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Riverbend DS Assocation Home Page » Resources » Patents » Alzheimer's Disease » Method for Detecting and Treating Alzheimer's Disease
Method for Detecting and Treating Alzheimer's Disease
Inventors: Potter; Huntington (Boston, MA)
Assignee: President and Fellows of Harvard College (Cambridge, MA)
Appl. No.: 678683
Filed: April 1, 1991
Primary Examiner: Kamm; William E.
Assistant Examiner: Lacyk; John P.
Attorney, Agent or Firm: Hamilton, Brook, Smith & Reynolds
United States Patent 5,297,562 March 29, 1994
I claim:
1. A method for detecting sporadic or inherited forms of Alzheimer's disease comprising testing an individual for the presence of a mosaic population of cells having two copies of chromosome 21 and cells which have three copies of chromosome 21 by administering to the individual a cholinergic agonist or antagonist and detecting increased sensitivity to the agonist or antagonist as an indication of the presence of a mosaic population.
2. A method of claim 1 wherein the agonist is pylocarpine.
3. A method of claim 1 wherein the antagonist is atropine.
4. A method of claim 1 wherein increased sensitivity is detected by monitoring the heart rate of the individual.
5. A method of claim 1 wherein increased sensitivity is detected by monitoring the mydriatic response of the eye.
6. A method of claim 1 wherein increased sensitivity is detected by monitoring sweat gland activity.
It has been appreciated for some time that Alzheimer's disease has a complex etiology. At least 15 percent of the cases appear to be due to the inheritance of an autosomal-dominant mutation, but the majority are "sporadic", showing no clear association with any identifiable genetic or environmental factor. Feldman, R. G., et al., Neurology, 13:811-824 1963; Heston, L. L., et al., Arch Gen. Psychiat., 38:1084-1090 (1981); Terry, R. D., Aging, 7:11-14 (1978); Jarvik, L. F. and Matsuyama, S. S., "The Biological Substrates of Alzheimer's Disease", Academic Press, pp. 17-20 (1986). Even identical twins can show a large discordance in the age of onset of the disease. Nee, L. E., et al., Neurology. 37:359-363 (1987). Yet despite this variation, Alzheimer's disease shows a uniform set of clinical and pathological features--progressive loss of memory and other intellectual functions beginning in middle to late life, coupled with neuronal cell loss in the higher centers of the brain. Price, D. L., Ann. Rev. Neurosci., 9:489-512 (1986).
When examined by histochemica) stains, Alzheimer's disease brains, particularly the hippocampus, neocortex, and amygdala, exhibit certain neuropathological protein deposits that serve as the defining characteristic of the disease. One such deposit, termed the neurofibrillary tangle, occurs inside neurons and is composed of "paired helical" protein filaments (PHF). Because they can be found in other neurodegenerative diseases, paired helical filaments are likely to be a common feature of dying neurons. The more definitive lesion of Alzheimer's disease is the "neuritic or senile plaque", which consists of a spherical, extracellular core of filamentous protein material surrounded by a halo of degenerating nerve cell processes. Extracellular protein filaments similar to those seen in the cores of neuritic plaques also accumulate in the walls of meningeal and intracortical blood vessels. The deposits of protein filaments in the cores of neuritic plaques and in blood vessels are referred to by the generic term "amyloid".
The first identical constituent of Alzheimer amyloid deposits was purified from meningeal blood vessels and its sequence determined by Glenner, G. G. and Wong, C. W., Biochem. Biophys. Res. Commun., 122:1131-1135 (1984). This protein, termed .beta. or A4, a is .about.42 amino-acid-long fragment of a larger protein that is a normal constituent of the brain and other tissues. A second protein component of Alzheimer amyloid deposits was identified as the serine protease inhibitor .alpha..sub.1 -antichymotrypsin (ACT).
While much has been learned about the biochemistry and expression of the aberrant protein deposits that characterize Alzheimer's disease, progress toward the development of methods for the diagnosis and treatment of the disease has been slow. This is due, at least in part, to the fact that the molecular basis for the disease pathology has remained obscure.
The subject invention relates to a method for detecting Alzheimer's disease comprising testing an individual for the presence of a mosaic population of cells. The mosaic population of cells includes normal cells having two copies of chromosome 21 and abnormal cells which contain 3 copies of chromosome 21. The mosaicism can be detected, for example, by in situ hybridization or by detecting increased sensitivity to cholinergic agonists or antagonists.
The invention enables detection of early signs of Alzheimer's disease prior to the onset of dementia. Also disclosed are methods for preventing the onset of dementia in Alzheimer's disease.
Applicant's invention was made possible by the development of a mechanistic theory which provides cohesiveness to apparently disparate experimental results in Alzheimer's Disease research. A brief review of the literature is essential to an appreciation of the invention.
Perhaps the most interesting clue to the cause of Alzheimer's disease is the fact that Down syndrome patients who live beyond the age of 30 or 40 develop dementia and neuropathology essentially indistinguishable from classic Alzheimer's disease. Olson, M. I. and Shaw, C. M., Brain. 92:147-156 (1969); Glenner, G. G. and Wong, C. W., Biochem. Biophys. Res. Commun., 122:1131-1135 (1984); Wisniewski, H. M. and Terry, R. D., In: Ford DH (ed) Progress in Brain Research, 40:1108-1109 (1988). The implication of this finding is that trisomy for chromosome 21--the pathogenetic cause of Down syndrome--is also capable of causing Alzheimer's disease, possibly through the overexpression of a gene residing on chromosome 21. Schweber, M., Ann. N.Y. Acad. Sci., 450:223-238 (1985).
On the other hand, almost all aged humans (and monkeys) develop some amyloid deposits which, by several criteria, appear to be identical to those that accumulate in much larger numbers and at an earlier time in Alzheimer's disease and Down syndrome (Wisniewski, H. M. and Terry, R. D., In: Ford DH (ed) Progress in Brain Research, 40:1108-1109 (1973); Selkoe, D. J., et al., Science, 235:873-877 (1987); Abraham, C. R. and Potter, H., Biotechnology, 7:147-153 (1989). Thus, any hypothesis for the pathogenesis of Alzheimer's disease should be able to explain not only the relation between the familial and sporadic forms of the disease but also how these are related to Down syndrome and to the "normal" process of aging.
The association between Alzheimer's disease and chromosome 21 has been reinforced by a number of recent clinical and experimental findings. These, and earlier results on the genetics, epidemiology, and cell biology of Alzheimer's disease, have been considered. In particular, its association with Down syndrome has been assessed.
A molecular basis for Alzheimer's disease, which is consistent with both the genetic and sporadic forms of the disease can be explained as arising from the accumulation of chromosome 21 trisomy cells during the life of the individual. That is, trisomy 21 cells, developing over time by unequal chromosome segregation during mitosis, may ultimately lead to Alzheimer's disease through the same (as yet unknown, and perhaps multistep) mechanism by which Down syndrome patients acquire the disease, but at a later age due to the modulating effect of the mosaicism.
The first specific model linking Alzheimer's disease to Down syndrome arose when the gene for the amyloid .beta.-protein was cloned and found to be located on chromosome 21. Goldgaber, D., et al., Science, 235:877 (1987); Kang, J., et al., Nature, 325:733 (1987); Tanzi, R. E., et al., Science, 235:880 (1987); Robakis, N. K., et al., Proc. Natl. Sci. U.S.A., 84:4190 (1987). The implication of these results seemed that accumulation of amyloid in Alzheimer's disease was caused by the overexpression of a routant .beta.-protein gene or by a duplication of the .beta.-protein gene on chromosome 21 that mimicked the gene-dosage effect of Down syndrome. The fact that some Alzheimer's disease families could be shown to harbor their autosomal dominantly-inherited mutation on chromosome 21 (St. George-Hyslop, P. H., et al., Science, 235:885-889 (1987)) and that the .beta.-protein precursor gene was apparently overexpressed in Down syndrome (Tanzi, R. E., et al., Science 235:880 (1987); Neve, et al., 1988) further implicated the .beta.-protein gene as a potential site for the disease locus.
Very recently, a variant form of the .beta.-protein precursor gene encoding a mutant .beta.-protein has been found in families with Hereditary Cerebral Hemorrhage with Amyloidosis of Dutch Origin, suggesting that this mutation may be the inherited defect in this disease (Van Broeckhoven, C., et al., Science, 248:1120-1122 (1990); Levy, E., et al., Science, 248:1124-1126 (1990). However, an early study suggesting that the .beta.-protein gene existed in three copies in Alzheimer's disease patients was not confirmed. Also the pattern of expression of the .beta.-protein gene was subtly altered in Alzheimer brain but not simply overexpressed (see Tanzi, R. E., et ., Science 235:880 (1987); Neve, R. L., et al., Neuron, 1:669-677 (1988); Palmert, M. R. et al., Science. 241:1080-1084 (1988); Higgins, G. A., et al., Proc. Natl. Acad. Sci., 85:1297-1301 (1988); and Golde, T. E., et al., Neuron 4:253-267 (1990)) for data and discussion of Alzheimer- and Down syndrome-specific changes in the expression of the several .beta.-protein precursor mRNAs). Finally, the actual location of a potential Alzheimer's disease mutation on chromosome 21 in some families was soon shown to be far from the .beta.-protein gene itself and closer to the centromere (Tanzi, et al., Nature 329:156-157 (1987); Van Broeckhoven, et al., Nature 329:153-155 (1987); Goate, et al., Lancet February 18:352 (1989)).
The finding in some families showing no linkage to any marker on chromosome 21 suggests that the inherited form of Alzheimer's disease is genetically heterogeneous (Schellenberg, et al., Science 241:1507-1510 (1988); St. George-Hyslop, et al., Nature 347:194-197 (1990)). Chromosome 19 (Roses, et al., Adv. Neurol. 15:185-196 (1990)) and possibly the region -of chromosome 14 now known to be close to the ACT gene (Weitkamp, et al., Amer. J. Hum. Genet. 35:443-453 (1983); Rabin, et al., Somatic Cell Mol. Genet. 12:209-214 (1986)) have been proposed as candidate locations for the disease locus. These results indicate that an aberrant biochemical pathway leading to the Alzheimer neuropathology can be initiated by mutation in a number of genes, including one on chromosome 21, but not the .beta.-protein precursor gene itself.
Chromosome 21 was further implicated in the etiology of Alzheimer's disease by the discovery that some families in which Alzheimer's disease is inherited as an autosomal dominant mutation produce a significantly higher-than-normal number of Down syndrome children (Heston and Mastri, Arch. Gen. Psychiatry 34:976-981 (1977); Heston, et al., Arch. Gen. Psychiat. 38:1084-1090 (1981); Heyman, et al., Ann. Neurol. 14:507-515 (1983)). In the first study, the total number of Down's cases was 11 out of 3,044 Alzheimer's disease relatives. The mothers' ages at the birth of their children were given as 21, 26, 30, 30, 35, 39, 40, 41 and 46, plus two unknown ages. The average maternal age (34) is higher than the average maternal age for all births, which is approximately 29. However, the results would still be significant if, for instance, the children of the two or three oldest mothers were not considered (the frequency of Down syndrome is 1.3 per thousand live births to mothers of all ages). The number of relatives analyzed in the second study was 1278, including 4 Down syndrome individuals conceived to mothers of ages 26, 31, 33, and 38. These numbers are small and the average maternal age is a little high, but even if the one case of age 38 were artificially removed, the results are also statistically significant. In contrast, other researchers have failed to confirm the increased incidence of Down syndrome in families with inherited Alzheimer's disease, but they report that the number of relatives they analyzed was too few for the lack of Down syndrome to be statistically significant (Whalley, et al., Brit. J. Psychiat. 140:249-256 (1982); Amaducci, et al., Neurology 36:922-931 (1986); Chandra, et al., Neurology 37:1295-1300 (1987)).
Recently, mouse chromosome 16, which is partially homologous to human chromosome 21, including the .beta.-protein gene, has been shown to result, when trisomic, in neurodegeneration somewhat like that seen in Alzheimer's disease (Richards et al., EMBO J. 10:297 (1991)). Because mouse chromosome 16 is much larger and contains many more genes than does human chromosome 21, trisomy 16 mice suffer many developmental abnormalities and do not survive to term. However, the specific effect of this trisomy on the nervous system can be tested by transplanting embryonic brain tissue from a trisomy 16 embryo into the brain of a normal adult. When the brains of such host mice with their trisomy 16 grafts were examined, it was found that some of the neurons in the graft had accumulated aberrant immunoreactivity similar to that found in and around degenerating neurons in Alzheimer's disease.
Specifically, thioflavin S, a histological marker for amyloid, showed positive staining within a few cells and around some blood vessels. In addition, antisera to the .beta.-protein precursor, to .beta.-protein itself, to ACT, to PHF, and to phosphorylated epitopes of tau labeled a few percent of cells in the trisomy 16 grafts. There was also some extracelular staining for ACT and .beta.-protein precursor. When dissociated cells from trisomy 16 embryos were transplanted, the effects were not observed, suggesting that cell-cell interaction or cell degeneration in the bulk trisomy 16 tissue grafts used by Richards and her colleagues may be necessary for the neuropathology to develop. Interestingly, although .beta.-protein precursor RNA was overexpressed approximately two-fold in trisomy 16 fetal mouse brains, it was overexpressed five-fold in the brains of chimerio (mosaic) mice having 40-50% trisomy 16 cells, again suggesting that a complex cell-cell interaction, affects the expression of this gene (Holtzman, et al., Soc. Neurosci. Abs. 469.6 (1990)).
The most recent link between Alzheimer's disease and chromosome 21 is evidenced by reports of two women whose lymphocytes were found to be mosaic for trisomy 21 and who, though not mentally retarded, had developed Alzheimer-like dementia by age 40 (Schapiro, et al., Neurology 39 Suppl. 1:169 (1989); Rowe, et al ., Lancet July 22:229 (1989); for discussion, see Hardy, et al., Lancet September 23:743 (1989)). In one case the woman also had a Down syndrome child. An unusual family with an inherited aberrant chromosome 22-derived marker chromosome was found by Percy M. E., et al., Am. J. Med. Genet., (1991) to also have a high frequency of Alzheimer's disease. The two living affected members of the family carried the marker chromosome and one was also found to be mosaic for trisomy 21; only lymphocytes were analyzed from the other patient (see relevant discussion below). The two patients reported by Schapiro and Rowe and their colleagues and possibly the mosaic individual reported by Percy and her colleagues demonstrate that it is not necessary for every cell of an individual to be trisomy 21 for the aberrant effects of this chromosome imbalance to result in early Alzheimer dementia. The later onset dementia of classic Alzheimer's disease could thus result from an even smaller percentage of trisomy 21 cells that may go undetected.
Our proposal, that Alzheimer's disease and Down syndrome result from unequal chromosome 21 segregation in somatic and germ cells respectively, reconciles a seemingly diverse body of literature. For instance, one immediate implication is that any genetic or environmental factor that increases the chances of forming chromosome 21 trisomic cells should increase the likelihood of developing Alzheimer's disease. Thus, in the families in which the disease is apparently inherited as an autosomal dominant mutation near the centromere of chromosome 21, the mutation probably resides in the centromere itself so as to cause an increased frequency of nondisjunction of chromosome 21. During mitosis, such nondisjunction would build up trisomy 21 somatic cells, eventually leading to Alzheimer's disease pathology, while during meiosis it would generate trisomy 21 germ cells and Down syndrome offspring, as consistent with the epidemiological evidence. Indeed, there are centromere mutations known in yeast that result in a 100-fold increase in chromosome nondisjunction (Gaudet and Fitzgerald-Hayes, Mol. Cell. Biol. 7:68-75 (1987)).
Of course chromosome segregation is a complex process under the control of many gene products (for review, see Murray and Szostak, Annu. Rev. Cell. Biol. 1:289-315 (1985)), and an inherited disorder of chromosome segregation could be caused by mutations at a number of loci. In this light, the fact that familial Alzheimer's disease appears to be genetically heterogeneous is not surprising, since any one of several mutations could lead to the development of trisomy 21 cells, both somatic and germline, with the consequent development of Alzheimer's disease in the individual and an increased frequency of Down syndrome offspring. Several researchers have suggested that a specific microtubule defect could lead directly to the neuronal pathology and indirectly to the increase in Down's offspring in Alzheimer's disease through chromosome nondisjunction (Heston and Mastri, Arch Gen. Psychiatry 34:976-981 (1977); Nordenson, et al., Lancet March 1,:481-482 (1980); Matsuyama and Jarvik, Proc Natl. Acad. Sci. 86:8152-8156 (1989).
Although improper chromosome segregation can result from a genetic mutation, it can also be caused by environmental agents. Of the many exogenous factors that influence chromosome segregation, microtubule-disrupting agents such as colchicine and low doses of radiation are perhaps the best studied (see, for example, Uchida, et al., Am. J. Hum. Genet. 27:419-429 (1975)). Aluminum, the consumption of which shows a weak, but significant association with the development of Alzheimer's disease (see, for example, Martyn, et al., Lancet 14 January 59-62 (1989)), also binds to microtubules and, in the form of aluminum silicate, causes chromosome nondisjunction in cultured cells (Paleker, et al., Carcinogen 8:553-560 (1987); for discussion see Ganrot, Environ. Health. Persp. 65:363-441 (1986)). Thus, the large proportion of Alzheimer's disease cases that arise in a sporadic manner not directly attributable to the inheritance of a genetic mutation can also be understood in the light of the chromosome 21 trisomy model.
An important prediction of this model is that it is the dividing cells in an individual that are most likely to develop chromosome 21 trisomy and lead to Alzheimer's disease. Extensive analysis by Rakic, Science 227:1054-1056 (1985) has shown that the only dividing cells in the brains of adult monkeys exposed to .sup.3 H-thymidine are glial cells and the endothelial cells lining blood vessels, while neurons, the cells most apparently affected by Alzheimer's disease, do not divide. The labeled glia were seen primarily in the hippocampus and the cerebral cortex. Thus cell division in the brains of adult primates occurs in those general regions that develop neuropathology in Alzheimer's disease, Down syndrome, and normal aging. Interestingly, astroglia in the hippocampus and cortex of Alzheimer's disease brain overexpress ACT, and astrocytes can be induced by kainic acid lesions to overexpress the B-protein precursor (Pasternack, et al., Am. J. Pathol. 135:827-834 (1989); Siman, et al., Neuron 3:275-285 (1989); for discussion of how overexpression of ACT or B-protein precursor can lead to amyloid formation, see Abraham and Potter, Biotechnology :147-153 (1989)).
Recently, two rapidly dividing peripheral tissues (skin and intestinal mucosa) have been reported to contain pre-amyloid deposits of .beta.-protein in sporadic Alzheimer patients and some aged, normal subjects (Joachim, et al., Nature 341:226-230 (1989)). Another region of active cell division, which has been shown to exhibit pathological changes in Alzheimer's disease, is the olfactory epithelium (Talamo et al., Nature 337:736-739 (1983)). Thus there seems to be a rough correlation between regions of cell division and areas where Alzheimer pathology can develop. Of course, mitotic nondisjunction could also occur early enough in embryogenesis to generate trisomy 21 in nondividing adult cells such as neurons.
Although it would seem reasonable that amyloid should develop in the regions, immediately surrounding aberrant cells (for instance trisomy 21 cells), the precedent provided by other amyloidoses suggests that this need not be the case. For instance, the autosomal-dominantly inherited diseases Familial Amyloidotic Polyneuropathy and Hereditary Cerebral Hemorrhage with Amyloidosis of both the Dutch and Icelandic types have very specific regions of amyloid deposition despite the fact that all cells in the body carry the point mutation in the affected amyloid gene (transthyretin, cystatin C, or .beta.-protein precursor, respectively), and that these genes are expressed in many parts of the body where the amyloid does not deposit (for review see Castano and Frangione, Lab. Invest. 58:122-132 (1988)). Thus, by analogy, the trisomy 21 cells that are relevant for the formation of amyloid pathology in Down syndrome (and, according to the hypothesis, Alzheimer's disease) need not reside in the brain at all. Indeed, some researchers believe that the .beta.-protein is transported to the brain by the circulation, having been generated elsewhere (see, for example, Selkoe, Neurobiol. Aging 10:873-877 (1989) for recent data and discussion).
In sum, both genetic and sporadic forms of Alzheimer's disease can be explained as arising from the effects of trisomy 21 cells accumulating during the life of the individual. A propensity to develop such cells can be genetic in origin (either due to an aberrant chromosome 21 centromere or to a mutation elsewhere in the genome affecting all chromosome segregation), or it can be caused by environmental factors. A combination of genetic and environmental influences on the formation of trisomic 21 cells is responsible for the observed variation in the age of onset of Alzheimer's disease in identical twins and in Alzheimer's disease families. In addition, the fact that almost 50% of the population over the age of 85 show some symptoms of Alzheimer's disease dementia (Evans, et al., JAMA 262:2551-2556 (1989)), and an even larger proportion show some of the same neuropathological lesions, indicates that all individuals may, to some degree, be subject to stochastic events that lead to aberrant chromosome segregation with increasing age. The possibility that further biochemical or genetic events may be required before full Alzheimer neuropathology arises is indicated by the mature age (20's to 30's) that Down syndrome patients begin to accumulate amyloid deposits.
Cytogenetic analysis of Alzheimer's disease patients has been carried out in a number of laboratories, with mixed reports of increased aneuploidy or other abnormalities as measured directly (Jarvik, et al., Arch. Gen. Psychiat. 30:186-190 (1974); Ward, et al., Am. J. Med. Genet. 3:137-144 (1979); Nordenson, et al., Lancet March 1:481-482 (1980); White, et al., Am. J. Med. Genet. 10:77-89 (1981); Buckton, et al., J. Med. Genet. 20:46-51 (1983); Moorhead and Heyman, Am. J. Med. Genet. 14:545-556 (1983)). Furthermore, premature centromere division (PCD), a correlate and potential cause of improper chromosome segregation in vitro and in vivo, was found to be positively correlated with age and to be increased in women with familial Alzheimer's disease (3.6% vs. 0.6% in age-matched controls), particularly affecting the X chromosome (Fitzgerald, et al., Ann. Hum. Genet. 38:417-428 (1975); Moorhead and Heyman, Am. J. Med. Genet. 14:545-556 (1983)). Trisomy 21, 18, and X occurred in the lymphocytes and fibroblasts of a woman apparently prone to PCD, who also had three trisomy conceptuses (Fitzgerald, et al., Hum. Genet. 72:58-62 (1986)). Patients with Roberts syndrome, a rare autosomal recessive disorder characterized by growth and mental retardation and craniofacial abnormalities, also shows PCD--there can be significant aneuploidy, usually involving chromosome loss rather than gain (except for trisomy 7) (see Romke, et al., Clin. Genet. 31:170-177 (1987), Jabs et al., Proc. Clin. Biol. Res. 318:111 (1989)). PCD can also be found that appears limited to the X chromosome and results, presumably by nondisjunction, in many cells with one or three X chromosomes (Fitzgerald, et al., Ann. Hum. Genet. 38:417-428 (1975)). Other Roberts syndrome families with extensive PCD have been found that exhibit normal karyotypes and phenotypes (Madan, et al., Am. Genet. 77:193-196 (1987)). Thus PCD need not result in nondisjunction, but when it does, severe developmental abnormalities can result if the autosomes are affected. The report by Fitzgerald and his colleagues (1986) is the only case of PCD in which trisomy of chromosomes other than the X chromosome were prevalent. Why Roberts syndrome generally results in chromosome loss rather than gain is not clear. Perhaps because of the severe mental retardation exhibited by these patients, neurological and pathological tests for Alzheimer's disease have not been reported.
The fact that the chromosomes that exhibit PCD in an individual do not necessarily correspond to those which ultimately are lost or gained to give an aberrant karyotype (there is a prevalence of trisomy 21, 18 and X in the general PCD case of Fitzgerald, et al., Hum. Genet. 72:58-62 (1986)), probably reflects differential cell viability. For instance, lymphocyte cultures from trisomy 21 mosaic individuals often show a lower proportion of trisomy cells than do, for instance, fibroblast cultures, and some patients with over 10% trisomy fibroblasts can show a normal karyotype in lymphocytes (out of, for example, 30 metaphases) (Pagon, et al., Am. J. Hum. Genet. 31:54-61 (1979); Ford, Trisomy 21, Springer, Berlin, Heidelberg and New York, pp 103-143 (1981)).
Thus, the fact that cytogenetic studies on Alzheimer patients have almost always relied on peripheral blood lymphocytes (for example Jarvik, et al., Arch. Gen. Psychiat. 30:186-190 (1974); Ward, et al., Am. J. Med. Genet. 3:137-144 (1979); Nordenson, et al., Lancet March 1:481-482 (1980); White, et al., Am. J. Med. Genet. 10:77-89 (1981); Buckton, et al., J. Med. Genet. 20:46-51 (1983); Moorhead and Heyman, Am. J. Med. Genet. 14:545-556 (1983)) may have prevented trisomy 21 mosaicism from being detected and linked to Alzheimer's disease. In these studies, fewer than 100 or even 50 lymphocyte metaphases per sample were examined, and the few percent with increased aneuploidy (generally a loss) for any chromosome in Alzheimer's disease was usually not significantly different from controls. The specific frequency of trisomy 21 was too low to be useful or was not stated.
The mechanism proposed herein can be tested by analysis of dividing cells from affected areas of the brain--glia, endothelial cells of the meningeal and cortical vessels, and the olfactory epithelium and possibly of skin fibroblasts. Procedures have recently been developed (Lichter, et al., Proc. Natl. Acad. Sci. U.S.A. 85:9664-9668 (1988); Fuscoe, et al., Genomics 5:100-109 (1989)) that allow the number of chromosome 21s to be counted in both metaphase and interphase nuclei. The methodology is based on in situ hybridization with, for instance, biotin-labeled chromosome 21-specific probes, that are then visualized by fluoresceine-labeled streptavidin. The advantage of this approach over standard cytogenetics is that both dividing and non-dividing cells can be studied, and, more important, the number of chromosomes in interphase nuclei in tissue sections can be counted (Lichter, et al., Proc. Natl. Acad. Sci. U.S.A. 85:9664-9668 (1988)). Because the number of cells that might harbor three copies of chromosome 21 in Alzheimer's brain or peripheral tissue might be very small, the finding of a small cluster of trisomy cells would be far more significant than the same number of cells found one at a time among a population of thousands of other cells after they have been disaggregated and induced to divide in culture to yield metaphase chromosome spreads. The large number of "normal" aged individuals that show some symptoms of Alzheimer's disease and some Alzheimer pathology (neurofibrillary tangles and amyloid deposits) will make it necessary to carry out careful comparisons between Alzheimer's disease patients and age-matched controls. Such an analysis would, of course, be made easier by concentrating on earlier onset (often familial) Alzheimer's cases. Although initial studies would seem to be best directed at searching for trisomy 21 cells in the brain, the possibility (discussed above) that Alzheimer amyloid deposits may arise from aberrant cells in the periphery suggests that a similar in situ hybridiztion analysis should also be carried out on various other tissues, for instance skin and the intestinal mucosa.
If Alzheimer's disease patients are found to be mosaic for trisomy 21, then we might expect them to exhibit some other abnormalities of Down syndrome in addition to dementia--for example, hypersensitivity to acetylcholine agonists and antagonists (see, Berg et al., Lancet 2:441 (1959); Harris and Goodman, N. Eng. J. Med. 279:407 (1968); Sacks and Smith, J. Neurol. Neurosurg. Psychiatry 52:1294 (1989)). Such characteristics, together with in situ hybridization for chromosome 21, form the basis of a diagnostic test for Alzheimer's disease.
Diagnosis for Alzheimer's disease before symptoms of dementia arise can be accomplished by determining whether the individual is indeed mosaic for trisomy 21. This can be carried out either directly by in situ hybridization as described above, or indirectly by measuring certain characteristics known to be associated with Down syndrome that arise due to the trisomy 21 nature of this disorder, and assay them for their presence in a suspected Alzheimer patient. Examples of such Down's patient features include Brushfield spots on the irises (Grouchy and Turleau, Clinical Atlas of Human Chromosomes, 2nd edition, Wiley, New York (1984)), hypersensitivity of heart rate, pupil contraction, and sweat production to acetylcholine agonists and antagonists (Berg et al., Lancet 2:441 (1959); Harris and Goodman, et al., N. Eng. J. Med. 279:407 (1968); Symon et al., J. Mental Defic. Res. 29:257 (1985); Reyes et al., J. Neural. Neurosurg. Psychiatr. 50:113 (1987); Sacks and Smith, J. Neurol. Neurosurg. Psychiatry 52:1294 (1989) and Inzelberg et al., Clin. Neurpharmacol. 13:241 (1990)). Many methods for monitoring hypersensitivity to cholinergic agonists and antagonists are well known in the art. In short, any characteristic of Down syndrome may be used as a basis for designing a diagnostic test for Alzheimer's disease.
Because the data indicate that Alzheimer's disease is a mosaic form of Down syndrome due to nondisjunction (but perhaps during meiosis followed by nondisjunction early in development to yield normal cells), much Alzheimer's disease may be prevented by preventing the nondisjunction from occurring, including such approaches as avoiding environmental agents that cause translocation by inducing chromosome nondisjunction, treatment with agents that reduce spontaneous nondisjunction or that obviate the effects of environmental agents, and mitotic inhibitors such as colcemid or methyl benzimidazole-2-yl-carbamate. Such treatment might include, but is not limited to, heavy metal chelaters, antoxidants, and promoters of microtubule assembly. Drugs that improve chromosome segregation will include those that affect DNA toposiomerase II (Holm et al., Mol. Cel. Biol. 9:159 (1989)), or centromere binding proteins such as CBF1 (Cai and Davis, Nature 349:704 (1991)), or DYS1 (Rockmill and Fogel, Genetics 119:261 (1988)). An additional approach may be to treat patients with drugs to which trisomy 21 cells may be particularly sensitive in the expectation that they will be preferentially killed and thus no longer pose a threat to the patient. This may be accomplished by killing cells that have an excess of certain cell surface markers known to be increased in cells from Down syndrome patients due to the trisomy 21. These include the cell surface marker S14 and interferon-.alpha. receptor.
|Source: http://www.uspto.gov/patft/
|Revised: February 3, 2001.


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This is me - grinning from ear to ear - and the pups with my new favorite quilt - a birthday gift from Candis. Thank you, Candis! :)
BEAUTIFUL! Well done Candis, Girlfriend!
Really like the larger print fabric!
Ahhhh Beautiful!! And the Quilt isn't bad either! Enjoy!
Wow, what a beautiful Birthday gift!!!
Very prefect Birthday Quilt as well as beautiful.
Pretty quilt, and three happy recipients!
Beautiful quilt. What a nice gift.

subset: commoncrawl


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Sky Sports News' 10-Year Anniversary
Sky Sports News just celebrated its 10th year of broadcast, commemorating the occasion with a host of congratulations from Ryan Giggs, a smiley Michael Owen, and Prime Minister Gordon Brown.
In the second half of the segment there was a walk down memory lane, reliving some of the sporting highlights from the last 10 years.
The report can be seen here.


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The old Mantra (and before, Hirigashi West) space is now Tacolicious. The space wasn't closed that long - bringing the already refined concept from the Marina to University Ave took no translation.
Somewhere, I read "fills a great gap between Sanchos and Reposado", thus my interest in checking them out.
GF nailed the place perfectly. I brought home a pair of tacos for her, and she said "I prefer El Grullense", and she's right. The tacos have too much filling, don't have enough onions and cilantro, and "add your own" salsa works - they have good salsas - but you need to leave more room on the taco.
The meats are good but not great (compared to "Old" EG). I rather liked the Fish Taco (listed as cod, my favorite of all fried fishes). The Carnitas is on the dry side but not stringy, with only a little pork-cooked-twice taste. I did like the beef braised in guajillo, good richness from the peppers and not dry. Price is 3.95 per taco (gasp!), but 4 for 14. 4 is a large dinner for a sensible person. $14 for dinner in that part of town is very reasonable. (EG's tacos are either 1.25$ or 1.50$), but for that you get loud mexican television, a cold drafty room, formica that gets cleaned every hour whether it needs it or not.
On the very positive side, the complimentary house salsa and chips is very, very good. On the takeout order for GF, the chips had made the paper bag nearly see-through. They gave us a huge amount of salsa (about a cup?) which seems unsustainable for a $8 togo order.
The atmosphere is the thing. There's no blaring music, so you can go with a group. Lights are low, suggesting intimacy. The bar area (mantra's bar looks the same) is paired off with couples. It's really pleasant and if they've done even a little work they'll have good drinks.
Oddly, the Tacolicious web pages says "Stanford! We're not Chipotle!" which kind of says it all. If their competition is Chipotle, they've distanced themselves by the lighting and the alcohol. It is kind of like Sancho's, but with enough seating, and without burritos.
Compared to Reposado --- no comparison, except R also has bustling atmosphere. I think R is a very good restaurant, punching well above it's weight with complex dishes like mole in the last visit - and I am very skeptical about mole.
At best Tacolicious is a place to suggest if you want to have a drink or two, with a taco added. It's a step down from the Mantra Happy Hour (the joy of squeezing so many appetizers and two rounds of drinks before cut-off time and rewarded with HALF OFF your bill).


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Definition of Abduction according to Legal Dictionary
The act of restraining another through the use or threat of deadly force or through fraudulent persuasion. The requisite restraint generally requires that the abductor intend to prevent the liberation of the abductee. Some states require that the abductee be a minor or that the abductor intend to subject the abductee to prostitution or illicit sexual activity.
Abduction defined in section 362 PPC
Whoever by force compels, or by any deceitful means induces, any person to go from any place, is said to abduct that person.
Ingredients of Abduction
1-by force compels
The word force in this section means actual force and not merely show of force or threat of force (AIR 1949 AII 710)
2-by any deceitful means induces
The expression deceitful includes the inducing of girl to leave her guardian's house on a pretext (AIR 1951 Raj 33)
Difference between kidnapping and abduction
Kidnapping as defined in section 360 and 361 PPC is by itself a substantive offence punishable u/s 363 whereas mere abduction as defined in section 362 is by itself is not substantive offence. It is only where the abduction is made in the circumstances stated to section 364, 365, 366, 367 and 369 that it is an offence.
- Section 364: kidnapping or abducting in order to murder
- Section 364-A: Kidnapping or abducting a person under the age of ten
- Section 365: Kidnapping or abducting with intent secretly and wrongfully to confine person
- Section 365-A: Kidnapping or abduction for extorting property, valuable security etc.
- Section 365-B: Kidnapping, abducting or inducing woman to compel for marriage etc.
- Section 367: Kidnapping or abducting in order to subject person to grievous hurt or slavery etc.
- Section 369 Kidnapping or abducting child under ten years with intent to steal from its person
Abduction by Father and View of Superior Courts in Pakistan
Although the Pakistan Penal Code recognizes kidnapping (whether from legal guardianship or from Pakistan) and abduction as crimes, the superior courts of Pakistan have consistently interpreted the relevant provisions to exclude abduction by a parent, particularly when the abducting parent is the father, because in their view "…father of a child being always a natural guardian along with the mother, can never be ascribed or attributed the offence of kidnapping of his own child…." (Muhammad Ashraf v. SHO and others 2001 P Cr. L J 31). While this view may exonerate the father from penal consequences it cannot protect him from actions for the production and custody of the child.
The problem of child abduction is most acute between the UK and Pakistan due to the high percentage of marriages between Pakistani and UK nationals whether residing in Pakistan or the UK. Seeing the pain and anguish caused to children who become victims of such cases, the superior judiciary of the two countries took it upon themselves to tackle this issue and in January 2003 signed the UK Pakistan Judicial Protocol on Children Matters in order to establish a formal mechanism that aggrieved parents could invoke in case a child of a mixed marriage was abducted from one to the other country.
Like the Convention, the Protocol stipulates that the courts of a country in which the child is habitually resident should decide the issue of custody. The Protocol adds that this decision should be made without regard to the nationality, culture and religion of either parent. The Protocol is unbiased and allows parents to invoke the jurisdiction of Pakistani courts if the child is habitually resident in Pakistan and of UK courts if UK is the child's normal home. The guiding principles of the Protocol are safeguarding the interests of the child and preventing an abducting parent from taking advantage of his illegal act and dictating the jurisdiction in which the question of the child's welfare may be decided.
Despite voluntarily accepting the Protocol, Pakistani judiciary has remained reluctant in following it. In a departure from this judicial silence, Justice Saqib Nisar in his judgment in what is known as "the Misbah case" followed the Protocol in principle, however he too did not actually refer to it. It is perhaps unfortunate from a purely legal perspective that the parties arrived at a compromise in an appeal before the Supreme Court and the Protocol did not become a binding precedent for all other courts in Pakistan.
Judges in Pakistan may well argue that the Protocol is not necessary because they are fully capable of determining the welfare of a child. While such a claim is indeed borne out by numerous judgments, it fails to take into account that the issue here is not of the competence of judiciary but of creating certainty in the legal system by dealing with cases between Pakistan and the UK consistently in accordance with the Protocol and in fact extending the principles to any transnational abductions.
The issue is also about providing a level playing field to both parents who are equal stakeholders in the welfare of their child rather than making it difficult, if not impossible, for one parent to approach the courts. Most importantly, the issue is of rescuing the child from being a mere pawn in the parental tussle, and recognizing him as an individual who has the legal right to have his welfare determined in accordance with the laws, standards and values of the country in which his parents — until their marital discord led them to think otherwise — themselves chose to raise him.
Abduction & Famous Case laws
- There can be no abduction when no force is used, or inducement made by deceitful means in taking away a person. (AIR 1971 SC 2064)
- An essential ingredient in definition of abduction is that a person must have been induced to go from any place. In the absence of this element there can be no abduction. (AIR 1925 Lah. 512)
Abduction Case laws in Favor of Prosecution
- In the case of grownup woman it would be an offence to carry her away by force against her own will even with the object of restoring her to her husband. (AIR 1942 Lah. 89)
- Abductee rightly picked up all the three accused in the identification parade. No motive for false implication. Incriminative recoveries form the accused including the ransom amount, pistol and live cartridges, mobile phone and motor cycle of abductee, further connected the accused with the commission of offence. (2007 P.Cr.L.J 1097)
- Abduction is done by some of the culprits, place of confinement is guarded by others and ransom is extorted by one or two of them. Object of all the culprits being to extort money, punishment could be the same irrespective of the role played by each of them. (2010 P.Cr.L.J 1281)
- Offence of abduction and murder accomplished by more than one persons while act of murder performed by one of them. The act was a joint act intended to be accomplish by the three men in cooperation with each other no hesitation in saying that the even though one of the accused merely stood by the outer wall from where he watched everything and did only as much as was required from him up to the time the first knife blow was struck, he was a person engaged in the performance of the act of abduction within the meaning of section 34 PPC. (PLD 1960 SC 254)
- Recovery of abductee from the accused, no enmity between the accused and the police or the complainant party, evidence fully corroborated. Charge of abduction held proved. (PLD 1983 FSC 196)
- Abduction is done by some of the culprits, place of confinement is guarded by others and ransom is extorted by one of two of them. Object of all the culprits being to extort money, punishment could be the same irrespective of the role played by each of them. (2010 P.Cr.L.J. 1281)


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Art's better when it's adhesive. Get 10 stickers, save 50%.
Pastel pen and ink drawing of a Chicken Dance.
animals animation apparel artist beautiful black blue car cartoon cartoonist chicken chickendance children childrens christmas color colorful cute farmanimals fashion fineart fowl framed freestyle funny girl graffiti graphic green harmony hip hoffard holiday humor humorous indie ink kid ladies laminated liberal love man men mounted orange original pastel peace pen
Ha Ha I love chickens! Great drawing.
Thanks… Glad you like it Helen!
very very good!!!…:)))
Know what's going be for Sunday dinner
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very imanginitive , great work.
Another fantastic on, Kimberly. You are sooooooo talented!
Thanks Jennib and Trace Lowe… Very happy you like it!
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Orswell Events works with corporations, service clubs, & other organizations to plan, promote and produce a wide range of events. We are pleased to produce and work with the events and companies below and encourage you to visit their websites by clicking on the logo. Contact us to start planning your next event.
Take a twirl Nov 24 thru Jan 1 $7 per session (ages 3+): Includes skates or bring your own. (credit/debit card only) Opens Black Friday | Sat Nov 24 10 am - 8 pm Weekends Nov 25 – Dec 31* Sat | 10 am - 8 pm Sun | 11 am - ...More
November 24th, 2017 - January 1st, 2018
Outdoor Synthetic Skating RinkLearn More Event Site
Every year, thousands of runners and walkers cross the finish line at the annual springtime running of Mercer Island Rotary's Half Marathon which includes 10K and 5K races along with a Kids' Dash, all designed to help raise funds and awareness to fight colon cancer and to benefit an array of other charitable causes supported by the Mercer Island Rotary Club Foundation.
March 18th, 2018
Half Marathon Run/Walk | 10K Run | 5K Run/Walk | Kids' RunLearn More Event Site
Join us for the 2nd annual Running of the Beavers to benefit the Ballard High School Foundation. The Foundation provides financial support to Ballard High School, a Seattle public school. The run will start and finish at beautiful Golden Gardens Park along the Ballard waterfront. You'll enjoy stunning views of Puget ...More
March 31st, 2018
5K Run/Walk | Kids' RunLearn More Event Site
The Seahawks 12K Run will start and finish at The Landing, run along the Southeast shore of Lake Washington and offer participants a unique opportunity to run around the Seahawks training facility, the Virginia Mason Athletic Center. Register now be a part of this unique event and spend the day with Blitz, the Sea Gals, Blue Thunder, Seahawks players and more!
April 15th, 2018
12K Run | 5K Run/Walk | Kids' RunLearn More Event Site
Whidbey Island is the perfect island weekend getaway where you can leave the city behind. As a destination vacation playground for many, the island provides a vehicle accessible getaway from the busier mainland. Providing picturesque ocean views and tranquil farmland, the full marathon and half marathon courses, along with our 10k and 5k, promise to be scenic from country back roads to waterfront coastlines, snow-capped mountains and rolling hills.
April 22nd, 2018
Marathon | Half Marathon | 10K | 5K | Kids' RunLearn More Event Site
Once again Downtown Bellevue will play host to one of Spring's premier running events! Save the date for the All In For Autism 10K/5K held on Sunday, April 29, 2018. The event offers a challenging 10K (6.2 miles) route as well as a 5K (3.1 miles) route for the whole family. ...More
April 29th, 2018
10K Run | 5K Run/Walk | Kids' RunLearn More Event Site
Offering one of the FLATTEST half marathon courses in Western Washington with less than 130 feet of cumulative elevation gain/loss over the 13.1 mile course, runners come from all over to gain their personal best! This race also serves as the Northwest USA Track & Field Half Marathon Championships, bringing in elite athletes from all ...More
September 3rd, 2018
Half Marathon Run/Walk | 4 Mile Run/Walk | Kids' RunLearn More Event Site
Enjoy a beautiful run through Seattle's most scenic spots. Then, celebrate your victory with fellow chocolatiers at our post-race party. Stuff your face with decadent fondue, watch the kids go crazy in the bounce house, pose for photos with Marsha & Mellow—the energy is infectious!
Coming in 2018!
15K | 5KLearn More Event Site
The St. Jude Rock 'n' Roll Nashville Marathon & 1/2 Marathon (formerly St. Jude Country Music Marathon & 1/2 Marathon) gives you the opportunity to enjoy an up close and personal tour of Nashville Music City, New York Times' top destination in the world! Be entertained en route with musical ...More
Coming in 2018!
Marathon | Half Marathon | 5KLearn More Event Site
2017 marks the 12th anniversary of the UW Bothell 5k Run/Walk! This growing race is expected to host nearly 1,000 runners and walkers, and will welcome over 1,500 people on campus! The event features not only the 5k Run/Walk through campus and downtown Bothell, but also includes the Cascadia Pups ...More
Coming in 2018!
5K Run/Walk | Kids' RunLearn More Event Site
Join us for the seventh anniversary of the West Seattle 5K Run to benefit West Seattle High School. Enjoy views of Puget Sound and the Seattle skyline on this scenic 5K route along West Seattle's Alki Beach. Afterwards, you can take advantage of "Celebrate Seattle Summer Streets" Car Free Sunday on Alki, ...More
Coming in 2018!
5K Run/WalkLearn More Event Site
ROCK the streets where it all began. The Suja Rock 'n' Roll Marathon & 1/2 Marathon returns for its 19th year on June 5, 2016. Run through historic neighborhoods including Balboa Park and Old Town. The Marathon, Half Marathon and Relay are packed with live entertainment on course that will keep you rockin' all the way to the finish line.
Coming in 2018!
Marathon | Half Marathon | 2-Person Half Relay | 5KLearn More Event Site
Over the past 39 years, the Shore Run/Walk has hosted thousands of participants and supporters that come together for one important cause, to support the fight against cancer through Fred Hutchinson Cancer Research Center! During the race, participants enjoy scenic courses along the western shore of Lake Washington and take part ...More
Coming in 2018!
10K Run | 5K Run/Walk | Kids' RunLearn More Event Site
During the 8th Annual Rock 'n' Roll Seattle Marathon & Half Marathon, participants will start and finish at Seattle Center, home of the iconic Space Needle, and take in the breathtaking scenery while passing through the streets of Seattle. Runners will enjoy racing in the pleasant temperatures of a Seattle ...More
Coming in 2018!
Marathon | Half MarathonLearn More Event Site
Raise a glass with us on Father's Day as the Washington Beer Commission presents the 2nd Annual Washington Beer Run at Marymoor Park! Register and receive a Sunday ticket and early admission to the Washington Brewers Festival, souvenir tasting glass and nine (4 oz) tasting tokens. The Washington Brewers Festival is ...More
Coming in 2018!
5K | Washington Beer FestivalLearn More Event Site
Participants of all ages will test their skills in this day-long, interactive and family-friendly event. Run the 40-yard dash, catch passes, hit the tackling dummy, test your jumping skills and try not to trip during the tire drill. Proceeds from the event will help Doug and the City of Renton ...More
Coming in 2018!
Family CombineLearn More Event Site
The Head for the Cure Foundation mission is to raise awareness and funding to inspire hope for the community of brain cancer patients, their families, friends, caregivers and other supporters, while celebrating their courage, spirit and energy.
Coming in 2018!
5K Run/Walk | Kids' RunLearn More Event Site
Bremerton Summer Brewfest features 30 Washington breweries pouring more than 70 craft beers. To highlight the creativity of our Washington brewers, many beers will be poured through randalls filled with unique ingredients. What is a Randall, you ask? Come to Summer Brewfest to learn more from our expert brewers while ...More
The Seattle Seahawks will open 11 training camp practices to fans at the Virginia Mason Athletic Center beginning July 30 and concluding August 16. Orswell Events coordinates management of attendee parking and shuttle plan.
NFL Training CampLearn More Event Site
The Washington Beer Commission is excited to announce the Washington Beer Collaboration Festival at the South Lake Union Discovery Center lawn. This festival will feature 25 unique collaboration beers from 50 different Washington breweries. These beers will highlight the creativity and collaborative spirit of the Washington Beer community. https://www.youtube.com/watch?v=s2_bsBVWWso
The 2017 Spirit of Bellevue Run/Walk offers a fun and mostly flat 5K (3.1 miles) run/walk route for the whole family, a Mile Challenge for those that like to push their limits, and a Kids Fun Run. For those who like to keep track, the Spirit of Bellevue is chip ...More
Coming in 2018!
5K Run | Mile Challenge | Kids' RunLearn More Event Site
Join your fellow Sounders FC fans and Give Us Your FULL 9K! The Sounders FC Rave Green Run features a 9K Run, 5K Run/Walk and 1K Kids' Dash. All participants receive a "Rave Green Run" Tech Shirt and a Sounders FC RAVE Finisher Medal. After the event, watch your Sounders FC while surrounded by Food ...More
Coming in 2018!
9K | 5K | Kids' Run | Viewing PartyLearn More Event Site
The Inland Northwest Craft Beer Festival will welcome 30 craft breweries pouring more than 100 types of beer. To commemorate America's other favorite pastime, the event will be held at Avista Stadium and features live music, great food and baseball-themed fun.
Register for Get Your Rear in Gear – Seattle, a 5K Run/Walk and Kids' Fun Run to help raise funds for colon cancer awareness efforts in the Seattle-area. Money raised will stay in our community to encourage screening and education for the nation's No. 2 cancer killer. With your help, ...More
Coming in 2018!
5K Run/WalkLearn More Event Site
Gear up, and return to campus for a Husky classic! Hit all the campus landmarks before crossing the finish line in the Quad. There's a Husky Pups Run for the littlest Dawgs, and all four-footed friends are welcome. At the Post-Dash Bash, you'll enjoy food, beverages, entertainment and a family-fun ...More
Coming in 2018!
10K | 5K | Kids' RunLearn More Event Site
2017 will mark Transamerica Rock 'n' Roll Denver Half Marathon's 8th year with the series since its inaugural race in 2010, and is a continuation of the Denver Marathon event that began in 2006. Throughout the years Denver runners have combined their love of the great outdoors, culture and music ...More
Coming in 2018!
Half Marathon | 10K | 5KLearn More Event Site
It's time to lace up those running shoes and grab your favorite costume! Rock 'n' Roll Los Angeles Halloween Half Marathon & 5k! Enjoy every spooktacular moment of the World's Largest Halloween Half Marathon as you rock through Downtown LA with live bands lining the course and celebrate with a ...More
Coming in 2018!
Half Marathon | 5KLearn More Event Site
The Winter Pineapple Classic is the Leukemia & Lymphoma Society's annual 5k run with obstacles. Started here in Seattle by a family enduring some of the most challenging times in their lives, the event continues to be a positive way to channel all the sadness a cancer diagnosis can bring, ...More
Coming in 2018!
5K Obstacle Fun RunLearn More Event Site
Rock 'n' Roll Las Vegas Marathon & Half Marathon to benefit the Crohn's & Colitis Foundation of America is coming to the Las Vegas Strip. This unique weekend experience includes live music, parties, Health & Fitness Expo, multiple running distances and more! Runners of all levels should join us for ...More
Coming in 2018!
Marathon | Half Marathon | 10K | 5KLearn More Event Site


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Shop Chargers
A "smart charger" should not be confused with a "smart battery". A smart battery is generally defined as one containing some sort of electronic device or "chip" that can communicate with a smart charger about battery characteristics and condition. A smart battery generally requires a smart charger it can communicate with (see Smart Battery Data). A smart charger is defined as a charger that can respond to the condition of a battery, and modify its charging actions accordingly.
The output current of a smart charger depends upon the battery's state. An intelligent charger may monitor the battery's voltage, temperature or time under charge to determine the optimum charge current and to terminate charging.
A typical intelligent charger fast-charges a battery up to about 85% of its maximum capacity in less than an hour, then switches to trickle charging, which takes several hours to top off the battery to its full capacity. -Wikipedia


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Five easy ways to impress your employer during an interview
Once you've put the hard work into your CV and cover letter, and the invitation to an interview finally lands in your inbox, what are the easiest ways to leave a good impression with your potential employer? Below are a few tips and tricks to point you in the right direction…
1. Punctuality
You need to start as you mean to go on, so making sure you turn up to your interview on time is absolutely crucial. In fact, you should always aim to arrive around 15 minutes before your allotted time, so that while reception alerts the interviewer to your arrival, you still have a few minutes to relax and go over your notes once more.
2. Dress sense
What you wear to an interview says a lot about you as a person, but it's important that you dress accordingly for the position. You might have a crazy and creative dress sense, but the interviewer needs to know that you're able to fit in with their team and show a professional side. Whether you're going to be working on the shop floor in uniform, or in the art department with no rules on attire, you need to show that you're able to represent the company to clients when needed, and a smart suit, shirt or blouse combination is best.
3. Always arrive prepared
It goes without saying that you should prepare for the kinds of questions you're likely to get asked, such as explaining your relevant experience, but a sure-fire way to impress is to drop in pieces of information about the company. For example, when talking about why you want to work for them, it would be useful to add: "I saw that you recent won an award for "X" – that made me feel like I would be working within a successful environment that I could learn from".
4. Demonstrate your knowledge of the field
In the same way that you want to show your knowledge of the company, try to show your understanding of the industry where possible. For example, if you're looking to move into the HR, it's likely they'll ask you about the challenges you would come up against, or ask for your opinion on how to improve things. Make sure you've thoroughly researched the competition if it's for a HR firm, and if it's in-house, the types of packages currently available that help to cut down on inefficiencies (such as the Cascade HR software here).
5. Ask the right questions
Finally, you should always aim to ask a couple of questions at the end of an interview, but if you really want to impress, try to work in information that's come up during the course of the conversation. For example, if they mentioned the company structure, ask more about the specific team you'd be working with. Plus, it's always good to show that you're keen to develop, so you can always ask about career opportunities.
Careers Advice
Where to begin?
Undecided about what to do next after university? Don't panic GradJobs will help you! It is important to remember that you are not alone – there are many who don't have any idea what to do after graduating.If you are unsure which career is right for you, or simply not sure where to start on your job hunt, then head to the Advice Clinic at the National Graduate...
Interview Advice
You've made it through the first round and you've got an interview! Yet, it's nerve-wracking going into a room and getting grilled to prove how you are the best candidate for the role. To create the right impression and make a positive impact at interview stage, there are a number of things you must take into consideration and prepare for...
Applying for a Job
From the perfect CV to cover letters, online applications, recruitment agencies, psychometric testing, job AND assessment centres, applying for a job can sometimes seem a little daunting, and that's before you've even secured an interview! Follow our step-by-step guides and handy tips from industry professionals to make you stand out from your...
Recruitment Exhibition
How the National Graduate Recruitment Exhibition can aid your job hunt
For many graduates, looking for their first job can be a daunting and unsettling process – not only are you moving away from university and the community that you have built but you are also having to take that first step into the working world...
Career advice videos
Online aptitudes tests
Are you prepared to tackle the intense recruitment process ahead of you? Get a head start on your peers by taking a psychometric aptitude test! Get full access and learn how to increase your chances of passing the tests successfully.
Take an aptitude test today >>


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I belive not all the villa are the same! I was in the last villa at the bottom and was a real paradise i love the fact that i can have breakfast at the villa lunch outside and i can cook my own food in...More
Getting you more information on this room
Getting you more information on this room
"Take some meat, garlic bread and condiments and get the chef to do a BBQ. It was amazing."
"Each villa has 2 bedrooms, which can accomodate 4 people. Individual rooms cannot be booked."


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The 27th Carr Center Cake Auction ended today.
The phones rang until the very end of the auction and several bids doubled in the last few minutes.
Director of the Carr Center, Kim Hosler said this weekend was very steady.
"I would say were holding our own it's not through any major thing that happened, no major giant bid has really thrown us up into our numbers its been a lot of real slow kind of average buying slow and steady wins the race. I think that's where we are," said Hosler.
Hosler said this is her first year as director and she didn't know what to expect.
"I thought I knew what the cake auction was from the outside in but actually from the inside out its totally different it takes on a life of its own, " said Hosler.
At the end of the event the total earnings for the event were around 130,000. We will update you with the latest amount as we get more information. Holser says she is grateful for everyone who participated and made this event possible.


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With Love Wherever You Are, By Dandi Daley Mackall
About the Book: After a whirlwind romance and wedding, Helen Eberhart Daley, an army nurse, and Lieutenant Frank Daley, M.D. are sent to the front lines of Europe with only letters to connect them for months at a time.
Surrounded by danger and desperately wounded patients, they soon find that only the war seems real―and their marriage more and more like a distant dream. If they make it through the war, will their marriage survive?
Based on the incredible true love story, With Love, Wherever You Are is an adult novel from beloved children's author Dandi Daley Mackall.
*Book given to me by the publisher but all thoughts are my own.
My Thoughts: As someone who loves romance novels, I absolutely enjoyed this book. It hits all the check points of being one that you will like, a handsome man in the military and a gorgeous women working to help people with a love at first sight and then separation and the drama that goes with this. While I assumed that this was just a beautifully written book, I later realized that this book is actually based on a true story, told by the main characters' daughter through their letters, which makes it even better.


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An adaptation for the BBC of the Royal Shakespeare's already legendary modern dress version of Shakespeare's Hamlet. Clearly much of the column inches initially generated were down to the fact that David Tennant was playing Hamlet.
At the time he was Britian's most popular actor thanks to his role as the Doctor in Doctor Who but its a true tour de force and Tennant proves what a great actor he really is.
Filmed on location and featuring the original stage cast the drama focuses on Hamlet having decisions to make following the murder of his father at the hands of his Uncle Claudius who is now also married to Hamlet's mother.
production details
UK / BBC 2 – Illuminations – The Royal Shakespeare Company / 1×185 minute episode / Broadcast Saturday 26 December 2009 @ 5.05pm
Writer: William Shakespeare / Director: Gregory Doran
DAVID TENNANT as Hamlet
MARIAH GALE as Ophelia
PATRICK STEWART as Claudius
PENNY DOWNIE as Gertrude
SAM ALEXANDER as Rosencrantz and Second Gravedigger
TOM DAVEY as Guildenstern
PETER DE JERSEY as Horatio
OLIVER FORD DAVIES as Polonious
EDWARD BENNETT as Laertes
MARK HADFIELD as Gravedigger
JOHN WOODVINE as Player King
RYAN GAGE as Oscric and Player Queen
SAMUEL DUTTON as Dumbshow King
JIM HOOPER as Dumbshow Queen and Priest
DAVID AJALA as Reynaldo and Dumbshow Poisoner
KEITH OSBORN as Marcellus
EWEN CUMMINGS as Barnardo
ROBERT CURTIS as Francisco/Fortinbras
RODERICK SMITH as Voltemand
ANDREA HARRIS as Cornelia
RICKY CHAMP as Lucianus
RIANN STEELE as Lady-in-Waiting
ZOE THORNE as Lady-in-Waiting


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14 Gauge Cold steel Galvanized Steel Wire is a low carbon steel wire used to pull made of wire according to different purposes, are not the same composition, the composition comprising: iron, cobalt, nickel, copper, carbon, zinc, as well as other elements.
14 Gauge Cold steel Galvanized Steel Wire is a wire made of mild steel to pull the hot metal billet rolled into 5mm thick steel bars, and then put it into the drawing device to pull within a different diameter line, and gradually narrow the aperture plate drawing , cooling, annealing, coating and other processing into a variety of different specifications of wire. Binding with wire by industry standard specifications are the following: 0.50mm diameter 25 # wire, 0.55mm diameter 24 # wire, 0.60mm diameter and 0.70mm diameter wire 23 # 22 # wire and so on.


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- Please select a date to see the proper prices!
- Meal can be requested on the spot
Best offer
55.20 € / person / night, no meal
Description of the accommodation:
Rooms, services Axis Vermar Conference & Beach Hotel Póvoa de Varzim is glad to host the guests of RevNGo.com for some pleasant days in Portugal. The hotel is offering 208 tasfefully furnished, nice rooms for those looking for a place to stay at in Póvoa de Varzim. The hotel is offering you freshly prepared fine local meals in its restaurant every day. Parking possibility for your vehicle is available nearby. The bar is an ideal place to host a personal meeting or a pleasant evening talk. Wireless Internet connection (WiFi) is available at the hotel, ensuring that you can stay up-to-date during your holiday. If you wish to learn more about the exact scope of services provided by Axis Vermar Conference & Beach Hotel Póvoa de Varzim (including any available for an extra fee), you will find them on the information sheet below.
Payment Advance payment by credit card or providing credit card guarantee may be necessary for finalizing the reservation, depending on the chosen date, room and price.
Arrival, opening hours The earliest time to arrive is 14:00, the latest time to leave the rooms is 24:00. You will be able to speak with the personnel in Portuguese and English languages.
Axis Vermar Conference & Beach Hotel Póvoa de Varzim rooms Rooms
- Please select a date to see the proper prices!
Accommodation services
Free WiFi in shared places
- Pool (Outdoor - seasonally open)
Garden, Bar, Elevator
Own restaurant
Hairdryer, Mini-bar


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Updated: Jan 15, 1:30pm – Alameda police provided this statement, "An officer received an ALPR hit in her vehicle when driving in the 1500 block of Lincoln Ave. on a stolen car that was going eastbound in the 1500 block Lincoln Ave. The car was stolen from Oakland. A felony vehicle stop was made in accordance with our policy and a person was arrested without incident and the car recovered."
Updated: Jan 15, 2:01pm – Grant Butterfield followed-up to his video with this explanation, "Driving north on Chestnut to stop at Lincoln looked left and saw what turned out to be the perpetrators car coming east at a non Alameda rate of speed with one of those new SUV vehicles hot on it. Dude pulled over right in front of me with, as you can see, that SUV right there. Lady cop exits SUV and immediately draws her very impressive hand gun. Second squad arrives with the short round cop coming to the passenger side of the SUV weapon drawn. No movement yet. Third car arrives with the officer in civilian clothes. He enters the scene weapon drawn with the fourth officer arriving shortly after that with the long gun shown in the video. They now get the guy to exit the car hands way up. They get him to pull his black hooded shirt up over his head and turn a 360."
Alameda police arrested a man at gunpoint today, at Lincoln Avenue and Chestnut Street, apparently after a car stop."
Details are still pending from Alameda police, but Grant Butterfield captured the police action and provided this raw video below:


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"Endoscopy Unit - flexible sigmoidoscopy"
About: Central Middlesex Hospital Central Middlesex Hospital London NW10 7NS
Posted via NHS Choices
I went in for a flexible sigmoidoscopy. The wait was long - over an hour - but they explained they were very busy, which I could see was true. But once called, the staff were brilliant, very helpful, very considerate. In conversations it became apparent that a number of staff worked straight through their lunch break (and got to grab a sandwich at about 4pm), which I thougth testified to the department's busyness and to the staff's commitment to care. Procedure itself went fine, one doctor was evidently training another in performing the procedure, but that was not a problem. Nurses were brilliant. You can be nervous having this sort of procedure. Staff were brilliant.


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LIMA, Peru (KRQE) – President Barack Obama is holding separate meetings with the leaders of Australia and Canada before he wraps up the final foreign trip of his presidency.
On Saturday, he tried to ease fears in Latin America that his successor will pull out of American trade deals. He asked Peruvians to give Trump a chance.
"Once they look at how it's working, I think they'll realize it's good for both the United States and our trading partners," President Obama said.
He said the President-elect will eventually see the benefits of those deals.
President Obama is also eventually expected to meet with Russian President Vladamir Putin. It would be the first meeting between the two since the White House blamed Russia for hacking Democratic Party email servers.


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How are you all doing with the challenge so far? I hope I am not overwhelming you with the assignments, but I really want to get the gardening side of things all planned out and ready to go. Some of you in warmer climates have started your seeds indoors already. I, on the other hand, won't be starting mine until next month. Either way, let's get our gardens planned out shall we?
During this challenge, it is important to know that we can't do it all. So, please, do not feel guilty if you can't do what others are doing! Some of us are more seasoned gardeners and/or have more space than others, some of us are more knowledgeable in making good use of our milk products or growing our own grains. Some of us are experts at harvesting and preserving, while others know more about raising our own meat.
That is one of the reasons I created the Replacing the Grocery Store Challenge Group on facebook. We can come together and share our knowledge, ask questions and make new friends. Let me tell you, in just one day we have over 180 people and it is a hoppin' page! Some of you are already connecting with each other and I am so excited to see the interaction!
After doing today's assignment, you should have a better idea of how much space you will need to plan out your garden. I will try to draw mine out and put it on here. Just know that I'm not an artist! It won't be pretty, but you can take a look into my little world and what it will hopefully look like soon!
Two books that I absolutely love are The Backyard Homestead and The Backyard Homestead, Guide to Raising Animals. If you want information on anything pertaining to being more self-sustainable without a whole lot of space, these are two of my favorites!
Day 4 challenge - Find out how much space is required for each vegetable.
Here we go again. Are you sick of math yet? I am actually, but it must be done in order to find out how much space is needed and if we need to adjust our servings if we do not have enough space.
Your last assignment was to figure out how many pounds you need for each veggie. You can't move on to step four unless you have step three done. I'm going to keep using beans as my example. So here is what I have after last assignment in the second column of my chart.
Remember, 45 is the number of average pounds per a 100 foot row. 14-23 is the average pounds per 100 foot square feet (remember, that is 10 x 10 or 20 x 5). And 104 is my number of pounds needed per year for beans.
Since we know the average pounds required for a certain amount of space, we can figure out how much we need. I usually go by the 100 foot rows as it is easier for me and my garden is usually laid out as such.
If it takes 45 pounds for a 100 foot row and I want 104 pounds of beans, then I must increase my rows to at least 2 100 foot rows. If you double the 45 pounds, you get 90. That is pretty close to 104, but since my family loves beans, I am just going to increase it to 3 100 foot rows.
Some of you might not have enough space for 100 foot rows, so just decrease your yields to whatever works for you. Once you figure out your yields and space, fill in the third and fourth columns. If you do have adjusted yields and changed your space required, make sure you go back and change your servings too. That way when you go back and look at your garden notes, you won't be confused and wondering why you had such poor yields!
If you haven't printed out the chart yet, here it is.
And if you want to cheat a little, here is mine! Remember, we are a family of seven.
Notice I haven't changed my servings yet where I adjusted my pounds. So, make sure you change those if need be.
We are almost done with the chart! Yes! We will celebrate with a giveaway next week!
If you missed the other assignments, go HERE and scroll down.


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I now know what it's like to be a hamster.
The experience came to me in Jones AT&T Stadium after Saturday evening's Texas Tech vs. Central Arkansas football game.
Having finished my work helping the Associated Press with coverage, I discovered two walk-in, human-size inflatable hamster balls - the ones used for a promotional race on the field during a break in the game.
What was I suppose to do?
I felt like a kid in a candy store.
Getting in it was easy.
Getting out - not so much.
(You can dive into the entry point just fine, but your weight keeps moving the exit hole to the floor when you try to leave.)
Why climb into an unattended human hamster ball, you ask?
I think English mountaineer George Mallory said it best when he was asked about climbing Mt. Everest.
"Because it's there."


text: Seller: ancientgifts (4,352) 100% , Location: Lummi Island, Washington, Ships to: Worldwide, Item: 381854529283 The First Crusade by Steven Runciman. NOTE: We have 75,000 books in our library, almost 10,000 different titles. Odds are we have other copies of this same title in varying conditions, some less expensive, some better condition. We might also have different editions as well (some paperback, some hardcover, oftentimes international editions). If you don't see what you want, please contact us and ask. We're happy to send you a summary of the differing conditions and prices we may have for the same title. DESCRIPTION: Hardcover: 240 pages. Publisher: Cambridge University Press; (1980). When Pope Urban II rose to his feet to address the multitudes gathered before him at the Council of Clermont in 1095 A.D., his appeal was simple: let Western Christendom march to the aid of their brethren in the East. Whether the Crusades are regarded as the most tremendous and romantic of Christian expeditions or the last of the barbarian invasions, they remain one of the most exciting and colorful adventure stories in history. The reasons for joining the Crusade varied widely; remittance from penance, a desire to see the Holy Places, or greed for the power and booty to be captured in the East. But the prize at the end of it all, be it spiritual or temporal, of the Holy City of Jerusalem. An army of mounted warriors, traveling with peasants, merchants and artisans, faced a journey over hostile terrain, meeting with unforeseen antagonism, desert heat, and the constant struggle to feed and water their troops and horses. Their journey's spectacular culmination was the long siege of Jerusalem, at the end of which the Crusaders, by a brilliant tactical maneuver, broke down its defenses and poured into the city which erupted in a bloody massacre. Steven Runciman's "History of the Crusades" is justly acclaimed as the most complete and fascinating account of the historic journey to save the Holy Lands from the Infidel. This abridgement makes accessible to a wider readership one of the most compelling historical narratives. CONDITION: GOOD. Clean, lightly read (BUT ex-library) hardcover w/dustjacket. Cambridge University (1980) 240 pages. Inside the book there is a library card pocket glued to the first free page (the first unprinted page in the book), a library stamp to the title page, and then a catalog number written in ink along the edge of the table of contents page. Otherwise the inside of the book is clean and without further markings. The book appears as if it was read perhaps once, by someone with a very "gentle touch". Perhaps it was merely flipped through a few times, it is very clean. Pages are clean, crisp, unmarked (except as noted previously), unmutilated, and remain well bound. From the outside there are of course library stampings to the top and bottom surfaces of the closed page edges (not visible of course on individual opened pages, only to the mass of closed page edges, which is sometimes referred to as the "page block"). There's also the customary call tag on the dustjacket spine heel. The dustjacket is encased in a mylar sleeve (as is customary with library-owned books), so except a little bit of crumpling at the spine heel, the dustjacket, protected since new, is virtually pristine - though we would note as customayy with ex-library books, the dustjacket is affixed to the underside of the covers. Beneath the dustjacket the full cloth covers are clean and evidence only very mild edge and corner shelfwear. Given the fact the book is a library discard it might lack the "sex appeal" of a "shelf trophy". Nonetheless for those not concerned with whether the book will or will not enhance their social status or intellectual reputation, it is an otherwise clean and only lightly read copy with "lots of miles left under the hood). Satisfaction unconditionally guaranteed. In stock, ready to ship. No disappointments, no excuses. PROMPT SHIPPING! HEAVILY PADDED, DAMAGE-FREE PACKAGING! Meticulous and accurate descriptions! Selling rare and out-of-print ancient history books on-line since 1997. We accept returns for any reason within 14 days! #1741g. PLEASE SEE IMAGES BELOW FOR SAMPLE PAGES FROM INSIDE OF BOOK. PLEASE SEE PUBLISHER, PROFESSIONAL, AND READER REVIEWS BELOW. PUBLISHER REVIEW: REVIEW: 'This abridgement, first published in 1980 has kept all the essential information and ease of style which marked the larger version. Sir Steven Runciman (1903-2000) was the pre-eminent historian of the Crusades and the Byzantine Empire. His acclaimed multipart "History of the Crusades" was first published from 1951-1954. PROFESSIONAL REVIEW: REVIEW: This is one of history's most extraordinary episodes made extraordinarily real. Written by an expert blessed with lucidity and styles, it reads magnificently. As an example of sustained and intelligent narrative it could hardly be bettered, it is a story that has everything. Sir Steven's great achievement was to make a complicated subject appear simple and then to write it up beautifully. No one is likely to surpass Sir Steven's powers of synthesis or the masterly way he writes. READER REVIEWS: REVIEW: Steven Runciman is well noted for his three-volume 'History of the Crusades' published in 1951. This paperback edition is an abridged excerpt of that work that focuses on specifically the First Crusade. This is a much "romanticized" narration of the First Crusades, as Mr. Runciman is well known for inscribing his passion for this event into his work. But do not let that stop you from reading this account. Mr. Runciman has added detail to this volume using quotes from actual chroniclers of the time to build and augment his story. This abridged paperback gives you contemporary descriptions of the political climate, the backgrounds of the main players, overviews of many of the campaigns and battles of the event and weaves it all into an interesting story filled with zealots, nobility, passion, intrigue and fire. Reading this you can easily get swept into the spiritual fervor and single minded determination that these people must have had. You also feel the impact of the battles and massacres in his descriptions of the sieges and taking of the various cities. Mr. Runciman does a very good job of making sure the reader becomes involved in the details of events as the Crusaders storm through the Holy Land to the city of Jerusalem. For a very well written and passionate account of the First Crusade this book will provide a good read as well as an historical overview of the event. REVIEW: The First Crusade comes alive in this book by Runciman. This is a great work that offers the "high points" of the late 11th century epic conflict between West and East. Runciman's writing style is very readable. The book may be read in a short time. He tells the Crusade's story chronologically using considerable topical details. If you want the main characters' names, the dates, and places that made Crusade history, Runciman has them. This book inspired further reading about the Templars and Hospitalers. This book is a must read for Crusade reader and those interested in Middle-Eastern history. It also speaks to early Christian-Muslim military action. REVIEW: This Canto abridged version gives in nearly 200 pages a good account of the motives of the "West" to start the crusades, the reasons why the Byzantines agreed, the very individual human motives of the kings, popes, clergyman, nobles, and poor. It also spells out what it takes to get (mostly on foot) from France to Jerusalem, with a large mass of poorly prepared people. A fascinating account. If you have romantic ideas about the crusades they will have been replaced by solid facts out of the every-day's crusaders lives at the end of this book. You'll have a better grasp of this era as a whole, and the place of the crusades in it. This is a good read that offers you the flavor, the look and feel, of the past. REVIEW: For an expert or someone not well-versed in the Crusades, there might not be a better resource than Steven Runciman's history of the Crusades. This book which focuses on the First Crusade relates the origins of the Crusades. Runciman also provides very interesting overview of Christian history in the process of describing the relationship of the Church in the east to Muslims and Jews. In doing so, the reader is impressed by the complexity of relations between the three major faiths that lay claim to the Holy Land, and how the complexity of these relations is not a new phenomenon. If anything, Volume One suggests that, freed from outside pressures, the "people of the book" can coexist. Runciman also conveys the human dynamic aspect of the early Crusades that might be lost. The relationships between the hermits and clergy that spawned the first crusade, the competition (of sorts) between the Frankish and German lords, their confrontations with Byzantine authorities (both ecclesiastical and secular) and those of the Middle East were the real drivers of the Crusades. In understanding how these human interactions developed and played out, the reader can better trace the ebb and flow of the cause-effect of actions and reactions that shaped the Crusades. I always ship books Media Mail in a padded mailer. This book is shipped FOR FREE via USPS INSURED media mail ("book rate"). The shipment will include free USPS Delivery Confirmation (you might be able to update the status of your shipment on-line at the USPS Web Site and free insurance coverage). If you are concerned about a little wear and tear to the book in transit, I would suggest a boxed shipment - it is an extra $1.00. Whether via padded mailer or box, we will give discounts for multiple purchases. International orders are welcome, but shipping costs are substantially higher. Most international orders cost an additional $12.99 to $33.99 for an insuredshipment in a heavily padded mailer, and typically includes some form of rudimentary tracking and/or delivery confirmation (though for some countries, this is only available at additional cost). There is also a discount program which can cut postage costs by 50% to 75% if you're buying about half-a-dozen books or more (5 kilos+). Rates and available services vary a bit from country to country. You can email or message me for a shipping cost quote, but I assure you they are as reasonable as USPS rates allow, and if it turns out the rate is too high for your pocketbook, we will cancel the sale at your request. ADDITIONAL PURCHASES do receive a VERY LARGE discount, typically about $5 per book (for each additional book after the first) so as to reward you for the economies of combined shipping/insurance costs. Your purchase will ordinarily be shipped within 48 hours of payment. We package as well as anyone in the business, with lots of protective padding and containers. All of our shipments are sent via insured mail so as to comply with PayPal requirements. We do NOT recommend uninsured shipments, and expressly disclaim any responsibility for the loss of an uninsured shipment. Unfortunately the contents of parcels are easily "lost" or misdelivered by postal employees – even in the USA. That's why all of our shipments include a USPS delivery confirmation tag; or are trackable or traceable, and are insured. We do offer U.S. Postal Service Priority Mail, Registered Mail, and Express Mail for both international and domestic shipments, as well United Parcel Service (UPS) and Federal Express (Fed-Ex). Please ask for a rate quotation. We will accept whatever payment method you are most comfortable with. If upon receipt of the item you are disappointed for any reason whatever, I offer a no questions asked return policy. Send it back, I will give you a complete refund of the purchase price (less our original shipping costs). Most of the items I offer come from the collection of a family friend who was active in the field of Archaeology for over forty years. However many of the items also come from purchases I make in Eastern Europe, India, and from the Levant (Eastern Mediterranean/Near East) from various institutions and dealers. Though I have always had an interest in archaeology, my own academic background was in sociology and cultural anthropology. After my retirement however, I found myself drawn to archaeology as well. Aside from my own personal collection, I have made extensive and frequent additions of my own via purchases on Ebay (of course), as well as many purchases from both dealers and institutions throughout the world - but especially in the Near East and in Eastern Europe. I spend over half of my year out of the United States, and have spent much of my life either in India or Eastern Europe. In fact much of what we generate on Yahoo, Amazon and Ebay goes to support The Hermitage Museum in St. Petersburg, as well as some other worthy institutions in Europe connected with Anthropology and Archaeology. I acquire some small but interesting collections overseas from time-to-time, and have as well some duplicate items within my own collection which I occasionally decide to part with. Though I have a collection of ancient coins numbering in the tens of thousands, my primary interest is in ancient jewelry. My wife also is an active participant in the "business" of antique and ancient jewelry, and is from Russia. I would be happy to provide you with a certificate/guarantee of authenticity for any item you purchase from me. There is a $2 fee for mailing under separate cover. Whenever I am overseas I have made arrangements for purchases to be shipped out via domestic mail. If I am in the field, you may have to wait for a week or two for a COA to arrive via international air mail. But you can be sure your purchase will arrive properly packaged and promptly - even if I am absent. And when I am in a remote field location with merely a notebook computer, at times I am not able to access my email for a day or two, so be patient, I will always respond to every email. Please see our "ADDITIONAL TERMS OF SALE." TRANSLATE Arabic Chinese French German Greek Indonesian Italian Hindi Japanese Korean Swedish Portuguese Russian Spanish


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It's Christmas and that means it's time for panto... oh yes it is!
It's lovely to see that the pantomime tradition is alive and well and still happening at Christmas time. People have been saying for yonks that the panto tradition is outdated. A newspaper lamented in 1876 that: "Every season convinces us more and more that pantomimes have had their day." But in truth, panto never dies.
Some of the happiest Christmas memories of my childhood are associated with being taken to the pantomime in Dublin, either to the Gaiety or the Olympia, and in the early days, to the Theatre Royal - alas, demolished in 1963. I will be ever grateful to my Aunty Maureen for arranging this annual treat, which seemed to open up a magical world of spectacle, of magic, of music, of story, of live audience interaction ("Oh yes he is."), of comedy, of ballet, of acrobatics, and of the gender-bending theatre tradition involving a principal boy, who was actually a girl with terrific legs, and a Dame, who was actually a man with a salty sense of humour.
I loved every pantomime, but the story of Dick Whittington and His Cat had a lasting influence. The Whittington story is very old; Samuel Pepys mentions it in his diary in 1668. Richard Whittington was a real person, born in Gloucester about 1350, and the panto tells the tale of his journey to London, where, he believed, "the streets were paved with gold". He sets out to walk to the capital, accompanied by his cat, who will prove very useful (the cat is always a great turn). He meets many obstacles - he is harassed, rejected, bullied, and has to serve as a kitchen slave to the evil Baron Fitzwarren (historically, it was a Lord Fitzwaryn). Each time Dick is disheartened and considers giving up, he hears the bells of London chiming, with the words: "Turn again, Whittington." Keep on keeping on. Never lose heart. Naturally, Whittington eventually triumphs, becomes Lord Mayor of London, marries Alice Fitzwarren, and lives happily ever after (with cat).
I remember now so clearly, sitting in the grand circle of the theatre, aged 10, and being thrilled to hear those words: "Turn again, Whittington." And then cheering loudly, with all the other children, as Dick took up his tramp's bundle and walked on.
All pantos are great. But Dick Whittington will always remain my favourite. It's an embellished version of an old folk tale, but it also captures the essence of a great narrative - it's about a journey. It's about overcoming difficulties. It's about seeking your destiny. And it's about persistence.
The most popular pantomimes have been going for centuries. Little Red Riding Hood first appeared in panto form in 1745 - when the Irish actress Peg Woffington appeared, stunningly, in breeches on the London stage, paving the way for the principal boy transvestite turn. Sleeping Beauty, Puss in Boots, Cinderella were all pantos by the 1830s, followed in the next decades by Jack and the Beanstalk, Mother Goose and Aladdin.
The original, rather terrifying, Babes in the Wood (based on a true story about young children perishing at the hands of a wicked uncle) was popular from its first performance in 1827 at Drury Lane. Thankfully, the ferocity of the narrative has been softened.
Beauty and the Beast has been performed in panto form since at least the 1870s. Robinson Crusoe was a panto in 1781, when the playwright Richard Brinsley Sheridan wrote the script.
Pantomime (which was an invention of the London stage but had its roots in ancient Greece and Rome) certainly changes and adapts, as any genre must: clowns were once a central feature of the panto, but they faded away, and are replaced today by comical or satirical acts.
A female playing the principal boy was considered somewhat outdated by the late Sixties, but was then revived in a fabulous performance by the late Cilla Black, as Jack in Jack and the Beanstalk, in 1983. The Ugly Sisters role has grown over the years - and also become more transgendered. Distinguished Shakespearean thespians like Sir Ian McKellan now relish doing a turn as the outrageous stepsisters, who have borne such names as Euthanasia and Asphyxia.
The pantomime historian Gerald Frow notes that a trend in panto has been the ever-increasing popularity of the villain. All audiences adore the villain at whom they can hiss and boo at full throttle.
There have been new pantos. The London stage introduced two pantos with Irish themes: one called Harlequin Pat or The Giant's Causeway, in 1830, which featured Brian Boru and St Patrick; another, in 1849, was called Harlequin and the Magic Fiddle and it starred Father Matthew, the temperance campaigner, and an Evil Spirit called 'Alcohol'. Neither was a hit, but maybe the Father Matthew panto could be given another try?
It's good to try new pantos, yet it's amazing how durable the old ones remain.
At Christmas 1974, a theatre list for pantomimes showing included Aladdin, Babes in the Wood, Robinson Crusoe, Cinderella, Beauty and the Beast, and Sleeping Beauty.
Not too different from the list of pantos on offer this season in Belfast.
Belfast Telegraph


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HMRC VAT output tax toolkit
- From:
- HM Revenue & Customs
- Part of:
- Tax agents toolkits, VAT, and Tax agent and adviser guidance
- Published:
- 1 July 2014
- Last updated:
- 18 July 2017, see all updates
Guidance for tax agents and advisers on completing VAT Returns on behalf of their clients.
This toolkit provided by HM Revenue and Customs is aimed at helping and supporting tax agents and advisers when completing returns on behalf of clients. It may also be of use to anyone who is completing a return.
Tax agents and advisers who don't complete their client's return can use it as a source of reference when advising clients on VAT matters or for reviewing client's VAT declarations at the year end.
Document information
Published: 1 July 2014
Updated: 18 July 2017
- The Agent toolkit for VAT output tax has been updated for 2016 to 2017.
- Revised VAT output toolkit (December 2016) published.
- VAT output toolkit updated for 2015 to 2016.
- Agent toolkit for VAT Output Tax has been updated.
- First published.
From: HM Revenue & Customs
Part of: Tax agents toolkits VAT Tax agent and adviser guidance