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Therapy of Genetic Disorders: Novel Therapies for Duchenne Muscular Dystrophy
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DOI: 10.1007/s40124-014-0044-x
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- Seto, J.T., Bengtsson, N.E. & Chamberlain, J.S. Curr Pediatr Rep (2014) 2: 102. doi:10.1007/s40124-014-0044-x
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Duchenne muscular dystrophy is an inherited, progressive muscle-wasting disorder caused by mutations in the dystrophin gene. An increasing variety of approaches are moving towards clinical testing that all aim to restore dystrophin production and to enhance or preserve muscle mass. Gene therapy methods are being developed to replace the defective dystrophin gene or induce dystrophin production from mutant genes. Stem cell approaches are being developed to replace lost muscle cells while also bringing in new dystrophin genes. This review summarizes recent progress in the field with an emphasis on clinical applications.
KeywordsDuchenne muscular dystrophy Dystrophin Gene therapy Adeno-associated viral vectors Antisense oligonucleotide Inducible pluripotent stem cell Mesoangioblast Myoblast Satellite cell
Duchenne muscular dystrophy (DMD) is the most common and severe form of childhood muscular dystrophy, affecting approximately 1 in 5,000 boys [1]. The disease is characterized by progressive muscle weakness with delayed motor and speech milestones and elevated serum creatine kinase levels. Patients demonstrate reduced motor skills by age 3–5 and typically lose ambulation by 12 years of age. Glucocorticoids (prednisone or deflazacort) are prescribed to slow disease progression, but to date there is no cure for this disease. Despite intensive clinical attention to respiratory support and management of cardiac complications [2], most patients do not live beyond age 30.
DMD is caused by loss of function mutations in the X-linked DMD gene (commonly called 'dystrophin') resulting in near complete deficiency of dystrophin in cardiac, skeletal and smooth muscles. The types of mutations that lead to DMD include: point mutations that can encode premature termination codons (nonsense mutations, or "stop codons"); deletions or exon–intron splice site mutations that disrupt the normal protein or open reading frame (ORF) of the dystrophin messenger RNA (mRNA); partial gene duplications that disrupt the normal ORF; and, rarely, point mutations or deletions that disrupt critical functional domains of dystrophin. Mutations that enable expression of partially functional dystrophin lead to the milder Becker muscular dystrophy (BMD). Clinical observations of a BMD patient who remained ambulatory past age 70 despite absence of 46 % of the dystrophin gene [3] lent proof of principle that restoring some functional dystrophin expression can ameliorate the disease severity of DMD. Expression of 20–30 % of normal dystrophin levels is sufficient to avoid muscular dystrophy in mice and humans, while lower levels can lead to various severities of BMD [4, 5].
Small Molecule Therapies
Approximately 10 % of DMD mutations are single-base "point" mutations that introduce premature stop codons into the dystrophin mRNA. One strategy to restore dystrophin expression in patients with such nonsense mutations is mutation suppression, specifically, of premature termination codon (PTC) mutations. Nonsense mutations signal an end to protein translation and result in production of a shortened, non-functional protein that is usually unstable and degraded in the cell. These 'PTC' mutations account for ~10 % of DMD cases [6] (see also http://www.umd.be/DMD/W_DMD/index.html). Certain antibiotics such as gentamicin can induce translational read-through of PTC mutations. At high concentrations, the binding of gentamycin to the protein production machinery in cells induces read-through of PTCs in mRNA, inserting a new amino acid to continue translation of the complete protein [7]. However, serious dose-limiting toxicities preclude the use of gentamicin in patients for this purpose. Drug discovery programs led to the identification of PTC124 (also known as ataluren), a compound shown to be more potent in PTC read-through than gentamicin [8], although recent in vitro studies have raised questions regarding the genuine read-through ability of ataluren [9, 10, 11]. Regardless of the mechanism, ataluren was somewhat effective in restoring functional dystrophin expression in mdx mice, resulting in improved strength and decreased injury in response to exercise-induced damage [8]. A phase I study in healthy volunteers established safety and tolerability at doses exceeding pre-clinical efficacy [12]. Phase 2b studies over 48 weeks involving DMD and BMD patients aged 5–20 years showed that patients receiving a low-dose treatment (20 mg/kg) experienced a significantly slower disease progression, demonstrating a 29-m improvement in a 6-min walk test (6MWT) compared to patients who received placebo (http://clinicaltrials.gov/show/NCT01182324; http://www.muscular-dystrophy.org/assets/0003/5427/2012-07_ataluren_update.pdf). Intriguingly, patients who received a higher dose (40 mg/kg) showed a similar decline as the placebo group, suggesting that ataluren may have an inverted bell-shaped dose–response curve. As of March 2013, a phase 3 study of ataluren was initiated, with recruitment restricted to DMD patients with PTC (stop codon) mutations. This will be a randomized, double-blind, placebo-controlled study with higher power to determine the potential efficacy and safety of low-dose ataluren (http://clinicaltrials.gov/show/NCT01826487).
The majority of DMD cases arise from partial dystrophin gene deletions or duplications or from mutations that affect the normal splicing of the dystrophin RNA transcript into mRNA. Each of these types of gene mutations is a problem when it disrupts the normal dystrophin mRNA open reading frame such that a functional dystrophin protein can not be produced in muscle cells. An approach to restore the normal mRNA reading frame involves exon skipping. This can be induced by short, synthetic fragments of nucleic acids known as "antisense oligonucleotides" (AONs), which are designed to bind (anneal) with RNA sequences that regulate how a gene's initial RNA transcript is spliced into a functional mRNA. By altering RNA splicing near the mutation on the precursor mRNA (pre-mRNA), the cell can be tricked into making a slightly shorter than normal mRNA that lacks a mutation and that carries an otherwise normal open reading frame (Fig. 1). This strategy is theoretically applicable to ~80 % of all DMD patients [13]. Recent drug development for exon skipping has targeted exon 51 of the DMD gene, as this could be applied to ~13 % of boys with DMD. Two types of AONs have been taken into clinical trials, each made using different nucleic acid chemistries. Drisapersen (previously known as PRO051, GSK-2402968) was developed by Prosensa and GSK. The other was eteplirsen (AVI-4658) developed by Sarepta Therapeutics. Therapeutic efficacy of these AONs has been demonstrated in several mouse models for DMD (mdx) and the dystrophic cxmd dog [14, 15, 16, 17]. Both compounds demonstrated safety and efficacy by direct intramuscular injections in patients, with restoration of dystrophin expression in the majority of muscle fibers near the injection site without severe treatment-related adverse effects [18, 19].
Initial phase 1/2A studies for both drisapersen and eteplirsen appeared promising, but disappointingly, neither compound succeeded in demonstrating significant improvements in the primary outcome measure, the 6MWT, in larger cohorts. In early phase 1/2A drisapersen trials involving 12 patients, a subset of patients who received the higher doses (4.0 and 6.0 mg/kg/week) showed some variable de novo dystrophin expression and demonstrated a mean improvement of 35 m in the 6MWT after 12 weeks of treatment [20••]. However, phase 3 trials where 125 patients (aged 5–16 years) were administered 6 mg/kg/week over 48 weeks did not result in statistically significant improvements in the 6MWD or in secondary measures of motor function when all patients were analyzed. However, Prosensa recently announced that when the analysis was confined to patients younger than 7, a 49-m difference was observed in the 6MWT in patients on a 96-week extension trial. Some of these studies also revealed kidney toxicity and low platelet counts in a few patients at high drug doses. To date, these latest results have only been discussed at conferences and in press releases (http://www.gsk.com/media/press-releases/2013/gsk-and-prosensa-announce-primary-endpoint-not-met-in-phase-iii-.html; http://www.thestreet.com/story/11854354/1/glaxo-dmd-drug-tied-to-serious-side-effects-hospitalizations.html; http://cureduchenne.com/blog/prosensa-reports-initial-findings-from-the-further-clinical-data-analyses-of-drisapersen-for-the-treatment-of-duchenne-muscular-dystrophy/). GSK recently announced that it would not continue studies of drisapersen and is returning rights to the drug to Prosensa, which will continue its development (http://us.gsk.com/html/media-news/pressreleases/2014/prosensa-regains-rights-to-drisapersen-from-gsk-and-retains-righ.html).
Similarly, early phase 2 studies for eteplirsen showed low and variable increases in dystrophin expression in 7 out of 19 patients (all but one who received the highest dose of 10 or 20 mg/kg over 12 weeks). There was a post-treatment increase in dystrophin protein expression from 9 to 16 % of normal controls; three patients showed between 15 and 55 % dystrophin-positive myofibers. Notably, restored dystrophin was shown to be functional and restored β-dystroglycan, α-sarcoglycan and nNOS expression in patients with exon 49–50 deletions, in keeping with the nNOS binding domain being encoded in exons 42–45. Inflammatory cell infiltrate was also reduced in the 10–20 mg/kg cohorts, suggesting that restored dystrophin is tolerated by the immune system [21, 22••]. In a second, more recent phase 2 study, increased dosage of eteplirsen was further assessed in a double-blind placebo-controlled test in 12 DMD boys aged 7–13 years [23]. Patients were administered with placebo, 30 mg/kg/week or 50 mg/kg/week of eteplirsen for 24 weeks, followed by an open-label extension study at the two doses through week 48. Results showed that at least 12 weeks of treatment was required to produce significant increases in dystrophin. At 48 weeks, the mean increase in dystrophin-positive fibers was 47 %, and the four patients in the placebo/delayed group (after 12 weeks of treatment) showed a significant increase of 38 %. Similarly, functional assessment by the 6MWT shows a divergence between the placebo and the eteplirsen groups at week 12, after which the treated group no longer showed a significant decline and stabilized. The placebo/delayed cohort likewise appeared to stabilize by 36 weeks (12 weeks after treatment). Comparison of the 48-week-treated group to the delayed group showed a significant difference of 67 m by week 48 in the 6MWT. Recent natural history data have shown that patients who could walk >350 m at baseline tend to stabilize over 1 year [24], and mean baseline 6MWT for all patients in the eteplirsen study was >350 m [23]. In a very recent press release, Sarepta announced continued stabilization of the 6MWT test in the phase 2b study where patients were continued on high-dose drug (30–60 mg/kg) for 120 weeks (http://investorrelations.sareptatherapeutics.com/phoenix.zhtml?c=64231&p=irol-newsArticle&ID=1891149&highlight=).
Despite these modest gains, the FDA declined to grant accelerated approval for eteplirsen, citing concerns about the study design (http://investorrelations.sareptatherapeutics.com/phoenix.zhtml?c=64231&p=RssLanding&cat=news&id=1875187). Moreover, there was growing concern over the disconnect between increased expression of dystrophin and clinical efficacy, at least in these relatively short trials, raising doubt about the quantification methods used to reliably assay dystrophin expression and the use of dystrophin as a biomarker to reasonably predict clinical benefit over 1 year. Another concern is the use of the 6MWT as the primary clinical endpoint. Although the 6MWT is to date the most reliable and sensitive global measure of lower extremity strength, biochemical inefficiencies, endurance and cardiorespiratory function [24, 25], the 6MWT excludes younger boys who cannot perform such a demanding test and older boys who are no longer ambulatory [26]. Therefore, it was suggested that future studies be designed to mathematically combine findings from a series of tests that measure a broader array of function in a larger range of patients. Redesign of this confirmatory study is currently underway, with dosing expected to initiate mid-2014.
Gene Replacement
Replacement of the defective DMD gene with a synthetic substitute using delivery vehicles such as recombinant adeno-associated virus (rAAV)-based vectors is another promising approach for safe, long-term therapy (Fig. 1). A significant advantage of gene replacement technologies is that they should be applicable to all patients, regardless of their underlying genetic mutation. Wild-type AAV is a small, non-pathogenic parvovirus that contains a 4.7-kb single-stranded DNA genome. Generation of rAAV delivery vectors involves removing all viral genes and replacing them with a therapeutic gene. Advantages of using rAAV-based vectors are that they can be produced at high titers on an industrial scale [27] and can stably persist for years in muscle cells. Of the many known serotypes, AAV6, 8 and 9 exhibit a high tropism for striated muscles, which is ideal for lessening off-target events in the treatment of muscular dystrophies [28, 29].
A significant limitation of rAAV vectors is that they can carry only a limited amount of DNA, i.e., they cannot deliver large genes. To accommodate this minimal carrying capacity of rAAV vectors, a common strategy is to insert miniaturized but highly functional copies of the dystrophin gene into the vector. These microdystrophin genes are deleted for sequences that code for several minimally essential regions in the dystrophin protein [30]. While there are numerous ways to generate a microdystrophin protein, and improved versions are still being developed, all share the feature of retaining only the most crucial functional domains, while taking care to retain structural flexibility and stability of the final protein [31]. Effective treatment of severely dystrophic mice was achieved by intravascular administration of rAAV6 vectors carrying microdystrophin, which restored dystrophin production in the respiratory, cardiac and limb muscles, improving muscle function and extending the lifespan [32, 33, 34, 35, 36].
Another strategy to overcome the limited carrying capacity of rAAV vectors is to co-deliver two or more rAAVs that have the gene of interest split between them, with reconstitution of the larger gene occurring inside the muscle cell. Reconstitution can be induced in various ways by specific design. One method is trans-splicing, where reconstruction of the larger gene occurs following a process where the various AAV vectors bind together and form large concatemers. A modification of this method involves splicing together of smaller protein pieces to produce a complete protein [37]. Still another modification involves co-infection of AAV vectors carrying overlapping portions of the desired gene, which reconstitutes the larger gene inside muscle cells by an exchange of DNA pieces known as "homologous recombination" [38••, 39, 40]. These 'two vector' methods have been used to deliver larger and more functional "minidystrophins" to dystrophic mice, resulting in somewhat greater physiological improvements compared to microdystrophin delivery [31, 38••, 40]. Recently, delivery of the entire dystrophin gene has been achieved using a triple-AAV vector system, although the efficiency is quite low [41].
Despite efficient gene transfer in mouse models of muscular dystrophy, a major obstacle in the field of AAV-mediated gene transfer is the host immune response. Unlike rodents, large animal models such as dogs and non-human primates, as well as humans, are born with a fully developed immune system, and immune responses against both the viral vector and the delivered therapeutic protein have been observed [42, 43, 44, 45, 46, 47••]. This highlights the need for pre-clinical testing in large animals before trialling in humans. In the only human trial to date of rAAV-mediated dystrophin gene transfer, intramuscular injections of a rAAV-minidystrophin into the biceps of six patients induced a minidystrophin-specific T cell immune response from as early as day 15 post-vector treatment in at least one patient, with none of the six patients displaying significant levels of vector-delivered dystrophin [45, 46]. Some of the patients also displayed elevated T-cell immune responses against the AAV vector [42]. Priming of the dystrophin T-cell activity was thought to have occurred through low levels of dystrophin that are produced naturally in rare, so-called 'revertant fibers' found in most DMD patients [45]. Recently, it was shown in a study of 70 DMD patients that ~28 % have anti-dystrophin T-cell immunity, with increasing age correlating with increased risk of anti-dystrophin immunity [47••]. Transient immunosuppression has been shown to be effective in preventing activation of T-cell-mediated immune responses and maintains production of vector-delivered microdystrophin in dog DMD models [48, 49], suggesting a need to incorporate an immunosuppressive regimen in future clinical trials.
In addition to cell-mediated responses to the AAV and therapeutic proteins, there have also been reports of pre-existing antibody (humoral) immunity against AAV (including AAV6) in some large animal models, especially in non-human primates and dogs [50, 51•, 52]. However, other groups have found no [53] or low titers of anti-AAV6 pre-existing neutralizing antibodies (NAbs) in dogs [54], suggesting that the source of the animals can skew results. NAbs against AAV2 have also been reported in many patients [46], and cross-reacting antibodies can cause sero-positivity against other serotypes [46, 53, 54, 55]. Proper patient screening and careful NAb titering are thus critical prior to future trials, which can also aid in selecting the AAV serotype with the best chance of success for particular patients.
A number of novel methods are being developed to overcome NAb inhibition and enhance gene transfer. Recently, it was found that empty AAV vehicles (i.e., carrying no genes) could act as "decoys" for NAbs when co-delivered with AAV vectors carrying a therapeutic gene [56]. Removal of NAbs by plasmapheresis can also enhance gene transfer [57•]. Directed evolution of AAV vectors is another strategy to enhance muscle tropism, overcome pre-existing neutralizing antibodies and allow for readministration with variants of the original vectors as required [46]. Other methods to reduce immune rejection include the use of muscle-specific gene regulatory switches to prevent protein production in non-muscle cells [58, 59, 60], sequence-optimization of the therapeutic gene to be delivered to reduce vector dosage [61], and thorough purification from contaminating viral gene products during vector preparation [27].
An increasing focus is being devoted to developing methods to deliver genes to dispersed muscle groups by using vector perfusion into the vasculature of isolated limbs. This approach includes the use of vascular ligatures, compression bandages or recirculation in the limb to increase gene transfer [48, 62, 63], simultaneous perfusion with agents that promote vector exit from capillaries to underlying muscles, such as histamine [64] and vascular endothelial growth factor [65], or delivering vector using high pressure injections [66, 67]. Importantly, efficient cardiac gene transfer, which is critical for DMD therapies, was achieved by direct "transendocardial injections" of rAAV vectors, with rAAV6 demonstrating the greatest cardiac targeting compared to rAAV8 and rAAV9 vectors in canine and non-human primate models [54, 68•]. In this method, vector is injected directly into cardiac muscle using catheters inserted into the cardiac vasculature. Direct infusion of vector via the jugular vein using rAAV6 and rAAV8 also resulted in good transgene delivery to canine heart and diaphragm [48, 69], with homogeneous gene expression being obtained in the heart 2.5 months after infusion [69]. Widespread gene delivery to the canine skeletal musculature was also achieved with rAAV9, though with relatively poor delivery to the heart [70, 71].
AAV vectors are also being used as a vehicle to deliver antisense oligonucleotides (AONs), since AONs by themselves have not worked well in the heart [72]. Embedding the antisense DNA sequence into an AAV vector carrying a small nuclear RNA (snRNA) particle protects it from degradation and improves the efficiency of pre-mRNA splice site modulation. A single administration of a rAAV expressing an ASO gene restored dystrophin expression and ameliorated pathology in muscles of dystrophic mice [73, 74]. Although the level of dystrophin restoration will decline over time as AAV vectors are lost, thus requiring repeat injections, recent studies in mice showed sustained exon skipping in the heart after 1 year [75]. Based on these promising results, AAV-mediated exon skipping is currently in preclinical stages to treat DMD patients (http://clinicaltrials.gov/ct2/show/NCT01385917).
Surrogate Genes
Delivery of surrogate genes, such as utrophin, could also potentially circumvent an immune response against dystrophin in DMD patients. Utrophin is a close evolutionary relative (paralog) of dystrophin, sharing 80 % amino acid sequence identity, and is normally produced in muscle at the neuromuscular and myotendinous junctions. Utrophin has also been found to partially compensate for the loss of dystrophin in DMD patients and animal models. rAAV-mediated delivery of microutrophin performed favorably relative to microdystrophin in dystrophic mdx:utrophin−/− (double knock out, dko) mice [76]. Upregulation of utrophin by treatment with SMT C1100, an orally bioavailable small molecule utrophin modulator, partially reversed dystrophic pathology in mdx mice [77•]. A phase 1B clinical trial of SMT C1100 commenced in December 2013 and is being carried out by Summit, a UK-based drug discovery company. In addition to utrophin, rAAV-mediated transfer of follistatin, a muscle-building gene, improved histology and increased muscle mass and strength in mdx mice and non-human primates [78]. It is in the phase 1 clinical trial for patients with BMD and Sporadic Inclusion Body Myositis (http://clinicaltrials.gov/ct2/show/NCT01519349). Recently, rAAV-mediated co-delivery of microdystrophin and follistatin was shown to fully restore force and resistance to eccentric contraction-induced injury in aged mdx mice, thus presenting a viable treatment option for DMD patients with advanced pathology [79•].
Cell Therapies
One caveat for dystrophin replacement therapies is that effectiveness in patients is dependent on both the number of remaining myofibers and the degree to which fibrotic connective tissue might limit the accessibility of myofibers to AAV vectors or small molecules. For patients in advanced stages of the disease, the use of gene replacement/correction in conjunction with cell therapies would likely have the greatest potential for an effective therapy.
While gene replacement therapies typically aim to stop the progression of muscle degeneration, cell therapies carry possibilities of both halting disease progression and restoring lost muscle mass. Resident muscle stem cells, termed satellite cells [80], are responsible for normal muscle maintenance and essential for muscle regeneration following injury [81, 82, 83]. Upon injury, satellite cells are activated to both self-renew and give rise to pools of proliferating myogenic progenitor cells (myoblasts), which fuse to repair damaged myofibers [83]. Throughout constant bouts of injury and repair in DMD patients, the capacity of resident satellite cells to self-renew and replenish injured muscle eventually diminishes, contributing to significant loss of muscle mass and function. A major feature of DMD is therefore a loss of regenerative capacity, and hence it could be amenable to stem cell therapy.
Based on promising results in animal models [84], cell therapies for DMD initially focused on local intramuscular injections of myoblasts derived from healthy donors to re-introduce dystrophin expression in muscles of DMD patients [85, 86, 87]. Unfortunately myoblast transfer strategies have thus far failed to produce adequate therapeutic effects, in part because of issues of poor survivability, limited migration from the injection site and immune rejection of transplanted cells [85, 88, 89, 90]. Expectations have been further tempered by challenges in expanding sufficient numbers of myogenic stem/progenitor cells in culture while preserving their ability to self-renew and efficiently engraft in vivo [91]. However, these early observations helped identify hurdles that needed to be overcome to improve treatment outcomes.
These findings led to the exploration of alternative cell sources with myogenic potential that could be more easily grown in culture while also being able to distribute to a wider range of affected muscles following systemic, intravascular delivery. Bone marrow-derived stem cells as well as muscle blood vessel-associated cells such as pericytes and mesoangioblasts (MABs) were shown capable of contributing to muscle regeneration, albeit with lesser efficiency than traditional myogenic stem/progenitor cells [92, 93]. Promising cell candidates eventually emerged, including MABs for which phase 1/2 clinical trials relying on transplantations of MABs derived from healthy HLA-matched donors are in progress (EudraCT no. 2011-000176-33). The next goal was to generate MABs from a dystrophic patient, correct the genetic mutation during cell expansion in culture, then transplant the corrected cells back into the patient (an approach known as ex vivo gene therapy). However, a recent report showed a drastic reduction of MABs in dystrophic patients, thereby limiting the ability to obtain sufficient number of cells for transplantation [94].
Induced pluripotent stem (iPS) cells have recently gained attention in re-programming strategies aimed at "manufacturing" ideal cell candidates that fulfill many of the identified needs for successful stem cell therapies of DMD. These iPS cells can be "induced" to a pluripotent, stem cell state by addition of several combinations of transcription factors important during early embryonic development [94]. iPS cells harbor virtually limitless expansion potential during which dystrophin vectors can be re-introduced to correct or bypass the genetic mutation [95, 96]. Corrected iPS cells can be subsequently directed toward adopting myogenic fates using various techniques, such as gene transfer of myogenic determination factors, and serve as a patient-specific cell source for autologous transplantation. Successful re-programming of iPS cells into stem/progenitor cells capable myogenic differentiation has been reported following gene-transfer of the regulatory genes encoding MyoD, Pax7 and Pax3 [97, 98••, 99].
MyoD is an extremely important regulator of gene transcription in muscle, which plays a key role during muscle regeneration where its expression in muscle stem (satellite) cells precedes myogenic differentiation [100]. The potency of MyoD for inducing myogenic fates in both muscle and non-muscle cell types has been well documented [101, 102]. A recent study aimed at stimulating muscle differentiation in human iPS cells modified with a MyoD gene that could be turned on or off reported up to 90 % myogenic reprogramming efficiency in vitro with the ability of reprogrammed cells to engraft into dystrophic muscles [97]. A possible drawback of using MyoD is that its expression leads to irreversible muscle differentiation, potentially reducing the chance for transplanted cells to become muscle stem cells (rather than myofibers) within transplanted muscles. However, recent data have indicated that subsets of iPS cell-derived MyoD-expressing cells are capable of forming muscle stem cells and engrafting into regenerating myofibers [103].
Other transcription factors that control the decision of stem cells to become myogenic cells are also attractive gene-transfer candidates to generate new muscle stem cells. Pax7 plays a key part in the function of satellite cells and is indispensible for adult skeletal muscle regeneration following injury [82]. The transcription factor Pax7 has also been used to convert human iPS cells into a muscle fate, and those cells were also able to partially restore dystrophin expression, generate new satellite (stem) cells and improve muscle function following transplantation into dystrophic mice [104]. Pax3, like Pax7, is expressed during myogenesis as well as embryonic development of non-muscle lineages such as those giving rise to the peripheral nervous system and melanocytes [105]. This necessitates careful sorting of cells derived via forced Pax3/7 gene expression in order to separate non-myogenic and possibly tumorigenic cells from myogenic cells prior to transplantation. Similarly, a version of the Pax3 transcription factor was used to generate myogenic stem cells from iPS cells genetically corrected with a micro-utrophin gene [98••]. Following activation of the Pax3 gene, cells were allowed to differentiate in culture prior to cell sorting for markers normally found on mesodermal cells destined to form muscle. The resulting stem/progenitor cells exhibited typical myogenic differentiation characteristics in culture and were able to generate functional microutrophin-expressing myofibers, migrate to stem cell harboring sites in muscle and improve muscle function following intramuscular injection into dystrophic mice [98••]. Importantly, these cells were also able to disseminate to several affected muscle groups following intravenous delivery.
iPS cells could potentially also solve the issue of obtaining sufficient MABs from dystrophic patients for autologous cell transplantation therapies. In two recent reports, iPS cells derived from both mice and humans with limb-girdle muscular dystrophy (LGMD) or DMD were used to generate α-sarcoglycan- or microdystrophin-corrected MABs for transplantation studies in immunodeficient mouse models of each condition [94, 103]. Following intramuscular and intraarterial administration, gene-corrected MABs were stimulated to adopt myogenic fates using an inducible version of MyoD [102]. Induced MABs engrafted a majority of affected muscles where they both fused with myofibers and formed new satellite/stem cells. Engrafted muscles exhibited a restoration of up to 25 % of normal expression levels of the mutant gene as well as significant morphological and physiological improvements. While promising, further studies are warranted to determine the safety and efficacy of these cell therapy approaches before translation into patients.
Development of therapeutics for the muscular dystrophies had progressed from basic studies in mice to ongoing early phase human clinical trials. While none of the methods being tested has yet risen to the level of a cure or major therapy, multiple approaches are showing significant promise, and it is becoming clear that treatments can and will be developed. It will be important to continue refining current approaches in animal models while expanding testing in patients. Recent clinical results also serve as a reminder that early encouraging success is no guarantee of long-term benefit, and it will be important to seek alternative strategies while refining those approaches already in advanced stages of testing.
We thank John Hall for critical reading of the manuscript. Supported by NIH grants R37AR40864 and R01AG033610 (to JSC). JTS was supported by an Early Career Fellowship from the NHMRC of Australia (Grant No. 1036656).


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Enjoy a healthy lifestyle for less, with our discounted products and services through UnitedHealth Allies®.
UnitedHealth Allies is administered by HealthAllies®, Inc., a discount medical plan organization located at 505 N. Brand Blvd., Suite 850, Glendale, CA, 91203, 1-800-860-8773. UnitedHealth Allies is not insurance. UnitedHealth Allies provides discounts at certain health care providers for medical services. UnitedHealth Allies does not make payments directly to the providers of medical services. The program member is obligated to pay for all health care services but will receive a discount from those health care providers who have contracted with the discount plan organization.Learn More (PDF)
Take advantage of discounts on frames and lenses, or even a discount on laser vision correction surgery.
Please note - if you have vision coverage through State of Texas Vision, contact Superior Vision for plan benefits and coverage information.
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To learn more, login to your account and click on "Providers and Facilities" and "Find Vision Care". You will need to provide your member identification information from your Medical ID card. Note - the vision care web pages will open in a new window. Close the newly opened window, if you wish to return to your myuhc.com/hs homepage.Learn More (PDF)
Find mental health and substance abuse resources when you login to your online account and click on "Behavorial Health".
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Mid-Week Advent services at Risen Lord Lutheran Church
Risen Lord Lutheran Church is having a mid-week advent service on Wednesdays starting at 7 p.m. with a soup supper prior to the service starting at 6 p.m. Risen Lord Lutheran is located at 5138 Taylorsville Road, Taylorsville. If you have any questions, please contact the church at 477-6557.
Tickets now on sale for annual Community Tree of Life
Tickets are on sale for the annual "Community Tree of Life" Christmas musical presentation which depicts the Biblical story of the birth and life of Christ.
I know it isn't even December yet, but do you feel it? The holiday season is upon us in full strength. Some TV networks are running Christmas programming 24 hours a day. The stores have had trees and decorations up since before Halloween. I'm exhausted already.
Volunteers from at least six different churches took part in serving the Community Thanksgiving Meal on Wednesday evening at Taylorsville Community Church. The free meal featured turkey and all the trimmings and was an outreach effort by the area churches.
The holiday season is well under way. Many of you enjoyed a bountiful Thanksgiving feast with your loved ones and will do so again during Christmas and New Year's Day.
It is hard to believe that the holiday season is upon us. I have family visiting for Christmas, so this means a bigger tree than normal; if you are going to travel to come see us, this is the least I can do. Plus, it is fun to find the "perfect" tree that fits your space and holds precious ornaments with style.
Once autumn leaves have fallen, mistletoe becomes highly visible on large trees throughout Kentucky. Phoradendron, the scientific name for Kentucky's most common variety of this parasitic plant, means tree thief. These small leafy plants are commonly found on twigs and branches of many hardwood species in the southern United States. Mistletoe extracts—steals— water, mineral elements and food from tree hosts; hence the name.
It that time of year when talk turns to turkeys. Technically, there is only one breed of turkey, with several varieties, although many people incorrectly refer to these varieties as breeds.
Turkeys are raised only for meat. They are not raised for egg production, as with chickens, ducks and quail. As a result, turkeys do not produce very many eggs.
The most common type of commercial turkey raised in the United States is the Broad-Breasted White. It has a larger breast than the other varieties of turkeys.
Free Thanksgiving Meal sponsored by local churches tonight
There will be a free Thanksgiving Meal served at Taylorsville Community Church as several local congregations are coming together to provide the meal on Wednesday, November 23 from 6 p.m. until 7:30 p.m. In addition to the free meal, there will also be complimentary family portraits taken. The church is located at 402 Garrard Street.
Tickets now on sale for annual Community Tree of Life
Copyright © 2017
The Spencer Magnet is your source for local news, sports, events, and information in Spencer County, KY and the surrounding area.


text:
Luna: Can't take much more
When Jason tourtured Loki a sob had escaped my lips. I stopped it with my hand and Dracula had heard. He looked at me amused.
I couldn't watch this is was just....... I can't take much more.
I turn on my heels and ran out of the room.
"Excuse me.... Loki find books for him with stronger tourcher spells" Dracula says behind me.
Then he's persuing me. And of course he gets me before I reach the door.
He drags me into a room.
"Let go of me" I shout trying to hit out at him.
He pins both my arms above my head in on grip then lightly stands on my feet but it holds them down.
"I don't think so" he says sternly.
"I just want to go home" I whisper.
"No, you'll be staying here" he says tilting up my chin. He smiles suddenly and I struggle before he presses his lip down on mine.
Then I just stop struggling. I mean there's no point and I hate to admit but...... him kissing me feels quite nice. He pulls back.
"You will be in this room" he says sternly then he's gone locking the door behind him.


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St. Petersburg, Fla. -- The Sembler Co. has added nearly 900,000 sq. ft. to its portfolio of third-party management and leasing assignments through the end of the year's second quarter.
New assignments include co-managing 672,259 sq. ft. of retail properties across Florida and Georgia with Community Reinvestment Partners II. Sembler will handle leasing for most of the properties.
Sembler has also taken on leasing and management assignments for a 75,000-sq.-ft. center in Windemere, Fla. and a 140,000-sq.-ft. center in Jacksonville, Fla.


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Category:Christ Church and Upton Chapel
This is a category about listed building number 1358233. (More images)
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Apartments Bibione & Bibione villa - lovely Bibione holidays!
Latest reviews
Imagine a holiday destination with wide golden beaches, calm shallow sea, crystal clear water and constant refreshing breeze. All that could become a reality if you chose to take a vacation in Bibione, Italy. Located just a few miles north of Venice, Bibione is an incredibly popular seaside resort with a relaxed and friendly atmosphere that makes it an ideal family holiday location. The inviting sandy beaches, which, due to their ideal location, attract the sun from morning until dusk and the surrounding natural beauty, typified by a lush cool pine forest, a promise unadulterated seaside fun as well as superb natural surroundings. You will definitely not run out of interesting activities to indulge as you explore this beautiful resort. The long beaches are perfect for a number of games and sporting activities such as beach volleyball, tennis and football. There are also a variety of fun outdoor activities that will keep you occupied during your holiday Bibione including cycling, surfing sailing and shopping. Taking a leisurely walk around the area will allow to to find your bearings in this region as well as presenting you with an opportunity to discover Bibione's diverse animal and plant population. Other tourist attractions worth a visit include the famous Casoni, the Bibione Lighthouse, the fishermen cottages and the deep, blue lagoon.
Holiday apartment Bibione & Holiday villa Bibione - a great place to stay
There is also a weekly market which takes place every Tuesday selling fresh produce and knick-knacks made by local artisans. With low prices and a lively Italian atmosphere, it's the perfect opportunity to splash the cash on some souveneers for your friends and family. The fresh produce attracts budding chefs and restaurateurs from all over the local area. Famous for its delicious, fresh ingredients, why not treat yourself to some of the freshly caught fish, a few crisp spears of asparagus and a bottle of regional wine and have a go at cooking one of Bibione's famous dishes, such as moonlight salad and tagliolini – guaranteed to tantalize your taste buds! After a long fun-filled day, you may well be tempted by the exclusive Bibione Spa Centre. Fully equipped with the latest equipments as well as variety of thermal treatments, the Spa Centre is a perfect place to relax and unwind in your holiday Bibione. If your budget won't quite stretch to cover a few treatments here though, don't worry – there's plenty of relaxation to be enjoyed within your Bibione apartment or villa. Indeed, sometimes, it's the simple things in life that prove to be the most effective stress-busting techniques. After just a few minutes sat basking in the evening sun on you Bibione holiday home terrace, the tensions of city life will fade away as the pink-orange sun sinks towards the horizon.
Looking for more great beach holiday destinations in Italy? Have a look on these lovely spots as well:
- Catania on the east coast of Sicily
- Pescara in Abruzzo-Molise
Rimini - one of the most famous beach resorts in Italy
Holiday Bibione - have a great time in Italy
In order to fully experience all that this seaside resort has to offer you need to find cosy Bibione accommodation to suit your tastes and preferences. Fortunately, we offer a wide variety of apartments Bibione and Bibione villas for you to choose from. With their tastefully furnished rooms equipped with all the mod-cons you could possibly need, spending your vacation in one of our Bibione apartments will guarantee a comfortable and relaxing break. Whether you plan to spend your vacation exploring all that Bibione has to offer or whether you prefer to enjoy the luxury between the four walls of your holiday home, the excellent locations of our Bibione apartments and villa will ensure a good time is had by all. And did you know that Slovenia is just a hundred kilometers away from Bibione? The Adriatic Coast of Slovenia is one of its most popular holiday regions. Surely a great opportunity to yet get to know another fascinating culture as well!


text: In late February, I wanted to try to learn how to graft, but seeing no capped drones, I gave up on that idea. However, since I now had shallow supers under the deep, I reversed them again. The supers that were above the bottom two had a mixture of brood and honey, with the uppermost box being empty. I alternated the empty frames with full ones. I didn't realize until I read your article on this website that I probably shouldn't have messed with the brood frames, but I guess when I broke up the honey dome, even though at the time I really didn't understand that. I also got pretty lucky with the temps above freezing and plenty of rain, so I didn't do any damage by trying things too early.


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- Coal Miner
- Join Date: 9/22/2010
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This thread was marked as Locked by citricsquid.
02-16 06:32:00 [SEVERE] Unknown biome "lionking.common.LKBiomeGenAridSavannah.Arid Savannah" 02-16 06:32:00 [SEVERE] Most likely, there is a biome ID conflict @170 02-16 06:32:00 [SEVERE] No conflict found. Most likely the biome was loaded after MSC. Tell the author of the mod to initialize their biomes during their load method.
Quote from RosyQ
I'm going to be streaming this, starting today. I'm planning to go live in about an hour or so, around 8 pm GMT+1. Feel free to drop by for lots of derp and the wonder of first exploration of this mod. twitch.tv/luciouslisa
Edit: The stream is now over. It lasted for ~3 hours and you can see the recording here. First impression: I absolutely LOVE this mod! Thanks for creating it, Mevans. <3
Quote from stevesteve223
THE MOD IS AWESOME but it crashes my game every time I try to enter the pride lands
Quote from Stet709
I showed this mod to my friend and his brother (who likes this mod as much as I do [maybe even more]) and my friend's brother brought up a question i haven't thought of until now.
"will the ticket booths show up in older maps before the mod was installed or is it just all maps created after the mod installation?
Quote from Mevans
Oh, so you've not used the mod before? Glad you enjoy it! I'll be having a look at that recording too.
Quote from RosyQ
No, I hadn't used it before. It's great though, I really enjoy playing it and my viewers seem to like it as well. I just finished a stream again, so you'll have some catching up to do.
I think I've found a bug btw. I found a dungeon, but not only does the spawner not show any mobs, but it also doesn't seem to work at all. Even in full darkness nothing spawns.
Quote from mrtonic
keep trying some times fixs or download it on skydaz just search skydaz mods
That link installs properly or it does for me it might fix the problem
post me back if the install fixed it
Quote from Saraman
I don't know if this has been reported yet or if I'm the only one experiencing this bug
When ever i go in the portal Minecraft crashes


text: BLOOMFIELD HILLS, Mich., March 22, 2012 /PRNewswire/ -- Taubman Centers, Inc. (NYSE: TCO) today announced the opening of City Creek Center in Salt Lake City, Utah. Thousands of visitors from near and far attended the grand opening of the only regional shopping center to open in the United States this year. According to the International Council of Shopping Centers, City Creek Center is the first enclosed regional shopping center to open in the United States in six years. (Photo: http://photos.prnewswire.com/prnh/20120322/DE74907) (Logo: http://photos.prnewswire.com/prnh/20080428/CLM116LOGO) City Creek Center is the retail component of City Creek, the 23-acre, mixed-use development on three blocks in the heart of downtown Salt Lake City. Architects, civic leaders, businesses and journalists from around the world were among those who came to see, tour and shop the 700,000-square-foot shopping center. Designed to showcase Utah's natural beauty, the unique indoor/outdoor space features a retractable roof, a 140-foot skybridge over Main Street, a 1200-foot-long re-creation of the historic City Creek, two 18-foot waterfalls and three fountains from the creators of the famed Bellagio fountains in Las Vegas. Nordstrom and Macy's anchor City Creek Center's world-class retail offerings. Of the 100 stores and restaurants, one-third are unique to the Salt Lake City market or the state, including Tiffany & Co., Michael Kors, Coach, Tumi and Brooks Brothers/Brooks Brothers Women. "Of the 100 stores and restaurants, we are pleased to open with 92 retailers today, with three more opening later this year," said Robert S. Taubman, Chairman, President and CEO of Taubman Centers. "The commitment of these retailers is a confirmation of their belief in the rebirth of downtown Salt Lake City." City Creek Center brings shoppers a variety of unique amenities, including a prehistoric-themed children's play area located in the Food Court, free wireless Internet access, a sidewalk snow-melt system, an outdoor fireplace and an airline flight monitor so travelers can check on their flights while they shop. The shopping center is also dog-friendly, as are many of its stores.


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Accommodations in CibeureumSee All
Explore popular vacation packages for Cibeureum, Indonesia and kick-start your vacation planning for free. Cibeureum is located at a short trip away from Jakarta a major city in Indonesia. Take a short trip from Cibeureum and set some time aside to explore the Jakarta. Dotted with places like Monas, Taman Mini Indonesia Indah, Ancol Dream Park; it will definitely be a good idea. A holiday in Cibeureum can generally be of 1-2 days.
Cibeureum is an affair to remember, follow this apt itinerary of the place and return home with a bunch of memories.
Explore the best journey planner for your visit to Cibeureum and create a flawless plan in few simple steps!
You may also be in interested in other popular destinations in Indonesia like Jakarta, Kuta, Manado


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Out of scores of complex geometric coloring pages, this one has an Oriental design of knotted lines in interwoven squares all centered in a pattern circular pattern. This PDF prints to 8.5x11 inch paper.
ColorWithFuzzy › 70+ Geometric Pages › Complex Geometric Coloring Pages
My PDF printable coloring pages are fun to customize and color. Add your name or write a birthday message in your favorite fonts, SIZES, and colors. You'll love my interactive coloring pages to print!
Get your favorite crayons, coloring pencils, and watercolors for my relaxing adult coloring pages! ~Fuzzy


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Check Out the new Remax App
Ask About This Home
This elegant 5 bedroom, 3 full & 2 half bath executive home sits on 5+ wooded, landscaped acres in one of McComb's most elite neighborhoods. The floor plan is ideal for entertaining. A foyer leads through beautiful French doors into a formal dining room, or straight ahead to a great room overlooking an expansive patio and pool area. Even with 20' high ceilings, this room is made cozy by a wood burning fireplace that has been converted to gas logs. The gourmet kitchen features top-line appliances, plus a breakfast area overlooking the patio/pool area. The large master suite has its own private patio and a huge walk in closet. A media room downstairs is equipped with surround sound speakers and provides the perfect place to enjoy movies and popcorn. And a study off the master suite includes office furniture. Exquisite floor and counter finishes include brick, hardwood, ceramic, and granite. Three full and two half baths make sure nobody has to wait in line. Also includes a huge workshop.


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National Geographic Magazine
National Geographic Magazine is the global leader in empowering people to navigate the world, providing authoritative, unbiased content that addresses today's complex issues, while uncovering the wondersof our time. Each issue captivates millions of curious readers withworld-class, award-winning photography and reporting that inspire them to make informed decisions and effect positive change. As part of the world's largest non-profit scientific, education, and entertainment organizations, National Geographic has unmatched reach to a national audience that influences opinions on the Beltway, in the board room, in Silicon Valley, and beyond.
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As coal industry sputters, some miners are moving on, Cleveland Fed study finds
Donald Trump promised 'to bring the coal industry back 100 percent.' Hillary Clinton was forced to walk back a remark about putting it 'out of business.' But a new study by the Federal Reserve Bank of Cleveland finds laid-off coal miners are beginning to bow to the inevitable and train for jobs in other industries.


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HiRise for iPhone 5, iPhone 6 + iPad Mini
Having your iPhone elevated by HiRise means you can FaceTime or Skype hands-free. Because HiRise lifts your iPhone in the air, it doesn't block or muffle your microphone or speakers. Speakerphone calls are crisp and clear. HiRise is also awesome for keeping an eye on your favorite iOS apps, like those for news, weather and sports scores.


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Item: BLU095
5,000 mcg of vitamin B12 in each serving
Natural raspberry flavor
Vegan friendly and gluten free
5,000 mcg 2 fl oz (59 mL) Liquid
Serving Size 1 Dropper (1/5 teaspoon or 1 mL)
Servings per container 59
|Amount Per Serving
|% Daily Value
|Vitamin B12(methylcobalamin)
|5,000 mcg
Daily Value based on a 2,000 calorie diet.
Other ingredients: Purified water, fructose, natural raspberry flavor, citric acid, sodium benzoate.
Directions: As a dietary supplement, take one full dropper (1/5 teaspoon or 1 mL) under the tongue daily or as directed by a healthcare practitioner.
Shake well before serving.
Refrigerate after opening.
CellularActive® is a registered trademark of Bluebonnet Nutrition Corporation
.33 lbs
5,000 mcg of vitamin B12 in each serving
Natural raspberry flavor
Vegan friendly and gluten free
With its natural raspberry flavor, Bluebonnet Liquid Methylcobalamin Vitamin B12 is a delicious way to get a serving of this important B vitamin. Vitamin B12 may be best known for supporting energy production, but it also plays a role in maintaining cardiovascular health. Free of milk, egg, fish, crustacean shellfish, tree nuts, peanuts, wheat, soybeans, yeast, gluten, barley and rice.
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We are dedicated to offering the highest quality products at the best price. Find out more about how we ensure such a high standard in everything we do.Learn More
5,000 mcg 2 fl oz (59 mL) Liquid


text:
Kindergarten Cop 2 DVD
£4.49 Available Ask us a question about this product
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Kindergarten Cop 2 DVD Product Description
Please note this is a region 2 DVD and will require a region 2 or region free DVD player in order to play.Don Michael Paul directs this sequel to the 1990 comedy 'Kindergarten Cop'. Dolph Lundgren stars as FBI Agent Reed who is required to go undercover as a kindergarten teacher in order to retrieve stolen data concerning the Witness Protection Programme. The key to getting the information back could well be the children themselves, but has all of Reed's rigorous training prepared him for his latest assignment? The cast also includes Bill Bellamy, Sarah Strange and Aleks Paunovic.
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text: Cognitive Testing Dr. Robert Coen Mercer's Institute for Research on Ageing St. James's Hospital, Dublin 8 1st National Memory Clinic Conference What is a memory clinic? Memory Clinics have been defined as independent clinics primarily aimed at improving practice in the identification, investigation and treatment of memory disorders, including dementia (Jolley et al 2006). Memory Clinics are primarily concerned with the early diagnosis and treatment of memory problems (Lindesay et al 2008). The focus on the individual needs of the person with early stage dementia is a characteristic that differentiates Memory Clinics from other dementia care services. "Memory Clinics in Ireland. A Guide for Family Members and Health Care Professionals" Compiled by Suzanne Cahill and Laura Maher in association with the Living with Dementia (LiD) Programme, School of Social Work and Social Policy, Trinity College Dublin and the Dementia Services Information and Development Centre (DSIDC), St James' Hospital, Dublin The process of assessing for dementia. (i) In a memory clinic cognitive assessment has key role in (i) establishing is there a problem (ii) Differential diagnosis From Hodges, Early Onset Dementia (ii) What level of detail is needed? • Screening? • Differential diagnosis? • Detailed neuropsychological analysis? MMSE > MoCA / ACE-R > CAMCOG > RBANS WAIS / WMS etc…. or a detailed specialist query e.g. what type of PPA (nonfluent, semantic, logopenic?) e.g. lobar vs AD BADS / DKEFS / FrSBe / VOSPB etc…. How early? • Alzheimer's Association International Conference on Alzheimer's disease, July 2010: first draft reports from 3 workgroups convened by National Institute on Aging (NIA) and Alzheimer's Association http://www.alz.org/research/diagnostic_criteria/ • Revised Criteria for Alzheimer's disease Dementia • Criteria for Mild Cognitive Impairment (MCI) due to AD – The symptomatic pre-dementia range of cognition and function • Criteria for Preclinical AD (up to 10 years before MCI stage) – It is likely that measured change in cognition over time will be more sensitive than any one-time measure. – Additional longitudinal studies of older individuals, perhaps combining biomarkers with measures sensitive to detecting very subtle cognitive decline, are clearly needed. Case characteristics vary • Type and severity of deficits very mild vs immediately evident… • Pre-morbid ability IQ 90, IQ 130… • Age, health status etc… Differential tolerance for testing… • Different cases will require a more or less detailed battery - testing should be tailored to the individual to address the referral question • Administered by whom? - depends on what's being administered…. Who should do the cognitive testing, using what tests? • That will depend on how detailed the testing needs to be • Many brief screening tests do not need specialist knowledge and training (though that's always desirable if available) • More detailed tests require a trained specialist or input from a trained specialist in interpreting the results – "Targeting neuropsychological tests at the appropriate level requires skilled judgement. Understanding the implications of this heterogeneity for diagnosis, intervention and advice requires the special skills of a clinical psychologist or clinical neuropsychologist". (British Psychological Society survey of UK Memory Clinics) Importance of Specialist interpretation Staffing Neuropsychologists are "optional" because (i) Not everyone needs detailed neuropsychological assessment (ii) They are as rare as hen's teeth….. "Diagnosis and Management of Dementia. A manual for memory disorders teams". Wilcock, GK et al Uni Press 1999. Is there one set of tests that everyone should use? Is there one set of tests that everyone should use? • No T ab le 2: Sum ma r y of ne u ro p s y ch o lo gi c al a n d o th er te sts T est Est im a ti o n of Pr em orb id IQ N atio n al A d u lt R e a di n g T est (N ART ) Sch o n e ll G ra d ed W o rd R e a d ing Test S p e e d a n d C a pacity of L a n g u a ge L e arn ing T est (S C O L P ) Num ber of Clin ics 12 ( 5 2) 3 (1 3 ) 1 (4) Scr ee n in g T e s ts M ini M e ntal State E xa m inat ion (MMS E) Ca m b rid ge C o g n itive E xa m inati o n (CAMC OG) M id d lesex El d erly As s es s m e nt of M en tal Sta te (M E AM S) 12 ( 5 2) 8 (3 5 ) 7 (3 0 ) Cog niti v e S cal e s W echs ler A dult Int e llig en c e Sc a le (Ver s ions R evi s ed or III) Alz h e im e rÕs Dise ase As s es s m e nt Sca le (ADA S) 11 ( 4 8) 2 (9) M e m o r y S cal e s Ri v e rm e a d B e hav io u ral Me m o ry T est A d ult Mem ory a n d Info rm ati o n P rocess ing Batter y ( A MI P B) W arr ing ton Re c o g niti o n M em ory Te st (WRMT ) W echs ler M em ory Sca le - R evis e d (WM S -R ) D oors a nd P e op le Test 7 (3 0 ) 6 (2 6 ) 6 (2 6 ) 4 (1 7 ) 2 (9) Ve r bal L e a r ni n g Na mes L e a rn ing Test H opk ins V e rb al L e a rni n g Test (H VL T) R ey A u ditory Ve rb a l L e a rni n g T est (R A V L T) Busch k e S elective Re m ind ing Test 5 (2 2 ) 2 (9) 3 (1 3 ) 1 (4) E x e c ut ive Fu nct io n an d P ro blem S olv in g B e nton Ve rbal F lu e ncy (F A S) W ei g lÕs Colour F o rm S ort ing Test T rail M aki n g T ests Wis c ons in Ca rd S orti n g Tests (lo ng a nd s hort fo rms) R ave n ÕsP rog ressive M atrices (incl u d ing C o lo ur ed ) B e hav iou ral As s es s m e nt of Dysexe c utive Syn d rome (B AD S) C o g nitive Est im ati o n T est L angua ge an d S ema ntic Fu n c ti o n Gr a d e d N am in g T est S em antic Fl u ency F ren c hay A p h asia Scr e en ing T est (F A ST ) Py ram ids a nd Pa lm T rees S p ee d, visu o -pe r c ept ual skills an d pr a xis Vis u al O bject S pa c e P e rc e ption Battery (V O S P) 11 ( 4 8) 6 (2 6 ) 5 (2 2 ) 3 (1 3 ) 3 (1 3 ) 2 (9) 2 (9) 9 (3 9 ) 3 (1 3 ) 2 (9) 2 (9) 5 (2 2 ) From British Psychological Society survey of UK Memory Clinics Recent update of previous PSIGE 1998 survey • Tests used by Psychologists in Memory Clinics vary • Covering the appropriate domains is probably more important than the specific tests used… T ab le 3. Th e ran ge of fun ct io ns co ve re d in n e u ro p s y ch o lo gi c al te s ti n g 1.1 1.2 1.3 1.4 1.5 1.6 1.7 1.8 life -long intel lect u al le v el attenti o n a nd c o nc e ntrati o n ori e ntat ion (t im e, pla c e a n d p ers o n) visual, a u di tory a n d tactile per c ept ion visuo -s pat ial skills la n g u a g e c o m p re h e nsi o n (o ral a nd re a di n g) la n g u a g e exp ressi o n (re p etition, flu ency, na mi n g, w ritin g ) me m o ry funct ion ing (re c o g niti o n, le a rni n g, re c all ; ver b al, n on -v e rbal; imme dia te, de lay e d; ever y day m em o ry, in c lu di n g p ros p ective me m o ry) 1.9 executi v e (fr o ntal) fu nctio n in g 1.10 psych om otor s pe e d 1.11 praxis 1.12 arit hm etic 1.13 ever y day funct ion e .g. h a ndl ing m o n ey "No prescribed list of tests has been recommended because of the individual nature of client's strengths and deficits" From British Psychological Society survey of UK Memory Clinics Recent update of previous PSIGE 1998 survey What is a neuropsychological assessment? Neuropsychological assessment goes beyond psychometrics • Clinical interview • Formal testing - tailored to client and referral question • Interpretation in context of what we know about - brain-behaviour relationships - multiple other factors that can affect performance • tests are of limited usefulness by themselves and must be interpreted in conjunction with other clinical, imaging and laboratory information (AAN 1996) Multi-disciplinary consensus is crucial for assessment and diagnosis…. Factors associated with inconsistent diagnosis of dementia between physicians and neuropsychologists. McKnight, Graham, Rockwood (1999) JAGS;47:1294-1299 – Canadian Study of Health Ageing "Physicians and neuropsychologists have different, complementary approaches to the diagnosis of dementia, and a consensus approach should be used". Purpose of Neuropsychological assessment profile presence / absence of cognitive deficits – nature and extent of deficits early detection differential diagnosis intervention -> strengths / weaknesses monitor change over time Coen 2011, Aging Health, 7(1), 155-162 This kind of battery is going to need a Psychologist….. Green 2000 What relatively brief cognitive tests are readily available and can be recommended? • I will overview some of the tests we have found useful in our memory clinic in MIRA This overview is by nature very selective. There are a wide variety of tests available… But first some BASICS! – Age? – Education? – Gender? – Vision? – Hearing? –Motivation / engagement –Anxiety –Fatigue –Depression –Dysphasia –drugs (psychotropic, social) –psychosocial stressors –pain –physical illness…. Any of these factors can affect performance. Therefore qualitative aspects of assessment are every bit as important as the quantitative aspects • MMSE is widely used • Better the devil you know…? • Has just been revised into briefer, standard and longer forms • Now comes with norms for age and ed Clock Drawing Test • Quick and easy to administer….. • …..not so quick and easy to interpret. CDT scoring systems (not exhaustive!) • Freedman et al (1994). Clock Drawing. A Neuropsychological Analysis. [15 point] • Goodglass & Kaplan (1983). [12 point] • Shulman et al (1986 / 1993). [6 point] • Wolf-Klein et al (1989). [10 point] • Sunderland et al (1989). [10 point] • Tuokko et al (1995). [Manual. 15 point + errors] • Mendez et al (1992). [CDIS. 20 point] • Rouleau et al (1992). [10 point + qualitative] • Shua-Haim et al (1997) [6 point] • Watson et al (1993). [10 point] • Manos et al (1999). [segmented, 10 point] • Royall et al (1998). [CLOX. Executive(?) 16 point] Free drawn CDT. Case CK. AD. MMSE 19/30. Artist. 10 past 11 - "couldn't remember which hand should be long". Time inaccurate. Is the error due to Semantic breakdown or attention failure? Free drawn CDT. Case MK. DLB. MMSE 19/30. Free drawn CDT. Case PC. AD with prominent frontal involvement. MMSE incomplete. Drew circle. Then turned over page and drew the numbers. Could not be persuaded to put numbers in circle. Montreal Cognitive Assessment (MoCA). Nasreddine et al 05. Can detect significant impairment when MMSE is ok e.g. MMSE≥26/30 Less verbal than MMSE Attention / executive function items available as a free download MoCA Nasreddine et al 2005, JAGS • Sensitvity high for MCI (90%) and for mild AD (100%). MMSE (cut <26) was 18% and 78% respectively. • BUT what about specificity? • Nasreddine et al • Smith et al 2007 • Bleecke et al - Specificity 87% - Specificity 50% - Specificity 44% • Luis et al 2009. MMSE insensitive to MCI/mild AD • MoCA cut-off ≤26, sens 97%, spec 35% • MoCA cut-off ≤23, sens 96%, spec 95% • Therefore the lower cut-off is likely to be more accurate MoCA things to watch out for…(Coen et al 2011) • Memory component may be failed for several reasons – – – – Items have been forgotten Poor instructions during learning phase Poor encoding Retreval failure (check with optional cueing component) Addenbrooke's Cognitive Examination (ACE) • A brief cognitive test battery to differentiate Alzheimer's disease and frontotemporal dementia. Mathuranath et al., Neurology 2000; 55:1613–1620 • ACE is a 100-point test battery assessing 6 cognitive domains. It incorporates the MMSE. – Cut-off <88/100 has sens 94% and spec 89% for dementia – Cut-off <82/100 has sens 84% and spec100% for dementia • VLOM ratio [verbal fluency + language] / [orientation + memory] to discriminate FTD from AD using <2.2 for FTD, >3.2 for AD – >3.2 AD vs non-AD, sens 75%, spec 84% – <2.2 FTD vs non-FTD, sens 58%, spec 97% Addenbrooke's Cognitive Examination - Revised (ACE-R) ACE subsequently extensively revised (Mioshi et al 2006). They report similar sens and spec. VLOM ratio still recommended in ACE-R. Therefore the ACE-R provides a brief and reliable bedside instrument for early detection of dementia, and offers an objective index to assist in differentiating AD and FTD in mildly demented patients. available as a free download, with detailed instructions and 3 parallel forms MIRA - CAMCOG(-R) as core additional tests added as required Currently out of print….. Twelve RBANS subtests yield 5 Indices (mean = 100 ± 15): •Immediate Memory •Visuospatial/Construction •Language •Attention •Delayed Memory. Original norms are age graded New norms both age and education graded (Duff K et al 2003 Clin Neuropsychologist) Which set should you use? Note that this is a common problem with normed cognitive tests RBANS in TUDA • RBANS is one of the key cognitive instruments being used in the Trinity, University of Ulster and Dept of Agriculture (TUDA) Cohort study. – TUDA: collaborative research programme to create a nutritional phenotype / genotype database in cohorts of OPD patients with a range of conditions including hypertension, osteoporosis and cognitive decline, to examining links between diet, genetics and health in adults over 60 years of age. • Clinical observation of the first 400 or so TUDA participants suggested that more were exhibiting cognitive impairment on RBANS than expected. • To compare norms RBANS was administered to 436 community dwelling elderly out-patients attending St. James's Hospital enrolled in the TUDA Study. Results • Using Manual norms 368 (84%) were impaired on at least one RBANS Index (see table below for % failing each). • Only 275 (63%) were impaired using Duff age & educationcorrected norms, which was considered more in line with clinical observation. Imm e di a te Me m ory Vi s u o sp a ti a l/ L a n g u a ge C o nstr u ct io n Atte n tion Delay e d Me m ory Ma n u a l no rms 205 /436 (47%) 234 /436 (54%) 147 /436 (34%) 216 /436 (50%) 235 /436 (54%) Duf f a ge correct e d 113 /436 (30%) 182 /436 (42%) 136 /436 (31%) 209 /436 (48%) 174 /436 (40%) Duf f a ge & e du correct e d 62/ 4 36 (14%) 167 /436 (38%) 123 /436 (28%) 154 /436 (35%) 130 /436 (30%) Interpreting RBANS The Clinical impression was that the Manual norms rate of "cognitive impairment" (84%) was excessive. Implication: The Manual norms may "pathologise" individuals who are not cognitively impaired. Subsequent chart review, which is almost completed, supports the above impression. The original norms do pick up on some cases missed by Duff norms, but the majority appear Clinically normal. This reinforced User Qualifications in RBANS Manual: "…easily administered and scored by clinical psychologists, speech pathologists, physicians and other health care professionals with experience in mental status assessment." "…the test results should ultimately be interpreted only by individuals with appropriate professional training in neuropsychological assessment" recommended reading - from brief cognitive testing to detailed neuropsychological assessment • Cognitive assessment for clinicians. Kipps, CM, Hodges, JR. J Neurol Neurosurg Psychiatry (2005); 76(Suppl 1), i22-i30 • Assessment: Neuropsychological testing of adults. Considerations for neurologists. Report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology (1996); 47, 592-599 • A review of screening tests for cognitive impairment. Cullen, B., O'Neill, B., Evans, J.J., Coen, R.F., Lawlor, B.A. J Neurol Neurosurg Psychiatry (2007); 78, 790-799


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A controversial law that facilitates redevelopment of old buildings by private developers is likely to be passed tomorrow with the majority of lawmakers indicating support, although others are making an attempt to defer the measure's effective date by a year.
Lawmakers from the pan-democratic camp and independent Regina Ip Lau Suk-yee have indicated they would propose amendments to the government proposal, which would allow developers to seek compulsory sale of a building after acquiring 80 per cent of the property interests in it, down from the present 90 per cent.
Among the several amendment items, Secretary for Development Carrie Lam Cheng Yuet-ngor said only deferral of the law's effective date by a year would be acceptable.
Speaking on a radio programme, the minister rejected criticism that the proposed law would rob people of their property: 'It's a situation of the majority versus the minority, instead of a developer acting against the minority owners,' she said.
If the law failed to pass, it would not be tabled again in the remainder of her term, she added.
Democrat legislator James To Kun-sun said the government should hold off on the measure until a mediation mechanism to settle disputes over acquisition prices - which the government had agreed to explore - was in place.
His party would also propose restricting the measure to industrial blocks, confining affected buildings to those with a repair order, and mandatory mediation between property owners and developers before a compulsory sale was considered.
The measure, to be introduced under the existing Land (Compulsory Sale for Redevelopment) Ordinance, would in its present format be confined to three types of buildings: those with all units but one acquired; any blocks older than 50 years; and industrial blocks outside industrial zones that are older than 30 years.
In the past few months, several homeowners forced to sell their flats under the existing law have come out in protest, saying they were not happy with the sale price determined by the Lands Tribunal.
Hong Kong Institute of Surveyors spokesman Dr Lawrence Poon Wing-cheung said auction prices determined by the tribunal in past cases were reasonable as owners received compensation equivalent to about 2.5 times the value of their property, on average.
'I don't think the majority owners would sell their flats to the developer if the price was too low,' Poon said, adding that an independent surveyor looked at each case.
He said a lower threshold would affect the interests of investors as their bargaining power would be weakened.
A total of 21 compulsory sale orders were issued and one case has been dismissed since the ordinance came into effect in 1999. Most owners were paid at least double their property's value, except those in Tai Yuen Street and McGregor Street during the financial crisis in early 2009.
The highest compensation went to owners of Chun Fai Terrace on Tai Hang Road, who were paid six times their property values in 2007.
The law will take effect on April 1 if the proposed amendments fail to win majority support in Legco.
The Democratic Alliance for the Betterment and Progress of Hong Kong, Liberal Party, Professional Forum and Economic Synergy support the government proposal.
The Federation of Trade Unions and non-affiliated legislators such as Samson Tam Wai-ho and Paul Tse Wai-chun said they had not decided whether to support the move for a one-year deferral.


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Newark Museum Holiday Fun Days
Various venues
Until Sat Dec 29 2012
- $
Not yet rated
Time Out says
Wed Nov 7 2012
The Newark Museum is celebrating the holidays with a museum-wide extravaganza. Tots can stroll through the exhibits and take part in different activities: a gallery scavenger hunt, cooking lessons from young chefs-in-training, a geology fossil hunt and more. Spend a day doing all the things you thought you could never do in a museum. All ages.
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released November 26 2010
Tilting your beret and dimensional perceptions, the latest instalment from Paris Tastemakers, Kitsuné Maison is here.
Breaking into the double-digits, KITSUNE MAISON 10 is a celebration of musical talent, a showcase featuring 25 of the best in electronic club, Parisian pop, Swedish folk, and countless other nation-bound genres.
It's an interracial house party, with a guest list including Yelle, Digitalism, Two Door Cinema Club, Black Strobe, Strangetalk as well as a whole collection of intercontinental content. This is diversity at its artistic best.
Dubbed 'The Fireworks Issue', KITSUNE MAISON 10 is an explosive addition to the Maison series, which has previously featured the talents of trend setters like Hot Chip, Klaxons, Bloc Party, Gossip, Soulwax, La Roux, Delphic, and Simian Mobile Disco.
There's more bang, more boom, more music, more Kitsune, more Maison... Just more of what you want, along with more of what you should be listening to.
KITSUNE MAISON 10: The Fireworks Issue, ionically charged and ready to launch, sir.


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PEUGEOT have unleashed two stunning concepts for their home Paris show in a fortnight.
First up is the 2008 Concept crossover model which will go into production next year to rival Nissan's sales hit, the Juke.
It will be powered by Peugeot's new 1.2litre three-cylinder engine, as well as the option of the latest diesel and petrol engines. Prices are expected to start from £13,500 to £14,000.
The RCZ is also getting a facelift but the most striking model will be their incredible Onyx supercar concept. A 3.7litre V8 hybrid delivers a stonking 600bhp, while the mid-engined, rear-drive car is mainly built from unprocessed raw materials and is underpinned by technology from their Le Mans prototype.
The wings and doors are made by hand from copper sheet. Other panels are carbon fibre and the windows and roof are made of a lightweight acrylic alternative to glass.
The passenger compartment is made from compressed felt and formed as a one-piece pod. The dashboard is made of wood produced from recycled NEWSPAPERS. Just think… this article could soon be part of a Peugeot interior!


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Is Bob Barker of 'The Price is Right' dead?
As of June 27th, 2011, NO! The 87-year old former game show host's namesake, the M/Y Bob Barker (that's a ship) had a collison on February 6th, 2010. Perhaps that is what you are thinking of...
Is bob barker from the price is right still alive?
Yes bob barker is still alive dont believe those rumors about him Sagula wrote this
Should Rosie o donnell replace BoB Barker on the price is right?
I think Bob is brilliant. By putting rosie in his place the show is going to tank. It will be cancelled and everybody will always say.... Bob is the only one that could do it. He will be a leg...
Read More »
How long was Bob Barker a TV show host?
Bob Barker was TV Show Host for The Price is Right for an amazing 35 years!
Do you think Rosie O'Donnell would be a good replacement for Bob Barker on Price is Right?
Yahhh i heard about that it. Its gonna be a friggin mess if she actually gets the job. Seriously what are they thinking, she's bound to let her temper get the best of her and when that happens lets...
Read More »


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Mobile App
BMGC Dehradun
Blue Mountains Group of Colleges
Total Students
Fees Range
How to reach
Blue Mountains Group of Colleges is situated at Blue Mountains Group of Colleges, Blue Mountains Estate, Sahastradhara Road, Dehradun, Uttarakhand. in Dehradun.
Courses Offered
- 3 Years
- Bachelor of Business Administration-B.B.A.
- Management - BBA / MBA / Diploma
Blue Mountains Group of Colleges - BMGC Dehradun - BMGC
The Blue Mountains Group of Colleges is in one of the most beautiful regions of the Doon Valley. It is the ideal location for students, to equip themselves for the challenges of working in the hospitality industry, away from the distractions of a major city, yet accessible to its facilities. The Institute offers 3year fulltime integrated BBA Programme in Hotel Management. The degree is Affiliated to Uttarakhand Technical University, Dehradun BMGC is one of the most prestigious hotel college run by professionals from the international hotel industry. An associate college of "Shanti Society For Education", a non profitable organization. The college boasts of having one of the largest campus in any state capital of the country. With a state of art facilities, the best equipped labs with real size restaurant, kitchens, reception, lobby and other operational areas. The college also accommodates facilities like basketball, badminton, cricket and football fields. A full-fledged operational attached hotel is due for the next year, to have real industry experience. The Scenic, peaceful atmosphere in " The Scenic, peaceful atmosphere in "The Blue Mountains" allows the students to concentrate in their studies, whilst benefiting from living within a tourism based community.For every course the college imparts practical training to its students that helps them to understand better, improve their demonstrative skills, eliminate hesitation and in this process strives to mould them into industry ready professionals.
Why join Blue Mountains Group of Colleges
The college infrastructure is well furnished with all the basic facilities for the students.
1 Type Courses Available
- 1 UG Courses
Blue Mountains Group of Colleges Placements
The College provides 100% assistance for placement along with career guidance. To enhance this there is an active placement cell with varied contacts & data bank of star hotels and other hospitality establishments, throughout the country & abroad. It is the only college with an appointed Industry Placement Manager, who continuously guides the students in career planning & placements.
Visiting Companies
Student Placement
Believing in the adage "Practice makes a man perfect", BMGC has lab kitchens, with workstations for students to venture into the world of cookery and food production. Labs for Front Office and food & Beverage Service demonstration, are also available in form of real size Hotel Reception and full-Fledged 55 Covers Restaurant, Coffee Shop & Mock Bar. The college has separate well furnished accommodation around the campus. However a fully operational 80rooms hotel is due to be built at the campus for accommodating the students, with real hotel experience, as it shall be run entirely by the students. The college maintains a "Human Resource and Development Center". Efforts are concentrated on constant development and innovation of resource materials, to aid Hotel education in India. Also, continuous Research is conducted in variety of fields connected with the Hotel industry such as, development of best practices & customer service, knowledge of major management systems in the areas of Marketing, Human Resource Management and Quality Management and lastly understanding the impact of technology & information systems on the operation of the hotel industry.
Try our extensive database of FAQs or submit your own question...
Latest Placement Record needed Ahsan Asked this 1 year, 11 months ago in Marketing - India
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|Aparte Toiletten
|Ligging vakantiehuis
|Minimum verblijf
|3 nachten
Welkom bij uw prive-strand aan Lake Huron! Dit huis is in onze familie al tientallen jaren en is onlangs gerenoveerd in 2015.
Gelegen net buiten de binnenstad AuGres, dit gezellige huis aan het strand is volledig bijgewerkt met nieuwe meubels, tegelvloer, apparaten, smart 55 "flatscreen-tv, WIFI, verf en decor!
Slaapkamer # 1 (boven uitzicht op het meer) heeft een queen bed en een uittrekbare bank.
De bovenverdieping heeft ook een loft met twee eenpersoonsbedden en een gedeelde badkamer.
Slaapkamer # 2 (beneden uitzicht op het meer) heeft een queen bed met een complete badkamer.
Eerste verdieping loopt naar uw eigen zandstrand. Ver van snelwegen en lawaai, u zult genieten om in een beschutte baai met schoon ondiep water en een zandbodem; geweldig om te zwemmen, waterspelen en kinderen! Naast de deur is een zwaar bebost braakliggend terrein waar u nog meer privacy geeft. Strand branden zijn perfect voor het roosteren marshmallows!
Dit meer huis ligt dicht bij golfbanen, kanoën, charter vissen, wandelen, varen en de stad (AuGres).
Nog meer entertainment kan worden gevonden op ongeveer 20 minuten rijden naar Tawas City.
Kom genieten van de tijd met familie en vrienden te ontspannen op een van de Michigan Grote Meren!
Thank you so much for the amazing winter getaway!!!!!! My husband and I were just looking for a quiet getaway for the week because all we seem to do is work. It was every thing we were hoping and then some. It was very clean,cozy, and relaxing. Thank you so much and we can't wait to book again.
Our first family vacation with adult children and grandkids. The house is beautiful, the kids ages were 3,5,6,6,17,18. It was a wonderful time and would make for a great comedy series. Our pet Toby scared the caretaker so she didn't come back for the trash, so after 10 days....there was a lot. If we would have thought about it, we would have taken care of it by finding out where the dump was. I replaced the homes decoration to early and one of the vases got broken, and needless to say, the same kid locked us out of the house before we could finish our clean up. We would love to come back if the owners are interested in our Dennis the Menace family. We still received some of our deposit back, which was greatly appreciated. We saw eagles, fox, turkey, raccoon, lots of chipmunks for morning entertainment (we didn't feed them). Water was great, chilly, but kids don't care.
This property was the best place for our family vacation. The pictures do not do it justice. The beach, yard and lake house our well maintained (and up to date). Our kids (3 & 5) loved the beach and the large waves that Lake Huron provided. We enjoyed walking along the beach, coffee on the patio (we spotted a bald eagle), splashing in the water and s'mores on the fire!
Many amenities are provided for you: towels, shampoo/conditioner, washer/dryer, hair dryer, pots, pans, dishes, etc. I overpacked!!
Looking forward to our next stay!
We absolutely loved our time here and we will definitely come back. The photos online do not do the cottage justice! Everything you need is right there for a perfect home away from home time. The view of the lake is gorgeous and also a spectacular view from the bedroom upstairs and downstairs. It was fun to have the fire pit so close to the lake and we really enjoyed that in the evening. My parents rented this house in hopes of it being handicapped accessible for my mother who uses a motorized wheelchair. It worked out for all of us. There are no steps and a walkway around the house. My mom was able to get around and we worked through any slight obstacle. I had read one review that mentioned some troubles with a couple of things so if you have very specific needs I would always recommend calling and asking anywhere you are renting first! The bathrooms and kitchen and living room were spacious enough for her to move about freely which weak really appreciated. We were happy to walk into a clean and updated cottage and had a nice note from the owners with some snacks and a bottle of wine. The little touches are nice. We loved it so much that we stayed an extra day- and the owners were more than generous. We can't wait to come back! 💖 Sarah, Eric, Dave and Peg
It is a beautiful cottage on a beautiful site. The cottage was nicely decorated and we felt right at home. It has a great beach area. It was enjoyed by the adults and the children!! We plan on returning next year.
Our stay at the house was very relaxing. Very nice home. Everything we needed was supplied. We loved sitting looking out at the lake.
I thought the home would have been a little more accomadating for my husband being he is in a wheelchair and paralyzed. He couldn't take a shower because it was just not big enough for him to transfer into. He could not go through the slider to the patio because it was not wide enough, so he would just go around from the side door. When he brushed his teeth and shaved that had to be done with a dishpan at the table because he couldn't get close enough to the vanities. Above all of this we made it work.
I would recommend you take wheelchair accessible off your listing because the only room that was easy to maneuver around was the kitchen.
I have checked out several listings for handicap and wheelchair accessible and the first thing I see is steps on the homes. People really need to understand the meaning of accessible.
I would highly recommend the lake house to anyone who is not impaired.The pictures on the website don't do it justice. Just so nice and relaxing.
Grote vissen
Lange wandelingen op het zandstrand
Fietsen & Wandelen
Films (Tawas)
Kanoën / Kyaking
|Minimum prijs
|Extra nachten
|Weekend overnachting
|Maandelijks *
Summer Rates
1 jun 2017 - 16 sep 2017
Wisseldag: zaterdag
3 nacht minimum verblijf
voor 3 nachten
2018 Summer Rates
2 jun 2018 - 8 sep 2018
3 nacht minimum verblijf
voor 3 nachten
3 nacht minimum verblijf
voor 3 nachten
There are 2 vacant wooded lots directly next door, making this beach house even more of a special and private paradise!
* Geschatte maandelijks tarief. Werkelijk tarief hangt af van de dagen in de maand u wilt verblijven.