarial anemia, although interpretation of these results was potentially limited by the sample size of each group. Furthermore, cytokine-induced NOS2 promoter activity determined using luciferase reporter constructs containing the proximal 7.3 kb region of the NOS2 promoter and the G-954C or C-1173T SNPs did not differ from NOS2 promoter constructs that lacked these polymorphisms. Taken together, these studies suggest that the relationship between NOS2 promoter polymorphisms and malaria severity is more complex than previously described.
Monocyte polarization in children with falciparum malaria: relationship to nitric oxide insufficiency and disease severity
(Scientific reports, 2016) Kalabamu, Florence S.; Kalingonji, Ayam R.; Mwaikambo, Esther D.
Abstract We earlier established that nitric oxide (NO) is protective against severe malaria and that arginine and NO levels are reduced in malaria patients. We now show that an M2-like blood monocyte phenotype is significantly associated with hypoargininemia, NO insufficiency, and disease severity in Tanzanian children with falciparum malaria. Compared to control children (n = 106), children with moderately severe (n = 77) and severe falciparum malaria (n = 129) had significantly higher mononuclear cell arginase 1 mRNA, protein, and enzyme activity; lower NOS2 mRNA; lower plasma arginine; and higher plasma IL-10, IL-13, and IL-4. In addition, monocyte CD206 and CD163 and plasma soluble CD163 were elevated. Multivariate logistic regression analysis revealed a significant correlation of risk of severe malaria with both plasma IL-10 and soluble CD163 levels. Monocyte M2 skewing likely contributes to NO bio insufficiency in falciparum malaria in children. Treatments that reverse the M2 polarization may have potential as adjunctive treatment for malaria.

Browse

Browsing Paediatrics and Child Health by Author "Mwaikambo, Esther D."

Results Per Page

Sort Options