Sub-chronic inhalation of high concentrations of manganese sulfate induces lower airway pathology in rhesus monkeys

BACKGROUND: Neurotoxicity and pulmonary dysfunction are well-recognized problems associated with prolonged human exposure to high concentrations of airborne manganese. Surprisingly, histological characterization of pulmonary responses induced by manganese remains incomplete. The primary objective of this study was to characterize histologic changes in the monkey respiratory tract following manganese inhalation. METHODS: Subchronic (6 hr/day, 5 days/week) inhalation exposure of young male rhesus monkeys to manganese sulfate was performed. One cohort of monkeys (n = 4–6 animals/exposure concentration) was exposed to air or manganese sulfate at 0.06, 0.3, or 1.5 mg Mn/m(3 )for 65 exposure days. Another eight monkeys were exposed to manganese sulfate at 1.5 mg Mn/m(3 )for 65 exposure days and held for 45 or 90 days before evaluation. A second cohort (n = 4 monkeys per time point) was exposed to manganese sulfate at 1.5 mg Mn/m(3 )and evaluated after 15 or 33 exposure days. Evaluations included measurement of lung manganese concentrations and evaluation of respiratory histologic changes. Tissue manganese concentrations were compared for the exposure and control groups by tests for homogeneity of variance, analysis of variance, followed by Dunnett's multiple comparison. Histopathological findings were evaluated using a Pearson's Chi-Square test. RESULTS: Animals exposed to manganese sulfate at ≥0.3 mg Mn/m(3 )for 65 days had increased lung manganese concentrations. Exposure to manganese sulfate at 1.5 mg Mn/m(3 )for ≥15 exposure days resulted in increased lung manganese concentrations, mild subacute bronchiolitis, alveolar duct inflammation, and proliferation of bronchus-associated lymphoid tissue. Bronchiolitis and alveolar duct inflammatory changes were absent 45 days post-exposure, suggesting that these lesions are reversible upon cessation of subchronic high-dose manganese exposure. CONCLUSION: High-dose subchronic manganese sulfate inhalation is associated with increased lung manganese concentrations and small airway inflammatory changes in the absence of observable clinical signs. Subchronic exposure to manganese sulfate at exposure concentrations (≤0.3 mg Mn/m(3)) similar to the current 8-hr occupational threshold limit value established for inhaled manganese was not associated with pulmonary pathology

Turning conflict into collaboration in managing commons: A case of Rupa Lake Watershed, Nepal

A growing body of literature on the commons has provided fascinating and intricate insights on how some local institutions have successfully managed to avoid a seemingly inevitable “tragedy of the commons” once popularized by Garrett Hardin. Primarily benefitting from the recent studies on the commonpool resources conducted by Elinor Ostrom and colleagues, polycentric selforganization and autonomy, rather than the direct state or market control over the commons, are often recognized as key features of the long enduring commons.However, these commons are quite diverse and the outcomes are often multiple and complex, accentuating the needs to differentiate among multiple commons outcomes. Furthermore, relatively under-reported are the cases where the degradation of common-pool resources are actually halted, and even restored. This study examines both the turbulent history of fishery mismanagement in Rupa Lake, Nepal and its reversal built around the participation, engagement and inclusiveness in the governance of its watershed. We find that Rupa Lake’s experience tells two stories. Reflecting Hardin’s dire forecast, the Rupa Lake watershed verged on collapse as population grew and seemingly selfish behaviorintensified under an open-access regime. But the users also found a way to rebound and reverse their course as they adopted a bottom-up approach to fishery management and established an innovative community institution, the ‘Rupa Lake Rehabilitation and Fishery Cooperative’, dedicated to the sustainable governance of the commons. This case highlights how one community at the threshold of ‘tragedy’ transformed itself by turning conflict into collaboration, which we hope contributes to the effort of better understanding multiple commons

Melioidosis in Tsunami Survivors

Eugene Athan, Anthony M. Allworth, Catherine Engler, Ivan Bastian, and Allen C. Chen

Variation in suspected cancer referral pathways in primary care: comparative analysis across the International Benchmarking Cancer Partnership

Background International variations in cancer outcomes persist and may be influenced by differences in the accessibility and organisation of cancer patient pathways. More evidence is needed to understand to what extent variations in the structure of primary care referral pathways for cancer investigation contribute to differences in the timeliness of diagnoses and cancer outcomes in different countries. Aim To explore the variation in primary care referral pathways for the management of suspected cancer across different countries. Design and setting Descriptive comparative analysis using mixed methods across the International Cancer Benchmarking Partnership (ICBP) countries. Method Schematics of primary care referral pathways were developed across 10 ICBP jurisdictions. The schematics were initially developed using the Aarhus statement (a resource providing greater insight and precision into early cancer diagnosis research) and were further supplemented with expert insights through consulting leading experts in primary care and cancer, existing ICBP data, a focused review of existing evidence on the management of suspected cancer, published primary care cancer guidelines, and evaluations of referral tools and initiatives in primary care. Results Referral pathway schematics for 10 ICBP jurisdictions were presented alongside a descriptive comparison of the organisation of primary care management of suspected cancer. Several key areas of variation across countries were identified: inflexibility of referral pathways, lack of a managed route for non- specific symptoms, primary care practitioner decision- making autonomy, direct access to investigations, and use of emergency routes. Conclusion Analysing the differences in referral processes can prompt further research to better understand the impact of variation on the timeliness of diagnoses and cancer outcomes. Studying these schematics in local contexts may help to identify opportunities to improve care and facilitate discussions on what may constitute best referral practice

Variation in suspected cancer referral pathways in primary care:comparative analysis across the International Benchmarking Cancer Partnership

BACKGROUND: International variations in cancer outcomes persist and may be influenced by differences in the accessibility and organisation of cancer patient pathways. More evidence is needed to understand to what extent variations in the structure of primary care referral pathways for cancer investigation contribute to differences in the timeliness of diagnoses and cancer outcomes in different countries. AIM: To explore the variation in primary care referral pathways for the management of suspected cancer across different countries. DESIGN AND SETTING: Descriptive comparative analysis using mixed methods across the International Cancer Benchmarking Partnership (ICBP) countries. METHOD: Schematics of primary care referral pathways were developed across 10 ICBP jurisdictions. The schematics were initially developed using the Aarhus statement (a resource providing greater insight and precision into early cancer diagnosis research) and were further supplemented with expert insights through consulting leading experts in primary care and cancer, existing ICBP data, a focused review of existing evidence on the management of suspected cancer, published primary care cancer guidelines, and evaluations of referral tools and initiatives in primary care. RESULTS: Referral pathway schematics for 10 ICBP jurisdictions were presented alongside a descriptive comparison of the organisation of primary care management of suspected cancer. Several key areas of variation across countries were identified: inflexibility of referral pathways, lack of a managed route for non-specific symptoms, primary care practitioner decision-making autonomy, direct access to investigations, and use of emergency routes. CONCLUSION: Analysing the differences in referral processes can prompt further research to better understand the impact of variation on the timeliness of diagnoses and cancer outcomes. Studying these schematics in local contexts may help to identify opportunities to improve care and facilitate discussions on what may constitute best referral practice

Stream segregation of concurrent speech and the verbal transformation effect:influence of fundamental frequency and lateralization cues

Repeating a recorded word produces verbal transformations (VTs); perceptual regrouping of acoustic-phonetic segments may contribute to this effect. The influence of fundamental frequency (F0) and lateralization grouping cues was explored by presenting two concurrent sequences of the same word resynthesized on different F0s (100 and 178 Hz). In experiment 1, listeners monitored both sequences simultaneously, reporting for each any change in stimulus identity. Three lateralization conditions were used – diotic, ±680-μs interaural time difference, and dichotic. Results were similar for the first two conditions, but fewer forms and later initial transformations were reported in the dichotic condition. This suggests that large lateralization differences per se have little effect – rather, there are more possibilities for regrouping when each ear receives both sequences. In the dichotic condition, VTs reported for one sequence were also more independent of those reported for the other. Experiment 2 used diotic stimuli and explored the effect of the number of sequences presented and monitored. The most forms and earliest transformations were reported when two sequences were presented but only one was monitored, indicating that high task demands decreased reporting of VTs for concurrent sequences. Overall, these findings support the idea that perceptual regrouping contributes to the VT effect

Polymorphic Variation in TIRAP Is Not Associated with Susceptibility to Childhood TB but May Determine Susceptibility to TBM in Some Ethnic Groups

Host recognition of mycobacterial surface molecules occurs through toll like receptors (TLR) 2 and 6. The adaptor protein TIRAP mediates down stream signalling of TLR2 and 4, and polymorphisms in the TIRAP gene (TIRAP) have been associated with susceptibility and resistance to tuberculosis (TB) in adults. In order to investigate the role of polymorphic variation in TIRAP in childhood TB in South Africa, which has one of the highest TB incidence rates in the world, we screened the entire open reading frame of TIRAP for sequence variation in two cohorts of childhood TB from different ethnic groups (Xhosa and mixed ancestry). We identified 13 SNPs, including seven previously unreported, in the two cohorts, and found significant differences in frequency of the variants between the two ethnic groups. No differences in frequency between individual SNPs or combinations were found between TB cases and controls in either cohort. However the 558C→T SNP previously associated with TB meningitis (TBM) in a Vietnamese population was found to be associated with TBM in the mixed ancestry group. Polymorphisms in TIRAP do not appear to be involved in childhood TB susceptibility in South Africa, but may play a role in determining occurrence of TBM

Vitamin E deficiency and risk of equine motor neuron disease

© 2007 Mohammed et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution Licens

SARS-CoV-2 Omicron is an immune escape variant with an altered cell entry pathway

Vaccines based on the spike protein of SARS-CoV-2 are a cornerstone of the public health response to COVID-19. The emergence of hypermutated, increasingly transmissible variants of concern (VOCs) threaten this strategy. Omicron (B.1.1.529), the fifth VOC to be described, harbours multiple amino acid mutations in spike, half of which lie within the receptor-binding domain. Here we demonstrate substantial evasion of neutralization by Omicron BA.1 and BA.2 variants in vitro using sera from individuals vaccinated with ChAdOx1, BNT162b2 and mRNA-1273. These data were mirrored by a substantial reduction in real-world vaccine effectiveness that was partially restored by booster vaccination. The Omicron variants BA.1 and BA.2 did not induce cell syncytia in vitro and favoured a TMPRSS2-independent endosomal entry pathway, these phenotypes mapping to distinct regions of the spike protein. Impaired cell fusion was determined by the receptor-binding domain, while endosomal entry mapped to the S2 domain. Such marked changes in antigenicity and replicative biology may underlie the rapid global spread and altered pathogenicity of the Omicron variant