Impact of insecticide interventions on the abundance and resistance profile of Aedes aegypti.

Insecticide-based vector control is the primary strategy for curtailing dengue transmission. We used a mathematical model of the seasonal population dynamics of the dengue mosquito vector, Aedes aegypti, both to assess the effectiveness of insecticide interventions on reducing adult mosquito abundance and to predict evolutionary trajectories of insecticide resistance. We evaluated interventions that target larvae, adults, or both. We found that larval control and adult control using ultra-low-volume insecticide applications can reduce adult mosquito abundance with effectiveness that depends on the frequency of applications. We also found that year-long continuous larval control and adult control, using either insecticide treatment of surfaces and materials or lethal ovitraps, imposed the greatest selection for resistance. We demonstrated that combined targeting of larvae and adults at the start of the dengue season is optimal. This intervention contrasts with year-long continuous larval control policies adopted in settings in which dengue transmission occurs.

Disability adjusted life years lost to dengue in Brazil.

OBJECTIVES: To assess the dengue burden in Brazil, and to compare it over three spatial scales: in the city of Rio de Janeiro, the state of Rio de Janeiro, and in Brazil overall. METHODS: We calculated disability adjusted life years (DALYs) lost to dengue per million individuals annually from 1986 through 2006. To calculate DALYs, we compiled data on the number of dengue cases by age, clinical syndrome and outcome. We evaluated the sensitivity of our results to multiplication factors used to adjust for inaccuracies in reporting using a Monte Carlo method. RESULTS: From 1986 through 2006, a mean of 56, 47 and 22 DALYs per million individuals annually were lost to dengue in the city of Rio de Janeiro, in the state of Rio de Janeiro and in Brazil, respectively. Over 80% of the dengue burden derived from dengue fever cases. The dengue burden was highest at the city-level with a maximum single-year estimate of 560 DALYs per million individuals for 2002. CONCLUSIONS: Assessment of dengue burden requires consideration of all clinical syndromes over multiple years. Our results indicate that the dengue burden is as high as the burden of other major infectious diseases that afflict the Brazilian population, including malaria. These results may prompt policy makers to elevate the prioritization of dengue control, and allocate resources needed to curtail the increasing dengue burden.

The transmission and control of XDR TB in South Africa: an operations research and mathematical modelling approach.

Extensively drug-resistant tuberculosis (XDR TB) has emerged as a threat to TB control efforts in several high-burden areas, generating international concern. XDR TB is now found in every region of the world, but appears most worrisome in the context of HIV and in resource-limited settings with congregate hospital wards. Here, we examine the emergence and transmission dynamics of the disease, incorporating the mathematical modelling literature related to airborne infection and epidemiological studies related to the operations of TB control programmes in resource-limited settings. We find that while XDR TB may present many challenges in the setting of resource constraints, the central problems highlighted by the emergence of XDR TB are those that have plagued TB programmes for years. These include a slow rate of case detection that permits prolonged infectiousness, the threat of airborne infection in enclosed spaces, the problem of inadequate treatment delivery and treatment completion, and the need to develop health systems that can address the combination of TB and poverty. Mathematical models of TB transmission shed light on the idea that community-based therapy and rapid detection systems may be beneficial in resource-limited settings, while congregate hospital wards are sites for major structural reform.

Reservoir interactions and disease emergence.

Animal populations act as reservoirs for emerging diseases. In order for transmission to be self-sustaining, a pathogen must have a basic reproduction number R0>1. Following a founding transmission event from an animal reservoir to humans, a pathogen has not yet adapted to its new environment and is likely to have an R0<1. However, subsequent evolution may rescue the pathogen from extinction in its new host. Recent applications of branching process theory investigate how the emergence of a novel pathogen is influenced by the number and rates of intermediate evolutionary steps. In addition, repeated contacts between human and reservoir populations may promote pathogen emergence. This article extends a stepping-stone model of pathogen evolution to include reservoir interactions. We demonstrate that the probability of a founding event culminating in an emerged pathogen can be significantly influenced by ongoing reservoir interactions. While infrequent reservoir interactions do not change the probability of disease emergence, moderately frequent interactions can promote emergence by facilitating adaptation to humans. Frequent reservoir interactions promote emergence even with minimal adaptation to humans. Thus, these results warn against perpetuated interaction between humans and animal reservoirs, as occurs when there are ecological or environmental changes that bring humans into more frequent contact with animal reservoirs.

Features discriminating SARS from other severe viral respiratory tract infections.

This study investigated the discriminatory features of severe acute respiratory syndrome (SARS) and severe non-SARS community-acquired viral respiratory infection (requiring hospitalization) in an emergency department in Hong Kong. In a case-control study, clinical, laboratory and radiological data from 322 patients with laboratory-confirmed SARS from the 2003 SARS outbreak were compared with the data of 253 non-SARS adult patients with confirmed viral respiratory tract infection from 2004 in order to identify discriminatory features. Among the non-SARS patients, 235 (93%) were diagnosed as having influenza infections (primarily H3N2 subtype) and 77 (30%) had radiological evidence of pneumonia. In the early phase of the illness and after adjusting for baseline characteristics, SARS patients were less likely to have lower respiratory symptoms (e.g. sputum production, shortness of breath, chest pain) and more likely to have myalgia (p < 0.001). SARS patients had lower mean leukocyte and neutrophil counts (p < 0.0001) and more commonly had "ground-glass" radiological changes with no pleural effusion. Despite having a younger average age, SARS patients had a more aggressive respiratory course requiring admission to the ICU and a higher mortality rate. The area under the receiver operator characteristic curve for predicting SARS when all variables were considered was 0.983. Using a cutoff score of >99, the sensitivity was 89.1% (95%CI 82.0-94.0) and the specificity was 98.0% (95%CI 95.4-99.3). The area under the receiver operator characteristic curve for predicting SARS when all variables except radiological change were considered was 0.933. Using a cutoff score of >8, the sensitivity was 80.7% (95%CI 72.4-87.3) and the specificity was 94.5% (95%CI 90.9-96.9). Certain clinical manifestations and laboratory changes may help to distinguish SARS from other influenza-like illnesses. Scoring systems may help identify patients who should receive more specific tests for influenza or SARS.

Basic fibroblast growth factor stimulates hepatocyte growth factor/scatter factor secretion by human mesenchymal cells.

Basic fibroblast growth factor (bFGF) together with other pleiotropic factors plays an important role in many complex physiological processes such as embryonic development, angiogenesis, and wound repair. Among these factors, hepatocyte growth factor/scatter factor (HGF/SF) which is secreted by cells of mesodermal origin exerts its mito- and motogenic activities on cells of epithelial and endothelial origin. Knowledge of the regulatory mechanisms of HGF/SF may contribute to the understanding of its role in physio-pathological processes. We observed that the secretion of HGF/SF by MRC-5 cells and by other fibroblast-derived cell cultures in conditioned media was enhanced by exposure to bFGF. HGF/SF was measured by the scatter assay, a bioassay for cell motility, and was further characterized by Western blot analysis with anti-HGF/SF antibodies. Exposure of MRC-5 cultures to 10 ng/ml of bFGF resulted already 6 h posttreatment in a threefold higher amount of scatter factor secreted into the medium as compared to untreated cultures. HGF/SF secretion was sustained after bFGF treatment for the following 72 h when increased amounts of HGF/SF were detected both in conditioned media as well as associated to the extracellular matrix. The secretion of HGF/SF in cell supernatants increased dose dependently upon treatment with bFGF starting from basal levels of 6 U/ml and reaching 27 U/ml at 30 ng/ml bFGF, plateauing thereafter. Upregulation of HGF/SF by IL-1, already described by others, was confirmed in this study. Based on our findings an articulated interaction can be speculated for bFGF, HGF/SF, and IL-1, e.g., in tissue regeneration during inflammatory processes or in wound healing.

Suramin modulates cellular levels of hepatocyte growth factor receptor by inducing shedding of a soluble form.

Several growth factor receptors undergo shedding from the cell surface as a result of limited proteolysis via mechanisms that are at present poorly understood. By Western blotting of the conditioned media and cell lysates of several cell lines expressing the hepatocyte growth factor receptor, we found that suramin, a pharmacological agent that inhibits the activity of many growth factors, was able to induce shedding of this receptor. Increased levels of soluble hepatocyte growth factor receptor were observed in the conditioned media of GTL-16, a cell line over-expressing the receptor, as early as ten minutes after initial exposure to the agent, and incubation of this line with 300 microM suramin caused a 50% reduction in cell-associated levels of receptor after 6 hours. Although protein kinase C activation by treatment of cells with phorbol esters has previously been found to stimulate shedding of the hepatocyte growth factor receptor, this hitherto undescribed activity of suramin was not affected by protein kinase C inhibitors. Since shedding represents a possible means of down-modulation of receptor activity, suramin may inhibit the hepatocyte growth factor ligand/receptor system, not only by abrogation of hepatocyte growth factor binding to intact receptor, but also by induction of receptor shedding.

Big endothelin-converting enzyme activities in subcellular fractions of bovine aortic endothelial cells.

A combination of HPLC elution patterns and peptide sequencing has been used to characterize two distinct activities present in subcellular fractions of bovine aortic endothelial cells (BAECs) capable of converting human big endothelin-1 (big ET-1) to mature (ET-1). A pepstatin-inhibitable activity with an acidic pH optimum present in a lysosome-enriched fraction cleaved big ET-1 at positions 18 and 21 at similar rates. A neutral pH activity present in a postlysosomal organelles subfraction was also able to convert big ET-1, and was inhibited by EDTA, but not by 1-chloro-3-tosylamido-4-phenyl-2-butanone (TPCK), an inhibitor of chymotrypsin-like serine proteases.