Most occupational and environmental research describes associations between specific occupational and environmental hazards and health outcomes, with little information available on population-level exposure, especially among unique subpopulations. The authors describe the prevalence of self-reported lifetime exposure to nine occupational and environmental hazards among 11,326 American Indian and Alaska Native (AI/AN) adults enrolled in the Education and Research Towards Health (EARTH) Study in the Southwest U.S. and Alaska. The top three hazards experienced by AI/AN people in Alaska were petroleum products, military chemicals, and asbestos. The top three hazards experienced by AI/AN living in the Southwest U.S. were pesticides, petroleum, and welding/silversmithing. The study described here found that male sex, lower educational attainment, AI/AN language use, and living in the Southwest U.S.(vs. Alaska) were all associated with an increased likelihood of hazard exposure. The authors' study provides baseline data to facilitate future exposure-response analyses. Future studies should measure dose and duration as well as environmental hazards that occur in community settings.

In the natural environment, microorganisms exist together in self-produced polymeric matrix biofilms. Often, several species, which can belong to both bacterial and fungal kingdoms, coexist and interact in ways which are not completely understood. Biofilm infections have become prevalent largely in medical settings due to the increasing use of indwelling medical devices such as catheters or prosthetics. These infections are resistant to common antimicrobial therapies because of the inherent nature of their structure. In terms of infectious biofilms, it is important to understand the microbe-microbe interactions and how the host immune system reacts in order to discover therapeutic targets. Currently, single infection immune response studies are thriving with the use of invertebrate models. This review highlights the advances in single microbial-host immune response as well as the promising aspects for polymicrobial biofilm study in five invertebrate models; Lemna minor (duck weed), Arabidopsis thaliana (thale cress), Dictyostelium discoideum (slime mold), Drosophila melanogaster (common fruit fly), and Caenorhabditis elegans (round worm). © 2012 Federation of European Microbiological Societies. Published by Blackwell Publishing Ltd. All rights reserved.

Background. In the UK, most people with mental health problems are managed in primary care. However, many individuals in need of help are not able to access care, either because it is not available, or because the individual's interaction with care-givers deters or diverts help-seeking. Aims. To understand the experience of seeking care for distress from the perspective of potential patients from "hard-to-reach" groups. Methods. A qualitative study using semi-structured interviews, analysed using a thematic framework. Results. Access to primary care is problematic in four main areas: how distress is conceptualised by individuals, the decision to seek help, barriers to help-seeking, and navigating and negotiating services. Conclusion. There are complex reasons why people from "hard-to-reach" groups may not conceptualise their distress as a biomedical problem. In addition, there are particular barriers to accessing primary care when distress is recognised by the person and help-seeking is attempted. We suggest how primary care could be more accessible to people from "hard-to-reach" groups including the need to offer a flexible, non-biomedical response to distress.

Flow coefficients v_{n} for n=2, 3, 4, characterizing the anisotropic collective flow in Au+Au collisions at sqrt[s_{NN}]=200  GeV, are measured relative to event planes Ψ_{n}, determined at large rapidity. We report v_{n} as a function of transverse momentum and collision centrality, and study the correlations among the event planes of different order n. The v_{n} are well described by hydrodynamic models which employ a Glauber Monte Carlo initial state geometry with fluctuations, providing additional constraining power on the interplay between initial conditions and the effects of viscosity as the system evolves. This new constraint can serve to improve the precision of the extracted shear viscosity to entropy density ratio η/s.

Preclinical animal models have supported much of the recent rapid expansion of neuroscience research and have facilitated critical discoveries that undoubtedly benefit patients suffering from psychiatric disorders. This overview serves as an introduction for the following chapters describing both in vivo and in vitro preclinical models of psychiatric disease components and briefly describes models related to drug dependence and affective disorders. Although there are no perfect animal models of any psychiatric disorder, models do exist for many elements of each disease state or stage. In many cases, the development of certain models is essentially restricted to the human clinical laboratory domain for the purpose of maximizing validity, whereas the use of in vitro models may best represent an adjunctive, well-controlled means to model specific signaling mechanisms associated with psychiatric disease states. The data generated by preclinical models are only as valid as the model itself, and the development and refinement of animal models for human psychiatric disorders continues to be an important challenge. Collaborative relationships between basic neuroscience and clinical modeling could greatly benefit the development of new and better models, in addition to facilitating medications development.

Heroin addiction is a wide-reaching problem with a spectrum of damaging social consequences. Currently approved heroin addiction medications include drugs that bind at the same receptors (e.g. opioid receptors) occupied by heroin and/or its metabolites in the brain, but undesired side effects of these treatments, maintenance dependence and relapse to drug taking remains problematic. A vaccine capable of blocking heroin's effects could provide an economical, long-lasting and sustainable adjunct to heroin addiction therapy without the side effects associated with available treatment options. Heroin, however, presents a particularly challenging vaccine target as it is metabolized to multiple psychoactive molecules of differing lipophilicity, with differing abilities to cross the blood brain barrier. In this review, we discuss the opiate scaffolding and hapten design considerations to confer immunogenicity as well as the specificity of the immune response towards structurally similar opiates. In addition, we detail different strategies employed in the design of immunoconjugates for a vaccine-based therapy for heroin addiction treatment.

Methamphetamine affects the hippocampus, a brain region crucial for learning and memory, as well as relapse to drug seeking. Rats self-administered methamphetamine for 1 h twice weekly (intermittent-short-I-ShA), 1 h daily (limited-short-ShA), or 6 h daily (extended-long-LgA) for 22 sessions. After 22 sessions, rats from each access group were withdrawn from self-administration and underwent spatial memory (Y-maze) and working memory (T-maze) tests followed by extinction and reinstatement to methamphetamine seeking or received one intraperitoneal injection of 5-bromo-2'-deoxyuridine (BrdU) to label progenitors in the hippocampal subgranular zone (SGZ) during the synthesis phase. Two-hour-old and 28-day-old surviving BrdU-immunoreactive cells were quantified. I-ShA rats performed better on the Y-maze and had a greater number of 2-h-old SGZ BrdU cells than nondrug controls. LgA rats, but not ShA rats, performed worse on the Y- and T-maze and had a fewer number of 2-h-old SGZ BrdU cells than nondrug and I-ShA rats, suggesting that new hippocampal progenitors, decreased by methamphetamine, were correlated with impairment in the acquisition of new spatial cues. Analyses of addiction-related behaviors after withdrawal and extinction training revealed methamphetamine-primed reinstatement of methamphetamine-seeking behavior in all three groups (I-ShA, ShA, and LgA), and this effect was enhanced in LgA rats compared with I-ShA and ShA rats. Protracted withdrawal from self-administration enhanced the survival of SGZ BrdU cells, and methamphetamine seeking during protracted withdrawal enhanced Fos expression in the dentate gyrus and medial prefrontal cortex in LgA rats to a greater extent than in ShA and I-ShA rats. These results indicate that changes in the levels of the proliferation and survival of hippocampal neural progenitors and neuronal activation of hippocampal granule cells predict the effects of methamphetamine self-administration (limited vs extended access) on cognitive performance and relapse to drug seeking and may contribute to the impairments that perpetuate the addiction cycle.Neuropsychopharmacology advance online publication, 28 December 2011; doi:10.1038/npp.2011.315.

BACKGROUND: The main theoretic advantage of proximal olecranon fracture intramedullary fixation is decreased soft-tissue irritation and, potentially, less subsequent hardware removal. Despite this possible benefit, questions remain as to whether intramedullary devices are capable of controlling olecranon fractures to the same extent as locking plates. This study evaluates the ability of a novel multidirectional locking nail to stabilize comminuted fractures and directly compares its biomechanical performance with that of locking olecranon plates. MATERIALS AND METHODS: We implanted 8 stainless steel locking plates and stainless steel intramedullary nails to stabilize a simulated comminuted fracture in 16 fresh-frozen cadaveric elbows. Flexion-extension, varus-valgus, gap distance, and rotational 3-dimensional angular displacement analysis was conducted over a 60° motion arc (30° to 90°) to assess fragment motion through physiologic cyclic arcs of motion and failure loading. Displacements in all planes were compared. RESULTS: Both implants showed less than 1° of motion in all measured planes and allowed less than 1 mm of gapping through all loads tested until ultimate failure. All failures occurred by sudden, catastrophic means. The mean failure weight for the nail was 14.4 kg compared with 8.7 kg for the plate (P =.02). The nail survived 1102 cycles, whereas the plate survived 831 cycles (P =.06). CONCLUSION: In simulated comminuted olecranon fractures, the multidirectional locking intramedullary nails sustained significantly higher maximum loads than the locking plates. The two implants showed no significant differences in fragment control or number of cycles survived. Surgeons can expect the multidirectional locking nails to stabilize comminuted fractures at least as well as locking plates.

Background and purpose  TLR7 agonists have been proposed to have potential in the treatment of allergic diseases. However, the therapeutic utility of current small molecular weight TLR7 agonists is limited by the compounds having systemic activity resulting in unwanted side effects. We have developed a series of TLR7-selective antedrugs, including SM-324405 and AZ12441970, which contain an ester group that is rapidly cleaved in plasma to reduce systemic exposure. Experimental approach  TLR7 activity of the parent ester and acid metabolite was assessed in vitro in reporter cells and primary cells from a number of species. Pharmacokinetics following a dose to the lungs was assessed in mice and efficacy evaluated in a mouse allergic airway model. Key results  Compounds were selective for TLR7 with no cross-over to TLR8 and were metabolically unstable in plasma with the acid metabolite showing substantially reduced activity in a number of assays. The compounds inhibited IL-5 cytokine production and induced IFNα which was implicated in mediating the inhibition of IL-5. When dosed into the lung the compounds were rapidly metabolised and short-term exposure of the antedrug was sufficient to activate the IFN pathway. AZ12441970 showed efficacy in a mouse allergic airway model with minimal induction of systemic IFNα consistent with the low plasma levels of compound. Conclusions and implications  The biological and metabolic profiles of these TLR7-selective antedrug compounds are consistent with a new class of compound that could be administrated locally for the treatment of allergic diseases whilst reducing the risk of systemic side effects.

Animal models of drug dependence have described both reductions in brain reward processes and potentiation of stress-like (or anti-reward) mechanisms, including a recruitment of corticotropin-releasing factor (CRF) signaling. Accordingly, chronic exposure to opiates often leads to the development of mechanical hypersensitivity. We measured paw withdrawal thresholds (PWTs) in male Wistar rats allowed limited (short access group: ShA) or extended (long access group: LgA) access to heroin or cocaine self-administration, or in rats made dependent on ethanol via ethanol vapor exposure (ethanol-dependent group). In heroin self-administering animals, after transition to LgA conditions, thresholds were reduced to around 50% of levels observed at baseline, and were also significantly lower than thresholds measured in animals remaining on the ShA schedule. In contrast, thresholds in animals self-administering cocaine under either ShA (1 h) or LgA (6 h) conditions were unaltered. Similar to heroin LgA rats, ethanol-dependent rats also developed mechanical hypersensitivity after eight weeks of ethanol vapor exposure compared to non-dependent animals. Systemic administration of the CRF1R antagonist MPZP significantly alleviated the hypersensitivity observed in rats dependent on heroin or ethanol. The emergence of mechanical hypersensitivity with heroin and ethanol dependence may thus represent one critical drug-associated negative emotional state driving dependence on these substances. These results also suggest a recruitment of CRF-regulated nociceptive pathways associated with escalation of intake and dependence. A greater understanding of relationships between chronic drug exposure and pain-related states may provide insight into mechanisms underlying the transition to drug addiction, as well as reveal new treatment opportunities.