Development of a Series of Kynurenine 3-Monooxygenase Inhibitors Leading to a Clinical Candidate for the Treatment of Acute Pancreatitis

Recently, we reported a novel role for KMO in the pathogenesis of acute pancreatitis (AP). A number of inhibitors of kynurenine 3-monooxygenase (KMO) have previously been described as potential treatments for neurodegenerative conditions and particularly for Huntington's disease. However, the inhibitors reported to date have insufficient aqueous solubility relative to their cellular potency to be compatible with the intravenous (iv) dosing route required in AP. We have identified and optimized a novel series of high affinity KMO inhibitors with favorable physicochemical properties. The leading example is exquisitely selective, has low clearance in two species, prevents lung and kidney damage in a rat model of acute pancreatitis, and is progressing into preclinical development.</p

Eager about beavers? Understanding opposition to species reintroduction, and its implications for conservation

The range of keystone species is increasing in some parts of the world, particularly Europe, through a combination of natural recolonization, government-sanctioned and covert reintroductions. Reintroductions are an important conservation tool, particularly in the increasingly popular approach of rewilding. There is relatively little understanding of the politics, broadly conceived, of species reintroduction, particularly around how people who live alongside these newly introduced species might react, and what underpins this reaction, and how the method of reintroduction affects reactions. Here, we explore these issues through a case of beavers in central Scotland, which were covertly reintroduced. We explore opposition to reintroduction as manifest in beaver killing and dam destruction by land managers, quantifying these using the sensitive ‘bean count’ method. We also explore what underpins land managers' reactions, particularly their views and values around land and land management. We found considerable resistance. We found that beaver killing and dam destruction were widespread, both before and after beavers became a protected species. Nevertheless, beaver populations and ranges in Scotland continue to grow. We found attitudes were grounded in a strong set of relational values around land custodianship. We find a range of views towards beavers, including widespread opposition, particularly regarding the covert nature of beaver introduction, the challenge beavers and beaver protection provide to ideas of proper land management and custodianship, and a lack of trust in formal methods of beaver governance. We argue that species reintroductions policies and research should give careful consideration to potential opposition, its material impacts on reintroduction projects and how it is grounded in wider environmental values and politics

Acute periodontal lesions

This is a review and update on acute conditions affecting the gingival tissues, including abscesses in the periodontium, necrotizing periodontal diseases, and other acute conditions that cause gingival lesions with acute presentation, such as infectious process not associated with oral bacterial biofilms, muco-cutanenous disorders, and traumatic and allergic lesions. A periodontal abscess is clinically important since it is a relatively frequent dental emergency, it can compromise the periodontal prognosis of the affected tooth, and because bacteria within the abscess have been identified, mainly by the type of etiology, and there are clear diffrences between those affecting a previously existing periodontal pocket ahd those affecting healthy sites. Therapy for this acute condition consists of drainage and tissue debridement, with individual evaluation of the need for systemic antimicrobial therapy. the definitive treatment of the pre-existing condition should be accomplished after the acute phase is controlled. Necrotizing periodontal disease (NPD) present three typical clinical features : papilla necrosis, gingival bleeding, and pain. Although the prevalence of these diseases is not high, their importance is clear, since they represent the most severe conditions associated with dental biofilm, with very rapid tissue destruction. In adittion to bacteria, the etiology of NPD includes numerous factors that alter the host response and predispose to these diseases, including HIV infection, malnutrition, stress, and tobacco smoking. The treatment consists of superficial debridement, careful mechanical oral hygiene, rinsing with chlorhexidine, and daily re-evaluation. Systemic antimicrobials may be used adjunctively in severe cases or in non-responding conditions and the best option is metronidazole.Once the acute disease is under control, definitive treatment should be provided, including the adequate therapy for the pre-existing gingivitis or periodontitis. Among other acute conditions affecting the periodontal tissues, but not caused by the microorganisms present in oral biofilms , are infectious diseases, muco-cutaneous diseases and traumatic or allergic lesions. In most cases, the gingival envolvement is not severe, though they are common and may prompt a dental emergency visit. These conditions may the direct result of a trauma or the consequence of the breaking of vesicles and bullae. A proper differential diagnosis is important for an adequate management of the case

Impact of a health marketing campaign on sugars intake by children aged 5–11 years and parental views on reducing children’s consumption

Background: The association between Free Sugars intake and non-communicable diseases such as obesity and dental caries is well documented and several countries are taking measures to reduce sugars intakes. Public Health England (PHE) instigated a range of approaches to reduce sugars, including a national health marketing campaign (Sugar Smart). The campaign aimed to raise awareness of the amount of sugars in foods and drinks and to encourage parents to reduce their children’s intake. The aim of this study was to determine whether the campaign was effective in altering dietary behaviour, by assessing any impact of the campaign on sugars intake among children aged 5–11 years. Parental perceptions of the campaign and barriers to reducing sugars intake were also explored.Methods: Parents of 873 children aged 5–11 years, identified from an existing PHE database, were invited to take part. Dietary information was collected online using Intake24 before, during, and at 1, 10 and 12 months following the campaign. Change in sugars intake was assessed using mixed effects linear regression models. One-to-one telephone interviews were conducted with a purposive sample of parents to explore perceptions of the campaign and identify barriers and facilitators to reducing children’s sugars intake.Results: Completion rates for dietary assessment ranged from 61 to 72% across the follow up time points. Qualitative telephone interviews were conducted with 20 parents. Total sugars intake decreased on average by ~ 6.2 g/day (SD 43.8) at peak campaign and the percentage of energy from total sugars significantly decreased immediately and 1 year post campaign. The percentage of energy from Free Sugars significantly decreased across all time points with the exception of the long term follow up at 12-months post campaign. The percentage of energy intake from total fat increased. Parents expressed a willingness to reduce sugars intakes, however, identified barriers including time constraints, the normalisation of sugary treats, and confusing information.Conclusions: A health marketing campaign had a positive impact in reducing sugars intake but reductions in sugars were not sustained. Parents want to reduce their child’s sugars intake but societal barriers and confusion over which sources of sugars to avoid hamper efforts to change

Changes in objectively measured activity behavior among women undergoing breast cancer treatment: Longitudinal cohort study

Purpose: Activity behaviors of breast cancer survivors (BCSs) during treatment are unlikely to be at levels sufficient enough to gain health benefits. Previous activity research among BCSs has been mainly posttreatment and generally cross-sectional. This study aimed to determine the prevalence and changes in objectively measured moderate-to-vigorous physical activity (MVPA), light physical activity (LPA), and sedentary behavior (SED) among BCSs undergoing adjuvant/palliative therapy.Methods: Participants completed baseline surveys and wore accelerometers to measure activity during waking hours during treatment and again 6 months later. Hierarchal linear modeling (HLM) was used to determine changes.Results: In total, 77 BCSs participated. Ninety-one percent provided physical activity (PA) data for 3 or more valid days at baseline (T1) and 72% at 6 months (T2); 29% met PA guidelines at T1 and 41% at T2. Daily LPA and SED did not change from T1 to T2 (133 vs 138 minutes; 595 vs 597 minutes). Controlling for body mass index at the intercept, HLM revealed that MVPA significantly increased from T1 to T2 (+5.62; P = .015).Conclusion: An increase in objectively measured total daily MVPA over 6 months was found, at which time, fewer BCSs were currently receiving chemo- or radiotherapy and may theoretically be feeling better. However, fewer T2 measures may bias and artificially inflate the results. Although total MVPA minutes increased at T2, less than half BCSs were meeting guidelines and had high amounts of LPA/SED during treatment, with insignificant change over time (71% at T1; 59% at T2). Practitioner intervention may help reduce SED while increasing LPA and MVPA behavior among those currently undergoing treatment

Submarine volcanic morphology of the western Galapagos based on EM300 bathymetry and MR1 side-scan sonar

Author Posting. © American Geophysical Union, 2007. This article is posted here by permission of American Geophysical Union for personal use, not for redistribution. The definitive version was published in Geochemistry Geophysics Geosystems 8 (2007): Q03010, doi:10.1029/2006GC001464.A compilation of high-resolution EM300 multibeam bathymetric and existing MR1 side-scan sonar data was used to investigate the volcanic morphology of the flanks of the western Galápagos Islands. The data portray an assortment of constructional volcanic features on the shallow to deep submarine flanks of Fernandina, Isabela, and Santiago Islands, including rift zones and groups of cones that are considered to be the primary elements in constructing the archipelagic apron. Ten submarine rift zones were mapped, ranging in length from 5 to 20 km, comparable in length to western Canary Island rift zones but significantly shorter than Hawaiian submarine rift zones. A detailed analysis of the northwestern Fernandina submarine rift, including calculated magnetization from a surface-towed magnetic study, suggests that the most recent volcanism has focused at the shallow end of the rift. Small submarine volcanic cones with various morphologies (e.g., pointed, cratered, and occasionally breached) are common in the submarine western Galápagos both on rift zones and on the island flanks where no rifts are present. At depths greater than ∼3000 m, large lava flow fields in regions of low bathymetric relief have been previously identified as a common seafloor feature in the western Galápagos by Geist et al. (2006); however, their source(s) remained enigmatic. The new EM300 data show that a number of the deep lava flows originate from small cones along the mid-lower portion of the NW submarine rift of Fernandina, suggesting that the deep flows owe their origin, at least in part, to submarine rift zone volcanism.Data collected on TN188 was funded by NSF grant OCE0326148 and NOAA grant NA04OAR460009 to S.M.W. Support for data collected on previous multibeam and MR1 cruises was provided by NSF grants OCE9811504 and OCE0002461 (D.J.F.)