Original Article
Detection of Borrelia burgdorferi DNA by Polymerase Chain Reaction in Synovial Fluid from Patients with Lyme Arthritis
N Engl J Med 1994; 330:229-234January 27, 1994
- Abstract
Background
Borrelia burgdorferi is difficult to detect in synovial fluid, which limits our understanding of the pathogenesis of Lyme arthritis, particularly when arthritis persists despite antibiotic therapy.
Methods
Using the polymerase chain reaction (PCR), we attempted to detect B. burgdorferi DNA in joint-fluid samples obtained over a 17-year period. The samples were tested in two separate laboratories with four sets of primers and probes, three of which target plasmid DNA that encodes outer-surface protein A (OspA).
Results
B. burgdorferi DNA was detected in 75 of 88 patients with Lyme arthritis (85 percent) and in none of 64 control patients. Each of the three OspA primer-probe sets was sensitive, and the results were moderately concordant in the two laboratories (kappa = 0.54 to 0.73). Of 73 patients with Lyme arthritis that was untreated or treated with only short courses of oral antibiotics, 70 (96 percent) had positive PCR results. In contrast, of 19 patients who received either parenteral antibiotics or long courses of oral antibiotics ( ≥ 1 month), only 7 (37 percent) had positive tests (P<0.001). None of these seven patients had received more than two months of oral antibiotic treatment or more than three weeks of intravenous antibiotic treatment. Of 10 patients with chronic arthritis (continuous joint inflammation for one year or more) despite multiple courses of antibiotics, 7 had consistently negative tests in samples obtained three months to two years after treatment.
Conclusions
PCR testing can detect B. burgdorferi DNA in synovial fluid. This test may be able to show whether Lyme arthritis that persists after antibiotic treatment is due to persistence of the spirochete.
Media in This Article
Figure 1
Natural History of Lyme Arthritis and PCR Results in 12 Untreated Patients.Table 1
Oligonucleotide Primer and Probe Sequences.Article Activity
- Article
Lyme disease is caused by the tick-borne spirochete Borrelia burgdorferi1. Weeks to months after the onset of disease, approximately 60 percent of untreated patients begin to have brief, intermittent attacks of arthritis that may recur for several years2. A small percentage of these patients have continuous arthritis for one year or longer, a condition we have termed “chronic Lyme arthritis”2,3. Eventually, both intermittent and chronic Lyme arthritis resolve, even in untreated patients2,4.
Lyme arthritis can usually be treated successfully with either a one-month course of doxycycline or amoxicillin or a two-week course of intravenous ceftriaxone or penicillin5-7. However, a small percentage of patients have persistent arthritis despite multiple courses of oral and intravenous antibiotic therapy5-7. In these patients there is an increased frequency of HLA-DR4 or, secondarily, HLA-DR2 in association with antibody reactivity to outer-surface proteins A and B (OspA and OspB) of the spirochete8,9. It has been unclear whether this treatment-resistant course results from persistent infection or from postinfective immune-mediated phenomena. The ability to demonstrate the presence or absence of B. burgdorferi in the joint would improve our understanding of the pathogenesis of Lyme arthritis.
B. burgdorferi can be cultured readily from the skin lesions of erythema migrans,10 but it has been difficult to detect the spirochete in joints; it has been recovered from the synovial fluid of only two patients with Lyme arthritis11,12. With immunohistologic techniques, spirochetal forms have been seen in synovial tissue,13 but this method of detection has been inconclusive. The polymerase chain reaction (PCR) has recently been used to amplify and detect B. burgdorferi DNA in cultured spirochetes,14,15 Ixodes dammini ticks,16,17 infected animals,18,19 and patients with Lyme disease20-33. In these studies, DNA sequences have been successfully detected in blood,20,21,30,32 cerebrospinal fluid,22-25,32,33 urine,21,25,28,32 skin,29-31 and (in eight cases) synovial fluid21,26,27,32. Thus, the PCR assay is capable of amplifying and detecting B. burgdorferi DNA, but its value as a reliable diagnostic test, particularly in synovial fluid, is not yet clear.
We report here on our evaluation of PCR testing as a diagnostic test for the presence of B. burgdorferi DNA in synovial fluid. If the test can reliably identify the presence of spirochetes, it may help to determine whether persistent arthritis after treatment is due to active infection or to an immune reaction that persists after the eradication of viable spirochetes.
Methods
Patients
During a 17-year period, samples of synovial fluid were collected from 127 patients with Lyme arthritis who were seen in the Lyme disease clinics at Yale-New Haven Hospital (1975 to 1987) or New England Medical Center (1987 to 1992). The following criteria were used to define Lyme arthritis: brief, intermittent attacks of oligoarticular arthritis, exposure in an area of endemic disease, an elevated antibody response to B. burgdorferi on enzyme-linked immunosorbent assay, and the exclusion of other known forms of arthritis. The synovial-fluid samples were divided into multiple aliquots and frozen at -70 °C; in most instances, the aliquot used for PCR testing was not opened before this study. Samples from 37 of the patients were collected in heparin, a known inhibitor of PCR amplification34; these samples were excluded from the study. Single samples were tested in 61 of the remaining 90 patients, and two to five serial samples were tested in 29. Clinical data collected from the charts of patients with Lyme arthritis were analyzed without knowledge of the results of PCR assays. During the same 17-year period, synovial fluid was also obtained from 69 control patients with other forms of arthritis. Seventeen of these samples were collected, processed, and stored in the same way as those from the patients with Lyme arthritis. Among the control patients, 20 had rheumatoid arthritis; 7 each had gout, osteoarthritis, and degenerative joint disease; 5 had juvenile rheumatoid arthritis; 2 each had pseudogout, psoriatic arthritis, scleroderma, spondyloarthropathy, and Reiter's syndrome; and 13 had other forms of arthritis.
PCR Assay
Synovial-fluid samples from case and control patients were processed in a blinded manner in two separate laboratories according to the following protocol. DNA was isolated from 100 to 200 microliters of synovial fluid with a commercially available kit (Isoquick, Microprobe, Bothell, Wash.) according to the manufacturer's specifications, modified by the addition of 20 μg of glycogen to each sample as a carrier during isopropanol precipitation. With each DNA extraction, synovial-fluid samples from case and control patients were processed simultaneously. Filter-barrier pipette tips and a dedicated set of pipettors were used to prepare all samples.
Three separate regions of the B. burgdorferi genome were targeted for PCR amplification by four sets of primers and probes (Table 1Table 1
Oligonucleotide Primer and Probe Sequences.). Sets 1, 2, and 3 targeted portions of the B. burgdorferi plasmid gene encoding OspA, and set 4 targeted a portion of the chromosomal DNA encoding 16S ribosomal RNA35. Sets 2 and 3 targeted the same sequence of the OspA gene for amplification, but used different internal probes for detection.Primers and probes were synthesized on an oligonucleotide synthesizer (Applied Biosystems, Foster City, Calif.), desalted on an oligonucleotide-purification cartridge (Glen Research, Sterling, Va.), and used without further purification. Total DNA was dissolved in 30 microliters of water; 5 microliters of this solution was added to a PCR mixture containing 50 pM of each primer (final concentration, 1.0 micro M), 200 micro M of each deoxynucleoside triphosphate, 10 mM TRIS-hydrochloride (pH 8.3), 50 mM potassium chloride, 17.5 mM magnesium chloride, 0.01 μg of bovine serum albumin per microliter, 10 percent glycerol, 0.5 percent Tween-20, and 1.25 units of Taq polymerase (Amplitaq, Perkin-Elmer Cetus, Norwalk, Conn.). Five micrograms of isopsoralen was added to the PCR mixture to inactivate products after amplification,36 and the total volume was adjusted to 50 microliters with water. The mixture was overlaid with one drop of mineral oil. Amplification reactions, which were performed in a thermal cycler (Perkin-Elmer Cetus) stored in a separate laboratory, consisted of 45 cycles of denaturation at 94 °C for 45 seconds, annealing at 50 °C for 45 seconds, and extension at 72 °C for 1 minute. The cycles were preceded by a four-minute phase at 94 °C and followed by a final seven-minute extension phase at 72 °C. After amplification, samples were immediately exposed to 20 mW of 300-to-400-nm light per square centimeter for 20 minutes to inactivate the products and were stored at -20 °C.
Control samples included with each amplification assay included samples with DNA extracted from control patients, three blank control samples with 5 microliters of water substituted for DNA, and a positive control sample with 60 pg of total B. burgdorferi DNA (strain 297). Amplification products were stored and analyzed in a separate area, and positive-displacement pipettes with disposable pistons were used to prepare all PCR reagents.
Amplified products (5 microliters) were resolved by 4 percent agarose gel electrophoresis (3 percent NuSieve and 1 percent SeaKem, FMC Corporation, Rockland, Me.) at 35 to 100 V for one to three hours. The gel was then stained with ethidium bromide and visualized, washed with water, washed in denaturation solution (1.5 M sodium chloride and 0.5 M sodium hydroxide) for 45 minutes, rinsed again with water, washed in neutralization solution (1.5 M sodium chloride and 0.5 M TRIS [pH 7.5]), and blotted. Blotting was performed overnight on a nylon membrane (Hybond-N, Amersham, Arlington Heights, Ill.) with 0.15 M sodium chloride and 0.015 M sodium citrate (SSC). The membrane was cross-linked with 0.12 J of ultraviolet light.
Membranes were washed in hybridization fluid (5x Denhardt's solution [1x Denhardt's solution is 0.02 percent Ficoll, 0.02 percent polyvinylpyrrolidone, and 0.02 percent bovine serum albumin], 0.75 M sodium chloride, 0.025 M sodium phosphate, 0.005 M ethylenediamine tetraacetate, 0.5 percent sodium dodecyl sulfate, and 100 μg of denatured salmon-sperm DNA per microliter) for four hours at 55 °C. An oligonucleotide probe end-labeled with phosphorus-32 was then added for 15 to 17 hours at 55 °C. After hybridization, the membranes were washed in 2x SSC and 0.1 percent sodium dodecyl sulfate for 10 minutes, 1x SSC and 0.1 percent sodium dodecyl sulfate for 20 minutes, and 0.2x SSC and 0.1 percent sodium dodecyl sulfate for 30 minutes. Finally, the membranes were exposed to Kodak XAR-5 film for 4 to 72 hours at -70 °C. Alternatively, the amplification products were detected by means of a chemiluminescent probe as described elsewhere37. DNA bands were rarely seen on ethidium-stained gels; samples were therefore considered positive on the basis of signal detection after hybridization.
Inhibition Assays
The initial samples from each patient with Lyme arthritis in which B. burgdorferi DNA was not detected and 62 of the 69 samples from the controls were tested for the presence of PCR inhibitors. One thousand copies (as determined by serial dilution) of the OspA2-OspA4 amplification product made without isopsoralen cross-linking were added to each sample and then amplified with primers OspA2 and OspA4. Samples that yielded no amplification signal were considered inhibitory and were excluded from the study.
Statistical Analysis
The similarity of groups was compared by Fisher's exact test, the distribution of values among the groups was compared by Wilcoxon rank-sum test, and concordance among test results was calculated with κ values according to the following formula: κ = (observed agreement - expected agreement) divided by (1 - expected agreement). All P values are two-tailed.
Results
In tests performed independently in two laboratories, B. burgdorferi DNA was detected with at least one primer-probe set in the initial samples of synovial fluid from 75 of the 90 patients with Lyme arthritis. In contrast, B. burgdorferi DNA was not found in any of the 69 control patients or in the blank control samples. In inhibition assays, 2 of the 15 negative samples from the patients with Lyme arthritis and 5 samples from control patients still produced negative results, indicating that inhibitors of PCR amplification were present. With these samples excluded, B. burgdorferi DNA was detected in the initial sample from 75 of 88 patients with Lyme arthritis but none of 64 control patients (Table 2Table 2
PCR Results in Synovial Fluid from Case and Control Patients.).Of the four primer-probe sets used in the two laboratories, the three OspA sets each detected B. burgdorferi DNA in 75 to 89 percent of the 75 patients with positive test results (Table 2). Forty-eight patients (64 percent) had positive results with all three OspA sets, whereas 18 patients (24 percent) had positive results with only one of the sets. Set 4, which detected chromosomal DNA encoding 16S ribosomal RNA, was less sensitive than the OspA primer-probe sets; 56 percent of the 75 patients had positive results with this set, and all of them also had positive results with OspA set 3. In laboratory 1, 88 percent of the patients had concordant results with the two OspA primer-probe sets used in that laboratory (kappa = 0.73). Between laboratories 1 and 2, 78 percent had concordant results with the OspA primer-probe sets that targeted the same gene segment (sets 2 and 3) (kappa = 0.54).
Clinical data from the 88 patients with Lyme arthritis were correlated with the PCR results from their initial samples of synovial fluid (Table 3Table 3
Clinical Data and PCR Results in Patients with Lyme Arthritis.). As compared with the 13 patients with negative results, the 75 patients in whom B. burgdorferi DNA was detected in joint fluid had significantly higher white-cell counts in synovial fluid (P<0.003), shorter durations of illness (P<0.02) and arthritis (P<0.03), and a longer duration of arthritis after aspiration (P = 0.03). Almost all of those with positive results were untreated or had only received short courses of oral antibiotic therapy (<1 month) before joint aspiration (P<0.001).Of the 88 patients in this study, 45 never received antibiotic therapy. B. burgdorferi DNA was detected in the synovial fluid of 43 of these patients (Table 4Table 4
PCR Results According to Antibiotic Treatment.). All 12 patients from whom serial samples were available for testing had detectable B. burgdorferi DNA in their first sample (Figure 1Figure 1Natural History of Lyme Arthritis and PCR Results in 12 Untreated Patients.). In 9 of the 12 patients, including the 3 who had chronic arthritis (one year or more of continuous joint inflammation), all additional samples were also positive months to years later during subsequent episodes of arthritis. In the remaining three patients, B. burgdorferi DNA was not detected in the last synovial-fluid sample, and their arthritis resolved within the next few months.Forty-three of the 88 patients received antibiotic therapy sometime during the course of Lyme disease. Of the 16 patients with pretreatment synovial-fluid samples available for testing, 15 had positive test results (Table 4). In another 12 patients with synovial fluid obtained two months to four years after short courses of oral antibiotic therapy, all samples were also positive. In 19 patients, 4 of whom also had pretreatment samples available for testing, synovial fluid was obtained after either long courses of oral antibiotics (doxycycline or amoxicillin for one month or more) or parenteral antibiotics (intravenous or intramuscular penicillin or intravenous ceftriaxone), regimens recommended for the treatment of Lyme arthritis38,39. In 7 of the 19 patients, B. burgdorferi DNA was detected in samples obtained 1 day to 17 months after the completion of antibiotic therapy. Three of these patients were treated with both oral and intravenous antibiotics, two received three weekly doses of intramuscular penicillin G benzathine, and two were given only oral antibiotics. The median duration of their oral treatment was 37 days (range, 20 to 58), and the median duration of intravenous therapy was 14 days (range, 14 to 20). In the remaining 12 patients, samples obtained one day to four years after antibiotic treatment were all negative. Seven of these patients were treated with intravenous antibiotics, two received intramuscular penicillin, and three were given only oral antibiotics. Their median duration of oral treatment was 48 days (range, 21 to 120), and the median duration of intravenous therapy was 30 days (range, 7 to 44). Although the patients with negative PCR results tended to have been treated longer than those with positive PCR results, the differences were not statistically significant. Of 10 patients who had chronic Lyme arthritis despite multiple courses of antibiotic therapy, 7 had negative test results in all post-treatment samples.
Altogether, of 73 patients with Lyme arthritis who were untreated or treated with short courses of oral antibiotics before testing, 70 (96 percent) had positive PCR results. In contrast, of 19 patients who received either parenteral antibiotics or long courses of oral antibiotics, only 7 (37 percent) had positive test results after treatment (P<0.001). In the 29 patients for whom serial samples were available, all pretreatment samples were positive. Once post-treatment samples became negative, all subsequent samples remained negative.
Discussion
We present evidence that PCR is a useful method for detecting B. burgdorferi DNA in synovial fluid from patients with Lyme arthritis. The main concern about this technique is that minute contamination may produce false positive results. To ensure that contamination did not influence our results, control samples of joint fluid were collected and stored like case samples, DNA extraction and PCR preparation were performed in a dedicated room, all PCR products were inactivated with isopsoralen after amplification, multiple blank control samples were included with each group of samples tested, and the samples were tested in a blinded manner in two separate laboratories. In both laboratories, nearly all joint-fluid samples from untreated patients with Lyme arthritis contained detectable B. burgdorferi DNA, most post-treatment samples did not, and all control samples were negative. This distribution would be extremely unlikely had the samples been contaminated.
In both laboratories, the sensitivity of each of the three OspA primer-probe sets was high (75 to 89 percent), and the results among these sets were moderately concordant. In contrast, the primer-probe set that detected chromosomal DNA was less sensitive. This discrepancy has been observed consistently in all our studies of B. burgdorferi detection in synovial fluid35. Multiple copies of OspA DNA segments may be contained within spirochetes, and these targets may therefore be more easily detected. Alternatively, spirochetes may not always be present in synovial fluid but may be capable of shedding OspA segments into the fluid from the surrounding synovium. Membrane vesicles containing extrachromosomal DNA are shed from the surface of the spirochete,40,41 and they have been postulated to be mediators of DNA transfer between organisms42. A third possibility is that plasmid DNA may persist in synovial fluid after the death of the spirochete. In our study and others,21,24 however, OspA DNA was detected primarily in untreated patients with clinically active disease. After antibiotic treatment, the PCR results were usually negative, which would not be expected if OspA DNA persisted after the spirochete had been killed. Likewise, in studies of experimental B. burgdorferi infection in mice, PCR results were almost always negative within two to four weeks after treatment with ceftriaxone (unpublished data). Another example of this phenomenon is the clearance of viral DNA from cerebrospinal fluid within one to four weeks after acyclovir treatment in patients with herpes simplex encephalitis43. Thus, it seems likely that the detection of OspA DNA in joint fluid indicates the presence of viable spirochetes. Further studies aimed at detecting potentially more labile spirochetal RNA molecules44 may help to confirm this hypothesis.
Since joint effusions resolved in most patients during the course of antibiotic therapy, it was usually not possible to obtain samples of synovial fluid after treatment. Of the patients with persistent effusions after one month of oral antibiotics or two weeks of intravenous antibiotics, approximately one third still had positive PCR results, suggesting that the spirochete may not have been eradicated. However, none of the patients with positive PCR results after treatment had received more than two months of oral antibiotics or three weeks of intravenous antibiotics. Most of the patients who had chronic arthritis despite multiple courses of antibiotic therapy had negative PCR results in all post-treatment samples. In these patients, the lack of response to antibiotics, the negative PCR results, and the association of this syndrome with immunogenetic and immune markers8,9 suggest that genetically susceptible persons may continue to have arthritis for months or even several years after the eradication of viable spirochetes from synovial fluid.
Despite the identification of B. burgdorferi as the cause of Lyme disease in 1982, it has been practically impossible to demonstrate the presence of the spirochete in synovial fluid. The PCR test of synovial fluid in Lyme arthritis now shows promise and may fill the role that culture serves in detecting common bacterial pathogens in septic arthritis. In addition, PCR results may prove useful when therapeutic decisions are made for patients with persistent Lyme arthritis despite multiple courses of antibiotic therapy.
Supported in part by grants (AR-20358, AR-40576, and AR-07570 to Dr. Steere; and AR-41497, AI-32403, and AI-30548 to Dr. Persing) from the National Institutes of Health and by the Eshe Fund.
We are indebted to Brenda Fung for many helpful suggestions, Michael Berne for synthesizing oligonucleotide primers and probes, Chris Schmid for statistical assistance, Tim Rotman for assistance in preparing the figures, and April Chang-Miller, Joseph Duffy, Paul Dellaripa, Robert Kalish, James Logan, and other members of the Mayo Section of Rheumatology and the New England Medical Center Division of Rheumatology/Immunology for providing synovial-fluid samples from control patients.
Source Information
From the Divisions of Rheumatology/Immunology (J.J.N., F.D., A.C.S.) and Pediatric Rheumatology (J.J.N., F.D.), New England Medical Center and Tufts University School of Medicine, Boston; and the Sections of Clinical Microbiology, Infectious Diseases, and Experimental Pathology, Mayo Foundation, Rochester, Minn. (B.J.R., P.N.R., D.H.P.).
Address reprint requests to Dr. Nocton at the Division of Rheumatology/Immunology, New England Medical Center, 750 Washington St., Boston, MA 02111.
- References
References
1
Steere AC . Lyme disease. N Engl J Med 1989;321:586-596
Full Text | Web of Science | Medline2
Steere AC ,Schoen RT ,Taylor E . The clinical evolution of Lyme arthritis. Ann Intern Med 1987;107:725-731
Web of Science | Medline3
Steere AC ,Gibofsky A ,Patarroyo ME ,Winchester RJ ,Hardin JA ,Malawista SE . Chronic Lyme arthritis: clinical and immunogenetic differentiation from rheumatoid arthritis. Ann Intern Med 1979;90:896-901
Web of Science | Medline4
Szer IS ,Taylor E ,Steere AC . The long-term course of Lyme arthritis in children. N Engl J Med 1991;325:159-163
Full Text | Web of Science | Medline5
Steere AC ,Green J ,Schoen RT , et al. Successful parenteral penicillin therapy of established Lyme arthritis. N Engl J Med 1985;312:869-874
Full Text | Web of Science | Medline6
Dattwyler RJ ,Halperin JJ ,Volkman DJ ,Luft BJ . Treatment of late Lyme borreliosis -- randomised comparison of ceftriaxone and penicillin. Lancet 1988;1:1191-1194
CrossRef | Web of Science | Medline7
Steere AC ,Levin RE ,Molloy PJ , et al. Antibiotic treatment of Lyme arthritis. Arthritis Rheum 1993;36:Suppl:S40-S40 abstract.
Web of Science8
Steere AC ,Dwyer E ,Winchester R . Association of chronic Lyme arthritis with HLA-DR4 and HLA-DR2 alleles. N Engl J Med 1990;323:219-223
Full Text | Web of Science | Medline9
Kalish RA ,Leong JM ,Steere AC . Association of treatment-resistant chronic Lyme arthritis with HLA-DR4 and antibody reactivity to OspA and OspB of Borrelia burgdorferi. Infect Immun 1993;61:2774-2779
Web of Science | Medline10
Berger BW ,Kaplan MH ,Rothenberg IR ,Barbour AG . Isolation and characterization of the Lyme disease spirochete from the skin of patients with erythema chronicum migans. J Am Acad Dermatol 1985;13:444-449
CrossRef | Web of Science | Medline11
Snydman DR ,Schenkein DP ,Berardi VP ,Lastavica CC ,Pariser KM . Borrelia burgdorferi in joint fluid in chronic Lyme arthritis. Ann Intern Med 1986;104:798-800
Web of Science | Medline12
Schmidli J ,Hunziker T ,Moesli P ,Schaad UB . Cultivation of Borrelia burgdorferi from joint fluid three months after treatment of facial palsy due to Lyme borreliosis. J Infect Dis 1988;158:905-906
CrossRef | Web of Science | Medline13
Steere AC ,Duray PH ,Butcher EC . Spirochetal antigens and lymphoid cell surface markers in Lyme synovitis: comparison with rheumatoid synovium and tonsillar lymphoid tissue. Arthritis Rheum 1988;31:487-495
CrossRef | Web of Science | Medline14
Rosa PA ,Schwan TG . A specific and sensitive assay for the Lyme disease spirochete Borrelia burgdorferi using the polymerase chain reaction. J Infect Dis 1989;160:1018-1029
CrossRef | Web of Science | Medline15
Nielsen SL ,Young KKY ,Barbour AG . Detection of Borrelia burgdorferi DNA by the polymerase chain reaction. Mol Cell Probes 1990;4:73-79
CrossRef | Web of Science | Medline16
Persing DH ,Telford SR III ,Spielman A ,Barthold SW . Detection of Borrelia burgdorferi infection in Ixodes dammini ticks with the polymerase chain reaction. J Clin Microbiol 1990;28:566-572
Web of Science | Medline17
Persing DH ,Telford SR III ,Rys PN , et al. Detection of Borrelia burgdorferi DNA in museum specimens of Ixodes dammini ticks. Science 1990;249:1420-1423
CrossRef | Web of Science | Medline18
Malloy DC ,Nauman RK ,Paxton H . Detection of Borrelia burgdorferi using the polymerase chain reaction. J Clin Microbiol 1990;28:1089-1093
Web of Science | Medline19
Lebech AM ,Hindersson P ,Vuust J ,Hansen K . Comparison of in vitro culture and polymerase chain reaction for detection of Borrelia burgdorferi in tissue from experimentally infected animals. J Clin Microbiol 1991;29:731-737
Web of Science | Medline20
Guy EC ,Stanek G . Detection of Borrelia burgdorferi in patients with Lyme disease by the polymerase chain reaction. J Clin Pathol 1991;44:610-611
CrossRef | Web of Science | Medline21
Williams WV ,Callegari P ,Freundlich B , et al. Molecular diagnosis of Borrelia burgdorferi infection (Lyme disease). DNA Cell Biol 1992;11:207-213
CrossRef | Web of Science | Medline22
Kruger WH ,Pulz M . Detection of Borrelia burgdorferi in cerebrospinal fluid by the polymerase chain reaction. J Med Microbiol 1991;35:98-102
CrossRef | Web of Science | Medline23
Jaulhac B ,Nicolini P ,Piemont Y ,Monteil H . Detection of Borrelia burgdorferi in cerebrospinal fluid of patients with Lyme borreliosis. N Engl J Med 1991;324:1440-1440
Web of Science | Medline24
Keller TL ,Halperin JJ ,Whitman M . PCR detection of Borrelia burgdorferi DNA in cerebrospinal fluid of Lyme neuroborreliosis patients. Neurology 1992;42:32-42
Web of Science | Medline25
Lebech A ,Hansen K . Detection of Borrelia burgdorferi DNA in urine samples and cerebrospinal fluid samples from patients with early and late Lyme neuroborreliosis by polymerase chain reaction. J Clin Microbiol 1992;30:1646-1653
Web of Science | Medline26
Nielsen SL ,Peter JB . B. burgdorferi persistently detected by polymerase chain reaction in synovial fluid of a patient with Lyme arthritis resistant to therapy. Clin Res 1990;38:402A-402A abstract.27
Malawista SE ,Schoen RT ,Moore TL ,Dodge DE ,White TJ ,Persing DH . Failure of multitarget detection of Borrelia burgdorferi-associated DNA sequences in synovial fluids of patients with juvenile rheumatoid arthritis: a cautionary note. Arthritis Rheum 1992;35:246-247
CrossRef | Web of Science | Medline28
Goodman JL ,Jurkovich P ,Kramber JM ,Johnson RC . Molecular detection of persistent Borrelia burgdorferi in the urine of patients with active Lyme disease. Infect Immun 1991;59:269-278
Web of Science | Medline29
Melchers W ,Meis J ,Rosa P , et al. Amplification of Borrelia burgdorferi DNA in skin biopsies from patients with Lyme disease. J Clin Microbiol 1991;29:2401-2406
Web of Science | Medline30
Rabb DC ,Lesher JL Jr ,Chandler FW . Polymerase chain reaction confirmation of Borrelia burgdorferi in benign lymphocytic infiltrate of dermis. J Am Acad Dermatol 1992;26:267-268
CrossRef | Web of Science | Medline31
Schwartz I ,Wormser GP ,Schwartz JJ , et al. Diagnosis of early Lyme disease by polymerase chain reaction amplification and culture of skin biopsies from erythema migrans lesions. J Clin Microbiol 1992;30:3082-3088
Web of Science | Medline32
Liebling MR ,Nishio MJ ,Rodriguez A ,Sigal LH ,Jin T ,Louie JS . The polymerase chain reaction for the detection of Borrelia burgdorferi in human body fluids. Arthritis Rheum 1993;36:665-675
CrossRef | Web of Science | Medline33
Luft BJ ,Steinman CR ,Neimark HC , et al. Invasion of the central nervous system by Borrelia burgdorferi in acute disseminated infection. JAMA 1992;267:1364-1367[Erratum, JAMA 1992;268:872.]
CrossRef | Web of Science | Medline34
Holodniy M ,Kim S ,Katzenstein D ,Konrad M ,Groves E ,Merigan TC . Inhibition of human immunodeficiency virus gene amplification by heparin. J Clin Microbiol 1991;29:676-679
Web of Science | Medline35
Persing DH ,Rutledge BJ ,Rys PN , et al. Target imbalance: disparity of Borrelia burgdorferi genetic material in synovial fluid from Lyme arthritis patients. J Infect Dis 1994;169:664-668
CrossRef36
Cimino GD ,Metchette KC ,Tessman JW ,Hearst JE ,Isaacs ST . Post-PCR sterilization: a method to control carryover contamination for the polymerase chain reaction. Nucleic Acids Res 1991;19:99-107
CrossRef | Web of Science | Medline37
Persing DH ,Mathiesen D ,Marshall WF , et al. Detection of Babesia microti by polymerase chain reaction. J Clin Microbiol 1992;30:2097-2103
Web of Science | Medline38
Rahn DW ,Malawista SE . Lyme disease: recommendations for diagnosis and treatment. Ann Intern Med 1991;114:472-481
Web of Science | Medline39
American Academy of Pediatrics Committee on Infectious Diseases: treatment of Lyme borreliosis
Web of Science | Medline40
Garon CF ,Dorward DW ,Corwin MD . Structural features of Borrelia burgdorferi -- the Lyme disease spirochete: silver staining for nucleic acids. Scanning Microsc Suppl 1989;3:109-115
Medline41
Whitmire WM ,Garon CF . Specific and nonspecific responses of murine B cells to membrane blebs of Borrelia burgdorferi. Infect Immun 1993;61:1460-1467
Web of Science | Medline42
Bergstrom S ,Garon CF ,Barbour AG ,MacDougall J . Extrachromosomal elements of spirochetes. Res Microbiol 1992;143:623-628
CrossRef | Web of Science | Medline43
Aurelius E ,Johansson B ,Skoldenberg B ,Staland A ,Forsgren M . Rapid diagnosis of herpes simplex encephalitis by nested polymerase chain reaction assay of cerebrospinal fluid. Lancet 1991;337:189-192
CrossRef | Web of Science | Medline44
Rotbart HA ,Levin MJ ,Murphy NL ,Abzug MJ . RNA target loss during solid phase hybridization of body fluids -- a quantitative study. Mol Cell Probes 1987;1:347-358
CrossRef | Web of Science | Medline
- Citing Articles (153)
Citing Articles
1
Gerold Stanek, Gary P Wormser, Jeremy Gray, Franc Strle. (2011) Lyme borreliosis. The Lancet
CrossRef2
Xin Li, Gail A. McHugh, Nitin Damle, Vijay K. Sikand, Lisa Glickstein, Allen C. Steere. (2011) Burden and viability of Borrelia burgdorferi in skin and joints of patients with erythema migrans or lyme arthritis. Arthritis & Rheumatism 63:8, 2238-2247
CrossRef3
Paul M Lantos. (2011) Chronic Lyme disease: the controversies and the science. Expert Review of Anti-infective Therapy 9:7, 787-797
CrossRef4
John W. McCall, Christine F. Baker, Thomas N. Mather, S. Theodore Chester, Scott D. McCall, Jennifer P. Irwin, Stephanie L. Young, Luiz G. Cramer, Matthias G. Pollmeier. (2011) The ability of a topical novel combination of fipronil, amitraz and (S)-methoprene to protect dogs from Borrelia burgdorferi and Anaplasma phagocytophilum infections transmitted by Ixodes scapularis. Veterinary Parasitology 179:4, 335-342
CrossRef5
Gary P. Wormser, Guiqing Wang. 2011. The Role of Culture and Nucleic Acid Amplification in Diagnosis of Lyme Borreliosis. , 159-183.
CrossRef6
Chinmoy Bhate, Robert A. Schwartz. (2011) Lyme disease. Journal of the American Academy of Dermatology 64:4, 639-653
CrossRef7
Robert T. Schoen. (2011) A case revealing the natural history of untreated Lyme disease. Nature Reviews Rheumatology 7:3, 179-184
CrossRef8
Alje P van Dam. (2011) Molecular diagnosis of Borrelia bacteria for the diagnosis of Lyme disease. Expert Opinion on Medical Diagnostics 5:2, 135-149
CrossRef9
A. C. Steere, E. E. Drouin, L. J. Glickstein. (2011) Relationship between Immunity to Borrelia burgdorferi Outer-surface Protein A (OspA) and Lyme Arthritis. Clinical Infectious Diseases 52:Supplement 3, s259-s265
CrossRef10
Hans-Iko Huppertz, Frank Dressler. 2011. LYME DISEASE. , 579-590.
CrossRef11
Michael P. Glotzbecker, Mininder S. Kocher, Robert P. Sundel, Benjamin J. Shore, Samantha A. Spencer, James R. Kasser. (2011) Primary Lyme Arthritis of the Pediatric Hip. Journal of Pediatric Orthopaedics 31:7, 787-790
CrossRef12
Tae Yeal Choi, Jung Oak Kang, Hyun Joo Pai. (2011) Evaluation of Automated Blood Culture System for Body Fluids Culture Other Than Blood. Korean Journal of Clinical Microbiology 14:1, 13
CrossRef13
Danièle Postic. 2010. Borrelia. .
CrossRef14
Adriana R. Marques. (2010) Lyme Disease: A Review. Current Allergy and Asthma Reports 10:1, 13-20
CrossRef15
Robert T. Schoen. 2010. Management of Lyme Disease. , 276-292.
CrossRef16
Pasi Huttunen, Maija Lappalainen, Eeva Salo, Tuula Lönnqvist, Pia Jokela, Timo Hyypiä, Heikki Peltola. (2009) Differential diagnosis of acute central nervous system infections in children using modern microbiological methods. Acta Paediatrica 98:8, 1300-1306
CrossRef17
Kathryn L. Jones, Gail A. McHugh, Lisa J. Glickstein, Allen C. Steere. (2009) Analysis of Borrelia burgdorferi genotypes in patients with lyme arthritis: High frequency of ribosomal RNA intergenic spacer type 1 strains in antibiotic-refractory arthritis. Arthritis & Rheumatism 60:7, 2174-2182
CrossRef18
Kathryn L. Jones, Robert J. Seward, Gil Ben-Menachem, Lisa J. Glickstein, Catherine E. Costello, Allen C. Steere. (2009) Strong IgG antibody responses to Borrelia burgdorferi glycolipids in patients with Lyme arthritis, a late manifestation of the infection. Clinical Immunology 132:1, 93-102
CrossRef19
Bettina Panagiota Iliopoulou, Brigitte T. Huber. (2009) Emergence of chronic Lyme arthritis: Putting the breaks on CD28 costimulation. Immunopharmacology and Immunotoxicology 31:2, 180-185
CrossRef20
R. Sorouri, R. Ranjbar, N. Jonaidi Jafari, A. Karami. (2009) Rapid Detection of Borrelia burgdorferi Strains by Nested Polymerase Chain Reaction. Pakistan Journal of Biological Sciences 12:5, 463-466
CrossRef21
Kit M. Song, Karl Craig Boatright, Jeff Drassler, Mark S. Strom, William B. Nilsson, Wesley Bevan, Jane L. Burns. (2009) The Use of Polymerase Chain Reaction for the Detection and Speciation of Bacterial Bone and Joint Infection in Children. Journal of Pediatric Orthopaedics 29:2, 182-188
CrossRef22
A. M. Ercolini, S. D. Miller. (2009) The role of infections in autoimmune disease. Clinical & Experimental Immunology 155:1, 1-15
CrossRef23
Raphael B Stricker, Lorraine Johnson. (2008) Chronic Lyme disease and the ‘Axis of Evil’. Future Microbiology 3:6, 621-624
CrossRef24
Bettina Panagiota Iliopoulou, Joseph Alroy, Brigitte T. Huber. (2008) Persistent arthritis in Borrelia burgdorferi- infected HLA-DR4-positive CD28-negative mice post-antibiotic treatment. Arthritis & Rheumatism 58:12, 3892-3901
CrossRef25
Allen C. Steere. (2008) Reply to Stricker and Johnson. Clinical Infectious Diseases 47:8, 1112-1113
CrossRef26
Allen C. Steere, Gail McHugh, Nitin Damle, Vijay K. Sikand. (2008) Prospective Study of Serologic Tests for Lyme Disease. Clinical Infectious Diseases 47:2, 188-195
CrossRef27
Maria E. Aguero-Rosenfeld. (2008) Lyme Disease: Laboratory Issues. Infectious Disease Clinics of North America 22:2, 301-313
CrossRef28
Yoram A. Puius, Robert A. Kalish. (2008) Lyme Arthritis: Pathogenesis, Clinical Presentation, and Management. Infectious Disease Clinics of North America 22:2, 289-300
CrossRef29
Henry M. Feder. (2008) Lyme Disease in Children. Infectious Disease Clinics of North America 22:2, 315-326
CrossRef30
F. Dressler, H.-I. Huppertz. (2008) Lyme-Arthritis bei Kindern und Jugendlichen. Zeitschrift für Rheumatologie 67:2, 121-127
CrossRef31
Fabio Tavora, Allen Burke, Ling Li, Teri J. Franks, Renu Virmani. (2008) Postmortem confirmation of Lyme carditis with polymerase chain reaction. Cardiovascular Pathology 17:2, 103-107
CrossRef32
Elise E. Drouin, Lisa Glickstein, William W. Kwok, Gerald T. Nepom, Allen C. Steere. (2008) Human homologues of a Borrelia T cell epitope associated with antibiotic-refractory Lyme arthritis. Molecular Immunology 45:1, 180-189
CrossRef33
Priya Kannian, Gail McHugh, Barbara J. B. Johnson, Rendi M. Bacon, Lisa J. Glickstein, Allen C. Steere. (2007) Antibody responses to Borrelia burgdorferi in patients with antibiotic-refractory, antibiotic-responsive, or non-antibiotic-treated lyme arthritis. Arthritis & Rheumatism 56:12, 4216-4225
CrossRef34
(2007) Arbobakterien (über Arthropoden übertragbare Bakterien). Bundesgesundheitsblatt - Gesundheitsforschung - Gesundheitsschutz 50:9, 1192-1207
CrossRef35
R. B. Stricker. (2007) Counterpoint: Long-Term Antibiotic Therapy Improves Persistent Symptoms Associated with Lyme Disease. Clinical Infectious Diseases 45:2, 149-157
CrossRef36
Eric Hoppa, Richard Bachur. (2007) Lyme disease update. Current Opinion in Pediatrics 19:3, 275-280
CrossRef37
Junghee J. Shin, Lisa J. Glickstein, Allen C. Steere. (2007) High levels of inflammatory chemokines and cytokines in joint fluid and synovial tissue throughout the course of antibiotic-refractory lyme arthritis. Arthritis & Rheumatism 56:4, 1325-1335
CrossRef38
Lynn Ivacic, Kurt D. Reed, Paul D. Mitchell, Nader Ghebranious. (2007) A LightCycler TaqMan assay for detection of Borrelia burgdorferi sensu lato in clinical samples. Diagnostic Microbiology and Infectious Disease 57:2, 137-143
CrossRef39
Peter Muir, William E. Oldenhoff, Alan P. Hudson, Paul A. Manley, Susan L. Schaefer, Mark D. Markel, Zhengling Hao. (2007) Detection of DNA from a range of bacterial species in the knee joints of dogs with inflammatory knee arthritis and associated degenerative anterior cruciate ligament rupture. Microbial Pathogenesis 42:2-3, 47-55
CrossRef40
J. Pourel, I. Chary-Valckenaere. (2007) Borreliosis de Lyme. EMC - Aparato Locomotor 40:2, 1-14
CrossRef41
Sebastian Schnarr, Juliane K. Franz, Andreas Krause, Henning Zeidler. (2006) Lyme borreliosis. Best Practice & Research Clinical Rheumatology 20:6, 1099-1118
CrossRef42
Gary P. Wormser, Raymond J. Dattwyler, Eugene D. Shapiro, John J. Halperin, Allen C. Steere, Mark S. Klempner, Peter J. Krause, Johan S. Bakken, Franc Strle, Gerold Stanek, Linda Bockenstedt, Durland Fish, J. Stephen Dumler, Robert B. Nadelman. (2006) The Clinical Assessment, Treatment, and Prevention of Lyme Disease, Human Granulocytic Anaplasmosis, and Babesiosis: Clinical Practice Guidelines by the Infectious Diseases Society of America. Clinical Infectious Diseases 43:9, 1089-1134
CrossRef43
Allen C. Steere. (2006) Lyme borreliosis in 2005, 30 years after initial observations in Lyme Connecticut. Wiener klinische Wochenschrift 118:21-22, 625-633
CrossRef44
Henry M. Feder, Micha Abeles, Megan Bernstein, Diane Whitaker-Worth, Jane M. Grant-Kels. (2006) Diagnosis, treatment, and prognosis of erythema migrans and Lyme arthritis. Clinics in Dermatology 24:6, 509-520
CrossRef45
Allen C. Steere, Sheryn M. Angelis. (2006) Therapy for Lyme arthritis: Strategies for the treatment of antibiotic-refractory arthritis. Arthritis & Rheumatism 54:10, 3079-3086
CrossRef46
Aruna K. Behera, Ethan Hildebrand, Jon Szafranski, Han-Hwa Hung, Alan J. Grodzinsky, Robert Lafyatis, Alisa E. Koch, Robert Kalish, George Perides, Allen C. Steere, Linden T. Hu. (2006) Role of aggrecanase 1 in Lyme arthritis. Arthritis & Rheumatism 54:10, 3319-3329
CrossRef47
J. S. Sartin, K. R. Oettel. (2006) A Morphealike Skin Condition Caused by Borrelia burgdorferi in an Immunocompromised Patient. Mayo Clinic Proceedings 81:9, 1259-1263
CrossRef48
Aaron R. Holmgren, Eric L. Matteson. (2006) Lyme myositis. Arthritis & Rheumatism 54:8, 2697-2700
CrossRef49
Nina Bhambhani, Eddys Disla, Girolamo Cuppari. (2006) Lyme Disease Presenting With Sequential Episodes of Ruptured Baker Cysts. JCR: Journal of Clinical Rheumatology 12:3, 160-162
CrossRef50
S. K. Singh, H. J. Girschick. (2006) Toll-like receptors in Borrelia burgdorferi-induced inflammation. Clinical Microbiology and Infection 0:0, 060508061430003-???
CrossRef51
Alison Abbott. (2006) Lyme disease: Uphill Struggle. Nature 439:7076, 524-525
CrossRef52
Raphael B. Stricker, Andrew Lautin, Joseph J. Burrascano. (2006) Lyme Disease: The Quest for Magic Bullets. Chemotherapy 52:2, 53-59
CrossRef53
A. Krause, P. Herzer. (2005) Frühdiagnostik der Lyme-Arthritis. Zeitschrift für Rheumatologie 64:8, 531-537
CrossRef54
Hillary Crandall, Ying Ma, Diane M. Dunn, Rhianna S. Sundsbak, James F. Zachary, Peter Olofsson, Rikard Holmdahl, John H. Weis, Robert B. Weiss, Cory Teuscher, Janis J. Weis. (2005) Bb2Bb3 Regulation of Murine Lyme Arthritis Is Distinct from Ncf1 and Independent of the Phagocyte Nicotinamide Adenine Dinucleotide Phosphate Oxidase. The American Journal of Pathology 167:3, 775-785
CrossRef55
Raphael B Stricker, Andrew Lautin, Joseph J Burrascano. (2005) Lyme disease: point/counterpoint. Expert Review of Anti-infective Therapy 3:2, 155-165
CrossRef56
RIIKKA TURUNEN, STURE ANDERSSON, IRMELI NUPPONEN, HANNU KAUTIAINEN, SANNA SIITONEN, HEIKKI REPO. (2005) Increased CD11b-Density on Circulating Phagocytes as an Early Sign of Late-Onset Sepsis in Extremely Low-Birth-Weight Infants. Pediatric Research 57:2, 270-275
CrossRef57
P. Brouqui, F. Bacellar, G. Baranton, R. J. Birtles, A. Bjoersdorff, J. R. Blanco, G. Caruso, M. Cinco, P. E. Fournier, E. Francavilla, M. Jensenius, J. Kazar, H. Laferl, A. Lakos, S. Lotric Furlan, M. Maurin, J. A. Oteo, P. Parola, C. Perez-Eid, O. Peter, D. Postic, D. Raoult, A. Tellez, Y. Tselentis, B. Wilske. (2004) Guidelines for the diagnosis of tick-borne bacterial diseases in Europe. Clinical Microbiology and Infection 10:12, 1108-1132
CrossRef58
Maurice M. Exner. 2004. Borrelia spp.. , 146-149.
CrossRef59
Stephen Batsford, John Dunn, Michael Mihatsch. (2004) Outer surface lipoproteins ofBorrelia burgdorferi vary in their ability to induce experimental joint injury. Arthritis & Rheumatism 50:7, 2360-2369
CrossRef60
S. K. Singh, H. J. Girschick. (2004) Lyme borreliosis: from infection to autoimmunity. Clinical Microbiology and Infection 10:7, 598-614
CrossRef61
Allen C. Steere, Jenifer Coburn, Lisa Glickstein. (2004) The emergence of Lyme disease. Journal of Clinical Investigation 113:8, 1093-1101
CrossRef62
Allen C. Steere, Lisa Glickstein. (2004) Elucidation of Lyme arthritis. Nature Reviews Immunology 4:2, 143-152
CrossRef63
Stefan Marlovits, Gelas Khanakah, Gabriele Striessnig, Vilmos V
csei, Gerold Stanek. (2004) Emergence of lyme arthritis after autologous chondrocyte transplantation. Arthritis & Rheumatism 50:1, 259-264
CrossRef64
Isabelle Renaud, Claude Cachin, Jean-Charles Gerster. (2004) Good outcomes of Lyme arthritis in 24 patients in an endemic area of Switzerland. Joint Bone Spine 71:1, 39-43
CrossRef65
Bettina Wilske. (2003) Diagnosis of Lyme Borreliosis in Europe. Vector-Borne and Zoonotic Diseases 3:4, 215-227
CrossRef66
Brandt P. Groh. (2003) Current concepts in pediatric rheumatology. Current Opinion in Orthopaedics 14:6, 385-391
CrossRef67
Gerold Stanek. (2003) Reflections on the Clinical and Epidemiological Studies Presented at the IX International Conference on Lyme Borreliosis and Other Tick-Borne Diseases and Future Directions. Vector-Borne and Zoonotic Diseases 3:4, 229-247
CrossRef68
Gerald Stanek, Franc Strle. (2003) Lyme borreliosis. The Lancet 362:9396, 1639-1647
CrossRef69
Mark S Hanson, Robert Edelman. (2003) Progress and controversy surrounding vaccines against Lyme disease. Expert Review of Vaccines 2:5, 683-703
CrossRef70
&NA;. (2003) DENOUEMENT???CONTINUED FROM P. 837. The Pediatric Infectious Disease Journal 22:9, 851-852
CrossRef71
Allen C. Steere, Ben Falk, Elise E. Drouin, Lee Ann Baxter-Lowe, Juergen Hammer, Gerald T. Nepom. (2003) Binding of outer surface protein A and human lymphocyte function-associated antigen 1 peptides to HLA-DR molecules associated with antibiotic treatment-resistant Lyme arthritis. Arthritis & Rheumatism 48:2, 534-540
CrossRef72
Stephen C Eppes. (2003) Diagnosis, Treatment, and Prevention of Lyme Disease in Children. Pediatric Drugs 5:6, 363-372
CrossRef73
Guiqing Wang. (2002) Direct Detection Methods for Lyme Borrelia , Including the Use of Quantitative Assays. Vector-Borne and Zoonotic Diseases 2:4, 223-231
CrossRef74
Patricia K. Coyle. (2002) Lyme disease. Current Neurology and Neuroscience Reports 2:6, 479-487
CrossRef75
Andrew Keat. (2002) Reactive arthritis or post-infective arthritis?. Best Practice & Research Clinical Rheumatology 16:4, 507-522
CrossRef76
Arthur Weinstein, Michael Britchkov. (2002) Lyme arthritis and post-Lyme disease syndrome. Current Opinion in Rheumatology 14:4, 383-387
CrossRef77
Mireia Guerau-de-Arellano, Brigitte T. Huber. (2002) Development of autoimmunity in Lyme arthritis. Current Opinion in Rheumatology 14:4, 388-393
CrossRef78
Bettina Wilske. (2002) Microbiological diagnosis in Lyme borreliosis. International Journal of Medical Microbiology 291, 114-119
CrossRef79
Pariwat Thaisetthawatkul, Eric L. Logigian. (2002) Peripheral Nervous System Manifestations of Lyme Borreliosis. Journal of Clinical Neuromuscular Disease 3:4, 165-171
CrossRef80
Cabot, Richard C.Harris, Nancy Lee, McNeely, William F., Shepard, Jo-Anne O., Ebeling, Sally H.Ellender, Stacey M.Peters, Christine C., Hajjar, Roger J.Kradin, Richard L.. (2002) Case 17-2002. New England Journal of Medicine 346:22, 1732-1738
Full Text81
Elena M Massarotti. (2002) Lyme arthritis. Medical Clinics of North America 86:2, 297-309
CrossRef82
Jonas Bunikis, Alan G Barbour. (2002) Laboratory testing for suspected lyme disease. Medical Clinics of North America 86:2, 311-340
CrossRef83
P.K Coyle, S.E Schutzer. (2002) Neurologic aspects of lyme disease. Medical Clinics of North America 86:2, 261-284
CrossRef84
Jovan Vukadinov, Sinisa Sevic, Grozdana Canak, Nadezda Madle-Samardzija, Vesna Turkulov, Radoslava Doder. (2002) Lyme disease: New knowledge regarding its physiopathology, diagnosis, therapy and prevention. Medicinski pregled 55:5-6, 207-212
CrossRef85
Alje P van Dam. (2001) Recent advances in the diagnosis of Lyme disease. Expert Review of Molecular Diagnostics 1:4, 413-427
CrossRef86
S. Schnarr, N. Putschky, M. C. Jendro, H. Zeidler, M. Hammer, J. G. Kuipers, J. Wollenhaupt. (2001) Chlamydia andBorrelia DNA in synovial fluid of patients with early undifferentiated oligoarthritis: Results of a prospective study. Arthritis & Rheumatism 44:11, 2679-2685
CrossRef87
Adriana R. Marques. (2001) Lyme disease: An update. Current Allergy and Asthma Reports 1:6, 541-549
CrossRef88
M. Schwaiger, O. Peter, P. Cassinotti. (2001) Routine diagnosis of Borrelia burgdorferi (sensu lato) infections using a real-time PCR assay. Clinical Microbiology and Infection 7:9, 461-469
CrossRef89
Philip J. Molloy, David H. Persing, Victor P. Berardi. (2001) False‐Positive Results of PCR Testing for Lyme Disease. Clinical Infectious Diseases 33:3, 412-413
CrossRef90
Steere, Allen C., . (2001) Lyme Disease. New England Journal of Medicine 345:2, 115-125
Full Text91
R.Mark Wooten, Janis J Weis. (2001) Host–pathogen interactions promoting inflammatory Lyme arthritis: use of mouse models for dissection of disease processes. Current Opinion in Microbiology 4:3, 274-279
CrossRef92
Linden T. Hu, Manuel A. Eskildsen, Catherine Masgala, Allen C. Steere, Elizabeth C. Arner, Michael A. Pratta, Alan J. Grodzinsky, Andrew Loening, George Perides. (2001) Host metalloproteinases in Lyme arthritis. Arthritis & Rheumatism 44:6, 1401-1410
CrossRef93
Allen C Steere, Dawn Gross, Abbie L Meyer, Brigitte T Huber. (2001) Autoimmune Mechanisms in Antibiotic Treatment-Resistant Lyme Arthritis. Journal of Autoimmunity 16:3, 263-268
CrossRef94
Daniel W. Rahn. (2001) Lyme Vaccine: Issues and Controversies. Infectious Disease Clinics of North America 15:1, 171-187
CrossRef95
E. D. Shapiro, M. A. Gerber. (2000) Lyme Disease. Clinical Infectious Diseases 31:2, 533-542
CrossRef96
G. P. Wormser, R. B. Nadelman, R. J. Dattwyler, D. T. Dennis, E. D. Shapiro, A. C. Steere, T. J. Rush, D. W. Rahn, P. K. Coyle, D. H. Persing, D. Fish, B. J. Luft. (2000) Practice Guidelines for the Treatment of Lyme Disease. Clinical Infectious Diseases 31:Supplement 1, S1-S14
CrossRef97
Susan V. Onrust, Karen L. Goa. (2000) Adjuvanted Lyme Disease Vaccine. Drugs 59:2, 281-299
CrossRef98
Anita F. Pöpperl, F. Noll. (2000) Diagnostische Wertigkeit serologischer Verfahren bei der Diagnostik einer Infektion mit Borrelia burgdorferi. Diagnostic Value of Serological Test-Systems Used in Diagnosis of Infection With Borrelia Burgdorferi. LaboratoriumsMedizin 24:4, 190-198
CrossRef99
George Perides, Linda M. Tanner-Brown, Manuel A. Eskildsen, Mark S. Klempner. (1999) Borrelia burgdorferi induces matrix metalloproteinases by neural cultures. Journal of Neuroscience Research 58:6, 779-790
CrossRef100
Jenifer Coburn, Wambui Chege, Loranne Magoun, Sarah C. Bodary, John M. Leong. (1999) Characterization of a candidate Borrelia burgdorferi beta3-chain integrin ligand identified using a phage display library. Molecular Microbiology 34:5, 926-940
CrossRef101
David Carlson, Jesus Hernandez, Bradley J. Bloom, Jenifer Coburn, John M. Aversa, Allen C. Steere. (1999) Lack ofBorrelia burgdorferi DNA in synovial samples from patients with antibiotic treatment-resistant lyme arthritis. Arthritis & Rheumatism 42:12, 2705-2709
CrossRef102
Susanne Priem, Juliane K. Franz, M. Gerd Rittig, G.R. Burmester, Andreas Krause. (1999) New avenues in the diagnosis of Lyme borreliosis using molecular biology. Zentralblatt für Bakteriologie 289:5-7, 681-686
CrossRef103
SUNIL K. SOOD. (1999) Lyme disease. The Pediatric Infectious Disease Journal 18:10, 913-925
CrossRef104
Jie Chen, Jodie A. Field, Lisa Glickstein, Philip J. Molloy, Brigitte T. Huber, Allen C. Steere. (1999) Association of antibiotic treatment-resistant lyme arthritis with T cell responses to dominant epitopes of outer surface protein A ofBorrelia burgdorferi. Arthritis & Rheumatism 42:9, 1813-1822
CrossRef105
Leonard H. Sigal. (1999) Lyme arthritis: Lessons learned and to be learned. Arthritis & Rheumatism 42:9, 1809-1812
CrossRef106
D. Hulínská, J. Votýpka, M. Valešová. (1999) Persistence of Borrelia garinii and Borrelia afzelii in patients with lyme arthritis. Zentralblatt für Bakteriologie 289:3, 301-318
CrossRef107
Janine Evans. (1999) Lyme disease. Current Opinion in Rheumatology 11:4, 281-288
CrossRef108
Ineke M. Van Der Heijden, Bert Wilbrink, Sjoerd G. T. Rijpkema, Leo M. Schouls, Peter H. M. Heymans, Jan D. A. Van Embden, Ferdinand C. Breedveld, Paul P. Tak. (1999) Detection ofBorrelia burgdorferi sensu stricto by reverse line blot in the joints of Dutch patients with Lyme arthritis. Arthritis & Rheumatism 42:7, 1473-1480
CrossRef109
J. Desmond O'Duffy, W. Leroy Griffing, Chin-Yang Li, Manal F. Abdelmalek, David H. Persing. (1999) Whipple's arthritis: Direct detection ofTropheryma whippelii in synovial fluid and tissue. Arthritis & Rheumatism 42:4, 812-817
CrossRef110
H. J. Girschick, S. Meister, H. Karch, H. I. Huppertz. (1999) Borrelia burgdorferi Downregulates ICAM-1 on Human Synovial Cells In Vitro. Cell Communication and Adhesion 7:2, 73-83
CrossRef111
S. E. Phillips, L. H. Mattman, D. Hulínská, H. Moayad. (1998) A proposal for the reliable culture ofBorrelia burgdorferi from patients with chronic lyme disease, even from those previously aggressively treated. Infection 26:6, 364-367
CrossRef112
Robert B Nadelman, Gary P Wormser. (1998) Lyme borreliosis. The Lancet 352:9127, 557-565
CrossRef113
Steere, Allen C., Sikand, Vijay K., Meurice, François, Parenti, Dennis L., Fikrig, Erol, Schoen, Robert T., Nowakowski, John, Schmid, Christopher H., Laukamp, SabineBuscarino, Charles, Krause, David S., the Lyme Disease Vaccine Study Group. (1998) Vaccination against Lyme Disease with Recombinant Borrelia burgdorferi Outer-Surface Lipoprotein A with Adjuvant. New England Journal of Medicine 339:4, 209-215
Full Text114
Krause, Peter J., Spielman, Andrew, Telford, Sam R., Sikand, Vijay K., McKay, Kathleen, Christianson, Diane, Pollack, Richard J., Brassard, Peter, Magera, Jenifer, Ryan, Raymond, Persing, David H., . (1998) Persistent Parasitemia after Acute Babesiosis. New England Journal of Medicine 339:3, 160-165
Full Text115
L SIGAL. (1998) Lyme borreliosis (Lyme disease): interactions of Borrelia burgdorferi sensu lato with human (and other mammalian) hosts. Bulletin de l'Institut Pasteur 96:3, 189-206
CrossRef116
DH Walker. (1998) TICK-TRANSMITTED INFECTIOUS DISEASES IN THE UNITED STATES. Annual Review of Public Health 19:1, 237-269
CrossRef117
James S. Louie, Michael R. Liebling. (1998) THE POLYMERASE CHAIN REACTION IN INFECTIOUS AND POST-INFECTIOUS ARTHRITIS. Rheumatic Disease Clinics of North America 24:2, 227-236
CrossRef118
Leonard H. Sigal. (1998) MUSCULOSKELETAL MANIFESTATIONS OF LYME ARTHRITIS. Rheumatic Disease Clinics of North America 24:2, 323-351
CrossRef119
Rolf Bauerfeind, Ulrich Kreis, Reinhard Weiß, Lothar H. Wieler, Georg Baljer. (1998) Detection of Borrelia burgdorferi in Urine Specimens from Dogs by a Nested Polymerase Chain Reaction. Zentralblatt für Bakteriologie 287:4, 347-361
CrossRef120
Robert W. Hoffman, Kim S. Wise. (1998) Reply. Arthritis & Rheumatism 41:4, 756-757
CrossRef121
Christopher J Sweeney, Majid Ghassemi, William A. Agger, David H. Persing. (1998) Coinfection With Babesia microti and Borrelia burgdorferi in a Western Wisconsin Resident. Mayo Clinic Proceedings 73:4, 338-341
CrossRef122
Bert Wilbrink, Ineke M. van der Heijden, Leo M. Schouls, Jan D. A. van Embden, Johanna M. W. Hazes, Ferdinand C. Breedveld, Paul P. Tak. (1998) Detection of bacterial DNA in joint samples from patients with undifferentiated arthritis and reactive arthritis, using polymerase chain reaction with universal 16S ribosomal RNA primers. Arthritis & Rheumatism 41:3, 535-543
CrossRef123
Viviane A. Dunand, Anne-Gabrielle Bretz, André Suard, Gérard Praz, Eric Dayer, Olivier Péter. (1998) Acrodermatitis chronica atrophicans and serologic confirmation of infection due to Borrelis afzelii and/or Borrelia garinii by immunoblot. Clinical Microbiology and Infection 4:3, 159-163
CrossRef124
John J Halperin. (1998) Nervous system Lyme disease. Journal of the Neurological Sciences 153:2, 182-191
CrossRef125
T. Häupl, S. Landgraf, P. Netusil, N. Biller, C. Capiau, P. Desmons, P. Hauser, G.-R. Burmester. (1997) Activation of monocytes by three OspA vaccine candidates: lipoprotein OspA is a potent stimulator of monokines. FEMS Immunology & Medical Microbiology 19:1, 15-23
CrossRef126
Mathilde H. Pioro, Brian F. Mandell. (1997) SEPTIC ARTHRITIS. Rheumatic Disease Clinics of North America 23:2, 239-258
CrossRef127
B. Svenungsson, Gudrun Lindh. (1997) Lyme borreliosis — an overdiagnosed disease?. Infection 25:3, 140-143
CrossRef128
Gabrielle Kingsley. (1997) Microbial DNA in the synovium—a role in aetiology or a mere bystander?. The Lancet 349:9058, 1038-1039
CrossRef129
G Mercier. (1997) Detection ofBorrelia burgdorferiDNA by polymerase chain reaction in urine specimens of patients with erythema migrans lesions. Molecular and Cellular Probes 11:2, 89-94
CrossRef130
Sjoerd G. T. Rijpkema, Dig J. Tazelaar, Marc J.C.H. Molkenboer, Gerda T. Noordhoek, Grietsje Plantinga, Leo M. Schouls, Joop F.P. Schellekens. (1997) Detection of Borrelia afzelii, Borrelia burgdorferi sensu stricto, Borrelia garinii and group VS116 by PCR in skin biopsies of patients with erythema migrans and acrodermatitis chronica atrophicans. Clinical Microbiology and Infection 3:1, 109-116
CrossRef131
Joseph Duffy, Mark R Pittlekow, Christopher P Kolbert, Barbara J Rutledge, David H Persing. (1997) Coinfection with Borrelia burgdorferi and the agent of human granulocytic ehrlichiosis. The Lancet 349:9049, 399
CrossRef132
Allen C. Steere. (1997) DIAGNOSIS AND TREATMENT OF LYME ARTHRITIS. Medical Clinics of North America 81:1, 179-194
CrossRef133
Zhinan Yin, Jürgen Braun, Lucia Neure, Peihua Wu, Ulrich Eggens, Andreas Krause, Thomas Kamradt, Joachim Sieper. (1997) T cell cytokine pattern in the joints of patients with lyme arthritis and its regulation by cytokines and anticytokines. Arthritis & Rheumatism 40:1, 69-79
CrossRef134
Ratanavadee Nanagara, Paul H Duray, H.Ralph Schumacher. (1996) Ultrastructural demonstration of spirochetal antigens in synovial fluid and synovial membrane in chronic lyme disease: Possible factors contributing to persistence of organisms. Human Pathology 27:10, 1025-1034
CrossRef135
Scott R. Granter, Raymond L. Barnhill, Paul H. Duray. (1996) Borrelial Fasciitis: Diffuse Fasciitis and Peripheral Eosinophilia Associated with Borrelia Infection. The American Journal of Dermatopathology 18:5, 465-473
CrossRef136
M. E. Bayer, Lanmin Zhang, Margret H. Bayer. (1996) Borrelia burgdorferi DNA in the urine of treated patients with chronic lyme disease symptoms. A PCR study of 97 cases. Infection 24:5, 347-353
CrossRef137
Kathleen Petri Seiler, Janis J Weis. (1996) Immunity to Lyme disease: protection, pathology and persistence. Current Opinion in Immunology 8:4, 503-509
CrossRef138
M. M. Picken, R. N. Picken, D. Han, Y. Cheng, F. Strle. (1996) Single-tube nested polymerase chain reaction assay based on flagellin gene sequences for detection ofBorrelia burgdorferi sensu lato. European Journal of Clinical Microbiology & Infectious Diseases 15:6, 489-498
CrossRef139
H. J. Girschick, H. I. Huppertz, H. R
CrossRef140
M.R. CRABILL, N.D. COHEN, L.J. MARTIN, R.B. SIMPSON, N. BURNEY. (1996) Detection of Bacteria in Equine Synovial Fluid by Use of the Polymerase Chain Reaction. Veterinary Surgery 25:3, 195-198
CrossRef141
Beno??t Jaulhac, Isabelle Chary-Valckenaere, Jean Sibilia, Rose-Marie Javier, Yves Piémont, Jean-Louis Kuntz, Henri Monteil, Jacques Pourel. (1996) Detection ofBorrelia burgdorferi by DNA amplification in synovial tissue samples from patients with lyme arthritis. Arthritis & Rheumatism 39:5, 736-745
CrossRef142
Marie Valešova, H. Mailer, J. Havlík, Dagmar Hulínská, Jana Hercogová. (1996) Behandlung der Lyme-Arthritis. Infection 24:1, 98-102
CrossRef143
H. -I. Huppertz, H. Karch, J. Heesemann. (1995) Diagnostic value of synovial fluid analysis in children with reactive arthritis. Rheumatology International 15:4, 167-170
CrossRef144
Helge Karch, Andreas Schwarzkopf, Herbert Schmidt. (1995) Amplification methods in diagnostic bacteriology (selected examples). Journal of Microbiological Methods 23:1, 55-73
CrossRef145
STEVEN J. PADULA, ALICIA SAMPIERI. (1995) T-Cell Receptor Use in Early Rheumatoid Arthritis. Annals of the New York Academy of Sciences 756:1 T-Cell Recept, 147-158
CrossRef146
Samuel M. Behar, Steven A. Porcelli. (1995) Mechanisms of autoimmune disease induction. Arthritis & Rheumatism 38:4, 458-476
CrossRef147
Hans-Iko Huppertz, Helge Karch, Hans-Joachim Suschke, Eva DÖRing, Gerd Ganser, Angelika Thon, Wassilios Bentas, . (1995) Lyme arthritis in european children and adolescents. Arthritis & Rheumatism 38:3, 361-368
CrossRef148
Bruno L. Schmidt, E. Aberer, C. Stockenhuber, H. Klade, F. Breier, A. Luger. (1995) Detection of Borrelia burgdorferi DNA by polymerase chain reaction in the urine and breast milk of patients with Lyme borreliosis. Diagnostic Microbiology and Infectious Disease 21:3, 121-128
CrossRef149
P. Toivanen, A. Toivanen. (1995) Role of Micro-organisms in the Pathogenesis of Arthritis: Lessons from Reactive and Lyme Arthritis. Scandinavian Journal of Rheumatology 24:s101, 191-197
CrossRef150
L. V. Stedingk, I. Olsson, H. S. Hanson, E. Åsbrink, A. Hovmark. (1995) Polymerase chain reaction for detection ofBorrelia burgdorferi DNA in skin lesions of early and late Lyme borreliosis. European Journal of Clinical Microbiology & Infectious Diseases 14:1, 1-5
CrossRef151
Krzysztof Kowal, Arthur Weinstein. (1994) Western blot band intensity analysis. Application to the diagnosis of lyme arthritis. Arthritis & Rheumatism 37:8, 1206-1211
CrossRef152
Allen C. Steere, Robert E. Levin, Philip J. Molloy, Robert A. Kalish, James H. , Abraham Iii, Nancy Y. Liu, Christopher H. Schmid. (1994) Treatment of lyme arthritis. Arthritis & Rheumatism 37:6, 878-888
CrossRef153
Rahn, Daniel W., . (1994) Lyme Disease -- Where's the Bug?. New England Journal of Medicine 330:4, 282-283
Full Text
