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Dr. Burke is Anna O. Stake Professor of Psychiatry and Vice Chair for Research in the Department of Psychiatry, Dr. Padala is assistant professor in the Department of Psychiatry, and Dr. Murman is associate professor in the Department of Neurological Sciences, all at the University of Nebraska Medical Center in Omaha.
Disclosure: Dr. Burke receives grant support from Eli Lilly, Forest, the National Institute of Mental Health, and Novartis. Dr. Padala receives grant support from the Alzheimer's Association and the Veterans Health Administration, and is on the speaker's bureau of Forest. Dr. Murman is a consultant to Elan Pharmaceutucals, Inc, and receives grant support from Elan Pharmaceuticals, Inc, and Wyeth.
Off-label disclosure: This article includes discussion of unapproved/investigational treatments for Alzheimer's disease.
Please direct all correspondence to: William J. Burke, MD, Vice Chair for Research, Department of Psychiatry, University of Nebraska Medical Center, 985580 Nebraska Medical Center, Omaha, NE 68198-5580; Tel: 402-552-6062; Fax: 402-552-6247; E-Mail: email@example.com.
Focus Points
• Accumulation of β-amyloid protein (Aβ) is a key neuropathologic feature of Alzheimer's disease.
• Considerable progress has been made in understanding how Aβ is generated and what steps lead to its accumulation.
• Numerous strategies have subsequently been developed targeted at either preventing the accumulation of Aβ or removing it once it is already present.
• The degree of success of these Aβ-targeted therapies will tell us a great deal about the role of Aβ in Alzheimer's disease and whether targeting Aβ will produce clinically relevant treatment.
Accumulation of β-amyloid protein (Aβ) in the brain is one of the key neuropathologic features of Alzheimer's disease. While current understanding of how Aβ is generated has grown there is still no approved treatment available that either prevents its formation or removes it from the brain. However, numerous treatment strategies are being tested that are aimed at each step of the amyloid pathway—from its initial liberation, to its early aggregation, and finally to the eventual formation of insoluble β-pleated sheets. Today, Aβ is the most accessible therapeutic target available for Alzheimer's disease. In the process of developing treatments based on Aβ modification, there is a great deal to learn not only about Alzheimer's disease but also about the normal function of the brain. This article discusses the current status of various strategies aimed at reducing amyloid burden in the brain.
Alzheimer's disease is the leading cause of dementia in the elderly. Prevalence estimates of Alzheimer's disease in the United States range from 5.7% to 10% among people 65–85 years of age and 25% to 45% in those ≥85 years of age.1 There are 5.2 million Americans with Alzheimer's disease in the US.
While the clinical diagnosis of Alzheimer's disease depends on recognition of typical cognitive deficits and behavioral disturbances, the neuropathologic hallmarks of the disease depend on detection of intra-cellular neurofibrillary tangles and extra-cellular amyloid plaques in the brain.2 The "amyloid hypothesis" is the most widely embraced theory for the causation of Alzheimer's disease and posits that the deposition of amyloid is an early crucial event that in turn leads to a cascade of other neuropathologic changes that culminate in the final full-blown disease. An implication of this theory is that if amyloid could be somehow kept from forming or removed once in place, it might offer a specific treatment for the disease.
One of the keys to understanding the mystery of Alzheimer's disease is elucidating the role of β-amyloid protein (Aβ). In the last 25 years research have moved from the first identification of Aβ as a significant component of the senile plaque of patients with the disease to an advanced understanding of many of the basic metabolic pathways that control the production of this protein. This article briefly reviews the current status of Aβ as a diagnostic marker, discusses the current understanding of how Aβ is processed in the brain, and reviews the many potential therapeutic strategies focused on reducing or preventing the accumulation of Aβ in the brain.
The Place of Amyloid in Alzheimer Disease
The ultimate diagnosis of Alzheimer's disease is based on neuropathologic criteria, with the accumulation of excessive Aβ being one of the key features. These criteria depend in part on such factors as the age-adjusted density of certain types of amyloid-containing plaques (neuritic vs. diffuse) in specific sampled brain areas.3-5 However, even though the quantification of Aβ plays a crucial role in diagnosis, Aβ accumulation in general is not specific since plaques are also seen in apparently normal aging. In fact, there is only a modest correlation between the amount of accumulated Aβ and the degree of cognitive impairment present in the individual case.6,7 Aβ also accumulates in the walls of arteries and arterioles in the leptomeninges and cerebral cortex as cerebral amyloid angiopathy (CAA) in both Alzheimer's disease and with aging.8
The strongest evidence that Aβ plays a key pathologic role in the disease process is based on the rare familial cases of Alzheimer's disease.9-13 The three identified genes that produce early-onset, autosomal dominant Alzheimer's disease each result in a significant increase in Aβ production. In addition, patients with Down syndrome have an extra copy of the amyloid precursor protein (APP) gene on chromosome 21 and very commonly have Alzheimer's disease-like changes in the brain with advancing age. In these cases, overproduction of amyloid or abnormalities in its processing seem sufficient to cause the dementia syndrome. However, the role that amyloid plays in typical late-onset Alzheimer's disease is much less clear.
The uncertain role of amyloid in common, late-onset Alzheimer's disease is highlighted by reports of the presence of amyloid in the brains of cognitively intact individuals. It has been appreciated for some time that there exist a group of individuals who are cognitively intact at the time of autopsy, despite high levels of Aβ in their brains.14 Similarly, the emergence of compounds such as Pittsburgh Compound-B (PIB), which binds to fibrillar Aβ deposits in plaques and to amyloid angiopathy,15-17 have allowed the detection of amyloid in vivo. Studies have shown the presence of Aβ not only in the brains of those with a clinical diagnosis of Alzheimer's disease but also in normal controls.15,18-20
The presence of amyloid in the brains of these patients without dementia implies either that amyloid can be present in normal patients without apparent cognitive impact or that it is present in people who have pre-clinical Alzheimer's disease. Long-term follow up of these cognitively normal, PIB+ people will be necessary to resolve this dilemma.20 While the interpretation of these findings is currently being debated, it is clear that the presence of Aβ, even if necessary, does not appear sufficient to have a simple, immediate causative role.
On balance, however, Aβ remains the most accessible therapeutic target currently available. Given the enormous attention that Aβ has been given, it is not surprising that there are numerous approaches to disease management underway. This article discusses a number of these approaches and how they purport to address the amyloid hypothesis (Table).
Formation of Aβ
Aβ is the end product of two sequential enzymatic cleavages of the integral membrane protein, APP (Figure).21,22 The generation of Aβ from APP occurs through the action of the enzymes β-secretase and γ-secretase. APP must first be processed by the β-secretase BACE (or BACE1, β site APP-cleaving enzyme) located on the extracellular side of APP, 28 residues from the membrane spanning region of APP. The next step in liberating Aβ is the action of the γ-secretase enzyme complex which contains four integral membrane proteins (one of which is presenilin). The known causes of familial Alzheimer's disease are the result of mutation in APP or one of two presenilin genes.13 The end product of all known mutations leading to familial Alzheimer's disease is an increase in the production of Aβ1-42. Altering the activity of β- and γ-secretase with the goal of reducing the formation of Aβ is therefore an attractive target for drug development.
Therapeutic Strategies Aimed at Reducing or Eliminating Aβ Immunotherapy
One the most fascinating approaches to eliminating excess Aβ in the brain of those with Alzheimer's disease is the attempt to do so by use of vaccines directed against Aβ or its components. This work began with the demonstration that human aggregated Aβ42 (AN1792) delivered to transgenic mice was effective in reducing cerebral Aβ plaque burden.23 This success led to the first human trial of AN1792 (with adjuvant) in 80 patients in the United Kingdom who had mild to moderate Alzheimer's disease.24 Fifty-nine percent of the immunized patients developed antibodies against Aβ and adverse events were felt to be acceptable, though one patient developed meningoencephalitis that was diagnosed after death and 219 days after discontinuing from the study.24 A second trial was suspended early in its course when approximately 6% of participants developed meningoencephalitis.25 Given the early interruption of this trial, only limited follow-up of this cohort has been possible; however, after 1 year 19.7% of the subjects had developed the predetermined antibody response.26 These individuals did not differ from the non-responders on several standard measures of cognition, function, or global change but did perform better on a composite neuropsychological test battery. In addition, responders unexpectedly had greater brain volume loss on magnetic resonance imaging than non-responders.27 A variety of possible reasons for this volume loss have been proposed, including volume reduction due to removal of amyloid plaques, fluid shifts of cerebrospinal fluid associated with amyloid mobilization, or even loss of neurons.27 While any of these mechanisms could in part explain the volume loss, it is clear that substantial removal of amyloid did occur in some of these patients at long-term follow-up.
A 6-year follow-up of eight participants from this trial who were immunized and who were examined neuropathologically revealed that cortical Aβ loads were lower than in an unimmunized control group.28 The degree of plaque removal varied significantly with the mean antibody response attained during the treatment study period. Seven of the eight subjects had severe end-stage dementia at the time of death, including those with virtually complete plaque removal. Overall, there was no evidence of improved survival or time to severe dementia in the immunized group. While these results come from only a very small sample they demonstrate that immunization can lead to amyloid clearance but do not suggest that such clearance is clinically beneficial.
A recent analysis29 of the cerebral vasculature of these same patients has revealed a striking increase in the number of blood vessels containing Aβ42 in the cerebral cortex and leptomeninges (14- and 7-fold increase, respectively) compared to an unimmunized control group of patients with Alzheimer's disease. Furthermore, in the patients who lived longest after immunization, there was a complete lack of CAA, mirroring the absence of plaques noted above. The authors suggest these findings support the hypothesis that Aβ immunization cause plaque Aβ42 to become soluble and then transit, at least in part, through the vessels of the central nervous system, resulting in a transient increase in CAA. These changes were associated with cortical microhemorrhages and microvascular lesion but not with CAA-related intracerebral hemorrages.29
One issue raised by these results is the timing and sequencing of the many neuropathologic processes that occur during the course of Alzheimer's disease. It has been proposed that the toxic effects of Aβ are an early event in the pathophysiology of Alzheimer's disease and once other neurodegenerative processes are initiated they may proceed even if Aβ is removed at a later point in time. This result makes the outcomes of ongoing immunotherapy critically important in order to determine if the overall approach will lead to meaningful response.
Given that the amyloid clearance induced by the AN1792 vaccine was felt to be due to antibody-based immunity while the cases of meningoencephalitis were thought to be due to cell-mediated immunity, another approach that is under active investigation is the use of monoclonal antibodies directed against Aβ ("passive immunization"). Passive immunization has several advantages compared to active immunization, including that monoclonal antibodies can be engineered to bind to Aβ at specific sites to limit activation of cell-mediated immunity, that the quantity of antibodies delivered to patients can be standardized and regulated, and that the infusion of antibodies can be stopped if side effects arise.
Bapineuzumab is a humanized monoclonal anti-Aβ antibody currently in phase 3 trials. Results of a 234 patient phase II trial30 presented at the International Conference on Alzheimer's Disease in 2008 were negative on pre-specified endpoints. However, in post-hoc analyses there was evidence of a statistically significant benefit in those patients who completed the trial and received all six planned injections as well as in the 33% of patients who lacked the ApoE4 allele ("noncarriers"). Twelve patients developed vasogenic edema, all in the treatment group and all of which resolved (one patient received steroid treatment). Ten of 12 patients with vasogenic edema were ApoE4 carriers and eight of the 12 were at the highest dose of the monoclonal antibody.31 Vasogenic edema can be detected on MRI as high-signal white matter intensities on fluid-attenuated inversion recovery sequences. The mechanism by which vasogenic edema occurred in these cases is not yet fully understood though changes in vascular permeability (ie, increased brain capillary permeability) associated with antibody-antigen interactions seem plausible. Vasogenic edema is often asymptomatic or can be associated with transient symptoms such as increased confusion, lethargy, headache, and dizziness. The MRI changes of vasogenic edema have universally resolved over time with serial imaging. Phase III trials are being conducted in ApoE4 subgroups separately, using the lower doses tested in the Phase II trials, especially in the ApoE4 carriers, to limit the risk of the development of vasogenic edema.
Another variation of immunotherapy that has demonstrated some modest initial success is the use of intravenous immunoglobulin (IVIg), a pooled human IgG antibody preparation that contains 90% of all IgGs and IgG subclasses.32 Among these antibodies are those that target Aβ. A small phase II trial33 with 24 patients with mild to moderate Alzheimer's disease has reported positive results at 9 months on the primary outcome measures and phase III trials are underway.
Preventing Formation of Fibrils
Considerable work has shown that not all forms of amyloid are equally toxic. As Aβ is generated from the processing of APP, it first exists in a soluble form that appears relatively non-toxic. It is when Aβ comes together to form oligomers (soluble aggregates of a few amyloid molecules joined together) on its way to fibrils that its toxicity first becomes manifest. Thus, methods to prevent the fibrillization of Aβ into insoluble β-pleated sheets have also been examined. One compound that is purported to be an inhibitor of fibrillogenesis, tramiprosate (a modification of the amino acid taurine),34 failed to demonstrate any clinical benefit in phase III trials and is no longer under development as a drug, though the manufacturer has introduced homotaurine as a nutraceutical.35
Secretase Inhibition
Inhibition of BACE is an appealing strategy since APP appears to be its single substrate. Knockout mice lacking BACE do not have detectable levels of Aβ and yet do not appear adversely affected. These two facts taken together suggest that compounds targeted at BACE that lower Aβ might be tolerated over a clinical time frame.36 However, clinical trials have lagged because of problems with blood-brain barrier penetration and bioavailability of compounds targeted at BACE.
Targeting γ-secretase as an alternative is challenging for a variety of reasons, including the facts that the enzyme structure is far more complex than BACE and is also responsible for processing other important transmembrane proteins—including Notch, which plays a crucial role in cell differentiation in many organ systems.37 While numerous potent γ-secretase inhibitors have been identified, their specificity for APP cleavage has been variable and therefore affects these other substrates. Therefore, any inhibition targeted at this enzyme must either be highly specific for APP or less specific but sufficiently transient in duration of effect to reduce levels of Aβ while simultaneously allowing some residual physiologic Notch functioning. γ-secretase inhibitors have reached clinical trials and at least one agent has demonstrated reduced plasma levels of Aβ with seemingly acceptable tolerability.38 LY450139, a γ-secretase inhibitor now in phase III trials, reduced plasma Aβ40 and Aβ42 concentrations after 20 weeks in a phase II trial.38
Manipulation of the APP secretases is a rapidly evolving arena for research and it seems likely that numerous agents will be tested. Not only do such agents hold promise as possible treatments for Alzheimer's disease, but they will also provide additional clues as to the true value of Aβ as a target for therapeutics.
γ-Secretase Modulation
Given the potential problems involved with inhibiting γ-secretase, an alternative approach proposes to target the substrate, in this case the site on APP where γ-secretase acts, rather than directly targeting the enzyme.39 The intent is to administer a compound which blocks the cleavage site so that it is not available to γ-secretase, thereby preventing the formation of Aβ. Such compounds have been described as "molecular cloaking devices" and reflect a new approach to therapeutics.40 This mechanism was proposed as the mechanism of action of tarenflurbil, which was being explored as a selective amyloid-lowering agent for Alzheimer's disease.41 Modest benefits in a Phase II trial42 of tarenflurbil were not seen in an 18-month Phase III trial that failed to show efficacy on either primary endpoint.43 The compound is no longer in development though many other potential modulators may yet be tested.
Zinc- and Copper-based Therapies
The recognition that both copper and zinc play a role in the process by which soluble forms of Aβ form oligomers has led to trials of compounds that can inhibit this process. The toxic oligomers of Aβ are dimers and trimers formed from Aβ monomers. This process is mediated in part by zinc and copper, which have been reported to be in high concentrations around excitatory N-methyl-D-aspartate synapses.44-46 Clioquinol, and more recently PBT2, have been proposed as potential therapies based on their ability to complex with low affinity to metals without perturbing metal homeostasis.44 As such, these compounds attenuate metal-protein interactions without being metal "chelators."
PBT2 was recently tested in a 78-patient safety trial.44 Patients treated with 250 mg of PBT2 had a dose-dependent and significant reduction in CSF Aβ42 concentration compared to placebo. Subjects taking 250 mg of PBT2 also showed significant improvements in category fluency and trail making part B compared to placebo. No serious adverse events were reported in subjects taking PBT2. Larger trials will be conducted.
Aβ is the target of multiple strategies designed to treat patients with Alzheimer's disease. Although the trials of active immunization were terminated early due to safety issues, follow-up studies show benefit in clearing amyloid plaques. The promise of immunotherapy is being evaluated by clinical trials using passive immunization and IVIg. Secretase inhibition is an attractive strategy which is being aggressively pursued, while γ-secretase modulators and metal protein attenuating compounds are also being explored for their ability to reduce amyloid burden. A key issue that remains to be solved is the appropriate timing of these potential interventions. It may be possible that removing amyloid at the point where dementia can be diagnosed clinically may be too late. Interventions targeted at the pre-clinical state may be required and will await better diagnostics. In the meantime, amyloid remains an attractive target for therapeutic intervention. PP
1. Hebert LE, Scherr PA, Bienias JL, Bennett DA, Evans DA. Alzheimer disease in the US population: prevalence estimates using the 2000 census. Arch Neurol. 2003;60(8):1119-1122.
2. Perl DP. Neuropathology of alzheimer's disease and related disorders. Neurol Clin. 2000;18(4):847-864.
3. Mirra SS, Heyman A, McKeel D, et al. The consortium to establish a registry for alzheimer's disease (CERAD). part II. standardization of the neuropathologic assessment of alzheimer's disease. Neurology. 1991;41(4):479-486.
4. Newell KL, Hyman BT, Growdon JH, Hedley-Whyte ET. Application of the national institute on aging (NIA)-reagan institute criteria for the neuropathological diagnosis of alzheimer disease. J Neuropathol Exp Neurol. 1999;58(11):1147-1155.
5. Braak H, Braak E. Neuropathological stageing of alzheimer-related changes. Acta Neuropathol. 1991;82(4):239-259.
6. Braak H, Braak E. Evolution of neuronal changes in the course of alzheimer's disease. J Neural Transm Suppl. 1998;53:127-140.
7. Terry RD, Masliah E, Salmon DP, et al. Physical basis of cognitive alterations in alzheimer's disease: Synapse loss is the major correlate of cognitive impairment. Ann Neurol. 1991;30(4):572-580.
8. Thal DR, Griffin WS, de Vos RA, Ghebremedhin E. Cerebral amyloid angiopathy and its relationship to alzheimer's disease. Acta Neuropathol. 2008;115(6):599-609.
9. Goate A, Chartier-Harlin MC, Mullan M, et al. Segregation of a missense mutation in the amyloid precursor protein gene with familial alzheimer's disease. Nature. 1991;349(6311):704-706.
10. Levy-Lahad E, Wasco W, Poorkaj P, et al. Candidate gene for the chromosome 1 familial alzheimer's disease locus. Science. 1995;269(5226):973-977.
11. Rogaev EI, Sherrington R, Rogaeva EA, et al. Familial alzheimer's disease in kindreds with missense mutations in a gene on chromosome 1 related to the Alzheimer's disease type 3 gene. Nature. 1995;376(6543):775-778.
12. Sherrington R, Rogaev EI, Liang Y, et al. Cloning of a gene bearing missense mutations in early-onset familial alzheimer's disease. Nature. 1995;375(6534):754-760.
13. Hardy J, Selkoe DJ. The amyloid hypothesis of alzheimer's disease: progress and problems on the road to therapeutics. Science. 2002;297(5580):353-356.
14. Dickson DW, Crystal HA, Mattiace LA, et al. Identification of normal and pathological aging in prospectively studied nondemented elderly humans. Neurobiol Aging. 1992;13(1):179-189.
15. Klunk WE, Engler H, Nordberg A, et al. Imaging brain amyloid in alzheimer's disease with Pittsburgh compound-B. Ann Neurol. 2004;55(3):306-319.
16. Ikonomovic MD, Klunk WE, Abrahamson EE, et al. Post-mortem correlates of in vivo PiB-PET amyloid imaging in a typical case of alzheimer's disease. Brain. 2008;131(Pt 6):1630-1645.
17. Lockhart A, Lamb JR, Osredkar T, et al. PIB is a non-specific imaging marker of amyloid-beta (abeta) peptide-related cerebral amyloidosis. Brain. 2007;130(Pt 10):2607-2615.
18. Mintun MA, Larossa GN, Sheline YI, et al. [11C]PIB in a nondemented population: potential antecedent marker of Alzheimer disease. Neurology. 2006;67(3):446-452.
19. Rowe CC, Ng S, Ackermann U, et al. Imaging beta-amyloid burden in aging and dementia. Neurology. 2007;68(20):1718-1725.
20. Aizenstein HJ, Nebes RD, Saxton JA, et al. Frequent amyloid deposition without significant cognitive impairment among the elderly. Arch Neurol. 2008;65(11):1509-1517.
21. George-Hyslop PS, Rossor M. Alzheimer's disease. unravelling the disease process. Lancet. 2001;358(suppl):S1.
22. Bornebroek M, Kumar-Singh S. A novel drug target in alzheimer's disease. Lancet. 2004;364(9447):1738-1739.
23. Schenk D, Barbour R, Dunn W, et al. Immunization with amyloid-beta attenuates alzheimer-disease-like pathology in the PDAPP mouse. Nature. 1999;400(6740):173-177.
24. Bayer AJ, Bullock R, Jones RW, et al. Evaluation of the safety and immunogenicity of synthetic Abeta42 (AN1792) in patients with AD. Neurology. 2005;64(1):94-101.
25. Orgogozo JM, Gilman S, Dartigues JF, et al. Subacute meningoencephalitis in a subset of patients with AD after Abeta42 immunization. Neurology. 2003;61(1):46-54.
26. Gilman S, Koller M, Black RS, et al. Clinical effects of Abeta immunization (AN1792) in patients with AD in an interrupted trial. Neurology. 2005;64(9):1553-1562.
27. Fox NC, Black RS, Gilman S, et al. Effects of abeta immunization (AN1792) on MRI measures of cerebral volume in alzheimer disease. Neurology. 2005;64(9):1563-1572.
28. Holmes C, Boche D, Wilkinson D, et al. Long-term effects of Abeta42 immunisation in alzheimer's disease: Follow-up of a randomised, placebo-controlled phase I trial. Lancet. 2008;372(9634):216-223.
29. Boche D, Zotova E, Weller RO, et al. Consequence of Abeta immunization on the vasculature of human alzheimer's disease brain. Brain. 2008;131(pt 12):3299-3310.
30. Grundman M, Black R. Clinical trials of bapineuzumab, a beta-amyloid-targeted immunotherapy in patients with mild to moderate alzheimer's disease. Alzheimers Dement. 2008;4(4):T166.
31. Elan and Wyeth present encouraging results from phase 2 clinical trial of bapineuzumab at International Conference on Alzheimer's Disease. Available at: www.elan.com/News/full.asp?ID=1180940. Accessed April 27, 2009.
32. Relkin NR, Szabo P, Adamiak B, et al. 18-month study of intravenous immunoglobulin for treatment of mild alzheimer disease. Neurobiol Aging. Feb 20, 2008. [Epub ahead of print]
33. Tsakanikas D, Shah K, Flores C, Assuras S, Relkin N. Effects of uninterrrupted intravenous immunoglobulin treatment of alzheimer's disease for nine months. Alzheimers Dement. 2008;4(4):T776.
34. Aisen PS, Gauthier S, Vellas B, et al. Alzhemed: A potential treatment for alzheimer's disease. Curr Alzheimer Res. 2007;4(4):473-478.
35. VIVIMIND. Available at: www.bellushealth.com/en/newsroom/?rkey=1609028453&view=96347-2&Start=0. Accessed April 27, 2009.
36. John V. Human beta-secretase (BACE) and BACE inhibitors: progress report. Curr Top Med Chem. 2006;6(6):569-578.
37. Evin G, Sernee MF, Masters CL. Inhibition of gamma-secretase as a therapeutic intervention for alzheimer's disease: Prospects, limitations and strategies. CNS Drugs. 2006;20(5):351-372.
38. Fleisher AS, Raman R, Siemers ER, et al. Phase 2 safety trial targeting amyloid beta production with a gamma-secretase inhibitor in alzheimer disease. Arch Neurol. 2008;65(8):1031-1038.
39. Kukar TL, Ladd TB, Bann MA, et al. Substrate-targeting gamma-secretase modulators. Nature. 2008;453(7197):925-929.
40. Kodadek T. Biochemistry: molecular cloaking devices. Nature. 2008;453(7197):861-862.
41. Aisen PS. Tarenflurbil: a shot on goal. Lancet Neurol. 2008;7(6):468-469.
42. Wilcock GK, Black SE, Hendrix SB, et al. Efficacy and safety of tarenflurbil in mild to moderate alzheimer's disease: A randomised phase II trial. Lancet Neurol. 2008;7(6):483-493.
43. Green RC, Schneider LS, Hendrix SB, Zavitz K, Swabb E. Effects of uninterrrupted intravenous immunoglobulin treatment of alzheimer's disease for nine months. Alzheimers Dement. 2008;4(4):T165.
44. Lannfelt L, Blennow K, Zetterberg H, et al. Safety, efficacy, and biomarker findings of PBT2 in targeting abeta as a modifying therapy for alzheimer's disease: A phase IIa, double-blind, randomised, placebo-controlled trial. Lancet Neurol. 2008;7(9):779-786.
45. Lee JY, Cole TB, Palmiter RD, Suh SW, Koh JY. Contribution by synaptic zinc to the gender-disparate plaque formation in human swedish mutant APP transgenic mice. Proc Natl Acad Sci U S A. 2002;99(11):7705-7710.
46. Schlief ML, Craig AM, Gitlin JD. NMDA receptor activation mediates copper homeostasis in hippocampal neurons. J Neurosci. 2005;25(1):239-246.


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Our undergraduate major in parks and recreation management is accredited by the Council on Accreditation for Parks, Recreation, Tourism, and Related Professions (COAPRT). COAPRT is, in turn, accredited by the Council on Higher Education Accreditation (CHEA).
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Minister David Bennett has announced the opening of a competition open to Year 13 students around New Zealand. The competition is multi-media, and asks students to express through thier choice of media, why the Battle of Passchendaele is a significant event.
There is a speech writing category for Year 12 students. The winner of this will read thier speech at the Pukeahu National War Memorial Park in Wellington for the national commemorative ceremony.
Passchendaele is a significant event in New Zealand's First World War history - involving students so that the develop an understanding of the significance of the events that happened 100 years ago allows us to keep New Zealand's history alive.
More information about the competition is avalibe from Veterans' Affairs.


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DirecTV App Bringing NFL to iPhone
DirecTV's popular NFL Sunday Ticket package, which makes every NFL game available to customers nationwide, is coming to the iPhone, DirecTV announced Monday that the SuperCast Mobile application will be released soon, in time for the start of the new NFL season in September.
To use the app, Bloomberg News reported, customers will have to pay both the $280 subscription fee for the package and an extra $100 upgrade for the mobile version. The offer is good through July 31.
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I'm working on a post on circumcision, and would love to hear your thoughts and input on the topic. I know it's controversial, and that I'm totally opening a can of worms here, but I would honestly love to hear what you all think.
I have a VERY concrete opinion on the subject, and am going to share it soon, but if you feel like sharing, I'd be interested in whether you circumcised your son, why or why not, and how do you feel about it now?
You can either leave a comment here, or send me a message. I won't post anything that you send privately.
Thanks for your input!!!


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ACE AMERICAN INSURANCE COMPANY v. AMERICAN SPECTRUM REALTY, INC.
ATTENTION: It is possible that this information may no longer be current and therefore may be inaccurate. The index contains both open and closed cases and is not a complete list of cases in which an ACE Insurance Group company is involved. This information is provided to give interested persons an idea of the issues disputed in the indexed cases. For a full understanding of a case, one should read the rest of the court file, including the response. For the most up-to-date and complete information on a case, visit www.pacer.gov or contact the clerk of the relevant court.
"I. Plaintiff ACE American Insurance Company brings this action for declaratory relief pursuant to 28 U.S.C. §2201 et sea., seeking a judicial declaration that ACE has no further duty to indemnify its insured, American Spectrum Realty, Inc. ("Defendant" or "ASR") for loss and/or damage caused by or resulting from Hurricane Ike, and that all other duties and obligations of ACE under the insurance policy at issue have been satisfied and discharged."
"WHEREFORE, ACE American Insurance Company prays that this Court, upon trial hereof, declare the rights and obligations of ACE American Insurance Company under Policy No. MAU 3712994A, and award Plaintiff ACE American Insurance Company its reasonable and necessary attorneys' fees and expenses incurred in adjusting ASR's claim and for the prosecution of this declaratory judgment action, and such other and further relief to which Plaintiff ACE American Insurance Company may be entitled at law or in equity."
42. ACE incorporates by reference paragraphs 1 - 41 as though fully set forth at length.
43. Pursuant to 28 U.S.C. § 2201, ACE requests the Court declare that ACE has indemnified ASR under the Policy for all of the damages sustained at the Properties caused by or resulting from Hurricane Ike in accordance with the terms, conditions, exclusions, limitations, sublimits and endorsements set forth therein."
The provided text is an excerpt from a document filed in this case. For a full understanding of the case, one should read the complete court file, including the response.


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Barden Circulation does it all
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Some of the most common bone fracture types include: Transverse fracture. A transverse fracture occurs when a bone breaks at a 90-degree angle to the long axis of the bone. ... Oblique fracture. ... Comminuted fracture. ... Greenstick fracture. ... Stress fracture. ... Pathologic fracture.
Types of Dreams Daydreams. You spend an average of 70-120 minutes a day, daydreaming or fantasizing from a perspective that transcends normal perception. ... Lucid Dreams. Lucid dreams occur when you 'wake up' while dreaming. ... Nightmares. ... Recurring Dreams. ... Dreams About Healing. ... Prophetic Dreams. ... Life Changing Dreams.
Sand types Coral sand" Coral sand" has several meanings. Find out what it really is. Gypsum sand A rare sand type composed of gypsum grains. Ooid sand Ooids are rounded pellets formed in a shallow wave agitated water. Silica sand Silica sand is almost pure quartz. Black sand There are two types of black sand.
Here are six common parasomnias that afflict sleepers: Sleepwalking. More commonly seen in children, sleepwalking (also called somnambulism) affects about 4 percent of American adults. ... REM sleep behavior disorder. ... Nightmares. ... Night terrors. ... Nocturnal sleep-related eating disorder. ... Teeth grinding.
The most important sleep disorders are: Insomnia. Sleep apnea. Restless legs syndrome. Narcolepsy.
These types of disasters include: Tornadoes and Severe Storms. Hurricanes and Tropical Storms. Floods. Wildfires. Earthquakes. Drought.
A common way to classify hazards is by category:biological - bacteria, viruses, insects, plants, birds, animals, and humans, etc.,chemical - depends on the physical, chemical and toxic properties of the chemical,ergonomic - repetitive movements, improper set up of workstation, etc.,
Hurricanes and tropical storms. Landslides & debris flow. Thunderstorms and lighting. Tornadoes. Tsunamis. Wildfire. Winter and ice storms. Sinkholes.


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Welcome to New Year's Eve at The Stables Country Club! Expect an evening of sumptuous food, great live music and of course delicious drinks. Let our specialist bartender mixed your favourite cocktail , enjoy a sumptuous 5 course and then sit back and relax to the sound of our very talented crooner who will sing all your Rat Pack classics! Then it's time to see in the New Year with our resident DJ and dancing until late!
Arrive 7pm | Dinner 7.45pm | Dancing until 2am
Event Dates:
31 December 2017
Entry Fee:
Book Tickets For:
Menu PDF: Download menu PDF
Information PDF: Download event info PDF
We are terribly sorry but all available places at this event have been taken,
if you would like to enquire about alternative dates for this event or alternative events, please
go back to the previous page or call +44(0)845 450 1320


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Google can be picky at times, well, most times. Here are the first things to consider when wanting to get your page ranked at the top!
What is On-Site Optimization?
On-Site SEO, or on-page optimization, is the practice of making sure the hundreds of elements on your site are the way search engines prefer. Some of the elements are minor, some are major, but taking care of them all will ensure that engines like Google will be able to easily scan and index your website. on-page optimization is a mixture of content and code and keeping these things in check will help earn you a high rank.
The benefits of optimizing your website extend beyond ranking high, most of the guidelines laid out by Google also help users interact with your website. All of these components come together to make you site easily accessible by both users and indexes.
Plan Your Keyword Before you Begin
Research your competitors, often times they've already researched the market for you!
Use tools like SEMrush to gain SEO insights on your industry, and select the keywords and phrases you should be competing for.
Also remember that simply spamming your website with keywords won't get you the same results it used to! Google and Bing have gotten very advanced and are wise to such tricks. It may be even better to look at your keywords as key topics. Consider a topic and make content about the topic that's better than anyone else!
User Engagement
The longer a user is on a page with the content you're wanting to rank for, the more valuable the keywords on-page are to Google. That's right, not all Keywords are equal.
After learning about the keywords and topics you want to pursue, it's time to get back to business.
Choose a URL and a Good Structure moving Forward
URL structure plays a massive role in Search Engine Optimization. An ideal URL is simple and doesn't contain many numbers or symbols. Google wants users to be able to look at a URL and know where they're going with ease.
- www.TulsaStables.com/schedule.online/time#132request
- https://www.TulsaStables.com/carriage-ride/reserve
See the difference?
Looking at the two URLs you can see that one is https:// which means it's a secure site. Google punishes sites that aren't secure, it's a lot harder to rank if you don't have that S. Here's a guide on how to secure your site!
Next let's look at the actual site, TulsaStable is good, clearly it's a Stable here in Tulsa, Oklahoma, but, the bottom one is much easier for a user to understand that they are on a page to reserve a carriage ride. Google like clear and concise URLs that are easy to understand from a general user's perspective. Try to use as few words and keep numbers out of your URL.
Checking your Headers and Content
The Headers, especially your <h1>, are one of the first things google scans on your page! So make sure you place your keywords there.
Use smaller headers throughout your content with words related to the topic. This helps keep readers engaged and also let's Google know that the content is consistently on topic. For example this section has the header "Checking your Headers and Content", those aren't exactly words I want to rank for, but they are words related to SEO and on On-Site optimization.
You may think you have a brilliant idea, just use phrases that have keywords you want to rank for over and over again throughout your content. Well, Google will actually give you a slap on the wrist for that, that's called keyword stuffing. In fact, if you're writing enough content about your topic you may find it hard not to overuse the words you want to rank for!
Page Speed
What exactly is Page Speed
Believe it or not Page Speed isn't quite as simple as it sounds, you might think that Page Speed is how long it takes a page to load, but that's actually Page Load Speed, or maybe you think it's how fast your website is, nope, that's Site Speed. Now all three of these speeds are important for your ranking, but we should start with Page Speed.
Page Speed is how long it takes the first byte of data from the web server to reach the browser, and it's something you have the least control over. Check your Page Speed here, if it's slow you may need to contact your web host, or move hosts all together. Page Load Speed and Site Speed can be optimized by changing you site layout and code, but the speed of your server is dependent on the company hosting your website. If you're big on upcoming technologies, you might check out cloud hosting, there's even some speculation that using Google's Cloud Platform to host your website will give you a boost in the rankings.
What's Next
This is just the start of your journey to the top, Keywords, URL structure, and Page Speed are the first things to consider, but there's a whole world of SEO ahead of you, if you want a more in depth guide to Local SEO, we already made one!
Growing cities [like Tulsa] can be tough to rank in, the best thing you can do is keep in mind what SEO does for you and continue to learn, but we know not everyone has time to stay up on the latest trends. We'll keep making in depth posts on best practices for you, and if you decide you'd like some help feel free to reach out to us, we're currently accepting new clients. If you want to see our work in action, check out my business partner Levi's house cleaning tulsa business.
Do you have any local SEO tips?
Leave a comment down below and let me know if this guide was helpful.


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On the third day of the convention, I did a green and white sweet lolita style.
Sweet lolita is the most popular and well-known of the lolita styles.
Think Madame Alexander doll dresses on real girls.
Sweet, young, lacy and pretty.
I didn't need a pattern for the skirt. A simple circle skirt would do. But what about a top?
I looked through my stash of patterns and found this one from Simplicity -
I used a pretty mint green & white cotton to make the version shown in blue above.
I had some various white cottons at home, so I cut out a circle skirt the length of the petticoat I had purchased on line. I found some fabric made of alternating strips of lace and eyelet, so I made an under layer around the bottom. Then I pinned the top layer up in swags, sewed them in place and trimmed the whole thing with a green ribbon to match the sleeve bows.
Then I made an Alice bow out of the mint green fabric, some lace and the emerald green ribbon. Sewed it to a headband & voila!
Oh, I also wore my early 18th century reproduction shoes (the style is called "Pompadour") from American Duchess. They are painted green and white.
And I didn't even remember until a few days before that it would be St. Patrick's Day when I was planning on wearing it. Happy accident with the colors!
I got professional photos! I wore the outfit to Costume Con 31 this weekend and was able to get pics. (From FantaScenes Photography...great guys!)


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Spring Green Car & Motorcycle Show 2015 -March 28, 2015 in Lawrenceville, GA 10a to 4pm Gwinnett Count Fairgrounds http://southeastwheelsevents.com/events/new-lawrenceville-car-bike-...
www.SouthEastWheelsEvents.com has worked providing a car & motorcycle show for the Spring Green Festival in Lawrenceville for three years now! The car collector hobby has boomed in recent years and shows displaying these "moving works of art" fit so well with community festivals. If you ask anyone what is his or her favorite car, they often reflect on the first cars they remember, and the first car they could afford. As interest in collector cars has increased and the need for them in the movie industry grows, the hobby even becomes a way of investing as values rise!
There is something about old cars and motorcycles that captures most people, at least as observers. A good car show is a celebration and a party; often with good food and great music. I started the www.SouthEastWheelsEvents.com website primarily as a place for folks to find out what Car Shows were going on each week. It is a social network site where members are able to post up car, truck and motorcycle shows for free, as well as club meetings, races, cruises and any dated event involving transport vehicles. We get 60,000 views a month looking to see what is coming up in the hobby!
Soon, we were asked to help put on events for different communities and charity organizations. While it is difficult to make money as a business; doing car shows; they are a great opportunity to raise funds for community service programs and people in need. Working with Spring Green, we are able to help raise funds for the Heart Of Gwinnett and the local Habitat for Humanity. Spectators for the Car & Motorcycle Show get in free and participants enter their vehicle with a small fee, which goes to cover the prizes, trophies and charity contribution. The Spring Green show typically attracts 75 to 100 vehicles. Appointed Show Judges select the trophy winners; top twenty best vehicles, Best Car, Best Motorcycle and BEST IN SHOW!
We are excited about this year as we have a bigger site at the Gwinnett Fair Grounds and have included a collector car and motorcycle auction; courtesy of the Rolling Steel Auctions from the Four Season Auction Gallery in Alpharetta; www.FSAGallery.com. The Car and Motorcycle Show will run from 11am to 4pm and the Auction will start at 2pm. We hope to see you there!
Mike Thies 770-883-0160 email@example.com
Little Red (my 1956 Porsche Street Rod), Me and my brother, Dan
Views: 151
Join SOUTH EAST USA WHEELS EVENTS-Car and Motorcycle Events Calendar


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Free ShippingOn orders above BHD 20
Click & CollectOrder online and collect in store
Home DeliveryWithin 1-2 business days
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Buy it whenever you like from Favourites in your account.
Enhance your girl's outfits as you team them with this eye-catching pair of tights with a pattern all over. They are snug to wear owing to the closed feet styling and can be conveniently washed in the machine.
Juniors Closed Feet Tights - Set of 2
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|Upcoming Dates
|Class Times
|Class Format
|Call 855-798-3942 for Class Schedule
CISM - Certified Information Security Manager
While information has become more easily accessible and readily available, the associated risks and security threats have not only increased in number, but also complexity. As a result, the importance of ensuring that an enterprise's information is protected has also increased. It is now more important than ever for executives to ensure that their IT security managers have the expertise needed to reduce risk and protect the enterprise.
Designed specifically for information security professionals who are preparing to sit for the CISM exam, the course focuses on the four content areas of the Certified Information Security Manager (CISM) job practice: information security governance, risk management and compliance, information security program development and management, information security incident management.
CISM Impacts Your Career and Your Organization
The demand for skilled information security management professionals is on the rise, and the CISM certification is the globally accepted standard of achievement in this area.
CISMs understand the business. They know how to manage and adapt technology to their enterprise and industry.
CISM Certification:
- Demonstrates your understanding of the relationship between an information security program and broader business goals and objectives
- Distinguishes you as having not only information security expertise, but also knowledge and experience in the development and management of an information security program
- Puts you in an elite peer network
- Is considered essential to ongoing education, career progression and value delivery to enterprises.
Why Employers Hire CISMs?
Enterprises and government agencies increasingly recognize, require and expect their IS and IT professionals to hold CISM certification.
CISM employees:
- Identify critical issues and customize company-specific practices to support the governance of information and related technologies
- Bring credibility to the enterprise for which they are employed
- Take a comprehensive view of information systems security management and their relationship to organizational success
- Demonstrate to enterprise customers their commitment to compliance, security and integrity; ultimately contributing to the attraction and retention of customers
- Ensure that there is improved alignment between the organization's information security program and its broader goals and objectives
- Provide the enterprise with a certification for Information security management that is recognized by multinational clients and enterprises, lending credibility to the enterprise
This course prepares students to pass the ISACA CISM certification exam.
In order to be awarded the CISM designation, students must meet the following requirements:
- Successfully pass the CISM exam.
- Adhere to ISACA's Code of Professional Ethics.
- Agree to comply with the Continuing Education Policy.
- Work experience in the field of information security.
- Submit an Application for CISM Certification.
Course Outline
Information Security Governance
Students will understand the broad requirements for effective information security governance, the elements and actions required to develop an information security strategy, and be able to formulate a plan of action to implement this strategy.
- Establish and maintain an information security strategy and align the strategy with corporate governance
- Establish and maintain an information security governance framework
- Establish and maintain information security policies
- Develop a business case
- Identify internal and external influences to the organization
- Obtain management commitment
- Define roles and responsibilities
- Establish, monitor, evaluate and report metrics
Information Risk Management and Compliance
Students will be able to manage information security risks.
- Establish a process for information asset classification and ownership
- Identify legal, regulatory, organizational and other applicable requirements
- Ensure that risk assessments, vulnerability assessments and threat analyses are conducted periodically.
- Determine appropriate risk treatment options.
- Evaluate information security controls
- Identify the gap between current and desired risk levels
- Integrate information risk management into business and IT processes
- Monitor existing risk.
- Report noncompliance and other changes in information risk
Information Security Program Development and Management
Students will be able to develop and manage an information security plan.
- Establish and maintain the information security program
- Ensure alignment between the information security program and other business functions
- Identify, acquire, manage and define requirements for internal and external resources
- Establish and maintain information security architectures
- Establish, communicate and maintain organizational information security standards, procedures, guidelines
- Establish and maintain a program for information security awareness and training
- Integrate information security requirements into organizational processes
- Integrate information security requirements into contracts and activities of third parties
- Establish, monitor and periodically report program management and operational metrics
Information Security Incident Management
Students will effectively manage information security within an enterprise and develop policies and procedures to respond to and recover from disruptive and destructive information security events.
- Establish and maintain an organizational definition of, and severity hierarchy for, information security incidents
- Establish and maintain an incident response plan
- Develop and implement processes to ensure the timely identification of information security incidents
- Establish and maintain processes to investigate and document information security incidents
- Establish and maintain incident escalation and notification processes
- Organize, train and equip teams to effectively respond to information security incidents
- Test and review the incident response plan periodically
- Establish and maintain communication plans and processes
- Conduct post-incident reviews
- Establish and maintain integration among the incident response plan, disaster recovery plan and business continuity plan
Cyber Security Course is your best choice for CISM training Course, CISM training Course training, CISM training Course certification, CISM training Course boot camp, CISM training Course certification training, CISM training Course certification course, CISM training Course course, CISM training Course class.


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Comply with Department of Defense RFID Mandate – easily, efficiently and affordably
Comply/RFID Manager organizes and submits RFID to Area Workflow (WAWF), including RFID and UID (where applicable).
You may also:
- Submit RFID data to VIM-ASAP (for clothing and textile manufacturers)
- Print RFID Pack Report for use in preparing shipment and for historical records
- Automatically uses MIL-Comply Labeling label data to eliminate additional data-entry
The standard process when used with MIL-Comply Labeling:
- Print shipping labels
- Review RFID data
- Submit RFID data to an existing WAWF shipment (set for Pack Later) with a few clicks. Or include RFID data with a Receiving Reported to be submitted by Comply/Shipper.
Using Comply/RFID manager lets you work at your pace, collaborate with your team, review before you submit to WAWF and never worry booted out of WAWF again.


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VANCOUVER — A pedestrian is in hospital with serious injuries following a crash with a police vehicle in Vancouver.
Police say in a news release that an on-duty officer collided with the pedestrian on Saturday night.
The pedestrian was taken to hospital and remained in serious condition on Sunday.
Police say the officer was not physically injured.
The Independent Investigations Office is now probing the incident, looking for physical evidence, interviewing witnesses and reviewing video footage.
The agency investigates all police-involved serious injuries and deaths across B.C.


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Currently in progress. For once, I wanted to start a typeface by designing its italics and see in which way it could influence the roman version. Calligraphy first inspired me and then I wanted to rationalize the forms, to make them more modern, more straight.
Jan — 2019Italic (regular on the way)from Light to Black
Inspired by the 19th century's legacy, I've drawn this font for my diploma project. This italian typeface uses Monotype's old witdth principle, used for the matrix. It means that this font is not monospaced, but it has a limited range of width, from 100 untits to 100 units, giving it a mechanical and straight aspect. Two versions of the ornamented style (plain and reversed) are available, so you can stack them and obtain new patterns.
Jun — 20184 styles +a set of ornaments
A few posters I have made to show the principles of my diploma font and ornaments, Giana system.
Jun — 2018from 297 x 420 mmto 600 x 850 mm
Here are some pictures of the exhibitions on which I was able to work with Margaret Gray. 01. PréhistoireCentre Pompidou
from Feb — 2019to Nov — 2019
Designed for the website and foundry of the DSAA Typo's class. Savon is a modern revival based on the mythic Garamond. It just wants to be discrete and simple, to enhance the other typefaces displayed on the foundry. Its ascenders and descenders are short to save some vertical spacing.Italic by Loan Bottex and Léo GuibertBold by Marion Sendral
Font in use:
Oblique Strategies
Jan — 20182 weights
Internship report on my 3-month Scottish experience with Atalanta.
Mar — 2018120 x 180 mm
Sans Douleur is a creative workshop founded in May 2015, based on the love of the homemade, the handmade and the well-made. The story begins as follows: an encounter between
Alexandre Martins
, born with a pencil in his hands, and Fanny Hamelin, born with a needle between her fingers. Both attracted by the world of tattoo and fashion design, they decided to combine the uniqueness of one with the serial character of the other in order to obtain unique pieces. The connection between tattoo and handmade embroidery involves key elements such as: the needle, manual work, mastery of the gesture as well as the creativity and rarity of each piece. By giving the name
Sans Douleur
the creators of the workshop wanted to suggest that embroidering a t-shirt was like a painless tattoo.
A book I have made from my visual researches for my diploma project. It covers architecture, fashion design, product design and patterns.
Feb — 2018148 x 210mm
Jersey is a modern Fat Face, adapted from a laser cut font project. It is redesign to be used as a dynamic print font.
June — 20171 weight
This is the english version of my french thesis. I became interested in fancy fonts, the subject on which my degree is based. I tried to trace a brief history, to question the status of these fonts. I also did a research on the current events and the contemporaneity of these fonts. In a last time, I analyzed this part of the typographic classification through the prism of kitsch, which is a notion that fascinates me.
Apr — 2018110 x 200mm
Bathilde is a sans serif Gothic inspired font. Designed in four weights — light, regular, bold & black — this typeface is an exercise in style. Here, the weight is not coming homogeneously all around the letter as it is generally the case, but only in its counterpunch, so that its width does not increase.
Mar — 20174 weights


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The Anxiety Disorder and Affective Disorders; Dissociative Disorders; Somatoform Disorders they will offer diagnosed categories and classifications for the use of diagnose and the treatments of mental disorders.
General Anxiety disorder primarily is the well known as the feeling of apprehension about the future and are more manageable than other anxiety disorders. Excessive disorders are categorized as and or described as acute stress disorder,(GAD) general anxiety disorder, (OCD)obsessive-compulsive disorder, panic disorders with or without agoraphobia, agoraphobia, anxiety disorders due to medical condition, (PTS) post traumatic stress disorder, social phobia disorder, specific phobia disorder and substance-induced disorder. The fears of anxiety are normal until such time as they are felt to have harm on one's self their mental and physical well being then one should seek the advice of a professional.
Most people that have GAD will have the sense of being tense or agitated some of the time and can be controlled with meditation or exercise or a relaxation technique. Pervasive worrying in this group of individuals can lead to being irritable, insomnia, achy muscles, depression and general distress (Behave Net, 1997-2010). One may find that it is hard to control all those feelings and would eventually have to seek the help of a physician to have relief. Individuals that suffer from GAD there is no evidence that gender is affected between the treated and non-treated in other words there is no prejudice whether it be female or male no difference anxiety is anxiety. The fact is that a genetic component has no significance for GAD and is not gender related in any way. Individuals that have a fixation on GAD have a perceived risk for overestimating how server of a real perceived danger can be. Therefore can dramatically underestimate their ability to cope. Cognitively speaking this can represent and can lead to bouts with excessive worry and lead to further anxiety. GAD can contribute to a wide range of physical and mental symptoms nausea, sweating, dry mouth, this may affect their ability to enjoy a social or work situation.
The mood and affective disorders leave a person to have fluctuations in their day to day moods, whereas most people usually have a general speaking positive mood , however some individuals will experience moods of highs or lows and may have some combination of the two. Mood instability can include, major depression episode, mood disorders that are due to a medical condition, substance abuse mood disorder, bipolar disorder, cyclothymiacs disorder, mixed episode, manic episode and dysthymic disorder. The fine line between the normal mood fluctuation of an individual and the abnormal stability of an individual may be hard to pinpoint and this is the case of Cyclothymic Disorder(CD).
The Cyclothymic Disorder has a fine between a full blown bipolar episode and normal mood fluctuations this disorder also can have less server however but more constant mood swings, where the mood may vary between hypomanic highs and dysthymic lows (Hansel & Damour, 2008). There may not be a genetic marker that would account for an onset episode of cycloyjymic disorder would occur later on in life, it has been known that the cyclothymiacs would be linked to genetic-familial predisposition to bipolar II disorder (Albayrak, Caykoylu, Kuloglu, 2007). It is a fact that individuals that have mood disorders has a very low opinion of themselves in their minds they tend to hold negative thoughts in the world that


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Written by Caitlin Jenkins, MSc Conservation Practice student, Cardiff University and volunteer at National Museum Cardiff.
While volunteering with natural history conservator Julian Carter at National Museum Cardiff, I was given the opportunity to work on a wallaby skeleton. This was the first skeleton of any kind I had conserved. Although it initially appeared to be in relatively good condition, there were lots of small areas needing attention that made it a surprisingly complicated job.
The first step was to remove dirt that had built up on the bones over the years. This was cleaned away using cotton swabs and small interdental brushes dipped in a sodium bicarbonate solution; care was taken to not over-wet the bones as this can damage them.
One of the main conservation tasks was to re-wire a portion of ribcage that was hanging loose and distorting the alignment of the left side. In keeping with the pre-existing work, this required me to stabilise the free end of each rib using a single piece of wire twisted at intervals. This provided support and appropriate spacing of the bones. I had previously made jewellery using a similar technique, so my experience came in handy during the fiddliest parts!


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Yesterday we got back together after three weeks apart.
We met at Lund central station, the very same place we met for our first irl meeting almost exactly 17 years ago.
After Wivan's five hour train ride Anders picked her up on the motorcycle, with the big backpack and all. It was a nice ride out to the place we get to stay at friends' outside Lund.
It's really nice to be back together, after weeks of impressions and experiences apart.
Anders and Wivan


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passing on of a mother's etiquette
goes through the daughter
She who carries out her mother's
values through her activities
behaviour and ethical transmissions
Keeping the house in order
is a technique handed gracefully
by the mother to the daughter
The discipline and decorum that which
distinguishes each one inadvertently
gets down to the daughter unobtrusively
as if like a distillation in process.
The speech and modulations might differ
but mostly tag with the mother's
The interaction and gait are very much similar
though with a little individualistic colour.
The perpetuation gets arrested once the mother
goes without a daughter and has only sons.
Sons do maintain the order but their nest
merges with their wives idiosyncrasies
making it more inclined to his in-laws.
Many traditional upkeep have been perpetuated
through the generations by the female descendants.
So, as the saying goes the wealth goes to the sons
and the values stick to the daughters.
Perpetuation— A Poetic Speech.
passing on of a mother's etiquette


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/!\ Please open this message to see links.
That's it! Working with the Japan / USA / Europe / North.A Catalogs as a base of framework, all the 2012 and 2013 models are now fully documented. A big thanks to Deejayk who helped me a lot here.
About 2013: a whole new line, the Iron Label series was introduced for the down-tunz maniacs, more 7/8-string models, and of course less extreme models like the SA or the ARZ are still here for good. 2013 is also the year the Edge Zero II has lost his ZPS system. Did it happen to all models at once since the beginning of 2013 or did it changed over the course of the year, that is the question. Feel free to share your view and talk about your favorite Ibanez on the forum!
As you can guess, we're now moving t…Read more >


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Tag Archives: Ivy League University
Everything You Need To Know About The SAT
Choosing a college is one of the most important decisions you will ever make as a student. However, choosing... Read More
5 Notable Filipinos Who Went To Harvard University
How can one talk about the best schools in the world without mentioning Harvard University in the conversation? (Hint:... Read More


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Definition of unique
1 : being the only one : sole his unique concern was his own comfort I can't walk away with a unique copy. Suppose I lost it?— Kingsley Amis the unique factorization of a number into prime factors
b : distinctively characteristic : peculiar sense 1 this is not a condition unique to California— Ronald Reagan
c : able to be distinguished from all others of its class or type : distinct sense 1 You will see an assortment of digital tags that let the Web site identify your computer as a unique visitor.— Peter H. Lewis
3 : unusual a very unique ball-point pen we were fairly unique, the sixty of us, in that there wasn't one good mixer in the bunch— J. D. Salinger
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Tha-Ka-Dhi-Mi! (Another way to say it...)
Taaqademy is a music school. We teach music – guitar, bass, drums, keyboards and vocals across the widest variety of genres and styles – but what we're truly after is inspiration. Lighting that spark behind the eyes. Injecting a sure shot of excitement. Delivering a creative experience that is addictive, uplifting - and just plain old great fun. Taaqademy's new ONLINE COURSES are now available around the world! Customized, structured and flexible, our online programs have something for every musical interest.
Taaqademy is run by musicians who play a variety of styles of music, in bands and as session musicians. Musicians who will work with you to develop your skills on the instrument(s) of your choice, so that you can play the music that's inside you. More than anything, you don't just learn to play an instrument by yourself, you learn to jam with other musicians and write your own music as well. The magic of communicating musically, creating and performing music together – that is special. That is Taaqademy.
Taaqademy is the regional centre for RockSchool exams. Grade 6 and above qualify for UCAS points!
Most of our classes at Taaqademy are one-on-one. This allows us to customize our extensive syllabus and curriculum to suit your needs as a beginner, intermediate or advanced musician.
Our five-pronged approach involves ear training, music theory, muscular training, sight-reading and ensemble playing, across all instruments and disciplines. With loads of performance experience under our collective belt, we bring a 'live' and 'fun' perspective to serious music education.
Periodic assessments allow you to track your progress and get a real picture of your strengths and weaknesses. Our association with RockSchool (a UK-based music examination board), Trinity College London, and ABSRM also gives you the opportunity to earn certifications that are valid worldwide.
ENSEMBLE or JAM SESSIONS
You could call this our 'USP'. With so many of our faculty members being live performers, it's natural that we'd want our students to experience the timeless excitement of being on stage. It won't go out of style, ever!
All four of our spaces in Bangalore are specially designed to allow ensembles to jam together, working on covers and originals, working on all the technical nitty gritty as well as showmanship. Our Ensemble courses also typically feature a visit to a full-fledged state-of-the-art recording studio for a quick session.
Launching soon, our group sessions will focus on teaching music theory and fundamentals, music appreciation, and more!
Occasionally, we organize special master classes or workshops with some of the top musicians in the country - or international stars who happen to be passing through. Best place to get updates - Facebook!
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Common Mistake: Overtrading
Almost everyone will have to go through this "need" to trade. The trick is to get through it quickly with awareness that you are doing it. It's certainly not a bad thing to overtrade when you are using a demo account and still learning/creating your trading plan, but once you go live and start attempting to become a professional trader you need to make sure it is out of your system.
Just like the common mistake I wrote about in my previous article, this is another one of those things that people will do no matter how many times they hear and read about it all over the Web. The fact is that if you follow some very basic price action concepts with good trade management and risk/reward you could have several solid trades per day. Other people may consider this overtrading but if you are following your plan correctly based on the "zoom level" you are watching then it is not a problem. An important note here is that a trading plan with 2-3 trades per day requires more experience and skill to remain profitable than a trading plan that gives you 2-3 trades per week. The further out your "zoom" the cleaner the picture.
The problems begin when you start taking trades outside of your plan because you are bored or you convince yourself you see a setup that isn't really there yet, you jump the gun you might say. Awareness is key here and avoiding it completely as a newcomer may prove difficult. Just try and remember this piece of advice and catch yourself when you do it and don't let it happen again.
I have a very solid price action concept that can be traded on various levels but as I stated above you need to make sure that you are following your plan, not how many trades you are taking. If you are trading a plan that averages 2-3 trades per day and you are taking 2-3 trades per day you probably are not overtrading. If you have researched your plan to the level that you should have researched your plan, based on your historical data and statistics you will know what this average number is. If you are trading a plan that averages 2-3 trades per week and you find yourself trading everyday then you are clearly overtrading and need to work on your discipline.
I know this all sounds very obvious and I certainly don't consider this an innovative article but what is obvious to some is not always obvious to others and my goal with these Forex articles is to just make sure these simple elements of trading are not lost, especially for those just starting out.


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I Think I Have An Ulcer: Red Wings 4, Kings 3 (SO)
Tuesday, October 28, 2008
Whenever the Kings play the Detroit Red Wings, there is always a feeling of dread that accompanies that thought. But, first off, I must say how glad I am to have watched this gave live instead of at home on the Rinkside View, which is horrific! In my very quick (a.k.a. lazy) search, I couldn't find any Rinkside View images. It's just as well; it's horrible and should be stricken from the record.
Getting to the actual game, the closer it got to the puck drop, the more worried I was getting. We were facing the Cup champs who had added Marian Hossa, you know, just as an addendum. My thought at the first faceoff? "Wow, let me go pee my pants actually." I think the most surprising move that Detroit made was putting Chris Osgood in net instead of Ty Conklin. First off, I'm always surprised when teams put their number one against my team; and secondly, I really wanted to see Conks play. I've seen Osgood play my team enough times; put in Conks next time!
In looking at the other lines, I'm not sure which line had more punch, the 2nd or 3rd. I'm going to argue that it was the 3rd line in that all three players were working their tails off whereas one third of the 2nd line was a bit invisible. As much as I love Alexander Frolov on the 3rd line and what he's doing, I'm sad at the same time. He's not really scoring at his regular clip and his offensive opportunities have been severely limited. I'm not surprised; it's just a bit hard to see him in a role change since I know he has the capability to put numbers up. That being said, he did score on Osgood, which I was extremely happy about. Question: What if Terry Murray tried Fro up on the top line with Kyle Calder/Matt Moulson on the left wing of the 3rd line? Worth a shot?
Jarett Stoll ended the night with a -1 but his contributions were shown elsewhere. He was 75% in the faceoff circle winning 15 and losing only 5. He was definitely fighting hard for every single faceoff he took, which was very nice to see; not that I'm saying he takes draws off sometimes. It's just that it's Detroit and there is a very, very large microscope on every single Red Wings game. When I watched the NHL Network's highlights after I returned to my humble abode, I thought they spent an ungodly amount of time reviewing this game. But then I remembered that it was because they were playing the Red Wings. Would they have spent that much time on the Kings if they were playing, say, the Florida Panthers? I think not.
Another player who had a great game was actually Kyle Quincey, our waiver wire acquisition from the Red Wings. He was playing a physical and intelligent game, and everything he was doing looked great. There's no one play I can thing of right now, but he just had a solid outing and I'm very happy with him. Speaking of, I'm also very happy with Sean O'Donnell. He's only done good things out there since he's joined the Kings. When I find myself surprised that he's still a physical player, I just remind myself that he used to play for the wretched Ducks. Getting back to the happy, I was super happy to see Brad Stuart again. B-Stu! Someone in my section yelled out that he sucked and I looked at KingsCast and said, "Actually... he doesn't..." *pout pout pout*
The Overtime frame was five minutes of ridiculousness. I'm sure the acids in my stomach were taking over and churning and churning and churning because I had a tummy ache for the rest of the evening. Ugh. So OT ends and they scrape the ice for the shootout. This was about the time where I knew we had lost. I was predicting that it was going to be Brownie, probably Moller, and Calder for the Kings and Henrik Zetterberg, Hossa, and Pavel Datsyuk for the Red Wings. I'm not sure if I got Calder right since we didn't even make it to the third round. Osgood essentially shoved his pads down Brownie's and Moller's throats while Datsyuk and Zetterberg gave Barbs a good ole "hello nurse" with their respective dekes.
Not surprisingly the Kings end with less than 20 shots on, while the Red Wings had 37. All in all, I thought the Kings played really well against the Red Wings. There were some great plays throughout the entire game with virtually none in the first period. Actually, the first half of the first period saw almost no offensive jump from either team, but the teams busted out some sick moves here and there by the end and got the energy in the arena up. In the end, it was a good game for both sides. I just wish we had came away with the two points.


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Coachella 2021
- Empire Polo Club, Indio CA, United States of America
- 9-11 April 2021 & 16-18 April 2021
Join our Waiting List and we will keep you up to date with priority access to tickets, discounts and exclusive news & offers, via email.Join Waiting List
The iconic Californian festival makes an eagerly awaited return
Coachella is North America's most famous music festival, held each April at its now iconic home at the Empire Polo Club in Indio, California.
A festival on every true music fan's bucket list, Coachella will make its eagerly anticipated return in April 2021 after a year off, once again returning with a world-beating lineup of some of music's biggest stars, covering a range of genres, including rock, indie, hip-hop and dance.
Coachella's illustrious history has seen it feature legendary headline sets from the likes of Beyoncé, Daft Punk, Prince, Radiohead, and Bob Dylan over its two decade-long lifespan.
To find out everything you need to know about the sale dates, payment plans and methods, and more check out our Coachella 2021 FAQs page here.
And if you want to read more, we've put together some of our favourite Coachella coverage over on our Magazine:
The Coachella 2021 lineup will be announced closer to the festival.
California's Empire Polo Club has hosted Coachella since its very first edition in 1999. Those iconic palm trees have become just as much a part of the festival as each year's incredible lineup.
Empire Polo Club, 81-800 Avenue 51, Indio CA, 92201, United States of America
The closest airports to the festival are Palm Springs, Los Angeles and Ontario.
The nearest airport is Palm Springs International Airport (PSP). If you are flying into here, take the 30 bus to B St at Buddy Rogers (28 minutes). Here transfer to the 111 bus and get off at Hwy 111 at Madison (57 minutes). Follow signs to the festival site from the bus stop.
There is also a shuttle bus system between Los Angeles International Airport (LAX) and the festival site. Please note that these shuttle services are not in any way connected with Festicket. More information can be found on the Coachella website.
As well, there is an "Any Line, Anytime" shuttle system stopping at various hotels. More information can be found on the Coachella website.
If you are driving to Coachella, you will want to enter the Empire Polo Club (81-800 Avenue 51, Indio, CA 92201) onto your sat nav. Average driving times are as follows:
From Los Angeles - Take the I-10 E (2 hours)
From San Diego - Take the I-15 N (2 hours 45 minutes)
From Las Vegas - Take the I-15 S (4 hours 30 minutes)
From San Francisco - Take the I-5 S (8 hours 30 minutes)
This is an all ages festival.
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Inquiry Engaging in the Practices of Science Page Keeley Science Specialist Maine Math & Science Alliance NSTA Past President [email protected]
Whos in the room? Our Goal and Approach To build an understanding of science as inquiry (K-12) as it applies to the current direction of science education and the
North Carolina standards. Tang Yan is a Chinese teacher visiting your school district. She wonders what your district means by inquiry
science. How would you describe inquiry science to Tang Yan? Describing Science as Inquiry Students take an active role in science learning.
Involves content and process. Investigating for the purpose of constructing understanding of natural phenomena, processes, and events. Gives priority to evidence and evidence-based explanations Mirrors science as practiced by scientists
Science as inquiry is key to organizing and guiding students' activities. Students in all grades and in every scientific discipline should have the opportunity ask questions, plan and conduct investigations, use appropriate tools and techniques to gather data, think critically and logically about relationships between evidence and explanations, and communicate
arguments. (from the NC standards) All this begs the questiondo students have to be involved in a hands-on investigation to inquire?
Not really. The key, often forgotten, aspect of inquiry is that it is an intellectual endeavor. Too many students have a knack for being physically but not intellectually engaged in science. So hands-on science may help many students to inquire, but skillful use of print materials can accomplish the same goal. It
is what the teacher and students do with the materialsbooks or lab equipment that makes the difference. (Dr. Michael Padilla) The National Science Education Standards define inquiry as the diverse ways in
which scientists study the natural world and propose explanations based upon evidence (NRC 1996, p. 23). Inquiry Study/Investigation
List some of the ways scientists study or investigate the natural world and give an example of each. Investigations
Remote observations Field studies Collections Systematic observations
Modeling (physical, mathematical, computer simulations) Literature studies Experiments Frayer Model for Scientific Experiment OPERATIONAL DEFINITION
EXAMPLES CHARACTERISTICS Scientific Experiment NON-EXAMPLES Scaffolding Experimentation Designing Experiments
Conducting Experiments Scaffold The structure and supports that a teacher or more knowledgeable helper provides to allow a learner to perform a task he or she cannot yet perform independently
~Vygotsky, 1978; Dixon-Krauss, 1996; Wertsch, 1991 Seed Germination What factors affect seed germination? Brainstorming Ideas Related to My Initial Question
Things I could change or vary when I `germinate my seeds: Type of seeds Amount of water Soil Amount of light Time to sprout
Things I could change Amount of water Temperature Type of seeds
Type of soil Things I could measure or observe Length of sprouts
Time it takes to sprout Color of sprouts Number of seeds sprouted
Identifying Variables Related to My Initial Question I will change the amount of water I will observe number of seeds sprouted I will not change the type of seed, the temperature, type of soil I will not measure the length of the sprouts, time it takes to sprout, color of the
sprouts Formulating a Testable Question When I change: the amount of water, What happens to: the number of seeds that sprouted? Guiding Question: How does the amount of
water affect the number of seeds that germinate? Hypothesis versus Prediction
When would students make a hypothesis? When would they make a prediction? Are there times when they would do neither? What is the difference between a hypothesis and prediction? At what grade level does the word hypothesis appear in the standards?
Developing the Procedure Materials: What I will change (independent or manipulated variable): How I will carry out the change: Number of samples: The data I will collect (dependent or responding
variable): How I will collect the data: How I will record the data: ? Your Classroom Where could you use this scaffold in your
curriculum to help students design their own experiments? What modifications could you make for your grade level? Part 1- DESIGNING THE EXPERIMENT What are you wondering about?
Things We Can Change Length of pendulum
Mass of the bob Release point of the pendulum Shape of the bob Things we can measure Period of the pendulum (time it takes to make one full swing) Number of complete swings in a given
time period (30 sec) How long it takes the pendulum to come to rest Number of swings before pendulum comes to rest 3 Experiment Groups Length
Mass of bob Angle of release Stop at C-E-R ! Scientific Experiment What changes would you make to your Frayer Model after designing and
conducting the pendulum experiment? From Inquiry to Scientific and Engineering Practices Card Sort Sort the cards into examples of:
Scientific Practices Engineering Design Both Scientific Practices and Engineering Design Engineering Design What is engineering design and how is it similar to and different from the practices of science?
The goals and objectives for technological design call for students to accumulate the skills necessary to: Identify and state a problem, need, or product Design a solution including cost and risk/benefit analysis Implement and evaluate the solution
Accurately record and communicate observations. Technology as Design (Engineering) Technology as design is analogous to science as inquiry. All students should engage in problem-solving by designing, building, and
testing solutions to real-world problems. By applying critical thinking skills and knowledge of materials, learners can compare and assess technological devices for costs, benefits, applications, practicality, environmental impact, safety, and convenience. Science and Engineering Practices
Asking questions, Defining a problem Developing and using models
Planning and carrying out investigations Analyzing and interpreting data Using mathematics, information and computer technology, and computational thinking Constructing explanations, Designing solutions Engaging in argument from evidence Obtaining, evaluating, and communicating information
Everyday Science Mysteries THE CROOKED The Crooked Swing SWING Engineering Design Process
Identify the problem Use scientific knowledge to define the problem Brainstorm possible solutions Identify constraints Select best possible solution Construct a model Test and evaluate model
Refine the design Communicate solution Science and Engineering Practices
Asking questions, Defining a problem Developing and using models Planning and carrying out investigations Analyzing and interpreting data Using mathematics, information and computer technology, and computational thinking
Constructing explanations, Designing solutions Engaging in argument from evidence Obtaining, evaluating, and communicating information Claims-Evidence-Reasoning (C-E-R)Framework Claim- Statement that answers the question. Evidence- Scientific data that support the
claim. Reasoning- Justification that connects the evidence to the claim, using a scientific principle when appropriate, or showing how other data do not support the claim. P-E-O Predict (commit to an outcome)
Explain (explain your thinking) Observe (test your prediction and observe results) If observations dont match the prediction: Construct new explanation Cookie Crumbles- Before
I think the whole cookie weighs more than all of the cookie crumbs. The broken cookie has smaller pieces that are lighter. Because the cookie is in tiny pieces, it loses some of its weight when the pieces are smaller.
Cookie Crumbs- After P-E-O The whole cookie and all its crumbs weigh the same. Our data showed the whole cookie on the napkin weighed 48 grams. We weighed all the crumbs and pieces and they were also 48 grams. All we did was break the cookie in pieces. There is still the same amount of cookie. Its just that there
are a lot of smaller pieces. Ice Cubes in a Bag- Before I think the mass of the water in the bag will be more than the mass of the ice in the bag. Ice cubes float in water. Because they float they are lighter than water so the mass is
less. Ice Cubes in a Bag- After The mass will stay the same. The mass of the ice in the bag was 244 grams. The mass after the ice melted was also 244 grams. The matter changed state but no new matter was added to the
bag or taken away. The number of molecules in both bags stayed the same. Pendulum Explanation Use the C-E-R Framework to write a scientific explanation about what affects the swing of a pendulum.
Claim Evidence Reasoning Developing and Using Models Science often involves the construction and use of a wide variety of models and simulations
to help develop explanations about natural phenomena. Framework for K-12 Science Education Look Back and Reflection I used to think _________ but now I know _________________________
Driving change for a healthy workplace Public Service
Osteon (Haversian) System
DDD Services: Supporting a Vision for a Good Life
Chapter 24 The Origin of Species - dps61.org
Title Of Presentation
Administrative Details - Tel Aviv University
Welcome to 191 RCACS!


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Protein-Bound Uremic Retention Solutes in Long Nocturnal Hemodialysis
|The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
|ClinicalTrials.gov Identifier: NCT00417105
Recruitment Status : Completed
First Posted : December 29, 2006
Last Update Posted : March 5, 2009
- Study Details
- Tabular View
- No Results Posted
- Disclaimer
- How to Read a Study Record
Although remarkable progress has been made, chronic kidney disease still poses a major burden on both individual patients, as well as on society as a whole. There is a strong inverse relationship between decreasing renal function, as estimated by glomerular filtration rate, and mortality rate, especially death due to cardiovascular disease. The exact cause(s) remain to be elucidated. Uremic toxins might play an important role.
In the course of decreasing renal function the concentration of numerous intracellular and extracellular compounds vary from the non-uremic state. But still increasing number of uremic retention solutes are being identified. Renal replacement strategies aim to remove potentially harmful substances from the body. Traditionally much attention has been paid to small water-soluble molecules such as urea nitrogen and creatinine. Based on the results of the recent HEMO and ADEMEX studies, increases of small water-soluble solute removal above the level reached with modern dialysis techniques - hemodialysis, peritoneal dialysis (HD, PD) - seem not to be advantageous with regard to patient outcome. These findings may point to the importance of other distinct groups of uremic retention solutes. In view of the data described above, protein-bound solutes might be good candidates.
Several advantages of long duration hemodialysis have been observed, including a better control of blood pressure by decreasing extracellular fluid volume, lowering peripheral vascular resistance and improving endothelium-dependent and -independent vasodilation. A normalization of heart rate variability and improvement of left-ventricular function was noted as well. Furthermore, anemia control has been shown to be easier and several nutritional parameters improved in patients treated with long duration HD. The therapy results in higher small water-soluble solute removal, phosphate removal and greater elimination of larger molecules (e.g. β2-microglobulin).
It seems an appealing question whether a better control of the serum levels of protein-bound solutes can be achieved by long duration (nocturnal) hemodialysis. This might be another advantage of this therapeutic modality, or may even in part explain the better outcome of patients treated this way.
The study compares intermittent hemodialysis with long nocturnal hemodialysis with respect to serum concentrations of several protein bound uremic toxins, as well as solute removal.
|Condition or disease
|End Stage Renal Disease
|Procedure: hemodialysis
|Study Type :
|Actual Enrollment :
|120 participants
|Observational Model:
|Time Perspective:
|Official Title:
|A Multicentric Observational Study on the Removal of Protein-Bound Uremic Retention Solutes in Nocturnal Hemodialysis: A Cross-Sectional Analysis
|Study Start Date :
|December 2006
|Actual Primary Completion Date :
|December 2008
|Actual Study Completion Date :
|December 2008
hemodialysis twice weekly 4 hours
Procedure: hemodialysis
group 1: twice weekly, four hours
nocturnal dialysis twice weekly 8 hours
Procedure: hemodialysis
group 2: twice weekly, eight hours
nocturnal hemodialysis, 8 hours every other night
Procedure: hemodialysis
group 3: every other day, eight hours
nocturnal hemodialysis, 8 hours, six times per week
Procedure: hemodialysis
group 4: six days a week, eight hours
- removal of protein-bound retention solutes [ Time Frame: 1 dialysis session ]
Biospecimen Retention: Samples Without DNA
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.
|Ages Eligible for Study:
|18 Years and older (Adult, Older Adult)
|Sexes Eligible for Study:
|Accepts Healthy Volunteers:
|Sampling Method:
|Probability Sample
Inclusion Criteria:
- Age > 18 years
- Maintenance hemodialysis (> 3 months duration)
- Informed consent
Exclusion Criteria:
- No consent
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00417105
|Australia, Victoria
|Monash Medical Centre
|Clayton, Victoria, Australia, 3168
|Geelong Hospital
|Geelong, Victoria, Australia, 3220
|Virga Jesse Ziekenhuis
|Hasselt, Limburg, Belgium, 3500
|Universitaire Ziekenhuizen Leuven
|Leuven, Vlaams-Brabant, Belgium, 3000
|Principal Investigator:
|Björn KI Meijers, MD
|Universitaire Ziekenhuizen Leuven
|Study Director:
|Pieter Evenepoel, MD, PhD
|Universitaire Ziekenhuizen Leuven
|Principal Investigator:
|Tom Dejagere, MD
|Virga Jesse Ziekenhuis
|Principal Investigator:
|Nigel Toussaint, MD
|Geelong Hospital
|Responsible Party:
|Pieter Evenepoel, University Hospitals Leuven
|ClinicalTrials.gov Identifier:
|Other Study ID Numbers:
|First Posted:
|December 29, 2006 Key Record Dates
|Last Update Posted:
|March 5, 2009
|Last Verified:
|March 2009
dialysis adequacy
chronic kidney disease
Kidney Failure, Chronic
Kidney Diseases
Urologic Diseases
Renal Insufficiency, Chronic
Renal Insufficiency


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OPINION: Georges St-Pierre's greatest performance
GSP's most impressive performance
GSP's most impressive performance
[themoneytizer id="23967-1″] Cain Velasquez, who is widely-regarded as one of the greatest heavyweights of
Demian Maia turned back the clock Saturday night at UFC Fortaleza, getting back in the
MMA legend Fedor Emelianenko fights Ryan Bader this weekend at Bellator 214 in the finals
Former UFC heavyweight champion Fabricio Werdum is not only one of the greatest heavyweights of
UFC's first event on ESPN+ was undoubtedly a great success. It featured some crazy upsets
UFC 232 is now officially in the books, marking the end of UFC events in
Well, it looks like another high-profile Jon Jones fight has nearly fallen through once again.
Back in October, there was some talk of a potential fight between Anderson Silva and Conor
UFC 231: Holloway vs. Ortega ended up being another great card which featured a stellar