Potentiation of sensory responses in ventrobasal thalamus in vivo via selective modulation of mGlu1 receptors with a positive allosteric modulator.

Metabotropic glutamate subtype 1 (mGlu1) receptor is thought to play a role in synaptic responses in thalamic relay nuclei. The aim of this study was to evaluate the positive allosteric modulator (PAM) Ro67-4853 as a tool to modulate thalamic mGlu1 receptors on single thalamic neurones in vivo. Ro67-4853, applied by iontophoresis onto ventrobasal thalamus neurones of urethane-anaesthetised rats, selectively enhanced responses to the agonist (S)-3,5-dihydroxy-phenylglycine (DHPG), an effect consistent with mGlu1 potentiation. The PAM was also able to enhance maintained responses to 10 Hz trains of sensory stimulation of the vibrissae, but had little effect on responses to single sensory stimuli. Thus Ro67-4853 appears to be a highly selective tool that can be useful in investigating how mGlu1 receptor potentiation can alter neural processing in vivo. Our results show the importance of mGlu1 in sensory processing and attention mechanisms at the thalamic level and suggest that positive modulation of mGlu1 receptors might be a useful mechanism for enhancing cognitive and attentional processes

Construction of an environmentally sustainable development on a modified coastal sand mined and landfill site-Part 2. Re-establishing the natural ecosystems on the reconstructed beach dunes

Mimicking natural processes lead to progressive colonization and stabilization of the reconstructed beach dune ecosystem, as part of the ecologically sustainable development of Magenta Shores, on the central coast of New South Wales, Australia. The retained and enhanced incipient dune formed the first line of storm defence. Placement of fibrous Leptospermum windrows allowed wind blown sand to form crests and swales parallel to the beach. Burial of Spinifex seed head in the moist sand layer achieved primary colonization of the reconstructed dune and development of a soil fungal hyphae network prior to introduction of secondary colonizing species. Monitoring stakes were used as roosts by birds, promoting re-introduction of native plant species requiring germination by digestive tract stimulation. Bush regeneration reduced competition from weeds, allowing native vegetation cover to succeed. On-going weeding and monitoring are essential at Magenta Shores until bitou bush is controlled for the entire length of beach. The reconstructed dunes provide enhanced protection from sand movement and storm bite, for built assets, remnant significant vegetation and sensitive estuarine ecosystems. © 2010 by the authors

Spatial prediction of malaria prevalence in an endemic area of Bangladesh

<p>Abstract</p> <p>Background</p> <p>Malaria is a major public health burden in Southeastern Bangladesh, particularly in the Chittagong Hill Tracts region. Malaria is endemic in 13 districts of Bangladesh and the highest prevalence occurs in Khagrachari (15.47%).</p> <p>Methods</p> <p>A risk map was developed and geographic risk factors identified using a Bayesian approach. The Bayesian geostatistical model was developed from previously identified individual and environmental covariates (p < 0.2; age, different forest types, elevation and economic status) for malaria prevalence using WinBUGS 1.4. Spatial correlation was estimated within a Bayesian framework based on a geostatistical model. The infection status (positives and negatives) was modeled using a Bernoulli distribution. Maps of the posterior distributions of predicted prevalence were developed in geographic information system (GIS).</p> <p>Results</p> <p>Predicted high prevalence areas were located along the north-eastern areas, and central part of the study area. Low to moderate prevalence areas were predicted in the southwestern, southeastern and central regions. Individual age and nearness to fragmented forest were associated with malaria prevalence after adjusting the spatial auto-correlation.</p> <p>Conclusion</p> <p>A Bayesian analytical approach using multiple enabling technologies (geographic information systems, global positioning systems, and remote sensing) provide a strategy to characterize spatial heterogeneity in malaria risk at a fine scale. Even in the most hyper endemic region of Bangladesh there is substantial spatial heterogeneity in risk. Areas that are predicted to be at high risk, based on the environment but that have not been reached by surveys are identified.</p

Challenges for standardization of Clostridium difficile typing methods

Typing of Clostridium difficile facilitates understanding of the epidemiology of the infection. Some evaluations have shown that certain strain types (for example, ribotype 027) are more virulent than others and are associated with worse clinical outcomes. Although restriction endonuclease analysis (REA) and pulsed-field gel electrophoresis have been widely used in the past, PCR ribotyping is the current method of choice for typing of C. difficile. However, global standardization of ribotyping results is urgently needed. Whole-genome sequencing of C. difficile has the potential to provide even greater epidemiologic information than ribotyping

Comparative effectiveness of interventions for preventing tuberculosis: systematic review and network meta-analysis of interventional studies

BACKGROUND: Tuberculosis (TB) is the leading infectious cause of death globally. Several preventive measures are employed to prevent TB, yet there is a paucity of evidence on the effectiveness of these interventions. Therefore, this study aimed to identify the most effective interventions for reducing TB incidence. METHODS: A systematic search was undertaken across five relevant databases including PubMed, SCOPUS, Web of Science, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov from inception to February 22, 2023. Bayesian network meta-analysis (NMA) was conducted to compare the effectiveness of preventive interventions including preventive therapy, nutritional intervention, targeted screening, and vaccination in reducing TB incidence. Subgroup analysis was conducted to investigate the effectiveness of TB preventive treatments. FINDINGS: Overall 82 articles were included in the NMA. Preventive therapy (OR = 0.44, 95% CrI 0.36-0.52), BCG vaccination (OR = 0.62, 95% CrI 0.39-0.98) and TB candidate vaccines (OR = 0.67, 95% CrI 0.46-0.98) were more effective than placebo or no intervention. When all active interventions were considered, preventive therapy ranked as the best intervention. Of the preventive treatments, isoniazid (OR = 0.46, 95% CrI 0.35-0.55), isoniazid plus rifampicin (OR = 0.56, 95% CrI 0.32-0.97), isoniazid plus rifapentine (OR = 0.49, 95% CrI 0.29-0.83), isoniazid plus ethambutol (OR = 0.39, 95% CrI 0.15-0.99), isoniazid plus streptomycin (OR = 0.12, 95% CrI 0.02-0.55), rifampicin (OR = 0.41, 95% CrI 0.18-0.92), and rifampicin plus pyrazinamide (OR = 0.51, 95% CrI 0.29-0.87) surpassed placebo/none. INTERPRETATION: Our study suggested that when all available preventive interventions are considered, preventive therapy is likely the most effective intervention. Within TB preventive treatments, isoniazid plus streptomycin is likely ranked at the top. This comparative study provides important information for policymakers and stakeholders, enabling them to make informed decisions on preventive strategies, whilst considering local resources and capacity constraints. FUNDING: Curtin University strategic scholarship and Australian National Health and Medical Research Council, through an Emerging Leadership Investigator grant

Information-Derived Mechanistic Hypotheses for Structural Cardiotoxicity

Adverse events resulting from drug therapy can be a cause of drug withdrawal, reduced and or restricted clinical use, as well as a major economic burden for society. To increase the safety of new drugs, there is a need to better understand the mechanisms causing the adverse events. One way to derive new mechanistic hypotheses is by linking data on drug adverse events with the drugs’ biological targets. In this study, we have used data mining techniques and mutual information statistical approaches to find associations between reported adverse events collected from the FDA Adverse Event Reporting System and assay outcomes from ToxCast, with the aim to generate mechanistic hypotheses related to structural cardiotoxicity (morphological damage to cardiomyocytes and/or loss of viability). Our workflow identified 22 adverse event-assay outcome associations. From these associations, 10 implicated targets could be substantiated with evidence from previous studies reported in the literature. For two of the identified targets, we also describe a more detailed mechanism, forming putative adverse outcome pathways associated with structural cardiotoxicity. Our study also highlights the difficulties deriving these type of associations from the very limited amount of data available

A Comparative Study of the Spatial Distribution of Schistosomiasis in Mali in 1984–1989 and 2004–2006

Geostatistical maps are increasingly being used to plan neglected tropical disease control programmes. We investigated the spatial distribution of schistosomiasis in Mali prior to implementation of national donor-funded mass chemotherapy programmes using data from 1984–1989 and 2004–2006. The 2004–2006 dataset was collected after 10 years of schistosomiasis control followed by 12 years of no control. We found that national prevalence of Schistosoma haematobium and S. mansoni was not significantly different in 2004–2006 compared to 1984–1989 and that the spatial distribution of both infections was similar in both time periods, to the extent that models built on data from one time period could accurately predict the spatial distribution of prevalence of infection in the other time period. This has two main implications: that historic data can be used, in the first instance, to plan contemporary control programmes due to the stability of the spatial distribution of schistosomiasis; and that a decade of donor-funded mass distribution of praziquantel has had no discernable impact on the burden of schistosomiasis in subsequent generations of Malians, probably due to rapid reinfection

Leptospirosis in American Samoa – Estimating and Mapping Risk Using Environmental Data

Leptospirosis is the most common bacterial infection transmitted from animals to humans. Infected animals excrete the bacteria in their urine, and humans can become infected through contact with animals or a contaminated environment such as water and soil. Environmental factors are important in determining the risk of human infection, and differ between ecological settings. The wide range of risk factors include high rainfall and flooding; poor sanitation and hygiene; urbanisation and overcrowding; contact with animals (including rodents, livestock, pets, and wildlife); outdoor recreation and ecotourism; and environmental degradation. Predictive risk maps have been produced for many infectious diseases to identify high-risk areas for transmission and guide allocation of public health resources. Maps are particularly useful where disease surveillance and epidemiological data are poor. The objectives of this study were to estimate leptospirosis seroprevalence at geographic locations based on environmental factors, produce a predictive disease risk map for American Samoa, and assess the accuracy of the maps in predicting infection risk. This study demonstrated the value of geographic information systems and disease mapping for identifying environmental risk factors for leptospirosis, and enhancing our understanding of disease transmission. Similar principles could be used to investigate the epidemiology of leptospirosis in other areas

Comparative Field Evaluation of Combinations of Long-Lasting Insecticide Treated Nets and Indoor Residual Spraying, Relative to Either Method Alone, for Malaria Prevention in an Area where the main Vector is Anopheles Arabiensis.

Long-lasting insecticidal nets (LLINs) and indoor residual spraying (IRS) are commonly used together in the same households to improve malaria control despite inconsistent evidence on whether such combinations actually offer better protection than nets alone or IRS alone. Comparative tests were conducted using experimental huts fitted with LLINs, untreated nets, IRS plus untreated nets, or combinations of LLINs and IRS, in an area where Anopheles arabiensis is the predominant malaria vector species. Three LLIN types, Olyset®, PermaNet 2.0® and Icon Life® nets and three IRS treatments, pirimiphos-methyl, DDT, and lambda cyhalothrin, were used singly or in combinations. We compared, number of mosquitoes entering huts, proportion and number killed, proportions prevented from blood-feeding, time when mosquitoes exited the huts, and proportions caught exiting. The tests were done for four months in dry season and another six months in wet season, each time using new intact nets. All the net types, used with or without IRS, prevented >99% of indoor mosquito bites. Adding PermaNet 2.0® and Icon Life®, but not Olyset® nets into huts with any IRS increased mortality of malaria vectors relative to IRS alone. However, of all IRS treatments, only pirimiphos-methyl significantly increased vector mortality relative to LLINs alone, though this increase was modest. Overall, median mortality of An. arabiensis caught in huts with any of the treatments did not exceed 29%. No treatment reduced entry of the vectors into huts, except for marginal reductions due to PermaNet 2.0® nets and DDT. More than 95% of all mosquitoes were caught in exit traps rather than inside huts. Where the main malaria vector is An. arabiensis, adding IRS into houses with intact pyrethroid LLINs does not enhance house-hold level protection except where the IRS employs non-pyrethroid insecticides such as pirimiphos-methyl, which can confer modest enhancements. In contrast, adding intact bednets onto IRS enhances protection by preventing mosquito blood-feeding (even if the nets are non-insecticidal) and by slightly increasing mosquito mortality (in case of LLINs). The primary mode of action of intact LLINs against An. arabiensis is clearly bite prevention rather than insecticidal activity. Therefore, where resources are limited, priority should be to ensure that everyone at risk consistently uses LLINs and that the nets are regularly replaced before being excessively torn. Measures that maximize bite prevention (e.g. proper net sizes to effectively cover sleeping spaces, stronger net fibres that resist tears and burns and net use practices that preserve net longevity), should be emphasized

Influence of Prior Influenza Vaccination on Antibody and B-Cell Responses

Currently two vaccines, trivalent inactivated influenza vaccine (TIV) and live attenuated influenza vaccine (LAIV), are licensed in the USA. Despite previous studies on immune responses induced by these two vaccines, a comparative study of the influence of prior influenza vaccination on serum antibody and B-cell responses to new LAIV or TIV vaccination has not been reported. During the 2005/6 influenza season, we quantified the serum antibody and B-cell responses to LAIV or TIV in adults with differing influenza vaccination histories in the prior year: LAIV, TIV, or neither. Blood samples were collected on days 0, 7–9 and 21–35 after immunization and used for serum HAI assay and B-cell assays. Total and influenza-specific circulating IgG and IgA antibody secreting cells (ASC) in PBMC were detected by direct ELISPOT assay. Memory B cells were also tested by ELISPOT after polyclonal stimulation of PBMC in vitro. Serum antibody, effector, and memory B-cell responses were greater in TIV recipients than LAIV recipients. Prior year TIV recipients had significantly higher baseline HAI titers, but lower HAI response after vaccination with either TIV or LAIV, and lower IgA ASC response after vaccination with TIV than prior year LAIV or no vaccination recipients. Lower levels of baseline HAI titer were associated with a greater fold-increase of HAI titer and ASC number after vaccination, which also differed by type of vaccine. Our findings suggest that the type of vaccine received in the prior year affects the serum antibody and the B-cell responses to subsequent vaccination. In particular, prior year TIV vaccination is associated with sustained higher HAI titer one year later but lower antibody response to new LAIV or TIV vaccination, and a lower effector B-cell response to new TIV but not LAIV vaccination