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US 5380716 A Résumé Highly sulfated oligosaccharides in the form of hexasaccharide and octasaccharide compounds which have antiproliferative activity with respect to smooth muscle cells are useful in treatment of conditions characterized by unwanted smooth muscle cell proliferation such as a result of trauma or disease states such as asthma, congestive heart failure and hypertension. The oligosaccharides have increased ability to inhibit the proliferation of smooth muscle cells and decreased ability to act as an anticoagulant as compared with commercial heparin and/or unseparated fragments of heparin.
Revendications(17) 1. A compound that inhibits the proliferation of smooth muscle cells to a greater extent than commercial heparin, and has a decreased ability to act as an anticoagulant as compared to commercial heparin, the compound having the following structural formula: ##STR14## wherein each of A, B, C, and D is independently H or SO3 R and each R is independently H or a cation, with the proviso that at least two of A, B, C or D is --SO3 R; noting that hydroxyl groups on the sugars have been omitted in Formulas I and I(a) for greater clarity and the * adjacent the carbon substituted with COOH indicates any possible stereochemistry in either I or I(a); R1 and R2 are each independently hydrogen or a unit having the following structure: ##STR15## wherein when a unit of Formula I(a) is connected at one end, the hydrogen at that end is not present; and each of E and F is independently hydrogen or SO3 R and noting that the hydroxyl group on the 3-position on each sugar is present but has been omitted for greater clarity and further noting that the 3-position is not sulfated.
2. The compound of claim 1, wherein at least three of A, B, C or D are --SO3 R.
3. The compound of claim 2, wherein all of A, B, C and D are --SO3 R.
4. The compound of claim 1, wherein R1 and R2 are H, and each R is H, ----Na+, K+, Ca2+ or NH4 + ----.
5. A hexasaccharide and octasaccharide compound that inhibits the proliferation of smooth muscle cells to a greater extent than commercial heparin, and has a decreased ability to act as an anticoagulant as compared to commercial heparin, the compound having the following structural formula: ##STR16## wherein n is 1 or 2 and each of A, B, C and D is independently H or SO3 R, wherein each R is independently H or a cation, with the proviso that at least two of said A, B, C and D are SO3 R; and wherein a hydroxyl group present on the 3 position of each sugar is present but has been omitted from the depiction; and noting that the 3-position is not sulfated; and wherein the asterisk on the carbons substituted with carboxyl indicates that the stereochemistry is not determined.
6. A compound of claim 5, wherein at least three of A, B, C or D are --SO3 R.
7. A compound of claim 5, wherein at least four of A, B, C or D are --SO3 R.
8. A compound of claim 5, wherein at least five of A, B, C or D are --SO3 R.
9. A compound of claim 5, wherein all of A, B, C and D are --SO3 R.
10. A compound of claim 5, wherein each R is H,----Na+, K+, Ca2+ or NH4 + ----.
11. A hexasaccharide and octasaccharide compound that inhibits the proliferation of smooth muscle cells to a greater extent than commercial heparin, and has a decreased ability to act as an anticoagulant as compared with commercial heparin the compound having the following structural formula: ##STR17## wherein n is 1 or 2 and each of A, B, C and D is independently H or SO3 R, wherein each R is independently H or a cation, with the proviso that at least two of said A, B, C and D are SO3 R; and wherein a hydroxyl group present on the 3 position of each sugar is present but has been omitted from the depiction and noting that the 3-position is not sulfated; and wherein the asterisk on the carbons substituted with carboxyl indicates that the stereochemistry is not determined.
12. A compound of claim 11, wherein at least three of A, B, C or D are --SO3 R.
13. A compound of claim 11, wherein at least four of A, B, C or D are --SO3 R.
14. A compound of claim 11, wherein at least five of A, B, C or D are --SO3 R.
15. A compound of claim 11, wherein all of A, B, C and D are --SO3 R.
16. A compound of claim 11, wherein each R is H, ----Na+, K+, Ca2+ or NH4 + ----.
17. A pharmaceutical composition that inhibits unwanted smooth muscle cell proliferation, comprising:
a pharmaceutically effective amount of a heparin digest derivative in the form of oligosaccharide fragments selected from the group consisting of a hexasaccharide or octasaccharide compound of claim 5 or pharmaceutically acceptable salts thereof which fragments have an increased ability to inhibit smooth muscle cell proliferation and a decreased ability to act as an anticoagulant as compared with commercial heparin; and a pharmaceutically acceptable carrier. Description This application is a continuation-in-part of U.S. Ser. No. 07/686,540 filed Apr. 17, 1991 (now abandoned), which application is a continuation-in-part of U.S. Ser. No. 07/400,661 filed Aug. 31, 1989 (U.S. Pat. No. 5,032,679 issued Jul. 16, 1991), which application is a continuation-in-part of U.S. Ser. No. 07/285,546 filed Dec. 15, 1988 (abandoned), all of which applications are incorporated herein by reference and to which applications is claimed priority under 35 USC Section 120. The invention relates to the use of carbohydrate preparations as therapeutic and diagnostic compositions. In particular, the invention relates to polysaccharides having six or more saccharide units and compositions containing such polysaccharides which are useful in treating diseases and conditions characterized by excessive smooth muscle cell proliferation. In the representations of oligomers produced synthetically and those derived from heparin, the following abbreviations are used: D-glucuronic acid=GlcA; L-iduronic acid=IdoA; D-glucosamine=GlcNH2 ; N-acetyl-D-glucosamine=GlcNAc; D-glucosamine N-sulfate=GlcNS; 2,5-anhydromannose=Man(2,5); 2,5-anhydromannitol=ManH(2,5); D-xylose=Xyl; glycosaminoglycan=GAG. The location of the O-linked sulfate residues is indicated by "S" and the number of the position of sulfation where the sulfate residue is linked to oxygen on the sugar residue. In these designations, also, the alpha and beta anomeric linkages are as those conventionally found in heparin and the indicated D or L configurations as conventionally found pertains. The locations of the sulfates are shown below the abbreviation for the sugar to which they apply, thus, for example, ##STR1## refer to L-iduronic acid and D-glucosamine N-sulfate with sulfates connected respectively at the 2 and 6 positions of the sugar residues. Proliferation of smooth muscle cells in blood vessel walls occurs in response to vascular injury, and in association with certain disease states (Austin, G. E., et al., J Am Coll Cardiol (1985) 6:369-375). The proliferation of these cells can have negative effects due to the production of excess proteins or other matrix molecules, which, along with the cells themselves, form pathologic lesions of, for example, atherosclerosis, renal hypertension, pulmonary hypertension, vasculitis, and post-surgical vascular retinosis. These results are distinguished from the acute response to trauma characterized by blood clotting. Glycosaminoglycans (GAG) are copolymers of alternating hexosamine and aldouronic acid residues which are found in sulfated forms and are synthesized as proteoglycans. They have collectively been called mucopolysaccharides, and those in heparin are more precisely called glycosaminoglycuronans. To place the compositions discussed below in context, it may be noted that heparin and heparan sulfate are members of the GAG family which are classified by the nature of the hexosamine/aldouronic acid repeating units. For example, in chondroitin sulfates, the aldouronic acid is primarily D-glucuronic acid, and the hexosamine is N-acetylated 2-amino-2-deoxy-D-galactose, more commonly known as N-acetyl galactosamine and abbreviated as GalNAc. In dermatan sulfate (chondroitin sulfate B) the aldouronic acid is mostly L-iduronic acid and the hexosamine is GalNAc. In keratan sulfate, the aldouronic acid is replaced by D-galactose, and the hexosamine is mostly N-acetylated 2-amino-2-deoxy-D-glucose, more commonly known as N-acetyl glucosamine and abbreviated as GlcNAc. In the compositions of interest herein, heparan sulfate and heparin, the hexosamine is mostly N-acetylated or N-sulfated glucosamine (GlcN), and the aldouronic acid is mostly L-iduronic in heparin and mostly D-glucuronic acid in heparan sulfate. Heparan sulfate is commonly considered to have a higher proportion of glucuronic acid than heparin. Problems of heterogeneity in preparations of heparan sulfate or heparin isolated from tissues make sharp distinctions difficult, since these oligosaccharides are related by the biosynthesis pathway, as explained below. Conventional heparin (used as an anticoagulant) has a molecular weight of 5-25 kDa and is extracted as a mixture of various chain lengths by conventional procedures. These procedures involve autolysis and extraction of suitable tissues, such as beef or porcine lung, intestine, or liver, and removal of other GAGs as well as nonpolysaccharide components. The molecular weight of the chains in the extract is significantly lower than the 60-100 kd known to exist in the polysaccharide chains of the heparin proteoglycan synthesized in the tissue. The GAG moiety is synthesized bound to a peptide matrix at a serine residue through a tetrasaccharide linkage region of the sequence D-GlcA-D-Gal-D-Gal-D-Xyl→protein, which is then elongated at the D-GlcA residue with alternate additions of GlcNAc and GlcA. The polysaccharide sidechains are modified by a series of enzymes which sequentially deacetylate the N-acetyl glucosamine and replace the acetyl group with sulfate, epimerize the hydroxyl at C5 of the D-glucuronic acid residue (to convert it to L-iduronic acid), sulfate the 0-2 of the resulting L-iduronic acid and the 0-6 of the glucosamine residue. Some of the chains are further sulfated at the 0-3 of the glucosamine residue, either at the heparan or heparin stage. This latter sulfation generates the active sequence required for antithrombin III binding and thus anticoagulation activity. Other chemically possible sulfation sites are on the 0-2 of D-glucuronic acid. Due to their obvious chemical similarity, isolated "heparin" may contain considerable amounts of what might otherwise be classified as heparan sulfate. There is an extensive body of art concerning depolymerization of heparin/heparan sulfate chains and separation of products by size. Particularly relevant is the report of Guo, Y. et al., Anal Biochem (1988) 168:54-62 which discloses the results of structure determination after the 2,5-anhydromannose at the reducing terminus is reduced to the corresponding 2,5-anhydromannitol. The involvement of heparin or heparan sulfate or degradation products thereof in smooth muscle proliferation has been recognized for some time. Heparin and heparan sulfate can slow or arrest the vascular smooth muscle cell proliferation associated with injury described hereinabove (Clowes, A. W., et al., Nature (1977) 265:625-626). The effect of heparan sulfate and heparin on smooth muscle cell proliferation is also described by Marcum, J. A., et al. in Biology of Proteoglycan, Academic Press (1987) pp. 301-343. The inhibition of vascular smooth muscle cell growth by heparin was further described by Casteliot, J. J., Jr., et al., J Biol Chem (1982) 257:11256-11260 and the effect of heparin on vascular smooth muscle cell growth in fetal tissue was described by Benitz, W. E., et al., J Cell Physiol (1986) 127:1-7. The effect of heparin as an inhibitor of both pericyte and smooth muscle cell proliferation was shown by Orlidge, A., et al., Microvascular Research (1986) 31:41-53, and these authors further showed that chondroitin sulfate and dermatan sulfate do not have this effect. A review of the effects of heparin and heparan sulfate on the proliferation of smooth muscle cells is by Benitz, W. E. in "The Pulmonary Circulation: Normal and Abnormal", Fishman, A. P., ed., University of Pennsylvania Press (1988). It is not clear by what mechanism these glycosaminoglycans operate, or to what extent they interact with other growth factors such as epithelial and fibroblast growth factors. It has been proposed that a 3-0 sulfate on glucosamine in an oligosaccharide of at least 5 sugars is important in this process and that both O-and N-sulfation is important (Casteliot, J. J., et al., J Cell Physiol (1984) 120:315-320; Casteliot, J. J., et al., J Cell Biol (1986) 102:1979-1984). Hexasaccharides-decasaccharides obtained from partial nitrous acid digestion of heparin bind to acidic fibroblast growth factor and aid its mitogenic activity in fibroblasts, but inhibit the proliferation of endothelial cells under some conditions (Barzu, T., et al., J Cell Physiol (1989) 140:538-548). The effective hexasaccharide was stated to have the structure: ##STR2## Others have indicated that the presence of 2-0-sulfate glucuronic acid is not necessary for antiproliferative activity (Wright, Jr., T. C., et al., J Biol Chem (1989) 264:1534-1542). In this article, size separated fragments of defined length prepared by nitrous acid cleavage and gel filtration were further separated according to charge for some assays. Partially digested heparin separated only according to size was tested with respect to stimulation of the growth of smooth muscle cells and epithelial cells. Similar results were found in both cases, although the results were not identical. Tetrasaccharides of the type tested were shown to have very low antiproliferative activity; hexasaccharides, octasaccharides, and decasaccharides were shown to be active to approximately the same level on a weight/volume concentration basis. Also tested was a synthetic pentapeptide which represents a unique sequence of the heparin required for the binding of heparin to antithrombin III; this pentapeptide was active in inhibiting proliferation for smooth muscle but not epithelial cells. The size-separated fractions were then treated chemically to produce "O-oversulfation" and this treatment enhanced the inhibitory activity; indeed, oversulfation of the tetrasaccharide fragment preparation yielded a tetrasaccharide fraction which was active in inhibiting proliferation. The converse process, comprising desulfation and reacetylation of the amino groups of glucosamine results in a reduction in antiproliferative activity. These fragments could, however, be made more active by subsequent oversulfation. Also capable of reducing the activity of the heparin fragments was reduction of the carboxyl groups so as to reduce the total negative charge. O-oversulfation partially restores this activity. These results with N-desulfated, N-acetylated fragments which are lacking in antiproliferative activity is distinguishable from previous results wherein similarly treated heparin retains the capacity to prevent cell division because of the size dependency of the antiproliferative activity-larger fragments being more powerful in general than smaller ones. When the size separated fraction was further fractionated according to charge, it was found that the most highly charged fractions showed the greatest activity. Furthermore, it was shown that although the synthetic pentasaccharide identified as the antithrombin III binding site is capable of inhibiting proliferation in smooth muscle cells, any treatment of heparin which would destroy the sequence corresponding to this pentapeptide (i.e., periodate treatment) does not destroy antiproliferative activity. Methods of synthesizing oligosaccharides are disclosed in U.S. Pat. No. 4,943,630 issued Jul. 14, 1990 which is incorporated herein by reference to disclose such methods. The present inventors have now found that an enhanced antiproliferative activity with respect to smooth muscle cells is associated with an oligosaccharide portion of the heparin or heparan sulfate GAGs which is highly sulfated and contains 6 or 8 saccharide units and have provided synthesis mechanisms for making polysaccharides containing 6 or more sugar residues, which oligosaccharides have enhanced antiproliferative activity with respect to smooth muscle cells. The invention provides a low molecular weight glycosaminoglycan (GAG) composition which has superior specific antiproliferative activity with regard to smooth muscle cells. The existence of this activity in a low molecular weight GAG provides the opportunity for effective pharmaceutical compositions which can be prepared by synthesis or by isolation of the composition from natural sources. Accordingly, in one aspect, the invention is directed to a process to prepare a sulfated polysaccharide having antiproliferative activity. The polysaccharides of the invention may be produced synthetically using a sequence of chemical reactions as disclosed herein or obtained by digesting heparin and carrying out separation procedures based on size and charge as disclosed herein. In order to produce the polysaccharide compounds of the invention synthetically it is first necessary to synthesize an iduronic acid synthon. Next, a glucosamine synthon is produced. The iduronic acid synthon and glucosamine synthon are reacted to produce a disaccharide synthon. The disaccharide units can be reacted to form oligosaccharides containing 4, 6, 8 or any multiple thereof of monosaccharide units and/or can be reacted with either an iduronic or glucosamine reaction synthon to provide oligosaccharides containing any odd number of saccharide units. In order to obtain the oligosaccharide compounds by digestion, the heparin is obtained from a natural source and subjected to digestion with nitrous acid under conditions which favor the formation of an oligosaccharide mixture containing large amounts of hexa- and octasaccharides. Following the digestion, the mixture is separated according to size and those factions corresponding to hexa- and octasaccharides are combined and recovered. The recovered portions are then separated according to charge in order to obtain the more highly charged fractions. These fractions will contain oligosaccharides which are highly sulfated. Polysaccharides sulfated at the 0-3 position of the GlcN (associated with anticlotting activity) are not encompassed by the present invention. The invention is also directed to pharmaceutical compositions comprised of the oligosaccharides of the invention either alone or in combination with excipients, i.e., pharmaceutically acceptable materials with no pharmacological effect. Such compositions may be administered to a patient in order to regulate smooth muscle cell proliferation. A primary object of the present invention is to provide synthetically produced oligosaccharides containing 6 or more monosaccharide units, which are highly sulfated at particular positions other than 0-3 positions of the GlcNs and which effect smooth muscle cell proliferation. Another important object of the present invention is to provide a method of obtaining hexa- and octasaccharide units from natural heparin and heparan sulfate which hexa- and octasaccharide units are effective in regulating smooth muscle cell proliferation and which do not process any significant degree of anticlotting activity. An advantage of the present invention is that the oligosaccharide units can be formulated into pharmaceutical compositions which can be administered to aid in the regulation of smooth muscle cell proliferation. A feature of the present invention is that the oligosaccharide units include monosaccharide residues which are sulfated at particular positions (other than the 0-3 position) which effected the ability of the oligosaccharide to regulate smooth muscle cell proliferation. These and other objects, advantages and features of the present invention will become apparent to those persons skilled in the art upon reading the details of the structure, synthesis and usage as more fully set forth below, reference being made to the accompanying figures and general structural formulas forming a part herein wherein like symbols refer to like molecular moieties throughout. FIGS. 1A and 1B show the elution profiles from gel filtration chromatography of reaction mixtures produced using varying amounts of nitrous acid. FIG. 2 shows the growth inhibition activity of the various sized fractions. FIGS. 3A and 3B show the elution profiles of hexasaccharide and octasaccharide subunits, respectively, from DEAE-Toyopearl chromatography. FIGS. 4A and 4B show the growth inhibition activity of various fractions collected in the elution profiles of FIGS. 3A and 3B. FIG. 5A shows the elution profile from reverse-phase ion-pairing HPLC for the S-6 fraction shown in FIG. 3A. FIG. 5B shows a comparable profile for the total hexasaccharide fraction. FIGS. 6A, 6B and 6C are charts showing possible sulfated positions for fifty-seven octasaccharides of the invention. Before the present oligosaccharides and processes for making and formulating such are described, it is to be understood that this invention is not limited to the particular oligosaccharides, formulations or processes described as such compounds, compositions and methods may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting since the scope of the present invention will be limited only by the appended claims. It must be noted that as used in this specification and the appended claims, the singular forms "a", "an" and "the" include plural referents unless the content clearly dictates otherwise. Thus, for example, reference to "an oligosaccharide" includes mixtures of oligosaccharides and, reference to "an octasaccharide" includes reference to mixtures of octasaccharides of the type described herein and reference to "the process step" or "the process" includes reference to various steps and processes of the type described herein which will be known to those skilled in the art or which will become apparent to those skilled in the art upon reading this disclosure and so forth. By "heparin/heparan sulfate" or "heparin" is meant a preparation obtained from tissues in a manner conventional for the preparation of heparin as an anticoagulant or otherwise synthesized and corresponding to that obtained from tissue. See Conrad, H. E., Heparin and Related Polysaccharides, Vol. 56, p. 18 of Annals of N.Y., Academy of Sc., Jun. 7, 1989, incorporated herein by reference. This preparation may include residues of D-glucuronic acid (GlcA), as characteristic of heparan sulfate as well as iduronic acid (IdoA) as characteristic of heparin. However, both GlcA and IdoA are present in both, they are present in different proportional amounts. The (IdoA)/GlcA ratio increases as heparan sulfate becomes more heparin-like. As described in the Background section above, the conversion of D-glucuronic acid to L-iduronic acid is a result of epimerization at the 5 carbon of GlcA residues in a heparan-type intermediate. This sequence of steps involved in such epimerization and conversion is understood in the art. To the extent that full conversion has not been made, heparan sulfate characteristics remain in the preparation. Because the precise nature of the polymeric chains in the preparations of heparin is not generally determined, and varies from preparation to preparation, the term "heparin/heparan sulfate" or "heparin" is intended to cover the range of mixtures encountered. Perhaps the main feature which distinguishes heparan sulfate from heparin is that the latter has anticoagulant activity. The "heparin/heparan sulfate" preparation can be obtained from a variety of mammalian tissues, including, if desired, human tissue. Generally, porcine or bovine sources are used, and vascularized tissues are preferred. A preferred source of heparin/heparan sulfate starting material is porcine intestinal mucosa, and preparations labeled "heparin" prepared from this tissue source are commercially available. In general, the heparin/heparan sulfate starting material is prepared from the selected tissue source by allowing the tissue to undergo autolysis and extracting the tissue with alkali, followed by coagulation of the protein, and then precipitation of the heparin-protein complex from the supernatant by acidification. The complex is recovered by reprecipitation with a polar nonaqueous solvent, such as ethanol or acetone or their mixtures, and the fats are removed by extraction with an organic solvent such as ethanol and proteins by treatment with a proteolytic enzyme, such as trypsin. Suitable procedures for the preparation of the heparin starting material are found, for example, in Charles, A. F., et al., Biochem J (1936) 30:1927-1933, and modifications of this basic procedure are also known, such as those disclosed by Coyne, E., in Chemistry and Biology of Heparin, Elsevier Publishers, North Holland, New York, Lunblad, R. L., et al., eds. (1981). The synthetic oligosaccharides of the present invention include at least 6 saccharide residue units and have the following general structural formula: ##STR3## (The hydroxyl groups on the 3-position of the sugars have been omitted for greater clarity) and the * adjacent the carbon substituted with COOH indicates (here and throughout the application) undetermined stereochemistry which may be any possible stereochemistry for the molecule; wherein each of the variables A, B, C and D are independently hydrogen or SO3 R with the proviso that at least 2 of the variables are SO3 R and each R is independently H+, Na+, or other suitable cation; and wherein R1 and R2 are each independently hydrogen, or one or more repeating units having the following structure: ##STR4## wherein when the unit of structural Formula I(a) is connected at one end the hydrogen is not present and the hydrogen at the end not connected is present and further wherein each of the variables E and F is independently hydrogen or SO3 R. Some preferred embodiments of the present invention include compounds of structural Formula I wherein each of A, B, C and D are --SO- 3 and either R1 or R2 is the unit of structural Formula I(a). Another preferred embodiment includes compounds of structural Formula I wherein each of A, B, C and D is --SO- 3 and both R1 and R2 are the unit of structural Formula I(a) and wherein each E and F of the unit I(a) is --SO- 3. Preferably, the heparin/heparan sulfate preparation used as a starting material is first purified by extraction with a solvent in which the heparin is insoluble, such as ethanol or acetone. The purified starting material is then depolymerized. Depolymerization in general can use various reagents, such as nitrous acid, heparinase or periodate. The antiproliferative compositions of the invention are obtainable when partial nitrous acid digestion is conducted under conditions which maximize formation of hexasaccharide and octasaccharide fragments. In typical procedures, the nitrous acid is prepared in situ by acidification of a solution of sodium nitrite at a concentration of 50 mM, and the reagent is used to treat the heparin at a concentration of about 60-180 mg/ml, at a pH of about 1.0 to about 2.0, preferably about 1.5. The reaction is conducted at room temperature and can be neutralized by addition of a suitable reagent at the desired stage of digestion. Other depolymerization methods can be used as long as they produce active components, i.e., components which (1) are predominantly hexa- and octasaccharides; (2) are heavily sulfated; (3) have substantial antiproliferation activity with respect to smooth muscle cells; and (4) have insignificant or no anticlotting activity. Isolated fragments can then be tested for their ability to inhibit smooth muscle cell proliferation. Fragments with high activity with respect to inhibiting the proliferation of smooth muscle cells and low activity with respect to their ability to inhibit blood coagulation (relative to commercial heparin) are preferred. The depolymerization results in a mixture of fragments that is then separated on the basis of size. A variety of size separation techniques are available, including gel permeation, density gradient centrifugation; especially preferred is gel filtration chromatography using a Sephadex or polyacrylamide gel system with a fractionation range of about 100-3500 daltons. A particularly preferred gel permeation resin is Biogel P10, and upon separation using this method, fragments which are disaccharides, tetrasaccharides, hexasaccharides, octasaccharides, and oligosaccharides of higher molecular weights are effectively separated. The fractions containing predominantly hexa- and octasaccharide units show enhanced activity in inhibiting the proliferation of smooth muscle cells. Verification of this property can be obtained using standard assays, such as those described in Castellot, J. J. Jr., et al., J Cell Biol (1986) 102:1979-1984. Other assay methods, such as those of Benitz, W. E., et al., J Cell Physiol (1986) 127:1-7 can also be used. The hexasaccharide fragments thus obtained are of the formula: ##STR5## wherein each of the variables A, B, C and D is independently H or SO3 R and each R is independently H or a cation, with the proviso that at least two of the variables A, B, C or D is --SO3 R. It is pointed out that hydroxyl groups on 3-positions of the sugars have been omitted for greater clarity and the * adjacent the COOH indicates undetermined stereochemistry. In the compounds of formula (II) the sugar at the reducing terminus is deaminated to form the 2,5-anhydromannose shown. When this compound is further reduced, the CHO shown becomes --CH2 OH; however, this reduction does not occur in the depolymerization reaction per se. This reduced form is a compound of the present invention as shown below in formula (IIa). ##STR6## In the --SO3 R, the cations represented by R can either be inorganic cations such as sodium, potassium, calcium, or ammonium ion or can be organic cations such as those obtained from quaternary amines; these salts are formed by simple neutralization. Based on the above formula (II) it can be seen that there are eleven different possible configurations with respect to the positions of --SO3 R moieties when 2 or more are present. These configurations are schematically shown in the following table wherein an "X" indicates a --SO3 R is present at the indicated A, B, C or D position. TABLE 1______________________________________ A B C D = SO3______________________________________1. X X X X2. X X X3. X X X4. X X X5. X X X6. X X7. X X8. X X9. X X10. X X11. X X______________________________________ In that each "R" can be any cation, the above eleven possible structures represent a significantly larger number of compounds, i.e., the acid and salt forms. The basic structure of the eleven possible configurations shown by formula (1) and the above table are put forth below. Regarding the structures II(1)-II(11) it is pointed out that hydroxyl groups on the 3-position of the sugars have been omitted for greater clarity. ##STR7## Representative compounds of the invention, wherein R is as above defined are set forth as follows. In these representations, the following abbreviations are used: L-iduronic acid=IdoA; D-glucosamine=GlcNH2 ; N-acetyl-D-glucosamine=GlcNAc; D-glucosamine N-sulfate=GlcNS; 2,5-anhydromannose=Man(2,5); 2,5-anhydromannitol=ManH(2,5). The location of the O-linked sulfate residues is indicated by "S" and the number of the position of sulfation where the SO3 R residue is linked to oxygen. In the designations below, the alpha and beta anomeric linkages are as those shown in formula 1 above and the indicated D or L configurations as set forth above pertains. The locations of the sulfates are shown below the abbreviation for the sugar to which they apply. The hexasaccharide and octasaccharide fragments obtained by digesting heparin and following the above-described procedures are of the formula: ##STR8## wherein n is 1 or 2, each of the variables A, B, C and D is independently H or SO3 R, wherein each R is independently H or a cation, with the proviso that at least two of said A, B, C and D are SO3 R. As in the Formulas I and II above, the hydroxyl groups in the 3 position of the sugars have been omitted for greater clarity and the asterisk next to the position of the carboxyl group indicates that the stereochemistry thereof is undetermined. In the compounds of formula (III) the sugar at the reducing terminus is deaminated to form the 2,5-anhydromannose shown. When this sugar is further reduced, the CHO shown becomes --CH2 OH; however, the reduction does not occur in the depolymerization reaction per se. The reduced compound is part of the present invention and is shown below as formula (IIIa) wherein each of the variables is defined as in formula III above. ##STR9## The cations represented by R can either be inorganic cations such as sodium, potassium, calcium, or ammonium ion or can be organic cations such as those obtained from quaternary amines and these salts are formed by simple neutralization. As above, the hydroxyls at the 3 positions are not shown in the structure, but are understood to be present, and the asterisk adjacent the position of the carboxyl groups indicates that the stereochemistry at these positions is undetermined. Based on the above formula (III) it can be seen that there are fifty-seven different possible configurations with respect to the position of the --SO3 R moieties when 2 or more are present. These configurations are schematically shown in FIGS. 6A, 6B and 6C wherein an "X" indicates a --SO3 R is present at the indicated A, B, A', B', C or D position wherein A' and B' represent the embodiments of A and B in the parenthesized disaccharide unit proximal to the dehydromannose or dehydromannitol residue. In that each "R" can be H or a cation, the fifty-seven possible structures represent a significantly larger number of compounds, i.e., the acid and salt forms. The basic structural formulae of the fifty-seven configurations are not put forth herein. However, these formulae can be deduced from formula III and FIGS. 6A, 6B and 6C by referring to the formulae II(1)-II(11) above. Preferred compounds of the invention are the hexasaccharides. However, the preferred octasaccharides include octasaccharides having antiproliferative activity with smooth muscle cells which have the formula ##STR10## wherein at least two of the six sugars in the middle --GlcNS--IdoA--GlcNS--IdoA--GlcNS--IdoA-- group include a sulfate; or a physiologically acceptable salt thereof. Especially preferred among these are octasaccharides wherein at least two IdoA--GlcNY units are ##STR11## Thus, preferred octasaccharides of the invention include any of the following octasaccharides, their pharmaceutically acceptable salts and mixtures of two or more of such octasaccharides and their salts ##STR12## The oligosaccharide compositions of the invention are useful in therapeutic applications for treatment of conditions or diseases which are characterized by excessive and destructive smooth muscle cell proliferation. These conditions frequently occur where the subject has been exposed to trauma, such as in the case of surgical patients. The trauma caused by wounds or surgery results in vascular damage and secondary smooth muscle cell proliferation, which secondary proliferation results in vascular resenosis. This undesirable result can occur after vascular graft surgery, heart transplantation, balloon or laser angioplasty, arterial traumatic injury, postsurgical repair of muscular arteries, long-term in-dwelling of arterial catheters, invasive arterial diagnostic procedures, kidney, lung or liver transplants, coronary artery bypass surgery, carotid artery bypass surgery, femoral popliteal bypass surgery, and intracranial arterial bypass surgery. In addition to secondary smooth muscle cell proliferation events occurring as a result of trauma, certain diseases are associated with unwanted vascular proliferation, although in these cases, too, it is assumed that some internal unknown injury has caused the secondary result. These disease states include Goodpasture syndrome, acute glomerulonephritis, neonatal pulmonary hypertension, asthma, congestive heart failure, adult pulmonary hypertension, and renal vascular hypertension. For all these diseases and conditions, administration of suitable amounts of the compositions of the invention is useful in treatment. Administration is by typical routes appropriate for polysaccharide compositions, and generally includes systemic administration, such as by injection. Particularly preferred is intravenous injection, as continuous injection over long time periods can be easily continued. Typical dosage ranges are in the range of 0.1-10 mg/kg/hr on a constant basis over a period of 5-30, preferably 7-14, days. Particularly preferred dosage is about 0.3 mg/kg/hr, or, for a 70 kg adult, 21 mg/hr or 540 mg/day. Other modes of administration are less preferred but may be more convenient. Injection subcutaneously at a lower dose or administered orally at a slightly higher dose than intravenous injection, or by transmembrane or transdermal or other topical administration for localized injury may also be effective. Localized administration through a continuous release device, such as a supporting matrix, perhaps included in a vascular graft material, is particularly useful where the location of the trauma is accessible. Formulations suitable for the foregoing modes of administration are known in the art, and a suitable compendium of formulations is found in Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pa., latest edition. The compositions of the invention may also be labeled using typical methods such as radiolabeling, fluorescent labeling, chromophores or enzymes, and used in a competitive assay for the amount of antiproliferative component in a biological sample. Suitable protocols for competitive assays of analytes in biological samples are well known in the art, and generally involve treatment of the sample, in admixture with the labeled competitor, with a specific binding partner which is reactive with the analyte such as, typically, an immunoglobulin or fragment thereof. The antibodies prepared according to the invention are useful for this purpose. The binding of analyte and competitor to the antibody can be measured by removing the bound complex and assaying either the complex or the supernatant for the label. The separation can be made more facile by preliminary conjugation of the specific binding partner to a solid support. Such techniques are well known in the art, and the protocols available for such competitive assays are too numerous and too well known to be set forth in detail here. The antibodies of the invention are useful in immunoassays, not only of the type described above involving competition between labeled composition and the analyte antiproliferation factor in the sample, but also for direct immunoassay for the factor. Alternate protocols involving direct assays are also of wide variety and well known. Typically, the analyte bound to antibody is detected by means of an additional reactive partner which bears a label or other means of detection. Thus, in typical sandwich assays, for example, the binding of the antibodies of the invention to analyte can be detected by further reaction with a labeled preparation of these same antibodies or by labeled antibody immunoreactive with this preparation by virtue of species differences. The antibodies of the invention can also be formulated into pharmaceutical compositions and used to stimulate the growth of smooth muscle cells in subjects for which this result is desirable. The following examples are put forth so as to provide those of ordinary skill in the art with a complete disclosure and description of how to make the compounds and compositions of the invention and are not intended to limit the scope of what the inventors regard as their invention. Efforts have been made to insure accuracy with respect to numbers used (e.g., amounts, temperature, etc.), but some experimental errors and deviations should be accounted for. Unless indicated otherwise, parts are parts by weight, temperature is in degrees centigrade, and pressure is at or near atmospheric. To 20 g of heparin dissolved in 160 ml water was added 690 mg solid NaNO2 to give a final HONO concentration of 50 mM in the deamination mixture. Approximately 70 ml 6M HCl was added dropwise while the mixture was stirred with a magnetic stirrer. The pH dropped slowly to 1.5 and was maintained at 1.5 by dropwise addition of either 6M HCl or 2M Na2 CO3. Initially, the addition of acid caused the reaction mixture to turn yellow, but, as the reaction reached completion (about 6 min, when N2 evolution ceased), the solution became clear. When the reaction was complete, 2M Na2 CO3 was added to bring the final pH up to 8.5. A fine white precipitate which sometimes appeared was removed by centrifugation and the supernatant was decanted, degassed under vacuum, and then loaded directly onto a BioGel P10 column. For the BioGel chromatography, two columns were connected in tandem, each approximately 5 cm in diameter, 128 cm in length, were packed with a total of 5 1. of BioGel P10. The columns were prepared and run in 0.5M NH4 HCO3 at a flow rate of 0.7 ml per min. The deamination mixture was loaded onto the column in the smallest possible volume (less than 160 ml). Fractions of 18 ml were collected and analyzed by the carbazole procedure. Fractions in individual peaks were combined and dried by extensive lyophilization to remove the NH4 HCO3. Peaks containing mixtures of di-, tetra-, hexa-, octa-, deca-, and higher oligosaccharides were obtained, with the higher oligosaccharides eluting early and the disaccharides eluting last. Solutions to be tested were made up in "complete medium", which is DMEM medium containing 10% fetal calf serum and penicillin/streptomycin. Bovine smooth muscle cells (SMC) were isolated from bovine pulmonary artery by the method of Ross, R. J., Cell Biol (1971) 172-186. SMC from passage 3-10 were plated at 350-700 cells per well in 96-well microtiter plates in the medium above and allowed to attach for 2-4 hr. The complete medium was replaced with DMEM supplemented with 0.1% fetal calf serum, and the cells were incubated for an additional period of about 24 to 72 hr to arrest cell growth. The low-serum medium was then replaced with complete medium containing the test samples. The cells were allowed to grow for up to 7 days with replicate plates sampled at regular intervals. Cell number was determined by removing the medium and washing the cells with phosphate-buffered saline, adding 75-150 ul lysis buffer, and assaying for lactate dehydrogenase (LDH) activity, as described by Brandley, B., et al., J Biol Chem (1987) 262:6431. The activity of LDH is proportional to cell number. The results of one such assay on oligosaccharides ranging in size from tetra- to tetradecasaccharide fractions are shown in FIG. 2. These results show that hexasaccharide and octasaccharide fractions are active in the antiproliferative assay; the tetrasaccharide fraction appears substantially less active. While high molecular weight fragments are also active in this assay, fragments of hexasaccharide length and longer have comparable activity to heparin on a concentration weight/volume basis and shorter oligosaccharides are more conveniently amenable to de novo synthesis. Hence, the minimal unit capable of antiproliferative activity is of interest. As shown in FIG. 2, 80% inhibition of proliferation is found at concentrations of the octasaccharide fraction as low as 15 ug/ml. Comparable inhibition is shown by the hexasaccharide fraction at about 60 ug/ml. The hexasaccharide and octasaccharide fractions obtained according to Example 1 were subjected to anion exchange chromatography on a 1×7 cm column of DEAE-toyopearl packed in 0.1M NH4 HCO3 and developed with a linear gradient from 0.01M to 1.0M NH4 HCO3 (total volume=600 ml). Approximately 20 mg of each oligosaccharide mixture was loaded onto the column. The results are shown in FIG. 3A and 3B for the hexasaccharides and octasaccharides respectively. The eluate was divided into six fractions of equivalent mass as shown in FIGS. 3A and 3B and assayed according to the method of Example 2 for ability to inhibit smooth muscle proliferation. The results of this assay are shown in FIGS. 4A and 4B. As shown in FIG. 4A, the ability to inhibit smooth muscle proliferation appears correlated with charge, as the highest charged fractions are considerably more effective. Fractions eluting early in either column do not appear to have substantial antiproliferative activity. However, fractions with high affinity for the anion exchanger are quite effective. For example, in the case of the hexasaccharide mixture, concentrations of roughly 75 ug/ml of any of the four highest charged fractions gave inhibition of smooth muscle proliferation in the assay equivalent to 60% of the maximum inhibition obtainable with commercial heparin;the highest charged four fractions of the octasaccharide anion exchange separation were capable of approximately 60-80% inhibition at 15-30 ug/ml. The DEAE-toyopearl chromatography was run on a larger scale using a 5 cm×27 cm column packed in 0.3M NH4 HCO3. Up to 3 g of oligosaccharide mixture was loaded onto this column and the column was washed successively with 2 1 volumes of 0.3M, 0.5M, 0.06M, 0.9M, and 1.2M NH4 HCO3. The fraction emerging in 0.9M NH4 HCO3, equivalent to the most highly sulfated pool from the smaller column, is recovered in yields of approximately 150 mg/g of starting oligosaccharide mixture. The unresolved hexasaccharides and the hexasaccharide fraction which is of the highest charged character obtained from the DEAE-Toyopearl column in Example 3 were subjected to reversed phase ion paring HPLC as described by Guo, Y., et al., Anal Biochem (1988) 168:54-62. The elution patterns for these procedures are shown in FIGS. 5A and 5B. FIG. 5A shows the elution profile from the highest charged fragment of DEAE-Toyopearl; FIG. 5B shows the results using the total hexasaccharide fraction. As a comparison of these profiles will indicate, the charge separated fraction is a greatly simplified mixture. The individual components of this simplified mixture are expected to have antiproliferative activity. The more highly charged fragments generally show (as compared with less highly charged fragments and/or commercial heparin) (1) a greater ability to inhibit the proliferation of smooth muscle cells and (2) a lesser ability to act as an anticoagulant. Further fractionation/separation processing can be carried out which improve factors (1) and (2) and also simultaneously aid in eliminating fragments which include oligosaccharides sulfated at the 3-position. It is pointed out that in order for a glucosamine to have anticoagulant activity it must be sulfated at the 3-position. Preferred oligosaccharide fragments of the invention possess characteristic (1) and (2) and (3) are highly charged and (4) include a very low (or no) amounts of saccharides sulfated at the 3-position as compared with fragments of commercial heparin. In order to obtain such preferred oligosaccharides, it is preferable to produce them synthetically rather than obtain them from digestion of heparin. As indicated above, the oligosaccharides of the invention which are particularly preferred have a number of distinct characteristics such as greater ability to inhibit proliferation of smooth muscle cells, lesser ability to act an as anticoagulant, high degrees of sulfation, and lack of sulfation at the 3-position. Although it is possible to obtain such particularly preferred oligosaccharides by the digestion of heparin and thereafter separation of the fragments obtained in accordance with methods described above, it is preferable to obtain such particularly preferred fragments using chemical synthesis methodologies. Chemical synthesis methodologies makes it possible to obtain highly pure reaction products all of which have the same structure and therefore characteristics. The following is a flow diagram which shows the synthesis of particularly preferred oligosaccharides. At the end of the structural synthesis schemes put forth below, a written description is provided which describes methods of carrying out such synthesis. ##STR13## Oligosaccharides, regardless of their size or whether their glucosamine unit is sulfated at 0-6, can be retrosynthesized to a common protected disaccharide unit. This disaccharide unit is open for chain extension in both directions; its thioglycoside function permits chain-extension towards the reducing end, whereas protection of its 0-4' position by the temporary chloracetyl group allows further chain-extensions towards the non-reducing end. The amino groups of the target compounds are masked as azido groups, which assure advantageous stereocontrol in glycosylation reactions. Benzyl (Bn) groups are used as permanent blocking groups for the hydroxyls which are nonsulfated in the target compounds, and the semi-permanent benzoyl (Bz) group is used for the OH's to be sulfated. The p-methoxybenzyl (MBn) group stands for hydroxyl groups the sulfation of which is optional in the target compounds. The disaccharide synthon should be available by glycosylating the protected 2-azido-2-deoxyglucopyranosyl derivative with the iduronosyl bromide. Though all the target oligosaccharides can be synthesized from this single disaccharide synthon, for the particular case of the reducing end this synthon can be substituted by another disaccharide unit (shown in brackets), which bears a methyl glycoside at the reducing end, and an amino group which is protected by a benzyloxycarbonyl (Z) group. This disaccharide can be synthesized by coupling the same iduronic acid donor with a glucosamine derivative shown in brackets. This retrosynthesis involves a novel and particularly advantageous blocking group strategy, which, in contrast to previous syntheses of sulfated oligosaccharides, permits the preparation of oligosaccharides with different sulfation patterns from the same protected derivative. The combination of an acyl-type (benzoyl) protecting group with the p-methoxybenzyl group allows specific deprotection and subsequent sulfation in any order, leading to structures which have sulfate groups in positions: a) masked by benzoyl groups in the protected derivative; b) masked by p-methoxybenzyl groups in the protected derivative; and c) masked by both benzoyl and p-methoxybenzyl groups in the protected derivative. A further advantage of the use of the p-methoxybenzyl group is that if selective removal of this group is not required it can be removed by catalytic hydrogenation in the same step as the permanent benzyl groups, thereby reducing the number of required synthetic steps. For the synthesis of the iduronic acid donor 3-O-benzyl-L-idose (van Boeckel, C. A. A. et al., Carbohydr Chem (1985) 4:293, incorporated herein by reference) was tritylated with trityl chloride in pyridine and the product, without isolation, was directly benzoylated by the addition of benzoyl chloride to the reaction mixture. The trityl group was removed by acid hydrolysis, and the primary hydroxyl group was oxidized by chromic acid, followed by esterification of the resulting carboxyl group with diazomethane. Conversion to the glycosyl bromide was achieved with titanium(IV) bromide. For the synthesis of the glucosamine synthon 2-azido-2-deoxy-D-glucose peracetate (Paulsen, H. et al., Chem Ber (1978) 111:2334, incorporated herein by reference) was converted into the thioglycoside in three steps by selective deacetylation with hydrazine acetate (Excoffier, G. et al., Carbohydr Res (1978) 39:368, incorporated herein by reference), followed by conversion of the resulting hemiacetal into the chloride, and subsequent thioglycosidation. The acetyl groups were removed by Zemplen-deacetylation, and the 4,6-O-p-methoxybenzylidene acetal was prepared by an acetal-exchange reaction. The 3-OH group was benzylated, and the 4,6-O-acetal ring was reductively opened with NaCNBH3 -trifluoroacetic acid (Johansson, R. et al., J Chem Soc (1984) 1:2371, incorporated herein by reference). The glucosamine synthon for the reducing end was synthesized by an analogous sequence from methyl 2-benzyloxycarbonylamino-2-deoxy-α-D-glucopyranoside (Heyns, K. et al., Chem Ber (1955) 88:188, incorporated herein by reference) by p-methoxybenzylidenation, benzylation, and reductive ring opening. Coupling of the 2-azido- and 2-benzyloxycarbonylamino-2-deoxy-D-glucose derivatives with the same iduronosyl bromide was performed using silver triflate, in combination with collidine as a buffer of the reaction medium, and resulted in the disaccharides. Both disaccharides were further functionalized to the disaccharide synthons. The compounds were debenzoylated and a single benzoyl group was introduced at the 0-2' position. In the case of the disaccharide thioglycoside derivative, the benzoylation was followed by chloroacetylation of the 0-4' position. The two disaccharide synthons were coupled by using dimethyl(methylthio)sulfonium triflate (Fugedi, P. et al., Carbohydr Res (1986) 149:C9, incorporated herein by reference) (DMTST) to give the tetrasaccharide with the required α-interglycosidic linkage. Selective removal of the chloroacetyl group followed by glycosylation with the same disaccharide donor would give the protected hexasaccharide, which can be sulfated and deprotected in different ways as discussed previously. Additional methods of synthesis may become apparent to those skilled in the art upon reviewing the above disclosure by itself and/or in combination with U.S. Pat. No. 4,943,630 issued Jul. 24, 1990, which patent is incorporated herein by reference to disclose methods of synthesizing oligosaccharides. While the present invention has been described with reference to specific embodiments thereof, it should be understood by those skilled in the art that various changes may be made and equivalence may be submitted without departing from the true spirit and scope of the invention. In addition, many modifications may be made to adapt a particular situation, material, composition of matter, process, process step or steps, to the objective, spirit and scope of the invention. All such modifications are intended to be within the scope of the claims appended hereto. Citations de brevets
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(Villanova University, 2002-01)In 1998, United States Senator Bill Bradley, a former NBA great, exemplified the prevailing Congressional sentiment regarding sports betting: ... I am not prepared to risk the values that sports instill in youth just to ...
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(2012)The University of Illinois is well-known historically for its accommodations for disabled students. To this day, the university proudly parades its reputation as a leader in opportunities for disabled students. This ...
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(2011-08)The main goal of our project was to discover whether or not diversity existed in athletics and the music program at the University of Illinois. We found in our research, and specifically in the survey we conducted, that ...
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(2014-05-30)Sport plays an integral part in forming Nigeria's identity. Most Nigerian men either engage actively or passively in sport; however, the same cannot be said for Nigerian women. There are inherent paternalistic structures ...
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LAURENCE LEBLANC | sur le site de Laurence Leblanc, artiste française qui vit et travaille à Paris. to the website of Laurence Leblanc. Laurence Leblanc is a french artist who currently lives and works in Paris. |
© 1998-2008 Laurence Leblanc / All rights reserved / Last update November 8, 2010 / Please visit this site often as there will be frequent updates. |


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Super 8 Verona/Madison
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Just to visit my son and his family for the day. New facility, great price. everything…
Clean and friendly but was disappointed that the pool was closed due to no heater and the…
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Select Local Merchants
Mattress Land Sleep Fit CenterRead MoreBecause no two bodies are alike, The Relaxologiists at Mattress Land use their exclusive bedFit diagnostic technology to determine the ideal snooze position for each customer, as well as the ideal mattress. Comfy Sleep surfaces come from premier brands such as Beautyrest, Sealy PosturePedic, Stearns and Foster, and SleepFit. Shoppers can also upgrade to latex mattresses or Custom mattresses made for each sleepier with separate sides, which accommodates the differing body types of spouses and accidentally conjoined mad scientists.411 West Haycraft AvenueCoeur D'Alene, ID US
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Integrated Scenarios of Regional Development in Two Semi-Arid States of North-Eastern Brazil
Döll, Petra and Krol, Maarten S. (2002) Integrated Scenarios of Regional Development in Two Semi-Arid States of North-Eastern Brazil. Integrated Assessment, 3 (4). pp. 308-320. ISSN 1389-5176
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Abstract: | Scenario analysis of the future is an important tool for supporting sustainability-oriented regional planning. To assist regional planning in two federal states in semi-arid North-eastern Brazil, Ceará and Piauí, we developed integrated qualitative¿quantitative scenarios that show potential developments of the agricultural and water resources situation as well as the internal migration until the year 2025. In these states, regional development is negatively influenced by the high seasonality of rainfall and El-Niño-related drought years. Two reference scenarios, 'Coastal Boom and Cash Crops' and 'Decentralisation - Integrated Rural Development' were developed. First, story lines were created and the development of the driving forces was quantified. Then, an integrated model, which includes modules for simulating water availability, water demand, and agricultural production and income, was applied to compute the temporal development of relevant system indicators in each of the 332 municipalities of Ceará and Piauí. These indicators encompass the fraction of the irrigation water demand than can be satisfied, the volume of water which is stored in the reservoirs at the beginning of the dry season, agricultural productivity and production as well as the internal migration among scenario regions. In addition, the impact of certain policy measures was assessed in the context of both reference scenarios. Reference and intervention scenarios were derived by an interdisciplinary group of scientists and were discussed and refined during policy workshops with planning agencies of Ceará. |
Item Type: | Article |
Copyright: | © 2002 Swets & Zeitlinger |
Faculty: | Engineering Technology (CTW) |
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Link to this item: | http://purl.utwente.nl/publications/55772 |
Official URL: | http://journals.sfu.ca/int_assess/index.php/iaj/article/view/98/ |
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Phone: 503-823-0000
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1111 S.W. 2nd Avenue, Portland, OR 97204
Phone: 503-823-0000
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1111 S.W. 2nd Avenue, Portland, OR 97204
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November 01, 2001 00:00
On October 30, 2001, at approximately 10:32 p.m., Portland Police Officers responded to a report of a dead body under an overpass. The overpass is near the intersection of SW Arthur and SW Naito Parkway. Homicide detectives responded to the scene and initiated a criminal investigation.An autopsy was conducted on October 31, 2001. Detectives state that the cause of death is homicidal violence. The victim has been identified as 43-year-old Larry Begay Sr. He is described as 5'8" tall, 150 pounds, with black hair and brown eyes, and was wearing dark blue jeans and a black jacket.
No arrests have been made in this case and anyone with information is requested to call Detective Sergeant Mike Larson at (503) 823-0457 or Detective Sergeant Rich Austria at (503) 823-0449.
Crime Stoppers is offering a cash reward of up to $1,000 for information that leads to an arrest in this investigation. Callers can remain anonymous. Call Crime Stoppers at (503) 823-HELP.
A photograph of Begay is available from the Portland Police Bureau's Identification at (503) 823-0382.
This investigation is continuing.
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should it always come first?
Marten, possibly more accurate words, but not necessarily very romantic for the most special day of your life?
Yes, my marriage might have failed, but i'm still a soppy old romantic at heart LOL
OW - why sell it to you - it has to be something you want to buy, not something that's sold to you. If you find the right person, and you're the right person for them, then it is for life, and you'll want to spend the rest of your life with them, through thick and thin...
Until you find that person though, well, there's nothing to sell....
From what we have been saying it may not turn out to be the most special day of your life. Life can be very hurtful and that day might, in retrospect, turn out to be the most nightmarish day of your life. This is why I think we need to tone down the wording. Some people don't even listen to the words they are saying and some are too immature (at any age) to understand what they mean - the guy is thinking 'sex' the girl is thinking 'baby'!
OW I wish I could sell the lifetime commitment to you but I cannot. I think that in most marriages the difference between staying together and splitting up will at any time be precarious. Some communicate and get through difficult times others give up easily. On the other hand there can be a 'paper trail' of problems over time and one or other partner just does not see the point anymore. I do think that many marriages lose focus and the spouses can become indifferent to each others needs whether it be sex, compliments, romance, pleasant surprises, sharing interests etc. If it happens and that lifelong commitment comes to an end it can make you feel that you are the only person in the world to which it has happened. You need to enter marriage with your eyes wide open.


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STEPHEN J. CANNELL, RIP Emmy-winning writer and producer Stephen J. Cannell, who died Sept. 30, left a rich TV legacy. In one of his final interviews last spring, Cannell talked to Retroality's Chris Mann about NBC's plans to "reimagine" his '70s TV hit The Rockford Files.
GOING UPHILL FAST Olympic gold medalist-turned-Alka Seltzer spokeswoman Lindsey Vonn on her Law & Order cameo and being America's newest golden girl.
GROWING UP WEREWOLF Ripped True Blood star Joe Manganiello tells how vintage film monsters inspired his childhood dream to become a werewolf.
A CASE FOR C.A.P.E.R. A diligent Kids show devotee delves deep to uncover artifacts from, interviews about and fan love for the long-lost '70s Saturday morning live-action series The Kids from C.A.P.E.R.
DIFF'RENT STANDARDS Why does TV's The Insider rip into yesteryear stars such as the late (and long-ailing) Gary Coleman while giving current celebs such as Two and a Half Men star Charlie Sheen a pass?
BIG-'BANG' BLOSSOM Nineties sitcom star Mayim Bialik on her Big Bang Theory gig, SNL spoofing and teenage awkwardness.
BIG-SCREEN "V"? Producer-director-writer Kenneth Johnson on his planned V motion picture and and his slew of re-imagined-by-others, iconic TV hits.
MUM'S THE WORD TV's Dr. Quinn, Jane Seymour, opens her heart and shares the healing thoughts of her late mother.
ECO GOSSIP GIRL Forget about the CW hit's kaput '80s spin-off. Lovely Kelly Rutherford�Gossip Girl's sassy socialite�shares her earth-friendly secrets from the '70s to today.
SKATE PLUS ATE '80s Olympic icon Brian Boitano on his Food Network show, his triple-lutzing South Park doppelganger and meeting Bronson "Balki" Pinchot.
SHE'S NOT DESPERATE Dexter's Julie Benz�now stirring it up on Desperate Housewives�talks about life after TV death.
VAN ARK "Y&R" SCOOP! DaytimeConfidential.com and others picked up our exclusive Q&A with Knots Landing's Joan Van Ark, who spills on her stint on The Young and the Restless
THREE'S CONTROVERSY: In this blog exclusive, Retroality's editor reveals that the late John Ritter initially doubted Suzanne Somers' cancer.
FARRAH'S STORY?: The iconic TV angel's producing partner, Craig Nevius, tells why he's suing Ryan O'Neal and Alana Stewart.
COME ON DOWN! A new book celebrates legendary Price is Right announcer Johnny Olson, while a Barker's Beauty reveals Rod Roddy's secret off-camera sadness
>>FOREVER GOOGLING in an e-sea of Britney "news" and Hanna Montana hell for the latest scoops on�and from�the pre-TMZ, made-for-TV celebs and primetime hits that helped you escape actual reality in the pre-reality-TV-obsessed '60s, '70s, '80s & '90s?
>>INSATIABLY CURIOUS about the Flower Power, Me Generation and Greed Decade influences�and current views and healthy passions�of classic Hollywood survivors and their inextricably linked, retro-inspired reality TV counterparts?
>>DREAM ON, televisionaries. Retroality.TV is your definitive voice of retrorealism, your uber guide to retrocentric boob-tube buzz and your 99% Britney-free online oasis where yesterday's fantasies meet today's reality
Author of the hit, acclaimed TV tell-all Come and Knock on Our Door, Retroality.TV editor Chris Mann served as Consulting Producer on NBC's hit 2003 telefilm Behind the Camera: The Unauthorized Story of Three's Company. He's also covered talent, legal issues and social trends as a freelance writer for the Los Angeles Times, TV Guide, emmy, Geek and other publications. Additionally, Chris pens and sometimes art directs celeb cover-story profiles and photo shoots for numerous healthy living magazines. click for more
JOHN RITTER RAVES: In this 1997 interview with RetroRewind.com's Dave Harris, the late, great John Ritter graciously shares supportive words for Chris Mann and Come and Knock on Our Door (see 4:40)
"I have to admit that Come and Knock on Our Door was the very best book I ever read about any TV show. I felt like I was on the set of Three's Company. The author (lemme just take this time to say that Chris Mann is a genius) captured every element of the show." -Bill Cassin (Scarsdale, NY)
"Chris Mann did a fantastic job on this book! I entered this reading experience expecting a superficial offering of one-sided stories about the trials and tribulations of this pop culture phenomenon known as Three's Company. I exited feeling satisfied at the invested hours I spent in reading this book." -Robert Nguyen (Orange Cty., CA)
"Chris has managed to tell the backstage story in a non-biased manner but has decided to let the stars tell their own sides, ensuring their integrity and the integrity of the book in the process. This book is anything but a tabloid. It tells the stories from those who experienced it. No commentaries are made. No opinions are offered. Just the facts.The show itself was dissected and Chris Mann speaks about the behind the scenes goings on as if he were there. -Roy J. Dlucca (Phoenix, AZ)
"Like so many others, I grew up watching Three's Company, so I couldn't wait to dive into this book. The behind the scenes stories are alternately funny and enlightening, and the author clearly went to great lengths to present all sides of the story. This is especially important, since opinions on the Somers situation vary widely." -J.T. Schweizer (Queens, NY)
"This book provides a great way to bring closure to an epic adventure from my childhood." -A reader
Last May, audiences were riveted as reality TV�s newest �bad girl,� Holly Robinson-Peete, took second place to America�s beloved, back-from-death's-door rock star, Bret Michaels, in NBC�s star-studded finale of Donald Trump�s Celebrity Apprentice.
Fast forward to Oct. 18. Both finalists return to television in �real-life� vehicles: Peete in the mom-centric CBS daytime gabfest The Talk�featuring an ensemble of estrogen-fueled TV vets�and Michaels in his newest VH1 reality series Life As I Know It.
Despite losing to the Rock of Love sensation in Trump�s live finale, Peete emerged from NBC�s strategically edited boardroom series rich with reality TV knowledge that�s sure to help her should The Talk veer into The View�s trademark woman-on-woman snarking and snarling. (Her Apprentice charity, The HollyRod Foundation [which chiefly funds autism research and resources for families struggling with the affliction], received a record $600,000 thanks to Peete�s business savvy and unyielding tenacity. In fact, Trump liked her so much, he never officially fired her--and he and Snapple awarded both HollyRod and Michaels' charity the finale's $250,000 grand prize.)
In these outtakes from my interview with Peete for the August Wellbella, the former 21 Jump Street star gets real about her Celebrity Apprentice gig�including her friendship with fellow music lover Michaels, her as-seen-on-reality-TV conflict with ironic rocker Cyndi Lauper and resulting online furor accusing Peete of being �anti-gay.� The former Hanging with Mr. Cooper star also reveals how she felt to be labeled for the first time as a �bitch� and to see �Holly hate� among TV viewers.
Before CBS picked up The Talk, Peete told me she�d love to do a talk show. �I�ve had opportunities to do films but I�ve always chosen family first,� the mom of three said. �But a talk show is a great platform to talk about things I�m passionate about.� Would the media-savvy competitor consider a stint on Dancing with the Stars? �Hell, no. One, I can�t dance. Two, I feel I already lost a couple of years of my life just on the Celebrity Apprentice,� she said. �I�m not coming on reality shows to get kicked off. I�m coming on to win. If I can�t dance like the Pussycat Dolls girl, then I�m not going on.�
Then a return appearance on Celebrity Apprentice next spring is out of the question? Not so fast. �I�m sure Mr. Trump will bring me back to do something next season. He�s alright by me. He won over a lot of people with that finale. He did the right thing, the graceful thing. And it was a brilliant PR move for him.�
In retrospect, how was your Celebrity Apprentice experience? It was a wild ride. You know that ride at Disneyland they call Mr. Toad�s Wild Ride? Well, I call this Mr. Trump�s Wild Ride. It was craaaaaaazyyy. It was not easy. I don�t remember having a whole lot of fun. And it was at moments excrutiating. But boy am I glad I did it. And I would do it again in a heartbeat.
But it was really difficult. And I have to say I�m really fortunate. I�ve had 25 years in the business. I�ve had a chance to see the trends of show business. I think I was really prepared media-savvy-wise to handle the sort of pressures I had to deal with. And that finale was really a very awkward, bizarre situation. I was sitting there next to someone who almost lost his life and yet (I) really, really wanted to fight for my charity�but didn�t want to say anything negative about him, because then I�d be Cruella de Ville.
My mom was moved that you remained standing for Bret during his intro in the live finale. Well, I appreciate that because it really was authentic. I really do like the guy and we�ve become friends. But there�s that competitive part of me that walked in and said, �You know what, I�m going to lose. I�m not gonna win. They�re not gonna pick me. They�re not gonna pick the mean, special-needs mom over the sweet, aging, ailing rocker. That ain�t gonna happen.� I walked in very clear and prepared, and I think that�s what really carried me through.
And I kept telling my kids, �Mommy has already won.� I didn�t want them to cry on camera or anything. We walked around the streets buying Compassion Berry in all the little stores of New York. It was really a win-win. And I have to tell you when that extra quarter of a million came (from Snapple), I almost peed in my pants. I had no clue (though) I knew they were gonna break me off a little somethin�-somethin�.
Well, you never got fired. Nope. Mr. Trump never said it. And you can tell he purposely never said it. Look, I have a much bigger picture in mind. I started this foundation with, like, 50 people in my back yard. And I�ve built it up every year. So I think they picked two good people to be in the finals. Who knew in the off season, in between, that this woud happen to Bret and that it would become Bretmania? You couldn�t predict that � Knowing for four months that he and I were going to be in the finals, I was really at peace with that part of it.
We did get along, and neither one of us wanted it to be Joan (Rivers) vs. Annie (Duke). I couldn�t even watch (the finale) last year, and I�d watched all of the episodes. But it just got too personal and mean-spirited last year. And when they called and asked me to do it, I said, �You guys, I can go toe-to-toe and I can be nasty when I need to be. But I�m not gonna sit there and lob personal insults in front of my children.� I can be a hard-ass, but I�m not gonna sit there and call someone a Nazi.
Did you ever feel in the doing of the show or the editing of the show that they were trying to hint toward that type of conflict with you and Cyndi Lauper? They did the best they could to make it appear as though we hated each other. And we really didn�t. We�re two different people. If I�m a reality producer, she is a dream cast member. She�s brilliant, she�s hilarious, she�s funny, she�s crazy. And then in comes me, Miss By-the-Book Corporate. I sit on five boards across the country. It was a perfect yin and yang.
What bothered me is when all of a sudden the LGBT community started coming after me, saying, �We hate Holly (because) she�s anti-gay.� Please. I have more gays that work for me than daggone Follies Bergere. That�s what bothered me most: that because we clashed, people automatically assumed that I was against her cause. That was disturbing.
You come in with: �Ooh, who�s that?� or �Oh, I hated her� or �That was my show!� You come in with that and you leave with something different, and that�s the journey that Celebrity Apprentice takes you on. What I liked about how it worked out is, yeah there were moments in there where I was like, �Oh, my gosh, there�s Holly hate out there,� and I�ve never been the kind of celebrity that you even associate the word �hate� with.� So it was a little bit awkward, but in the end I have to tell you that it was a journey. When people have strong feelings toward you and then in the end you sort of win them over, that�s when they feel even closer to you.
How did your drive and your awareness of image give you an edge for keeping your message on track during Celebrity Apprentice�despite having everything you said, every look on your face being captured and edited? I wasn�t aware of that; that�s the problem. I�m looking around saying, �Okay, I�m very media-savvy. I know a lot. But the one area where I definitely learned is reality.� I�d never done reality before, and it�s definitely a learning curve. That was the hard part. What I learned is when they�re in the editing room, they�re like, �Okay, we need an eye roll. Let�s go to Holly. We need a neck move. Well, let�s go to Holly.� They create the characters: �Holly�s gonna be the mean, bullying, special-needs mom, and Cyndi�s gonna be the quirky, eclectic, (good-natured) one.� So let�s say Cyndi has a moment of her (being ornery). They�re not gonna cut that in because it doesn�t work with their storytelling. They have to edit to the storylines they�re creating. So if you give it to �em, they�re gonna use it. That�s what I�d try to do differently�I�d try to keep it off my face. But I�ve never been good with keeping how I feel off my face.
The first episode in they had Carol Leifer calling me a �dumb bitch.� I�m like, �Okay, I don�t know how many more bitches I�m gonna be on the this show.� I almost said that in the finale. Ivanka said, �You didn�t come off mean.� I almost said, �Now come on, now. I set a record for the most money raised. But I think I almost set a record for the number of times someone�s been called the B word on national TV.� I was �a dumb B,� �a bee-yotch.� I thinks someone even called me �Aunt B.� I was the most crazy thing in the world. That�s a new one for me in my career. A new height.
Cyndi certainly got her digs in. Had you met her before the show? I�ve know Cyndi Lauper for years�every time I met her she never remembered me. She never remembered who the hell I was. (Laughs.) I�ve always admired her and loved her. Now, that�s different than having to meet time challenges with her and to hit that micro-mini deadline. But you cannot really truthfully, correctly edit that in there. They just edited the conflict. In the end, that�s what makes a really good reality show. Nobody wants to see us skipping through the poppies and holding hands. But I think as a result Cyndi and I gained a lot of respect for each other because we both took a lot of crap from what was shown.
And Sharon Osbourne�s ride was so different than everyone�s. She just sort of disconnected herself: �I�m not even going to the final.� She had a (scheduling) conflict but I don�t know that she was thrilled with the way she was depicted. She�s been pretty verbal about that. She comes from reality (TV), and so does Bret. I come from scripted (TV), so this whole concept of the editor being the writer was all new to me. It�s a new way of looking at television, and if I�m being honest, it was a steep learning curve. Until you�ve done one of these shows and then watched them edit it � Hindsight is 20/20 and in the end, it�s $600,000 for families affected by autism. That�s a philanthropic lottery right there.
How has Bret�s recent health scares and your respective experiences with children with health issues bonded you? To be honest with you, when we talk�I mean, it�d be really lovely to say we�re so bonded because we have this mutual, personal connection through our kids�we bonded because we make each other laugh. We get on the phone and start cracking on people and laughing about stuff. And we listen to music together. I love music, and he plays songs for me. We bonded as friends. I think we�re more connected on the fact that we just vibe well. It wasn�t until I worked with him on the task with Cyndi that I really made that connection. We started finding out that our senses of humor were very compatible and it was like, �Oh, this guy is cool.� I�d been judging him. When he was with the guys I was like, �Oh, here comes Bret.� He was always sticking his head in and trying to find cameras. I was like, �Oh, man, it�s Rock of Love.� I think I was very judgmental about who he was, and then I spent some really interesting time with him.
That�s the biggie. When you spend some really concentrated time with people � and you come off in most of these situations with a level of respect. With some people it�s like, �Okay, if I don�t see them again, I�m cool.� And most people are like, �Oh, that�s how you and Cyndi are.� But we had such a great moment at the finale. We laughed about how we were at it. Yes, we definitely had some conflicts, but we really like each other. We�re both moms and our kids were bonding at the finale. And it was that moment of, �Ahh, we�re cool.� So that was really good.
Her singing on the boardroom table in the finale was strangely fitting. It was the most bizarre, surreal stuff I�ve ever seen in my life. I was like, �Who�s gonna come out next?� But when I went back to the hotel that night, I felt like that right thing happened. I�m too show business-savvy to not understand that they made the right decision. So I�m really thrilled.
On a sad note, you tweeted about the tragic passing of Gary Coleman, who ironically died from the same thing that almost took Bret. Did you know Gary? I�d met Gary many times over the years. When I first moved to California, my mom worked for an agency that represented either Conrad Bain or Charlotte Rae. As a result I would go with my mom to the sets of these shows�it was like Take Your Daughter to Work Day. I remember being on the set of Diff�rent Strokes and thinking, �One day, I�m gonna be on a sitcom.� I wanted to be Dana Plato, Danielle Spencer��Dee� from What�s Happening?!�and Kristy McNichol.
But I spent a lot of time on the set of Diff�rent Strokes and I really got a chance to see the brilliance that was Gary Coleman. He became a punchline and it really was tragic because he was a brilliant comic genius with unmatched timing. So it really hurt to hear he went the way he went. He�d survived so many health issues.
Your dad was the original Gordon on Sesame Street. How did growing up exposed to realities of the business prepare you for fame? I was so blessed to have a mother and a father in the business. My father was very discouraging about me being in the business. My dad was �Gordon� and I wanted to be on (Sesame Street) and he didn�t want me to be one of those showbiz kids. He knew it wasn�t a good scene for some adults, let alone kids. I begged and pleaded to get on. I had that one line where I said, �Hi Daddy.� I kept saying �Hi Daddy� and they wanted me to say �Hi Gordon.�
I still did this, that and the other here and there�a little Afterschool Special and my mom would take to do, like, a McDonald�s commercial. But I didn�t stop my life for it and I�m glad I didn�t. My dad said, �If you go to college I will support you in anything you want to do. But I need you to go to college.� My mom and my dad were divorced but in both their own ways they were instrumental�my dad in his discouragement but his encouragement of my education, and my mom in her showbiz savvy.
She always used to tell me, the number-one lesson in this business to keep working is to be good to the crew. If you�re good to the gaffer, the craft service person and the rest of the crew, they go on to every other production and the words gets around: �Oh, that Holly, she�s so nice and she�s so professional. She brought in lunch one day.� I didn�t do it because she told me; I did it because it came naturally. But if you�re good to the crew, they�re good to you. And that�s something I carried with me and I think helped me have a really good run in the �80s and �90s.
RETROALITY KITSCHIN'! Visit our daily Kitschin' blog for the latest retro-pop news, views and musings about TV reimaginings, reinventions and all things Retroality.
'90s BABE BOUNCES BACK Baywatch star Nicole Eggert on her FunnyorDie.com video, depression and being resilient.
IN SEARCH OF ANSWERS From her 21 Jump Street days to her HollyRod Foundation actress Holly Robinson-Peete has spent decades helping heal her family and others.
AN ALL-NEW SNATCH! Move over, Mr. Belvedere! Sit on it, Mrs. C! Here's the '80s' hottest sitcom provocateur!
SAVED BY THE TACO BELL? He used to crush taco stands but now Extra's Mario Lopez is a lean, mean, fat-burning machine.
JUST SHOOT ME, WELLBELLA! Hot in Cleveland's Wendie Malick on staying young at any age, Betty White's joyous laugh lines and living beyond yourself.
OH, LORD, ANOTHER REMAKE: Hawaii Five-0's Jack Lord will be reincarnated as hip actor Alex O'Loughlin in CBS's reboot of the iconic Seventies police drama premiering this fall. Check out Chris Mann's recent Los Angeles Times story on 2010's batch of TV redos.
SUMMER REALITY MAKEOVER Biggest Loser's Jillian Michaels on her new NBC reality series Losing It With Jillian
DOWN-TO-EARTH ACTIVIST Splash's Daryl Hannah tells why she can't eat seafood�or any once-living creature�as she saves the planet. Read her Q&A with Chris Mann in the April issue of Vegetarian Times magazine.
CAPER QUEST: Check out this fantastic new site about the '70s Saturday morning kid show The Kids from C.A.P.E.R.
'HOLLYWOOD'-BOUND: Exclu- sive! Meet the Bionic Woman, Mini-Me, Jane Russell & more! Coming: Gena Lee Nolin Q&A!
'HOLLYWOOD SHOW'-&-TELL: Retroality.TV has the scoop on the Feb. 13-14 event featuring a hot Knots Landing reunion, Baywatch babes, Lindsay "The Bionic Woman" Wagner, Hugh "Wyatt Earp" O'Brian and more! See Chris Mann's exclusive story in the Los Angeles Times
JANET OR CHRISSY?: Joyce DeWitt and Suzanne Somers sing and dance for their suppers in these bitchin' 1979 commericals for L'eggs and Ace Hardware.
SCOOBY-DOO-ME: Retroality editor Chris Mann interviews Scooby-Doo film scribe and director-producer James Gunn about his Spike.com series PG-Porn in the Nov. 2009 issue of Geek Monthly.
DANGEROUS CURVES AHEAD Kim Kardashian shares her health and beauty secrets in this new interview with Retroality editor Chris Mann


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Here is a wealth of astute and warmhearted counsel on many of life's most difficult ethical dilemmas. Joseph Telushkin outlines his ten commandments of character, explaining why each one is so vital, and then addresses perplexing issues that can and often do crop up in our lives relating to family, friends, work, community, medical ethics, and money, such as:
• How honest should you be when you are asked to give a reference?
• How much assistance should you give your son with his college application essay?
• Is it wrong to receive a kidney from an executed prisoner in China?
• What should you do if your father begs you to end his life rather than allow him to descend into the hell of Alzheimer's?
• Should a brother give up part of his inheritance if his sister has children and considerable expenses and he doesn't?
• Should a dying woman reveal to her husband that their son is not really his?
Many of us are finding it increasingly hard to tread the fine line between right and wrong. In The Ten Commandments of Character, Telushkin faces these issues squarely and shows us how to live a life of true integrity.
"At a time when so many people are looking for moral guidance, we are lucky to have Joseph Telushkin as our guide and teacher. I am thoroughly impressed by his wisdom and good sense."—Rabbi Harold Kushner, author of When Bad Things Happen to Good People
From the Hardcover edition.
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Aquatopia Safety Audible Bath Thermometer AquatopiaI used this item when my 4 year old son was a baby, and now I use this with my new baby girl. I love this item, especially when I was a new mom! Beeps when too hot OR cold, and provides a digital temperature reading. Perfect gift for a first time mommy or daddy!Dec 3,2014
Aquatopia Deluxe Safety Bath Time Easy Kneeler AquatopiaI use this to give my son a bath and save my knees. I love that it easily folds up with the velcro tabs. I did remove the padded bottom to wash. I don't recommend it in a top loader! It's just too stiff and ended up getting ripped, just a small spot (and that's my fault so I can't complain).Aug 5,2014


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Edmunds Gages
Please visit: Edmunds Gages Mailing Address: 45 Spring Lane Farmington, CT 06032 US
Universal Gaging Amplifier for Air and Electronic Gaging At IMTS 2012, Edmunds Gages will be exhibiting its Accu-Touch readout, a universal gaging amplifier that provides visual displays of shop floor or production-based dimensional measurements.
Advanced Gaging Amplifier Edmunds Gages has introduced the advanced data analysis measurement monitor (ADAMM) that provides air-to-electronic and LVDT-based signal conditioning, data gathering, analysis and storage in one unit. According to the company, the amplifier is designed to bridge the gap between "stop light" single element amplifiers with virtually no data retention and personal computers being used on the shop floor. This eliminates the need for individual amplifiers with separate data collectors to display, record, analyze and store measurement information.
Moving Parts, Moving Data, Keeping People This Plant's labor-saving automation includes hardware for updating CNC offsets to adjust for gradual process changes. When the plant adopted its automated system, management thought carefully about the impact on staffing.


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Motive Skateboards 'dimensions' Full
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Motive Skateboards first Video production featuring Jack Edwards, Paul Carter, Layth Sami, Leo Smith, Dylan Hughes, Barney Page, Dave Snaddon and Sean Smith, Edited by Ciaran O'connor.
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Meantime that man, with that
covetousness of his which was now notorious and the common talk of every one, as he
took a violent fancy to some exceedingly beautiful and very ancient statues at
Thermae placed in the public place, began to beg of Sthenius to promise him his
countenance and to aid him in taking them away. But Sthenius not only refused, but
declared to him that it was utterly impossible that most ancient statues, memorials
of Publius Africanus, should ever be taken away out of the town of the Thermitani,
as long as that city and the empire of the Roman people remained uninjured.
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