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2.  Differential Effect of Regional Drug Pressure on Dihydrofolate Reductase and Dihydropteroate Synthetase Mutations in Southern Mozambique 
The prevalence and frequency of the dihydrofolate reductase (dhfr) and dihydropteroate synthetase (dhps) mutations associated with sulfadoxine–pyrimethamine (SP) resistance at 13 sentinel surveillance sites in southern Mozambique were examined regularly between 1999 and 2004. Frequency of the dhfr triple mutation increased from 0.26 in 1999 to 0.96 in 2003, remaining high in 2004. The dhps double mutation frequency peaked in 2001 (0.22) but declined to baseline levels (0.07) by 2004. Similarly, parasites with both dhfr triple and dhps double mutations had increased in 2001 (0.18) but decreased by 2004 (0.05). The peaking of SP resistance markers in 2001 coincided with a SP–resistant malaria epidemic in neighboring KwaZulu-Natal, South Africa. The decline in dhps (but not dhfr) mutations corresponded with replacement of SP with artemether–lumefantrine as malaria treatment policy in KwaZulu-Natal. Our results show that drug pressure can exert its influence at a regional level rather than merely at a national level.
PMCID: PMC3748784  PMID: 18256426
3.  Experimental Infection of Eastern Gray Squirrels (Sciurus carolinensis) with West Nile Virus 
Eastern gray squirrels (Sciurus carolinensis) have shown high West Nile virus (WNV) seroprevalence, and WNV infection has been suggested as a cause of morbidity and mortality in this species. We experimentally infected nine eastern gray squirrels with WNV to determine the clinical effects of infection and to assess their potential role as amplifying hosts. We observed no morbidity or mortality attributable to WNV infection, but lesions were apparent in several organs. We detected mean viremias of 105.1 and 104.8 plaque-forming units (PFU)/mL on days 3 and 4 post-infection (DPI) and estimated that ~2.1% of Culex pipiens feeding on squirrels during 1–5 DPI would become infectious. Thus, S. carolinensis are unlikely to be important amplifying hosts and may instead dampen the intensity of transmission in most host communities. The low viremias and lack of mortality observed in S. carolinensis suggest that they may be useful as sentinels of spillover from the enzootic amplification cycle.
PMCID: PMC3632857  PMID: 18784241
4.  Diagnosis of Pediatric Pulmonary Tuberculosis by Stool PCR 
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.
PMCID: PMC2912504  PMID: 19052299
5.  Artemether Treatment of Prepatent Schistosoma japonicum Induces Resistance to Reinfection in Association with Reduced Pathology 
Artemether (ART) is a well-described antimalarial with efficacy against juvenile schistosomes, with 7-day-old schistosomula being particularly susceptible. Both ART-affected worms and parasites developing from irradiated cercariae die at similar times after infection. Our aim was to determine if ART treatment of prepatent schistosomiasis japonica may result in the generation of a protective immune response. Female CBA mice were treated with a single dose of ART at defined time points after percutaneous infection with a virulent Chinese mainland strain of Schistosoma japonicum. Half of the mouse cohorts were subjected to homologous parasite strain reinfection after drug treatment to assess protective effects of ART therapy. Two independent trials demonstrated that a statistically significant (58% and 50%) reduction in challenge worm burden occurred after reinfection of those mice treated with ART at two weeks p.i. A reduction in the IL-4 response to soluble worm antigen preparation (SWAP) was also seen in ART-treated mice but with no correlation to reinfection resistance. In the Chinese mainland strain used, ART treatment of prepatent infection at the appropriate time point induced resistance to reinfection. There was also an anti-pathology effect observed in ART-treated mice that remained significant after reinfection.
PMCID: PMC2756499  PMID: 18541772
6.  Modeling the Financial and Clinical Implications of Malaria Rapid Diagnostic Tests in the Case-management of Older Children and Adults in Kenya 
Using data on clinical practices for outpatients 5 years and older, test accuracy, and malaria prevalence, we model financial and clinical implications of malaria rapid diagnostic tests (RDTs) under the new artemether-lumefantrine (AL) treatment policy in one high and one low malaria prevalence district in Kenya. In the high transmission district, RDTs as actually used would improve malaria treatment (61% less over-treatment but 8% more under-treatment) and lower costs (21% less). Nonetheless, the majority of patients with malaria would not be correctly treated with AL. In the low transmission district, especially because the treatment policy was new and AL was not widely used, RDTs as actually used would yield a minor reduction in under-treatment errors (36% less but the base is small) with 41% higher costs. In both districts, adherence to revised clinical practices with RDTs has the potential to further decrease treatment errors with acceptable costs.
PMCID: PMC2582142  PMID: 18541764
7.  Wastewater quality and the risk of intestinal nematode infection in sewage farming families in Hyderabad, India 
The use of sewage or wastewater in agriculture is becoming increasingly common as a result of global water scarcity. Intestinal nematode infections have been identified as the main health risk associated with this practise. To protect consumer and farmer health the WHO has set an intestinal nematode water quality standard. However because of a lack of well designed studies the validity of this guideline is questioned. This paper presents the findings of a study on the risk of intestinal nematode infections in farming families occupationally exposed to untreated and partially treated wastewater in Hyderabad, India.
The study found an increased risk of hookworm (OR: 3.5, 95% CI 2.2-5.5), Ascaris lumbricoides (OR: 5.3, 95% CI: 2.0-14) and Trichuris trichiura (OR: 5.6, 95% CI: 1.8-18) infection when untreated wastewater (150 intestinal nematode ova/L) was used for crop production. The use of partially treated wastewater (28 intestinal nematode ova/L) was only associated with an increased risk (OR: 3.2, 95% CI: 1.2-8.6) of Ascaris lumbricoides infection. The findings of the study suggest that the current WHO intestinal nematode guideline of 1 ova/L is sufficient to protect farmer health.
PMCID: PMC2665018  PMID: 18840745
8.  High-dose Primaquine Regimens against Relapse of Plasmodium vivax Malaria 
Plasmodium vivax causes debilitating but usually non-lethal malaria in most of Asia and South America. Prevention of relapse after otherwise effective therapy for the acute attack requires a standard daily dose of primaquine administered over 14 days. This regimen has < 90% efficacy in Thailand, and is widely regarded as ineffective because of poor compliance over the relatively long duration of dosing. We evaluated the efficacy, safety, and tolerability of alternative primaquine dosing regimens combined with artesunate among 399 Thai patients with acute, symptomatic P. vivax malaria. Patients were randomly assigned to one of six treatment groups: all patients received artesunate, 100 mg once a day for 5 days. Groups 1–5 then received primaquine, 30 mg a day for 5, 7, 9, 11, and 14 days, respectively. Group 6 received primaquine, 30 mg twice a day for 7 days. The 28-day cure rates were 85%, 89%, 94%, 100%, and 96%, respectively. Treatment of P. vivax malaria with artesunate for 5 days followed by high-dose primaquine, 30 mg twice a day for 7 days, was highly effective, well-tolerated, and equivalent or superior to the standard regimen of primaquine therapy.
PMCID: PMC3129604  PMID: 18458306
9.  Short Report: Consensus Guidelines for Dosing of Amoxicillin-Clavulanate in Melioidosis 
Melioidosis is an infectious disease endemic to northern Australia and Southeast Asia. In response to clinical confusion regarding the appropriate dose of amoxicillin-clavulanate, we have developed guidelines for the appropriate dosing of this second-line agent. For eradication therapy for melioidosis, we recommend 20/5 mg/kg orally, three times daily.
PMCID: PMC3034162  PMID: 18256414
10.  Evaluation of the Efficacy of a Recombinant Subunit West Nile Vaccine in Syrian Golden Hamsters 
The efficacy of a recombinant subunit West Nile (WN) vaccine candidate was determined in a hamster model of encephalitis. Animals included young, aged, and immunocompromised animals in an effort to simulate key groups at risk of WN virus–induced disease. Groups of aged (12 month old), weanling, and adult hamsters rendered leukopenic after immunization were immunized subcutaneously with a WN virus recombinant envelope protein (WN-80E) with or without WN virus non-structural protein 1 (NS1) mixed with adjuvant or adjuvant alone. A challenge dose of wild-type WN virus was administered to produce 40–100% mortality in the control hamsters. The recombinant antigen preparations containing WN-80E with or without WN NS1 gave similar results. Hamsters in both groups had a strong antibody response after immunization, and none of the aged or weanling animals became ill or developed detectable viremia after challenge with WN virus at 2 weeks after booster vaccination. However, mortality among the control animals (administered adjuvant without antigen) at 2 weeks after booster challenge was 40–60%. In hamsters rendered leukopenic after immunization, survival rates up to 80% were observed, and a low-level viremia was detected in the vaccinated and challenged hamsters. The survival rate was significantly (P < 0.05) higher in animals vaccinated with a higher dose of WN-80E than a lower dose. The addition of NS1 did not significantly affect survival after challenge. In contrast, all of the control animals that received adjuvant only developed a very high level of viremia, and the mortality rate was 100%. These findings indicate that the recombinant WN vaccines induced antibody in and afforded protection to young and aged hamsters and immunosuppressed hamsters.
PMCID: PMC2765405  PMID: 19052311
11.  Short Report: Elevated Levels of Alanine Aminotransferase and Hepatitis A in the Context of a Pediatric Malaria Vaccine Trial in a Village in Mali 
A Phase 1 study of the apical membrane antigen malaria vaccine AMA1-C1/Alhydrogel was conducted in 2–3-year-old children in a village in Mali. A high frequency of elevated levels of alanine aminotransferase (ALT) caused by hepatitis A was seen, with 8 of 36 children diagnosed by specific IgM antibody over the course of the study. Hepatitis A is a common cause of asymptomatic elevations of ALT levels in children, particularly in less-developed settings. Investigators should be aware of the frequency of hepatitis A in this age group to guard against inadvertently facilitating transmission at study facilities and to properly evaluate symptomatic or asymptomatic elevations of ALT levels.
PMCID: PMC2605069  PMID: 19052315
12.  A Magnetic Resonance Imaging Study of Intestinal Dilation in Trypanosoma cruzi–infected Mice Deficient in Nitric Oxide Synthase 
Infection with Trypanosoma cruzi causes megasyndromes of the gastrointestinal (GI) tract. We used magnetic resonance imaging (MRI) to monitor alterations in the GI tract of T. cruzi–infected mice, and to assess the role of nitric oxide (NO) in the development of intestinal dilation. Brazil strain–infected C57BL/6 wild-type (WT) mice exhibited dilatation of the intestines by 30 days post-infection. Average intestine lumen diameter increased by 72%. Levels of intestinal NO synthase (NOS) isoforms, NOS2 and NOS3, were elevated in infected WT mice. Inflammation and ganglionitis were observed in all infected mice. Intestinal dilation was observed in infected WT, NOS1, NOS2, and NOS3 null mice. This study demonstrates that MRI is a useful tool to monitor intestinal dilation in living mice and that these alterations may begin during acute infection. Furthermore, our data strongly suggests that NO may not be the sole contributor to intestinal dysfunction resulting from this infection.
PMCID: PMC2701742  PMID: 18981519
13.  Burden of Cerebral Malaria in Central India (2004–2007) 
A study on the clinicoepidemiology of cerebral malaria (CM) and mild malaria (MM) among adults and children attending NSCB medical college hospital Jabalpur and civil hospital Maihar, Satna, in central India was undertaken. Of 1,633 patients, 401 were Plasmodium falciparum and 18 P. vivax. Of 401, 199 CM patients and 112 MM patients were enrolled. Severe complications among CM patients were jaundice (26%), acute renal failure (22%), respiratory distress (22%), severe malaria anemia (18%), hypotension (17%), hepatic encephalopathy (7.0%), and hematuria (5%). Among CM cases, seizures and severe malaria anemia were significantly higher in children (P < 0.0001) compared with adults, whereas jaundice (P < 0.0025), acute renal failure (P < 0.0001), and hematuria (P ≤ 0.05) were significantly higher among adults. Mortality was high among adults with multiple organ failures. Overall case fatality rate was 21%. Neurologic sequelae at discharge from the hospital were 3%, whereas at follow-up, only 1% had persistent neurologic sequelae.
PMCID: PMC2710578  PMID: 18840756
14.  Filarial/Human Immunodeficiency Virus Coinfection in Urban Southern India 
The disease course of human immunodeficiency virus (HIV) is often altered by existing or newly acquired coinfections. Treatment or prevention of these concomitant infections often improves the quality and duration of life of HIV-infected persons. The impact of helminth infections on infections with HIV is less clear. However, HIV is frequently most problematic in areas where helminth infections are common. In advance of the widespread distribution of drugs for elimination of lymphatic filariasis, we assessed the prevalence of active Wuchereria bancrofti infection among HIV-positive patients in Chennai, India at two time points separated by four years. We found that the overall prevalence of W. bancrofti infections among HIV-positive persons was 5–9.5%, and there were no quantitative differences in circulating filarial antigen levels between HIV-positive and HIV-negative filarial-infected patients.
PMCID: PMC2596056  PMID: 18840744
15.  Identifying the Reservoir Hosts of the Lyme Disease Spirochete Borrelia burgdorferi in California: The Role of the Western Gray Squirrel (Sciurus griseus) 
We investigated the role of the western gray squirrel (Sciurus griseus) as a reservoir host of the Lyme disease spirochete Borrelia burgdorferi. A survey of 222 western gray squirrels in California showed an overall prevalence of B. burgdorferi infection of 30%, although at a county level, prevalence of infection ranged from 0% to 50% by polymerase chain reaction. Laboratory trials with wild-caught western gray squirrels indicated that squirrels were competent reservoir hosts of the Lyme disease bacterium and infected up to 86% of feeding Ixodes pacificus larvae. Infections were long-lasting (up to 14 months), which demonstrated that western gray squirrels can maintain B. burgdorferi trans-seasonally. Non-native eastern gray squirrels (Sciurus carolinensis) and fox squirrels (Sciurus niger) were infrequently infected with B. burgdorferi.
PMCID: PMC2592199  PMID: 18840740
16.  Predictive Spatial Models for Risk of West Nile Virus Exposure in Eastern and Western Colorado 
In the absence of a vaccine for use in humans against West Nile virus (WNV), mosquito control and personal protection against mosquito bites are the only measures available to prevent disease. Improved spatial targeting is desirable for costly mosquito and WNV surveillance and control schemes. We used a multivariate regression modeling approach to develop spatial models predicting high risk of exposure to WNV in western and eastern Colorado based on associations between Geographic Information System–derived environmental data and zip code of residence for 3,659 human WNV disease cases from 2002 to 2006. Models were robust, with user accuracies for correct classification of high risk areas of 67–80%. The importance of selecting a suitable model development area in an ecologically and climatically diverse environment was shown by models based on data from the eastern plains landscape performing poorly in the mountainous western part of Colorado and vice versa.
PMCID: PMC2581834  PMID: 18840749
17.  Shifting Prevalence of Major Diarrheal Pathogens in Patients Seeking Hospital Care during Floods in 1998, 2004, and 2007 in Dhaka, Bangladesh 
Bangladesh experienced severe flooding and diarrheal epidemics in 2007. We compared flood data from 2007 with 2004 and 1998 for diarrheal patients attending the ICDDR,B hospital in Dhaka. In 2007, Vibrio cholerae O1 (33%), rotavirus (12%), and enterotoxigenic Escherichia coli (ETEC) (12%) were most prevalent. More severe dehydration was seen in 2007 compared with 2004 and 1998 (P < 0.001). In 2007, V. cholerae O1 Inaba (52%) and Ogawa (48%) were seen, whereas in 2004 and 1998 it was primarily Inaba and the Ogawa types, respectively (P < 0.001). In 2007, 51% of ETEC produced the heat labile toxin (LT) (P < 0.001 compared with 2004), 22% expressed the heat stable (ST) (P < 0.001), and 27% were ST/LT positive (P = 0.231). The CS7 colonization factor (CF) was the most prevalent in 2007 (20% compared with 6% in 2004; P = 0.05). Our findings demonstrate alterations in clinical features and phenotypic changes of major bacterial pathogens in the recent Bangladesh flood.
PMCID: PMC2749297  PMID: 18981509
18.  Case Report: Septicemic Plague in a Community Hospital in California 
Diagnosis of a case of septicemic plague acquired in rural California was delayed because of a series of confounding events, resulting in concern about reliance on community hospitals as sentinels for detecting potential bioterrorism-related events. An epizootic study confirmed the peri-domestic source of Yersinia pestis infection.
PMCID: PMC2746638  PMID: 18541761
19.  The Effects of Midgut Serine Proteases on Dengue Virus Type 2 Infectivity of Aedes aegypti 
Dengue viruses (DENV) cause significant morbidity and mortality worldwide and are transmitted by the mosquito Aedes aegypti. Mosquitoes become infected after ingesting a viremic bloodmeal, and molecular mechanisms involved in bloodmeal digestion may affect the ability of DENV to infect the midgut. We used RNA interference (RNAi) to silence expression of four midgut serine proteases and assessed the effect of each RNAi phenotype on DENV-2 infectivity of Aedes aegypti. Silencing resulted in significant reductions in protease mRNA levels and correlated with a reduction in activity except in the case of late trypsin. RNA silencing of chymotrypsin, early and late trypsin had no effect on DENV-2 infectivity. However, silencing of 5G1 or the addition of soybean trypsin inhibitor to the infectious bloodmeals significantly increased midgut infection rates. These results suggest that some midgut serine proteases may actually limit DENV-2 infectivity of Ae. aegypti.
PMCID: PMC2745300  PMID: 18689635
20.  Rapid Suppression of Onchocerca volvulus Transmission in Two Communities of the Southern Chiapas Focus, Mexico, Achieved by Quarterly Treatments with Mectizan 
The impact of quarterly Mectizan (ivermectin) treatments on transmission, microfiladermia, and ocular lesions was evaluated in two formerly hyperendemic communities (Las Golondrinas and Las Nubes II) located in the main endemic focus for onchocerciasis in Southern Chiapas, Mexico. The data suggest that Onchocerca volvulus transmission has been suppressed after elimination of microfiladermia in these two communities. Increasing the frequency of Mectizan treatment to four times per year appears to have resulted in the rapid suppression of transmission in communities with residual transmission.
PMCID: PMC2570542  PMID: 18689630
21.  Epidemiology of Cryptosporidiosis in North American Travelers to Mexico 
We studied 1,179 North American travelers who visited Mexico from 2005 to 2007. Travelers' diarrhea (TD) was reported by 521 (44%) participants. Among subjects with TD, 218 cases were examined for cryptosporidiosis by polymerase chain reaction (PCR) and enzyme-linked immunoassays (ELISA). There were 14 (6%) cases of cryptosporidiosis and 141 cases (64%) of bacterial diarrhea. Compared with bacterial diarrhea, a longer stay in Mexico was a risk factor for cryptosporidiosis. Additionally, Cryptosporidium cases passed greater number of watery stools (P < 0.05), suffered more episodes of diarrhea (P ≤ 0.05), and were more likely to experience tenesmus (P ≤ 0.05) compared with bacterial causes of TD. ELISA detected seven (3%) cases of Cryptosporidium, whereas PCR identified an additional seven cases (6%). Speciation by 18SrRNA sequencing showed that 13 cases were caused by C. parvum and only 1 case was caused by C. hominis. ELISA showed a sensitivity of 50% and specificity of 100% compared with PCR.
PMCID: PMC2560987  PMID: 18689626
22.  Women’s Experiences Living with Epilepsy in Zambia 
Epilepsy-associated stigma is a well-recognized phenomenon that adversely impacts the lives of people with epilepsy (PWE). The burden of stigma follows power differentials, with socially and economically disenfranchised groups being particularly susceptible. To guide instrument development for quantitative studies, we conducted a series of focus group discussions among PWE and found that women with epilepsy experienced especially adverse social and economic problems because of epilepsy-associated stigma. The social burden of the disease largely outweighed the medical burden. Women revealed seizure worries related to accidental and intentional injury and the risk of breaking taboos as well as limitations in role fulfillment and extremes of social rejection by family and community. Our findings have implications for access to care and care delivery for vulnerable populations with epilepsy.
PMCID: PMC2556284  PMID: 18689619
23.  Short Report: Detection of Plasmodium falciparum Histidine-rich Protein II in Saliva of Malaria Patients 
Detection of Plasmodium falciparum parasites in patients with malaria necessitates drawing blood, which increases the risk of accidental infections and is poorly accepted in communities with blood taboos. Thus, non-invasive, cost-effective malaria tests that minimize the need for blood collection are needed. Plasmodium falciparum histidine-rich protein II (PfHRP II) levels in plasma and saliva were compared in malaria–positive and –negative patients in Ghana. Plasma and saliva obtained from 30 thick-film positive and 10 negative children were evaluated for PfHRP II by ELISA. Among the 30 children with positive blood smear, 16 (53%) were PfHRP II positive in plasma and 13 (43%) had PfHRP II positive saliva. The sensitivity of PfHRP II detection was 53% for plasma and 43% for saliva. The specificity was 100% with no false positive for both plasma and saliva when compared with blood smear. Thus, rapid detection of PfHRP II antigen in saliva may be a useful non-invasive and cost-effective malaria diagnostic technique.
PMCID: PMC2710580  PMID: 18458305
24.  Pathogenesis of XJ and Romero Strains of Junin Virus in Two Strains of Guinea Pigs 
Argentine hemorrhagic fever (AHF), a systemic infectious disease caused by infection with Junin virus, affects several organs, and patients can show hematologic, cardiovascular, renal, or neurologic symptoms. We compared the virulence of two Junin virus strains in inbred and outbred guinea pigs with the aim of characterizing this animal model better for future vaccine/antiviral efficacy studies. Our data indicate that this passage of the XJ strain is attenuated in guinea pigs. In contrast, the Romero strain is highly virulent in Strain 13 as well as in Hartley guinea pigs, resulting in systemic infection, thrombocytopenia, elevated apartate aminotransferase levels, and ultimately, uniformly lethal disease. We detected viral antigen in formalin-fixed, paraffin-embedded tissues. Thus, both guinea pig strains are useful animal models for lethal Junin virus (Romero strain) infection and potentially can be used for preclinical trials in vaccine or antiviral drug development.
PMCID: PMC2700623  PMID: 18689636
25.  Short Report: Comparison of Oral Infectious Dose of West Nile Virus Isolates Representing Three Distinct Genotypes in Culex quinquefasciatus 
Phylogenetic analysis of West Nile virus in North America has identified replacement of the originally introduced clade, Eastern United States (NY99), by the North American clade. In addition, the transient emergence of other clades and genetic variants has also been observed. In this study, we investigated the potential role of the mosquito in the selection of these clades and genetic variants. We determined the relative susceptibility of Culex quinquefasciatus to infection with isolates from the Eastern U.S. clade, the North American clade, and the Southeast coastal Texas clade. Although significant differences were observed in 50% oral infectious dose values between the Eastern U.S. and two attenuated North American genetic variants compared with the North American and Southeast coastal Texas clade viruses, these differences did not correlate with persistence of the genotype in nature. These results indicate that selection of these viral genotypes was independent of viral oral infectivity in the mosquito.
PMCID: PMC2699256  PMID: 19052310

Results 1-25 (48)