text:
This invention provides benzene derivatives which are leukotriene antagonists, formulations of those derivatives, and a method of using those derivatives for the treatment of conditions characterized by an excessive release of leukotrienes.
1. A compound of the Formula ##STR14## and pharmaceutically acceptable salts thereof, wherein: R1 is hydrogen, C1 -C6 alkyl, C3 -C8 cycloalkyl, phenyl-substituted-(C1 -C3 alkyl), phenyl, or phenyl substituted with a halo, C1 -C4 alkyl, or C1 -C4 alkoxy functionality;
R2 is C1 -C10 alkyl, C2 -C6 alkenyl, benzyl, or 2-phenylethyl;
R3 is hydrogen, bromo, or chloro; ##STR15## straight or branched chain C1 -C4 alkylidene; Q is a bond or straight or branched chain C1 -C4 alkylidene;
R4 is COR9, or 5-tetrazolyl; and p is 0, 1, or 2; where
each R is independently hydrogen, C1 -C3 alkyl or C1 -C4 alkanoyl;
each R5 and R6 is independently hydrogen, C1 -C3 alkyl, phenyl, or benzyl;
each R7 and R8 is independently hydrogen, C1 -C4 alkoxy, halo, hydroxy, amino, nitro, or C1 -C4 alkyl; and
R9 is hydroxy.
2. A compound of claim 1 wherein R1 is methyl.
3. A compound of claim 2 of the formula ##STR16## and pharmaceutically acceptable salts thereof wherein: R2 ' is C1 -C6 alkyl, especially propyl; and
A' is --O--, --CO--, or --CHOH--.
4. A compound of claim 3 wherein R2 ' is propyl.
5. The compound of claim 4 which is 1-[2-hydroxy-3-propyl-4-({4-[3-(1H-tetrazol-5-yl)benzoyl]-phenoxy}methyl)phenyl]ethanone or a pharmaceutically acceptable salt thereof.
6. The compound of claim 4 which is 1-[2-hydroxy-3-propyl-4-({4-[4-(1H-tetrazol-5-yl)benzoyl]-phenoxy}methyl)phenyl]ethanone or a pharmaceutically acceptable salt thereof.
7. The compound of claim 4 which is 1-{2-hydroxy-4-[(4-{hydroxy[3-(1H-tetrazol-5-yl)phenyl]-methyl}phenoxy)methyl]-3-propylphenyl}ethanone or a pharmaceutically acceptable salt thereof.
8. The compound of claim 4 which is 1-[2-hydroxy-3-propyl-4-({4-[4-(1H-tetrazol-5-yl)phenoxy]-phenoxy}methyl)phenyl]ethanone or a pharmaceutically acceptable salt thereof.
9. A method of treating a mammal suffering from or susceptible to any condition characterized by an excessive release of leukotrienes, which comprises administering to said mammal a leukotriene antagonizing amount of a compound of claim 1.
10. A method of treating a mammal suffering from or susceptible to any condition characterized by an excessive release of leukotrienes, which comprises administering to said mammal a leukotriene antagonizing amount of a compound of claim 4.
11. A method according to claim 10 employing 1-[2-hydroxy-3-propyl-4-({4-[3-(1H-tetrazol-5-yl)benzoyl]phenoxy}methyl)phenyl]ethanone or a pharmaceutically acceptable salt thereof.
12. A method according to claim 10 employing 1-[2-hydroxy-3-propyl-4-({4-[4-(1H-tetrazol-5-yl)-benzoyl]phenoxy}methyl)phenyl]ethanone or a pharmaceutically acceptable salt thereof.
13. A method according to claim 10 employing 1-{2-hydroxy-4-[(4-{hydroxy[3-(1H-tetrazol-5-yl)-phenyl]methyl}phenoxy)methyl]-3-propylphenyl}ethanone or a pharmaceutically acceptable salt thereof.
14. A method of treating a mammal suffering from or susceptible to an immediate hypersensitivity reaction of the type represented by asthma, which comprises administering to said mammal a therapeutically-effective amount of a compound of claim 1.
15. A pharmaceutical formulation comprising a compound of claim 1 in association with a pharmaceutically acceptable carrier.
16. A pharmaceutical formulation comprising a compound of claim 4 in association with a pharmaceutically acceptable carrier.
17. A pharmaceutical formulation according to claim 16 employing 1-[2-hydroxy-3-propyl-4-({4-[3-(1H-tetrazol-5-yl)benzoyl]phenoxy}methyl)phenyl]ethanone or a pharmaceutically acceptable salt thereof.
18. A pharmaceutical formulation according to claim 16 employing 1-[2-hydroxy-3-propyl-4-({4-[4-(1H-tetrazol-5-yl)benzoyl]phenoxy}methyl)phenyl]ethanone or a pharmaceutically acceptable salt thereof.
19. A pharmaceutical formulation according to claim 16 employing 1-{2-hydroxy-4-[(4-{hydroxy[3-(1H-tetrazol-5-yl)phenyl]methyl}phenoxy)methyl]-3-propylphenyl}ethanone or a pharmaceutically acceptable salt thereof.
20. A pharmaceutical formulation according to claim 16 employing 1-[2-hydroxy-3-propyl-4-({4-[4-(1H-tetrazol-5-yl)phenoxy]phenoxy}methyl)phenyl]ethanone or a pharmaceutically acceptable salt thereof.
Research in the area of allergic reactions of the lung has provided evidence that arachidonic acid derivatives formed by the action of lipoxygenases are related to various disease states. Some of these arachidonic acid metabolites have been classified as members of a family of eicosatetraenoic acids termed leukotrienes. Three of these substances are currently thought to be major components of what has been previously called slow reacting substance of anaphylaxis (SRS-A).
It is the object of this invention to provide novel chemical agents which are selective leukotriene antagonists that can be used therapeutically in the treatment of allergic disorders such as asthma, where leukotrienes are thought to be causal mediators.
This invention provides for compounds of the Formula I ##STR1## and pharmaceutically acceptable salts thereof, wherein: R1 is hydrogen, C1 -C6 alkyl, C3 -C8 cycloalkyl, phenyl-substituted-(C1 -C3 alkyl), phenyl, or phenyl substituted with a halo, C1 -C4 alkyl, or C1 -C4 alkoxy functionality;
R2 is C1 -C10 alkyl, C2 -C6 alkenyl, benzyl, or 2-phenylethyl;
R3 is hydrogen, bromo, or chloro; ##STR2## straight or branched chain C1 -C4 alkylidene; Q is a bond or straight or branched chain C1 -C4 alkylidene;
R4 is COR9, 5-tetrazolyl, or 3-(1,2,5-thiadiazolyl); where
each R is independently hydrogen, C1 -C3 alkyl, or C1 -C4 alkanoyl;
each R5 and R6 is independently hydrogen, C1 -C3 alkyl, phenyl, or benzyl;
each R7 and R8 is independently hydrogen, C1 -C4 alkoxy, halo, hydroxy, amino, nitro, or C1 -C4 alkyl; and
R9 is hydroxy or C1 -C4 alkoxy.
Further provided by this invention is a method for treating immediate hypersensitivity conditions such as asthma, using compounds of Formula I above and pharmaceutical formulations for these compounds.
The present invention relates to new organic compounds that are useful in the treatment of immediate hypersensitivity reactions. A preferred group of compounds are the compounds of Formula I wherein:
(a) R1 is C1 -C6 alkyl, especially methyl,
(b) R2 is C1 -C6 alkyl, especially propyl,
(c) R3 is hydrogen,
(d) R5 is hydrogen,
(e) R6 is hydrogen,
(f) Z is ##STR3## --NH--, or especially --O--, (g) A is --O--, --CO--, or --CHOH--, and
(h) R4 is --COOH or 5-tetrazolyl.
An especially preferred group of compounds are those of Formula Ia: ##STR4## and pharmaceutically acceptable salts thereof wherein: R2 ' is C1 -C6 alkyl, especially propyl; and
A' is --O--, --CO--, or --CHOH--.
The following definitions refer to the various terms used throughout this disclosure.
The term "C1 -C10 alkyl" refers to the straight and branched aliphatic radicals of 1 to 10 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, amyl, isoamyl, sec-amyl, sec-isoamyl (1,2-dimethylpropyl), tert-amyl (1,1-dimethylpropyl), hexyl, isohexyl (4-methylpentyl), sec-hexyl (1-methylpentyl), 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 1,2,2-trimethylpropyl, 1,1,2-trimethylpropyl, heptyl, isoheptyl (5-methylhexyl), sec-heptyl (1-methylhexyl), 2,2-dimethylpentyl, 3,3-dimethylpentyl, 4,4-dimethylpentyl, 1,2-dimethylpentyl, 1,3-dimethylpentyl, 1,4-dimethylpentyl, 1,2,3-trimethylbutyl, 1,1,2-trimethylbutyl, 1,1,3-trimethylbutyl, octyl, isooctyl (6-methylheptyl), sec-octyl (1-methylheptyl), tert-octyl (1,1,3,3-tetramethylbutyl), nonyl, 1-, 2-, 3-, 4-, 5-, 6-, or 7-methyloctyl, 1-, 2-, 3-, 4-, or 5-ethylheptyl, 1-, 2-, or 3-propylhexyl, decyl, 1-, 2-, 3-, 4-, 5-, 6-, 7-, or 8-methylnonyl, 1-, 2-, 3-, 4-, 5-, or 6-ethyloctyl, 1-, 2-, 3-, or 4-propylheptyl, and the like. The term "C1 -C10 alkyl" includes within its definition the terms "C1 -C3 alkyl", "C1 -C4 alkyl", and "C1 -C6 alkyl".
The term "C3 -C8 cycloalkyl" refers to the saturated alicyclic rings of three to eight carbon atoms such as cyclopropyl, methylcyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclooctyl, and the like.
The term "C2 -C6 alkenyl" refers to straight and branched radicals of two to six carbon atoms such as ethenyl, allyl, isopropenyl, butenyl, isobutenyl, 3-methyl-2-butenyl, n-hexenyl, and the like.
The term "halo" refers to fluoro, chloro, bromo, and iodo. The term "C1 -C4 alkoxy" refers to straight and branched alkoxy radicals of up to four carbon atoms, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, and the like.
The term "C1 -C4 alkylidene" refers to straight and branched chain divalent alkyl radicals of one to four carbon atoms such as --CH2 --, --CH2 CH2 --, --CH(CH3)--, --C(CH3)2 --, --CH(CH3)CH2 --, --CH(CH3)CH(CH3)--, --CH2 CH2 CH2 --, --CH(CH3)CH2 CH2 --, --CH2 CH(CH3)CH2 --, and the like.
The term "C1 -C4 alkanoyl" refers to formyl, acetyl, propionyl, butanoyl, and isobutanoyl.
The pharmaceutically acceptable base addition salts of this invention include salts derived from inorganic bases, such as ammonium and alkali and alkaline earth metal hydroxides, carbonates, bicarbonates, and the like, as well as salts derived from basic organic amines, such as aliphatic and aromatic amines, aliphatic diamines, hydroxy alkylamines, and the like. Such bases useful in preparing the salts of this invention thus include ammonium hydroxide, potassium carbonate, sodium bicarbonate, calcium hydroxide, methylamine, diethylamine, ethylenediamine, cyclohexylamine, ethanolamine, and the like. The potassium and sodium salt forms are particularly preferred.
It is recognized that if R5 is different from R6, alkyl or alkylidene functionalities are branched, etc., various stereoisomers will exist. This invention is not limited to any particular stereoisomer but includes all possible individual isomers and racemates of the compounds of Formula I.
Some of the compounds of this invention may be prepared by the reaction of a compound of the Formula II ##STR5## wherein Za is --O--, --NR--, or --S--, with a compound of the formula III ##STR6## wherein X is a suitable leaving group, such as halo, preferably chloro, and D is --R4, a precursor of --R4, halo, cyano, or a protected acid ester such as a benzhydryl ester. This procedure is useful in preparing the compounds of this invention designated by Formula I' ##STR7## either directly (when D is --R4) or indirectly from intermediates IV ##STR8## wherein D' is a precursor to --R4, halo, cyano, or a protected acid ester.
The reaction between compounds II and III is usually performed employing equimolar amounts although ratios other than equimolar amounts are completely operative. The reaction is best carried out in a nonreactive solvent such as ketones, especially acetone or methyl ethyl ketone, or dimethylformamide, and in the presence of a base, preferably an alkali metal hydroxide or carbonate, preferably potassium carbonate. Especially when X is chloro, a catalyst such as potassium or sodium iodide may be added to increase the reaction rate. The reaction may be carried out at temperatures of about ambient temperature up to the boiling point of the reaction mixture, the latter being preferred.
In the case where D(D') is cyano, the resulting intermediate IV may be converted to the compounds of this invention by the following methods. Compounds of Formula I' wherein R4 is --COOH may be obtained by hydrolysis of the intermediate cyano derivative. This is generally accomplished by heating the cyano derivative in aqueous alcohol in the presence of a base such as sodium hydroxide. Alternatively, the carboxylic acid derivatives (I', R4 is --COOH) may be prepared by the hydrolysis of the corresponding ester derivatives. This may be accomplished by an aqueous hydrolysis as described above or, especially in the case of a diphenylmethyl (benzhydryl) ester, using methods known in the art such as treating with formic acid and triethylsilane followed by an aqueous workup, acidic hydrolysis, treatment with trifluoroacetic acid in anisole, or catalytic hydrogenation. The required benzhydryl ester starting materials (III, D is a benzhydryl ester) may be prepared from the corresponding carboxylic acids (III, D is --COOH) in the usual ways, such as treatment with diphenyldiazomethane in methylene chloride or heating with benzhydrol and a mineral acid in a solvent such as toluene with the azeotropic removal of water. The compounds of Formula I' wherein R4 is --COO(C1 -C4 alkyl) may be prepared by conventional methods of esterification from the respective acid derivatives or are prepared directly by the methods described below. Salts may be prepared by treating the corresponding acids (R4 is --COOH) with an appropriate base in the normal manner.
The compounds of Formula I' wherein R4 is 5-tetrazolyl are prepared by treating the cyano intermediate with an alkali metal azide such as sodium azide, ammonium chloride, and (optionally) lithium chloride in a non-reactive high-boiling solvent such as N,N-dimethylformamide, preferably at temperatures from 60� C. to the reflux temperature of the reaction mixture. Alternatively, tri-n-butyltin azide or tetramethylguanidinium azide may be used in place of the alkali metal azide, ammonium chloride, and lithium chloride. It is preferred that the tetrazole functionality be introduced from the corresponding cyano group as one of the last, if not the last, step of the chemical sequence.
When employing intermediate III wherein D is halo, those skilled in the art will recognize that dihalo intermediate III is non-symmetrically substituted and that X should be a better leaving group than D in order for the desired product IV to be formed. If D is the better leaving group in compound III, III can first be converted to a different intermediate III (e.g., reaction of III (D is halo) with an alkali metal cyanide to give III (where D is --CN)) which can then be reacted with compound II as previously described.
The compounds of Formula IV wherein D' is halo may be transformed into the compounds of this invention in the following manner. When compounds of Formula IV (D' is halo) are heated with an alkali metal cyanide, such as sodium cyanide, in the presence of a high boiling, nonreactive solvent, such as N,N-dimethylformamide, at elevated temperatures (50� C. to the reflux temperature of the solvent), the intermediate cyano compound of Formula IV (D' is cyano) is produced which may then be transformed into the acid, ester, or tetrazole derivatives as described previously.
Alternatively, I' may be prepared by reacting the appropriate benzyl derivative V ##STR9## with a derivative of Formula VI ##STR10## to give compounds I' directly or indirectly through intermediate IV.
Other compounds of Formula I are prepared in a similar manner as taught for the compounds of Formula I'. The compounds of Formula I are prepared directly or indirectly by treating a bromo-compound of the Formula VII ##STR11## with a strong base, such as lithium diisopropylamide, in an inert solvent, such as diethyl ether, at low temperatures, preferably -20� to 0� C., to prepare the lithium salt of VII which is then reacted with III' ##STR12## to provide compounds I directly (when D is --R4) or intermediates VIII. ##STR13## Compounds VIII can then be transformed into I by the same methods of transformation as previously described for converting compounds IV into I'.
The benzhydrol derivatives (A═--CHOH) are readily prepared by reduction of the corresponding benzophenones (A═C═O) by reduction with sodium borohydride. The benzhydrol derivative can be alkylated or acylated by conventional means to form the alkoxy and acyloxy derivatives (A═CHOR). The various amine functionalities (Z or A═NH) may similarly be alkylated or acylated to provide the corresponding alkyl and acyl derivatives. As will be apparent to those skilled in the art, the order of such transformations, upon final products or intermediates thereto, may depend upon the presence of other functional groups.
The 3-(1,2,5-thiadiazoles) of this invention can be prepared by reacting intermediates corresponding to III, I', VI, VIII, and the like where R4 or D is --CH(NH2)CONH2 with N-methyl-N-(trimethylsilyl)trifluoroacetamide and thionyl chloride. Once again, the preparation and transformation of such amino acid related intermediates are known to skilled artisans.
The thio derivatives and intermediates of this invention (p is 0) may be transformed into the corresponding sulfoxide (p is 1) compounds upon treatment with a mild oxidizing agent, such as hydrogen peroxide in methanol or an alkali metal periodate in aqueous alcohol. The corresponding sulfones (p is 2) are prepared from the thio or sulfoxide compounds on treatment with a strong oxidizing agent such as hydrogen peroxide in acetic acid or m-chloroperbenzoic acid in methanol.
In addition, various compounds of Formula I can be prepared from other compounds, precursors, or intermediates of Formula I by standard methods such as hydrolysis, esterification, alkylation, oxidation, reduction, aminolysis, halogenation, and the like, as are well known to those skilled in the art. In the prior discussion, the terms "precursors" and "precursor to --R4 " mean those compounds, either related to the final compounds I or any intermediates or starting materials, which can be transformed into the desired functionality --R4. These include the cyano intermediates and intermediates which may be transformed into the title products by any of the above mentioned methods known to those skilled in the art.
Intermediates II and V are disclosed in European Patent Application Publication No. 132,366 which is expressly incorporated into this application by reference. All other intermediate compounds and necessary reagents are either commercially available, known in the literature, or can be prepared according to methods known in the art.
As is well known in the art, the R3 chloro and bromo derivatives may be prepared by halogenation of the corresponding hydrogen compounds (R3 is hydrogen) of this invention (I) or of the intermediates XV.
The following preparations and examples further illustrate the preparation of the starting materials, intermediates, and compounds of the invention. The examples are illustrative only and are not intended to limit the scope of the invention. Where structures were confirmed by infra-red or proton nuclear magnetic resonance analysis, the compound is so designated by "IR" and/or "NMR", respectively.
A mixture of 50 g. of 3-cyanobenzoic acid and 100 ml. of thionyl chloride were stirred overnight in 500 ml. of methylene chloride. The solvent and excess thionyl chloride were removed in vacuo providing 55.3 g. of crude subtitle intermediate which was used without further purification.
Analysis for C8 H4 ClNO: Calculated: C, 58.03; H, 2.44; N, 8.46; Found: C, 58.24; H, 2.61; N, 8.26.
Under a nitrogen atmosphere, 16.5 g. of 3-cyanobenzoyl chloride were added to 80 ml. of methylene chloride. The temperature was brought to approximately 0� C. by means of an external ice bath and kept cold while 20 g. of aluminum chloride were added in portions. A solution of 10.8 g. of anisole in 20 ml. of methylene chloride were added to the reaction solution. The mixture was allowed to warm to room temperature and stirred overnight. The mixture was poured into a mixture of ice water/hydrochloric acid and extracted with ethyl acetate. The layers were separated and the organic layer was washed with water, dried, and concentrated in vacuo. The residue was crystallized from toluene/hexane to which a small amount ethyl acetate had been added to provide 7.7 g. of the desired subtitle intermediate, m.p. 85�-88� C.
Analysis for C15 H11 NO2 : Calculated: C, 75.94; H, 4.67; N, 5.90; Found: C, 75.88; H, 4.83; N, 5.99.
C. Preparation of 4-(3-cyanobenzoyl)phenol.
To a solution of 7 g. of 4-(3-cyanobenzoyl)anisole and 75 ml. of methylene chloride were added 11.8 g. of aluminum chloride. The reaction was stirred overnight at room temperature and then heated at reflux for 24 hours. The cooled reaction mixture was poured into ice water/hydrochloric acid and extracted with ethyl acetate. The layers were separated and the organic layer was washed with water, dried, and concentrated in vacuo. The residue was crystallized from toluene/hexane to which a small amount ethyl acetate had been added to provide 5.3 g. of the desired subtitle intermediate, m.p. 153�-157� C.
Analysis for C14 H9 NO2 : Calculated: C, 75.33; H, 4.06; N, 6.27; Found: C, 75.10; H, 4.07; N, 6.22.
Under a nitrogen atmosphere, 1.96 g. of potassium t-butoxide was stirred at room temperature in 50 ml. of ethanol. Five grams of the intermediate from Example 1C were added followed by the addition of 3.39 g. of 4-acetyl-3-hydroxy-2-propylbenzyl chloride and 2.25 g. of sodium iodide. The reaction was stirred at room temperature for 4 days. Two hundred milliliters of water were added, the solution was acidified with hydrochloric acid, and, after 2 hours, the resulting precipitate was recovered by filtration. The solid was dissolved with ethyl acetate, dried, and concentrated in vacuo. The residue was dissolved in toluene containing a small amount ethyl acetate and hexane was added. The resulting precipitate was recovered by filtration and purified by high pressure liquid chromatography over silica gel eluting with 9:1 toluene/ethyl acetate providing 3.6 g. of the desired subtitle intermediate, m.p. 146�-148� C.
Analysis for C20 H23 NO4 : Calculated: C, 75.72; H, 5.61; N, 3.38; Found: C, 76.34; H, 5.79; N, 3.46.
A mixture of 3.5 g. of the nitrile of Example 1D and 13.28 g. of tri-n-butyltin azide were heated at reflux in glyme for 3 days. The cooled reaction mixture was poured into acidified ice water and stirred for 1 hour. The mixture was extracted with ethyl acetate and the organic layer was washed with water, dried, and concentrated in vacuo. Purification by high pressure liquid chromatography over silica gel eluting with 9:1 methylene chloride/methanol to which 0.5% acetic acid had been added to provide 2.5 g. of the title product, m.p. 208�-214� C. Recrystallization from ethyl acetate/hexane provided material having the following analysis.
Analysis for C26 H24 N4 O4 : Calculated: C, 68.41; H, 5.30; N, 12.27; Found: C, 68.18; H, 5.48; N, 12.13.
The following compounds were prepared from the corresponding nitrile according to the procedure of Example 1E.
2. 1-[2-Hydroxy-3-propyl-4-({4-[4-(1H-tetrazol-5-yl)-benzoyl]phenoxy}methyl)phenyl]ethanone,
54% yield, m.p. 185�-188� C.
Analysis for C26 H24 N4 O4 : Calculated: C, 68.41; H, 5.30; N, 12.27; Found: C, 66.38; H, 5.56; N, 11.70.
3. 1-{2-Hydroxy-4-[(4-{hydroxy[3-(1H-tetrazol-5-yl)-phenyl]methyl}phenoxy)methyl]-3-propylphenyl}ethanone,
75% yield, m.p. 152�-155� C.
Analysis for C26 H26 N4 O4 : Calculated: C, 68.11; H, 5.72; N, 12.22; Found: C, 68.24; H, 6.00; N, 11.92.
4. 1-[2-Hydroxy-3-propyl-4-({4-[4-(1H-tetrazol-5-yl)-phenoxy]phenoxy}methyl)phenyl]ethanone,
81% yield, m.p.=177�-180� C.
Analysis for C25 H24 N4 O4 : Calculated: C, 67.55; H, 5.44; N, 12.60; Found: C, 67.67; H, 5.72; N, 12.38.
5. 1-[2-Hydroxy-3-propyl-4-({4-[3-(1H-tetrazol-5-yl)-phenoxy]phenoxy}methyl)phenyl]ethanone,
19% yield, m.p.=60�-70� C. (glass).
Analysis for C25 H24 N4 O4 : Calculated: C, 67.55; H, 5.44; N, 12.60; Found: C, 66.35; H, 5.72; N, 11.94.
The compounds of Formula I should be useful in treating any condition, including clinical conditions, which is characterized by excessive release of leukotrienes C4, D4, or E4. These conditions include immediate type hypersensitivity reactions such as asthma. Evidence obtained over the past few years has shown the presence of leukotrienes in sputum of patients with chronic bronchitis (Turnbull, et al., Lancet II, 526 (1977)) and cystic fibrosis (Cromwell, et al., Lancet II, 164 (1981)), suggesting a role of leukotrienes in the pathology of those diseases. Furthermore, Lewis and colleagues [Int. J. Immunopharmacology, 4, 85 (1982)] have recently detected material in rheumatoid synovial fluid that reacts antigenically with antibody to LTD4. This may hallmark the existence of leukotriene permeability factors that, together with LTB4, augment the inflammatory process in the diseased joints. Therefore, the compounds described in this invention should also alleviate some of the symptoms of chronic bronchitis and cystic fibrosis and possibly rheumatoid arthritis by virtue of their ability to antagonize leukotrienes.
The term "excessive release" of leukotrienes refers to an amount of leukotrienes sufficient to cause the particular condition associated with such amount. The amount of leukotriene which is considered to be excessive will depend on a variety of factors, including the specific leukotriene(s) involved, the amount of leukotriene required to cause the particular condition, and the species of the mammal involved. As will be appreciated by those skilled in the art, the success of treating a mammal suffering from or susceptible to a condition characterized by an excessive release of leukotrienes with a compound of formula I will be measured by the regression or prevention of the symptoms of the condition.
Leukotriene antagonism was demonstrated by the following test procedure:
Male, Hartley guinea pigs weighing 200-450 grams were killed by decapitation. A section of terminal ileum was removed, the lumen cleaned, and the tissue divided into 2.5 cm. segments. The ilea were mounted in 10 ml. tissue baths containing Krebs-bicarbonate solution of the following composition in mmoles/liter: KCl, 4.6; CaCl2.2H2 O, 1.2; KH2 PO4, 1.2; MgSO4.7H2 O, 1.2; NaCl, 118.2; NaHCO3, 24.8; and dextrose, 10.0. The bath fluid was maintained at 37� C. and aerated with 95 percent oxygen and 5 percent CO2. In addition, the buffer contained 1�10-6 M atropine to reduce ileal spontaneous activity. Isometric measurements were made with a Grass FTO3C force-displacement transducer and recorded on a Grass polygraph as change in grams of force. A passive force of 0.5 g. was applied to the tissues. After an appropriate equilibration period, single submaximal control responses to pure LTD4 were obtained. Following a five minute exposure of the ileum to an experimental drug, the control concentration of LTD4 was added to the tissue bath. The response of the ileum to LTD4 in the presence of the drug was compared to the response in the absence of the drug. Various degrees of LTD4 antagonism were obtained using 2-4 different concentrations of an experimental compound on a single ileum. The antagonist concentration that produced 50% inhibition of the LTD4 responses (-log IC50) was interpolated from these data using linear regression.
The testing of the compounds of Formula I in these two procedures is summarized in Table I.
TABLE I__________________________________________________________________________Percent inhibition of LTD4 evoked ileal contractionsCompoundofExample Compound ConcentrationNo. 3 � 10-7 M 1 � 10-7 M 3 � 10-8 M 1 � 10-8 M 3 � 10-9 M 1 � 10-9 -log IC50__________________________________________________________________________1 98% 80% 53% 21% 8.582 72% 32% 8.293 81% 75% 40% 7.894 80% 53% 25% 7.08__________________________________________________________________________
The compounds or formulations of the present invention may be administered by the oral and rectal routes, topically, parenterally, e.g., by injection and by continuous or discontinuous intra-arterial infusion, in the form of, for example, tablets, lozenges, sublingual tablets, sachets, cachets, elixirs, suspensions, aerosols, ointments, for example, containing from 1 to 10% by weight of the active compound in a suitable base, soft and hard gelatin capsules, suppositories, injectable solutions and suspensions in physiologically acceptable media, and sterile packaged powders adsorbed onto a support material for making injectable solutions. Advantageously for this purpose, compositions may be provided in dosage unit form, preferably each dosage unit containing from about 5 to 500 mg. (from about 5 to 50 mg. in the case of parenteral or inhalation administration, and from about 25 to 500 mg. in the case of oral or rectal administration) of a compound of Formula I. Dosages of from about 0.5 to 300 mg./kg. per day, preferably 0.5 to 20 mg./kg., of active ingredient may be administered although it will, of course, readily be understood that the amount of the compound or compounds of Formula I actually to be administered will be determined by a physician, in the light of all the relevant circumstances including the condition to be treated, the choice of compound to be administered and the choice of route of administration and therefore the above preferred dosage range is not intended to limit the scope of the present invention in any way.
The formulations of the present invention normally will consist of at least one compound of Formula I mixed with a carrier, or diluted by a carrier, or enclosed or encapsulated by an ingestible carrier in the form of a capsule, sachet, cachet, paper or other container or by a disposable container such as an ampoule. A carrier or diluent may be a solid, semisolid or liquid material which serves as a vehicle, excipient or medium for the active therapeutic substance.
Some examples of the diluents or carrier which may be employed in the pharmaceutical compositions of the present invention are lactose, dextrose, sucrose, sorbitol, mannitol, propylene glycol, liquid paraffin, white soft paraffin, kaolin, fumed silicon dioxide, microcrystalline cellulose, calcium silicate, silica, polyvinylpyrrolidone, cetostearyl alcohol, starch, modified starches, gum acacia, calcium phosphate, cocoa butter, ethoxylated esters, oil of theobroma, arachis oil, alginates, tragacanth, gelatin, syrup, methyl cellulose, polyoxyethylene sorbitan monolaurate, ethyl, lactate, methyl and propyl hydroxybenzoate, sorbitan trioleate, sorbitan sesquioleate and oleyl alcohol and propellants such as trichloromonofluoromethane, dichlorodifluoromethane and dichlorotetrafluoroethane. In the case of tablets, a lubricant may be incorporated to prevent sticking and binding of the powdered ingredients in the dies and on the punch of the tableting machine. For such purpose there may be employed for instance aluminum, magnesium or calcium stearates, talc or mineral oil.
Preferred pharmaceutical forms of the present invention are capsules, tablets, suppositories, injectable solutions, creams and ointments. Especially preferred are formulations for inhalation application, such as an aerosol, and for oral ingestion.
The following formulation examples may employ as active compounds any of the compounds of this invention. The examples are illustrative only and are not intended to limit the scope of the invention in any way.
Hard gelatin capsules are prepared using the following ingredients:
______________________________________ Quantity (mg/capsule)______________________________________1-[2-hydroxy-3-propyl-4-({4-[3-(1H--tetrazol-5-yl)benzoyl]-phenoxy}methyl)phenyl]ethanonehydrochloride 250Starch 200Magnesium stearate 10______________________________________
The above ingredients are mixed and filled into hard gelatin capsules in 460 mg. quantities.
A tablet is prepared using the ingredients below:
______________________________________ Quantity (mg/tablet)______________________________________1-{2-hydroxy-4-[(4-{hydroxy[3-(1H--tetrazol-5-yl)phenyl]-methyl}phenoxy)methyl]-3-propylphenyl}ethanone sulfate 250Cellulose, microcrystalline 400Silicon dioxide, fumed 10Magneium stearate 5______________________________________
The components are blended and compressed to form tablets each weighing 665 mg.
An aerosol solution is prepared containing the following components:
______________________________________ Weight %______________________________________1-[2-hydroxy-3-allyl-4-({4-[4-(1H--tetrazol-5-yl)-1,6-dichlorobenzoyl]-phenoxy}methyl)phenyl]hexanone 0.25Ethanol 30.00Propellant 11 10.25(trichlorofluoromethane)Propellant 12 29.75(Dichlorodifluoromethane)Propellant 114 29.75(Dichlorotetrafluoroethane)______________________________________
The active compound is dissolved in the ethanol and the solution is added to the propellant 11, cooled to -30� C. and transferred to a filling device. The required amount is then fed to a container and further filled with the pre-mixed propellants 12 and 114 by means of the cold-filled method or pressure-filled method. The valve units are then fitted to the container.
Tablets each containing 60 mg. of active ingredient are made up as follows:
______________________________________1-[2-hydroxy-3-propyl-4-({4-[4-(1H--tetrazol-5-yl)phenoxy]phenoxy}-methyl)phenyl]ethanone 60 mg.Starch 45 mg.Microcrystalline cellulose 35 mg.Polyvinylpyrrolidone 4 mg.(as 10% solution in water)Sodium carboxymethyl starch 4.5 mg.Magnesium stearate 0.5 mg.Talc 1 mg.Total 150 mg.______________________________________
The active ingredient, starch and cellulose are passed through a No. 45 mesh U.S. sieve and mixed thoroughly. The solution of polyvinylpyrrolidone is mixed with the resultant powders which are then passed through a No. 14 mesh U.S. sieve. The granules so produced are dried at 50�-60� C. and passed through a No. 18 mesh U.S. sieve. The sodium carboxymethyl starch, magnesium stearate and talc, previously passed through a No. 60 mesh U.S. sieve, are then added to the granules which, after mixing, are compressed on a tablet machine to yield tablets each weighing 150 mg.
Capsules each containing 80 mg. of medicament are made as follows:
______________________________________2-hydroxy-3-ethyl-4-[{4-[4-(1H--tetrazol-5-yl)phenylsulfonyl]-phenylamino}methyl)benzophenone 80 mg.Starch 59 mg.Microcrystalline cellulose 59 mg.Magnesium stearate 2 mg.Total 200 mg.______________________________________
The active ingredient, cellulose, starch and magnesium stearate are blended, passed through a No. 45 mesh U.S. sieve, and filled into hard gelatin capsules in 200 mg. quantities.
Suppositories each containing 225 mg of active ingredient are made as follows:
______________________________________1-{2-hydroxy-3-methyl-4-[(4-{4-[4-(1H--tetrazol-5-yl)phenyl]butyl}-phenoxy)methyl]phenyl}ethanone 225 mg.Unsaturated or saturated fattyacid glycerides to 2,000 mg.______________________________________
The active ingredient is passed through a No. 60 mesh U.S. sieve and suspended in the fatty acid glycerides previously melted using the minimum heat necessary. The mixture is then poured into a suppository mold of nominal 2 g. capacity and allowed to cool.
Suspensions each containing 50 mg. of medicament per 5 ml. dose are made as follows:
______________________________________1-[2-hydroxy-3-isopropyl-5-chloro-4-({4-[2-(1H--tetrazol-5-yl)benzoyl]-phenylsulfinyl}methyl)phenyl]ethanone 50 mg.Sodium carboxymethyl cellulose 50 mg.Sugar 1 g.Methyl paraben 0.05 mg.Propyl paraben 0.03 mg.Flavor q.v.Color q.v.Purified water to 5 ml.______________________________________
The medicament is passed through a No. 45 mesh U.S. sieve and mixed with the sodium carboxymethylcellulose, sugar, and a portion of the water to form a suspension. The parabens, flavor and color are dissolved and diluted with some of the water and added, with stirring. Sufficient water is then added to produce the required volume.
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In search of Hill Farmstead beers. Have never had any so I'd be open to almost anything.
I have a barrel aged Kopi speedway stout, I think about 750-800 bottles were released.
I could expand if we were talking about a big trade. I'm from Cleveland, Ohio. So if any beers I get in distro interest you then let me know, and also if you had an Ann or Mimosa I would be most generous, of course.
Pm me with any questions.
This is closed.

subset: commoncrawl


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Impossibility Challenger seeks to inspire people from all walks of life to experience the spirit of self-transcendence in a unique way. It serves as a platform for anyone who wants to push the limits of human possibility and tries to establish a new World Record or personal record in non-Olympic disciplines. Impossibility Challenger is sponsored by the Sri Chinmoy Center and was first organized in Zurich, Switzerland in 1982. From 2002 to 2010 in took place in Munich, Germany and later also in New Zealand and Hungary.
This year's Impossibility Challenger will take place on 6th and 7th of December in the Stadium of Leiria, Leiria city, Portugal. Impossibility Challenger os sponsored by the Sri Chinmoy Centers. The City Hall of Leiria sponsors the Stadium and welcomes the realization of the event.
Image from Leiria stadium
If you are interested to partcipate with a record, please fill out the application form. If you plan to try a Guinness World Record you need to get in touch with the Guinness Book of Records www.guinnessworldrecords.com approx. 8-10 weeks before your attempt, to learn about their rules and regulations. New records can also be published at www.recordholders.org, a record holder club founded by Ralf Laue in Germany
On 7 December between 9 and 11:30 there will be an attempt to break a Guinness Record for the most people doing Laughter Yoga together lead by a Yoga teacher from Portugal.
We are looking for 13.000 people who would like to participate this laughter record in the stadium of Leiria.
Participation in this record is free of charge. :-)
Here is a special link to sign for participating in the record, and everybody is welcome.
For those seeking a place to stay here is a list of sugestions for the city of Leiria.
During the last 12 years the Impossibility Challenger featured even Ashrita Furman with several records. Ashrita is THE man in the world with the most Guinness World records. He established over 500 Guinness World Records and currently still holds over 200.
Ashrita Furman breaking the record on Longest Time Balancing on Swiss Ball (Stonehenge)
Some vídeos from previous editions of impossibility Challenger:
1986 a 1991
Biggest ballon hat in the world and fastest mile in a shopping car. :-)
Vídeo of Impossibility Challenger from 2012 edition in Hungary
© 2014 Impossibility Challenger.


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Beaverton's Features
November 20, 2014
Put a bird on it - or maybe 5,000 of them
Man aiming for species-spotting record part of Wild Arts fest Noah Strycker has lived for months at a time in some of the most remote places on Earth Antarctica, Costa Rica, the Galapagos…
November 20, 2014
Meals on Wheels People hosts Thanksgiving dinners
Meals on Wheels People will deliver more than 1,000 turkey dinners to homebound seniors on Thanksgiving Day. The organization will also host community Thanksgiving dinners at several locations…
November 08, 2014
World War II talk coming up at Washington County Museum
Local historian Sig Unander will be presenting a documentary about the forgotten heroes of World War II, The Aztec Eagles, an elite corps of Mexican Air Force pilots who flew missions for the…
November 05, 2014
It's raining: Time to go newt exploring
Tualatin Hills Nature Park hosts Newt Day activities on Saturday Rain or shine, Newt Day returns to the Tualatin Hills Nature Park on Saturday from noon to 4 p.m. at the Nature Park Interpretive…
November 05, 2014
Community events honor Veterans Day
Special programs invite public to pay tribute Families looking to honor veterans can participate in an array of community celebrations marking Veterans Day. Here are a few events close to home:…
November 01, 2014
World War I anniversary inspires new exhibit
All military veterans get in free to Washington County Museum in November The donation of a World War I uniform worn by Washington County resident William Crandalls father, Sgt. John Crandall,…
October 30, 2014
The patient photographer
Loren Nelson's photography exhibit steps back in time through the perspective of a blacksmith shop established in 1890 Virtually untouched since its doors closed for business in 1962, the…
October 30, 2014
Does your group want to perform?
Bridgeport Village recently announced a new program called Season of Sounds. This program will give school choirs, bands and theater groups the chance to perform at Bridgeport Village in…
October 30, 2014
Military veterans are invited to special patriotic tribute
Tigard High hosts early Veteran's Day celebration on Nov. 7 Tigard High Schools leadership class invites all veterans to its annual recognition ceremony Friday, Nov. 7, to honor all those who…
October 29, 2014
Zoo comedy night is going to the animals
Event supports Portland Audubon and Tanzanian Carnivore Project Cackling geese, laughing hyenas and hard-to-amuse humans all stand to benefit from the Oregon Zoos second annual comedy night…
Oct 25, 2014
State seeks input on senior issues and disability concerns
The state of Oregon wants to hear from people about the services it should be providing for seniors and people with disabilities. Aging and People with Disabilities, a division of the Oregon…
Oct 24, 2014
Westside Economic Alliance welcomes Bonamici, Schrader
U.S. Rep. Suzanne Bonamici will be in Tigard next week to discuss her plans for the 114th Congress. The Oregon Democrat from Beaverton will speak at the Westside Economic Alliances breakfast…
Oct 23, 2014
The greatest pumpkin of all
West Coast Giant Pumpkin Regatta was record setting and a sight to behold I didn't know you could ride in a pumpkin, one woman said to another as they walked around the perimeter of Tualatin's…
Oct 23, 2014
Irish music takes spotlight in intimate concert
Music in Small Spaces is Saturday in Beaverton library Music in Small Spaces, sponsored by the Beaverton Arts Commission, presents "An Afternoon of Irish Music" on Saturday at 2 p.m. in the…
Oct 23, 2014
PCC Rock Creek hosts Harvest Festival
Hay rides, pumpkins and more are on tap for Saturday event Need a pumpkin? No problem. Portland Community Colleges Rock Creek Campus is hosting its annual Harvest Festival from 10 a.m. to 2…
Oct 23, 2014
Women take to silks in 'Frida'
Pendulum Aerial Arts reunites trio of talented performers Pendulum Aerial Arts presents Frida A Rare Evening of Women in Circus with special guest artists French aerial pioneer Fred Deb and…
Oct 18, 2014
Blitzen Trapper tips hat to Neil Young classic at Doug Fir Lounge
Taxed voices aside, band nobly navigates twists of "Harvest" album Blitzen Trapper's good-hearted gesture to add a second, all-ages show on Friday evening at Doug Fir Lounge nearly cost…
Oct 17, 2014
Cedar Mill Cider Festival returns Sunday
Community event offers festive food, music and fun for all The Tualatin Hills Park and Recreation District will host the eighth annual Cedar Mill Cider Festival on Sunday from 1 to 4 p.m. at the…
Oct 17, 2014
Finding their sound
Marianna Thielen and Reece Marshburn create music and perform as The Bylines, they have a show this Saturday, Oct. 18 Marianna Thielen and Reece Marshburn didnt want to be that couple the…
Oct 17, 2014
Artists share insight into creative process
Washington County Open Studios tour is this weekend The fifth annual Washington County Open Studios art tour returns this weekend, with dozens of artists ready to showcase their creations. The…


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Stocks edge higher as Syria, oil worries lingerBy KEN SWEET
tHE aSSOCIATED pRESS | August 29,2013AP Photo
Trader Gregory Rowe, left, works on the floor of the New York Stock Exchange.NEW YORK (AP) The stock market edged higher Wednesday as investors continued to focus on the likelihood of a U.S.-led attack on Syria.
The Dow Jones industrial average rose 68 points, or 0.5 percent, to 14,844 in early afternoon trading. The Standard & Poors 500 index gained nine points, or 0.5 percent, to 1,639. The Nasdaq composite rose 26 points, or 0.7 percent, to 3,605.
The escalating tensions between the U.S. and Syria hit the stock market hard Tuesday, sending the Dow down 170 points. Traders pushed gold to a three-month high and crude oil rose to its highest level in a year and a half.
The quick rise in the price of oil has worried investors. Costlier oil almost always translates into higher fuel expenses for businesses and consumers, weighing on consumer spending and the economy. While Syria produces little oil, a regional conflict in the Middle East could lead to supply disruptions in an area where half the worlds proven oil reserves lie.
When you add it all up -- the problems in Libya, Egypt, Syria -- youre looking to 3 million barrels a day in potential production outages, said Nick Koutsoftas, a commodities-focused portfolio manager at Cohen & Steers.
Oil rose $1.03, or 0.9 percent, to $110.03 a barrel. It went as high as $112 a barrel overnight.
Energy companies were among the biggest gainers in the S&P 500. Shares of oil producer EOG Resources rose $4.39, or 3 percent, $160.66. Dow component Chevron climbed $3.04, or 2.6 percent, to $121.80.
While the selling in stocks appears to have abated for now, the overall trend for the market has been down over the last couple of weeks. The S&P 500 has lost 4.6 percent since reaching an all-time high on Aug. 2, while the Dow is down 5.6 percent. Fund managers said investors will have little reason to enter the market until next weeks employment report or until the Federal Reserve holds its mid-September policy meeting.
You may be watching stock prices, but youre not placing any orders in this market, said Chris Hyzy, chief investment officer at U.S. Trust.
Before Syria grabbed the headlines, the focus had been on the Federal Reserve and whether the central bank was going to pull back on its massive bond-buying program, which has kept interest rates extremely low.
If oil prices remain at these elevated levels, the Fed may have to delay easing back on its bond purchases, said Quincy Krosby, market strategist with Prudential Financial.
The Fed would see higher oil prices, particularly if they linger at these higher levels, as a definite hindrance to employment and consumer spending, Krosby said.
Hyzy said oil would have to rise above $125 a barrel before it has a noticeable impact on consumer spending. Cohen & Steers Koutsoftas said he believes the U.S. consumer has gotten used to higher fuel costs, and oil would have to go to $150 a barrel before it might impact consumer behavior.
The Syria standoff comes during what is typically a quiet week for stocks. There is little economic data being released and only a handful of corporate earnings. Its also the week before Labor Day, when many on Wall Street are on vacation. Volume on the New York Stock Exchange on Monday was the lowest of any full day of trading this year.
The next big day for the market will come next week, when investors get the August jobs report on Sept. 6, Hyzy and Krosby said.MORE IN National / World BusinessDr. Timothy Houchin became the medical director for Rutland Mental Health Services on Oct. 31. Full StoryChristmas music serenaded visitors as they trickled in to the Franklin Conference Center at the... Full StoryIt's time for a head start on the end-of-the-year predictions. Full Story
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- RICHARD'S POOR ALMANACK: In 1944, U.S. begins B-29 bombing raids on Japanese main islands; in 1950, Great Appalachian Storm begins to form; 1963, Lee Oswald killed by Jack Ruby; 1974, D.B. Cooper hijacks Seattle-bound airliner; 1974, 'Lucy' found.
- RICHARD'S POOR ALMANACK: On this day in 1927, striking Colo. miners attacked with machine guns by state police; 1877, Thomas Edison announces invention of the phonograph, 1959, Alan Freed fired by WABC 770 AM for accepting payola to promote records.
- RICHARD'S POOR ALMANACK: On this day in 1863, President Abraham Lincoln delivers short speech in Gettysburg, Pa.; in 1984, a Pemex LNG facility destroyed by series of gas explosions, 600 people are killed; in 1998, Senate builds fire under Bill Clinton.
- RICHARD'S POOR ALMANACK: On this day in 1831 – Independent South American super-state, Gran Colombia, dissolved; 1856 - Fort Buchanan built to control Apache warriors; 1970 - William Calley Jr. goes on trial after 1968 massacre at My Lai, Vietnam.
- RICHARD'S POOR ALMANACK: Wisconsin Sen. Joe McCarthy takes advantage of Cold War jitters and builds a tidy little fiefdom for himself on Capitol Hill. It's all good, but pride goes before you know darn well what. The junior senator is damaged going down.
- RICHARD'S POOR ALMANACK: On this day in 1927, Leon Trotsky is expelled from the Soviet Communist Party, leaving Joseph Stalin in control of the Soviet Union; in 1970, Oregon DOT tries to dynamite a dead whale off a beach with a rather shocking result.


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A Natural Portrait Photographer
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About MeHi I am a 21 year old business and marketing student studying in London. I am looking to build my portfolio so am looking to work with photographers who are also wishing to do the same in a mutually beneficial arrangement. I am open minded about shoot ideas (implied nudity but no nipples or pubic area) however I believe I have a more commercial look (uk size 10-12) rather than high fashion/editorial.
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Fantage Cheats, Secrets, Glitches, Info & Help.
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Witchme | Cheats | Glitches | Secrets
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The Taboo Naughty but Nice Sex Show was held at the Edmonton Expo Centre on Nov. 23, 2014.
The crisis inside the Wildrose party grew deeper Monday as two MLAs crossed the floor to join the Progressive Conservatives.
Think of cancer as a wound refusing to heal. Malignant cells are inflamed. The body tries to mend itself, but the response doesn't just fail, it speeds the growth and spread of the cancer. Chemotherapy or radiation attacks the tumour, but the body resists, doubling and redoubling efforts to bolster the very cells that will eventually kill it.


text: In Pictures: 25 essential business apps for iPhone 5 The iPhone 5 is here, so it's time to start loading it up with apps. Jeff Vance (ARN) 0 - - - - print email prev next Loading... FlipboardRather than simply consolidating social media feeds as many aggregators do, Flipboard turns them into a "Social Magazine." Frankly, this app looks best suited to tablets, or to smartphones with gigantic screens, such as the Samsung Galaxy Note, but the concept is very cool regardless. Flipboard isn't solely focused on social media feeds. You can also pull in news feeds, travel deals and plenty more, all reformatted into a magazine-style layout that is easy to navigate and just plain looks good.Developer: FlipboardCost: FreeAvailable on Android too? Yes. It was just recently ported to Android, but recent reviews (and my own testing) find it to be glitchy and slow on Android. Prev Next 17/26 Comments on this image There are currently no comments for this image. Comments are now closed. Close In Pictures: 25 essential business apps for iPhone 5 26 images


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End WDFW's Kill Order!
The Huckleberry wolf pack is in trouble after Director of the Washington Dept. of Fish and Wildlife Phil Anderson issued a kill order on a third of its wolves.
Demand that WDFW rescinds this dastardly action against Washington wolves!
Take Action: Sign the Petition »
Thank you for your daily click for rainforest preservation. Together, over the past fourteen years, we have established protections for over 41,000 acres of rainforest habitat — that is huge!
But there is plenty more work to do. Rainforests are the lungs of our planet, and without them we will suffocate. Find out how you can do more to help us keep breathing through our charity partners!
Right whales of the North Atlantic are under constant threat, whether from commercial fishermen or energy-searching sonic blasters, and are in danger of losing their habitat. The NMFS agrees that something must be done in favor of these gorgeous creatures, but as of yet has refused to make a move. Tell Director Donna Wieting it's time for a change!
During that short period when fall becomes winter, chipmunks tend to get a bit competitive in the search for and storage of food. Some chipmunks are fully prepared for the winter, while others try to mooch off of the planners. When the two meet, the result is a storm or squeaks, squeals, and flying fur!
Click to see some amazing rodent acrobatics!


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Alan Kenneth Mackenzie Clark (13 April, 1928 - 5 September, 1999), the British Conservative politician, historian and diarist
Christopher Eric Hitchens (born April 13, 1949), the British-American author, journalist and literary critic
David Elliott Drew (born April 13, 1952) British politician
Frederick Frelinghuysen (April 13, 1753-April 13, 1804), the American lawyer, soldier, and statesman from New Jersey
George Jacob Holyoake (13 April 1817 - 22 January 1906), English secularist and co-operator, born in Birmingham, England
Evi is our best selling mobile app that can answer questions about local knowledge, weather, books, music, films, people and places, recipe ideas, shopping and much more. Over the next few months we will be adding all of Evi's power to this site.
Until then, to experience all of the power of Evi you can download her app for free on iOS, Android and Kindle Fire here.


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New Federal Courthouse Opens in Austin; $304M Apple Campus Underway
Austin's federal courthouse has found a new home in an eight-story, 252,420-square-foot building of stone and glass. Located in the downtown area, the $123 million project opened three years and three months since breaking ground in 2009. Sitting on the site of the old Shell building, the new facility features…Continue reading →
340 Luxury Apartments to be Built on South Lamar
South Lamar Boulevard is swarming with construction projects that will add circa 1,300 new apartments and more than 100,000 square feet of restaurants and shops south of downtown. One of these projects is developed by Hanover Co., which is expected to soon break ground on a luxury apartment project just…Continue reading →
Velocis Buys Two Austin Shopping Centers in $60M Deal
Dallas-based Velocis, a commercial real estate investment fund, recently purchased two Austin shopping centers totaling over 350,000 square feet of retail space. With the acquisition of West Woods Shopping Center and Springdale Shopping Center, Velocis now has circa $160 million of assets under management.…Continue reading →
Los Angeles Company Buys 2,044-unit Riata Apartment Complex in Northwest Austin
Los Angeles-based IMT Capital LLC, along with affiliate IMT Residential, has made its largest acquisition ever, closing a deal on the 2,044-unit Riata apartment complex. The deal represents one of the largest apartment portfolios ever sold in Austin, according to the Austin Business Journal. The portfolio had been on the…Continue reading →
AMLI Residential to Add 279-unit Building to Mueller Community
AMLI Residential has announced it will build a 279-apartment building at the Mueller master-planned community in Northeast Austin. The homebuilder expects to break ground on the mixed-use building in the first quarter of 2013, with the first units available in the third or fourth quarter of 2014, reports the Austin-American…Continue reading →
Apartment Project at RunTex Site Gets Green Light
The Austin City Council has recently approved a zoning change that allows developers to move ahead with a six-story apartment project worth $35 million in downtown Austin. Phoenix-based Alliance Residential Co. plans to build about 220 luxury apartments on the 1.53-acre site that is currently occupied by a RunTex store…Continue reading →
HID Global Picks Austin for $36M Plant
HID Global Corp. has chosen Austin for its new manufacturing and distribution facility. After months of negotiations, which began early this year, the identity security company announced the decision to build a 200,000-square-foot operations center in Northeast Austin. According to the Austin Business Journal, HID is expected to create 147…Continue reading →
Tezzaron Saves Austin Research Fab
Tezzaron Semiconductor Corp. has announced it will buy the wafer fabrication plant on Montopolis Drive in southeast Austin, preventing more than 100 layoffs. Formerly run by SVTC Technologies LLC, the plant is the only facility of its kind on the continent. According to J.T. Ayers, Tezzaron's CEO, the plant supports…Continue reading →
Blueprints for $120M Austin Public Library Nearly Complete
The new Austin Public Library will feature a light-filled atrium, street-level cafe and multiple gathering spaces, according to the most recent designs unveiled by its architects. Designs, which have been in the works for the past three years, show that the six-story building will also include a street-level bookstore and…Continue reading →
Developers Break Ground on Denizen Multifamily Project
With site preparation finally complete, foundations for the first townhomes at the Denizen project were poured last week.…Continue reading →
New GM Technology Center to Employ 500 IT Workers
By Camelia Bulea, Associate Editor General Motors has announced plans to open a technology center in Northwest Austin, which is expected to hire about 500 IT workers. The company is recruiting software developers, project managers, database experts, business analysts and other information technology professionals. In an official statement, GM justified…Continue reading →
Austin Student Housing Market on the Upswing
By Camelia Bulea, Associate Editor The local student housing market has shown obvious signs of improvement in the past year, with several private and public projects being delivered in the last few weeks and more scheduled to come. The Austin Business Journal reports that two of the largest projects to…Continue reading →


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Hacking & Security Posts - Page 19
Rady Children's Hospital facing lawsuit related to data breach
Following a data breach suffered by Rady Children's Hospital in June 2013, a mother has filed a lawsuit against the company related to a security breach that led her daughter's medical records to be exposed.
The Rady data breach occurred when an employee emailed a spreadsheet containing patient admittance records from July 1, 2012 to June 30, 2013 to four job applicants. The records included patient names, birth dates, primary medical diagnoses, medical record numbers, insurance carrier information, and admittance and discharge dates.
"This is not one or two records dropped in the parking lot," said David A. Miller, an attorney representing the mother, in a statement to the media. "The people they gave this information to didn't even work there. They were job applicants."
Continue reading 'Rady Children's Hospital facing lawsuit related to data breach' (full post)
Kanguru launches USB 3.0 flash drive using trusted secure firmware
USB portable data storage company Kanguru has released an unencrypted USB 3.0 flash drive, utilizing onboard trusted firmware that defends against malicious firmware-based attacks. The drive has read speeds up to 230MB/s with 85MB/s write speed, Kanguru noted. Storage capacities range in size: 8GB, 16GB, 32GB, 64GB and 128GB, with a starting price of $29.95 for the 8GB drive. The flash drive also has a strong aluminum housing to keep it safe from any significant external damage.
"Our Kanguru Defender series of secure, hardware encrypted USB drives is immune to a potential attack like 'BadUSB' because of the digitally signed secure firmware," said Nate Cote, Kanguru EVP, in a press statement. "With the release of the new Kanguru FlashTrust, we now offer this same level of firmware protection to the multi-billion dollar market segment of unencrypted USB device users."
As many users and business workers rely on flash drives, there has been an increase in secure flash drives - IronKey, Kingston secure USB flash drives, Imation Defender, Kanguru, and the Apricorn Aegis secure key, among others. There is a good selection of secure products that can be chosen, using various security protocols to keep data safe.
Amobile Spy unveils Android spy app so you can snoop on your kids
Amobile Spy recently launched the iKeyMonitor Android Spy App, a custom app designed to help parents track what their children do using their smartphones.
The app has the ability to log passwords and keystrokes, monitor WhatsApp message recording, Web history tracking, capture screenshots, log email reporting and 2-side SMS/call logging. The keylogger monitors everything from Facebook, Twitter, Gmail, Skype, Yahoo Messenger and other popular social media or communication apps.
"iKeyMonitor Android Keylogger offers simple, secure, and secret ways to record the activities on Android devices with incredible monitoring features," said Kyle Davis, Amobile Development Department Manager, in a press statement. "We're also giving users smart features to review the logged data remotely."
Continue reading 'Amobile Spy unveils Android spy app so you can snoop on your kids' (full post)
Jailbroken iOS devices being targeted, exploited by new theft malware
A new Chinese malware infected more than 75,000 jailbroken Apple iPhones, with the malware hijacking 22 million advertisements. AdThief, also known as Spad, is the iOS malware and was able to covertly operate around four months - and only works on jailbroken devices. Although originally found by researcher Claud Xiao in March, Fortinet senior mobile researcher Axelle Apvrille took a closer look at AdThief.
Operating on 15 different mobile adkits, the malware changed a developer or affiliate ID so the attacker would collect the revenue. Eight of the adkits are Chinese, and jailbreaking devices is a rather common technique among Chinese consumers. Security experts continually warn users that jailbroken smartphones and tablets pose significant threats to users.
The Chinese hacker, known as Rover12421 did contribute to the code, but denied saying he or she is behind the entire project.
Malware increasingly targeting virtual machines as threats evolve
Newer generations of malware are finding their way to virtual machines - and instead of fleeing like before - are still executing when on VM. At least 70 percent of companies plan to utilize server virtualization by the end of 2015, so malware reaching the virtual machines could prove problematic.
In a study of 200,000 malware samples, analyzed on both VM and non-VM machines by Symantec, only 18 percent wouldn't operate on a virtual machine.
"The host server, as well as any virtual machine running on it, needs to be protected against malware," said Liam O'Murch, Symantec Security Response researcher, in a statement to SCMagazine. "To achieve this, advanced malware protection with proactive components that go beyond the classical static antivirus scanner needs to be in place. This can be agentless on the hypervisor or in the guest image themselves."
Continue reading 'Malware increasingly targeting virtual machines as threats evolve' (full post)
Foreign-based attackers disrupt Tuscaloosa police phone system
Suspected foreign-based cyberattackers hit the Tuscaloosa Police Department earlier in the week, disrupting phone lines at the Alabama station for a short time. The distributed denial-of-service (DDoS) attack took place 5:30 p.m. local time on Tuesday, with the phone system slammed by irrelevant phone calls.
Cyberattacks are not uncommon, but are highly disruptive when they hit police and emergency responders. The TPD is working with federal authorities and will no longer allow blocked numbers or international phone numbers to dial non-911 administration lines. The changes will have no impact on 911 emergency lines reaching the call center, officials noted.
Another local business received up to 184 phone calls in a short time before unplugging the phone - with the caller reportedly saying they were trying to collect a debt.
Author of Android "Heart App" malware arrested in just 17 hours
An unnamed 19-year-old software engineering student, identified only as "Li," was arrested just 17 hours after his "Heart App" Google Android malware infected more than 100,000 phones. The malware was able to spread so quickly by relying on the contact lists of compromised devices, with users downloading the fake app, which then sent out a text urging users to download the app as well.
Chinese wireless carriers were quick to block more than 20 million infected messages from being sent out to new users. The 19-year-old will be identified following completion of the investigation by Shenzhen police, where the student went for vacation. It seems the custom malware was designed just as proof of his ability to write code.
To uninstall the malware, Sophos recommends the following: head to Settings | Apps | Downloaded and uninstall XXshenqi app.
Edward Snowden says NSA has sophisticated cyberwarfare technology
Although the U.S. government is desperate to improve its own cyber defense ability, the NSA already has sophisticated cyberwarfare tools at its disposal. A custom program is able to track down cyberattacks from foreign-based criminals, and then can respond with an attack in an automated fashion without a security specialist present.
Dubbed "MonsterMind," the NSA uses the software to identify traffic patterns - likely from Eastern Europe and China - able to block attacks from damaging U.S. infrastructure and automatically respond against attackers.
"The government has used excessive secrecy to prevent real debate over the wisdom and legality of many of its most sweeping surveillance programs," said Alex Abdo, ACLU staff attorney, in an email to ComputerWorld. " This newly described program is just another example of that secrecy. If the government truly is scanning all internet traffic coming into the United States for suspicious content, that would raise significant civil liberties questions."
Manchester United won't let fans bring tablets, laptops into stadium
New "security intelligence" has led Manchester United to ban tablets and laptops from the Old Trafford stadium located in Old Trafford, Greater Manchester. Greater Manchester Police will not be involved in the ban, and includes both smaller and larger tablets. Smartphones that are 5.9" x 3.9" or smaller will still be allowed into the arena without a problem.
Stadium officials noted it would be "impractical" for each fan to power up tablets and laptops as they enter the arena - unlike at airports, where passengers will be able to quickly show that they have a legitimate electronic device.
The TSA may request passengers flying into the United States to power on their mobile devices - a move that Britain has matched - at the risk of some type of explosive device hidden inside.
Security firm Trend Micro finds threats plague consumers, companies
The first two quarters of 2014 again revealed cyberthreats, data breaches and high-risk cyber vulnerabilities that companies struggle to keep up with, according to a new report from security firm Trend Micro.
Consumers face issues such as data theft of customer names, passwords, email addresses, home addresses, phone numbers, and birth dates. Cybercriminals are finding ways to steal this type of information directly from consumers, or compromising companies.
"Organizations must treat information security as a primary component of a long-term business strategy rather than handling security issues as a tertiary, minor setbacks," said Raimund Genes, Trend Micro CTO, in a press statement. "Similar to having a business strategy to improve efficiency, a well-thought-out security strategy should also improve current protection practices that achieve long-term benefits. The incidents observed during this quarter further establish the need for a more comprehensive approach to security."
Continue reading 'Security firm Trend Micro finds threats plague consumers, companies' (full post)


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Dan Cutforth (l) and Jane Lipsitz with Never Say Never director Jon M. Chu
Monica Reyhani: How was the premiere?
Jane Lipsitz: It was amazing. It was a purple carpet, and it was overwhelming. You know there was so much press, and screaming fans, and I mean it was a huge, huge event. And it was incredibly exciting for us.
Dan Cutforth: It was actually the first time I've been back to Nokia since the Emmys.
MR: I can't even imagine what it's like being even in his vicinity right now, with all those kids. What is that like?
JL: It's sort of like the thing that you see in movies. We've all seen Hard Day's Night. You can't really describe it in words until you're actually in the midst of it. I was on the road with him for two weeks when we were shooting the film, and it's a really unique experience, and it's an incredible moment in time for this teen idol. And I think it's really kind of refreshing to know that in every generation, there's still this genuine love of a pop icon. It just felt really innocent and '90s, really touching in a way that this is an ongoing tradition or a right of passage for young girls, teenagers.
MR: Did the fan-demonium cause any unexpected either problems or anything during production?
JL: Actually, I think our crew had an amazing time on the road, because if they just walked out, the girls were screaming at them. Our audio guy would walk down the line and just lift his hand in the air and the girls would go nuts. So I think it was a really fun experience for everyone on the road, just because by association everyone sort of became part of that, an extension of that level of fame.
MR: That poor audio guy!
JL: He loved it.
M: So the vibe on set was just really joyous?
JL: Yeah it was. Although, I will say at one point there actually was a moment at Madison Square Garden, and we saw a couple of white-faced producers come running in the door. It reached such a level of pandemonium that I think there was a moment where they were in fear for their well-being.


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New York Yankees v Tampa Bay Rays
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Chris Archer of the Tampa Bay Rays pitches during the second inning... News Photo 485683085American League,Chris Archer - Baseball Player,Florida - USA,Gulf Coast States,Horizontal,Major League Baseball,Match - Sport,New York Yankees,Pitcher,Second Inning,Sport,St. Petersburg - Florida,Tampa Bay Rays,Tropicana Field,USAPhotographer Brian BlancoCollection: Getty Images Sport 2014 Getty ImagesST. PETERSBURG, FL - APRIL 19: Chris Archer #22 of the Tampa Bay Rays pitches during the second inning of a game against the New York Yankees on April 19, 2014 at Tropicana Field in St. Petersburg, Florida. (Photo by Brian Blanco/Getty Images)


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Smock discusses the "new American family" on NPR
Pfeffer and colleagues re-examine impacts of community college attendance
Frey explains the minority-majority remapping of America
Apply for 2-year NICHD Postdoctoral Fellowships that begin September 2015
PSC Fall 2014 Newsletter now available
Martha Bailey and Nicolas Duquette win Cole Prize for article on War on Poverty
Michigan's graduate sociology program tied for 4th with Stanford in USN&WR rankings
Monday, Dec 1
Linda Waite, Health & Well-Being of Adults over 60
Lin, J.Y., T.R. Ten Have, and Michael R. Elliott. 2009. "Nested Markov Compliance Class Model in the Presence of Time-Varying Noncompliance." Biometrics, 65(2): 505-513.
We consider a Markov structure for partially unobserved time-varying compliance classes in the Imbens-Rubin compliance model framework. The context is a longitudinal randomized intervention study where subjects are randomized once at baseline, outcomes and patient adherence are measured at multiple follow-ups, and patient adherence to their randomized treatment could vary over time. We propose a nested latent compliance class model where we use time-invariant subject-specific compliance principal strata to summarize longitudinal trends of subject-specific time-varying compliance patterns. The principal strata are formed using Markov models that relate current compliance behavior to compliance history. Treatment effects are estimated as intent-to-treat effects within the compliance principal strata.
DOI:10.1111/j.1541-0420.2008.01113.x (Full Text)
PMCID: PMC2700859. (Pub Med Central)
Country of focus: United States of America.
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Tons of Lives
Rated : 4.05 based on 19 votes.
Tons of Lives
The awesome Nintendo DS handheld version of Mario has been turned into a flash game and it brings all the great action of the original handheld game onto your PC screen for you to relive this excellent Mario adventure.
If you have any problems viewing this game please fill out the details below. Before reporting a broken link / game please make sure of the following:
Super Mario 63
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This is a nice game, but it has nothing to do with the Nintendo DS. It uses Allstar graphics.
Guest (Mar 07, 2011)
i like the game.............................oh and FIRST!!!!!!!!
Guest (Mar 06, 2011)
this game is so cool


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Ginkgo Firenze Stainless Mirror Finish Flatware - Set of 20Item # HN-GKG067
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Very disappointed This place is closed. A friend recommended Serafino but when we went we found out it's been closed since May. Not even notice on door.I asked one neighbour she told me that they moved somewhere in Sliema
In June 2011, found this great little restaurant tucked just off the main Selima Creek waterfront. Once found, several evenings were enjoyed at this excellent restaurant. Imagine our disappointment to find it was closed up when we arrived this year. However some detective work found that the team had moved to a new location on the Qui-Si-Sana Road in Sliema....
The service and food were excellent. We enjoyed it as the food in the hotel was not good.
Dined here one evening. Its location is well described in other reviews. Delightful decor and excellent food. Quite a small restaurant but very stylish. Quite a large menu but our choices were superbly prepared and presented. Complimentary bruscetta and olives. Staff were very charming and efficient. Would certainly recommend it. They also had quite a large wine list but I...
Tucked away down a side street near the ferries sliema what a find. Theres a junction on the strand with a shop called Square Deal bear right as you approach it see a sign for Club Sin and take the street on the right opposite,ten yards up Serafinos.
Its lovely inside very modern decor probably only about ten tables classy...
This is a busy little restaurant the food was decent and had a good choice although my veal was a bit tough... but this seemed to be with most meats. I think they must cut it different to England. The portions were on the small side but on the whole we had a good night and for a better class...
We went here twice and enjoyed it both times> The wait staff was different at lunch than at dinner but both times they were excellent.. The food was great and the whole experience much better than in the really touristy spots a few blocks away.
I was actually looking for another place but since I didn't find it I went to Serafino.
Restaurant is located in St.Dominic Street, very close to the Strand.
The place was almost full but there was still some table available. I was a bit suspicious because of the menu. Too many dishes in list. Even a Serbian/Bulgarian salad and actually,...
had our 1st anniversary there with my wife. would recommend everyone to visit. nice place, great food, good service. as a starter we took the stuffed mushrooms and for the main course, being a chef myself, i made my own twist by choosing the salmon and requested for the serfanio sauce instead. it was a perfect match. my wife enjoyed...
Excellent service together with delicious food,makes this restuarant one of our favourites in Sliema.
The Seafood Platte is like a piece of art,so beautiful and so rich,it´s served for two and it´s almost impossible to eat all of it.
Starters "on the house"small bruschettas,while you wait for the main course.
We have been there many times,lunch,dinner,winter,spring and fall,and we have...
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Director Christopher Denham talks Tribeca horror "PRESERVATION"—and what's up with "AREA 51"!
Actor Christopher Denham made his directorial debut with the chilling domestic horror feature HOME MOVIE in 2008, and now he's back with PRESERVATION, premiering at this month's Tribeca Film Festival. He gave us a few words about the film—and an update on the years-in-coming AREA 51.Read more »


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User talk:Lukario 666
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Brazilian Portuguese names
Where are you getting these names? Are you translating them yourself, or do they come from the anime? --SnorlaxMonster 10:44, 1 January 2011 (UTC)
- At least Wood Horn's translation was his own.----無限の知性 ◎ DENNOU◆ZENSHI 10:47, 1 January 2011 (UTC)
- eu traduzo pelo o que eu sei pelo o que vi no anime - unsigned comment from Lukario 666 (talk • contribs)
- I don't actually speak Portuguese (so Google Translate helped me), but from what you told me, if you are taking the names directly from the anime, this is fine; however, you cannot create your own translations like you did for Wood Horn, Magic Room and Purgatory, which only have Japanese names. I also doubt that Wild Charge's translation is accurate, but it could be official due to being revealed in multiple languages. Please remove all names you translated yourself—only those which are official can stay. Also, please reply here instead of on my talk page. --SnorlaxMonster 13:11, 5 January 2011 (UTC)
- eu traduzo pelo o que eu sei pelo o que vi no anime - unsigned comment from Lukario 666 (talk • contribs)


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heaven.I wondered tonight as I wandered besides the sea, the sky shrinking and the moon casting a pastel glow against the waves. I wondered as to whether this was heaven, a long sandy beach, quiet at sundown, ragged and beautiful.heaven.1 day ago in Short Stories More Like This
So I stood for a while until the waves lapped over my boots and I remembered soon, the tide would come in and sweep me away.
And then I contemplated instead upon whether heaven could really exist and if it did, could it ever be truly perfect?
Compton Bay, 28.10.14
The Best Thing About MondaysThe best thing about Mondays is the anxiety that floods into my body, starting at my feet and slowly rising up into my guts, my chest, my throat. It drowns me.The Best Thing About Mondays3 days ago in Short Stories More Like This
I wake up when it's still dark outside, and I rub the troubled sleep from my eyes with tired hands. I leave the warmth of my bed to face the cold day ahead of me.
The best thing about Mondays is waiting for my eyes to adjust to the morning gloom as they focus on old scrapbooks and half-finished novels I've lost interest in reading. I'm slowly removing myself from my own life.
I get dressed in the dark, hair falling in messy tangles down my back. As I sling my bag over my shoulder, my glasses fall down the bridge of my nose, but I can't bring myself to care.
The best thing about Mondays is when I step outside my building and the chill in the air is enough for my breath to be seen and for goosebumps to rise in waves over my skin. My mind tells me it's cold, but I feel no difference in my bones.
The best thing about Mondays is clim
His First (one shot) The child screeched late that night. The tired couple moaned from lack of sleep.His First (one shot)5 days ago in Short Stories More Like This
This wasn't the first time
"Jase, please go put her to sleep..."
" It's your turn..." Jase rolled on his side away from his wife.
" Jase," she muffled from her pillow. " I've been changing dirty diapers for weeks. You can put her to sleep..."
The child screamed louder.
Jase sighed heavily and threw himself out of bed. He glanced at the time and groaned. It was too early for this. He strolled into his daughters room, right outside of his own, and let his eyes adjust to the new environment. The child squirmed in her bed, reaching for anything that would hold her.
" Elizabeth... Hey..." The young father walked to his daughters craddle and swooped her up gently in his arms.
She was a miracle.
Next to marring the woman of his dreams, his little girl was the only spark of hope. She was precious to him.
He rocked his baby girls gently in his arms, singing
A Sibling Bond Scarlett rested on a tree branch, swinging her legs back and forth. She looked around the snow covered forest while she waited for someone; her older brother James. He had forgotten something at home and went back to get it really quick. A formed on her lips when he came into view. She was about to call out to him when he was close enough to hear her clearly when something cold hit her in the face. With a yelp, she fell off the branch backwards and landed on her back. Her foot became entangled in some sticks on the ground. She sat up and brushed the cold substance off her face. She looked down and discovered it was snow. James was laughing as he got closer.A Sibling Bond1 day ago in Short Stories More Like This
"I wish I had a camera, you should have seen your face." He continued to laugh.
"Glad you found it amusing." Scarlett said. She struggled to get up because of her stuck foot.
"Need some help?" James asked.
Scarlett gave
I Love you so, so Much it HurtsHiro never liked being trapped in small spaces, and he never liked the idea of being alone in small spaces either. Luckily Tadashi was always the one to help him out. He knew that Hiro was embarrassed by his morbid fear of small spaces. So he kept it quiet to keep Hiro happy. Luckily on a day like today Hiro had Tadashi to be there for him when it came to his claustrophobia. They were leaving the university one day after Tadashi had shown him some new stuff that he was working on. The boys then entered the elevator and began to head up.I Love you so, so Much it Hurts3 days ago in Short Stories More Like This
However the elevator gave out halfway up and the boys found themselves trapped inside. "Oh my God! were stuck!" Hiro stuttered as he started clutching the wall in fear. "No! no we can't be stuck! I don't wanna be stuck in here! we need to get out! it's too cramped in here! and the walls are closing in! and why does it feel so hot in here?!" Hiro started to fumble with his sweater feeling sweat pouring down his face.
"And.. and.. and!" Hiro couldn't spea
Golden Rule: Scarred MessageGolden Rule: Scarred MessageGolden Rule: Scarred Message3 days ago in Short Stories More Like This
Chapter 1:
"Hey Ashni." Spoke Seiko as Ashni turned to him. He was holding a piece of mail that was dipped in brown. There was a red seal on it. Ashni blinked as Seiko continued "Here's to you, my queen." "Thank... you?" Ashni asked, blinking again. Seiko took it as an excuse and exited out of Ashni's room. She looked at the mail before her and blinked. She shouldn't have received any mail at this time of day. She glanced around at the room before allowing her right paw to open the flap of the mail. Releasing it from its prison, she took out the black piece of paper. She blinked again and raised her eyebrow. "This... wasn't expected." She wondered as she stood up. Walking across the room, she came across her own dipping paint and a group of clippers hanged above her.
She dipped the black paper into the paint and took it out. The drops of white dripped underneath as Ashni wiped the paper with her paw and hanged it up using one of the clippers. She gave
Good Morning "Good morning?" Nightmare flicked his eyes' gaze from the stacked words of his book to the doorway. A small amount of light found its way into the bedroom. Most likely from a torch or candle in the hallway. Lock hung her head and held a pillow in her arms.Good Morning7 hours ago in Short Stories More Like This
"Can I sleep with you?" She asked softly. Her eyes were glued to her feet in embarrassment. None of her usual piercings were in, nor did she wear her back brace, much to Nightmare's despair.
"Isn't it a little early in the day and a little too late in your life for you to ask something like this?" Lord Nightmare sighed and padded the puffy comforter next to him. Lock obliged and slunk over to him. She slid under the covers and laid the pillow down. Shaking his head, the merciful ruler patted his castilian on the head. "Good night."
BunnyWhen he called my name and asked me to come and sit up on his lap, patting his knees with that funny smile of his. I had been busy tapping the glass on the office aquarium and I watched as the fish came at me, then turned and scattered like leaves in the afternoon breeze.Bunny1 day ago in Short Stories More Like This
Funny the things you remember. I remember the fish tank and the purple shirt that I was wearing, but I don't remember how I got there or what I was doing before that that day.
I turned and ran to papa and sat on his lap; I could still smell the smoke on him from a cigarette that he must have had before this whole event. He always smelled like smoke and I became accustomed to it, even enjoying it at times. His kisses were wet, and I complained when he would kiss me and wipe them off with the back of my small, ungraceful hand.
I remember looking around the waiting room, wondering at all of the sad faces sitting there. I remember that one man in particular was sitting crossed legged on the floor, the way that they
Uncle.Uncle.Uncle.2 days ago in Short Stories More Like This
"Mommy? Is Uncle Josiah coming to see us today?"
I looked down at my 5 year old daughter Nevaeh. Her dark black hair curly to perfection in her ponytails. Her brown eyes full of hope to see her favorite uncle.
"He is. How did you know?"
A mischievous grin appeared on her face. "I called him. And I told him to come see us. And to take you out on a date. Because he loves you."
I looked at her in disbelief. "He said yes to this? How could you? You know he is really busy with his band. You can't tear him away like that. What if he cancelled something really important just because you wanted to see him?"
"I'm sorry Mommy. I didn't think of that. Will he forgive me?"
"I think so. He does love you even when you are naughty."
With this she started jumping up and down excitedly.
I let her continue as I finished getting ready for our date. If you could call it that. It's more like a friendly dinner with the father of your 2 children. I still love him dearly but am saddened by the fact he
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5-Year-old child sustains serious burns at school
The parents of a five-year-old Grade R pupil, Surprise Mulwanndwa Mutenda, are furious, following an incident where the pupil sustained critical burns during school hours.
The parents of a five-year-old Grade R pupil, Surprise Mulwanndwa Mutenda, are furious, following an incident where the pupil sustained critical burns during school hours.
The Limpopo toilet saga last week returned to haunt one of the schools in Vhembe.
"We are going to stand firm as Makhado Council and fight and defend our people!"
'n Leraar van Louis Trichardt se aansoek om ontslag van die kriminele klagte teen hom, het verlede week in die plaaslike Distrikshof misluk.
Newly appointed Beit Bridge town secretary Mr Loud Ramakgapola says he envisions turning the border town into a modern urban centre, as well as strengthening the twinning agreement that the council has with Musina Municipality.
The Chairman's Association (CA), the official opponent in the name-change saga of Louis Trichardt, this week released a statement in reaction to the Makhado Municipality's resolution to change the name to Makhado.
What was supposed to be the final inspection tour of the Vhembe District Municipality's borehole project west of Louis Trichardt, turned out to be unsatisfactory, according to Vhembe, and an embarrassment, according to AfriForum.
"Die waardasierol is steeds wettig," het die Makhado Munisipaliteit hierdie week gesê.
The hip hop youth culture in Limpopo will explode when the talented and hardworking Ramzeey finally releases his much-awaited full-length album, Muraga (Foundation).
A 66-year-old tourist's life is still hanging in the balance after being attacked by a wounded buffalo at the Pafuri River Camp on Friday, 14 November.
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Where: Saal agter Agapé Christensentrum in Makhado (Louis Trichardt)
Start: 24 Nov (08:00 AM)
End: 28 Nov (15:00 PM)
Vollies hou Kersmark
Where: Makhado (Louis Trichardt)
Start: 24 Nov (10:00 AM)
End: 29 Nov (13:00 PM)
Vetkoet-en-maalvleis te koop
Where: Harcourts, Kroghstraat 126, Louis Trichardt
Start: 28 Nov
NG Kerk Soutpansberg vier 60ste verjaardag
Where: NG Kerk Soutpansberg kerkterrein, Makhado (Louis Trichardt)
Start: 28 Nov
End: 30 Nov
P&L MTB Bike Champs
Where: Louis Trichardt
Start: 29 Nov
Op die Berg Musiekfees
Where: AGS Levubu-gemeente
Start: 29 Nov
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