A One Health Framework for the Evaluation of Rabies Control Programmes: A Case Study from Colombo City, Sri Lanka

<div><p>Background</p><p>One Health addresses complex challenges to promote the health of all species and the environment by integrating relevant sciences at systems level. Its application to zoonotic diseases is recommended, but few coherent frameworks exist that combine approaches from multiple disciplines. Rabies requires an interdisciplinary approach for effective and efficient management.</p><p>Methodology/Principal Findings</p><p>A framework is proposed to assess the value of rabies interventions holistically. The economic assessment compares additional monetary and non-monetary costs and benefits of an intervention taking into account epidemiological, animal welfare, societal impact and cost data. It is complemented by an ethical assessment. The framework is applied to Colombo City, Sri Lanka, where modified dog rabies intervention measures were implemented in 2007. The two options included for analysis were the control measures in place until 2006 (“baseline scenario”) and the new comprehensive intervention measures (“intervention”) for a four-year duration. Differences in control cost; monetary human health costs after exposure; Disability-Adjusted Life Years (DALYs) lost due to human rabies deaths and the psychological burden following a bite; negative impact on animal welfare; epidemiological indicators; social acceptance of dogs; and ethical considerations were estimated using a mixed method approach including primary and secondary data. Over the four years analysed, the intervention cost US $1.03 million more than the baseline scenario in 2011 prices (adjusted for inflation) and caused a reduction in dog rabies cases; 738 DALYs averted; an increase in acceptability among non-dog owners; a perception of positive changes in society including a decrease in the number of roaming dogs; and a net reduction in the impact on animal welfare from intermediate-high to low-intermediate.</p><p>Conclusions</p><p>The findings illustrate the multiple outcomes relevant to stakeholders and allow greater understanding of the value of the implemented rabies control measures, thereby providing a solid foundation for informed decision-making and sustainable control.</p></div

Total and Methyl Mercury Contents and Distribution Characteristics in Cicada, Cryptotympana atrata (Fabricius)

Total and methyl mercury concentrations of cicada bodies, wings, and exuviae were investigated to study the mercury distribution characteristics. Results indicated that total and methyl mercury concentrations of cicada bodies were 2.64 mg/kg and 123.93 ng/g on average, respectively. In cicada tissues, total mercury concentrations were found to increase in the order of exuviae (0.50 mg/kg on average) < wings (0.98 mg/kg on average) < cicada bodies (2.64 mg/kg on average) and methyl mercury concentrations of cicada bodies were 123.93 ng/g on average and were the highest. Methyl mercury concentrations accounted for about 4.69% of total mercury in cicada bodies and most mercury was in inorganic forms in cicada. Sex differences of total mercury concentrations were significantly great (F = 8.433, p < 0.01) and total mercury concentrations of the males, which were 3.38 mg/kg on average, were much higher. Correlation analysis showed that neither total nor methyl mercury concentrations of cicada bodies was significantly related to the corresponding contents of soil (r = 0.0598, p > 0.05)

Zebrafish Model for Functional Screening of Flow-Responsive Genes

OBJECTIVE: Atherosclerosis is initiated at branches and bends of arteries exposed to disturbed blood flow that generates low shear stress. This mechanical environment promotes lesions by inducing endothelial cell (EC) apoptosis and dysfunction via mechanisms that are incompletely understood. Although transcriptome-based studies have identified multiple shear-responsive genes, most of them have an unknown function. To address this, we investigated whether zebrafish embryos can be used for functional screening of mechanosensitive genes that regulate EC apoptosis in mammalian arteries. APPROACH AND RESULTS: First, we demonstrated that flow regulates EC apoptosis in developing zebrafish vasculature. Specifically, suppression of blood flow in zebrafish embryos (by targeting cardiac troponin) enhanced that rate of EC apoptosis (≈10%) compared with controls exposed to flow (≈1%). A panel of candidate regulators of apoptosis were identified by transcriptome profiling of ECs from high and low shear stress regions of the porcine aorta. Genes that displayed the greatest differential expression and possessed 1 to 2 zebrafish orthologues were screened for the regulation of apoptosis in zebrafish vasculature exposed to flow or no-flow conditions using a knockdown approach. A phenotypic change was observed in 4 genes; p53-related protein (PERP) and programmed cell death 2-like protein functioned as positive regulators of apoptosis, whereas angiopoietin-like 4 and cadherin 13 were negative regulators. The regulation of perp, cdh13, angptl4, and pdcd2l by shear stress and the effects of perp and cdh13 on EC apoptosis were confirmed by studies of cultured EC exposed to flow. CONCLUSIONS: We conclude that a zebrafish model of flow manipulation coupled to gene knockdown can be used for functional screening of mechanosensitive genes in vascular ECs, thus providing potential therapeutic targets to prevent or treat endothelial injury at atheroprone sites

Pro-apoptotic Bax is the major and Bak an auxiliary effector in cytokine deprivation-induced mast cell apoptosis

The process of apoptosis in immune cells like mast cells is essential to regain homeostasis after an inflammatory response. The intrinsic pathway of apoptosis is ultimately controlled by the pro-apoptotic Bcl-2 family members Bax and Bak, which upon activation oligomerize to cause increased permeabilization of the mitochondria outer membrane leading to cell death. We examined the role of Bax and Bak in cytokine deprivation-induced apoptosis in mast cells using connective tissue-like mast cells and mucosal-like mast cells derived from bax−/−, bak−/− and bax−/−bak−/− mice. Although both Bax and Bak were expressed at readily detectable protein levels, we found a major role for Bax in mediating mast cell apoptosis induced by cytokine deprivation. We analyzed cell viability by propidium iodide exclusion and flow cytometry after deprivation of vital cytokines for each mast cell population. Upon cytokine withdrawal, bak−/− mast cells died at a similar rate as wild type, whereas bax−/− and bax−/−bak−/− mast cells were partially or completely resistant to apoptosis, respectively. The total resistance seen in bax−/−bak−/− mast cells is comparable with mast cells deficient of both pro-apoptotic Bim and Puma or mast cells overexpressing anti-apoptotic Bcl-2. These results show that Bax has a predominant and Bak a minor role in cytokine deprivation-induced apoptosis in both connective tissue-like and mucosal-like mast cells

A relocatable ocean model in support of environmental emergencies

During the Costa Concordia emergency case, regional, subregional, and relocatable ocean models have been used together with the oil spill model, MEDSLIK-II, to provide ocean currents forecasts, possible oil spill scenarios, and drifters trajectories simulations. The models results together with the evaluation of their performances are presented in this paper. In particular, we focused this work on the implementation of the Interactive Relocatable Nested Ocean Model (IRENOM), based on the Harvard Ocean Prediction System (HOPS), for the Costa Concordia emergency and on its validation using drifters released in the area of the accident. It is shown that thanks to the capability of improving easily and quickly its configuration, the IRENOM results are of greater accuracy than the results achieved using regional or subregional model products. The model topography, and to the initialization procedures, and the horizontal resolution are the key model settings to be configured. Furthermore, the IRENOM currents and the MEDSLIK-II simulated trajectories showed to be sensitive to the spatial resolution of the meteorological fields used, providing higher prediction skills with higher resolution wind forcing.MEDESS4MS Project; TESSA Project; MyOcean2 Projectinfo:eu-repo/semantics/publishedVersio

Cyclosporine-A-induced nephrotoxicity in children with minimal-change nephrotic syndrome: long-term treatment up to 10 years

The impact of cyclosporine A (CsA) therapy in patients with steroid-dependent nephrotic-syndrome (SDNS) on long-term renal function is controversial. Data beyond 5 years are rare. Long-term renal function was evaluated in children with SDNS with and without CsA therapy, especially beyond 5 years. Twenty children were treated with CsA (study group) for a mean of 5.4 ± 2.2 years (ten patients for 5–11 years). Glomerular filtration rate (GFR) was calculated before and after 3 and 12 months and at latest follow-up of therapy. Fifteen children with cyclophosphamide-treated SDNS without CsA served as controls. In the study group, GFR decreased within 12 months from 136 ± 19 to 120 ± 31, to 114 ± 14 ml/min per 1.73 m2 at latest follow-up (p < 0.0001). Patients with CsA > 5 years had a GFR of 111 ± 14 ml/min per 1.73 m2 at latest follow-up without a GFR below 90 ml/min per 1.73 m2. No CsA toxicity was found in biopsies. In the control group, GFR dropped within 3 months, from 137 ± 27 to 130 ± 24, to 126 ± 19 ml/min per 1.73 m2 at latest follow-up (p = 0.1). Patients with and without nephrotoxic CsA therapy showed a drop in GFR. In CsA-treated patients, GFR was about 12% lower at latest follow-up compared with patients without nephrotoxic therapy but always remained within normal range. CsA seems to be safe, even in long-term treatment for more than 5 years

Pharmacokinetic analysis of two different docetaxel dose levels in patients with non-small cell lung cancer treated with docetaxel as monotherapy or with concurrent radiotherapy

<p>Abstract</p> <p>Background</p> <p>Previous pharmacokinetic studies with docetaxel have mostly used 3-weekly (75 mg/m²and 100 mg/m²) or weekly regimens (35–40 mg/m²). The pharmacokinetics and radiosensitizing efficacy of weekly 20 mg/m²docetaxel, has however not been well characterized. We examined the pharmacokinetics of weekly docetaxel when administered with concurrent radiotherapy and compared the results with a 3-weekly 100 mg/m²regimen.</p> <p>Methods</p> <p>Thirty-four patients with non small cell lung cancer (NSCLC) were included in this study, 19 receiving 100 mg/m²docetaxel 3-weekly as single therapy, and 15 receiving 20 mg/m²docetaxel weekly with concurrent radiotherapy. A newly developed HPLC method was used for measuring docetaxel levels, capable of quantifying docetaxel in plasma down to the nanomolar level.</p> <p>Results</p> <p>The HPLC method showed detectable concentrations of docetaxel in plasma even after 72 hours. In the present study we have demonstrated that median docetaxel plasma levels of 3 nM can be obtained 72 hours after a dose of 20 mg/m².</p> <p>Conclusion</p> <p>The pharmacokinetics of docetaxel is characterized by great inter-individual variability and at some time points plasma concentrations for 20 mg/m²and 100 mg/m²docetaxel were overlapping. Extrapolation of these results indicates that radio sensitizing docetaxel concentrations may be present for as long as 1 week, thus supporting the use of 20 mg/m²weekly docetaxel.</p