US3682835A - Liquid blood serum control standard - Google Patents
Liquid blood serum control standard Download PDFInfo
- Publication number
- US3682835A US3682835A US92533A US3682835DA US3682835A US 3682835 A US3682835 A US 3682835A US 92533 A US92533 A US 92533A US 3682835D A US3682835D A US 3682835DA US 3682835 A US3682835 A US 3682835A
- Authority
- US
- United States
- Prior art keywords
- serum
- blood serum
- control standard
- sodium
- blood
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
Links
- 210000002966 serum Anatomy 0.000 title abstract description 65
- 239000007788 liquid Substances 0.000 title abstract description 16
- 239000002904 solvent Substances 0.000 abstract description 17
- 210000002381 plasma Anatomy 0.000 abstract description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 abstract description 12
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 abstract description 10
- 239000003456 ion exchange resin Substances 0.000 abstract description 9
- 229920003303 ion-exchange polymer Polymers 0.000 abstract description 9
- -1 ALKALINEEARTH METAL CATION Chemical class 0.000 abstract description 8
- 102000004895 Lipoproteins Human genes 0.000 abstract description 8
- 108090001030 Lipoproteins Proteins 0.000 abstract description 8
- 238000004458 analytical method Methods 0.000 abstract description 6
- 238000001035 drying Methods 0.000 abstract description 6
- 238000000605 extraction Methods 0.000 abstract description 5
- 229910052784 alkaline earth metal Inorganic materials 0.000 abstract description 3
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 24
- 239000000306 component Substances 0.000 description 19
- 239000011347 resin Substances 0.000 description 14
- 229920005989 resin Polymers 0.000 description 14
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 12
- 239000011734 sodium Substances 0.000 description 12
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 10
- 239000011591 potassium Substances 0.000 description 10
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 9
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 9
- 229960001031 glucose Drugs 0.000 description 9
- 238000000034 method Methods 0.000 description 9
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 8
- 229960005069 calcium Drugs 0.000 description 8
- 229910052791 calcium Inorganic materials 0.000 description 8
- 239000011575 calcium Substances 0.000 description 8
- DDRJAANPRJIHGJ-UHFFFAOYSA-N creatinine Chemical compound CN1CC(=O)NC1=N DDRJAANPRJIHGJ-UHFFFAOYSA-N 0.000 description 8
- 229910052700 potassium Inorganic materials 0.000 description 8
- 229910052708 sodium Inorganic materials 0.000 description 8
- 239000000463 material Substances 0.000 description 7
- 229920001467 poly(styrenesulfonates) Polymers 0.000 description 7
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- 239000007983 Tris buffer Substances 0.000 description 6
- 239000002585 base Substances 0.000 description 6
- 239000008103 glucose Substances 0.000 description 6
- 102000004169 proteins and genes Human genes 0.000 description 6
- 108090000623 proteins and genes Proteins 0.000 description 6
- 229910001415 sodium ion Inorganic materials 0.000 description 6
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 6
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 5
- BHPQYMZQTOCNFJ-UHFFFAOYSA-N Calcium cation Chemical compound [Ca+2] BHPQYMZQTOCNFJ-UHFFFAOYSA-N 0.000 description 5
- 239000002253 acid Substances 0.000 description 5
- 229910001424 calcium ion Inorganic materials 0.000 description 5
- 239000003729 cation exchange resin Substances 0.000 description 5
- 239000003153 chemical reaction reagent Substances 0.000 description 5
- 239000012153 distilled water Substances 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- MYRTYDVEIRVNKP-UHFFFAOYSA-N 1,2-Divinylbenzene Chemical compound C=CC1=CC=CC=C1C=C MYRTYDVEIRVNKP-UHFFFAOYSA-N 0.000 description 4
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 4
- 239000004793 Polystyrene Substances 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- LEHOTFFKMJEONL-UHFFFAOYSA-N Uric Acid Chemical compound N1C(=O)NC(=O)C2=C1NC(=O)N2 LEHOTFFKMJEONL-UHFFFAOYSA-N 0.000 description 4
- TVWHNULVHGKJHS-UHFFFAOYSA-N Uric acid Natural products N1C(=O)NC(=O)C2NC(=O)NC21 TVWHNULVHGKJHS-UHFFFAOYSA-N 0.000 description 4
- 229940109239 creatinine Drugs 0.000 description 4
- 239000001257 hydrogen Substances 0.000 description 4
- 229910052739 hydrogen Inorganic materials 0.000 description 4
- 229920002223 polystyrene Polymers 0.000 description 4
- 229910001414 potassium ion Inorganic materials 0.000 description 4
- 239000001509 sodium citrate Substances 0.000 description 4
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 4
- 229940116269 uric acid Drugs 0.000 description 4
- 102000009027 Albumins Human genes 0.000 description 3
- 108010088751 Albumins Proteins 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 3
- PNNCWTXUWKENPE-UHFFFAOYSA-N [N].NC(N)=O Chemical group [N].NC(N)=O PNNCWTXUWKENPE-UHFFFAOYSA-N 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 210000004369 blood Anatomy 0.000 description 3
- 239000008280 blood Substances 0.000 description 3
- 229940023913 cation exchange resins Drugs 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 239000008121 dextrose Substances 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- UUCCCPNEFXQJEL-UHFFFAOYSA-L strontium dihydroxide Chemical compound [OH-].[OH-].[Sr+2] UUCCCPNEFXQJEL-UHFFFAOYSA-L 0.000 description 3
- 229910001866 strontium hydroxide Inorganic materials 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- BPYKTIZUTYGOLE-IFADSCNNSA-N Bilirubin Chemical compound N1C(=O)C(C)=C(C=C)\C1=C\C1=C(C)C(CCC(O)=O)=C(CC2=C(C(C)=C(\C=C/3C(=C(C=C)C(=O)N\3)C)N2)CCC(O)=O)N1 BPYKTIZUTYGOLE-IFADSCNNSA-N 0.000 description 2
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- XUIIKFGFIJCVMT-GFCCVEGCSA-N D-thyroxine Chemical compound IC1=CC(C[C@@H](N)C(O)=O)=CC(I)=C1OC1=CC(I)=C(O)C(I)=C1 XUIIKFGFIJCVMT-GFCCVEGCSA-N 0.000 description 2
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 2
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 2
- FKNQFGJONOIPTF-UHFFFAOYSA-N Sodium cation Chemical compound [Na+] FKNQFGJONOIPTF-UHFFFAOYSA-N 0.000 description 2
- 108090000340 Transaminases Proteins 0.000 description 2
- 239000001110 calcium chloride Substances 0.000 description 2
- 229960002713 calcium chloride Drugs 0.000 description 2
- 235000011148 calcium chloride Nutrition 0.000 description 2
- 229910001628 calcium chloride Inorganic materials 0.000 description 2
- 239000004202 carbamide Substances 0.000 description 2
- 239000001569 carbon dioxide Substances 0.000 description 2
- 229910002092 carbon dioxide Inorganic materials 0.000 description 2
- 150000008280 chlorinated hydrocarbons Chemical class 0.000 description 2
- NEHMKBQYUWJMIP-UHFFFAOYSA-N chloromethane Chemical compound ClC NEHMKBQYUWJMIP-UHFFFAOYSA-N 0.000 description 2
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 2
- 150000002170 ethers Chemical class 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- BHEPBYXIRTUNPN-UHFFFAOYSA-N hydridophosphorus(.) (triplet) Chemical compound [PH] BHEPBYXIRTUNPN-UHFFFAOYSA-N 0.000 description 2
- 229930195733 hydrocarbon Natural products 0.000 description 2
- 150000002430 hydrocarbons Chemical class 0.000 description 2
- 150000002576 ketones Chemical class 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 2
- 235000019796 monopotassium phosphate Nutrition 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 230000000717 retained effect Effects 0.000 description 2
- 239000000523 sample Substances 0.000 description 2
- 239000001632 sodium acetate Substances 0.000 description 2
- 235000017281 sodium acetate Nutrition 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 239000010421 standard material Substances 0.000 description 2
- 239000012607 strong cation exchange resin Substances 0.000 description 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
- 229940034208 thyroxine Drugs 0.000 description 2
- XUIIKFGFIJCVMT-UHFFFAOYSA-N thyroxine-binding globulin Natural products IC1=CC(CC([NH3+])C([O-])=O)=CC(I)=C1OC1=CC(I)=C(O)C(I)=C1 XUIIKFGFIJCVMT-UHFFFAOYSA-N 0.000 description 2
- 229940045136 urea Drugs 0.000 description 2
- AJDIZQLSFPQPEY-UHFFFAOYSA-N 1,1,2-Trichlorotrifluoroethane Chemical compound FC(F)(Cl)C(F)(Cl)Cl AJDIZQLSFPQPEY-UHFFFAOYSA-N 0.000 description 1
- ZJQIXGGEADDPQB-UHFFFAOYSA-N 1,2-bis(ethenyl)-3,4-dimethylbenzene Chemical group CC1=CC=C(C=C)C(C=C)=C1C ZJQIXGGEADDPQB-UHFFFAOYSA-N 0.000 description 1
- GZCWLCBFPRFLKL-UHFFFAOYSA-N 1-prop-2-ynoxypropan-2-ol Chemical compound CC(O)COCC#C GZCWLCBFPRFLKL-UHFFFAOYSA-N 0.000 description 1
- 102000013563 Acid Phosphatase Human genes 0.000 description 1
- 108010051457 Acid Phosphatase Proteins 0.000 description 1
- 102100036475 Alanine aminotransferase 1 Human genes 0.000 description 1
- 108010082126 Alanine transaminase Proteins 0.000 description 1
- 102000002260 Alkaline Phosphatase Human genes 0.000 description 1
- 108020004774 Alkaline Phosphatase Proteins 0.000 description 1
- ATRRKUHOCOJYRX-UHFFFAOYSA-N Ammonium bicarbonate Chemical compound [NH4+].OC([O-])=O ATRRKUHOCOJYRX-UHFFFAOYSA-N 0.000 description 1
- 229910000013 Ammonium bicarbonate Inorganic materials 0.000 description 1
- 239000004382 Amylase Substances 0.000 description 1
- 102000013142 Amylases Human genes 0.000 description 1
- 108010065511 Amylases Proteins 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- 101100039010 Caenorhabditis elegans dis-3 gene Proteins 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- 101710088194 Dehydrogenase Proteins 0.000 description 1
- 239000004338 Dichlorodifluoromethane Substances 0.000 description 1
- ZGTMUACCHSMWAC-UHFFFAOYSA-L EDTA disodium salt (anhydrous) Chemical compound [Na+].[Na+].OC(=O)CN(CC([O-])=O)CCN(CC(O)=O)CC([O-])=O ZGTMUACCHSMWAC-UHFFFAOYSA-L 0.000 description 1
- 229920000209 Hexadimethrine bromide Polymers 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- NPYPAHLBTDXSSS-UHFFFAOYSA-N Potassium ion Chemical compound [K+] NPYPAHLBTDXSSS-UHFFFAOYSA-N 0.000 description 1
- 102000003929 Transaminases Human genes 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 235000012538 ammonium bicarbonate Nutrition 0.000 description 1
- 239000001099 ammonium carbonate Substances 0.000 description 1
- 235000019418 amylase Nutrition 0.000 description 1
- 239000003146 anticoagulant agent Substances 0.000 description 1
- 229940127219 anticoagulant drug Drugs 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 239000013060 biological fluid Substances 0.000 description 1
- 239000012472 biological sample Substances 0.000 description 1
- 239000012503 blood component Substances 0.000 description 1
- 235000013877 carbamide Nutrition 0.000 description 1
- 229920001429 chelating resin Polymers 0.000 description 1
- 235000012000 cholesterol Nutrition 0.000 description 1
- 229940107161 cholesterol Drugs 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000004132 cross linking Methods 0.000 description 1
- 125000000753 cycloalkyl group Chemical group 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- PXBRQCKWGAHEHS-UHFFFAOYSA-N dichlorodifluoromethane Chemical compound FC(F)(Cl)Cl PXBRQCKWGAHEHS-UHFFFAOYSA-N 0.000 description 1
- 235000019404 dichlorodifluoromethane Nutrition 0.000 description 1
- UMNKXPULIDJLSU-UHFFFAOYSA-N dichlorofluoromethane Chemical compound FC(Cl)Cl UMNKXPULIDJLSU-UHFFFAOYSA-N 0.000 description 1
- IRXRGVFLQOSHOH-UHFFFAOYSA-L dipotassium;oxalate Chemical compound [K+].[K+].[O-]C(=O)C([O-])=O IRXRGVFLQOSHOH-UHFFFAOYSA-L 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- NBVXSUQYWXRMNV-UHFFFAOYSA-N fluoromethane Chemical group FC NBVXSUQYWXRMNV-UHFFFAOYSA-N 0.000 description 1
- SLGWESQGEUXWJQ-UHFFFAOYSA-N formaldehyde;phenol Chemical class O=C.OC1=CC=CC=C1 SLGWESQGEUXWJQ-UHFFFAOYSA-N 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 235000001727 glucose Nutrition 0.000 description 1
- ZFGMDIBRIDKWMY-PASTXAENSA-N heparin Chemical compound CC(O)=N[C@@H]1[C@@H](O)[C@H](O)[C@@H](COS(O)(=O)=O)O[C@@H]1O[C@@H]1[C@@H](C(O)=O)O[C@@H](O[C@H]2[C@@H]([C@@H](OS(O)(=O)=O)[C@@H](O[C@@H]3[C@@H](OC(O)[C@H](OS(O)(=O)=O)[C@H]3O)C(O)=O)O[C@@H]2O)CS(O)(=O)=O)[C@H](O)[C@H]1O ZFGMDIBRIDKWMY-PASTXAENSA-N 0.000 description 1
- 229920000669 heparin Polymers 0.000 description 1
- 229960001008 heparin sodium Drugs 0.000 description 1
- GPRLSGONYQIRFK-UHFFFAOYSA-N hydron Chemical compound [H+] GPRLSGONYQIRFK-UHFFFAOYSA-N 0.000 description 1
- 229910001410 inorganic ion Inorganic materials 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 238000005342 ion exchange Methods 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 238000010979 pH adjustment Methods 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 239000013618 particulate matter Substances 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 150000002989 phenols Chemical class 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 235000011118 potassium hydroxide Nutrition 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 239000013557 residual solvent Substances 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 235000002639 sodium chloride Nutrition 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000011343 solid material Substances 0.000 description 1
- 238000000638 solvent extraction Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 229940061610 sulfonated phenol Drugs 0.000 description 1
- 102000014898 transaminase activity proteins Human genes 0.000 description 1
- 150000003626 triacylglycerols Chemical class 0.000 description 1
Classifications
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/96—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving blood or serum control standard
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J39/00—Cation exchange; Use of material as cation exchangers; Treatment of material for improving the cation exchange properties
- B01J39/04—Processes using organic exchangers
- B01J39/05—Processes using organic exchangers in the strongly acidic form
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2496/00—Reference solutions for assays of biological material
- G01N2496/05—Reference solutions for assays of biological material containing blood cells or plasma
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2496/00—Reference solutions for assays of biological material
- G01N2496/80—Multi-analyte reference solutions containing cholesterol, glucose and the like
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10T—TECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
- Y10T436/00—Chemistry: analytical and immunological testing
- Y10T436/10—Composition for standardization, calibration, simulation, stabilization, preparation or preservation; processes of use in preparation for chemical testing
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10T—TECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
- Y10T436/00—Chemistry: analytical and immunological testing
- Y10T436/10—Composition for standardization, calibration, simulation, stabilization, preparation or preservation; processes of use in preparation for chemical testing
- Y10T436/102499—Blood gas standard or control
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10T—TECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
- Y10T436/00—Chemistry: analytical and immunological testing
- Y10T436/10—Composition for standardization, calibration, simulation, stabilization, preparation or preservation; processes of use in preparation for chemical testing
- Y10T436/103332—Bilirubin or uric acid standard or control
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10T—TECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
- Y10T436/00—Chemistry: analytical and immunological testing
- Y10T436/10—Composition for standardization, calibration, simulation, stabilization, preparation or preservation; processes of use in preparation for chemical testing
- Y10T436/104165—Lipid, cholesterol, or triglyceride standard or control
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10T—TECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
- Y10T436/00—Chemistry: analytical and immunological testing
- Y10T436/10—Composition for standardization, calibration, simulation, stabilization, preparation or preservation; processes of use in preparation for chemical testing
- Y10T436/104998—Glucose, ketone, nitrate standard or control
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10T—TECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
- Y10T436/00—Chemistry: analytical and immunological testing
- Y10T436/10—Composition for standardization, calibration, simulation, stabilization, preparation or preservation; processes of use in preparation for chemical testing
- Y10T436/105831—Protein or peptide standard or control [e.g., hemoglobin, etc.]
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10T—TECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
- Y10T436/00—Chemistry: analytical and immunological testing
- Y10T436/10—Composition for standardization, calibration, simulation, stabilization, preparation or preservation; processes of use in preparation for chemical testing
- Y10T436/106664—Blood serum or blood plasma standard or control
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10T—TECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
- Y10T436/00—Chemistry: analytical and immunological testing
- Y10T436/10—Composition for standardization, calibration, simulation, stabilization, preparation or preservation; processes of use in preparation for chemical testing
- Y10T436/107497—Preparation composition [e.g., lysing or precipitation, etc.]
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10T—TECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
- Y10T436/00—Chemistry: analytical and immunological testing
- Y10T436/10—Composition for standardization, calibration, simulation, stabilization, preparation or preservation; processes of use in preparation for chemical testing
- Y10T436/108331—Preservative, buffer, anticoagulant or diluent
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10T—TECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
- Y10T436/00—Chemistry: analytical and immunological testing
- Y10T436/10—Composition for standardization, calibration, simulation, stabilization, preparation or preservation; processes of use in preparation for chemical testing
- Y10T436/109163—Inorganic standards or controls
Definitions
- a liquid control standard for use in the analysis of blood serum which standard is prepared from anticoagulantstored blood plasma by treating the defibrinated plasma with ion exchange resin to reduce the alkali and alkalineearth metal cation level followed by drying, removing the lipoprotein component by extraction with a fat solvent and then reconstituting the product with water.
- This invention relates to a liquid blood serum control standard and method of preparation thereof.
- Blood serum is a complex biological fluid containing numerous components of substantial physiological importance. In the normal or average healthy person the concentrations of these components fall within certain reasonably well-defined limits. When one or more of these components is determined upon analysis to fall outside of these acceptable limits, various diseases or pathological conditions of the body systems are indicated.
- control standards used in actual practice is the freeze-dried serum which is reconstituted with aqueous ammonium bicarbonate prior to use as described in US. Pat. 3,466,249.
- a complete liquid control standard which does not require such reconstitution would be convenient and find much use in practice.
- liquid blood serum is treated with a strong acid cation exchange resin to reduce the sodium, potassium and calcium level in the serum, and the pH of the serum is maintained at, or adjusted to, about its original level by sufficient alkaline reagent which does not contain any sodium, potassium, calcium or ammonium ions.
- the resin-treated and pH-adjusted serum is then dried and the lipoprotein component is extracted with a fat solvent.
- the serum which is thereby essentially free of lipoprotein is reconstituted with water to provide a base liquid blood serum.
- materials can be added to the base liquid blood serum to provide the final control standard.
- the method of preparing the liquid blood serum control standard of this invention is particularly adapted for use with defibrinated blood plasma containing high concentrations of the inorganic ions: sodium, potassium and calcium, for example, stored blood plasma containing the anticoagulants sodium citrate, potassium oxalate, heparin sodium or sodium ethylene diamine tetraacetate, citrated blood plasma (containing sodium citrate or sodium citrate and dextrose), ACD blood plasma (containing citric acid, sodium citrate and dextrose), and CPD blood plasma (containing citrate, phosphate and dextrose).
- stored blood plasma containing the anticoagulants sodium citrate, potassium oxalate, heparin sodium or sodium ethylene diamine tetraacetate
- citrated blood plasma containing sodium citrate or sodium citrate and dextrose
- ACD blood plasma containing citric acid, sodium citrate and dextrose
- CPD blood plasma containing citrate, phosphate and dextrose
- Defibrination can be carried out by the addition of, for example, calcium ions to citrated blood or Polybrene (hexadimethrene bromide) to heparinized blood.
- strong acid cation exchange resins which can be employed in the practice of this invention are the sulfonic acid cation exchange resins.
- These resins can be, for example, sulfonated phenol, sulfonated polystyrene, sulfonated phenolformaldehyde, sulfonated oopolymers of monoalkenyl aromatic hydrocarbons with from about 0.5 to about 25 weight percent of a dialkenyl cross-linking compound, e.g., divinylbenzene, divenyltoluene, divinylxylene and the like resins.
- a dialkenyl cross-linking compound e.g., divinylbenzene, divenyltoluene, divinylxylene and the like resins.
- Resins of this type are commercially available under the trademarks Dowex 50, (Dow Chemical Co.), Amberlite IR-120 (Rohm & Haas Co., Inc.), Driolite C-3 (Chemical Process Co., Inc.), and Diaion SK #1 (Mitsubishi Chemical Industiries Ltd.).
- Dowex 50 is a sulfonated polystyrene cross-linked with divinylbenzene such as described in US. Pat. 2,366,007.
- a preferred resin is a polystyrene nuclear sulfonic acid ion exchange resin on the hydrogen cycle such as Dowex 50, 50 to 100 mesh.
- the blood serum is mixed with the ion exchange resin preferably in proportions of from about 25 to about 100 grams of resin per liter of serum.
- mixing about 40 grams of Dowex 50 resin with one liter of serum has been found to provide excellent results whereby the sodium ion level is reduced from a range of about 165 to 205 milliequivalents per liter of serum to a range of about to milliequivalents per liter of serum.
- a preferred alkaline reagent for maintaining or adjusting the pH of the serum to about its original level is a tris buffer [tri(hydroxy methyl)aminomethane].
- the tris buffer preferably is an aqueous solution of from about 30 to about 50 grams of tris per liter of distilled water and has a pH of from about 5.8 to about 6.8 prior to drying.
- an important blood component to be contained in the control standard is urea nitrogen or blood urea nitrogen (BUN).
- BUN urea nitrogen or blood urea nitrogen
- the BUN preferably is determined by the Bertholet test or by a modified-Bertholet test such as described, for example, in US. Pats. 3,119,751, 3,467,499 and Re. 26,125. It has been found, however, that the use of tris buffer interferes with the determination of BUN by these Bertholet or modified- Bertholet tests. Unexpectedly, the use of lithium hydroxide or strontium hydroxide does not interfere with these BUN tests and, at the same time, retains the unique advantages of the tris buffer in being free from potassium, sodium, calcium and ammonium ions.
- the preferred lithium hydroxide employed in this invention preferably is an aqueous solution of from about 50 to about 70 grams of lithium hydroxide per liter of distilled Water.
- the drying of the resin-treated and pH-ad usted serum preferably is carried out by conventional freeze dry ng or lyophilization methods whereby the serium is dried from the frozen state under a high vacuum and ice or other frozen solvent rapidly sublimes to yield a porous solid.
- fat solvents which can be employed in this invention are organic solvents such as esters, ethers, ketones, hydrocarbons and chlorinated hydrocarbons.
- organic solvents such as light paraffinic petroleum fractions or naphthas, particularly of the hexane or heptane types, cyclic hydrocarbons such as cyclohexane, chlorinated solvents such as chloroform and carbon tetrachloride, ethers such as diethyl ether, and ketones such as acetone and butanone.
- a preferred fat sol vent is a fluorocarbon or Freon such as monofiuorotr chloromethane, dichlorodifluoromethane, monochlorodifiuoromethane, monofluorodichloromethane and various mixtures thereof.
- the solvent extraction is carried out by thoroughly admixing the dried serum with the fat solvent and then separating the undissolved material from the fat solvent.
- the dried serum is mixed with the solvent preferably in proportions of from about 30 to about 90 grams of serum per liter of solvent for about to about 60 minutes with stirring.
- the fat solvent can be removed by filtering and the like separation procedures, with any residual solvent being allowed to evaporate from the retained dry serum particles.
- the serum which is the essentially free from lipoprotein is reconstituted to about its original volume or in other suitable proportions with water, preferably distilled water, to provide the base liquid blood serum control standard.
- Illustrative of the blood serum components which can be included in the control standard of this invention are substances selected from the group consisting of albumin, acid phosphatase, alkaline phosphatase, amylase, bilirubin, calcium, carbon dioxide, chloride, cholesterol, creatinine, glucose, haemoglobin, lactic dehydrogenase, phosphorous, potassium, sodium, total protein, transaminases such as serum glutamic oxalacetic transaminase and serum glutamic pyruvic transaminase, triglycerides, urea nitrogen, uric acid and other such substances found in blood serum.
- transaminases such as serum glutamic oxalacetic transaminase and serum glutamic pyruvic transaminase, triglycerides, urea nitrogen, uric acid and other such substances found in blood serum.
- a preferred control standard of this invention contains predetermined concentrations of the following blood serum components in admixture: sodium, potassium, chloride, phosphorous, calcium, BUN, glucose, uric acid, creatinine, total protein, protein bound iodine (FBI) and carbon dioxide (HCO).
- the base liquid serum can be brought to the desired predetermined levels of these components by adding suitable amounts of appropriate materials containing the components.
- the following materials can be added, respectively: sodium acetate, potassium hydroxide, sodium chloride, potassium dihydrogen phosphate, calcium chlo ride, urea, glucose, uric acid, creatinine, dried blood serum, thyroxine and sodium bicarbonate.
- This control standard is storage stable at customary refrigerated temperatures (4 C.) for three months and provides suitable assay values for these components.
- Citrated human blood serum is defibrinated by the addition of calcium ions followed by filtration.
- the resulting serum is then mixed with a polystyrene nuclear sulfonic acid ion exchange resin on the hydrogen cycle (Dowex 50, 50 to 100 mesh) in a ratio of 40 grams of resin per liter of serum to reduce the level of the sodium and potassium ion (and calcium ion when present) in the serum.
- a polystyrene nuclear sulfonic acid ion exchange resin on the hydrogen cycle (Dowex 50, 50 to 100 mesh) in a ratio of 40 grams of resin per liter of serum to reduce the level of the sodium and potassium ion (and calcium ion when present) in the serum.
- the pH of the serum is maintained at or adjusted to a level of about 62:02 with an aqueous solution of lithium hydroxide.
- the sodium ion level is reduced by this ion exchange treatment from a range of about 165 to 205 milliequivalents per liter of serum to a range of about to milliequivalents per liter of serum.
- the pH of the final treated serum is checked and adjusted to 62:02 with lithium hydroxide.
- the resin-treated and pH-adjusted serum is lyophilized and then extracted with Freon TF (trichlorotrifiuoroethane) by thoroughly admixing 75 grams of the dried serum with 1500 ml. of the Freon.
- the mixture is filtered through Whatman #1 filter paper and the residual solid material is spread to dry.
- the dry material is then reconstituted with distilled Water and filtered to remove any remaining particulate matter. This product is retained as the base liquid blood serum control standard and assayed for desired components.
- control standards were prepared having predetermined low, medium and high concentrations as follows:
- the above prepared, essentially lipoprotein-free dried serum is divided into three parts and reconstituted to three different levels with distilled Water using the below-stated protein levels as the base.
- the reconstituted samples were assayed as follows:
- the adjusted control standard material is sterile filtered through a Millipore filter (0.22 micron) and placed in vials for use as therfinal control standards which can then be made available to clinical laboratories and other such analytical and testing laboratories having a need for blood serum control standards.
- a liquid blood serum control standard from anticoagulant-stored blood plasma comprising thoroughly admixing the defibriuated plasma with a strong cation exchange resin to substantially reduce the sodium, potassium and calcium ion level in the serum followed by drying, removing the lipoprotein component by extraction with a fat-solvent and then reconstituting the serum with water the pH of said resintreated serum being adjusted to or maintained at a pH of from about 5.8 to about 6.8 with a reagent selected from the group consisting of aqueous lithium hydroxide, strontium hydroxide and tris(hydroxymethyD-amiuomethane.
- ion exchange resin is a polystyrene nuclear sulfonic acid ion exchange resin on the hydrogen cycle.
- the cation exchange resin is a polystyrene nuclear sulfonic acid ion exchange resin on the hydrogen cycle and is mixed with the defibrinated plasma in proportions of from about 25 to about 100 grams of resin per liter of said plasma, in which the fat-solvent is a chlorinated hydrocarbon and is mixed with the dried serum in proportions of from about .30 to about grams of resin per liter of solvent.
- a liquid blood serum control standard comprising anticoagulant-stored blood plasma which is defibrinated, resin-treated with strong cation exchange resin to substantially reduce the sodium, potassium and calcium ion level followed by drying, removing the lipoprotein component by extraction with a fat-solvent and then reconstituting the serum with water, the pH of said resintreated serum being adjusted to or maintained at a pH of from about 5.8 to about 6.8 with a reagent selected from the group consisting of aqueous lithium hydroxide, strontium hydroxide and tris(hydroxymethyl)-aminomethane.
Abstract
A LIQUID CONTROL STANDARD FOR USE IN THE ANALYSIS OF BLOOD SERUM, WHICH STANDARD IS PREPARED FROM ANTICOAGULANTSTORED BLOOD PLASMA BY TREATING THE DEBFIBRINATED PLASMA WITH ION EXCHANGE RESIN TO REDUCE THE ALKALI AND ALKALINEEARTH METAL CATION LEVEL FOLLOWED BY DRYING, REMOVING THE LIPOPROTEIN COMPONENT BY EXTRACTION WITH A FAT SOLVENT AND THEN RECONSTITUTING THE PRODUCT WITH WATER.
Description
3,682,835 Patented Aug. 8, 1972 3,682,835 LIQUID BLOOD SERUM CONTROL STANDARD Allan L. Louderback, Temple City, Calif., assignor to Baxter Laboratories, Inc., Morton Grove, Ill. No Drawing. Filed Nov. 24, 1970, Ser. No. 92,533 Int. Cl. (109k 3/00 US. Cl. 252-408 5 Claims ABSTRACT OF THE DISCLOSURE A liquid control standard for use in the analysis of blood serum, which standard is prepared from anticoagulantstored blood plasma by treating the defibrinated plasma with ion exchange resin to reduce the alkali and alkalineearth metal cation level followed by drying, removing the lipoprotein component by extraction with a fat solvent and then reconstituting the product with water.
This invention relates to a liquid blood serum control standard and method of preparation thereof.
Blood serum is a complex biological fluid containing numerous components of substantial physiological importance. In the normal or average healthy person the concentrations of these components fall within certain reasonably well-defined limits. When one or more of these components is determined upon analysis to fall outside of these acceptable limits, various diseases or pathological conditions of the body systems are indicated.
In recent years various automated procedures have been developed for conveniently analyzing multiple components of blood serum. Illustrative of the analytical equipment for these purposes are the Technicon AutoAnalyzer, the
Warner Chillcott Robot Chemist and the Beckman Dis- 3 crete Analyzer. These instruments are capable of rapidly and sequentially determining the concentrations of a host of blood serum components in a single sample, for example, up to a dozen or more values.
In the performance of the analytical tests made by the above and similar equipment on blood serum and other biological samples, it is necessary to use laboratory standard materials or so-called reference or control standards for purposes of calibration and control of the instrument. Accurate results in the use of these instruments, particularly in the case of multi-automated procedures, are dependent upon rigid and constant standardization of the biochemical determinations.
Illustrative of the control standards used in actual practice is the freeze-dried serum which is reconstituted with aqueous ammonium bicarbonate prior to use as described in US. Pat. 3,466,249. For certain purposes, a complete liquid control standard which does not require such reconstitution would be convenient and find much use in practice.
Accordingly, it is an object of this invention to provide a liquid blood serum control standard.
It is another object of this invention to provide a stable blood serum reference standard which can be used for the direct calibration and control of multi-automated analytical procedures.
Other objects and advantages of the invention Will be apparent to those skilled in the art after reading the present disclosure.
In accordance with the present invention, liquid blood serum is treated with a strong acid cation exchange resin to reduce the sodium, potassium and calcium level in the serum, and the pH of the serum is maintained at, or adjusted to, about its original level by sufficient alkaline reagent which does not contain any sodium, potassium, calcium or ammonium ions. The resin-treated and pH-adjusted serum is then dried and the lipoprotein component is extracted with a fat solvent. The serum which is thereby essentially free of lipoprotein is reconstituted with water to provide a base liquid blood serum. Depending upon the analysis of the starting material and the desired concentration of various components in the final product, materials can be added to the base liquid blood serum to provide the final control standard.
The method of preparing the liquid blood serum control standard of this invention is particularly adapted for use with defibrinated blood plasma containing high concentrations of the inorganic ions: sodium, potassium and calcium, for example, stored blood plasma containing the anticoagulants sodium citrate, potassium oxalate, heparin sodium or sodium ethylene diamine tetraacetate, citrated blood plasma (containing sodium citrate or sodium citrate and dextrose), ACD blood plasma (containing citric acid, sodium citrate and dextrose), and CPD blood plasma (containing citrate, phosphate and dextrose).
Defibrination can be carried out by the addition of, for example, calcium ions to citrated blood or Polybrene (hexadimethrene bromide) to heparinized blood.
Examples of strong acid cation exchange resins which can be employed in the practice of this invention are the sulfonic acid cation exchange resins. These resins can be, for example, sulfonated phenol, sulfonated polystyrene, sulfonated phenolformaldehyde, sulfonated oopolymers of monoalkenyl aromatic hydrocarbons with from about 0.5 to about 25 weight percent of a dialkenyl cross-linking compound, e.g., divinylbenzene, divenyltoluene, divinylxylene and the like resins. Resins of this type are commercially available under the trademarks Dowex 50, (Dow Chemical Co.), Amberlite IR-120 (Rohm & Haas Co., Inc.), Driolite C-3 (Chemical Process Co., Inc.), and Diaion SK #1 (Mitsubishi Chemical Industiries Ltd.). A preferred resin is Dowex 50 which is a sulfonated polystyrene cross-linked with divinylbenzene such as described in US. Pat. 2,366,007.
Other suitable strong acid cation exchange resins which can be used in this invention will be apparent to those skilled in the art and can be prepared by reference to a text such as Kunin, Ion Exchange Resins, John Wiley & Sons, Inc., New York, 1950.
A preferred resin is a polystyrene nuclear sulfonic acid ion exchange resin on the hydrogen cycle such as Dowex 50, 50 to 100 mesh.
The blood serum is mixed with the ion exchange resin preferably in proportions of from about 25 to about 100 grams of resin per liter of serum. Thus, mixing about 40 grams of Dowex 50 resin with one liter of serum has been found to provide excellent results whereby the sodium ion level is reduced from a range of about 165 to 205 milliequivalents per liter of serum to a range of about to milliequivalents per liter of serum.
A preferred alkaline reagent for maintaining or adjusting the pH of the serum to about its original level is a tris buffer [tri(hydroxy methyl)aminomethane]. The tris buffer preferably is an aqueous solution of from about 30 to about 50 grams of tris per liter of distilled water and has a pH of from about 5.8 to about 6.8 prior to drying.
According to one aspect of this invention, an important blood component to be contained in the control standard is urea nitrogen or blood urea nitrogen (BUN). The BUN preferably is determined by the Bertholet test or by a modified-Bertholet test such as described, for example, in US. Pats. 3,119,751, 3,467,499 and Re. 26,125. It has been found, however, that the use of tris buffer interferes with the determination of BUN by these Bertholet or modified- Bertholet tests. Unexpectedly, the use of lithium hydroxide or strontium hydroxide does not interfere with these BUN tests and, at the same time, retains the unique advantages of the tris buffer in being free from potassium, sodium, calcium and ammonium ions. The preferred lithium hydroxide employed in this invention preferably is an aqueous solution of from about 50 to about 70 grams of lithium hydroxide per liter of distilled Water.
The drying of the resin-treated and pH-ad usted serum preferably is carried out by conventional freeze dry ng or lyophilization methods whereby the serium is dried from the frozen state under a high vacuum and ice or other frozen solvent rapidly sublimes to yield a porous solid.
The lipoprotein content of the dried serum is then removed by extraction with a fat solvent, Examples of fat solvents which can be employed in this invention are organic solvents such as esters, ethers, ketones, hydrocarbons and chlorinated hydrocarbons. Examples of these organic solvents are hydrocarbons such as light paraffinic petroleum fractions or naphthas, particularly of the hexane or heptane types, cyclic hydrocarbons such as cyclohexane, chlorinated solvents such as chloroform and carbon tetrachloride, ethers such as diethyl ether, and ketones such as acetone and butanone. A preferred fat sol vent is a fluorocarbon or Freon such as monofiuorotr chloromethane, dichlorodifluoromethane, monochlorodifiuoromethane, monofluorodichloromethane and various mixtures thereof.
The solvent extraction is carried out by thoroughly admixing the dried serum with the fat solvent and then separating the undissolved material from the fat solvent. The dried serum is mixed with the solvent preferably in proportions of from about 30 to about 90 grams of serum per liter of solvent for about to about 60 minutes with stirring. The fat solvent can be removed by filtering and the like separation procedures, with any residual solvent being allowed to evaporate from the retained dry serum particles.
The serum which is the essentially free from lipoprotein is reconstituted to about its original volume or in other suitable proportions with water, preferably distilled water, to provide the base liquid blood serum control standard.
Illustrative of the blood serum components which can be included in the control standard of this invention are substances selected from the group consisting of albumin, acid phosphatase, alkaline phosphatase, amylase, bilirubin, calcium, carbon dioxide, chloride, cholesterol, creatinine, glucose, haemoglobin, lactic dehydrogenase, phosphorous, potassium, sodium, total protein, transaminases such as serum glutamic oxalacetic transaminase and serum glutamic pyruvic transaminase, triglycerides, urea nitrogen, uric acid and other such substances found in blood serum.
A preferred control standard of this invention contains predetermined concentrations of the following blood serum components in admixture: sodium, potassium, chloride, phosphorous, calcium, BUN, glucose, uric acid, creatinine, total protein, protein bound iodine (FBI) and carbon dioxide (HCO The base liquid serum can be brought to the desired predetermined levels of these components by adding suitable amounts of appropriate materials containing the components. For the twelve foregoing blood serum components, the following materials can be added, respectively: sodium acetate, potassium hydroxide, sodium chloride, potassium dihydrogen phosphate, calcium chlo ride, urea, glucose, uric acid, creatinine, dried blood serum, thyroxine and sodium bicarbonate. This control standard is storage stable at customary refrigerated temperatures (4 C.) for three months and provides suitable assay values for these components.
The following examples will further illustrate the present invention although the invention is not limited to these specific examples.
EXAMPLE 1 Citrated human blood serum is defibrinated by the addition of calcium ions followed by filtration. The resulting serum is then mixed with a polystyrene nuclear sulfonic acid ion exchange resin on the hydrogen cycle (Dowex 50, 50 to 100 mesh) in a ratio of 40 grams of resin per liter of serum to reduce the level of the sodium and potassium ion (and calcium ion when present) in the serum. As the hydrogen ion is released into the serum by the exchange for sodium and potassium ions, the pH of the serum is maintained at or adjusted to a level of about 62:02 with an aqueous solution of lithium hydroxide. The sodium ion level is reduced by this ion exchange treatment from a range of about 165 to 205 milliequivalents per liter of serum to a range of about to milliequivalents per liter of serum. The pH of the final treated serum is checked and adjusted to 62:02 with lithium hydroxide. The resin-treated and pH-adjusted serum is lyophilized and then extracted with Freon TF (trichlorotrifiuoroethane) by thoroughly admixing 75 grams of the dried serum with 1500 ml. of the Freon. The mixture is filtered through Whatman #1 filter paper and the residual solid material is spread to dry. The dry material is then reconstituted with distilled Water and filtered to remove any remaining particulate matter. This product is retained as the base liquid blood serum control standard and assayed for desired components.
In this example, three control standards were prepared having predetermined low, medium and high concentrations as follows:
Control standard concentration I N o 1 N 0 3 No 1, low medium high concenconcenconcen- Component tration traticn tration Sodium (meet/l) Potassium (meq./l.) 3 5 Calcium (Ing., percent) 6 10 14 Chloride (meq./l.) 80 100 120 BUN (mg., percent)... 10 40 so Creatinine (mg, percent) 1.0 4.0 7.0 Urlc acid (mg, percent) 3. 5 7. 5 11. 5 Glucose (mg, ercent) 80 400 Total protein (2111., 4. 5 6.0 7. 2 Albumin (mg percent). 2. 7 3.6 4.3 COz(I-ICOa)- 18 25 35 PB! g, percent) 4. 3 6.0 9.0 P (mg. percent). 3 8 13 1 Each concentration is within i10% ol the stated value.
In order to prepare these three levels, the above prepared, essentially lipoprotein-free dried serum is divided into three parts and reconstituted to three different levels with distilled Water using the below-stated protein levels as the base. The reconstituted samples were assayed as follows:
Reconstituted sample concentration Component N0. 1 N 0. 2 No.3
Sodium (meqJl. 72. 8 96. 9 102 Potassium (meq ll.) 1. 14 1. 52 1.6 Calcium (mg percent). 3. 93 5. 23 5. 5 Chloride (meq./l.) 72.11 95.95 101 BUN (mg, pereent). 7. 14 9. 5 10 Creatlnino (mg, percent) 0. 57 0.76 0.8 Urle acid (mg, percent) 2.14 2. 7 3 Glucose (mg, percent) 61.4 81.7 86 Total protein (mg 4. 5 6.0 6.3 Albumin (mg percent)- 2. 7 3. 6 3. 8 COAHCOr) 1. 76 2.35 2. 47 PBI g, percent). 3.07 4.09 4. 3 P (mg, percent) 2.43 3.23 3.4
Reconstituted Samples 1, 2 and 3 were then used to make the foregoing control standards of low, medium and high concentrations by addition of suitable amounts of the appropriate materials as follows:
Amount added to samples Material added No. 1 N o. 2 N0. 3
Sodium acetate (grams) 2. 38 1. 53 0. 467 Potassium hydroxide (m1 1.01 1. 16 1.382 Calcium chloride (grams) 3. 45 7. 97 0. 142 Sodium chloride (grams)... 0. 239 0.058 0. 513 Urea (grams) 0. 034 0. 366 0. 84 Creatim'ne (mg.) 2. 5s 19. 44 37. 2 Uric acid (grams) 0. 008 0. 029 0. 051 Glucose (grams) 0.112 0.470 1. 884 Dried serum (grams).-- 0 9 Sodium bicarbonate (mg 818. 1,141. 6 1, 639. 5 Thyroxine 1.) 20. 2 31. 3 77. Potassium dihydrogen phosphate (grams) 1. 500 0. 126 0. 253
The adjusted control standard material is sterile filtered through a Millipore filter (0.22 micron) and placed in vials for use as therfinal control standards which can then be made available to clinical laboratories and other such analytical and testing laboratories having a need for blood serum control standards.
Various other examples and modifications of the foregoing examples will be apparent to those skilled in the art after reading the foregoing specification and the appended claims without departing from the spirit and scope of the invention. All such further examples and modifications are included within the scope of the invention as defined in the following claims.
What is claimed is:
1. The method of making a liquid blood serum control standard from anticoagulant-stored blood plasma comprising thoroughly admixing the defibriuated plasma with a strong cation exchange resin to substantially reduce the sodium, potassium and calcium ion level in the serum followed by drying, removing the lipoprotein component by extraction with a fat-solvent and then reconstituting the serum with water the pH of said resintreated serum being adjusted to or maintained at a pH of from about 5.8 to about 6.8 with a reagent selected from the group consisting of aqueous lithium hydroxide, strontium hydroxide and tris(hydroxymethyD-amiuomethane.
2. The method of claim 1 in which the reagent for pH adjustment or maintenance is aqueous lithium hydroxide.
3. The method of claim 1 in which the ion exchange resin is a polystyrene nuclear sulfonic acid ion exchange resin on the hydrogen cycle.
4. The method of claim 1 in which the cation exchange resin is a polystyrene nuclear sulfonic acid ion exchange resin on the hydrogen cycle and is mixed with the defibrinated plasma in proportions of from about 25 to about 100 grams of resin per liter of said plasma, in which the fat-solvent is a chlorinated hydrocarbon and is mixed with the dried serum in proportions of from about .30 to about grams of resin per liter of solvent.
5. A liquid blood serum control standard comprising anticoagulant-stored blood plasma which is defibrinated, resin-treated with strong cation exchange resin to substantially reduce the sodium, potassium and calcium ion level followed by drying, removing the lipoprotein component by extraction with a fat-solvent and then reconstituting the serum with water, the pH of said resintreated serum being adjusted to or maintained at a pH of from about 5.8 to about 6.8 with a reagent selected from the group consisting of aqueous lithium hydroxide, strontium hydroxide and tris(hydroxymethyl)-aminomethane.
References Cited UNITED STATES PATENTS 3,466,249 9/1969 Anderson 252--408 ROBERT F. BURNETT, Primary Examiner M. E. McC-AMISH, Assistant Examiner US. Cl. X.R.
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US9253370A | 1970-11-24 | 1970-11-24 |
Publications (1)
Publication Number | Publication Date |
---|---|
US3682835A true US3682835A (en) | 1972-08-08 |
Family
ID=22233688
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US92533A Expired - Lifetime US3682835A (en) | 1970-11-24 | 1970-11-24 | Liquid blood serum control standard |
Country Status (15)
Country | Link |
---|---|
US (1) | US3682835A (en) |
AU (1) | AU464164B2 (en) |
BE (1) | BE775340A (en) |
CA (1) | CA962193A (en) |
CH (1) | CH542446A (en) |
DE (1) | DE2156604A1 (en) |
ES (1) | ES397245A1 (en) |
FR (1) | FR2116164A5 (en) |
GB (1) | GB1359232A (en) |
IL (1) | IL38093A (en) |
IT (1) | IT941771B (en) |
LU (1) | LU64243A1 (en) |
NL (1) | NL7116167A (en) |
SE (1) | SE376309B (en) |
ZA (1) | ZA717532B (en) |
Cited By (24)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3897363A (en) * | 1973-08-10 | 1975-07-29 | Baxter Laboratories Inc | Blood control standard |
US3955925A (en) * | 1973-11-12 | 1976-05-11 | Proksch Gary J | Preparation of optically clear serum |
US3958939A (en) * | 1975-01-08 | 1976-05-25 | Coulter Electronics, Inc. | Method for clarification of lipemic serum |
US4007008A (en) * | 1975-07-30 | 1977-02-08 | Becker Milton J | Preparation of reference serum from animal blood |
US4011045A (en) * | 1975-02-14 | 1977-03-08 | Bonderman Dean P | Turbidity reduction in triglyceride standards |
US4045176A (en) * | 1975-06-13 | 1977-08-30 | Proksch Gary J | Preparation of optically clear serum |
US4054488A (en) * | 1975-08-14 | 1977-10-18 | Marbach Edward P | Preservation of glucose in blood samples |
US4056484A (en) * | 1974-12-31 | 1977-11-01 | Behringwerke Aktiengesellschaft | Stable blood plasma, process for preparing it and its use as comparative plasma in coagulation tests |
US4116635A (en) * | 1977-03-14 | 1978-09-26 | Jaeger Mark A | General purpose in vitro anticoagulant |
US4127502A (en) * | 1977-06-10 | 1978-11-28 | Eastman Kodak Company | Stabilizers for reconstituted, lyophilized samples |
DE2927841A1 (en) * | 1978-07-17 | 1980-02-07 | Beckman Instruments Inc | METHOD FOR PRODUCING A BIOLOGICAL COMPOSITION FOR USE AS A BLOOD SERUM REFERENCE COMPOSITION FOR DIAGNOSTIC ANALYZING PURPOSES |
US4190573A (en) * | 1974-02-14 | 1980-02-26 | Behringwerke Aktiengesellschaft | Process for the isolation of the polyvalent proteinase inhibitor |
US4219440A (en) * | 1979-06-06 | 1980-08-26 | Coulter Electronics, Inc. | Multiple analysis hematology reference control reagent and method of making the same |
US4264471A (en) * | 1979-06-04 | 1981-04-28 | E. I. Du Pont De Nemours And Company | Serum and plasma clarification process |
US4324687A (en) * | 1979-02-15 | 1982-04-13 | Louderback Allan Lee | Blood biochemistry control standard |
US4325832A (en) * | 1979-03-05 | 1982-04-20 | Beckman Instruments, Inc. | Enzyme reference composition |
US4789545A (en) * | 1986-03-31 | 1988-12-06 | New York Blood Center, Inc. | Removal of lipid soluble process chemicals from biological materials by extraction with naturally occurring oils or synthetic substitutes thereof |
US4806486A (en) * | 1985-01-31 | 1989-02-21 | Stichting Gastransport | Calibration liquid for ion-specific electrodes, process for preparing them and their application |
US4956299A (en) * | 1986-12-31 | 1990-09-11 | Ciba Corning Diagnostics Corp. | Complement stabilization |
US5028542A (en) * | 1990-02-07 | 1991-07-02 | Boehringer Mannheim Corporation | Glucose measurement control reagent and method of making the same |
US6268481B1 (en) | 1997-05-29 | 2001-07-31 | Medical Analysis Systems, Inc. | Covalently coupled troponin complexes |
US6509192B1 (en) * | 1992-02-24 | 2003-01-21 | Coulter International Corp. | Quality control method |
US20040137419A1 (en) * | 2003-01-15 | 2004-07-15 | V.I. Technologies, Inc. | Methods for removing microbicidal compounds from compositions |
CN101930009A (en) * | 2009-11-19 | 2010-12-29 | 首都医科大学附属北京朝阳医院 | Serum calcium standard substance |
-
1970
- 1970-11-24 US US92533A patent/US3682835A/en not_active Expired - Lifetime
-
1971
- 1971-11-05 CA CA126,995A patent/CA962193A/en not_active Expired
- 1971-11-08 IL IL38093A patent/IL38093A/en unknown
- 1971-11-09 ZA ZA717532A patent/ZA717532B/en unknown
- 1971-11-10 GB GB5221371A patent/GB1359232A/en not_active Expired
- 1971-11-10 AU AU35540/71A patent/AU464164B2/en not_active Expired
- 1971-11-11 LU LU64243D patent/LU64243A1/xx unknown
- 1971-11-15 DE DE19712156604 patent/DE2156604A1/en active Pending
- 1971-11-16 BE BE775340A patent/BE775340A/en unknown
- 1971-11-18 CH CH1683971A patent/CH542446A/en not_active IP Right Cessation
- 1971-11-22 ES ES397245A patent/ES397245A1/en not_active Expired
- 1971-11-23 SE SE7114976A patent/SE376309B/xx unknown
- 1971-11-23 FR FR7142762A patent/FR2116164A5/fr not_active Expired
- 1971-11-23 IT IT31516/71A patent/IT941771B/en active
- 1971-11-24 NL NL7116167A patent/NL7116167A/xx unknown
Cited By (29)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3897363A (en) * | 1973-08-10 | 1975-07-29 | Baxter Laboratories Inc | Blood control standard |
US3955925A (en) * | 1973-11-12 | 1976-05-11 | Proksch Gary J | Preparation of optically clear serum |
US4190573A (en) * | 1974-02-14 | 1980-02-26 | Behringwerke Aktiengesellschaft | Process for the isolation of the polyvalent proteinase inhibitor |
US4056484A (en) * | 1974-12-31 | 1977-11-01 | Behringwerke Aktiengesellschaft | Stable blood plasma, process for preparing it and its use as comparative plasma in coagulation tests |
US3958939A (en) * | 1975-01-08 | 1976-05-25 | Coulter Electronics, Inc. | Method for clarification of lipemic serum |
US4011045A (en) * | 1975-02-14 | 1977-03-08 | Bonderman Dean P | Turbidity reduction in triglyceride standards |
US4045176A (en) * | 1975-06-13 | 1977-08-30 | Proksch Gary J | Preparation of optically clear serum |
US4007008A (en) * | 1975-07-30 | 1977-02-08 | Becker Milton J | Preparation of reference serum from animal blood |
US4054488A (en) * | 1975-08-14 | 1977-10-18 | Marbach Edward P | Preservation of glucose in blood samples |
US4116635A (en) * | 1977-03-14 | 1978-09-26 | Jaeger Mark A | General purpose in vitro anticoagulant |
US4127502A (en) * | 1977-06-10 | 1978-11-28 | Eastman Kodak Company | Stabilizers for reconstituted, lyophilized samples |
DE2825391A1 (en) * | 1977-06-10 | 1978-12-21 | Eastman Kodak Co | SERUM MATRIX OR SERUM DERIVED COMPOSITION |
DE2927841A1 (en) * | 1978-07-17 | 1980-02-07 | Beckman Instruments Inc | METHOD FOR PRODUCING A BIOLOGICAL COMPOSITION FOR USE AS A BLOOD SERUM REFERENCE COMPOSITION FOR DIAGNOSTIC ANALYZING PURPOSES |
US4324687A (en) * | 1979-02-15 | 1982-04-13 | Louderback Allan Lee | Blood biochemistry control standard |
US4325832A (en) * | 1979-03-05 | 1982-04-20 | Beckman Instruments, Inc. | Enzyme reference composition |
US4264471A (en) * | 1979-06-04 | 1981-04-28 | E. I. Du Pont De Nemours And Company | Serum and plasma clarification process |
US4219440A (en) * | 1979-06-06 | 1980-08-26 | Coulter Electronics, Inc. | Multiple analysis hematology reference control reagent and method of making the same |
US4806486A (en) * | 1985-01-31 | 1989-02-21 | Stichting Gastransport | Calibration liquid for ion-specific electrodes, process for preparing them and their application |
US4789545A (en) * | 1986-03-31 | 1988-12-06 | New York Blood Center, Inc. | Removal of lipid soluble process chemicals from biological materials by extraction with naturally occurring oils or synthetic substitutes thereof |
US4956299A (en) * | 1986-12-31 | 1990-09-11 | Ciba Corning Diagnostics Corp. | Complement stabilization |
US5028542A (en) * | 1990-02-07 | 1991-07-02 | Boehringer Mannheim Corporation | Glucose measurement control reagent and method of making the same |
US6509192B1 (en) * | 1992-02-24 | 2003-01-21 | Coulter International Corp. | Quality control method |
US20030092184A1 (en) * | 1992-02-24 | 2003-05-15 | Coulter International Corporation | Quality control method |
US20050095719A1 (en) * | 1992-02-24 | 2005-05-05 | Young Carole J. | Quality control method |
US6268481B1 (en) | 1997-05-29 | 2001-07-31 | Medical Analysis Systems, Inc. | Covalently coupled troponin complexes |
US20040137419A1 (en) * | 2003-01-15 | 2004-07-15 | V.I. Technologies, Inc. | Methods for removing microbicidal compounds from compositions |
WO2004065008A1 (en) * | 2003-01-15 | 2004-08-05 | V.I. Technologies, Inc. | Methods for removing microbicidal compounds from compositions |
CN101930009A (en) * | 2009-11-19 | 2010-12-29 | 首都医科大学附属北京朝阳医院 | Serum calcium standard substance |
CN101930009B (en) * | 2009-11-19 | 2013-09-11 | 首都医科大学附属北京朝阳医院 | Serum calcium standard substance |
Also Published As
Publication number | Publication date |
---|---|
FR2116164A5 (en) | 1972-07-07 |
CH542446A (en) | 1973-09-30 |
LU64243A1 (en) | 1972-06-02 |
SE376309B (en) | 1975-05-12 |
IL38093A0 (en) | 1972-01-27 |
BE775340A (en) | 1972-03-16 |
ES397245A1 (en) | 1975-03-01 |
DE2156604A1 (en) | 1972-05-31 |
IL38093A (en) | 1974-07-31 |
AU464164B2 (en) | 1975-08-21 |
ZA717532B (en) | 1972-07-26 |
NL7116167A (en) | 1972-05-26 |
CA962193A (en) | 1975-02-04 |
IT941771B (en) | 1973-03-10 |
GB1359232A (en) | 1974-07-10 |
AU3554071A (en) | 1973-05-17 |
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