To assess public health risks of rotavirus via drinking water consumption, a cell culture-PCR assay was developed and optimized for the detection of infectious environmental rotavirus strains in ...naturally contaminated source waters for drinking water production. Infectious rotavirus concentrations were estimated by an optimized cell culture-PCR assay as most probable numbers by using the presence or absence of replicated virus in different sample volumes. Infectious rotavirus was detected in 11 of 12 source water samples in concentrations varying from 0·19 (0·01-0·87) to 8·3 (1·8-34·0) infectious PCR detectable units per litre (IPDU/l), which was not significantly different from the concentrations of infectious enterovirus in these samples. In 55% of the samples, rotavirus genomes were 1000 to 10 000 times (3 log₁₀-4 log₁₀) more abundantly present than infectious rotavirus particles, whereas in the remaining 45% of the samples, rotavirus genomes were less than 1000 times (<3 log₁₀) more abundantly present. The broad variation observed in the ratios of rotavirus RNA and infectious particles demonstrates the importance of detecting infectious viruses instead of viral RNA for the purposes involving estimations of public health risks.
Removal or inactivation of viruses in drinking water treatment processes can be quantified by measuring the concentrations of viruses or virus indicators in water before and after treatment. Virus ...reduction is then calculated from the ratio of these concentrations. Most often only the average reduction is reported. That is not sufficient when treatment efficiency must be characterized in quantitative risk assessment.
We present three simple models allowing statistical analysis of series of counts before and after treatment: distribution of the ratio of concentrations, and distribution of the probability of passage for unpaired and paired water samples.
Performance of these models is demonstrated for several processes (long and short term storage, coagulation/filtration, coagulation/sedimentation, slow sand filtration, membrane filtration, and ozone disinfection) using microbial indicator data from full-scale treatment processes.
All three models allow estimation of the variation in (log) reduction as well as its uncertainty; the results can be easily used in risk assessment. Although they have different characteristics and are present in vastly different concentrations, different viruses and/or bacteriophages appear to show similar reductions in a particular treatment process, allowing generalization of the reduction for each process type across virus groups.
The processes characterized in this paper may be used as reference for waterborne virus risk assessment, to check against location specific data, and in case no such data are available, to use as defaults.
During 2007–2010, over 4000 persons in The Netherlands contracted Q-fever, a zoonosis caused by the bacterium Coxiella burnetii. Goats and sheep are the main reservoir of C. burnetti and infected ...animals shed the bacterium with their urine, faeces and birth products. Human infections may occur through direct contact with infected animals, or through inhalation of contaminated dust particles or aerosols. Discharge of waste water from Q fever contaminated goat farms may result in the presence of C. burnetii in sewage water and aerosols at sewage water treatment plants (SWTPs) which may pose a health risk for workers or neighbouring residents. The objectives of this study were to determine the presence of C. burnetii at SWTPs and to optimize available detection methods. In March–July 2011, sewage influent and aeration tank samples from four SWTPs receiving discharge from Q fever positive goat farms were examined by using a multiplex real-time PCR detecting C. burnetii DNA by targeting IS1111 and com1 genes. Influent (44%; n=16/36) and active sludge (36%; n=13/36) samples were positive with low C. burnetii DNA content. Percentage positive samples per SWTP were 28–61%. Positive samples were most frequent in March 2011 and least frequent in May 2011. The presence of C. burnetii DNA in sewage water samples suggests that SWTPs receiving waste water from Q fever contaminated goat farms may contribute to the spread of C. burnetii to the environment. The low levels of C. burnetii DNA in sewage water during the decline of the Q fever outbreak in The Netherlands in 2011 indicate a low health risk for SWTP workers and residents.
In the Netherlands, safe and sufficient drinking water is provided to the general population by ten drinking water companies. To guarantee safe drinking water the World Health Organization (WHO) ...developed a Water Safety Plan (WSP), a Risk Assessment and a Risk Management (RA/RM) framework. The objective of the study was to identify legally required RA approaches, to document application of RA/RM activities at Dutch drinking water companies and to determine to what extent these RA/RM activities as a whole cover all the elements of the WHO WSP approach. This study could be of interest to both managers of large water utilities and decision makers.
The assessment was performed by means of a policy review and interviews with two to four staff members involved in RA/RM from all ten Dutch drinking water companies combined with a joint workshop. The drinking water companies are well aware of the potential hazards and risks that can influence the drinking water quality. To guarantee the supply of safe and sufficient drinking water, the Dutch drinking water sector uses six different legally required RA/RM approaches. This study shows that by using the six legally required RA/RM approaches, all WSP steps are covered. WSP entails a generic risk assessment for identifying all hazards and hazardous events from source to tap, whereas the six legally required RA/RM each focus on specific risks at an advanced level. Each risk assessment provides information on specific hazards and hazardous events covering a part of the water supply chain. These legal requirements are complemented with additional RA/RM activities at sector and water company level such as codes of practices and standard operating procedures. The outcomes of all RA/RM approaches combined provide information from source to tap. When using multiple RA/RM approaches, it is crucial to share and combine information derived from the different activities.
Abstract Galantamine is an acetylcholinesterase inhibitor and memantine is a non competitive antagonist of NMDA receptors that are being used to treat Alzheimer's disease (AD) patients. The fact that ...drugs with different mechanisms of action are available to treat AD introduces the prospect of prescribing drug combinations to amplify drug efficacy. This study was planed to evaluate the potential neuroprotective effects of galantamine combined with memantine in a transient global cerebral ischemia model in gerbils. Animal groups included in the study were: sham, ischemia, and ischemia plus galantamine (1 mg/kg and 10 mg/kg), memantine (10 mg/kg and 20 mg/kg), 1 mg/kg galantamine plus 10 mg/kg memantine, and 10 mg/kg galantamine plus 10 mg/kg memantine, respectively. Surviving pyramidal neurons in the CA1 subfield of the hippocampus, TUNEL, caspase-3 and SOD-2 immunohistochemistries, and the object placement test were evaluated 72 h after reperfusion. Memantine did not exert a clear neuroprotective effect, nor did it prevent spatial memory loss. In a previous study using the same experimental model, galantamine was neuroprotective and improved spatial memory. In this study, the association of 10 mg/kg memantine with 10 mg/kg galantamine increased the number of living pyramidal neurons, reduced TUNEL, active caspase-3 and SOD-2 immunoreactivity, and preserved spatial memory after ischemia-reperfusion injury; however, the effects of the combination were not statistically different from those observed in animals treated with galantamine alone. We believe these results are of interest from a clinical point of view because the association of both drugs is being used in clinical practice and in clinical trials to treat Alzheimer's disease and vascular dementia.
Annual overviews of waterborne disease outbreaks associated with untreated recreational water use provided by authorities responsible for bathing-water quality and public health in The Netherlands ...revealed 742 outbreaks during 1991–2007 mainly comprising of skin conditions (48%) and gastroenteritis (31%) and involving at least 5623 patients. The number of outbreaks per bathing season correlated with the number of days with temperatures over 25°C (r=0·8–0·9), but was not reduced through compliance with European bathing-water legislation (r=0·1), suggesting that monitoring of faecal indicator parameters and striving for compliance with water-quality standards may not sufficiently protect bathers. Bathing sites were prone to incidental faecal contamination events or environmental conditions that favoured the growth of naturally occurring pathogens. Identification of all possible contamination sources, awareness of changes that might negatively affect water quality, and provision of adequate information to the public are important preventive measures to protect public health.
Our preclinical work showed a dramatic synergy between interleukin-12 (IL-12) and trastuzumab for stimulation of natural killer cell cytokine secretion. We aimed to determine the safety profile of ...IL-12 when given in combination with trastuzumab and paclitaxel to patients with metastatic HER2-overexpressing cancers. Paclitaxel was given i.v. at 175 mg/m(2) every 3 weeks. Trastuzumab was given on day 1 each week (4 mg/kg initially and 2 mg/kg thereafter) in combination with injections of IL-12 on days 2 and 5 starting in cycle 2. This trial accrued 21 patients with metastatic HER2-positive tumors (breast, 7; colon, 6; esophagus, 4; stomach, 2; pancreas, 1; thyroid, 1). The IL-12 component was dose-escalated in cohorts of three patients. The dose-limiting toxicity was grade 3 fatigue at the 300 ng/kg dose level in two patients. The recommended phase II dose was 200 ng/kg administered s.c. There was one complete response in a patient with breast cancer, partial responses in 4 patients (breast, 2; esophageal, 2), and stabilization of disease lasting 3 months or greater (SD) in 6 other patients. All but one response occurred in patients with HER2 3+ disease. Two SD patients completed 1 year of therapy. Ten patients had progressive disease. There was increased activation of extracellular signal-regulated kinase in peripheral blood mononuclear cells and increased levels of IFN-gamma and several chemokines in patients with clinical benefit (complete response, partial response, or SD), but not in patients with progressive disease. IL-12 in combination with trastuzumab and paclitaxel therefore exhibits an acceptable toxicity profile and has activity in patients with HER2-overexpressing cancers.
The use of roof-collected rainwater as a freely available and sustainable alternative to drinking water produced by drinking water companies increases worldwide. Initially, rainwater is free of ...microbial contamination, but it may become contaminated by animals and humans or, alternatively, human pathogens may grow in stored rainwater resulting in a significant human health risk from infectious diseases. This three-year study demonstrated that rainwater stored in different reservoirs in The Netherlands was frequently faecally contaminated and incidentally contained potential human pathogens such as Campylobacter, Cryptosporidium, Giardia, Aeromonas hydrophila and Legionella. Analysis of samples during a period with variable weather conditions showed a correlation between rainfall intensity and faecal indicator counts and increased detection of pathogens after heavy rainfall incidents. Outside temperature had a limited effect on both the temperature and the microbiological quality of the water in the reservoirs, which did not comply with Dutch drinking water legislation and should thus not be consumed without treatment. In general, a health risk may arise from exposure to pathogens when contaminated droplets are inhaled, ingested or come into contact with the skin. Health risks may be reduced by regular cleaning of the collection, storage and transport means, but to assess their efficacy field intervention studies are required.
Bacterial DNA contains a high frequency of unmethylated CpG motifs that stimulate immune cells via TLR9. NK cells express a low-affinity activating receptor for the Fc portion of IgG (FcgammaRIIIa), ...but were not thought to express TLR9 protein. The direct response of NK cells to CpG oligodeoxynucleotides (ODN) in the presence of FcR stimulation was investigated. Human NK cells cultured in the presence of CpG ODN plus immobilized IgG or Ab-coated tumor cells secreted large amounts of IFN-gamma (>2000 pg/ml), whereas cells stimulated with Ab alone, CpG ODN alone, or Ab and control ODN produced negligible amounts. Enhanced secretion of IL-8, macrophage-derived chemokine, and MIP-1alpha was also observed after costimulation. NK cell cytokine production was not the result of interactions with APCs or their cytokine products. Flow cytometric analysis revealed that 36 +/- 3.5% of human NK cells expressed basal levels of TLR9. TLR9 expression in human NK cells was confirmed by immunoblot analysis. Only TLR9-expressing NK cells responded to CpG ODN and Ab, because cytokine production was not observed in NK cells from TLR9-deficient mice. Mice receiving CpG ODN and HER2/neu-positive tumor cells treated with an anti-HER2 Ab exhibited enhanced systemic levels of IFN-gamma compared with mice receiving either agent alone. TLR9-/- animals reconstituted with TLR9+/+ NK cells secreted IFN-gamma in response to CpG ODN and Ab-coated tumor cells. These findings indicate that CpG ODN can directly enhance the NK cell cytokine response to Ab-coated targets via activation of TLR9.
Legionnaires Disease incidence has risen in the Netherlands in recent years. For the majority of the cases, the source of infection is never identified. Two Dutch wastewater treatment plants (WWTPs) ...have previously been identified as source of outbreaks of Legionnaires Disease (LD) among local residents. The objective of this study is to examine if LD patients in the Netherlands are more exposed to aerosols originating from WWTPs than controls.
An atmospheric dispersion model was used to generate nationwide exposure maps of aerosols from 776 WWTPs in the Netherlands. Municipal sewage treatment plants and industrial WWTPs were both included. Exposure of LD cases and controls at the residential address was compared, in a matched case-control design using a conditional logistic regression. Cases were notified LD cases with onset of disease in the period 2013–2018 in the Netherlands (n = 1604).
Aerosols dispersed over a large part of the Netherlands, but modelled concentrations are estimated to be elevated in close proximity to WWTPs. A statistically significant association was found between LD and the calculated annual average aerosol concentrations originating from WWTPs (odds-ratio: 1.32 (1.06–1.63)). This association remained significant when the two outbreak-related WWTPs were removed from the analysis (odds-ratio: 1.28 (1.03–1.58)).
LD cases were more exposed to aerosols from WWTPs than controls. This indicates that exposure to aerosols dispersed from WWTPs caused Legionnaires Disease in residents living near WWTPs in the period 2013–2018. In order to investigate which characteristics of WWTPs are associated with an increased LD risk, the WWTP database should be updated and more data is needed on the presence and survival of aerosolized Legionella bacteria to improve the Legionella dispersion modelling. Furthermore, it is recommended to further investigate how aerosol dispersion of WWTPs can effectively be reduced in order to reduce the potential health risk.
•Exposure to aerosols from WWTPs likely caused LD in people near WWTPs in 2013–2018.•Atmospheric dispersion from wastewater treatment plants (WWTPs) was modelled.•Nationwide exposure maps were made for aerosols from 776 WWTPs in the Netherlands.•Spatial distribution of Legionnaires' disease (LD) was compared to exposure maps.•LD cases were estimated to be more exposed to aerosols from WWTPs than controls.
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