Recent Publications by Tulane Public Health Researchers


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The Department of Tropical Medicine
Selected Recent Publications

Researchers	Title	Publication	Abstract
Jacquerioz FA, Croft AM.	Drugs for preventing malaria in travellers.	Cochrane Database Syst Rev. 2009 Oct 7;4:CD006491.	BACKGROUND: Malaria infects 10,000 to 30,000 international travellers each year. It can be prevented through anti-mosquito measures and drug prophylaxis. However, antimalaria drugs have adverse effects which are sometimes serious. OBJECTIVES: To compare the effects of currently used antimalaria drugs when given as prophylaxis to non-immune adult and child travellers who are travelling to regions with Plasmodium falciparum resistance to chloroquine. Specifically, to assess the efficacy, safety, and tolerability of atovaquone-proguanil, doxycycline, and mefloquine compared to each other, and also when compared to chloroquine-proguanil and to primaquine. SEARCH STRATEGY: In August 2009 we searched the Cochrane Infectious Diseases Group Specialized Register, CENTRAL (The Cochrane Library 2008, Issue 4), MEDLINE, EMBASE, LILACS, BIOSIS, mRCT, and reference lists. We handsearched conference proceedings and one specialist journal, and contacted researchers and drug companies. We searched PubMed for drug-related deaths. SELECTION CRITERIA: Randomized and quasi-randomized controlled trials of any antimalaria drug regimen currently used by non-immune international travellers. DATA COLLECTION AND ANALYSIS: We independently extracted data and assessed eligibility and risk of bias using a standardized data collection form. We resolved any disagreement through discussion. We combined dichotomous outcomes using risk ratio (RR) and continuous data using mean difference (MD), presenting both with 95% confidence intervals (CI). MAIN RESULTS: Eight trials (4240 participants) met the inclusion criteria. Evidence on comparative efficacy from head-to-head comparisons was limited. Atovaquone-proguanil compared to doxycycline had similar adverse events reported. Compared to mefloquine, atovaquone-proguanil users had fewer reports of any adverse effect (RR 0.72, 95% CI 0.6 to 0.85), gastrointestinal adverse effects (RR 0.54, 95% CI 0.42 to 0.7), neuropsychiatric adverse events (RR 0.86, 95% CI 0.75 to 0.99), and neuropsychiatric adverse effects (RR 0.49, 95% CI 0.38 to 0.63), besides a better total mood disturbance score (MD -7.20, 95% CI -10.79 to -3.61). Similarly, doxycycline users had fewer reported neuropsychiatric events than mefloquine users (RR 0.84, 95% CI 0.73 to 0.96). We also examined these three regimens against chloroquine-proguanil; this latter regimen had more reports of any adverse effect (RR 0.84, 95% CI 0.73 to 0.96) and of gastrointestinal adverse effects (RR 0.71, 95% CI 0.6 to 0.85). AUTHORS' CONCLUSIONS: Atovaquone-proguanil and doxycycline are the best tolerated regimens, and mefloquine is associated with adverse neuropsychiatric outcomes.
Koehler JW, Bolton M, Rollins A, Snook K, deHaro E, Henson E, Rogers L, Martin LN, Krogstad DJ, James MA, Rice J, Davison B, Veazey RS, Prabhu R, Amedee AM, Garry RF, Cogswell FB.	Altered immune responses in rhesus macaques co-infected with SIV and Plasmodium cynomolgi: an animal model for coincident AIDS and relapsing malaria.	PLoS One. 2009 Sep 23;4(9).	BACKGROUND: Dual epidemics of the malaria parasite Plasmodium and HIV-1 in sub-Saharan Africa and Asia present a significant risk for co-infection in these overlapping endemic regions. Recent studies of HIV/Plasmodium falciparum co-infection have reported significant interactions of these pathogens, including more rapid CD4+ T cell loss, increased viral load, increased immunosuppression, and increased episodes of clinical malaria. Here, we describe a novel rhesus macaque model for co-infection that supports and expands upon findings in human co-infection studies and can be used to identify interactions between these two pathogens. METHODOLOGY/PRINCIPAL FINDINGS: Five rhesus macaques were infected with P. cynomolgi and, following three parasite relapses, with SIV. Compared to macaques infected with SIV alone, co-infected animals had, as a group, decreased survival time and more rapid declines in markers for SIV progression, including peripheral CD4+ T cells and CD4+/CD8+ T cell ratios. The naïve CD4+ T cell pool of the co-infected animals was depleted more rapidly than animals infected with SIV alone. The co-infected animals also failed to generate proliferative responses to parasitemia by CD4+ and CD8+ T cells as well as B cells while also having a less robust anti-parasite and altered anti-SIV antibody response. CONCLUSIONS/SIGNIFICANCE: These data suggest that infection with both SIV and Plasmodium enhances SIV-induced disease progression and impairs the anti-Plasmodium immune response. These data support findings in HIV/Plasmodium co-infection studies. This animal model can be used to further define impacts of lentivirus and Plasmodium co-infection and guide public health and therapeutic interventions.
Wolf H, Mendez M, Gilman RH, Sheen P, Soto G, Velarde AK, Zimic M, Escombe AR, Montenegro S, Oberhelman RA, Evans CA.	Diagnosis of Pediatric Pulmonary Tuberculosis by Stool PCR.	Am J Trop Med Hyg. 2008 Dec;79(6):893-898.	Pediatric pulmonary tuberculosis diagnosis is difficult because young children are unable to expectorate sputum samples. Testing stool for tuberculosis DNA from swallowed sputum may diagnose pulmonary tuberculosis. Hospitalized children with suspected tuberculosis had stool, nasopharyngeal, and gastric aspirates cultured that confirmed pulmonary tuberculosis in 16/236 patients. Twenty-eight stored stools from these 16 children were used to evaluate stool polymerase chain reaction (PCR) for tuberculosis diagnosis compared with 28 stool samples from 23 healthy control children. Two DNA extraction techniques were used: fast-DNA mechanical homogenization and Chelex-resin chemical extraction. DNA was tested for tuberculosis DNA with a hemi-nested IS6110 PCR. PCR after Fast-DNA processing was positive for 6/16 culture-proven tuberculosis patients versus 5/16 after Chelex extraction (sensitivity 38% and 31%, respectively). All controls were negative (specificity 100%). If sensitivity can be increased, stool PCR would be a rapid, non-invasive, and relatively bio-secure initial test for children with suspected pulmonary tuberculosis.
Kang S, Sim C, Byrd BD, Collins FH, Hong YS.	Ex vivo promoter analysis of antiviral heat shock cognate 70B gene in Anopheles gambiae.	Virol J. 2008 Nov 5;5:136.	Background The Anopheles gambiae heat shock cognate gene (hsc70B) encodes a constitutively expressed protein in the hsp70 family and it functions as a molecular chaperone for protein folding. However, the expression of hsc70B can be further induced by certain stimuli such as heat shock and infection. We previously demonstrated that the An. gambiae hsc70B is induced during o'nyong-nyong virus (ONNV) infection and subsequently suppresses ONNV replication in the mosquito. To further characterize the inducibility of hsc70B by ONNV infection in An. gambiae, we cloned a 2.6-kb region immediately 5' upstream of the starting codon of hsc70B into a luciferase reporter vector (pGL3-Basic), and studied its promoter activity in transfected Vero cells during infection with o'nyong-nyong, West Nile and La Crosse viruses. Results Serial deletion analysis of the hsc70B upstream sequence revealed that the putative promoter is likely located in a region 1615-2150 bp upstream of the hsc70B starting codon. Sequence analysis of this region revealed transcriptional regulatory elements for heat shock element-binding protein (HSE-bind), nuclear factor kappaB (NF-kappaB), dorsal (Dl) and fushi-tarazu (Ftz). Arbovirus infection, regardless of virus type, significantly increased the hsc70B promoter activity in transfected Vero cells. Conclusion Our results further validate the transcriptional activation of hsc70B during arbovirus infection and support the role of specific putative regulatory elements. Induction by three taxonomically distinct arboviruses suggests that the HSC70B protein may be expressed to cope with cellular stress imposed during infection.
Jacquérioz FA, Belizán JM, Buekens P.	Recommendations to increase the impact of maternal and childbirth health systematic reviews in the Americas.	Paediatr Perinat Epidemiol. 2008 Jan;22 Suppl 1:61-6.	This paper summarises the discussions and the recommendations formulated during a meeting in March 2007 on the challenges and strategies to increase the impact of maternal and childbirth health systematic reviews in the Americas. The discussions addressed three specific themes: (1) performing systematic reviews (2) updating existing reviews, and (3) diffusing and implementing evidence into practice. Practical recommendations were devised for each theme in small group discussions.
Kang S, Hong YS.	RNA interference in infectious tropical diseases.	Korean J Parasitol. 2008 Mar;46(1):1-15.	Introduction of double-stranded RNA (dsRNA) into some cells or organisms results in degradation of its homologous mRNA, a process called RNA interference (RNAi). The dsRNAs are processed into short interfering RNAs (siRNAs) that subsequently bind to the RNA-induced silencing complex (RISC), causing degradation of target mRNAs. Because of this sequence-specific ability to silence target genes, RNAi has been extensively used to study gene functions and has the potential to control disease pathogens or vectors. With this promise of RNAi to control pathogens and vectors, this paper reviews the current status of RNAi in protozoans, animal parasitic helminths and disease-transmitting vectors, such as insects. Many pathogens and vectors cause severe parasitic diseases in tropical regions and it is difficult to control once the host has been invaded. Intracellularly, RNAi can be highly effective in impeding parasitic development and proliferation within the host. To fully realize its potential as a means to control tropical diseases, appropriate delivery methods for RNAi should be developed, and possible off-target effects should be minimized for specific gene suppression. RNAi can also be utilized to reduce vector competence to interfere with disease transmission, as genes critical for pathogenesis of tropical diseases are knockdowned via RNAi.
Coleman CA, Muller-Trutwin MC, Apetrei C, Pandrea I.	T regulatory cells: aid or hindrance in the clearance of disease.	J Cell Mol Med 2007;11(6):1291-1325.	CD4+ CD25+ T regulatory cells (Tregs) are classified as a subset of T cells whose role is the suppression and regulation of immune responses to self and non-self. Since their discovery in the early 1970s, the role of CD4+ CD25+ Tregs in both autoimmune and infectious disease has continued to expand. This review exam-ines the recent advances on the role CD4+ CD25+ Tregs may be playing in various diseases regarding pro-gression or protection. In addition, advances made in the purification and manipulation of CD4+ CD25+ Tregs using new cell markers, techniques and antibodies are discussed. Ultimately, an overall understanding of the exact mechanism which CD4+ CD25+ Tregs implement during disease progression will enhance our ability to manipulate CD4+ CD25+ Tregs in a clinically beneficial manner.
Mzayek F, Hassig S, Sherwin R, Hughes J, Chen W, Srinivasan S, Berenson G.	The association of birth weight with developmental trends in blood pressure from childhood through mid-adulthood: the Bogalusa Heart Study.	Am J Epididemiol 2007;166(4):413-20.	Low birth weight has been found to be associated with cardiovascular mortality and morbidity and with an adverse profile of several cardiovascular risk factors. The inverse association between birth weight and blood pressure was consistently reported from many populations. Using longitudinal data from the Bogalusa Heart Study (Louisiana), the authors investigated the association between birth weight and progression of blood pressure through early adulthood, comparing that relation between African Americans and Whites. Birth data of 2,275 participants, screened two or more times in the Bogalusa Heart Study between 1973 and 2001, were retrospectively obtained from birth certificates and were linked to their clinical, laboratory, and socioeconomic and lifestyle data in the Bogalusa Heart Study data sets. Birth weight was inversely associated with systolic blood pressure, diastolic blood pressure, and pulse pressure (p<or=0.01 for all). For every 1-kg increase in birth weight, systolic blood pressure dropped by 1.9 mmHg (95% confidence interval: -2.6, -1.3), diastolic blood pressure by 0.7 mmHg (95% confidence interval: -1.2, -0.2), and pulse pressure by 1.2 mmHg (95% confidence interval: -1.7, -0.7). The interaction of birth weight with ethnicity was not significant for any outcome. Birth weight was inversely associated with later blood pressure. The strength of that association did not differ between African Americans and Whites.
Fair J, Jentes E, Inapogui A, Kourouma K, Goba A, Bah A, Tounkara M, Coulibaly M, Garry RF, Bausch DG.	Lassa virus-infected rodents in refugee camps in Guinea: a looming threat to public health in a politically unstable region.	Vector Borne Zoonotic Dis 2007;7(2):167-71.	Rodent-borne and other communicable diseases are of particular concern to vulnerable populations in complex humanitarian emergencies. We assessed the risk of Lassa fever to refugees and humanitarian aid workers in the Forest Region of Guinea by trapping rodents and testing them for the presence of Lassa virus infection. Our study provides a point prevalence of Lassa virus-infected rodents in various refugee camps in Guinea, suggesting that the risk of disease may be highest in camps further south toward the border with Liberia. The methodology used represents a potential model for rapid public health assessments in the setting of complex humanitarian emergencies.
Gautam R, Carter AC, Katz N, Butler IF, Barnes M, Hasegawa A, Ratterree M, Silvestri G, Marx PA, Hirsch VM, Pandrea I, Apetrei C	In vitro characterization of primary SIVsmm isolates belonging to different lineages.	Virology. 2007 Jun 5. 362(2):257-70	We report in vitro characterization of 11 SIVsmm strains of six lineages co-circulating in naturally infected sooty mangabeys (SMs) from US Primate Centers and showed no major differences in the in vitro replication pattern between different SIVsmm lineages. Primary SIVsmm isolates utilized CCR5 and Bonzo co-receptors in vitro. SIVsmm growth in human T cell lines was isolate-, not lineage-specific, with poor replication on Molt4-Clone8, CEMss and PM1 cells and better replication on MT2, SupT1 and CEMx174 cells. All primary SIVsmm isolates replicated on SM and human PBMCs. In vitro replication in macaques varied widely, with moderate to high replication in pig-tailed macaque PBMCs, enhanced by CD8+ T cell depletion, and highly variable replication on rhesus macaque (Rh) PBMCs. Primary SIVsmm isolates replicated in Rh monocyte-derived dendritic cells (MDDCs) and monocyte-derived macrophages (MDMs). Invivo, SIVsmm isolates replicated at high levels in all SIVsmm-infected Rh. The poor in vitro replication of primary SIVsmm isolates in Rh cells did not correlate with in vivo replication, emphasizing the value of in vivo studies.
Brindley PJ, Pearce EJ	Genetic manipulation of schistosomes	Int J Parasitology	In contrast to the situations with model organisms and parasitic protozoa, progress with gene manipulation with schistosomes has been delayed by impediments that include our inability to maintain the life cycle in vitro, absence of immortalized cell lines, large genome sizes, unavailability of drug resistance markers, and other difficulties. However, in the past few years, tangible progress has been reported towards development of tools for gene manipulation and transgenesis of schistosomes, and there is reason to believe that the filed is on the verge of transformation into an era where genetic manipulation is routine. Recent reports dealing with approaches and tools to manipulate the genome and gene expression in schistosomes are reviewed here.
Pandrea I, Apetrei C, Gordon S, Barbercheck J, Dufour J, Bohm R, Sumpter B, Roques P, Marx PA, Hirsch VM, Kaur A, Lackner AA, Veazey RS, Silvestri G	Paucity of CD4+CCR5+ T cells is a typical feature of natural SIV hosts	Blood. 2007 Feb 1. 109(3):1069-76	In contrast to lentiviral infections of humans and macaques, simian immunodeficiency virus (SIV) infection of natural hosts is nonpathogenic despite high levels of viral replication. However, the mechanisms underlying this absence of disease are unknown. Here we report that natural hosts for SIV infection express remarkably low levels of CCR5 on CD4+ T cells isolated from blood, lymph nodes, and mucosal tissues. Given that this immunologic feature is found in 5 different species of natural SIV hosts (sooty mangabeys, African green monkeys, mandrills, suntailed monkeys, and chimpanzees) but is absent in 5 nonnatural/recent hosts (humans, rhesus, pigtail cynomolgus macaques, and baboons), it may represent a key feature of the coevolution between the virus and its natural hosts that led to a nonpathogenic infection. Beneficial effects of low CCR5 expression on CD4+ T cells may include the reduction of target cells for viral replication and a decreased homing of activated CD4+ T cell to inflamed tissue.
Bausch DG, Nichol ST, Muyembe-Tamfum JJ, Borchert M, Rollin PE, Sleurs H, Campbell P, Tshioko FK, Roth C, Colebunders R, Pirard P, Mardel S, Olinda LA, Zeller H, Tshomba A, Kulidri A, Libande ML, Mulangu S, Formenty P, Grein T, Leirs H, Braack L, Ksiazek T, Zaki S, Bowen MD, Smit SB, Leman PA, Burt FJ, Kemp A, Swanepoel R, the International Scientific and Technical Committee for Marburg Hemorrhagic Fever Control in the Democratic Republic of the Congo	Marburg Hemorrhagic Fever Associated with Multiple Genetic Lineages of Virus	N Engl J Med 2006; 355:909-919, Aug 31, 2006	Background An outbreak of Marburg hemorrhagic fever was first observed in a gold-mining village in northeastern Democratic Republic of the Congo in October 1998. Methods We investigated the outbreak of Marburg hemorrhagic fever most intensively in May and October 1999. Sporadic cases and short chains of human-to-human transmission continued to occur until September 2000. Suspected cases were identified on the basis of a case definition; cases were confirmed by the detection of virus antigen and nucleic acid in blood, cell culture, antibody responses, and immunohistochemical analysis. Results A total of 154 cases (48 laboratory-confirmed and 106 suspected) were identified (case fatality rate, 83 percent); 52 percent of cases were in young male miners. Only 27 percent of these men reported having had contact with other affected persons, whereas 67 percent of patients who were not miners reported such contact (P<0.001). Most of the affected miners (94 percent) worked in an underground mine. Cessation of the outbreak coincided with flooding of the mine. Epidemiologic evidence of multiple introductions of infection into the population was substantiated by the detection of at least nine genetically distinct lineages of virus in circulation during the outbreak. Conclusions Marburg hemorrhagic fever can have a very high case fatality rate. Since multiple genetic variants of virus were identified, ongoing introduction of virus into the population helped perpetuate this outbreak. The findings imply that reservoir hosts of Marburg virus inhabit caves, mines, or similar habitats.
Oberhelman RA, Soto-Castellares G, Caviedes L, Castillo ME, Kissinger P, Moore DA, Evans C, Gilman RH	Improved recovery of Mycobacterium tuberculosis from children using the microscopic observation drug susceptibility method	Pediatrics. 118(1):e100-6, 2006 Jul	Objectives The diagnosis of pulmonary tuberculosis presents challenges in children, because symptoms are nonspecific, sputa are not accessible, and Mycobacterium tuberculosis cultures and smears often are negative. The Microscopic Observation Drug Susceptibility technique is a simple, inexpensive method for Mycobacterium tuberculosis isolation with superior speed and sensitivity over Lowenstein-Jensen culture in studies of adults with pulmonary tuberculosis. The objective of this study was to determine whether Microscopic Observation Drug Susceptibility culture can improve the sensitivity and speed of Mycobacterium tuberculosis recovery among Peruvian children with symptoms suggestive of pulmonary tuberculosis. Methods Two specimens of each type (gastric aspirate, nasopharyngeal aspirate, and stool specimens) were collected from each patient, examined by auramine stain, and cultured by Microscopic Observation Drug Susceptibility and Lowenstein-Jensen techniques. Patients (n=165) were enrolled between April 2002 and February 2004 at the Instituto de Salud del Nino, the major pediatric hospital in Lima, Peru. Inclusion criteria were age < or = 12 years, Stegen-Toledo clinical score > or = 5 points, and absence of antituberculous therapy. The main outcome measurements were (1) proportion of specimens that were culture positive by Microscopic Observation Drug Susceptibility versus Lowenstein-Jensen and (2) days required for positive culture result, stratified by specimen type and auramine stain result. Results Fifteen (9%) patients had at least 1 positive Mycobacterium tuberculosis culture (from stool in 3 cases, nasopharyngeal aspirate in 8 cases, and gastric aspirate in 15 cases). Thirty-eight culture-positive specimens were obtained (22 gastric aspirate, 12 nasopharyngeal aspirates, and 4 stools). Microscopic Observation Drug Susceptibility provided significantly more positive cultures than Lowenstein-Jensen (33 of 38 specimens culture positive by Microscopic Observation Drug Susceptibility vs 21 of 38 by Lowenstein-Jensen). This was attributed to enhanced recovery of Mycobacterium tuberculosis from auramine-negative specimens (19 of 23 by Microscopic Observation Drug Susceptibility vs 9 of 23 by Lowenstein-Jensen), in contrast to similar detection rates for the 2 tests with auramine-positive samples. Similar results were found for analyses that were limited to gastric aspirates. Isolation was faster by Microscopic Observation Drug Susceptibility than Lowenstein-Jensen. Conclusions Isolation of Mycobacterium tuberculosis from children with suspected pulmonary tuberculosis by Microscopic Observation Drug Susceptibility demonstrated greater yield and faster recovery than by Lowenstein-Jensen method, significantly improving local capabilities to detect pediatric tuberculosis in resource-poor settings.
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