Inhibition of Activin A suppressed tumor necrosis factor-α secretion and improved histopathological conditions in malarial mice

@#Malaria infection still remains as one of the most prominent parasitic diseases afflicting mankind in tropical and subtropical regions. The severity of malaria infection has often been associated to exuberant host immune inflammatory responses that could possibly lead to severe immunopathological conditions and subsequent death of host tissues. Activin A is a protein belonging to the transforming growth factor-beta (TGF-β) family that regulates multiple physiological processes and pathological-associated diseases. The biological roles of activin A have been associated with manipulation of inflammation-related processes and modulation of host immune responses. This implies that activin A protein could play a role in malaria pathogenesis since malaria infection has been closely linked to severe immune responses leading to death, However, the actual in vivo role of activin A in malaria infection remains elusive. Hence, this study was undertaken to investigate the involvement of activin A in malaria infection as well as to assess the modulating effects of activin A on the cytokine releases (TNF-α, IFN-γ and IL-10) and histopathological changes in major affected organs (kidney, liver, lung, brain and spleen) in malarial mice infected with Plasmodium berghei ANKA. Our results showed that the concentrations of plasma activin A were significantly increased in malarial mice throughout the study periods. Also. the systemic activin A level was positively correlated with malaria parasitemia. This indicates that activin A could play a role in malaria pathogenesis and malaria parasitemia development. Plasma TNF-α, IFN-γ and IL-10 cytokine levels were significantly increased in malarial mice at day-5 post infection, suggesting that these cytokines attributed to severe malaria pathogenesis. Histopathological features such as sequestration of parasitized red blood cells (pRBCs) and hemozoin formation were amongst the most common pathological conditions observed in tissues of major affected organs (kidney, liver, lung, brain and spleen) in malarial mice. Neutralization of activin A production via recombinant mouse activin RIIA Fc chimera (rmActivin RIIA Fc chimera) had significantly reduced the parasitemia levels in malarial mice. The release of TNF-α cytokine was significantly reduced as well as the sequestration of parasitized pRBCs and hemozoin formation in major affected organs in malarial mice were also alleviated following inhibition of activin A production. Overall, this preliminary study suggests that activin A could play an immune modulation role in malaria pathogenesis through modulation of TNF-α release that benefits host from severe pathological destructions provoked by intensified inflammatory responses. Further studies are warranted to elucidate the precise mechanism of immune modulation mediated by activin A and its associated immune-modulation mediators in regulating the inflammatory responses elicited during the course of malaria infection.

Progression of malaria induced pathogenicity during chloroquine therapy

@#Treatment Failure with chloroquine is one of the challenges that faced the dedicated efforts to eradicate malaria This study aims at investigating the impact of treatment failure with chloroquine on the progression of the disease-induced histo-pathogenic and immunogenic outcomes. To achieve this, Rane’s protocol with modifications was applied on a model of Plasmodium berghei ANKA infected ICR mice to determine the dose response curve of chloroquine and to screen the treatment impact on the disease progression. Chloroquine was given at 1, 5, 10, 15 and 20 mg/kg once the parasitemia reached to 20-30% (the experimental initiation point). During the subsequent days, the mice were monitored for changes in the clinical signs, hematology parameters and the progress of the parasitemia until the parasitemia reached to 60-70% (the experimental termination point) or up to 10 days after chloroquine administration in case of achieving a complete eradication of the parasite. At the end, the mice were exsanguinated and their blood and organs were collected for the biochemistry and the histology study. A complete eradication of the parasite was achieved at 20 mg/kg while recrudescence was observed at the lower doses. At 1 mg/kg, the parasite growth was comparable to that of the positive control. The histo-pathogenic and immunogenic changes were stronger in the groups that experienced recrudescence (at 5 and 10 mg/kg). All in all, the study highlights the possibility of having a worsened clinical condition when chloroquine is given at its sub-therapeutic doses during malaria treatment.

Dynamics of antibiotic usage in the Intensive Care Unit at the University Hospital of the West Indies / Dinámica del uso de Antibióticos en la Unidad de Cuidados Intensivos del Hospital Universitario de West Indies

OBJECTIVE: To determine antibiotic usage patterns in the Intensive Care Unit (ICU) at the University Hospital of the West Indies (UHWI). METHOD: A cross-sectional, analytical study of consecutive patients admitted to the ICU was conducted between July and December 2007. Exclusion criteria were HIV-positive patients, patients < 12 years and those discharged or who died within 48 hours of admission. Data were collected from medical records, stored and analysed using the SPSS Version 12. RESULTS: Of the 150 eligible patients, 109 had complete data (73%). Mean age was 50.8 ± 20.7 years, with mean APACHE II score of 15.6 ± 6.7. Forty-five patients (41.3%) received prophylactic antibiotics, most commonly ceftriaxone (31.7%) and metronidazole (19.0%). Appropriate discontinuation within 24 hours occurred in only 11.1%. Two-thirds of patients (67.9%) were treated with empiric antibiotics, most commonly piperacillin/tazobactam (32.1%), ceftazidime (27.5%) or metronidazole (27.5%). Reasons for empiric choice were primarily coverage of organisms based on presumed source of sepsis (45.6%), and broad spectrum, high-powered coverage (23.5%). Courses ranged from 1 - 42 days and were adequate based on subsequent cultures in 71% of cases. Culture reports took between 2 - 8 days with a mean of 3.7 days to become available. De-escalation was practised in only 2 of 26 (7.7%) cases and intravenous to oral switch therapy in only 3.3%. Thirty-two (29.4%) patients died, with sepsis being a cause in 12 (37.5%). CONCLUSIONS: Improved attention to discontinuation of prophylactic antibiotics, appropriate duration of antibiotic courses and de-escalation are essential if the antibiotic practices in the ICU at the UHWI are to compare favourably with international recommendations.

OBJETIVO: Determinar los patrones de uso de antibióticos en la Unidad de Cuidados Intensivos (UCI) en el Hospital Universitario de West Indies. MÉTODO: Se llevó a cabo un estudio analítico transversal de un número de pacientes consecutivos ingresados a la UCI entre julio y diciembre de 2007. Los criterios de exclusión fueron los siguientes: pacientes positivos al VIH, pacientes < 12 años, y pacientes dados de alta o fallecidos dentro de las 48 horas de su ingreso. Los datos fueron tomados de las historias clínicas, y luego almacenados y analizados usando la versión doce de SPSS. RESULTADOS: De los 150 pacientes elegibles, 109 completaron los datos (73%). La edad promedio fue 50.8 ± 20.7 años, con una puntuación APACHE II media de 15.6 ± 6.7. Cuarenta y cinco pacientes (41.3%) recibieron antibióticos profilácticos, por lo general ceftriaxona (31.7%) y metronidazol (19.0%). Una descontinuación adecuada dentro de las 24 horas se produjo en sólo 11.1%. Dos tercios de los pacientes (67.9%) recibieron tratamiento antibiótico empírico, por lo general con piperacillinatazobactam (32.1%), ceftazidima (27.5%) o metronidazol (27.5%). Las razones para la opción empírica fueron principalmente la cobertura de organismos sobre la base de fuentes de sepsis presuntiva (45.6%), y el espectro ancho, cobertura de alta potencia (23.5%). Los cursos fluctuaron de 1 - 42 días y fueron adecuados a juzgar por los cultivos subsiguientes en 71% de los casos. Los reportes de cultivos tomaron entre 2 - 8 días con un promedio de 3.7 días para hallarse disponibles. El desescalamiento fue practicado en sólo 2 de 26 (7.7%) de los casos y cambio de terapia intravenosa a oral en sólo 3.3%. Treinta y dos (29.4%) pacientes murieron, siendo la sepsis la causa en 12 (37.5%). CONCLUSIONES: Una mayor atención en cuanto a descontinuar el uso de antibióticos profilácticos, una duración apropiada de cursos antibióticos, y el desescalamiento, son esenciales si se quiere que las prácticas antibióticas en las UCI en el HUWI puedan compararse favorablemente con las recomendaciones que se hacen a nivel internacional.

A survey of physicians' knowledge and attitudes regarding antimicrobial resistance and antibiotic prescribing practices at the University Hospital of the West Indies / Un estudio sobre los conocimientos y actitudes de los médicos en relación con la resistencia antimicrobiana y la práctica de prescripción de antibióticos en el Hospital Universitario de West Indies

OBJECTIVE: To identify physicians' knowledge and attitudes regarding antimicrobial resistance and antibiotic prescribing practices at the University Hospital of the West Indies (UHWI). METHODS: A cross-sectional survey of physicians at the UHWI was conducted between September 2008 and April 2009 using a 28-item, self-administered questionnaire. Eligible physicians from several specialities were identified from departmental rotas. RESULTS: A total of 174 physicians completed the questionnaire, a response rate of 73%. Most physicians considered antibiotic resistance to be an extremely important global problem (55%) but less significant nationally (35%). Factors identified as important in producing resistance included wide-spread use of antibiotics (91%), inappropriate empiric choices (79%) and use of broad-spectrum agents (70%). Hand-washing was not considered to be important in reducing resistance. Useful interventions included access to current information on local resistance patterns (90%), institutional specific antibiotic guidelines (89%) and educational programmes (89%). Antibiotic cycling (40%) and restriction (35%) were regarded as less helpful. Knowledge of resistance-prone antibiotics and specific resistant organisms at the UHWI was poor, except for methicillin-resistant Staphylococcus aureus (MRSA). Empiric therapy for common infections was appropriate in most cases, and antibiotic choices were guided by availability of drugs (89%) and patient factors such as renal disease or allergy (80%). Only 45% of physicians would de-escalate to a narrow-spectrum antibiotic guided by a microbiology report, and consultants were more likely to de-escalate therapy than junior staff (p = 0.002). CONCLUSIONS: Although physicians were aware of the problem of resistance to antibiotics and the contributory factors, their practice did not reflect measures to reduce it. Continuing educational programmes and institution-specific antibiotic prescribing guidelines are needed.

OBJETIVO: Identificar los conocimientos y actitudes de los médicos con respecto a la resistencia antimicrobiana y la práctica de prescripción de antibióticos en el Hospital Universitario de West Indies (UHWI). MÉTODOS: Se llevó a cabo un estudio transversal en UHWI, entre septiembre del 2008 y abril del 2009 de abril, usando un cuestionario autoadministrado de 28 puntos. Los médicos elegibles de varias especialidades fueron identificados de las listas departamentales. RESULTADOS: Un total de 174 médicos completaron el cuestionario, para una tasa de respuesta del 73%. La mayor parte de los médicos consideró que la resistencia antibiótica constituye un problema sumamente importante desde un punto de vista global (55%) pero menos significativo desde una perspectiva nacional (35%). Los factores identificados como importantes en la formación de la resistencia incluyeron el uso generalizado de antibióticos (91%), las elecciones empíricas inapropiadas (79%), y el uso de agentes de amplio espectro (70%). El lavarse las manos no se consideró importante para la reducción de la resistencia. Las intervenciones útiles incluyeron el acceso a la información corriente sobre patrones de resistencia locales (90%), normas institucionales específicas sobre el uso de antibióticos (89%) y programas educativos (89%). El ciclo (40%) y la restricción (35%) de los antibióticos se consideraron menos útiles. El conocimiento de antibióticos con tendencia a la resistencia y organismos resistentes específicos en el HUWI era pobre, excepto en el caso del Staphylococcus aureus resistente a la meticilina (SARM). La terapia empírica para las infecciones comunes fue apropiada en la mayoría de los casos, y las opciones antibióticas estuvieron dictadas por la disponibilidad de medicamentos (89%) y factores relacionados con los pacientes, tales como enfermedades renales o alergias (80%). Sólo el 45% de los médicos desescalarían a un antibiótico de estrecho espectro guiado por un informe microbiológico, y los consultantes mostraron una tendencia mayor a desescalar la terapia, en comparación con la observada en el personal subalterno (p = 0.002). CONCLUSIONES: Aunque los médicos tenían conciencia del problema de la resistencia a los antibióticos y los factores contribuyentes, su práctica no reflejó las medidas para reducirla. Se necesitan programas de educación continua y normas institucionales específicas para la prescripción de antibióticos.