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A new series of degradable polymeric matrices were prepared by blending polymers that degrade by hydrolysis such as poly(L-lactic acid)(PLA), and nonionic Pluronic™ surfactants, block copolymers of polyethyleneoxide (PEO) and polypropyleneoxide (PPO). The water content of the polymer blend films was controlled by mixing different types of block copolymers and by adjusting their amount. In aqueous solution, the blends revealed the typical liquid-crystalline phase transition of Pluronic™ polymers, suggesting the formation of a gel-like structure within the polymer skeleton. Poly(lactic acid) degradation rates were not affected by the blending procedure, although the hydration degree in these matrices was higher. When used as drug-releasing matrices, these blends extended protein release and minimized the initial protein burst, as compared to the pure polymer.
1. A method for controlled release comprising
blending a biocompatible, non-toxic polymer degrading by hydrolysis selected from the group consisting of poly(lactic acid), poly(glycolic acid), polyorthoesters, polyanhydrides, and poly(amino acids) and block copolymers of polyethyleneoxide and polypropyleneoxide in a ratio between 10:90 and 90:10 of polymer to block copolymer,
mixing into the blend a compound to be released, and
delivering the blend containing the compound to the site where release is to be achieved.
2. The method of claim 1 wherein the compound is selected from the group consisting of inorganic compounds, proteins, carbohydrates, and non-protein organic molecules.
3. The method of claim 1 wherein the blend is formed into microspheres for controlled release of the incorporated compound.
The United States government has rights in this invention by virtue of grants from the National Science Foundation.
This is generally in the area of polymeric controlled drug delivery devices, and specifically in the area of polymer/Pluronic™ blends for controlled delivery.
Recently, a variety of biodegradable polymers have been widely used as implantable biomaterials, such as prosthetics and tissue support matrices, and as drug delivery devices. The main advantage of using the biodegradable polymer is that no retrieval of the device is needed after a particular usage. The degradation time of the polymer as well as the release properties of a particular drug from the polymer can also be varied, for example, from months to years and from linear to staggered release, by varying molecular weight and chemical composition of the polymer. The chemical composition is varied by selection of the monomers and copolymerization with other biodegradable monomers. The ratios of amorphous to crystalline and hydrophilic to hydrophobic properties are largely responsible for determining the degradation time.
Although widely used and approved for use in vivo by the United States Food and Drug Administration, it is difficult to obtain the desired release profile using many of these biocompatible, biodegradable polymers such as poly(lactic acid) (PLA). PLA is widely used since the degradation product, lactic acid, is metabolized in the body. There have been several studies on protein delivery using PLA as a matrix, in which a significant portion of the loaded protein was often released at the initial stage as a single burst, rather than over an extended period of time, regardless of the rate of degradation of the matrix.
Two methods have been utilized to improve the release profile of compounds from these polymers: copolymerization of the lactic acid with glycolic acid to form poly(lactide-glycolide) copolymers and mixing the compound encapsulated in PLA with the same compound encapsulated in other polymers or copolymers. However, neither method has been totally successful in achieving the desired release rate, or has proven to be difficult to control during manufacture and administration.
Due to processing considerations, the mechanical properties of the polymer are important. The polymer must be sufficiently hard but flexible to allow incorporation of drug, must be soluble in solvents not denaturing the protein to be encapsulated, or melt at a low enough temperature to allow incorporation of the drug without denaturation of the drug. These are particularly a problem with many of the heat labile drugs.
Polymer blends, a physical mixture of two different polymers, exhibit advantageous physical and mechanical properties that each individual polymer does not have. Depending on thermodynamic compatibilities of the two chosen polymers, different degrees of phase separated blends can be obtained. However, only a few applications of polymer blending technology for drug delivery matrices have been attempted, as reported by Younes and Cohn, European Polymer J. 11, 765 (1988). For example, PLA has been blended with degradable and nondegradable polymers such as poly(D-lactic acid), as reported by Loomis, et al., ACS Polymer Preprint 32, 55 (1990), poly(glycolic acid), as reported by Cha and Pitt, Biomaterials 11, 108-111 (1990), and poly(ethylene-vinyl acetate), as reported by Dollinger and Swan, ACS Polymer Preprint 32, 429 (1990), in an effort to modify PLA morphology and its degradation profile.
It is therefore an object of the present invention to provide biodegradable polymeric compositions for controlled drug delivery, and methods for making and using the compositions, wherein the compositions have desired mechanical and release properties as compared with PLA polymeric compositions for controlled drug delivery.
Biodegradable, biocompatible matrices for drug delivery, including films and microspheres, are formed by blending polymers degrading by hydrolysis such as poly(lactic acid) and Pluronic™ surfactants (block copolymers of polyethyleneoxide (PEO) and polypropyleneoxide (PPO)). Physico-chemical and morphological properties such as phase separation behaviors, degradation rates and surface properties of PLA/Pluronic™ blend films have been characterized by differential scanning calorimetry (DSC), infrared spectroscopy (IR), gel permeation chromatography (GPC) and scanning electron microscopy (SEM). (PEO/PPO/PEO) block copolymers exhibit a wide range of hydrophilicity/hydrophobicity as a function of PEO/PPO ratio, so that one can adjust the degree of phase separation with the polymer. Water content of the polymer can be controlled by blending different kinds of block copolymers and by adjusting the relative ratios. Other polymers that can be blended with the Pluronics™ include polyanhydrides, polyorthoesters, and poly(amino acids).
Compounds to be delivered are incorporated into the polymeric composition by mechanical mixing, or by solvent or melt casting. The blends are biocompatible, biodegradable, and exhibit desirable release profiles of the incorporated compounds, as demonstrated using PLA/Pluronic™ blends containing bovine serum albumin.
FIG. 1 are graphs of the percent water content of PLA/L-101 (FIG. 1A) and PLA/F-108 (FIG. 1B) blend films without bovine serum albumin (BSA) loading incubated in pH 7.4 and at 37° C. PLL(F) X indicates PLA/L-101 (F-108) with X weight fraction of L-101 (F-108) in the blend.
FIG. 2 is a graph of the percent remaining weight of PLA/L-101 (PLL) and PLA/F-108 (PLF) blends without BSA loading after one week incubation in buffer, as a function of the percent Pluronic™.
FIG. 3 is a graph of the weight average molecular weight degradation profiles for PLA and PLA/L-101 (70/30) blend films without BSA loading as a function of time (days).
FIG. 4 is a graph of the fractional release over time (hours), demonstrating the effect of Pluronic™ blending on BSA release. Weight fractions of Pluronic™ are 20%.
FIG. 5 is a graph of the fractional release over time (days), demonstrating the effect of L-101 blending on BSA release. PLL X indicates X% weight fraction of L-101.
Biodegradable, biocompatible matrices for drug delivery, including films and microspheres, are formed by blending polymers degrading by hydrolysis such as poly(lactic acid) and Pluronic™ surfactants (block copolymers of polyethyleneoxide (PEO) and polypropyleneoxide (PPO)). (PEO/PPO/PEO) block copolymers exhibit a wide range of hydrophilicity/hydrophobicity as a function of PEO/PPO ratio, so that one can adjust the degree of phase separation with PLA. Water content of the polymer can be controlled by blending different kinds of block copolymers and by adjusting the relativeratios.
Physico-chemical and morphological properties of polymer/Pluronic™ blends can be characterized by differential scanning calorimetry (DSC), infrared spectroscopy (IR), gel permeation chromatography (GPC) and scanning electron microscopy (SEM). DSC studies of PLA/Pluronic™ blend films suggest that some degree of Pluronic™ miscibility in the amorphous region of PLA can be obtained by selecting polymer surfactants with suitable hydrophobicities, which results in formation of films with an overall intact surface morphology (SEM). In aqueous solution, the blends revealed the typical liquid-crystalline phase transition of Pluronic™ polymers, suggesting the formation of a gel-like structure within the PLA skeleton. PLA degradation rates were not affected by the blending procedure although the hydration degree in these matrices was higher, suggesting a complex mechanism of hydrogen bond formation between the carboxylic groups of PLA and the ethers of the surfactant polymers. When used as drug-releasing matrices, these blends extended protein release and minimized the initial protein burst, compared to the pure polymer.
Polymers degrading by hydrolysis:
Polymers that can be blended with the Pluronics™ include poly(lactic acid), poly(glycolic acid), polyorthoesters, polyanhydrides, and poly(amino acids). The polymers are biocompatible and biodegradable, beingsusceptible to hydrolysis. The polymers can be blended with the Pluronics™ alone, or in combination with other polymers. The polymers are all well known in the drug industry, many approved by the U.S. Food and Drug Administration for administration to patients, and either available commercially or synthesizable using published methodology.
Nonionic Pluronic™ surfactants, polyethyleneoxide (PEO)/polypropyleneoxide (PPO)/polyethyleneoxide (PEO) block (ABA type), (PEO/PPO/PEO) block copolymers, exhibit a wide range of hydrophilicity/hydrophobicity as a function of the PEO/PPO ratio, so that one can expect to obtain different phase separated morphologies with polymers such as PLA as well as different degrees of hydration of the matrix. In particular, hydration plays an important role in determining polymer degradation via hydrolysis of the ester backbone. These polymeric surfactants exhibited minimal toxicities in vivo and some of them are in clinical use, as described by BASF Corporation in their 1989 Technical Bulletin; Attwood, et al., Int. J. Pharm. 26,25 (1985); and U.S. Pat. No. 4,188,373 to Krezanoski.
These materials can be obtained from BASF Corporation.
Methods for blending Polymers and Pluronics™:
The polymer and Pluronic™ are blended in a ratio of between approximately 10:90 and 90:10. For drug delivery purposes, a preferred ratio is in the range of between 80:20 and 60:40, polymer to Pluronic™.
The blends can be prepared by mixing polymer and Pluronic™ in solution prepared by dissolution in an appropriate solvent or by melt mixing, usingstandard techniques known to those skilled in the art. Examples of suitablesolvents include hexane, methylene chloride, chloroform, and other organic solvents in which both the polymer and block copolymers are soluble. In general, solvent preparation is used to prepare porous matrices and melt mixing is used to prepare relatively non-porous matrices. Selection of theappropriate method is also dependent on the material to be incorporated. For example, for delivery of a temperature labile protein from a PLA/blockcopolymer blend, the protein would be incorporated using the solvent preparation, since PLA has a melting temperature of 170° C. On the other hand, polyanhydrides have melting temperatures that are lower, for example, 80° C., so the melt mixing technique might be useful in this case.
Compositions to be incorporated into the polymeric compositions:
In the preferred embodiment, biologically active compounds are incorporatedinto the polymer blends. These include inorganic compounds, proteins (including peptides), carbohydrates, and other types of organic molecules such as steroids. Non-biological materials such as pesticides, herbicides,and fertilizers can also be incorporated.
The polymeric composition is designed to meet the required biocompatibilityneeds (low, in the case of herbicides, high, in the case of controlled drugdelivery) and degradation rate, ranging from weeks to many months.
The present invention will be further understood by reference to the following examples.
A series of PLA/PEO-PPO-PEO blend films were prepared by a solvent casting method. Physical and morphological studies of the resultant films were carried out using differential scanning calorimetry (DSC), infrared spectroscopy (IR), scanning electron microscopy (SEM), and gel permeation chromatography (GPC). A model protein drug, bovine serum albumin, was loaded into the polymer blend films to examine the effect of morphologicalchanges in polymer blends on protein release patterns (i.e., extent of initial protein burst and release period).
PLA (MW 100,000) was obtained from Polysciences. GPC analysis revealed a weight average and number average molecular weight of 71,000 and of 60,000, respectively. Three (PEO/PPO/PEO) block copolymers were physicallyblended with the PLA. Pluronics™, (PEO/PPO/PEO) block copolymers, F-108,L-101, and P-104, were obtained from BASF Performance Chemicals, Parsippany, N.J. These copolymers are also known as Poloxamers, especiallyin Europe and Japan. All other reagents were analytical grade.
For blend film preparation, PLA was dissolved in 3 ml of methylene chloridewith varying amounts of Pluronic™ (BASF Corp.). The amount of polymer mixture was 0.5 g. The polymer solution was cast onto a pre-silanized glass petri-dish and the solvent was evaporated at room temperature overnight and under vacuum.
For protein loaded blend films, 20 mg of fluorescein isothiocyanate labelled bovine serum albumin (FITC-BSA) (Sigma Chemical Co.) dissolved in0.5 ml of 0.1 M phosphate buffer pH 7.4 was emulsified in the polymer solution with sonication and/or subsequent vortex mixing, and then cast onto the glass plate.
PLA, poly(lactic acid-glycolic acid) (PLGA) and PLA/Pluronic™ microspheres were prepared according to S. Cohen, et al., Pharm. Res. (in press 1991), as follows using a modified solvent evaporation method using a double emulsion. Briefly, 10 mg protein was dissolved in 50 μl double-distilled water and poured into 1 g polymer dissolved in 1 ml methylene chloride. The mixture was mixed for 1 min. using a vortex mixer at maximum speed (Vortex Genie, Scientific Inc.) or probe sonicated (ModelVC-250, Sonic & Materials Inc.) at output 4 (50 W), for 30 sec. to form thefirst inner emulsion (W1 /O). The emulsion was poured, under vigorous mixing using a magnetic bar, into 2 to 5 ml of aqueous 0.1% to 1% polyvinyl alcohol (PVA) saturated with methylene chloride to form the second emulsion [(W1 /O)W2 ]. The resulting double emulsion was poured into 200 ml 0.1% to 0.3% PVA and continuously stirred for 3 hr at room temperature until most of the methylene chloride evaporated, leaving solid microspheres. The microspheres were collected by centrifugation (Sorvall DoPont Model RC-5B, 1000 g for 10 min.), sized using sieves with apertures of 100 μm, and freeze-dried (16 hr, Freeze Dryer, lab Conc) into a powder.
The following methods were used to analyze the resulting materials.
Dry blend films without BSA loading were incubated in phosphate buffered saline (PBS) pH 7.4 at 37° C. At preset time intervals, hydrated samples were taken and weighed after blotting the surface water with tissue. Weight change of the blend films was based on the difference of dry weights before and after 1 week incubation at 37° C. in the buffer. The wet weight included the amount of free water in the pore region of the matrix, the amount of bound water associated with the polymer, and the dry weight of the polymer. Dry weights were determined after complete drying of the hydrated samples under vacuum for over 24 hr.Water contents were then calculated based on the difference in dry and wet weights.
IR (Perkin Elmer Model 1420) spectra were taken by dissolving the blend films in methylene chloride and casting them onto sodium chloride cells.
DSC (Perkin Elmer 7 Series) thermograms were taken using a standard aluminum pan. Nitrogen was used as a sweeping gas and the heating rate was10° C./min. 3-5 mg samples were loaded without further heat treatment. For hydrated samples, volatile sample sealer was used to prevent water evaporation during heating. All the samples for DSC were dehydrated or hydrated blend films without BSA loading.
Samples were coated with gold particles to a thickness of 200-500 A. Surface morphology of PLA/Pluronic™ blend films was examined using an Amary 1000 A scanning electron microscope at 20 kv electron beam radiation.
The molecular weight of PLA was determined by a Perkin Elmer Series 10 Liquid Chromatograph with a LC-25 RI detector and using a Phenomenex PL gel 5μ Mixed column. Chloroform was used as an eluant. Chromatograms were processed by GPC 5 software to calculate the weight average molecularweight of the polymer using polystyrene as a standard.
Protein (FITC-BSA) loaded polymer blend films were punctured in the shape of discs (6.35 mm in diameter and about 0.5 mm in thickness) and incubatedin 5 ml of PBS, pH 7.4, at 37° C. to characterize the release rates.The amount of released FITC-BSA at various time intervals was assayed by monitoring the absorbance at 495 nm of the PBS.
The amount of protein in the microspheres was determined by two methods: directly by recovering the protein from the microspheres and indirectly bymeasuring the residual unentrapped protein in the outer water phase. Three methods for protein extraction can be used: (1) microspheres are dissolvedin 3 ml methylene chloride and the protein extracted into 4 ml distilled water: (2) microspheres are dissolved in 2 ml 90% acetonitrile aqueous solution and protein extracted into 8 ml 0.1 M phosphate buffer, pH 7.4; and (3) microspheres are suspended in distilled water and bath-sonicated for 15 min. The aqueous solution is filtered through a 0.45 μm filter (Acro LC25, Gelman Sciences Inc.) and the amount of protein determined by absorbance at 495 nm (Fast Scan 553, Perkin Elmer).
Pluronic™ surfactants exhibit a wide range of different hydrophilic/hydrophobic properties depending on the molar ratio of the hydrophilic ethylene oxide (EO) unit and the hydrophobic propylene oxide (PO) unit in their block copolymers. Table 1 lists the physico-chemical properties of the three Pluronic™ surfactants examined, F-108, P-104, and L-101. L-101 which has a low ratio of EO to PO is the most hydrophobic(i.e., least water soluble).
TABLE 1______________________________________Physical characteristics of Pluronics ™Pluronic ™ F-108 P-104 L-101______________________________________Physical State solid paste liquidat room temperatureWater soluble moderate insolublesolubilityMolecular 14,600 5,900 3,800weightEthylene oxide 80 40 10weight %______________________________________
Since these block copolymers have an amphiphilic structure, normally found in surfactants, they exhibit temperature dependent theological properties in aqueous solutions, that is, gelation above a certain temperature, as reported by Wanka, et al., Colloid & Polymer Sci., 268, 101-117 (1990). The gel formation is particularly pronounced in water soluble Pluronic ™ surfactants which have high EO/PO ratios. Water-Pluronic™ interactions may play an important role in such a thermal phase transitionof aqueous polymer solutions.
A typical biodegradable PLA is relatively hydrophobic and has a semi-crystalline structure. Degradation proceeds via nonenzymatic, hydrolytic breakage of the ester backbone bond. Water accessibility to these bonds determines the rate of degradation. It takes months to years for complete degradation of PLA matrices, depending on the molecular weights, as reviewed by Holland, et al., J. Controlled Release 4, 155-180 (1986). Blending PLA with Pluronic™ produces different degrees of matrix hydration depending on the selection and amount of Pluronic™ blended with the PLA. Degradation is accelerated by a high water concentration in the vicinity of the hydrolytically-labile ester bond, as demonstrated using a variety of blend films, PLA/L-101, PLA/F-108, and PLA/P-104 (denoted as PLL, PLF and PLP).
The PLA/L-101 blend films are mechanically strong enough to handle, while the PLA/F-108 blend films are brittle with increasing F-108 amount.
FIG. 1 shows the hydration degree for blends of PLA with L-101 and F-108 without BSA loading as a function of incubation time in PBS, pH 7.4, at 37° C. All blends showed high water content relative to the homogenous PLA; the water content increased with increasing amounts of Pluronic™ in the blends. The more hydrophilic F-108 blends exhibited higher water contents than the L-101 blends. These blends showed an initial overshoot followed by a decrease in the water content. It is believed that this is due to a rapid diffusion of the highly water solubleF-108 out of the blend, as water penetrates and dissolves it. This is supported by the weight change measurements of the PLA/P-108 (70/30) blendthat showed a net dry weight loss of more than 20% after one week incubation in PBS. Initially, it was thought that the PLA/F-108 blends might exhibit a small dry weight loss due to a gelation phenomenon at 37° C, caused by temperature-dependent water F-108 interactions in the pore of the blend matrix. The weight loss study was separately carriedout after one week incubation, since leaching of F-108 (M.W. 14,600) out ofthe blend matrix could have been a complex mixture of processes such as water diffusion-in, F-108 dissolution, and F-108 diffusion-out. However, the results showed that F-108 leaches out of the polymer blend film upon hydration, presumably leaving water-filled pores, which might be used to create highly porous biodegradable matrices to be manipulated as a scaffold for certain applications such as cell delivery. The porosity of the polymer matrix can be controlled by adjusting the amount of incorporated Pluronic™.
A relatively high amount of the hydrophobic L-101 was still retained in theblend matrices after this time period, as shown in FIG. 2. In the case of PLA/P-104 (80/20) blend, the % weight decrease after 1 week was 7.5%, an intermediate value between L-101 (4.5%) and F-108 (2.6%) blends having thesame initial ratios of Pluronic™ (20%), showing that the water solubility of Pluronic™ is indeed an important parameter in determiningthe amount of Pluronic™ leaching out of the blend matrices. The presenceof the L-101 in the blend films was further confirmed by IR spectra acquired after a 30 day incubation. A broad band at 2870 cm-1, corresponding to the --CH2 -- stretching on the PO unit of L-101, appeared and its size increased with the increasing amount of L-101 in theblend. The peaks at 2980 and 2930 cm-1 are assigned to --CH anti-symmetric stretching and --CH3 stretching band of PLA.
The thermodynamic compatibility between PLA and Pluronic™ is expected tovary depending on the type of Pluronic™. Although the water solubility of Pluronic™ changes with the ratio of PEO/PPO, the solubility parameters of hydrophobic PPO segment (7.5 -9.9), reported by Olabisi, et al., Chapter 3 in Polymer-polymer Miscibility (Academic Press, NY 1979), and PLA (9.5-9.8), reported by Cohen and Younes, J. Biomed. Mater, Res. 22, 993-1009 (1988), are close so some degree of phase mixing can be expected. Nevertheless, since no significant acid-base interaction and/or hydrogen bonding between PLA and Pluronic™ can be expected except for those between the hydroxyl and carboxyl end groups in PLA, and the backbone ether and terminal hydroxyl group in Pluronic™, PLA/Pluronic™ blends might have a phase separated domain structure, especially since the PLA/Pluronic™ blend films are all opaque, indicating the phase separated structure, while the homo-PLA film is translucent. However, the physical appearance of the blend film is only indirectly indicative of polymer miscibility, and the degree of phase separation can not be assessed quantitatively. Thus, DSC studies were carried out to examine and quantify the extent of phase separation. A shift in glass transition temperature (Tg) provides direct evidence of polymer miscibility, as reported by Olabisi, et al., (1979), the teachingsof which are incorporated herein. While PLA has a clear Tg around 55.9° C., the PLA/Pluronic™ blends exhibited a rather broad endotherm around the glass transition temperature of PLA, making it hard to determine the precise Tg as a function of Pluronic™ weight fraction.Nevertheless, the estimated Tg's for the blends were lower than that of PLA, as shown in Table 2, suggesting the disturbed amorphous region of PLAby the Pluronic™ which may act as a plasticizer.
The crystalline melting temperature (Tm) of PLA is another method usedto evaluate the extent of phase separation in the blend. When two polymers are compatible in the amorphous state, the Tm is depressed as a result of the disturbed order in the crystalline phase. As shown in Table 2, a slight shift in Tm of PLA was observed upon blending more hydrophobic Pluronic™ surfactant with the PLA, while Tm is essentially the same when blending with F-108 and P-104. These results indicate a phase separation in the cases of F-108 and P-104 blends, and a slight phase mixing in the hydrophobic L-101/PLA blend. The crystalline melting enthalpy (H) data shows the higher crystallinity values in blends of F-108 and P-104 than in L-101 blend or PLA. Since Tm is related tocrystalline structure and size and delta H to crystallinity, this result implies that it is the crystallinity of PLA which is affected by blending with the hydrophilicity/ hydrophobicity of Pluronic™ while the crystalline structure of PLA is not disturbed very much.
The hydrophilicity/hydrophobicity of Pluronic™ appears to affect the nucleation and growth crystalline spherulites by changing the interfacial free energy between the crystalline and amorphous phase in the PLA. The hydrophobic L-101/PLA blend has a much smaller crystalline size than the F-108/PLA blend. There is also the phase mixing possibility between the amorphous regions of PLA and Pluronic™ surfactants because these regions have more polymer chain flexibility than the crystalline region for polymer-polymer miscibility. H decreases with the increase in Pluronic™ amount due to the smaller weight fraction of PLA in the blends. Although the calculated crystallinities (normalized to PLA fraction in the blend) are higher for the F-108 than that for the L-101 (Table 2), the decrease in delta H in the blends is more pronounced for the L-101 than the F-108 with increasing amount of Pluronic™ surfactants. This indicates that the hydrophobic L-101 may be more readilyintermixed with the polymer chains of PLA in the amorphous region and is consistent with the finding that a smaller amount of L-101 is leached out during the incubation in buffer (see FIG. 2). Due to the leaching of the hydrophilic F-108 from the blend, only PLA/L-101 blends were further investigated for protein delivery applications.
TABLE 2______________________________________Effect of Pluronic ™ blending on PLA crystalline meltingenthalpy. Weight fraction of Pluronic ™ is 20% in theblend.PLA/Pluronic ™ Blends Tm, °C. H, J/g PLA Tg, °C.______________________________________PLA (M.W 71,000) 177.3 46.8 55.9PLA/F-108 177.3 50.7 47.9PLA/P-104 177.1 49.4 N/APLA/L-101 176.5 46.1 52.9______________________________________
Since blend films will be incubated in aqueous solutions, both in testing and in subsequent in vivo use, phase separation between PLA and the Pluronic™ L-101 should be considered in the presence of a third component, water. It is expected that water will preferably interact with the hydrophilic ethylene oxide part of a Pluronic™ surfactant that is entangled in the amorphous region of PLA. (PEO/PPO/PEO) block copolymers exhibit a complicated self-aggregation behavior in aqueous solution due tomicelle formation. It has been reported that water-nonionic polymeric surfactant interactions lead to a liquid crystalline phase at low water concentrations. Thus, it is conceivable that in aqueous solution, an L-101-water liquid crystalline phase will be formed within the porous region of PLA.
The term "liquid crystalline" as used herein refers to any self-assembled and ordered molecular structure which includes the "gel" formation, often found in hydrophilic Pluronic™ surfactant-water system above a certain temperature range. DSC studies were carried out to prove the existence of such a liquid crystalline phase. A DSC thermogram of PLA/L-101 blend films, dried after 7 days incubation, did not show any noticeable peaks except for a very broad Tg around 60° C. and a crystalline melting peak of PLA around 175° C. In contrast, the hydrated films showed an apparent liquid crystalline phase transition peak which appears to shift to higher temperatures with an increasing amount of L-101 in the blend. It is suggested that a more ordered liquid crystalline phase may beformed as more L-101 is incorporated. The very broad endotherm for the PLA sample, apparently a typical Tg, may be due to the disturbed glassy structure by the hydration.
The surface compactness of the PLA/L-101 blends was examined by SEM. The homo PLA film surface has spherulites, crystalline domains along with pores which are probably formed by the rapid evaporation of the organic solvent. On the other hand, the surface of PLA/L-101 (80/20) film has a rough morphology without pores. The spherulite sizes are smaller than those observed with the PLA film, supporting the DSC data of a slight Tm shift for the PLA/L-101 blends. A magnified view of the surface revealed that the PLA crystalline domains (spherulites) are covered by L-101 which appears to be also crystallized radially, suggesting the formation of ordered liquid crystalline phase in the hydrated state. Although L-101 is a liquid at room temperature, it is possible that PEO segments are crystallized while PPO segments are anchored on the spherulites. The SEMs also indicate that a rapid crystallization of PLA upon solvent removal induces spherulite formation, while the polymeric L-101 may be entangled within the amorphous PLA chains, producing an overall nonporous surface. The same surface morphology was observed after 1 week of hydration, again implying that no significant loss of L-101 fromblend has occurred with time.
PLA has been known to degrade slowly because of its hydrophobic and semi-crystalline structure which does not allow fast water penetration. The degradation rate is proportional to water and ester concentrations, and is autocatalyzed by the generated carboxylic end groups. It can be expressed as follows:
Degradation rate=k[H2 O][COOH][Ester]
When Pluronic™ L-101 is blended with PLA, it is expected that the PLA degradation rate will be modified due to changes in water concentration. Amore hydrated sample will be hydrolyzed faster due to water accessibility in the vicinity of the ester bonds.
FIG. 3 shows that the change in the molecular weights of PLA and PLA/L-101 (70/30) blend are approximately 10,000 higher than those of the homo PLA at all time points. This might be due to nonspecific chain entanglement and/or complex formation between PLA and L-101 polymer chain (MW 3,800) inchloroform via hydrogen bonding between the terminal carboxylic groups and the ether bonds of L-101. In fact, it is known that the polymers containing carboxylic acid groups are readily miscible with polyethers viahydrogen bonding. After an induction period of 30 days, both the PLA and the PLA/L-101 blend apparently start to degrade at a similar rate. The time lag observed in the degradation may be due to the slow hydration ratein the PLA crystalline region. Weight loss measurements revealed that the films retained their mass during the degradation period. This is consistent with the fact that random hydrolytic chain cleavage of the polymer backbone proceeds until a critical molecular weight is reached, from which weight loss begins with the diffusion of cleaved water soluble fragments out of matrix. The apparent similarity of the degradation rates for both samples suggests that L-101 does not significantly affect the overall degradation of PLA. This might be explained by the two opposite effects that are imposed by L-101 blending on PLA degradation. On one hand, L-101 increases matrix hydration, thereby enhancing the degradation rate. On the other hand, formation of hydrogen bonds between the terminal carboxylic groups of PLA and ether bonds of L-101 reduces the autocatalytic contribution of free carboxylic acid, thus decreasing the rate of degradation. Although the increasing hydration cleaves the ester linkage, the generated terminal carboxylic groups are not available for further catalytic degradation because of immediate hydrogen bonding with ether bonds.
Protein release from polymeric matrices have been extensively studied in the past years, where variable release profiles were achieved by selectingsuitable polymer matrices, shape, preparation method, protein loading, and particle size, and may other factors, as reviewed by Langer, et al., Methods in Enzymology 112, 399-422 (1985) and Cohen, et al., Pharm. Res. 8, 713-720 (1991). When matrices are prepared by solvent casting, the evaporation rate of the organic solvent plays an important role in the formation of pores in the matrix, eventually leading to protein dumping atan initial stage, i.e., the "burst" effect. Slow removal of the organic solvent at low temperatures is one way to decrease the burst effect.
The possibility of decreasing the protein burst was examined by blending PLA with Pluronisc™, based on studies showing that blends of PLA and L-101 produced films with an intact surface morphology. FIG. 4 shows the effect of different Pluronic™0 blends on BSA release. The relatively hydrophobic Pluronic™, L-101, was more effective than the hydrophilic F-108 in decreasing the initial protein burst as well as prolonging the release period. These results agree with the finding that the relatively hydrophilic Pluronic™ F-108 is quickly leached out, at the initial stage of incubation, leading to a fast BSA release, while the PLA/L-101 blend film, where L-101 is entangled with the amorphous PLA chains, delayed BSA release. The PLA/P-104 blend which has a moderate hydrophilicity/hydrophobicity exhibits an intermediate burst.
The slow release of BSA may be explained by the morphological changes that occur in the interconnecting porous channels of PLA blended with L-101 upon hydration. When blend films are incubated in aqueous solution, water penetrates into the matrices to first hydrate the amorphous region of the PLA/Pluronic™ blend. As a result, the PLA/L-101 blend acquires a liquidcrystalline phase which fills the pores. This phase holds the BSA moleculeswithin the pores and prevents their fast release. This is supported by the finding that the release rates of BSA can be controlled by the amount of L-101 that is incorporated into the blends, as shown in FIG. 5. Thirty percent (w/w) L-101 in the blend resulted in a system that controlled the release of BSA for more than 80 days while the 10% in the blend more than 95% of the BSA was released after 3 days of incubation.
There have been a few studies on the liquid crystalline phase formed by nonionic surfactant-water interaction, yet its physical nature is not wellunderstood. It was reported by Tiemessen, et al., J. Controlled Release 13,73-81 (1990), that a mixture of water and nonionic surfactant, Brij 96 (polyoxyethylene(10) oleylether) possibly exhibits a variety of liquid crystalline structures such as lamellar, viscous isotropic, and hexagonal gel, depending on the mixing ratio. The different liquid crystalline phases demonstrated different diffusion coefficients for a particular drugdue to changes in the morphology of the aqueous porosities and tortuosities. Protein release from the liquid crystalline phase should occur via arrays of hydrophilic and aqueous pores created by the self-assembled hydrophobic domains. It is, therefore, likely that the macromolecular protein has a low effective diffusion coefficient in such acreamy gel structure, since the aqueous porous channels have a relatively small volume compared to the hydrophobically organized domains.
In summary, it has been shown that PLA can be physically blended with nonionic polymeric surfactants, Pluronics™, to form a matrix where the surfactant may be entangled in the amorphous region of PLA. Upon hydration, the blends acquire an additional liquid crystalline phase that is now imbedded between the PLA crystalline phase, producing an overall intact surface morphology. This results in drug release profiles with a minimum initial protein burst and a longer term release.
Modifications and variations of the polymeric compositions, and methods of manufacture and use thereof, will be obvious to those skilled in the art from the foregoing detailed description. Such modifications and variationsare intended to come within the scope of the following claims.
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|Spiritual Care & Support Groups
Support Groups
Whether you are newly diagnosed with cancer, in the midst of treatment or in remission, support is crucial to your well-being.
CHI Health St. Francis facilitates several groups and services that provide spiritual and emotional support, encouragement and education about cancer treatment. It also provides resources to help those living with cancer and their families cope with illness.
Find the help and the hope you need to continue on your journey by talking and sharing with others who are facing similar struggles with cancer.
The Cansurmount Program is sponsored by the American Cancer Society with the cooperation of CHI Health St. Francis. It is a support group designed to help individuals with cancer and their families learn to live each day with hope and gain strength to look toward the future. The Cansurmount program meets on the first Wednesday of each month at 1:30 p.m. in the Telehealth Conference Room, 2nd Floor of the Memorial Health Center, 2116 West Faidley Avenue.
Breast Cancer Support Group
This program helps women with breast cancer develop coping strategies. The goal of the group is to provide support to each individual, recognizing the personal, emotional and spiritual needs that are unique to women. This group meets the second Tuesday of each month at 7 p.m. in Conference Room 4, CHI Health St. Francis, 2620 West Faidley Avenue.
From Surviving to Thriving
This is a support group designed to help those dealing with life after completing cancer treatment. Surviving cancer is a life experience that needs to be shared and understood. From Surviving to Thriving is designed to provide cancer survivors with opportunities for increased support and education. Those attending will also learn about the resources available to improve quality of life. All cancer survivors are encouraged to attend this support group. From Surviving to Thriving meets on the second Wednesday of each month at 3 p.m. in the Telehealth Conference Room, 2nd Floor of the Memorial Health Center, 2116 West Faidley Avenue.
Metastatic Cancer Support Group
This support group is for people diagnosed with metastatic cancer. Participants receive education and support from staff and each other related to experiences unique to them. This group meets the third Wednesday of each month at 1:30 p.m. in the Telehealth Conference Room, 2nd floor of the Memorial Health Center, 2116 West Faidley Avenue.
Multiple Myeloma Support Group
This support group is for those diagnosed with multiple myeloma. This group provides support, education and caring for those diagnosed and their family members. Group members meet the third Wednesday of each month at 10 a.m. in the basement of Home Federal Bank, 3311 W. Stolley Park Road, in Grand Island. For information, please contact Dr. Jim Omel at (308) 381-0289.
Look Good ... Feel Better
Look Good ... Feel Better is a program to help those with cancer learn how to handle the personal appearance changes that may result from chemotherapy or radiation treatment. Those wanting to attend the class should complete an application form, which is available from their navigator or the patient and family counselor. This group is a public service program developed by the American Cancer Society and the National Cosmetology Association. This support group meets monthly in Conference Room A, lower level of the Memorial Health Center, 2116 West Faidley Avenue.
Wig Bank
The American Cancer Society's Wig Bank receives donated wigs that are cleaned and sanitized. Patients with cancer can receive a free wig along with a fitting and style for a minimal charge. For more information, call the area office of the American Cancer Society at (308) 237-1631 or 1-877-532-7099.
Healing Spirit Newsletter
This newsletter provides interesting, up-to-date information on various topics relevant to anyone whose life has been touched by cancer. It also provides detailed information and announcements about upcoming educational opportunities and community events. If you would like to receive this quarterly newsletter, please call (308) 398-6787.
Tobacco Cessation Classes
The American Lung Association's Freedom From Smoking® classes are available to anyone in the community interested in quitting tobacco products. Meeting with a small group ensures personal attention from the facilitator and provides support from others who are in the same situation. To sign up or learn more, call Ann Tvrdy or Connie Hameloth at the Cancer Treatment Center, (308) 398-5450.
About the Groups
There is no charge for attending any of the group meetings. For more information on any of these groups, call the Cancer Rehab Coordinator at the St. Francis Cancer Treatment Center at (308) 398-5450 or 1-800-998-2119.

subset: commoncrawl


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A Stranger Paradise
Photographic essays exploring Colombia and China
28th May – 13th June
As part of the 2012 Auckland Festival of Photography – www.photographyfestival.org.nz
Auckland photographers Brodie Quinn and Edward Howie come together to explore the notion of 'A Stranger Paradise'.
This exhibition brings together essays from China and Colombia depicting the life of two distinct places, cultures and traditions. The images show how both photographers became strangers immersed in the daily lives of these distant places to give an outsiders view of culture, practices, environment, and spaces in a sometimes humorous light. The ensuing body of work invites you into their experiences and travels throughout China and Colombia, searching for those stranger moments of others' lives. "Paradise" is an elusive notion with diverse depictions often found in absurd places. It is this subjective notion of someone's paradise which is explored in this exhibit of stranger encounters.
Both essays evolved from many months travel through the respective countries. With the constant motivation to capture the unique and the absurd, the ugly and the beautiful, both photographers have collated their travelogues into one show. Presenting their work in a unique fashion A Stranger Paradise embraces the old and uses recycled wooden frames and glass of many shapes and sizes – re-tooled and re-loved. Ditching the traditional gallery display model with all images hung at eye-level, evenly spaced, A Stranger Paradise is a collage of images flowing and fitting together to create an immersive narrative with the photographs working together to engage the viewer and explore the spaces and interactions of these communities.
Norman King Square, Ernie Mays St
Northcote Shopping Centre
North Shore, Auckland
Opens 5pm – 7pm Saturday 26th May
Hours 10am – 4pm (closed Queen's Birthday)


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by Natalie DiBlasio, USA TODAY
Boston and its suburbs were in lockdown Friday morning as a massive manhunt intensified for Dzhokhar Tsarnaev, 19, the surviving Boston bomb suspect.
Tsarnaev was a wrestler at the Cambridge Rindge and Latin School in Cambridge, Mass. He was named a Greater Boston League Winter All Star in 2011.
Cambridge Rindge and Latin School did not immediately respond to USA TODAY's phone calls. Many Boston-area schools were closed Friday.
Jacob Colbath-Hess, a freshman at Harvard University, was a member of the class of 2012 at Cambridge Rindge and Latin School but first met Tsarnaev in middle school.
"I don't really know how to react to this....he was a funny, sweet, goofy kid," said Colbath-Hess. "It's not something you would expect from someone you know."
Police have identified Tsarnaev's older brother, Tamerlan Tsarnaev, 26, as the other bombing suspect, killed during the manhunt at MIT.
The brothers had been living together on Norfolk Street in Cambridge. An uncle, Ruslan Tsarni of Montgomery Village, Md., told the Associated Press that the men lived together near Boston and have been in the United States for about a decade. They came from the Russian region near Chechnya, which has been plagued by an Islamic insurgency stemming from separatist wars.
Dzhokhar was a wrestler at the Cambridge Rindge and Latin School in Cambridge, Mass. He was named a Greater Boston League Winter All Star in 2011.
In May of 2011, as a high school senior, Dzhokhar was awarded a $2,500 City Scholarship from the City of Cambridge to pursue higher education.
Before moving to the United States, he attended School No. 1 in Makhachkala, the capital of Dagestan, a predominantly Muslim republic in Russia's North Caucasus that has become an epicenter of the Islamic insurgency that spilled over from Chechnya.
His profile on the Russian social networking site Vkontakte says he lists his languages as English, Russian and Nohchiyn Mott (a Chechen language). His worldview is described as "Islam" and he says his personal goal is "career and money."
A "joke" posted on the profile page, translated from Russian, says: "There is a car... in the car sits a Dagestani, a Chechen and an Ingush. Question - who is driving? The answer: - The Police."
This is an old joke that has been told with a myriad of ethnic "passengers," meant to imply that if a certain ethnic person is in the car, the only reason would be because they had been arrested, says Andrea McCarren of WUSA-TV in Washington, D.C., who had the posts translated.
The father of the suspects in the Boston Marathon bombing claims that his son who is still on the loose is a smart and accomplished young man.
Anzor Tsarnaev spoke with the Associated Press by telephone from the Russian city of Makhachkala on Friday after police said one of his sons, Tamerlan, had been killed in a shootout and the other, Dzhokhar, was being intensely pursued.
"My son is a true angel," the elder Tsarnaev said. "Dzhokhar is a second-year medical student in the U.S. He is such an intelligent boy. We expected him to come on holidays here."


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Participate in This Event or find another event
Saturday, June 13, 2015
Goucher College
1021 Dulaney Valley Road, Towson, MD Map it
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26 teams and 244 participants have raised $77,747.67
Total above may not reflect all participants, teams, and donations
THANK YOU to our participants, team captains, sponsors, and ELT members for a great relay this year. We appreciate your support and dedication in fighting back against cancer! Because of your efforts, we have successfully surpassed our $70,000 goal. Hope you all had as much fun as we did and we will see you next year. With any comments, questions, or concerns, please contact your ACS staff partner Nichole at email@example.com. We will be accepting donations until August 31st. Thanks again, everyone! Have a great summer.
The American Cancer Society Relay For Life is the world's largest and most impactful fundraising event to end cancer. It unites communities across the globe to celebrate people who have battled cancer, remember loved ones lost, and take action to finish the fight once and for all. Today, with the support of thousands of volunteers like you, the American Cancer Society is helping save more than 400 lives a day. And we won't stop until we finish the fight against cancer! Please join us!
Remember or honor a loved one who has battled cancer with a luminaria tribute bag >>
Cancer survivors and caregivers find a community of hope and support >>
Find out more details about your community Relay For Life event >>
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Best Amusement Park St. Louis 2006 - NASCAR SpeedPark
5555 St. Louis Mills Blvd.
Hazelwood, MO 63042
St. Louis is not without amusement areas that possess their own unique charm, but there ain't no how, no way any of them could top a theme park that has something called the Tot Rods. All right, so it's just a circular course stocked with kid-size classic cars, and there's no paint-swapping allowed and on top of that, you're too big to even bother standing in line. But the NASCAR SpeedPark has about a jillion other things to do. Fancy carnival games of chance? Yup, they've got 'em, and some of them look to have been transported from a mid-'70s hillbilly county fair, particularly the Big Bertha beanbag toss (it must be seen to be believed). Is Lazer Tag making a comeback? Who cares at NASCAR SpeedPark it never went out of style! Rock climbing has nothing to do with Talladega, but a two-story rock wall awaits your scramble. Of course, some go to the NASCAR SpeedPark expecting NASCAR-themed events. Literalists. There are indeed five courses for you to race on, but you only care about two of them. The Champion is the indoor, figure-eight course that climbs two stories and wraps around the arcade area, and it shakes with the thunder of open-cockpit electric cars. But you'll probably want to head straight for the Mini-Motor Speedway: A three-quarter-mile oval for five-eighths-scale Nextel Cup model cars, a course so serious you need to be at least sixteen years old and have a valid driver's license to get behind the wheel. Now all you need to do is line up a sponsor, grow some sideburns and declare your hatred of Tony Stewart.


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All around the campus, your fellow Penn employees are gearing up to share the spirit of the holiday season with those less fortunate. Here are a few of the events and gift drives taking place this month:The annual Penn VIPS Holiday Toy Drive runs from now through Dec. 16. Wrapped or unwrapped toys may be left at any of 20 drop-off points across the campus, including Civic House, the Franklin Building, Van Pelt-Dietrich Library Center and the Museum. Gifts will be distributed to needy families and shelters in West Philadelphia. For more information, contact Penn VIPS at 898-2020. Operation Santa Claus, now in its 11th year, will throw a party for young and old on Monday, Dec. 21, in the Club Room of the Faculty Club. Residents of three West Philadelphia nursing homes and children from St. Vincent's Orphanage will receive gifts and a holiday lunch with surprise entertainment. Gifts and cash donations are needed to make the party a success. Contributions may be delivered to Yvonne Oronzio, 212 Franklin Building, through Dec. 17; for more information or suggested gifts, call her at 898-4210. Gloria Emerson in the Health System's Division of Medical Genetics is also spearheading a gift drive for elderly residents of local nursing homes as well as working with a program in the Office of the President to send holiday and/or birthday greetings to homebound senior citizens. Inexpensive unwrapped gifts and suggested recipients are both welcome in Emerson's office (1 Maloney Building, HUP) no later than Dec. 17. You may also call her at 662-4740 for more information.
Front page for this issue | Pennsylvania Current home page
Originally published on December 3, 1998


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By Linda D. KozarynAmerican Forces Press Service
WASHINGTON, Jan. 21, 1999 U.S. officials are consulting with NATO allies to see what course of action should be taken to deal with the latest violence in Kosovo. Designated NATO forces are now on 48- hour alert.
Yugoslav forces killed more than 40 ethnic Albanians Jan. 15 in the village of Racak. Two unarmed international monitors shot during the massacre escaped serious injury. Two days later, Yugoslav officials expelled William Walker, the American head of the monitoring mission.
At the Pentagon Jan. 20, Defense Secretary William S. Cohen said Yugoslav President Slobodan Milosevic has clearly violated the cease-fire agreement he made last fall.
"That is a breach of an agreement not only with NATO itself, but the Organization of Security Cooperation in Europe and virtually every organization that is currently trying to bring some peace and stability to that region," Cohen said. He said U.S. Army Gen. Wesley Clark, supreme allied commander Europe, and U.S. and NATO officials are consulting closely to determine actions to be taken.
NATO air strikes remain an option, the secretary said. "It's quite clear NATO has the capability to not only threaten air strikes, but to carry them out," he said.
However, Cohen said, the United States does not intend to be an air force for the Kosovar Liberation Army. "We believe there should be an agreement dealing with providing greater autonomy for the Kosovars, but have not supported their drive for independence. So it's going to require compliance on both sides, not just one," he said.
Cohen repeated the view he voiced last fall: "NATO's credibility is on the line." In October, NATO approved an activation order for phased air strikes against Yugoslav forces and then put it on hold. "The activation order remains in effect, and we are prepared to execute that if that is the will of the NATO membership, said Cohen.
In response to the October threat of a NATO air campaign, Milosevic agreed to withdraw some military and special police forces from Kosovo and to allow international officials to monitor activities in the southern Yugoslav province.
Since then, persistent conflicts and sporadic violence have continued, and tensions have steadily increased between Yugoslav forces and ethnic Albanian liberation forces. The Jan. 15 massacre, witnessed by international monitors, brought the crisis to boiling.
Two days before the attack, Clark told the newspaper Stars and Stripes" that the relative peace in Kosovo was very fragile. He said widespread fighting will return to Kosovo if a new agreement between ethnic Albanian rebels and Yugoslav officials isn't reached in the coming weeks.
He predicted the combination of ongoing rebel buildups, growing Serbian frustration and better weather would prompt both sides to either sign a peace deal or return to civil war. "When these things come together in the February-March time frame, we're going to reach a period of great danger," Clark said Jan. 13 while visiting NATO forces in Macedonia.


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Alongside our nomination for Choice Music Prize – Irish Album of The Year, we are also nominated for the Song of year award for Goldstar! You can vote for us by going to the Meteor page here.
You can also vote by texting '2′ to (00353) 857114444, voting only takes a couple of seconds, we really do appreciate your support!
You can vote each day by text until the 4th March. See www.Meteor.ie for terms


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Ariana Grande proves she's pop's princess, Cee Lo Green backtracks on his rape statements, Demi Lovato is launching a new business, and more in First Dibs.
Ariana Grande proves she's pop's princess, Cee Lo Green backtracks on his rape statements, Demi Lovato is launching a new business, and more in First Dibs.
Hopefully you've never been cheated on, and will never be cheated on. But it happens — so often in fact, that even our favorite stars aren't immune to falling victim to adulterous ways. Everyone from Beyonce to Rihanna knows what it's like to feel the sting of a cheater, and all have songs not only to prove it, but to help you out when you find yourself in the same awful position. From Blu Cantrell's "Hit Em Up Style" to Cee Lo's "F–k you", there's a song to suit every mood as well.
Being on the 9 to 5 work grind can be rough, which is why each week, every one of us is secretly counting down to an occurrence that is everything sacred and holy – the weekend!!! And we have your back in giving you the best jams to get you in the mood and let loose this Friday and many more to come. Don't worry, you can thank us later… Besides, you deserve it!
Dolly Parton lands in the hospital, Jennifer Lopez claims her famous curves weren't always a welcome sight, and British duo Disclosure talk about their dream collaboration.
50 Cent didn't take much of a gamble with "My Life," the first single off Street King Immortal which he describes as his "recovery, his comeback." The song is radio-friendly and carefully calibrated for success, with features from a hip hop legend (that'd be: Eminem) and a chart-topping pop star (cue: Adam Levine) and a thoughtful role-out strategy that includes a radio premiere yesterday, a live-debut on The Voice last night (see below) and this geared up new video.
The big-budget video finds the song's stars on the lam, in fancy cars and on foot as they run from helicopters and spotlights. "The video is kind of abstract; it's kind of metaphoric in a sense, like the paranoia of feeling like we're being chased," Eminem told MTV News last month, explaining that they're running to keep their personal lives safe from fame and fortune's trappings because, "Whether it's true or not, it's kind of how we feel."
Finally, a good reason to watch football! [MTV]
Fred Durst broke the news in an interview, wherein he explained that, "say in 2000, there were 35 million people who connect to this band. Twelve years later, lots of those people have moved on. We were a moment in time and it's over." That said, Bizkit guitarist Wes Borland has since tweeted otherwise, writing that, "LB has not called it quits. That article is insane. Thanks for your concerns, but we're all good over here." Either way, sounds like there's fire in the hole. [PopDust] Read more…
In a recent Rolling Stone article, A$AP Rocky explained that "nowadays, everybody wanna be weird. We know how to manifest being weird. We know we some weird-ass looking motherf**kers, and we know we do some weird sh*t." He continued, "But at the same time, we some geniuses."
While we're not entirely sure that we agree with the "genius" tag, it does seem that suddenly every artist is out to "out-weird" each other. Whether it's what Ke$ha's studding, what shoes Lil Wayne's rocking, or what Lil B's prophesizing, artists are competing to be the most unique and we just can't get enough of it. Normal is just so boring, isn't it? The art of music is all about expressing individuality in its purest form, and artists who don't just let their tunes do the talking are the most appealing to us. We love these artists for embracing their individuality, their unique weirdness, that sets them apart. Brace yourself for our list of the Top 10 Weirdos in Music Today (And Why We Love Them For It).
Kelly Clarkson is taking a leaf out of Taylor Swift's book and including cover songs in her set while she's on tour promoting Stronger. But unlike Swift, she's not following a city-by-city guide to pop-stars — instead she's letting the fans choose! She said on stage at the Riverdome in Bossier City, "'Cause I got here by fans voting for me 10 years ago, so it's still cool that y'all are still involved in the show," before proceeding to play Madonna's "Crazy For You." Kelly's version of the song was heartfelt and reverent, and if we didn't know better we would have assumed it was one of her own songs!
In Texas, Kelly covered Pistol Annies' "Hell On Heels," (watch it after the jump) to a clearly ecstatic audience. Like Madonna's pop classic, Kelly covered the country track to perfection, and we're quietly impressed by her ability to slip between genres with such ease. Her sultry performance was just perfect for the sexy track, and we're even thinking she could join the Annie's for a duet. Earlier in the tour, Kelly also gave great performances of Coldplay's "Fix You", Carrie Underwood's "I Know You Won't" and Cee Lo Green's "Forget You", proving definitively that the girl can sing just about anything. We're looking forward to seeing what else she throws out on tour, and wouldn't mind making a few requests of our own!
Madonna redefined the word 'spectacular' with her Super Bowl half time show over the weekend. In what we're sure cost the debt of several small third world countries, Madonna's show was a no-holds-barred exercise in precision choreography and aesthetic decadence. Ushered in on the shoulders of an army of Roman Empire soldiers on a giant, regal float complete with gold throne, Madonna vogued to open the set, and what better song to vogue to than "Vogue"? After the perfectly synchronized, slow pace of Madonna's voguing, the veteran broke seamlessly into "Music," showing off some serious athletic agility and surely making America forget that she's a woman in her 50s.
"Music" got a cool mash-up from guests LMFAO, who mixed the classic Madonna track with their hit "Party Rock Anthem." The LMFAO boys shared a fun synchronized shuffle and some awkward slap-stick visual narrative with Madonna for the remix, ripping off her gladiator style skirt to reveal a simple black dress just in time for her new single "Give Me All Your Luvin.'" Nicki Minaj and M.I.A. joined Madge on stage for a gold pom pom filled dance extravaganza which wasn't entirely without controversy (and what would a Madonna show be without controversy?), courtesy of M.I.A. and an inconspicuous enough little bird (more on that later).
Cee Lo Green rang in the New Year on Saturday night in controversial fashion, stirring up John Lennon fans by changing the words to the late Beatles' iconic song, "Imagine." On stage at Times Square on New Year's Eve, instead of singing the original, "Imagine there's no countries / It isn't hard to do / Nothing to kill or die for / And no religion too," Cee Lo decided to change the last stanza to, "And all religion's true." Not only did Cee Lo take it upon himself to essentially change the whole meaning of the song — which envisages a world without any borders, including race, sex and religion, that relies on common humanity to bind people — he also did so wearing a lavish fur coat and sunglasses, which only added to the vitriol Cee Lo received.
Fans took to Twitter to vent their frustration; @ElayneBoosler Tweeted, "If Cee Lo Green is going to sing 'nothing 2 kill or die 4′, he shouldn't b wearing FUR when he does. Shallow asshat. #tailsofjoy," while @Ash_Brew wrote, "John Lennon is turning over in his grave as Cee Lo Green butchers 'Imagine' in Times Square," and @Franky_1189 said, "Thanks Cee Lo Green, you just destroyed an amazing song and ended 2011 on a horrible note. Literally. #imagine." Cee Lo allegedly Tweeted an apology, "Yo I meant no disrespect by changing the lyric guys! I was trying to say a world were u could believe what u wanted that's all," however the remorseful Tweet appears to have been since taken down and replaced with a simple "Happy new year everyone!!!!!!"


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Learn More About The World to Come:
Recommended videos:
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America and Israel—Full Rupture Foretold!
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Stay Informed:
Many wonder about America and Britain's role in Bible prophecy in the last days. Are they mentioned? If so, where—and what is their future?
You may wish to read...
This free literature is available at rcg.org.
America and Britain in Prophecy
All nations are now rushing toward the grand smash conclusion foretold to occur in the "last days." Humanity plunges ahead—blind, pleasure-crazed and largely detached from important world events occurring daily. American, British, Canadian and other Western leaders would take action, if they only knew what lies ahead. Great prophetic truths, revealing amazing—indeed astonishing—climactic changes soon to stagger all civilization, go unrecognized. But Western leaders, with the rest of the world, remain in ignorance—WHY? Now you can learn what vast millions have not understood!
The Bible's Greatest Prophecies Unlocked! – A Voice Cries OutMore Information
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Featured in this broadcast:
When Christ Returns...
Are We in the Last Days?
The Beast of Revelation (Part 1)
The Book of Revelation—Unlocked! (Part 1)
Is the End Near?
World Peace—How It Will Come!
The Final Antichrist – Who and What
World Economic Crisis—And You!
Copyright © 2015 The World to Come. All Rights Reserved.


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On the bright side, tax
advisors believe this new rule will allow marines to deduct the cost of their work uniforms from
their taxes. In the past, the IRS had ruled
that the cost of utilities, fatigues and BDUs were not deductible as
they could be worn off base. The IRS reasoned that, if you could go into a store or restaurant,
your uniform was not limited to the workplace, and was therefore not
deductible. The high tech camies worn today are not cheap, and a marine can go
through several hundred dollars worth a year.
� 1998 -
2015 StrategyWorld.com. All rights Reserved. StrategyWorld.com, StrategyPage.com, FYEO, For Your Eyes Only and Al Nofi's CIC are all trademarks of StrategyWorld.com Privacy Policy


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To coincide with this week's release of the expanded edition of The Bravest Man In The Universe, here's the video for Bobby Womack's It's Been A Long Night.
The new track appears as one of four additions to the album, with the video also shot during the band's New York recording sessions.
Bobby will be appearing on The Jonathan Ross Show this weekend, for a chat with the host and performance alongside Damon Albarn, Richard Russell, Tic, Remi Kabaka and Kwes. If you're in the UK you can watch the programme on ITV1, 9:20pm GMT on Saturday 23.


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NEW ORLEANS (AP) Robert Griffin III of the Washington Redskins has won The Associated Press 2012 NFL Offensive Rookie of the Year award, beating out two other sensational first-year quarterbacks.
MINNEAPOLIS (AP) Pau Gasol had 22 points and 12 rebounds in his return to the starting lineup and Kobe Bryant nearly had a triple-double in leading the Los Angeles Lakers to a 111-100 victory ove
INDIANAPOLIS (AP) Indiana did it again Friday night.
And this time, the Pacers beat Miami at its own game.
NEW ORLEANS (AP) Fear the dreadlocks, San Francisco.
INDIANAPOLIS (AP) Pacers coach Frank Vogel says Danny Granger could be back on the court before the All-Star break in mid-February.


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Document Type
- Article (1)
- Conference Proceeding (1)
- FAIR - from a few-body perspective (2010)
- In the next years the Facility for Antiproton and Ion Research FAIR will be constructed at the GSI Helmholtzzentrum fur Schwerionenforschung in Darmstadt, Germany. This new accelerator complex will allow for unprecedented and pathbreaking research in hadronic, nuclear, and atomic physics as well as in applied sciences. This manuscript will discuss some of these research opportunities, with a focus on few-body physics.
- Measurements of proton-induced reactions on ruthenium-96 in the ESR at GSI (2011)
- 8th International Conference on Nuclear Physics at Storage Rings Stori11, October 9-14, 2011 Laboratori Nazionale di Frascati, Italy. Storage rings offer the possibility of measuring proton- and alpha-induced reactions in inverse kinematics. The combination of this approachwith a radioactive beamfacility allows, in principle, the determination of the respective cross sections for radioactive isotopes. Such data are highly desired for a better understanding of astrophysical nucleosynthesis processes like the p-process. A pioneering experiment has been performed at the Experimental Storage Ring (ESR) at GSI using a stable 96Ru beam at 9-11 AMeV and a hydrogen target. Monte-Carlo simulations of the experiment were made using the Geant4 code. In these simulations, the experimental setup is described in detail and all reaction channels can be investigated. Based on the Geant4 simulations, a prediction of the shape of different spectral components can be performed. A comparison of simulated predictions with the experimental results shows a good agreement and allows the extraction of the cross section.


text: Meta Battle Subway PokeBase - Pokemon Q&A Login Register All Activity Questions Unanswered Tags Users Ask a Question Rules Chat Haxorus EV training. 0 votes Can anyone tell me how to properly EV train Haxorus. Like how much vitamins should give it and which ones do i use? Also what Nature should it have? ev-training asked Jul 19, 2012 by devilpuncher6 Please log in or register to add a comment. Please log in or register to answer this question. 1 Answer 1 vote I'd suggest 4 HP / 252 Atk / 252 Spd with a Jolly Nature. Give it 10 Protein and 10 Carbos. Now, EV train. I'd suggest holding a Macho Brace. In Unova, beat these Pokemon while holding Macho Brace, using Haxorus (Thinking of common Pokemon): 1 Audino 38 Herdier 38 Emolga / Liepard If you don't have a Macho Brace: 2 Audino 76 Herdier 76 Emolga / Liepard Another one is 36 HP / 252 Atk / 220 Spd Give it 3 HP Ups, 10 Proteins, and 10 Carbos. With Macho Brace: 2 Audino 38 Herdier 30 Emolga / Liepard Without: 3 Audino 76 Herdier 60 Emolga / Liepard answered Jul 19, 2012 by Mewderator edited Jul 19, 2012 by Mewderator Show 5 previous comments Where's the Staller variant? xP commented Jul 20, 2012 by Psychic x Staller Haxorus?? I think you have him confused Archeops commented Jul 20, 2012 by 5th of November Ok last question on the ev training do i start from lvl 1 and do i fight 38 herdiers and liepards every lvl or just once? Please help that part confuses me. commented Jul 27, 2012 by devilpuncher6 All you have to do is keep on fighting them. That's it. commented Jul 27, 2012 by Mewderator And you said jolly is the best nature? What about adament nature? commented Jul 27, 2012 by devilpuncher6 Please log in or register to add a comment. Related questions Can I ev train a level 100 haxorus in my white 2? How did my Lv61 Primeape (w/ no EV training) outspeed Blue's Lv73 Alakazam? Blissey EV Training?? Horde Ev training questions? I haven't EV trained. Can Super Training save me? EV training changes in gen 6? Something weird happening with my ev training? EV training torchic(and others) in Emerald? Useful Meta Posts How to change your username How to add a user avatar Why was my post hidden? The points system Question etiquette Flags vs Downvotes Anime FAQ


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Prime Pacific Bank to close Lynnwood branch
The branch at 4710 196th St. SW will close on Sept. 20, said bank president and CEO Glenn Deutsch. The move will affect about 160 customers. The bank will sell the building after its closure.
Deutsch said the consolidation will improve Prime Pacific's operational efficiencies. When the bank opened the headquarters office at 2502 196th St. SW in 2009, he said, it was thought that a large number of customers would resist driving across I-5 to do their banking. That hasn't panned out.
"We thought there would be a bigger division of customers," Deutsch said.
"When we bought the new building, merging the two branch operations was a consideration," board chairman Tim McMahon said in a statement. "From a shareholder perspective, this move makes good sense; additionally, it will continue to give customers access to all of our banking services."
The consolidation will improve Prime Pacific Bank's profitability and capitalization, Deutsch said, but it's not related to the bank's 2009 order from the Treasury Department's Office of Comptroller of the Currency to improve capitalization. The bank completed two stock offerings in the past year to raise capital and is "growing the rest organically," he said.
Prime Pacific Bank has complied with most other elements of the federal order, Deutsch said.
The bank is operationally profitable, but the cost of working through "bad credits" from the 2008 recession continues to be a drag, he said.
Prime Pacific Bank officials said customers have already been notified and expect the branch transfer will be seamless. Customers will maintain their same account information.
Prime Pacific Bank was founded in May 1995 as a full-service community bank. It has $110 million in deposits, Deutsch said.
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The rain held off until the end of the day, meaning 44 shotgun sports competitors, shooting for more than 60 sponsors, were able to finish the annual Joe Young Memorial Shotgun Tournament, hosted by the Ashe County Wildlife Club on Saturday, Aug. 17.
The number of competitors and sponsors were close to club records, which is considered an achievement in a tough economy. All of the money raised by this year's tournament goes to completing the clubhouse, in front of which 30 rifle bays will face a new 300-yard rifle range with a high clay backstop.
Tony Johnson was the overall winner with a score of 91 out of 100 skeet and sporting clays. Mike Stephens had the highest score in Men's Class A (most experienced shooters) with 90 out of 50 skeet and 50 sporting clay. Men's Class B winner was Curtis May with 77 clays. Arlen Bard was winner of Men's Class C with 67 clays.
Pat Elliott won the Ladies category with 72 clays. Krystal Foster won the Youth category with 82 clays. Krystal's score resulted in a lot of good natured grumbling at the club's monthly meeting as the female teenager beat most of the adult men participating in the shotgun event
"Krystal beat most of us out there. In fact, she placed ninth overall, just eight clays away from the best overall score of Tony Johnson's 91 clays," said Danny Laurence, the Ashe County Wildlife Club's Joe Young chairman.
"But that is really what we like to see; youth getting involved early in the shooting sports. Young people like Krystal, and another young lady, Mick Blackburn, who finished second with 76 clays, and Dylan Howell, who finished third in the Youth category with 67 clays, are literally the future of shooting sports so we welcome it when they learn how to handle firearms safely – and when they beat us men who have been doing it for a long time."
The Ashe County Wildlife Club features trap, skeet and sporting clay ranges, the 300-yard rifle range and a pistol range. Membership is $100 per year with lifetime memberships available. New members pay $125 to join, then renew at $100 per year.
The Club supports the 4-H Shooting Sports Club, and is the range used for practice by several area law enforcement agencies.


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Police launch appeal for missing man Kieran 'Lally' McColl
Posted: May 11, 2014|
POLICE are appealing for help to find a missing man.
Kieran McColl, also known as Lally, was last seen in Stone town centre at 10pm on Thursday.
The 21-year-old is described as having a stocky build and being 5ft 8 tall, with a pale completion and blond shaven hair.
On the night he was last seen, he was wearing dark grey pinstripe trousers, a dark blue jumper, a white striped shirt with a white collar, grey tie, a gold chain necklace and a zipped black and white hooded coat.
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Officers are said to be increasingly concerned as the missing man suffers from epilepsy and needs regular medication.
A Staffordshire Police spokesman said: "Since he was reported missing, officers have been conducting a detailed investigation to locate Kieran, including using the police helicopter to search the surround areas, however there have been no confirmed sightings since Thursday night."
Anyone with information is urged to call Staffordshire Police on the non-emergency 101 number.


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Indicator Report - Utah Population Characteristics: Poverty, Children Age 17 and Under
Why Is This Important?Poverty takes into account both income and family size, and has both immediate and long-lasting effects on health. Income provides an assessment of the financial resources available to individual persons or families for basic necessities (e.g., food, clothing, and health care) to maintain or improve their well-being. Persons living in poverty are worse off than persons in more affluent households for many of the indicators tracked by the Utah Department of Health.
Poverty in the early years of a child's life, more than at any other time, has especially harmful effects on continuing healthy development and well-being, including developmental delays and infant mortality. Well-being in later childhood, such as teen pregnancy, substance abuse, and educational attainment, is also influenced by early childhood poverty.
Data NotesHispanic persons may be of any race.
The ACS data are based on a sample and are subject to sampling variability. The degree of uncertainty for an estimate arising from sampling variability is represented through the use of a margin of error. The value shown here is the 90 percent margin of error. The margin of error can be interpreted roughly as providing 90 percent probability that the interval defined by the estimate minus the margin of error and the estimate plus the margin of error (the lower and upper confidence bounds) contains the true value.
Data SourcesU.S. Bureau of the Census. American Community Survey.
Other Views
DefinitionPercentage of children (age 17 and under) living in households whose income is at or below the federal poverty threshold.
How We Calculated the Rates
Page Content Updated On 04/02/2015, Published on 04/08/2015


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Research@StAndrews:FullText >
The foundation of the Reformation Studies Institute in 1993 reflects the university's continuing commitment to enhancing St Andrews' established reputation in this field of scholarship. In the centuries since the Reformation St Andrews has cultivated a tradition of excellence in Reformation studies. Its library boasts a rich collection which has been carefully developed over the years and which dates back to contemporary works from the reformers' own libraries. The Institute provides a focus for the university's advanced work in this area.
With its established group of Faculty members, research students and students taking our taught postgraduate course, St Andrews now boasts one of the largest concentrations of scholars active in this field in any European university. The Institute has a distinctly international flavour, partly through our students, and partly through our partnership relationships with similar institutions in Germany, Switzerland and the United States. It sponsors a graduate seminar, conferences and visits from distinguished outside academics.
For more information please visit the St Andrews Reformation Studies Institute home page.
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On the Plains with Custer : Tales from Before the West Was Wonby SABIN,EDWIN
Trade Paper
Questions About This Book?
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Renting is easy, fast, and cheap! Renting from eCampus.com can save you hundreds of dollars compared to the cost of new or used books each semester. At the end of the semester, simply ship the book back to us with a free UPS shipping label! No need to worry about selling it back.
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This historical western was written before Custer was known as General, a time when those who knew and marched with Custer were still alive. Edwin L. Sabin tells the story of a man who was "as great in peace as in war" from the perspective of Ned Fletcher, a bugler who served under the general. From the westward expansion of Northern Pacific Railway, to Custer's encounters with Sitting Bull and the famous Battle of the Little Bighorn, this account of Custer's adventures is told in an engaging manner and is based upon extensive research. Sabin muses on what really happened at the Battle of Little Bighorn and weaves us a tale that seamlessly combines entertaining storytelling with factual accuracy. While there were no survivors from Custer's Last Stand (or Battle of the Greasy Grass, as it is referred to by Native Americans), the author was able to piece out this quintessential American story from records, Mrs. Custer's writings, and news articles from that time. With the help of the dutiful young soldier, Ned Fletcher, this story embodies what Sabin is best known for-western tales that imbue lessons in good and evil.


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Below is the poem entitled Inside Music which was written by poet
suleimon bamidele
BALOGUN. Please feel free to comment on this poem. However, please remember, PoetrySoup is a place of encouragement and growth.
Read Poems by
suleimon bamidele
Suleimon Bamidele BALOGUN
A prelude towards love is
Without prejudice,
An admirer of love sees the inside of
The power of love is motivated by Music,
For the power lies in Music,
And it uniqueness is in the sound.
Music awoke the spirit to Love,
To see the heart and hear her cry;
For Love is without presage
But happiness and sensational joy did
brings to the Heart


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East falls short again
Sep. 11, 2013 @ 05:49 AM
With just over six minutes left in the game, the East Rutherford Cavaliers led Tuscola 21-14. But in an eerily similar fashion to the Cavaliers' Week 2 loss at North Gaston, the defense allowed the Mountaineers to drive the length of the field, score a touchdown and complete a two-point conversion for a 22-21 lead and eventual win.
"It was just a repeat of North Gaston," East Rutherford head coach Clint Bland said. "There's nothing left to say. We play three good quarters or three and a half but we just can't seem to finish a football game for whatever reason. I hate to sound like a broken record from last week but it's the truth."
Now for the second straight week, the Cavaliers approach a week of practice with a bitter taste in their mouths.
"It's very frustrating," Bland said. "You put more time in after you lose and coach the kids as hard can and you still don't get the results you want on Friday night."
But like last Monday, the Cavaliers try not to dwell on a disappointing Friday night.
"After a loss we try to move on," Bland said. "We had a great day of practice Monday. We just tell the players to keep their heads up, keep working hard and keep preaching that good things are going to happen."
Speaking of good things, quarterback Austin Hollifield continues to impress Bland with his arm and legs.
"Austin played well," Bland said. "He keeps progressing and doing exactly what I expect him to do."
The Cavalier offense is having success on the ground but Bland is contemplating a move that would put the ball in the air more often than not.
"I've kept us in a spread more as of late. I may do away with the I-formation entirely," Bland said. "Normally, I'd like to run the ball more. I feel that in order to be a good high school football team you have to establish the run. But, I just think we're a better team in the spread and we need to put more reps into that."
However, it doesn't seem to be the offense that is putting the team in bad situations.
"We're averaging 30 points a game but it just isn't enough," Bland said. "The defense will keep coming up with good game plans but it comes down to the kids making the plays. We're putting ourselves into position to make plays but we just aren't making them. It just comes down to tackling and making a play."
And with SMAC opponent Kings Mountain waiting on them Friday night, the Cavaliers aren't changing up much in practice this week to break the slide.
"We're not changing a whole lot. We're just going to keep doing what we're doing," Bland said. "The good thing is that the kids are still working hard. We're 0-3 and sometimes kids will start laying down or giving up. We don't have any of that. Something good is going to happen to us pretty soon I hope."


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The subsequent day plus how deep that contemporary abdominal muscles will also helps to smooth the ridges which you may realize the trunk. Few if any abdominal exercises movement is crucial to this exercise is some good old fashioned sit up.
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