text:
|Publication number||US5019393 A|
|Application number||US 07/227,728|
|Publication date||28 May 1991|
|Filing date||3 Aug 1988|
|Priority date||3 Aug 1988|
|Publication number||07227728, 227728, US 5019393 A, US 5019393A, US-A-5019393, US5019393 A, US5019393A|
|Inventors||Ralph K. Ito, Frank W. LoGerfo|
|Original Assignee||New England Deaconess Hospital Corporation|
|Export Citation||BiBTeX, EndNote, RefMan|
|Patent Citations (12), Referenced by (139), Classifications (15), Legal Events (6)|
|External Links: USPTO, USPTO Assignment, Espacenet|
The subject matter of this application is related to applicants' copending application Ser. No. 227,700, entitled "HIRUDIN-COATED BIOCOMPATIBLE SUBSTANCE", filed on even date herewith.
The technical field of the present invention is prosthetic vascular materials, and more specifically is biocompatible, thromboresistant substances and methods of their preparation.
Exposure of blood to artificial surfaces usually leads to deposition of a layer of adherent platelets, accompanied by activation of the intrinsic coagulation system, and ultimately to the formation of a thrombus. In fact, significant blood/materials interaction can occur on a single pass through a prosthetic arterial graft. The types of blood proteins initially adsorbed or bound to synthetic surfaces may include proteins involved in contact coagulation. Contact coagulation or the extrinsic pathway of coagulation is a complex pathway of biochemical events that induces fibrin formation, platelet and complement activation, chemotaxis, kinin generation, and activation of fibrinolytic components. In addition, each of these events augments subsequent biochemical pathways often controlled by positive and negative feedback loops. Thus, thrombosis induced by contact with artificial materials is a major obstacle in the development and use of internal prostheses and extracorporeal devices such as artificial vessels and organs, and cardiopulmonary bypass and hemodialysis equipment.
Materials having varying degrees of thromboresistance have been utilized in vascular prostheses with limited success. These materials include corroding (self-cleaning) metals, synthetic polymers such as polydimethyl siloxane, Teflon, acylates and methacrylates such as Dacron, electrets, anionic copolymers, and hydrogels for a review see Salzman et al. (1987) in Hemostasis and Thrombosis, Basic Principles and Clinical Practice (Colman et al., eds.) J. B. Lippincott Co., Phila., Pa., pp. 1335-1347).
To decrease the chances of thrombosis due to extended periods of contact with such artificial materials, patients have been treated with systemically administered anti-coagulant, anti-platelet, and thrombolytic drugs. These include any compound which selectively inhibits thromboxane synthetase without affecting prostacycline synthetase, affects platelet adherence as well as aggregation and release, enhances vascular PGI2 production, and/or inhibits both thrombin- and thromboxane-mediated platelet aggregation. Such compounds include aspirin, sulfinpyrazone, dipyridamole, ticlopidine, and suloctidil. However, treatment with these drugs often elicits unwanted side effects including systemic hemmorhaging and the inability to initiate and complete desired clotting elsewhere in the body.
To improve on the thromboresistance of artificial materials, biologically active molecules having thrombolytic, anticoagulating, thrombogenesis-inhibiting, and/or platelet inhibiting abilities have been linked thereto. For example, heparin has been bound to artificial surfaces to reduce cooagulation by activating variuous inhibitors of the intrinsic clotting system (Salzman et al. (1987) in Hemostasis and Thrombosis: Basic Principles and Clinical Practice. 2nd Ed., (Colman et al., eds.), Lippincott Co., Phila., Pa., pp. 1335-1347). However, heparin enhances platelet responses to stimuli such as ADP or collagen, and promotes two adverse primary blood responses towards synthetic surfaces: platelet adhesion and aggregation. In addition, although surface-bound heparin/antithrombin complex may be passive towards platelets, the wide variety of effects it has on interactions with endothelial cell growth factor, inhibition of smooth muscle proliferation, and activation of lipoprotein lipase raises questions as to what adverse effects it may induce over time.
Anti-platelet agents such as PGE1, PGI2 (experimental use only), cyclic AMP, and aspirin have also been attached to solid polymer surfaces. These agents discourage the release of platelet factors that stimulate adverse healing responses in the vicinity of a vascular graft. They may also reduce platelet-aided thrombus formation by inhibiting platelet adhesion.
The exposure of many artificial surfaces to albumin prior to vascular contact results in reduced reactivity with platelets (NIH Publication No. 85-2185, Sept., 1985, pp. 19-63). Therefore, albumin has been used to coat extracorporeal surfaces before cardiopulmonary by-pass surgery. However, long-term thermoresistance has not been achieved by this procedure.
Fibrinolytically active streptokinase and urokinase, alone or in combination with heparin have been attached to artificial surfaces by Kusserow et al (Trans. Am. Soc. Artif. Intern. Organs (1971) 17:1). These enzymes reduce excessive fibrin deposition and/or thrombotic occlusions. However, the long term assessment of their ability to confer thromboresistance to a synthetic surface has not been determined.
Surface active agents such as Pluronic F-68 have also been immobilized on artificial surfaces, but do not appear to offer long term blood compatibility (Salyer et al. (1971) Medical Applications of Plastics. Biomed. Materials Res. Sym. (Gregor, ed.) No. 1 pp. 105).
Therefore, what is needed are better biocompatible materials which are thromboresistant in the long term and whose active components do not cause detrimental side affects.
An object of the present invention is to provide a synthetic, biocompatible, thromboresistent material useful for implantable and extracorporeal devices in contact with bodily fluids.
Another object is to provide an immobilized thrombogenesis inhibitor which is biologically active, and a method of preparing the same.
Still another object of this invention is to provide a method of inhibiting platelet aggregation, the release of platelet factors, and thrombogenesis at the localized site of the graft or prosthesis-blood interface, thus avoiding the systemic effect of antiplatelet and antithrombosis drugs.
Materials and methods are disclosed herein for the provision of biocompatible, thromboresistant substances useful as a component of implantable or extracorporeal devices in contact with the blood.
It has been discovered that a synthetic, biocompatible material can be made into a thromboresistant substance by immobilizing to it, by way of a base coat layer, a thrombogenesis inhibitor other than hirudin, or an active analog or fragment thereof, in such a way that does not compromise its thrombogenesis inhibiting activity.
The term "thrombogenesis inhibitor" is used herein to describe molecules which interfere with or inhibit the formation of a thrombus. Such molecules include those which interfere or inhibit the intrinsic and extrinsic coagulation system, platelet adherence, aggregation, or factor release or activity, or the release or active of tissue factors. Included are native, synthetic, or recombinant proteins, or active analogs, fragments, derivatives, or fusion products thereof, and mixture thereof which can interfere and inhibit the formation of a thrombus. Thrombogensis inhibitors useful for imparting thromboresistance to the substance include proteins which are mambrane-bound in their native state (e.g., adenosine triphosphatase (ATPase), adenosine diphosphatase (ADPase), and 3'-nucleotidase), and those which are normally soluble in vivo (e.g., tissue plasminogen activator (tPA), urokinase (UK), and streptokinase (SK)). However, other molecules which inhibit or interfer with the activity of other thrombogenesis inhibitors are useful as well.
Synthetic materials contemplated by the instant invention are preferably polymers such as Dacron, nylon, polyurethane, cross-linked collagen, polytetrafluoroethylene, polyglycolic acid, and mixtures thereof, the most preferred polymeric material being Dacron. Other synthetic materials might also be used.
At least one layer of biocompatible material is adhered to at least one surface of the synthetic material. This base coat layer contains a component which is capable of binding the thrombogenesis inhibitor. Examples of such base coat components include proteins, peptides, lipoproteins, glycoproteins, glycosaminoglycans, hydrogels, synthetic polymers, and mixtures thereof. In preferred aspects of the invention, the base coat layer includes a protein component such as serum albumin or fibronectin from, for example, human or bovine sources, or mixtures of these proteins. Other materials might also be used to form the base coat layer.
In accordance with the invention, the thrombogenesis inhibitor is immobilized on the synthetic material via a base coat layer which is adhered to least one surface cf the synthetic material. The base coat layer contains a component capable of binding the thrombogenesis inhibitor without compromising the biological activity of the inhibitor.
In exemplary aspects of the invention, the synthetic material is activated prior to having the base coat layer adhered thereto so as to enhances its ability to bind the base coat base layer. For example, in one preferred aspect, the synthetic material is contacted with a solution which makes available at least one chemically active group (e.g., a carboxylic acid group) in the material for binding to a bifunctional cross-linking reagent (e.g., carbodiimide). The material so treated is then put into contact with a solution containing the cross-linking carbodiimide reagent for a time sufficient to allow the chemically active group to bind thereto.
In another embodiment, the synthetic material may be contacted with a solution which removes impuritities therein and/or thereon prior to the activation step described above.
The immobilization step may be carried out by initially contacting the thrombogenesis inhibitor with at least one molecule of a bifunctional cross-linking reagent for a time sufficient to allow linking of the reagent to the inhibitor, and then binding the thrombogenesis inhibitor-linked reagent to the base coat. The bound thrombogenesis inhibitor retains its thrombogenesis inhibiting activity when bound to the reagent. The bifunctional cross-linking reagent useful for such an immobilization step may be heterobifunctional (e.g., N-succinimidyl 3-(2-pyridyldithio)propionate (SPDP)), homobifunctional (e.g., ethylene glycolbis (succinimidylsuccinate) (EGS)), or a mixture of both.
The term "bifunctional cross-linking reagent" is defined herein as a molecule having the ability to bind to, and therefore link, two reactive groups on, for example, one molecule or two separate molecules. If the bifunctional cross-linking reagent binds two different types of groups, it is a "heterobifunctional" cross-linking reagent. However, if the bifunctional cross-linking reagent binds only to two similar groups, it is "homobifunctional".
Prior to the binding step, the thrombogenesis-linked reagent :nay be subjected to chromatographic procedures to remove impurities mixed in with it.
In an alternative aspect of the invention, the base coat adhered to the synthetic material may be linked at the same time to at least one molecule of a bifunctional cross-linking reagent. In this embodiment, the method further includes binding the thrombogenesis inhibitor-linked reagent to the base coat-linked reagent, thereby linking the thrombogenesis inhibitor to the material-adhered base coat layer.
In another aspect of the invention, the base coat-linked reagent is reduced prior to the binding step. Reduction results in the formation of sulhydryl groups from the reagent on the base coat which can react with the inhibitor-linked bifunctional cross-linking reagent via a substitution reaction to form an S--S bond, thereby covalently linking the thrombogenesis inhibitor to the base coat.
In yet another aspect of the invention, the base coat is linked to the thrombogenesis inhibitor before it is linked to the synthetic, biocompatible material.
The invention will next be described in connection with certain illustrated embodiments. However, it should be clear that various modifications, additions, and deletions can be made without departing from the spirit or scope of the invention.
The foregoing and other objects of the present invention, the various features thereof, as well as the inventions thereof may be more fully understood from the following description when read together with the accompanying drawings in which:
FIG. 1 is a diagrammatic representation of the pathways involved in thrombogenesis; and
FIG. 2 is a diagrammatic representation of platelet involvement in thrombogenesis.
This invention provides biocompatible, thromboresistant substances useful for implantable and extracorporeal devices in contact with the vascular system, and methods for their fabrication.
The substances provided by this invention include a synthetic biocompatible substance having a thrombogenesis-inhibiting reagent linked thereto via a biocompatible base coat adhered to the material's surface.
The material useful in a prosthetic extracorporeal or implantable device may be composed of any biocompatible, synthetic, preferably polymeric material having enough tensile strength to withstand the rigors of blood circulation, and having groups onto which a base coat can be directly or indirectly bound. Examples of such synthetic materials are polytetrafluoroethylene (Teflon) and Dacron, nylon, and the like. The material may have any dimensions suitable for the purpose for which it is being used. For example, it may be an integral part of an implanted heart valve or of an extracorporeal device used for hemodialysis or cardiopulmonary by-pass surgery, or it may be used to coat catheters or to line the interior of a vascular graft.
The synthetic material, when obtained, may be coated with or contain various noncovalently adhered impurities whose removal may be prerequisite for the adherence of a base coat thereto. For example, lubricants on commercial quality Dacron can be removed by contacting the Dacron with a solution containing, for example, various detergents, solvents, or salts, which loosen and/or solubilize these impurities.
TABLEs 1 and 2 outline representative methods of preparing the biocompatible, thromboresistant substance, where "Da" refers to a synthetic material composed of woven Dacron fibers, and "HSA" refers to human serum albumin.
TABLE 1______________________________________STEP PROCESS______________________________________(1) Da. + NaOH → Da-COOH(2) Da-COOH + EDC → Da-EDC(3) Da-EDC + HSA → Da-HSA + urea (EDC by-product)(4) Da-HSA + SPDP → Da-HSA-SPDP(5) Da-HSA-SPDP + DTT → Da-HSA-SH + P-2-T(6) Inhibitor + SPDP → Inhibitor-SPDP(7) Da-HSA-SH + Inhibitor-SPDP → Da-HSA-S-S-Inhibitor + P-2-T______________________________________
TABLE 2__________________________________________________________________________STEP PROCESS__________________________________________________________________________(1) HSA + SPDP → HSA-SPDP(2) HSA-SPDP + DTT → HSA-SH + P-2-T(3) Inhibitor + SPDP → Inhibitor-SPDP(4) HSA-SH + Inhibitor-SPDP → HSA-S-S-Inhibitor + P-2-T(5) Da + NaOH → Da-COOH(6) Da-COOH + EDC → Da-EDC(7) Da-EDC + HSA-S-S-Inhibitor → Da-HSA-S-S-Inhibitor + urea (EDC by-product)__________________________________________________________________________
Initially, the material may be activated so as to enhance the binding of the base coat layer. This activating step increases the number of chemically active groups in the material. For example, alkaline hydrolysis may be performed to increase the number of reactive carboxylic acid groups in the Dacron to which a bifunctional cross-linking reagent such as carbodiimide may be bound. Ultimately, the base coat will adhere to the bound carbodiimide groups on the material. However, this method must be performed with care, as alkaline hydrolysis partially degrades the Dacron, resulting in a fraying of the material's fibers.
At least one base coat layer is adhered to at least one surface of the synthetic material.
This layer, either adhered to the material or unbound, provides components for attachment of the thrombogenesis inhibitor. Such components provide more binding sites for the inhibitor than the synthetic material, alone, thereby amplifying the amount of inhibitor which may be bound. Useful components include proteins, peptides, lipoproteins, glycoproteins, glycosaminoglycans, synthetic polymers, and mixtures thereof. Proteins such as serum albumin and fibronectin are particularly useful for this purpose as they are known to have anti-thrombogenic properties, themselves, are very desirable as base coat components (Lyman et al. (1965) Trans. Am. Soc. Artif. Intern. Organs 11:301; Falb et al. (1971) Fed. Proc. 30: 1688). An HSA molecule, for example, has 65 amino groups available as binding sites.
Attachment of the base coat to the artificial surface may be covalent in nature. Methods to covalently bind proteins to Dacron involve attack of the free reactive succinimide ester group of the cross-linking reagent to primary amino groups on a protein. As shown in the example in Table 1, to covalently adhere the base coat to Dacron, the Dacron is initially treated with 0.5 N NaOH and reacted with carbodiimide before it is coated with HSA (base coat) in phosphate buffered saline (PBS).
A thrombogenesis inhibitor useful as a coating for surfaces in contact with blood, bodily fluids, or tissues, is then covalently adhered to the base coat via the component. Inhibitor-coated substances are ideal for implantable use in devices which are in direct contact with blood. For example, by-pass grafts used to replace blood vessels often become filled with blood clots or thrombi, resulting in restricted blood flow. Since the inhibitor-coated substance is resistant to formation of blood clots, thrombosis and subsequent blockage of the bypass graft will be prevented. Likewise when catheters are placed into the vascular system for a diagnostic or therapeutic purposes, a blood clot often forms on the outside of the catheter. The clot may be washed off the catheter by flowing blood, or be jarred loose by manipulation of the catheter, increasing the possibility of embolism and blockage of the circulation to vital organs. Inhibitor-coated substances provide similar advantages for artificial or prosthetic heart valves, intraaortic balloon pumps, total or artificial heart or heart assist devices, intracaval devices, and any device in contact with the bloodstream. In addition, inhibitor-coated devices provide advantages for intracavity devices such as intraperitoneal dialysis catheters and subcutaneous implants where the thrombin-induced inflammmatory reactions would be diminished.
Thrombogenesis inhibitors useful for these purposes include molecules which interfere with, or inhibit thrombogenesis. These include ATPase, ADPase, 5'-nucleotidase, streptokinase, urokinase, tissue plasminogen activator, anticoagulants, platelet inhibitors (e.g., prostacycline and aspirin), and active analogs, fragments, derivatives, and fusion products thereof, or mixtures thereof.
ADPase reduces platelet aggregation by degrading ADP. ADP is stored in the dense granules of platelets and can be released by thrombin, epinephrine, collagen, and other stimulants. When released, ADP promotes platelet receptor binding to fibrinogen and to von Willebrand Factor, two proteins essential for aggregation, and then promotes thromboxane synthesis, platelet aggregation, more ADP release, and thus, self-enhances platelet aggregation.
ATPase catalyzes the conversion of ATP to ADP, which can then be acted upon by ADPase, as described above.
5'-nucleotidase (AMPase), like ADPase, degrades ADP. It also degrades AMP, a competitive antagonist for ADP receptor birding, to adenosine, a platelet inhibitor. Adenosine inhibits platelet aggregation by increasing intracellular levels of cyclic AMP. High levels of cyclic AMP inhibit mobilization of calcium ions from platelet storage pools. Free calcium ions within the platelet stimulates release of additional ADP from platelet dense granules, and is necessary for platelet aggregation, hence thrombogenesis (see FIG. 2).
The thrombogenesis inhibitor is directly or indirectly immobilized on the base coat via the use of a bifunctional cross-linking reagent. In particular, a heterobifunctional cross-linking reagent which has two different reactive groups at each end of a linear molecule, and can therefore bind two different reactive groups on other molecules or on a different region of the same molecule, is most useful as a bifunctional cross-linking agent. For example, photoreactive cross-linkers, such as sulfosuccinimidyl 2-(m-azodo-o-nitro-benzamido)ethyl-1, 3'-dithio-propionate (SAND), or N-succinimidyl-6-(4;azoido-2'-nitrophenyl-amino) hexanoate (SANPAH) have a photoreactive group that can directly insert into C--H bonds of the base coat by photochemical coupling, while the other group remains free to bind to proteins.
Other useful and preferable cross-linking reagents (such as SPDP) and their characteristics are found in TABLE 3. In TABLE 3, the "Double-Agent Number" listed for each reagent is the commercial designation for the reagent as made available by Pierce Chemical Co. (Rockford, Ill.).
TABLE 3______________________________________CROSS-LINKING REAGENTS (part A) ReactiveDouble- Double- towards:Agent Agent Bifunctionality Photo-Number Acronym Homo Hetero NH.sub.2 SH Reactive______________________________________21551 ANB-NOS X X X20106 APB X X X20107 APG X X21559 APTP X X X21579 BS.sup.3 X X22319 BMH X X21554 BSOCOES X X21524 DFDNB X X20047 DIDS X X21664 DMA X X20666 DMP X X20668 DMS X X22585 DSP X X21555 DSS X X20590 DST X X20665 DTBP X X22590 DTBPA X X21577 DTSSP X X21550 EADB X X X21565 EGS X X23700 FNPA X X X21560 HSAB X X X26095 MABI X X X22310 MBS X X X27715 NHS-ASA X X X20669 PNP-DTP X X X21552 SADP X X X21549 SAND X X X22588 SANPAH X X X27716 SASD X X X22325 SIAB X X X X22320 SMCC X X X22315 SMPB X X X21557 SPDP X X X21556 Sulfo- X X BSOCOES20591 Sulfo- X X DST21556 Sulfo- X X EGS22312 Sulfo- X X X MBS21553 Sulfo- X X X SADP22589 Sulfo- X X X SANPAH22327 Sulfo- X X X SIAB22322 Sulfo- X X X SMCC22317 Sulfo- X X X SMPB26101 TRAUT'S X X______________________________________CROSS-LINKING REAGENTS (part B)Agent Acronym Chemical Name______________________________________ANB-NOS N-5-azido-2-nitrobenzoyloxysuccinimideAPB p-azidophenacyl bromideAPG P-azidophenyl glyoxalAPTP n-4-(azidophenylthio)phthalimideBS.sup.3 bis(sulfosuccinimidyl) suberateBMH bis maleimidohexaneBSOCOES bis[2-(succinimidooxycarbonyloxy)- ethyl]sulfoneDFDNB 1,5-difluoro-2,4-dinitrobenzeneDIDS 4,4'-diisothiocyano-2,2'-disulfonic acid stilbeneDMA dimethyl adipimidate-2 HClDMP dimethyl pimelimidate-2 HClDMS dimethyl suberimidate-2 HClDSP dithiobis(succinimidylpropionate)DSS disuccinimidyl suberateDST disuccinimidyl tartarateDTBP dimethyl 3,3'-dithiobispropionimidate- 2-HClDTBPA 4,4'-diothiobisphenylazideDTSSP 3,3-dithiobis(sulfosuccinimidyl- propionate)EADB ethyl-4-azidophenyl 1,4-dithio- butyrimidateEGS ethylene glycolbis(succinimidyl- succinateFNPA 1-azido-4-fluoro-3-nitobenzeneHSAB N-hydroxysuccinimidyl-4-azidobenzoateMABI methyl-4-azidobenzoimidateMBS m-maleimidobenzoyl-N-hydroxysulfo- succinimide esterNHS-ASA N-hydroxysuccinimidyl-4-azidosalicylic acidPNP-DTP p-nitrophenyl-2-diazo-3,3,3-trifluoro- propionateSADP N-succinimidyl(4-axidophenyl)-1,3'-di- thiopropionateSAND sulfosuccinimidyl 2-(m-azido-o-nitro- benzamido)-ethyl-1,3'-dithiopropionateSANPAH N-succinimidyl-6(4'-azido-2'-nitro- phenyl-amino)hexanoateSASD sulfosuccinimidyl 2-(p-azidosalicyl- amido)ethyl-1,3'-dithio-propionateSIAB N-succinimidyl(4-iodoacetyl)amino- benzoateSMCC succinimidyl 4-(N-maleimidomethyl)- cyclohexane-1-carboxylateSMPB succinimidyl 4-(p-maleimidophenyl)- butyrateSPDP N-succinimidyl 3-(2-pyridyldithio) propionateSulfo- bis[2-(sulfosuccinimidooxy-carbonyl-BSOCOES oxy)ethyl]sulfoneSulfo-DST disulfosuccinimidyl tartarateSulfo-EGS ethylene glycolbis(sulfosuccinimidyl- succinate)Sulfo-MBS m-maleimidobenzoyl-N-hydro-xysulfo- succinimide esterSulfo-SADP sulfosuccinimidyl(4-azidophenyldithio)- propionateSulfo- sulfosuccinimidyl 6-(4'azido-2'-nithro-SANPAH phenylamino)hexanoateSulfo- sulfosuccinimidyl(4-iodoacetyl)amino-SIAB benzoateSulfo-SMCC sulfosuccinimidyl 4-(N-maleimido- methyl)cyclohexane-1-carboxylateSulfo-SMPB sulfosuccinimidyl 4-(p-maleimido- phenyl)butyrateTRAUT'S 2-iminothiolane-HCl______________________________________
The cross-linking reagent is applied to the base coat in amounts such that the desired binding site density is achieved. Binding site density is that amount of cross-linking reagent, in terms of moles/g synthetic material, to bind to the base coat while providing confluent coverage of the surface.
To put the inhibitor in condition for linkage to the base coat, the cross-linking reagent may be initially coupled separately to both the base coat and to the inhibitor. The kinetic constants of the inhibitors are compared before and after coupling to evaluate effects of the procedure on their kinetic constants. The inhibitor should remain biologically active after being coupled. Therefore, standard activity assays specific for the inhibitor to be immobilized are performed using a standard thrombin solution to evaluate this capacity.
The protein component of, the base coat may be bound to the thrombogenesis inhibitor forming a conjugate prior to its adherence to the synthetic material. The conjugate can then be bound to the synthetic material as described for base coat binding to achieve the same effect (TABLE 2). In addition, the thrombogenesis inhibitor conjugate retains biological activity, and can be used as an agent to increased half life in the circulation as it is not easily cleared by the kidney.
SPDP will react with terminal as well as epsilon amino groups, Since derivatization of a terminal amino group can inactivate a biologically active protein, T-BLOCK (Pierce Chemical Co., Rockford, Ill.) may be used to block that group during SPDP-derivatization. The T-BLOCK is then removed after derivatization to restore biological activity.
The invention will be further understood from the following, non-limiting examples.
Dacron polyester 52 (DuPont) is sectioned into 1.0 cm lengths. The lubricant on and in the woven surface is removed by washing once for 1 hr with carbon tetrachloride, and twice with 100% CH3 OH. The methanol is removed by multiple water washes, followed by one wash in phosphate buffered saline, pH 7.4 (PBS).
The graft material is then subjected to alkaline hydrolysis to increase available COOH groups. The material is treated with 0.5 M NaOH at 50° C. for 1 hr. It is then washed with H2 O repeatedly, and the following steps initiated immediately.
The activated material is placed into 100.0 ml of 10 mM water-soluble carbodiimide (EDC) in deionized water, pH 4.6-5.0, for 1 hour at RT with constant stirring. The material is removed and washed in PBS, to remove excess unbound EDC.
The base coat is applied to the lumen of the Dacron graft material. The derivatized Dacron material is incubated in a 5% HSA solution in PBS at 1 ml/cm2 graft material for 24 hr at RT with constant stirring. The graft is removed and washed in PBS to remove nonspecifically bound HSA. Approximately 20 mg protein/mg Dacron is covalently bound.
The HSA-bound Dacron material is incubated in a 1.0 mM solution of SPDP in PBS, pH 7.4, to bind SPDP to the HSA (100 mM SPDP/cm2 base coat). Incubation is terminated after 30-40 min at RT. The graft is washed with PBS to remove nonspecifically bound SPDP.
The SPDP-linked material is dried and weighed to obtain its absolute weight. It is then placed in a 50 mM solution of dithiotreitol (DTT) for 5 min at RT. This reaction releases pyridine-2-thione (P-2-T) from the bound SPDP and simultaneously forms free sulphydryl (SH) groups on the base coat. The released P-2-T is quantitated by absorption spectrophotometry at 343 nm using its extinction coefficient (E=8.08×103), and is directly proportional to the quantity of bound SPDP or binding sites. The number of binding sites are calculated and expressed as moles of sites/g of Dacron.
The material is then washed 5 times in PBS and 4 times in dH2 O.
Albumin-free SK (KabiVitrum, Stockholm, Sweden) is filter-transfered with use of a PD-10 column (Pharmacia, Piscataway, N.J.) to remove contaminants and amino acid preservatives, and to transfer SK into 0.1 M PBS buffer, pH 7.5. 0.5 ml fractions are collected, absorbance values at 280 nm recorded, and desired fractions pooled. The molar concentration of pooled SK is determined using its absorptivity coefficient at 280 nm (A280 1.0%/1.0 cm=7.5). The concentration of pooled SK is then set to approximately 0.1 mM in PBS buffer. A 20 mM SPDP solution is prepared in absolute ethanol just prior to use and mixed with SK in various mole to mole ratios (i.e., 1:10). The mixture is allowed to incubate for 30 min at 23° C. It is then filter-transferred into PBS buffer, pH 7.5 using a PD-10 column equilibrated with PBS buffer, pH 7.5. 0.5 ml fractions are collected, absorbance measurements at 280 nm recorded, and desired fractions (i.e., A280 greater than 1.8) pooled. The pool contains SK linked to 2-pyridine disulphide (SK-2-PD) in PBS buffer, pH 7.5.
The binding of SPDP to SK can be quantitated by the addition of DTT which liberates pyridine-2-thione (P-2-T) from SPDP bound to SK, and which can be measured spectrophotometrically at 343 nm. From this measurement, the moles of SPDP bound to SK can be calculated. Each P-2-T released represents one covalent attachment of SPDP to SK. One mole of SK binds per 1.2 moles SPDP in the present studies.
The reduced SPDP-linked base coat (having free SH groups) is washed with PBS to remove the DTT. SPDP-linked SK is then added to the graft at 50.0 mg/cm2 Dacron. The solution is incubated overnight at RT to allow the binding of SPDP-SK to SH groups on the Dacron graft. The Dacron material with SK covalently immobilized thereto is then washed and stored in PBS.
SK, when mixed with human plasminogen forms an active proteolytic complex that can be quantitated using the chromogenic substrate, S-2251 (KabiVitrum A.B., Stockholm, Sweden). A standard curve is constructed using known concentrations of SK (500-10,000 units/ml). A 60 ml aliquot of each standard is added to 120 ml of 0.2 mM human plasminogen (American Diagnostica, Greenwich, Conn.), and incubated at 37° C. for 10 min. SK-plasminogen complex is formed as well as free plasma which interferes with the analysis. This interference is eliminated by the addition of 60 ml of 2.0 mg/ml soybean trypsin inhibitor which inhibits all free plasma. The quantitative analysis of SK-plasminogen is accomplished by addition of 420 ml of 0.86 mM S-2251 in 50 mM Tris-HCl, 12 mM NaCl, pH 7.4, and monitoring the change in absorbance per min at 405 nM at 37° C. The immobilized SK is substituted for the standard solution in the assay. The measured activity of the material on S-2251 is then equated to the standard curve.
I. Immobilized UK Activity Analysis
The activity of immobilized UK is evaluated against a standard curve generated using soluble UK in concentrations of from 10 to 1000 units of UK (refered here as CTA units). The chromogenic substrate, S-2444 (KabiVitrum AB, Stockholm, Sweden), is used at 0.3 mM to measure activity of UK standards by monitoring change in absorbance at 405 nm in 50.0 mM Tris, 12.0 mM NaCl, pH 8.8 at 37° C. A standard curve is thus generated. A section of material with immobilized or bonded UK is placed into the substrate under the same conditions, and the change in absorbance is recorded. The activity of the immobilized UK is evaluated by comparison to the activity of the standard curve.
The invention may be embodied in other specific forms without departing from the spirit or essential characteristics thereof. The present embodiments are therefore to be considered in all respects as illustrative and not restrictive, the scope of the invention being indicated by the appended claims rather than by the foregoing description, and all changes which come within the meaning and range of equivalency of the claims are therefore intended to be embraced therein.
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|U.S. Classification||424/423, 424/422, 530/300, 523/112, 424/425, 424/424, 604/266, 604/890.1, 424/426, 523/113|
|Cooperative Classification||A61L33/0047, A61L33/0029|
|European Classification||A61L33/00H2F, A61L33/00H3|
|3 Aug 1988||AS||Assignment|
Owner name: NEW ENGLAND DEACONESS HOSPITAL CORPORATION, 185 PI
Free format text: ASSIGNMENT OF ASSIGNORS INTEREST.;ASSIGNORS:ITO, RALPH K.;LO GERFO, FRANK W.;REEL/FRAME:004916/0400
Effective date: 19880803
|14 Nov 1994||FPAY||Fee payment|
Year of fee payment: 4
|14 Apr 1997||AS||Assignment|
Owner name: BETH ISRAEL DEACONESS MEDICAL CENTER, INC., THE, M
Free format text: MERGER;ASSIGNOR:NEW ENGLAND DEACONESS HOSPITAL CORPORATION;REEL/FRAME:008454/0489
Effective date: 19961001
|22 Dec 1998||REMI||Maintenance fee reminder mailed|
|30 May 1999||LAPS||Lapse for failure to pay maintenance fees|
|27 Jul 1999||FP||Expired due to failure to pay maintenance fee|
Effective date: 19990528

domain: chemistry


text:
And general manager garth snow TAPS influence
I think they can stay right where they are and come out of the first five rounds with a starting center, a linebacker that won’t start but is active on game day, and a safety of some sort.If @mirandalambert is over Blake why take that dig.Many of the six core values that Blank holds at the very heart of his business ventures embody selflessness in many ways, including give back to others and put people first.
The team’s trip to the AFC Championship was just the third in franchise history and the first since the 1999 season.On Monday, UConn received a verbal commitment from No.The uber-talented Boston Celtics guard can opt out of his contract next summer to become a free agent.Six of those points came from the foul line where Ford went 8 for 8 and Jock Perry’s 3-pointer just before the buzzer gave Saint Mary’s a 42 lead at the half.ON POINT At least one Rangers defenseman has recorded a point in 27 of the team’s last 29 games, including all 27 games which the team has registered a goal over the span.They are the happiest, sweetest, most loved kids in the entire world, so no one needs to worry about that.
Horston was named MVP of the game; she declined to comment on her future at the postgame news conference.Cain’s back-to-back 3s stretched the lead to 77 with 9 remaining.The Washington Redskins made their big splash this offseason when they signed free agent safety Landon Collins to a six-year deal.Aloha Stadium is, of course, no stranger to the NFL.Why he shouldn’t: Ladd might seem like the obvious candidate but he’s not.
NOTES & TRANSACTIONS View More.- AJ McCarron March 20 McCarron, a former Alabama standout, has played in 12 NFL games, including seven for the Cincinnati Bengals in 2015 when he took over for an injured Andy Dalton.Max Strus made three free throws with 1 remaining to pull DePaul within 66.

domain: news


text:
Get a glimpse into our company and investor data—powered by the PitchBook Platform
Provider of loan financing. The company offers credit lending and loan financing services for commercial services in Naperville, Illinois.
This information is reserved for PitchBook Platform users. To explore Midwest Business Credit‘s full profile, request access.
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domain: economics


After three decades of keeping mum, Barbara Walters is disclosing a past affair with married U.S. Sen. Edward Brooke, whom she remembers as “exciting” and “brilliant.”
Appearing on The Oprah Winfrey Show scheduled to air Tuesday, Walters shares details of her relationship with Brooke, which lasted several years in the 1970s, according to a transcript of the show provided to the Associated Press.
A moderate Republican from Massachusetts who took office in 1967, Brooke was the first African-American to be popularly elected to the Senate. Both he and Walters knew that public knowledge of their affair could have ruined his career as well as hers, Walters says.
At the time, the twice-divorced Walters was a rising star in TV news and co-host of NBC’s Today show, but would soon jump to ABC News. Her affair with Brooke, which never before came to light, had ended before he lost his bid to Democrat Paul Tsongas of Lowell for a third term in 1978. Brooke’s loss followed his bitter public divorce.
Brooke has since remarried. Calls to a listing for Brooke in Miami by the Associated Press were not immediately returned yesterday.
On Oprah, Walters discusses her new memoir, Audition, which covers her
long career in television, as well as her off-camera life. Winfrey asks Walters if she was in love.
“I was certainly — I don’t know — I was certainly infatuated.”
“I was certainly involved,” Walters says. “He was exciting. He was brilliant. It was exciting times in Washington.”
MTV at Brew’d Awakening
Ryan Decker, a senior at Chelmsford High School, is competing to be the next Mr. CHS and MTV’s Made wants to help. The reality show that helps people reach their dreams by getting “made,” filmed Decker with Miss Massachusetts Jacqueline Bruno Wednesday night at Brew’d Awakening in Lowell. MTV crews shot the pair, who ordered hot chocolates, at a front table in the funky Market Street cafe.
Bruno must have been sharing tips on ways to win over the judges in this competitive school-wide talent show.
Reached by phone, a tight-lipped Decker wouldn’t tell us much more, per an MTV gag order. Good luck Ryan. The show is scheduled to air in June.
Time 100: Bush, Murdoch and … Madea?
What would Madea have to say about all this?
The creator of the feisty matriarch — playwright, actor and filmmaker Tyler Perry — made Time magazine’s list of the world’s 100 most influential people
He joined the usual suspects, including President Bush, media mogul Rupert Murdoch, New York City Mayor Michael Bloomberg, Barack Obama, John McCain and Hillary Clinton.
The 2008 list includes more than three times as many men as women and draws nominees from 23 countries, a magazine spokeswoman said.
Others on the list include Federal Reserve Chairman Ben Bernanke, the Dalai Lama, U.S. Defense Secretary Robert Gates, Chinese President Hu Jintao, African National Congress President Jacob Zuma, Mexican golfer Lorena Ochoa, singer Mariah Carey, personal-finance adviser Suze Orman and — yawn — Oprah Winfrey, who has made the list five times, more often than anyone else.
It’s Emmys time again
The View, Rachael Ray and The Ellen DeGeneres Show are among this year’s Daytime Emmy Award nominees.
The programs will compete for best talk show, while the new category of best informative talk show pits nominees Dr. Phil, The Tyra Banks Show and A Place of Our Own against each other. Nominations for best daytime serial went to General Hospital, Guiding Light, One Life to Live and The Young and the Restless.
Winners will be announced June 20 in Los Angeles.
The View hosts Barbara Walters, Elisabeth Hasselbeck, Joy Behar, Whoopi Goldberg and Sherri Shepherd are among the nominees for best talk show host — and get another a chance to break their 10-time losing streak in the category. Have they talked to Susan Lucci? Even All My Children’s reining soap diva managed a win after an endless string of best actress nominations.
Know what the local glitterati are up to? Send tips to firstname.lastname@example.org or call (978) 970-4833. Compiled by Kathleen Pierce and wire services. For more celebrity news and local gossip, visit www.thesunblog.com/frosting.


text:
ENGLEWOOD, N.J. (CBSNewYork) — Gridlock in Washington means the Bush tax cuts could expire at the end of the year. A new study says that would mean Tri-State Area taxpayers would pay billions more to the Internal Revenue Service.
The economy gives diners plenty to chew over at It’s Greek To Me restaurant.
“I feel like the middle class is really suffering,” one patron told CBS 2’s Tony Aiello on Thursday.
President Barack Obama now wants to keep Bush tax cuts for the middle class, but when it comes to families making more than $250,000 a year he has others ideas.
“We do not need more tax cuts for folks who are already doing really well,” the president said.
In our high-wage, high-cost-of-living region, a quarter million strikes many as still middle class.
“If you’re going to increase and want more taxes, go for the people making much more, the million dollars or more,” one person said.
The impact will be felt in Englewood and other local economies if Washington can’t decide to keep all of the Bush tax cuts, or just most of them. The worst case scenario would come about if there’s no agreement and all the tax cuts expire.
A new “Tax Foundation” analysis shows that if the tax cuts expire at the end of the year Connecticut taxpayers will send $10 billion or more to Uncle Sam next year. New Jerseyans will send an extra $21.5 billion to the IRS. And New Yorkers will see their collective tax bill jump more than $50 billion.
“Most economists, including those at the Federal Reserve, predict that in the absence of some sort of tax relief, the scheduled tax increases at the end of this year will lead to a severe recession,” said The Tax Foundation’s Will McBride.
“People I think want to keep their money. They want to have control over their future, and fortune,” restaurant owner Yanni Papaioannou said.
Both of which right now are in the hands of a gridlocked congress.
The president said he will veto any deal that does not raise taxes on “the rich” — by his definition, families clearing more than $250,000 per year.
Please offer your thoughts in the comments section below …


Element Six, a producer of synthetic diamond for industrial applications, has entered the water jet cutting market with a range of water jet cutting inserts based on synthetic diamond that can dramatically improve the life of nozzles that deliver the cutting jet.
The diamond inserts, developed by Element Six, have undergone testing with a number of leading water jet manufacturers, leading to approval by several companies in Europe. Tests in the North American market are expected to be complete in mid-2007.
Water jet cutting is a technique that has a number of industrial applications. It is capable of cutting everything from chocolate bars to steel, paper to plastic or wood and granite. Currently the market for such equipment is growing at a rate of around 12 per cent a year, according to the company.
In use, a fine jet of water (plus abrasive for cutting harder materials) is produced under high pressure that can be used to cut materials. To do so, the water is forced through a nozzle assembly that contains an insert. But if the insert is affected by wear, misalignment and damage, it can causing a deterioration in the performance of the system.
‘Element Six has developed a range of synthetic diamond inserts that can outperform other insert materials used within the nozzle,’ explained René Diks, marketing and sales manager for industrial components at Element Six. ‘In comparison with sapphire inserts, for example, the life of a diamond insert is fifteen to twenty times better.’
Tests proved that after 1000 hours of operation with pure water at 3500 bar there were no measurable changes in jet quality and water usage. Tests with abrasive water jet cutting proved that after 100,000 cycles (on/off cycles) there were no measurable changes in jet quality and water usage.
The nozzle inserts are available in a variety of bore diameters ranging from 100 µm to 400 µm. The choice of geometry its determined by the application, with diameters between 100 µm and 200 µm optimised for pure water cutting, and the larger diameter range of 200 µm to 400 µm designed for abrasive cutting, though specially tailored bore geometries can also be offered. The outer geometry of the insert is fixed and, therefore, the mounting procedure for all bores is similar.


Oil steadies above $33 on chance of production cut
Following the further slide in oil price this month, there have been calls for a downward review of the oil benchmark price of $38 proposed by President Muhammadu Buhari for this year’s budget.
Russia’s energy minister said Thursday that Moscow was ready to take part in an OPEC meeting aimed at establishing possible “coordination” in the face of low oil prices due largely to a supply glut.
Russian officials have decided they should talk to Saudi Arabia and other OPEC countries about output curbs to bolster oil prices, the head of Russia’s pipeline monopoly said.
Instead, he suggests a sustained recovery in oil prices would probably require “stronger foundations”.
While the similar headlines on the possible OPEC-Russia cooperation have caused brief rallies in oil prices previous year, the recent rhetoric is different in the matter of the involvement of parties from Russia, the analysts said in a report, obtained by Trend.
The Organization of the Petroleum Exporting Countries is considering a request from cash-strapped Venezuela to hold an emergency meeting.
Brent crude was up USD 1.41 at USD 34.51 a barrel by 9:39 am ET, after hitting a session peak of USD 35.84.
Saudi Arabian officials did not immediately comment on the proposal but a senior Gulf OPEC delegate said: “Gulf OPEC countries and Saudi Arabia are willing to cooperate for any action to stabilize the worldwide oil market”.
Russian Federation last met with Saudi Arabia in November and there have been no approaches since, Novak said.
But some analysts believe Russian Federation is actually likely to increase production this year to protect its economy.
Crude prices have fallen from $115 per barrel in June 2014 to around $27 a barrel this month – a 77 percent decline to reach their lowest levels since 2003.
Sources familiar with the matter told Reuters that Iran is reluctant to restrain supply as it wants to claw back market share and feels that its economic situation is less affected by the low oil price because of the lifting of sanctions. Anticipation that OPEC and non-OPEC producers could coordinate production cuts has been around all week, and a closing gain on Thursday would be the third in a row.
He is the chief executive of Russia’s biggest oil producer, Rosneft and has repeatedly made clear in public that Russian Federation – now the world’s largest oil producer – will not blink first in the battle with OPEC over market share and pricing.
Kelly said the proposed cuts were unlikely to happen.


Cold rolling colddeformed tubecoldfinished tube completion continuous casting hot stretch reduction mill hydro descaling hydrocarbons hydrostatic testing.nduction erw induction furnace sizing sizing mill slag slag inclusions slimesludge spout stand steel steel grade steelworks stenciling.Consult Now
10. use of solar energy for desizing and scouring enables almost 4050 energy saving. 11. cold pad batch method for reactive dyeing by sodium silicate for fixation of the dyestuff gives 100 energy saving. 12. low temperature curing of.
1989 and realizing reduction in surface imperfections, which was followed by an increase in the rolling speed through the renewal of the finishing mill motors and laying machines in 20012004. on the other hand, the rolling mills ashole had not.
2. how can this potential energy use reduction be achieved? benchmarking provideseans to determine the potential for energy reduction.enchmarking study isomparison of the competitive situation among similar types of mills producing the same product 1. the energy use forarticular mill can be compared with that for sim.
514 intergrated industrial systems i2s, 2hi cold reduction mill,crew down cylinders, ujoint drive, exit pinch, 1988 yoder brothers machinery holland, oh ryan yoder.
A more commonly used jaw crusher between dodge jaw crusher and blake jaw crusher is the later oneb there are only four methods namely compression, impact, attrition andcutting, which the size reduction equipments employc cutting machines mainly employ attrition for size reduction of solidsd operating principles of dodge and blake jaw.
Abstract. the effects of carbide size prior to cold rolling, cold reduction and heating rate in annealing onalue, and texture of coldrolled steel sheets were investigated.the main results obtained were as followshen the carbide size prior to cold rolling is large,alue can be improved withaster heating rate in annealing..oreover, the cold reduction of peak r.
And processed throughet of sizingshaping rolls which coldform it intoound 9, square 10 or rectangular 11 section. formsquare weldsquare erw process in the weld mill, driven forming dies progressively shape the at stripy forming the top two cornersf the square or rectangular tube in the initial forming station.
Bauermeisters type 250.1 and type 250.2 roll mills are used to accurately crush brittle to mediumhard products. the type 250.1 roll mill uses productspecific rolls and works in two crushing stages, while the type 250.2 can work in variable capacities in up to three crushing stages, using productspecific rolls.
By the numerous sizes, sections, finishes and type compositions required. accuracy of dimensions is influenced by many factors such as whether the steel is hammered or rolled, the composition of steel, the size of the order, the mill design, heating practice, reduction between passes, roll wear, and roll pressure. the cumulative.
Chapter 10 particle size reduction 10.1 introduction to create particles inertain size and shape to increase the surface area available for next process to liberate valuable minerals held within particles size reduction process extremely energyintensivef all electricity generated is used in size reduction.
Check the data on the mill cert and report the reduction ratio to your customer. if your rolled bar hasigh enough rr that might be acceptable. re rolled vs forged bar redpicker materials 16 jul 13 1827.orged bar is produced by taking an ingot or bloom and forging it down to size by, generally, two opposing flat dies. witholled.
Cold reduction mill sheet and strip are cold reduced to the desired thickness for the following reasons to obtain the desired surface. to impart desired mechanical properties. to make gauges lighter than the hot strip mill can produce economically. to produce sheet and strip of more uniform thickness.
Cold reduction mills are controlled by process computers, and since tcrsss mill is one of the most advanced designs, coils are rolled to the closest dimensional tolerances. electrolytic cleaning tcrss employsighly efficient electrolytic cleaning system for removing the cold rolling lubricant from the strip.
Cold rolled product cold rolled product is made from the hotrolled product. when the hotrolled product is cooled, then that is rerolled in the room temperature. it is known as cold rolled product. it is used to do to get more exact or perfect dimensions and to make the surface quality better. there are such cold rolled products.
Cold rolling colddeformed tubecoldfinished tube completion continuous casting hot stretch reduction mill hydro descaling hydrocarbons hydrostatic testing.nduction erw induction furnace sizing sizing mill slag slag inclusions slimesludge spout stand steel steel grade steelworks stenciling.
Cold rolling shapes requireseries of shaping operations, usually along the lines of sizing, breakdown, roughing, semiroughing, semifinishing, and finishing. if processed bylacksmith, the smoother, more consistent, and lower levels of carbon encapsulated in the steel makes it easier to process, but at the cost of being more expensive.
Coldpressed oil market outlook 2026. the global coldpressed oil market size was valued at 24.62 billion in 2018, and is expected to grow atagr of 5.3 to reach 36.40 billion by 2026. oils obtained through cold pressed are expeller extracted inontrolled temperature setting. the controlled temperature lies below 4920 f.
Coldrolling the starting material for coldrolled steel sheet is pickled hotrolled breakdown coil from the continuous hotstrip mill. the total reduction achieved by coldrolling generally will vary from about 50 to 90.
Coyote steel amp co. 2030 cross street eugene, oregon 97402 usa no.andbook of steel sizes amp weights for industry phone tollfree.
From labpilot to production requirements, hosokawa micron powder systems offersomplete line of size reduction technologies. whether you call it size reduction, micronization, milling, pulverizing, jet milling, air milling, or simply grinding, we can help. our broad application expertise allows us to help you select the technology that works best for your application. we.
Fully coldreduced tubing is the cold reduction of both the weld seam and base metal parent material. the minimum reduction is generally 20 of the total area and achieves optimum metallurgical conditions. bead worked tubing is the cold reduction of the weld seam only, generally reducing the weld seam only by 210.
Growth reduction in total energy grain growth via atomic diffusion summary strength is increased by making dislocation motion difficult. particular ways to increase strength are todecrease grain sizesolid solution strengtheningprecipitate strengtheningcold work heating annealing can reduce dislocation density and.
History soda pulping process patented, 1854. soda recovery via incineration patented, 1865. first successful soda mill, 1866. kraft pulping process patented by dahl, 1884. first commercially viable kraft mill, sweden, 1885. kraft recovery furnace, 1930s.
Hole sizes for cold form tapping these charts are supplied asecommendation only. finding the correct drill size forpiralock tap may beut and try process not all drills are alike to get good results, verify the actual hole size being produced by the drill.
In fact, the combination of cold reduction and annealing lead toefinement of the steel that provides very desirable and unique forming properties for subsequent use by the customer. the hotrolled, pickled coils incoming to the cold reduction mill have to.
Large droplet sizes, which can impinge through the layer of water on the roll surface. using nozzles andood nozzle arrangement can make the roll cooling process much more effective. this can lead toemarkable reduction of the coolant volume being used and at the same time toeduction of the roll temperatures figure 4.
Method is more efficient in achieving fine particle size. rod mills horizontal rods are used instead of balls to grind. granularity of the discharge material is 4010 mm. the mill speed varies from 12 to 30 rpm. planetary mill high energy mill widely used for producing metal, alloy, and composite powders. fluid energy grinding or jet milling.
Mill characteristics length, diameter, rotation speed, lifters feed characteristics work index reduction ratio under given load and particle size requirement, capacity isunction of mill length and diameterld 2n.s related to mill diameter which decreases with larger diameters constant equal to 4.
Mineral oils, paraffin, fatty acids are used for cold rolling. normally, foe ferrous alloys no lubricant is used. 1.7 rolling mill control production of continuous sheets and strips is one of the attractive features of modern rolling mills. however, control of sheet thickness and crosssection iseal challenge. in order to.
Mpe manufactures industrial size reduction equipment critical for the production of many food, chemical, and mineral fcm goods and products. our stateoftheart granulizers produce the most accurate particle size distributions that improve product yields and reduce unwanted fines. from cereal and peanuts to quartz and zinc, our grinding.


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Essay on Denial Of Responsibility : Telling Self
• Denial of Injury: telling self that no party was directly affected by the purchase.
• Denial of Victim: telling self that the affected party deserved the situation in which they are.
• Condemning the condemners: pointing out that those who criticize engage in other disapproved activities that are alike.
• Appeal to higher loyalties: telling self that the unethical behaviors are the results of an attempt to help or be involved with a higher order ideal or value in mind.
However, in the case of child labor and sweatshops, those who knowingly buy the brands, tend to be less inclined to rationalization when the troubles come closer to them, such as in the Nike case (Chatzidakis, Hibbert and Smith, 2007). On the other hand, investors don’t react the same way. All the boycotts and protest didn’t affect Nike’s stock price as one could think (appendix 2). Looking at a chart showing the stock price from 1995 (before the scandal surfaced) and 2004, when Nike’s image was fixed, the ups and downs are not in accordance with the PR stunts Nike had pulled over the years.
Zara and slave labor
In 2013, Zara was criticized for being involved in slave labor in South America; Zara did not have any financial repercussion; their sales have been increasing faster than ever (appendix 4). This is mostly due to people who don’t feel like they can change a similar situation by simply…

domain: sociology


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Pastor Y Yich (57) from Gia Lai province in Vietnam’s Central Highlands is a member of a banned evangelical denomination who has worked for many years for freedom of religion and indigenous rights for his fellow Montagnard people. He was arrested in 2013, charged with “undermining national solidarity policy” and sentenced to twelve years in prison, where he has reportedly been beaten and tortured. Following his expected release in 2025, he must serve three to five years’ probation.
Pastor Y Yich was arrested on 13 May 2013 and accused of violating Article 87 of the Penal Code, “undermining national solidarity policy“. On 14 November 2013, he was sentenced to twelve years in prison for spreading Dega Protestantism, using the internet to communicate with Montagnard pastors and “FULRO reactionaries”* in the US and meeting with former prisoners of conscience. Following his expected release in 2025, he must serve three to five years’ probation.
Dega Protestantism (Tin Lanh Dega) is an activist Montagnard church movement that emerged in Vietnam’s Central Highlands in 2000 and combines evangelical Christianity with aspirations for religious freedom, protection of ancestral lands and, for some, autonomy or self-rule.
All religious groups in Vietnam need government permission to operate and banned groups such as Dega Protestants and Ha Mon Catholics suffer harsh persecution including police harassment and imprisonment. The government claims that they were instigated by Montagnards overseas as a cover for political activities, and several government websites discuss the need to “eradicate the evil cults”, i.e. unapproved Montagnard Christian denominations. Since 2001, the authorities have forced thousands of Dega Protestants and Ha Mon Catholics to renounce their faith.
In 2017, Pastor Yich was awarded the annual human rights award by the Vietnam Human Rights Network, based in California, USA, an award to encourage Vietnamese religious and political prisoners of conscience.
Pastor Yich has been transferred to prison in Mang Yang District, Gia Lai province from An Phuoc Prison, Binh Duong province, where he suffered poor health due to torture in detention plus high blood pressure, joint pain, stomach inflammation, hepatitis and kidney stones. Prison authorities have denied him medical treatment and have refused to give him medicines brought by visiting family members.
In 2020, the pastor’s son reported that he had lost all his teeth when prison officers beat him and in November 2021 the Office of the UN High Commissioner for Human Rights reported that Pastor Yich’s health had seriously deteriorated and that he was being denied medical treatment.
Pastor Yich was first arrested by the provincial government of Gia Lai on 18 December 2006, accused of “undermining the solidarity policy” and sentenced to four years in prison.
After serving four years in Xuan Phuoc Prison, Phu Yen province, he was released on 18 September 2011 and put on probation for three years. He returned to his home in Aluk village, where he continued to work for religious freedom and human rights.
Pastor Yich and his wife Amying H’Dom have five children, born between 1986 and 1997. A daughter has been able to visit the pastor in prison, but prison authorities have refused to give him medicines supplied by family.
In December 2020, Pastor Yich’s son Mrui reported death threats and harassment against him and his family by village and district authorities in an apparent attempt to force him to renounce his faith. He told Radio Free Asia, “Village, district officers continuously visit our home to monitor us, they invited [meaning summoned] me five, six times, threatened to bash me and kill me, forcing me to abandon my faith.”
18 December 2006 Pastor Yich was accused of “undermining the solidarity policy” and sentenced to four years in prison.
18 September 2011 The pastor was released and returned home to serve three years’ probation.
13 May 2013 Pastor Yich was arrested again and accused of “undermining national solidarity policy”.
14 November 2013 Pastor Yich was sentenced to twelve years in prison plus three to five years’ probation for spreading Dega Protestantism, using the internet to communicate with Montagnard pastors and “FULRO reactionaries” in the US and meeting with former prisoners of conscience.
2017 Pastor Yich was awarded the annual human rights award by the Vietnam Human Rights Network.
December 2020 Pastor Yich’s son reported death threats and harassment against him and his family by village and district authorities in an apparent attempt to force him to renounce his faith.
*FULRO (Front Unifié de Lutte des Race Opprimées, the United Struggle Front for the Oppressed Races) was a Montagnard resistance movement in the Central Highlands that dissolved in 1992. The authorities continue to accuse Montagnards from unapproved churches of using their religion to organise a separatist political movement and revive FULRO.
Sources: Association VPEF, Human Rights Watch, Montagnard Prisoners of Conscience Serving Prison Sentences and House Arrest Amounting to Eight or More Years (Campaign to Abolish Torture in Vietnam, June 2021), Office of the High Commissioner for Human Rights, Radio Free Asia, Vietnam Human Rights List (Vietnam Human Rights Network), Vietnamese and American Christian Lutheran Fellowship Candidate Profile Introduction for Vietnam Human Rights of 2017 (Pastor Nguyen Cong Chinh, President of the Lutheran Church in Vietnam & USA), Vietnam’s Persecution against Montagnards (Prepared by Boat People SOS January 2021)
Photo: Campaign to Abolish Torture in Vietnam


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Olivia, Holy Via - Yoga Instructor in Phuket, Thailand
On the beautiful island of Phuket, Thailand, is where Olivia has been living since 1994. She has been teaching yoga since 2004 in various hotels on the Island and still is ( to name a few: Evason Six Senses Spa, the Vijiit Resort, Meridien Yacht Club, The Raja, Villa Zolitude, Villa Salika ) in Phuket. She also gives yoga lessons at her house, in the area of Rawai, Phuket, where there is an opened air yoga room, mainly for very small groups, from 3 to maximum 5 people and she is also giving yoga lessons at the Phuket Academy of Dance, Chalong. She is also available for private lessons.
She started studying yoga in Phuket with an American woman and soon realized the importance of this ancient art as a tool for a better way of living. Originally from Italy, she travelled a lot as working for a tour operator, spending several months living in different countries and learning different cultures.
She was particularly attracted to Asia countries…favorite places are Bali, Sri Lanka, Maldives and India, which gave her unforgettable experiences. She went to India first to learn about an Indian Master, a Holy Man, later on she came to Thailand where she decided to stay, on the island of Phuket. Olivia is grateful to this land which also gave her the gift of her daughter Benedetta. Soon there was the need to go to India again and learn more about yoga. Olivia and her lovely daughter went to Mysore and stayed there for a few months to obtain a certificate to be a yoga instructor and be able to teach in Thailand.
She studied at the Mandala yogashala where Shashadri was teaching. Her first approach to yoga was the Ashtanga sequence, one with very dynamic form of moving from one posture to the other. Later on she felt the need to move at her own pace, following her inner voice and inspiration when choosing the positions (Asanas).
Why Holy Via?
The name "Holy Via" is my trademark.....It sounds like my name....i like it because yoga is also holy and Via, means road or path in italian; yoga is a holy path if you wish so......

domain: geography


Ed Sheeran and John Mayer Performed ‘Thinking Out Loud’ at the 2015 Grammys and We Can’t Deal With It [VIDEO]
While just hearing the opening notes of beyond beautiful song is enough to send us into convulsions, the fact that the two guitar gods got together on stage to completely kill that song dead (in the best possible way, of course) left us turning into Alex Mack-like puddles on the floor.
While Mayer shredded his hot pink guitar (perfectly appropriate for the romantic song) the red-headed Brit belted out those notes and leaving us crazy weak in the knees. Seriously -- there are two reasons that the entire Grammys audience (minus Kim Kardashian for some blasphemous reason) got on their feet after their performance and their names are Ed Sheeran and John Mayer.
Watch Ed Sheeran and John Mayer's unbelievable performance of 'Thinking Out Loud' in the video above.
See the Best Dressed Celebs at the 2015 Grammy Awards Red Carpet


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Potential Agency Problems
An agency relationship occurs when a principal hires an agent to perform some duty. A conflict, known as an "agency problem", arises when there is a conflict of interest between the needs of the principal and the needs of the agent.
In finance, the two primary agency relationships that exist are between:
Managers and stockholders
Managers and creditors
1. Stockholders versus Managers
- If the manager owns less than 100% of the firm's common stock, a potential agency problem between mangers and stockholders exists.
- Managers, at times, may make decisions that have the potential to be in conflict with the best interests of the shareholders. For example, managers may grow their firm to escape a takeover attempt to increase their own job security. However, a takeover may be in the shareholders' best interest.
2. Stockholders versus Creditors
- Creditors decide to loan money to a corporation based on the riskiness of the company, its capital structure and its potential capital structure. All of these factors will affect the company's potential cash flow, which is the main concern of creditors.
- Stockholders, however, have control of such decisions through the managers.
- Since stockholders will make decisions based on their best interest, a potential agency problem exists between the stockholders and creditors. For example, managers could borrow money to repurchase shares to lower the corporation's share base and increase shareholder return. Stockholders will benefit; however, creditors will be concerned given the increase in debt that would affect future cash flows.
Motivating Managers to Act in Shareholder's Best Interest
Four primary mechanisms are used to motivate managers to act in stockholders' best interests:
- Managerial compensation
- Direct intervention by stockholders
- Threat of firing
- Threat of takeovers
1. Managerial Compensation
Managerial compensation should be constructed not only to retain competent managers, but to align managers' interests with those of stockholders as much as possible.
- This is typically done with an annual salary plus performance bonuses and company shares.
Company shares are typically distributed to managers either as:
- Performance shares, where managers will receive a certain number shares based on the company's performance.
- Executive stock options, which allow the manager to purchase shares at a future date and price. With the use of stock options, managers are aligned closer to the interest of the stockholders as they themselves will be stockholders.
2. Direct Intervention by Stockholders
Today, the majority of a company's stock is owned by large institutional investors, such as mutual funds and pensions. As such, these large institutional stockholders have the ability to exert influence on mangers and, as a result, the firm's operations.
3. Threat of Firing
If stockholders are unhappy with current management, they can encourage the existing board of directors to change the existing management, or stockholders may even re-elect a new board of directors that will accomplish the task.
4. Threat of Takeovers
If a stock price deteriorates because of management's inability to run the company effectively, competitors or stockholders may take a controlling interest in the company and bring in their own managers.
To learn more about governance, please see the article, Governance Pays.
InvestingStockholders’ equity represents the equity that shareholders own in a company.
Managing WealthPreferred and common stocks are different in two key ways.
InvestingFinancial statements don't tell you everything about a company's health. Investigate the management behind the numbers!
Financial AdvisorEquities and corporate bonds often play a significant role regarding the diversification of an investor's portfolio. We put both asset classes in contrast.
InvestingLearn the nuances of multiple metrics that measure a firm's equity and debt capitalization, while determining Chevron's own capital structure.
Managing WealthAn agency relationship exists when one person -- called a principal -- hires another person -- the agent -- to act on his behalf. Agency theory is concerned with resolving problems that develop ...
Small BusinessA firm’s relationship manager works to maintain positive relationships with its customers and partner firms.
Managing WealthTaking a company public doesn't mean founders must completely give up calling the shots. Before the IPO, consider these tactics to keep control after it.
Small BusinessA takeover happens when one company makes a bid to acquire a target company.
InvestingEarnings reports tell investors how a publicly-traded company is performing, but aren’t always easy to decipher.

domain: finance


The Emir of Qatar. Credit: Doha News FB page.
Nestled in the Arabian Peninsula, Qatar is a nation that belies its small geographical size with its oversized influence in global and regional politics. Known for its vast reserves of oil and natural gas, Qatar has transformed itself into an affluent, modern state with significant economic and diplomatic clout. Its capital, Doha, is a bustling hub of cultural and political activity, reflecting the nation’s ambitious vision on the world stage. This article delves into Qatar’s multifaceted foreign policy, particularly its relationship with Hamas, its approach to the Arab Israeli conflict, and its response to the October 7th Hamas attack on Israel, offering U.S. citizens a clearer understanding of this influential Middle Eastern player.
Qatar’s Relationship with Hamas:
Qatar has a distinctive relationship with Hamas, the Palestinian organization that governs the Gaza Strip. This relationship, marked by Qatar’s political endorsement and financial support, has made it a key player in Palestinian affairs. Qatar’s assistance to Hamas in Gaza, often in the form of humanitarian aid and infrastructure projects, is seen as a lifeline for the embattled region. However, this support also attracts criticism, with some international observers arguing that it indirectly contributes to the ongoing conflict by empowering Hamas. Qatar’s ties with Hamas are a critical aspect of its foreign policy, showcasing its willingness to engage with groups often shunned by other nations.
Qatar and the Arab Israeli Conflict:
Qatar’s role in the broader Arab-Israeli conflict is characterized by a balancing act between engaging with Israel and supporting Palestinian causes. Unlike many Arab states, Qatar has maintained channels of communication with Israel, while simultaneously supporting Palestinian groups. This dual approach is part of a larger strategy that aims to establish Qatar as a mediator in the region, capable of dialoguing with diverse parties. However, this strategy is not without its critics, who question the effectiveness and motivations behind Qatar’s diplomatic maneuvers.
The October 7th Hamas Attack on Israel and Qatar’s Response:
The October 7th Hamas attack on Israel put the spotlight on Qatar, given its close ties with Hamas. In response to the attack, Qatar advocated for de-escalation and emphasized the importance of adhering to ceasefire agreements. This stance highlights the complex position Qatar occupies, trying to balance its support for Palestinian causes with the need to maintain good relations with other key global players, including the United States and Israel.
Qatar’s strategic position in Middle Eastern politics is a reflection of its unique approach to foreign policy. By understanding Qatar’s relationship with Hamas, its nuanced role in the Arab-Israeli conflict, and its diplomatic responses to regional crises, American readers can gain a deeper insight into the intricate workings of Middle Eastern geopolitics. As Qatar continues to navigate these complex waters, its actions will undoubtedly have a significant impact on the region’s future dynamics and its relationships with global powers.


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PRINCETON — Richard Jacques, 76, of Canton, Conn., was sentenced to four years in prison after pleading guilty to the Class 2 felony of aggravated criminal sexual abuse.
Jacques entered his guilty plea March 12 before Associate Circuit Judge C. J. Hollerich. In addition to the prison sentence, Jacques was ordered to pay fines, fees and court costs totaling $1,772 from bond posted.
In March 2012, an 11-year-old Bureau County girl reported to her parents that she had been sexually abused by Jacques. After an investigation by the Bureau County Sheriff’s Department and the Department of Children and Family Services, Jacques was indicted on Aug. 15, 2012, for the Class 2 felony. The incident occurred during the summer of 2011 when Jacques visited the victim’s family.
This is Jacques’ first felony conviction.


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Tea cup Maltese puppies for sale
Gorgeous male and female Teacup Maltese Puppies for sale. They will come with four weeks kennel club insurance and puppy pack. They are so loving and so unforgettable. Wormed, weaned, vet health checked, vaccinated, adored. Please contact for more information if interested.Please interested persons should contact for more information and picture of the puppies.

domain: pet


Shares of Cadence Pharmaceuticals (CADX) surged this morning after the developer said that it plans to resubmit its marketing application for the pain therapy Ofirmev within 30 days. Citing problems with a third-party manufacturer, the FDA denied approval back in February.
The FDA did not ask for any new data or stability studies, and Cadence says that after a meeting with regulators on Friday the biotech plans to continue to work with the manufacturer. Cadence shares jumped 13 percent on the news about Ofirmev, an intravenous formulation of acetaminophen.
"We believe that last week's meeting with FDA was an important step forward to address the observations from the FDA's inspection of our third party manufacturer's facility and move toward potential approval of Ofirmev," said CEO Ted Schroeder. "Based upon our discussions with the agency, we believe that it is appropriate to promptly resubmit the NDA for Ofirmev and intend do so within the next 30 days."
- here's Cadence's release
- and here's the story from Reuters


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Story | Jan 12, 2015 | 12:46 PM
A collection of news and information related to Kim Jong Il published by this site and its partners.
Top Kim Jong Il Articles see all
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Story | Jan 14, 2015 | 11:15 PMNorth Korean leader Kim Jong Un is looking increasingly likely to visit Russia in his first trip abroad since taking power three years ago, giving the world an unprecedented chance to see him at work on the international stage.
Story | Jan 12, 2015 | 5:45 AM
Story | Jan 1, 2015 | 8:52 PM
North Korean leader Kim Jong Un said in a New Year's speech Thursday that he is open to more talks or even a summit with his South Korean counterpart, a statement welcomed by Seoul, which in turn urged the North to take concrete steps toward normalization...
Story | Dec 26, 2014 | 1:47 PM
Well, what a year, huh? Crazy stuff in politics, in sports, in entertainment. Really crazy in entertainment. Let's take, for example, the explosion of the Sony computer-hacking scandal into an international event with the pulling of the comedy "The...


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The Gridley High football team won its season opener 43-14 over Wheatland on Friday night at Bulldog Stadium.
Cameron Carr, a senior, led the Bulldogs with 18 carries, 339 yards and four touchdowns on the ground. Carr also completed 4-of-6 passes for 53 yards and one touchdown. Shay Carr hauled in a touchdown catch while Ryan Smith had a rushing touchdown on 11 carries and 43 yards.
Gridley (1-0) plays at Sutter at 7:30 p.m. Thursday.
Durham 26, Hamilton 6: After a scoreless first quarter, Durham put up a 13-6 advantage in the second quarter against the host Braves on Friday night.
Durham added on with touchdowns in the third and fourth quarter to pull away for a 26-6 victory on the road.
Durham (1-1) hosts Live Oak at 7:30 p.m. Friday.
Hamilton (0-2) plays at Biggs at 7 p.m. Thursday.
Durham 3, Paradise 1: The Trojans defeated the Bobcats 25-22, 27-25 20-25 and 25-14 at home Friday.
Karena Bryant led Durham with 16 kills, 10 digs four aces. Bella Pendley added seven kills. Abby Thorpe collected 20 assists and four aces.
Durham (2-0) plays at Las Plumas at 7 p.m. Wednesday.
Prep field hockey
Pleasant Valley 6, Lassen 0: The Vikings shut out Lassen Friday night at home.
Kiley Rechs led PV with three goals and an assist, Zoe Nunez-Bauer added two goals, Brooklyn Longueira added two assists and one goal, Mallory Ratner and Contessa Whittaker each added an assist.
Savanah Cresswell recorded four saves for the Vikings.

domain: sports