text:
|Publication number
|Publication type
|Application number
|Publication date
|Feb 9, 1999
|Filing date
|May 15, 1991
|Priority date
|Sep 10, 1985
|Fee status
|Also published as
|Publication number
|Elias Klein
|Original Assignee
|Research Corporation Technologies, Inc.
|Export Citation
|BiBTeX, EndNote, RefMan
|Patent Citations (21), Non-Patent Citations (15), Referenced by (15), Classifications (20), Legal Events (4)
|External Links: USPTO, USPTO Assignment, Espacenet
This is a divisional of application Ser. No. 182,708, filed on Apr. 18, 1988 now U.S. Pat. No. 5,039,609 which is a continuation-in-part of Ser. No. 774,261 filed Sep. 10, 1985 now abandoned.
The present invention relates to a novel method of performing peritoneal dialysis. More specifically, it relates to the use of relatively low molecular weight peptides as osmotic agents in a peritoneal dialysate.
Another aspect of the present invention relates to an improved method for the enzymatic hydrolysis of proteins to produce low molecular weight peptides for use in peritoneal dialysis.
In still another aspect of the present invention the novel process may be applied to the enzymatic hydrolysis of oligosaccharides such as starch to produce products free of enzymes, high molecular weight starch fractions and insoluble starch material. If desired, this novel process may also be applied to glucose as well.
The normal function of the mammalian kidney includes such activity as maintaining a constant acid-base and electrolyte balance, removing excess fluids and removing undesirable products of the body's metabolism from the blood. In an individual with end stage renal disease, this functioning of the kidney may be reduced to as low as 5% or less of the normal level. When renal function has decreased to this point, artificial means must then be employed to substitute for the kidney activity, if life is to be sustained. This is accomplished clinically by the use of dialysis. One of the most common methods for achieving this is hemodialysis, in which the patient's blood is passed through an artificial kidney dialysis machine. In the machine, a synthetic non-permeable membrane acts as an artificial kidney with which the patient's blood is contacted on one side; on the opposite side of the membrane is a dialyzing fluid or dialysate, the composition of which is such that the undesirable products in the patient's blood will naturally pass across the membrane by diffusion, into the fluid. The blood is thus cleansed, in essentially the same manner as the kidney would have done, and the blood is returned to the patient's body. This method of dialysis requires the patient to be physically "hooked up" to the machine for several hours, often several times a week. For obvious reasons, this technique, although efficient, presents a number of inconveniences.
Some of the disadvantages associated with hemodialysis, which requires extracorporeal treatment of the blood, are overcome by the use of techniques which utilize the patient's own peritoneum as the required semipermeable membrane. The peritoneum is the membraneous lining of the body cavity which contains large numbers of blood vessels and capillaries and is thus capable of acting as a natural semipermeable membrane. Dialysis solution is introduced into the peritoneal cavity, via a catheter in the abdominal wall. A suitable period of residence time for the dialysate is allowed to permit the exchange of solutes between it and the blood; fluid removal is achieved by providing a suitable osmotic gradient from the blood to the dialysate to permit water outflow from the blood. Thus, the proper acid-base, electrolyte and fluid balance is returned to the blood and the dialysis solution is simply drained from the body cavity through the catheter. Although more than one type of peritoneal dialysis exists, the technique known as continuous ambulatory peritoneal dialysis (CAPD) is particularly favored, since it does not require the patient to remain tied to machinery while the solute and fluid exchange is accomplished. The only sedentary period required is during infusion and draining of the dialysis solution.
One of the most difficult aspects of peritoneal dialysis, and yet one of the most important, is finding a suitable osmotic agent for inclusion in the dialysate, by which the required osmotic gradient would be achieved. By osmotically active agent, as used herein, is meant a substance present in the dialysis solution which is capable of maintaining the osmotic gradient required to cause transport of water and toxic substances across the peritoneum into the dialysis solution. The appropriate agent should fulfill at least two critical criteria. First, it must be, to a greater or lesser extent biologically inert, i.e., non-toxic and yet metabolizable, and second, should preferably not rapidly cross the peritoneal membrane into the blood; this would allow maintenance of the maximum ultrafiltration gradient, and also would prevent toxicity or accumulation of unwanted substances in the blood. Absence of toxicity is particularly important, since nearly any substance placed in the peritoneum will eventually find its way into the circulation, whether by a slow lymphatic drain, or by dialysis across the peritoneal membrane. To date, no known substance has completely satisfied these needs, although a number of different materials have been used with varying success. The agent which has currently achieved the most widespread acceptance is glucose. Glucose has the advantage of being non-toxic, and is so readily metabolizable if it enters the blood. The major problem with its use, however, is that it is readily taken up into the blood from the dialysate. Although, as noted above, any substance will eventually find its way into the circulation, glucose crosses the peritoneum so rapidly that the osmotic gradient is broken down within 2-3 hours of infusion. This may even cause a reversal of the direction of ultrafiltration, causing the unwanted result of water being reabsorbed from the dialysate toward the end of the time allowed for exchange. Further, the amount of glucose which is taken in may represent a large proportion of the patient's energy intake, possibly being as high as 12-35%; while this does not significantly affect a non-diabetic patient, it can be a severe metabolic burden to a patient whose glucose tolerance is already impaired. This added burden may be implicated in the hyperglycemia and obesity, observed in a number of CAPD patients. Diabetic patients suffer from the further inconvenience and risk of having to add insulin to the peritoneal dialysate, in order to reduce the risks of hypoglycemina resulting from the added glucose load.
Use of glucose also presents problems in the preparation of the dialysate. Sterilization of the dialysate is typically accomplished by heating which, at physiological pH, will cause glucose to caramelize. To compensate for this, the pH of the dialysate is usually adjusted to within the pH range of 5.0-5.5. This low pH, so far below that which is normal for the body, may be responsible for the pain experienced by some patients on inflow, and could also cause sclerosis of the peritoneal membrane, which will in turn cause a decrease in solute clearance (Schmidt, et al., Arch. Int. Med., 141: 1265-1266, 1980).
These disadvantages make the finding of a suitable alternative to glucose as an osmotic agent highly desirable. A number of substances have been proposed to meet the criteria of being biologically inert, not readily crossing the peritoneal membrane, being non-toxic and exerting adequate osmotic pressure a flow concentrations. To date, none of the suggested materials has proven to be an adequate substitute for glucose. For example, the use of dextrans (Gjessing, Acta Med. Scan., 185: 237-239, 1960) or polyanions (U.S. Pat. No. 4,339,433) has been proposed because of their high molecular weight, which should minimize their diffusion across the peritoneum into the blood. However, the role of the lymphatic system in the process of solute transport apparently limits the advantages of the high molecular weight per se (Allen, et al., Amer. J. Physiol., 119: 776-782, 1937). Also, with respect to the polyanions, it is unclear as to what the toxic effects of these would be, since most are non-metabolizable. Similar problems with metabolism are observed with compounds such as sorbitol, xylitol and glucose polymers. Sorbitol which is very slowly metabolized has been associated with instances of hyperosmolar coma and death (Raja, et al., Ann. Int. Med., 73: 993-994, 1970), and is no longer used. Both xylitol and glucose polymers also have a tendency to accumulate in the blood, and may be associated with unpleasant side effects (Bazyato, et al., Trans Amer. Soc. Artif. Interm. Organs, 28: 280-286, 1982). Fructose, which is comparable to glucose in its osmotic capacity, also exhibits many of the same disadvantages; because of its higher cost, it has not achieved widespread use.
More promising is the proposed use of amino acids to replace glucose. Amino acids are well-tolerated, with no known adverse side effects (Oren, et al., Perit. Dial. Bull, 3: 66-72). Because of their lower molecular weight, they exert a higher osmotic effect, on a mass basis, than glucose. This also probably results, however, in a more rapid uptake into the blood, causing a rapid loss of osmotic gradient. Although, unlike glucose, amino acid uptake may be beneficial, in that it may compensate for the protein loss observed in many CAPD patients, there is a considerable disadvantage in the almost prohibitive costs of amino acid solutions when compared with glucose. Furthermore, the rapid uptake of amino acids results in a considerable nitrogen burden, with a significant increase in blood urea nitrogen levels. Thus, it appears that even amino acids do not provide the appropriate substitutes.
The present invention, however, now provides improvement in the method for peritoneal dialysis which employs an osmotic agent which is not only a safe and beneficial alternative to glucose, but which also is economically feasible. It has now been unexpectedly discovered that a mixture of relatively low molecular weight oligopeptides (300-2000 daltons) derived from the enzymatic hydrolysis of a high quality protein, such as whey protein, may be used as an effective osmotic agent in a peritoneal dialysis solution; in comparison with an amino acid solution, the somewhat higher molecular weight of the peptides prevents the rapid uptake into the blood, allowing a more effective maintenance of the osmotic gradient as well as preventing the unwanted increase of nitrogen in the blood. The peptide mixture, which is ultimately, although very slowly, absorbed into the serum further provides a valuable dietary supplement, being derived from high-quality protein. Finally, the present peptide mixture provides an inexpensive and easily obtainable source of osmotic agent. Other peptide mixtures, used for medicinal purposes, have been previously described. For example, U.S. Pat. No. 4,427,658 describes a protein hydrolysate derived from enzymatic hydrolysis of whey protein. In that case, nearly total enzymatic hydrolysis was claimed to be performed, with no separation of larger from smaller peptides. Therefore, the resulting product apparently contains peptides of much larger sizes, possibly up to 5000 daltons or more, in the final mixture. These may pose antigenic and/or allergic risks since pinocytotic uptake from the peritoneum to the blood is known. This is significantly different from the carefully separated, relatively low molecular weight mixtures of the present invention.
The present invention relates to a composition useful in peritoneal dialysis which comprises an osmotically effective amount of a mixture of peptides, the mixture substantially consisting of peptides having a molecular weight of between 300-2000 daltons, and equivalent weight between 150-1500, in combination with an electrolytically osmotically-balanced peritoneal dialysis solution.
It also relates to a method of peritoneal dialysis which comprises administering to a patient in need of dialysis a therapeutically effective amount of a peritoneal dialysate comprising an osmotically effective amount of the low molecular weight peptides as noted above.
It further relates to a peritoneal dialysate which comprises as an osmotically active agent the above-mentioned mixture of small peptides.
The present invention also provides a method for the isolation of low molecular weight solutes which comprises contacting the aqueous solution with one side of a dialysis membrane capable of allowing the transport of the solutes, simultaneously contacting the opposite side of the membrane with substantially pure water derived from a reverse osmosis unit fed from a reservoir, the water having a sufficient solute concentration to allow transport of the solutes across the membrane into the water, directing the water and transported solutes to the reservoir, and accumulating transported solutes in the reservoir by solute retention of reverse osmosis membrane.
As indicated earlier, the present invention also provides a novel process for the enzymatic hydrolysis of proteins and oligosaccharides.
FIG. 1 shows a diagrammatic representation of the combined dialysis-reverse osmosis scheme of isolation.
FIG. 2 shows the pattern of elution of the peptide mixture prepared in Example 1B.
FIG. 3 shows the average amount of peptides, expressed as amine end group, remaining in the peritoneum over a 60-minute period.
FIG. 4 shows the average amount of glucose remaining in the peritoneum over a 60 minute period.
FIGS. 5A and 5B show the decrease in both supernatant and sedimentary carbohydrate in the membrane reactor vessel.
FIG. 6 shows the molecular weight distribution of the oligosaccharides formed by enzymatic cleavage and transferred into the RO accumulator circuit.
The present pharmaceutical compositions contain as the active osmotic agent, peptide fractions of differing molecular weight distributions, each peptide having an upper molecular weight cut-off of 2000 daltons. Generally speaking, the peptides' amino acid compositions are not particularly important, and, of course, will vary according to the source protein from which the mixture is derived. The most important feature is the selection of a low molecular weight population, which must be large enough to prevent rapid transport across the peritoneal membrane, and yet small enough to maintain the required osmotic gradient, as explained above. It has been determined that the most effective size range of the included peptides is about 300-2000 daltons; the equivalent weight should be between about 150-1500, with the preferred average equivalent weight being between about 250-750.
The peptide mixtures may be readily prepared by hydrolysis of larger proteins. Protein hydrolysis may be accomplished by a number of known methods. For example, a common hydrolysis technique is boiling the protein in the presence of strong mineral acids or alkalis. This has the unfortunate effect, however, of potentially destroying or at least altering a number of the liberated amino acids. It also is difficult to control the product which is produced; acid hydrolysis will not necessarily break the protein in the same position in every case and thus results in an unpredictable product. The reaction is also quite rapid, and unless carefully monitored, will result in collection of individual amino acids rather than the desired mixture of small peptides. Thus, acid hydrolysis is not deemed suitable for the present purpose. A second possibility for hydrolytic tools are a number of chemical reagents, such as hydroxyamine or 2-nitro-5-thiocyano benzoate, each of which will cleave a protein only at specific parts in the chain. The preferred choice is the use of enzyme hydrolysis to yield the desired peptide mixtures. Enzyme hydrolysis has the important advantage of being relatively easy to control, so that complete hydrolysis does not occur, and the product is of the desired molecular weight composition.
There is a broad selection of enzymes from which a suitable hydrolytic agent may be chosen. Some of the possible choices are, among others, trypsin, chymotrypsin, papain, pepsin, or certain microbial proteases. A mixture of proteolytic enzymes, such as pancreatin (chymotrypsin and trypsin), may also be used. Each of these generally cleave protein at a specific site; for example, trypsin will cleave a protein only at the carboxyl side of lysine and arginine residues. Chymotrypsin will preferentially attack at the carboxyl side of an aromatic amino acid. Pepsin prefers to cleave hydrophobic amino acids. The various specificities of other proteolytic enzymes is well known and readily available to the experienced chemist. Because of this specificity, the end-product peptide mixture will differ depending, at least in part, on which enzyme is used for hydrolysis. However, as is demonstrated below, the actual composition of the peptide mixture is of little or no importance, provided the proper osmolality is obtained, and the peptides are within the desired size range. It will be readily apparent to one skilled in the art which types of enzymes are useful for the present purpose.
Another variable which affects the type of product produced is, of course, the type of protein which is hydrolyzed. Although virtually any type of dietary protein is a suitable substrate, it is preferred that the protein used is a high quality protein. By the term high quality protein, as used in the present specification and claims, is meant a protein which contains a high proportion, generally 30 at least 50%, and preferably in the range of 60% to 70%, of the essential amino acids, i.e., lysine, leucine, isoleucine, methionine, phenylalanine, threonine, tryptophan, valine and histidine. Generally speaking, animal protein tends to be of a higher quality in this sense than vegetable protein; particularly good sources of high quality protein are collagen, certain bovine milk proteins, such as whey, and egg protein, particularly ovalbumin, although any protein which supplies the appropriate proportions of amino acids is useful. However, certain types of protein, such as casein, which contain a high percentage of phosphorus, are not appropriate substrates because of the necessity of limiting phosphorus intake in uremia. The reason for a preference for high grade protein is that, although the peptides do not, as do amino acids, readily diffuse across the peritoneal membrane, some diffusion is inevitable. Since at least some of the peptides in the mixture will eventually pass into the bloodstream it is desirable to insure that what does enter is of nutritional value. The dialysate thus serves also, to some extent, as a parenteral feeding supplement, should diffusion across the membrane occur.
The most preferred protein substrate for peptide production is milk whey protein. Whey protein is the material which remains in solution following the acidification of milk, i.e., after the precipitation of the phosphoprotein casein. Whey protein is made up primarily of β-lactoglobulin, α-lactalbumin, immunoglobulin and bovine serum albumin with over 60% being composed of the β-lactoglobulin and α-lactalbumin fractions. The amino acid composition of these two proteins is well known, as shown in Table 1. Whey protein has the advantages of being both easily obtainable and relatively inexpensive to produce.
TABLE 1______________________________________AMINO ACID COMPOSITION OF β-LACTOGLOBULINAND A α-LACTALBUMINβ-LACTOGLOBULIN α-LACTALBUMIN______________________________________9 Asp(D) 134 Asn(N) 83 Asx(B) --8 Thr(T) 77 Ser(S) 79 Glu(E) 89 Gln(Q) 57 Glx(Z) --8 Pro(P) 23 Gly(G) 614 Ala(A) 35 Cys(C) 810 Val(V) 64 Met(M) 110 Ile(I) 822 Leu(L) 134 Tyr(Y) 44 Phe(F) 42 Try(W) 415 Lys(K) 122 His(H) 33 Arg(R) 1______________________________________
The individual whey proteins are readily isolatable by virtue of their fractional solubility in ammonium sulfate solution. A number of schemes exist for separation of the protein from various substances by its solubility in 264 g/l of ammonium sulfate (see, for example, Armstrong, et al., Biochem. Biophys. Acta, 147: 60-72, 1967; Aschaffenberg, et al., Biochem. J., 65: 273-277, 1957; Cervone, et al., Biochem. Biophys. Acta, 295: 555-563, 1973). Alternately, it is also possible to obtain the individual whey proteins commercially (Sigma); or as mixed protein concentrates (Express Foods).
It will be immediately clear to the skilled chemist as aforesaid, that the actual peptide composition will vary according to the source of the protein and the enzyme used for hydrolysis. The enzyme is controlling because, as noted above, each enzyme attacks the protein at a specific amino acid or acids. Thus, the use of, for example, trypsin, will produce the same group of small peptides with each use, provided the substrate is the same. Therefore, given a controlled set of reaction conditions, it will always be possible to produce a predictable peptide mixture using the same pure enzyme and the same starting protein. It is true that most commercial enzymes may be contaminated with small amounts of other proteases. These contaminants may be responsible for the production of considerable amounts of free amino acids, if the peptides are allowed to remain in contact with the enzyme. Removal of peptides in the desired size from the reactor as they are produced avoids the problem of production of unwanted amino acids to a large extent. It will be readily understood, in fact, that the actual composition of the peptide mixture, at least with respect to what peptides are present, is to a large extent irrelevant. The critical factor is ensuring that the size of the peptides produced is maintained within the prescribed 300-2000 dalton limit.
As noted above it is important to monitor the hydrolytic process as it proceeds, in order to ensure that the hydrolysis yields the appropriate molecular weight peptide compositions. This is easily done because of the relative slowness at which the enzymatic process proceeds, but to insure further that significant amounts of amino acids do not become part of the mixture, the reaction may be run at a temperature and/or pH which is other than optimum for the enzyme being used, so that the rate of enzyme cleavage is kept very low. The conditions required to produce the desired mixture will necessarily be varied depending on the enzyme employed. Since enzymatic hydrolysis of protein is such a well-known procedure, the conditions required for optimum proteolysis using any number of different enzymes is readily available in the literature (see, for example, U.S. Pat. Nos. 4,427,658 and 4,145,445 for just a few of the known procedures). It is within the ability of the average chemist, without undue experimentation, to select the procedure which is best suited to the substrate and enzyme being used given the available information.
Although the present invention may, as noted, employ any proteolytic enzyme, or combination of enzymes, a particularly preferred enzyme is pancreatin, or alternately, its component enzymes, chymotrypsin and trypsin. In order to further reduce the problem of obtaining excessive amounts of amino acids because of the potentially contaminating proteases, the ratio of enzymes to substrate should be kept fairly low, within the range of 0.5% to a maximum of about 5.0%. After the hydrolysis procedure is completed, and the desired peptide combination is obtained, the peptides may be purified and separated from the reaction mixture by a number of different methods. To a large extent, the final molecular weight range will also be dependent on the method of separation employed, as noted below.
The preferred products of the present invention are therapeutic compositions comprising a mixture of peptides produced by enzymatic hydrolysis of a high quality protein, the mixture having the following characteristics:
a) the mixture consists substantially of peptides having molecular weights of between 300 and 2000 daltons;
b) the mixture contains no more than 5 mole percent of free amino acid;
c) the mixture contains at least 50% essential amino acids in peptide form;
d) the mixture is osmotically effective when added in sufficient amount to a peritoneal dialysate solution; and
e) the mixture has a component equivalent weight of between about 150 to 1500.
Particularly preferred compositions are those in which the high quality protein is whey protein, which is hydrolyzed by a combination of trypsin and chymotrypsin, and the final mixture has an essential amino acid content of about 60-70%. These compositions may be used therapeutically as the osmotic agents in peritoneal dialysis solutions, as noted above, but because of their high levels of essential amino acids, may also be employed as part of a parenteral feeding supplement.
As the foregoing discussion makes clear, the characteristic of the final product which is most important is that the peptides contained in the solution be within a very specific molecular weight range, i.e., between about 300 to about 2000 daltons. The equivalent weight of the peptide molecules, which is the expression of the molecules' molecular weight relative to the charge on the molecule, is preferably in the range of 150 to 1500. The charge on the molecules contributes to the overall osmotic coefficient of the mixture and solution. Molecules of greater molecular weight than 2000 daltons create very little osmotically induced ultrafiltration, and very small molecules leak too quickly into the circulation. It is thus important that it be possible to control the hydrolytic reaction and the resultant product in some manner which will assure that the required molecular weight range be obtained.
A number of different methods exist in the art for isolating and/or purifying the peptide components of a solution. For example, trichloroacetic acid (TCA) may be used to precipitate whatever remaining protein and enzyme there is in the reaction solution. Alternately, a water-miscible protein precipitating solvent, such as acetonitrile (ACN) protein precipitates at about 35-45% ACN with the peptides remaining in solution. Further, one may use the volume exclusion method, adding polyethylene oxide to cause a phase separation. However, none of these methods can assure that the exact product desired, i.e., a peptide mixture of specific molecular weight composition, will be obtained.
Ultrafiltration is a technique which is most frequently employed when a final product of specific molecular weight is desired. However, ultrafiltration also has a severe disadvantage associated with it, in that reliable separation cannot be obtained unless there is at least about a ten-fold difference in molecular weight of the components to be separated. In fact, when experimentally employed in connection with resolution of the present product, it was routinely found that molecules of molecular weight much higher than 2000 daltons would appear in the final solution, regardless of the chosen 2000 molecular weight cut-off of the ultrafiltration filter (see Example 2). Quite simply, then, there is not currently available any reliable method for directly isolating low molecular weight products from a parent mixture which is heterogeneous in the molecular sizes of its components.
In connection with the preparation of the present osmotic agents, however, a system for the isolation of low molecular weight solutes from a heterodisperse molecular weight mixture has been developed. The present method, which is based on the simple but unexpected combination of dialysis and reverse osmosis, has proven to be particularly amenable to the peptide separation required for the present product. However, its use is not limited to peptides; it may, in fact, be used for separation of virtually any type of low molecular weight solutes as, for example, starch or glucose as indicated hereinbefore. By "low molecular weight", as used in the present specification and claims, is meant molecules of about 5000 daltons or less in size.
In general terms, the process, diagrammatically represented in FIG. 1, proceeds as follows: the aqueous solution containing the solutes to be isolated is perfused through a dialyzer unit and is returned to the source reservoir ("reactor" of FIG. 1). The dialyzer membrane is washed on the opposite side from the aqueous solution with a stream of fresh water provided by a reverse osmosis unit. The reverse osmosis unit produces, under pressure, a supply of substantially pure water, providing a sufficient concentration gradient to allow the dialysis of the relatively concentrated solutes across the membrane and into the stream. Since species with a molecular weight greater than 2000 daltons do not generally dialyze at a significant rate across a dialysis membrane, these larger species will remain in solution and be returned to the source reservoir, while low molecular weight (less than 2000 daltons) product will pass into the fresh water stream and flow into the reverse osmosis reservoir. When the fluid from the reverse osmosis reservoir is pressurized, the reverse osmosis element permeates only pure water which is, in turn, contacted with the dialyzer membrane where it will again accumulate the dialyzable, low molecular weight species and transport them to the reverse osmosis reservoir where they are concentrated. The process may be continued until such a time as the back. osmotic pressure in the reverse osmosis reservoir significantly impedes the production of fresh water, or until the source material is used up. The concentrated products so produced may then be further isolated by known methods, or used as is, depending on the requirements.
The principles behind both the dialysis process and the reverse osmosis process are well known and need not be discussed in great detail here. Reverse osmosis is routinely used for purification of water (see, U.S. Pat. No. 3,774,763) and can be characterized as a process in which high pressure on a concentrated solution allows passage, through a semipermeable membrane, of the solvent from the concentrated solution to a more dilute fluid (e.g., water or air). This procedure simultaneously purifies the solvent and isolates the solutes contained therein. Dialysis may be defined as a passive process in which the result is the transfer of solute molecules from a liquid having high solute concentration to a liquid having low solute concentration, via transport of the solutes across a membrane separating the two liquids. The use of dialysis alone is to a large extent presently limited to the separation of very small molecules from very large molecules, as in the case of hemodialysis.
Various membrane separation methods have been previously combined to achieve different ends. For example, U.S. Pat. No. 3,472,765 applies a combination of reverse osmosis and ultrafiltration for the separation of microorganisms in a biological reaction system from their carrier liquid or their desirable metabolic products. This method, to a large extent, relies upon the presumed molecular weight cut-off of the ultrafiltration membranes. Similarly, U.S. Pat. No. 4,000,065 combines reverse osmosis and ultrafiltration to purify aqueous solutions containing low levels of organic contaminants which may have molecular weights of less than 10,000. This method depends a great deal on the limited solubility ranges of the contained contaminants and also relies heavily on ultrafiltration to produce the desired result. Each of these processes claims to be able to separate out small molecular weight substances from aqueous solutions; however, neither describes a separation procedure in which a product containing a narrow range of low molecular weight solutes can be separated from other solutes which are very close in molecular weight. The further unreliability of the ultrafiltration membrane cut-off points has been previously discussed. Thus, neither of these procedures would appear to be suitable for producing the present product. U.S. Pat. No. 3,774,763 describes a method of water purification using reverse osmosis, said purified water being then possibly used for a hemodialysis unit. However, the reverse osmosis procedure is complex, requiring a number of additional elements such as deionizers, and further, once the water is purified, there is no continued interaction with a dialysis unit.
The novel process described herein, however, does not require that the solutes be of low solubility in the aqueous solution, nor does it involve the disadvantages associated with the ultrafiltration procedures. Instead, the present process utilizes the inherent limitations of the dialysis procedure to an advantage, to separate out from a heterogeneous mixture of compounds which may be very close in molecular weight, molecules of 2000 daltons or less, and augments the separation with use of a reverse osmosis process to both provide a continual source of pure water for the dialysis procedure and to continuously accumulate the dialyzable product in concentrated form in the reverse osmosis reservoir. The final product yielded is one which meets the requirements of a solution containing a specified range of low molecular weight peptides. The process is simple, requiring essentially only a two-step procedure which can be repeated continually until the concentration of solute in the reverse osmosis reservoir is such as to prohibit the production of sufficient pressure to continue the reverse osmosis step. The process has the further advantage of not necessarily requiring any further separation or purification procedures upon its completion.
The elements to be used in the present procedure may be any dialysis and reverse osmosis apparatus known in the art. Each unit may also be operated in accordance with known procedures with respect to temperature, pressures, feed rates, and so on. The operating pressure in the dialyzer should generally be no more than 500 mm, preferably less. The operating pressure for the high pressure portion of the reverse osmosis unit must be in excess of the osmotic pressure of the solution in the reverse osmosis reservoir and must be sufficiently elevated so as to produce a fresh water permeate stream against which the solute containing stream from the reactor is dialyzed. The typical operating pressure of the reverse osmosis unit in production of the present product is between 150 and 300 psi, and preferably between 200 and 250 psi; however, it will be apparent to the experienced worker that the pressure may be varied in accordance with product to be isolated, if it is other than small peptides. Suitable connections for the two units are any type of low pressure tubing composed of an inert, non-toxic material such as plastic or silicon. The exception is the connection between the pump and circulating line of the reverse osmosis which requires high pressure plastic lines.
A wide variety of membranes suitable for use in dialysis and reverse osmosis processes are known in the art (see, for example, Kirk-Othmer Ed., Encyclopedia of Chemical Technology, 3rd ed., Vol. 7, "Dialysis", 1979 and Vol. 20, "Reverse Osmosis", 1982). Virtually any of the known membranes with dialytic properties may be employed in dialysis; these may be made of, for example, cellulose, cellulose acetate, ethylene vinyl alcohol, polyacrylonitrile or polymethylmethyacrylate. In the preparation of peptide mixtures, cellulose membranes are preferably used, particularly hollow fiber membranes, and the associated dialyzers. These membranes are available in a range of permeabilities, most of which are suitable for the present procedure. The choice of which membrane to use is made based upon the average size of the desired molecules required. For example, a membrane of "normal" permeability, such as is contained in the HF-140 dialyzer (Cobe Laboratories), is generally impermeable to anything with a molecular weight of over 1500; however, if a slightly larger molecular weight size is desired, certain types of fibers, such as D2-HDF (Enka), are still permeable up to a molecular weight of 3000-4000 daltons. The permeabilities of the commercially available membranes are known, and it is within the skill of the experienced worker to determine which of the membranes is best suited to his purpose, depending on the size and type of molecule to be isolated. With respect to reverse osmosis membranes, any membrane with a high level of retention of electrolytes is suitable. Thin film composite membranes, in a spiral wound configuration, have proven particularly useful in the present process. However, hollow fiber membranes may also be used effectively in the present procedure.
In addition to the choice of membrane, if the source of the solute containing solution is a biological reactor, the average size of the final product mixture may be controlled by limiting the rate of enzymatic cleavage, or the rate of the microbial metabolic process producing the product. For example, when a process of enzymatic cleavage is involved, the rate of the reaction may be kept down by maintaining a low level of enzyme relative to substrate. The rate may also be altered by running the reaction at a temperature or pH which is less than optimum for the enzyme or micororganism bring utilized. Such modifications are well within the ability of one skilled in the art. It will also be apparent to the skilled worker that modifications of the reaction process may be combined with the choice of membrane to most efficiently and accurately produce the desired product. In other words, assuming that the molecular weight of the desired product is known, it is a relatively simple matter to determine, by routine, brief runs through the present procedure, which combination gives the most satisfactory results for the product of interest.
As noted above, the present method is particularly well suited to the preparation of mixtures of low molecular weight peptide mixtures and may be used commercially in connection with hydrolysis of other types of proteins, such as soybean, egg or milk proteins. It may also be readily applied to use with any other heterogeneous, non-peptide mixture from which it is necessary or desirable to isolate low molecular weight species as, for example, it may be applied to the enzyme hydrolysis of polysaccharides such as starch. For example, in many biologically based processes, the desired low molecular weight products are frequently produced in the presence of a number of hormonal and protein contaminants, from which separation of the product presents a serious problem. This can be achieved, for example, in the processing of corn starch hydrolysate to isolate low molecular weight maltodextrins. When corn starch is hydrolyzed enzymatically, the high molecular weight starch is cleaved randomly to produce progressively smaller dextrins. As the process continues, the enzyme activity can be stopped at certain points, to obtain a polydisperse mixture of polyglucoses (maltodextrins) that are used in the food processing industry as baking additives or sweeteners. If the enzyme activity is allowed to continue, the end product is glucose. The use of the present process allows the continuous isolation of maltodextrins of low molecular weight from an enzyme reactor, a procedure which has not been previously possible. Similarly, certain fractions of heparin, an anticoagulant, possess antithrombotic activity without the anticoagulant activity. Although quite valuable, such fractions are difficult to separate from the larger molecule because of their size (about 3000 daltons). The present method provides a means by which the desirable fragment may be readily separated from a heterogeneous mixture of compounds.
With respect to the present product, the purified peptide mixture can be combined with any osmotically balanced aqueous solution appropriate for use as a peritoneal dialysate. Useful dialysate must contain, in order to be effectively osmotically balanced for the present purpose, a concentration of electrolytes sufficient to cause diffusion of water and undesirable metabolic products across the peritoneum. There is no "standard" dialysis solution, since the requirements may vary from one individual to the next. A usual solution would contain, for example, specific quantities of sodium, chloride, lactate, magnesium and calcium. The contents of a typical dialysate solution is presented in Table 2, without the amount of osmotic agent specified; in a glucose solution, glucose monohydrate would typically be added in an amount from about 1.5-4.25%. It will be understood that this represents just one example of a possible solution and that variations in the pattern will be apparent to the skilled artisan. The proportion of the peptide mixture in the dialysate can vary, but normally comprises in the range of about 1 to 15% by weight of dialysate solution. In any event, the amount of peptide used should be sufficient to confer, with supporting electrolytes an osmolality of about 300 to about 500 mOsm/l (280 mOssm/l being normal serum osmolality, and the electrolytes themselves usually contributing an osmolality of about 260 mOsm/l). Administration of the dialysate is achieved in the manner which is usually followed for peritoneal dialysis. Exemplary modes of peritoneal dialysis are described in Peritoneal Dialvsis, K. Nolph, ed., Martinus Nighoff Publishers, 1981. The particular treatment regime required by any individual patient is readily determinable by the patient's physician.
TABLE 2______________________________________Components of a typical peritoneal lavage solution (in meq/l)______________________________________ Na 132.0 Ca 3.5 Mg 0.5 Cl 96.0 lactate anion 40.0______________________________________
The present invention may be more clearly understood by reference to the following non-limiting examples:
The following Example shows a method of preparing the peptide mixture.
A. 150 grams of SAVOR PRO (Express Foods, Inc., Louisville, Ky.), a 75% whey protein concentrate was dissolved in 3 l of distilled water and dialyzed to remove residual lactose and salts. This treatment served to decrease the conductivity of the solution from 700 to 26 micromhos.
The pH of the solution was adjusted to 8.0, and the solution brought to 40� C. The solution was then transferred to an enzyme reactor and circulated through the dialyzer (as diagrammed in FIG. 1). The dialysate side of the dialyzer was supplied pure water from the output of a reverse osmosis (R.O.) unit, utilizing a thin film composite, spiral wound element (Film-Tec). The dialysate was returned to the product reservoir vessel from which the R.O. unit was supplied. The circulation rate through the R.O. from the product reservoir was ten times as great as its pure water production rate, in order to maximize the latter; the unit was operated at a pressure of about 200-250 psi. With both circuits in operation, 1.5 gms. each of Sigma trypsin and chymotrypsin were added to the enzyme reactor. As enzyme cleavage proceeded, the pH of the reaction was maintained by addition of NaOH. As peptides smaller than 2000 daltons formed in the reactor, they were dialyzed through the dialysis membranes (HF-140 hemodialyzer, Cobe Laboratories; Lakewood, Colo.) into the product reservoir, where they remained, since the R.O. unit was retentive of even small electrolytes such as NaCl. The reactor was allowed to run for two hours, with samples taken every 10 minutes.. The product reservoir continued to increase in peptide concentration and osmolality. The final product obtained from the product reservoir was 46.5 grams (31% yield) with an average equivalent weight of 408. Analysis of the product on a P2 gel exclusion column using 30% acetic acid as eluent showed essentially no peptide in the void volume of the resin, indicating all peptides are less than 1800 daltons.
B. The reaction of A was repeated exactly, but using a more permeable dialyzer (Fresenius D-6 dialyzer, Bad Homburg, FGR; D2-HDF fibers, Enka AG). This allowed extraction of a higher percentage of larger peptide fragments than was possible in A. The elution was conducted as in A, and the results are presented in FIG. 2. The equivalent weight of the preparation was 483.
The following Example shows a procedure in which the peptide mixture is purified by ultrafiltration rather than by dialysis and reverse osmosis.
a. A 3% solution of whey protein concentrate (85% protein) was brought to pH=8. Trypsin from Sigma Chem. Co. (#T2395) was added at a ratio of 1:100 on protein after the solution had been brought to 50� C. The osmolality of the starting protein solution (by freezing point depression) was 47 mOsm/l. At the end of 30 mins reaction time the solution was ultrafiltered through a cellulose membrane (limiting cut-off=5000 daltons). When the pH was brought back to the starting value, the osmolality was 112 mOsm/l. Gel exclusion chromatography of the ultrafiltrate indicated that despite the low cut-off designated by the manufacturer a small portion of the starting α-lactalabumin (M.Wt.=14,200 permeated the ultrafilter, in addition to a wide molecular weight range of peptide product.
b. A 5% whey protein solids solution in deionized water was found to have an osmolality of 18 mOsm/l. The solution was dialyzed to reduce electrolyte content and then showed an osmolality of 13 mOsm/l. An ultrafiltrate (through a nominal 20,000 dalton cut-off membrane) of this solution had an osmolality of only 3 mOsm/l while the retentate increased to 19 mOsm/l, indicating that there was very little low molecular weight solute (i.e., lactose, salts, etc.) contributing to the osmolality of the starting whey solution. When the UP retentate was reacted with trypsin at pH=8, the resulting hydrolysate had an osmolality of 59 mOsm/l. The hydrolysate was ultrafiltered through the same type of membrane as above; the filtrate osmolality was found to be 21 mOsm/l. The ultrafiltration experiments showed that the protein digestion was not complete and that the product obtained by ultrafiltration of the hydrolysate contained significant quantities of large peptide fragments. GPC analyses confirmed that the ultrafiltrate contained not only large peptides, but also some of the starting α-lactalbumin.
The following represent the electrolyte components of the peritoneal dialysate solution used herein (gm/l):
______________________________________ NaCl 5.38 CaCl2 0.257 MgCl2 0.0508 Na lactate 4.48______________________________________
The above components provide an osmolality of about 260 mOsm/l. To the above mixture is added 61.1 grams of the peptide mixture per water which provides an osmolality of approximately 126 mOsm/l, giving the solution as a whole an osmolality approximately equivalent to that of a 2.5% glucose solution.
Utilizing the peptide mixture of Example 1B in a solution as described in Example 3, experiments were carried out to compare the effectiveness of the low molecular weight peptides as osmotic agents relative to the effectiveness of glucose.
The trials employed four rabbits, tested in an A-B sequence, so that each rabbit served as its own control. Each animal was dialyzed with either 2.5% glucose, or alternately, with sufficient peptide to bring the osmolality of the solution to approximately that of the 2.5% glucose solution (385 mOsm/l). Each animal's peritoneal cavity was loaded to approximately 50 ml of dialysate per kg of body weight. The instilled volumes and gain in fluid (due to osmotic ultrafiltration) at the end of 60 minutes are listed in the following table:
______________________________________Glucose Solution Peptide Solution Vol. ml. Vol. ml. Vol. ml. Vol. ml.Animal t = 0 t = 60 Gain % t = 0 t = 60 Gain %______________________________________#1 190.0 192.0 .01 204.4 232.0 13.5#2 142.3 161.0 12.9 139.0 164.0 18.0#3 175.9 189.0 7.4 183.2 200.0 9.2#4 168.8 177.0 5.5 157.3 172.0 9.3Avg. 6.5 12.5______________________________________
At the same osmolality as glucose, the peptides show a nearly 100% increase in osmotic pumping activity at 60 minutes, apparently due to the lower rate of loss of peptide compared to glucose in the circulation. FIGS. 3 and 4 show plots of the average amine-end-group concentrations vs. time and the glucose vs. time in the peritoneum. These verify that only 20% of the peptide (measured by end groups) is lost, compared with nearly 35% of the glucose being lost. These results are even more significant in view of the fact that the glucose had not yet equilibrated to plasma levels at 60 minutes.
The following example shows the application of the described process to the enzymatic hydrolysis of polysaccharides.
A 2% dispersion of Amioca maize starch was prepared by mixing the starch into boiling water and stirring for 15 minutes. The solution was opalescent, indicating the presence of a hydrogel. This dispersion was pumped through the bore of a Baxter 1211L dialyzer at a rate of 200 ml/min, while dialysate (500 ml/min) perfused the outside of the fibers. The dialysate was produced by the R.O. module and high pressure pump as described in Example 1. A mixture of alpha and beta amylase in acetate buffer was added to yield a final concentration in the. starch dispersion of 0.0583 U/ml. Samples were taken from the enzyme reactor tank and the RO accumulator tank for analyses. The enzyme activity in the reactor samples was quenched by addition of 15N NaOH to inactivate the enzyme; supernatant aliquots were isolated from the hydrogel by spinning these samples at 20,000 rpm for 15 minutes. The accumulator samples were free of enzyme activity and required no inactivation. Both sets of samples were analyzed for carbohydrate content by the phenol sulfuric acid assay for reducing sugars and by high pressure liquid chromatography.
As described earlier, FIG. 5 shows the decrease in both supernatant and sedimentary carbohydrate membrane reactor vessel. Approximately 40% of the high molecular weight starch has been hydrolyzed and transferred out of the reactor system through the dialyzer.
FIG. 6 shows the molecular weight distribution of the oligosaccharides formed by enzymatic cleavage and transferred into the RO accumulator circuit. The oligosaccharides are free of enzymes, high molecular weight starch fractions, and any insoluble starch material.
|Cited Patent
|Filing date
|Publication date
|Jun 25, 1959
|Oct 30, 1962
|Borden Co
|Dermatological preparation
|Apr 5, 1976
|Mar 20, 1979
|Fuji Oil Company, Limited
|Modified protein compositions and preparation thereof
|Jan 9, 1981
|Jul 13, 1982
|Baxter Travenol Laboratories, Inc.
|Additives for peritoneal dialysis solutions
|Dec 9, 1981
|Jan 24, 1984
|Institut National De La Recherche Agronomique
|Total enzymatic hydrolysate from whey proteins and process of obtaining the same
|Sep 20, 1982
|Apr 17, 1984
|University Of Illinois Foundation
|Protein hydrolysis
|Oct 2, 1981
|Jul 31, 1984
|Institut National De La Sante Et De La Recherche Medicale
|Biologically active substances, their obtainment from human casein and compositions containing said substances
|May 15, 1981
|Mar 4, 1986
|Baxter Travenol Laboratories, Inc.
|Method for using dialysis solution containing glycerol
|Mar 27, 1986
|Oct 6, 1987
|Engenics, Inc.
|Production of lactic acid by continuous fermentation using an inexpensive raw material and a simplified method of lactic acid purification
|Jun 16, 1986
|Jan 31, 1989
|Niesen Lawrence J
|Ultrafiltration apparatus
|Nov 16, 1987
|Jul 11, 1989
|Albuglobe Aktiebolag
|Process for treating whey proteins, and product obtained
|Feb 6, 1989
|Mar 6, 1990
|Thomas Gilchrist
|Hydrolyzed sodium casein compositions for dialysis procedures
|Nov 18, 1988
|Aug 13, 1991
|Nestec S.A.
|Preparation of a hypoallergenic whey protein hydrolyzate and food
|Dec 18, 1986
|May 12, 1992
|Samuelsson Ernst Gunnar
|Peptide preparation, a process for producing it and use of the peptide preparation
|Jun 24, 1980
|Jan 7, 1981
|Institut National De La Recherche Agronomique (Inra)
|Total enzymatic hydrolysate of lactoserum proteins, production and applications
|Oct 2, 1981
|Apr 14, 1982
|Institut National De La Sante Et De La Recherche Medicale (Inserm)
|Biologically active compounds, their obtention from human casein and compositions containing them
|Apr 29, 1982
|Dec 1, 1982
|Miles Laboratories, Inc.
|Method for the preparation of a protein hydrolyzate from whey protein
|Title not available
|Title not available
|Apr 16, 1982
|Nov 25, 1982
|Travenol Lab Baxter
|Dialysis solution containing clycerol
|Jun 7, 1982
|Jan 20, 1983
|Baxter Travenol Lab
|Peritoneal dialysis solution containing carbohydrate polymers
|Aug 27, 1986
|Mar 12, 1987
|Research Corporation Limited
|Medicinal composition
|(1972) Worthington Enzyme Manual, 122 123.
|(1972) Worthington Enzyme Manual, 122-123.
|Barman (1969) Enzyme Handbook, Springer Verlag, New York, 618 621.
|Barman (1969) Enzyme Handbook, Springer-Verlag, New York, 618-621.
|Chemical Abstracts, No. 165635u, vol. 93, No. 17, p. 459, Oct. 27, 1980.
|Klein et al. (1986) Trans. Am. Soc. Artif. Intern. Organs, 32, 550 553.
|Klein et al. (1986) Trans. Am. Soc. Artif. Intern. Organs, 32, 550-553.
|Lehninger (1978) "Partial Hydrolysis of Polypeptide Chains", Biochemistry, Worth Publishers, Inc. New York, 106.
|Lehninger (1978) Partial Hydrolysis of Polypeptide Chains , Biochemistry, Worth Publishers, Inc. New York, 106.
|McGary, T.J. et al. (1981) Trans. Am. Soc. Artif. Intern. Organs 27: 314 318.
|McGary, T.J. et al. (1981) Trans. Am. Soc. Artif. Intern. Organs 27: 314-318.
|Nolph, K. et al. (1978) Trans. Am. Soc. Artif. Intern. Organs 24 : 162 168.
|Nolph, K. et al. (1978) Trans. Am. Soc. Artif. Intern. Organs 24: 162-168.
|Wood et al. (1974) "Primary Structure of Polypeptides", Biochemistry: A Problems Approach, W. A. Benjamin, Inc., Menlo Park, CA, 42, 46-48.
|Wood et al. (1974) Primary Structure of Polypeptides , Biochemistry: A Problems Approach, W. A. Benjamin, Inc., Menlo Park, CA, 42, 46 48.
|Citing Patent
|Filing date
|Publication date
|May 21, 1999
|Apr 10, 2001
|Nissho Corporation
|Peritoneal dialysis fluid
|Mar 3, 2000
|Jan 29, 2002
|Kansas University Medical Center
|Post-Amadori inhibitors of Advanced Glycation reactions
|Apr 6, 2000
|Aug 20, 2002
|Kansas University Medical Center Research Institute Inc.
|Dialysis solutions and methods
|May 8, 2000
|Oct 7, 2003
|Devisco Foods International, Inc.
|Treatment of hypertension in mammals with hydrolyzed whey proteins
|Oct 30, 2000
|Feb 14, 2006
|Davisco Foods International
|Enzymatic treatment of whey proteins for the production of antihypertensive peptides and the resulting products
|Jul 25, 2003
|May 30, 2006
|Baxter International Inc.
|Dialysis solutions with reduced levels of glucose degradation products
|Apr 14, 2004
|Apr 24, 2007
|Baxter International, Inc.
|Peritoneal dialysis solution containing modified icodextrins
|Jul 11, 2002
|Jan 23, 2003
|Kansas University Medical Center
|Dialysis solutions and methods
|Dec 20, 2002
|Jun 24, 2004
|Leo Martis
|Biocompatible dialysis fluids containing icodextrins
|Apr 14, 2004
|Sep 30, 2004
|Annamaria Naggi
|Peritoneal dialysis solution containing modified icodextrins
|Jul 25, 2003
|Jan 27, 2005
|Paul Zieske
|Dialysis solutions with reduced levels of glucose degradation products
|Oct 29, 2004
|Jul 7, 2005
|Landry Donald W.
|Hemodialysis solutions and uses thereof
|Oct 5, 2004
|Jul 7, 2005
|Ash Stephen R.
|Method for iron delivery to a patient by transfer from dialysate
|Feb 10, 2006
|Jun 15, 2006
|Leo Martis
|Biocompatible dialysis fluids containing icodextrins
|Jun 22, 2006
|Oct 12, 2006
|Bart Degreve
|Bicarbonate-based peritoneal dialysis solutions
|U.S. Classification
|514/15.4, 435/68.1, 426/41, 426/42
|International Classification
|Cooperative Classification
|European Classification
|Jul 10, 2001
|Certificate of correction
|Aug 28, 2002
|Maintenance fee reminder mailed
|Feb 10, 2003
|Lapse for failure to pay maintenance fees
|Apr 8, 2003
|Expired due to failure to pay maintenance fee
Effective date: 20030209


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The color pros at Pantone would approve of these must-have shades—and we couldn't agree more. Universally flattering on all skin tones, each hue is daring, but not so out-there that we can't wear it in the office or to dinner with Grandma.
Liked the color, but I already have one just like it. The best part is the size, how many times have used an entire bottle of polish? Never. They always dry out and get thick after a few months anyway, with this bottle you can try more shades because they're cheaper and smaller.4

subset: commoncrawl


text:
- EcuadorAgricultureFunding via Cooperativa San Jose
Jorge RenanEcuadorAgricultureFunding via Fundacion Alternativa
Abad AvelinoEcuadorAgricultureFunding via Fundacion Alternativa
Mauricio Michael
Update on Mauricio MichaelMauricio Michael, 21, is single with no children and lives with his parents in Ventanas in Los Ríos Province.
He is a member of the "Luchando por Una Misma Causa" (Striving for the Same Cause) communal bank which is located in Recinto La Primavera belonging to Ventanas Canton. This communal bank is involved in agricultural work related to short cycle corn and rice farming.
Mauricio Michael farms corn and beans. He will use the money to buy seed, supplies, fertilizer, urea and Ranger (insecticide). With the help of the loan he will be able to improve his crops. He'll make his purchases in Ventanas. His dream is to remodel his house and install an irrigation system for the crops.
The challenges he faces are the locust plague. In his free time he likes to chat online.
Es Integrante de la VRC Luchando por una misma Causa, se encuentra ubicada en el recinto la Primavera, perteneciente al Cantón Ventanas, esta ventanilla se dedica a labores Agrícolas de ciclo corto siembra de maíz, arroz.
Mauricio Michael se dedica a la Agricultura al siembra de maíz, fréjol. El dinero lo Utilizará para comprar semillas, insumos, abonos,urea, ranger. Con la ayuda del crédito podrá mejorar los cultivos. Las compras las realizará en la ciudad Ventanas. El sueño es remodelar la casa y poner un sistema de riego a los sembríos.
Los desafíos a los que se enfrenta son las plagas la langosta. En el tiempo libre le gusta chatear en el internet.
Previous Loan DetailsMauricio Michael, 21, is single living with his parents in Ventanas Canton in Los Ríos Province. The members of the "Luchando por Una Misma Causa" (Striving for the Same Cause) communal bank are located in Recinto La Primavera belonging to Ventanas Canton. This communal bank is involved in chor... More from Mauricio Michael's previous loan »
Additional Information
About Cooperativa San JoseThis loan is administered by Cooperativa San Jose, a 45,000-member credit union located high in the Andes Mountains of Ecuador's poorest province, Bolivar. They offer a unique loan called "Ventanillas Rurales" [Window to the Countryside], which uses a group guarantee but is an individual loan with a savings component, mostly to rural borrowers. Due to low savings rates and a history of macroeconomic instability, many traditional loans in Ecuador demand interest rates that are prohibitively high for some borrowers. There is also a high incidence of extortionist black-market lending in Ecuador. CSJ helps mitigate these problems by providing a less onerous and more appropriate option. Join CSJ's Lending Team!
Concurrent and Successive Loans
Our Field Partners often work with borrowers over a series of loans as the borrowers build credit, take out bigger loans, and expand their businesses. In order to make it easier for our Field Partners to post loans for borrowers who have been listed on Kiva before, we allow them to post successive and concurrent loans for their Kiva borrowers. This means that our Field Partners are able to post a borrower's second, third, etc., loan on Kiva without having to re-enter all of the borrower's information.
This borrower has been listed on Kiva before, so you'll see an updated loan description, as well as excerpts of the original descriptions from earlier loans. Most borrowers take out loans consecutively, meaning that they receive a second loan after having repaid the first. However, sometimes our Field Partners give out concurrent loans, allowing borrowers to take out one primary loan and a secondary "add-on" loan along with it. These "add-on" loans are typically smaller than the borrower's primary loan and serve a different purpose. Because Field Partners can now post loans as successive and concurrent loans, you will be able to track borrower progress over time and see the various ways a borrower is working with our Field Partners through funds from Kiva's lenders.
About Ecuador
51View loans »
US Dollars
Success!! The loan was 100% repaid
- Repayment Term
- 9 months (Additional Information)
- Repayment Schedule
- At end of term
- Pre-Disbursed:
- Nov 15, 2012
- Listed
- Nov 21, 2012
- Currency Exchange Loss:
- Ended:
- Jul 17, 2013


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Electron Energy Distribution Function
Annette Meiners | August 4, 2014
The electron energy distribution function (EEDF) plays an important role in plasma modeling. Various approaches can be used to describe the EEDF, such as Maxwellian, Druyvesteyn, or using a solution of the Boltzmann equation. Today, we will demonstrate the influence the EEDF has on a plasma model's results. Additionally, we present a way to compute the EEDF with the Boltzmann Equation, Two-Term Approximation interface.
Alexandra Foley | August 1, 2014
Wei Guo | July 30, 2014
We have all experienced the boredom and frustration of being stuck in a traffic jam. Very often, traffic congestion comes and goes for no obvious reason. Employing the analogy to gas dynamics, we can now simulate traffic flow using the equation-based modeling capabilities of COMSOL Multiphysics and gain a better understanding of why congestion happens.
Temesgen Kindo | July 28, 2014
In a previous blog entry, we discussed the join feature in COMSOL Multiphysics in the context of stationary problems. Here, we will address parametric, eigenfrequency, frequency domain, and time-dependent problems. Additionally, we will compare and contrast the built-in with and at operators versus solution joining.
Lexi Carver | July 24, 2014
Modular orthopedic devices, common in replacement joints, allow surgeons to tailor the size, material, and design of an implant directly to a patient's needs. This flexibility and customization is counterbalanced, however, by a need for the implant components to fit together correctly. With parts that are not ideally matched, micro-motions and stresses on mismatched surfaces can cause fretting fatigue and corrosion. Researchers at Continuum Blue Ltd. have assessed changes to femoral implant designs to quantify and prevent this damage.
Mark Fowler | July 22, 2014
Alexandra Foley | July 31, 2014
The Swiss steel company SMS Concast has been leveraging multiphysics simulation to optimize the steelmaking process of continuous casting. Through research conducted using COMSOL Multiphysics, the R&D team at SMS Concast was able to implement a new technique that allowed a steelmaking plant in Taiwan to reduce yearly CO2 emissions by about 40,000 tons.
Bridget Cunningham | July 29, 2014
Imagine a mode of air travel that is both fuel efficient and environmentally friendly. The mechanical modeling of torque transfer components in fully superconducting rotating machines have helped researchers draw new conclusions on how to optimize aircraft design and potentially achieve electric propulsion. A research team investigated the stress and heat distribution in these machines and presented their results at the COMSOL Conference 2013 in Boston.
Alexandra Foley | July 25, 2014
In the 2012 edition of Multiphysics Simulation, we featured an article about modeling spinal cord stimulation to determine the effect that scar tissue can have on electrical current distribution during the treatment of chronic pain. Recently, the full-length paper by Beth Israel Deaconess researchers Jeffrey Arle, Kris Carlson, Longzhi Mei, and Jay Shils was published in the journal Neuromodulation.
Mark Fowler | July 23, 2014
Bridget Cunningham | July 21, 2014
In chemistry, separation using differences in migration patterns plays an important role in understanding the properties of different chemical species. To help identify small chemical differences between molecules, researchers use a type of electrophoresis known as isoelectric focusing. With the use of an applied electric potential, this technique helps to define and separate molecules based on their varying isoelectric points. Let's take a closer look at this separation method.


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text: Webexclusive Multi-Colored Flip Flop String Lights Item #: 133700 $14.99 $12.97 Qty: Sorry, this item is currently unavailable online. Ship to Home Ship to Store (FREE) Are you looking for some unique décor for your next summer party? Look no further than these festive Multi-Colored Flip Flop String Lights! String of lights measures approximately 8 ft. in length Each light measures 1.5L x 3H in. Crafted of plastic A string of ten (10) miniature flip flop-shaped LED lights Features a green plug-in cord Care: Safe for indoor and covered outdoor use. This item is available at Kirklands.com only, not available in stores. Sorry, this item is currently unavailable online.


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Made In The USA!
The Penn Scale Heirloom Series - 1304B "Gourmet" Mechanical Kitchen Scale
Rugged accuracy & decorative flair make this scale a must have.
4 pound capacity x 1/4 ounce resolution
|"In A Nutshell"
|Main Color
|Blue, Copper, Green, Red, White or Black
|Tare Feature
|Yes, with counterweight
|Pan Size
6.5" x 10" x 2.5"
|Weighing Modes
Weighing Modes
|Mode: Pounds
|Capacity: 4 lb
|Resolution: 1/4 oz
Product Details
Perfect For Baking When ya weigh what you're putting into your recipes, you have a much better chance of your recipes coming out just right every time. Use this kitchen scale for mixing and portioning batches of dough, ingredients for recipes, candies, coffees and more! Perfect for use in a bakery, professional kitchen or even home sweet home for all your measuring needs.
Durable Cast Iron Construction There's nothing wimpy about this mechanical kitchen scale. Penn Scale designed the 1304B with an all cast iron construction and powder coated finish to prevent rusting. This mechanical balance also has case hardened steel pivots and bearings for extra durability.
Six Colors To Choose From This great looking baker's scale comes in six different colors, Blue, Red, Green, Copper, White & Black, each with a polished brass weighing beam and large, brass scoop.
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FDA Approved Coating Penn Scale made sure their baker's scales are safe for your foods and ingredients. This scale's durable coating is FDA approved safe for use with foods.
1 YEAR MANUFACTURER'S WARRANTY This mechanical scale comes with a one year warranty against manufacturing defects.
Customer Reviewswrite your review
I would say that this scale lives up to what I expected and I am a very nit picky person. It's beautiful, works perfectly and I'll probably be able to pass this on.Reviewed by: Jeff from South Louisiana on (7/27/2012)
Questions and Answersask a question
A: Hey there Christine,
No, unfortunately we do not. We do not deal in the sale of previously owned scales. Craigslist or eBay would be examples of marketplaces for the sale of your scale.
Take care,


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Fixed PriceDelivery by April 26, 2013
I am looking for a simple app which will allow users to see Nasdaq stocks on their mobile . I think it would be a feed which would allow users to view the stock price at realtime on the screen. There should be ability to add stock price. Integration with ads is required.
This should be a simple app . If you have done similar apps, Please send me the google play link
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text:
Emily Ratajkowski on why she defended Kim Kardashian's nude selfie
The model also called Piers Morgan 'attention seeking'
The model also called Piers Morgan 'attention seeking'
The journalist and TV presenter claimed Mr Trump would be 'more moderate' in the White House
Morgan criticised the actress for wearing an outfit where her bra was visible to an awards ceremony
The 69-year-old actress posted a photo of herself in her underwear and dedicated it to the outspoken talk show host
The talk show host and former newspaper editor posted a series of disparaging tweets about the 69-year-old actress
Lorraine has since addressed the incident, saying she sometimes forgets she's on TV when saying things
HIs comments were not well received
Morgan says he expects to be 'annoying' on the show
Mr Morgan was embroiled in a war of words with civil rights activist DeRay Mckesson
BBC show thrashes ITV's Splash, where viewing figures dived
England's biggest critic attempts to show Alastair Cook's boys how it's done - with minimal success
A comedy video where a man mimics the way a number of wild animals eat took the top slot with 88 million views
Twitter shares climbed to a near all-time high in New York trading yesterday as investors cheered a series of new products introduced by the social media giant.
DJ Jo Whiley has criticised Britain's Got Talent and The Voice - saying that contestants do not know what they are letting themselves in for.
Over on ITV, the Champions League final pulled in 3.5 million viewers
The Apprentice is back, but this time with a bit of a twist.
This could cause a rumble between two of TV's best friends - a survey has revealed women would rather bed Dec than Ant.


text:
May 28, 2016
The next time Meridian and Lauderdale County have a weather emergency, or any other kind of major emergency, both governments will apparently work closely together.
The two entities have agreed in principle to have a joint Emergency Operations Center at the old Bellsouth building on 14th Street in Meridian.
The building is owned by the county, but it has invited the city to use one half of it, free of charge, during the next emergency.
A wall will be placed in the middle of the building to give the two entities some privacy.
Click Here to access the online Public Inspection File
Viewers with disabilities can get assistance accessing this station's FCC Public Inspection File by contacting the station with the information listed below. Questions or concerns relating to the accessibility of the FCC's online public file system should be directed to the FCC at 888-225-5322, 888-835-5322 (TTY), or email@example.com.


text:
The Grammys, Briefly
If you skipped last night's Grammy Awards and want to catch up on the outfits, here's a red-carpet gallery from HuffPo and another from The Cut, where they're focusing on the "Biggest Violators of the Grammys' No-Nipple Rule." Meanwhile, CNN has a two-minute video montage of the show itself, and a full list of the winners can be found here. Carly Rae was robbed.
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Posted by Patrick Traylor on 04/18/2013 6:29pm PDT tags: photo
The ''Pura Raza Espanola'' or Pure Spanish Breed mares belonging to breeder Francisco Jose Rodriguez will be turned into horse meat for export come July, barring an unlikely reprieve. The horses at "La Yeguada de Cuatro Vientos" ranch in Almonte, in the southern Spanish region of Andalusia are victims of a wrenching economic downturn that has wiped out fortunes, turned housing developments into ghost towns and left more than a quarter of the Spanish population out of work.
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My recent urinalysis shows occult blood (2+) in my urine.
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My recent urinalysis shows occult blood (2+) in my urine. It also shows 0-5 wbc, 5-10 rbc, moderate epithelial cells, 2+ bacteria, and 1+ mucus. In the past, blood was always found in my urine. Two years ago I had a CAT Scan and cystoscopy done and nothing was found. My new doctor has said nothing about these results, she mentioned other things in my lab results but not this. What do you think?
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Did your doctor put you on any antibiotics? If so can you tell me the name of it?
What other things did your doctor talk to you about?
Also, are you having burning or pain when you urinate?
Does it feel like when you urinate it is hard to start the flow of urine or it feels like you are not emptying your bladder all the way?
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Reply to Pam's Post: Hi. No, my doctor didn't put me on any antibiotics. It doesn't hurt or burn when I urinate...everything seems fine. My doctor talked about my blood test, how my insulin levels are on the high normal side and she prescribed Metformin to lower them and help me lose weight. When I saw a urologist a couple of years ago, he ordered the CAT Scan and cystoscopy. I never had an infection back then either. They couldn't find anything wrong. What does 2+ mean?
replied 9 years ago.
Actually 2+ indicates the amount of blood seen in the urine. You have some white blood cells, but not enough to be concerned. This is present usually in infection. 2+ bacteria is also the amount of bacteria present in the urine. The doctor may feel like since you are not presenting with symptoms such as I have indicated above, he really doesn't want to put you on antibiotics. A lot of times people will take too much antibiotic therapy, and then eventually you become immune to them. So doctors now will not put you on anything unless you are having symptoms of an infection. If you do develop any of the symptoms above indicating a bladder infection, I would let him know.
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- GhanaFoodFunding via ID Ghana
TahiruGhanaConstructionFunding via Ghana Women Fund Ltd
Nkome Nfa 1...GhanaFoodFunding via ID Ghana
Dwen Daakye Group
His only problem now has to do with adequate funds to buy raw materials as we approach Christmas festivities. He requests a loan to remain in business and also to take care of his family. He believes it is not possible to realize his dream of expansion by himself. He would be grateful for assistance. Apart from the above business, he is also doing carpentry work and manufactures furniture like beds, tables, chairs, etc.
He is the leader of a trust bank group called "Dwen Daakye," which means "think of the future." He is the one sitting in front in the group photograph. Most of the members of this group are petty traders, food vendors and/or farmers. In this group, members guarantee for one another as social collateral to access the loan and peer pressure to repay the loan.
Additional Information
This is a Group Loan
In a group loan, each member of the group receives an individual loan but is part of a larger group of individuals. The group is there to provide support to the members and to provide a system of peer pressure, but groups may or may not be formally bound by a group guarantee. In cases where there is a group guarantee, members of the group are responsible for paying back the loans of their fellow group members in the case of delinquency or default.
Kiva's Field Partners typically feature one borrower from a group. The loan description, sector, and other attributes for a group loan profile are determined by the featured borrower's loan. The other members of the group are not required to use their loans for the same purpose.
About Ghana
26View loans »
Success!! The loan was 100% repaid
- Repayment Term
- 8 months (Additional Information)
- Repayment Schedule
- Monthly
- Pre-Disbursed:
- Nov 5, 2009
- Listed
- Nov 10, 2009
- Currency Exchange Loss:
- Possible
- Ended:
- Jun 15, 2010


text:
Colbert Nation: Another country shows at Olympics
VANCOUVER, British Columbia Bringing his nation to the Winter Olympics, Stephen Colbert made peace with Canada, sang with Michael Buble and persuaded Bob Costas to climb aboard a stuffed moose.
Then he got down to cheering the U.S. speedskaters he helped bail out.
The Colbert Nation arrived at the Vancouver Games on Wednesday for a taping of his faux talk show in a most un-winterlike setting: a muddy park along the downtown waterfront on a morning that turned out sunny and unseasonably warm. In the afternoon, he headed to the Olympic Oval in suburban Richmond to chat with several U.S. skaters before the men's 1,000 meters, in which American world-record holder Shani Davis was favored to win gold.
Colbert proudly wore yet another title on the back of his red jacket - "assistant sports psychologist," which he can now add to Sir (he was knighted, sort of, by Jordan's Queen Noor) and Dr. (owing to an honorary degree in fine arts that he uses to dispense medical advice).
The host of "The Colbert Report," a late-night show in which he portrays a dimwitted conservative pundit, formed an unlikely alliance with U.S. Speedskating after its main sponsor went bust. Colbert's fans stepped in to donate more than $300,000 to the program, and it was only natural he would attend the Olympics after getting so much comic fodder out of it the past few months.
Colbert started a mock feud with Canada, calling them "syrup suckers" and "iceholes," but he seemed to have plenty of fans north of the border judging by several thousand who turned out at Creekside Park to watch him conduct interviews with Buble, Costas and 1980 hockey gold medalist Mike Eruzione from a temporary stage adorned with a moose, totem pole and stuffed beaver.
"Stephen! Stephen! Stephen!" the crowd chanted, one of them holding up a sign that said "Colbert for Prime Minister."
"This is a welcome we couldn't have imagined in our wildest dreams," Colbert said. "I take back everything I've said about Canada."
Working on bits that will air on future shows, Colbert persuaded Buble to join him in a rendition of "The Star-Spangled Banner," sung to the tune of "O Canada."
"I'll bite: Why Canada?" Colbert asked the Canadian singer, staying in character all the way. "Why not just more United States?"
Eruzione, who scored the winning goal for the U.S. in its epic upset of the Soviet Union at the 1980 Lake Placid Games, was up next. His exploits led to a natural question: How many times has he been offered pot since arriving in cannabis-friendly British Columbia.
"Twice," Eruzione said. "Last night and this morning when I woke up."
Costas was introduced by Colbert as "the host of NBC's $820 million Olympic coverage, but I got him at a discount." The diminutive sportscaster had barely gotten on stage when the crowd started chanting "Ride the moose! Ride the moose! Ride the moose!"
"Don't worry, he'll ride the moose," Colbert said, flashing a grin. "Let him talk for a few minutes first."
The crowd groaned when Costas refused to anoint Vancouver as the best Olympic host city he's seen.
"I do my pandering between 8 and midnight Eastern time for a higher price than this," he said.
But Costas won them back by going along with the moose gag, struggling to swing his left leg over the animal while Colbert held it around the neck, preventing it from tipping over.
Colbert also showed a Canadian-ized version of his popular segment "Better Know a District," in which he humorously profiles U.S. congressional districts and also interviews their elected representatives.


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Lin's Antiques and Collectibles
Another lovely Florence Ceramics figurine ÔÇô this one is Jenevieve! SheÔÇÖs in wonderful condition but as so often happens, some of the lace is damaged on her dress. She also has teeny ding on a fold in her dress ÔÇô thatÔÇÖs it! (Any other spots in photos are camera glare.) Although lovely, sheÔÇÖs not in perfect condition and is priced accordingly.
Excellent condition Florence Ceramics figurine ÔÇô Irene! She has green dress with gold accents, measures 6ÔÇŁ tall, and is marked: Florence Ceramics, Irene. Lovely!
Excellent condition Hummel wall plaque! This is the ÔÇťBaybeeÔÇŁ plaque ÔÇô a little boy somewhat startled by a bee. Plaque measures 4 ┬żÔÇŁ diameter, back is marked 30/OA, Hummel, small bee in a ÔÇťVÔÇŁ, M.I. Hummel, Western Germany. The marking indicates production period of 1960/72. Super collectible item!
This spaghetti trimmed Santa planter is a little different ÔÇô he has brown ÔÇťbootsÔÇŁ! He measures 6ÔÇŁ tall and has the original ÔÇťHand Painted, Royal, JapanÔÇŁ sticker/label on bottom. Prior owner put felt around bottom edges so it wouldnÔÇÖt scratch furniture. Neat collectible in super condition!
Another super Napco spaghetti trimmed Santa planter! Santa is 6ÔÇŁ tall, trimmed in gold and one side of his toy sack (planter) has ÔÇťBest WishesÔÇŁ and the back has ÔÇťMerry XmasÔÇŁ. Super condition!
Very pretty spaghetti trimmed Santa planter! Made by Napco, Santa is 6ÔÇŁ tall, trimmed in gold and one side of his toy sack (planter) has ÔÇťBest WishesÔÇŁ and the back has ÔÇťMerry XmasÔÇŁ. Super condition ÔÇô has minor crazing and a fleck of missing green color on the holly in his hand.
This is such a pretty Fenton piece ÔÇô itÔÇÖs a blue glass butterfly! Has the Fenton sticker and is signed on bottom ÔÇô itÔÇÖs somewhat smeared but appears to be ÔÇťb. stephensÔÇŁ. Great collectible and a neat gift!
This is an adorable Lefton shaker set! ItÔÇÖs a poodle pair all dressed up for an evening out. He measures 3 ┬╝ÔÇŁ tall, sheÔÇÖs 3 1/8ÔÇŁ tall, and both shakers are in wonderful condition. The glue on one of her rhinestone eyes is slightly discolored, there are 2 teeny dings on her skirt, and neither shaker has a stopper. She does have the original Lefton sticker/label. Really cute set!
This is such a pretty Fenton figurine! ItÔÇÖs a girl in a long dress and sheÔÇÖs ÔÇťholdingÔÇŁ a bouquet of flowers ÔÇô she could be a bridesmaid/attendant or could be going to a prom or banquet. Measures 7ÔÇŁ tall, is marked Fenton, and is in excellent condition. The attention to detail is outstanding ÔÇô a lovely addition to a collection or would be a wonderful gift!
This is a very collectible item that is difficult to find! Made by Lefton, this is a pink ashtray with an attached pink spaghetti poodle. Super condition with minor wear t the gold color ÔÇô thatÔÇÖs it! There is a small rough place on edge that is production ÔÇô has color and glaze ÔÇô not detrimental. Super collectible!
This is a cutie ÔÇô a little brown bear figurine made by Kreiss! Measures 2ÔÇŁ tall (at tallest), 1 ┬ŻÔÇŁ wide (at widest), and 3 ┬żÔÇŁ long (at longest). Stamped on bottom: Kreiss & Company. Also has original stamped price of 10 cents! Little bear is in excellent condition.
All Items : Pottery and Stoneware : Shawnee : Pre 1970 item #625141 (stock #M2580)
Beautiful colors and oodles of gold trim on these Shawnee figurines! This is the little oriental girl and boy, marked USA, 601 (602), he measures 5 1/8ÔÇŁ tall, sheÔÇÖs 5 ┬ŻÔÇŁ, and both are in excellent condition!
Excellent condition Lefton figurine! This one is titled ÔÇťTypistÔÇŁ, measures 6 ┬żÔÇŁ tall, and is number 5688. it has the red and gold foil sticker/label. This figuring is shown in Karen BartonÔÇÖs ÔÇťTwentieth Century Lefton China and CollectiblesÔÇŁ with a 2001 price guide value of $75.00.
These Lefton figurines are adorable! They are described in reference books as ÔÇťHummel-likeÔÇŁ and indeed they are. Figurines measure 4 ┬ŻÔÇŁ tall, both have original Lefton foil stickers/labels, and are stamped Lefton China, Hand Painted. They are both numbered TWD02539. Excellent condition!
All Items : Pottery and Stoneware : California : Pre 1970 item #613895 (stock #M2534)
This is a cute little guy ÔÇô a sitting elf! Measures 3 3/8ÔÇŁ tall (at tallest), 3 ┬żÔÇŁ wide (foot to foot, and heÔÇÖs in excellent condition ÔÇô has minor crazing ÔÇô thatÔÇÖs it!
Very pretty birthday girl figurine by Josef! SheÔÇÖs the March, aquamarine birthday girl, measures 3 ┬żÔÇŁ tall, and has the original Josef sticker on side and is stamped on bottom. Excellent condition!
Lin's Antiques and Collectibles
Absolutely beautiful, absolutely mint condition ÔÇô this listing has Florence CeramicÔÇÖs ÔÇťStory HourÔÇŁ with the boy and girl figurine! There is no broken lace or fingers ÔÇô there is a SMALL production ÔÇťpopÔÇŁ on the little boyÔÇÖs sleeve (at wrist) that received color and glaze, it is not damage.
Per the ÔÇťComplete Book of Florence CeramicsÔÇŁ by Kline, Webrspaun, and Kline, ÔÇťStory HourÔÇŁ represents some of Florence WardÔÇÖs finest work...
Per the ÔÇťComplete Book of Florence CeramicsÔÇŁ by Kline, Webrspaun, and Kline, ÔÇťStory HourÔÇŁ represents some of Florence WardÔÇÖs finest work...
These little brown bunnies are so cute! The tallest one is 2 ┬╝ÔÇŁ tall, the other is 2ÔÇŁ tall, both have fuzzy brown flocking ÔÇťfurÔÇŁ, and their eyes may be glass (IÔÇÖm not certain). One has the black and gold foil Josef label/sticker and one that is black and gold ÔÇťJapanÔÇŁ. Neat collectibles!


text:
Viewing All 65 Photos
Certified photos by travelers like you. What's this?
Patricia P USA
December 2011
Hubby & I at the Farallon Islands
July 2015
Great tail shot
Love the Golden Gate in the background of this picture.
John J United Kingdom
May 2015
There she blows!
My previous photo was Phalaropes this is the Humpback Whale as if you had not already guessed!
John J United Kingdom
May 2015
There she blows
This is what we came for, a Humpbacked Whale appears after just 40 minutes.
John J United Kingdom
May 2015
Informative and entertaining Tour Guide
This is our tour guide who kept us interested throughout the trip.


text:
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JERUSALEM, Israel - In his first year as chairman of the Jewish Agency, Natan Sharansky had the pleasure of presiding over the biggest increase in aliyah (immigration to Israel under the Law of Return) in 10 years.
In 2009, a total of 16,244 Jews immigrated to Israel, a 17 percent increase over last year, which saw 13,859 new arrivals.
"After 10 years during which we saw less and less immigrants, we now see an increase," Sharansky told reporters at a press conference at the Jewish Agency's Jerusalem headquarters on Sunday.
"This year there were more immigrants from the former Soviet Union, more immigrants from the United States, from Britain and from South Africa. There's an increase from almost everywhere," Sharansky said.
"Every oleh [immigrant] who arrives in Israel strengthens it and represents a crucial strategic asset for the country," he said.
Eli Cohen, director-general of the Jewish Agency's aliyah department, reported a 17 percent increase in English-speaking olim (immigrants) from 4,511 in 2008 to 5,294 in 2009.
Around 2,600 Jews emigrated from Europe, up from 2,402 the previous year. South American immigrants numbered 1,230, compared with 1,078 last year.
There was a 21 percent increase - from 5,867 to 7,120 - of immigration from the former Soviet Union.
"It's symbolic that a change for the better in aliyah is taking place on the 20th anniversary of aliyah from the former Soviet Union," Immigration and Absorption Minister Sofa Landver said.
The agency's "Aliyah on a Red Carpet" program has helped immigrants acclimate to their new home. Almost immediately after arriving in Israel, new arrivals attend aliyah fairs, which walk them through some of the practical necessities, such as opening an Israeli bank account, choosing one of four national health care programs, etc.
Israelis living abroad are also returning. A new government program offering financial incentives, such as tax benefits and help finding jobs, is bringing increasing numbers back home.
Sharansky said he hopes the government will facilitate the aliyah of an estimated 8,700 Ethiopian Jews, many of whom already have family in the country. In January, another 250 Ethiopians will make Israel their home.
Over the past 10 years, some 221,000 Jews have immigrated to their historic homeland, irrefutable evidence of biblical prophecy being fulfilled.
Haaretz and The Jerusalem Post contributed to this report.
Bringing Israel's Lost Tribe Home
Lost Tribes of Jews from China, India Make 'Aliyah'
Russian Blitz Spurs 'Aliyah'
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The Terrorists Funded by the WestBassam Tawil
The New Israel Fund and those who support it are helping terroristsRonn Torossian
Column one: Fighting fire with fireCaroline B. Glick
Op-Ed: There is no 'radical Islam' and there is no 'moderate Islam'Dr. Mordechai Kedar
'Narrow' escapesRuthie Blum
Why Palestinians Do Not Want Cameras on the Temple MountKhaled Abu Toameh
Social Media Killed My FatherYoni Kempinski and Ari Soffer
Iran's New Palestinian Terror Group: Al SabireenKhaled Abu Toameh


text:
The Guinness Book of World Records is not what it once was.
Thirty years ago, it was a pocket-size paperback front-loaded with the world's anatomical freaks: oldest, tallest, shortest, heaviest. I still have my yellowed, dog-eared 1982 copy, the victim of doubtlessly record hours in the hands of a tween.


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@ Bob you turd whatever ur still yelling its all BullSh!t, Yellow Flag pass??? it was an Orange Yellow Flag indicating the track is slippery but doesnt force drivers to stay behind or not overtaking...if you already mis that point its clear ur a sour grape no mather who ur fan of, and the dry line in a wet situation is the driving line not the inside curbes when wet get slippery, i agree with the guy who is asking for ur smoke cuase here its legal but i cant be so delusional or halucinating from it like you did or do....