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WO2001085771A1 - Virus s-ttv apparente au virus ttv - Google Patents

Virus s-ttv apparente au virus ttv Download PDF

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Publication number
WO2001085771A1
WO2001085771A1 PCT/JP2001/003954 JP0103954W WO0185771A1 WO 2001085771 A1 WO2001085771 A1 WO 2001085771A1 JP 0103954 W JP0103954 W JP 0103954W WO 0185771 A1 WO0185771 A1 WO 0185771A1
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Prior art keywords
dna
seq
ttv
nucleotide sequence
measuring
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English (en)
Japanese (ja)
Inventor
Kenji Abe
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Eisai Co Ltd
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Eisai Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/005—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from viruses
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/70—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving virus or bacteriophage
    • C12Q1/701—Specific hybridization probes
    • C12Q1/706—Specific hybridization probes for hepatitis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2750/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA ssDNA viruses
    • C12N2750/00011—Details
    • C12N2750/00021—Viruses as such, e.g. new isolates, mutants or their genomic sequences
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2750/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA ssDNA viruses
    • C12N2750/00011—Details
    • C12N2750/00022—New viral proteins or individual genes, new structural or functional aspects of known viral proteins or genes

Definitions

  • the present invention relates to DNA and protein of s-TTV, a TTV-related virus newly isolated from chimpanzee, and uses thereof.
  • Conventional technology s-TTV, a TTV-related virus newly isolated from chimpanzee, and uses thereof.
  • TTV TT virus
  • TTV is a non-enveloped, circular single-stranded DNA virus with a genome size of 3,852 nucleotides and an open reading frame capable of encoding three proteins of 770, 202, and 105 amino acids.
  • the sedimentation coefficient is 1.31 to 1.34 g / ml in cesium chloride solution, and from these properties, it is considered to be the closest relative to the Circoviridae virus in the animal virus family (Miyata, J. Virol. 73, 3582). -3586 (1999 Takahashi, Hepatol. Res. 12, 111-120 (1998).
  • TTV has diverse base sequences and is classified into several genotypes.
  • TTV genome is found in the serum and liver tissue of hepatitis patients, it may be a causative virus of certain unknown and acute hepatitis hepatitis (Charton, Hepatology 28, 839-842 (1998), Okamoto, Hepatol. Res. 10, 1-16 (1998)
  • TTV infection does not cause liver lesions in particular (Naoumov, Lancet 352, 195-197 (1998)).
  • TTV is a very common virus that is widely transmitted to healthy people worldwide (Abe, J. Clin. Microbiol. 37, 2703-2705 (1999)).
  • TTV transmission route of TTV
  • its clinical positioning and the conditions for establishing infection.
  • no appropriate animal model has been found to examine these factors.
  • the present inventor considered that a novel TTV-related virus may be involved in human diseases such as chronic hepatitis and attempted to detect a new TTV-related virus from chimpanzees.
  • an object of the present invention is to clone a novel viral DNA associated with TTV, to establish an antibody and DNA measurement method for diagnosing infection with the novel TTV virus, and to provide a novel TTV-related virus.
  • the present inventors succeeded in obtaining a PCR product of TTV-related virus DNA from chimpanzee serum by using the primers shown in SEQ ID NO: 5 and SEQ ID NO: 6. Further, the PCR product was cloned to determine the entire nucleotide sequence of the TTV-related virus. Then, it was confirmed that the determined nucleotide sequence of the TTV-related virus did not show high homology with the TTV DNA found so far, and was a novel TTV-related virus s-TTV.
  • DNA comprising the nucleotide sequence of SEQ ID NO: 1 or SEQ ID NO: 11.
  • An s-TTV DNA comprising a nucleotide sequence having a homology of 70% or more with the DNA comprising the nucleotide sequence of SEQ ID NO: 1.
  • An s-TTV DNA comprising a nucleotide sequence having a homology of 80% or more with the DNA comprising the nucleotide sequence of SEQ ID NO: 1.
  • An s-TTV DNA comprising a nucleotide sequence having 90% or more homology with the DNA comprising the nucleotide sequence of SEQ ID NO: 1.
  • DNA of SEQ ID NO: 26 and a DNA comprising a nucleotide sequence complementary to at least 15 consecutive nucleotide sequences of the nucleotide sequence of SEQ ID NO: 1 or SEQ ID NO: 11, or
  • S-TTV DNA that is amplified using as primer.
  • 7.1 measuring an antibody against s-TTV comprising the step of measuring the binding of a peptide consisting of at least eight consecutive amino acid sequences of the amino acid sequence encoded by the DNA described in any one of 1 to 5 to the antibody how to.
  • a method comprising immobilizing a peptide consisting of at least eight consecutive amino acid sequences of the amino acid sequence encoded by the DNA according to any one of 1 to 5, and measuring an antibody that binds to the peptide
  • a method for measuring an antibody against s-TTV A method for measuring an antibody against s-TTV.
  • a measurement reagent for measuring an antibody against s-TTV comprising a peptide comprising at least eight consecutive amino acid sequences of the amino acid sequence encoded by the DNA according to any one of 1 to 5 as a component.
  • a DNA comprising at least 15 consecutive nucleotide sequences of the nucleotide sequence of SEQ ID NO: 1 or SEQ ID NO: 11, and at least 15 consecutive DNAs of the nucleotide sequence of SEQ ID NO: 1 or SEQ ID NO: 11
  • Purify DNA consisting of a base sequence complementary to the base sequence
  • a method for measuring s-TTV DNA which includes amplifying s-TTV-derived DNA as a primer.
  • a method for measuring s-TTV DNA comprising the step of amplifying s-TTV-derived DNA using as a primer.
  • a DNA comprising at least 15 consecutive nucleotide sequences of the nucleotide sequence of SEQ ID NO: 1 or SEQ ID NO: 11, and at least 15 consecutive nucleotides of the nucleotide sequence of SEQ ID NO: 1 or SEQ ID NO: 11
  • a measurement reagent for measuring s-TTV DNA which comprises DNA consisting of a nucleotide sequence complementary to the nucleotide sequence as a component.
  • the measurement reagent for measuring s-TTV DNA according to 12, wherein the nucleotide sequence complementary to at least 15 consecutive nucleotide sequences of the nucleotide sequence described above is the DNA according to SEQ ID NO: 27.
  • a reagent for diagnosing non-A non-B non-C hepatitis according to 12 or 13;
  • Embodiments of the present invention are described below l) Method for cloning s-TTV DNA, 2) Insertion into vector, expression of s-TTV protein and production of antibody, 3) Antibody to s-TTV The details of the assay method, 4) .s-TTV DNA assay method, and 5) .s-TTV infected animal model are described in this order. 1) .s-TTV DNA Cloning
  • primers can be set based on the nucleotide sequence of s-TTV described in SEQ ID NO: 1 or SEQ ID NO: 11, and PC can be performed to perform cloning.
  • a DNA purified from human or chimpanzee serum is used as a template, and a continuous base sequence of 15 or more bases, preferably 20 or more bases, of the base sequence of SEQ ID NO: 1 or SEQ ID NO: 11
  • a combination of the base sequence thus obtained and a continuous base sequence of 15 bases or more, preferably 20 bases or more downstream of 100 bp to 3.5 bases from the base sequence, more preferably SEQ ID NO: 5 PCR is performed using, as primers, a DNA consisting of the nucleotide sequence of the combination of SEQ ID NO: 6, or the combination of SEQ ID NO: 7 and SEQ ID NO: 8, or the combination of SEQ ID NO: 9 and SEQ ID NO: 10.
  • the amplified DNA band is cut out and inserted into an appropriate vector, for example, pT7Blue (R) T, pUC, pBlueScript, and the nucleotide sequence is determined.
  • the nucleotide sequence is 70%, preferably 80% A clone containing a%, more preferably 90% homologous nucleotide sequence is selected.
  • the material used to purify DNA as a template is not limited to serum.
  • DNA purified from an organ suspected to be infected can be used.
  • the chimpanzee serum used in the present invention is stored at ⁇ 80 ° C. in a usable state at the Diagnostics Research Laboratory, Tsukuba Research Laboratory, Inc.
  • the region coding for the cloned s-TTV DNA protein should be expressed in an appropriate expression vector, E. coli, or pGEXZT, pRSET, pTvCHis, or insect cell SF9.
  • E. coli or pGEXZT, pRSET, pTvCHis, or insect cell SF9.
  • it can be inserted into pACYMl or, if using mammalian cells as a host, into pSR restriction ApCMV.
  • fusion protein with, for example, GST, His DNA, etc., and furthermore, a region which is more likely to be an antigenic determinant than the s-TTV amino acid sequence, at least 8, preferably 10 It is permissible to select a region consisting of at least two consecutive amino acid sequences and express it as a fusion protein with GST or the like. It is also allowed to further insert a selection marker for selecting cells into which the gene has been introduced Q , such as a neomycin resistance gene.
  • the expression vector into which s-TTV DNA has been inserted is introduced into host cells such as Escherichia coli, insect cells, and mammalian cells. Introduction into host cells is performed according to the method described in, for example, Sambruck, J., Fritsch, EF, and Maniatis, T. (1989) Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, etc. be able to.
  • the cells After the introduction of the vector into the host cell, if a selection marker has been inserted into the vector, the cells are cultured in the presence of the corresponding drug, and cells containing the introduced gene are selected.
  • Proteins containing the s-TTV amino acid sequence expressed in host cells into which the expression vector has been introduced can be purified by appropriately combining conventional methods such as various chromatography, electrophoresis, and gel filtration methods. It is possible. For example, when expressed as a fusion protein with GST or His tag, it is possible to purify using a Daltathione Sepharose column and a Nickel Sepharose column, respectively.
  • the purified protein containing the s-TTV amino acid sequence is used to immunize mammals to produce antibodies.
  • the mammal is a non-human mammal, and is preferably a goat, a rabbit, a rodent, or the like suitable for immunization.
  • rodents which can be used for preparing monoclonal antibodies after obtaining antisera, are preferable.
  • the purified protein containing the s-TTV amino acid sequence is subjected to an appropriate treatment to enhance immunogenicity, if necessary, for example, a treatment with Freund's complete adjuvant to form an emulsion, and then subcutaneously or intraperitoneally into a mammal. It is administered to a foot pad or the like for immunization.
  • Blood is collected from the immunized animal by an appropriate method, and an antiserum against the protein is further purified from the blood to obtain an antibody against the protein.
  • an organ containing antibody-producing cells such as spleen and lymph nodes is removed from the immunized mammal, and lymphocytes are separated therefrom.
  • the isolated lymphocytes are subjected to cell fusion using appropriate myeloma cells, for example, P3 cells, for example, using PEG, and RPMI-1640 medium containing an appropriate medium, for example, 10% FCS, 10% ORIGEN HCF (manufactured by ICGS).
  • the monoclonal antibody secreted into the culture supernatant of the fused cells is analyzed to select the fused cells that produce the desired antibody. If necessary, clone the fused cells using an ultra-dilution method.
  • the obtained antibody against the s-TTV protein can be used, for example, for measuring the S-TTV antigen by an antigen sandwich method or the like, or for measuring the antibody against the s-TTV antigen by a competition method.
  • a specific antibody against s-TTV is obtained by reacting human or animal serum and plasma with an immobilized antigen and labeling a substance that specifically reacts with human or animal antibody, for example, labeling for human antibody.
  • the reaction is performed by reacting an antibody, labeled protein A, or the like.
  • the antigen to be immobilized it is preferable to use an s-TTV protein / fusion protein purified from a host into which the aforementioned expression vector containing s-TTV DNA has been introduced, and in some cases, may be an antigenic determinant.
  • the peptide in the region, which consists of at least 8, preferably 10 or more consecutive amino acid sequences, alone or in a complex with a protein such as albumin.
  • these polypeptides serving as antigens are selected from a region containing a sequence specific to s-TTV, for example, SEQ ID NO: 26 or 27.
  • Enzyme labels, radioactive labels and the like are widely used as typical labels, and furthermore, substances that have a strong and specific binding to a specific substance (for example, avidin) (for example, pio (Chin) is also permitted.
  • the labeling substance a method corresponding to the labeling is used, for example, the enzyme activity is measured for an enzyme label, the radioactivity is measured for a radioactive label, and the antibody titer in serum and plasma is measured.
  • s-TTV DNA measurement is preferable for s-TTV detection because it has higher sensitivity than the above-mentioned s-TTV antigen measurement.
  • Detection of s-TTV DNA is performed by a DNA amplification technique using primers, and is particularly preferably performed by PCR.
  • the primer comprises a continuous base sequence of 15 bases or more, preferably 20 bases or more of the base sequence of SEQ ID NO: 1 or SEQ ID NO: 11, and 100 bp to 3.5 kb from the base sequence.
  • a continuous base sequence of 15 or more bases preferably a combination of complementary sequences of 20 or more bases, more preferably a combination of SEQ ID NO: 5 and SEQ ID NO: 6, or a combination of SEQ ID NO: 7 and SEQ ID NO: 8
  • the most preferred primers for detecting s-TTV are And a DNA comprising a combination of SEQ ID NO: 26 or SEQ ID NO: 27, which is a sequence specific to s-TTV, and more preferably a nucleotide sequence of the combination of SEQ ID NO: 26 and SEQ ID NO: 27.
  • Conditions such as the number of PCEs, temperature, and time, and whether or not to use nested PCR can be determined as appropriate.
  • the amplified DNA can be conveniently subjected to agarose or polyacrylamide electrophoresis. Higher sensitivity methods using fluorescently labeled primers ⁇ Methods using radioactive probes have also been reported, but DNA detection methods are not limited to these methods.
  • the measurement of s-TTV DNA results in detection of s-TTV.
  • s-TTV infects chimpanzees
  • monkeys preferably chimpanzees
  • s-TTV infects chimpanzees
  • monkeys preferably chimpanzees
  • chimpanzee infection is established by inoculating chimpanzee with infected serum. Thereafter, the progress of infection can be monitored by measuring anti-s-TTV antibody or s-TTV DNA in serum. Whether or not the target disease state has occurred can be determined from a disease-specific marker and a histopathological image.
  • a novel virus s-TTV DNA related to TTV is cloned, and s-TTV DNA measurement, s-TTV antigen measurement, and anti-s-TTV antibody measurement can be performed. It has become possible to detect infection or track the progress of infection.
  • SEQ ID NOS: 1-27 are as set forth in the annex attached to the present specification, and the disclosure of the present invention includes these.
  • FIG. 1 shows the structure of the s-TTV CH65-1 strain gene.
  • DNA was extracted from 100 chimpanzee sera. DNA extraction was performed using a commercially available kit (SepaGene RV-R; Sanko Jyunyaku Co., Ltd., Tokyo, Japan). The obtained nucleic acid precipitate was dissolved in HNase-free and DNase-free water.
  • PCR products were stained with ethidium bromide after 2% agarose gel electrophoresis and detected under UV irradiation.
  • the PCR product was extracted and purified from agarose gel using a commercially available kit (QIAquick gel extraction kit; Qiagen Inc., Chatsworth, Calif., USA). Was.
  • the recovered PCR product was subcloned into the EcoRV site of a Bluescript II SK (-) vector (Stratagene, La Jolla, Calif, USA) by a conventional method.
  • ABI PRISM BigDyeTM Terminator Cycle Sequencing Ready Reaction kit For nucleotide sequence determination, use the ABI PRISM BigDyeTM Terminator Cycle Sequencing Ready Reaction kit.
  • Fragment E was obtained by PCR using the DNAs of SEQ ID NOs: 7 and 8 (Okamoto, Hepatol. Res. 10, 1-16 (1998)) as primers. Primers of the DNAs of SEQ ID NO: 9 and SEQ ID NO: 10
  • Fragment K was amplified by PCR (Okamoto, Hepatol. Res. 10, 1-16 (1998)) and the nucleotide sequence was determined in the same manner. The sequence of the GC-rich region of Fragment II was further confirmed by the Maxam-Gilbert method (Maxam, Methods Enzymology 65, 499-560 (1980)).
  • the CH71 strain was isolated in the same manner from chimpanzee serum of an individual different from the chimpanzee from which the CH65-1 strain was isolated.
  • Fragment A was obtained by performing PCR using the DNAs of SEQ ID NOS: 15 and 16 as primers, followed by nested PCR using the DNAs of SEQ ID NOs: 17 and 18 as primers .
  • semi-nested PCR using the DNAs of SEQ ID NOs: 15 and 20 as primers was performed. Obtained Fragment M.
  • semi-nested PCR was performed using the DNAs of SEQ IDs 23 and 22 as primers to obtain Fragment N. Obtained.
  • nucleotide sequences of Fragment A, M, and N were determined, and based on these nucleotide sequences, the entire nucleotide sequence of s-TTV different from the CH65-1 strain was determined (SEQ ID NO: 11) to obtain CH71 strain.
  • Example 3 Detection of s-TTV gene from hepatitis patient serum DNA was extracted from human serum of IOOI using a commercially available kit (SepaGene RV-R; Sanko Jyunyaku Co., Ltd., Tokyo, Japan) and dissolved in RNase-free and Dnase-free water. Using the extracted DNA as type III, PCR was performed with 1st round PCR using human TTV-specific primers and 2nd round (nested) PGR with s-TTV-specific primers to obtain the s-TTV gene from human serum. Was detected.
  • primers, primers, nucleotides, and AmpliTaq Gold DNA Polymerase are added to the extracted DNA solution and heated at 95 ° C for 10 minutes. Forty cycles of PCR were performed. The PCR conditions were 94 ° C for 20 seconds, 60 ° C for 20 seconds, and 72 ° C for 30 seconds, using a Perkin-Elmer 9600 or 9700 Thermal Cycler (Perkin-Elmer, Norwalk, Conn.). Primers reported by Takahashi et al.
  • oligo nucleotides of SEQ ID NOS: 24 and 25 were synthesized based on the nucleotide sequence of human TTV.
  • a part of the 1st round PG reaction solution was made into a type II, and 2nd round (nested) PGR was performed. After heating at 95 ° C for 10 minutes, 40 cycles of PCR were performed at 94 ° C for 20 seconds, 68.5 ° C for 20 seconds, and 72 ° C for 30 seconds.
  • primers s-TTV sequence-specific SEQ ID NOs: 26 and 27 were used. After 2% agarose gel electrophoresis, the PCR product was stained with etidumimide and detected under UV irradiation.
  • the positive rate was 100 out of 100 blood donors in Japan (1%), while 7 out of 183 patients with liver disease (3.8%) was positive (3.8%) (Table 1).
  • Table 1 Total number of s-TTV infections detected in humans s-TTV positive (positive rate)
  • nucleotide sequence of the PCR product was determined and confirmed to be s-TTV type sequence (Table 2).
  • the nucleotide sequence was determined using ABI PRISM BigDyeTM Terminator Cycle Sequencing Ready Reaction kit (Perkin-Elmer, Norwalk, Conn., USA) and ABI PRISMTM 310 Genetic Analyzer (Applied Biosystems, Foster City, Calif., USA). .
  • ⁇ ⁇ corresponds to the Human TTV TA278 strain shown at the top.

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Abstract

L'invention concerne des moyens de détection d'un virus apparenté au virus TTV sachant que ce nouveau virus est censé provoquer des maladies chez l'homme telles que l'hépatite chronique. L'ADN du virus s-TTV, apparenté au virus TTV, est cloné ce qui permet de tester l'ADN du virus s-TTV, un antigène s-TTV et un anticorps anti-s-TTV. Il en résulte la possibilité de détecter une infection provoquée par le virus s-TTV ou bien de suivre le processus d'infection. On peut ainsi examiner les relations entre le virus s-TTV et des maladies de l'homme et on peut construire des modèles animaux prouvant ces relations.
PCT/JP2001/003954 2000-05-11 2001-05-11 Virus s-ttv apparente au virus ttv Ceased WO2001085771A1 (fr)

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JP2000-340614 2000-11-08
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE10334562B4 (de) 2003-07-29 2005-06-09 Erbe Elektromedizin Gmbh Chirurgisches Instrument

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999058638A2 (fr) * 1998-05-13 1999-11-18 Innogenetics N.V. Nouvelles sequences de virus tt pour l'utilisation en diagnostic et pour la prevention et le traitement d'infections ttv
JP2000125881A (ja) * 1998-10-19 2000-05-09 Srl Inc Ｔｔウイルスの遺伝子型分類方法

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999058638A2 (fr) * 1998-05-13 1999-11-18 Innogenetics N.V. Nouvelles sequences de virus tt pour l'utilisation en diagnostic et pour la prevention et le traitement d'infections ttv
JP2000125881A (ja) * 1998-10-19 2000-05-09 Srl Inc Ｔｔウイルスの遺伝子型分類方法

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
ABE K. ET AL.: "TT virus infection in nonhuman primates and characterization of the viral genome: identification of simian TT virus isolates", J. OF VIROL., vol. 74, no. 3, February 2000 (2000-02-01), pages 1549 - 1553, XP002944851 *
INAMI T. ET AL.: "Full-length nucleotide sequence of a simian TT virus isolate obtained from a chimpanzee: evidence for a new TT virus-like species", VIROLOGY, vol. 277, November 2000 (2000-11-01), pages 330 - 335, XP002944852 *
OKAMOTO H. ET AL.: "Species-specific TT viruses and cross-species infection in nonhuman primates", J. OF VIROL., vol. 74, no. 3, February 2000 (2000-02-01), pages 1132 - 1139, XP002944853 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE10334562B4 (de) 2003-07-29 2005-06-09 Erbe Elektromedizin Gmbh Chirurgisches Instrument

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