2010 Lyme & TBD Abstracts  - ARCHIVE

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Infect Immun. 2010 Dec;78(12):5307-13. Epub 2010 Oct 4.

Role of adrenomedullin in Lyme disease.
Marre ML, Darcy CT, Yinh J, Akira S, Uematsu S, Steere AC, Hu LT.

Graduate Program in Immunology, Sackler School of Graduate Biomedical Sciences, Tufts University, 155 Harrison Avenue, Boston, Massachusetts 02111, USA.

Borrelia burgdorferi stimulates a strong inflammatory response during infection of a mammalian host. To understand the mechanisms of immune regulation employed by the host to control this inflammatory response, we focused our studies on adrenomedullin, a peptide produced in response to bacterial stimuli that exhibits antimicrobial activity and regulates inflammatory responses by modulating the expression of inflammatory cytokines. Specifically, we investigated the effect of B. burgdorferi on the expression of adrenomedullin as well as the ability of adrenomedullin to dampen host inflammatory responses to the spirochete. The concentration of adrenomedullin in the synovial fluid of untreated Lyme arthritis patients was elevated compared with that in control osteoarthritis patient samples. In addition, coculture with B. burgdorferi significantly increased the expression of adrenomedullin in RAW264.7 macrophages through MyD88-, phosphatidylinositol 3-kinase (PI3-K)-, and p38-dependent signaling cascades. Furthermore, the addition of exogenous adrenomedullin to B. burgdorferi-stimulated RAW264.7 macrophages resulted in a significant decrease in the induction of proinflammatory cytokines. Taken together, these results suggest that B. burgdorferi increases the production of adrenomedullin, which in turn negatively regulates the B. burgdorferi-stimulated inflammatory response.


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Arch Dis Child. 2010 Dec;95(12):1013-6. Epub 2010 Aug 10.

Seroprevalence of Borrelia IgG antibodies among young Swedish children in relation to reported tick bites, symptoms and previous treatment for Lyme borreliosis: a population-based survey.
Skogman BH, Ekerfelt C, Ludvigsson J, Forsberg P.

Department of Pediatrics, Falun General Hospital, Falun, Sweden. barbro.hedinskogman@ltdalarna.se

BACKGROUND: Lyme borreliosis (LB) is the most common tickborne infection in Sweden and the seroprevalence of Borrelia immunoglobulin G (IgG) antibodies varies between 2% and 26%. The seroprevalence in young Swedish children is unknown and the relation to clinical data has not been previously studied.

OBJECTIVE: To determine the seroprevalence of Borrelia IgG antibodies in serum of young Swedish children and to relate it to gender, geographical location, reported tick bites, symptoms and previous treatment for LB.

METHODS: 2000 healthy 5-year-old children (n=2000) were randomly selected from among participants of a larger prospective population-based study, the ABIS (All Babies in Southeast Sweden) study. Serum samples were collected and a Borrelia specific ELISA test (Dako) were performed for IgG antibody detection. Clinical data were collected from questionnaires completed by the parents.

RESULTS: The seroprevalence of Borrelia IgG antibodies was 3.2% (64/2000). Previous tick bite had been noted in 66% of these seropositive children but the majority (94%) had not previously been treated for LB. In addition, another 55 children reported a history of LB but were negative to Borrelia IgG antibodies in serum. Many of these seronegative children had received treatment for erythema migrans (n=24), which is a clinical diagnosis. Whether children were correctly treated or overtreated for LB is however unknown. No differences in gender, geographical location or reported tick bites were found when comparing Borrelia-seropositive children (n=64) and seronegative children with previous LB (n=55).

CONCLUSION: This population-based study demonstrates a Borrelia IgG antibody seroprevalence of 3.2% in young Swedish children. Very few of these seropositive children report previous symptoms or treatment for LB. Thus the findings suggest that exposure to the Borrelia spirochaete (with subsequent antibody response in serum) does occur in young children, mostly without giving rise to clinical LB. Future studies on cell-mediated immune responses are needed to investigate explanatory immunological mechanisms.


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Microb Pathog. 2010 Dec;49(6):363-8. Epub 2010 Aug 9.

Expression and sequence diversity of the complement regulating outer surface protein E in Borrelia afzelii vs. Borrelia garinii in patients with erythema migrans or neuroborreliosis.
Panelius J, Ranki A, Meri T, Seppälä I, Meri S.

Haartman Institute, Department of Bacteriology and Immunology, P.O. Box 21, University of Helsinki, Helsinki, FIN-00014, Finland. jaana.panelius@helsinki.fi

Outer surface protein E (OspE) is a complement factor H-binding virulence factor of borrelial subspecies. It is usually absent from in vitro grown Borrelia garinii, although in vivo B. garinii causes neuroborreliosis (NB). We analyzed the presence and sequence spectrum of the ospE genes in vivo in Borrelia spirochetes. DNA samples from the skin, serum and cerebrospinal fluid (CSF) of patients with infections caused by Borrelia afzelii or B. garinii were studied, and anti-OspE antibodies in the corresponding patient sera were detected by IgG ELISA using recombinant OspE as an antigen. ospE genes were found in 20 of 23 erythema migrans (EM) skin biopsies with B. afzelii, in 2 EM skin biopsies with unknown underlying subspecies, in 5 of 9 EM biopsies with B. garinii, and in 1 of 4 CSF samples of NB patients with B. garinii infection. All OspE sequences from B. garinii samples were identical. In contrast, OspE of B. afzelii origin showed more variation. Anti-OspE antibodies were found in 8/21 (38.0%) sera from patients with B. afzelii-associated EM. In conclusion, our results indicate that all borrelial subspecies, but not necessarily all strains, causing human infections can carry ospE genes to protect themselves against complement attack in vivo.


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Arch Dis Child. 2010 Nov;95(11):910-4. Epub 2010 Jun 28.

Clinical presentation of childhood neuroborreliosis; neurological examination may be normal.
Broekhuijsen-van Henten DM, Braun KP, Wolfs TF.

Department of Paediatrics, Isala Clinics, Zwolle, The Netherlands. d.m.broekhuijsen@isala.nl

OBJECTIVE: Neuroborreliosis has its highest incidence in children and the older people. Signs and symptoms are different between the different age groups. The aim of this study was to describe the clinical spectrum of neuroborreliosis in children.

DESIGN: The Dutch Paediatric Surveillance system registered cases of childhood neuroborreliosis during 2 years. All Dutch paediatric hospitals took part in this surveillance. Criteria for reporting cases were strictly defined.

RESULTS: 89 cases of neuroborreliosis were reported; in 66 cases diagnosis was confirmed. Facial weakness was one of the presenting symptoms in 47 cases (71%) and the only symptom in nine children (14%). The five complaints most frequently reported were: malaise, headache, fatigue, fever and neck pain. 52 children (79%) had one or more objective neurological signs at presentation, of which facial nerve palsy, other cranial nerve abnormalities and meningeal signs were most frequent. 14 patients (21%), however, had no neurological signs at physical examination. In these patients, the number of subjective complaints was higher, and the time interval to diagnosis was longer compared with those with objective neurological abnormalities.

CONCLUSIONS: In this study, 79% of paediatric neuroborreliosis patients presented with neurological signs, most often facial nerve palsy. 21% presented in an atypical way without neurological signs. A thorough neurological examination is essential once neuroborreliosis is considered in children. Even in the absence of neurological signs, neuroborreliosis may be suspected in children with typical antecedents and multiple symptoms. Cerebrospinal fluid investigations are then required to confirm the diagnosis.


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Drug Discov Today. 2010 Nov;15(21-22):933-42. Epub 2010 Aug 26.

PET tracers for the peripheral benzodiazepine receptor and uses thereof.
Schweitzer PJ, Fallon BA, Mann JJ, Kumar JS.

College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA.

The peripheral benzodiazepine receptor (PBR) is expressed on the outer mitochondrial membrane of activated microglia and is implicated in the pathophysiology of a variety of central nervous system and peripheral diseases. The abundant receptor concentration makes PBR a potential biomarker and an attractive target for quantification in vivo using positron emission tomography. PBR can be an important target for monitoring disease progression, for evaluating the effect of therapy, and for investigating new treatment modalities. PBR is also emerging as a potential target in the treatment of neuroinflammatory and neuropsychiatric disorders. Here, we review the positron emission tomography radioligands employed for imaging PBR in living brain and their applications.


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BMC Res Notes. 2010 Nov 1;3(1):273. [Epub ahead of print].

Early Lyme disease with spirochetemia - diagnosed by DNA sequencing.
Lee SH, Vigliotti VS, Vigliotti JS, Jones W, Williams J, Walshon J.

BACKGROUND: A sensitive and analytically specific nucleic acid amplification test (NAAT) is valuable in confirming the diagnosis of early Lyme disease at the stage of spirochetemia.
FINDINGS: Venous blood drawn from patients with clinical presentations of Lyme disease was tested for the standard 2-tier screen and Western Blot serology assay for Lyme disease, and also by a nested polymerase chain reaction (PCR) for B. burgdorferi sensu lato 16S ribosomal DNA. The PCR amplicon was sequenced for B. burgdorferi genomic DNA validation. A total of 130 patients visiting emergency room (ER) or Walk-in clinic (WALKIN), and 333 patients referred through the private physicians' offices were studied. While 5.4% of the ER/WALKIN patients showed DNA evidence of spirochetemia, none (0%) of the patients referred from private physicians' offices were DNA-positive. In contrast, while 8.4% of the patients referred from private physicians' offices were positive for the 2-tier Lyme serology assay, only 1.5% of the ER/ WALKIN patients were positive for this antibody test. The 2-tier serology assay missed 85.7% of the cases of early Lyme disease with spirochetemia. The latter diagnosis was confirmed by DNA sequencing.
CONCLUSION: Nested PCR followed by automated DNA sequencing is a valuable supplement to the standard 2-tier antibody assay in the diagnosis of early Lyme disease with spirochetemia. The best time to test for Lyme spirochetemia is when the patients living in the Lyme disease endemic areas develop unexplained symptoms or clinical manifestations that are consistent with Lyme disease early in the course of their illness.

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Appl Environ Microbiol. 2010 Nov;76(22):7650-2. Epub 2010 Sep 24.

Elimination of lyme disease spirochetes from ticks feeding on domestic ruminants.
Richter D, Matuschka FR.

Abteilung Parasitologie, Institut für Pathologie, Charité Universitätsmedizin Berlin, Malteserstraße 74-100, 12249 Berlin, Germany. drichter@charite.de.

To determine whether and which spirochetes are cleared from Ixodes ricinus ticks during feeding on ruminants, ticks were removed from goats and cattle grazing on tick-infested pastures. Although about a quarter of ticks questing on the pasture were infected by spirochetes, no molted ticks that had previously engorged to repletion on ruminants harbored Lyme disease spirochetes. Borrelia miyamotoi spirochetes, however, appear not to be eliminated. Thus, the more subadult ticks are diverted from reservoir-competent hosts to zooprophylactic ruminants, the smaller the risk of infection by Lyme disease spirochetes is.

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Infect Immun. 2010 Nov;78(11):4593-600. Epub 2010 Sep 7.

The chemokine receptor CXCR2 ligand KC (CXCL1) mediates neutrophil recruitment and is critical for development of experimental Lyme arthritis and carditis.
Ritzman AM, Hughes-Hanks JM, Blaho VA, Wax LE, Mitchell WJ, Brown CR.

Deletion of the chemokine receptor CXCR2 prevents the recruitment of neutrophils into tissues and subsequent development of experimental Lyme arthritis. Following footpad inoculation of Borrelia burgdorferi, the agent of Lyme disease, expression of the CXCR2 ligand KC (CXCL1) is highly upregulated in the joints of arthritis-susceptible mice and is likely to play an important role in the recruitment of neutrophils to the site of infection. To test this hypothesis, we infected C3H KC(-/-) mice with B. burgdorferi and followed the development of arthritis and carditis. Ankle swelling was significantly attenuated during the peak of arthritis in the KC(-/-) mice. Arthritis severity scores were significantly lower in the KC(-/-) mice on days 11 and 21 postinfection, with fewer neutrophils present in the inflammatory lesions. Cardiac lesions were also significantly decreased in KC(-/-) mice at day 21 postinfection. There were, however, no differences between C3H wild-type and KC(-/-) mice in spirochete clearance from tissues. Two other CXCR2 ligands, LIX (CXCL5) and MIP-2 (CXCL2), were not increased to compensate for the loss of KC, and the production of several innate cytokines was unaltered. These results demonstrate that KC plays a critical nonredundant role in the development of experimental Lyme arthritis and carditis via CXCR2-mediated recruitment of neutrophils into the site of infection.

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J Bacteriol. 2010 Oct 8. [Epub ahead of print].

Whole Genome Sequences of Thirteen Isolates of Borrelia burgdorferi.
Schutzer SE, Fraser-Liggett CM, Casjens SR, Qiu WG, Dunn JJ, Mongodin EF, Luft BJ.

Department of Medicine, University of Medicine and Dentistry of New Jersey-New Jersey Medical School, Newark, NJ 07103; Institute for Genome Sciences, University of Maryland, School of Medicine, Department of Microbiology and Immunology, Baltimore, MD 21201; Department of Pathology, Division of Microbiology and Immunology, University of Utah Medical School, Salt Lake City, UT 84112; Department of Biological Sciences, Hunter College of the City University of New York, New York, NY 10021; Biology Department, Brookhaven National Laboratory, Upton, NY 11793; Department of Medicine, Health Science Center, Stony Brook University, Stony Brook, NY 11794.

Borrelia burgdorferi is a causative agent of Lyme disease in North America and Eurasia. The first complete genome sequence of B. burgdorferi strain 31, available for more than a decade, has assisted research on the pathogenesis of Lyme disease. Because a single genome sequence is not sufficient to understand the relationship between genotypic and geographic variation and disease phenotype, we determined the whole genome sequences of 13 additional B. burgdorferi isolates that span the range of natural variation. These sequences should allow improved understanding of pathogenesis and provide a foundation for novel detection, diagnosis, and prevention strategies.

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J Med Entomol. 2010 Jul;47(4):695-8.

Trial of a minimal-risk botanical compound to control the vector tick of Lyme disease.
Rand PW, Lacombe EH, Elias SP, Lubelczyk CB, St Amand T, Smith RP Jr.

Vector-Borne Disease Laboratory, Maine Medical Center Research Institute, 75 John Roberts Road, Suite 9B, South Portland, ME 04106, USA. randp@mmc.org

We compared the application of IC2, a minimal-risk (25B) botanical compound containing 10% rosemary oil, with bifenthrin, a commonly used synthetic compound, and with water for the control of Ixodes scapularis Say (= Ixodes dammini Spielman, Clifford, Piesman & Corwin), on tick-infested grids in Maine, in an area where Lyme disease is established and other tick-borne diseases are emerging. High-pressure sprays of IC2, bifenthrin, and water were applied during the peak nymphal (July) and adult (October) seasons of the vector tick. No ticks could be dragged on the IC2 grids within 2 wk of the July spray, and few adult ticks were found in October or the following April. Similarly, no adult ticks could be dragged 1.5 wk after the October IC2 spray, and few the following April. No ticks were found on the bifenthrin grids after either spray through the following April, whereas substantial numbers of ticks remained throughout on the grids sprayed with water. Thus, IC2 appears to be an effective, minimum-risk acaricide to control the vector tick of Lyme disease.

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J Infect Dis. 2010 Jun 15;201(12):1849-58.

Recognition of Borrelia burgdorferi by NOD2 is central for the induction of an inflammatory reaction.
Oosting M, Berende A, Sturm P, Ter Hofstede HJ, de Jong DJ, Kanneganti TD, van der Meer JW, Kullberg BJ, Netea MG, Joosten LA.

Department of Medicine, Nijmegen Institute of Infection, Inflammation, and Immunity, Radboud University Nijmegen Medical Center, Nijmegen, the Netherlands.

Toll-like receptor 2 (TLR2) plays an important role in the recognition of Borrelia bacteria, the causative agent of Lyme disease, but the existence and importance of additional receptors in this process has been hypothesized. In the present study, we confirmed the role played by TLR2 in the recognition of Borrelia bacteria but also demonstrated a crucial role for the intracellular peptidoglycan receptor NOD2 for sensing the spirochete. Cells from individuals who were homozygous for the loss-of-function mutation 3020insC in the NOD2 gene were defective with respect to cytokine release after stimulation with Borrelia species, and this was confirmed in peritoneal macrophages from mice lacking RICK, the adaptor molecule used by NOD2. In contrast, NOD1 played no major role in the recognition of Borrelia spirochetes. This raises the intriguing possibility that recognition of Borrelia spirochetes is exerted by TLR2 in combination with NOD2 and that both receptors are necessary for an effective induction of cytokines by Borrelia species. The interplay between TLR2 and NOD2 might not only be necessary for the induction of a proper immune response but may also contribute to inflammatory-induced pathology.

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Clin Vaccine Immunol. 2010 Jun;17(6):904-9. Epub 2010 Apr 14.

Rapid, simple, quantitative, and highly sensitive antibody detection for lyme disease.
Burbelo PD, Issa AT, Ching KH, Cohen JI, Iadarola MJ, Marques A.

Neurobiology and Pain Therapeutics Section, 49 Convent Drive, Building 49, Room 1C20, NIDCR, NIH, Bethesda, MD 20892-4410, USA. burbelop@nidcr.nih.gov

There is currently a need for improved serological tests for the diagnosis and monitoring of Lyme disease, an infection caused by Borrelia burgdorferi. In the present study, we evaluated luciferase immunoprecipitation systems (LIPSs) for use for profiling of the antibody responses to a panel of B. burgdorferi proteins for the diagnosis of Lyme disease. Initially, serum samples from a cohort of patients and controls (n = 46) were used for training and were profiled by the use of 15 different B. burgdorferi antigen constructs. For the patient sera, the antibody responses to several B. burgdorferi antigens, including VlsE, flagellin (FlaB), BmpA, DbpA, and DbpB, indicated that the antigens had high levels of immunoreactivity. However, the best diagnostic performance was achieved with a synthetic protein, designated VOVO, consisting of a repeated antigenic peptide sequence, VlsE-OspC-VlsE-OspC, Analysis of an independent set of serum samples (n = 139) used for validation showed that the VOVO LIPS test had 98% sensitivity (95% confidence interval [CI], 93% to 100%; P < 0.0001) and 100% specificity (95% CI, 94% to 100%; P < 0.0001). Similarly, the C6 peptide enzyme-linked immunosorbent assay (ELISA) also had 98% sensitivity (95% CI, 93% to 100%; P < 0.0001) and 98% specificity (95% CI, 90% to 100%; P < 0.0001). Receiver operating characteristic analysis revealed that the rates of detection of Lyme disease by the LIPS test and the C6 ELISA were not statistically different. However, the VOVO LIPS test displayed a wide dynamic range of antibody detection spanning over 10,000-fold without the need for serum dilution. These results suggest that screening by the LIPS test with VOVO and other B. burgdorferi antigens offers an efficient quantitative approach for evaluation of the antibody responses in patients with Lyme disease.

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PLoS One. 2010 Jun 11;5(6):e10980.

Establishing the Proteome of Normal Human Cerebrospinal Fluid.
Schutzer SE, Liu T, Natelson BH, Angel TE, Schepmoes AA, Purvine SO, Hixson KK, Lipton MS, Camp DG, Coyle PK, Smith RD, Bergquist J.

Department of Medicine, University of Medicine and Dentistry of New Jersey-New Jersey Medical School, Newark, New Jersey, USA. schutzer@umdnj.edu

BACKGROUND: Knowledge of the entire protein content, the proteome, of normal human cerebrospinal fluid (CSF) would enable insights into neurologic and psychiatric disorders. Until now technologic hurdles and access to true normal samples hindered attaining this goal. METHODS AND PRINCIPAL FINDINGS: We applied immunoaffinity separation and high sensitivity and resolution liquid chromatography-mass spectrometry to examine CSF from healthy normal individuals. 2630 proteins in CSF from normal subjects were identified, of which 56% were CSF-specific, not found in the much larger set of 3654 proteins we have identified in plasma. We also examined CSF from groups of subjects previously examined by others as surrogates for normals where neurologic symptoms warranted a lumbar puncture but where clinical laboratory were reported as normal. We found statistically significant differences between their CSF proteins and our non-neurological normals. We also examined CSF from 10 volunteer subjects who had lumbar punctures at least 4 weeks apart and found that there was little variability in CSF proteins in an individual as compared to subject to subject. CONCLUSIONS: Our results represent the most comprehensive characterization of true normal CSF to date. This normal CSF proteome establishes a comparative standard and basis for investigations into a variety of diseases with neurological and psychiatric features.

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Philos Ethics Humanit Med. 2010 Jun 9;5:9.

The Infectious Diseases Society of America Lyme guidelines: a cautionary tale about the development of clinical practice guidelines.
W Johnson L, Stricker RB.

California Lyme Disease Association, Ukiah, CA, USA.

Flawed clinical practice guidelines may compromise patient care. Commercial conflicts of interest on panels that write treatment guidelines are particularly problematic, because panelists may have conflicting agendas that influence guideline recommendations. Historically, there has been no legal remedy for conflicts of interest on guidelines panels. However, in May 2008, the Attorney General of Connecticut concluded a ground-breaking antitrust investigation into the development of Lyme disease treatment guidelines by one of the largest medical societies in the United States, the Infectious Diseases Society of America (IDSA). Although the investigation found significant flaws in the IDSA guidelines development process, the subsequent review of the guidelines mandated by the settlement was compromised by a lack of impartiality at various stages of the IDSA review process. This article will examine the interplay between the recent calls for guidelines reform, the ethical canons of medicine, and due process considerations under antitrust laws as they apply to the formulation of the IDSA Lyme disease treatment guidelines. The article will also discuss pitfalls in the implementation of the IDSA antitrust settlement that should be avoided in the future.

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Mil Med. 2010 May;175(5):367-9.

An unexpected case of Lyme disease in a soldier serving in northern Iraq.
Fisher JB, Curtis CE.

Tropic Lightning TMC, Bldg. 677, Schofield Barracks, HI 96857, USA.

Lyme disease is a tick-transmitted disease caused by the spirochete Borrelia burgdorferi. Cases have been reported across the United States, Canada, and Europe. Additional cases have been described in other parts of the world including Japan, Mexico, and Turkey. We report an unexpected case of Lyme disease from Iraq.

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PLoS One. 2010 May 14;5(5):e10650

Genotypic variation and mixtures of Lyme Borrelia in Ixodes ticks from North America and Europe.
Crowder CD, Matthews HE, Schutzer S, Rounds MA, Luft BJ, Nolte O, Campbell SR, Phillipson CA, Li F, Sampath R, Ecker DJ, Eshoo MW.

Ibis Biosciences, Carlsbad, California, United States of America.

BACKGROUND: Lyme disease, caused by various species of Borrelia, is transmitted by Ixodes ticks in North America and Europe. Studies have shown the genotype of Borrelia burgdorferi sensu stricto (s.s.) or the species of B. burgdorferi sensu lato (s.l.) affects the ability of the bacteria to cause local or disseminated infection in humans.

METHODOLOGY/PRINCIPAL FINDINGS: We used a multilocus PCR electrospray mass spectrometry assay to determine the species and genotype Borrelia from ticks collected in New York, Connecticut, Indiana, Southern Germany, and California and characterized isolates from parts of the United States and Europe. These analyses identified 53 distinct genotypes of B. burgdorferi sensu stricto with higher resolution than ospC typing. Genotypes of other members of the B. burgdorferi sensu lato complex were also identified and genotyped including B. afzelii, B. garinii, B. lusitaniae, B. spielmanii, and B. valaisiana. While each site in North America had genotypes unique to that location, we found genotypes shared between individual regions and two genotypes found across the United States. Significant B. burgdorferi s.s. genotypic diversity was observed between North America and Europe: only 6.6% of US genotypes (3 of 45) were found in Europe and 27% of the European genotypes (3 of 11) were observed in the US. Interestingly, 39% of adult Ixodes scapularis ticks from North America were infected with more than one genotype of B. burgdorferi s.s. and 22.2% of Ixodes ricinus ticks from Germany were infected with more than one genotype of B. burgdorferi s.l.

CONCLUSIONS/SIGNIFICANCE: The presence of multiple Borrelia genotypes in ticks increases the probability that a person will be infected with more than one genotype of B. burgdorferi, potentially increasing the risks of disseminated Lyme disease. Our study indicates that the genotypic diversity of Borrelia in ticks in both North America and Europe is higher then previously reported and can have potential clinical consequences.

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J Antimicrob Chemother. 2010 Jun;65(6):1137-44. Epub 2010 Apr 9.

Efficacy of antibiotic prophylaxis for the prevention of Lyme disease: an updated systemic review and meta-analysis.
Warshafsky S, Lee DH, Francois LK, Nowakowski J, Nadelman RB, Wormser GP.

Department of Medicine, New York Medical College, Valhalla, NY 10595, USA. stephen@doctorsw.com.

BACKGROUND: The clinical value of antibiotic prophylaxis in preventing Lyme disease remains uncertain, owing to a meta-analysis lacking sufficient power to demonstrate efficacy and a more recent trial showing effectiveness but lacking precision. Our objective was to update our prior meta-analysis on antibiotic prophylaxis for the prevention of Lyme disease, to obtain a more precise estimate of treatment effect. METHODS: Clinical trials were identified by searching MEDLINE, Embase, the Cochrane Library and trial registries, and by an assessment of the bibliographies of retrieved articles and reviews. Trials were selected if their patients were randomly allocated to a treatment or placebo group within 72 h following an Ixodes tick bite and had no clinical evidence of Lyme disease at enrollment. Details of the trial design, patient characteristics, interventions and outcomes were extracted from each article. Study quality was assessed using the Jadad scale. RESULTS: Four placebo-controlled clinical trials were included for review. Among 1082 randomized subjects, the risk of Lyme disease in the placebo group was 2.2% [95% confidence interval (CI), 1.2%-3.9%] compared with 0.2% (95% CI, 0.0%-1.0%) in the antibiotic-treated group. Antibiotic prophylaxis significantly reduced the odds of developing Lyme disease compared with placebo (pooled odds ratio=0.084; 95% CI, 0.0020-0.57; P=0.0037). CONCLUSIONS: The available evidence to date supports the use of antibiotic prophylaxis for the prevention of Lyme disease in endemic areas following an Ixodes tick bite. Pooled data from four placebo-controlled trials suggests that one case of Lyme disease is prevented for about every 50 patients who are treated with antibiotics.

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Environ Health Perspect. 2010 Jul;118(7):909-14. Epub 2010 Mar 25.

Active and passive surveillance and phylogenetic analysis of Borrelia burgdorferi elucidate the process of Lyme disease risk emergence in Canada.
Ogden NH, Bouchard C, Kurtenbach K, Margos G, Lindsay LR, Trudel L, Nguon S, Milord F.

Centre for Food-Borne, Environmental and Zoonotic Infectious Diseases, Public Health Agency of Canada, Saint-Hyacinthe, Québec, Canada. nicholas_ogden@phac-aspc.gc.ca

BACKGROUND: Northward expansion of the tick Ixodes scapularis is driving Lyme disease (LD) emergence in Canada. Information on mechanisms involved is needed to enhance surveillance and identify where LD risk is emerging.

OBJECTIVES: We used passive and active surveillance and phylogeographic analysis of Borrelia burgdorferi to investigate LD risk emergence in Quebec.

METHODS: In active surveillance, we collected ticks from the environment and from captured rodents. B. burgdorferi transmission was detected by serological analysis of rodents and by polymerase chain reaction assays of ticks. Spatiotemporal trends in passive surveillance data assisted interpretation of active surveillance. Multilocus sequence typing (MLST) of B. burgdorferi in ticks identified likely source locations of B. burgdorferi.

RESULTS: In active surveillance, we found I. scapularis at 55% of sites, and we were more likely to find them at sites with a warmer climate. B. burgdorferi was identified at 13 I. scapularis-positive sites, but infection prevalence in ticks and animal hosts was low. Low infection prevalence in ticks submitted in passive surveillance after 2004-from the tick-positive regions identified in active surveillance-coincided with an exponential increase in tick submissions during this time. MLST analysis suggested recent introduction of B. burgdorferi from the northeastern United States.

CONCLUSIONS: These data are consistent with I. scapularis ticks dispersed from the United States by migratory birds, founding populations where the climate is warmest, and then establishment of B. burgdorferi from the United States several years after I. scapularis have established. These observations provide vital information for public health to minimize the impact of LD in Canada.

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J Rheumatol. 2010 May;37(5):1049-55. Epub 2010 Apr 1.

Outcomes of children treated for Lyme arthritis: results of a large pediatric cohort.
Tory HO, Zurakowski D, Sundel RP.

Department of Pediatrics, Yale-New Haven Children's Hospital, New Haven, CT 06520-8064, USA.  heather.tory@yale.heather.tory@yale.eduedu

OBJECTIVE: Children often develop arthritis secondary to Lyme disease; however, optimal treatment of Lyme arthritis in pediatric patients remains ill-defined. We sought to characterize the outcomes of a large cohort of children with Lyme arthritis treated using the approach recommended by the American Academy of Pediatrics and the Infectious Diseases Society of America.

METHODS: Medical records of patients with Lyme arthritis seen by rheumatologists at a tertiary care children's hospital from 1997 to 2007 were reviewed. Patients were classified with antibiotic responsive or refractory arthritis based on absence or presence of persisting joint involvement 3 months after antibiotic initiation. Treatment regimens and outcomes in patients with refractory arthritis were analyzed.

RESULTS: Of 99 children with Lyme arthritis, 76 had arthritis that responded fully to antibiotics, while 23 developed refractory arthritis. Most patients with refractory arthritis were successfully treated with nonsteroidal antiinflammatory drugs (6 patients), intraarticular steroid injections (4), or disease-modifying antirheumatic drugs (DMARD) (2). Five were lost to followup. Six patients with refractory arthritis were initially treated elsewhere and received additional antibiotic therapy, with no apparent benefit. Three subsequently required DMARD, while 3 had gradual resolution of arthritis without further therapy. Antibiotic responsiveness could not be predicted from our clinical or laboratory data.

CONCLUSION: Lyme arthritis in children has an excellent prognosis. More than 75% of referred cases resolved with antibiotic therapy. Of patients with antibiotic refractory arthritis, none in whom followup data were available developed chronic arthritis, joint deformities, or recurrence of infection, supporting current treatment guidelines.

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Brain Behav Immun. 2010 Mar 17. [Epub ahead of print]

Anti-neural antibody reactivity in patients with a history of Lyme Borreliosis and persistent symptoms.
Chandra A, Wormser GP, Klempner MS, Trevino RP, Crow MK, Latov N, Alaedini A.

Department of Neurology and Neuroscience, Cornell University, New York, NY, USA.

Some Lyme disease patients report debilitating chronic symptoms of pain, fatigue, and cognitive deficits despite recommended courses of antibiotic treatment. The mechanisms responsible for these symptoms, collectively referred to as post-Lyme disease syndrome (PLS) or chronic Lyme disease, remain unclear. We investigated the presence of immune system abnormalities in PLS by assessing the levels of antibodies to neural proteins in patients and controls. Serum samples from PLS patients, post-Lyme disease healthy individuals, patients with systemic lupus erythematosus, and normal healthy individuals were analyzed for anti-neural antibodies by immunoblotting and immunohistochemistry. Anti-neural antibody reactivity was found to be significantly higher in the PLS group than in the post-Lyme healthy (p<0.01) and normal healthy (p<0.01) groups. The observed heightened antibody reactivity in PLS patients could not be attributed solely to the presence of cross-reactive anti-borrelia antibodies, as the borrelial seronegative patients also exhibited elevated anti-neural antibody levels. Immunohistochemical analysis of PLS serum antibody activity demonstrated binding to cells in the central and peripheral nervous systems. The results provide evidence for the existence of a differential immune system response in PLS, offering new clues about the etiopathogenesis of the disease that may prove useful in devising more effective treatment strategies.

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J Neurobiol Dis. 2010 Mar;37(3):534-41. Epub 2009 Nov 26.

Inflammation and central nervous system Lyme disease.
Fallon BA, Levin ES, Schweitzer PJ, Hardesty D.

Department of Psychiatry, Columbia University, New York, NY, USA; New York State Psychiatric Institute, New York, NY, USA.

Lyme disease, caused by the bacterium Borrelia burgdorferi, can cause multi-systemic signs and symptoms, including peripheral and central nervous system disease. This review examines the evidence for and mechanisms of inflammation in neurologic Lyme disease, with a specific focus on the central nervous system, drawing upon human studies and controlled research with experimentally infected rhesus monkeys. Directions for future human research are suggested that may help to clarify the role of inflammation as a mediator of the chronic persistent symptoms experienced by some patients despite antibiotic treatment for neurologic Lyme disease.

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Clin Infect Dis. 2010 Feb 15;50(4):512-20.

Antibiotic Treatment Duration and Long-Term Outcomes of Patients with Early Lyme Disease from a Lyme Disease-Hyperendemic Area.
Kowalski TJ, Tata S, Berth W, Mathiason MA, Agger WA.

Section of Infectious Disease and Departments of Medical Education, Gundersen Lutheran Medical Foundation, La Crosse, WI 54601. USA. TJKowals@gundluth.TJKowals@gundluth.orgorg.

BACKGROUND: The length of antibiotic therapy and long-term outcomes in patients with early Lyme disease are incompletely described. We report the long-term clinical outcomes of patients with early localized and early disseminated Lyme disease based on the duration of antibiotic therapy prescribed. METHODS: A retrospective cohort study and follow-up survey of patients diagnosed as having early localized and early disseminated Lyme disease from 1 January 2000 through 31 December 2004 was conducted in a Lyme disease-hyperendemic area. RESULTS: Six hundred seven patients met the study inclusion criteria. Most patients (93%) were treated with doxycycline for treatment durations of 10 days, 11-15 days, or 16 days in 17%, 33%, and 47% of doxycycline-treated patients, respectively. Treatment failure criteria, defined before performing the study, were met in only 6 patients (1%). Although these 6 patients met a priori treatment failure criteria, 4 of these patients' clinical details suggested reinfection, 1 was treated with an inappropriate antibiotic, and 1 developed facial palsy early in therapy. Reinfection developed in 4% of patients. The 2-year treatment failure-free survival rates of patients treated with antibiotics for 10 days, 11-15 days, or 16 days were 99.0%, 98.9%, and 99.2%, respectively. Patients treated with antibiotics for 16 days had lower 36-item Short-Form Health Survey social functioning scores on the follow-up survey. No other differences were found in follow-up clinical status or 36-item Short-Form Health Survey scores by duration of antibiotic treatment. CONCLUSIONS: Patients treated for 10 days with antibiotic therapy for early Lyme disease have long-term outcomes similar to those of patients treated with longer courses. Treatment failure after appropriately targeted short-course therapy, if it occurs, is exceedingly rare.

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Minerva Med. 2010 Feb;101(1):1-7.

Safety of intravenous antibiotic therapy in patients referred for treatment of neurologic Lyme disease.
Stricker RB, Green CL, Savely VR, Chamallas SN, Johnson L.

Union Square Medical Associates, San Francisco, CA, USA. rstricker@usmamed.com.

AIM: Although intravenous antibiotic therapy is recommended for neurologic Lyme disease, safety concerns have been raised about treatment beyond 30 days in patients with persistent neurologic symptoms. The goal of our study was to evaluate the safety of extended intravenous antibiotic therapy in patients referred for treatment of neurologic Lyme disease. METHODS: We enrolled 200 consecutive patients with significant neurologic symptoms and positive testing for Borrelia burgdorferi. Patients were treated with intravenous antibiotics using various intravascular devices (IVDs). Standard IVD care was administered to all patients, and monitoring for medication reactions and IVD complications was performed on a weekly basis. RESULTS: The mean length of intravenous antibiotic treatment was 118 days (range, 7-750 days) representing 23,654 IVD-days. Seven patients (3.5%) experienced allergic reactions to the antibiotic medication, and two patients (1.0%) had gallbladder toxicity. IVD complications occurred in 15 patients (7.5%) representing an incidence of 0.63 per 1,000 IVD-days. The IVD problems occurred an average of 81 days after initiation of treatment (range, 7-240 days). There were six suspected line infections for an incidence of 0.25 per 1,000 IVD-days. Only one of the IVD infections was confirmed, and no resistant organisms were cultured from any patient. None of the IVD complications were fatal. CONCLUSION: Prolonged intravenous antibiotic therapy is associated with low morbidity and no IVD-related mortality in patients referred for treatment of neurologic Lyme disease. With proper IVD care, the risk of extended antibiotic therapy in these patients appears to be low.

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Clin Infect Dis. 2010 Jan 1;50(1):20-6.

2-Tiered Antibody Testing for Early and Late Lyme Disease Using Only an Immunoglobulin G Blot with the Addition of a VlsE Band as the Second-Tier Test.
Branda JA, Aguero-Rosenfeld ME, Ferraro MJ, Johnson BJ, Wormser GP, Steere AC.

Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA. branda.john@mgh.harvard.edu.

BACKGROUND: Standard 2-tiered immunoglobulin G (IgG) testing has performed well in late Lyme disease (LD), but IgM testing early in the illness has been problematic. IgG VlsE antibody testing, by itself, improves early sensitivity, but may lower specificity. We studied whether elements of the 2 approaches could be combined to produce a second-tier IgG blot that performs well throughout the infection. METHODS: Separate serum sets from LD patients and control subjects were tested independently at 2 medical centers using whole-cell enzyme immunoassays and IgM and IgG immunoblots, with recombinant VlsE added to the IgG blots. The results from both centers were combined, and a new second-tier IgG algorithm was developed. RESULTS: With standard 2-tiered IgM and IgG testing, 31% of patients with active erythema migrans (stage 1), 63% of those with acute neuroborreliosis or carditis (stage 2), and 100% of those with arthritis or late neurologic involvement (stage 3) had positive results. Using new IgG criteria, in which only the VlsE band was scored as a second-tier test among patients with early LD (stage 1 or 2) and 5 of 11 IgG bands were required in those with stage 3 LD, 34% of patients with stage 1, 96% of those with stage 2, and 100% of those with stage 3 infection had positive responses. Both new and standard testing achieved 100% specificity. CONCLUSIONS: Compared with standard IgM and IgG testing, the new IgG algorithm (with VlsE band) eliminates the need for IgM testing; it provides comparable or better sensitivity, and it maintains high specificity.

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Med Microbiol Immunol. 2010 Jan 6. [Epub ahead of print]

Presence of Borrelia burgdorferi in endomyocardial biopsies in patients with new-onset unexplained dilated cardiomyopathy.
Palecek T, Kuchynka P, Hulinska D, Schramlova J, Hrbackova H, Vitkova I, Simek S, Horak J, Louch WE, Linhart A.

1st Medical Faculty, 2nd Medical Department - Clinical Department of Cardiology and Angiology, Charles University of Prague, Prague, Czech Republic. tpalec@lf1.cuni.cz.

Dilated cardiomyopathy (DCM) represents the third most common cause of heart failure and the most frequent cause of heart transplantation. Infectious, mostly viral, and autoimmune mechanisms, together with genetic abnormalities, have been reported as three major causes of DCM. We hypothesized that Lyme disease (LD), caused by spirochete Borrelia burgdorferi (Bb), might be an important cause of new-onset unexplained DCM in patients living in a highly endemic area for LD such as the Czech Republic. We performed endomyocardial biopsy (EMB) in 39 consecutive patients presenting with symptomatic unexplained left ventricular (LV) systolic dysfunction lasting no more than 12 months. In eight subjects (21%), Bb was detected in the EMB sample by polymerase chain reaction or by electron microscopy. None of these patients exhibited any form of atrioventricular block or other extracardiac manifestation of Bb infection. Serological testing identified IgG antibodies against Bb in only two cases and IgM antibodies in none. All affected patients were treated with intravenous ceftriaxone for 3 weeks. At 6 months follow-up, LV morphology and function as well as functional status of these patients significantly improved. In conclusion, Bb infection may represent an important cause of new-onset unexplained DCM in patients living in endemic regions such as the Czech Republic. Because the antibiotic treatment appears to be markedly effective and serological examination does not provide a tool for diagnosing the disease, EMB focused on the detection of Bb should be performed in all patients from endemic areas with new-onset unexplained DCM not responding to conventional therapy.

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