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Recent Articles on Lyme Disease and the Heart

1. Kardiol Pol. 2009 May;67(5):516-20.

[May Lyme borreliosis lead to heart transplantation? - a case report]

[Article in Polish]

Maroszyńska-Dmoch E, Wozakowska-Kapłon B.

I Oddział Kardiologii, Swietokrzyskie Centrum Kardiologii, 25-736 Kielce.

A case of a 65-year-old man, who used to work as a forester for many years, with end-stage dilated cardiomyopathy and subsequent heart transplantation is described. Eight years later the diagnosis of Lyme borreliosis was established, which was the likely cause of cardiac disease in this patient.

PMID: 19521937 [PubMed - indexed for MEDLINE]

2. PLoS Pathog. 2009 May;5(5):e1000447. Epub 2009 May 22.

The urokinase receptor (uPAR) facilitates clearance of Borrelia burgdorferi.

Hovius JW, Bijlsma MF, van der Windt GJ, Wiersinga WJ, Boukens BJ, Coumou J, Oei A, de Beer R, de Vos AF, van 't Veer C, van Dam AP, Wang P, Fikrig E, Levi MM, Roelofs JJ, van der Poll T.

Center for Experimental and Molecular Medicine (CEMM), Academic Medical Center, University of Amsterdam, AMC, Amsterdam, The Netherlands. j.w.hovius@amc.uva.nl

The causative agent of Lyme borreliosis, the spirochete Borrelia burgdorferi, has been shown to induce expression of the urokinase receptor (uPAR); however, the role of uPAR in the immune response against Borrelia has never been investigated. uPAR not only acts as a proteinase receptor, but can also, dependently or independently of ligation to uPA, directly affect leukocyte function. We here demonstrate that uPAR is upregulated on murine and human leukocytes upon exposure to B. burgdorferi both in vitro as well as in vivo. Notably, B. burgdorferi-inoculated C57BL/6 uPAR knock-out mice harbored significantly higher Borrelia numbers compared to WT controls. This was associated with impaired phagocytotic capacity of B. burgdorferi by uPAR knock-out leukocytes in vitro. B. burgdorferi numbers in vivo, and phagocytotic capacity in vitro, were unaltered in uPA, tPA (low fibrinolytic activity) and PAI-1 (high fibrinolytic activity) knock-out mice compared to WT controls. Strikingly, in uPAR knock-out mice partially backcrossed to a B. burgdorferi susceptible C3H/HeN background, higher B. burgdorferi numbers were associated with more severe carditis and increased local TLR2 and IL-1beta mRNA expression. In conclusion, in B. burgdorferi infection, uPAR is required for phagocytosis and adequate eradication of the spirochete from the heart by a mechanism that is independent of binding of uPAR to uPA or its role in the fibrinolytic system.

PMCID: 2678258 PMID: 19461880 [PubMed - indexed for MEDLINE]

3. PLoS One. 2009;4(4):e5412. Epub 2009 Apr 30.

A novel fibronectin binding motif in MSCRAMMs targets F3 modules.

Prabhakaran S, Liang X, Skare JT, Potts JR, Höök M.

Institute of Biosciences and Technology, Texas A&M Health Science Center, College Station, Texas, United States of America.

BACKGROUND: BBK32 is a surface expressed lipoprotein and fibronectin (Fn)-binding microbial surface component recognizing adhesive matrix molecule (MSCRAMM) of Borrelia burgdorferi, the causative agent of Lyme disease. Previous studies from our group showed that BBK32 is a virulence factor in experimental Lyme disease and located the Fn-binding region to residues 21-205 of the lipoprotein. METHODOLOGY/PRINCIPAL FINDINGS: Studies aimed at identifying interacting sites between BBK32 and Fn revealed an interaction between the MSCRAMM and the Fn F3 modules. Further analysis of this interaction showed that BBK32 can cause the aggregation of human plasma Fn in a similar concentration-dependent manner to that of anastellin, the superfibronectin (sFn) inducing agent. The resulting Fn aggregates are conformationally distinct from plasma Fn as indicated by a change in available thermolysin cleavage sites. Recombinant BBK32 and anastellin affect the structure of Fn matrices formed by cultured fibroblasts and inhibit endothelial cell proliferation similarly. Within BBK32, we have located the sFn-forming activity to a region between residues 160 and 175 which contains two sequence motifs that are also found in anastellin. Synthetic peptides mimicking these motifs induce Fn aggregation, whereas a peptide with a scrambled sequence motif was inactive, suggesting that these motifs represent the sFn-inducing sequence. CONCLUSIONS/SIGNIFICANCE: We conclude that BBK32 induces the formation of Fn aggregates that are indistinguishable from those formed by anastellin. The results of this study provide evidence for how bacteria can target host proteins to manipulate host cell activities.

PMCID: 2671840 PMID: 19404402 [PubMed - indexed for MEDLINE]

4. Pediatrics. 2009 May;123(5):e835-41.

Lyme carditis in children: presentation, predictive factors, and clinical course.

Costello JM, Alexander ME, Greco KM, Perez-Atayde AR, Laussen PC.

Harvard Medical School, Division of Cardiac Intensive Care, Department of Cardiology, Children's Hospital Boston, 300 Longwood Ave, Bader 600, Boston, MA 02115, USA. john.costello@cardio.chboston.org

Comment in: Pediatrics. 2009 May;123(5):1408.

OBJECTIVES: We sought to identify predictive factors for Lyme carditis in children and to characterize the clinical course of these patients. METHODS: We reviewed all cases of early disseminated Lyme disease presenting to our institution from January 1994 through July 2008, and summarized the presentation and course of those patients with carditis. A case-control study was used to identify predictive factors for carditis. Controls were patients with early disseminated Lyme disease without carditis. RESULTS: Of 207 children with early disseminated Lyme disease, 33 (16%) had carditis, 14 (42%) of whom had advanced heart block, including 9 (27%) with complete heart block. The median time to recovery of sinus rhythm in these 14 patients was 3 days (range: 1-7 days), and none required a permanent pacemaker. Four (12%) of 33 patients with carditis had depressed ventricular systolic function, 3 (9%) of whom required mechanical ventilation, temporary pacing, and inotropic support. Complete resolution of rhythm disturbances and myocardial dysfunction occurred in 24 (89%) of 27 patients for whom follow-up data were available. Most patients with carditis also had other systemic Lyme involvement. By using multivariate logistic regression analysis, we found that children >10 years of age, those with arthralgias, and those with cardiopulmonary symptoms were more likely to have carditis. CONCLUSIONS: The spectrum of presentation for children with Lyme carditis is broad, ranging from asymptomatic, first-degree heart block to fulminant myocarditis. Variable degrees of heart block are the most common manifestation and occasionally require temporary pacing. Transient myocardial dysfunction, although less common, can be life-threatening. Advanced heart block resolves within 1 week in most cases. In children with early disseminated Lyme disease, older age, arthralgias, and cardiopulmonary symptoms independently predict the presence of carditis.

PMID: 19403477 [PubMed - indexed for MEDLINE]

5. Z Rheumatol. 2009 May;68(3):239-52; quiz 253-4.

[Lyme borreliosis]

[Article in German]

Krause A, Fingerle V.

Rheumakliniken Berlin-Buch und Berlin-Wannsee, Immanuel-Krankenhaus, Königstr. 63, 14109, Berlin, Deutschland. a.krause@immanuel.de

Lyme borreliosis is a multi-system infectious disease that primarily affects the skin, nervous system, heart, and joints. It is caused by the tick-borne spirochete Borrelia burgdorferi sensu lato. Diagnosis is made on the basis of clinical symptoms and supported by a positive serology. Antibiotic therapy should be started immediately after the diagnosis has been established and is administered according to stage and symptoms of the disease. Doxycycline, amoxicillin, and ceftriaxone are the antibiotics of choice. Early Lyme disease is almost always cured by one antibiotic course that also prevents subsequent disease manifestations. After antibiotic therapy of late disease manifestations, symptoms resolve only slowly and remission is usually achieved after weeks or even months. Chronic or therapy-resistant disease courses and residual symptoms after therapy are rare.

PMID: 19387665 [PubMed - indexed for MEDLINE]

6. J Antimicrob Chemother. 2009 Jun;63(6):1163-72. Epub 2009 Apr 17.

Assessment of methylthioadenosine/S-adenosylhomocysteine nucleosidases of Borrelia burgdorferi as targets for novel antimicrobials using a novel high-throughput method.

Cornell KA, Primus S, Martinez JA, Parveen N.

Department of Chemistry and Biochemistry, Boise State University, IA 83725-1520, USA.

BACKGROUND: Lyme disease is the most prevalent tick-borne disease in the USA with the highest number of cases (27 444 patients) reported by CDC in the year 2007, representing an unprecedented 37% increase from the previous year. The haematogenous spread of Borrelia burgdorferi to various tissues results in multisystemic disease affecting the heart, joints, skin, musculoskeletal and nervous system of the patients. OBJECTIVES: Although Lyme disease can be effectively treated with doxycycline, amoxicillin and cefuroxime axetil, discovery of novel drugs will benefit the patients intolerant to these drugs and potentially those suffering from chronic Lyme disease that is refractory to these agents and to macrolides. In this study, we have explored 5'-methylthioadenosine/S-adenosylhomocysteine nucleosidase as a drug target for B. burgdorferi, which uniquely possesses three genes expressing homologous enzymes with two of these proteins apparently exported. METHODS: The recombinant B. burgdorferi Bgp and Pfs proteins were first used for the kinetic analysis of enzymatic activity with both substrates and with four inhibitors. We then determined the antispirochaetal activity of these compounds using a novel technique. The method involved detection of the live-dead B. burgdorferi by fluorometric analysis after staining with a fluorescent nucleic acids stain mixture containing Hoechst 33342 and Sytox Green. RESULTS: Our results indicate that this method can be used for high-throughput screening of novel antimicrobials against bacteria. The inhibitors formycin A and 5'-p-nitrophenythioadenosine particularly affected B. burgdorferi adversely on prolonged treatment. CONCLUSIONS: On the basis of our analysis, we expect that structure-based modification of the inhibitors can be employed to develop highly effective novel antibiotics against Lyme spirochaetes.

PMCID: 2734086 PMID: 19376840 [PubMed - indexed for MEDLINE]

7. Curr Probl Dermatol. 2009;37:51-110. Epub 2009 Apr 8.

Clinical manifestations and diagnosis of lyme borreliosis.

Strle F, Stanek G.

Department of Infectious Diseases, University Medical Center Ljubljana, Ljubljana, Slovenia. franc.strle@kclj.si

Lyme borrelosis is a multi-systemic disease caused byBorrelia burgdorferisensu lato. A complete presentation of the disease is an extremely unusual oberservation, in which a skin lesion follows a tick bite, the lesion itself is followed by heart and nervous system involvement, and later on by arthritis; late involvement of the eye, nervous system, joints and skin may also occur. Information on the relative frequency of individual clinical manifestations of Lyme borreliosis is limited; however, the skin is most frequently involved and skin manifestations frequently represent clues for the diagnosis. The only sign that enables a reliable clinical diagnoisis of Lyme borreliosis is a typical erythema migrans. Laboratory confirmation of a borrelial infection is needed for all manifestations of Lyme borreliosis, with the exception of typical skin lesions. Copyright 2009 S. Karger AG, Basel.

PMID: 19367097 [PubMed - indexed for MEDLINE]

8. Praxis (Bern 1994). 2009 Mar 18;98(6):330-4.

[Elevated transaminases - what to do if everything was done?]

[Article in German]

Lepper PM, Dufour JF.

Klinik für Allgemeine Innere Medizin, Universitätsspital Bern (Inselspital), Bern, Germany.

Transaminases, gamma-GT and alcalic phosphatase are classically termed as liver enzymes, however they can be found in almost every organ. Elevated levels of the transaminases ALAT (alanin-aminotransferase) and ASAT (aspartat-aminotransferase) are signs of disturbed permeability of the cells, in which these enzymes can be found. In contrast to ALAT, which is mainly liver-specific, the ASAT is found in other organs as well, e.g. heart and skeletal muscle. At a mild elevation of these enzymes a reevaluation is recommended, however if an elevation persists and is suspicious for a liver disease, a specific work up is necessary. In this manuscript, we discuss often overlooked problems and provide a diagnostic algorithm for the workup of elevated liver enzymes.

PMID: 19291640 [PubMed - indexed for MEDLINE]

9. PLoS Pathog. 2009 Mar;5(3):e1000326. Epub 2009 Mar 6.

A chromosomally encoded virulence factor protects the Lyme disease pathogen against host-adaptive immunity.

Yang X, Coleman AS, Anguita J, Pal U.

Department of Veterinary Medicine, University of Maryland, College Park, Maryland, United States of America.

Borrelia burgdorferi, the bacterial pathogen of Lyme borreliosis, differentially expresses select genes in vivo, likely contributing to microbial persistence and disease. Expression analysis of spirochete genes encoding potential membrane proteins showed that surface-located membrane protein 1 (lmp1) transcripts were expressed at high levels in the infected murine heart, especially during early stages of infection. Mice and humans with diagnosed Lyme borreliosis also developed antibodies against Lmp1. Deletion of lmp1 severely impaired the pathogen's ability to persist in diverse murine tissues including the heart, and to induce disease, which was restored upon chromosomal complementation of the mutant with the lmp1 gene. Lmp1 performs an immune-related rather than a metabolic function, as its deletion did not affect microbial persistence in immunodeficient mice, but significantly decreased spirochete resistance to the borreliacidal effects of anti-B. burgdorferi sera in a complement-independent manner. These data demonstrate the existence of a virulence factor that helps the pathogen evade host-acquired immune defense and establish persistent infection in mammals.

PMCID: 2644780 PMID: 19266024 [PubMed - indexed for MEDLINE]

10. J Immunol. 2009 Mar 15;182(6):3728-34.

Local production of IFN-gamma by invariant NKT cells modulates acute Lyme carditis.

Olson CM Jr, Bates TC, Izadi H, Radolf JD, Huber SA, Boyson JE, Anguita J.

Department of Veterinary and Animal Sciences, University of Massachusetts at Amherst, Amherst, MA 01003, USA.

The Lyme disease spirochete Borrelia burgdorferi is the only known human pathogen that directly activates invariant NKT (iNKT) cells. The number and activation kinetics of iNKT cells vary greatly among different strains of mice. We now report the role of the iNKT cell response in the pathogenesis of Lyme disease using C57BL/6 mice, a strain with optimal iNKT cell activation that is resistant to the development of spirochetal-induced inflammation. During experimental infection of B6 mice with B. burgdorferi, iNKT cells localize to the inflamed heart where they are activated by CD1d-expressing macrophages. Activation of iNKT cells in vivo results in the production of IFN-gamma, which we demonstrate ameliorates the severity of murine Lyme carditis by at least two mechanisms. First, IFN-gamma enhances the recognition of B. burgdorferi by macrophages, leading to increased phagocytosis of the spirochete. Second, IFN-gamma activation of macrophages increases the surface expression of CD1d, thereby facilitating further iNKT activation. Collectively, our data demonstrate that in the resistant background, B6, iNKT cells modulate the severity of murine Lyme carditis through the action of IFN-gamma, which appears to self-renew through a positive feedback loop during infection.

PMCID: 2679988 PMID: 19265151 [PubMed - indexed for MEDLINE]

11. PLoS Pathog. 2009 Feb;5(2):e1000293. Epub 2009 Feb 13.

Detailed analysis of sequence changes occurring during vlsE antigenic variation in the mouse model of Borrelia burgdorferi infection.

Coutte L, Botkin DJ, Gao L, Norris SJ.

Department of Pathology and Laboratory Medicine, University of Texas Medical School at Houston, Houston, Texas, United States of America.

Lyme disease Borrelia can infect humans and animals for months to years, despite the presence of an active host immune response. The vls antigenic variation system, which expresses the surface-exposed lipoprotein VlsE, plays a major role in B. burgdorferi immune evasion. Gene conversion between vls silent cassettes and the vlsE expression site occurs at high frequency during mammalian infection, resulting in sequence variation in the VlsE product. In this study, we examined vlsE sequence variation in B. burgdorferi B31 during mouse infection by analyzing 1,399 clones isolated from bladder, heart, joint, ear, and skin tissues of mice infected for 4 to 365 days. The median number of codon changes increased progressively in C3H/HeN mice from 4 to 28 days post infection, and no clones retained the parental vlsE sequence at 28 days. In contrast, the decrease in the number of clones with the parental vlsE sequence and the increase in the number of sequence changes occurred more gradually in severe combined immunodeficiency (SCID) mice. Clones containing a stop codon were isolated, indicating that continuous expression of full-length VlsE is not required for survival in vivo; also, these clones continued to undergo vlsE recombination. Analysis of clones with apparent single recombination events indicated that recombinations into vlsE are nonselective with regard to the silent cassette utilized, as well as the length and location of the recombination event. Sequence changes as small as one base pair were common. Fifteen percent of recovered vlsE variants contained "template-independent" sequence changes, which clustered in the variable regions of vlsE. We hypothesize that the increased frequency and complexity of vlsE sequence changes observed in clones recovered from immunocompetent mice (as compared with SCID mice) is due to rapid clearance of relatively invariant clones by variable region-specific anti-VlsE antibody responses.

PMCID: 2632889 PMID: 19214205 [PubMed - indexed for MEDLINE]

12. Clin Pediatr (Phila). 2009 Feb 3. [Epub ahead of print]

Asymptomatic, Transient Complete Heart Block in a Pediatric Patient With Lyme Disease.

Heckler AK, Shmorhun D.

Lyme Disease, caused by the spirochete Borrellia burgdorferi, is the most common vector-borne disease in the United States. Clinically, it primarily affects the skin, joints, nervous system, and heart. Lyme carditis occurs in 4%-10% of adults with Lyme disease. Transient variable-level atrioventricular blocks, occurring in 77% of adults with Lyme carditis, are the most common cardiac manifestation. Up to 50% of Lyme carditis patients may develop complete heart block. The incidence of Lyme carditis in the pediatric population is not well established. We present a pediatric patient with a transient asymptomatic complete heart block resulting from Lyme carditis, an under-recognized complication of Lyme disease in the pediatric population.

PMID: 19190204 [PubMed - as supplied by publisher]

13. Int J Cardiol. 2009 Jan 23. [Epub ahead of print]

Borrelia-like organism in heart capillaries of patient with Lyme-disease seen by electron microscopy.

Lalosevic D, Lalosevic V, Stojsic-Milosavljevic A, Stojsic D.

Faculty of Medicine, Department of Histology and Embryology, St. Hadjuk Veljkova 3, 21000 Novi Sad, Serbia; Clinical Center of Vojvodina, Novi Sad, Serbia.

A case of a patient who developed an acute myocarditis due to Lyme disease is reported. An increased serum antibody titer to Borrelia burgdorferi suggested a diagnosis and in addition of basic clinical methods, endomyocardial biopsy performed and analyzed by transmission electron microscopy. The lumen of myocardial capillaries was founded mostly filled with detritus and fibrin precipitate, between them several bacterial fragments were identified. The electron-microscopic characteristics of the microorganisms in this specimen, revealing irregularly coiled appearance and consistent thickness of 0.2 mum, correspond to the spiral-like structure of Lyme disease borrelia. The presence of fibrin deposits on the capillary endothelium and necrosis of myocardiocytes, suggests that the cardiopathy in our patient was represent borrelia-mediated damage of the hearth microcirculation.

PMID: 19168240 [PubMed - as supplied by publisher]

14. Int J Med Microbiol. 2009 Jun;299(5):373-80. Epub 2009 Jan 15.

Tick saliva affects both proliferation and distribution of Borrelia burgdorferi spirochetes in mouse organs and increases transmission of spirochetes to ticks.

Horká H, Cerná-Kýcková K, Skallová A, Kopecký J.

Laboratory of Vector-Host Interactions, Institute of Parasitology, Biology Centre AS CR, Faculty of Science, University of South Bohemia, Branisovská 31, 370 05 Ceské Budejovice, Czech Republic. helca@paru.cas.cz

Ixodes ricinus tick saliva-activated transmission of Borrelia burgdorferi sensu stricto spirochetes was studied on the C3H/HeN mouse model. The influence of the feeding of uninfected nymphs on the proliferation and distribution of intradermally inoculated spirochetes was compared with the effect of co-inoculated saliva or salivary gland extract (SGE), respectively. Spirochete loads in murine tissues were evaluated using real-time q-PCR. SGE induced significantly increased spirochete numbers in the skin on the days 4 and 6 post-infection (p.i.). On the other hand, decreased bacterial load in the heart of SGE-treated mice was demonstrated in comparison with control animals. The inoculation of tick saliva increased spirochete load in the urinary bladder on day 6 p.i., while the number of spirochetes in the heart declined on day 6 p.i. The feeding of I. ricinus nymphs raised the spirochete load in the bladder on the days 4 and 6 p.i. On day 6, the number of spirochetes found in the heart was significantly lower than in controls. The prevalence of spirochetes in ticks infected by feeding on mice was more than 10 times higher when the mice were infected with the mixture of spirochetes and saliva or SGE, in comparison with spirochetes alone. The presence of SGE in the infectious inoculum increased the spirochete burden per tick from 0 to almost 28,000. Taken together, these results show a very early effect of tick saliva on the proliferation and distribution of Borrelia spirochetes in the host, probably due to the effect of saliva on the host innate immunity mechanisms.

PMID: 19147403 [PubMed - indexed for MEDLINE]

15. Dtsch Med Wochenschr. 2009 Jan;134(1-2):23-6. Epub 2008 Dec 17

[Reversible complete heart block by re-infection with Borrelia burgdorferi with negative IgM-antibodies]

[Article in German]

Guenther F, Bode C, Faber T.

Innere Medizin III, Kardiologie und Angiologie, Universitätsklinikum Freiburg, Freiburg, Germany. felix.guenther@uniklinik-freiburg-de

PAST HISTORY AND PHYSICAL EXAMINATION: A 38-year-old farmer presented at his general practitioner with dizziness. Physical examination was notable for a heart rate of 35 beats/min. The electrocardiogram (ECG) showed a complete (third degree) heart block with a bradycardic ventricular escape rhythm. The patient reported having had an rash on his right lower leg six weeks previously. After spreading centrifugally it had turned pale in its centre, then regressed and finally disappeared. After having been supplied with a temporary pacemaker in a county hospital the patient was transferred to our hospital. ADMISSION FINDINGS: The ECG showed pacemaker stimulation of the ventricle at about 60 beats/min. Without this stimulation the complete atrioventricular block persisted. Coronary heart disease was excluded by angiography and levocardiography revealed normal systolic left ventricular function. Serological findings were a positive titre of IgG-antibodies against Borrelia while the IgM titre was negative. THERAPY AND COURSE: The heart block disappeared under antibiotic therapy with ceftriaxon within eight days, after first changing to transitory second and first-degree atrioventricular block, and the pacemaker was removed. The patient did not develop any neurological symptoms. CONCLUSION: Cardiac involvement in Lyme disease can be the only manifestation of borreliosis. Possible reversibility under antibiotic therapy is an important aspect of diagnosis. In spite of atypical serology the combination of history, symptoms and serological findings will lead to the diagnosis Lyme disease.

PMID: 19090448 [PubMed - indexed for MEDLINE]

16. Proc Natl Acad Sci U S A. 2008 Dec 16;105(50):19863-8. Epub 2008 Dec 5.

NKT cells prevent chronic joint inflammation after infection with Borrelia burgdorferi.

Tupin E, Benhnia MR, Kinjo Y, Patsey R, Lena CJ, Haller MC, Caimano MJ, Imamura M, Wong CH, Crotty S, Radolf JD, Sellati TJ, Kronenberg M.

Divisions of Developmental Immunology and Vaccine Discovery, La Jolla Institute for Allergy and Immunology, 9420 Athena Circle Drive, La Jolla, CA 92037, USA.

Borrelia burgdorferi is the etiologic agent of Lyme disease, a multisystem inflammatory disorder that principally targets the skin, joints, heart, and nervous system. The role of T lymphocytes in the development of chronic inflammation resulting from B. burgdorferi infection has been controversial. We previously showed that natural killer T (NKT) cells with an invariant (i) TCR alpha chain (iNKT cells) recognize glycolipids from B. burgdorferi, but did not establish an in vivo role for iNKT cells in Lyme disease pathogenesis. Here, we evaluate the importance of iNKT cells for host defense against these pathogenic spirochetes by using Valpha14i NKT cell-deficient (Jalpha18(-/-)) BALB/c mice. On tick inoculation with B. burgdorferi, Jalpha18(-/-) mice exhibited more severe and prolonged arthritis as well as a reduced ability to clear spirochetes from infected tissues. Valpha14i NKT cell deficiency also resulted in increased production of antibodies directed against both B. burgdorferi protein antigens and borrelial diacylglycerols; the latter finding demonstrates that anti-glycolipid antibody production does not require cognate help from Valpha14i NKT cells. Valpha14i NKT cells in infected wild-type mice expressed surface activation markers and produced IFNgamma in vivo after infection, suggesting a participatory role for this unique population in cellular immunity. Our data are consistent with the hypothesis that the antigen-specific activation of Valpha14i NKT cells is important for the prevention of persistent joint inflammation and spirochete clearance, and they counter the long-standing notion that humoral rather than cellular immunity is sufficient to facilitate Lyme disease resolution.

PMCID: 2604993 PMID: 19060201 [PubMed - indexed for MEDLINE]

17. Minerva Med. 2008 Oct;99(5):489-96.

Severity of Lyme disease with persistent symptoms. Insights from a double-blind placebo-controlled clinical trial.

Cameron D.

Northern Westchester Hospital, Mount Kisco, NY, USA. cameron@lymeproject.com

Comment in: Minerva Med. 2009 Apr;100(2):171-2.

Lyme disease is a global health concern and is the world's leading tick borne infection caused by the spirochete, Borrelia burgdorferi, that has been associated with numerous neurologic, rheumatologic and psychiatric manifestations. The symptoms of Lyme disease have been characterized as either severe or ''related to the aches and pains of daily living.'' A randomized double-blind, placebo-controlled clinical trial (RCT) was conducted in a primary internal medicine practice in Westchester County, New York, USA. A total of 84 adults with Lyme disease with persistent symptoms (LDPS) were studied; 52 received amoxicillin and 34 received placebo. The subjects received either placebo or amoxicillin 3 g per day orally for 3 months. The SF-36 was used as the outcome measure of the patient's perceived Quality of Life (QOL). For subjects enrolling in this RCT, the average SF-36 physical component summary (PCS) of QOL (40+/-9, range 29-44) and mental component summary (MCS) of QOL (39+/-14, range 23-46) were worse than the general USA population and worse than individuals with diabetes, heart disease, depression, osteoarthritis or rheumatoid arthritis. The improvements in the SF-36 measure of QOL for subjects randomized to amoxicillin vs. placebo was significant (46% vs 18%, P=0.007). It is important for clinicians to be aware that LDPS can be severe. A significant gain in the QOL for subjects randomized to amoxicillin in this RCT without serious adverse events is consistent with the goal of improving patient's QOL and consequently worthy of further study.

PMID: 18971914 [PubMed - indexed for MEDLINE]

18. Microbiology. 2008 Nov;154(Pt 11):3420-9.

Modification of Borrelia burgdorferi to overproduce OspA or VlsE alters its infectious behaviour.

Xu Q, McShan K, Liang FT.

Department of Pathobiological Sciences, Louisiana State University, Baton Rouge, LA 70803, USA.

The surface lipoproteins of the Lyme disease spirochaete Borrelia burgdorferi directly interact with tissue microenvironments during mammalian infection, and thus potentially affect various aspects of infection. To investigate the influence of surface antigen synthesis on infectious behaviour, B. burgdorferi was modified to constitutively produce the well-characterized surface lipoproteins OspA and invariant VlsE. Although increasing OspA or VlsE production did not significantly affect synthesis of other surface lipoproteins or spirochaetal growth in vitro, overexpressing vlsE resulted in increased ospA but decreased ospC expression, and overexpressing ospA led to decreased ospC and vlsE expression in severe combined immunodeficient (SCID) mice. Increasing the expression of either ospA or vlsE did not alter the ID(50), but affected spirochaetal dissemination and significantly reduced tissue spirochaete loads in SCID mice. In immunocompetent mice, increased vlsE expression resulted in quick clearance of infection, while constitutive ospA expression led to a substantial ID(50) increase and severely impaired dissemination. Furthermore, B. burgdorferi with constitutive ospA expression persisted in the skin tissue but was cleared from both heart and joints of chronically infected immunocompetent mice. Taken together, the study indicates that increasing production of OspA or invariant VlsE influences lipoprotein gene expression in the murine host and alters the infectious behaviour of B. burgdorferi.

PMID: 18957595 [PubMed - indexed for MEDLINE]

19. Evid Based Complement Alternat Med. 2009 Sep;6(3):283-95. Epub 2007 Oct 15.

Novel Diagnosis of Lyme Disease: Potential for CAM Intervention.

Vojdani A, Hebroni F, Raphael Y, Erde J, Raxlen B.

Immunosciences Lab., Inc., 8693 Wilshire Blvd., Suite 200, Beverly Hills, CA 90211, USA. drari@msn.com.

Lyme disease (LD) is the most common tick-borne disease in the northern hemisphere, producing a wide range of disabling effects on multiple human targets, including the skin, the nervous system, the joints and the heart. Insufficient clinical diagnostic methods, the necessity for prompt antibiotic treatment along with the pervasive nature of infection impel the development and establishment of new clinical diagnostic tools with increased accuracy, sensitivity and specificity. The goal of this article is 4-fold: (i) to detail LD infection and pathology, (ii) to review prevalent diagnostic methods, emphasizing inherent problems, (iii) to introduce the usage of in vivo induced antigen technology (IVIAT) in clinical diagnostics and (iv) to underscore the relevance of a novel comprehensive LD diagnostic approach to practitioners of Complementary and Alternative Medicine (CAM). Utilization of this analytical method will increase the accuracy of the diagnostic process and abridge the time to treatment, with antibiotics, herbal medicines and nutritional supplements, resulting in improved quality of care and disease prognosis.

PMCID: 2722197 PMID: 18955246 [PubMed - in process]

20. Can Fam Physician. 2008 Oct;54(10):1381-4.

Lyme disease: a zoonotic disease of increasing importance to Canadians.

Ogden NH, Artsob H, Lindsay LR, Sockett PN.

Centre for Foodborne, Environmental and Zoonotic Infectious Diseases, Public Health Agency of Canada. Nicholas_Ogden@phac-aspc.gc.ca

PMCID: 2567255 PMID: 18854461 [PubMed - indexed for MEDLINE]

21. Microb Pathog. 2008 Nov-Dec;45(5-6):355-60. Epub 2008 Sep 20.

Borrelia burgdorferi expression of the bba64, bba65, bba66, and bba73 genes in tissues during persistent infection in mice.

Gilmore RD Jr, Howison RR, Schmit VL, Carroll JA.

Division of Vector-Borne Infectious Diseases, Centers for Disease Control and Prevention, 3150 Rampart Rd, Fort Collins, CO 80521, USA. rbg9@cdc.gov

Borrelia burgdorferi, the etiological agent of Lyme disease in humans, is vectored between mammalian hosts in nature by Ixodes ticks. The organism adapts to diverse environments encountered throughout the enzootic cycle by differentially expressing essential gene products to survive the specialized conditions, whether in ticks or warm-blooded hosts. However, little is known regarding the identity and/or function of B. burgdorferi genes expressed during colonization of tissues during mammalian infection. Experimental evidence has shown that a group of genes (formerly classified as paralogous gene family 54) contiguously localized on the 54-kilobase linear plasmid of B. burgdorferi, are among the most highly regulated by in vitro conditions resembling mammalian infection. In this study, we employed quantitative reverse transcription-PCR to measure temporal gene expression of a subset of this B. burgdorferi gene family (bba64, bba65, bba66, and bba73) in tissues during chronic murine infection. The goal was to gain insight into the role of these genes in infectivity and pathogenesis by identifying when the genes are induced and whether they are expressed in specific target tissues. B. burgdorferi bba64, bba65, bba66, and bba73 expression was measured from infected mouse tissues relative to expression in in vitro culture conditions at specific times post-infection. bba64 expression was highly upregulated in bladder, heart, and spleen tissues throughout the infection period, contrasting with the sharp downregulation previously observed in ear tissues. bba65, bba66, and bba73 demonstrated upregulated differential expression in various tissues over 1 year post-infection. These results suggest an essential role for these genes in borrelial survival, persistence, and/or pathogenesis.

PMID: 18848981 [PubMed - indexed for MEDLINE]

22. PLoS One. 2008 Oct 3;3(10):e3340.

Common and unique contributions of decorin-binding proteins A and B to the overall virulence of Borrelia burgdorferi.

Shi Y, Xu Q, Seemanaplli SV, McShan K, Liang FT.

Department of Pathobiological Sciences, Louisiana State University, Baton Rouge, Louisiana, USA.

As an extracellular bacterium, the Lyme disease spirochete Borrelia burgdorferi resides primarily in the extracellular matrix and connective tissues and between host cells during mammalian infection, where decorin and glycosaminoglycans are abundantly found, so its interactions with these host ligands potentially affect various aspects of infection. Decorin-binding proteins (Dbps) A and B, encoded by a 2-gene operon, are outer surface lipoproteins with similar molecular weights and share approximately 40% identity, and both bind decorin and glycosaminoglycans. To investigate how DbpA and DbpB contribute differently to the overall virulence of B. burgdorferi, a dbpAB mutant was modified to overproduce the adhesins. Overproduction of either DbpA or DbpB resulted in restoration of the infectivity of the mutant to the control level, measured by 50% infectious dose (ID(50)), indicating that the two virulence factors are interchangeable in this regard. Overproduction of DbpA also allowed the mutant to disseminate to some but not all distal tissues slightly slower than the control, but the mutant with DbpB overproduction showed severely impaired dissemination to all tissues that were analyzed. The mutant with DbpA overproduction colonized all tissues, albeit generating bacterial loads significantly lower than the control in heart and joint, while the mutant overproducing DbpB remained severely defective in heart colonization and registered bacterial loads substantially lower than the control in joint. Taken together, the study indicated that DbpA and DbpB play a similar role in contribution to infectivity as measured by ID(50) value but contribute differently to dissemination and tissue colonization.

PMCID: 2556102 PMID: 18833332 [PubMed - indexed for MEDLINE]

23. Prague Med Rep. 2007;108(4):339-47.

Significance of Borrelia infection in development of dilated cardiomypathy (a pilot study).

Bartůnĕk P, Gorican K, Veiser T, Táborský M, Hulínská D.

Charles University in Prague, First Faculty of Medicine and General Teaching Hospital, Fourth Department of Internal Medicine, Prague, Czech Republic. petr.bartunek@lf1.cuni.cz

A heart involvement known as Lyme carditis (LC), a consequence of Lyme borreliosis (LB), is relatively rare in contrast to the involvement of skin, joints and nervous system; it accounts for < 4% of all these patients in European countries. However, the diagnosis of the disease belongs to the most difficult challenges. While various forms of AV blocks dominate in the USA as confirmed by the literature, there is a clear predominance of arrhythmias of various incidence in the Czech Republic. The authors of this article focused on the form belonging to the rarest manifestations of LC, namely dilated cardiomyopathy (DCMP). The goal was to elucidate the etiological participation of Borrelia infection in the development of DCMP, which has attracted controversial opinions so far. In total, 33 patients with DCMP were enrolled in the study, 23 males and 10 females, with mean age 57.7 years (range 24-76 years). ELISA NRLB KC 90 method was used in all blood samples for detection of Borrelia infection (BI), Western blot method was used for confirmation, followed by identification of DNA of pathogenic Borreliae using PCR method. Bioptic material was examined by electronmicroscopy with an attempt to detect Spirochaetae in myocardium. 16 patients were excluded from the study owing to the absence of signs of LB. The study group included 17 patients (3 females, 13 males) with mean age 58 years (range 43-76 years), in whom the presence of Bb was proved by identification of DNA of pathogenic Borreliae or by electronmicroscopic detection of Spirochetae in myocardial bioptic sample. The findings obtained during the study confirmed that BI very probably participated in the development of dilated cardiomyopathy. It may be concluded that most of cases were either unapparent forms of LB or insufficiently treated cutaneous forms of this disease.

PMID: 18780646 [PubMed - indexed for MEDLINE]

24. Int J Cardiol. 2009 Oct 2;137(2):167-71. Epub 2008 Aug 5.

Lyme carditis: sequential electrocardiographic changes in response to antibiotic therapy.

Manzoor K, Aftab W, Choksi S, Khan IA.

Lyme disease is a tick-borne spirochetal infection that may involve heart. The cardiac manifestations of Lyme disease including varying degrees of atrioventricular heart block occur within weeks to months of the infecting tick bite. This report describes a 43 year-old man with Lyme carditis who presented with complete heart block. The heart block resolved with ceftriaxone therapy. Lyme carditis should be considered in the differential diagnosis in patients who present with new onset advanced heart block.

PMID: 18684533 [PubMed - in process]

25. J Clin Microbiol. 2008 Oct;46(10):3540-3. Epub 2008 Jul 23.

Detection of Borrelia bissettii in cardiac valve tissue of a patient with endocarditis and aortic valve stenosis in the Czech Republic.

Rudenko N, Golovchenko M, Mokrácek A, Piskunová N, Ruzek D, Mallatová N, Grubhoffer L.

Biology Centre, Institute of Parasitology AS CR and Faculty of Science, University of South Bohemia in Ceské Budejovice, Branisovská 31, 37005, Ceské Budejovice, Czech Republic. natasharudenko@hotmail.com

Molecular analysis of a clinical sample confirmed the presence of Borrelia bissettii DNA in cardiac valve tissue from a patient with endocarditis and aortic valve stenosis. This evidence strongly supports the involvement of B. bissettii in Lyme disease in Europe.

PMCID: 2566110 PMID: 18650352 [PubMed - indexed for MEDLINE]

26. Pol Merkur Lekarski. 2008 May;24(143):433-5.

[Borreliosis--simultaneous Lyme carditis and psychiatric disorders--case report]

[Article in Polish]

Legatowicz-Koprowska M, Gziut AI, Walczak E, Gil RJ, Wagner T.

Institute of Rheumatology in Warsaw, Department of Pathology, Poland. mlkoprowska@gmail.com

Borreliosis is a multisystemic disease transmitted by ticks. Its diagnosis still remains a challenge because of the varied clinical picture and of difficulties in detection of the etiological agent (Borrelia burgdorferi). We report a case of a 53-years-old woman admitted to the Clinic of Cardiology due to life-threatening arhythmias with simultaneous deficits in concentration and memory. A suspicion of borreliosis was driven from the presence of cardiac symptoms as well as of psychiatric and from the case histories of a tick bite. The diagnosis was confirmed both by specific serological test and endomyocardial biopsy which revealed spirochetes. The patient responded to treatment with doxycyclin and ceftriaxone. Cardiologic disorders retreated entirely, while cognitive deficits did only partly.

PMID: 18634389 [PubMed - indexed for MEDLINE]

27. Clin Vaccine Immunol. 2008 Sep;15(9):1429-35. Epub 2008 Jul 16.

Oral immunization with recombinant lactobacillus plantarum induces a protective immune response in mice with Lyme disease.

del Rio B, Dattwyler RJ, Aroso M, Neves V, Meirelles L, Seegers JF, Gomes-Solecki M.

Department of Microbiology and Immunology, New York Medical College, Valhalla, New York,USA.

Mucosal immunization is advantageous over other routes of antigen delivery because it can induce both mucosal and systemic immune responses. Our goal was to develop a mucosal delivery vehicle based on bacteria generally regarded as safe, such as Lactobacillus spp. In this study, we used the Lyme disease mouse model as a proof of concept. We demonstrate that an oral vaccine based on live recombinant Lactobacillus plantarum protects mice from tick-transmitted Borrelia burgdorferi infection. Our method of expressing vaccine antigens in L. plantarum induces both systemic and mucosal immunity after oral administration. This platform technology can be applied to design oral vaccine delivery vehicles against several microbial pathogens.

PMCID: 2546682 PMID: 18632920 [PubMed - indexed for MEDLINE]

28. Vnitr Lek. 2008 Apr;54(4):430-3.

[Lyme carditis--rare cause of dilated cardiomyopathy and rhythm disturbances]

[Article in Czech]

Cepelová J.

Interní klinika 1. lékarské fakulty UK a UVN Praha. cepelovaj@seznam.cz

Case report of young woman presents involvement of dilated cardiomyopathy and rhythm disturbances in 18 months after infection of tick, with direct assessment of spirochetes in myocardial tissue. Cardial decompensation occured after asthma exacerbation, complicated by bronchopneumonia. Rhythm disturbances and heart failure gradually subside after parenteral antibiotic treatment and peroral treatment of heart failure. Nevertheless there is a long-lasting persistence of dilated cardiomyopathy with significant systolic dysfunction, which is supposedly last consequence of Borrelia infection. Resynchronic therapy combinated with cardioverter-defibrilator primary considering was postponed for improvement clinical condition and myocardial electric stability. There is demonstrating complicated serologic diagnostics of Lyme disease in discussion. Lyme carditis would be part of differential diagnosis in rhythm disturbances and cardiomyopathy of unknown etiology, including serious or fatal events.

PMID: 18630624 [PubMed - indexed for MEDLINE]

29. Pol Arch Med Wewn. 2008 May;118(5):314-7.

Neuroborreliosis with extrapyramidal symptoms: a case report.

Biesiada G, Czapiel J, Sobczyk-Krupiarz I, Garlicki A, Mach T.

Department of Infectious Diseases, Division of Gastroenterology, Hepatology, and Infectious Diseases, Jagiellonian University School of Medicine, Kraków, Poland. gbiesiada@op.pl

The disease of Lyme is a tick-borne infection. It involves skin, the nervous system, joints and the heart. Spirochaeta Borrelia burgdorferi is the etiologic agent of the disease. In the majority of cases, clinical symptoms, like migrating erythema, occur from 3 to 30 days, sometimes to 3 months after a bite from a tick. The early disseminated infection involves multiple migrating erythema, neuroborreliosis, arthritis, myocarditis and other organ-related symptoms. The late stage of chronic infection involves chronic atrophic leg dermatitis, neurological and rheumatological symptoms, and other organ-related symptoms which persist for above 12 months. The diagnosis of the disease of Lyme is based upon specific clinical symptoms confirmed by serologic tests. The two-step diagnostic protocol including the ELISA method, confirmed by the Western-blot test, is optimal. The present article describes a case of a 59-year-old man, a computer specialist, who often spends his free time walking in woods for recreation, and who was bitten by a tick 3 years before hospitalization. The bite resulted in migrating erythema that subsided without antimicrobial treatment. In spite of this, the man had not changed his hobby exposing himself to bites from ticks. One year later, multiple migrating erythema and extrapyramidalis symptoms appeared without any other organ malfunctions. In the current year, the patient was admitted to the Infectious Diseases Hospital, and received antibiotics (ceftriaxon) with following neurological improvement. Several months later, extrapyramidal symptoms increased. On the day of admission to the hospital, the neurologic examination showed abnormalities of upper and lower limbs movements (propulsive walking and the right lower leg traction), the right hand tremor, pouts of the face, and sleepiness.

PMID: 18619183 [PubMed - indexed for MEDLINE]

30. J Parasitol. 2008 Jun;94(3):767-9.

Suppression of Th2 cytokines reduces tick-transmitted Borrelia burgdorferi load in mice.

Zeidner NS, Schneider BS, Rutherford JS, Dolan MC.

Division of Vector-Borne Infectious Diseases, Centers for Disease Control and Prevention, Fort Collins, Colorado 80521, USA. Naz2@cdc.gov

Previous work has indicated that both Borrelia burgdorferi and the process of tick feeding (saliva) modulate the host immune response. Molecules have been identified in tick saliva that effect T cell proliferation by binding to specific cytokines, thereby promoting a Th2 cytokine response that does not afford protection against tick-transmitted B. burgdorferi in mice. Moreover, reconstitution of a Th1-biased T cell response prior to spirochete challenge effectively neutralizes tick modulation of host immunity and affords protection against tick transmission of spirochetes. The current studies were undertaken to determine the effect of neutralizing specific Th2 cytokines prior to tick feeding and subsequent transmission of B. burgdorferi. The results indicate that suppression of both IL-4 and IL-5 prior to the feeding of B. burgdorferi-infected ticks significantly decreased spirochete load in target organs such as joint, bladder, heart, and skin of the Lyme disease-susceptible host.

PMID: 18605798 [PubMed - indexed for MEDLINE]

31. Infect Immun. 2008 Aug;76(8):3530-8. Epub 2008 Jun 9.

A novel immunoprecipitation strategy identifies a unique functional mimic of the glial cell line-derived neurotrophic factor family ligands in the pathogen Trypanosoma cruzi.

Lu B, PereiraPerrin M.

Parasitology Research Center, Department of Pathology, Tufts University School of Medicine, 150 Harrison Avenue, Boston, MA 02111, USA.

The journey of the Chagas' disease parasite Trypanosoma cruzi in the human body usually starts in the skin after an insect bite, when trypomastigotes get through the extracellular matrix to bind specific surface receptors in the epidermis and dermis to enter cells, where they differentiate and replicate. As the infection spreads to the heart, nervous system, and other parts of the body via the circulatory system, the parasite must also cope with additional receptors in the immune system and vascular endothelium. The molecular underpinnings that govern host cell receptor recognition by T. cruzi counterreceptors remain largely unknown. Here, we describe an immunoprecipitation strategy designed to concurrently identify host receptors and complementing parasite counterreceptors. Extracellular domains of growth factor receptors fused to human immunoglobulin G (IgG) Fc were incubated with parasite lysates, immunoprecipitated on protein G-Sepharose, and eluted with Laemmli sample buffer. Possible T. cruzi counterreceptors pulled down by the receptor-Fc bait were visualized on immunoblots probed with multispecific high-affinity IgG from chronic chagasic sera and on sodium dodecyl sulfate-polyacrylamide gel electrophoresis gels stained with silver or Coomassie blue. In screening receptors important for nervous system repair, this parasite counterreceptor immunoprecipitation (PcIP) assay identified 7 to 11 polypeptides (molecular masses, 14 kDa to 55 kDa) that bound to the coreceptors of glial cell line-derived neurotrophic factor (GDNF) family ligands (GFLs) GFRalpha-1, -2, and -3. Binding was specific because the T. cruzi mimic of host GFLs, named TGFL, did not react with GFL coreceptor tyrosine kinase RET and with other neurotrophic receptors. The polypeptides were located on the parasite outer membrane and bound noncovalently to each other. TGFL eluted from the GFL receptor/protein G affinity column with 0.5 M NaCl, pH 7.5, and potently promoted neurite outgrowth and cell survival in a GFL-sensitive mouse pheochromocytoma cell line. Given that GFLs are neuron survival factors crucial for development and maintenance of central and peripheral nervous systems, it may be that T. cruzi mimicry of host GFLs helps in mutually beneficial host repair of infected and damaged nervous tissue. As there are >30 growth factor receptor-Fc chimeras commercially available, this PcIP assay can be readily adapted to identify receptors/counterreceptors in other T. cruzi invasion sites and in other infections such as Lyme disease, amebiasis, and schistosomiasis.

PMCID: 2493206 PMID: 18541656 [PubMed - indexed for MEDLINE]

32. Clin Infect Dis. 2008 Jul 15;47(2):188-95.

Prospective study of serologic tests for lyme disease.

Steere AC, McHugh G, Damle N, Sikand VK.

Center for Immunology and Inflammatory Diseases, Division of Rheumatology, Allergy and Immunology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA. asteere@partners.org

Comment in: Clin Infect Dis. 2008 Jul 15;47(2):196-7. Clin Infect Dis. 2008 Oct 15;47(8):1111-2; author reply 1112-3.

BACKGROUND: Tests to determine serum antibody levels-the 2-tier sonicate immunoglobulin M (IgM) and immunoglobulin G (IgG) enzyme-linked immunosorbent assay (ELISA) and Western blot method or the IgG of the variable major protein-like sequence-expressed (VlsE) sixth invariant region (C6) peptide ELISA method-are the major tests available for support of the diagnosis of Lyme disease. However, these tests have not been assessed prospectively. METHODS: We used these tests prospectively to determine serologic responses in 134 patients with various manifestations of Lyme disease, 89 patients with other illnesses (with or without a history of Lyme disease), and 136 healthy subjects from areas of endemicity and areas in which the infection was not endemic. RESULTS: With 2-tier tests and the C6 peptide ELISA, only approximately one-third of 76 patients with erythema migrans had results that were positive for IgM or IgG seroreactivity with Borrelia burgdorferi in acute-phase samples. During convalescence, 3-4 weeks later, almost two-thirds of patients had seroreactivity with the spirochete B. burgdorferi. The frequencies of seroreactivity were significantly greater among patients with spirochetal dissemination than they were among those who lacked evidence of disseminated disease. Of the 44 patients with Lyme disease who had neurologic, heart, or joint involvement, all had positive C6 peptide ELISA results, 42 had IgG responses with 2-tier tests, and 2 patients with facial palsy had only IgM responses. However, among the control groups, the IgG Western blot was slightly more specific than the C6 peptide ELISA. The differences between the 2 test systems (2-tier testing and C6 peptide ELISA) with respect to sensitivity and specificity were not statistically significant. CONCLUSIONS: Except in patients with erythema migrans, both test systems were sensitive for support of the diagnosis of Lyme disease. However, with current methods, 2-tier testing was associated with slightly better specificity.

PMID: 18532885 [PubMed - indexed for MEDLINE]

33. Int J Cardiol. 2008 Sep 16;129(1):15-21. Epub 2008 May 27.

Cardiac implications of Lyme disease, diagnosis and therapeutic approach.

Lelovas P, Dontas I, Bassiakou E, Xanthos T.

Laboratory for Research of the Musculoskeletal System, University of Athens, School of Medicine, Greece.

Lyme is a tick-borne disease. The genetic diversity of Borreliae its distribution worldwide and its epidemiology have been related to different clinical manifestations. Carditis is a rare manifestation of Lyme disease. The commonest abnormality is atrioventricular block of various degrees, though other rhythm abnormalities have been reported. Pericarditis, myocarditis, cardiomyopathy and degenerative valvular disease have been associated with B. burgdorferi. Temporary pacing might be required in unstable patients. The majority of the conduction disturbances have a benign prognosis, if the infectious agent is identified and treated appropriately.

PMID: 18508142 [PubMed - indexed for MEDLINE]

34. BMC Microbiol. 2008 May 28;8:82.

Assessment of decorin-binding protein A to the infectivity of Borrelia burgdorferi in the murine models of needle and tick infection.

Blevins JS, Hagman KE, Norgard MV.

Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA. jon.blevins@utsouthwestern.edu

BACKGROUND: Decorin-binding proteins (Dbps) A and B of Borrelia burgdorferi, the agent of Lyme disease, are surface-exposed lipoproteins that presumably bind to the extracellular matrix proteoglycan, decorin. B. burgdorferi infects various tissues including the bladder, heart, joints, skin and the central nervous system, and the ability of B. burgdorferi to bind decorin has been hypothesized to be important for this disseminatory pathogenic strategy. RESULTS: To determine the role of DbpBA in the infectious lifecycle of B. burgdorferi, we created a DbpBA-deficient mutant of B. burgdorferi strain 297 and compared the infectious phenotype of the mutant to the wild-type strain in the experimental murine model of Lyme borreliosis. The mutant strain exhibited a 4-log decrease in infectivity, relative to the wild-type strain, when needle inoculated into mice. Upon complementation of the DbpBA-mutant strain with DbpA, the wild-type level of infectivity was restored. In addition, we demonstrated that the DbpBA-deficient mutant was able to colonize Ixodes scapularis larval ticks after feeding on infected mice and persist within the ticks during the molt to the nymphal state. Moreover, surprisingly, the DbpBA-mutant strain was capable of being transmitted to naïve mice via tick bite, giving rise to infected mice. CONCLUSION: These results suggest that DbpBA is not required for the natural tick-transmission process to mammals, despite inferences from needle-inoculation experiments implying a requirement for DbpBA during mammalian infection. The combined findings also send a cautionary note regarding how results from needle-inoculation experiments with mice should be interpreted.

PMCID: 2430964 PMID: 18507835 [PubMed - indexed for MEDLINE]

35. Scand J Rheumatol. 2008 May-Jun;37(3):161-72.

Borreliosis: recent research, diagnosis, and management.

Hytönen J, Hartiala P, Oksi J, Viljanen MK.

Department of Medical Microbiology and Immunology, University of Turku, Turku, Finlad. jukka.hytonen@utu.fi

Lyme borreliosis (LB) is a tick-borne infection caused by the spirochete Borrelia burgdorferi sensu lato. The disease covers a wide spectrum of clinical manifestations affecting the skin, nervous and musculoskeletal systems, the heart, and the eyes. The diagnosis must be based on clinical suspicion and on symptoms and signs observed during a thorough interview and examination of the patient. Laboratory results either support or oppose the conclusions that are drawn from history and clinical examination. Antibiotic therapy is curative in most patients with LB. Unfortunately, some patients develop chronic symptoms, such as arthritis, that do not respond to antibiotics. In these patients, treatment with non-steroidal anti-inflammatory drugs or corticosteroids is recommended, while the role of immunomodulatory drugs, such as tumour necrosis factor (TNF)-alpha inhibitors, remains open. In this review we focus, after presenting the history and basics of LB, on the pathogenesis, diagnosis, and treatment of LB, as well as on recent advances in selected aspects of the field.

PMID: 18465449 [PubMed - indexed for MEDLINE]

36. Vector Borne Zoonotic Dis. 2008 Oct;8(5):623-33.

Borrelia bissettii isolates induce pathology in a murine model of disease.

Schneider BS, Schriefer ME, Dietrich G, Dolan MC, Morshed MG, Zeidner NS.

Division of Vector-Borne Infectious Diseases, National Center for Infectious Diseases, Centers for Disease Control and Prevention, Fort Collins, Colorado, USA. bradley.schneider@pasteur.fr

The spirochete Borrelia burgdorferi is a tick-borne pathogen that causes Lyme disease. Although B. burgdorferi sensu lato is a diverse group of bacteria, only three genospecies, B. burgdorferi sensu stricto, Borrelia afzelii, and Borrelia garinii, are known to be pathogenic and commonly recognized to cause human disease. To assess the potential of another common genospecies, Borrelia bissettii, to induce disease, a mouse model was employed. Two Colorado isolates of B. bissettii (CO-Bb) induced lesions of the bladder, heart, and femorotibial joint 8 weeks after inoculation into mice. In contrast, two British Columbia (BC-Bb) isolates, could not be cultured or amplified by PCR from target organs, and did not induce lesions. Consistent with pathology and culture results, the antibody response in mice to BC-Bb was minimal compared to CO-Bb, indicating either transient localized infection or rapid immune clearance of BC-Bb. Although sequence analysis of the rrf (5S)-rrl (23S) intergenic spacer region indicated 99% homology between CO-Bb and BC-Bb, polyacrylamide gel electrophoresis (PAGE) analysis indicated five distinct protein differences between these low-passage isolates. These studies support the prospect that B. bissettii may indeed be the causative agent of Lyme borreliosis cases in Eastern Europe, associated with the atypical Borrelia strain 25015, and in other regions. To our knowledge, this is the first evidence that B. bissettii can induce pathology in a vertebrate host.

PMID: 18454594 [PubMed - indexed for MEDLINE]

37. Mol Microbiol. 2008 Jul;69(1):15-29. Epub 2008 Apr 28.

Essential protective role attributed to the surface lipoproteins of Borrelia burgdorferi against innate defences.

Xu Q, McShan K, Liang FT.

Department of Pathobiological Sciences, Louisiana State University, Baton Rouge, LA 70803, USA.

Comment in: Mol Microbiol. 2008 Jul;69(1):1-4.

To initiate infection, a microbial pathogen must be able to evade innate immunity. Here we show that the Lyme disease spirochete Borrelia burgdorferi depends on its surface lipoproteins for protection against innate defences. The deficiency for OspC, an abundantly expressed surface lipoprotein during early infection, led to quick clearance of B. burgdorferi after inoculation into the skin of SCID mice. Increasing expression of any of the four randomly chosen surface lipoproteins, OspA, OspE, VlsE or DbpA, fully protected the ospC mutant from elimination from the skin tissue of SCID mice; moreover, increased OspA, OspE or VlsE expression allowed the mutant to cause disseminated infection and restored the ability to effectively colonize both joint and skin tissues, albeit the dissemination process was much slower than that of the mutant restored with OspC expression. When the ospC mutant was modified to express OspA under control of the ospC regulatory elements, it registered only a slight increase in the 50% infectious dose than the control in SCID mice but a dramatic increase in immunocompetent mice. Taken together, the study demonstrated that the surface lipoproteins provide B. burgdorferi with an essential protective function against host innate elimination.

PMCID: 2574894 PMID: 18452586 [PubMed - indexed for MEDLINE]

38. Dermatol Ther. 2008 Mar-Apr;21(2):101-9.

Lyme borreliosis treatment.

Vanousová D, Hercogová J.

Department of Dermatovenereology, 2nd Medical School, Charles University, University Hospital Bulovka, Prague, Czech Republic. daniela.vanousova@centrum.cz

Lyme borreliosis is the most common human tick-borne illness in the Northern Hemisphere. The causative agent is the spirochete Borrelia burgdorferi species complex, and the hard-shell ticks of the genus Ixodes is responsible for pathogen transmission from animals to humans. The incidence of the disease is increasing year by year and although lyme disease is not fatal, it can affect the skin, heart, nervous, and musculoskeletal system with an impairment of quality of life. The appropriate diagnosis of lyme disease should be promptly treated by antibiotics to prevent late stage of the disease. The choice of antibiotics depends on many factors such as the stage of the disease, the drug efficacy, adverse effects, type of delivery, duration of treatment, and cost. Treatment failure occurs as a result of many reasons, re-infection is possible. The recommended treatment schedule in the Czech Republic is presented.

PMID: 18394084 [PubMed - indexed for MEDLINE]

39. Congenit Heart Dis. 2007 Sep;2(5):338-41.

Complete heart block due to Lyme carditis in two pediatric patients and a review of the literature.

Silver E, Pass RH, Kaufman S, Hordof AJ, Liberman L.

New York Presbyterian Hospital, Columbia University, Division of Pediatric Cardiology, Arrhythmia Service, New York, NY, USA.

Carditis is a common manifestation of adult patients with Lyme disease affecting 4-10% of Lyme patients in the United States. However, children with Lyme disease rarely present with acute carditis. The management of pediatric patients with complete heart block (CHB) secondary to Lyme carditis has not been well described. We report the acute management of 2 pediatric patients that presented in CHB secondary to Lyme disease.

PMID: 18377450 [PubMed - indexed for MEDLINE]

40. South Med J. 2008 Feb;101(2):202-4.

Chest pain in a military recruit.

Beck AS, Okulicz JF, Rasnake MS.

Department of Internal Medicine and Department of Infectious Diseases, Wilford Hall Medical Center, Lackland AFB, Texas 78236, USA. amy.beck@lackland.af.mil

Comment in: South Med J. 2008 Feb;101(2):125-6.

Lyme borreliosis remains an important and common vector-borne illness in the United States, Europe, and Asia. In the majority of cases, it presents as a localized rash that seldom causes further complications with antibiotic treatment. If left undetected however, various neurologic, cardiovascular, and musculoskeletal manifestations may occur. Reported here is the case of a basic military trainee who first presented with cardiac manifestations of Lyme disease, highlighting this tick-borne illness as a rare, easily forgotten, and treatable cause of complete heart block.

PMID: 18364626 [PubMed - indexed for MEDLINE]

41. J Med Microbiol. 2008 Apr;57(Pt 4):463-8.

A sustained-release formulation of doxycycline hyclate (Atridox) prevents simultaneous infection of Anaplasma phagocytophilum and Borrelia burgdorferi transmitted by tick bite.

Zeidner NS, Massung RF, Dolan MC, Dadey E, Gabitzsch E, Dietrich G, Levin ML.

Division of Vector-Borne Infectious Diseases, Centers for Disease Control and Prevention, Fort Collins, CO 80522, USA. Naz2@cdc.gov

Current prophylaxis for infected tick bites consists of personal protective measures directed towards ticks. This study compared the efficacy of a single oral dose of doxycycline with that of a single injection of sustained-release doxycycline in a model of Lyme borreliosis and Anaplasma phagocytophilum infection. Dosages of doxycycline were equilibrated based on previously determined peak plasma levels in mice [oral, 2.4 microg (ml plasma)(-1); sustained release, 1.9 microg (ml plasma)(-1)] determined 8 h after inoculation. In challenge experiments where five Borrelia burgdorferi-infected and five A. phagocytophilum-infected nymphs were used per mouse, only 20 and 30 % of mice were protected from B. burgdorferi and A. phagocytophilum infection, respectively, using oral doxycycline. In contrast, 100 % of mice receiving sustained-release doxycycline were protected from A. phagocytophilum infection, as indicated by real-time PCR of blood samples, quantitative PCR and culture isolation of spleen samples, and protected against B. burgdorferi infection as demonstrated by culture of ear, heart and bladder. Although 15-40 copies of A. phagocytophilum could be amplified from the spleens of mice treated with sustained-release doxycycline, no viable A. phagocytophilum from these spleens could be cultured in HL-60 cells. In contrast, 7/10 mice receiving oral doxycycline were PCR- and culture-positive for A. phagocytophilum, with copy numbers ranging from 800 to 10 000 within the spleen, as determined by quantitative PCR. Other correlates with A. phagocytophilum infection included a significant difference in spleen mass (mean of 110 mg for sustained-release treatment versus a mean of 230 mg for oral treatment) and the number of splenic lymphoid nodules (mean of 8 for sustained-release treatment versus mean of 12.5 for oral doxycycline) as determined by histopathology. These studies indicate that a single injection of a sustained-release formulation antibiotic may offer a viable prophylactic treatment option for multiple infectious agents in patients presenting with tick bites.

PMID: 18349366 [PubMed - indexed for MEDLINE]

42. Ned Tijdschr Geneeskd. 2008 Feb 2;152(5):293.

[Total atrioventricular block following a tick bite]

[Article in Dutch]

Peeters AJ, Dijkmans BA, Sedney MI.

Comment on: Ned Tijdschr Geneeskd. 2007 Sep 1;151(35):1941-4.

PMID: 18333548 [PubMed - indexed for MEDLINE]

43. Cardiovasc Pathol. 2008 Mar-Apr;17(2):103-7. Epub 2007 May 11.

Postmortem confirmation of Lyme carditis with polymerase chain reaction.

Tavora F, Burke A, Li L, Franks TJ, Virmani R.

Department of Pulmonary and Mediastinal Pathology, Armed Forces Institute of Pathology, Washington, DC, USA.

BACKGROUND: Cardiac involvement in Lyme disease is uncommon and typically manifests clinically by conduction disturbances. Postmortem identification of Borrelia burgdorferi has never been reported in a case of Lyme carditis. METHODS AND RESULTS: We describe the case of a 37-year-old Caucasian man with a 1-month history of fevers, rash, and malaise who died unexpectedly on the day after he underwent medical evaluation. The only clinical cardiac abnormality found was that of second-degree atrioventricular block. At autopsy, a diffuse carditis, characterized by infiltrates of macrophages, lymphocytes, and eosinophils and primarily in an interstitial, endocardial, and perivascular distribution, was found. Serologic testing from blood drawn on the day before his death demonstrated IgG and IgM antibodies against B. burgdorferi, confirmed by Western blot. Postmortem polymerase chain reaction (PCR) performed in myocardial tissue amplified B. burgdorferi DNA encoding outer-surface protein A. CONCLUSIONS: Lyme carditis should be considered in the differential diagnosis of interstitial myocarditis with mixed inflammatory infiltrates. This diagnosis can be confirmed by PCR testing.

PMID: 18329555 [PubMed - indexed for MEDLINE]

44. Pacing Clin Electrophysiol. 2008 Mar;31(3):322-6.

Paroxysmal AV block in children with normal cardiac anatomy as a cause of syncope.

Silver ES, Pass RH, Hordof AJ, Liberman L.

Division of Pediatric Cardiology, Morgan Stanley Children's Hospital, Columbia University, New York, New York 10032, USA.

BACKGROUND: Syncope due to episodes of paroxysmal atrioventricular (AV) block, defined as transient advanced second or third-degree block, is rarely reported in pediatric patients without congenital heart disease. METHODS: We reviewed our institutional arrhythmia database from January 1988 to January 2007 to identify all patients less than 18 years of age with normal cardiac anatomy and episodes of syncope associated with paroxysmal AV block. Demographic and clinical information was collected. RESULTS: Six patients were identified (Table I). Five of the six patients were female, with an average age of 9.3 +/- 4.4 years. Patients had episodes of syncope for an average of 5.6 +/- 3.3 years prior to diagnosis. All patients had normal physical examinations, electrocardiograms, and echocardiograms. None were on medications known to interfere with AV nodal function, and laboratory evaluation including Lyme titers were negative. Five of the six patients' episodes were atypical for vasovagal syncope (except patient 6). All patients had documented paroxysmal AV block on either inpatient cardiac monitor, Holter monitor, or event recorder at the time of syncope. There was maintenance or acceleration of the sinus rate during episodes of syncope in all patients (mean atrial rate 107 +/- 37 bpm). All six patients had permanent transvenous pacemakers implanted with resolution of symptoms over a mean follow-up of 5.2 +/- 6.3 years. CONCLUSION: Paroxysmal AV nodal block is a rare finding in pediatric patients, but should be considered as a possible etiology in patients presenting with episodes atypical for vasovagal syncope. Pacemaker therapy prevented future episodes in all six of our patients.

PMID: 18307627 [PubMed - indexed for MEDLINE]

45. Infect Immun. 2008 Mar;76(3):1239-46. Epub 2008 Jan 14.

Both decorin-binding proteins A and B are critical for the overall virulence of Borrelia burgdorferi.

Shi Y, Xu Q, McShan K, Liang FT.

Department of Pathobiological Sciences, Louisiana State University, Skip Bertman Drive at River Road, Baton Rouge, LA 70803, USA.

Both decorin-binding proteins (DbpA and DbpB) of the Lyme disease spirochete Borrelia burgdorferi bind decorin and glycosaminoglycans, two important building blocks of proteoglycans that are abundantly found in the extracellular matrix (ECM) and connective tissues as well as on cell surfaces of mammals. As an extracellular pathogen, B. burgdorferi resides primarily in the ECM and connective tissues and between host cells during mammalian infection. The interactions of B. burgdorferi with these host ligands mediated by DbpA and DbpB potentially influence various aspects of infection. Here, we show that both DbpA and DbpB are critical for the overall virulence of B. burgdorferi in the murine host. Disruption of the dbpBA locus led to nearly a 10(4)-fold increase in the 50% infectious dose (ID50). Complementation of the mutant with either dbpA or dbpB reduced the ID50 from over 10(4) to roughly 10(3) organisms. Deletion of the dbpBA locus affected colonization in all tissues of infected mice. The lack of dbpA alone precluded the pathogen from colonizing the heart tissue, and B. burgdorferi deficient for DbpB was recovered only from 42% of the heart specimens of infected mice. Although B. burgdorferi lacking either dbpA or dbpB was consistently grown from joint specimens of almost all infected mice, it generated bacterial loads significantly lower than the control. The deficiency in either DbpA or DbpB did not reduce the bacterial load in skin, but lack of both significantly did. Taken together, the study results indicate that neither DbpA nor DbpB is essential for mammalian infection but that both are critical for the overall virulence of B. burgdorferi.

PMCID: 2258843 PMID: 18195034 [PubMed - indexed for MEDLINE]

46. J Immunol. 2007 Dec 15;179(12):8076-82.

CD28 deficiency exacerbates joint inflammation upon Borrelia burgdorferi infection, resulting in the development of chronic Lyme arthritis.

Iliopoulou BP, Alroy J, Huber BT.

Department of Pathology, Tufts University School of Medicine, Boston, MA 02111, USA.

Lyme disease, caused by the tick-borne spirochete Borrelia burgdorferi (Bb), is a multisystem illness, affecting many organs, such as the heart, the nervous system, and the joints. Months after Bb infection, approximately 60% of patients experience intermittent arthritic attacks, a condition that in some individuals progresses to chronic joint inflammation. Although mice develop acute arthritis in response to Bb infection, the joint inflammation clears after 2 wk, despite continuous infection, only very rarely presenting with chronic Lyme arthritis. Thus, the lack of an animal system has so far prevented the elucidation of this persistent inflammatory process that occurs in humans. In this study, we report that the majority of Bb-infected CD28-/- mice develop chronic Lyme arthritis. Consistent with observations in chronic Lyme arthritis patients, the infected mutant, but not wild-type mice present recurring monoarticular arthritis over an extended time period, as well as anti-outer surface protein A of Bb serum titers. Furthermore, we demonstrate that anti-outer surface protein A Abs develop in these mice only after establishment of chronic Lyme arthritis. Thus, the Bb-infected CD28-/- mice provide a murine model for studying chronic Lyme arthritis.

PMID: 18056348 [PubMed - indexed for MEDLINE]

47. Pediatr Rev. 2007 Dec;28(12):455-61.

Index of suspicion.

Holmes M, Rodriguez RL, Silver ES, Chan B, Festekjian A.

Dell Children's Medical Center of Central Texas, Austin, Tex, USA.

PMID: 18055643 [PubMed - indexed for MEDLINE]

48. Internist (Berl). 2008 Jan;49(1):27-33.

[Inflammatory cardiac diseases by primary extracardial diseases]

[Article in German]

Brehm M, Rellecke P, Strauer BE.

Klinik für Kardiologie, Pneumologie und Angiologie, Heinrich-Heine Universität, Moorenstrasse 5, 40225, Düsseldorf, Deutschland. brehm@med.uni-duesseldorf.de

As systemic immunological disorders, internal diseases in gastroenterology, rheumatology and infectiology can, in addition to the bowels, potentially involve the musculo-skeletal system, the immunological system and heart structures. All structures and functions of the heart can be affected. Pericarditis in lupus erythematosus and chronic inflammatory bowel disease, myocarditis in HIV infection and lyme disease are examples of cardiac manifestations of internal diseases. The pathogenetic causes can be manifold, such as direct cytotoxic effects in HIV or Borrelia burgdorferi infections, induced vasculitis and local activation of coagulation factors as in lupus erythematosus or chronic inflammatory bowel disease. Improved treatment options have led to more long-lasting courses of internal diseases, such as in infectious diseases, lupus erythematosus and chronic inflammatory bowel disease, thus cardiovascular complications such as pericarditis and myocarditis gain increasing importance as a consequence of chronic disease and therapy-related damage.

PMID: 17992497 [PubMed - indexed for MEDLINE]

49. Acta Cardiol. 2007 Oct;62(5):519-22.

Think outside the heart! Case report of Lyme disease.

Beuselinck B, Willems R.

Department of Cardiology, University Hospitals Leuven, Leuven, Belgium.

We report an interesting case of a young drug addict admitted to the emergency department with a high degree A-V block. The diagnosis of Lyme carditis was made and there was a progressive regression of the A-V block under antibiotic therapy. However, by focusing on the cardiac manifestations and misled by the patient's drug abuse, concomitant neurological manifestations were picked up late in the hospitalization. Missing the diagnosis of Lyme-meningoencephalitis could have compromised the patient's long-term prognosis. Therefore we stress the importance to think outside the heart as cardiologists!

PMID: 17982976 [PubMed - indexed for MEDLINE]

50. J Pediatr Health Care. 2007 Nov-Dec;21(6):399-400.

Bradycardic child: what's to blame?

Kline AM.

Pediatric Intensive Care Unit, Children's Memorial Hospital, Chicago, IL, USA. akline@childrensmemorial.org

PMID: 17980807 [PubMed - indexed for MEDLINE]

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