, a runner who demonstrates considerably less than 45?of knee flexion may

, a runner who demonstrates considerably less than 45?of knee flexion may suggest Aprotinin web reduced shock absorption, and (R)-K-13675 dose intervention may be warranted. Some data exist suggesting that lower knee flexion (<40? may be associated with certain subgroups of patients with patellofemoral pain.22 Knee stiffness, a variable that includes both reduced knee flexion and/or increased knee flexion moment during stance phase, may be associated with tibial stress fractures.23 Hip Extension During Late Stance Reduced hip extension during late stance is a common observation in the recreational runner (Fig. 6). It is traditionally believed that lack of hip extension may be associated with reduced flexibility of the iliopsoas muscle. However, the optimal amount of hip extension during running remains elusive. It is possible that the required amount of hip extension is not the same for each runner, but related to other characteristics of their running form. For example, a fairly slow runner may have a very compact stride, demonstrate approximately 10?of peakAuthor Manuscript Author Manuscript Author Manuscript Author ManuscriptPhys Med Rehabil Clin N Am. Author manuscript; available in PMC 2016 February 01.SouzaPagehip extension and not require any intervention. However, a different runner, with a long stride and perhaps a faster pace, may also have approximately 10?of hip extension, but also concurrently demonstrate a significant overstride pattern (landing with the foot out in front of the center of mass) with higher impact loading and braking forces. The latter runner may require stride modification or improved hip extension during running to modify these forces that could contribute to injury. Commonly observed compensations for persons with reduced hip extension include (1) increased lumbar spine extension, (2) bounding, a strategy to increase float time to increase overall stride length in the absence of adequate hip extension, (3) increased overstriding, including excessive reaching during initial contact as a strategy to increase stride length, and (4) increased cadence to increase running speed in the presence of a limited hip extension. Trunk LeanAuthor Manuscript Author Manuscript Author ManuscriptOverstridingTrunk lean is a variable that has received little attention in the scientific literature. However, this is not the case in the popular running non eer-reviewed literature. Many running styles, including ChiRunning, pose running, and even barefoot running have included cues for novice runners to increase trunk lean. A focus on leaning “from the ankles,” rather than increasing hip flexion to achieve the trunk lean, seems to be a priority for some styles. Many running experts suggest that trunk lean is a key component to correct running posture. However, very little has been done on the research side of this issue. A recent article by Teng and Powers24 demonstrated that a small increase in trunk lean ( 7? resulted in a significant lowering of the stress across the patellofemoral joint without a significant increase in ankle demand, suggesting that this strategy may be important for runners with patellofemoral pain. The overall findings were that reduced trunk flexion (more upright posture) was associated with greater knee loads. In contrast, increased trunk flexion shifted demand away from the knee joint, and to the hip and ankle (although the latter was not statistically higher).25 However, the authors warn that this study was performed in healthy subj., a runner who demonstrates considerably less than 45?of knee flexion may suggest reduced shock absorption, and intervention may be warranted. Some data exist suggesting that lower knee flexion (<40? may be associated with certain subgroups of patients with patellofemoral pain.22 Knee stiffness, a variable that includes both reduced knee flexion and/or increased knee flexion moment during stance phase, may be associated with tibial stress fractures.23 Hip Extension During Late Stance Reduced hip extension during late stance is a common observation in the recreational runner (Fig. 6). It is traditionally believed that lack of hip extension may be associated with reduced flexibility of the iliopsoas muscle. However, the optimal amount of hip extension during running remains elusive. It is possible that the required amount of hip extension is not the same for each runner, but related to other characteristics of their running form. For example, a fairly slow runner may have a very compact stride, demonstrate approximately 10?of peakAuthor Manuscript Author Manuscript Author Manuscript Author ManuscriptPhys Med Rehabil Clin N Am. Author manuscript; available in PMC 2016 February 01.SouzaPagehip extension and not require any intervention. However, a different runner, with a long stride and perhaps a faster pace, may also have approximately 10?of hip extension, but also concurrently demonstrate a significant overstride pattern (landing with the foot out in front of the center of mass) with higher impact loading and braking forces. The latter runner may require stride modification or improved hip extension during running to modify these forces that could contribute to injury. Commonly observed compensations for persons with reduced hip extension include (1) increased lumbar spine extension, (2) bounding, a strategy to increase float time to increase overall stride length in the absence of adequate hip extension, (3) increased overstriding, including excessive reaching during initial contact as a strategy to increase stride length, and (4) increased cadence to increase running speed in the presence of a limited hip extension. Trunk LeanAuthor Manuscript Author Manuscript Author ManuscriptOverstridingTrunk lean is a variable that has received little attention in the scientific literature. However, this is not the case in the popular running non eer-reviewed literature. Many running styles, including ChiRunning, pose running, and even barefoot running have included cues for novice runners to increase trunk lean. A focus on leaning “from the ankles,” rather than increasing hip flexion to achieve the trunk lean, seems to be a priority for some styles. Many running experts suggest that trunk lean is a key component to correct running posture. However, very little has been done on the research side of this issue. A recent article by Teng and Powers24 demonstrated that a small increase in trunk lean ( 7? resulted in a significant lowering of the stress across the patellofemoral joint without a significant increase in ankle demand, suggesting that this strategy may be important for runners with patellofemoral pain. The overall findings were that reduced trunk flexion (more upright posture) was associated with greater knee loads. In contrast, increased trunk flexion shifted demand away from the knee joint, and to the hip and ankle (although the latter was not statistically higher).25 However, the authors warn that this study was performed in healthy subj.

Ampal CA1 subfield in individuals with MCI compared to NCI (Fig.

Ampal CA1 subfield in individuals with MCI compared to NCI (Fig. 4), which correlated with the subject’s Mini-Mental State Exam score (MMSE), but not with NFT Braak stage or apolipoprotein E (ApoE) status, a genetic risk factor for AD (Scheff et al., 2006). Unlike the outer molecular layer, CA1 receives input from the Schaffer collaterals arising from CA3 and not from the glutamatergic purchase BMS-214662 neurons of the entorhinal cortex, suggesting differential responses to synapse loss within the hippocampus based upon afferent innervation or chemical phenotype, some of which precipitate synaptic reorganization. A recent report characterized changes in the dendritic branching of the basilar tree of hippocampal CA1 pyramidal neurons. In this study, formalin-fixed tissue autopsy obtained from University of Kentucky Alzheimer’s Disease Center who died with a clinical diagnosis of NCI, MCI or AD was prepared for Golgi impregnation (Fig. 5). Camera lucida drawings of the basilar tree of randomly selected CA1 neurons were analyzed for alterations in dendritic arbor Pyrvinium pamoate supplier amount, distribution and complexity (Mervis et al., 2013). Quantitation showed a significant increase in dendritic length (18 ) and complexity (23 ) in CA1 neurons in MCI compared to NCI. Conversely, there was a significant reduction in branch length (-39 ) and arbor complexity (-25 ) during the progression from MCI to AD (Fig. 5). These findings suggest that the observed increase in CA1 dendritic parameters from NCI to MCI may be another example of a neuroplastic compensatory response to a loss of afferent input early in the course of the disease, which is not maintained as the disease progresses. The role that the reported reduction in total synapse number plays in CA1 neuroplasticity remains unknown. However, these examples of early CA1 neural reorganization may represent a viable window for potential therapeutic strategies aimed at restoring or maintaining hippocampal function during the transition from MCI to AD. Future studies should determine whether alterations in specific synapse subtypes (i.e., perforated vs. non-perforated) are differentially affected and their relation to cognitive decline and brain pathology during the onset of AD. Interestingly, the size of the synaptic contacts was found to be substantially larger in AD cortex compared to non-demented aged controls (Scheff et al., 1990), which was suggested to be part of a compensatory mechanism found in regions of the neocortex and hippocampus (see review Scheff and Price, 2006). These investigators found that as the number of synapses declined in a given region, the size of the residualAuthor Manuscript Author Manuscript Author Manuscript Author ManuscriptNeuroscience. Author manuscript; available in PMC 2016 September 12.Mufson et al.Pagesynapses increased. This synaptic compensatory response was also observed early in the course of the AD (DeKosky and Scheff, 1990). Neuronal structural alterations may not be the only factor(s) contributing to cognitive decline and hippocampal plasticity in MCI. For example, studies have reported significant reductions in synaptic vesicle trafficking-related genes in the AD brain, which interrupt the efficacy of normal synaptic transmission (Yao et al., 2003; Murphy et al., 2003; Kennedy et al., 2005). Counts et al. (2014) examined progressive changes in the expression classes of synaptic gene within single CA1 neurons in subjects who died with a clinical diagnosis of NCI, MCI or moderate AD obtain.Ampal CA1 subfield in individuals with MCI compared to NCI (Fig. 4), which correlated with the subject’s Mini-Mental State Exam score (MMSE), but not with NFT Braak stage or apolipoprotein E (ApoE) status, a genetic risk factor for AD (Scheff et al., 2006). Unlike the outer molecular layer, CA1 receives input from the Schaffer collaterals arising from CA3 and not from the glutamatergic neurons of the entorhinal cortex, suggesting differential responses to synapse loss within the hippocampus based upon afferent innervation or chemical phenotype, some of which precipitate synaptic reorganization. A recent report characterized changes in the dendritic branching of the basilar tree of hippocampal CA1 pyramidal neurons. In this study, formalin-fixed tissue autopsy obtained from University of Kentucky Alzheimer’s Disease Center who died with a clinical diagnosis of NCI, MCI or AD was prepared for Golgi impregnation (Fig. 5). Camera lucida drawings of the basilar tree of randomly selected CA1 neurons were analyzed for alterations in dendritic arbor amount, distribution and complexity (Mervis et al., 2013). Quantitation showed a significant increase in dendritic length (18 ) and complexity (23 ) in CA1 neurons in MCI compared to NCI. Conversely, there was a significant reduction in branch length (-39 ) and arbor complexity (-25 ) during the progression from MCI to AD (Fig. 5). These findings suggest that the observed increase in CA1 dendritic parameters from NCI to MCI may be another example of a neuroplastic compensatory response to a loss of afferent input early in the course of the disease, which is not maintained as the disease progresses. The role that the reported reduction in total synapse number plays in CA1 neuroplasticity remains unknown. However, these examples of early CA1 neural reorganization may represent a viable window for potential therapeutic strategies aimed at restoring or maintaining hippocampal function during the transition from MCI to AD. Future studies should determine whether alterations in specific synapse subtypes (i.e., perforated vs. non-perforated) are differentially affected and their relation to cognitive decline and brain pathology during the onset of AD. Interestingly, the size of the synaptic contacts was found to be substantially larger in AD cortex compared to non-demented aged controls (Scheff et al., 1990), which was suggested to be part of a compensatory mechanism found in regions of the neocortex and hippocampus (see review Scheff and Price, 2006). These investigators found that as the number of synapses declined in a given region, the size of the residualAuthor Manuscript Author Manuscript Author Manuscript Author ManuscriptNeuroscience. Author manuscript; available in PMC 2016 September 12.Mufson et al.Pagesynapses increased. This synaptic compensatory response was also observed early in the course of the AD (DeKosky and Scheff, 1990). Neuronal structural alterations may not be the only factor(s) contributing to cognitive decline and hippocampal plasticity in MCI. For example, studies have reported significant reductions in synaptic vesicle trafficking-related genes in the AD brain, which interrupt the efficacy of normal synaptic transmission (Yao et al., 2003; Murphy et al., 2003; Kennedy et al., 2005). Counts et al. (2014) examined progressive changes in the expression classes of synaptic gene within single CA1 neurons in subjects who died with a clinical diagnosis of NCI, MCI or moderate AD obtain.

Monly used and widely available OTC medications and nutritional supplements were

Monly used and widely available OTC medications and nutritional supplements were safe and posed no short- or long-term threat to their health. Many used such products to improve their running performance, yet their risk normalized or neutralized by their presence at running expos, in running publications and at vitamin retail stores. Well aware that some substances–EPO, anabolic steroids, HGH–are banned and may be SKF-96365 (hydrochloride)MedChemExpress SKF-96365 (hydrochloride) dangerous to health, these runners took for granted the surveillance and safety of products they could procure legally, under the belief that is something was not banned it would be safe. This belief makes runners vulnerable to tainted or dangerous products that are freely available and not considered harmful, even though non-elite athletes routinely feel they make correct decisions and engaging in adequate self-surveillance that is required in contemporary neoliberal citizenship (Rose 1999). As such, a product recommended as an effective and legal substance by another runner or by a retail sales clerk may contain substances that are either banned by agencies such as WADA and/or may pose a serious health risk. The recent controversy over the supplement ingredient DMAA illustrates availability cannot be substituted for safety.NIH-PA Author BIM-22493 biological activity Manuscript NIH-PA Author Manuscript NIH-PA Author ManuscriptSurveill Soc. Author manuscript; available in PMC 2014 November 04.HenningPageTogether, these perceptions and knowledge gaps result in a blind spot in the internalized anti-doping gaze. Runners do the work of self-surveillance believing they are acting as good citizens by conforming to anti-doping regulations and following expert advice on how to be healthy, as far as they understand these rules and recommendations. With regard to nutritional supplements, this self-surveillance blind spot can have major negative health repercussions. WADA and its affiliates claim athlete health is a top priority, yet its policies and methods confuse non-elite runners and lull them into a false sense of security. The nonelites in this research engaged in self-surveillance and did seek to conform to the clean ideal by avoiding what they understood to be prohibited or dangerous substances. However, their knowledge of anti-doping regulations was inadequate for avoiding all but the most commonly discussed prohibited enhancement products. Relying on their incomplete and often incorrect understandings of which substances are potentially harmful, these runners may wrongly presume they are avoiding harmful PEDs by focusing their attention on supplements that are commonly found in drug stores and nutritional supplement shops. This finding demonstrates how the quest to eradicate doping in sports using the surveillancebased system of regulations and banned substances seem to work against the underlying goals of anti-doping agencies in non-elite sports populations.NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author ManuscriptAcknowledgmentsThe author was supported by NIDA grant (T32 DA007233); points of view are the author’s alone.
NIH Public AccessAuthor ManuscriptJ Res Adolesc. Author manuscript; available in PMC 2015 June 01.Published in final edited form as: J Res Adolesc. 2014 June 1; 24(2): 235?51. doi:10.1111/jora.12124.NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author ManuscriptSerious Delinquency and Gang Participation: Combining and Specializing in Drug Selling, Theft and ViolenceRachel A. Gordon, University of Illinois at Chi.Monly used and widely available OTC medications and nutritional supplements were safe and posed no short- or long-term threat to their health. Many used such products to improve their running performance, yet their risk normalized or neutralized by their presence at running expos, in running publications and at vitamin retail stores. Well aware that some substances–EPO, anabolic steroids, HGH–are banned and may be dangerous to health, these runners took for granted the surveillance and safety of products they could procure legally, under the belief that is something was not banned it would be safe. This belief makes runners vulnerable to tainted or dangerous products that are freely available and not considered harmful, even though non-elite athletes routinely feel they make correct decisions and engaging in adequate self-surveillance that is required in contemporary neoliberal citizenship (Rose 1999). As such, a product recommended as an effective and legal substance by another runner or by a retail sales clerk may contain substances that are either banned by agencies such as WADA and/or may pose a serious health risk. The recent controversy over the supplement ingredient DMAA illustrates availability cannot be substituted for safety.NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author ManuscriptSurveill Soc. Author manuscript; available in PMC 2014 November 04.HenningPageTogether, these perceptions and knowledge gaps result in a blind spot in the internalized anti-doping gaze. Runners do the work of self-surveillance believing they are acting as good citizens by conforming to anti-doping regulations and following expert advice on how to be healthy, as far as they understand these rules and recommendations. With regard to nutritional supplements, this self-surveillance blind spot can have major negative health repercussions. WADA and its affiliates claim athlete health is a top priority, yet its policies and methods confuse non-elite runners and lull them into a false sense of security. The nonelites in this research engaged in self-surveillance and did seek to conform to the clean ideal by avoiding what they understood to be prohibited or dangerous substances. However, their knowledge of anti-doping regulations was inadequate for avoiding all but the most commonly discussed prohibited enhancement products. Relying on their incomplete and often incorrect understandings of which substances are potentially harmful, these runners may wrongly presume they are avoiding harmful PEDs by focusing their attention on supplements that are commonly found in drug stores and nutritional supplement shops. This finding demonstrates how the quest to eradicate doping in sports using the surveillancebased system of regulations and banned substances seem to work against the underlying goals of anti-doping agencies in non-elite sports populations.NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author ManuscriptAcknowledgmentsThe author was supported by NIDA grant (T32 DA007233); points of view are the author’s alone.
NIH Public AccessAuthor ManuscriptJ Res Adolesc. Author manuscript; available in PMC 2015 June 01.Published in final edited form as: J Res Adolesc. 2014 June 1; 24(2): 235?51. doi:10.1111/jora.12124.NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author ManuscriptSerious Delinquency and Gang Participation: Combining and Specializing in Drug Selling, Theft and ViolenceRachel A. Gordon, University of Illinois at Chi.

Ions in Barrett’s Esophagus [113,114] and ulcerative colitis [115], among a variety

Ions in Barrett’s Esophagus [113,114] and ulcerative colitis [115], among a variety of other cancer-predisposing diseases. Navin et al recently used the profile of CGH-identified copy number changes to study the clonal architecture of different regions of advanced breast cancers through phylogenetic inference [116]. Direct genomic sequencing provides the most detailed means possible of identifying clonal mutant markers. In contrast to conventional capillary-based techniques where individual PCR products or bacterial clones must be sequenced individually, a powerful new class of “Next Generation” sequencing technologies allows for simultaneous genotyping of tens of billions of base pairs [117]. The rapidly decreasing costs associated with these platforms have recently made it feasible to sequence the entire aggregate genome of a tissue sample without any regional targeting. From a clone detection perspective this means that multiple types of mutations of all functional varieties (both likely passengers and suspected drivers) can be simultaneously assessed. While it only takes a single clonal mutation to identify an expanded population, the redundancy conferred by screening the entire genome provides a huge amount of additional lineage data with the potential to be used for subanalyses such as approximation of a clone’s mitotic age or the phylogenetic relationship between different clones. The digital manner in which these novel sequencing technologies operate lend them a much greater dynamic range of sensitivity than conventional techniques, making it possible to resolve populations that are subclonal relative to a collected sample. Such an ability means that in situations where spatial coherence of an expanding clone is not maintained, for example in myelodysplasia preceding blood cancers, detection at an early stage can still be accomplished [118]. Similarly, a tolerance for clone mixing should allow for convenient, minimally invasive sampling techniques that disrupt cohesive growth patterns in epithelial tissues such as cell isolation from lavage, scrapings or body fluids rather than biopsy. The relatively high error rate of individual sequencing reads currently limits the average depth to which rare subclonal mutations can be accurately detected to about 2 orders of magnitude below pure clonality [26]. A variety of improvements at the level of chemistry, hardware and analysis are continuing to enhance this resolution for all current platforms [118,119]. An even newer generation of exotic “Fourth Generation” sequencing technologies on the horizon promises ultra-long read lengths with the ability to continuously re-sequence theNIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author ManuscriptSemin Cancer Biol. Author manuscript; available in PMC 2011 October 15.Salk and HorwitzPagesame molecule for extremely accurate detection of rare molecular populations [120?22]. The pace of innovation in this area is staggering. Perhaps the only thing that can be stated with certainty about the technologies that will be available five years in the I-CBP112 web future is that they will look nothing like those from five years in the past.NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript9. The complex interpretation of clonality: false negatives, positives and Cibinetide web assumptionsThe reasoning associated with clonality determination is complex and many potential confounders exist. In this section we highlight seven important ideas for consi.Ions in Barrett’s Esophagus [113,114] and ulcerative colitis [115], among a variety of other cancer-predisposing diseases. Navin et al recently used the profile of CGH-identified copy number changes to study the clonal architecture of different regions of advanced breast cancers through phylogenetic inference [116]. Direct genomic sequencing provides the most detailed means possible of identifying clonal mutant markers. In contrast to conventional capillary-based techniques where individual PCR products or bacterial clones must be sequenced individually, a powerful new class of “Next Generation” sequencing technologies allows for simultaneous genotyping of tens of billions of base pairs [117]. The rapidly decreasing costs associated with these platforms have recently made it feasible to sequence the entire aggregate genome of a tissue sample without any regional targeting. From a clone detection perspective this means that multiple types of mutations of all functional varieties (both likely passengers and suspected drivers) can be simultaneously assessed. While it only takes a single clonal mutation to identify an expanded population, the redundancy conferred by screening the entire genome provides a huge amount of additional lineage data with the potential to be used for subanalyses such as approximation of a clone’s mitotic age or the phylogenetic relationship between different clones. The digital manner in which these novel sequencing technologies operate lend them a much greater dynamic range of sensitivity than conventional techniques, making it possible to resolve populations that are subclonal relative to a collected sample. Such an ability means that in situations where spatial coherence of an expanding clone is not maintained, for example in myelodysplasia preceding blood cancers, detection at an early stage can still be accomplished [118]. Similarly, a tolerance for clone mixing should allow for convenient, minimally invasive sampling techniques that disrupt cohesive growth patterns in epithelial tissues such as cell isolation from lavage, scrapings or body fluids rather than biopsy. The relatively high error rate of individual sequencing reads currently limits the average depth to which rare subclonal mutations can be accurately detected to about 2 orders of magnitude below pure clonality [26]. A variety of improvements at the level of chemistry, hardware and analysis are continuing to enhance this resolution for all current platforms [118,119]. An even newer generation of exotic “Fourth Generation” sequencing technologies on the horizon promises ultra-long read lengths with the ability to continuously re-sequence theNIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author ManuscriptSemin Cancer Biol. Author manuscript; available in PMC 2011 October 15.Salk and HorwitzPagesame molecule for extremely accurate detection of rare molecular populations [120?22]. The pace of innovation in this area is staggering. Perhaps the only thing that can be stated with certainty about the technologies that will be available five years in the future is that they will look nothing like those from five years in the past.NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript9. The complex interpretation of clonality: false negatives, positives and assumptionsThe reasoning associated with clonality determination is complex and many potential confounders exist. In this section we highlight seven important ideas for consi.

. This exploratory analysis can provide further information on functional similarities between

. This exploratory analysis can provide further information on functional similarities between regions, and, more specifically, on the extent to which activation profiles of category-selective regions are inherited from EVC. As for the replicability of within-category ranking (Fig. 5), we combined data across subjects either by concatenating or averaging the activation profiles across subjects. The concatenation MLN1117 web approach is sensitive to inter-region correlations of activation profiles even if the particular activation profiles differ across subjects. The averaging approach is sensitive to inter-region correlations of activation profiles that are consistent across subjects. We investigated the inter-region correlations for (1) the full activation profile, (2) the within-face activation profile, and (3) the withinplace activation profile. Statistical inference was performed by a standard one-sided test on Spearman’s r. p CBR-5884 biological activity values were corrected8658 ?J. Neurosci., June 20, 2012 ?32(25):8649 ?Mur et al. ?Single-Image Activation of Category Regionsfor multiple testing using Bonferroni correction based on the total number of tests performed. Figure 7 shows the inter-region correlation results. The main pattern that emerges is that activation profiles are correlated between hemispheres for corresponding regions, and between hIT and EVC (red blocks on diagonals). We subsequently inspected the within-face correlation between FFA and EVC, and the within-place correlation between PPA and EVC. The within-face activation profile was correlated between left but not right FFA and EVC, and the within-place activation profile was not significantly correlated between PPA and EVC. Results were similar across ROI sizes. These results suggest that EVC is not a major contributor to the within-category activation profiles of PPA and right FFA. We then inspected the correlation between category-selective regions (FFA/PPA) and EVC for the full activation profile (top row). The full activation profile was correlated between EVC and both categoryselective regions, especially PPA. One interpretation of this finding would be that some degree of category selectivity is already present at the level of EVC, implying that low-level feature differences contribute to some extent to categoryselective responses. For places, this seems a plausible interpretation, consistent with our finding that single-image activation of EVC can discriminate places from nonplaces at an above-chance level (Fig. 2). For faces, this interpretation seems less likely: the correlation between EVC and FFA is not significant for the subjectaverage activation profile, suggesting that the correlation is driven by subjectspecific effects (e.g., idiosyncratic arousal effects) and not by face-selectivity of responses (shared across subjects in FFA). Categorical, yet graded Figure 8 summarizes our results. Singleimage activation profiles of categoryselective regions (1) show near-perfect discrimination of preferred from nonpreferred images and no preference inversions for particular object images, (2) show a step-like drop-off at the category boundary, and (3) are graded within and outside the preferred category. It can further be noted that single-image category selectivity is stronger in right than left FFA. In addition, gradedness seems to be more pronounced in FFA; the category step seems to be more pronounced in PPA. In sum, our findings indicate that the activation profiles of category-selec-Figure.. This exploratory analysis can provide further information on functional similarities between regions, and, more specifically, on the extent to which activation profiles of category-selective regions are inherited from EVC. As for the replicability of within-category ranking (Fig. 5), we combined data across subjects either by concatenating or averaging the activation profiles across subjects. The concatenation approach is sensitive to inter-region correlations of activation profiles even if the particular activation profiles differ across subjects. The averaging approach is sensitive to inter-region correlations of activation profiles that are consistent across subjects. We investigated the inter-region correlations for (1) the full activation profile, (2) the within-face activation profile, and (3) the withinplace activation profile. Statistical inference was performed by a standard one-sided test on Spearman’s r. p values were corrected8658 ?J. Neurosci., June 20, 2012 ?32(25):8649 ?Mur et al. ?Single-Image Activation of Category Regionsfor multiple testing using Bonferroni correction based on the total number of tests performed. Figure 7 shows the inter-region correlation results. The main pattern that emerges is that activation profiles are correlated between hemispheres for corresponding regions, and between hIT and EVC (red blocks on diagonals). We subsequently inspected the within-face correlation between FFA and EVC, and the within-place correlation between PPA and EVC. The within-face activation profile was correlated between left but not right FFA and EVC, and the within-place activation profile was not significantly correlated between PPA and EVC. Results were similar across ROI sizes. These results suggest that EVC is not a major contributor to the within-category activation profiles of PPA and right FFA. We then inspected the correlation between category-selective regions (FFA/PPA) and EVC for the full activation profile (top row). The full activation profile was correlated between EVC and both categoryselective regions, especially PPA. One interpretation of this finding would be that some degree of category selectivity is already present at the level of EVC, implying that low-level feature differences contribute to some extent to categoryselective responses. For places, this seems a plausible interpretation, consistent with our finding that single-image activation of EVC can discriminate places from nonplaces at an above-chance level (Fig. 2). For faces, this interpretation seems less likely: the correlation between EVC and FFA is not significant for the subjectaverage activation profile, suggesting that the correlation is driven by subjectspecific effects (e.g., idiosyncratic arousal effects) and not by face-selectivity of responses (shared across subjects in FFA). Categorical, yet graded Figure 8 summarizes our results. Singleimage activation profiles of categoryselective regions (1) show near-perfect discrimination of preferred from nonpreferred images and no preference inversions for particular object images, (2) show a step-like drop-off at the category boundary, and (3) are graded within and outside the preferred category. It can further be noted that single-image category selectivity is stronger in right than left FFA. In addition, gradedness seems to be more pronounced in FFA; the category step seems to be more pronounced in PPA. In sum, our findings indicate that the activation profiles of category-selec-Figure.

In living organisms21,23,39 (Fig. 4m). Therefore, the REY-enrichment process by biogenic

In living organisms21,23,39 (Fig. 4m). Therefore, the REY-enrichment process by biogenic Ca-phosphate in pelagic sediments has long been studied by a number of investigators17,18,21?4,40?2. Some have suggested that biogenic Ca-phosphate incorporates REY via pore water in the sediment column23,40. Others have argued that Ca-phosphate takes up REY from a variety of carrier phases (e.g. Fe n-oxyhydroxides, pellets, and organic debris) that absorb REY from seawater and are readily decomposed at the sediment ater interface17,22,41,42. Although the StatticMedChemExpress Stattic complete process remains an open question, the characteristic REY patterns indicate that seawater is the ultimate source of the REY presently captured in biogenic Ca-phosphate22,25,41 (Fig. 4m). Simple quantitative estimation in this study suggested the possibility that seawater can contain the flux of REY precipitation required to explain the observed very high REY concentrations ( REY + Ce > 1,000 ppm) in bulk REY-rich mud with a sedimentation rate less than 0.5 m/Myr (Supplementary Fig. S19). Such circumstances may Necrosulfonamide price facilitate the concentration of REY in biogenic Ca-phosphate via diffusion of REY from seawater or the transfer of REY from original carriers to Ca-phosphate during the early diagenetic processes because of the prolonged exposure to seawater at the sediment surface and in the bioturbated and well-ventilated uppermost sediment layer17,18,22,41. In addition, biogenic Ca-phosphate enriched in REY might be stabilised through recrystallisation as insoluble apatite17. Moreover, the amount of Ca-phosphate in a unit volume of sediment also increases with a depression of the sedimentation rate17,18. Hence, the low sedimentation rate is considered to be crucial for the formation of REY-rich mud. Actually, the spatiotemporal distribution of high-IC1, -IC4, and -IC7 muds overlapped with the oligotrophic North Pacific and South Pacific gyres and with water depths greater than the CCD, both of which prevented the fast accumulation of dilutive components with low REY content such as biogenic carbonate and silica. If we assume that deep-sea sediments can continuously acquire REY from the overlying deep-sea water prior to burial, the REY-enrichment in sediments can occur in a time scale of 105 years considering the sedimentation rate of <0.5 m/Myr with a typical thickness of 0.1 m for the well-ventilated uppermost sediment layer43. This timescale of REY enrichment is significantly longer than that of global ocean circulation, which is 103 years44. Both IC1 and IC4 indicated statistical independent geochemical features of pelagic red clay mainly composed of detrital aluminosilicates involving abundant Si, Al, Fe, Mg, and K without significant contributions of biogenic carbonate and silica. Fe and Mn of hydrothermal or hydrogenous origins could have also been incorporated without dilution in high-IC1 and high-IC4 sediments, resulting in an increase in the contents of these elements. In addition, in deposition slow enough to allow biogenic Ca-phosphate grains to concentrate REY and to accumulate significantly in the sediment, the P and REY contents of these sediments also increase concurrently. Although sediments enriched in biogenic Ca-phosphate contain several percent of Ca, the significant dilution effect of biogenic carbonate, which contains several tens of percent of Ca, generally creates negative trends in these ICs as a whole in the spaces of Ca and other elements, including REY. The differenc.In living organisms21,23,39 (Fig. 4m). Therefore, the REY-enrichment process by biogenic Ca-phosphate in pelagic sediments has long been studied by a number of investigators17,18,21?4,40?2. Some have suggested that biogenic Ca-phosphate incorporates REY via pore water in the sediment column23,40. Others have argued that Ca-phosphate takes up REY from a variety of carrier phases (e.g. Fe n-oxyhydroxides, pellets, and organic debris) that absorb REY from seawater and are readily decomposed at the sediment ater interface17,22,41,42. Although the complete process remains an open question, the characteristic REY patterns indicate that seawater is the ultimate source of the REY presently captured in biogenic Ca-phosphate22,25,41 (Fig. 4m). Simple quantitative estimation in this study suggested the possibility that seawater can contain the flux of REY precipitation required to explain the observed very high REY concentrations ( REY + Ce > 1,000 ppm) in bulk REY-rich mud with a sedimentation rate less than 0.5 m/Myr (Supplementary Fig. S19). Such circumstances may facilitate the concentration of REY in biogenic Ca-phosphate via diffusion of REY from seawater or the transfer of REY from original carriers to Ca-phosphate during the early diagenetic processes because of the prolonged exposure to seawater at the sediment surface and in the bioturbated and well-ventilated uppermost sediment layer17,18,22,41. In addition, biogenic Ca-phosphate enriched in REY might be stabilised through recrystallisation as insoluble apatite17. Moreover, the amount of Ca-phosphate in a unit volume of sediment also increases with a depression of the sedimentation rate17,18. Hence, the low sedimentation rate is considered to be crucial for the formation of REY-rich mud. Actually, the spatiotemporal distribution of high-IC1, -IC4, and -IC7 muds overlapped with the oligotrophic North Pacific and South Pacific gyres and with water depths greater than the CCD, both of which prevented the fast accumulation of dilutive components with low REY content such as biogenic carbonate and silica. If we assume that deep-sea sediments can continuously acquire REY from the overlying deep-sea water prior to burial, the REY-enrichment in sediments can occur in a time scale of 105 years considering the sedimentation rate of <0.5 m/Myr with a typical thickness of 0.1 m for the well-ventilated uppermost sediment layer43. This timescale of REY enrichment is significantly longer than that of global ocean circulation, which is 103 years44. Both IC1 and IC4 indicated statistical independent geochemical features of pelagic red clay mainly composed of detrital aluminosilicates involving abundant Si, Al, Fe, Mg, and K without significant contributions of biogenic carbonate and silica. Fe and Mn of hydrothermal or hydrogenous origins could have also been incorporated without dilution in high-IC1 and high-IC4 sediments, resulting in an increase in the contents of these elements. In addition, in deposition slow enough to allow biogenic Ca-phosphate grains to concentrate REY and to accumulate significantly in the sediment, the P and REY contents of these sediments also increase concurrently. Although sediments enriched in biogenic Ca-phosphate contain several percent of Ca, the significant dilution effect of biogenic carbonate, which contains several tens of percent of Ca, generally creates negative trends in these ICs as a whole in the spaces of Ca and other elements, including REY. The differenc.

, a runner who demonstrates considerably less than 45?of knee flexion may

, a runner who demonstrates considerably less than 45?of knee 3-MA price flexion may suggest reduced shock absorption, and intervention may be warranted. Some data exist order Oxaliplatin suggesting that lower knee flexion (<40? may be associated with certain subgroups of patients with patellofemoral pain.22 Knee stiffness, a variable that includes both reduced knee flexion and/or increased knee flexion moment during stance phase, may be associated with tibial stress fractures.23 Hip Extension During Late Stance Reduced hip extension during late stance is a common observation in the recreational runner (Fig. 6). It is traditionally believed that lack of hip extension may be associated with reduced flexibility of the iliopsoas muscle. However, the optimal amount of hip extension during running remains elusive. It is possible that the required amount of hip extension is not the same for each runner, but related to other characteristics of their running form. For example, a fairly slow runner may have a very compact stride, demonstrate approximately 10?of peakAuthor Manuscript Author Manuscript Author Manuscript Author ManuscriptPhys Med Rehabil Clin N Am. Author manuscript; available in PMC 2016 February 01.SouzaPagehip extension and not require any intervention. However, a different runner, with a long stride and perhaps a faster pace, may also have approximately 10?of hip extension, but also concurrently demonstrate a significant overstride pattern (landing with the foot out in front of the center of mass) with higher impact loading and braking forces. The latter runner may require stride modification or improved hip extension during running to modify these forces that could contribute to injury. Commonly observed compensations for persons with reduced hip extension include (1) increased lumbar spine extension, (2) bounding, a strategy to increase float time to increase overall stride length in the absence of adequate hip extension, (3) increased overstriding, including excessive reaching during initial contact as a strategy to increase stride length, and (4) increased cadence to increase running speed in the presence of a limited hip extension. Trunk LeanAuthor Manuscript Author Manuscript Author ManuscriptOverstridingTrunk lean is a variable that has received little attention in the scientific literature. However, this is not the case in the popular running non eer-reviewed literature. Many running styles, including ChiRunning, pose running, and even barefoot running have included cues for novice runners to increase trunk lean. A focus on leaning “from the ankles,” rather than increasing hip flexion to achieve the trunk lean, seems to be a priority for some styles. Many running experts suggest that trunk lean is a key component to correct running posture. However, very little has been done on the research side of this issue. A recent article by Teng and Powers24 demonstrated that a small increase in trunk lean ( 7? resulted in a significant lowering of the stress across the patellofemoral joint without a significant increase in ankle demand, suggesting that this strategy may be important for runners with patellofemoral pain. The overall findings were that reduced trunk flexion (more upright posture) was associated with greater knee loads. In contrast, increased trunk flexion shifted demand away from the knee joint, and to the hip and ankle (although the latter was not statistically higher).25 However, the authors warn that this study was performed in healthy subj., a runner who demonstrates considerably less than 45?of knee flexion may suggest reduced shock absorption, and intervention may be warranted. Some data exist suggesting that lower knee flexion (<40? may be associated with certain subgroups of patients with patellofemoral pain.22 Knee stiffness, a variable that includes both reduced knee flexion and/or increased knee flexion moment during stance phase, may be associated with tibial stress fractures.23 Hip Extension During Late Stance Reduced hip extension during late stance is a common observation in the recreational runner (Fig. 6). It is traditionally believed that lack of hip extension may be associated with reduced flexibility of the iliopsoas muscle. However, the optimal amount of hip extension during running remains elusive. It is possible that the required amount of hip extension is not the same for each runner, but related to other characteristics of their running form. For example, a fairly slow runner may have a very compact stride, demonstrate approximately 10?of peakAuthor Manuscript Author Manuscript Author Manuscript Author ManuscriptPhys Med Rehabil Clin N Am. Author manuscript; available in PMC 2016 February 01.SouzaPagehip extension and not require any intervention. However, a different runner, with a long stride and perhaps a faster pace, may also have approximately 10?of hip extension, but also concurrently demonstrate a significant overstride pattern (landing with the foot out in front of the center of mass) with higher impact loading and braking forces. The latter runner may require stride modification or improved hip extension during running to modify these forces that could contribute to injury. Commonly observed compensations for persons with reduced hip extension include (1) increased lumbar spine extension, (2) bounding, a strategy to increase float time to increase overall stride length in the absence of adequate hip extension, (3) increased overstriding, including excessive reaching during initial contact as a strategy to increase stride length, and (4) increased cadence to increase running speed in the presence of a limited hip extension. Trunk LeanAuthor Manuscript Author Manuscript Author ManuscriptOverstridingTrunk lean is a variable that has received little attention in the scientific literature. However, this is not the case in the popular running non eer-reviewed literature. Many running styles, including ChiRunning, pose running, and even barefoot running have included cues for novice runners to increase trunk lean. A focus on leaning “from the ankles,” rather than increasing hip flexion to achieve the trunk lean, seems to be a priority for some styles. Many running experts suggest that trunk lean is a key component to correct running posture. However, very little has been done on the research side of this issue. A recent article by Teng and Powers24 demonstrated that a small increase in trunk lean ( 7? resulted in a significant lowering of the stress across the patellofemoral joint without a significant increase in ankle demand, suggesting that this strategy may be important for runners with patellofemoral pain. The overall findings were that reduced trunk flexion (more upright posture) was associated with greater knee loads. In contrast, increased trunk flexion shifted demand away from the knee joint, and to the hip and ankle (although the latter was not statistically higher).25 However, the authors warn that this study was performed in healthy subj.

Ampal CA1 subfield in individuals with MCI compared to NCI (Fig.

Ampal CA1 subfield in individuals with MCI compared to NCI (Fig. 4), which correlated with the subject’s Mini-Mental State Exam score (MMSE), but not with NFT Braak stage or apolipoprotein E (ApoE) status, a genetic risk factor for AD (Scheff et al., 2006). Unlike the outer molecular layer, CA1 receives input from the Schaffer collaterals arising from CA3 and not from the glutamatergic neurons of the entorhinal cortex, suggesting differential responses to synapse loss within the Litronesib price hippocampus based upon afferent innervation or chemical phenotype, some of which precipitate synaptic reorganization. A recent report characterized changes in the dendritic branching of the basilar tree of hippocampal CA1 pyramidal neurons. In this study, formalin-fixed tissue autopsy obtained from University of Kentucky Alzheimer’s Disease Center who died with a clinical diagnosis of NCI, MCI or AD was prepared for Golgi impregnation (Fig. 5). Camera lucida drawings of the basilar tree of randomly selected CA1 neurons were analyzed for alterations in dendritic arbor amount, distribution and complexity (Mervis et al., 2013). Quantitation showed a significant increase in dendritic length (18 ) and complexity (23 ) in CA1 neurons in MCI compared to NCI. Conversely, there was a significant reduction in branch length (-39 ) and arbor complexity (-25 ) during the progression from MCI to AD (Fig. 5). These findings suggest that the observed increase in CA1 dendritic parameters from NCI to MCI may be another example of a neuroplastic compensatory response to a loss of afferent input early in the course of the disease, which is not maintained as the disease progresses. The role that the reported reduction in total synapse number plays in CA1 neuroplasticity remains unknown. However, these examples of early CA1 neural reorganization may represent a viable window for potential therapeutic strategies aimed at restoring or maintaining hippocampal function during the transition from MCI to AD. Future ML240MedChemExpress ML240 studies should determine whether alterations in specific synapse subtypes (i.e., perforated vs. non-perforated) are differentially affected and their relation to cognitive decline and brain pathology during the onset of AD. Interestingly, the size of the synaptic contacts was found to be substantially larger in AD cortex compared to non-demented aged controls (Scheff et al., 1990), which was suggested to be part of a compensatory mechanism found in regions of the neocortex and hippocampus (see review Scheff and Price, 2006). These investigators found that as the number of synapses declined in a given region, the size of the residualAuthor Manuscript Author Manuscript Author Manuscript Author ManuscriptNeuroscience. Author manuscript; available in PMC 2016 September 12.Mufson et al.Pagesynapses increased. This synaptic compensatory response was also observed early in the course of the AD (DeKosky and Scheff, 1990). Neuronal structural alterations may not be the only factor(s) contributing to cognitive decline and hippocampal plasticity in MCI. For example, studies have reported significant reductions in synaptic vesicle trafficking-related genes in the AD brain, which interrupt the efficacy of normal synaptic transmission (Yao et al., 2003; Murphy et al., 2003; Kennedy et al., 2005). Counts et al. (2014) examined progressive changes in the expression classes of synaptic gene within single CA1 neurons in subjects who died with a clinical diagnosis of NCI, MCI or moderate AD obtain.Ampal CA1 subfield in individuals with MCI compared to NCI (Fig. 4), which correlated with the subject’s Mini-Mental State Exam score (MMSE), but not with NFT Braak stage or apolipoprotein E (ApoE) status, a genetic risk factor for AD (Scheff et al., 2006). Unlike the outer molecular layer, CA1 receives input from the Schaffer collaterals arising from CA3 and not from the glutamatergic neurons of the entorhinal cortex, suggesting differential responses to synapse loss within the hippocampus based upon afferent innervation or chemical phenotype, some of which precipitate synaptic reorganization. A recent report characterized changes in the dendritic branching of the basilar tree of hippocampal CA1 pyramidal neurons. In this study, formalin-fixed tissue autopsy obtained from University of Kentucky Alzheimer’s Disease Center who died with a clinical diagnosis of NCI, MCI or AD was prepared for Golgi impregnation (Fig. 5). Camera lucida drawings of the basilar tree of randomly selected CA1 neurons were analyzed for alterations in dendritic arbor amount, distribution and complexity (Mervis et al., 2013). Quantitation showed a significant increase in dendritic length (18 ) and complexity (23 ) in CA1 neurons in MCI compared to NCI. Conversely, there was a significant reduction in branch length (-39 ) and arbor complexity (-25 ) during the progression from MCI to AD (Fig. 5). These findings suggest that the observed increase in CA1 dendritic parameters from NCI to MCI may be another example of a neuroplastic compensatory response to a loss of afferent input early in the course of the disease, which is not maintained as the disease progresses. The role that the reported reduction in total synapse number plays in CA1 neuroplasticity remains unknown. However, these examples of early CA1 neural reorganization may represent a viable window for potential therapeutic strategies aimed at restoring or maintaining hippocampal function during the transition from MCI to AD. Future studies should determine whether alterations in specific synapse subtypes (i.e., perforated vs. non-perforated) are differentially affected and their relation to cognitive decline and brain pathology during the onset of AD. Interestingly, the size of the synaptic contacts was found to be substantially larger in AD cortex compared to non-demented aged controls (Scheff et al., 1990), which was suggested to be part of a compensatory mechanism found in regions of the neocortex and hippocampus (see review Scheff and Price, 2006). These investigators found that as the number of synapses declined in a given region, the size of the residualAuthor Manuscript Author Manuscript Author Manuscript Author ManuscriptNeuroscience. Author manuscript; available in PMC 2016 September 12.Mufson et al.Pagesynapses increased. This synaptic compensatory response was also observed early in the course of the AD (DeKosky and Scheff, 1990). Neuronal structural alterations may not be the only factor(s) contributing to cognitive decline and hippocampal plasticity in MCI. For example, studies have reported significant reductions in synaptic vesicle trafficking-related genes in the AD brain, which interrupt the efficacy of normal synaptic transmission (Yao et al., 2003; Murphy et al., 2003; Kennedy et al., 2005). Counts et al. (2014) examined progressive changes in the expression classes of synaptic gene within single CA1 neurons in subjects who died with a clinical diagnosis of NCI, MCI or moderate AD obtain.

Monly used and widely available OTC medications and nutritional supplements were

Monly used and widely available OTC medications and nutritional supplements were safe and posed no short- or long-term threat to their health. Many used such products to improve their running performance, yet their risk normalized or neutralized by their presence at running expos, in running publications and at vitamin retail stores. Well aware that some substances–EPO, anabolic steroids, HGH–are banned and may be dangerous to health, these runners took for granted the surveillance and safety of products they could procure legally, under the belief that is something was not banned it would be safe. This belief makes runners vulnerable to tainted or dangerous products that are freely available and not considered harmful, even though non-elite athletes routinely feel they make correct decisions and engaging in adequate self-surveillance that is required in contemporary neoliberal citizenship (Rose 1999). As such, a product recommended as an effective and legal substance by another runner or by a retail sales clerk may contain substances that are either banned by agencies such as WADA and/or may pose a serious health risk. The recent controversy over the supplement ingredient DMAA illustrates availability cannot be substituted for safety.NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author ManuscriptSurveill Soc. Author manuscript; available in PMC 2014 November 04.HenningPageTogether, these perceptions and knowledge gaps result in a blind spot in the internalized anti-doping gaze. Runners do the work of self-surveillance believing they are acting as good citizens by conforming to anti-doping Pamapimod web regulations and following expert advice on how to be healthy, as far as they understand these rules and recommendations. With regard to nutritional supplements, this self-surveillance blind spot can have major negative health repercussions. WADA and its affiliates claim athlete health is a top priority, yet its policies and methods confuse non-elite runners and lull them into a false sense of security. The nonelites in this research engaged in self-surveillance and did seek to conform to the clean ideal by avoiding what they understood to be prohibited or dangerous substances. However, their knowledge of anti-doping regulations was inadequate for avoiding all but the most commonly discussed prohibited enhancement products. Relying on their incomplete and often incorrect understandings of which substances are potentially harmful, these runners may wrongly presume they are avoiding Resiquimod mechanism of action harmful PEDs by focusing their attention on supplements that are commonly found in drug stores and nutritional supplement shops. This finding demonstrates how the quest to eradicate doping in sports using the surveillancebased system of regulations and banned substances seem to work against the underlying goals of anti-doping agencies in non-elite sports populations.NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author ManuscriptAcknowledgmentsThe author was supported by NIDA grant (T32 DA007233); points of view are the author’s alone.
NIH Public AccessAuthor ManuscriptJ Res Adolesc. Author manuscript; available in PMC 2015 June 01.Published in final edited form as: J Res Adolesc. 2014 June 1; 24(2): 235?51. doi:10.1111/jora.12124.NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author ManuscriptSerious Delinquency and Gang Participation: Combining and Specializing in Drug Selling, Theft and ViolenceRachel A. Gordon, University of Illinois at Chi.Monly used and widely available OTC medications and nutritional supplements were safe and posed no short- or long-term threat to their health. Many used such products to improve their running performance, yet their risk normalized or neutralized by their presence at running expos, in running publications and at vitamin retail stores. Well aware that some substances–EPO, anabolic steroids, HGH–are banned and may be dangerous to health, these runners took for granted the surveillance and safety of products they could procure legally, under the belief that is something was not banned it would be safe. This belief makes runners vulnerable to tainted or dangerous products that are freely available and not considered harmful, even though non-elite athletes routinely feel they make correct decisions and engaging in adequate self-surveillance that is required in contemporary neoliberal citizenship (Rose 1999). As such, a product recommended as an effective and legal substance by another runner or by a retail sales clerk may contain substances that are either banned by agencies such as WADA and/or may pose a serious health risk. The recent controversy over the supplement ingredient DMAA illustrates availability cannot be substituted for safety.NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author ManuscriptSurveill Soc. Author manuscript; available in PMC 2014 November 04.HenningPageTogether, these perceptions and knowledge gaps result in a blind spot in the internalized anti-doping gaze. Runners do the work of self-surveillance believing they are acting as good citizens by conforming to anti-doping regulations and following expert advice on how to be healthy, as far as they understand these rules and recommendations. With regard to nutritional supplements, this self-surveillance blind spot can have major negative health repercussions. WADA and its affiliates claim athlete health is a top priority, yet its policies and methods confuse non-elite runners and lull them into a false sense of security. The nonelites in this research engaged in self-surveillance and did seek to conform to the clean ideal by avoiding what they understood to be prohibited or dangerous substances. However, their knowledge of anti-doping regulations was inadequate for avoiding all but the most commonly discussed prohibited enhancement products. Relying on their incomplete and often incorrect understandings of which substances are potentially harmful, these runners may wrongly presume they are avoiding harmful PEDs by focusing their attention on supplements that are commonly found in drug stores and nutritional supplement shops. This finding demonstrates how the quest to eradicate doping in sports using the surveillancebased system of regulations and banned substances seem to work against the underlying goals of anti-doping agencies in non-elite sports populations.NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author ManuscriptAcknowledgmentsThe author was supported by NIDA grant (T32 DA007233); points of view are the author’s alone.
NIH Public AccessAuthor ManuscriptJ Res Adolesc. Author manuscript; available in PMC 2015 June 01.Published in final edited form as: J Res Adolesc. 2014 June 1; 24(2): 235?51. doi:10.1111/jora.12124.NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author ManuscriptSerious Delinquency and Gang Participation: Combining and Specializing in Drug Selling, Theft and ViolenceRachel A. Gordon, University of Illinois at Chi.

Deration when interpreting experimental findings. (i) Identification of a mutation in

Deration when interpreting experimental findings. (i) Identification of a AZD-8835 chemical information mutation in a clonal population does not indicate causality Any mutation in a cell that undergoes clonal expansion will be passed onto progeny, irrespective of functional status (Fig. 3A,B). Given the size of the genome, more mutations carried by a neoplastic clone will be passengers than drivers [27, 29, 30]. To demonstrate driver status, supporting functional studies and/or repeated observations of a mutated loci in neoplastic clones from independent individuals are needed. (ii) Mutational marking of a clone is stochastic and not guaranteed A clone may exist and not be detected if none of the genomic sites being screened carry a unique mutation permitting it to be distinguished from the germline (Fig. 3C). The more sites examined, the higher the probability of Cycloheximide manufacturer Detection becomes. Restricting a marker panel to suspected driver sites precludes detection of pathological clones driven by unknown factors. (iii) Elevated mutation rates facilitate clone detection but are not an absolute requirement Screening of mutational hotspots makes it practical with conventional technologies to have a reasonable probability of detecting a clone by random passenger mutations. Clones derived from a mutator lineage or cells residing in a highly mutagenic environment should be more densely marked with identifiable passengers (Fig. 3D), potentially reducing the number of markers needing to be interrogated to identify them. Emerging high-throughput sequencing technologies will eventually obviate the need to restrict screening to a fraction of the genome. (iv) Identification of one or more clonal mutations is not proof of genetic instability in the absence of collateral information Detection of a mutation requires clonal expansion with most traditional methods of aggregate DNA analysis. The probability of identifying clonal mutations in an expanded population is a function of the number of sites screened, the mutability of these sites and the number of cell divisions having occurred in the lineage leading up to the final expansion. Particularly when considering hotspots, mutations will be occasionally detectable in any clonally-derived population at a statistically definable frequency. Because mutations are not routinely encountered in normal tissues, it is tempting to explain their presence in preneoplastic populations as the result of “genetic instability” (an elevated mutation rate). However, the phenomenon is more precisely explained by the fact that expansion does not routinely occur in most normal tissues. An elevated mutation rate itself will have no observable effect on clonal mutation frequency in the absence of expansion (Fig. 3E). To determine mutation rate from a clonal mutation frequency it is necessary to (A) know that the population being assessed is clonal and (B) have some metric of the number of cell divisions that occurred in the period between the zygote and the founding of the final clonalSemin Cancer Biol. Author manuscript; available in PMC 2011 October 15.Salk and HorwitzPageoutgrowth. To infer that a rate is elevated, it is also necessary to know the normal in vivo mutation rate, which is, in turn, impossible to measure by this approach given that large clonal expansions do not routinely occur in normal adult tissue. Considering these complexities, the lack of resolution as to whether mutation rates are elevated in cancer is not surprising [1,8?1]. (v) Detectabili.Deration when interpreting experimental findings. (i) Identification of a mutation in a clonal population does not indicate causality Any mutation in a cell that undergoes clonal expansion will be passed onto progeny, irrespective of functional status (Fig. 3A,B). Given the size of the genome, more mutations carried by a neoplastic clone will be passengers than drivers [27, 29, 30]. To demonstrate driver status, supporting functional studies and/or repeated observations of a mutated loci in neoplastic clones from independent individuals are needed. (ii) Mutational marking of a clone is stochastic and not guaranteed A clone may exist and not be detected if none of the genomic sites being screened carry a unique mutation permitting it to be distinguished from the germline (Fig. 3C). The more sites examined, the higher the probability of detection becomes. Restricting a marker panel to suspected driver sites precludes detection of pathological clones driven by unknown factors. (iii) Elevated mutation rates facilitate clone detection but are not an absolute requirement Screening of mutational hotspots makes it practical with conventional technologies to have a reasonable probability of detecting a clone by random passenger mutations. Clones derived from a mutator lineage or cells residing in a highly mutagenic environment should be more densely marked with identifiable passengers (Fig. 3D), potentially reducing the number of markers needing to be interrogated to identify them. Emerging high-throughput sequencing technologies will eventually obviate the need to restrict screening to a fraction of the genome. (iv) Identification of one or more clonal mutations is not proof of genetic instability in the absence of collateral information Detection of a mutation requires clonal expansion with most traditional methods of aggregate DNA analysis. The probability of identifying clonal mutations in an expanded population is a function of the number of sites screened, the mutability of these sites and the number of cell divisions having occurred in the lineage leading up to the final expansion. Particularly when considering hotspots, mutations will be occasionally detectable in any clonally-derived population at a statistically definable frequency. Because mutations are not routinely encountered in normal tissues, it is tempting to explain their presence in preneoplastic populations as the result of “genetic instability” (an elevated mutation rate). However, the phenomenon is more precisely explained by the fact that expansion does not routinely occur in most normal tissues. An elevated mutation rate itself will have no observable effect on clonal mutation frequency in the absence of expansion (Fig. 3E). To determine mutation rate from a clonal mutation frequency it is necessary to (A) know that the population being assessed is clonal and (B) have some metric of the number of cell divisions that occurred in the period between the zygote and the founding of the final clonalSemin Cancer Biol. Author manuscript; available in PMC 2011 October 15.Salk and HorwitzPageoutgrowth. To infer that a rate is elevated, it is also necessary to know the normal in vivo mutation rate, which is, in turn, impossible to measure by this approach given that large clonal expansions do not routinely occur in normal adult tissue. Considering these complexities, the lack of resolution as to whether mutation rates are elevated in cancer is not surprising [1,8?1]. (v) Detectabili.