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The subject matter of this disclosure links Alzheimer's Disease with somatic mosaicism of cells trisomic for chromosome 21. Disclosed are methods of detecting Alzheimer's Disease in an individual by measuring certain characteristics known to be associated with Down syndrome that arise due to the trisomy nature of that disorder.
1. A method for detecting Alzheimer's Disease in an individual comprising:
a) determining pupil diameter for both eyes of the individual;
b) administering to one eye of the individual a cholinergic antagonist at a concentration sufficient to produce a detectable difference in pupil diameter in an individual without Alzheimer's Disease compared with an individual with Alzheimer's Disease;
c) determining pupil diameter for both eyes of the individual at periodic intervals following the administration of the cholinergic antagonist; and
d) comparing the pupil diameter of the eye treated with the cholinergic antagonist and the pupil diameter of the untreated eye at corresponding periodic intervals following the administration of the cholinergic antagonist, a substantial difference in the percent change in diameter between the treated and untreated eyes being diagnostic of Alzheimer's Disease.
2. The method of claim 1, wherein the cholinergic antagonist is administered in an amount determined to induce minimal, but detectable, mydriasis in an individual not afflicted with Alzheimer's Disease.
3. A method of claim 1 wherein the substantial change in pupil diameter of the one eye compared with the pupil diameter following administration of the cholinergic antagonist is at least about 10%.
4. A method of claim 2 wherein the cholinergic antagonist is tropicamide.
5. A method of claim 4 wherein the tropicamide concentration is less than about 0.1%.
6. A method of claim 5 wherein the tropicamide concentration is about 0.01%.
7. A method for detecting Alzheimer's Disease in an individual comprising:
a) determining pupil diameter for one eye of the individual;
b) administering to the one eye of the individual a cholinergic antagonist at a concentration sufficient to produce a detectable difference in pupil diameter in an individual without Alzheimer's Disease compared with an individual with Alzheimer's Disease;
c) determining pupil diameter for the one eye of the individual at a time following the administration of the cholinergic antagonist suitable for detecting mydriasis in the one eye of the individual; and
d) comparing the pupil diameter in step c) for the one eye with the pupil diameter determined in step a) for the one eye,
wherein a substantial difference in the pupil diameter determined in step c) for the one eye compared with the pupil diameter determined in step a) for the one eye is diagnostic of Alzheimer's Disease.
8. The method of claim 7 wherein the cholinergic antagonist is administered in an amount determined to induce minimal, but detectable mydriasis in an individual who does not have Alzheimer's Disease.
9. A method of claim 8 wherein the substantial change in pupil diameter determined in step c) for the one eye compared with the pupil diameter determined in step a) for the one eye is at least about 10%.
10. The method of claim 8 wherein the cholinergic antagonist is tropicamide.
11. The method of claim 10 wherein the tropicamide concentration is less than about 0.1%.
12. The method of claim 11 wherein the tropicamide concentration is about 0.01%.
13. A method for detecting Alzheimer's disease in an individual who does not have the symptoms characteristic of Alzheimer's Disease comprising:
a) determining pupil diameter of one or both eyes of the individual who does not have the symptoms characteristic of Alzheimer's Disease;
b) administering to an eye, referred to as the treated eye, whose pupil diameter was determined in step a) a cholinergic antagonist at a concentration sufficient to produce a detectable difference in pupil diameter in an individual without Alzheimer's Disease compared with an individual with Alzheimer's Disease;
c) determining pupil diameter for the treated eye at a sufficient period of time following the administration of the cholinergic antagonist for detecting mydriasis in the treated eye; and
d) comparing the pupil diameter determined in step c) for the treated eye with the pupil diameter determined in step a) for one of the eyes,
wherein a substantial difference in the pupil diameter determined in step c) for the treated eye compared with the pupil diameter determined in step a) for the one eye is diagnostic of Alzheimer's Disease in the individual who does not have the symptoms characteristic of Alzheimer's Disease.
14. The method of claim 13, wherein the cholinergic antagonist is administered in an amount determined to induce minimal, but detectable, mydriasis in an individual not afflicted with Alzheimer's Disease.
15. A method of claim 14 wherein the substantial change in pupil diameter determined in step c) for the treated eye compared with the pupil diameter determined in step a) for one of the eyes is at least about 10%.
16. The method of claim 14 wherein the cholinergic antagonist is tropicamide.
17. The method of claim 16 wherein the tropicamide concentration is less than about 0.1%.
18. The method of claim 17 wherein the tropicamide concentration is about 0.01%.
19. A method for aiding in the diagnosis of Alzheimer's disease in an individual comprising:
a) determining pupil diameter of one or both eyes of the individual;
b) administering to an eye, referred to as the treated eye, whose pupil diameter was determined in step a) a cholinergic antagonist at a concentration sufficient to produce a detectable difference in pupil diameter in an individual without Alzheimer's Disease compared with an individual with Alzheimer's Disease;
c) determining pupil diameter for the treated eye at a sufficient period of time following the administration of the cholinergic antagonist for detecting mydriasis in the treated eye; and
d) comparing the pupil diameter determined in step c) for the treated eye with the pupil diameter determined in step a) for one of the eyes,
wherein a substantial difference in the pupil diameter determined in step c) for the treated eye compared with the pupil diameter determined in step a) for the one eye indicates that the individual should be tested further for Alzheimer's Disease.
This application is a continuation of application Ser. No. 08/109,749 filed Aug. 20, 1993 now abandoned, which is a Continuation-In-Part of U.S. Ser. No. 07/678,683 Apr. 1, 1991 now U.S. Pat. No. 5,297,562.
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 histochemical 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 β or A4, a is �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 α1 -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.
The FIGURE is a diagram representing results obtained in studies of mydriasis following tropicamide administration to one eye in each of five patients diagnosed as probable Alzheimer's patients and 13 negative control patients who did not exhibit symptoms characteristic of Alzheimer's Disease. FIG. 1 shows in graphical form the percent change in pupil diameter of the treated eye versus the untreated eye at eight different sampling intervals occurring at 0, 2.5, 8, 15, 22, 29 41 and 53 minutes. FIG. 1 also compares the change in pupil diameter of patient's diagnosed as probable Alzheimer's patients (- - AD) and patients without the symptoms characteristic of Alzheimer's Disease (- - CN).
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. NY 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 βprotein 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. USA, 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 β-protein gene or by a duplication of the β-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 β-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 β-protein gene as a potential site for the disease locus.
Very recently, a variant form of the β-protein precursor gene encoding a mutant β-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 β-protein gene existed in three copies in Alzheimer's disease patients was not confirmed. Also the pattern of expression of the β-protein gene was subtly altered in Alzheimer brain but not simply overexpressed (see Tanzi, R. E., et al., 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 β-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 β-protein gene itself and closer to the centromere (Tanzi, et al., Nature 329:156-157 (1987b); Van Broeckhoven, et al., Nature 329:153-155 (1987); Goate, et al., Lancet Feb. 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. 51:185-196 (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 β-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 β-protein gene, has been shown to result, when trisomic, in neurodegeneration somewhat like that seen in Alzheimer's disease. 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 β-protein precursor, to β-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 extracellular staining for ACT and β-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 β-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 Jul. 22,:229 (1989); for discussion, see Hardy, et al., Lancet Sep. 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 Mar. 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 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 7:147-153 (1989)).
Recently, two rapidly dividing peripheral tissues (skin and intestinal mucosa) have been reported to contain pre-amyloid deposits of β-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. 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 β-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 β-protein is transported to the brain by the circulation, having been generated elsewhere (see, for example, Selkoe, Neurobiol. Aging 10:387-3395 (1989b) 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 Mar. 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). 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., Hum. 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).
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 Mar. 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 USA 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. USA 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. 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, hypersensitivity of heart rate, pupil contraction, and sweat production to acetylcholine agonists and antagonists. 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.
One example of such a diagnostic test is set forth in the Exemplification section which follows. Specifically, it is shown below that the administration of the cholinergic antagonist tropicamide, when administered to individuals identified as probable Alzheimer's disease patients at a concentration having a minimal but detectable effect on non-demented individuals, results in a substantial percent change in pupil diameter when compared with an untreated eye of the same individual. More specifically, tropicamide was administered to probable Alzheimer's patients at a concentration of less than 0.1% (the specific concentration was 0.01%) and resulted in about a 2-fold or greater percent change in pupil diameter.
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, or centromere binding proteins such as CBF1, or DYSi. 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-α receptor.
The mydriatic response to administration of the cholinergic antagonist tropicamide was studied in 5 patients diagnosed as probable Alzheimer's patients. In addition, 13 negative control patients who did not exhibit symptoms characteristic of Alzheimer's disease were included in the study.
Subjects had normal findings on a brief-neurological examination and a bedside neuro-ophthalmological examination that evaluated saccades, smooth pursuit, visual fields to confrontation and partial field optokinetic nystagmus. All subjects' pupils were examined for a narrow angle anterior chamber to eliminate subjects at risk for narrow angle glaucoma. Subjects were disqualified from participation if they had small pupils (less than 2 mm diameter), unusual pupil shapes, star cataracts or incipient cataracts that might affect accurate measurement of pupil diameter. All non-demented controls had normal findings on a short neuropsychological battery and no diseases of the central nervous system by history. Medication use in patients and controls was comparable. No subject was taking medications with known interaction effects with tropicamide.
Pupil diameter was measured using an Applied Science Laboratories video based, near infrared pupil center to corneal reflection system. This system, used to measure eye movements, also measures pupil diameter sampled continuously at 60 hertz. The system is non-invasive and requires no subject attachments or restraints. For this study, subjects were seated in a comfortable room with dim ambient illumination 1.5 m in front of a TV screen.
The subjects' pupils were imaged by the system as they sat viewing the TV screen set at a uniform low illumination. Subjects were directed to look at the center of the screen while the eye was initially imaged. Once the eye was adequately imaged and subjects had ample time to adjust to ambient illumination, a short calibration procedure was run to ensure accurate monitoring of subjects' eye position.
A very dilute solution of tropicamide (0.01%) was used to induce pupil dilation in this trial. Tropicamide in a solution strength of 0.5 to 1.0% induces maximal mydriasis in 20 to 40 minutes in normal healthy subjects. The short action time of this agent was chosen to limit the time required to reach a maximal mydriatic response. After baseline pupil measurements were determined for each eye, a single drop of the tropicamide solution was added to one of the eyes (randomly chosen). Pupil diameter data was sampled from both eyes for 30 second epochs over the course of an hour at 0, 2.5, 8, 15, 22, 29, 41 and 53 minute intervals. Between measurement epochs, subjects were shown segments from the video tape Fantasia in order to reduce anxiety, fatigue and boredom from sitting in a semidarkened room.
The percent change in diameter in the treated versus the untreated eyes was compared for all patients. Dependent variables consisted of the overall percent change from baseline in the treated and untreated eyes, and the percent change in treated and untreated eyes compared to baseline at each sampling interval. The Mann-Whitney one tailed test for all between group comparisons. The results of these experiments are summarized in the FIGURE which shows the pupil diameter measurements observed in the treated eyes of both probable Alzheimer's patients and non-demented controls. The pupil diameter determinations for untreated eyes of non-demented and probable Alzheimer's patients were substantially identical,
These data demonstrate that the overall dilation effect seen in probable Alzheimer's patients was significantly greater than that observed in the non-demented controls. Data for probable Alzheimer's disease patients are significant at p<0.05 level beginning at 15 minutes. No differences were found for the untreated eye at any sampling epoch or for the mean change over the seven sampling epochs.
Those skilled in the art will know, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. These and all other equivalents are intended to be encompassed by the following claims.
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Khloe Kardashian Fuels French Montana Dating Rumors
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By Sonam Malik | April 8, 2014 8:25 PM EST
Khloe Kardashian is reportedly dating rapper French Montana. Since the last few days, rumors are rife that Kardashian has given her heart to a new guy. The alleged lovebirds were seen enjoying a night out at 1 Oak nightclub in Hollywood on Friday. Moreover, Montana has also made Kardashian his partner in his house hunting plans.
Khloe Kardashian
"French is on the hunt for a new pad and took Khloe along to check one out -- a 4,800 sq. ft. Hollywood Hills home that rents for $29,000/month. It's a 4 bedroom, 4 bath house with a wine and cigar cellar, a sauna, and screening room," TMZ quoted a source.
The alleged couple is also spending a lot of time together and they were also seen spending the weekend at Pink Rhino in Phoenix, where as per reports, they were very close but never posed for a photo together.
The reports of the couple getting close to each other have been circulating for a while. However, some sources have revealed that the relationship between the two is of nothing more than friends.
"Nobody is occupying her time in a romantic way and yes, she's good friends with Frenchie but it's strictly platonic and in no way romantic," Hollywoodlife quoted an insider. "She has a gazillion friends in hip hop and he's one of them ... She's just having a good time, being Khloe and wants to express her life through pictures."
Despite reports, buzz is strong that Kardashian has moved on from her ex husband Lamar Odom. Kardashian served Odom with divorce papers last December. However, NBA star has still not signed the papers yet.
The couple pulled the plug on their relationship when Odom allegedly took to drugs and got involved in an extra marital affair, but Odom has often stated that he still loves the reality star and she will always be his wife.
(Edited by Vanilla Sharma)
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Well they are the experts! Mad Men cast star in clever Emmys campaign that could have been created by Sterling Cooper & Partners
Mad Men has come up with a clever campaign in the hope of taking home some Emmy awards this year.
A series of fake advertisements have been created that very well could have been the brainchild of the show's fictional agency Sterling Cooper & Partners.
And the billboards, posters and online banners are hoping to play on their vintage style to earn the show, which is in its final season, its first Emmy since 2011.
Made by Sterling Cooper & Partners?: Mad Men's Emmy campaign has turned its cast (including Jon Hamm, pictured) into stars of pretend adverts
The campaign turns the series, which is based in an advertising company in the 1960s, on its head using stills that were originally taken to promote different seasons of Mad Men.
While in fact plugging the show as something 'for your consideration' for Emmy nominations, the campaign is disguised as adverts for other products.
The man of the hour every hour, Don Draper (played by Jon Hamm), appears in a rather hilarious poster for sunglasses.
Red hot: Christina Hendricks stars on a billboard disguised as advertising a fake hair dye brand called FYC, i.e. For Your Consideration
'She loves pearls, but prefers gold': The adverts look as though they were the brainchild of Sterling Cooper & Partners, the advertising agency where the show is set in the 1960s
It reads: 'A knight in shining armor. An illusive and mysterious lover. A shrewd, talented businessman.
A caring father. A frightened and isolated introvert. He's a complex and unpredictable man, and he's got the look and frames that demand attention.'
Christina Hendricks' Joan Holloway features in a pretend ad for hair dye, which is cheekily called 'FYC', i.e. For Your Consideration.
'Blondes have more fun. But redheads get nods,' the poster reads, before a dated selling point at the bottom.
Pulling out all the stop: The show is hoping the wordy, vintage nature of the pretend ads, such as this one starring Elisabeth Moss, will draw in Emmy nominations and wins
Look familiar?: The posters and billboards feature stills that were originally taken to promote various seasons of the show, such as this one of Jessica Pare, which was taken ahead of the current seventh season
'What's her secret?' it says. 'A little bit of color and a whole lot of talent. That's one heck of a combination that's hard to beat.'
One image shows January Jones' Betty Draper peering through a jewellery shop window, and has the tagline: 'She loves pearls but prefers gold.'
Beauty products were also the focus of Elisabeth Moss and Vincent Kartheiser's fake adverts, with Moss's Peggy Olson pretending to plug facial powder and Kartheiser's Pete Campbell promoting hair products.
Smooth operator: John Slattery's fake ad is for men's clothing, and encourages a buyer to 'get the recognition you deserve'
Hoping for the best: Vincent Kartheiser features in one image. The campaign is hoping to break the spell and win Mad Men its first Emmy since 2011, and 16th to date
Jessica Pare, Kiernan Shipka and John Slattery star in advertisements pretending to sell clothing.
The campaign is certainly garnering a lot of attention, but whether it will result in nods, and even wins for the show remains to be seen.
It isn't a pipe dream however as the series, currently on hiatus halfway through its seventh and final season, has won 15 Emmys to date.
Emmy nominees will be announced on July 10 and the ceremony will take place on August 25.
'Show her you noticed': Kiernan Shipka appears in a pretend advert for a fake clothing line cleverly called Statuette's
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FILE - In this Thursday, Sept. 13, 2012 file photo, Kate, the Duchess of Cambridge visits the Kranji Commonwealth War Memorial in Singapore. Prince William and his wife Catherine are expecting their first child. St. James?s Palace announced the pregnancy Monday, saying that the Duchess of Cambridge, formerly known as Kate Middleton has a severe form of morning sickness and is currently in a London hospital. William is at his wife?s side. (AP Photo/Nicolas Asfouri, Pool, File)
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Family displaced when fire hits Berks home
Published On: Dec 30 2013 06:24:40 AM CST
Updated On: Dec 30 2013 11:17:09 AM CST
Updated On: Dec 30 2013 11:17:09 AM CST
A fire Sunday in Berks County forced a family of four from their home.
It happened around 1 p.m. in the 1700 block of Mount Laurel Road in Muhlenberg Township.
The house suffered a large amount of damage.
The American Red Cross is assisting the family with food and clothing.
No one was home when the fire broke out and officials are still searching for the cause.
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Book Clubs & Writers' Groups
Library Branch
If you enjoy reading a range of literature & talking to others about books, this group is for you....
Meets on alternate Saturdays: Starting at 10:30 a.m....
Sat Nov 29
Sat Dec 13
Sat Dec 27
Join other children's book lovers for a lively discussion of new and old favourites.
Mon Dec 01
Mon Jan 05
Mon Feb 02
Mon Mar 02
Monthly evening book club. Please phone 416-393-7697 for more information.
Tue Dec 02
Library staff will treat you to some new reading suggestions, and a lovely cup of tea!
Wed Dec 03
Discuss new books and old favourites with library staff. Light refreshments provided. Call the library for more information.
Fri Dec 05
Fri Jan 09
Fri Feb 06
Fri Mar 06
The group invites new and experienced poets of all ages to bring their work to our monthly meetings. Bring a poem with six to ten copies for review by other attendees. The group will listen to you read your poem and offer c...
Sat Dec 06
Sat Jan 03
Sat Feb 07
Sat Mar 07
Monthly afternoon book club. Please phone 416-393-7697 for more information.
Mon Dec 08
Mon Jan 12
Mon Feb 09
Mon Mar 09
Anne Isenberg directs discussions of classical and contemporary literature from around the world, including Canada....
Tue Dec 09
Tue Jan 13
Tue Feb 10
Tue Mar 10
An hour long book talk and get together
Tue Dec 09
Tue Jan 13
Tue Feb 10
Tue Mar 10


text:
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text:
PORT CHESTER, N.Y. - Armand J. Mannetti, a longtime resident of Port Chester, recently of Southport, Conn., died Sunday, March 9. He was 93.
Mannetti was born Feb. 10, 1921, in Guardia Lombardi, Italy, to Felix and Amelia Mannetti. He worked as a furniture salesman for Wayside Furniture in Milford, Conn.
Mannetti is survived by his daughter, Lisa (Terry Kane) Mannetti of Port Chester; son, Peter (Ruth Krebs) Mannetti of Denver, Colo.; three grandchildren; and three great-grandchildren. He was predeceased by his parents; and wife, Anne.
Calling hours are Wednesday, March 12 and Thursday, March 13 from 2 to 4 and 7 to 9 p.m. at the Ballard-Durand Funeral Home. A Mass of Christian burial will be celebrated at 10:30 a.m. Friday, March 14 at Corpus Christi Church in Port Chester. Interment will be in the St. Mary's Cemetery in Rye Brook.
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text:
clunchLine breaks: clunch
Pronunciation: /klʌn(t)ʃ /
Definition of clunch in English:
noun[mass noun] British
Soft limestone capable of being easily worked: they used clunch for most domestic building [as modifier]: sections of clunch wall in the stable
More example sentences
- The original walls were clunch and were pilfered by a bastard son of Henry the Eighth to build Berkhamsted Place.
- As it's a large square Norman keep and it's still in good condition, clunch can be a very hard stone and weather well.
- There are useful resources within the parish: flints for tool making and building, a band of hard chalk called clunch also for building, and areas of woodland and gravel.
early 19th century: perhaps from dialect clunch 'lumpy, thickset'.
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Word of the day Sprachgefühl
Pronunciation: ˈSHpräkɡəˌf(y)o͞ol
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Police handling of investigation into attorney's death questioned
03/13/2013 // West Palm Beach , Florida, US // JusticeNewsFlash // Justice News Flash // (press release)
Albuquerque, NM – The New Mexico attorney general's office is looking into the Albuquerque police department's handling of an investigation into a prominent civil rights attorney's death. As reported by the Associated Press (AP), over two years after Mary Han was found in her garage dead from what was said to be a suicide, authorities are now questioning whether the investigation surrounding the circumstances of her death was not handled properly.
The state's attorney general's office has also reportedly requested that federal officials take a look at the case.
Relatives of Han, who have expressed doubt that she committed suicide, have filed a lawsuit against the city, citing the investigation was mishandled.
Han's daughter, Katherine, is quoted in the report as stating, "I would like to know what happened to my mother someday… To have an important person removed from their life without explanation is something no one should ever have to deal with. It's more about peace of mind."
Justice News Flash delivers the latest in New Mexico legal news.
Media Information:
Address: 215 South Olive Suite 300 W. Palm Beach FL 33401
Phone: 866-598-1315
Url: http://justicenews.visionsmartnews.com/police-handling-of-investigation-into-attorneys-death-questioned_8904.html
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- Bill Cosby rape accuser questions why no one listened before


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Arts Feature
Summertime Theater Dreams
Leigh Hile reports on youth theater, The Vortex and The Bard.
Culture Shock
He's got character, enigmatically simple and dance dance la revolución
Get an art-smart jump on your week with Culture Shock. Khaled Hosseini reads, clay artist Andrew Van Assche's new show opens and Festival Flamenco Internacional dances onstage.
Book Review
Part Two in "Keepers of Life" Series Is a Keeper
This week's book reviews.
Today's Events
In Nature's Light at Hunter Kirkland Contemporary
Featuring new works by Gregory Frank Harris.
Saara Ekström: Careless Water at Richard Levy Gallery
Atomic STEaM Photography Show at National Museum of Nuclear Science and HistoryMore Recommented Events ››
Low Life Happy Hour • 11.28.2014
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Casinos: Mass. Withholding Tax On Winnings Will Turn Off Gamblers, Cut Take
Companies looking to win a Massachusetts casino license say the state needs to change how it taxes winnings to avoid discouraging gamblers and cutting the state's and casino's take.
Springfield Fights Repeal Of Mass. Casino Law
The city of Springfield is asking the state's highest court to keep a proposed repeal of the Massachusetts casino gambling law off the November state ballot.
Remaining Mass. Casino Hopefuls To Make Pitches
The three companies hoping to operate the first resort casinos in Massachusetts are getting a chance to make direct pitches to the state gambling commission.
Poll: Majority In Massachusetts Like Casinos, Just Not In Their Towns
A new poll is telling us what many people have already begun to suspect.
Suffolk Downs Reconsidering Options After Voters Reject Plan
Suffolk Downs says it will reconsider its options after voters rejected a plan to build a casino.
Keller @ Large: Election Day Winners And Losers
So who were the winners and losers on municipal election day here in Massachusetts?
Voters In 3 Mass. Locations Cast Casino Ballots
Voters in three Massachusetts communities are heading to the polls to help decide the fate of two proposed casinos.
Key Votes Slated On 2 Mass. Casino Projects
Two Massachusetts casino proposals are facing key votes.
Casino Panel Qualifies Two For Gambling Bids
The state gambling commission has cleared Mohegan Sun to bid for the sole resort casino license in western Massachusetts.
2 Casino Deadlines Approaching
A pair of deadlines is approaching as the state's casino process moves forward.


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transportation management jobs
Manager Print Production
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Field Organizer
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The Field Organizer will be responsible for helping to implement a field program for a targeted state legislative race. Duties include: · Implementing all aspects of field...30+ days ago from Democratic Gain
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Oregon gold rush isn't what it used to be
|| Print |
|Archives - April 2008
|Tuesday, April 01, 2008
STATEWIDE There may be gold in them thar Oregon hills, but nobody's mining it. Even with gold prices hovering at all-time highs in the neighborhood of $1,000 per ounce, the same dozen or so mining companies that have held mining claims for years continue to pass on Oregon while looking elsewhere, usually overseas, to capitalize on the global gold rush.
Gold spurred the settlement of northeastern and southwestern Oregon in the 19th century, but the industry has never recovered from high labor costs, tightening state regulations and the downfall of gold prices. Those prices have bounced back spectacularly as the dollar has weakened, but there are no mining companies in Oregon positioned to capitalize, says Gary Lynch of the Oregon Department of Geology and Mineral Industries.
Healthcare pullbackNews
Thursday, November 20, 2014
Each month for Oregon Business, we assess factors that are shaping current capital market activity—and what they mean to investors. Here we take a look at two major developments regarding possible rollbacks of the Affordable Care Act (ACA).
Read more...
What I'm ReadingNovember/December 2014
Wednesday, October 22, 2014
Peter Lizotte at ACME Business Solutions and Roger Busse at Pacific Continental Bank share their favorite reads.
Read more...
The clean fuels opportunityNews
Monday, November 10, 2014
A market for low-carbon transportation fuels has a chance to flourish in Oregon if regulators adopt the second phase of the state's Clean Fuels Program.
Read more...
Healthcare PerspectiveNovember/December 2014
Wednesday, October 22, 2014
A conversation with Majd El-Azma, president and CEO of LifeWise Health Plan of Oregon, followed by the Healthcare Powerlist.
Read more...
Woman of SteelNovember/December 2014
Wednesday, October 22, 2014
Tamara Lundgren tackles the challenges—without getting trampled.
Read more...
Water WorldNovember/December 2014
Wednesday, October 22, 2014
Fred Ziari aims to feed the global population.
Read more...
Election SeasonNovember/December 2014
Wednesday, October 22, 2014
We didn't intend this issue to have an election season theme. But politics has a way of seeping into the cracks and fissures.
Read more...
|A Complex Portrait: Immigration, Jobs and the Economy
|Revenge Forestry
|Woman of Steel
|The Bookseller
|Kill the Meeting
|Political Clout
|Ferguson bakery saved by crowdfunding
|Obamacare yields more than 1M applicants in first week of open enrollment
|Price of already-built homes in Seattle area drops
|Apple hits record-high value
|Fed's ability to regulate questioned
|Budweiser to move away from Clydesdales
|Mergers lucrative for departing CEOs, but not necessarily shareholders
Is your business ready to join us in the call for action? This opening panel includes Oregon businesses who will discuss why they signed the Oregon Climate Declaration, the investments they are making to reduce carbon emissions, and how their actions are affecting their companies.
Get ready for two days of special events produced with the EPA, Portland Timbers and ISOS before and after the GoGreen Conference on October 16.
Plenty of employers seem "dazed and confused" after the recent vote to legalize marijuana. In light of Measure 91 passing, what are some issues for private-sector Oregon employers to consider?
Rotary's Oregon Ethics in Business aims to raise consciousness about business ethics by honoring exceptional companies.
Barran Liebman's annual employment law seminar is an industry classic.
Is my drug-free workplace policy up in smoke?
More than 400 "Change Makers" will gather to invest in a socially sustainable community.
Sussman Shank LLP is pleased to announce that Dallas G. Thomsen and Victor J. Roehm have become partners of the firm.


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I bought a coach ticket on US Air, but last night I flew First Class. I don't know how it happened; I suppose it could have been luck, randomness or even Christmas cheer.
I tweeted my thanks to @USAirways and as of the time of this writing, there's been no response (update: they did respond!). That should not be a surprise, since 16% of businesses don't acknowledge comments on social media — good or bad. And that's the part that makes me think my hour-long flight in luxury was a mistake and not selflessness on behalf of an airline.
And we see this all too often in business: every change, be it to pricing, terms of service, or the space in between seats on an aircraft are made for the convenience of the business and not the customer. While I'm a die hard capitalist and disciple of Adam Smith, I have a hard time reconciling this with the very reason businesses exist: to solve problems.


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Mobile Site You Are Here > HR Home > Coaches > Bill LaForge
News: s-r blog:Surf Sports Reference Faster – Buy Ad-Free Access on all sites
Born: September 2, 1951 in Edmonton, Alberta
Died: June 19, 2005
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Blog week in review
posted at 10:35 am on April 29, 2006 by Michelle
The Pajamas Media gang has a new podcast up. Listen here.
Breaking on Hot Air
FBI nabs two aspiring Ferguson protesters with guns, explosives
Note from Hot Air management: This section is for comments from Hot Air's community of registered readers. Please don't assume that Hot Air management agrees with or otherwise endorses any particular comment just because we let it stand. A reminder: Anyone who fails to comply with our terms of use may lose their posting privilege.


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Two PhD positions in Bioinorganic Chemistry
Marie Curie Actions Co-fund. More
Marie Curie Actions. More
European Research Council. More
'HR Excellence in Research' logo awarded to institutions actively implementing the European Charter and Code for Researchers. More
Add to My Favorites
For an interdisciplinary ERC (EU) funded research project [http://cordis.europa.eu/projects/index.cfm?fuseaction=app.details&TXT=Mocomodels&FRM=1&STP=10&SIC=&PGA=&CCY=&PCY=&SRC=&LNG=en&REF=101595] we are looking to recruit two highly motivated PhD students with a well above average academic record and a completed or soon to be completed Diploma or Masters degree in Chemistry or equivalent. The research area, the two PhD students are intended to work in, is based on organic and inorganic synthese...
Please note that some fellowship programmes might not be available in English. This depends on publication policy applied by Naturejobs. Thank you for your understanding!
Biological sciences
|Eligible destination country/ies for fellows
|Eligibility of fellows: country/ies of residence
|Eligibility of fellows: nationality/ies
|Website of Fellowship Programme
|Career Stage
|Experienced researcher or 4-10 yrs (Post-Doc)
|Research Profile
|Not defined
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Ph D Studentship/Marie Sklodowska Curie Esr Fellowship: Supramolecular Chemistry, University of Cambridge, United Kingdom, 3 days ago
Fixed-term: The funds for this post are available for 36 months. We invite applications for a 3-year Marie Sklodowska-Curie Early Stage Researcher (MSC-ESR) Fellowship to start in April or Octobe...
Ph D Candidate In Protein Chemistry, Leiden University, Netherlands, 7 days ago
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Apply no later than 6 January 2015 Apply for the job at DTU Chemistry by completing the following form. Apply online One PhD position is open in the group NanoChemistry at Department of Chemistry,...
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The School of Clinical Medicine is offering eight fully funded PhD studentships commencing in October 2015 and seeks applications from outstanding, highly motivated students. The studentships are...
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ReferenceBBSRC-DTP-MCO-2015Closing DateSunday, 21st December 2014DepartmentUniversity of Nottingham & Rothamsted Research BBSRC Doctoral Training Partnership The University of Nottingham, in colla...


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President Obama meets Steve Jobs to discuss economy, technology [u]U.S. President Barack Obama and Apple Chief Executive Steve Jobs are scheduled to meet Thursday to talk about economy and technology issues.
Update: The meeting took place Thursday afternoon. During the meeting, Jobs and Obama "discussed American competitiveness and education, especially reforms such as the President's Race to the Top initiative," a White House spokesperson said in a statement. The two also talked about "energy independence and ways to increase job creation," Reuters reports.
White House press secretary Robert Gibbs said earlier Thursday that Obama and Jobs would meet at a San Francisco Hotel for about 45 minutes, Bloomberg reports. Jobs, who has supported Democratic candidates and organizations before, last met with Obama in 2008 during the presidential campaign.
This is a meeting the president was interested in having, Gibbs said. Hes eager to talk to him about the economy, innovation and technology, education.
According to the report, Obama is in the San Francisco Bay Area to help raise money for the Democratic National Committee. Google vice president Marissa Mayer and clean technology venture capitalist Steve Westly will each host a fundraiser at their homes Thursday. Tickets to the event at Mayer's house cost $30,000 a head, reports the San Francisco Chronicle. A Democratic Party official told Bloomberg that the DNC hopes to raise as much as $1.8 million from the two events.
Obama has embarked on a five-state trip to raise money for his fellow Democratic candidates. On Friday, he'll attend an event in Los Angeles for incumbent Senator Barbara Boxer, who is being challenged by former HP CEO and Republican Carly Fiorina.
On Topic: General
- Best Buy slashes $100 off iPad Air 2 (from $399), $200 off MacBook Pro with CD/DVD ($899), $150 off iMacs (from $899)
- Natalie Portman rumored for troubled Steve Jobs biopic
- Judge rules Apple entitled to potential ongoing royalties from patent-infringing Samsung products
- Union pushes Apple for better treatment of campus security guards
- More secrets could come from GT Advanced bankruptcy as Apple divulges details to creditors


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Pocket Frogs Answers for iPhone - iPodHome / iPhone - iPod /
Game Questions & Answers (Q&A) service lets you ask questions about video games for game consoles or PC games. So ask your Pocket Frogs question for iPhone - iPod and get answers from real gamers or answer questions and share your insights and experience with the rest of the gaming community.
- Developer: NimbleBit
- Publisher: NimbleBit
- Genre: Miscellaneous Edutainment
- Release Date: Sep 11, 2010
- ESRB: Not Set
Question & Answers
Random frogs popping up while playing
How can I get or receive random frogs that pop up while playing pocket frogs, entering the pond or racing a frog?
Answer from: bigchlo1002
Well i dont understand your question. but if its a frog you want than add me for game center and ill send you watever frog you want! but the only way to get a frog that you see is to breed it, win it, or just recieve one!
game center name. bigchlo1002
Answer from: Longtail <3
You can't. If it's in the pond, you can only breed with it, If in the race, win the race then press on the desired frog.
Pocket Frogs - Gameplay
- Aug 24, 2014, Views: 42
Pocket Frogs - Review
- Aug 24, 2014, Views: 45
Pocket Frogs - Trailer
- Aug 24, 2014, Views: 35
Pocket Frogs - Free App Let's Play
- Aug 24, 2014, Views: 33
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Police find Fla. babysitter topless, incoherent in parking lot
Updated On: Aug 21 2012 11:39:17 AM CDT
A central Florida babysitter is behind bars after police officers said they found her topless and incoherent in a hotel parking lot.
Melbourne police were investigating calls that a child was alone Thursday night. They found the 5-year-old boy playing video games with the hotel staff. He said his mother had gone to the casino and left him with a babysitter.
MUGSHOTS: Who Got Arrested In South Florida?
Police found 47-year-old Stacey Kerres lying topless in the middle of the parking lot and said she appeared lethargic and incoherent as she struggled to talk. According to police reports, she told officers she didn't know where the child was.
WATCH LIVE ON MOBILE: WPBF 25 News At Noon
Florida Today reported Kerres was charged with child neglect.
The Department of Children and Families is investigating. No attorney was listed for Kerres.
More From WPBF: Email alerts | Mobile | Social
Copyright 2012 by The Associated Press. All rights reserved. This material may not be published, broadcast, rewritten or redistributed.
Family vacation to Disney World turns to tragedy after 5 killed in late-night crash in Louisiana
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Jury announces verdict in night of drinking murder case