text:
A pharmaceutical composition including a mixture of active compounds (A) a pharmaceutically active polypeptide, and (B) an enhancer compound which enhances the systemic absorption of the polypeptide in the lower respiratory tract of a patient, the mixture being in the form of a dry powder for inhalation in which at least 50% of the total mass of the active compounds consists of primary particles having a diameter less than or equal to about 10 microns, the primary particles optionally being formed into agglomerates.
1. A composition consisting essentially of (A) a polypeptide, (B) one or more substances which enhance the absorption of said polypeptide in the lower respiratory tract, and (C) optionally one or more non-hygroscopic additives, said composition being in the form of a dry powder suitable for inhalation from a dry powder inhaler, wherein at least 50% of the total mass of (A) and (B) consists of primary particles having a diameter of up to about 10 microns, provided that each of said one or more substances is selected from the group consisting of a C8-C16 fatty acid, a salt of said fatty acid, a salt of glycyrrhizine acid, an acyl carnitine, and an alkyl saccharide.
2. The composition of
3. The composition of
4. The composition of
5. The composition of
6. The composition of
7. The composition of
8. The composition of
9. The composition of
10. The composition of
11. The composition of
12. The composition of
13. The composition of
14. The composition of
15. The composition of
16. A composition consisting essentially of (A) a polypeptide, (B) one or more phospholipids that enhance the absorption of said polypeptide in the lower respiratory tract, and (C) optionally one or more non-hygroscopic additives, said composition being in the form of a dry powder suitable for inhalation from a dry powder inhaler, wherein at least 50% of the total mass of (A) and (B) consists of primary particles having a diameter of up to about 10 microns.
17. The composition of
18. The composition of
19. The composition of
20. The composition of
21. The composition of
22. The composition of
23. The composition of
24. The composition of
25. The composition of
26. The composition of
27. The composition of
28. The composition of
29. The composition of
30. The composition of
31. The composition of
32. The composition of
33. The composition of
34. The composition of
35. The composition of
36. The composition of
37. The composition of
38. The composition of
39. The composition of
40. The composition of
41. The composition of
42. The composition of
43. The composition of
This application is a continuation of U.S. Ser. No. 08/583,217 filed Jan. 4, 1996, now abandoned; which is a continuation-in-part of U.S. Ser. No. 08/265,237, filed Jun. 23, 1994, now abandoned. The invention relates to methods and compositions for delivery of medically useful peotides and proteins.
Although the advent of recombinant DNA technology has resulted in a rapidly expanding list of peptide-based drugs, a major drawback of peptide-based therapy has acutely hampered realization of the full potential of this field: in general, peptide-based drugs cannot be orally administered in effective doses, since they are rapidly degraded by enzymes in the gastrointestinal tract before they can reach the bloodstream. Unless the polypeptide of interest can be altered to make it relatively resistant to such enzymes, the only practical method of delivering the drug is likely to be a parenteral route, such as by intravenous, intramuscular, or subcutaneous injection. Administration by other parenteral routes (e.g., by absorption across nasal, buccal or rectal membranes, or via the lung) has met with limited success.
It has been found that when a peptide or protein (hereinafter collectively referred to as a polypeptide) is combined with an appropriate absorption enhancer and is introduced into the lung in the form of a powder of appropriate particle size, it readily enters the pulmonary circulation by absorption through the layer of epithelial cells in the lower respiratory tract. This is conveniently accomplished by inhalation of the powder from an inhaler device which dispenses the correct dose of powdered polypeptide/enhancer in a particle size which maximizes deposition in the lower respiratory tract, as opposed to the mouth and throat. (For ease of reference, the polypeptide and enhancer are hereinafter collectively referred to as the "active compounds"). To accomplish this preferential delivery into the lung, as much as possible of the active compounds should consist of particles having a diameter less than approximately 10 μm (e.g., between 0.01-10 μm, and ideally between 1-6 μm). In preferred embodiments, at least 50% (preferably at least 60%, more preferably at least 70%, still more preferably at least 80%, and most preferably at least 90%) of the total mass of active compounds which exits the inhaler device consists of particles within the desired diameter range.
The invention thus includes a pharmaceutical composition containing a mixture of active compounds (A) a pharmaceutically active polypeptide and (B) an enhancer compound which enhances the systemic absorption of the polypeptide in the lower respiratory system (preferably the lungs) of a patient, the mixture being in the form of a dry powder suitable for inhalation, in which at least 50% of the total mass of active compounds (A) and (B) consists of primary particles having a diameter less than or equal to about 10 microns. The primary particles may be packaged as such, or may optionally be formed into agglomerates, which then are substantially deagglomerated prior to entry into the respiratory tract of the patient. The composition may of course contain other ingredients as needed, including other pharmaceutically active agents, other enhancers, and pharmacologically acceptable excipients such as diluents or carriers. Therefore, the therapeutic preparation of the present invention may contain only the active compounds or it may contain other substances, such as a pharmaceutically acceptable carrier. This carrier may largely consist of particles having a diameter of less than about 10 microns so that at least 50% of the resultant powder as a whole consists of optionally agglomerated primary particles having a diameter of less than about 10 microns; alternatively, the carrier may largely consist of much bigger particles ("coarse particles"), so that an "ordered mixture" may be formed between the active compounds and the said carrier. In an ordered mixture, alternatively known as an interactive or adhesive mixture, fine drug particles (in this invention, the active compounds) are fairly evenly distributed over the surface of coarse excipient particles (in this invention, the pharmaceutically acceptable carrier). Preferably, the active compounds are not in the form of agglomerates prior to formation of the ordered mixture. The coarse particles may have a diameter of over 20 microns, such as over 60 microns. Above these lower limits, the diameter of the coarse particles is not of critical importance, so various coarse particle sizes may be used, if desired, according to the practical requirements of the particular formulation. There is no requirement for the coarse particles in the ordered mixture to be of the same size, but the coarse particles may advantageously be of similar size within the ordered mixture. Preferably, the coarse particles have a diameter of 60-800 microns.
The polypeptide may be any medically or diagnostically useful peptide or protein of small to medium size, i.e. up to about 40 kD molecular weight (MW), for which systemic delivery is desired. The mechanisms of improved polypeptide absorption according to the present invention are generally applicable and should apply to all such polypeptides, although the degree to which their absorption is improved may vary according to the MW and the physico-chemical properties of the polypeptide, and the particular enhancer used. It is expected that polypeptides having a molecular weight of up to 30 kD will be most useful in the present invention, such as polypeptides having a molecular weight of up to 25 kD or up to 20 kD, and especially up to 15 kD or up to 10 kD. Any desired polypeptide may be easily tested for use in the present invention with a particular enhancer, by in vivo or in vitro assays, as described herein.
The enhancer compound used in the compositions of the present invention can be any compound which enhances the absorption of the polypeptide through the epithelium of the lower respiratory tract, and into the systemic circulation. By "enhances absorption" is meant that the amount of polypeptide absorbed into the systemic circulation in the presence of enhancer is higher than in the absence of enhancer. Preferably the amount of polypeptide absorbed is significantly higher (p<0.05) in the presence of enhancer. The suitability of any potential enhancer for use in the present invention may be easily assessed, by means of in vivo or in vitro assays, as described herein.
The amount of polypeptide absorbed according to the present invention is preferably at least 150% of the amount absorbed in the absence of enhancer. In preferred embodiments, absorption of polypeptide is at least doubled, more preferably tripled, and most preferably quadrupled in the presence of the enhancer, compared to in its absence.
The enhancer is preferably a surfactant such as a salt of a fatty acid, a bile salt, a bile salt derivative, an alkyl glycoside, a cyclodextrin, or a phospholipid. The enhancer may be, for example, a sodium, potassium, or organic amine (e.g., lysine) salt of the fatty acid, and the fatty acid is preferably capric acid or another fatty acid of 8-16 carbon atoms. The preferred enhancer is sodium caprate. The ratio of polypeptide to enhancer will preferably vary from about 9:1 to about 1:1. Although proportions of enhancer greater than 1:1 would presumably enhance uptake as well as or better than lower proportions, it is believed that the amount of enhancer used should be no higher than necessary to acheive the desired level of enhancement, since excess enhancer may trigger unwanted side effects, such as local irritation.
Also within the invention is a method of administering systemically a pharmaceutically active polypeptide, by causing a patient to inhale the pharmaceutical composition of the invention, wherein at least 50% of the total mass of the active compounds at the point of entry to the respiratory tract of the patient consists of particles having a diameter less than or equal to about 10 microns. This is preferably accomplished by the use of an inhaler device from which the patient inhales the powder. Where the powdered composition is in the form of agglomerates of primary particles, the device is preferably configured to induce substantial deagglomeration of the agglomerates upon inhalation of the powder from the device by the patient, so that the majority of the agglomerates break down into particles having a diameter less than or equal to about 10 microns, prior to entry of the powder into the respiratory system of the patient. This deagglomeration would occur inside the device, and is typically induced by the air turbulence created in the device by the force of inhalation. Agglomerates are in general preferably not formed in the ordered mixture. In the case of an ordered mixture, the active compounds should be released from the large particles preferably upon inhalation, either by mechanical means in the inhaler device or simply by the action of inhalation, or by other means, the active compounds then being deposited in the lower respiratory tract and the carrier particles in the mouth.
The inhaler device is preferably a single dose dry powder inhaler, but may alternatively be a multi dose dry powder inhaler.
The invention also includes processes for the manufacture of a pharmaceutical composition suitable for administration by inhalation. In one such process, a solution is first provided in which are dissolved (a) a pharmaceutically active polypeptide and (b) an enhancer compound which enhances the systemic absorption of the polypeptide in the lower respiratory tract of a patient. The solvent is then removed from the solution to yield a dry solid containing the polypeptide and the enhancer, and the dry solid is pulverized to produce a powder. A second such process involves dry mixing (a) a pharmaceutically active polypeptide and (b) an enhancer compound, and micronizing the obtained mixture. Yet a third suitable process includes the steps of providing a first micronized preparation containing a polypeptide and a second micronized preparation containing an enhancer compound, and mixing the two micronized preparations together. When a carrier is to be included other than when an ordered mixture is desired, this may be added to the solution, or to the dry-mixture of the pharmaceutically active polypeptide prior to micronization, or micronised carrier may be dry mixed with the other micronised components. In producing an ordered mixture, micronised polypeptide and enhancer are mixed with a suitable carrier.
FIG. 1 is a graph illustrating the effects of different concentrations of sodium caprate enhancer on the transport of a marker compound (mannitol) through a monolayer of cultured epithelial cells.
FIG. 2 is a graph illustrating the effects of different concentrations of sodium caprate enhancer on the transport of a marker compound (mannitol) through a monolayer of cultured epithelial cells, in the presence of a polypeptide (sodium caprate:polypeptide 1:3 by weight).
FIG. 3 is a graph of plasma polypeptide concentration as a function of time after inhalation of the polypeptide alone, the polypeptide with sodium caprate in a ratio of 90:10, and the polypeptide with sodium caprate in a ratio of 75:25.
Some of the preferred embodiments of the invention are generally described below.
The Polypeptide
The polypeptide is preferably a peptide hormone other than insulin. Examples of polypeptides include vasopressin, vasopressin polypeptide analogs, desmopressin, glucagon, corticotropin (ACTH), gonadotropin, calcitonin, C-peptide of insulin, parathyroid hormone (PTH), growth hormone (HG), human growth hormone (hGH), growth hormone releasing hormone (GHRH), oxytocin, corticotropin releasing hormone (CRH), somatostatin or somatostatin polypeptide analogs, gonadotropin agonist or gonadotrophin agonist polypeptide analogs, human atrial natriuretic peptide (ANP), human thyroxine releasing hormone (TRH), follicle stimulating hormone (FSH), and prolactin.
Other possible polypeptides include growth factors, interleukins, polypeptide vaccines, enzymes, endorphins, glycoproteins, lipoproteins, and polypeptides involved in the blood coagulation cascade, that exert their pharmacological effect systemically. It is expected that most if not all polypeptides of small to medium size, relatively high water solubility, and an isoelectric point between approximately pH 3 and pH 8 can be effectively delivered by the methods of the invention.
The Enhancer
The use of an absorption enhancer is of critical importance, as the polypeptide alone is poorly absorbed through the lung. The enhancer used can be any of a number of compounds which act to enhance absorption through the layer of epithelial cells lining the lower respiratory tract, and into the adjacent pulmonary vasculature. The enhancer can accomplish this by any of several possible mechanisms, including the following:
(1) Enhancement of the paracellular permeability of a polypeptide by inducing structural changes in the tight junctions between the epithelial cells.
(2) Enhancement of the transcellular permeability of a polypeptide by interacting with or extracting protein or lipid constituents of the membrane, and thereby perturbing the membrane's integrity.
(3) Interaction between enhancer and polypeptide which increases the solubility of the polypeptide in aqueous solution. This may occur by preventing formation of insulin aggregates (dimers, trimers, hexamers), or by solubilizing polypeptide molecules in enhancer micelles.
(4) Decreasing the viscosity of, or dissolving, the mucus barrier lining the alveoli and passages of the lung, thereby exposing the epithelial surface for direct absorption of the polypeptide.
Enhancers may function by only a single mechanism set forth above, or by two or more. An enhancer which acts by several mechanisms is more likely to promote efficient absorption of a polypeptide than one which employs only one or two.
For example, surfactants are a class of enhancers which are believed to act by all four mechanisms listed above. Surfactants are amphiphilic molecules having both a lipophilic and a hydrophilic moiety, with varying balance between these two characteristics. If the molecule is very lipophilic, the low solubility of the substance in water may limit its usefulness. If the hydrophilic part overwhelmingly dominates, however, the surface active properties of the molecule may be minimal. To be effective, therefore, the surfactant must strike an appropriate balance between sufficient solubility and sufficient surface activity.
Another surfactant property that may be of importance is the net charge of the surfactant at the pH value in the lung (approximately 7.4). At pH 7.4, some polypeptides have a negative net charge. This will result in an electrostatic repulsion between molecules, which will in turn prevent aggregation and thereby increase the solubility. If the surfactant also is negatively charged, it can interact with the polypeptide by, for example, hydrophobic interactions, and additional repulsion among the polypeptide molecules will occur. In such case an anionic surfactant will possess the additional advantage (compared to those having neutral or net positive charge at physiological pH) of enhancing absorption by helping stabilize the polypeptide in the monomeric state.
A number of different compounds potentially useful as enhancers in the methods of the invention were tested in rats, as described in Example 2 below. Other substances with known absorption-enhancing properties, or with physical characteristics which make them likely candidates for use in the method of the invention, can be readily tested by one of ordinary skill in that in vivo assay, or alternatively in the in vitro assay described in Example 1.
It is possible that a combination of two or more enhancer substances also gives satisfactory results. The use of such a combination in the method of the invention is considered to be within the invention.
An enhancer useful in the methods of the invention will combine effective enhancement of polypeptide absorption with (1) lack of toxicity in the concentrations used and (2) good powder properties, i.e., lack of a sticky or waxy consistency in the solid state. Toxicity of a given substance can be tested by standard means, such as by the MTT assay, for example as described in Int. J. Pharm., 65 (1990), 249-259. The powder properties of a given substance may be ascertained from published data on the substance, or empirically.
One very promising type of enhancer is the salt of a fatty acid, e.g., a sodium, potassium, or lysine salt of a saturated or unsaturated fatty acid. It has been found that the sodium salt of saturated fatty acids of carbon chain length 10 (i.e., sodium caprate), 12 (sodium laurate) and 14 (sodium myristate) perform well in the method of the invention. The potassium and lysine salts of capric acid have also been found to be effective in the method of the invention. If the carbon chain length is shorter than about 8, the surface activity of the surfactant may be too low, and if the chain length is longer than about 16, decreased solubility of the fatty acid salt in water limits its usefulness.
Most preferably in the present invention, the substance which enhances the absorption of polypeptide in the lower respiratory tract is sodium caprate.
Different counterions may change the solubility of the saturated fatty acid salt in water, such that an enhancer having a carbon length other than 8-16 would prove even more advantageous than the enhancers specifically mentioned hereinabove. Salts of unsaturated fatty acids may also be useful in the present invention since they are more water soluble than salts of saturated fatty acids, and can therefore have a longer chain length than the latter and still maintain the solubility necessary for a successful enhancer of polypeptide absorption.
All of the bile salts and bile salt derivatives tested (sodium salts of ursodeoxycholic acid, taurocholic acid, glycocholic acid, and taurodihydrofusidic acid) effectively enhance polypeptide absorption in the lung. Examples of suitable bile salts include salts (e.g., sodium or potassium salts) of fatty acids such as cholic acid, chenodeoxycholic acid, glycocholic acid, taurocholic acid, glycochenodeoxycholic acid, taurochenodeoxycholic acid, deoxycholic acid, glycodeoxycholic acid, taurodeoxycholic acid, lithocholic acid, and ursodeoxycholic acid. Preferred are the trihydroxy bile salts, such as the salts (e.g., potassium and sodium salts) of cholic, glycocholic and taurocholic acids. Particularly preferred are sodium taurocholate and potassium taurocholate.
Phospholipids were also tested as enhancers. It was found that a single-chain phospholipid (lysophospatidylcholine) was an effective enhancer, while two double-chain phospholipids (dioctanoylphosphatidylcholine and didecanoylphosphatidylcholine) were not. This may be explained by the fact that the double-chain phospholipids are much less soluble in water than their single-chain counterparts; however, it is reasonable to expect that double-chain phospholipids of shorter chain length, having greater water-solublility than their longer chain counterparts, will be of use as enhancers in the present invention so that both single- and double-chain phospholipids may be used. Examples of single-chain phospholipids include lysophosphatidylcholine, lysophosphatidylglycerol, palmitoylphosphatidylglycerol, palmitoylphosphatidylcholine, lysophosphatidylethanolamine, lysophosphatidylinositol, and lysophosphatidylserine. Examples of double-chain phospholipids include diacylphosphatidylcholine, diacylphosphatidylglycerol, diacylphosphatidylethanolamine, diacylphosphatidylinositol, and diacylphosphatidylserine.
One glycoside, octylglucopyranoside, was tested as an enhancer in the present invention and was found to have some absorption enhancing properties. Other alkyl glycosides such as the alkyl glucosides (e.g., decyl glucoside, dodecyl glucoside, and alkyl thioglucopyranoside) and alkyl maltosides (e.g., decyl maltoside and dodecyl maltoside) would also be expected to exhibit absorption enhancing properties in the methods of the present invention.
The cyclodextrins and derivatives thereof effectively enhance nasal absorption, and may function similarly in the lung. Dimethyl-β-cyclodextrin has been tested and was found to have an absorption enhancing effect.
Other potentially useful surfactants are sodium salicylate, sodium 5-methoxysalicylate, and the naturally occurring surfactants such as salts (e.g., sodium or potassium salts) of glycyrrhizine acid, saponin glycosides, and acyl carnitines such as decanoyl carnitine, laureyl carnitine, myristoyl carnitine, and palmitoyl carnitine.
For ionic enhancers (e.g., the anionic surfactants described above), the nature of the counterion may be important. The particular counterion selected may influence the powder properties, solubility, stability, hygroscopicity, and local/systemic toxicity of the enhancer or of any formulation containing the enhancer. It may also affect the stability and/or solubility of the polypeptide with which it is combined. In general, it is expected that monovalent metallic cations such as sodium, potassium, lithium, rubidium, and cesium will be useful as counterions for anionic enhancers. Ammonia and organic amines form another class of cations that is expected to be appropriate for use with anionic enhancers having a carboxylic acid moiety. Examples of such organic amines include ethanolamine, diethanolamine, triethanolamine, 2-amino-2-methylethylamine, betaines, ethylenediamine, N,N-dibensylethylenetetraamine, arginine, hexamethylenetetraamine, histidine, N-methylpiperidine, lysine, piperazine, spermidine, spermine and tris(hydroxymethyl)aminomethane.
Since effective enhancement of polypeptide absorption in the lung was observed for a number of the enhancers tested, it is expected that many more will be found which also function in this manner. Starch microspheres effectively enhance the bioavailability of polypeptide delivered via the nasal membranes and were tested as an enhancer in the methods of the invention. Although they proved to be of little use for delivery via the pulmonary route in the animal model utilized herein, it is thought that this was mainly due to technical difficulties which, if overcome, may lead to successful delivery via the pulmonary route.
Chelators are a class of enhancers that are believed to act by binding calcium ions. Since calcium ions help maintain the dimensions of the space between cells and additionally reduce the solubility of a polypeptide, binding of these ions would in theory both increase the solubility of polypeptides, and increase the paracellular permeability of polypeptides. Although one chelator tested, the sodium salt of ethylenediaminetetraacetic acid (EDTA), was found to be ineffective in enhancing absorption of insulin in the rat model tested, other calcium ion-binding chelating agents may prove to be more useful.
Proportions of Polypeptide and Enhancer
The relative proportions of polypeptide and enhancer may be varied as desired. Sufficient enhancer must be present to permit efficient absorption of the inhaled polypeptide; however, the amount of enhancer should be kept as low as possible in order to minimize the risk of adverse effects caused by the enhancer. Although each particular polypeptide/enhancer combination must be tested to determine the optimal proportions, it is expected that to achieve acceptable absorption of the polypeptide, more than 10% of the polypeptide/enhancer mixture must be enhancer; for most types of enhancers, the proportion of enhancer should be more than 15% or more than 20% and will preferably be between 25% and 50%. The preferred ratio for each polypeptide/enhancer (or polypeptide/enhancer/diluent) combination can be readily determined by one of ordinary skill in the art of pharmacology by standard methods, based on such criteria as efficient, consistent delivery of the optimal dosage, minimization of side effects, and acceptable rate of absorption.
No further ingredients are needed for the action of the preparation, but may be included if desired. For example, the amount of powder which constitutes a single dose of a given polypeptide/surfactant combination could be increased (e.g., for use in an inhaler apparatus which by design requires a large powder volume per dose) by diluting the powder with pharmaceutically acceptable diluents. Other additives may be included to facilitate processing or to improve the powder properties or stability of the preparation. A flavouring agent could be added so that the proportion of the powder which is inevitably deposited in the mouth and throat would serve to give the patient positive feedback that a dose had been delivered from the inhaler device. Any such additive should have the following properties: (a) it is stable and does not disadvantageously affect the stability of the polypeptide and enhancer; (b) it does not disadvantageously interfere with absorption of the polypeptide; (c) it has good powder properties, as that term is understood in the pharmaceutical arts; (d) it is not hygroscopic; and (e) it has no adverse effects in the airways in the concentrations used. Useful types of such additives include mono-, di-, and polysaccharides, sugar alcohols, and other polyols: for example, lactose, glucose, raffinose, melezitose, lactitol, maltitol, trehalose, sucrose, mannitol, and starch. As reducing sugars such as lactose and glucose have a tendency to form complexes with proteins, non-reducing sugars such as raffinose, melezitose, lactitol, maltitol, trehalose, sucrose, mannitol and starch may be preferred additives for use in the present invention. Such additives may constitute anywhere from 0% (i.e., no additive) to nearly 100% of the total preparation.
In a preferred embodiment, this invention provides a therapeutic preparation of a pharmaceutically active polypeptide and a substance which enhances the absorption of said polypeptide in the lower respiratory tract, which preparation is in the form of a dry powder preparation suitable for inhalation of which at least 50% by mass consists of (a) particles having a diameter of less than about 10 microns or (b) agglomerates of said particles; in another preferred embodiment, the invention provides a therapeutic preparation comprising a pharmaceutically active polypeptide, a substance which enhances the absorption of polypeptide in the lower respiratory tract, and a pharmaceutically acceptable carrier, which preparation is in the form of a dry powder suitable for inhalation of which at least 50% by mass consists of (a) particles having a diameter of less than about 10 microns, or (b) agglomerates of said particles; and in a further preferred embodiment this invention provides a therapeutic preparation comprising active compounds (A) a pharmaceutically active polypeptide and (B) a substance which enhances the absorption of said polypeptide in the lower respiratory tract, wherein at least 50% of the total mass of active compounds (A) and (B) consists of particles having a diameter of less than about 10 microns, and a pharmaceutically acceptable carrier, which preparation is in the form of a dry powder preparation suitable for inhalation in which an ordered mixture may be formed between the active compounds and the pharmaceutically acceptable carrier.
The described powder preparation could be manufactured in several ways, using conventional techniques. In many cases, the purified polypeptide can be obtained from commercial sources. Alternatively, the polypeptide of interest can be purified from a naturally occurring source using standard biochemical techniques, or can be obtained by expression of prokaryotic or eukaryotic cells genetically engineered to contain a nucleotide sequence which encodes the polypeptide and has appropriate expression control sequences linked thereto (including a transgenic animal engineered to manufacture the desired peptide or protein, for example in its milk). Such methods are standard in the art (e.g., see Sambrook et al., Molecular Cloning: A Laboratory Manual; Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y., 1989). Peptides (i.e., polypeptides having 30 or fewer amino acid residues) can be readily synthesized by known chemical means.
Absorption enhancers as described above are also generally available from commercial sources, or can be manufactured using published methods. For ionic enhancers, the counterion associated with the enhancer can be replaced with another, if desired, using standard ion exchange techniques.
In manufacturing of the described powder preparation it will in general be necessary to micronize the powder in a suitable mill, e.g. a jet mill, at some point in the process, in order to produce primary particles in a size range appropriate for maximal deposition in the lower respiratory tract (i.e., under 10 μm). For example, one can dry mix polypeptide and enhancer powders, and then micronize the substances together; alternatively, the substances can be micronized separately, and then mixed. Where the compounds to be mixed have different physical properties such as hardness and brittleness, resistance to micronisation varies and they may require different pressures to be broken down to suitable particle sizes. When micronised together, therefore, the obtained particle size of one of the components may be unsatisfactory. In such case it would be advantageous to micronise the different components separately and then mix them.
It is also possible first to dissolve the components in a suitable solvent, e.g. water, to obtain mixing on the molecular level. This procedure also makes it possible to adjust the pH-value to a desired level, for instance to improve absorption of the polypeptide. The pharmaceutically accepted limits of pH 3.0 to 8.5 for inhalation products must be taken into account, since products with a pH outside these limits may induce irritation and constriction of the airways. To obtain a powder, the solvent must be removed by a process which retains the polypeptide's biological activity. Suitable drying methods include vacuum concentration, open drying, spray drying, and freeze drying. Temperatures over 40° C. for more than a few minutes should generally be avoided, as some degradation of certain polypeptides may occur. Following the drying step, the solid material can, if necessary, be ground to obtain a coarse powder, then, if necessary, micronized.
If desired, the micronized powder can be processed to improve the flow properties, e.g., by dry granulation to form spherical agglomerates with superior handling characteristics, before it is incorporated into the intended inhaler device. In such a case, the device would be configured to ensure that the agglomerates are substantially deagglomerated prior to exiting the device, so that the particles entering the respiratory tract of the patient are largely within the desired size range. Where an ordered mixture is desired, the active compound may be processed, for example by micronisation, in order to obtain, if desired, particles within a particular size range. The carrier may also be processed, for example to obtain a desired size and desirable surface properties, such as a particular surface to weight ratio, or a certain ruggedness, and to ensure optimal adhesion forces in the ordered mixture. Such physical requirements of an ordered mixture are well known, as are the various means of obtaining an ordered mixture which fulfills the said requirements, and may be determined easily by the skilled person according to the particular circumstances.
A preferred inhalation apparatus would have the following design characteristics: protection of the powder from moisture and no risk of occasional large doses; in addition as many as possible of the following are desired: protection of the powder from light; high respirable fraction and high lung deposition in a broad flow rate interval; low deviation of dose and respirable fraction; low retention of powder in the mouthpiece—this is particularly important for a multidose inhaler, where polypeptide retained in the mouthpiece could degrade and then be inhaled together with subsequent doses; low adsorption to the inhaler surfaces; flexibility in dose size; and low inhalation resistance. The inhaler is preferably a single dose inhaler although a multi dose inhaler, such as a multi dose, breath actuated, dry powder inhaler for multiple use, may also be employed. Peferably the inhaler used is a unit dose, breath actuated, dry powder inhaler for single use.
A number of dry powder formulations containing a polypeptide and various enhancers have been prepared and tested in an in vivo assay, and are described below. Also described is an in vitro assay useful for testing polypeptide/enhancer combinations.
A standard in vitro assay utilizing an epithelial cell line, CaCo-2 (available through the American Type Culture Collection (ATCC), Rockville, Md., USA), has been developed to assess the ability of various enhancer compounds to promote transport of markers across an epithelial cell monolayer, as a model for the epithelial cell layer which functions in the lung to separate the alveolus from the pulmonary blood supply.
In this assay, the enhancer and polypeptide or other marker are dissolved in aqueous solution at various proportions and/or concentrations, and applied to the apical side of the cell monolayer. After 60 min incubation at 37° C. and 95% RH (relative humidity), the amount of the marker on the basolateral side of the cells is determined, e.g., by use of a radioactively labelled marker.
For the enhancer tested, sodium caprate, the amount of marker (mannitol, MW 360) which appears on the basolateral side is dependent upon the concentration of enhancer used, at least up to 16 mM sodium caprate (FIG. 1). This is true even when the polypeptide insulin is added to the enhancer/mannitol mixture (1:3 sodium caprate:insulin, by weight) (FIG. 2). This concentration of sodium caprate (16 mM) was also found to promote absorption across the cell monolayer of two low molecular weight peptides, insulin (MW 5734) and vasopressin (MW 1208). The amount of insulin which passed across the monolayer doubled in the presence of 16 mM sodium caprate, compared to the amount in the absence of any enhancer; the amount of vasopressin which was absorbed across the monolayer increased 10-15 times compared to the amount in the absence of any enhancer.
In contrast, no increase in transport rate was observed for larger proteins such as cytochrome C (MW 12,300), carbonic anhydrase (MW 30,000) and albumin (MW 69,000) when tested at up to 16 mM sodium caprate. It is expected that at higher concentrations of sodium caprate, the permeability of the cells will be further increased, permitting the transport of larger polypeptides; however, the potential cytotoxicity of sodium caprate may prevent the use of substantially higher concentrations of this particular enhancer.
Other enhancers may permit transportation of larger polypeptides; these may also be tested in this in vitro model of epithelial cell permeability, which can be used as a screening tool for rapidly testing any desired polypeptide/enhancer combination for usefulness in the methods of the invention.
Each of the compounds listed in Table I was tested for its ability to enhance uptake of a polypeptide (insulin) in a rat model. The results with insulin are taken as indicative of the enhancer's potential for enhancement of absorption of other polypeptides.
Various forms of insulin were employed in the different trials: recombinant human, semisynthetic human or bovine. Each formulation was prepared as above, drying and processing the insulin/enhancer or insulin/enhancer/lactose solution to produce an inhalable powder. The powder was administered to rats by inhalation, and the blood glucose levels of the rats were subsequently monitored as a measure of insulin uptake. These levels were compared to the corresponding values obtained from rats which had inhaled insulin formulations without enhancer.
The same in vivo model system could be used to test any given peptide or protein for usefulness in the methods of the invention, by delivering by the same inhalation method a formulation containing the desired peptide or protein combined with an enhancer, and assaying for the concentration of the desired peptide or protein in the systemic circulation of the test animal (e.g., by standard immunoassays or biochemical assays as appropriate for the given peptide or protein).
Human hormone (hGH, MW 22 kD, source Humatrope from Lilly, 3 parts was mixed with sodium caprate (1 part). The mixture was milled in a Retsch mechanical mill to a particle size of mass median diameter 6.7 μm.
The resultant powder was administered intratraceally in rats and the uptake of hGH compared with that of a powder, MMD 9.6 μm, comprising hGH and mannitol in the same proportions and prepared in the same way as above.
The results indicated an improvement in the uptake of hGH in the formulation including sodium caprate, compared with the uptake in the formulation without enhancer.
Insulin is herein used as indicative of other polypeptides according to the present invention.
Biosynthetic human insulin (53 g) was micronised in an Airfilco Jet Mill (Trade Mark, Airfilco Process Plant Limited), with pressurised nitrogen (feed pressure 7 bar, chamber pressure 5 bar), to a mass median diameter of 2.4 micrometers.
Sodium caprate (170 g) was micronised in an Airfilco Jet Mill (TM), with pressurised nitrogen (feed pressure 5 bar, chamber pressure 3 bar), to a mass median diameter of 1.6 micrometers.
The micronised biosynthetic human insulin (45 g) and sodium caprate (14.26 g) were dry mixed according to the following procedure: Half of the insulin was added to a mixing device comprising a mixing cylinder of volume 4.4 liters divided, by a sieve of width 1 mm, into two compartments, with a metal ring in each compartment to aid mixing and stirring. The sodium caprate and finally the rest of the insulin, were added. The mixing cylinder was closed, turned 180 degrees, and mounted in a motorised shaking apparatus. The motor was turned on and shaking continued for approximately two minutes, until all the insulin and sodium caprate had passed through the sieve. The motor was turned off and the mixing cylinder turned 180 degrees, again mounted on the shaking apparatus and shaking was again effected until all the powder had passed through the sieve. This procedure was repeated a further eight times to give a total mixing time of approximately 20 minutes.
The preparation so obtained was administered to 5 dogs by inhalation, at a dosage level of 1 U./kg, and the plasma insulin level determined at various time points after administration.
The results obtained were compared with the plasma insulin levels obtained when biosynthetic insulin, micronised as above to a mass median diameter of 2.4 micrometers, were administered to five dogs in the same way and at the same dosage levels, and with the plasma insulin levels obtained when a therapeutic preparation of insulin and sodium caprate in a ratio of 90:10 was administered to five dogs in the same way and at the same dosage levels as above. In this case the therapeutic preparation was prepared as follows: Human semisynthetic insulin was gel filtrated to reduce the zinc content from 0.52% to 0.01% relative to content of insulin. Insulin (4.5 g) and sodium caprate (0.5 g) were dissolved in water (232 ml). The solution was stirred until clear and the pH adjusted to 7.0. The solution was concentrated by evaporation at 37° C. over a period of about two days. The obtained solid cake was crushed, and sieved through a 0.5 mm sieve, and the resultant powder micronised through a jet mill to particles with a mass median diameter of 3.1 micrometers.
The results of these comparisons are presented in FIG. 3 (p=0.0147 for the difference between 75:25 and 100:0). The results demonstrate some improvement in the bioavailability of insulin with the 90:10 formulation, and a dramatic improvement in the bioavailability of insulin with the 75:25 preparation including sodium caprate, as compared to insulin alone.
Patent Citations
Non-Patent Citations
Referenced by
Legal Events
Original Image


text:
Redefining Verification Performance (Part 2)
In my last blog, I gave a few examples of different ways of thinking about getting more work done by finding solutions that increase amount of work accomplished per cycle, instead of just a brute-force approach to the problem. Before I talk about advanced verification solutions, I want to talk about why performance even matters.
First, we all intuitively know that the sooner we find a bug, the cheaper it is to fix. Doug Josephson and Bob Gottlieb attempt to quantify this notion in their chapter "Silicon Debug," from the book Advances in Electronic Testing: Challenges and Methodologies (Springer, 2006). Figure 1 summarizes their findings in terms of the relative cost of finding bugs within a typical design cycle. Notice that a functional bug that prevents us from achieving first silicon success can cost us 10,000 X or more to fix than if it was found during the initial design phase.
Obviously, speed, accomplishment, efficiency, and quality of results are all important attributes to getting more work done, finding bugs sooner, and thus reducing cost.
Let's look and see how the industry as a whole is doing in achieving first silicon success. Figure 2 shows the 2002 and 2004 Ron Collett International functional verification studies and the late 2007 FarWest Research functional verification study. You can see that there is a continual downward trend in achieving first silicon success.
Figure 3 list the types of bugs that caused a respin, where functional bugs account for the largest contributor.
So this is the state of the industry today. But what about tomorrow's design? What additional performance requirements will be required to meet tomorrow challenges? Will brute force approaches to achieving verification performance really enable us to get more work done?
Figure 4 shows the International Technology Roadmap for Semiconductors' projected growth of transistors on a chip. Let's focus on the ten-year span from 2008 to 2018.
You can see that, within ten years, there is about a 10x increase in the number of transistors on a chip. Now obviously, not everyone will be creating behemoth designs that take advantage of all the available transistors in 2018. Yet, for the sake of argument, it is interesting to calculate what theoretical maximum increase in verification effort would be required to verify a large design in 2018 compared to 2008, as shown in Figure 5. The verification effort grows at a double-exponential rate with respect to the Moore's Law curve. Hence, if the number of transistors per chip increases 10X between 2008 and 2018, then the verification effort would increase 1024X.
Obviously, verification performance matters! Certainly, we as an industry can't afford a 1000x increase in verification teams. Nor will brute force verification approaches to the problem scale.
In my next blog, I'll discuss ideas on ways to improving verification performance.
Post Author
Posted August 8th, 2010, by Harry Foster
Post Tags
Post Comments
About Verification Horizons BLOG
This blog will provide an online forum to provide weekly updates on concepts, values, standards, methodologies and examples to assist with the understanding of what advanced functional verification technologies can do and how to most effectively apply them. We're looking forward to your comments and suggestions on the posts to make this a useful tool. Verification Horizons BLOG
@dennisbrophy Tweets
- Loading tweets...
@dave_59 Tweets
- Loading tweets...
@jhupcey Tweets
- Loading tweets...
One comment on this post | ↓ Add Your Own
Commented on August 11, 2010 at 7:02 pm
By Tweets that mention Redefining Verification Performance (Part 2) « Verification Horizons BLOG -- Topsy.com
[…] This post was mentioned on Twitter by Mentor Graphics, Olivier Coudert. Olivier Coudert said: Stressing the exp growth of verification costs RT @mentor_graphics: "Redefining Verification Performance." http://bit.ly/aTdjb4 […]
Add Your Comment
Recent Posts
- No to Know VIP – Part 2
- Driving More Accurate Dynamic Power Estimation
- NEW Formal & CDC Courses on Verification Academy
- It's Time for a New Verification Debug Data API (DDA)
- Accellera Portable Stimulus Working Group Accepting Technology Contributions
- Part 6: The 2014 Wilson Research Group Functional Verification Study
- An Agile Evolution in SoC Verification Panel @ DAC
- UVM Debug. A contest using class based testbench debug…
- No to Know VIP
- Part 5: The 2014 Wilson Research Group Functional Verification Study

subset: commoncrawl


text:
There are two ways to subscribe to our blog. You can receive an email that comes at most once a day with our latest blog posts OR you can subscribe to our RSS feed.
VCIR Winter consistently draws a highly qualified, engaged audience of over 300 leading venture capitalists, CEOs, entrepreneurs and service providers from around the region and across the country. If you are interested in demonstrating your support for the entrepreneurial community, become a sponsor of Venture Capital in the Rockies. Please contact Ryan Pollock or Dave Eberly, the conference co-chairs, for more information.
Sponsorship Benefits
Copyright © 2015 VCIR Winter. All Rights Reserved.


text:
Palate MP3 Player
Posted on June 5, 2012 by saya
What's the weirdest way you can think of to listen to music? Quite recently a student at Parson School of Design in New York pointed out that possibly we can feel music through our bones by sticking an MP3 player to the palate… Soooooo weird! The device includes a motor hooked up to the headphone jack of an iPod that lies flush against the wearer's palate, and it will start playing music as you control the iPod with your tongue. Are you interested in it? Either answer you may give, please check the video for more detail.
Designer: Aisen Chacin


text:
paid those chics their money!! man *** u yard barker
If you're a fan of the Lingerie Football League, you're not going to like the tone from a press release from the league office that has some wondering what will become of brand. Talk of focusing on "the sport" and "its athletes" seems to point to the league possibly changing with a focus towards attracting a mainstream TV package within the United States. Via: As the LFL heads into its 4th season in the United States, the league is preparing to further brand the sport internationally. LFL officials have announced there will be a major re-branding next week, which could include as much as a name change, new uniforms, and game equipment modification. The move is rumored to position the brand with a greater focus on the athletics of the sport and its athletes. Mitchell S. Mortaza, Founder & Chairman of the Lingerie Football League, was quoted as saying, "This is the next step in the maturation of our now global sport. While the Lingerie Football League name has drawn great media attention allowing us to showcase the sport to millions, we have now reached a crossroad of gaining credibility as a sport or continuing to be viewed as a gimmick. In the coming years we will establish this sport in Canada, the US, Australia, Europe and Asia as the most known form of American football globally. In order to reach the next milestone, we feel the focus has to be the sport and our amazing athletes." The league spent 2012 on hiatus in the United States, then expanded into Canada and played all-star games in Australia. Mortaza mentioned in December that ESPN would be featuring the LFL in the spring, yet not elaborating on details. It should be noted that players aren't paid for playing in the LFL. The league contends that it needs more ticket sales to make that a possibility. More than 5,000 people have signed a Change.org petition to stop the sport in Australia over its practice of not paying players. The LFL plans to announce a league name change, new logo and overall brand shift during a January 9 press conference. [LFL 360] Filed under: Lingerie Football League
these chics only get paid on the weekends
paid those chics their money!! man *** u yard barker
focus on the sport and the athleticism? lol no one gives a rats ass about that we are just looking at all the babes in their sexy outfits good luck with that if you change their uniforms in anyway i guarantee you the lfl will go down in flames
NFL News
Delivered to your inbox
You'll also receive Yardbarker's daily Top 10, featuring the best sports stories from around the web. Customize your newsletter to get articles on your favorite sports and teams. And the best part? It's free!
USWNT romps Japan 5-2 to win third Women's World Cup title
Report: JPP 'severely injured' hand in fireworks mishap
Blatter: European politicians helped Qatar land World Cup
Report: Cavs considering trading for Joe Johnson
Andrew Quarless found hiding in plant after firing gun
Odell Beckham: I don't want to be known only for 'the catch'
Borland on retirement: Health 'more important' than money
Three NBA teams that improved most early in offseason
Adam Eaton gets 4th of July surprise from brother
Clippers in talks with JaVale McGee, Amar'e Stoudemire
|Best of Yardbarker
|NFL News
|MLB News
Today's Best Stuff
For Bloggers
Join the Yardbarker Network for more promotion, traffic, and money.
Company Info
What is Yardbarker?
Yardbarker is the largest network of sports blogs and pro athlete blogs on the web. This site is the hub of the Yardbarker Network, where our editors and algorithms curate the best sports content from our network and beyond.
|© 2015 Yardbarker, Inc. All rights reserved. Use of this website (including any and all parts and components) constitutes your acceptance of these Terms of Use and Privacy Policy. (What's New?)


text:
Film-ticket sales rise, cheering industry
Posted: December 27, 2012 at 1:19 a.m.
The big deal for Hollywood is not the record $10.8 billion studios took in domestically in 2012 — it's the fact that the number of tickets sold went up for the first time in three years.
This story is only available from our archives.
Business, Pages 21 on 12/27/2012
« Previous Story
China opens world's longest high-speed rail l...
China started service on its 1,428-mile-long high-speed train line, the longest in the world, Wednesday as the nation continues to boost its investment in rail networks, in... Read »
Next Story »
Home prices in October up over year ago
Home prices rose in most major U.S. cities in October compared with a year ago, pushed up by rising sales and ... Read »


text:
- Attorney General Brad D. Schimel
- Fighting Crime
- Victim Assistance
- Consumer Protection
- Media Center
- About Department of Justice
- Topical Index
This Google™ translation feature is provided for informational purposes only.
The Office of the Attorney General is unable to guarantee the accuracy of this translation and is therefore not liable for any inaccurate information resulting from the translation application tool.
Please consult with a translator for accuracy if you are relying on the translation or are using this site for official business.Contact the Department of Justice
MADISON — Attorney General J.B. Van Hollen announced today that on January 9, 2012, the Wisconsin Department of Justice, acting as special prosecutor for Waukesha County, filed a criminal complaint in Waukesha County Circuit Court charging James D. Gardetto, a Milwaukee county resident, with: two counts of Felony Bail Jumping, one count of Mandatory Disclosure Prior To Sale, one count of Misrepresentation, one count of Obstructing An Officer: Giving False Information, and one count of Fraudulent Writings.
According to the criminal complaint, James Gardetto engaged in unfair trade practices between June 29, 2011, and August 24, 2011, by misrepresenting his business affiliations and locations to consumers of television repair services. Additionally, Gardetto provided a false business address to a police detective who was investigating his practices. Most of the charged conduct occurred after Gardetto was ordered by a Wisconsin State Circuit Court, in the context of a felony case, not to commit any new crimes as a condition of his release.
A criminal complaint is a document that alleges that a crime was committed by a person or a corporation. The defendant is presumed innocent unless and until proven guilty.
The charges are the result of an investigation by the Wisconsin Department of Agriculture, Trade and Consumer Protection. Wisconsin Statute Chapter 950 Victim Services are being provided by the Office of the Waukesha County District Attorney. Assistant Attorney General Eric D. Défort represents the State of Wisconsin as the special prosecutor.
A copy of the criminal complaint is available at:


text:
Today marks the 22nd anniversary on the tragic loss of an outstanding Marxist ideologue and revolutionary Communist, Jabulani Nobleman Nxumalo. The beloved "Mzala" was one of the greatest cadres ever produced by the vanguard party of the working class, the SA Communist Party (SACP) and African National Congress (ANC) Alliance.
Comrade Mzala departed during a significant moment of our revolution, during a time his soaring intellectual capacity and ideological brilliance were most needed. The apartheid autocracy had nearly conceded defeat, and the doors for a negotiated settlement were wide open. It was a confused time, given the heroic victory of uMkhonto weSizwe (MK), Angolan troops and Cuban allies against the apartheid SADF in the battle of Cuito Cuanavale on the one hand, but the triumph of capitalist barbarity over Socialism in the Soviet Union on the other. On the home front, the working class and poor had begun to exercise a dual power, forcing the apartheid regime out of many townships, and compelling the release of all political prisoners, unbanning of political parties and unconditional return of all exiles.
We remember this great revolutionary and thinker of the working class being confronted by the triple crisis of poverty, unemployment and inequality – which 22 years ago were already severe, but which in many ways worsened since. Had Mzala lived and continued to build the Communist movement, we may not have suffered the neoliberal economic policy choices imposed on our democratically-elected government by the minerals-energy complex and finance oligarchy. We may not have suffered such co-option of key leaders who occupied strategic positions in the State and there imposed neoliberal policies without consultation and often in contradiction to the Reconstruction and Development Programme and Freedom Charter mandates.
We are now the most unequal large society on earth. We were rated by the World Economic Forum as having the earth's most militant working class in 2012. And are we also the country with amongst the highest number of service delivery protests in the world.
A Fighter in the battle of ideas!
For those who take the time to learn about his role, Comrade Mzala continues to be a source of inspiration to the toiling and exploited workers of our country, and to the unemployed and marginalised working class youth who demand jobs with dignity and a living wage.
Dump the Neoliberal NDP and Advance the Freedom Charter!
In memory of this gigantic figure and product of mass struggles, we call on the ANC-led government to dump the National Development Plan (NDP) because of its embedded neoliberalism. Like the imposition of Gear in 1996, it accepts the macroeconomic parameters as given, and worsens our vulnerability to world capitalist crisis. We dare not allow it to become the policy vision for the country for the next coming twenty years, for that would lead to the same results as we have suffered under existing neoliberal policy: social tensions rising to the point of explosion. Instead we need the ambition of the Freedom Charter, starting with the crucial nationalisation of strategic industries that the capitalist class show sustained incapacity to manage, in the genuine interests of all South Africans.


text:
I just had a fascinating Twitter exchange with my colleague and good friend Alan Lepofsky.
I had tweeted: "Reason #71 why I hate email: I start my day playing catch-up."
Alan replied: "And does the same thing not happen in social software? At least in email its all in one place."
And I thought to myself: No, Alan, It's really no the same thing.
I can see where Alan is coming from. He has argued eloquently that shifting correspondence from email to activity streams doesn't really accomplish anything. Of course on some level Alan's right: Messages are messages, whether they come through email or an activity stream.
But there's a huge, fundamental, monumental difference between email and activity streams: Posts to an activity stream are usually public inside the enterprise. (Or at least posted to a group.)
The transparent nature of the activity stream changes everything. When I reply to a post in an activity stream (a "Signal" in Socialtext-ese), I'm not only writing for the person to whose Signal I'm replying. I'm writing for everyone who has access to that conversation thread.
That's a totally different mindset. When I go through my emails, it's a series of updates–usually reactive–to individuals: Don't do this, that is approved, can't make this meeting, missed you at that conference. When i go through Signals, it's an opportunity to model, to muse, to question, to inspire in a uniquely public and transparent way: This is how we should think about this, help me understand that, I'm making this a personal priority, let's celebrate the awesome job she did on that.
So maybe it's just my Meyers-Briggs type but no, I don't feel like I'm playing catch-up on Signals. There's work waiting for me there, to be sure, but it's work that adds to my energy, rather than taking it away.


text:
Just wanted to introduce myself and say thanks for all of the good info. I'm hoping to start building a neapolitan oven sometime in the next year or so and I've gotten lots of good ideas from the forum. Thanks again! Pete
Re: Hello
Welcome, Pete.
Are you thinking about the fornobravo low dome as in the pompeii plans (18" dome in 42" oven) or the more radical low dome (14", if I remember correctly) that has been posted here recently?
Re: Hello
Thanks for the welcome. I'm looking to replicate a neapolitan pizza oven as closely as possible within a reasonable budjet and amount of space. The closest thing on this site would probably be the low dome pompei or the oven that johnrbeck is creating. So much good info and help available here, I'm glad I found this forum. Peteg
|All times are GMT -7. The time now is 10:05 AM.
Powered by vBulletin® Copyright ©2000 - 2015, Jelsoft Enterprises Ltd.
Search Engine Friendly URLs by vBSEO 3.6.0
© 2006/10 Forno Bravo, LLC


text:
39 CFR 3060.11 - Valuation of assets.
For the purposes of 39 U.S.C. 2011, the total assets of the Postal Service theoretical competitive products enterprise are the greater of:
(a) The percentage of total Postal Service revenues and receipts from competitive products times the total net assets of the Postal Service, or
(b) The net assets related to the provision of competitive products as determined pursuant to § 3060.12.
Title 39 published on 2014-07-01.
No entries appear in the Federal Register after this date, for 39 CFR Part 3060.


text:
A collection of news and information related to William R. Haine published by this site and its partners.
Top William R. Haine Articles
Displaying items 1-7
Auditor General reappointed amid praise for handling Blagojevich case
Illinois Senate approves gay marriage
Illinois lawmakers approve concealed carry gun bill
On the 'Scholarship' list in SpringfieldStory | Jan 31, 2012Where do our lawmakers stand on the issue of legislative scholarships -- those tuition waivers that members of the state house and senate have traditionally been allowed to dispense to constituents? As part of the renewed effort to abolish that......
Best hope for gay marriage foes? PseudonymsStory | Jan 3, 2013If Hollywood decides many years from now to make an epic motion picture detailing the fight for gay marriage in Illinois, perhaps the film director will mercifully change Sen. Christine Radogno to "Sen. Christine Randolph," and Sen. James Meeks to......
Change would let religions out of same-sex adoptionsStory | May 11, 2011 | 6:15 PMRep. Dwight Kay (R-Edwardsville) introduced an amendment to the civil unions law today that would ensure religious child welfare agencies can turn away committed same-sex couples who want to adopt children or provide foster homes. Kay could not be...
Quinn stands by opposition to conceal carry in IllinoisStory | Jun 22, 2011 | 12:57 PMSPRINGFIELD --- Gov. Pat Quinn today stood solidly today behind his opposition to allowing concealed weapons in Illinois even though Wisconsin is on the verge of becoming the 49th state with some form of such a law. "We must ensure the safety of...


text:
When it comes to lower body workouts, no regime is complete without some form of squatting exercise. When performed correctly, the squat can produce incredible gains in both strength and size whilst targeting several key muscle groups – including the quadriceps, hamstrings, gluteals and the core. Conversely, when performed badly, the squat has the ability at the very least to cause injury and at worst to result in an exercise ending injury.
Don't let this put you off however! As long as the follow the necessary guidelines of lifting correctly and don't ever substitute good form, then you can continue to reap the rewards of this incredible compound exercise for years to come. The purpose of this article is to highlight 5 commonly reported mistakes associated with squatting in the hope that you can recognise them and steer well clear.
It's sometimes easier to say what not to do than what to do so with that in mind let us take a look at our first common squatting mistake;
Don't let squatting get the better of you. By remembering strict form at all times and avoiding these 5 common mistakes often made by individuals then you are on your way to getting the most out of your squatting routine and reaping the rewards it brings.


text:
Boy Scout Troop 123 of Manchester is please to announce that Brendan Sullivan has achieved the rank of Eagle Scout.
Brendan is the son of Paul and Melissa Sullivan of Manchester. He is a senior at University High School of Science and Engineering, graduating with honors. Brendan was also selected to the National Honor Society. He was also chosen as All Conference at first baseman and the team's MVP.


text:
Addis Ababa — ChildFund Ethiopia yesterday launched a three year strategic programme designed to improve the well-being of deprived, vulnerable and excluded children as well as families in target areas in Addis .
The organization also announced that it has already allocated close to 148 million birr for the implementation of the programme which will be carried out with partner organizations.
Addis Ababa Area Coordinator Sisay Worku said that the strategic programme was designed following rigorous research and identification of child vulnerability in various parts of the city with the participation of children.
Partner organizations implementing the programme include Arada Child and Family Development Organization, Sheger Child and Development Charitable Society, Merkato Child and Fmily Charitable Society, Kore Child and Family Development Organization, as well as the Ethiopian Orthodox Church-Child and Family Development Organization.
According to Sisay , the study indicated that child vulnerability in different parts of the city ranges from sex abuse and child labour to lack of proper nutrition." Hence, the strategic plan was designed in a way to addresses specific problems in different parts of the city."
The components of the strategic plan include, among others, rehabilitation of abused children, facilitation of educational opportunities and building family income.
Organization Country Director Charless Danzoll said that the implementation of the strategic plan will also contribute to the realization of the national Growth and Transformation Plan( GTP).
ChildFund belongs to the bigger family of ChildFund International, which operates in 31 countries.


text:
The Original Brazilian Blow dry uses products from the Inoar Professional range. It smoothes waves, tames unruly curls, eliminates frizz and makes hair highly flickable and swooshy. The Inoar products contain Argan oil which can only be found in Morocco and is enriched with Keratin and is trusted by silky locked Hollywood stars like Jennifer Lopez, Penelope Cruz and Kate Moss. This quality treatment is safe on coloured and bleached hair and leaves hair soft and manageable for up to 12 weeks, just in time for winter's frizzy hair weather.
Though not sisters in blood, the Sunkissed Sisters have all the charm and intimacy of a family business. They're highly skilled in making every guest look as if they could be one of their beautiful sisters and make you feel like part of the family. Under the gentle strong hands of Candice and Shannon, you can be sure to get a top quality feel-good treatment and a salon chat of the highest calibre.
Enjoy 12 weeks of silky smooth hair without 'did I switch the straightener off?' moments.
Hairy fact: Arabians believed that ink cures the terrible disease ﻇﻛﻑﻼﻘﻄﺙﺟﻄ ﺖﮠﮧﮛﮀ ﮄﭶﭺﮔﮤﮝﮚ, more commonly known as 'split ends'. Dames and damsels would dip the ends of their hair in ink to repair the damage and also give hair that grungy look.


text:
Arturo Rodríguez
From Wikipedia, the free encyclopedia
This article is about the boxer, not the president of the United Farm Workers.
|Olympic medalist
Arturo Rodríguez
|Medal record
|Men's Boxing
|1928 Amsterdam
Arturo "El Mono" (The Monkey) J. Rodríguez Jurado (May 26, 1907 – November 22, 1982) was an Argentine boxer who competed in the 1924 Summer Olympics and in the 1928 Summer Olympics.
In 1924, he lost his first fight against Thyge Petersen and was eliminated in the first round of the light heavyweight class.
Four years later, Rodríguez won the gold medal in the heavyweight class after winning the final against Nils Ramm.
|This biographical article related to an Argentine boxer is a stub. You can help Wikipedia by expanding it.
- 1907 births
- 1982 deaths
- Argentine people of African descent
- Argentine boxers
- Light-heavyweight boxers
- Heavyweight boxers
- Olympic boxers of Argentina
- Boxers at the 1924 Summer Olympics
- Boxers at the 1928 Summer Olympics
- Olympic gold medalists for Argentina
- Olympic medalists in boxing
- Male boxers
- Argentine boxing biography stubs


text:
The following is an archive of a post made to our
'vox mailing list'
by one of its subscribers.
On Fri, 26 Oct 2001, Peter Jay Salzman wrote:
> begin: John C. Alden <firstname.lastname@example.com> quote
> > At 12:05 AM 10/26/01 -0700, you wrote:
> > >begin: Mark K. Kim <firstname.lastname@example.com> quote
> > >> On Thu, 25 Oct 2001, Peter Jay Salzman wrote:
> > >
> > >it all goes into the equation of running a well-oiled system.
> > >
> > >pete
> >
> > You're supposed to OIL these things? Sheesh, no one told me!
> well, not all machines. you're only supposed to oil the really hot CPU's.
> there's a couple of benefits:
> 1. because of the heat generated by cpu's, the cpu pins have a tendancy to
> oxidize against the walls of the pin inserts. oiling the pins will help
> prevent cpu's from getting stuck. particular socket type cpu's.
I should oil my memory also.
> 2. oil helps transfer the heat away from the CPU. this also helps the cpu
> run faster.
Is this how Intel got to 2GHz?
> for these reasons, it's highly recommended to apply a light coating of oil on
> your cpu. there are special oils made for the CPU. if you have an AMD chip,
I didn't see any at Fry's. :( Does anyone want to get in on a special
order direct from AMD? We can save on shipping.
> the thing is, any light-weight cpu oil would work just as fine. i personally
> use normal cooking vegetable oil. my guess is that something peanut oil
> would probably be too heavy for this particular application.
But you have an Athlon. Aren't you violating the warranty by using just
veggie oil??
> ps- oil also helps in the hot-swapping of IDE devices.
Good idea. It'll help get stubborn power connectors off. If I open the
drive, I may be able to oil the spindle to make it run at 10000RPM.
Hosting provided by:
Sunset Systems
Sunset Systems offers preconfigured Linux
systems, remote system administration and
custom software development.
LUGOD: Linux Users' Group of Davis
PO Box 2082, Davis, CA 95617
Contact Us
LUGOD is a 501(c)7 non-profit organization
based in Davis, California
and serving the Sacramento area.
"Linux" is a trademark of Linus Torvalds.


text:
The DOE General Competencies are the personal and professional attributes that are critical to successful performance. A competency model is a collection of competencies that together define successful performance in a particular work setting. Competency models can be developed for specific jobs, job groups, organizations, occupations or industries.
Fundamental Competencies
- Interpersonal Skills - Treats others with courtesy, sensitivity, and respect. Considers and responds appropriately to the needs and feelings of different people in different situations. Perceives, assesses, and positively influences one's own and other individuals' emotions.
- Oral Communication - Makes clear and convincing oral presentations. Listens effectively; clarifies information as needed.
- Integrity/Honesty - Behaves in an honest, fair, and ethical manner. Shows consistency in words and actions. Models high standards of ethics.
- Written Communication - Writes in a clear, concise, organized, and convincing manner for the intended audience.
- Continual Learning - Assesses and recognizes own strengths and weaknesses; pursues self-development.
- Public Service Motivation - Shows a commitment to serve the public. Ensures that actions meet public needs; aligns organizational objectives and practices with public interests.
Leading Change
- Creativity and Innovation - Develops new insights into situations; questions conventional approaches; encourages new ideas and innovations; designs and implements new or cutting edge programs/processes.
- External Awareness - Understands and keeps up-to-date on local, national, and international policies and trends that affect the organization and shape stakeholders' views. Demonstrates awareness of the organization's impact on the external environment.
- Flexibility - Openness to change and new information; adapts rapidly to new information, changing conditions, or unexpected obstacles.
- Resilience - Deals effectively with pressure; remains optimistic and persistent, even under adversity. Recovers quickly from setbacks. Identifies stress factors and applies learned coping skills to mitigate those factors.
- Strategic Thinking - Formulates objectives and priorities, and implements plans consistent with the long-term interests of the organization in a global environment. Capitalizes on opportunities and manages risks.
- Vision - Takes a long-term view and builds a shared vision with others; acts as a catalyst for organizational change. Influences others to translate vision into action.
Leading People
- Conflict Management - Encourages creative tension and differences of opinions. Anticipates and takes steps to prevent counter-productive confrontations. Manages and resolves conflicts and disagreements in a constructive manner.
- Leveraging Diversity - Fosters an inclusive workplace where diversity and individual differences are valued and leveraged to achieve the vision and mission of the organization.
- Developing Others - Develops the ability of others to perform and contributes to the organization by providing ongoing feedback and opportunities to learn through formal and informal methods.
- Team Building - Inspires and fosters team commitment, spirit, pride, and trust. Facilitates cooperation and motivates team members to accomplish group goals.
Results Driven
- Accountability - Determines objectives, sets priorities, and delegates work. Holds self and others accountable for measurable high-quality, timely, and cost-effective results - monitors and evaluates plans, focuses on results, and measures attainment of outcomes. Accepts responsibility for mistakes. Complies with established control systems and rules.
- Customer Service - Balances interests of a variety of clients, and readily readjusts priorities to respond effectively to pressing and changing demands for information, advice and assistance. Anticipates and meets the needs of clients; achieves quality end products; and commits to continuous improvement of services.
- Decisiveness - Makes well-informed, effective, and timely decisions, even when data are limited or solutions produce unpleasant consequences; perceives the impact and implications of decisions.
- Entrepreneurship - Positions the organization for future success by identifying new opportunities; builds the organization by developing or improving products or services. Takes calculated risks to accomplish organizational objectives.
- Problem Solving - Identifies and analyzes problems; weighs relevance and accuracy of information; generates and evaluates alternative solutions; makes recommendations.
- Technical Credibility - Understands and appropriately applies current laws, policies, and best business practices related to a specialized expertise.
Business Acumen
- Financial Management - Understands the organization's financial processes. Prepares, justifies, and administers the program or project budget. Oversees procurement and contracting to achieve desired results. Monitors expenditures and uses cost-benefit thinking to set priorities.
- Human Capital Management - Builds and manages workforce based on organizational goals, budget considerations, and staffing needs. Ensures that employees are appropriately recruited, selected, appraised, and rewarded; takes action to address performance problems. Manages a multi-sector workforce and a variety of work situations.
- Technology Utilization - Keeps up-to-date on technological developments. Makes effective use of technology to achieve results. Familiarity and effectiveness with the application of e-communications, including e-mail, wireless devices, text messaging, audio/video files, etc., including the exercise of proper e-mail etiquette and the use of standard, DOE provided, computer applications to meet work requirements and updates capabilities as needed. (Examples are Microsoft Word, Outlook, Access, Excel, PowerPoint, and corporate information systems.) Ensures access to and security of information technology (IT) systems.
- Workplace Safety - Demonstrates safe work practices appropriate for the position and work environment.
- Knowledge of DOE Business - Understands and supports the various business lines of the Department. Knows how position and organizational functions foster, relate and connect to the Department's mission.
Building Coalitions
- Partnering - Develops networks and builds alliances; collaborates across boundaries to build strategic relationships and achieve common goals.
- Political Savvy - Identifies the internal and external politics that impact the work of the organization. Perceives organizational and political reality and acts accordingly.
- Influencing/Negotiating - Persuades others; builds consensus through give and take; gains cooperation from others to obtain information and accomplish goals.


text:
|Page: 1 of 1
|Sort By:
Hotels & Resorts Alachua, Florida - An intimate tropical setting and immaculate suites are the hallmarks of our lovely boutique hotel. Only 6 rooms, all with full kitchens and most with ocean views and private balconies, make for a truly relaxing getaway.
Hotels & Resorts Alachua, Florida - Your Vacation Romance and Destination Specialist. Give us a call for special pricing and bookings
Hotels & Resorts Alachua, Florida - Quality Inn Alachua is located approximately 18 miles from the University of Florida and 20 miles from Gainesville Regional Airport.
Hotels & Resorts Alachua, Florida - Conveniently located at the intersection of Interstate 75 and U.S. Highway 441, the Econo Lodge Alachua is just minutes from the University of Florida.
Find great deals on quality hotels & resorts in Alachua Florida, or indulge at one of our luxury resorts. Take advantage of the many amenities that can be included with your stay such as in-room internet access, wifi, room service, fitness center, pool, hot tub, steam room, and shuttle services to and from the airport. Browse our hotels and resorts in Alachua Florida and plan your Alachua Florida vacation today!


text:
The earlier you detect any cancer, the better your chance of surviving it. Learn about things you can do to help detect three of the most common cancers faced by women - breast cancer, colon cancer, and cervical cancer. Also review the recommended schedule for cancer screenings.
You might think that heart disease is a man's problem. In fact, heart disease is the number one killer among women. Even breast cancer claims fewer lives. That's why you need to take action to keep your heart healthy - and lower your risk of having a heart attack or stroke
With so many fad diets in the news, it's easy to lose sight of what healthy eating looks like. But there's really no mystery. Good nutrition means a long-term commitment healthy daily habits.


text:
Kay, Linda and Reilly, Rosemary C. and Connolly, Kate and Cohen, Stephen (2010) Help or harm? Symbolic violence, secondary trauma and the impact of press coverage on a community. Journalism Practice, 4 (4). pp. 421-438. ISSN 1751-2786
Concordia University Libraries
Physical Address: 1400 de Maisonneuve Blvd West, Montreal, Quebec, Canada
Mailing Address: 1455 de Maisonneuve Blvd West, Montreal, Quebec, Canada H3G 1M8
Telephone (1) 514-848-2424
Contact Us |
| Legal
Back to Top


text:
Book Search
Gramsci and Marxist Theory (RLE: Gramsci)
Series: Routledge Library Editions: Gramsci
This book familiarizes the English-speaking reader with the debate on the originality of Gramsci's thought and its importance for the development of Marxist theory. The contributors present the principal viewpoints regarding Gramsci's theoretical contribution to Marxism, focussing in particular on...
Published March 13th 2014 by Routledge
On the Political
Series: Thinking in Action
Since September 11th, we frequently hear that political differences should be put aside: the real struggle is between good and evil. What does this mean for political and social life? Is there a 'Third Way' beyond left and right, and if so, should we fear or welcome it?This thought-provoking book...
Published April 15th 2005 by Routledge
Deconstruction and Pragmatism
Deconstruction and pragmatism constitute two of the major intellectual influences on the contemporary theoretical scene; influences personified in the work of Jacques Derrida and Richard Rorty. Both Rortian pragmatism, which draws the consequences of post-war developments in Anglo-American...
Published September 5th 1996 by Routledge


text:
Look Inside | Enlarge Cover
Enlarge Cover
Shaw Books | Mar 07, 2000
Shaw Books
| Mar 07, 2000
Shaw Books
| Feb 05, 2014
| 112 Pages
Living on Solid GroundMost couples struggle at some point in their relationship with hard questions of marriage and family life, such as, what is God's primary purpose for marriage? What does it mean for a man to be the head of a home? Is divorce ever acceptable? How do we raise children who will love God? What does God have to say about the way we communicate, or about sexual intimacy?Authors Steve and Dee Brestin have wrestled with these questions in their own marriage and have found that God's Word is the only reliable blue-print for marriage and family life. This study will guide you through the encouragement that the Bible gives for those relationships. Jesus told us the storms will come and batter our homes, but if we obey him, our house will stand firm.
STEVE and DEE BRESTIN have written several books and Fisherman Bible Studyguides, including Friendship and Higher Ground. Dee is also the author of Falling in Love with Jesus (coauthored with Kathy Troccoli) and The Friendships of Women.
DEE BRESTIN is the author of several Fisherman guides including Proverbs and Parables and Building Your House on the Lord. She also has written Falling in Love with Jesus(with Kathy Troccoli) and The Friendships of Women. She and her husband,… More about Dee Brestin
Visit other sites on the Penguin Random House Network


text:
follow Dictionary.com
1713, from shell (n.) + lac (see lacquer). Translates French laque en écailles "lac in thin plates."
1876, from shellack (n.). The slang sense of "beat soundly" is 1920s, perhaps from the notion of shellac as a "finish." Shellacked "drunk" is from 1922 (cf. plastered). Related: Shellacking.
To pay; shell out: to shell at least a buck (1948+)
Related Terms


text:
Original recipe yields 4 servings
Amount per serving ({{servings}} total)
Based on a 2,000 calorie diet
Ready In
It may have been that this recipe just didnt work for my family. But the combination of milk and lime juice , just didnt sit well w/ my taste...
YUCK...The sauce was so thick, I could have spackled the wall with it!!! 1/2 cup of flour was just way too much. Cardboard has better flavor. I tried to follow the recipe, but in the end couldn...
It was pretty easy to make since it used common ingredients. I had no tomato paste, so I used a half a 16-oz can of Italian-seasoned diced tomatoes, which added flavor to the sauce.


text:
The Godfather is one of the best movies of all time. Which means DVDs and behind-the-scenes footage has been shared time and time again about the making of the film. But James Caan tells one story we hadn't heard yet … Continued
opie & anthony
'He was like a little girl,' says James Caan of The Godfather's Luca Brasi
WATCH: Stephen Merchant recounts epic party foul on O&A
Today everyone is talking about Stephen Merchant's epic lip syncing battle with Joseph Gordon Levitt and Jimmy Fallon on Late Night. But last week he was known better (at least among his fellow comedians) for another epic moment–an epic party … Continued
Watch: Wolverine eats a cronut
Wolverine wants a cronut? The Opie and Anthony Show delivers. Or Dominique Ansel, the man who invented the cronut, delivers.
Why Anthony Bourdain supports military action in Syria
While the United States hems and haws over military action in Syria, chef, author and TV personality Anthony Bourdain made his stance clear on The Opie & Anthony Show. "If we bomb Syria, right, it's completely against our national interests … Continued
Breaking Bad cast: It's so hard to say goodbye
Dean Norris and Betsy Brandt can't believe Breaking Bad is over. The pair, who played DEA agent Hank Schrader and his wife, Marie, sat down with Opie and Anthony to talk about the show's fifth and final season and how … Continued
WATCH: Ozzy Osbourne Talks Drugs, Blackouts and "Breaking Bad" [EXPLICIT]
Ozzy Osbourne has a storied past. With Black Sabbath reuniting and set to top the charts for the first time in 43 years with their new album "13," Osbourne sat down with Jim Norton on "The Opie and Anthony Show" … Continued
WATCH: Crispin Glover Shares Sordid Details from the Set of "Back to the Future"
Actor Crispin Glover (a.k.a. George McFly) sat down with Opie & Anthony and comedian Jim Norton to discuss his controversial exclusion from the second "Back to the Future" movie. From lawsuits and lies to conspiracies and alternate endings, he sets … Continued
WATCH: Van Halen's Extreme Game of "Hot Lava?"
Van Halen lead singer David Lee Roth sat down with comedian Jay Mohr on SiriusXM's Opie & Anthony to reminisce about his childhood, using the an anecdote of jumping from bed to bed and never touching the floor aka "playing … Continued
WATCH: Courtney Love Reveals Music's Dirty Little Auto-Tune Secret
Courtney Love doesn't think there's any shame in accutuning vocals. But she does think Anthony Kiedis needs a little help from the auto-tuning software to hit the right notes, while Mary J. Blige sounds better without it. Love sits down … Continued
LISTEN: Courtney Love Gives Advice to Amanda Bynes
If anyone knows a thing or two about hard times in the public eye, it's Courtney Love. So her advice to Amanda Bynes to "get yourself together" may not have been meant as criticism as much as a piece of … Continued


text:
Check Availability
My mother has been without AC for 2 weeks and she has a medical condition. The Management states it will be another week of 90 degree heat before she can get an AC unit in the apartment. When the Property manager… Full Review ▶
No pizza deilvery is made to this location, and at no time has anyone said they couldn't, except the pizza companies! The office can't even get pizza during the day. Full Review ▶
This WAS a pretty good place to start over. Having been a single mom with 3 kids and no where to go...this place was heaven! The office was inside of Desert Winds (the center of Caravan Circle), but it was relocated… Full Review ▶
I am a past resident of Silver Creek/Desert Winds Apartments and I have to say my living experiene there was nothing but good. When looking for an apt, I toured many different subsicized locations and was very pleased with the appearance… Full Review ▶
I delivered pizzas to this place several times and by the order of the property mgmt.we are not allowed to enter beyond the gates b/c the apartment complex's insurance can't be held liable if a person gets killed on their property.… Full Review ▶
Laundry On-Site
Rent Trends
|Avg. Monthly Rent
|$ {{complexPricing.averageMonthlyRent}}
|$ {{complexPricing.minMonthlyRent}} - $ {{complexPricing.maxMonthlyRent}}
Disclaimer: Rental rates have been collected from Internet users and represent snapshots of a rental prices over time. These rates may not be a reliable indicator of current rents or the price offered to new residents. How to use this information.
0 Images for this Property
Nearby Apartments
- 0%
Regents301 Caravan Cir, Jacksonville, FL 32216 17 Reviews
- 100%
Riverview Apartments301 Caravan Circle,, Jacksonville, FL 32216 1 Reviews
- 0%
Peyton Ridge Apartments1800 Corporate Square Blvd, Jacksonville, FL 32216 0 Reviews


text:
We just moved in here on 3/2/12. This place is gross, we want to get out of our lease too. The roaches is a huge problem, me and my husband have both been sick. We do our dishes and Laundry and put them in totes right away. This place does not feel like home at all, we can't even unpack. We are just trying to keep the place as clean as possible so our little guy does not get sick. We had to put our job search on hold for the first three weeks because all our time and money was due to trying to clean this filthy place. I asked for some kind of compensation for what we have been through already, but all they can do is give me $100 off rent. These apartments are not worth the price. They need to be condemmed, I wish they would have told us about the critters and how dirty everything was before we signed that damn lease. I wish the people in the office had to live here and live out of totes as well and worry about getting sick. It is not right to charge people to live in these conditions. I am not paying my rent this month if we get kicked out it would be a blessing, our old landlord in Minnesota wants us back so I know it is not our fault. We are great tenants, but I don't agree with living in this hell hole and paying for it. I don't like the concept of paying rent for the cockroaches to have a place to live. It does stink here.
I've looked into breaking my lease already, the penalty is the 1st months rent since it was free!! I have found another place to live already I just need to come up with the deposit etc so I can move. Hopefully it will be by the end of April. I'm tired of living with roaches, I also live out of plastic bins.
Nearby Apartments
- 74%
Oasis Place650 Sierra Vista Drive, Las Vegas, NV 89109 38 Reviews
- 0%
Blue Harbor Club Apartments3380 Swenson St, Las Vegas, NV 89109 5 Reviews
- 40%
Kona Loha Apartments594 Sierra Vista Dr, Las Vegas, NV 89109 5 Reviews


text:
Football: Coach Stewart Quotes
MORGANTOWN, W.Va. – WVU football coach Bill Stewart quotes from Tuesday's press conference
Opening Statement
It was a physical football game against Syracuse. I told you guys that after the game and on Sunday and Monday during the teleconference calls. It was a hard hitting game. We were certainly on the disappointing end of that, and I do not like that.
I hope that it serves as a wake up call to our football program so that we can get back on track. We have a big chore awaiting us in Connecticut this Friday night.
The good news about the game is that even though it was hard-hitting, we came out relatively injury free.
I know that the Mountaineers' hearts and spirits are bruised, and now we have a chance in three days to remedy that situation. It is never fun being on the losing end of any football game.
On Syracuse's play and putting pressure on the quarterback
They used some blitzes, and they let it all fly. I think if we would have been able to score early, instead of throwing the interception, to go up 21-10, our game plan could have changed a little bit as well.
On WVU's offense
I see use playing hard. I see us not making a lot of mental mistakes. I see us compete. I see us make plays.
It was good to see Noel (Devine) running again. I saw him get hit in the open field, and it kind of shocked me a little bit. But it was good to see him back and to get over 100 yards.
I thought Ryan Clarke ran hard, and I thought at times we caught the ball well. Our young sophomore quarterback (Geno Smith) struggled. It happens and you just work to get that back on track.
I didn't like the way we finished. I thought we were going to win at the end of the game, and I thought we had the calls to win. But you have to give the opponents credit. They made some plays and we didn't.
You make the offense more consistent by finishing and by getting better, and by getting the ball in to play-makers' hands. It is just hard work. I don't think there is any magic wand to wave. You block, you tackle, you work and you get better.
On the tight end position
They both (Will Johnson and Tyler Urban) play now. Will Johnson is playing pretty well. That is not to say that Tyler isn't. When there is an injury and you go down for a couple of games and someone steps in and plays well, I don't see much reason to change that.
Tyler is going to play more, and we are going to go 50/50 with them. Both are good players.
I think both guys are playing and blocking well. I would like to get the ball to the tight end.
On Geno Smith rebounding
He is steady, even if he didn't play his best. I don't think we have to tell the offensive line they didn't play their best, and the entire offense. But I am not going to let one side of the ball dictate why we lost.
On Connecticut being a good team
They are a BIG EAST team, and anything can happen. We play pretty tough football in this league.
I will go back to what I said when I took this job. You better respect all and fear none. You better play each and every outing like it is your last. And you better enjoy the fruits of your hard work and efforts in practice. Go out, get under the lights and play football. Do not worry about what your opponent does. Worry about what we do.
On taking one game at a time
We are at round No. 3, game No. 3, and when you lose that mindset, you will get beat.
On having another quick turnaround
I wish that we could have played tonight. I can't wait to get back on the saddle. I want to play, and I want to make amends. We want to get back to Mountaineer winning.
On Terence Garvin and the rest of the defense
He (Terence Garvin) is in a hit position, and he is doing very well.
I told Anthony Leonard how proud I was of him this weekend. He was our player of the game (against Syracuse). He was written off and told that his feet were too slow, that he was club footed and that he was not Reed Williams. He has proven that if you pay your dues and pay attention to details, you will do well.
On playing weeknight games
I like the fact that we (the BIG EAST) get to play in Thursday and Friday night games. It is due to the fact that we play good football.
Football: KJ Dillon Preseason
Football: Tony Gibson Preseason
Football: Skyler Howard Preseason
Coach Dana Holgorsen
2015 Bob Huggins Fantasy Camp
Womens Soccer: Ashley Lawrence Goal vs. NL


text:
The leaves and bird are hand carved from solid Linden wood. When the cuckoo clock reaches the hour the door opens, a cuckoo appears and calls along with the clocks gong strike. After the cuckoo is finished a Swiss made music box movement plays one of two delightful melodies.
This musical cuckoo clock is hand made in Germany. The mechanical brass movements are driven by three weights and time escapes with the tick of a traditional pendulum. The cuckoo call sound is made by two mechanized wooden whistles with bellows inside the clock case.


text:
The following is an archive of a post made to our
'vox mailing list'
by one of its subscribers.
On Monday 11 August 2003 01:42 pm, Ryan Castellucci wrote:
> OK, guys, here's the scoop... Somebody 0wned my system at
> work, running debian testing. Installed this lovely password
> logger, and snagged my password when I used SCPed a file.
> I found a log file at /usr/lib/mem/mem
> Bastards....
> Anyone wanna help me do a post-mortem on the box to find out
> how it was exploited?
> _______________________________________________
> vox mailing list
> email@example.com
> http://lists.lugod.org/mailman/listinfo/vox
That could be interesting. How through of a post are you planning?
Mike Wenk
vox mailing list
Hosting provided by:
Sunset Systems
Sunset Systems offers preconfigured Linux
systems, remote system administration and
custom software development.
LUGOD: Linux Users' Group of Davis
PO Box 2082, Davis, CA 95617
Contact Us
LUGOD is a 501(c)7 non-profit organization
based in Davis, California
and serving the Sacramento area.
"Linux" is a trademark of Linus Torvalds.


text:
|« Back to Article
UH adds two junior college players
By Joseph Duarte | December 19, 2012 | Updated: December 19, 2012 9:35pm
The University of Houston added two junior college transfers Wednesday – cornerback Turon Walker and defensive end Trevor Harris.
Walker (5-11, 185 pounds) had five interceptions in 11 games this season at Diablo Valley College in Pleasant Hill, Calif.
Harris (6-5, 230) had 2 1/2 sacks and four tackles for loss in seven games at ASA College in Brooklyn, N.Y.
Both players will enroll at UH for the spring semester.
Billy Cosh, a quarterback from Butler (Kan.) Community College, will undergo surgery on Thursday to repair a torn anterior cruciate ligament in his knee. Cosh, who threw for 2,586 yards and 25 touchdowns this season, has not officially signed with the Cougars.


text:
Vandy women hard to disrupt
Posted: January 14, 2013 at 3:39 a.m.
Arkansas couldn't slow down one of the SEC's best offenses Sunday.
This story is only available from our archives.
Sports, Pages 13 on 01/14/2013
« Previous Story
Henley wins rookie face-off
Russell Henley made a lasting impression in his rookie debut on the PGA Tour with a record-setting performance... Read »
Next Story »
Patriots beat Texans, get Ravens rematch
Tom Brady is so good at this playoff thing he seems to be going for a championship every year. Read »


text:
Pewter & Glass Fantasy Chess Set
Pewter and Glass Good and Evil Fantasy Chess SetThis deluxe chess set include super heavy pewter pieces showing living and skeletal fantasy figures. The glass board floats between two opposing castles with a battleground underneath.
This set is a fantastic option for someone looking for a true fantasy theme chess set. The pieces are ultra heavy and durable, and it makes a great display and statement piece.