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Summary:. Clinical and pathological features in 23 children who developed acute renal failure from what was subsequently proven to be diethylene glycol poisoning are presented. Symptoms of cases included anuria, fever, diarrhoea and vomiting. Eighteen (78.3%) had hepatomegaly, 11 (47.8%) had evidence of respiratory dis tress and 7 (30.4%) had acidotic breathing. Seven (30.4%) of the children were dehydrated on physical examination. Alteration in the level of consciousness was observed in 13 (56.5%) children. The major biochemical abnormalities were acidosis and elevated blood urea nitrogen. Although serum bilirubin was normal in those in whom it was determined, the liver enzymes were elevated in the 2 patients in whom they were determined. Patients were treated as for acute renal failure of renal origin and four children had peritoneal dialysis. Twenty-two (95.6%) of the patients died and outcome was unknown in the remaining patient who was dis charged against medical advice. Autopsies in 7 patients revealed a characteristic nephrotoxic acute tubular necrosis and centrilo bular hepatic necrosis characterized by vacuolar and ballooning degeneration of the metabolically active renal tubular cells and hepatocytes.

Summary: In order to evaluate the usefulness of simple pre-laparotomy parameters in differentiat ing intrahepatic cholestasis (IHC) from extrahepatic cholestasis (EHC), 27 infants with cholestatic jaundice were studied prospectively. On initial evaluation, the following data was collected: birthweight, age at observation of jaundice, presence and consistency of hepatomegaly, splenomegaly, direct serum bilirubin, alkaline phosphatase, haematocrit, prothrombin time, per oxide haemolysis test and duodenal intubation and aspiration test. The sensitivity, specificity, negative and positive predictive values of each parameter were determined, while the definitive diagnosis was confirmed by exploratory laparotomy and intra-operative cholangiography in 12 cases of the clinical course of the disease. Patients with EHC reported to hospital late while the presence of acholic 'stools within 10 days of admission, hepatomegaly of >3 cm, peroxide haemolysis of >80 percent lysis and/or the presence or absence of bilious fluid on duodenal aspiration aided differential diagnosis of infantile cholestasis in the infants. The specificity of acholic stools, hepatomegaly and duodenal aspiration tests was 73.3 percent, 66.7 percent and 93.3 percent respectively, while the corresponding negative predictive values were 78.6 percent, 100 percent and 100 percent, respectively. These simple parameters in a set-up with limied diagnostic facilities, experience and expertise, should encourage immediate exploratory laparotomy, wedge liver biopsy and intraoperative cholangiography.

Summary: In order to determine the relative frequencies of the different causes of severe anaemia among patients with sickle cell anaemia (SCA), 104 con secutive patients with SCA presenting over an eight-month period with severe anaemia (PCV 15 percent) were studied at the children's emergency ward, University College Hospital, Ibadan. They accounted for 8.2 percent of all admissions and 24.2 percent of those who had severe anaemia. Among the patients with SCA, hyperhaemolytic, acute splenic sequestration and aplastic crises constituted 49,20 and 12.5 percent of the anaemic crises, respectively. Ten patients (9.6 percent) showed mixed features and could not be definitely classified. The frequency rate of glucose-6-phosphate dehydrogenase (G-6-PD) deficiency was similar between patients with hyperhaemolytic and those with other forms of anaemic crisis, a finding which suggests that G 6-PD deficiency neither aggravates nor ameliorates haemolysis in SCA. The mortality in the series was 8.7 percent. Six of the patients who died had hyperhaemolysis while the other three had acute splenic sequestration crisis. Five of these deaths occurred despite emergency blood transfusion.

Summary: The three types of severe anaemic crises recognised in sickle-cell anaemia (SCA) are aplastic, acute splenic sequestration and hyperhaemolytic. However, among 104 consecutive SCA cases admitted to the Children Emergency Ward of the University College Hospital, Ibadan with severe anaemic crises recently, were ten (9.6 percent) children who had mixed features and did not fall neatly into any of the three recognised categories. The distributions of the sex and admission haematocrits in these ten children with mixed' anaemic crises were similar to those of the 94 others with easily classified (pure) anaemic crises. However, using statistical test appropriate for the small numbers involved, Salmonella bacteraemia was significantly more common (5/10) among the patients with ‘mixed' anaemic crises than in those (5/94) with pure crises (P=0.0006). The relative risk of Salmonella bacteraemia in ‘mixed' crises was 9.4 times that among those with pure crises (95%CI=3.28-26.98). Although none of the “mixed cases died, compared with a mortality of 9.6 percent among the 'pure cases, the difference was not significant (P=0.42). Bacteraemia appears to be associated with mixed' indeterminate) anaemic crises in SCA. This finding suggests that such patients would benefit from appropriate antibiotic therapy.

The occurrence and infestation rate of ectoparasites on rodents live-trapped from January 1989 to August 1991 on a research farm in the rainforest zone, southwestern Nigeria were studied. The murid (8 spp.). cricetid (1 sp.) scittrid (1 sp.) and hystricomorph (l sp.) rodentscaught were hosts to 16 ectoparasite species comprising the Acarina (62.1 %), Anoplura (33.1 %), Siphonaptera (3.3%), Dermaptera (1.4%) and Diptera (0.1 %). Laelaps muricola Triigardh was the most widespread and abundant on rodent hosts, and a hippoboscid fly, the least. Thryonomys swinderianus Temminek, Cricetontys ganibianus Waterhouse and Arvicanthis niloticas Desmarest.,which are most hunted by agricultural workers on the farm, had the highest infestation rates. Some of theectoparasites have been implicated in transmission of rodent-borne diseases to man. [ABSTRACT FROM AUTHOR]

Abstract: Malaria remains a major parasitic disease in Africa, with 300–500 million new infections each year. There is therefore an urgent need for the development of new effective measures, including vaccines. Plasmodium falciparum merozoite surface protein-119 (MSP-119) is a prime candidate for a blood-stage malaria vaccine. Blood samples were collected from children aged 10 days to 15 years in the months of January–March (N =351) and October–November (N =369) corresponding to the dry and rainy seasons, respectively. P. falciparum infection was determined by microscopy and enzyme linked immunosorbent assay (ELISA) was used to determine the total IgG and IgG subclasses. There was a significant increase in the mean anti-MSP-119 antibody titre in the dry season (p <0.05), compared to the rainy season. A significantly positive correlation between the anti-MSP-119 antibody titre and parasite density (p <0.01, r =0.138) was observed. In the rainy season, unlike in the dry season, P. falciparum positive children had higher anti-MSP-119 antibody titres than P. falciparum negative children and this difference was significant (p <0.05). When all individuals were grouped together, the anti-MSP-119 antibody titre increased with age in both seasons (r =0.186 and 0.002), this increase was more apparent in the dry season. However, when the study population was divided into P. falciparum positive and negative groups, it was observed that in the rainy season, there was a negative correlation between anti-MSP-119 titre and age in P. falciparum positive individuals, while those who were P. falciparum negative had a positive correlation between anti-MSP-119 titre and age. Analysis of anti-MSP-119 IgG subclass showed that IgG1 and IgG3 mean titres were highest in both the dry and rainy seasons with an increase in the mean antibody titres for IgG1, IgG2 and IgG3 in the rainy season. In the dry season there was a positive correlation between IgG1, IgG2, and IgG3 titres with age, while IgG4 was negative, whereas in the rainy season there was a positive correlation between IgG2 and IgG4 (non-cytophilic antibodies) with age and a negative correlation for IgG1 and IgG3 (cytophilic antibodies) with age. Seasonal differences in the level of MSP-119 IgG subclass titres were observed for P. falciparum negative and positive individuals. Only samples, which were positive for IgG2 and IgG4, showed positive correlation between parasitemia and total IgG. The incidence of P. falciparum infection, which increases during the rainy season, might be an important determinant of anti-MSP-119 antibody levels in children living in Igbo-Ora and the results point to the fact that non-cytophilic antibodies to MSP-119 in children might be associated with an increase in total IgG and parasitemia. [Copyright &y& Elsevier]

Over 200 million malaria cases globally lead to half-million deaths annually. The development of malaria prevalence prediction systems to support malaria care pathways has been hindered by lack of data, a tendency towards universal "monolithic" models (one-size-fits-all-regions) and a focus on long lead time predictions. Current systems do not provide short-term local predictions at an accuracy suitable for deployment in clinical practice. Here we show a data-driven approach that reliably produces one-month-ahead prevalence prediction within a densely populated all-year-round malaria metropolis of over 3.5 million inhabitants situated in Nigeria which has one of the largest global burdens of P. falciparum malaria. We estimate one-month-ahead prevalence in a unique 22-years prospective regional dataset of > 9 × 10 4 participants attending our healthcare services. Our system agrees with both magnitude and direction of the prediction on validation data achieving MAE ≤ 6 × 10 -2 , MSE ≤ 7 × 10 -3 , PCC (median 0.63, IQR 0.3) and with more than 80% of estimates within a (+ 0.1 to - 0.05) error-tolerance range which is clinically relevant for decision-support in our holoendemic setting. Our data-driven approach could facilitate healthcare systems to harness their own data to support local malaria care pathways.

Over 200 million malaria cases globally lead to half a million deaths annually. Accurate malaria diagnosis remains a challenge. Automated imaging processing approaches to analyze Thick Blood Films (TBF) could provide scalable solutions, for urban healthcare providers in the holoendemic malaria sub-Saharan region. Although several approaches have been attempted to identify malaria parasites in TBF, none have achieved negative and positive predictive performance suitable for clinical use in the west sub-Saharan region. While malaria parasite object detection remains an intermediary step in achieving automatic patient diagnosis, training state-of-the-art deep-learning object detectors requires the human-expert labor-intensive process of labeling a large dataset of digitized TBF. To overcome these challenges and to achieve a clinically usable system, we show a novel approach. It leverages routine clinical-microscopy labels from our quality-controlled malaria clinics, to train a Deep Malaria Convolutional Neural Network classifier (DeepMCNN) for automated malaria diagnosis. Our system also provides total Malaria Parasite (MP) and White Blood Cell (WBC) counts allowing parasitemia estimation in MP/μL, as recommended by the WHO. Prospective validation of the DeepMCNN achieves sensitivity/specificity of 0.92/0.90 against expert-level malaria diagnosis. Our approach PPV/NPV performance is of 0.92/0.90, which is clinically usable in our holoendemic settings in the densely populated metropolis of Ibadan. It is located within the most populous African country (Nigeria) and with one of the largest burdens of Plasmodium falciparum malaria. Our openly available method is of importance for strategies aimed to scale malaria diagnosis in urban regions where daily assessment of thousands of specimens is required., (© 2020 The Authors. American Journal of Hematology published by Wiley Periodicals, Inc.)

Background: Cerebral malaria (CM), is a life-threatening childhood malaria syndrome with high mortality. CM is associated with impaired consciousness and neurological damage. It is not fully understood, as yet, why some children develop CM. Presented here is an observation from longitudinal studies on CM in a paediatric cohort of children from a large, densely-populated and malaria holoendemic, sub-Saharan, West African metropolis., Methods: Plasma samples were collected from a cohort of children with CM, severe malarial anaemia (SMA), uncomplicated malaria (UM), non-malaria positive healthy community controls (CC), and coma and anemic patients without malaria, as disease controls (DC). Proteomic two-dimensional difference gel electrophoresis (2D-DIGE) and mass spectrometry were used in a discovery cohort to identify plasma proteins that might be discriminatory among these clinical groups. The circulatory levels of identified proteins of interest were quantified by ELISA in a prospective validation cohort., Results: The proteome analysis revealed differential abundance of circulatory complement-lysis inhibitor (CLI), also known as Clusterin (CLU). CLI circulatory level was low at hospital admission in all children presenting with CM and recovered to normal level during convalescence (p < 0.0001). At acute onset, circulatory level of CLI in the CM group significantly discriminates CM from the UM, SMA, DC and CC groups., Conclusions: The CLI circulatory level is low in all patients in the CM group at admission, but recovers through convalescence. The level of CLI at acute onset may be a specific discriminatory marker of CM. This work suggests that CLI may play a role in the pathophysiology of CM and may be useful in the diagnosis and follow-up of children presenting with CM.

Background: Elevated transcranial Doppler (TCD) velocities accurately predict stroke risk in children with sickle cell disease (SCD). Chronic blood transfusion, the gold standard for primary stroke prevention, is faced with numerous challenges in Africa. Hydroxyurea (HU) has been shown to reduce elevated TCD velocities in children with SCD., Aim: To determine the effectiveness of HU in reducing the risk of primary stroke in a cohort of Nigerian children with SCD and elevated velocities treated with HU., Methods: Children with SCD and TCD velocities ≥170 cm/sec treated with HU were prospectively followed with 3-monthly TCD and neurological evaluations for ≥12 months to determine the incidence of primary stroke., Results: One hundred and four children, 53 males, and 51 females were enrolled into the study. Their ages ranged from 2 to 16 years with a mean of 6 years. At first TCD examination, velocities ranged from 173 to 260 cm/sec with conditional and abnormal risk velocities in 60 (57.7%) and 44 (42.3%) children, respectively. Follow up ranged from 1 to 8 years with a mean of 3.6 years. Mean TCD velocities showed a significant decline from 198.2 (standard deviation [SD] = 15.6) cm/sec to 169.3 (SD = 21.4) cm/sec (P < 0.001). One stroke event occurred in the cohort, giving a stroke incidence of 0.27/100 person years., Conclusion: HU significantly reduces TCD velocities in Nigerian children with SCD and elevated TCD velocities, with a corresponding reduction in the incidence of primary stroke. HU may represent a potential alternative for primary stroke prevention in low and middle income countries where the burden of SCD resides., (© 2018 Wiley Periodicals, Inc.)

Severe Malarial Anemia (SMA), a life-threatening childhood Plasmodium falciparum malaria syndrome requiring urgent blood transfusion, exhibits inflammatory and hemolytic pathology. Differentiating between hypo-haptoglobinemia due to hemolysis or that of genetic origin is key to understand SMA pathogenesis. We hypothesized that while malaria-induced hypo-haptoglobinemia should reverse at recovery, that of genetic etiology should not. We carried-out a case-control study of children living under hyper-endemic holoendemic malaria burden in the sub-Saharan metropolis of Ibadan, Nigeria. We show that hypo-haptoglobinemia is a risk factor for childhood SMA and not solely due to intravascular hemolysis from underlying schizogony. In children presenting with SMA, hypo-haptoglobinemia remains through convalescence to recovery suggesting a genetic cause. We identified a haptoglobin gene variant, rs12162087 (g.-1203G > A, frequency = 0.67), to be associated with plasma haptoglobin levels (p = 8.5 × 10 -6 ). The Homo-Var:(AA) is associated with high plasma haptoglobin while the reference Homo-Ref:(GG) is associated with hypo-haptoglobinemia (p = 2.3 × 10 -6 ). The variant is associated with SMA, with the most support for a risk effect for Homo-Ref genotype. Our insights on regulatory haptoglobin genotypes and hypo-haptoglobinemia suggest that haptoglobin screening could be part of risk-assessment algorithms to prevent rapid disease progression towards SMA in regions with no-access to urgent blood transfusion where SMA accounts for high childhood mortality rates.

Cerebral malaria (CM) is a severe complication of Plasmodium falciparum infection. This encephalopathy is characterized by coma and is thought to result from mechanical microvessel obstruction and an excessive activation of immune cells leading to pathological inflammation and blood-brain barrier alterations. IL-22 contributes to both chronic inflammatory and infectious diseases, and may have protective or pathogenic effects, depending on the tissue and disease state. We evaluated whether polymorphisms (n = 46) of IL22 and IL22RA2 were associated with CM in children from Nigeria and Mali. Two SNPs of IL22, rs1012356 (P = 0.016, OR = 2.12) and rs2227476 (P = 0.007, OR = 2.08) were independently associated with CM in a sample of 115 Nigerian children with CM and 160 controls. The association with rs2227476 (P = 0.01) was replicated in 240 nuclear families with one affected child from Mali. SNP rs2227473, in linkage disequilibrium with rs2227476, was also associated with CM in the combined cohort for these two populations, (P = 0.004, OR = 1.55). SNP rs2227473 is located within a putative binding site for the aryl hydrocarbon receptor, a master regulator of IL-22 production. Individuals carrying the aggravating T allele of rs2227473 produced significantly more IL-22 than those without this allele. Overall, these findings suggest that IL-22 is involved in the pathogenesis of CM., Competing Interests: The authors declare no competing financial interests.

Cerebral malaria (CM) is a neurological complication of infection with Plasmodium falciparum that is partly caused by cytokine-mediated inflammation. It is not known whether interleukin-17 (IL-17) cytokines, which regulate inflammation, control the development of CM. To evaluate the involvement of IL-17 cytokines in CM, we analyzed 46 common polymorphisms in IL17A, IL17F, and IL17RA (which encodes the common receptor chain of the members of the IL-17 family) in two independent African populations. A case-control study involving 115 Nigerian children with CM and 160 controls from the community (CC) showed that IL17F reference single nucleotide polymorphism (SNP) 6913472 (rs6913472) (P = 0.004; odds ratio [OR] = 3.12), IL17F rs4715291 (P = 0.004; OR = 2.82), IL17RA rs12159217 (P = 0.01; OR = 2.27), and IL17RA rs41396547 (P = 0.026; OR = 3.15) were independently associated with CM. A replication study was performed in 240 nuclear Malian family trios (two parents with one CM child). We replicated the association for 3 SNPs, IL17F rs6913472 (P = 0.03; OR = 1.39), IL17RA rs12159217 (P = 0.01; OR = 1.52), and IL17RA rs41396547 (P = 0.04; OR = 3.50). We also found that one additional SNP, IL17RA rs41433045, in linkage disequilibrium (LD) with rs41396547, was associated with CM in both Nigeria and Mali (P = 0.002; OR = 4.12 in the combined sample). We excluded the possibility that SNPs outside IL17F and IL17RA, in strong LD with the associated SNPs, could account for the observed associations. Furthermore, the results of a functional study indicated that the aggravating GA genotype of IL17F rs6913472 was associated with lower IL-17F concentrations. Our findings show for the first time that IL17F and IL17RA polymorphisms modulate susceptibility to CM and provide evidence that IL-17F protects against CM., (Copyright © 2016, American Society for Microbiology. All Rights Reserved.)

Background: Sickle cell anaemia (SCA) is the leading genetic disorder in Nigeria. Elevated velocities ≥170 cm/sec occur in about a third of Nigerian children with SCA. Chronic blood transfusion for stroke prevention is faced with a myriad of challenges in our practice., Objectives: To evaluate the effectiveness of hydroxyurea (HU) in reducing flow velocities in a cohort of Nigerian children with SCA and elevated velocities treated with HU., Methods: An observational study was carried out on a cohort of Nigerian children with SCA and elevated velocities identified on routine transcranial Doppler (TCD) screening. HU was recommended in those with TCD velocities ≥ 170cm/sec as stipulated in our hospital protocol. Outcomes were compared after ≥12 months of observation., Results: Fifty children with elevated TCD velocities were studied; 31 consented to HU therapy and 19 declined. Children on HU showed a statistically significant decline in mean velocities from 199.7 [17.1] cm/sec to 165.8 [20.7] cm/sec (P < 0.001) with a significant increase in mean packed cell volume from 21.1 [3.4] to 25.0 [2.8]%. Children without treatment had a significant rise in mean velocities from 190.2 [10.8] cm/sec to 199.7 [14.9] cm/sec (P = 0.003). Children with conditional risk velocities on HU were less likely to convert to abnormal risk (P < 0.001). Two stroke events occurred, one in each group. No adverse effects of HU were recorded in the cohort., Conclusion: HU appears to significantly reduce TCD velocities in Nigerian children with SCA and elevated velocities ≥170 cm/sec with beneficial effect on the haematological profile. HU may provide an effective approach to primary stroke prevention, particularly in Africa., (© 2015 Wiley Periodicals, Inc.)

Unlabelled: Severe malarial anemia (SMA) in semi-immune individuals eliminates both infected and uninfected erythrocytes and is a frequent fatal complication. It is proportional not to circulating parasitemia but total parasite mass (sequestered) in the organs. Thus, immune responses that clear parasites in organs may trigger changes leading to anemia. Here, we use an outbred-rat model where increasing parasite removal in the spleen escalated uninfected-erythrocyte removal. Splenic parasite clearance was associated with activated CD8(+) T cells, immunodepletion of which prevented parasite clearance. CD8(+) T cell repletion and concomitant reduction of the parasite load was associated with exacerbated (40 to 60%) hemoglobin loss and changes in properties of uninfected erythrocytes. Together, these data suggest that CD8(+) T cell-dependent parasite clearance causes erythrocyte removal in the spleen and thus anemia. In children infected with the human malaria parasite Plasmodium falciparum, elevation of parasite biomass (not the number of circulating parasites) increased the odds ratio for SMA by 3.5-fold (95% confidence intervals [CI95%], 1.8- to 7.5-fold). CD8(+) T cell expansion/activation independently increased the odds ratio by 2.4-fold (CI95%, 1.0- to 5.7-fold). Concomitant increases in both conferred a 7-fold (CI95%, 1.9- to 27.4-fold)-greater risk for SMA. Together, these data suggest that CD8(+)-dependent parasite clearance may predispose individuals to uninfected-erythrocyte loss and SMA, thus informing severe disease diagnosis and strategies for vaccine development., Importance: Malaria is a major global health problem. Severe malaria anemia (SMA) is a complex disease associated with partial immunity. Rapid hemoglobin reductions of 20 to 50% are commonly observed and must be rescued by transfusion (which can carry a risk of HIV acquisition). The causes and risk factors of SMA remain poorly understood. Recent studies suggest that SMA is linked to parasite biomass sequestered in organs. This led us to investigate whether immune mechanisms that clear parasites in organs trigger anemia. In rats, erythropoiesis is largely restricted to the bone marrow, and critical aspects of the spleen expected to be important in anemia are similar to those in humans. Therefore, using a rat model, we show that severe anemia is caused through CD8(+) T cell-dependent parasite clearance and erythrocyte removal in the spleen. CD8 activation may also be a new risk factor for SMA in African children., (Copyright © 2015 Safeukui et al.)

Systemic inflammation and sequestration of parasitized erythrocytes are central processes in the pathophysiology of severe Plasmodium falciparum childhood malaria. However, it is still not understood why some children are more at risks to develop malaria complications than others. To identify human proteins in plasma related to childhood malaria syndromes, multiplex antibody suspension bead arrays were employed. Out of the 1,015 proteins analyzed in plasma from more than 700 children, 41 differed between malaria infected children and community controls, whereas 13 discriminated uncomplicated malaria from severe malaria syndromes. Markers of oxidative stress were found related to severe malaria anemia while markers of endothelial activation, platelet adhesion and muscular damage were identified in relation to children with cerebral malaria. These findings suggest the presence of generalized vascular inflammation, vascular wall modulations, activation of endothelium and unbalanced glucose metabolism in severe malaria. The increased levels of specific muscle proteins in plasma implicate potential muscle damage and microvasculature lesions during the course of cerebral malaria.

Background & Objectives: Malaria and G6PD deficiency-related haemolyses are known causes of hospital admissions in Nigeria and pose great danger to child survival but data on interactions of these two pathologies are scarce. This study was carried out to determine the association between features of Plasmodium falciparum infection and G6PD status., Methods: G6PD and haemoglobin were typed by fluorescent spot test and electrophoresis respectively, in 1120 children with microscopically-proven falciparum malaria. Clinical features of malaria were compared between G6PD normal and deficient children., Results: There were 558 males and 562 females with median age of 35 months (range, 6 months-12 yr). In males, prevalence of G6PD-deficiency in patients with uncomplicated malaria (UM), severe malarial anaemia (SMA) and cerebral malaria (CM) was 23.4, 7 and 16.7%, respectively compared with 11.1, 7.3 and 4.4%, respectively among females. In both males and females, convulsion and rectal temperature above 38°C were less likely presentations among G6PD-deficient compared with G6PD-normal children (p <0.05). The proportions of children with pallor, convulsion and impaired consciousness were significantly lower among G6PD-deficient than normal males (p <0.05) but these features were not different between deficient and normal females (p >0.05)., Interpretation & Conclusion: Convulsions, pallor and elevated temperature were more frequent features of malaria in G6PD normal than deficient children. G6PD-deficient male children are protected against impaired consciousness. These differences may offer useful hints in malaria treatment and researches in endemic regions.

Background: Transcranial Doppler (TCD) sonography of major cerebral arteries is now recommended for routine screening for stroke risk in children with sickle cell disease (SCD)., Methods: We performed TCD studies on children with sickle cell anemia (SCA) seen at the pediatric hematology clinic over a period of 2 years. TCD scans were repeated yearly in children with normal flow velocities and every 3 months in children with elevated velocities. Findings were correlated with clinical variables, hematologic indices, and arterial oxygen saturation. Predictors of elevated velocities were identified by multiple linear regressions., Results: We enrolled 237 children and performed a total of 526 TCD examinations. Highest time-averaged maximum flow velocities were ≥170 cm/s in 72 (30.3%) cases and ≥200 cm/s in 20 (8.4%). Young age, low hematocrit, low hemoglobin, and arterial oxygen desaturation <95% showed significant correlations with presence of increased cerebral flow velocities., Conclusions: Low hematocrit, low hemoglobin concentration, young age, and low arterial oxygen desaturation predicted elevated cerebral blood flow velocities and, invariably, increased stroke risk, in children with SCA. Children who exhibit these features should be given high priority for TCD examination in the setting of limited resources., (Copyright © 2013 Wiley Periodicals, Inc.)

Aims and Objectives: To compare the outcome after a first clinical stroke, following treatment with and without hydroxyurea (HU)., Subjects and Methods: A retrospective review of a cohort of Nigerian children with SCD, who had suffered a first stroke, was carried out. Outcomes in the group of children who received and did not receive HU were compared., Results: Thirty two children presented with stroke and one died of haemorrhagic stroke at presentation. All the children had haemoglobin SS phenotype, and ischaemic stroke was the predominant form seen. Mean age at first clinical stroke was 7 years, 7 months (SD=2 years, 4 months). Thirteen children received HU while 18 declined HU therapy. Maximum dose of HU ranged from 20-25 mg/kg/ day. The secondary stroke incidence of 7/100 person years in the HU group was significantly lower than the 28/100 person years in the non-HU group (P=0.001, OR 3.808, 95% CI 1.556, 9.317). Children who did not receive HU were more likely to drop out of school and to have moderate-severe motor disabilities requiring caregiver assistance for daily living., Conclusion: In settings where facilities for chronic blood transfusion are not accessible or feasible, HU therapy should be considered for secondary stroke prevention in children with SCD.

Cerebral malaria (CM) and severe malarial anemia (SMA) are the most serious life-threatening clinical syndromes of Plasmodium falciparum infection in childhood. Therefore, it is important to understand the pathology underlying the development of CM and SMA as opposed to uncomplicated malaria (UM). Increased levels of hepcidin have been associated with UM, but its level and role in severe malarial disease remains to be investigated. Plasma and clinical data were obtained as part of a prospective case-control study of severe childhood malaria at the main tertiary hospital of the city of Ibadan, Nigeria. Here, we report that hepcidin levels are lower in children with SMA or CM than in those with milder outcome (UM). While different profiles of pro- and anti-inflammatory cytokines were observed between the malaria syndromes, circulatory hepcidin levels remained associated with the levels of its regulatory cytokine interleukin-6 and of the anti-inflammatory cytokine inerleukin-10, irrespective of iron status, anemic status, and general acute-phase response. We propose a role for hepcidin in anti-inflammatory processes in childhood malaria.

Biomarker discovery aims to find small subsets of relevant variables in 'omics data that correlate with the clinical syndromes of interest. Despite the fact that clinical phenotypes are usually characterized by a complex set of clinical parameters, current computational approaches assume univariate targets, e.g. diagnostic classes, against which associations are sought for. We propose an approach based on asymmetrical sparse canonical correlation analysis (SCCA) that finds multivariate correlations between the 'omics measurements and the complex clinical phenotypes. We correlated plasma proteomics data to multivariate overlapping complex clinical phenotypes from tuberculosis and malaria datasets. We discovered relevant 'omic biomarkers that have a high correlation to profiles of clinical measurements and are remarkably sparse, containing 1.5-3% of all 'omic variables. We show that using clinical view projections we obtain remarkable improvements in diagnostic class prediction, up to 11% in tuberculosis and up to 5% in malaria. Our approach finds proteomic-biomarkers that correlate with complex combinations of clinical-biomarkers. Using the clinical-biomarkers improves the accuracy of diagnostic class prediction while not requiring the measurement plasma proteomic profiles of each subject. Our approach makes it feasible to use omics' data to build accurate diagnostic algorithms that can be deployed to community health centres lacking the expensive 'omics measurement capabilities.

Background: Haemoglobinuria is one of the manifestations of severe malaria and results from severe intravascular haemolysis. Glucose-6-phosphate dehydrogenase (G6PD) deficiency has been implicated in its aetiology. Haemoglobinuria may be associated with severe anaemia and, less frequently, acute renal failure., Methods: A prospective case-control study was carried out to determine the incidence of haemoglobinuria as confirmed by dipstick urinalysis, microscopy and spectrophotometric measurement, among children with severe malaria. A total of 251 children presenting at the Children's Emergency Ward with severe malaria were recruited over a period of 21 months. The G6PD status and the outcomes of severe malaria in children with and without haemoglobinuria was studied with respect to renal failure, the recurrence of haemoglobinuria and blood pressure changes over a three-month follow-up period., Results: It was found that the incidence of haemoglobinuria among children with severe malaria is 19.1%. Children <5 years constituted 76.8% of all the study patients. Patients with haemoglobinuria had median age of 52.5 months, which was significantly higher than 35 months in patients without haemoglobinuria (p=0.001). Although, haemaglobinuria was commoner among boys (54.2%) than girls (45.8%), the difference was not statistically significant. There were no significant differences between children with and without haemoglobinuria regarding their nutritional status or parasite densities. Among the clinical features of the study patients, only jaundice was significantly associated with haemoglobinuria (p=0.0001). Renal failure occurred in three out of 48 children with haemoglobinuria and in none of the 203 without. There was not recurrence of haemoglobinuria in the follow-up period. At discharge, blood pressure was elevated in six children (one previously haemoglobinuric), but all returned to normal within the follow-up period., Conclusions: Haemoglobinuria was a prominent feature of severe malaria and it was significantly associated with jaundice at presentation. Haemoglobinuria was commoner in older children than younger children but not related to sex. G6PD deficiency was not an independent predictor of the occurrence or outcome of haemoglobinuria. Blood pressure was not affected by haemoglobinuria on admission nor during follow-up.

Transcranial Doppler (TCD) ultrasonography helps to identify children with sickle cell disease (SCD) who are at an increased risk of stroke,making primary stroke prevention a reality. A cross-sectional study of145 Nigerian children aged ≥3 years with SCD was carried out to describe the pattern of cerebral blood flow (CBF) abnormalities. The mean time-averaged mean velocity (TAMV) was 152 ±27.0 cm/sec and122 ±22.0 cm/sec in Hb SS and Hb S1C group, respectively. Abnormal velocities were recorded in six (4.7%) of the Hb SS patients and none of the Hb S1C while conditional risk (CR) velocities were recorded in 19.7% of Hb SS (low conditional 11.0%, high conditional 8.7%) and low conditional in 5.6% of Hb S1C cases. Cerebral flow velocities showed a negative correlation with age and hematocrit. Compared with African-American children, Nigerian children with Hb SS disease have a considerably higher prevalence of CR velocities.

Background: Sickle cell disease is a common genetic disorder in Nigeria., Objectives: To determine the steady state haematocrit, liver size and spleen size in children with sickle cell disease and the factors that influence them., Methods: This was a retrospective study of children with sickle cell disorders who attended the anaemia clinic of the Children's Outpatient Department, University College Hospital, Ibadan between the years 2000-2009. Relevant data extracted from their case notes included socio-demographic variables, haemoglobin phenotype, steady state haematocrit and liver and splenic sizes. Means were compared with t-test and correlation tested with Pearson correlation. Statistical significance was set at p < 0.05., Results: A total of 415 (Male: female ratio 1.1:1) children were studied and 385 (92.8%) and 30 (7.2%) of the children were of haemoglobin (Hb) SS and Hb SC phenotypes respectively. Their ages ranged from 0.5-17 years with a mean (SD) of 7.3 (4.4) years. Mean (SD) steady state haematocrit for children with HbSC was 28.3 (4.5) % and significantly higher than 24.1 (3.7) % in HbSS. Mean steady state haematocrit was also higher in children from higher than lower socio-economic classes. There was a negative correlation of haematocrit with age, with hepatomegaly and splenomegaly. Steady state hepatomegaly occurred more frequently in HbSS than in HbSC., Conclusion: Haemoglobin phenotype, age and socio-economic status have some modifying influences on the steady-state features of sickle cell disease in Nigerian children. In addition, increasing liver and spleen sizes seem to be related to a decreasing haematocrit.

Background: Cerebral malaria (CM) and severe malarial anemia (SMA) are the most serious life-threatening clinical syndromes of Plasmodium falciparum infection in childhood. Therefore it is important to understand the pathology underlying the development of CM and SMA, as opposed to uncomplicated malaria (UM). Different host responses to infection are likely to be reflected in plasma proteome-patterns that associate with clinical status and therefore provide indicators of the pathogenesis of these syndromes., Methods and Findings: Plasma and comprehensive clinical data for discovery and validation cohorts were obtained as part of a prospective case-control study of severe childhood malaria at the main tertiary hospital of the city of Ibadan, an urban and densely populated holoendemic malaria area in Nigeria. A total of 946 children participated in this study. Plasma was subjected to high-throughput proteomic profiling. Statistical pattern-recognition methods were used to find proteome-patterns that defined disease groups. Plasma proteome-patterns accurately distinguished children with CM and with SMA from those with UM, and from healthy or severely ill malaria-negative children., Conclusions: We report that an accurate definition of the major childhood malaria syndromes can be achieved using plasma proteome-patterns. Our proteomic data can be exploited to understand the pathogenesis of the different childhood severe malaria syndromes.

Introduction: Glucose-6-phosphate dehydrogenase (G6PD) deficiency (Gd-) contributes to morbidity and mortality in sub-Saharan Africa but recent data on the interaction between Gd- and malaria among children is scarce. We hypothesised that, being a haemolytic factor, Gd- makes severe malarial anaemia (SMA) more common and even more severe., Methodology: We selected 930 children aged 0.5-12 years attending a reference hospital with microscopically proven falciparum malaria. G6PD and haemoglobin were typed by the fluorescent spot test and electrophoresis, respectively. Molecular typing by PCR and restriction enzyme digestion was also performed on 15% of randomly selected samples. Haematocrit (PCV) values, haemoglobin type, blood group, presence of sickle cell trait (HbAS), and parasite counts were compared between G6PD-normal and deficient children., Results: Prevalence of Gd- was 16.4% and 8.1% among boys and girls with malaria, respectively. Mean PCV was 22.8% in deficient children compared with 21.0% in normal children (p = 0.041). In boys, 2.7% of Gd- had PCV ≤ 10%, as compared to 13.6% in Gd+ (p = 0.005). Similarly, 21.3% of Gd- had PCV ≤ 15% compared with 39.4% in Gd+ (p = 0.003). No such difference was found among girls. Overall, HbAS was typed in 7.6% and was more common in Gd- (13.0%) than in Gd+ (6.8%), but the difference was not statistically significant (p = 0.058). The mean parasite counts were significantly lower in Gd- (15477.5/µl) than in Gd+ (19784.4/µl; p = 0.013), and it was independent from HbAS., Conclusion: Gd- males but not females were significantly less likely to develop severe malarial anaemia.

Objectives: To determine the frequency of early deaths and the associated risk factors in children suffering from cancer at the University College Hospital, Ibadan., Design: A retrospective study involving review of case notes of children suffering from cancer., Setting: Department of Paediatrics, University College Hospital, Ibadan, Nigeria., Subjects: All cases of childhood cancer managed in the Department between January 1998 and December 2004. Inclusion criteria were histological or cytological confirmation of diagnosis, suggestive clinical features and availability of details about the course of the illness., Main Outcome Measures: Interval between diagnosis and death, rate of early death (death within 30 days of diagnosis) and risk factors for early death., Results: Eighty eight cases of childhood cancer were seen out of whom 52 died during the period. Four cases with incomplete data were excluded from subsequent statistical analysis. There were 29 (34.5%) early deaths defined as death within 30 days of diagnosis. The odds of early death were increased in the presence of bilateral kidney involvement, masses in the liver, splenic masses, pulmonary metastasis and stage D of Burkitt lymphoma. Logistic regression analysis revealed that pulmonary metastasis was a significant independent predictor ofearly death., Conclusions: Early childhood cancer mortality rate is high. Early diagnosis and referral for appropriate care may reduce childhood cancer mortality in Nigeria.

Malaria remains an important public heath concern in Nigeria because of its impact on child and maternal health, but the contribution of severe malaria to morbidity among Nigerian children was scantly reported. This study was undertaking to document the hospital-burden of severe malaria among children in Ibadan in order to reflect on the impacts and health implications of the current malaria control strategies. A review of 6-year case records of all children admitted to the emergency ward of the University College Hospital Ibadan was carried out. Cases of severe malaria were defined as those children in whom parasitaemia were confirmed with blood film microscopy and any of the WHO case definitions for severe malaria was documented. Severe malaria cases constituted 11.3% of 16 031 admissions (2000-05) with 89.1% being children <5 years old. Cerebral malaria accounted for about one-fifth (19.7%) of all severe malaria cases. The yearly proportional morbidity rate from severe malaria ranged from 8.7% to 13.2% with significant increase from 2000 to 2004 (X2 = 48.49; df = 5; P < 0.001). Severe malaria accounted for 12.4% of all paediatric deaths with an estimated overall case fatality rate of 9.6%. Deaths from malaria were significantly associated with wasting (Z-score for weight-for-height

We reviewed our records over a 15-year period to determine whether or not the impression that stroke complicating sickle cell disease was less common than reported in North America. Records of children aged 16 years and below with a diagnosis of stroke seen at the University College Hospital, Ibadan, Nigeria between 1988 and 2002 were examined. Thirty-nine such patients were identified but only 31 had detailed records available for study. Twenty-seven of these had sickle cell disease, 26 with haemoglobin genotype SS and 1 with Hb S+C. Sickle cell disease was therefore responsible for 87% of stroke seen in children at our centre. With an average clinic population of about 500 patients with sickle cell disease, the hospital frequency of stroke among these patients is estimated at 5.4%. The mean age of occurrence of the first stroke was 6.8 years ranging from 17 months to 11 years. Of the 7 patients who had CT scans of the brain done, 5 had evidence of cerebral infarction while 2 had intracerebral haemorrhage. While only 2 deaths occurred among the cases reviewed, morbidity was significant with only 6 patients achieving complete recovery. Recurrent stroke occurred after an average of 25.6 months in 8 of 13 patients who were followed up (61.5%). The incidence of stroke among African children with sickle cell disease appears to be not as high as reported in patients from North America.

As the production of NADPH in the pentose phosphate pathway is the main antioxidant defence mechanism available to the Plasmodium falciparum, we have studied the expression of P. falciparum glucose 6-phosphate dehydrogenase-6-phosphogluconolactonase (PfG6PD-6PGL) in G6PD-deficient and normal erythrocyte host cells. Both erythrocytes infected in vitro with a laboratory isolate and erythrocytes from natural human infections were used. Total RNA was prepared from parasites collected from five G6PD-deficient and nine G6PD-normal children in Ibadan, Nigeria, selected after screening 189 rural schoolchildren and 68 clinical malaria patients, and was subjected to Northern blot analysis. The probe was a cDNA fragment of the G6PD domain of the PfG6PD-6PGL gene, with an internal control probe of P. falciparum 18S ribosomal RNA. Quantification was performed using a phosphoimager. Relative to internal control, the abundance of PfG6PD-6PGL mRNA (mean +/- standard deviation) was lower in parasites from G6PD-deficient children (0.29 +/- 0.27) than in G6PD-normal control subjects (0.74 +/- 0.26) (P = 0.014, Mann-Whitney U-test). Although confirmation in a larger study is required, our results suggest a lower relative abundance of PfG6PD-6PGL, and presumably antioxidant activity, in malaria parasites from G6PD-deficient hosts, thus extending the current knowledge of the mechanism of G6PD-deficiency related host protection.

Plasmodium berghei glucose-6-phosphate dehydrogenase-6-phosphogluconolactonase (G6PD-6PGL) is a bifunctional enzyme with significant sequence similarity in both the 6PGL and G6PD domains to the Plasmodium falciparum enzyme. A recombinant form of the P. berghei enzyme was found to have both G6PD and 6PGL activities, and therefore catalyses the first two steps in the pentose phosphate pathway. Genes encoding very similar proteins are also found in three other malarial parasites, Plasmodium yoelii, Plasmodium chabaudi and Plasmodium knowlesi. All of these predicted enzymes contain unique parasite insertions in corresponding positions in the G6PD domain but the insertions differ in size and sequence. Such insertions are a common feature of malarial proteins but their origin and function is unknown. Excision of the insertion sequence in the P. berghei protein renders the G6PD domain inactive, although the 6PGL activity is unaffected. Replacing the insertion sequence in P. berghei with the insertion sequence from P. falciparum restores some of the G6PD activity and also enhances 6PGL activity. We conclude that although the insertions are evolving rapidly they have an essential role in the activity of the bifunctional enzyme.

The hypothesis that chloroquine-induced pruritus (CIP) may be determined by certain genetic factors was tested by investigating the epidemiology of CIP with respect to certain genetic red cell markers namely, haemoglobin genotype, glucose-6-phosphate dehydrogenase (G6PD) deficiency and the ABO blood groups. Three hundred consecutive patients treated for malaria with chloroquine at the University College Hospital, Ibadan, Nigeria were recruited into the study. They were observed over 3 days for presence of CIP. ABO blood groups, G6PD and Hb genotypes were determined appropriately for each patient. One hundred and twenty four (41.3%) of the patients responded positively to CIP. There was a reduced frequency of the sickle cell trait (HbAS) among itchers relative to non-itchers. This suggests that the trait may be protective against CIP. G6PD deficiency was also found to be relatively more common among itchers than non-itchers. This indicates that G6PD deficiency may increase susceptibility to CIP. There was however no difference in the distribution of itchers among the different ABO blood groups. It was concluded that CIP may be associated with certain genetic red cell markers particularly Hb and G6PD types which are known malaria markers but not ABO blood groups.

Malaria merozoite surface protein 1 (MSP1) is cleaved in an essential step during erythrocyte invasion. The responses of children to natural malaria infection included antibodies that inhibit this cleavage and others that block the binding of these inhibitory antibodies. There was no correlation between the titer of the antibody to the 19-kDa fragment of MSP1 and its inhibitory activity. These findings have implications for the design of MSP1-based vaccines.

Plasmodium falciparum glucose 6-phosphate dehydrogenase (Pf Glc6PD), compared to other Glc6PDs has an additional 300 amino acids at the N-terminus. They are not related to Glc6PD but are similar to a family of proteins (devb) of unknown function, some of which are encoded next to Glc6PD in certain bacteria. The human devb homologue has recently been shown to have 6-phosphogluconolactonase (6PGL) activity. This suggests Pf Glc6PD may be a bifunctional enzyme, the evolution of which has involved the fusion of adjacent genes. Further functional analysis of Pf Glc6PD has been hampered because parts of the gene could not be cloned. We have isolated and sequenced the corresponding Plasmodium berghei gene and shown it encodes an enzyme (Pb Glc6PD) with the same structure as the P. falciparum enzyme. Pb Glc6PD is 950 amino acids long with significant sequence similarity in both the devb and Glc6PD domains with the P. falciparum enzyme. The P. berghei enzyme does not have an asparagine-rich segment between the N and C halves and it contains an insertion at the same point in the Glc6PD region as the P. falciparum enzyme but the insertion in the P. berghei is longer (110 versus 62 amino acids) and unrelated in sequence to the P. falciparum insertion. Though expression of this enzyme in bacteria produced largely insoluble protein, conditions were found where the full-length enzyme was produced in a soluble form which was purified via a histidine tag. We show that this enzyme has both Glc6PD and 6PGL activities. Thus the first two steps of the pentose phosphate pathway are catalysed by a single novel bifunctional enzyme in these parasites.

This short report describes the results of a rapid, simple and cost effective immunodiagnostic test for malaria in Ibadan, Nigeria. A total of 77% patients presenting at the children outpatient clinic, University College Hospital with malaria symptoms were screened for malaria parasites by microscopy using Giemsa stain and by the immunochromatographic card test. The immunodiagnostic test had a sensitivity of 93.1% and a specificity of 95.8%, making a good alternative for malaria diagnosis especially in rural areas without electricity, where microscopy is not possible, and a decision is to be made on when to start treatment.