text:
Bea lives in Charlotte, NC. In addition to writing science fiction and fantasy (and a smidgen of horror) she enjoys a good read, working crossword puzzles, walking, drawing, and painting. She is a retired electronics technician and admits to having worked at a variety of other jobs during her life, including being a dishwasher, a busgirl, a house maid, a motel/hotel maid, working in a fast-food joint, a telephone operator, and a store clerk. There have been other, not-so-glamorous jobs, including picking cotton. She also daydreams a lot.
Seedby Bea Cannon
View All Available Formats & Editions
Abandoned on an alien planet, Second must learn to co-exist with a group of primitives in order to survive.
- LendMe LendMe™ Learn More
Abandoned on an alien planet, Second must learn to co-exist with a group of primitives in order to survive.
Product Details
- 2940045099004
- Publisher:
- Bea Cannon
- Publication date:
- 11/19/2012
- Series:
- Boucher's World
- Sold by:
- Smashwords
- Format:
- NOOK Book
- File size:
- Age Range:
- 18 Years
Meet the Author
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Seed based on 0 ratings. 2 reviews.
I did so enjoy this book from start to finish! The characters made me fall in love with them from the very beginning. Kudos to this author, and may you continue to give us such fantastic entertainment!
Survival, tolerance and love. Does it get any better than that? Dawn


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Athens Automobile Parts Supplies Used Rebuilt Wholesale Manufacturers
1. Pitts Auto Parts
14363 Blackburn RdAthens, AL 35611
2. All BMW Parts -- Bavarian Auto Recycling Inc.
Serving the Athens Area.
From Business: As one of the largest BMW parts recyclers in the US, we specialize in rebuilt, new, and used BMW parts for all BMW car models. Our recycled BMW parts inventory incl…
3. All European Engines & Transmissions - Bavarian Engine Exchange, Inc
Serving the Athens Area.
From Business: Thank you for choosing Bavarian Engine Exchange to help with your used and rebuilt European Engine & Transmission needs. We are committed to providing you with cons…
4. Tom's Parts And Salvage
fast works hard to get u the right part
5. B & B Motors & Auto Parts
26210 State Line RdArdmore, AL 35739
6. Gibson Motors
4224 Old Railroad Bed RdHarvest, AL 35749
7. King's Auto Salvage
2018 Gordon Terry PkwyDecatur, AL 35601
8. CFC Recycling
Serving the Athens Area.
From Business: Please contact us for more information!
9. Hokes Bluff Auto Parts
Got any kind of part you may need down home country folks.
Showing1-9 of 9results

subset: commoncrawl


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responsible for any additional fees the local carrier in your country
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We generally charge 1-2 dollars for packing and handling. However,
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The vanishing particle physicist and the puzzle he left behind
Ettore Majorana was an Italian physicist, the best of his generation, who disappeared in mysterious circumstances in 1938.
Ettore Majorana was an Italian physicist, the best of his generation, who disappeared in mysterious circumstances in 1938.
It is being called the most severe health emergency of modern times. But are the fears of mass contagion in the west overblown?
Michael Brooks's science column.
Responsibility for treatment of infected people falls on human health services. It is difficult to create an alliance against rabies until animal and human health experts co-ordinate.
Scientists have a simple recipe for creating a more human-like mouse: just alter its DNA very slightly.
Chinese researchers have recently reported a case of a woman found to have no cerebellum, a part of the brain that usually contains half of its neurons.
Tim Berners-Lee has publicly called for programmers to develop better, more user-friendly cryptography. That way, he says, we can all get back to living private lives again.
Either our understanding of how stars form needs a big overhaul, or one of the current missions of the European Space Agency could turn out to be something of a white elephant.
Attributing emotions to birds is not a flight of fancy. Emotions are a feature of evolution: they arose to help creatures navigate the world safely and with maximum reward.
Drug trials rarely tell the whole story as many drugs have side effects that emerge only after deployment in the population at large. Yet unexpected effects can sometimes be surprisingly good.


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BOLTON Wanderers star Alex Baptiste has been arrested after allegedly attacking a man who touched his wife's bottom.
The 28-year-old defender was arrested on suspicion of actual bodily harm after a brawl outside UBER bar in Poulton le Flyde, near Blackpool. He has since been bailed.
A man was knocked unconscious and lost several teeth in the alleged incident, which happened at 1.35am on Saturday, June 28.
Baptiste, who lives in Lytham, Lancashire, has since been bailed.
UBER bar describes itself as "a sophisticated social playground".
One eyewitness said: "What happened was virtually under the noses of the two officers. It was one punch but one big punch."
A 23-year-old man, from Poulton le Fylde, was also arrested on suspicion of assault and has also been bailed.
Bolton Wanderers have just embarked on a pre-season tour of Scandinavia in which they will be playing friendly matches against Swedish and Danish clubs.
A Bolton Wanderers spokesman declined to comment.
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HOME MLB Atlanta Braves Gear Atlanta Braves Accessories Atlanta Braves Accessories Toys & Games (71 items) Product ID: 844670
Main Content
- Instructions included
- Officially licensed MLB game
- Runs approximately 15 minutes
- Tin case measures approximately: 2" tall/4" in diameter
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- Ages 7 and up
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Native Plants
Q. Who is Mr. Smarty Plants?
A: There are those who suspect Wildflower Center volunteers are the culpable and capable culprits. Yet, others think staff members play some, albeit small, role. You can torture us with your plant questions, but we will never reveal the Green Guru's secret identity.
Did you know you can access the Native Plant Information Network with your web-enabled smartphone?
Ask Mr. Smarty Plants is a free service provided by the staff and volunteers at the Lady Bird Johnson Wildflower Center.
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Tuesday - April 04, 2006
From: Austin, TX
Region: Southwest
Topic: Diseases and Disorders
Title: Possible reasons for death of Wax Myrtle (Morella cerifera) in Austin
Answered by: Nan Hampton and Joe Marcus
QUESTION:Several wax myrtles in my neighborhood appear to have died. Should we have the soil or tree checked for fungus, or should we atrribute the death to freeze or age of the trees?
ANSWER:Generally, the wax myrtle (Morella cerifera, synonym = Myrica cerifera) is a hardy plant resistant to predation and disease. It is moderately drought tolerant, but the recent drought conditions may have stressed the plants making them more susceptible to pathogens, nematodes, insects, or extreme temperatures. The Florida Extension Service of the University of Florida reports a wilt disease caused by the fungus Fusarium oxysporum that is lethal to the wax myrtle. If you suspect that disease has killed the plants, you can have them tested by sending them to the Texas Plant Disease Diagnostic Laboratory (TPDDL). You need to contact your county office of the Texas Cooperative Extension to determine how to send your sample. Another suggestion is to have an arborist look at your wax myrtles to see if he or she can determine the cause of their death.
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April 07, 2011 - My redbud has knots all over the limbs. Its been this way for a few years now. I can not find a way to take care of this problem. I don't even know what is causing this. Can you help me?
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July 08, 2013 - I am 84 yrs old and have a 50 year old pin? oak. No more acorns, but the leaves are falling in clumps and are still alive. Every day I fill a huge garden bag with them. I live on a fixed income and...
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February 20, 2009 - I have a transplanted a Texas persimmon tree from the wild. It has some globes in the leaves. It seems like some pest injected something from underside of leaves. Any suggestion? What is happening t...
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Pentair fit suction cover in grey only. Guaranteed to fit the original Pentair suction. Total outside diameter is 4-1/4" EXTREMELY rare part - in stock. The cap and the screw are NLA. The 5" diameter version is NLA.
Replacement suction cover. Diameter : 95mm


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Pablo Martinez Monsivais, Associated Press
WASHINGTON — Drew Storen sat at his locker, staring straight ahead. Whatever solo thoughts he had were frequently interrupted by teammates offering hugs, sympathy and encouragement.
Making the rounds in the clubhouse, meanwhile, was part-owner Mark Lerner, son of principal owner Ted Lerner. Mark Lerner patted players on the shoulder and shook their hands. He wiped a tear from his eye as he spoke to slugger Michael Morse.
"Someone just said to me, 'We've learned to win now,'" Lerner said. "And that's no easy task."
The Washington Nationals did indeed bring winning baseball back to the nation's capital at long last. They also collapsed in the postseason in a way that will be tough to forget.
The Nationals' historic season came to an end Friday night with a 9-7 loss to the St. Louis Cardinals in Game 5 of the NL division series. Washington sported the best record in baseball during the regular season, but the newfangled "Natitude" of a roster flush with young postseason neophytes blew a six-run lead against the experienced club that won the World Series a year ago.
Storen took the mound with a two-run lead in the ninth and gave up four runs, allowing two-run singles to Daniel Descalso and Pete Kozma. Storen had two Cardinals batters down to their last strike with two outs, but he walked Yadier Molina and David Freese to keep the inning going.
"We had it right there, and the most disappointing thing I'll say is that I just let these guys down," Storen said. "I know there's an unbelievable crowd and unbelievable support, but for the amount of adversity we dealt with this year, for it to come down to that was kind of tough."
It was the largest comeback ever in a winner-take-all postseason game, according to STATS LLC. No other club in this sort of ultimate pressure situation had come back from more than four runs down.
Storen threw five pitches with two strikes and two outs in the ninth. All were balls.
"I think he just tried to be too fine," manager Davey Johnson said. "He's got a great-moving fastball. Just need to throw it over."
Storen said he had no problems with the umpire's strike zone. The Cardinals were just disciplined at the plate when it counted.
"I made good pitches," he said. "I wouldn't change a thing. I have no regrets."
The Nationals had been let down by their bats in the first four games of the series, scoring only nine runs. But they greeted Adam Wainwright with a double, triple and homer by Jayson Werth, Bryce Harper and Ryan Zimmerman in the first inning and chased the St. Louis starter with home runs by Harper and Morse in the third.
The Cardinals battled back, cutting into the 6-0 deficit with a run in the fourth, two in the fifth, one in the seventh and one in the eighth. Descalso's solo homer in the eighth off Tyler Clippard made it a one-run game, but the Nationals pulled back ahead by two in the bottom of the inning on Kurt Suzuki's RBI single.
But Storen, who regained the closer's job late in the season after Clippard struggled, couldn't finish the job. The season of Natitude was over, and a Cardinals team that's shown a knack for winning elimination games was moving on.
"They've proven that if there's a team out there to do it, it's going to be them," shortstop Ian Desmond said. "It's a good group of guys over there. I think they got the leg up on us in experience, and now next year we can say we've got a little experience."
Certainly the way the team is built, a winning postseason team shouldn't be far behind.
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Alicen Kandt
Alicen Kandt is a Senior Mechanical Engineer at the National Renewable Energy Laboratory (NREL) in the Integrated Applications Center (IAC). Alicen provides assistance in assessing technical and economic potential of renewable energy and energy efficiency opportunities as well as providing technical support of projects. She also maintains and improves spreadsheet screening tools and teaches workshops detailing how to use screening and design tools for renewable technologies. Alicen holds a MS in Mechanical Engineering from the University of Colorado at Boulder and a BS in Mathematics from the University of Puget Sound.
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Registration for the Society of Women Engineers' 2016 Invent It Build It program in Philadelphia, PA is open now. This is a hands-on engineering event, for middle and high school girls with an informational program for parents and educators Be sure to go to the SWE website to sign up and reserve your space!
IIBI Registration on the SWE website


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The Fair Labor Standards Act makes it illegal to punish an employee who reports violations, real or perceived, to the U.S. Department of Labor (DOL). If you learn about such a report, don't punish the messenger. Address the complaint.
Recent case: Lee Ann Benge worked in the HR department at Highgate Holdings. She thought some employees had been improperly classified as exempt when they were really hourly employees. She urged the company to fix the problem.
When nothing happened, she called the DOL and requested an audit. After telling her boss what she had done, her bonus was cut and she was fired for being a poor "fit" for the company.
She sued, alleging retaliation. The court said the case should go to trial because her activities were protected. (Benge v. Highgate Holdings, No. 3:09-CV-1404, ND TX, 2010)
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The Diabetes and Cancer Link
What you need to know.
By Theresa Garnero, APRN, BC-ADM, MSN, CDE
One more thing to add to the "forewarned is forearmed" list: researchers have found several connections between diabetes and cancer.
Although that may come as frightening news, some of the evidence may come as a surprise: some types of cancer rates are higher while rates of other types are lower in people with diabetes, a common medicine for type 2 may prevent cancer, and a cancer drug may help prevent type 1 diabetes.
Research Findings
A recent large-scale study following over 125,000 people with type 2 diabetes lead by Dr. Kari Hemminki of the German Cancer Research Center, found an increased risk for 24 types of cancer. The most significant rates were for pancreatic and liver cell cancers (elevated by factor 6 and more than 4 times the risk respectively compared to the general population). Since pancreatic cancer and diabetes both involve the pancreas, evidence remains unclear on whether diabetes causes or results from the cancer. Risk for cancers of the kidneys, thyroid, esophagus, small intestine, and nervous system were more than twice the rates of those without diabetes.
Other studies have found the following:
1. Meta-analyses from 15 studies and 2.5 million people with diabetes resulted in a 30 percent more likelihood of developing colorectal cancer. Women with type 2 over the age of 55 had double the risk.
2. Women with diabetes had a 20 percent greater risk of developing breast cancer. People with breast cancer treated with chemotherapy and metformin have better outcomes.
3. Metformin use is associated with an anti-cancer effect as those who take it have substantially lower cancer rates (62 percent lower risk of pancreatic cancer and up to 37 percent reduced risk for all cancers). Notably, research has also shown that people with diabetes already diagnosed with cancer may respond better to chemotherapy when treated simultaneously with metformin.
4. Those who take both Actos or Avandia and metformin have a 35 percent reduction in cancer mortality.
5. Further research is needed to better understand the risks and mechanisms that appear to link insulin with tumor growth. This finding may have more to do with insulin resistance rather than a direct effect of insulin itself.
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Recipe Shuffle
Low-Fat Caesar Salad Chile Grilled Chicken Pistachio-Crusted Rack of Lamb Portuguese Beef Ranch Salad Jerk Beef Roast with Brown Rice Oven Fried Parmesan Chicken Five-Spice Vegetable Potstickers Peach-Banana Milkshake English Muffin Breakfast Pizza
It's a known quantity that The Other Half and I handle our diabetes, and the rest of our medical issues, differently. Although he is more diligent about keeping to a time schedule for medications, his meal choices run further from green plants than mine do (sadly cold weather, persistent chill, budget, and tight schedules keep me further from five-a-day than I should like to be — hey, cheap frozen diet meal manufacturers, could you please make something that has vegetable...


text:
|Publication number
|Publication type
|Application number
|Publication date
|Nov 10, 1987
|Filing date
|Apr 7, 1986
|Priority date
|Apr 9, 1985
|Fee status
|Also published as
|Publication number
|Yuichi Yamamoto, Tadashi Sameshima
|Original Assignee
|Terumo Kabushiki Kaisha
|Export Citation
|BiBTeX, EndNote, RefMan
|Patent Citations (31), Non-Patent Citations (6), Referenced by (9), Classifications (22), Legal Events (7)
|External Links: USPTO, USPTO Assignment, Espacenet
NH2 (CH2)n NH2
NH2 (CH2)n NH2
NH2 (CH2)n NH2
NH2 (CH2)n NH2
This invention relates to immunoglobulin adsorbents and apparatus for adsorbing immunoglobulins using such adsorbents useful in the treatment of various diseases including autoimmune diseases such as myathenia gravis, articular rheumatism, lupus erythematosus, etc., immunity-related diseases such as glumerulonephritis, bronchial asthma, polyneuritis, etc., organ transplantation such as transplanted kidney rejection, AOB incompatible bone marrow transplantation, etc., tumor, hypertension, and hepatic insufficiency.
In recent years, plasma exchange therapeutics have been employed for the purpose of treating autoimmune diseases, immunity-related diseases, organ transplantation, tumor, hypertension, hepatic insufficiency and other diseases. In the plasma exchange therapeutics, however, all the plasma components are indiscriminately removed so that useful components in plasma are lost. Several problems are pointed out including shortness of useful components in plasma or plasma preparations used as a make-up and probable complication of serum hepatitis and allergy. It is thus believed desirable to depurate the patient's own plasma before it is transfused.
A variety of methods have been devised for removal of pathogenic substances, for example, cascade method using a membrane filter (see H. G. Sieberth, Plasma Exchange, p. 29, F. K. Schattauer Verlag, Stuttgart-New York, 1980), double filtration (see, Tetsuzo Agishi et al., Kidney and Dialysis, 10(3), 475, 1981), freeze filtration (A. L'Abbate et al., Proc. Eur. Dial. Transplant. Assoc., 14, 486, 1977), and plasma salting-out treatment (see, Oe Hiroaki et al., Artificial Organs, 14(1), 472, 1985). These methods are on the way of clinical trial.
However, removal of unnecessary pathogenic substances is insufficient under the current circumstances. Clinical application will invite hypoproteinemia unless plasma make-up is used.
Other therapeutics are by the use of various medicines. Because of probable side-effects, a careful attention must be paid to their use. For example, their dose and administration period should be limited as low as possible.
There is the need for a depurant and depuration apparatus capable of selectively adsorbing and removing particular pathogenic substances in plasma without inducing a side-effect. There are known a number of depurants for such purposes, including
(1) affinity adsorbents,
(2) porous resins such as Amberite XAD-7 sold by Rohm & Haas,
(3) ion-exchange materials such as carboxymethyl cellulose and diethylaminoethyl agarose, and
(4) porous inorganic materials such as porous glass and ceramics.
However, these depurants have several drawbacks. The porous resins and ion-exchange materials have low adsorptivity and poor adsorption specificity. They also adsorb albumin in body fluid to induce an anomalous change in osmotic pressure so that they cannot be used as a safe therapeutic member. The porous inorganic materials are not yet sufficient for practical use despite their relatively high adsorptivity and adsorption specificity.
The affinity adsorbents are generally classified into biological and physicochemical affinity adsorbents. The biological affinity adsorbents exhibit excellent adsorption specificity. However, most biological affinity adsorbents use a physiologically active high molecular weight compound as a ligand (material having affinity to a target material) and are thus expensive and difficult to gain. It is difficult to maintain the activity during preparation of adsorbents and columns, sterilization, stock storage, transportation, and shelf storage. A side effect must be taken into account because the biological affinity adsorbents can exert physiological functions other than affinity upon contact with blood. There is the likelihood that the ligand be released or dissolved away. Since most ligands are heterogeneous proteins, there occurs a problem of side effect due to antigenicity. On the other hand, the physicochemical affinity adsorbents have the advantages that they can be produced in a mass scale and their activity is stable. There are many physicochemical affinity adsorbents which are highly safe when contacted with blood.
A number of such adsorbents are known in the art, for example, porous materials having carboxyl group or sulfonate group at the surface as disclosed in Japanese Patent Application Kokai Nos. 56-147710, 57-56038, 57-75141, 57-170263, and 57-197294; hydrophilic carriers having a hydrophobic amino acid attached thereto as disclosed in Japanese Patent Application Kokai Nos. 57-122875, 58-15924, 58-165859, and 58-165861; hydrophilic carriers having denatured IgG attached thereto as disclosed in Japanese Patent Application Kokai Nos. 57-77624, 57-77625, and 57-156035; porous materials having methylated albumin attached thereto as disclosed in Japanese Patent Application Kokai Nos. 55-120875 and 55-125872; hydrophilic carriers having saccharide attached thereto as disclosed in Japanese Patent Application Kokai Nos. 57-134164 and 58-133257; and porous materials having purine base or pyrimidine base or saccharide phosphate attached thereto as disclosed in Japanese Patent Application Kokai Nos. 57-192560, 58-61752, and 58- 98142. In order to carry out extracorporeal circulation body fluid depuration therapy for the treatment of diseases, there is the need for an adsorbent which can more efficiently remove pathogenic substances than these prior art adsorbents while having less or little adverse effect on body fluid.
Therefore, an object of the present invention is to provide a novel and improved immunoglobulin adsorbent which can selectively and efficiently adsorb specific proteins such as immunoglobulins and immune complexes which are pathogenic substances in diseases related to living body immunity function such as autoimmune diseases, allergy, and cancer, exhibits minimized non-specific adsorption, and is safe and easy to sterilize.
Another object of the present invention is to provide an immunoglobulin adsorbing apparatus using the improved adsorbent.
According to a first aspect of the present invention, there is provided an adsorbent for an immunoglobulin comprising a hydroxyl-containing water-insoluble carrier. A diamine compound having the general formula:
NH2 (CH2)n NH2
wherein n is an integer having a value of 3 to 9, such as a diamine selected from the group consisting of 1,3-propanediamine, 1,6-hexanediamine, and 1,9-diaminononane is attached to the carrier through a silane coupling agent or a derivative thereof. A heterocyclic compound is further attached to the diamine through a difunctional reagent.
Preferably, the difunctional reagent is a difunctional reagent capable of bonding amino groups with each other and said heterocyclic compound is a heterocyclic compound having an amino group or having an amino group incorporated therein.
Preferably, the heterocyclic compound is a sulfa drug in the form of a sulfonamide.
Preferably, the silane coupling agent is selected from the group consisting of γ-glycidoxypropyltrimethoxysilane, γ-glycidoxypropylmethyldiethoxysilane, β-(3,4-epoxycyclohexyl)-ethyltrimethoxysilane, γ-aminopropyltriethoxysilane, and N-β(aminoethyl)-γ-aminopropyltrimethoxysilane.
Preferably, the difunctional reagent is selected from the group consisting of dialdehydes, bisepoxides, alkylimide esters, and diisocyanates. The most preferred difunctional reagent is glutaraldehyde.
Preferably, the sulfa drug is selected from the group consisting of sulfathiazole, sulfamethizole, and sulfisomezole.
Preferably, the water-insoluble carrier is comprised of a porous inorganic material predominantly comprising silicon dioxide and having a silanol group. Preferably, it is in the form of particles having a particle diameter in the range between 0.05 mm and 5 mm and a mean pore diameter between 1000 angstrom and 5000 angstrom.
According to a second aspect of the present invention, there is provided an apparatus for adsorbing an immunoglobulin comprising
a vessel having an inlet and an outlet for passing body fluid therethrough,
an adsorbent charged in said vessel, the adsorbent being as defined above, and
means for preventing the adsorbent from flowing out of the vessel.
Preferably, a filter disposed in the vessel as the means for preventing the adsorbent from flowing out of the vessel.
These and other objects, features, and advantages of the present invention will be seen by reference to the description, taken in connection with the accompanying drawings, in which:
FIG. 1 is a schematic view in cross section of an immunoglobulin adsorbing apparatus according to the present invention;
FIG. 2 is a block diagram showing a hemocatharsis system using the apparatus of the present invention; and
FIGS. 3 and 4 are diagrams illustrating percent IgM adsorption as a function of average pore diameter of carriers having sulfathiazole heterocylic compound attached thereto.
The present invention in its first aspect provides an adsorbent for an immunoglobulin comprising a hydroxylcontaining water-insoluble carrier to which a diamine compound having the general formula:
NH2 (CH2)n NH2
wherein n is an integer having a value of 3 to 9 is attached through a silane coupling agent or a derivative thereof, with a heterocyclic compound being attached to the diamine through a difunctional reagent.
The substances that are to be adsorbed and removed in the practice of the present invention are broadly proteins contained in body fluid and more precisely, common immunoglobulins, IgA, IgD, IgE, IgG, and IgM, autoantibodies, complexes between immunoglobulins, and complexes between an immunoglobulin and another substance, particularly an antigen as shown in Table 1. For brevity of description, these substances are generally referred to as pathogenic substances, hereinafter.
TABLE 1__________________________________________________________________________Autoimmune diseases and autoantibodies(based on the classification by Roitt)*Autoimmune diseases Autoantibodies__________________________________________________________________________Class I (Organ-specific)Hashimoto's disease, Primary myxedema antithyroglobrin antibody, secondary colloid antibody, cytoplasmic microsome antibody, cell surface antibodythyrotoxicosis antibody for TSH receptor on thyroid cell surfacePernicious anemia, atrophic gastritis intrinsic factor, gastric parietal cell microsome antibodyAddison's disease adrenocortical cytoplasmic antibodyorchtis, male infertility spermatozoa antibodyclimacterium precox steroid-producing interstitial cytoplasmic antibodies of adrenal, ovary and testismultiple sclerosis brain cell antibodyClass II (intermediate)Goodpasture's syndrome glomerular and alveolar basement membrane antibodiesglomerulonephritis glomerular basement membrane antibodymyasthenia gravis antibody for acetylcholine receptorpemphigus vulgaris epidermic inter-spine-cellular desmosome antibodypemphigoid skin basement membrane antibodylens-induced uveitis corpus vitreum antibodysympathetic ophthalmia uveal antibodyantoimmune hemolytic aneria erythrocyte antibodyidiopathic thrombocytopenic purpura platelet antibodyprimary biliary cirrhosis mitochondria antibodyactive chronic hepatitis smooth muscle antibody, antinuclear antibodyulcerative colitis colon lipopolysaccharide antibodySjogren's syndrome salivary duct antibody, mitochondria antibody, antinuclear antibody thyroid antibody, anti-IgG antibodypolyneuritis myelinic antibodyjuvenile diabetes insulin receptor antibodyClass III (Non-organ-specific)systemic lupus erythematosus (SLE) DNA antibody, nucleoprotein antibody, antibodies in non-liquid components of blood, coagulation factor antibody, denatured IgG antibody, Wassermann's antigen antibodydiscoid lupus erythematosus (DLE) antinuclear antibody, anti-IgG antibodydermatomyositis, scleroderma, anti-IgG antibody (Rheumatoid factor),chronic rheumatism antinuclear antibody__________________________________________________________________________ *Tsuruta & Sakurai Ed., Biomaterial Science Vol. 2, Nankodo, Tokyo, 1982
The heterocylic compounds used in the practice of the present invention are cyclic compounds having one or more heteroatoms along with carbon atoms in the ring. They include five-membered heterocylic compounds such as furan and its derivatives, thiophene and its derivatives, dithiolan and its derivatives, pyrrole and its derivatives, and azoles; six-membered heterocylic compounds such as pyridine and its derivatives, quinoline and related compounds, pyrazine and related compounds, pyran and pyrone and their related compounds, phenoxadine, phenothiadine, pteridine and alloxazine compounds, purine bases, nucleic acid, hemin, chlorophyll, vitamine B12 and phthalocyanine, or alkaloids and other fused ring heterocyclic compounds. The preferred heterocyclic compounds are chemotherapeutic agents and their derivatives, pyrimidine related compounds, pyridine related compounds, and pyrazine related compounds.
Most preferred among these chemotherapeutic agents and their derivatives, pyrimidine related compounds, pyridine related compounds, and pyrazine related compounds are sulfa agents. Examples of the heterocyclic compounds which are sulfa agents are given below.
______________________________________List of heterocyclic compounds/sulfa agentsGen-eralname Structural formula______________________________________Sulfa- pyri- dine ##STR1##Sulfa- thia- zole ##STR2##Sulfa- diazine ##STR3##Sulf- amera- zine ##STR4##Sulfa- succi- dine ##STR5## Sulfa- metha- zine ##STR6##Sulfisom- idine ##STR7##Sulf- isox- azole ##STR8##Sulfa- meth- izole ##STR9##Phthal- ylsulfa- thia- zole ##STR10##Sulfa- dimeth- oxine ##STR11##Sulfa- mono- meth- oxine ##STR12##Sulfisom- ezole ##STR13##Sulfa- meth- oxypy- rida- zine ##STR14##Sulfa- phena- zole ##STR15##______________________________________
Also included are composites between a sulfa agent and a dye having a pK value of 4.0 to 9.0, 2-thiouracil, isonicotinic acid hydrazide, and luminol. Illustrative examples of the dyes having pK 4.0 to 9.0 are those indicators and histochemical dyes that are described in H. J. Conn's Biological Stains, R. D. Lillie, The Willians & Wilkins Company, Baltimore, 1977, and having a pK value of 4.0 to 9.0. It is preferred that the dyes have a pK value approximately equal to the isoelectric point of a pathogenic substance. Thus the preferred dyes have the above-defined pK range.
Some illustrative non-limiting examples of the dyes are shown below.
(4,4'-(3H-2,1-benzoxathiol-3-ylidene),*bisphenol s,s'-dioxide
The sulfa agents and the compounds of sulfa agents combined with dyes having pK 4.0-9.0 ensure better results when the sulfa agent is selected from sulfathiazole, sulfamethizole, and sulfisomezole, and the dye having pK 4.0-9.0 is selected from Lacmoid, Brilliant yellow, and Phenol red. These sulfa agents are N1 -heterocyclic compounds whose hetero-rings belong to the azole family, and more specifically, they are thiazole, 2-methylthiadiazole, and 2-methylisoxazole.
The hetero-atoms of the pyridines, pyrimidines and azoles which are the preferred heterocyclic compounds used in the practice of the present invention have a lone pair and act as a proton acceptor. Hetero-rings having less dissociation groups exhibit hydrophobic properties. The sulfonamide moiety of the sulfa agents, the thiol or hydroxyl group of 2-thiourecil, the acid amide moiety of isonicotinic acid hydrazide, and the carbonyl and imino groups of luminol have hydrogen bondability. It is thus interpreted that preferred results are obtained in the adsorption of pathogenic substances, particularly globulin substances by the heterocyclic compounds because the hydrophobic properties of a predominant portion of the heterocyclic compounds, the electrostatic properties of the hetero-atoms, and the hydrogen bondability near the predominant portion all make interactions with amino acid residues of the globulin compounds at the site to be adsorbed and the stereo structure of the heterocylic compounds adequately mates with an intramolecular pocket of the globulin compounds.
In connection with the above-mentioned mechanism, it is believed that a variety of interactions are involved in the adsorption of pathogenic substances by the adsorbents of the present invention. Typical interactions involved include:
(1) hydrophobic bonding,
(2) electrostatic bonding,
(3) hydrogen bonding,
(4) van der Waals-London interactions,
(5) coordination bonding, and
(6) steric adaption.
The heterocylic compounds may generally be fixed to the surface of the insoluble carriers by utilizing a covalent bond, an ionic bond, physical adsorption, embedding, and settlement on the carrier surface followed by insolubilization. The use of a covalent bond is preferred when the stability of a ligand in body fluid is taken into account.
In order to covalently bond the heterocyclic compound to the surface of the insoluble carrier, any desired coupling agents may be used depending on the functional groups on both of them. More illustratively, the hydroxyl group of the insoluble carrier may be covalently bonded to the amino group of the heterocyclic compound using cyan halides such as cyan bromide, halo-triazines, bromoacetyl bromide, epihalohydrins such as epichlorohydrin, bisepoxides such as 1,4-butanediol-diglycidyl ether, and silane coupling agents such as γ-glycidoxypropyltrimethoxysilane (GOPTS).
Because of ease of handling, silane coupling agents are selected herein as the coupling agents which can readily form a covalent bond with the insoluble carriers having a hydroxyl group and form a stable covalent bond with the heterocyclic compounds having an active hydrogen-containing functional group such as an amino, hydroxyl, thiol, and carboxyl group under moderate conditions.
Some illustrative non-limiting examples of the silane coupling agents include
γ-glycidoxypropyltrimethoxysilane (GOPTS),
γ-glycidoxypropylmethyldiethoxysilane having the formula: ##STR17## β-(3,4-epoxycyclohexyl)ethyltrimethoxysilane having the formula: ##STR18## γ-aminopropyltriethoxysilane having the formula:
H2 N(CH2)3 Si(OCH2 CH3)3, and
N-β(aminoethyl)-γ-aminopropyltrimethoxysilane having the formula:
H2 N(CH2)2 NH(CH2)3 Si(OCH3)2.
It should be understood that the last two compounds have a terminal organic functional group in the form of an amino group must be bonded to a terminal amino group of a spacer as will be described later, with glutaraldehyde or the like. The most preferred silane coupling agent is γ-glycidoxypropyltrimethoxysilane (GOPTS).
In affinity chromatography, when an affinity ligand attached to an insoluble carrier bonds with a target substance in a specific and reversible manner, the length and type of a spacer or intermediate carbon chain for supporting the ligand are important. P. O'Carra et al. reports that the length and type of a spacer are important factors and an extremely long spacer bonds with a substance in a sample via hydrophobic interaction. See P. O'Carra et al., Spacer arms in affinity chromatography: the need for a more rigorous approach, Biochem. Soc. Trans., 1(1973), 289-290.
We have made a series of experiments in which the methoxy group of GOPTS was reacted with a hydroxyl group on insoluble carriers, particularly, a hydroxyl group on the surface of silica gels having different pore diameters, then various diamine compounds as a spacer were bonded to the epoxy group of GOPTS, and heterocylic compounds were covalently bonded to the diamine through difunctional reagents. We have found that a diamine compound having the general formula:
NH2 (CH2)n NH2
wherein n is an integer having a value from 3 to 9 are excellent spacers for use in the immunoglobulin adsorbents of the present invention. The preferred diamine compounds are 1,3-propanediamine, 1,6-hexanediamine, and 1,9-diaminononane. The spacer or ligand becomes too short or long to allow sufficient interactions to occur in the adsorption of a pathogenic substance when n falls outside the range of 3-9.
The difunctional reagents with which the heterocyclic compounds were covalently bonded to the diamine compounds include
dialdehydes such as glutaraldehyde and p-phthaldehyde having the formula: ##STR19## bisepoxides as 1,4-butanediol-diglycidyl ether having the formula: ##STR20## alkylimide esters such as diethylmalonimidate having the formula: ##STR21## diisocyanates such as hexamethylene diisocyanate having the formula:
Most preferred among them is glutaraldehyde.
When the heterocylic compounds as such have not a group capable of reacting with the aldehyde group of glutaraldehyde, an aldehyde-reacting group is previously incorporated in the heterocylic compounds.
The insoluble carriers used herein preferably possess a hydrophilic surface compatible with water medium and have a hydroxyl group capable of reacting with GOPTS.
In order to efficiently remove pathogenic substances by adsorption, the insoluble carriers are preferably in the form of a porous body having a great surface area. Particularly preferred carriers are inorganic porous bodies predominantly comprising silicon dioxide and having a silanol group because they possess a high mechanical strength and permit autoclave sterilization and because silicon dioxide is available in plenty and thus inexpensive. The preferred carriers are porous bodies. For the purpose of adsorbing and removing IgM having a molecular weight as high as 900,000 and immune complexes having a molecular weight of about 600,000 or higher, the preferred porous bodies have a mean pore diameter in the range between 300 angstrom and 5000 angstrom, more preferably in the range between 1000 angstrom and 3000 angstrom.
Measurement of mean pore diameter is made by means of a mercury porosimeter. Mercury is forcedly penetrated into a porous body. Then the volume of pores is determined by the amount of mercury penetrated and the pore diameter is determined by the pressure required for penetration.
The shape of the insoluble carriers may take any desired known shapes including particulate, fiber, hollow fiber, and membrane shapes. Particulate, especially spherical carriers are preferred because of smooth passage of body fluid and unlikely collapse and chipping.
The particulate carriers preferably have an average particle diameter in the range between 0.05 mm and 5 mm in view of body fluid flow rate and flow pressure. The average particle diameter is calculated by classifying particles through sieves as defined in JIS Z 8801, determining a median between the upper and lower limit particle diameters for each class as a particle diameter for the class, and weight averaging the particle diameters of all the classes.
As previously described with respect to the preferred ligands used in the practice of the present invention, the hetero-atoms of the heterocyclic compounds possess a lone pair in the outermost electron shell and act as a proton acceptor. Hetero-rings having less dissociation groups exhibit hydrophobic properties. The sulfonamide moiety of the sulfa agents have hydrogen bondability.
The spacer for the ligand including the coupling agent segment has a hydroxyl group having hydrogen bondability and exhibits increased hydrophobic property with a longer carbon chain, the length of which is correlated to the area the ligand molecule occupies and to the fitting of the ligand in a specific molecular pocket of a substance to be adsorbed.
On the other hand, the inorganic porous body having the ligand attached thereto has silicon and oxygen atoms of siloxane or hydroxyl groups of silanol at the surface of silicon dioxide based beads and thus possesses hydrogen bondability and electrostatic bondability.
Then, it is believed that in the course of adsorption of a pathogenic substance by an adsorbent, combined interactions of hydrophobic bond, electrostatic bond, and hydrogen bond occur between the amino acid residues of the pathogenic substance and the adsorbent, and the ligand on the adsorbent properly fits in the intramolecule pocket of the pathogenic substance, ensuring favorable results.
In general, adsorbents consisting of hydrophobic compounds have a great amount of useful proteins attached such as albumin in body fluid and are thus unsuitable for the selective removal of pathogenic substances. Inversely, adsorbents consisting of hydrophilic compounds or compounds having many charged groups can have only an extremely small amount of proteins attached so that they are unsuitable for the removal of pathogenic substances. Adsorbents having a proper combination of various interactions are preferred adsorbents for immunoglobulins.
As previously described, various interactions, particularly interactions (1) to (6) are involved in the reaction of the ligand with a material to be adsorbed or immunoglobulin (Ig). The length of the ligand has a significant influence on these interactions.
As the methylene chain of the spacer, diamine compound in the present invention, in the ligand increases its length, the spacer exhibits increased hydrophobic properties, that is, hydrophobic bonding (1) is enhanced. The length of the ligand is closely related to steric adaption (6) and determines whether the distal end of the ligand can contact amino acid residues in the deep of the pocket of Ig. When the methylene chain of the spacer or diamine compound is represented by (CH2)n, the length of the ligand, that is, the sum of the lengths of silane coupling agent, diamine compound, and heterocyclic compound has the following approximate value in angstrom calculated from atomic distance.
Likewise, the length of the diamine compounds has the following value in angstrom.
Thus, preferably the diamine compounds have a length of from about 5 to about 20 angstrom and the ligands have a length of from about 40 to about 55 angstrom. Sufficient interactions do not occur when the diamine compounds and the ligands have lengths outside the above-specified ranges.
The immunoglobulin adsorbing apparatus of the present invention includes a vessel having an inlet and an outlet for the passage of body fluid therethrough. The adsorbent as defined above is charged and retained in the vessel.
The materials of which the vessel is made may include glass, stainless steel, polyethylene, polypropylene, polycarbonate, polystyrene, polymethylmethacrylate, etc. with the polypropylene and polycarbonate being preferred because of autoclave sterilization and ease of handling. The vessel is further provided with means for preventing the adsorbent from flowing out of the vessel. Illustratively, a filter is disposed between the adsorbent and the inlet and outlet which has a screen mesh or opening sufficient to allow passage of body fluid, but prevent passage of the adsorbent. The filter may be formed of any desired materials as long as they are physiologically inert and mechanically strong. The preferred filters are of mesh polyester and polyamide.
Referring to FIG. 1, there is illustrated in cross section a preferred embodiment of the immunoglobulin adsorbing apparatus of the present invention.
The apparatus includes a cylindrical vessel 1 having an inlet 4 and an outlet 5 for the passage of body fluid. A mass of immunoglobulin adsorbent 2 is charged in the vessel 1 and retained between a pair of filters 3 and 3' disposed in the vessel near the inlet 4 and the outlet 5. Body fluid is introduced into the vessel 1 via the inlet 4, passed through the adsorbent mass for treatment, and discharged through the outlet 5.
FIG. 2 illustrates a hemocatharsis system. Blood is pumped from an inlet 6 by means of a pump 7 to a plasma separator 8 where it is separated into plasma and corpuscle components. The separated plasma is fed to the immunoglobulin adsorbing apparatus 1 shown in FIG. 1 by means of a pump 7' where it is subjected to adsorption. The treated plasma is combined with the corpuscle component in a plasma-corpuscle mixer 9 and then fed to a desired destination via an outlet 10.
Examples of the present invention are given below along with comparative examples. GOPTS means gamma-glycidoxypropyltrimethoxysilane and DMF means dimethylformamide. Water used is distilled water.
Porous silica gel beads (manufactured by Fuji-Davidson Chemical K.K.) having a particle diameter in the range from 74 to 149 μm and different pore diameters of 324, 460, 685, 906, 971, and 2361 Å as shown in Table 2 were immersed in a 5 w/v % GOPTS aqueous solution which had been adjusted to pH 9 with potassium hydroxide. A heat treatment was effected to cause a silanol group on the surface of silica gel to react with the methoxy group of GOPTS to produce a GOPTS-grafted silica gel. This process is represented by reaction scheme 1.
The GOPTS-grafted silica gel was added to a distilled water (H2 O)-DMF solution of 0.1 M diamine compound, namely 1,3-propanediamine, 1,6-hexanediamine and 1,9-diaminononane which are within the scope of the present invention, dodecamethylenediamine and p-phenylenediamine which are outside the scope of the present invention. After deaeration and addition of pyridine and tri-n-butylamine catalysts, the reaction mixture was warmed to cause the epoxy group of GOPTS to react with the amino group of the diamine compound. Reaction scheme 2 represents the process wherein the amine compound used is 1,3-propanediamine.
The reaction product was washed with water and DMF, and then immersed in an aqueous solution of 5 v/v % glutaraldehyde. After deaeration, the mixture was adjusted to pH 7 with sodium hydroxide and agitated at room temperature to effect the reaction. The product was washed with water. This process is represented by reaction scheme 3.
The reaction product was immersed in a solution of 0.1 M a heterocyclic compound as shown in Table 2 in a 2:3 (by volume) mixed solution of DMF and pH 8/10 mM calcium chloride aqueous solution. The reaction mixture was deaerated to remove air in the pores and then agitated at room temperature to effect the reaction. Reaction scheme 4 represents the process wherein sulfathiazole is employed as the heterocyclic compound.
The reaction product was washed with water and DMF, and then immersed in an aqueous solution of 1 M ethanol amine for blocking the unreacted epoxy and/or aldehyde groups. The mixture was deaerated and allowed to react at room temperature.
The reaction product was washed with water. Then, an optional treatment, for example, reducing treatment was effected to stabilize the bond resulting from the reaction between the aldehyde group of glutaraldehyde and an aldehydereacting group such as an amino group of the heterocyclic compound.
When sulfathiazole was used as in reaction scheme 4, for example, the reaction product was immersed in a solution of 1 w/v % sodium boron hydride in pH 8/10 mM calcium chloride solution to reduce the azomethin bond resulting from the reaction between the amino group of sulfathiazole and the aldehyde group of glutaraldehyde. This process is represented by reaction scheme 5. ##STR22##
The product was repeatedly washed with water, a pH 4/0.02 M acetate buffer solution containing 0.5 M sodium chloride, and a pH 10/0.2 M carbonate buffer solution, further washed with acetone, and dried at 120� C. for 2 to 3 hours under vacuum. Samples weighing 1 gram were taken from the dry product and placed in glass tubes of 15.5 mm diameter �100 mm long (Larbo� , manufactured by Terumo K.K.). These adsorbents were tested for adsorption performance.
For comparison purposes, there were prepared untreated silica gel beads having no ligand and spacer-free adsorbents, that is, GOPTS-grafted silica gels wherein the epoxy group of GOPTS was directly reacted with heterocyclic compounds (as shown in Table 2) without a spacer. One gram samples of them were subjected to a similar adsorption test.
The adsorption test was carried out by adding 3 ml of pH 7.2/8 mM phosphate buffer solution (PBS) containing 137 ml sodium chloride and 2.6 mM potassium chloride to the test tube charged with the adsorbent. After deaeration with an aspirator (A-2S type, manufactured by Tokyo Rikakiki K.K.), 3 ml of bovine plasma containing 6 IU/ml heparin as an anticoagulant and 50 μl /ml ACD was added to the tube. The soaked adsorbent was incubated at 37� C. for 90 minutes in a warm air circulating incubator (P(S)-212 type, manufactured by Tabai K.K.) with stirring by a blood mixer (BM-101 type, manufactured by Kayagaki Irika Kogyo K.K.). The contents of the reaction tube were transferred to a small column in the form of a 5-ml volume disposable syringe (manufactured by Terumo K.K.) with the aid of 1 ml PBS. The column was washed with 5 ml PBS and the eluent was collected and metered. The quantity of immunoglobulin M (IgM) was determined by a simple radial immunodiffusion (SRID) technique. This value was subtracted from the net quantity of IgM in the eluent obtained by repeating a similar procedure without using the adsorbent, to determine the quantity of IgM adsorbed by the adsorbent. Percent adsorption was calculated by dividing the quantity of IgM adsorbed by the net quantity of IgM in the eluent obtained without the adsorbent.
The results are shown in Table 2. Based on these data, the percent IgM adsorption is plotted in FIGS. 3 and 4 as a function of the average pore diameter of carriers when the heterocyclic compound used was sulfathiazole.
TABLE 2______________________________________(Bovine plasma) CarrierHeterocyclic average pore IgMcompound Spacer diameter, Å adsorption______________________________________Examplessulfathiazole 1,3-propanediamine 324 6.7 460 13.9 685 21.1 971 35.9 2361 46.6sulfathiazole 1,6-hexanediamine 324 6.9 460 14.1 685 22.5 971 27.2 2361 34.1sulfathiazole 1,9-diaminononane 324 0 460 10.8 685 18.8 971 16.0 2361 34.6Comparative Examplessulfathiazole dodecamethylenediamine 324 4.9 460 11.5 685 19.8 971 14.0 2361 21.2untreated silica gel 324 5.4 460 8.5 685 18.0 971 21.5 2361 18.6______________________________________
As evident from Table 2 and FIGS. 3 and 4, more efficient adsorption and removal of IgM was achieved when 1,3-propanediamine and 1,6-hexanediamine were used as a spacer, particularly when 1,3-propanediamine was used.
Further, the data indicate that average particle diameters of 900 Å or more results in higher adsorption.
The procedure of Example 1 and Comparative Example 1 was repeated using normal human plasma instead of bovine plasma and heterocyclic compounds as shown in Table 3. An adsorption test was carried out to determine the percent adsorption of IgM by the adsorbents.
The results are shown in Table 3.
TABLE 3______________________________________(Normal human plasma) CarrierHeterocyclic average pore IgMcompound Spacer diameter, Å adsorption______________________________________Examplessulfathiazole 1,3-propanediamine 906 100.0sulfathiazole 1,3-propanediamine 2361 92.0sulfathiazole 1,6-hexanediamine 906 94.1sulfathiazole 1,6-hexanediamine 2361 81.8sulfathiazole 1,9-diaminononane 906 100.0sulfathiazole 1,9-diaminononane 2361 59.3sulfamethizole 1,6-hexanediamine 906 78.3sulfamethizole 1,6-hexanediamine 2361 62.8sulfisomezole 1,6-hexanediamine 906 96.1sulfisomezole 1,6-hexanediamine 2361 83.8sulfisomezole 1,9-diaminononane 906 82.6sulfisomezole 1,9-diaminononane 2361 72.9Comparative Examplessulfathiazole -- 906 79.4sulfathiazole -- 2361 50.5sulfathiazole dodecamethylenedia- 906 35.3 minesulfathiazole dodecamethylenedia- 2361 31.0 minesulfathiazole p-phenylenediamine 906 73.5sulfathiazole p-phenylenediamine 2361 33.3untreated silica gel 906 76.5untreated silica gel 2361 59.0sulfamethizole -- 906 60.9sulfamethizole -- 2361 38.8sulfamethizole dodecamethylenedia- 906 27.1 minesulfamethizole dodecamethylenedia- 2361 23.8 minesulfamethizole p-phenylenediamine 906 56.4sulfamethizole p-phenylenediamine 2361 25.6sulfisomezole -- 906 79.3sulfisomezole -- 2361 62.1sulfisomezole dodecamethylenedia- 906 43.4 minesulfisomezole dodecamethylenedia- 2361 38.1 minesulfisomezole p-phenylenediamine 906 80.7sulfisomezole p-phenylenediamine 2361 41.0______________________________________
As evident from Table 3, more efficient adsorption and removal of IgM was achieved when 1,3-propanediamine, 1,6-hexanediamine, and 1,9-diaminononane were used as a spacer, particularly when 1,3-propanediamine was used.
Substantially equivalent results were obtained when other heterocyclic compounds such as sulfapyridine, sulfadiazine, sulfisomidine, 2-thiouracil, luminol, and isonicotinic acid hydrazide were used.
The immunoglobulin adsorbent of the present invention wherein a diamine compound having the general formula:
NH2 (CH2)n NH2
wherein n is an integer having a value of 3 to 9, such as 1,3-propanediamine, 1,6-hexanediamine, or 1,9-diaminononane is attached to a hydroxyl-containing water-insoluble carrier through a silane coupling agent or a derivative thereof and a heterocyclic compound is attached to the diamine through a difunctional reagent can selectively and efficiently adsorb and remove such proteins as immunoglobulins and immune complexes which are pathogenic substances in body fluid. Since the ligand is a relatively low molecular weight organic compound, the adsorbent can be readily sterilized without an error.
The present invention is usable in general applications where body fluid is depurated through adsorption for regeneration, and particularly effective in the treatment of polyclonal immunoglobulin M diseases (chronic hepatitis, cirrhosis, scleroderma, lymphomatosis, congenital rubella, congenital syphilis, congenital toxoplasmosis, tripanosomal infectious disease, subacute sclerosing panencephalitis, and other diseases where IgM increases), immune complex diseases (glomerulonephritis, systemic lupus erythematosus (SLE), chronic rheumatism, periarteritis nodosa, serum sickness, chronic graft-versus-host disease (GVHD), and other diseases where immune complexes increase), and transplantation (AOB incompatibility bone-marrow transplantation, etc.).
The immunoglobulin adsorbents of the present invention is not only used as a therapeutic instrument by filling a vessel therewith, but also useful as members for the isolation, purification, and detection of such proteins as immunoglobulins and immune complexes.
|Cited Patent
|Filing date
|Publication date
|Oct 4, 1974
|Jan 4, 1977
|Barrett M James
|Covalently bound biological substances to plastic materials and use in radioassay
|Apr 7, 1975
|Nov 22, 1977
|Summa Corporation
|Immobilized immunoadsorbent
|Jun 22, 1978
|May 13, 1980
|Asahi Kasei Kogyo Kabushiki Kaisha
|Adsorbent for adsorbing organic compounds adsorbed on proteins
|Feb 21, 1980
|Mar 23, 1982
|Nippon Soda Company Limited
|Adsorbent for urokinase containing agarose
|Apr 3, 1981
|May 24, 1983
|Kuraray Co., Ltd.
|Column for adsorption of blood proteins
|Nov 20, 1981
|Oct 11, 1983
|Asahi Kasei Kogyo Kabushiki Kaisha
|Dried, sterilized, gamma-globulin-fixed column and a process for preparing the same
|Jul 7, 1982
|Dec 13, 1983
|Kuraray Co., Ltd.
|Blood purification device
|May 17, 1982
|Feb 7, 1984
|Asahi Kasei Kogyo Kabushiki Kaisha
|Immune adsorbent and adsorbing device
|Jan 15, 1982
|Feb 21, 1984
|Asahi Kasei Kogyo Kabushiki Kaisha
|Immune adsorbent, adsorbing device and blood purifying apparatus
|Aug 22, 1983
|Sep 18, 1984
|Kuraray Co., Ltd.
|Blood purification method
|Title not available
|Feb 24, 1982
|Sep 8, 1982
|Unilever Plc
|A process and apparatus for the recovery of immunoglobulines
|Apr 26, 1982
|Nov 10, 1982
|The Public Health Laboratory Service Board
|Affinity chromatography using metal ions
|Title not available
|Title not available
|Title not available
|Title not available
|Title not available
|Title not available
|Title not available
|Title not available
|Title not available
|Title not available
|Title not available
|Title not available
|Title not available
|Title not available
|Title not available
|Title not available
|Title not available
|Jan 27, 1983
|Aug 4, 1983
|Malmqvist, Magnus
|Silanization of surfaces
|L Abbate, A., et al., Selective Removal of Plasma Cryoglobulins in Cryoglobulinaemia , Proc. Eur. Dial. Transport Assoc., vol. 14, pp. 486 494 (1977).
|L'Abbate, A., et al., "Selective Removal of Plasma Cryoglobulins in Cryoglobulinaemia", Proc. Eur. Dial. Transport Assoc., vol. 14, pp. 486-494 (1977).
|Ohe, H., et al., Artificial Organs, vol. 14 (1), p. 472 (1985).
|Sieberth, H. G., "The Elimination of Defined Substances from the Blood and from Separated Plasma, Plasma Exchange-International Symposium in Cologne, Jun. 6 and 7, 1980.
|Sieberth, H. G., The Elimination of Defined Substances from the Blood and from Separated Plasma, Plasma Exchange International Symposium in Cologne, Jun. 6 and 7, 1980.
|Tetsuzo Agishi, et al., Kidney and Dialysis, vol. 10 (3), p. 475 (1981).
|Citing Patent
|Filing date
|Publication date
|May 13, 1988
|Sep 5, 1989
|Imre Cororation
|Anti-human IGM immunoadsorbent and process for producing said immunoadsorbent
|May 11, 1993
|Sep 20, 1994
|Hitachi, Ltd.
|Apparatus for measuring glycohemoglobin
|Oct 22, 1997
|Jun 25, 2002
|Renal Solutions, Inc.
|Continuous flow-through peritoneal dialysis (CFPD) method with control of intraperitoneal pressure
|May 14, 2002
|Sep 2, 2004
|Cook Christian John
|Kinetic assay
|Dec 19, 2008
|Jun 24, 2010
|Baxter International Inc.
|Systems and methods for obtaining immunoglobulin from blood
|Jan 24, 1997
|Dec 9, 1998
|Kaneka Corporation
|Adsorbent for immunoglobulins and complexes thereof, adsorption method, and adsorption device
|Sep 1, 1997
|Sep 2, 2009
|Upfront Chromatography A/S
|Isolation of immunoglobulins
|Jul 27, 2001
|Feb 7, 2002
|Aesku.Lab Diagnostika
|Device for treating immune diseases
|Dec 18, 2009
|Jun 24, 2010
|Baxter International Inc.
|Systems and methods for obtaining immunoglobulin from blood
|U.S. Classification
|210/289, 502/402, 210/502.1
|International Classification
|Cooperative Classification
|European Classification
|Apr 7, 1986
Owner name: TERUMO KABUSHIKI KAISHA T/A TERUMO CORPORATION, 44
Free format text: ASSIGNMENT OF ASSIGNORS INTEREST.;ASSIGNORS:YAMAMOTO, YUICHI;SAMESHIMA, TADASHI;REEL/FRAME:004539/0172
Effective date: 19860325
|Jun 14, 1988
|Certificate of correction
|May 3, 1991
|Fee payment
Year of fee payment: 4
|Apr 24, 1995
|Fee payment
Year of fee payment: 8
|Jun 1, 1999
|Maintenance fee reminder mailed
|Nov 7, 1999
|Lapse for failure to pay maintenance fees
|Jan 18, 2000
|Expired due to failure to pay maintenance fee
Effective date: 19991110


text:
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text:
Blackwater Founder's Mercenary Army Abandoned in Somali Desert
Well-Armed Fighters Left to Fend for Themselves as UAE Pulls Funds
Last year it was revealed that Blackwater USA founder Erik Prince had been put in charge of building a mercenary army in northern Somalia, with funding from the United Arab Emirates and a goal of attacking the various pirate factions along the Somali coast.
It apparently seemed like a good idea at the time, but the United Arab Emirates has gotten sick of throwing money at the operation and pulled the plug. Now, the hundreds of mercenaries are sitting on a secret desert base with potentially millions of dollars in heavy weapons illegally smuggled into Somalia and nothing to do.
The decision apparently came after an April incident when the fighters attacked and killed a South African trainer. The corporation put in charge of the mission, the shadowy Sterling Corporate Services, insisted at the time that it was an isolated incident, but quickly withdrew its trainers, leaving the recruits stranded on a base in the Puntland desert.
But they likely won't stay on that base for long, as those familiar with the situation say that the fighters, who were not ideologically motivated to join the anti-piracy fight in the first place, are liable to take their weapons and head out looking for new employers, with pirates among the likely bidders.
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text:
|By PR Newswire
Article Rating:
|December 20, 2012 01:45 PM EST
LONDON, December 20, 2012 /PRNewswire/ --
New platform release enables easy-option sharing of charts, insight and commentary with forex social trading communities
MahiFX, the proprietary-built trading platform providing retail FX traders access to institutional level technology and pricing, has launched a new 'just one click' functionality that gives traders the ability to instantly share their trading inspiration and strategies with their social trading community and friends. The new platform feature lets clients export charting screenshots of their trades along with user-generated commentary and analysis instantly via Facebook.
(Logo: http://photos.prnewswire.com/prnh/20121025/570905-a )
Part of MahiFX's accelerated platform development programme, the new feature has been introduced in response to the growing interest in social trading amongst retail FX traders keen to share insight, knowledge and trading tips. Traders can now login to Facebook directly from within the MahiFX API and share screenshots of chosen trades in both the Book view and Analysis tab. And to promote knowledge share and discussion, traders have the facility to add comments to each individualised screenshot.
For a screenshot please click here.
"Retail FX trading is an increasingly open and collaborative endeavour," says David Cooney, MahiFX CEO. "As the market democratises it's unsurprising that traders will gravitate towards communities that share trading insight and practical trading advice. In addition to the educational tools that we provide on our site and blog, this new social trading feature will serve to foster knowledge share and provide our traders with an open, transparent and novel means to learn and discuss the markets, differing trading strategies and tactics in order to inform their own personal trading strategy."
MahiFX is headed by David Cooney, former global co-head of currency options and e-FX trading at Barclays Capital and responsible for the award-winning e-commerce platform BARX and Susan Cooney, former head of e-FX Institutional Sales in Europe for Barclays Capital.
For a screenshot please click here.
As a market maker MahiFX is able to provide traders direct access to institutional-level execution speeds and spreads through its proprietary-built, fully automated pricing and risk management technology.
To view this release and images online please click here.
About MahiFX forex trading platform
MahiFX launched its new proprietary-built browser-based foreign exchange (Forex) trading platform in February 2012.
Developed by a team of ex-interbank traders, analysts, statisticians and developers, MahiFX provides retail FX customers access to the same tight spreads and cutting edge technology as institutional FX traders. Prices are tradeable - there are no 'from' prices, hidden costs, slippage, re-quotes or minimum trade sizes. Traders also have access to news and economic updates around the clock.
MahiFX global operations are headquartered in Christchurch, New Zealand with offices in London, UK with development and support teams in both locations for 24 hour service. The company is regulated by The Australian Securities and Investments Commission (ASIC), Australia's corporate, markets and financial services regulator.
Trading foreign exchange on margin carries a high level of risk, and may not be suitable for everyone. Read full disclaimer here.
Media Enquiries:
Michele McDermott-Fox
The Top Floor
[email protected]
In his keynote at 18th Cloud Expo, Andrew Keys, Co-Founder of ConsenSys Enterprise, provided an overview of the evolution of the Internet and the Database and the future of their combination – the Blockchain. Andrew Keys is Co-Founder of ConsenSys Enterprise. He comes to ConsenSys Enterprise with capital markets, technology and entrepreneurial experience. Previously, he worked for UBS investment bank in equities analysis. Later, he was responsible for the creation and distribution of life sett...
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There are several IoTs: the Industrial Internet, Consumer Wearables, Wearables and Healthcare, Supply Chains, and the movement toward Smart Grids, Cities, Regions, and Nations. There are competing communications standards every step of the way, a bewildering array of sensors and devices, and an entire world of competing data analytics platforms. To some this appears to be chaos. In this power panel at @ThingsExpo, moderated by Conference Chair Roger Strukhoff, Bradley Holt, Developer Advocate a...
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Cognitive Computing is becoming the foundation for a new generation of solutions that have the potential to transform business. Unlike traditional approaches to building solutions, a cognitive computing approach allows the data to help determine the way applications are designed. This contrasts with conventional software development that begins with defining logic based on the current way a business operates. In her session at 18th Cloud Expo, Judith S. Hurwitz, President and CEO of Hurwitz & ...
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In his general session at 18th Cloud Expo, Lee Atchison, Principal Cloud Architect and Advocate at New Relic, discussed cloud as a 'better data center' and how it adds new capacity (faster) and improves application availability (redundancy). The cloud is a 'Dynamic Tool for Dynamic Apps' and resource allocation is an integral part of your application architecture, so use only the resources you need and allocate /de-allocate resources on the fly.
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A strange thing is happening along the way to the Internet of Things, namely far too many devices to work with and manage. It has become clear that we'll need much higher efficiency user experiences that can allow us to more easily and scalably work with the thousands of devices that will soon be in each of our lives. Enter the conversational interface revolution, combining bots we can literally talk with, gesture to, and even direct with our thoughts, with embedded artificial intelligence, wh...
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Internet of @ThingsExpo, taking place November 1-3, 2016, at the Santa Clara Convention Center in Santa Clara, CA, is co-located with 19th Cloud Expo and will feature technical sessions from a rock star conference faculty and the leading industry players in the world. The Internet of Things (IoT) is the most profound change in personal and enterprise IT since the creation of the Worldwide Web more than 20 years ago. All major researchers estimate there will be tens of billions devices - comp...
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Machine Learning helps make complex systems more efficient. By applying advanced Machine Learning techniques such as Cognitive Fingerprinting, wind project operators can utilize these tools to learn from collected data, detect regular patterns, and optimize their own operations. In his session at 18th Cloud Expo, Stuart Gillen, Director of Business Development at SparkCognition, discussed how research has demonstrated the value of Machine Learning in delivering next generation analytics to imp...
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There is little doubt that Big Data solutions will have an increasing role in the Enterprise IT mainstream over time. Big Data at Cloud Expo - to be held November 1-3, 2016, at the Santa Clara Convention Center in Santa Clara, CA - has announced its Call for Papers is open. Cloud computing is being adopted in one form or another by 94% of enterprises today. Tens of billions of new devices are being connected to The Internet of Things. And Big Data is driving this bus. An exponential increase is...
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Connected devices and the industrial internet are growing exponentially every year with Cisco expecting 50 billion devices to be in operation by 2020. In this period of growth, location-based insights are becoming invaluable to many businesses as they adopt new connected technologies. Knowing when and where these devices connect from is critical for a number of scenarios in supply chain management, disaster management, emergency response, M2M, location marketing and more. In his session at @Th...
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Amazon has gradually rolled out parts of its IoT offerings, but these are just the tip of the iceberg. In addition to optimizing their backend AWS offerings, Amazon is laying the ground work to be a major force in IoT - especially in the connected home and office. In his session at @ThingsExpo, Chris Kocher, founder and managing director of Grey Heron, explained how Amazon is extending its reach to become a major force in IoT by building on its dominant cloud IoT platform, its Dash Button strat...
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industrial company for a multi-year contract initially valued at over $4.0 million. In addition to DataV software, Bsquare will also provide comprehensive systems integration, support and maintenance services. DataV leverages advanced data analytics, predictive reasoning, data-driven diagnostics, and automated orchestration of remediation actions in order to improve asset uptime while reducing service and warranty costs.
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text: Dirty Money (Diddy, Kalenna and Dawn Richard) – Angels Trailer (directed by Hype Williams) By admin | September 8, 2009 [COMMENTS] Dirty Money (Diddy, Kalenna and Dawn Richard) – Angels Trailer (directed by Hype Williams) Share this video Tweet Related Videos YFN Lucci Feat. Migos & Trouble "Key To The Streets" Video Schoolboy Q – By Any Means (Part 1) Lil Dicky XXL Freshman Freestyle 2 Chainz ft. Lil Wayne – MFN Right (Remix) Chanel West Coast Ft. Rockie Fresh "The Life" Video News & Songs › ‹ Kanye West – Father Stretch My Hands (Remix) Cash Out Feat. Playboi Carti – Hard To Breathe Lil Uzi Vert – Stole Your Love Cash Out – Flood The Streets Puff Daddy ft. Bobby Shmurda, Rowdy Rebel, French Montana & Chinx – Shmoney Ain't A Problem 50 Cent Arrested For Using Profanity In Public Talib Kweli – You Tried It (Diabolic Diss) Shy Glizzy Feat. Fat Trel – Checklist Young Scooter & Young Dolph – Count Up Jace – Oh No Skooly – Hatred K Camp Feat. Tasha Cavour – Lately


text:
Organic Heirloom Bean Easy Grow Tips
These varieties are extremely productive. You may expect about 15 pounds of organic heirloom beans from a single narrow 30' row.
Avoid planting in soil that stays wet. Heirloom bean diseases thrive in wet conditions, and the roots may not get enough oxygen.
Organic heirloom beans like soil that is slightly acid, about 6.5. This can be achieved by adding mulched pine needles, peat moss or sulfur.
Try wide row growing for bush beans. Make your heirloom bean rows three across instead of just one. Three wide is perfect because most people can reach across that width. You can grow 3 times the amount of organic heirloom beans in the same space, you reduce the amount of area for weeds, and you'll save on water.
|Organic Bulls Blood Beet Seeds
Delicious leaves that are magenta with roots that are sweet and juicy. This old heirloom was selected around the 1840s...
|Kellog's Breakfast Tomato Seeds
Kellog's Breakfast is a giant vibrant orange beefsteak that produces tons of fruit late in the season. Fruits are in clumps of 2-3 and weigh normally more than a pound each. Some will get to be as big as 20 ounces. You must have excellent staking!


text:
BT HomeHub 5: Wi-Fi ac support, Gigabit Ethernet, the partner for your 300mbps Infinity broadband
BT will be launching the BT HomeHub 5 later in 2013, following hot on the heels of the HomeHub 4. The BT HomeHub 5 will bring with it support for the latest 802.11ac Wi-Fi protocol, as well as including Gigabit Ethernet connections to give you faster home networking.
The BT HomeHub 5 was shown to us by BT during a HomeHub 4 briefing. Although we don't have the full details of the exact specifications of the new BT HomeHub 5, it was described to us as the perfect partner for BT Infinity broadband, enhancing the offering over the current BT HomeHub 3 and the more recent BT HomeHub 4 that's rolling out (pictured above).
In the same breath, we were also told that BT would soon be offering 300mbps home broadband. We've known for a while that this was undergoing trials, and it looks like BT is ready to roll out the ultrafast broadband service.
READ: BT Infinity 300 to launch in 2013
Aside from the faster networking capabilities of the new HomeHub 5, it will also integrate the modem and router into the same unit - currently there's a separate modem with the HomeHub only acting as the router, supplying additional network connections and Wi-Fi.
In real terms, BT says it will be more power efficient, as you'll only be powering the one device, but in practical terms, it means you'll get a plug socket back.
The design remains the same as the current BT HomeHub 4, except the bar on the front is light blue and from the quick glance we had of the device today, from the exterior we couldn't spot any other changes.
BT remained tight-lipped on the pricing of the HomeHub 5, but said it wouldn't be charging the sort of price you'd pay on the high street for a device of the same capabilities. It will be provided as standard to new BT Infinity customers following launch, or as an upgrade option similar to the existing arrangements in place for upgrading from HH3 to HH4.
Whatever the case, it's worth holding on to your cash: if you're a BT Infinity customer, it's the dual-band, Wi-Fi ac, Gigabit Ethernet packing HomeHub 5 that you'll want to upgrade to, ready to support the next wave of superfast devices, like the new Apple MacBook Air.
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