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1.
Microbes Infect ; 10(4): 342-8, 2008 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-18396436

RESUMO

Mannose-binding lectin (MBL) is a serum protein which initiates innate immune responses to microbial pathogens by binding to non-self surface oligosaccharides. MBL deficiency is the most common congenital immunodeficiency of human and has been shown to predispose to infections, particularly in children and immune compromised. In a matched case-control study among 870 Ghanaian children, we examined the influence of six polymorphisms of the MBL2 gene on Plasmodium falciparum infection and severe malaria. A missense mutation resulting in low MBL activity (MBL2*C) was found in 35% of healthy controls, but in 42% of asymptomatically infected children (P=0.01), and in 46% of patients with severe malaria (P=0.007). Heterozygosity for MBL2*C was associated with increased odds of infection (odds ratio (OR), 1.6; 95% confidence interval (CI), 1.1-2.1), severe malaria (OR, 1.7; 95% CI, 1.2-2.4), and of severe anemia in particular (OR, 2.3; 95% CI, 1.4-3.8). The population attributable fraction of severe malaria cases attributable to MBL2*C heterozygosity was 17%. Our results suggest that the MBL pathway of the complement system is a critical determinant of both, susceptibility to P. falciparum infection and manifestation of severe malaria, particularly in young children in whom specific immune responses are weak or absent.


Assuntos
Malária/genética , Malária/imunologia , Lectina de Ligação a Manose/genética , Plasmodium falciparum/imunologia , Polimorfismo Genético , Anemia , Animais , Estudos de Casos e Controles , Criança , Pré-Escolar , Feminino , Frequência do Gene , Gana , Heterozigoto , Humanos , Lactente , Malária/complicações , Masculino , Lectina de Ligação a Manose/metabolismo , Mutação de Sentido Incorreto , Ligação Proteica
2.
Antimicrob Agents Chemother ; 51(9): 3273-81, 2007 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-17638703

RESUMO

Morbidity and mortality from malaria remain unacceptably high among young children in sub-Saharan Africa. Intermittent preventive treatment in infancy (IPTi) involves the administration of antimalarials alongside routine vaccinations and might be an option in malaria control. In an area of intense, perennial malaria transmission in northern Ghana, 1,200 children received IPTi with sulfadoxine-pyrimethamine or placebo at approximately 3, 9, and 15 months of age. Children were followed up until 24 months of age to assess morbidity and adverse events. During the intervention period (3 to 18 months of age), IPTi reduced the incidences of malaria and severe anemia by 22.5% (95% confidence interval, 12 to 32%) and 23.6% (95% confidence interval, 4 to 39%), respectively, and reduced hospitalizations and episodes of asymptomatic parasitemia by one-third. Protection was pronounced in the first year of life and not discernible in the second. The malaria-protective effect was largely confined to a period of 1 month after sulfadoxine-pyrimethamine treatments. Following the intervention, protection against asymptomatic parasitemia persisted. In contrast, a significant rebound of severe malaria, predominantly severe malarial anemia, occurred among children having received IPTi. Although the treatment was generally well tolerated, one case of moderately severe skin reaction followed sulfadoxine-pyrimethamine treatment. IPTi reduces malaria and anemia in infants in northern Ghana. Extension of IPTi into the second year of life by administering a dose at 15 months of age provided no substantial benefit beyond a 1-month prophylactic effect. Although this simple intervention offers one of the few available malaria-preventive measures for regions where malaria is endemic, the observed rebound of severe malaria advises caution and requires further investigation.


Assuntos
Antimaláricos/uso terapêutico , Controle de Infecções/métodos , Malária/prevenção & controle , Pirimetamina/uso terapêutico , Sulfadoxina/uso terapêutico , Anemia/epidemiologia , Anemia/etiologia , Interpretação Estatística de Dados , Método Duplo-Cego , Combinação de Medicamentos , Feminino , Seguimentos , Gana/epidemiologia , Hospitalização , Humanos , Lactente , Recém-Nascido , Malária/complicações , Malária/epidemiologia , Masculino , Resultado do Tratamento
3.
Antimicrob Agents Chemother ; 51(9): 3407-9, 2007 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-17562799

RESUMO

Surveillance of Plasmodium falciparum crt(K76T) [Pfcrt(K76T)], a resistance marker of chloroquine and, limitedly, amodiaquine, in >4,000 children in northern Ghana revealed a prevalence of 79%. Pfcrt(K76T) was heterogeneously distributed and associated with chloroquine use, low parasitemia, and the dry season. Widespread chloroquine resistance challenges the regional life span of amodiaquine as a partner drug in artemisinin combination therapy.


Assuntos
Antimaláricos/farmacologia , Resistência a Medicamentos/genética , Genes de Protozoários/genética , Malária Falciparum/epidemiologia , Malária Falciparum/parasitologia , Plasmodium falciparum/genética , Adolescente , Adulto , Idoso , Amodiaquina/farmacologia , Animais , Artemisininas/uso terapêutico , Criança , Cloroquina/farmacologia , Quimioterapia Combinada , Feminino , Genótipo , Gana/epidemiologia , Humanos , Lactonas/uso terapêutico , Masculino , Pessoa de Meia-Idade , Parasitemia/parasitologia , Vigilância da População , Sesquiterpenos/uso terapêutico
4.
Trans R Soc Trop Med Hyg ; 101(7): 637-42, 2007 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-17467758

RESUMO

Despite widespread resistance, chloroquine remains widely used in West Africa, particularly in home treatment. We examined chloroquine blood levels on admission to a referral hospital with respect to the manifestation of severe malaria in 290 Ghanaian children. Of the patients, 78% exhibited chloroquine concentrations (subtherapeutic, 35%; therapeutic, 37%; supratherapeutic, 6%) and 11% died. Most parasites (78%) carried the pfcrt-T76 chloroquine resistance mutation. High drug concentrations correlated with reduced parasitaemia but also with selection of resistant parasites, lower respiratory and heart rates, increased plasma lactate levels and impaired consciousness. Geometric mean chloroquine concentrations tended to be higher in children who died than in survivors (1.135 vs. 778nmol/l; P=0.09). Supratherapeutic drug levels (>5000nmol/l) were associated with fatal outcome (odds ratio 8.6; 95% CI 1.4-51.7). Residual chloroquine concentrations were found to be abundant in children with severe malaria and to be associated with alterations in the clinical manifestation of the disease and its case fatality. This may result from toxic effects of the drug and/or reflect preceding overtreatment in children with acute life-threatening disease. In areas of intense chloroquine resistance and frequent pre-treatment, additional administration of chloroquine at hospital admission is not only ineffective but may even further endanger patients.


Assuntos
Antimaláricos/sangue , Cloroquina/sangue , Malária Falciparum/sangue , Plasmodium falciparum/genética , Animais , Antimaláricos/efeitos adversos , Criança , Pré-Escolar , Cloroquina/efeitos adversos , Relação Dose-Resposta a Droga , Resistência a Medicamentos/genética , Feminino , Gana/epidemiologia , Humanos , Lactente , Malária Falciparum/tratamento farmacológico , Malária Falciparum/epidemiologia , Masculino , Proteínas de Membrana Transportadoras/genética , Plasmodium falciparum/efeitos dos fármacos , Proteínas de Protozoários/genética , Falha de Tratamento
5.
Microbes Infect ; 7(11-12): 1204-10, 2005.
Artigo em Inglês | MEDLINE | ID: mdl-16002312

RESUMO

A role of the heart in the pathophysiology of severe Plasmodium falciparum malaria has recently been suggested. The objective of the present study was to substantiate this finding in a large group of African children and to correlate results with metabolic conditions in these children. Furthermore, the impact of a potential cardiac impairment on outcome in severe cases was assessed. Results may have important implications on the currently ongoing debate on fluid management in severe malaria patients. Plasma levels of N-terminal pro-brain natriuretic peptide (NT-proBNP), heart-type fatty acid-binding protein (H-FABP), myoglobin and creatine kinase muscle-brain (CK-MB) were compared in 400 African children with severe and mild falciparum malaria. Plasma levels of these markers were correlated with lactate and glucose blood levels, indicators for hypovolemia, and with clinical outcome. Children suffering from severe malaria and children who died (n = 22) exhibited high to very high levels of cardiac markers, respectively. Cardiac factors themselves were not predictive of fatal outcome, while, in multivariate analysis, lactic acidosis was the most important biochemical predictor of death in the severe malaria group. Lactic acidosis and hypoglycemia, however, result in cardiac impairment as defined by elevated levels of circulating cardiac proteins. Our results point to hypovolemia as a major underlying cause of lactic acidosis and hypoglycemia in African children with severe falciparum malaria. These deleterious metabolic conditions contribute to myocardial affection which was evident but not predictive per se of fatal outcome.


Assuntos
Creatina Quinase Forma MB/sangue , Proteínas de Ligação a Ácido Graxo/sangue , Cardiopatias/etiologia , Malária Falciparum/complicações , Mioglobina/sangue , Peptídeo Natriurético Encefálico/sangue , Fragmentos de Peptídeos/sangue , Glicemia , Criança , Pré-Escolar , Gana , Humanos , Hipovolemia/etiologia , Lactente , Ácido Láctico/sangue , Malária Falciparum/sangue
6.
Trop Med Int Health ; 10(6): 512-20, 2005 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-15941413

RESUMO

The therapeutic efficacy of sulfadoxine-pyrimethamine (SP) alone, SP plus amodiaquine (AQ), and SP plus artesunate (AS) was assessed in a randomized, placebo-controlled, and double-blind trial among 438 children with uncomplicated Plasmodium falciparum malaria in northern Ghana. Clinical and parasitological responses were monitored for 28 days following treatment; 86%, 98% and 97% of SP-, SP + AQ-, and SP + AS-treated patients achieved adequate clinical and parasitological response (ACPR) within 2 weeks, respectively. Parasite clearance was better with SP + AS than with SP or SP + AQ treatment but re-infections were more common. Polymerase chain reaction (PCR)-corrected rates of ACPR at day 28 were 72.2% for SP, 94.1% for SP + AQ (P < 0.0001), and 94.5% for SP + AS (P < 0.0001). Gametocyte prevalence and density 1 week after treatment were highest in children treated with SP, and lowest in patients receiving SP + AS. No severe adverse events attributable to study medication were observed. In northern Ghana, more than one of four children suffered SP treatment failure within 4 weeks. Both SP + AQ and SP + AS are efficacious alternative therapeutic options in this region. Although SP + AS and SP + AQ treatments have virtually identical cure rates, rapid parasite clearance and pronounced gametocidal effects are the advantages of the former, whereas cost and a lower rate of late re-infections are those of the latter.


Assuntos
Amodiaquina/uso terapêutico , Antimaláricos/uso terapêutico , Artemisininas/uso terapêutico , Malária Falciparum/tratamento farmacológico , Pirimetamina/uso terapêutico , Sesquiterpenos/uso terapêutico , Sulfadoxina/uso terapêutico , Animais , Artesunato , Pré-Escolar , Método Duplo-Cego , Combinação de Medicamentos , Quimioterapia Combinada , Feminino , Genótipo , Humanos , Lactente , Masculino , Contagem de Ovos de Parasitas/métodos , Plasmodium falciparum/genética , Resultado do Tratamento
7.
Am J Trop Med Hyg ; 71(2): 167-72, 2004 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-15306705

RESUMO

The symptoms of severe malaria and their contribution to mortality were assessed in 290 children in northern Ghana. Common symptoms were severe anemia (55%), prostration (33%), respiratory distress (23%), convulsions (20%), and impaired consciousness (19%). Age influenced this pattern. The fatality rate was 11.2%. In multivariate analysis, circulatory collapse, impaired consciousness, hypoglycemia, and malnutrition independently predicted death. Children with severe malaria by the current World Health Organization (WHO) classification, but not by the previous one (1990), showed relatively mild clinical manifestations and a low case fatality rate (3.2%). In hospitalized children with severe malaria in northern Ghana, severe anemia is the leading manifestation, but itself does not contribute to mortality. In this region, malnutrition and circulatory collapse were important predictors of fatal malaria. The current WHO criteria serve well in identifying life-threatening disease, but also include rather mild cases that may complicate the allocation of immediate care in settings with limited resources.


Assuntos
Malária Falciparum/mortalidade , Índice de Gravidade de Doença , Fatores Etários , Anemia/fisiopatologia , Criança , Pré-Escolar , Feminino , Gana/epidemiologia , Humanos , Lactente , Malária Falciparum/epidemiologia , Malária Falciparum/fisiopatologia , Masculino , Fatores de Risco , Organização Mundial da Saúde
8.
J Infect Dis ; 190(5): 1006-9, 2004 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-15295709

RESUMO

Hemoglobin (Hb) C has been reported to protect against severe malaria. It is unclear whether relative resistance affects infection, disease, or both. Its extent may vary between regions and with disease pattern. We conducted a case-control study of children with severe malaria, asymptomatic parasitemic children, and healthy children in Ghana. HbAC did not prevent infection but reduced the odds of developing severe malaria and severe anemia. Protection was stronger with HbAS. The frequencies of HbCC and HbSC decreased, from healthy children to asymptomatic parasitemic children to children with severe malaria. These data support the notion that natural selection of HbC occurs because of the relative resistance it confers against severe malaria but argue against the notion that HbC offers resistance to infection.


Assuntos
Hemoglobina C , Malária Falciparum/imunologia , Malária Falciparum/fisiopatologia , Animais , Estudos de Casos e Controles , Criança , Pré-Escolar , Feminino , Gana/epidemiologia , Hemoglobina C/análise , Hemoglobina C/genética , Humanos , Imunidade Inata , Lactente , Malária Falciparum/genética , Malária Falciparum/mortalidade , Masculino , Plasmodium falciparum/patogenicidade , Índice de Gravidade de Doença
9.
Blood ; 104(7): 2003-6, 2004 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-15198952

RESUMO

The high frequency of alpha(+)-thalassemia in malaria-endemic regions may reflect natural selection due to protection from potentially fatal severe malaria. In Africa, bearing 90% of global malaria morbidity and mortality, this has not yet been observed. We tested this hypothesis in an unmatched case-control study among 301 Ghanaian children with severe malaria and 2107 controls (62% parasitemic). In control children, alpha(+)-thalassemia affected neither prevalence nor density of Plasmodium falciparum. However, heterozygous alpha(+)-thalassemia was observed in 32.6% of controls but in only 26.2% of cases (odds ratio [OR], 0.74; 95% confidence interval [CI], 0.56-0.98). Protection against severe malaria was found to be pronounced comparing severe malaria patients with parasitemic controls (adjusted OR in children < 5 years of age, 0.52; 95% CI, 0.34-0.78) and to wane with age. No protective effect was discernible for homozygous children. Our findings provide evidence for natural selection of alpha(+)-thalassemia in Africa due to protection from severe malaria.


Assuntos
Malária Falciparum/sangue , Malária Falciparum/prevenção & controle , Talassemia alfa/sangue , Talassemia alfa/genética , Estudos de Casos e Controles , Criança , Pré-Escolar , Controle de Doenças Transmissíveis , Doenças Transmissíveis/complicações , Doenças Transmissíveis/epidemiologia , Feminino , Gana , Heterozigoto , Homozigoto , Humanos , Lactente , Malária Falciparum/epidemiologia , Masculino , Análise Multivariada , Razão de Chances , Reação em Cadeia da Polimerase , Talassemia alfa/complicações , Talassemia alfa/epidemiologia
10.
Trans R Soc Trop Med Hyg ; 98(5): 302-10, 2004 May.
Artigo em Inglês | MEDLINE | ID: mdl-15109555

RESUMO

Haemoglobin (Hb) S, HbC, and alpha(+)-thalassaemia confer protection from malaria. Accordingly, these traits may influence the multiplicity of infection (MOI) of Plasmodium falciparum and the presence of distinct parasite genotypes. In 840 febrile children in northern Ghana, we typed the P. falciparum merozoite surface protein genes (msp1, msp2) and examined effects of the Hb variants on MOI and parasite diversity. HbAC, HbAS, heterozygous, and homozygous alpha(+)-thalassaemia occurred in 21, 5, 29 and 4% of the children, respectively. Plasmodium falciparum was detected in 95%. The haemoglobinopathies did not influence MOI, nor did the Hb type bias the distribution of the msp allelic families. However, IC type parasites were most common among patients with homozygous alpha(+)-thalassaemia (93%), less frequent in heterozygotes (89%), and least frequent in alpha-globin normal children (84%, P(chi2 trend) = 0.03). The opposite was seen for Mad20 type parasites (34%, 47%, 53%, P(chi2 trend) = 0.02). Only a few of the 72 individual msp alleles were selected by the haemoglobinopathies. HbC and alpha(+)-thalassaemia are frequent in northern Ghana. In symptomatic children, the effect of Hb variants on parasite multiplicity and diversity appears to be limited. This may reflect an actual lack of influence or indicate abrogation in symptomatic malaria.


Assuntos
Antígenos de Protozoários/genética , Hemoglobinopatias/complicações , Malária Falciparum/complicações , Proteína 1 de Superfície de Merozoito/genética , Plasmodium falciparum/genética , Proteínas de Protozoários/genética , Adolescente , Adulto , Alelos , Anemia Falciforme/complicações , Animais , Criança , Feminino , Doença da Hemoglobina C/complicações , Humanos , Malária Falciparum/parasitologia , Masculino , Pessoa de Meia-Idade , Talassemia alfa/complicações
11.
Trans R Soc Trop Med Hyg ; 97(6): 697-701, 2003.
Artigo em Inglês | MEDLINE | ID: mdl-16117966

RESUMO

Plasmodium falciparum malaria is a predominant reason for health care utilization among children in sub-Saharan Africa. Despite the spread of resistance, chloroquine (CQ) is the most commonly used antimalarial. Little is known about the pattern of CQ use and resistance to the drug prior to attendance at a health care facility, and its impact on clinical presentation in children attending health care facilities in endemic regions. In a cross-sectional study among 840 febrile children presenting at a primary health care facility in northern Ghana from September to December 2000, CQ blood levels were measured by enzyme-linked immunosorbent assay and parasite isolates were genotyped for the CQ resistance markers pfcrt T76 and pfmdr1 Y86. Plasmodium falciparum was present in 95% by polymerase chain reaction and CQ was detected in 64% of the children. Concentrations of CQ in blood ranged from 31 to 3897 nmol/L (median 198 nmol/L). The pfcrt T76 and pfmdr1 Y86 resistance markers were detected in 84% and 57% of the isolates, respectively, and were selected by CQ. A significant trend for higher frequencies of the resistance markers with increasing CQ concentrations was observed. In this typical primary health care setting in sub-Saharan Africa, CQ use prior to attendance at a health care facility and CQ-resistant P. falciparum are frequent. As CQ selects resistant P. falciparum genotypes, CQ should be omitted as a first-line drug even in primary health care facilities when self-treatment with CQ is common.


Assuntos
Antimaláricos/uso terapêutico , Cloroquina/uso terapêutico , Resistência a Medicamentos , Malária Falciparum/tratamento farmacológico , Proteínas de Membrana/sangue , Plasmodium falciparum/genética , Animais , Antimaláricos/sangue , Pré-Escolar , Cloroquina/sangue , Estudos Transversais , Feminino , Febre/parasitologia , Gana/epidemiologia , Humanos , Lactente , Malária Falciparum/epidemiologia , Masculino , Proteínas de Membrana Transportadoras , Plasmodium falciparum/efeitos dos fármacos , Reação em Cadeia da Polimerase/métodos , Polimorfismo de Fragmento de Restrição , Proteínas de Protozoários
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