Publications

OBJECTIVES

Acute febrile illnesses consistent with malaria are the most common presentation at health clinics in sub-Saharan Africa, accounting for 30-50% of outpatient visits. The symptoms of acute HIV infection can mimic acute malaria. We investigated whether acute HIV infections could be identified among adults with suspected malaria at rural health centers in Uganda.

DESIGN

A cross-sectional study of 1000 consecutive patients referred for malaria blood smears at each of seven government health centers, of which 2893 (41%) were 13 years or older and tested for HIV.

METHODS

HIV enzyme immunoassay antibody testing was performed on dried blood spots and confirmed by western blot. Enzyme immunoassay-nonreactive and enzyme immunoassay-reactive, western blot-unconfirmed samples were pooled (10/pool) and tested for HIV RNA by nucleic acid amplification testing. We defined acute HIV infection as HIV-1 RNA positive with a negative or indeterminate HIV-1 western blot pattern and early HIV infection as HIV-1 RNA positive with a positive western blot pattern, but with a BED-corrected optical density of below 0.8.

RESULTS

Of 2893 patients evaluated, 324 (11%) had test results indicating HIV infection. Overall, 30 patients (1.0%) had acute HIV infection, 56 (1.8%) had early HIV infection, and 238 (8%) had established HIV infection. Acute HIV infections were more prevalent at sites with higher HIV prevalence and lower malaria endemicity.

CONCLUSION

At multiple sites in Uganda, 1-3% of adults with suspected malaria had acute or early HIV infection. These findings highlight a major opportunity for expanding recognition of acute and early HIV infection in Africa.

BACKGROUND

Inhaled corticosteroids (ICSs) are considered first-line treatment for persistent asthma, yet there is significant variability in treatment response. Dual-specificity phosphatase 1 (DUSP1) appears to mediate the anti-inflammatory action of corticosteroids.

OBJECTIVE

We sought to determine whether variants in the DUSP1 gene are associated with clinical response to ICS treatment.

METHODS

Study participants with asthma were drawn from the following multiethnic cohorts: the Genetics of Asthma in Latino Americans (GALA) study; the Study of African Americans, Asthma, Genes & Environments (SAGE); and the Study of Asthma Phenotypes and Pharmacogenomic Interactions by Race-ethnicity (SAPPHIRE). We screened GALA study participants for genetic variants that modified the relationship between ICS use and bronchodilator response. We then replicated our findings in SAGE and SAPPHIRE participants. In a group of SAPPHIRE participants treated with ICSs for 6 weeks, we examined whether a DUSP1 polymorphism was associated with changes in FEV(1) and self-reported asthma control.

RESULTS

The DUSP1 polymorphisms rs881152 and rs34507926 localized to different haplotype blocks and appeared to significantly modify the relationship between ICS use and bronchodilator response among GALA study participants. This interaction was also seen for rs881152 among SAPPHIRE but not SAGE participants. Among the group of SAPPHIRE participants prospectively treated with ICSs for 6 weeks, rs881152 genotype was significantly associated with changes in self-reported asthma control but not FEV(1).

CONCLUSION

DUSP1 polymorphisms were associated with clinical response to ICS therapy and therefore might be useful in the future to identify asthmatic patients more likely to respond to this controller treatment.

Electrical cardiac forces have been previously hypothesized to play a significant role in cardiac morphogenesis and remodeling. In response to electrical forces, cultured cardiomyocytes rearrange their cytoskeletal structure and modify their gene expression profile. To translate such in vitro data to the intact heart, we used a collection of zebrafish cardiac mutants and transgenics to investigate whether cardiac conduction could influence in vivo cardiac morphogenesis independent of contractile forces. We show that the cardiac mutant dco(s226) develops heart failure and interrupted cardiac morphogenesis following uncoordinated ventricular contraction. Using in vivo optical mapping/calcium imaging, we determined that the dco cardiac phenotype was primarily due to aberrant ventricular conduction. Because cardiac contraction and intracardiac hemodynamic forces can also influence cardiac development, we further analyzed the dco phenotype in noncontractile hearts and observed that disorganized ventricular conduction could affect cardiomyocyte morphology and subsequent heart morphogenesis in the absence of contraction or flow. By positional cloning, we found that dco encodes Gja3/Cx46, a gap junction protein not previously implicated in heart formation or function. Detailed analysis of the mouse Cx46 mutant revealed the presence of cardiac conduction defects frequently associated with human heart failure. Overall, these in vivo studies indicate that cardiac electrical forces are required to preserve cardiac chamber morphology and may act as a key epigenetic factor in cardiac remodeling.

BACKGROUND

Combination therapies are now recommended to treat uncomplicated malaria. We used a longitudinal design to assess the incidence of malaria and compare the efficacies of 3 combination regimens in Kampala, Uganda.

METHODOLOGY/PRINCIPAL FINDINGS

Children aged 1-10 years were enrolled from randomly selected households in 2004-05 and 2007, and were followed at least monthly through 2008. Insecticide-treated bednets (ITNs) were provided in 2006. Children were randomized upon their first episode, and then treated for all episodes of uncomplicated malaria with amodiaquine/sulfadoxine-pyrimethamine (AQ/SP), artesunate/amodiaquine (AS/AQ), or artemether/lumefantrine (AL). Risks of parasitological failure were determined for each episode of uncomplicated malaria and clinical parameters were followed. A total of 690 children experienced 1464 episodes of malaria. 96% of these episodes were uncomplicated malaria and treated with study drugs; 94% were due to Plasmodium falciparum. The rank order of treatment efficacy was AL > AS/AQ > AQ/SP. Failure rates increased over time for AQ/SP, but not the artemisinin-based regimens. Over the 4-year course of the study the prevalence of asymptomatic parasitemia decreased from 11.8% to 1.4%, the incidence of malaria decreased from 1.55 to 0.32 per person year, and the prevalence of anemia (hemoglobin <10 gm/dL) decreased from 5.9% to 1.0%. No episodes of severe malaria (based on WHO criteria) and no deaths were seen.

CONCLUSIONS/SIGNIFICANCE

With ready access to combination therapies and distribution of ITNs, responses were excellent for artemisinin-containing regimens, severe malaria was not seen, and the incidence of malaria and prevalence of parasitemia and anemia decreased steadily over time.

TRIAL REGISTRATION

isrctn.org ISRCTN37517549.

BACKGROUND

Recurrence is a major cause of treatment failure after allogeneic transplantation for acute myelogenous leukemia (AML) and myelodysplastic syndrome (MDS), and treatment options are very limited. Azacitidine is a DNA methyltransferase inhibitor with activity in myeloid disease. The authors hypothesized that low-dose azacitidine administered after transplant would reduce recurrence rates, and conducted a study to determine a safe dose/schedule combination.

METHODS

Forty-five high-risk patients were treated. Median age was 60 years; median number of comorbidities was 3; 67% were not in remission. By using a Bayesian adaptive method to determine the best dose/schedule combination based on time to toxicity, the authors investigated combinations of 5 daily azacitidine doses, 8, 16, 24, 32, and 40 mg/m2, and 4 schedules: 1, 2, 3, or 4 cycles, each with 5 days of drug and 25 days of rest. Cycle 1 started on Day +40.

RESULTS

Reversible thrombocytopenia was the dose-limiting toxicity. The optimal combination was 32 mg/m2 given for 4 cycles. Median follow-up was 20.5 months. One-year event-free and overall survival were 58% and 77%, justifying further studies to estimate long-term clinical benefit. No dose significantly affected DNA global methylation.

CONCLUSIONS

Azacitidine at 32 mg/m2 given for 5 days is safe and can be administered after allogeneic transplant for at least 4 cycles to heavily pretreated AML/MDS patients. The trial also suggested that this treatment may prolong event-free and overall survival, and that more cycles may be associated with greater benefit.

The mechanisms underlying schistosomiasis-induced pulmonary hypertension (PH), one of the most common causes of PH worldwide, remain unclear. We sought to determine whether Schistosoma mansoni causes experimental PH associated with pulmonary vascular remodeling in an interleukin (IL)-13-dependent manner. IL-13Ralpha1 is the canonical IL-13 signaling receptor, whereas IL-13Ralpha2 is a competitive nonsignaling decoy receptor. Wild-type, IL-13Ralpha1(-/-), and IL-13Ralpha2(-/-) C57BL/6J mice were percutaneously infected with S. mansoni cercariae, followed by i.v. injection of eggs. We assessed PH with right ventricular catheterization, histological evaluation of pulmonary vascular remodeling, and detection of IL-13 and transforming growth factor-beta signaling. Infected mice developed pulmonary peri-egg granulomas and arterial remodeling involving predominantly the vascular media. In addition, gain-of-function IL-13Ralpha2(-/-) mice had exacerbated vascular remodeling and PH. Mice with loss of IL-13Ralpha1 function did not develop PH and had reduced pulmonary vascular remodeling. Moreover, the expression of resistin-like molecule-alpha, a target of IL-13 signaling, was increased in infected wild-type and IL-13Ralpha2(-/-) but not IL-13Ralpha1(-/-) mice. Phosphorylated Smad2/3, a target of transforming growth factor-beta signaling, was increased in both infected mice and humans with the disease. Our data indicate that experimental schistosomiasis causes PH and potentially relies on up-regulated IL-13 signaling.

BACKGROUND

Public health triangulation is a process for reviewing, synthesising and interpreting secondary data from multiple sources that bear on the same question to make public health decisions. It can be used to understand the dynamics of HIV transmission and to measure the impact of public health programs. While traditional intervention research and meta-analysis would be ideal sources of information for public health decision making, they are infrequently available, and often decisions can be based only on surveillance and survey data.

METHODS

The process involves examination of a wide variety of data sources and both biological, behavioral and program data and seeks input from stakeholders to formulate meaningful public health questions. Finally and most importantly, it uses the results to inform public health decision-making. There are 12 discrete steps in the triangulation process, which included identification and assessment of key questions, identification of data sources, refining questions, gathering data and reports, assessing the quality of those data and reports, formulating hypotheses to explain trends in the data, corroborating or refining working hypotheses, drawing conclusions, communicating results and recommendations and taking public health action.

RESULTS

Triangulation can be limited by the quality of the original data, the potentials for ecological fallacy and "data dredging" and reproducibility of results.

CONCLUSIONS

Nonetheless, we believe that public health triangulation allows for the interpretation of data sets that cannot be analyzed using meta-analysis and can be a helpful adjunct to surveillance, to formal public health intervention research and to monitoring and evaluation, which in turn lead to improved national strategic planning and resource allocation.

BACKGROUND

Bone marrow cell treatment has been proposed as a therapy for myocardial infarction, but the optimal timing and number of injections remain unknown.

METHODS

Myocardial infarction was induced in mice followed by ultrasound-guided injection of mouse bone marrow cells at different time points post myocardial infarction (Days 3, 7, and 14) as monotherapy and at Days 3+7 as "double" therapy and at Days 3+7+14 as "triple" therapy. Controls received saline injections at Day 3 and Days 3+7+14. Left ventricular ejection fraction was evaluated post myocardial infarction prior to any therapy and at Day 28. Hearts were analyzed at Day 28 for infarct size and survival of donor cells.

RESULTS

Left ventricular ejection fraction decreased from 55.3±0.9% to 37.6±0.6% (P<.001) 2 days post myocardial infarction in all groups. Injection of bone marrow cells at Day 3 post myocardial infarction resulted in smaller infarct size (17.8±3.6% vs. 36.6±7.1%; P=.05) and improved LV function (left ventricular ejection fraction 40.3±2.0% vs. 31.1±8.3%; P<.05) compared to control. However, delayed therapy at Day 7 or 14 did not. Multiple injections of bone marrow cells, either double therapy or triple therapy, did not result in reduction in infarct size, but led to improvements in left ventricular ejection fraction at Day 28 compared to control (39.9±3.6% and 38.8±5.5% vs. 34.8±5.3%; all P<.05). The number of donor cells surviving at Day 28 did not correlate with improvement in left ventricular ejection fraction.

CONCLUSIONS

Injection of bone marrow cells at Day 3 reduced infarct size and improved left ventricular function. Multiple injections of bone marrow cells had no additive effect. Delaying cell therapy post myocardial infarction resulted in no functional benefit at all. These results will help inform future clinical trials.

OBJECTIVE

To examine the prospective association of depressive symptoms with circulating C-reactive protein (CRP) and to determine the direction of that association.

METHODS

Using data from 2,544 healthy participants in the Coronary Artery Risk Development in Young Adults study (ages, 33-45 years; 55% female; 42% black), we examined the prospective association of depressive symptoms, as measured by the Centers for Epidemiologic Studies Depression Scale, with circulating CRP 5 years later.

RESULTS

Depressive symptoms in the Coronary Artery Risk Development in Young Adults study Year 15 predicted CRP at Year 20, independent of demographic characteristics, biological and medical risk factors, health behaviors, and Year 15 CRP. This association, however, was conditional on race such that the increase in CRP with increasing depressive symptoms was present in blacks but not whites. In neither blacks nor whites did Year 15 CRP predict Year 20 depressive symptoms. Among black participants, when examined in separate analyses, higher scores on the depressed affect and somatic symptoms subscales of the Centers for Epidemiologic Studies Depression Scale and lower scores on the positive affect subscale were associated with greater Year 20 CRP. The interpersonal problems subscale was unrelated to CRP. When all four subscale scores were entered simultaneously in the same model, black participants' scores on the positive affect and somatic symptoms subscales emerged as independent predictors of Year 20 CRP, whereas the depressed affect and interpersonal problems subscales did not.

CONCLUSIONS

Depressive symptoms may be linked more closely to inflammation in blacks than in whites.