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Recent research progress has given detailed knowledge on the molecular pathogenesis of Alzheimer's disease (AD), which has been translated into an intense, ongoing development of disease-modifying treatments. Most new drug candidates are targeted on inhibiting amyloid β (Aβ) production and aggregation. In drug development, it is important to co-develop biomarkers for Aβ-related mechanisms to enable early diagnosis and patient stratification in clinical trials, and to serve as tools to identify and monitor the biochemical effect of the drug directly in patients. Biomarkers are also requested by regulatory authorities to serve as safety measurements. Molecular aberrations in the AD brain are reflected in the cerebrospinal fluid (CSF). Core CSF biomarkers include Aβ isoforms (Aβ40/Aβ42), soluble APP isoforms, Aβ oligomers and β-site APP-cleaving enzyme 1 (BACE1). This article reviews recent research advances on core candidate CSF and plasma Aβ-related biomarkers, and gives a conceptual review on how to implement biomarkers in clinical trials in AD.
We face a global epidemic of Alzheimer's disease (AD) as the world's population ages. In 2006, the worldwide prevalence of AD was 26.6 million, and by 2050 the prevalence will quadruple. The current worldwide cost related to dementia is approximately $160 billion (Wimo et al., 2006). Without a significant improvement in prevention and treatment of AD, our healthcare and socioeconomic systems will not be able to carry the financial burden of AD in the future. However, interventions that delay disease onset or progression by only 1 year would reduce the disease prevalence by more than 9 million cases in 2050. Effective strategies for preventing and treating AD are therefore urgently needed before the national economies are overwhelmed by the financial burden of this growing epidemic.
Intense research efforts over the last 3 decades have given detailed knowledge on the molecular pathogenesis of AD. AD is a complex progressive condition with sequentially interacting pathological cascades, including the aggregation of amyloid β (Aβ) with plaque development, hyperphosphorylation and aggregation of tau protein with formation of tangles, together with downstream processes such as inflammation and oxidative stress, all of which contribute to loss of synaptic integrity, effective neural network connectivity and progressive regional neurodegeneration (Blennow et al., 2006). Research advances from pathological, neurochemical and genetic studies give increasing support to the "amyloid cascade hypothesis" (Hardy and Selkoe, 2002), which states that an imbalance between the production and clearance or degradation or clearance of Aβ in the brain is the initiating event in AD, ultimately leading to synaptic and neuronal dysfunction and degeneration with subsequent cognitive disturbances (Fig. 1).
These research advances have been translated into several new drug candidates with disease-modifying potential, several of which are now evaluated in clinical trials (Wisniewski and Konietzko, 2008). This foreshadows a new era of causal mechanistic treatment beyond symptomatic therapy. This new type of disease-modifying drugs can be expected to be most effective if initiated very early in the disease process, before the neurodegenerative process is too severe. However, current diagnostic manuals, such as the DSM-IV and ICD-10, warrant dementia, i.e., an advanced stage and severity of the disease, to make a clinical diagnosis of AD. Thus, there is a great need for improved diagnostic tools. New research criteria for diagnosis of AD implementing biomarkers to allow early identification have recently been proposed (Dubois et al., 2007).
Novel concepts of disease-modifying treatment also challenge current approaches for drug development. Drug trials on clinically diagnosed AD cases employing outcome measures based on clinical rating scales will not be sufficient to identify an effect of the new type of drugs in short-term and small-medium sized clinical trials. Biomarkers may speed up this process by serving as alternative outcomes to clinical measures. More accurate outcomes may also be achieved by enriching the population with patients with a disease-specific biomarker pattern, thus minimizing the risk of including patients who do not suffer from AD.
This review is focused on biochemical markers for the amyloidogenic process in AD in cerebrospinal fluid (CSF) and plasma. We use the term "biomarker" in a general sense to describe any measurable neurochemical indicator that is used to assess the risk or presence of disease. Biomarkers may facilitate the ability to reliably diagnose AD in the very early and perhaps even pre-clinical disease stages. They may also provide objective and reliable measures of drug safety and disease-modifying treatment efficacy in clinical drug trials in AD. Since the neuropathological changes of AD likely precede symptoms by years or decades, and it may well be optimal to treat the neuropathology as early as possible, biomarkers of pre-clinical AD are likely to play a pivotal role in the development of the next generation of therapies.
Criteria for an ideal biomarker for AD have been proposed by a consensus group on molecular and biochemical markers of AD (authors, 1998). The key features of an ideal AD biomarker are that it should detect a fundamental feature of the neuropathology, and have a diagnostic sensitivity for AD exceeding 80% together with specificity above 80% for distinguishing AD from other dementias. It should also be reliable, reproducible, non-invasive, simple to perform, and inexpensive. Recommended steps to establish a biomarker include confirmation by at least two independent studies conducted by qualified investigators with the results published in peer-reviewed journals, and validation in neuropathologically confirmed cases. Beyond these criteria for early and accurate diagnosis, it would be especially useful if the biomarker could track natural disease progression as well as the beneficial effect of disease-modifying therapies.
To facilitate clinical drug development for AD, it is of particular importance to be able to make accurate diagnoses early in the disease process, and to have biochemical measures that reflect the pharmacodynamic effects of treatment. For these reasons the National Institute on Aging (NIA) commissioned a working group on biomarkers as part of its Alzheimer's Disease Neuroimaging Initiative (ADNI) (Frank et al., 2003). A wide range of biological measures with possible relevance to AD were considered and then classified into categories of "Feasible, core," "Feasible, non-core" and "Uncertain feasibility." Feasibility was determined by the availability of a validated assay for the biological measure in question, with properties that included high precision and reliability of measurement, where reagents and standards were well described. Core analytes were those judged by the group to have reasonable evidence for association with key mechanisms of pathology implicated in AD, while non-core analytes were felt to be less clearly connected with mechanisms of pathogenesis or neurodegeneration in AD.
Key neuropathological hallmarks of AD are amyloid plaques and neurofibrillary tangles (Braak and Braak, 1991; Thal et al., 2002). Amyloid plaques are relatively insoluble dense cores of 5–10 nm thick amyloid fibrils with a surrounding "halo" of dystrophic neurites, reactive astrocytes and activated microglia. The main proteinaceous component of amyloid plaques is the Aβ peptide. Aβ is not a single molecular entity, but rather is composed of a family of peptides produced by proteolytic cleavage of the type I transmembrane spanning glycoprotein Aβ precursor protein (APP) (Selkoe, 1999) (Fig. 2). Once released by proteolytic cleavage, the Aβ peptide may exist in solution and can be detected in CSF and plasma. This makes diverse species of Aβ peptides highly interesting and promising candidate biological markers (for review see Blennow and Hampel, 2003; Frank et al., 2003).
The pathogenic mechanisms that allow Aβ monomers to self-associate to form oligomeric and ultimately polymeric structures are not yet completely understood, but, as depicted schematically in Fig. 3, it is clear that Aβ can exist as monomers, dimers, oligomers, protofibrils, fibrils and fibrillar aggregates (Walsh and Selkoe, 2007). Moreover, the propensity for self-association of Aβ seems to depend on the peptide's primary sequence such that the Aβ42 variant, which makes up less than 10% of total Aβ, is more prone to aggregate than the more abundant Aβ40. Proposed mechanisms for Aβ-mediated "neurotoxicity" include structural damage to the synapse, oxidative stress, altered calcium homeostasis, induction of apoptosis, structural damage, chronic inflammation and neuronal formation of amyloid pores (Lashuel et al., 2002; Pratico, 2002; Selkoe, 1999).
Treatment trials with anti-amyloid drugs, such as active and passive immunization (Dodel et al., 2003) and β- and γ-secretase inhibitors (Wolfe, 2002), in AD patients will serve as the ultimate proof-of-concept regarding the validity of the amyloid cascade hypothesis. To this end, results from recent trials using biomarker candidates that signal effects of drugs targeting Aβ have been reported (Hock et al., 2003; Siemers et al., 2007). Advances in the development of core feasible neurochemical candidate biomarkers implemented as safety measures, enrichment and stratification variables as well as primary and secondary outcomes in clinical trials are currently paralleled by the development of multimodal structural and functional neuroimaging indicators (Hampel et al., 2008). These markers and technologies have been already implemented as secondary endpoints in trials aimed at abrogating the generation and accumulation of Aβ to make a claim for disease modification. They are currently under intense discussion by regulatory authorities such as the US Food and Drug Administration (FDA) and the European Medicines Agency (EMEA) (Frank et al., 2003) in an effort to revise and update guideline documents. To be finally accepted by regulatory authorities as surrogate endpoints in clinical trials of potential AD modifying therapies both neurochemical and imaging biomarker candidates should respond to treatment, predict clinical response and be compellingly related to the pathophysiological processes, such as to the Aβ-related mechanisms of neurodegeneration in AD (Broich, 2007).
This section of our article aims to provide an updated concise and comprehensive review on core candidate biomarkers with diagnostic potential and possible utility for monitoring the effects of disease-modifying therapies for AD. These biomarker candidates include APP isoforms, BACE1 protein level and activity, Aβ isoforms including Aβ42 and Aβ40, and autoantibodies against Aβ.
APP is an integral membrane protein with a large extracellular domain, a single transmembrane region and a short cytoplasmic domain (Fig. 2) (Haass, 2004). The biological function of APP remains uncertain. The γ-secretase released intracellular domain (ICD) of APP (AICD) has been suggested to function as a transcription factor, but genes regulated by AICD have not been unambiguously identified (Anliker and Muller, 2006). Extensive investigations using behavioural models (Conboy et al., 2005), neuronal cultures and APP knockout mice suggest that APP may serve as a receptor for and appears to play a role during axonal regeneration (Chen and Tang, 2006) and as a regulator of neural activity, connectivity, plasticity and memory (Conboy et al., 2005; Turner et al., 2003) and in the anterograde transport of vesicles along axons (Stokin et al., 2005), although it should be noted that considerable controversy exists regarding the last observation (Lazarov et al., 2005).
Large soluble APP (sAPP) fragments are present in CSF (Seubert et al., 1992); however, the results from studies on CSF levels of total, α- or β-cleaved sAPP in AD have been contradictory, ranging from an increase (Lewczuk et al., in press), to no significant change (Hock et al., 1998; Olsson et al., 2003; Zetterberg et al., 2008) or a slight decrease (Lannfelt et al., 1995; Palmert et al., 1990; Prior et al., 1991; Sennvik et al., 2000; Van Nostrand et al., 1992). In therapeutic studies, the CSF level of α-sAPP may be useful as a marker of α-secretase activation or β-secretase inhibition.
In 1999, several independent research groups published evidence demonstrating that a significant part of the β-secretase activity originates from an integral membrane aspartyl protease encoded by the BACE1 gene (Hussain et al., 1999; Sinha et al., 1999; Vassar et al., 1999; Yan et al., 1999). Studies on BACE1-knockout mice harboring FAD mutations or being wild-type for the PS and APP genes indicate that BACE1 is indeed the major APP-cleaving β-secretase in the brain (Laird et al., 2005; Roberds et al., 2001). Given the fact that BACE1 knockout mice have a very mild phenotype, BACE1 has been considered a promising target for therapy. However, the recently identified role of BACE1 in myelination (Hu et al., 2006; Willem et al., 2006) and the finding that genetic ablation of BACE1 results in Schizophrenia-like changes (Savonenko et al., 2008) have raised some concerns about this approach.
Recently, it was discovered that BACE1 activity can be measured in CSF. A first pilot study showed increased BACE1 activity in CSF from AD cases (Holsinger et al., 2004); this finding is consistent with the observation that BACE1 is upregulated in the AD brain and has been confirmed in subsequent studies, using different assay formats (Holsinger et al., 2006; Verheijen et al., 2006; Zhong et al., 2007). Importantly, recent studies show elevated BACE1 activity and protein levels in CSF of MCI patients (Zhong et al., 2007), and BACE1 activity in MCI cases that progress to AD with dementia (Zetterberg et al., 2008). These results suggest that upregulation of BACE1 may be an early pathogenic factor in AD. Interestingly, increased CSF BACE1 activity may be associated with the APOE ε4 allele in both AD and MCI subjects (Ewers et al., 2008). Taken together these results recommend CSF BACE1 activity as a promising potential candidate biomarker to monitor amyloidogenic APP metabolism in the CNS.
To date, more than 30 different studies have been published analysing the diagnostic accuracy of the highly fibrillogenic 42 amino acid form of Aβ (Aβ42) in CSF (Blennow and Hampel, 2003). A 50% decrease in CSF Aβ42 control levels in AD patients has been found in most of the studies. The mean sensitivity and specificity to discriminate between AD and normal aging are both higher than 85% (Blennow, 2004). Other than in non-demented, aged individuals, normal CSF Aβ42 is found in psychiatric disorders, such as depression, and in neurological disorders such as Parkinson's disease and progressive supranuclear palsy (Blennow, 2004). However, a mild to moderate decrease in CSF Aβ42 may be found in a percentage of patients with frontotemporal dementia and vascular dementia (Hulstaert et al., 1999; Riemenschneider et al., 2002b; Sjogren et al., 2002; Sjogren et al., 2000), suggesting that the diagnostic performance of CSF Aβ42 alone in the discrimination between AD and other forms of dementia caused by different neurodegenerative mechanisms is insufficient. The reduced CSF level of Aβ42 in AD is believed to be caused by deposition of Aβ42 in senile plaques, with lower levels diffusing to CSF. Accordingly, studies have found a strong correlation between low Aβ42 in CSF and high numbers of plaques in the neocortex and hippocampus (Strozyk et al., 2003) or high retention of Pittsburgh Compound-B (PIB) in positron emission tomography (PET) scans that directly reflect plaque pathology in the living brain (Fagan et al., 2006; Forsberg et al., 2008). However, some studies have also found a marked reduction in CSF Aβ42 in disorders without Aβ plaques, such as Creutzfeldt–Jakob disease (CJD) (Otto et al., 2000), amyotrophic lateral sclerosis (Sjogren et al., 2002) and multiple system atrophy (Holmberg et al., 2003). These findings suggest that there may be other reasons for low CSF Aβ42 in addition to deposition of Aβ in plaques. Factors that may contribute to reduced Aβ42 levels, in addition to deposition in senile plaques, include formation of Aβ42 oligomers that escape ELISA detection (Stenh et al., 2005), association with other molecules that block access to epitopes recognized by detection antibodies, e.g., binding of Aβ42 to apolipoprotein E4 or other chaperone-like amyloid-binding proteins, such as β-trace protein (Kanekiyo et al., 2007), or cystatin C (Sastre et al., 2004), and sequestering of Aβ42 in the plasma membrane or intracellularly with lower levels diffusing to CSF (LaFerla et al., 2007). CSF levels of Aβ42, especially together with total tau (t-tau) can distinguish subjects with MCI who are likely to progress to AD with high sensitivity, specificity and predictive values, and may even be useful as markers for pre-clinical AD (Table 1).
CSF Aβ40 is unchanged or slightly increased in AD (Fukuyama et al., 2000; Hansson et al., 2007; Kanai et al., 1998; Mehta et al., 2000; Shoji et al., 1998). Consequently, a decrease in the ratio of Aβ42/Aβ40 (or increase in the ratio of Aβ40/Aβ42) in CSF has been found in AD in several papers (Fukuyama et al., 2000; Hansson et al., 2007; Kanai et al., 1998; Mehta et al., 2000; Shoji et al., 1998). This decrease in the ratio of Aβ42/Aβ40 seems more pronounced than the reduction of CSF Aβ42 alone (Hansson et al., 2007; Vigo-Pelfrey et al., 1993). Of note, some recent studies in individuals with genetically determined AD support that the ratio of Aβ42/Aβ40 may be more important to the neurobiology of AD than the absolute level of Aβ42 (Bentahir et al., 2006; Kumar-Singh et al., 2006).
Besides Aβ40 and Aβ42, the major products of concerted BACE1- and γ-secretase-mediated cleavages of APP (Fig. 2), CSF contains several at least 20 truncated Aβ isoforms. The N- and C-terminal heterogeneity of Aβ peptides in part reflects the use of alternative cleavage sites by both BACE1 which can cleave either at Asp1 or at Glu11 and γ-secretase which can liberate Aβ terminating at residues 38, 40, 42 and 43 (Fig. 4). In addition several of the other Aβ isoforms detected in CSF likely arise due to partial degradation by the action of one or more Aβ degrading enzymes found in CSF. Using urea-based sodium dodecyl sulfate–polyacrylamide gel electrophoresis (SDSPAGE) and immunoblot, it is possible to separate several C-terminally truncated Aβ peptides in CSF, including Aβ37, Aβ38, Aβ39, Aβ40, and Aβ42 (Wiltfang et al., 2002). In AD, elevated CSF levels of both Aβ40 and Aβ38 are found, along with a reduction in Aβ42. Similar data have been obtained using surface-enhanced laser desorption/ionization time-of-flight mass spectrometry (Lewczuk et al., 2003; Sergeant et al., 2003). Other promising findings include those of different N-terminally truncated Aβ species present in protein extracts from AD brains (Sergeant et al., 2003). Some of these fragments are also detectable in human CSF and may be of diagnostic utility in early AD (Vanderstichele et al., 2005). A recent study identified a set of 18 different N- and C-terminally truncated Aβ peptides in CSF using immunoprecipitation–mass spectrometry (Portelius et al., 2006a). Their relative abundance pattern distinguished AD from controls with an accuracy of 86% (Portelius et al., 2006b). This technique has recently been optimized for large-scale studies by automation and the use of isotopically labelled internal standards that reduce the coefficients of variation for the different Aβ fragments to 5–15% (Portelius et al., 2007). Further studies on large patient and control series are now needed to determine the diagnostic potential of Aβ fragment signatures in CSF more precisely.
Many studies have examined plasma levels of Aβ in AD but the findings are contradictory (Table 2). Some groups report high concentrations in plasma of either Aβ42 or Aβ40 in AD, although with a broad overlap between patients and controls, whereas most groups find no change (Irizarry, 2004). Some studies have also reported high plasma Aβ42 in non-demented elderly people who later developed either progressive cognitive decline or AD (Mayeux et al., 2003; Pomara et al., 2005). Contrary to these data, one recent study found an association between high Aβ40, low Aβ42, and risk of dementia (van Oijen et al., 2006), a result that is in general agreement with the findings from other studies, finding a weak association between low plasma Aβ42/Aβ40 ratio and risk of future MCI or AD in a healthy, elderly population (Graff-Radford et al., 2007). Apart from disease-related factors, the opposing data may be due to analytical difficulties. The peptide is very hydrophobic and binds, not only to certain test tube walls, but also to several plasma proteins, including albumin (Kuo et al., 1999) and low-density lipoprotein receptor-related protein-1 (Sagare et al., 2007). Additionally, measurement of soluble Aβ has been achieved using assays that cannot identify the aggregation state of the species detected and may under detect Aβ oligomers (Stenh et al., 2005). Both plasma protein binding and oligomerization could mask Aβ epitopes, resulting in the measurement of only a fraction of Aβ. This possible confounder might differ between ELISA methods, which could explain some of the contradictory results. Moreover, the development of anti-Aβ oligomer-specific antibodies should obviate concerns about epitope masking due to Aβ self-association and may provide a useful system to measure Aβ oligomer levels in both CSF and plasma. Indeed a small number of preliminary studies suggest that measurement of Aβ oligomers will be of benefit (Georganopoulou et al., 2005; Pitschke et al., 1998). If this holds true in larger studies one would anticipate that combining measurement of disease-linked assembly forms (oligomers) of Aβ together with measurement of tau in CSF together with brain imaging will provide a highly specific and sensitive means of measuring both early and incipient AD. Indeed even in absence of structure-specific assays plasma Aβ might still be useful as a marker to identify and monitor biochemical effects of new amyloid-targeting drugs, a hypothesis that is supported by recent studies on γ-secretase inhibitors (Fleisher et al., 2008; Siemers et al., 2005, 2007, 2006) and immunotherapy (Relkin et al., 2008).
Work in transgenic mouse models has suggested that antibodies directed at Aβ, generated by passive or active immunization, may help clear Aβ and reduce cognitive/mnemonic deficits (Bard et al., 2000; Schenk et al., 2000). Although active immunization does not so far appear viable in humans, owing to uncontrolled inflammatory responses following multiple administrations of the immunogen, it has generated ancillary interest in the possibility that humans may naturally develop antibodies to Aβ. However, some of these antibodies will be in pre-formed anti-Aβ antibody complexes and the variable results obtained in different studies may in part be explained due to use of assays that differ in their ability to detect anti-Aβ antibody complexes. Thus, disrupting anti-Aβ antibody complexes is essential in order to accurately measure total anti-Aβ antibody levels. A recent study employing such a strategy did indeed find significant differences in serum antibodies to Aβ between AD and aged-matched control subjects (Gustaw et al., 2008).
Whether such antibodies might be helpful, harmful, or neutral with respect to the development and progression of AD remains undetermined. Likewise, it is unclear what conditions induce formation of such antibodies, or how specific they are to AD. A plaque-killing assay to detect the presence of anti-Aβ antibodies revealed that approximately 50% of AD and 50% of control cases were positive (Xu and Gaskin, 1997). These findings are generally consistent with the report of Hyman et al. (2001) who found low but detectable anti-Aβ autoantibodies in just over 50% of all patients, and modest levels in under 5% of all patients. In CSF, however, significantly lower titers of anti-Aβ antibodies have been observed in AD compared to ND subjects using an ELISA (Dodel et al., 2002; Du et al., 2001, 2003). Recent data from Henkel and co-workers (2007) provide further support that IgG-Aβ complexes in CSF may be a protective factor against AD, but their potential as biomarkers is uncertain.
CSF biomarkers may be valuable in clinical trials in at least four different ways: as diagnostic markers, for patient stratification, as safety markers and to detect and monitor biochemical drug effects (Table 3). The first generation of MCI clinical drug trials, such as the donepzil and vitamin E trials (Petersen et al., 2005), recruited unselected heterogeneous MCI cases, meaning, that probably around half of the cases did not have AD-type neurodegeneration. This may have seriously reduced the ability to identify potential efficacy of a drug candidate. There could be reduced costs and numbers of recruited subjects in future trials that are enriched and stratified for MCI subjects using clinically meaningful CSF biomarkers (Hansson et al., 2006).
Since AD is a disorder with a slow progression of symptoms, identification of a change in the slope of deterioration due to intervention with a disease-modifying drug candidate will require very large patient cohorts and treatment duration of several years. Small, short-term clinical trials may be valuable to verify a biochemical effect also in patients with AD, before the expensive and time-consuming step is taken to larger phase II or III clinical trials. A summary of biomarkers as surrogate measures for treatment effects on Aβ-related mechanisms is presented in Table 4.
Presently, it is uncertain how the Aβ1–42 concentration in CSF might respond to treatment with efficacious drugs that target pathways leading to Aβ, production, fibrillization and/or amyloidosis in man (Gilman et al., 2005; Siemers et al., 2006). Studies in transgenic mice, however, provide evidence that reduced CSF Aβ1–42 levels are to be expected for short-term treatment with inhibitors of γ-secretase (Lanz et al., 2003, 2004). Similar results have recently been seen in a phase IIa study of the Aβ clearance-enhancing compound PBT2 (Lannfelt et al., 2008). Based on longitudinal studies of conditions involving acute neuronal injury (Hesse et al., 2001; Zetterberg et al., 2006) and data from the interrupted phase IIa AN1792 trial (Gilman et al., 2005), t-tau should decrease towards normal levels if a treatment is successful in inhibiting the neurodegenerative process in AD. The same may be expected for p-tau, although there are still no studies backing this hypothesis. The usefulness of other Aβ-related biomarkers, e.g., BACE1 activity, as biomarkers for treatment efficacy remains to be investigated. Nevertheless, the low intra-individual variability of CSF tau proteins and Aβ42 in 6-month and 2-year studies of AD and MCI patients is an important prerequisite for the use of these biomarkers that may reflect the effects of disease-modifying AD therapies in clinical trials (Blennow et al., 2007; Zetterberg et al., 2007).
Besides the use of CSF biomarkers to identify and monitor the biochemical effects of a disease-modifying drug, they may also be valuable tools for safety monitoring in trials with drugs with potential serious side effects, such as immunotherapy. The phase IIa AN1792 trial was interrupted since 6% of cases developed meningoencephalitis (Orgogozo et al., 2003). In routine clinical practice, CSF analysis is the standard method to diagnose encephalitis. Typical findings are an increase in CSF mononuclear cells together with signs of blood–brain barrier damage and intrathecal immunoglobulin production (Table 5). CSF may thus be a valuable tool as safety measures in this type of trials.
Pre-clinical studies have benefited from the use of transgenic (Tg) rodents that express mutant forms of the human APP or PS genes. In these Tg mice, plaque deposition increases with time and defects in cognitive and synaptic function are observed (Spires and Hyman, 2005). Such genetically engineered mice are commonly used to evaluate if a drug candidate will reduce "Aβ burden," i.e., the number or extent of Aβ plaques in the brain. A pioneering study showed that immunization with Aβ1–42 in APP Tg mice reduced both Aβ burden and cognitive deficits (Lemere et al., 2006). However, the predictive value for translating data on drug effects from AD Tg mice to patients with AD seems to be low. In fact, there are more than 100 molecules that reduce Aβ plaque burden in these animal models, several of which have been found to lack any preventive effect or any clinical effect in treating patients with AD (Blennow et al., 2006). AD Tg mice have a huge over-expression of Aβ and develop plaques much faster than AD cases, and thus probably are much more responsive to anti- Aβ treatment than humans with sporadic AD.
APP transgenic mice over-expressing Aβ42 show learning and memory disruption, but do not show a significant loss of neurons, indicating that the transgenic rodents are incomplete models of neurodegenerative disease, and suggesting that Aβ1–42-induced memory deficits may involve more subtle neuronal alternations leading to synaptic defects in the absence of overt neuron loss (Jacobsen et al., 2006; Kamenetz et al., 2003). The extent to which these animal models recapitulate the AD phenotype depends on whether AD is primarily considered a disease of Aβ amyloid deposition that also manifests neurodegeneration, or whether it is primarily a neurodegenerative disease that secondarily manifests Aβ amyloid deposition (Swerdlow, 2007). These uncertainties call for caution when translating data from mice to man.
There is an extensive body of literature supporting the notion that analysis of Aβ42 in CSF together with other core feasible biomarkers, including t-tau and p-tau phosphorylated at either threonine 231 or 181, have reliably high diagnostic and predictive performance in identifying AD, even in the early symptomatic, predementia and clinical dementia stages (Hampel et al., 2004; Hansson et al., 2006; Zetterberg et al., 2003). Core feasible biological marker candidates of mechanisms related to AD pathology are in an ever-maturing development process and should inform regulatory guideline documents regarding study design and approval for novel compounds claiming disease modification. The more general use of CSF biomarkers in clinical practice may be justified, especially if some of the new disease-modifying treatments prove to have a positive clinical effect. The awareness of medical progress in the population will lead subjects with very mild or even only subtle subjective cognitive disturbances to seek medical advice, though in many cases the symptoms will be unrelated to AD neurodegeneration. Diagnostic tools, such as CSF biomarkers, may thus be needed to diagnose AD-spectrum disease at a very early stage in order to select appropriate candidates for treatment.
The authors are clearly aware that besides neurochemical candidate markers, a wide range of mostly computer-based analysis methods of structural and functional neuroimaging data hold great promise to substantially support early detection, prediction of cognitive decline and conversion to AD as well as mapping of effects of therapy on the brain (Hampel et al., 2008). These emerging in vivo-imaging tools, however, are often very expensive and not widely distributed or accessible for clinical use. Automated approaches are in the process of earlier testing. The rate of hippocampal atrophy assessed by labor-intensive manual MR-volumetry is currently the best MR-derived biomarker. However, other neuroimaging approaches show promise, including fully automated, observer- and a priori hypothesis-independent MR-based voxel- and deformation-based morphometry (VBM, DBM) (Teipel et al., 2004, 2007a), cortical thickness analysis (Lerch et al., 2005; Teipel et al., 2009), and region-of-interest analyses of the medial temporal lobe and the basal forebrain (Teipel et al., 2005). The application of machine learning algorithms to fMRI data (Mourao-Miranda et al., 2005) and structural and functional connectivity studies of altered neuronal fiber pathways organized in cognitive networks in the AD brain (Bokde et al., 2006; Teipel et al., 2007b) using diffusion tensor imaging, fMRI and PET, or even direct labeling of Aβ plaques with recently developed radioligands in molecular imaging yield particularly promising perspectives.
Combination and integration of multimodal imaging, genetic and neurochemical markers is still in its infancy; however, there are early studies combining CSF and MRI markers (Hampel et al., 2005) or CSF pattern and regional cerebral blood flow for added value (Haense et al., 2008; Hansson et al., 2009).
These complementary methods, among many others, need further evaluation in ongoing large-scale multi-center initiatives, such as ADNI. Presently, there are only a few studies in which the diagnostic accuracy and indication of the effects of new disease-modifying therapies of different biomarker candidates (CSF Aβ, t-tau, p-tau, MRI based region-of-interest measurement of hippocampal and whole brain atrophy, and 11C-PIB-PET) are progressing to an advanced stage of qualification as biomarkers with characteristic functions and directly compared. Moreover, this dynamically developing field requires additional data on added value, as well as cost-benefit analyses of individual and combinations of biomarkers. A reasonable 5-year perspective is that the utility of these biomarkers will be conclusively established and qualified in large-scale prospective and controlled multi-center trials, such as the US and European ADNI studies as well as in ongoing population-based prospective studies (Mueller et al., 2005). Most important, ongoing anti-amyloid drug development programs may demonstrate the utility of core feasible CSF biomarkers in early dose-finding studies, and in later proof-of-mechanism and concept studies. If so, it is reasonable to anticipate that such markers will eventually allow the selection of asymptomatic individuals at very high risk for later neurodegeneration who are therefore candidates for anti-amyloid therapy. It appears plausible that the biomarkers (as surrogate markers or markers of mechanisms of action) themselves will become the primary targets of therapy; that is, like in other areas of medicine (i.e., in oncology or in cardio-vascular diseases) drug candidates may be approved for to treat abnormal levels of the biomarker. In other words, CSF biomarkers of Aβ amyloid dysregulation may become true surrogate markers of AD neurodegeneration.
The authors wish to thank Ms. Barbara Asam, Mr. Alfred T. Welzel and Ms. Yvonne Hoessler for technical assistance in the preparation of the manuscript. Our colleagues also are thanked for their contributions to the work summarized here which has been supported in part by grants from the Science Foundation Ireland (SFI), the Health Research Board (Ireland), the Health Service Executive (HSE; Ireland), Trinity College Dublin, the Alzheimer Association, to H.H., NIH (P30 AG10124, UO1 AG24904), and the Marian S. Ware Alzheimer Program. J.Q.T. is the William Maul Measy-Truman G. Schnabel Jr. M.D. Professor of Geriatric Medicine and Gerontology. H.Z. and K.B. are supported by the Swedish Research Council, the Swedish Brain Power project and the Alzheimer's Association. The ADNI is a partnership of collaborators at the National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering, academic investigators, pharmaceutical companies, the US Food and Drug Administration, the NIH Foundation, the Alzheimer's Association, and the Institute for the Study of Aging all of whom contributed to the development of the ADNI.
PubMed Central Canada is a service of the Canadian Institutes of Health Research (CIHR) working in partnership with the National Research Council's national science library in cooperation with the National Center for Biotechnology Information at the U.S. National Library of Medicine(NCBI/NLM). It includes content provided to the PubMed Central International archive by participating publishers.


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Psalm 55:6 "Oh that I had wings like a dove! I would fly away and be at rest."
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used for decorations
(Posted on 6/10/13)
- ok for the price Review by Kat
used it to make a tail for a fox costume. It looked great, but shed feathers the entire night all over my house...I was not thrilled about that.
(Posted on 10/28/12)
- was good for the money Review by Mommy8118
This product could have been better but it was ok for the price. But any time we even moved the feathers started flying off of these boas. Great for one time use only.
(Posted on 8/12/12)
- I would buy this again Review by Dawn
The boas were great. Everyone loved them. They are very colorful. They arrived by the date stated at the time of order. The did shed but still held up.
(Posted on 4/13/12)
- Good product for the price Review by jj
We are using them for decorations at a Roaring 20s party.
Was pleased with the quick delivery.
(Posted on 3/8/12)
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Happy Hanukkah: Games & Party Ideas
Stock up on party supplies from Windy City Novelties to make sure your Hanukkah celebration this year is a big hit!
Black, White & Gold New Year's Eve Party Ideas
Spend New Year's Eve with loved ones when you host a Black, White & Gold New Year's Eve Party with these helpful and creative party tips!
Ideas on Decorating for Hanukkah Celebrations This Year
Invite friends and family over for a Hanukkah celebration! Decorate the party space in blue, white and silver and serve traditional foods while making memories.


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text: I don't exactly remember hearing this when I first bought the console on launch day, but when I shake the controller, I hear a rattle inside. I assume it's the motion and rumble things. But like I said, I don't think it's always been there. Can anybody else confirm for me if theirs rattles? But that's not what I want to talk about. The touch screen, I found out there's this one area on the screen where if I try to write over it using MiiVerse, the whole thing gets messed up and just does a bunch of scribbles. I've tried cleaning it but it doesn't do anything. Should I contact Nintendo about this or try and take it back to EBGames for an exchange? I don't even know if I could get one because I don't think I have the receipt anymore.


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MOUNT HOOD, Ore. (KOIN) — Things aren't always what they appear to be.
That was the case for detectives investigating the death of 68-year-old Frank Wilson whose body was found at Trillium Lake last September.
What they thought was possibly a suicide turned out to be much more mysterious.
Wilson's daughter Kim tells KOIN 6 News it appeared her father was having a mental breakdown before his death. She said he was distant and wanted to be left alone.
"I got in contact with his doctor… told him what was going on and how uncharacteristic the behavior was for him," Kim recalled.
Doctors had recently diagnosed Wilson with some medical issues. At the same time, he struggled with the idea of retiring. Kim says he refused help at the time.
Wilson also had a concealed weapon permit and often carried a gun.
One day he left for work and never came home. His body was found on September 24 inside his parked pickup at one of his favorite places: Trillium Lake.
"Some of the initial opinions were that there was a potential that this was self-inflicted," Clackamas County Detective Bill Terway said, noting that further investigations revealed some puzzling clues. "Wilson was shot multiple times in the chest and there was no firearm located in his vehicle or near his vehicle."
State Medical Examiner Karen Gunson performed the autopsy on Wilson's body. She recalled finding clues that led her to believe his death wasn't a suicide after all.
"There was more than one gunshot wound and the location… was very atypical for a suicide," Gunson said. "High in the left shoulder and sharply downward toward the back… that's a very awkward motion. The window was down so it would have been easy to shoot somebody while they're sitting in the truck."
But there was another mysterious clue: Investigators found drops of blood outside the truck that formed a trail about 70 yards down the parking lot.
And a week after Wilson's body was discovered, a weapon was found in the woods. Detectives learned it was Wilson's own gun that was used in his death.
"It could be that somebody is walking away carrying the weapon that has blood on it," Gunson said. "It's hard to say how that blood trail got there."
The handful of clues left investigators stumped and with very few answers. But there was one thing they were sure of: They knew exactly when Wilson died.
"Frank Wilson was wearing a Fitbit, a fitness tracker watch," Detective Terway said.
He may not have known it, but Wilson left investigators with a vital clue.
"You can see at a certain time the heart rate stops… [it] monitors your heart rate," Gunson said. "And it just ceases, so we know that's the precise time he died."
It's the first time in Oregon forensic history that a fitness tracker has been used to determine a time of death. It's the one certain thing in a case of so many unknowns.
As Wilson's family struggles to comprehend the circumstances behind his death, Detective Terway says he's confident the case will someday be resolved.
"People don't hold secrets and when they do have secrets they normally want to tell somebody," he said. "I think, eventually, we will find the answer. Whether it's by accident or on purpose… I think we will find a resolution to this case."
Is it murder or not? Investigators can't rule out suicide at this point, although the evidence doesn't seem to point that way. They're also staying tight lipped about fingerprint evidence left on the gun that was found in the woods near Trillium Lake.


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Words that start with clein
Found 2 words that start with clein. Browse our Scrabble Word Finder, Words With Friends cheat dictionary, and WordHub word solver to find words starting with clein. Or use our Unscramble word solver to find your best possible play! Related: Words that end in clein, Words containing clein
- Scrabble
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STARmeterSEE RANK
Down 1,422 this week
Ashraf Barhom
Ashraf Barhom was born on January 8, 1979 in Ma'alot-Tarshiha, Israel. He is an actor, known for The Kingdom (2007), Agora (2009) and Clash of the Titans (2010). See full bio »
Born:in Ma'alot-Tarshiha, Israel
More at IMDbPro » Contact Info: View agent, manager and legal


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This is a time when those interested in serving on our board can get together with current members to get an idea of how our board works and to discuss board membership.
If you are interested in finding out more about the Board of Directors, please contact Brooke at (512) 396-3404, ext. 248 or by email.
We are eager to share information on our current operations and plans for the future. Our "working board" offers many opportunities to get involved.


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Meet Me In the Middle Lace Dress
50% Off Everything
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style #AGG99326Add to Crushes
Meet Me In the Middle Lace Dress
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$17.00 $34.00
Colour: blue
CAD Size: L
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Details and CareFabric: 100% polyester. Machine wash. Model wears size S/M
Size Chart
Not sure about your size? We've got you. Click below for the size chart.
Shipping and Returns
Shipping info
+ We'll cover duty and tax costs on all orders.
Delivery option Delivery times Delivery cost Canada Standard Up to 8 business days $11.00 Canada Express 4 business days $30.00
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Returns info
We hope you are satisfied with all of your purchases but if you ever need to return an item, you can do so within 28 days from the date your parcel was dispatched.
Please note, we cannot offer refunds on pierced jewellery or on swimwear if the hygiene seal is not in place or has been broken.
Click here to view our full Returns Policy.


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Anaheim Truck Accident Attorneys
In Anaheim, California, high volume of truck traffic is quite common on the streets of this popular Orange County city, but with it, truck accidents have become rampant.
If you have been involved in a truck accident in Anaheim, call Bisnar Chase Anaheim Accident Injury Lawyers now at 949-203-3814. We will listen to the details of your incident during your free consultation, and if you are entitled to compensation, we will do all the hard work for you while you recover.
Truck Accident Statistics
The enormous difference in mass and size between trucks and passenger cars often spells disaster for motorists. In fact, it has been estimated that as many as 10% of all fatal accidents are caused by semi-trucks.
Near 5,000 Fatal truck crashes happened nation-wide in the past year and the numbers aren't looking any better. On average fifty people per day are killed or injured in a truck accident.
In crashes involving a truck or tractor trailer and a passenger vehicle, the occupants of the passenger vehicle are 50 times more likely to be killed than the truck driver due to the mass of the truck versus a normal-sized vehicle.
What Causes Truck Accidents:
The various causes of truck accidents include:
- Driver Fatigue
- Intoxicated Drivers
- Texting/Distracted Drivers
- Defective Equipment
- Substandard Inspections
- Weather Conditions
- Hazardous Materials
Who's At Fault in a Truck Accident Case?
In truck accident cases, it can be challenging to resolve who is truly at fault. Perhaps a negligent tractor trailer driver caused a collision in Anaheim because he was drowsy after spending too many hours driving the road. Perhaps the driver of a car caused the accident because she was speeding.
In many cases, neither driver is at fault. Often, truck accidents are caused by weakly maintained vehicles, improperly loaded vehicles or defective truck parts. We know how to determine who was at fault and take action against them.
Our attorneys are experienced Anaheim truck accident lawyers who have represented truck and other auto accident victims for over 30 years.
With that said, if both parties are not at fault, how do you take legal action? The simplified answer is to prove negligence.
Proving Negligence in a Truck Accident Case
To receive adequate compensation, you must be able to prove that somewhere in the course of your Anaheim truck accident, someone's negligence cause you pain and suffering. The following can constitute for negligence of a third party:
- Speeding Over the Posted Limit
- Failure to Check Blind Spots
- Intoxicated Driving (Drugs/Alcohol)
- Driving While Sleep Deprived
- Road Rage
- Neglect of Vehicle Maintenance
- Overall Reckless Driving
How to File a Truck Accident Claim
Before filing your claim, you must be able to prove without a doubt that there was an individual or a group of individuals whose negligence caused you pain and suffering. If you can do that, you may proceed with legal action.
It is also highly recommended that you hired an experienced attorney who knows truck accident law and the streets of Anaheim to assist you. The laws concerning truck accident are very complex and only a skilled attorney can help you receive maximum compensation for you injuries.
If you also lost a loved one in the aftermath of a truck accident, you may be able to additionally list this wrongful death to your pain and suffering when you and your lawyer are fighting for compensation.
You can fight fight for both your injuries as well as your deceased since the court views wrongful death as a civil action and not a matter that would be dealt with in criminal court. If the court rules in your favor, you may be able to receive compensation for:
- Medical Expenses
- Therapy
- Lost Wages
- Funeral Costs
- Lost of Companionship/Lost of a Loved One
Why Choose Bisnar Chase?
Since 1978, Bisnar Chase Personal has been serving people in and around Anaheim California, specializing in vehicle and truck accident law.
Our Anaheim truck accident attorneys know what to look for when analyzing trucking accidents. Call us for a free consultation at: 949-203-3814 and get the best options and legal team for your case.


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Looking For More Attention? Drop Some Pounds
At least that's what Skinny Water is promising in their latest advertisement. The ad shows a woman facing a throng of cameramen snapping her picture, elegant earrings dropping to the top of the headline which says: "Skinny Always Gets the Attention." Take a look:


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There's been an abundance of superhero films and there's something off with these films! A vast majority are about Marvel and/or DC characters. Personally, I feel that there are more interesting and better developed characters in independent comics. Don't get me wrong... I love both companies, but here's my list of some characters that could and should have their very own movies, and outshine mainstream heroes.
Brain Boy
Think of Brain Boy as an Americanized version of James Bond with Charles Xavier (Professor X) mental abilities. Matt Price aka "Brain Boy" works for a U.S. secret agency using his powerful psychic abilities to fight communists and anyone that's an"enemy of freedom". This would make a cool superhero-espionage film.
Ruben is probably the most backwards superhero on this entire list for two big reasons. He gets his powers from drinking alcohol and taking drugs! The story of Ruben, aka Buzzkill is a dramatic yet very fresh take on being a superhero. As we see a godlike being sitting in AA meetings and using a fake name talking about him being an alcoholic. There's a lot to Ruben that's shrouded in mystery... Someone in Hollywood needs to jump on this project.
Imagine a special suit that allows you to move through our world undetected and untouchable within a dark parallel dimension. Sounds great, right? There's a catch to all of this, but what if you couldn't fully control this suit? We find this out through the story of Scott Travers in Blackout. A sci-fi, political superhero Dark Horse comic book.
The Blaze Brothers
If Kill Bill, Pulp Fiction, The Boondock Saints and Wanted had a love child it would be called "The Blaze Brothers". The story is about two orphaned half brothers, Jack and Billy Blaze. Raised by a Chinese martial arts master and trained by the US government to carry out black op assassinations. After a failed mission that almost left the two brothers dead, they decided to resign and use their skills as debt collectors for a powerful Japanese crime lord, Mr. Yamamoto. Things get hectic after Yamamoto believes that The Blaze Brothers have dishonored him, now there's a $2million bounty on their heads! The brothers must every hitman, assassin and gang member in the city.
Quantum & Woody
They (upset Fantastic Four fans) tell us two people of different skin color can't be related or be a "real" family. Quantum and Woody defy all odds as a comical superhero team up that will have you in tears of laughter. Before these two became superheroes, Eric and Woodrow Henderson were inseparable - Adopted brothers, best friends and brilliant minds. Years later, they are estranged siblings, petty rivals and washed-up losers.
After the murder of their father Derek it leads them to a random scientific accident giving them a whole new purpose and powers as a superhero team, kinda.
Think of these guys as a buddy cop movie disguised as superheores.
"She might be the villain of her own story... But, the world can never know the truth!"
"Furious" is a fresh take on being a superhero in today's society - We follow the world's first superhero, The Beacon who can't catch a break against her arch nemesis... The media! Our hero has fallen victim to the media after cameras caught her beating a group of thugs to mush. As she tries to tell her side of the story the media keeps rewording everything she says and turning her into the villain. Not only that the media have gone as far as changing her name to "Furious". Can The Beacon control her anger or will she fall prey to it?
I would love to see this movie as it combines the "realistic" effect of today's media and how easy it is turn anyone into a "villain".
Artesia Afire
An epic fantasy where the hero/main character is a warrior-queen by the name of "Artesia". Artesia is the pagan version of Joan of Arc wielding an enchanted sword similar to Excalibur. In the story of Artesia every character has a unique trait or personality that makes them stand out. Including the fact that the majority of females are bisexual including Artesia being a sexually open minded character. She is tall, intelligent, sexually open, brilliant-strategists and a fearless leader.
What makes her stand out overall as a character is that the author recognizes she can't defeat all of her foes with brute strength since some characters are just much larger than her. So she defeats them with her wits and always outsmarting her enemy. There's so much to this story from Artesia finding the slain (female_ knight in the woods surrounded by the corpses of her attackers. Artesia, then takes the knight's sword which happens to be a powerful magical sword that can inflict wounds and kill otherworldly creatures that cannot be killed by mere steel.
This could be the next Highlander/Lord of the Rings epic!
Jaycen Wise
Jaycen Wise may very well be one of my new favorite heroes. Why you ask? Because from what I've read about him he's AWESOME! Wise is the last of his kind, hailing from the African Empire of Kush, which dominated the ancient world spreading wisdom, knowledge and peace throughout the land. As an immortal warrior, scholar/philosopher Jaycen must destroy the forces of darkness and ignorance.
The story of Jaycen Wise is a constant adventure of one individual trying to better themselves spiritually, emotionally, physically and mentally over their lifetime as an immortal. Filled with action and espionage you'll love the story of Jaycen Wise... This would certainly make a great film adaptation. I'm looking at four actors for this role - Isaiah Washington, Chiwetel Ejiofor, Idris Elba and Dayo Okeniyi.
Creator of Jaycen Wise talks about the idea behind Wise and more...
Jaycen Wise is "The anti-Indiana Jones" .
I'll have another article similar to this with more characters and information! As for now I hope you enjoyed reading my list of indie heroes!


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Bermagui & Surrounds
Bermagui is a small fishing town on the South Coast of NSW in the Bega Valley Shire between Tathra and Tilba by road. Surrounded by National Parks and State Forests. The beaches are stunning and never crowded. Great surfing and swimming spots. Inland towns like Cobargo and Bega have great communities interested in the environment and sustainable farming. There is a thriving art scene with Bunga St Studio, Ivy Hill and Narek Galleries, showcasing local artists.
Four Winds Festival
Contemporary and classical music in a beautiful natural amphitheatre on alternate Easter weekends is now running year round with music, arts and literary events every month and hosting resident musicians.
Sculpture on the Edge
Held in March annually since 2007 and features some of Australia's finest sculptors as well as emerging artists.
Spring ReBoot in Bermagui Run, Refresh, Relax and Renew
Fun runs, Massage, Yoga, Boot camps, Whale-watching, Walks and more. 26th - 27th September.
Bermagui Markets held on the last Sunday of each month in Dickinson Park from 8.30 -12.30.
Bermagui Produce Markets at the Fishermen's Coop every Thursday from 3:00 - 6:00
Sage Produce Markets at Moruya Tuesdays 3:00 - 5:00 (Winner 2 years Best Market Delicious Magazine)
SCPA Markets Bega every 2nd Friday Littleton Gardens
The historic rural village of Cobargo, on the NSW Far South Coast, hosts the Cobargo Folk Festival, now moving into its third decade.
First held in 1996, this festival of music, dance, song, comedy, poetry, fun and fine food and drink attracts thousands of visitors to one of the most beautiful regions of Australia, the lush Bega Valley.
Hundreds of performers from around the country and overseas provide a weekend of memories across a range of musical genres that now make up our vibrant folk culture.


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Match Amazing Speakers
With Great Clients
Match Amazing Speakers
With Great Clients
Match Amazing Speakers
With Great Clients
Jon Wuebben is the CEO of Content Launch, which offers the first content marketing software built for small and medium sized businesses (SMB's) and digital agencies. Content Launch also provides content writing and content strategy services for hundreds of companies and digital agencies.
Jon has spoken at a wide range of marketing industry events including Content Marketing World, Online Marketing Summit, South by Southwest (SXSW), Marketing Profs B2B Forum, Search Marketing Expo (SMX), Social Media Marketing World, New Media Expo, Intelligent Content Conference, Content Marketing Retreat, Lavacon, ADMA (Australia), BIA Kelsey Small Business Forum, the Media Relations Summit and for many organizations, including Hubspot, Intuit, the American Marketing Association and Shop.org as well as industry groups in the areas of content marketing, content strategy, entrepreneurship and now, the future of marketing.
Jon has been listed as a thought leader in the marketing industry by countless publications since 2008.
Jon wrote Future Marketing: Winning in the Prosumer Age to help companies plan for future marketing strategy. He draws on the latest research, data and predictions across multiple disciplines to show readers:
This talent's exact fee falls somewhere within the stated fee range on the speaker's page. To learn the exact fee, complete the "Check Availability" form located on the speaker's page, or call Eagles Talent Speakers Bureau at 1-800-345-5607. We look forward to working with you.
Working with Eagles Talent ...
We have worked with many speaker bureaus, but none of them come close to the level of service and support that Eagles Talent does ... You raise the bar for your industry and from a speakers standpoint, you are the Ritz-Carlton."
--The DiJulius Group
Selecting from thousands of speakers and entertainers can be overwhelming. In only a few steps, put our team into action to help you.
We specialize in guiding clients through the booking process. We focus on your theme, budget and message for your group. We guarantee a response time of same business day or sooner.
If you require immediate attention, call us at


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Post Traumatic Stress
All children and adolescents experience stressful events that can affect them both emotionally and physically. Most often their negative reactions to stress are brief, and they recover without further problems. However, some children and adolescents who experience trauma develop an anxiety related response that can overwhelm their ability to cope with daily demands. Some of these young people will be diagnosed with Post Traumatic Stress Disorder (PTSD). Students with PTSD develop extreme fear, helplessness and psychological distress while constantly preparing themselves to "fight, flight, or freeze." Despite persistent efforts to avoid stimuli associated with the trauma, children and adolescents with PTSD frequently re-experience the trauma through recurrent or distressing dreams or memories.
The symptoms of post trauma stress and Post Traumatic Stress Disorder may last from several months to many years. Early intervention and close collaboration among parents, schools, and other service professionals are essential for positive recovery.
Post Trauma Booklet for Parents, Guardians and Child Serving Professionals or Post Trauma Quick Fact Sheet (for easier printing) - opens in PDF format
Post Traumatic Stress School and Classroom Strategies - opens in PDF format
Post Trauma Stress Home and Family Strategies - opens in PDF format
Electronic templates for these booklets and strategy sheets are available to organizations, schools, and communities for a nominal fee so they may be adapted to reflect your community's own local resources. Use the contact us button at the top of the page for more information or call the Students FIRST Project at 802-488-6706.


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Template >> Logo - 20 Grunge Logos 201851 by vuuuds @ CreativeMarket
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How-to Create a Position Report with Sample Essays
Edit Report How to Revise On Your GCSEs They could not be far, they could be considerably, but everybody in England Ireland has to confront them at some time within their lives! The better you do inside your GCSEs, the simpler it will be for you really to find a job. Studying is a great method to be sure you don't get distressed in these exams! Advertisement Actions Prepare all your supplies. The fundamental products you need might be laptops for writing pens and writing notices or possibly a legitimate mat. (more…)
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Ways to use Scrivener to start out and Finish a Tough Draft
Ways to use Scrivener to start out and Finish a Tough Draft
What makes you creating?
What makes you making? 1: evaluation Andamp; ability to remember
The simple answer to this query happens because you have to. You have to generate essays so as to be evaluated to be able to get sufficiently credits or a suitable indicate to succeed to the next a part of your training course. Even so, serious about writing articles like this means you only look at it to provide a unfortunate chore. On the other hand, make an attempt thinking about penning being an important and basic a natural part of knowing and exploring. (more…)
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Just how to Compose a Position Paper with Trial Essays
How to Open an Auto Body Shop Nevertheless, knowing how to make a damaged vehicle appear to be new is not enough to make sure enterprise success: you can also require some noise advice on how to start an automobile bodyshop. Ad Get courses on repairing cars in a vocational school and spend some time functioning at a preexisting auto-body look. Advertising Consider wanting more away for greater business prospects. Be sure you include taxes and workers' wages. Enroll your auto-body shop. Look for a site for your auto body store. (more…)
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MULLIN Graveside services for Mildred Clark Pearce, 94, of Levelland will be at 3 p.m. Sunday at Oakview Cemetery in Mullin with Charles Taylor officiating.
Arrangements are under the direction of Geo. C. Price Funeral Directors of Levelland.
She died Friday, Feb. 22, 2002.
She was born Nov. 8, 1907, in Mullin and moved to Levelland in September 2001 from Abilene. She taught at Valley View Elementary School in Abilene for more than 40 years and served as a substitute teacher for several years after her retirement. She was a member of First Baptist Church in Abilene.
Survivors include a son, Stephen of Rockwall; two daughters, Stephanie Crothers of Terrell and Suzanne Leggitt of Levelland; a sister, Selma Riddle of Tulsa, Okla.; seven grandchildren; and eight great-grandchildren.
© 2017. All Rights Reserved. | Contact Us


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The December countdown can take the H-O-L-L-Y out of your D-A-Y-S when you celebrate with your family. You connive strategies to cope with your family drama. Besides the old standby, 'el vino', to make it through the day, you imagine bursting through the door just when everyone is sitting down to dinner. Or, you fake a stomachache or another party commitment just to bolt from your family chaos. All your imagination doesn't change the reality of the next several hours.
What if you could use body language to silently flip-the-script of the holiday chaos with your family? Imagine how calm you'll feel if you're finally in the driver's seat navigating through those problem situations. You may not be able to forget the past, but you can maneuver the present by shifting gears using body language to create a more peaceful atmosphere.
Learn some body language tricks to turn the tide this holiday season.
1) "Demolishing the Monopolizer" situation: You're talking to your mom and Aunt Jane interrupts your conversation. You look at Aunt Jane with a surprised expression, yet she continues to talk. You try to get the upper hand by talking over her. Within minutes both of your voices escalate louder and stronger vying for your mom's attention. You notice your mom's face grimace as she looks for an escape. How do you solve?
"Demolishing the Monopolizer" solution: Close the physical gap by invading Aunt Jane's space by standing slightly behind her. Position yourself within 12 to 18 inches of her shoulder. You want to be close enough so that she notices the physical invasion. Hook your thumb under your chin while placing your index finger vertically across both of your lips and purse your lips slightly as if to say "shhh." Next, tilt your head slightly away from Aunt Jane and rotate your face to look directly at her with a hard stare. Watch how quickly she'll physically pull away, allowing you to finish your conversation. You'll be able to demolish Aunt Jane's monopolizing with these simple yet subtle body language moves.
2) "Put-Downer" situation: You're sitting at the dinner table when your brother, Jack, walks up to you and smarts off about the job you didn't get. Others at the table sense your tension and stare to see what will happen. You can't believe Jack opened his mouth when he said he'd keep the news to himself.
"Put-Downer" solution: Before you say a word, level the playing field by physically getting up from the table and standing next to him. By standing up, you send the message that you're a contender and you're putting him on notice. You shift your power by looking at him at eye level. This simple moves changes the energy of the conversation.
3) "Fake It Until You Can Take It" situation: You're dreading listening to your Cousin Charlie's tall tales of his fishing expeditions because he exaggerates his catches. He has an uncanny way of cornering you for what feels like hours without an apparent exit. As much as you try to focus on his crazy stories, you find yourself rolling your eyes, crossing your arms or looking away which tends to hurt his feelings. You want to appear interested even though you don't care to know the difference between a trout and a flounder. How do you solve?vel the playing field by physically getting up from the table and standing next to him. By standing up, you send the message that you're a contender and you're putting him on notice. You shift your power by looking at him at eye level. This simple moves changes the energy of the conversation.
"Fake It Until You Can Take It" solution: Feigning interest starts with the eyes. Imagine an upside down triangle with the base of the triangle across the eyebrow line with the tip of the nose being the tip of the triangle. While looking at Cousin Charlie adjust your focus anywhere within the upside down triangle. If you must look away, look down as it's a natural break in eye contact. Periodically, tilt your head slightly to one side and nod. Nodding is a nonverbal sign of listening. Cousin Charlie will appreciate your attention and won't realize that you're planning your get-away.
With these clever body language secrets you can bring back the H-O-L-L-Y into your D-A-Y-S.
The original version of this article was published under the title: Home for the Holidaze at four hens and a rooster.


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It takes a special kind of person to become a true marksman, and an even greater person to become a hit man. You must not only be an amazing shot and have lightning fast trigger fingers, but you must be able to adapt to any situation and think outside the box to turn any environment into an advantage for your benefit.
In Ricochet Kills 3, the third installment by Coolbuddy you will don the black trench coat and your mission is to take out every mafia looking dude you can see. They will all be pretty sharply dressed, as you'd expect from the Italians.
There are 70 levels to complete in this game and your trick shooting skills will be tested to the limit by some incredibly bouncy bullets. Use every geometry lesson that you ever attended to ricochet your ammo off of wooden boxes, metal beams, and high explosives in this high octane-shooting rampage.
Your character, the silhouetted trench coat wearing marksman, will always stay in a single position on the screen and you will fire by clicking the left on you mouse pad. Move your mouse or cursor to take aim and point it where you want your bullet to start its path of madness. Keeping the single position helps you hone in on the exact area needed for the diamond shot of a lifetime.
You fire with a limited amount of bullets, as every good marksman only needs a few, so plans the trajectory of you bullet well before firing. After your bouncy bullet has made a few ricochets it will disappear so always go for the shortest path to destruction as possible. The more rounds that you fire will give you a lower score.
This game is very well put together and ricochet 3 is no exception. It's a worthy sequel to an already fun and addictive series.
Plays: 41085
Plays: 21454
Plays: 210857
Ricochet Kills 2: Players Pack
Plays: 66048
Plays: 188807
Plays: 57964
Plays: 98195
Plays: 8798


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Perth - Thousands of police flooded Perth on Thursday ahead of the Commonwealth Heads of Government Meeting, with swathes of the city declared "security areas" under new powers to clamp down on protests.Groups of police stand on virtually every street corner in the central business district, where Queen Elizabeth II will formally open the 54-nation grouping's three-day meeting on Friday.And F/A-18 Hornet fighters are patrolling the skies above the West Australian capital, where leaders from the mainly former British colonies will tackle issues ranging from reform to human rights.Most Commonwealth leaders are attending, although Indian Prime Minister Manmohan Singh has pulled out without giving a reason while Britain's David Cameron is arriving late so he can attend eurozone debt crisis talks.Authorities, determined that anti-capitalism demonstrators inspired by the Occupy Wall Street protests will not hijack the event, have given police special powers to deal with any protests.Under the new laws, police can search people at will and ban known activists from entering special zones, which have been barricaded and signposted.Police have not revealed the number of officers on duty but reports estimate about half the state's 6 000-strong force is involved in the operation, along with an additional 800 drafted in from New Zealand and elsewhere in Australia."We won't be disclosing exactly how many police officers are going to be in and around venues... but there will be a large police presence," said West Australian Police Deputy Commissioner Chris Dawson.Protests so far have been small, with about 40 people peacefully standing vigil on Tuesday night outside a venue where Prime Minister Julia Gillard was giving a speech.Planned march The major potential flashpoint is a march planned by the CHOGM Action Network on Friday, in solidarity with the global Occupy movement against corporate greed and the growing rich-poor divide.The network is also concerned about alleged human rights violations in Commonwealth countries, accusing Sri Lankan President Mahendra Rajapakse and Rwandan leader Paul Kagame of war crimes.Spokesperson Alex Bainbridge said the demonstrators planned to occupy the city centre's Forrest Place for three days but West Australian Premier Colin Barnett said police would not allow that to happen."If they're just sitting there quietly with a couple of banners, that's OK," Barnet told reporters this week. "[But] people won't be setting up camps."If they disrupt the public they will be removed, but that decision will be made on the spot by the senior police."Opposition lawmaker Peter Tinley, a former member of the elite SAS special forces unit, said sending F/A-18 fighter jets to patrol Perth's skies was a show of force designed to intimidate protesters."It is often seen as important that you have an overt show of security. Nothing reinforces that impression more strongly than having a bunch of F/A-18s flying over your city," he told the West Australian newspaper.There have been a handful of arrests so far, including two men caught sticking up posters for a demonstration planned for Friday and an environmental activist who said he unwittingly entered the security area after being banned."I think it's a bit silly. I'm not a violent person, I've never endorsed violence," the activist Sean Gransch told reporters. He faces up to a year in jail for breaching the exclusion order.
[ SOS ] Complaint about Human Rights Violations by IBM China on Centennial
[ Editorial ] How Much IBM Can Get Away with is the Responsibility of the Media
Tragedy of Labor Rights Repression in IBM China
IBM detained mother of ex-employee on the day of centennial


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can i have sex with this? its just so awesome!!! and SEXY!
dam ive been using this awesome thing for past 2hours and you know what I LIKE IT.and much love to person that made this (in a non gay way)
This thing owns many thanks
Anakin1121 (05-27-2010),NOOB (06-21-2011)
Last edited by Perturabo; 05-25-2010 at 08:26 PM.
ArchNemesis (05-26-2010),NOOB (06-21-2011)
War3z, i wanna do some nasty things to you (no homo!) just because your that awesome. You are the apple in my eye. But anyways, i had trouble at first, but turned down my sensitivity and then it was all good. THanks so much now i can sniper like a beast!
Originally Posted by VindictusModsOriginally Posted by sd333221
Aimbot is a lil too fast other one is recommended if you don't wann get called " hax "
On another note: If you guys have questions about this hack, please read the previous release thread, it has a bunch of useful information in there!
we are all lucky that people make this hacks and make it public, and thanks war3zdude, i'mma wait till your next hack release, and till your ban is lifted.
Is there a way to make the hack work and still play in full screen? 0_0
NOOB (06-21-2011),tylerawarren550 (05-25-2010)
how the heck do you take of those aim lines?


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Getting around Chicago via public transportation is easier than many large cities in my opinion! There is a blue line "L" that takes you directly from O'Hare airport into the Loop or from Midway, the Orange Line "L" also takes you into the loop. For full information, check out this great CTA map
Even better, we have a bus tracking system which traces buses online or via GPS on your mobile phone (app and data package required).
Otherwise, taxi's are plenty in the city! There is currently a fuel surcharge of $1.00 and there is a $0.50 extra charge for each additional person in the cab.
Should you be so lucky – you may encounter Chicago's CASH CAB!
Whether you like it or not, Chicago is a BIG DRINKING TOWN. There are $1 beer specials every night or there is a 1/2 price wine special every other block. The other thing to note is the number of bars there are in Chicago. There is LITERALLY a watering hole of somekind on every other corner! See the whole list!
Ok – so we're pretty family oriented too. I devised a list that may be of interest to families looking for baby/toddler friendly places where the parents can focus on the quality of food! check out this blog entry about the Mag Mile and hanging with kids.
Wine – Higher end restaurants usually have a sommelier, especially if they are Michelin Star rated. 2010 was the inaugural year for Chicago to enter the Michelin Guide
Beer – there are some fantastic brew pubs in Chicago offering a large selection of local microbrews. Also one of my favorite stores with a great selection of cold beer is LUSH (they have 3 locations in the city)
BYOB – there are a TON of BYOB selections in Chicago – Check out The BYOB guide of Chicago
Tipping in Chicago
In this big city – the average tip is 18.2% of the food bill before taxes. Many people from Europe or even Canada always complain how high the tip is. As I am originally from Canada, I understand where they are coming from (the average tip there is about 12%) but keep in mind that most restaurant workers in the US are not covered by a socialized medical plan or even a company medical plan for that matter; should they have an emergency, your server likely pays out of their own pocket. At least that is how I justify giving a larger tip.
City Dining
There is often a robust crowd of both young and old in Chicago – people of all backgrounds flock to the restaurants and reservations are often recommended. You can use OpenTable.com to make reservations but still doesn't guarantee that you'll be seated right away. The busiest dinning times are between 7-10pm.
Suburban Dining
Suburbanites dine early. And usually the crowd is older. The younger ones tend to flock to the pubs or are home with their young family. This is an observation I have made in the last year of living in the burbs…correct me if I am wrong!
There is no smoking in any establishments in Illinois to my knowledge.
Where to Stay
We get this question alot. For obvious reasons, anywhere downtown is a good choice as the transit system is economical and fairly decent but you pay for it. The average hotel room in Chicago during the summer is upwards of $250.00. You could stay near the airport but you may spend 45-50 mins each way coming into the city and back. You could try Craigslist and VRBO- it is my hope that most people are honest on there and I've had friends visiting who have had great success finding a place to stay.


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Madison Julius Cawein
The Dream Child - Poem by Madison Julius Cawein
There is a place (I know it well)
Where beech trees crowd into a gloom,
And where a twinkling woodland well
Flings from a rock a rippling plume,
And, like a Faun beneath a spell,
The silence breathes of beam and bloom.
And here it was I met with her,
The child I never hoped to see,
Who long had been heart's-comforter,
And soul's-companion unto me,
Telling me oft of myths that were,
And of far faerylands to-be.
She stood there smiling by the pool,
The cascade made below the rocks;
Innocent, naked, beautiful,
The frail gerardia in her locks,
A flower, elfin-sweet and cool,
Freckled as faery four-o -clocks.
Her eyes were rain-bright; and her hair
An amber gleam like that which tips
The golden leaves when Fall comes fair;
And twin red berries were her lips;
Her beauty, pure and young and bare,
Shone like a star from breasts to hips.
Oft had I seen her thus, of old,
In dreams, where she played many parts:
A form, possessing in its mold
The high perfection of all Arts,
With all the hopes to which men hold,
And loves for which they break their hearts.
And she was mine. Within her face
I read' her soul. . . . Then, while she smiled,
A sudden wind swept through the place
And she was gone. My heart beat wild;
The leaves shook and, behold, no trace
Was there of her, the faery child.
Only a ray of gold that hung
Above the water; and a bough,
Rain-bright and berried, low that swung:
Yet, in my heart of hearts, somehow,
I felt (I need not search among
The trees) that she was hiding now.
Comments about The Dream Child by Madison Julius Cawein
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text:
Published on February 7, 2008
Author: Rebecca
Source: authorstream.com
Acknowledgement Systems: Acknowledgement Systems Lorie Spanjers Alliance Trainer, AEA 8 Carol Bauer PBS Trainers, AEA 8 Outcomes for this Session: Outcomes for this Session Understand the rationale for developing a school-wide acknowledgement system Identify guidelines for developing an effective school-wide acknowledgement system Understand factors that cause staff members to balk at use of positive rewards/reinforcers Identify ways to encourage the use of positive rewards/reinforcers in classrooms & schools Evidence-based features of SW-PBS: Evidence-based features of SW-PBS Prevention Define and teach positive social expectations Acknowledge positive behavior Arrange consistent consequences for problem behavior On-going collection and use of data for decision-making Continuum of intensive, individual interventions Administrative leadership – Team-based implementation (systems that support effective practices) Slide 4: Primary Prevention: School-/Classroom- Wide Systems for All Students, Staff, & Settings Secondary Prevention: Specialized Group Systems for Students with At-Risk Behavior Tertiary Prevention: Specialized Individualized Systems for Students with High-Risk Behavior ~80% of Students ~15% ~5% CONTINUUM OF SCHOOL-WIDE INSTRUCTIONAL & POSITIVE BEHAVIOR SUPPORT School-wide Acknowledgement Systems: Rationale: School-wide Acknowledgement Systems: Rationale Focuses staff and student attention on desired behaviors Increases the likelihood that desired behaviors will be repeated Fosters a positive school climate Reduces the need for time consuming disciplinary measures, increasing student time on-task Social & academic behaviors/skills are learned and taught in the same manner.: Social & academic behaviors/skills are learned and taught in the same manner. New behaviors are taught by explanation, modeling, practice, & feedback New behaviors become durable with practice & feedback Behaviors become useful when effective & relevant Correct behaviors are taught & strengthened to replace error behaviors School-wide Acknowledgement Systems: Guidelines: School-wide Acknowledgement Systems: Guidelines Keep it simple The system should be for all students Make sure that rewards reflect the interests of the students (ask them!) Students should be eligible to earn rewards throughout the day contingent upon appropriate behavior Increase reinforcement before difficult times Deliver reinforcement unpredictably (you never know when you will get a surprise!) – but consistently Refrain from using the loss of rewards as a strategy for motivating desired behaviors…earned = kept School-wide Acknowledgement Systems: Guidelines: School-wide Acknowledgement Systems: Guidelines Provide staff with opportunities to recognize students in common areas who are not in their classes Encourage staff to reinforce students and students to earn the rewards Share data with staff Teach principles of reinforcement Principles of Reinforcement: Why Use Positive Reinforcement?: Principles of Reinforcement: Why Use Positive Reinforcement? Effective and evidence-based Teaches new skills Punishment alone is ineffective Leads to long term/lasting change Motivates and engages youth, staff and families More positive environment Reinforcement: Consequence events influence likelihood of future behavior occurrences: Reinforcement: Consequence events influence likelihood of future behavior occurrences Behaviors that are followed by Pleasing/reinforcing events are more likely to occur in future Aversive/punishing events are less likely to occur in future Most people find common consequence outcomes, objects, & events to be pleasing/reinforcing E.g., money, social contact, smiles, applause, recreation, escape or avoidance of tedious task, food, praise, academic/vocational success Slide 11: Most individuals find both external & internal events to be pleasing/reinforcing E.g., positive self-statements, relief from discomfort, hunger satisfaction, tension release, etc. Some people require more (or less) externally-provided pleasing/reinforcing events to maintain their efforts Reinforcement Reinforcers are acquired, take many forms, & are individually effective: Reinforcers are acquired, take many forms, & are individually effective Most social & tangible objects & events are initially neutral but become reinforcing/rewarding by being associated with other already reinforcing/rewarding objects & events Reinforcers can be any object or event "What is reinforcing/rewarding/pleasing" is affected by learning history, culture, community, etc. Activity: Activity Individually, look over the handout for Activity One at the back of your packet. Identify personal reinforcers for the activities listed. Share with members of your group. Formal & frequent use of positive rewards/reinforcers for appropriate student behavior contributes to development of environments that are described as positive, caring, safe, facilitating, etc.: Formal & frequent use of positive rewards/reinforcers for appropriate student behavior contributes to development of environments that are described as positive, caring, safe, facilitating, etc. Incentives: You were seen Exhibiting Dexter PRIDE This entitles you to a "Leave 5 minutes early for breakfast pass". ____________________________ Given by ____________________________ Incentives You have exhibited exemplary Dexter PRIDE This entitles you to a "Free Car Wash". See Mr. Gomez to set up an appointment ____________________________ Given by ____________________________ Dexter High School: Dexter, NM Slide 16: Incentives Slide 19: Student's Name__________ observer's initials Parent's Signature _______________ Date______ This student was noticed being: (mark all that apply) C a r e s considerate accountable respectful enthusiastic safe White Mt. Intermediate: Ruidoso, NM Slide 20: Rewards and Prizes Weekly drawings- Parent Council donates popcorn to be given to a winning student from each class. Teachers have option of having additional weekly drawings. Monthly drawing for a winner from each class to attend pizza party with the principal. Each 9 weeks a drawing for 2 winning students (one per grade level) to take his or her family to dinner at a local restaurant. White Mt. Intermediate: Ruidoso, NM Slide 21: P.A.W.S. Rewards Program was caught following the P.A.W.S. guidelines. P = Please listen A = Always be prepared W = Work/act responsibly S =Show respect Caught by: 2 tickets: candy treat first in line for lunch 10 tickets: 15 min. computer time lunch with an adult video for the weekend earn back Wolverine letter 50 tickets (whole class): popcorn party extra 30 minute recess 30 minute video School Example : School Example Tickets given out by all staff to students found meeting school-wide expectations When a student is observed following the school-wide expectation, circle it on the buck and acknowledge the student for the appropriate behavior observed Write the students name on the buck Sign and date the buck in order to prevent theft Only BLUE BUCKS are given by substitute teachers and are worth two points Bucks should not be taken away from students once they are earned Slide 23: 1st in line for lunch (gets to leave class 2 minutes early) Free pop Snack from vending machine Open Campus for you and a friend for lunch (with parent signatures) Free entry to a home sporting event Preferred parking for a week Cougar Traits t-shirt Cougar Traits Lanyard Free homework assignment (not on a major project or test) Free piece of pizza from Casey's (donated ½) Free video rental (donated by local store) Free gas from Casey's (we purchased in 2.00 coupons) Percentage off a haircut or product at local salons (donated) Prizes for Weekly Drawings Sample Secondary Rewards: Sample Secondary Rewards Business Donations for Monthly Raffle 10 minutes early to lunch Duffle Bags with School Logo Hamburger Cook Out with Karaoke Every Year a One Day Workshop designated to improve student character & Life Skills Webster City Middle School: Webster City Middle School How Low Can You Go?Webster City High School: How Low Can You Go?Webster City High School Additional School Examples: Additional School Examples "A, B, C" dances each grading period School bucks to use in a school store on a regular basis (weekly) "Caught Being Good" certificates Weekly lottery drawings Positive parent telephone contacts Positive office referrals Coupons (homework, tardy, athletic event ticket) Cougar Traits in the Community Student Name __________________________________Displayed the Cougar Trait of: RespectResponsibilityCaringCitizenship(Circle the trait you observed)Signature _____________________________________________If you would like to write on the back the details of what you observed feel free! Thank you for supporting our youth.: Cougar Traits in the Community Student Name __________________________________Displayed the Cougar Trait of: RespectResponsibilityCaringCitizenship(Circle the trait you observed)Signature _____________________________________________If you would like to write on the back the details of what you observed feel free! Thank you for supporting our youth. Slide 29: To build staff moral we began recognizing the positive things we were seeing among the adults in our building. Staff Examples: Staff Examples Team Action Planning: Acknowledgement System: Team Action Planning: Acknowledgement System What is your acknowledgement system? How frequently does it occur? Are you using verbal reinforcement? Is it consistent? Is it visible (do all staff, students, family know what it is and how it works)? Is it accessible to all? Use Activity Two Handout to review or generate ideas for your team's Acknowledgement System action plan. Consider: Why do educators rebel at use of positive acknowledgements (misrules)?: Why do educators rebel at use of positive acknowledgements (misrules)? Use of extrinsic rewards will inhibit development of intrinsic motivation. Students don't need rewards & acknowledgements to do what's right. A strong, aversive natural consequence will get the message across. Give them time, & maturity will kick in. If they can't do it on their own, they shouldn't be in this course. Why do educators rebel (continued): Why do educators rebel (continued) Any students who need me to tell them what's right and wrong aren't going to make it my class. I teach biology. I don't and shouldn't have to teach respect and responsibility. It's obvious to me, just look at her family. When I was his age, I had to do it all on my own….no breaks & privileges in my class. Are Rewards Dangerous?: Are Rewards Dangerous? "…our research team has conducted a series of reviews and analysis of (the reward) literature; our conclusion is that there is no inherent negative property of reward. Our analyses indicate that the argument against the use of rewards is an overgeneralization based on a narrow set of circumstances." Judy Cameron, 2002 "…programs that show increased intrinsic motivation are those programs that incorporate the elements of good, comprehensive behavioral intervention…" Akin-Little, Little, Eckert, & Lovett, 2004 "The undermining effect of extrinsic reward on intrinsic motivation remains unproven" Steven Reiss, 2005 "What the Worlds Greatest Managers Do Differently" -- Buckingham & Coffman 2002, Gallup Interviews with 1 million workers, 80,000 managers, in 40 companies. : "What the Worlds Greatest Managers Do Differently" -- Buckingham & Coffman 2002, Gallup Interviews with 1 million workers, 80,000 managers, in 40 companies. Create working environments where employees: Know what is expected Have the materials and equipment to do the job correctly Receive recognition each week for good work Have a supervisor who cares, and pays attention Receive encouragement to contribute and improve Can identify a person at work who is a "best friend" Feel the mission of the organization makes them feel like their jobs are important See the people around them committed to doing a good job Feel like they are learning new things (getting better) Have the opportunity to do their job well Create learning environments where students:: Create learning environments where students: Know what is expected Have the materials and equipment to do the job correctly Receive recognition each week for good work Have a teacher who cares, and pays attention Receive encouragement to contribute and improve Can identify a person at school who is a "best friend" Feel the mission of the school makes them feel like their jobs are important See the people around them committed to doing a good job Feel like they are learning new things (getting better) Have the opportunity to do their job well Team Activity:: Team Activity: Working as a team, take turns asking and answering the questions on the Activity Three handout (i.e., one team member reads a question and another answers it- then switch roles!) Keep a quick pace. After reading and answering a question, members can respond with a short statement if desired. Remember to keep responses brief and keep moving! When you have finished, take 5 minutes as a group and discuss your responses to the information presented. School-wide Acknowledgement Systems: Challenges: School-wide Acknowledgement Systems: Challenges Remaining focused on the positive Providing meaningful rewards Maintaining consistency with all staff Tracking your reward system Keeping it interesting & exciting Remembering that what reinforces one student will not necessarily work for others School-wide Acknowledgement Systems: Solutions: School-wide Acknowledgement Systems: Solutions Keep ratios of reinforcement to correction high (5:1 minimum) Gather input from students Train staff on use of rewards and review often Develop data-based system for monitoring and documenting appropriate behaviors Use reward "menus" so students can gain preferred options
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AcknowledgementSyst Mar2007; UniversalTrainingAug2011-Day2; UniversalTraining-March2011-Day2; Horner Start up Challenges; Start up Challenges ...
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