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Publication Open Access Laboratory prediction of the requirement for renal replacement in acute falciparum malaria.(2011-08-03) Hanson, Josh; Hasan, Md Mahtab Uddin; Royakkers, Annick A; Alam, Shamsul; Prakaykaew Charunwatthana; ประกายแก้ว จรูญวรรธนะ; Maude, Richard J; Douthwaite, Sam T; Yunus, Emran Bin; Mantha, Murty L; Schultz, Marcus J; Faiz, M Abul; White, Nicholas J; Day, Nicholas P; Dondorp, Arjen M; Hanson, Josh; Mahidol University. Faculty of Tropical Medicine. Mahidol-Oxford Tropical Medicine Research Unit. Shoklo Malaria Research Unit.later requirement for RRT. In particular, laboratory indices of acute tubular necrosis (ATN) and acute kidney injury (AKI) that are used in other settings were examined. RESULTS: Data from 163 patients were available for analysis. Whether... to the limited availability of RRT. Patients with impaired renal function on admission (creatinine clearance < 60 ml/min) (n = 84) had their laboratory indices of ATN/AKI analysed. The plasma creatinine level had the greatest area under the ROC curve (AUC): 0Publication Open Access Nuclear factor kappa B in urine sediment: a useful indicator to detect acute kidney injury in Plasmodium falciparum malaria(2014-03-07) Chuchard Punsawad; Parnpen Viriyavejakul; พรรณเพ็ญ วิริยเวชกุล; Parnpen Viriyavejakul; Mahidol University. Faculty of Tropical Medicine. Department of Tropical PathologyBACKGROUND: Acute kidney injury (AKI) is one of the major complications of Plasmodium falciparum malaria, especially among non-immune adults. It has recently been revealed that activation of transcription factor nuclear factor kappa B (NF-κBPublication Open Access Acute Renal Failure in Patients with Severe Falciparum Malaria: Using the WHO 2006 and RIFLE Criteria(2013) Vipa Thanachartwet; วิภา ธนาชาติเวทย์; Varunee Desakorn; วารุณี เทศะกรณ์; Duangjai Sahassananda; ดวงใจ สหัสสานนท์; Kyaw Win, Ko Ko Yazar; Thanom Supaporn; Vipa Thanachartwet; Mahidol University. Faculty of Tropical Medicine. Department of Clinical Tropical Medicine.9% (190 patients) had acute kidney injury (AKI). The requirement for RRT was 11.6% (5 patients) in patients with RIFLE-I and 44.9% (48 patients) in patients with RIFLE-F. The in-hospital mortality gradually increased with the severity of AKIPublication Open Access The role of previously unmeasured organic acids in the pathogenesis of severe malaria(2015) Herdman, M. Trent; Natthida Sriboonvorakul; Leopold, Stije J.; Sam Douthwaite; Sanjib Mohanty; M. Mahtab Uddin Hassan; Maude, Richard J.; Kingston, Hugh WF; Katherine Plewes; Prakaykaew Charunwatthana; Kamolrat Silamut; Woodrow, Charles J.; Kesinee Chotinavich; Hossain, Md. Amir; Faiz, M. Abul; Saroj Mishra; Natchanun Leepipatpiboon; White, Nicholas J.; Day, Nicholas PJ; Joel Tarning; Dondorp, Arjen M.; Mahidol University. Faculty of Tropical Medicine. Mahidol-Oxford Tropical Medicine Research UnitIntroduction: Severe falciparum malaria is commonly complicated by metabolic acidosis. Together with lactic acid (LA), other previously unmeasured acids have been implicated in the pathogenesis of falciparum malaria. Methods: In this prospective study, we characterised organic acids in adults with severe falciparum malaria in India and Bangladesh. Liquid chromatography-mass spectrometry was used to measure organic acids in plasma and urine. Patients were followed until recovery or death. Results: Patients with severe malaria (n=138), uncomplicated malaria (n=102), sepsis (n=32) and febrile encephalopathy (n=35) were included. Strong ion gap (mean±SD) was elevated in severe malaria (8.2 mEq/L±4.5) and severe sepsis (8.6 mEq/L±7.7) compared with uncomplicated malaria (6.0 mEq/L±5.1) and encephalopathy (6.6 mEq/L±4.7). Compared with uncomplicated malaria, severe malaria was characterised by elevated plasma LA, hydroxyphenyllactic acid (HPLA), α-hydroxybutyric acid and β-hydroxybutyric acid (all P<0.05). In urine, concentrations of methylmalonic, ethylmalonic and α-ketoglutaric acids were also elevated. Multivariate logistic regression showed that plasma HPLA was a strong independent predictor of death (odds ratio [OR] 3.5, 95 % confidence interval [CI] 1.6–7.5, P=0.001), comparable to LA (OR 3.5, 95 % CI 1.5–7.8, P=0.003) (combined area under the receiver operating characteristic curve 0.81). Conclusions: Newly identified acids, in addition to LA, are elevated in patients with severe malaria and are highly predictive of fatal outcome. Further characterisation of their sources and metabolic pathways is now needed.Publication Open Access Nuclear factor kappa B modulates apoptosis in the brain endothelial cells and intravascular leukocytes of fatal cerebral malaria(2013) Chuchard Punsawad; Yaowapa Maneerat; Urai Chaisri; Kwannan Nantavisai; Parnpen Viriyavejakul; Mahidol University. Faculty of Tropical Medicine. Department of Tropical PathologyBackground: Cerebral malaria (CM) caused by Plasmodium falciparum is known to be associated with the sequestration of parasitized red blood cells (PRBCs) in the microvasculature and the release of soluble cytokines. In addition, the involvement of signaling molecules has gained wide interest in the pathogenesis of CM. An important signaling factor, nuclear factor kappa B (NF-κB) is known to regulate apoptosis. This work aimed to study the expression of NF-κB p65 and its correlation with apoptosis in the brain of fatal CM. Methods: The expression of NF-κB p65 and cleaved caspase-3 in the brain of fatal P. falciparum malaria cases was investigated by immunohistochemistry. Histopathological features were analysed together with the correlations of NF-κB p65 and cleaved caspase-3 expression. Results: NF-κB p65 activation and cleaved caspase-3 expression were significantly increased in the neurons, glial cells, vascular endothelial cells (ECs) and intravascular leukocytes of the brain in fatal CM, compared with the control brain (p < 0.001) and non-cerebral malaria (NCM) (p = 0.034). The percentage of neurons that expressed nuclear NF-κB p65 showed a positive correlation with the total score of histopathological changes (rs = 0.678; p = 0.045). Significant positive correlations were established between vascular ECs NF-κB index and ECs apoptotic index (rs = 0.717; p = 0.030) and between intravascular leukocytes NF-κB index and leukocytes apoptotic index (rs = 0.696; p = 0.037) in fatal CM. Conclusions: This study documented that NF-κB p65 is one of the signaling factors that modulates apoptosis in the brain ECs and intravascular leukocytes of fatal CM.Publication Open Access A clinicopathological correlation of the expression of the angiopoietin-Tie-2 receptor pathway in the brain of adults with Plasmodium falciparum malaria(2013) Panote Prapansilp; Isabelle Medana; Nguyen Thi Hoan Mai; Day, Nicholas PJ; Phu, Nguyen Hoan; Yeo, Tsin W; Hien, Tran Tinh; Nicholas J White; Anstey, Nicholas M; Turner, Gareth DH; Mahidol University. Faculty of Tropical Medicine. Mahidol-Oxford Tropical Medicine Research UnitBackground: Plasma angiopoietin (Ang)-2 is associated with disease severity and mortality in adults and children with falciparum malaria. However the mechanism of action of the angiopoietins in fatal malaria is unclear. This study aimed to determine whether the expression of Ang-1 and Ang-2 and their receptor Tie-2 in cerebral endothelial or parenchymal cells was specific to cerebral malaria (CM), correlated with coma or other severe clinical features, and whether plasma and CSF levels of these markers correlated with the clinical and neuropathological features of severe and fatal malaria in Vietnamese adults. Methods: Immunohistochemistry was performed for Ang-1, Ang-2 and Tie-2 on post-mortem brain tissue from fatal malaria cases and controls. Quantitative ELISA for plasma and cerebrospinal fluid levels of Ang-1, Ang-2 and Tie-2 was done to compare fatal cases with surviving patients from the same study. Results: Immunohistochemistry revealed significant differences in expression in endothelial and parenchymal cells compared to controls. However there was no significant difference in expression of these markers on endothelial cells, astroglial cells or neurons between CM and non-cerebral malaria cases. Immunostaining of Ang-1, Ang-2 and Tie-2 was also not associated with Plasmodium falciparum-infected erythrocyte sequestration in the brain. However Ang-1 and Ang-2 expression in neurons was significantly correlated with the incidence of microscopic haemorrhages. Plasma levels of Ang-2 and Ang-2/Ang-1 ratio were associated with the number of severe malaria complications and were significant and independent predictors of metabolic acidosis and fatal outcome. Conclusions: The independent prognostic significance of Ang-2 and the Ang-2/Ang-1 ratio in severe malaria was confirmed, although immunohistochemistry in fatal cases did not reveal increased expression on brain endothelium in cerebral versus non-cerebral cases. Activation of the Ang-Tie-2 pathway in severe malaria is therefore related to acidosis, number of severity criteria and outcome, but is not a specific event in the brain during cerebral malaria.Publication Open Access Chloroquine is grossly under dosed in young children with malaria: implications for drug resistance.(2014-01-23) Ursing, Johan; Eksborg, Staffan; Rombo, Lars; Bergqvist, Yngve; Blessborn, Daniel; Rodrigues, Amabelia; Kofoed, Poul-Erik; Ursing, Johan; Mahidol University. Faculty of Tropical Medicine. Mahidol Oxford Research Unit.BACKGROUND: Plasmodium falciparum malaria is treated with 25 mg/kg of chloroquine (CQ) irrespective of age. Theoretically, CQ should be dosed according to body surface area (BSA). The effect of dosing CQ according to BSA has not been determined but doubling the dose per kg doubled the efficacy of CQ in children aged <15 years infected with P. falciparum carrying CQ resistance causing genes typical for Africa. The study aim was to determine the effect of age on CQ concentrations. METHODS AND FINDINGS: Day 7 whole blood CQ concentrations were determined in 150 and 302 children treated with 25 and 50 mg/kg, respectively, in previously conducted clinical trials. CQ concentrations normalised for the dose taken in mg/kg of CQ decreased with decreasing age (p<0.001). CQ concentrations normalised for dose taken in mg/m(2) were unaffected by age. The median CQ concentration in children aged <2 years taking 50 mg/kg and in children aged 10-14 years taking 25 mg/kg were 825 (95% confidence interval [CI] 662-988) and 758 (95% CI 640-876) nmol/l, respectively (p = 0.67). The median CQ concentration in children aged 10-14 taking 50 mg/kg and children aged 0-2 taking 25 mg/kg were 1521 and 549 nmol/l. Adverse events were not age/concentration dependent. CONCLUSIONS: CQ is under-dosed in children and should ideally be dosed according to BSA. Children aged <2 years need approximately double the dose per kg to attain CQ concentrations found in children aged 10-14 years. Clinical trials assessing the efficacy of CQ in Africa are typically performed in children aged <5 years. Thus the efficacy of CQ is typically assessed in children in whom CQ is under dosed. Approximately 3 fold higher drug concentrations can probably be safely given to the youngest children. As CQ resistance is concentration dependent an alternative dosing of CQ may overcome resistance in Africa.Publication Open Access Mast cell activation in the skin of Plasmodium falciparum malaria patients.(2015-02-07) Panop Wilainam; ภานพ วิไลนาม; Rungrat Nintasen; Parnpen Viriyavejakul; พรรณเพ็ญ วิริยเวชกุล; Parnpen Viriyavejakul; Mahidol University. Faculty of Tropical Medicine. Department of Tropical Pathology.; Mahidol University. Faculty of Veterinary Science. Department of Preclinic and Applied Animal Science.BACKGROUND: Mast cells (MCs) play an important role in the immune response and inflammatory processes. Generally, MCs can be stimulated to degranulate and release histamine upon binding to immunoglobulin E (IgE). In malaria, MCs have been linked to immunoglobulin (Ig) E-anti-malarial antibodies. This study investigated the response of MCs in the skin of patients with Plasmodium falciparum malaria. METHODS: Skin tissue samples were examined from ten uncomplicated and 20 complicated P. falciparum malaria cases. Normal skin tissues from 29 cases served as controls. Pre- and post-treatment tissues were included. Histopathological changes of the skin were evaluated using haematoxylin and eosin stain. MCs were investigated using toluidine blue staining. The percentage of MC degranulation was compared among groups and correlated with clinical data. RESULTS: MC degranulation was significantly higher in the complicated P. falciparum (43.72% ± 1.44) group than the uncomplicated P. falciparum (31.35% ± 3.29) (p <0.05) and control groups (18.38% ± 1.75), (p <0.0001). MC degranulation correlated significantly with the degree of parasitaemia (r s = 0.66, p <0.0001). Associated pathological features, including extravasation of red blood cells, perivascular oedema and leukocyte infiltration were significantly increased in the malaria groups compared with the control group (all p <0.001). CONCLUSIONS: MCs in the skin dermis are activated during malaria infection, and the degree of MC degranulation correlates with parasitaemia and disease severity.Publication Open Access Liver changes in severe Plasmodium falciparum malaria: histopathology, apoptosis and nuclear factor kappa B expression.(2014-03-17) Parnpen Viriyavejakul; พรรณเพ็ญ วิริยเวชกุล; Vasant Khachonsaksumet; วสันต์ ขจรศักดิ์สุเมธ; Chuchard Punsawad; ชูชาติ พันธ์สวัสดิ์; Parnpen Viriyavejakul; Mahidol University. Faculty of Tropical Medicine. Department of Tropical Pathology.; Mahidol University. Center for Emerging and Neglected Infectious Diseases.BACKGROUND: Liver involvement in severe Plasmodium falciparum infection is commonly a significant cause of morbidity and mortality among humans. The clinical presentation of jaundice often reflects a certain degree of liver damage. This study investigated the liver pathology of severe P. falciparum malaria as well as the regulation and occurrence of apoptosis in cellular components of formalin-fixed, paraffin-embedded liver tissues. METHODS: The liver tissues used in the study came from patients who died from P. falciparum malaria with hyperbilirubinaemia (total bilirubin (TB)≥ 51.3 μmol/L or 3 mg/dl) (12 cases), P. falciparum malaria without hyperbilirubinaemia (TB<51.3 μmol/L) (10 cases); and patients who died due to accidents, whose liver histology was normal (the control group) (10 cases). The histopathology of the liver tissue was studied by routine histology method. Caspase-3 and nuclear factor kappa B (NF-κB) p65 expressions were determined using immunohistochemistry. RESULTS: The severity of liver histopathology, occurrence of apoptosis and NF-κB p65 activation in P. falciparum malaria were associated with higher TB level. Significant correlations were found between NF-κB p65 expression and apoptosis in Kupffer cells and lymphocytes in the portal tracts. CONCLUSIONS: Hyperplastic Kupffer cells and portal tract inflammation are two main features found in the liver tissues of severe P. falciparum malaria cases. In addition, NF-κB is associated with Kupffer cells and lymphocyte apoptosis in severe P. falciparum malaria.Publication Open Access Mass primaquine treatment to eliminate vivax malaria: lessons from the past(2014) Anatoly Kondrashin; Baranova, Alla M; Ashley, Elizabeth A; Judith Recht; White, Nicholas J; Sergiev, Vladimir P; Mahidol University. Faculty of Tropical Medicine. Mahidol-Oxford Tropical Medicine Research Unit) deficiency. Primaquine is the only generally available 8-aminoquinoline. Testing for G6PD deficiency is not widely available, and so whilst it is widely recommended, primaquine is often not prescribed. In the past, some countries aiming for vivax malaria... eradication deployed mass treatments with primaquine on a massive scale, without G6PD testing. In Azerbaijan, Tajikistan (formerly USSR), North Afghanistan and DPR Korea 8,270,185 people received either a 14-day “standard” or a 17-day “interrupted