Cost-effectiveness of active case-finding of household contacts of pulmonary tuberculosis patients in a low HIV, tuberculosis-endemic urban area of Lima, Peru.

We compared the cost-effectiveness (CE) of an active case-finding (ACF) programme for household contacts of tuberculosis (TB) cases enrolled in first-line treatment to routine passive case-finding (PCF) within an established national TB programme in Peru. Decision analysis was used to model detection of TB in household contacts through: (1) self-report of symptomatic cases for evaluation (PCF), (2) a provider-initiated ACF programme, (3) addition of an Xpert MTB/RIF diagnostic test for a single sputum sample from household contacts, and (4) all strategies combined. CE was calculated as the incremental cost-effectiveness ratio (ICER) in terms of US dollars per disability-adjusted life years (DALYs) averted. Compared to PCF alone, ACF for household contacts resulted in an ICER of $2155 per DALY averted. The addition of the Xpert MTB/RIF diagnostic test resulted in an ICER of $3275 per DALY averted within a PCF programme and $3399 per DALY averted when an ACF programme was included. Provider-initiated ACF of household contacts in an urban setting of Lima, Peru can be highly cost-effective, even including costs to seek out contacts and perform an Xpert/MTB RIF test. ACF including Xpert MTB/RIF was not cost-effective if TB cases detected had high rates of default from treatment or poor outcomes.

Geographic predictors of primary multidrug-resistant tuberculosis cases in an endemic area of Lima, Peru.

SETTING: Peru reports among the highest multidrug-resistant tuberculosis (MDR-TB) rates in the Americas, with a growing proportion in previously untreated tuberculosis (TB) cases. The identification of clusters of primary MDR-TB compared with drug-susceptible TB (DS-TB) could help prioritize interventions. OBJECTIVE: To examine the clustering of primary MDR-TB case residences and their proximity to high-risk locations in San Juan de Lurigancho District, Lima, Peru. DESIGN: Enrolled primary MDR-TB and primary DS-TB cases were interviewed and their primary residence was recorded using handheld Global Positioning System devices. Kuldorff's spatial scan statistic was used for cluster detection (SaTScan(TM), v. 9.1.1). Identified clusters were visualized in Quantum Geographic Information Systems software (v1.8.0). The following cluster centers were tested: a health centre with the highest TB and MDR-TB rates (Clinic X), a hospital and two prisons. Using regression analyses, we examined predictors of primary MDR-TB cases. RESULTS: A statistically significant cluster of primary MDR-TB cases was identified within a 2.29 km radius around Clinic X. Proximity to Clinic X remained a significant predictor of primary MDR-TB in adjusted regression analyses. CONCLUSION: We identified a hotspot of primary MDR-TB cases around Clinic X in a TB-endemic area. Causes of this clustering require investigation; targeted interventions for this high-risk area should be considered.

An exploration of spatial risk assessment for soil protection: estimating risk and establishing priority areas for soil protection.

Methods for the spatial estimation of risk of harm to soil by erosion by water and wind and by soil organic matter decline are explored. Rates of harm are estimated for combinations of soil type and land cover (as a proxy for hazard frequency) and used to estimate risk of soil erosion and loss of soil organic carbon (SOC) for 1 km(2)pixels. Scenarios are proposed for defining the acceptability of risk of harm to soil: the most precautionary one corresponds to no net harm after natural regeneration of soil (i.e. a 1 in 20 chance of exceeding an erosion rate of <1 tha(-1)y(-1) and SOC content decline of 0 kg t(-1)y(-1) for mineral soils and a carbon stock decline of 0 tha(-1)y(-1) for organic soils). Areas at higher and lower than possible acceptable risk are mapped. The veracity of boundaries is compromised if areas of unacceptable risk are mapped to administrative boundaries. Errors in monitoring change in risk of harm to soil and inadequate information on risk reduction measures' efficacy, at landscape scales, make it impossible to use or monitor quantitative targets for risk reduction adequately. The consequences for priority area definition of expressing varying acceptable risk of harm to soil as a varying probability of exceeding a fixed level of harm, or, a varying level of harm being exceeded with a fixed probability, are discussed. Soil data and predictive models for rates of harm to soil would need considerable development and validation to implement a priority area approach robustly.

Long-term treatment efficacy in primary inflammatory breast cancer by hormonal receptor- and HER2-defined subtypes.

BACKGROUND: Subtypes defined by hormonal receptor (HR) and HER2 status have not been well studied in inflammatory breast cancer (IBC). We characterized clinical parameters and long-term outcomes, and compared pathological complete response (pCR) rates by HR/HER2 subtype in a large IBC patient population. We also compared disease-free survival (DFS) and overall survival (OS) between IBC patients who received targeted therapies (anti-hormonal, anti-HER2) and those who did not. PATIENTS AND METHODS: We retrospectively reviewed the records of patients diagnosed with IBC and treated at MD Anderson Cancer Center from January 1989 to January 2011. Of those, 527 patients had received neoadjuvant chemotherapy and had available information on estrogen receptor (ER), progesterone receptor (PR), and HER2 status. HR status was considered positive if either ER or PR status was positive. Using the Kaplan-Meier method, we estimated median DFS and OS durations from the time of definitive surgery. Using the Cox proportional hazards regression model, we determined the effect of prognostic factors on DFS and OS. Results were compared by subtype. RESULTS: The overall pCR rate in stage III IBC was 15.2%, with the HR-positive/HER2-negative subtype showing the lowest rate (7.5%) and the HR-negative/HER2-positive subtype, the highest (30.6%). The HR-negative, HER2-negative subtype (triple-negative breast cancer, TNBC) had the worst survival rate. HR-positive disease, irrespective of HER2 status, had poor prognosis that did not differ from that of the HR-negative/HER2-positive subtype with regard to OS or DFS. Achieving pCR, no evidence of vascular invasion, non-TNBC, adjuvant hormonal therapy, and radiotherapy were associated with longer DFS and OS. CONCLUSIONS: Hormone receptor and HER2 molecular subtypes had limited predictive and prognostic power in our IBC population. All molecular subtypes of IBC had a poor prognosis. HR-positive status did not necessarily confer a good prognosis. For all IBC subtypes, novel, specific treatment strategies are needed in the neoadjuvant and adjuvant settings.

Statin use in primary inflammatory breast cancer: a cohort study.

BACKGROUND: Some studies have suggested that statins, which have cholesterol-lowering and anti-inflammatory properties, may have antitumor effects. Effects of statins on inflammatory breast cancer (IBC) have never been studied. METHODS: We reviewed 723 patients diagnosed with primary IBC in 1995-2011 and treated at The University of Texas MD Anderson Cancer Center. Statin users were defined as being on statins at the initial evaluation. Based on Ahern et al's statin classification (JNCI, 2011), clinical outcomes were compared by statin use and type (weakly lipophilic to hydrophilic (H-statin) vs lipophilic statins (L-statin)). We used the Kaplan-Meier method to estimate the median progression-free survival (PFS), overall survival (OS) and disease-specific survival (DSS), and a Cox proportional hazards regression model to test the statistical significance of potential prognostic factors. RESULTS: In the multivariable Cox model, H-statins were associated with significantly improved PFS compared with no statin (hazard ratio=0.49; 95% confidence interval=0.28-0.84; P<0.01); OS and DSS P-values were 0.80 and 0.85, respectively. For L-statins vs no statin, P-values for PFS, DSS, and OS were 0.81, 0.4, and 0.74, respectively. CONCLUSION: H-statins were associated with significantly improved PFS. A prospective randomised study evaluating the survival benefits of statins in primary IBC is warranted.

Effects of human population density and proximity to markets on coral reef fishes vulnerable to extinction by fishing.

Coral reef fisheries are crucial to the livelihoods of tens of millions of people; yet, widespread habitat degradation and unsustainable fishing are causing severe depletion of stocks of reef fish. Understanding how social and economic factors, such as human population density, access to external markets, and modernization interact with fishing and habitat degradation to affect fish stocks is vital to sustainable management of coral reef fisheries. We used fish survey data, national social and economic data, and path analyses to assess whether these factors explain variation in biomass of coral reef fishes among 25 sites in Solomon Islands. We categorized fishes into 3 groups on the basis of life-history characteristics associated with vulnerability to extinction by fishing (high, medium, and low vulnerability). The biomass of fish with low vulnerability was positively related to habitat condition. The biomass of fishes with high vulnerability was negatively related to fishing conducted with efficient gear. Use of efficient gear, in turn, was strongly and positively related to both population density and market proximity. This result suggests local population pressure and external markets have additive negative effects on vulnerable reef fish. Biomass of the fish of medium vulnerability was not explained by fishing intensity or habitat condition, which suggests these species may be relatively resilient to both habitat degradation and fishing.

Examining self and partners for syphilis among men who have sex with men: five US cities, 2009-2011.

To increase self-examination for syphilis among men who have sex with men (MSM), we developed educational materials to increase knowledge of primary and secondary syphilis manifestations. Materials were piloted in five cities' infectious disease or MSM clinics. Self- and partner-examination behaviour was assessed with an anonymous questionnaire. Of 1459 participants, 914 men had had sex with a man in the previous three months; the 171 MSM who reported having read the materials were significantly more likely to examine themselves (anus, adjusted prevalence ratio [aPR] 1.3, 95% confidence interval [CI] 1.15-1.52), mouth, penis and skin, and their partners' anus (aPR 1.3, 95% CI 1.03-1.73) and mouth (aPR 1.6, 95% CI 1.1-2.26). Further research is needed to determine whether educational materials affect early detection and treatment of primary and secondary syphilis and reduce transmission.

Increased influenza-related healthcare utilization by residents of an urban aboriginal community.

Most studies describing high rates of acute respiratory illness in aboriginals have focused on rural or remote communities. Hypothesized causes include socioeconomic deprivation, limited access to healthcare, and a high prevalence of chronic disease. To assess influenza rates in an aboriginal community while accounting for healthcare access, deprivation and chronic disease prevalence, we compared rates of influenza-related outpatient and emergency-department visits in an urban Mohawk reserve (Kahnawá:ke) to rates in neighbouring regions with comparable living conditions and then restricted the analysis to a sub-population with a low chronic disease prevalence, i.e. those aged <20 years. Using medical billing claims from 1996 to 2006 we estimated age-sex standardized rate ratios. The rate in Kahnawá:ke was 58% greater than neighbouring regions and 98% greater in the analysis of those aged <20 years. Despite relatively favourable socioeconomic conditions and healthcare access, rates of influenza-related visits in Kahnawá:ke were elevated, particularly in the younger age groups.

Prevalence of and risk factors for hepatitis C virus infection among STD clinic clientele in Miami, Florida.

OBJECTIVES: Hepatitis C virus (HCV) is the most common chronic blood borne viral infection in the United States. We assessed the HCV prevalence, risk factors, and sensitivity of the Centers for Disease Control and Prevention's (CDC) routine screening criteria among clients of a large urban sexually transmitted disease (STD) clinic. METHODS: Participants were recruited from a public STD clinic in Miami, Florida, and were interviewed regarding known and potential risk factors. The survey assessed CDC screening criteria, as well as other risk factors (for example, intranasal drug use, history of incarceration, exchanging sex for money, number of lifetime sex partners, and history of an STD). Testing was done by enzyme immunoassay (EIA) and confirmed by recombinant immunoblot assay (RIBA). RESULTS: The prevalence of anti-HCV positivity was 4.7%. Four variables were significantly associated with being anti-HCV positive, independent of confounding factors. These included injection drug use (odds ratio (OR) = 31.6; 95% confidence intervals (CI) 11.0 to 90.5); history of incarceration (OR = 3.0; 95% CI 1.1 to 8.1); sexual contact with an HCV positive person (OR 12.7; 95% CI 2.5 to 64.7); and older age (OR 1.4; 95% CI 1.2, 1.6). The sensitivity of CDC's routine screening criteria was 69% and specificity was 91%. CONCLUSIONS: The prevalence of anti-HCV in this clinic was similar to that determined in studies of comparable populations. Having sexual contact with an HCV positive person and history of incarceration were independently associated with being anti-HCV positive. CDC's screening criteria identified approximately two thirds of the anti-HCV positive participants.

Population pharmacokinetics of the new antimalarial agent tafenoquine in Thai soldiers.

AIMS: To describe the population pharmacokinetics of tafenoquine in healthy volunteers after receiving tafenoquine for malaria prophylaxis. METHODS: The population consisted of 135 male Thai soldiers (mean age 28.9 years; weight 60.3 kg). All soldiers were presumptively treated with artesunate for 3 days plus doxycycline for 7 days to remove any pre-existing malaria infections. After the treatment regime, 104 soldiers (drug group) received a loading dose of 400 mg tafenoquine base daily for 3 days followed by 400 mg tafenoquine monthly for 5 consecutive months. In the placebo group, 31 soldiers were infected with malaria during the study period. They were re-treated with artesunate for 3 days plus doxycycline for 7 days followed by a loading dose of 400 mg tafenoquine daily for 3 days and then 400 mg tafenoquine weekly for prophylaxis. Blood samples were randomly collected from each soldier on monthly and weekly prophylaxis. Plasma tafenoquine concentrations were measured by h.p.l.c. Population pharmacokinetic modelling was performed using NONMEM. RESULTS: A one-compartment model was found best to describe the pharmacokinetics of tafenoquine after oral administration. Age and weight influenced volume of distribution (V/F), and subjects who contracted malaria had higher clearance (CL/F), but none of these factors was considered to have sufficient impact to warrant change in dosing. The population estimates of the first-order absorption rate constant (Ka), CL/F and V/F were 0.694 h(-1), 3.20 l h(-1) and 1820 l, respectively. The intersubject variability in these parameters (coefficient of variation, CV%) was 61.2%, 25.3% and 14.8%, respectively. The absorption and elimination half-lives were 1.0 h and 16.4 days, respectively. The residual (unexplained) variability was 17.9%. CONCLUSIONS: The population pharmacokinetics of orally administered tafenoquine have been determined in Thai soldiers under field conditions. This information, together with its known potent antimalarial activity, portends well for the application of tafenoquine as a useful prophylactic drug or for short-term radical treatment of vivax malaria.

Use of HIV health care in HIV-seropositive crack cocaine smokers and other active drug users.

PURPOSE: We assessed the use of HIV care among HIV-seropositive crack cocaine smokers and other active drug users in Miami-Dade County, FL. METHODS: Personal interviews were conducted with 327 adults recruited from inner city neighborhoods. Cross-tabulations and logistic modeling were used to analyze the relationship between selected variables and use of HIV care. RESULTS: One-third of respondents had not seen a provider for HIV-related health care in the past 12 months. Among those who had seen a provider, only 33.8% were receiving highly active antiretroviral therapy (HAART). Factors associated with utilization of HIV-related health care were age, race, having a usual source of care, health insurance, time elapsed since time of diagnosis, and reports of moderate to extreme interference of pain with daily activities. IMPLICATIONS: These findings suggest the need to develop, implement, and evaluate intervention strategies to improve use of HIV medical care among active drug users.

Strategies to decrease tuberculosis in us homeless populations: a computer simulation model.

CONTEXT: The rate of tuberculosis (TB) among US homeless persons may be 20 times that of the general adult population. Studies suggest that the majority of urban homeless TB cases are attributable to ongoing transmission of TB. Optimal TB-control strategies in both chronically and transiently homeless populations are not known. OBJECTIVE: To examine the effects of TB-control strategies on projected TB cases and deaths in US homeless populations using a computer-based simulation model. DESIGN, SETTING, AND POPULATION: The US general population and a theoretical population of 2 million homeless individuals in 1995 were divided into 18 clinical states based on the risk for or presence of TB and human immunodeficiency virus (HIV) infection in a semi-Markov model. MAIN OUTCOME MEASURES: Prevalence of transiently and chronically homeless individuals with active TB and deaths from TB as a function of public health measures taken to control and eliminate TB, including improvement of treatment effectiveness, improvement in access to treatment, and vaccination with BCG. RESULTS: A 10% increase in access to treatment among homeless persons with active TB produced larger declines in predicted TB cases and deaths after 10 years (cases and deaths among chronically homeless persons decreased 12.5% and 19.8% and among transiently homeless persons dropped 35.9% and 32.4%, respectively) than improvements in the effectiveness of treatment programs (cases and deaths among chronically homeless persons declined 7.2% and 3.1% and among transiently homeless persons dropped 10.9% and 4.1%, respectively). A 10% increase in access to treatment among homeless persons with latent TB infection led to a 6.7% decline in TB among chronically homeless persons and a 5.7% decline among transiently homeless persons, while a 10% improvement in effectiveness of treatment for latent TB infection was associated with declines of 3.0% and 3.3%, respectively. When treatment for latent TB infection was modeled to be the same in vaccinated and nonvaccinated populations, BCG vaccination led to TB case declines of 15.4% and 21.5% in chronically and transiently homeless populations, respectively. CONCLUSIONS: Overcoming barriers faced by homeless individuals in accessing TB treatment programs will be crucial to reducing the burden of TB in this high-risk group. Increased treatment access, improvement in the effectiveness of treatment programs, and BCG vaccination of HIV-negative homeless individuals have the best chance to markedly decrease TB morbidity and mortality.

Phase 2 trial of WR6026, an orally administered 8-aminoquinoline, in the treatment of visceral leishmaniasis caused by Leishmania chagasi.

There are no recognized orally administered treatments for any of the leishmaniases. The 8-aminoquinoline WR6026 is an orally administered analog of primaquine that cured 50% of patients with kala-azar in Kenya at a dose of 1 mg/kg/day for 28 days. A further phase 2, open-label, dose-escalating safety and efficacy study was performed for kala-azar in Brazil. Cure rates for Brazilian patients treated for 28 days were as follows: 1 mg/kg/day: 0 of 4 (0%); 1.5 mg/kg/day: 1 of 6 (17%); 2.0 mg/kg/day: 4 of 6 (67%); 2.5 mg/kg/day: 1 of 5 (20%); and 3.25 mg/kg/day: 0 of 1 (0%). Nephrotoxicity that was not anticipated from preclinical animal studies or from phase 1 studies was seen at 2.5 mg/kg/day in 2 patients and in the single patient administered 3.25 mg/kg/day. WR6026 demonstrated the unusual clinical features of lack of increased efficacy against Brazilian kala-azar with increased dosing above 2 mg/kg/day and toxicity that was not present in previous investigations.

Comparative pharmacokinetics and effect kinetics of orally administered artesunate in healthy volunteers and patients with uncomplicated falciparum malaria.

The single-dose pharmacokinetics of 100 mg of orally administered artesunate (AS) were studied in 6 patient volunteers with uncomplicated falciparum malaria and in 6 healthy volunteers. Plasma concentrations of both the parent drug, AS, and its major metabolite, dihydroartemisinin (DHA), were measured simultaneously by high-performance liquid chromatography (HPLC) with electrochemical detection (ECD). The antimalarial activity of each plasma sample measured by an in vitro bioassay (BA) was used to derive activity concentrations. Artesunate was absorbed rapidly and then almost completely hydrolyzed to DHA in patients, whereas hydrolysis was incomplete in healthy volunteers. The mean +/- standard deviation (SD) maximum concentration (Cmax) of AS was 296+/-110 nmol/L, the time to peak blood level (tmax was 0.71+/-0.66 hr, the half-life (t1/2,z) was 0.41+/-0.34 hr, and the bioavailability over 12 hr (area under the curve [AUC](0-12)) was 253+/-185 nmol hr/L. Measured by HPLC, the Cmax and AUC(0-12) values of DHA in patients with malaria were significantly greater than in volunteers (1,948+/-772 and 1,192+/-315 nmol/L; 4,024+/-1,585 and 1,763+/-607 nmol hr/L, respectively; P < or = 0.05). These differences were even greater when measured by BA. The Cmax for patients with malaria was 2,894+/-2,497 and 795+/-455 nmol/L for volunteers, and AUC(0-12) was 5,970+/-3,625 and 1,307+/-391 nmol hr/L, respectively (P < or = 0.05). In contrast, DHA parameter estimates for t1/2,z and tmax were similar between patients and healthy volunteers, with values of 0.80+/-0.30 versus 0.87+/-0.06 hr and 1.50+/-0.55 versus 1.13+/-0.52 hr, respectively (P > 0.5). Both drug metabolism and tissue protein binding could contribute to the differences between the antimalarial activity of artemisinin drugs in healthy volunteers and malaria infected patients.

Behavioral and neural toxicity of the artemisinin antimalarial, arteether, but not artesunate and artelinate, in rats.

Three artemisinin antimalarials, arteether (AE), artesunate (AS), and artelinate (AL) were evaluated in rats using an auditory discrimination task (ADT) and neurohistology. After rats were trained on the ADT, equimolar doses of AE (25 mg/kg, in sesame oil, n=6), AS (31 mg/kg, in sodium carbonate, n=6), and AL (36 mg/kg, in saline, n=6), or vehicle (sodium carbonate, n=6) were administered (IM) for 7 consecutive days. Behavioral performance was evaluated, during daily sessions, before, during, and after administration. Histological evaluation of the brains was performed using thionine staining, and damaged cells were counted in specific brainstem nuclei of all rats. Behavioral performance was not significantly affected in any rats treated with AS, AL, or vehicle. Furthermore, histological examination of the brains of rats treated with AS, AL, and vehicle did not show damage. In stark contrast, all rats treated with AE showed a progressive and severe decline in performance on the ADT. The deficit was characterized by decreases in accuracy, increases in response time and, eventually, response suppression. When performance on the ADT was suppressed, rats also showed gross behavioral signs of toxicity that included tremor, gait disturbances, and lethargy. Subsequent histological assessment of AE-treated rats revealed marked damage in the brainstem nuclei, ruber, superior olive, trapezoideus, and inferior vestibular. The damage included chromatolysis, necrosis, and gliosis. These results demonstrate distinct differences in the ability of artemisinins to produce neurotoxicity. Further research is needed to uncover pharmacokinetic and metabolic differences in artemisinins that may predict neurotoxic potential.

Preventing tuberculosis with bacillus Calmette-Guérin vaccine: a meta-analysis of the literature.

This article reviews a previously published meta-analysis of 1264 titles or abstracts and 70 selected studies for evaluation of the efficacy of bacillus Calmette-Guérin (BCG) vaccine in preventing tuberculosis. Following review, data from 26 studies were included in the analysis. These 26 studies reveal that vaccination with BCG significantly reduces the risk of tuberculosis by an average of 50%. This level of protection persists across a number of subgroups defined by age at vaccination and study design. Vaccination with BCG was significantly associated with a reduction in the incidence of pulmonary tuberculosis and extrapulmonary disease. In general, the results of this meta-analysis lend weight and confidence to arguments favoring the use of BCG vaccine.

Pediatric tuberculosis: what needs to be done to decrease morbidity and mortality.

OBJECTIVE: Tuberculosis (TB) control programs have been less successful among children than among adults in the United States. Between 1992 and 1997, the rate of decline of TB cases among 0- to 14-year-old children was less than the rate of decline among any other age group of US-born persons. Because of the higher prevalence of active TB among adults and their higher infectivity, most programs for TB in the United States have targeted adults. The inherent assumption has been that by targeting adults, from whom children may become infected, TB morbidity and mortality among children also will be reduced effectively. METHODS: Using a semi-Markov model that divided the US population into age groups <15 years old and >/=15 years old and into 18 clinical states based on the risk for or presence of TB and human immunodeficiency virus infection, we developed a computer-based simulation model to examine the effect of a range of potential TB control strategies on projected TB cases and deaths in children. We compare the impact of interventions targeted at children with the impact of interventions targeted at adults on pediatric morbidity and mortality. RESULTS: After 10 years, a 5% increase in the number of adults with TB who enter treatment would only lead to a.05% decline in TB cases among children, compared with predicted cases without this intervention. Improving treatment efficacy among those adults who are already receiving treatment for their TB leads to a smaller decline in cases among children of only.003%. In contrast, a 5% increase in the number of children who enter treatment leads to a 25% decline, after 10 years, in the number of TB cases among children and a 16% decline in the number of TB deaths. In the presence of immigration of tuberculin-positive children, the benefit of targeting programs directly at children is magnified. CONCLUSIONS: Marginal changes in programs targeted directly at children are significantly more effective at further reducing pediatric TB morbidity and mortality than the same changes in programs targeted at adults with the indirect goal of reducing spread to children. Marginal increases in the number of children who enter treatment are far more effective at decreasing morbidity and mortality than equivalent marginal increases in treatment effectiveness. Unfortunately, declining insurance coverage and increasing restrictions on services to immigrants have made it harder for those who are at greatest risk of TB to get medical care. Marginal increases in preventive therapy rates substantially reduce future pediatric TB cases and deaths among children with TB infection and human immunodeficiency virus.

Arteether-induced brain injury in Macaca mulatta. I. The precerebellar nuclei: the lateral reticular nuclei, paramedian reticular nuclei, and perihypoglossal nuclei.

Malaria poses a threat across several continents: Eurasia (Asia and parts of Eastern Europe), Africa, Central and South America. Bradley (1991) estimates human exposure at 2,073,000,000 with infection rates at 270,000,000, illnesses at 110,000,000, and deaths at 1,000,000. Significant mortality rates are attributed to infection by the parasite Plasmodium falciparum, with an estimated 90% among African children. A worldwide effort is ongoing to chemically and pharmacologically characterize a class of artemisinin compounds that might be promising antimalarial drugs. The U.S. Army is studying the efficacy and toxicity of several artemisinin semi-synthetic compounds: arteether, artemether, artelinic acid, and artesunate. The World Health Organization and the U.S. Army selected arteether for drug development and possible use in the emergency therapy of acute, severe malaria. Male Rhesus monkeys (Macaca mulatta) were administered different daily doses of arteether, or the vehicle alone (sesame oil), for a period of either 14 days, or 7 days. Neuropathological lesions were found in 14-day arteether treated monkeys in the precerebellar nuclei of the medulla oblongata, namely: (1) the lateral reticular nuclei (subnuclei magnocellularis, parvicellularis, and subtrigeminalis), (2) the paramedian reticular nuclei (subnuclei accessorius, dorsalis, and ventralis), and the perihypoglossal nuclei (n. intercalatus of Staderini, n. of Roller, n. prepositus hypoglossi). The data demonstrate that the simina meduallry precerebellar nuclei have a high degree of vulnerability when arteether is given for 14 days at dose levels between 8mg/kg per day and 24 mg/kg per day. The neurological consequences of this treatment regimen could profoundly impair posture, gait, and autonomic regulation, while eye movement disorders might also be anticipated.

A reproducible nonlethal animal model for studying cyanide poisoning.

Previous studies using bolus intravenous injections of sodium cyanide have been used to model the sudden exposure to high concentrations of cyanide that could occur on the battlefield. This study was designed to develop a model that would simulate the type of exposure to cyanide gas that could happen during actual low-level continuous types of exposure and then compare it with the bolus model. Cardiovascular and respiratory recordings taken from anesthetized dogs have been used previously to characterize the lethal effects of cyanide. The intravenous, bolus injection of 2.5 mg/kg sodium cyanide provides a model in which a greater than lethal concentration is attained. In contrast, our model uses a slow, intravenous infusion of cyanide to titrate each animal to its own inherent end point, which coincides with the amount of cyanide needed to induce death through respiratory arrest. In this model, therapeutic intervention can be used to restore respiration and allow for the complete recovery of the animals. After recovery, the same animal can be given a second infusion of cyanide, followed again by treatment and recovery, providing a reproducible end point. This end point can then be expressed as the total amount of cyanide per body weight (mg/kg) required to kill. In this study, the average dose of sodium cyanide among 12 animals was 1.21 mg/kg, which is approximately half the cyanide used in the bolus model. Thus, titration to respiratory arrest followed by resuscitation provides a repetitive-use animal model that can be used to test the efficacy of various forms of pretreatment and/or therapy without the loss of a single animal.