Screened and unscreened hearing threshold levels for the adult population: Results from the Nord-Trøndelag Hearing Loss Study Niveles de umbrales auditivos tamizados y no tamizados en la población adulta. Resultados del estudio Nord-TrøndeIag sobre hipoacusias

This paper presents normative data of hearing threshold levels of a population screened with various criteria, as compared to unscreened population data. Computer-controlled pure-tone audiometry was administered to the adult population in Nord-Trøndelag County, Norway, during 1995–1997. The 51 975 participants also provided questionnaire information about occupational and leisure noise exposure, previous ear infections, and head injury. While screening had little effect on the median hearing threshold levels of young adults, there was a substantial effect when screening men above 40 years of age for a history of noise exposure. Screening for known ear-related disorders and diseases resulted in small effects on the mean hearing threshold levels. The median hearing thresholds of both the screened and the unscreened sample exceeded the age and sex specific thresholds specified by the ISO 7029.     

The “Path” Not Taken: Exploring Structural Differences in Mapped- Versus Shortest-Network-Path School Travel Routes

Objectives. School route measurement often involves estimating the shortest network path. We challenged the relatively uncritical adoption of this method in school travel research and tested the route discordance hypothesis that several types of difference exist between shortest network paths and reported school routes.Methods. We constructed the mapped and shortest path through network routes for a sample of 759 children aged 9 to 13 years in grades 5 and 6 (boys = 45%, girls = 54%, unreported gender = 1%), in Toronto, Ontario, Canada. We used Wilcoxon signed-rank tests to compare reported with shortest-path route measures including distance, route directness, intersection crossings, and route overlap. Measurement difference was explored by mode and location.Results. We found statistical evidence of route discordance for walkers and children who were driven and detected it more often for inner suburban cases. Evidence of route discordance varied by mode and school location.Conclusions. We found statistically significant differences for route structure and built environment variables measured along reported and geographic information systems–based shortest-path school routes. Uncertainty produced by the shortest-path approach challenges its conceptual and empirical validity in school travel research.Recent policy and research on children’s school travel has responded to reports of decadal declines in active school travel (AST)—that is, traveling to or from school under one’s own power, typically on foot or using a bicycle—in many Western nations.1–6 Evidence of a similar trend is also beginning to emerge in some cities in the global south.7 AST decline has been matched by increased prevalence of overweight and obesity in children and youths.8–10 Children driven to and from school and other activities miss transport-centered opportunities for physical activity and health benefits11–13 that, when combined with physical activity from other sources, could produce an active healthy lifestyle that may be sustained into adulthood.14–19 Understanding how to encourage AST could progress through development of valid evidence about the relationship between school travel route characteristics and travel mode choice.School travel research has often examined the relationship between travel mode choice and home, school, and route environments.20 Underpinning this work is the hypothesis that built environment (BE) features may enable or restrict household transport choices. A mix of BE effects, with some indication of difference by age, time of day, location (e.g., home, route, or school), and measurement approach (e.g., objective or subjective assessment), have been found.21–23 Studies of home, school, and travel mode without route information have suggested that both objective measures and perceptions of BE features and their use (i.e., traffic on busy roads) predict AST.21,23–25 Reported effects are not always in the same direction across studies. The odds of walking have been shown to increase with residential density in some studies but not in others.21,23,24 Marked differences in BE effects have also been reported when separate models are estimated for the morning and afternoon school travel periods.21 For example, and unique to their school-to-home model, Larsen et al.21 found that the effect of mixed land use (AST is more likely with mixed land use) intensified for the trip home; residential density became significant, along with income (i.e., AST is more likely in lower income neighborhoods); and a street tree effect (i.e., trees provide shade and are a direct and indirect measure of neighborhood aesthetics), significant in the morning model, was not reproduced.Route-based studies extend the home, school, and travel mode work by including BE features that children might experience along their route that could influence a household’s school travel decisions. For example, a child’s possible interaction with busy roads while walking to or from school could underlie a parent’s decision to drive. Route-based studies have typically involved measuring BE characteristics along and around assumed routes modeled using a geographic information systems (GIS)–based shortest-network-path algorithm.26–32 Although several diverse route effects have been reported, all studies have reproduced the finding that children are less likely to walk as route distance increases.26–32 Here again, different effects are reported for to- and from-school trips.26,27 For example, Larsen et al.26 reported significant effects for the presence of street trees, detached housing, and land use mix, that did not materialize in their school-to-home model. Findings regarding route directness, typically measured as the deviation of an assumed GIS-estimated route from the straight-line distance between home and school, have also been inconsistent. For adults, route directness is often associated with the use of active modes. In the school travel literature, the opposite effect,28,30 or no effect,26,27 has been found. Several studies have reported some relationship between major roads (crossed or along a route) and AST.26,28,30 Again, though, road-type effects may emerge for the school-to-home trip only26 or not at all.27 Child and parent self-report data have also indicated that a major road crossing may act as an AST barrier.31 Lastly, although land use mix appears to be associated with AST, in both route- and non–route-based studies25,26 scholars have appeared less certain about how land use in general (e.g., residential density, mix, street-facing windows) relates to or produces children’s transport. The literature presently projects the view that certain types of land use place some combination of more “eyes on the street” and more people (children and adults) in the street, thereby affecting adult risk perceptions regarding social fears and traffic.22,25 With the attenuation of adult risk perception, children may be more likely to engage in AST.22,25Notably, BE features that associate with school travel-mode choice seem to vary within and across studies set in different locations. Perhaps one of the problems is that, for route-based work in particular, the assumed GIS-based route is not an accurate approximation of the actual route traveled. The statistical validity of shortest-network-path route estimation is questionable; the method may not produce an accurate approximation of actual student travel routes. In this article, we challenge the relatively uncritical use of the GIS-based shortest-network-path approach often used to produce school travel routes (to and from) and route environments when observed or reported route data are absent. The research is organized around 1 question: Do quantifiable differences exist between mapped (reported) routes to and from school and school routes estimated using a GIS-based shortest-path algorithm? We addressed this question by testing the route discordance hypothesis that several types of difference exist between shortest-path route estimates and school routes mapped by child respondents.     

Validity and Reliability of Tools to Measure Muscle Mass,Strength, and Physical Performance in Community-Dwelling Older People: A Systematic Review

BackgroundThis study critically appraises the measurement properties of tools to measure muscle mass, strength, and physical performance in community-dwelling older people. This can support the selection of a valid and reliable set of tools that is feasible for future screening and identification of sarcopenia.MethodsThe databases PubMed, Cumulative Index to Nursing and Allied Health Literature (CINAHL), and Cochrane were systematically searched (January 11, 2012). Studies were included if they investigated the measurement properties or feasibility, or both, of tools to measure muscle mass, strength, and physical performance in community-dwelling older people aged ≥60 years. The consensus-based standards for the selection of health status measurement instruments (COSMIN) checklist was used for quality appraisal of the studies.ResultsSixty-two publications were deemed eligible, including tools for muscle mass (n = 16), muscle strength (n = 15), and physical performance (n = 31). Magnetic resonance imaging, computed tomography, and a 4-compartment model were used as gold standards for muscle mass assessment. Other frequently used measures of muscle mass are dual-energy x-ray and the bioelectrical impedance (BIA); however, reliability data of the BIA are lacking. Handheld dynamometry and gait speed or a short physical performance battery provide a valid and reliable measurement of muscle strength and physical performance, respectively.ConclusionsIt can be concluded that several tools are available for valid and reliable measurements of muscle mass, strength, and performance in clinical settings. For a home-setting BIA, handheld dynamometry and gait speed or a short physical performance battery are the most valid, reliable, and feasible. The combination of selected instruments and its use for the screening and identification of sarcopenia in community-dwelling older people need further evaluation.     

Heterogeneous expression and functional relevance of the ubiquitin carboxyl‐terminal hydrolase L1 in melanoma

The expression of ubiquitin carboxyl‐terminal hydrolase 1 (UCHL1) is deregulated in human cancer cells with tumor inhibiting or promoting functions. Due to less knowledge on the role of UCHL1 in melanoma progression, the expression pattern and function of UCHL1 as well as the deregulated signaling pathways were characterized. A large number of melanoma cell lines, tissue microarrays of melanoma lesions and control tissues were analyzed for UCHL1 expression using PCR, Western blot and/or immunohistochemistry. The analysis revealed that melanocyte cultures, 24 of 331 melanoma lesions, two of 18 short‐term cultures and two of 19 melanoma cell lines tested, respectively, heterogeneously expressed UCHL1. The low frequency of UCHL1 expression in melanoma cells was due to gene silencing by promoter DNA hypermethylation. Using different transfection models an enzyme activity‐dependent growth promoting function of UCHL1 via the activation of the mitogen‐activated protein kinase signaling pathway was found in melanoma cells. Under oxygen stress a dose‐dependent effect of UCHL1 was detected, which was mediated by a dynamic modification of the PI3K‐Akt signaling. Thus, the aberrant UCHL1 expression in melanoma cells is linked to dynamic changes in growth properties and signal transduction cascades suggesting that UCHL1 provides a novel marker and/or therapeutic target at least for a subset of melanoma patients.     

Progressive resistance training rebuilds lean body mass in head and neck cancer patients after radiotherapy – Results from the randomized DAHANCA 25B trial

Purpose

The critical weight loss observed in head and neck squamous cell carcinoma (HNSCC) patients following radiotherapy is mainly due to loss of lean body mass. This is associated with decreases in muscle strength, functional performance and Quality of Life (QoL). The present study investigated the effect of progressive resistance training (PRT) on lean body mass, muscle strength and functional performance in HNSCC patients following radiotherapy.

Patients and methods

Following radiotherapy HNSCC patients were randomized into two groups: Early Exercise (EE, n = 20) initiated 12 weeks of PRT followed by 12 weeks of self-chosen physical activity. Delayed Exercise (DE, n = 21) initiated 12 weeks of self-chosen physical activity followed by 12 weeks of PRT. Lean body mass, muscle strength, functional performance and QoL were evaluated at baseline and after week 12 and 24.

Results

In the first 12 weeks lean body mass increased by 4.3% in EE after PRT and in the last 12 weeks by 4.2% in DE after PRT. These increases were significantly larger than the changes after self-chosen physical activity (p ? 0.005). Regardless of PRT start-up time, the odds ratio of increasing lean body mass by more than 4% after PRT was 6.26 (p < 0.05). PRT significantly increased muscle strength, whereas functional performance increased significantly more than after self-chosen physical activity only after delayed onset of PRT. Overall QoL improved significantly more in EE than DE from baseline to week 12.

Conclusion

PRT effectively increased lean body mass and muscle strength in HNSCC patients following radiotherapy, irrespectively of early or delayed start-up.     

Cytochrome P450‐mediated metabolism of the synthetic cannabinoids UR‐144 and XLR‐11

In recent years, synthetic cannabinoids have emerged in the illicit drug market, in particular via the Internet, leading to abuse of these drugs. There is currently limited knowledge about the specific enzymes involved in the metabolism of these drugs. In this study, we investigated the cytochrome P450 (CYP) enzymes involved in the metabolism of the two synthetic cannabinoids (1‐pentyl‐1H‐indol‐3‐yl)‐(2,2,3,3‐tetramethylcyclopropyl)methanone (UR‐144) and [1‐(5‐fluoropentyl)‐1H‐indol‐3‐yl)](2,2,3,3‐tetramethylcyclopropyl)methanone (XLR‐11). This study extends previous studies by identifying the specific CYP enzymes involved in the metabolism of UR‐144 and XLR‐11 utilizing a panel of nine recombinant enzymes (CYP1A2, 2B6, 2C8, 2C9, 2C18, 2C19, 2D6, 3A4, and 2E1). This is followed by an investigation of the effect of specific inhibitors targeted against CYP1A2, 2B6, 2C9, 2C19, 2D6 and 3A4 in human liver microsomes (HLM). Incubations of UR‐144 and XLR‐11 with recombinant CYP enzymes revealed that UR‐144 and XLR‐11 are extensively metabolized by CYP3A4 at the tetramethylcyclopropyl (TMCP) moiety, but also CYP1A2 and CYP2C19 showed activity. Inhibition of CYP3A4 in HLM attenuated the metabolism of UR‐144 and XLR‐11, while inhibition of the other CYP enzymes in HLM had only minor effects. Thus, CYP3A4 is the major contributor to the CYP mediated metabolism of UR‐144 and XLR‐11 with minor contributions from CYP1A2. Users of UR‐144 and XLR‐11 are thus subject to the influence of potential drug‐drug interactions, if they are concomitantly medicated with CYP3A4 inducers (e.g. some antiepileptics) or inhibitors (e.g. some antifungal drugs). Copyright © 2015 John Wiley & Sons, Ltd.     

Characterization of DNA–protein complexes by nanoparticle tracking analysis and their association with systemic lupus erythematosus

Nanotechnology enables investigations of single biomacromolecules, but technical challenges have limited the application in liquid biopsies, for example, blood plasma. Nonetheless, tools to characterize single molecular species in such samples represent a significant unmet need with the increasing appreciation of the physiological importance of protein structural changes at nanometer scale. Mannose-binding lectin (MBL) is an oligomeric plasma protein and part of the innate immune system through its ability to activate complement. MBL also serves a role as a scavenger for cellular debris, especially DNA. This may link functions of MBL with several inflammatory diseases in which cell-free DNA now appears to play a role, but mechanistic insight has been lacking. By making nanoparticle tracking analysis possible in human plasma, we now show that superoligomeric structures of MBL form nanoparticles with DNA. These oligomers correlate with disease activity in systemic lupus erythematosus patients. With the direct quantification of the hydrodynamic radius, calculations following the principles of Taylor dispersion in the blood stream connect the size of these complexes to endothelial inflammation, which is among the most important morbidities in lupus. Mechanistic insight from an animal model of lupus supported that DNA-stabilized superoligomers stimulate the formation of germinal center B cells and drive loss of immunological tolerance. The formation involves an inverse relationship between the concentration of MBL superoligomers and antibodies to double-stranded DNA. Our approach implicates the structure of DNA–protein nanoparticulates in the pathobiology of autoimmune diseases.

Autoimmune diseases involve a chronic inflammatory response, which often leads to severe organ damage. Innate immunity, especially the complement system, serves a crucial role in instructing the adaptive immune response by facilitating transport of antigen into the lymph nodes and spleen (1–3). Engineered nanoparticles are targets for innate immunity (4, 5). So far it remains unclear whether physiologically formed nanoparticles also can manipulate the immune response or even be a source of autoinflammatory pathologies. Systemic lupus erythematosus (SLE) is a prototypic and potentially fatal multisystem autoimmune disease (6). B cells develop antibodies (Ab) to double-stranded (ds) DNA and spread a loss of host self-tolerance in expanding germinal centers (GCs) (7), which increases the SLE disease activity index (SLEDAI) (6). A missing link remains in our understanding of how dsDNA becomes a strong antigenic stimulus in the GC environment. Furthermore, the physiological significance of such stimulation has recently gained attention from the increasing number of other inflammatory diseases where cell-free DNA appear to play role (8).Mannose (or mannan)-binding lectin (MBL) is part of innate immunity against infections along with other proteins of the complement system. It also contributes to aberrant chronic inflammation with damage to vascularized host tissue, especially the kidney (9). A recent study showed that MBL binds glycosylated proteins in a nanoparticulate vaccine formulation. This augments immunity by strengthening the formation of antigen-reactive GCs (10). MBL binds dsDNA, presumably as a scavenger of cellular debris (11). In animal models of SLE, MBL deficiency is protective (12), while clinical studies did not associate MBL with SLE (13, 14).The 26-kDa MBL protein chain contains a tertiary structure with an N-terminal cysteine-rich segment, followed by a collagen-like region and a C-terminal Ca²⁺-dependent carbohydrate recognition domain (15, 16). Assembly of the collagen triple helix makes a structural trimer unit (MBL₃) (17, 18), which further oligomerizes into polydisperse structures with 3 to 8× MBL₃ units. In purified recombinant protein, atomic force microscopy (AFM) identified forms as large as 16 trimer units (16× MBL₃) (19), and small-angle X-ray scattering spectroscopy (SAXS) characterized anisotropic oligomers with an ∼150-nm long axis (20). Especially the SAXS data suggested a type of oligomerization, which involves juxtaposition of a number of ∼6× MBL₃ units, into resulting molecular ultrastructures that we here term superoligomers. Unfortunately, AFM and SAXS are unsuited for analyzing the MBL structural organization in complex samples such as liquid biopsies, including blood (21). Consequently, it is unclear if superoligomeric (sp)MBL exists in vivo and what its relevance is to human disease.Nanoparticle tracking analysis (NTA) relates the Brownian motion of particles in liquid to their hydrodynamic radius. Motion is tracked by particle scattering of projected laser light (Fig. 1A) or by emission from long-lived fluorescent dyes (Fig. 1D), as recently demonstrated with biotinylated protein aggregates using streptavidin-coupled quantum dots (QDs) (22). Monoclonal Ab-conjugated QDs enable specific targeting of proteins in fluorescence microscopy (23). In principle, a similar application is possible in NTA to characterize changes in the structural organization of proteins, even in complex samples based on the emittance of the QDs (Fig. 1 B–D).Open in a separate windowFig. 1.NTA for detection of MBL oligomers as purified protein and in bioliquids. (A) Principles of detection in NTA based on light scatter. Raw protein, including MBL, scatters laser light, which permits tracking of diffusion in a simple medium without other scattering constituents. (B and C) Design of a QD-based reporter system for detection of MBL. Commercially available 20-nm QDs with a Cd · Se core, Zn · S shell, and a pegylated surface with a chemistry linker enabling covalent coupling to glycan structure in IgG was conjugated to monoclonal Ab to either human MBL or murine MBL-C (or isotypic control Ab) of choice (B). The overall dimensions of the reporter permitted repeated binding to spMBL, here shown with a ligand (dsDNA)-driven lateral oligomerization (C). In both B and C, all items are drawn approximately to scale (scale bars indicated). (D) Detection in NTA based on QD emission. With the MBL Ab-QD reporter, the fluorescent emission at 655 nm permits detection among other constituents of a complex bioliquid such as diluted plasma.Here, we used NTA to characterize the structural variation of MBL oligomers in plasma from SLE patients. The concentration of spMBL is vastly increased in patients, amplified by MBL’s interaction with dsDNA. The spMBL concentration correlates directly with disease activity as may be explained by the large hydrodynamic radii of the oligomers, which pushes spMBL into blood vessel walls, adding to the vascular damage seen in SLE. An even wider link to SLE morbidity derives from the influence of spMBL on the autoimmune pathology, mechanistically supported by an animal model of SLE where spMBL is connected to the formation of autoreactive GC B cells.