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Interleukin-2 and Interleukin-6 Gene Promoter Polymorphisms, and Early Failure of Dental Implants

Campos, Maria Isabela Guimarães MS*; Godoy dos Santos, Maria Cristina Leme MS*; Trevilatto, Paula Cristina PhD; Scarel-Caminaga, Raquel Mantuaneli PhD; Bezerra, Fabio Jose DDS§; Line, Sergio Roberto Peres PhD*

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doi: 10.1097/01.id.0000188470.54417.98
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Abstract

Dental implant success is directly related to the stability of osseointegration. Bone is a dynamic tissue continuously remodeled through resorption and formation,1 controlled by local production of cytokines, such as interleukins (ILs).2 IL-2 and IL-6 are important mediators of inflammatory response and exert several biologic activities. IL-2 is produced by T-helper 1 cell, and has both pro-inflammatory and antiinflammatory actions. This cytokine is involved in B-cell activation and stimulates macrophages, natural killer cells, and T-cell proliferation, which mediate cellular immune response.3 IL-2 has been also implicated in the stimulation of osteoclasts in both normal and pathologic bone resorption.4 IL-6 is a multifunctional cytokine with a central role in host defense5 and can be produced by many cell types, such as monocytes/macrophages,6 fibroblasts,7 endothelial cells,8 T cells,9 and mast cells.10 IL-6 plays an important role in T-lymphocyte proliferation, B-lymphocyte differentiation, and complement cascade activation.11 In addition, this cytokine also acts synergistically with IL-1β, inducing bone resorption.12,13

The failure of a dental implant is not an usual situation14–16 and can be classified as “early” when osseointegration fails to occur, or “late” when the achieved osseointegration is lost after a period of function.17 The evidence that implant failures tend to cluster in subsets of individuals18–20 may indicate that specific host characteristics, such as genetic factors, could disturb the osseointegration process.21 A gene polymorphism can be defined as a specific nucleotide base change that occurs in more than 1% of the population. Some polymorphisms alter gene expression and function, causing an effect on the individual's phenotype and conferring susceptibility to diseases.22 A biallelic base-exchange polymorphism at positions –33023 and –17424 were described in the IL-2 and IL-6 genes, respectively. These polymorphisms are functionally important because they have been associated with increased transcription and expression of those cytokines,23,25 and have also been linked to an increased risk of developing several diseases,3,25–28 including chronic periodontitis.29–31

Like any healing process, implant osseointegration initiates with a local inflammatory response, in which ILs play an important role. Excessive levels of bone resorptive cytokines, such as IL-2 and IL-6, could lead to abnormal bone loss, affecting osseointegration success. Therefore, it seems reasonable to analyze if individuals with the ability to produce higher quantities of these ILs would be more susceptible to implant loss. The aim of the present study was to investigate the relationship between the early failure of dental implants and single nucleotide polymorphisms in the IL-2 gene at position –330 and IL-6 gene at position –174.

Materials and Methods

Subject Selection

A total of 74 white subjects were screened from private practices of periodontics and the patient pool of the Surgery Service of the Dentistry School of Piracicaba (UNICAMP). This study was performed with the approval of the UNICAMP Ethics Committee (protocol 006/02), and informed consent was obtained from all subjects. All subjects were in good general health and did not have any of the exclusion criteria: smoking habits; history of chronic illness, such as cardiovascular diseases, diabetes, osteoporosis, immune or bleeding disorders; and previous radiotherapy or chemotherapy exposure. Also excluded were patients who had loaded implants during the osseointegration period, history of any postoperative complication, such as infection, and use of any regenerative procedure previous or concomitant to implant surgery. All patients had been treated with implant systems that followed the Brånemark protocol of 2 surgical stages. The baseline clinical parameters for the subject population are presented in Table 1. The subjects were divided into 2 groups.

Table 1
Table 1:
Baseline Clinical Parameters of the Subject Population (n = 74)
  1. Control group: 40 patients with ≥1 healthy implants. These patients had at least 1 implant that had been functioning for a minimal period of 1 year.
  2. Test group: 34 patients with ≥1 implants that failed early. The implants were considered lost early when they presented with mobility and/or pain before or during the abutment connection and needed to be removed.

Analysis of Genetic Polymorphisms

From all subjects, epithelial buccal cells were sampled by the method described by Trevilatto and Line.32 Samples were incubated overnight with 100-ng/mL proteinase K (Sigma Chemical Co., St. Louis, MO) at 52°C with agitation. Deoxyribonucleic acid (DNA) was purified by sequential phenol/chloroform extraction and salt/ethanol precipitation.33 DNA concentration was estimated by measurements of optical density 260/280.

The amplification reactions (polymerase chain reaction [PCR]) were performed in a Perkin-Elmer GeneAmp 2400 thermal cycler, with 500-ng DNA in a volume of 50 μL reaction mixture containing 10-mM Tris-HCl (pH 8.3), 50 mM KCl, 1.5 mM MgCl2, deoxyribonucleotides (200 μM each), and 2 U Taq DNA polymerase (Amersham Pharmacia Biotech, Uppsala, Sweden). The reactions were incubated for 5 minutes at 95°C, followed by 35 cycles of 1 minute at 95°C, 1 minute at 55°C, and 1 minute at 72°C, and a final extension at 72°C for 7 minutes. The primer sequences and restriction enzymes are detailed later.

Polymorphism in the IL-2 gene at position -330.

The following primers were used for PCR amplification of genomic DNA: 5′-TATTCACATGTTCAGTGTAGTTCT-3′ and 5′-CATTGTGGCAGGAGTTGAGGT-3′, both 1.25 μM. The amplification products were digested with 1 U/20 μL reaction of MaeI (C and darrTAG) at 45°C overnight to detect allele G (410 bp) and allele C (374 bp + 26 bp).

Polymorphism in the IL-6 gene at position -174.

The following primers were used for PCR amplification of genomic DNA: 5′-TTGTCAAGACATGCCAAGTGCT-3′ and 5′-GCCTCAGAGACATCTCCAGTCC-3′, both 1 μM. The amplification products were digested with 1 U/25 μL reaction of NlaIII (CATG and darr) at 37°C overnight to detect allele G (227 bp + 59 bp + 13 bp) and allele C (118 bp+ 109 bp+59 bp +13 bp). Products of restriction digestion were visualized by electrophoresis on vertical 10% polyacrylamide gels in 1X tris-borate-edetic acid (89 mM tris-borate, 89 mM boric acid, 2 mM ethylenediaminetetraacetic acid), followed by rapid silver staining method.34

Data Analysis

Using the CLUMP program, Monte Carlo simulations were used to assess the allele ratio and genotype distribution between patients with implants that failed early and control subjects.35 This program is designed for use in genetic case-control studies, in which multiple allele are being considered, and the observed frequencies of some allele are rare. A P value <0.05 was considered significant.

Results

There was no significant difference in the genotype distribution between controls and subjects with implants that failed early for the IL-2 (T-330G) (P = 0.33) and IL-6 (G-174C) (P = 0.37) polymorphisms. Regarding the frequency of allele, there was no statistical variation in any of the polymorphisms between the 2 groups: IL-2 (T-330G) (P = 0.48) and IL-6 (G-174C) (P = 0.57). The allele frequencies and genotype distributions are shown in Table 2.

Table 2
Table 2:
Allele and Genotype Frequencies of the IL-2 (T-330G0) and Il-6 (g-174C) Polymorphisms Between Control and Test Groups

Considering the whole study population, the frequency of allele T, the IL-2 (-330) polymorphism, was 65.5%, and genotype T/T was observed in 31.0% of the individuals. Regarding the IL-6 (-174) polymorphism, the allele G frequency was 73.0%, and the genotype G/G was observed in 48.6% of the subjects. The genotype distribution of the IL-2 (-330) polymorphism was not consistent with the expectations of Hardy-Weinberg equilibrium in both control and test groups, while the IL-6 polymorphism (-174) showed equilibrium only in the test group. The large number of heterozygotes in the sample probably causes the lack of equilibrium presented by the 2 polymorphisms. It could occur as a result of the genetic heterogeneity of the Brazilian population.

Discussion

The early failure of dental implants has been associated with several factors, such as infection, overheating, premature loading, and impaired healing.36 However, in some situations, the clinical factors solely do not explain why some patients lose their implants.37 Patients treated with dental implants presented increased levels of IL-6 and IL-8 during the first day after implantation, reflecting a normal response of a local inflammatory process implicated in tissue repair.38 High levels of ILs have also been found in diseased implant sites when compared to healthy ones.39–42 This result suggests that despite the physiologic role of cytokines in bone metabolism, high levels of these molecules may lead to increased bone loss, resulting in a less favorable outcome or implant failure. Furthermore, because some polymorphisms are associated with increased production of inflammatory mediators, their analysis should be useful for identifying individuals with a predisposition to implant loss.

A few studies have analyzed the relationship between genetic polymorphisms of the host response and implant failure. Wilson and Nunn43 assessed the presence of an IL-1 composite genotype, comprising allele T of IL-1A (-889) and IL-1β (+3953) polymorphisms44 in 27 patients who had implants that failed or more than 50% bone loss. Their analysis did not provide a positive correlation between IL-1 composite genotype and the implant loss. However, this result might have been influenced by some variables, such as the presence of smokers and existence of late and early failure implants in the same sample. They found that smoking is such a strong risk factor (almost 2.5) for implant failure that it could overcome the effect of IL-1 genotype.

Rogers et al45 also found no association between the IL-1 composite genotype and failure of dental implants. Recently, it has been shown that IL-1 composite genotype alone does not appear to influence the risk for peri-implant bone loss, but the risk is significantly higher when the IL-1 genotype is associated with smoking.46 Shimpuku et al47,48 suggest that polymorphisms in the bone morphogenetic protein-4 and IL-1β (-511) genes could influence early marginal bone loss around implants. Also, a polymorphism in the promoter region of matrix metalloproteinase-1 gene was recently shown to be associated with early implant failure in nonsmokers.49 In the same population, polymorphisms in the tumor necrosis factor-α (G-308A) and transforming growth factor-β1 (C-509T and G-800A) were not associated with early implant failure.50,51

To our knowledge, for the first time, this study analyzed the relationship between early implant failure and polymorphisms in the IL-2 (T-330G) and IL-6 (G-174C) genes. The lack of association in our results could be a consequence of the sample size. Our data were derived from 74 patients, which gave moderate power to detect a small effect of the polymorphisms on implant loss. In fact, early implant failure is not frequent, and when smokers are excluded, the study population is substantially reduced. Another possible explanation for our negative results is that we analyzed only 1 promoter polymorphism in each gene. A gene may have several polymorphic sites that act in synergy, so the study of a single nucleotide polymorphism will give only a partial view of the effect of the genetic variations on that gene. Terry et al52 showed that the relationship between IL-6 expression and the IL-6 (-174) polymorphism is not as simple as might be expected. They suggested that IL-6 transcription is influenced by a complex interaction of promoter polymorphisms in the IL-6 gene that should be analyzed in haplotypes.

Bone formation involves several steps from recruitment of osteoblast precursor cells to calcification of the extracellular matrix, and a variety of cytokines, growth factors, and other macromolecules take part in these events. It is possible that functional polymorphisms in other inflammatory mediator or growth factor genes could have a more determinant role in early osseointegration failure. The interaction of the individual role of each polymorphic locus should be examined because the susceptibility to implant loss is likely to be influenced by an association of multiple polymorphisms in different genes.

An in vitro study showed that allele T of IL-2 (-330) polymorphism influences cytokine production in peripheral blood lymphocytes,9 and an increase in IL-2 production has been associated with acute rejection event.53 Allele G of IL-6 (-174) polymorphism has been associated with increased IL-6 serum levels.25 The G/G genotype was linked to type II diabetes mellitus in Native Americans and Caucasians,54 Alzheimer disease in an Italian population,55 and type I diabetes in Caucasian subjects.27 In the Brazilian population, the genotype T/T of IL-2 (-330) and G/G of IL-6 (-174) genes were associated with susceptibility to chronic periodontal disease, suggesting that allele T of IL-2 and allele G of IL-6 promoter polymorphisms may play a role in the pathogenesis and development of periodontitis.30,31 However, our results showed that both polymorphisms do not appear to influence the lack of success of dental implant osseointegration.

Regarding the Brazilian population, allele frequencies of the IL-2 gene polymorphism were similar to those reported by Scarel-Caminaga et al.56 The genotype G/G was not observed in our study, agreeing with other studies that showed very low frequencies for this genotype.23,53,56,57 Considering the IL-6 (-174) polymorphism, the frequency of allele G was very similar to that reported by Trevilatto et al31 in a Brazilian Caucasian population, however, it was higher than that reported for European Caucasians.24,25 Cox et al53 showed that the allele and genotype distributions for both IL-2 and IL-6 gene polymorphisms differed significantly between white subjects and African-Americans, confirming the correlation between ethnicity and polymorphisms. Therefore, it is possible that analyses in other populations or ethnic groups may render results that differ from the present study.

Different types of implants can stimulate the production of IL-1β and tumor necrosis factor-α.58 It was shown that titanium particles can alter the release of IL-259 and IL-6,60–62 affecting the immune response and contributing to implant pathologic conditions. These data indicate that although we have found no association between dental implant loss and polymorphisms in IL genes, the role of these cytokines in the failure of implants remains to be clarified.

Conclusions

We did not find an association between IL-2 (T-330G) and IL-6 (G-174C) gene polymorphisms and early implant failure, suggesting that the presence of those polymorphisms alone does not constitute a risk factor for the loss of dental implants. Despite the negative results presented by this and other studies, polymorphisms in other inflammatory mediator genes should be evaluated to clarify the real role of genetic factors in implant failure. The discovery of genetic markers related to implant loss would lead to a more strict selection of patients and, in the future, individual therapeutics could be developed, increasing implant success rates.

Disclosure

The authors claim to have no financial interest in any company or any of the products mentioned in this article.

Acknowledgments

The authors thank Dr. Alexandre S. Guedes Coelho (Department of General Biology of Federal University of Goiás) for his assistance in the statistical analysis. This work was supported by CNPq grant 131363/2002-6 and FAPESP grant 01/11920-6. MIGC and MCLGS contributed equally to this work.

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Abstract Translations [German, Spanish, Portugese, Japanese]

AUTOR(EN): Maria Isabela Guimaràes Campos, MS*, Maria Cristina Leme Godoy dos Santos, MS**, Paula Cristina Trevilatto, PhD***, Raquel Mantuaneli Scarel-Caminaga, PhD****, Fabio Jose Bezerra*****, Sergio Roberto Peres Line, PhD******. *Abteilungen für Morphologie, zahnmedizinische Fakultät von Piracicaba, staatliche Universität von Campinas, Piracicaba, SP, Brasilien. **Abteilungen für Morphologie, zahnmedizinische Fakultät von Piracicaba, staatliche Universität von Campinas, Piracicaba, SP, Brasilien. ***Zahnmedizinische Fakultät, kirchlich-katholische Universität von Paraná (PUC-PR), Curitiha, PR, Brasilien. ****Abteilung für Morphologie, zahnmedizinische Fakultät, Universität des Staates von Sao Paulo, UNESP, Araraquara, SP, Brasilien. *****Privat prakti-zierender Arzt, Facharzt für Orthodontie, Salvador, BA, Brasilien. ******Abteilungen für Morphologie, zahnmedizinische Fakultät von Piracicaba, staatliche Universität von Campinas, Piracicaba, SP, Brasilien. Schriftverkehr:Sergio Roberto Peres Line, PhD, Faculdade de Odontologia de Piracicaba/UNICAMP, Departamento de morfología, Av. Limeira, 901, CP 52, CEP 13414 –903, Piracicaba, SP, Brasilien. Telefon:+55-019-34125333, Fax: +55-019-34125218. eMail:serglin@fop.unicamp.br

Promotorpolymorphie der Gene IL-2 und IL-6 in Zusammenhang mit einem frühzeitigen Versagen von Zahnimplantaten

ZUSAMMENFASSUNG:Hintergrund: Es konnte gezeigt werden, dass einzelne Nukleotidpolymorphismen im Promotorbereich der menschlichen Gene des Typs IL-2 (T-330G) und IL-6 (G-174C) die transkriptionale Aktivität dieser Zytokine verändert und daher mit der Entstehung verschiedener Erkrankungen in Verbindung gebracht werden können. Die vorliegende Studie zielte darauf ab, eine mögliche Verbindung zwischen diesen einzelnen Nukleotidpolymorphismen und einem frühzeitigen Fehlschlagen einer Implantierungsbehandlung zu ermitteln. Methoden: Beispielhaft ausgewählte 74 Nichtraucher wurden in zwei Versuchsgruppen unterteilt: zum einen die Testgruppe mit 34 Patienten mit einem durchschnittlichen Alter von 49,3 Jahren und einem bzw. mehreren nicht mehr funktionstüchtigen Implantaten sowie der Kontrollgruppe mit 40 Patienten mit einem durchschnittlichen Alter von 43,8 Jahren und einem bzw. mehreren voll erhaltenen Implantaten. Genome DNA aus der Mundschleimhaut wurde mittels Polymerase-Kettenreaktion verstärkt und unter Anwendung des Restriktionsfragmentlängenpolymorphismus analysiert. Monte Carlo Simulationen (p < 0.05) wurden durchgeführt, um Unterschiede in der Häufigkeit der Allelen und Genotypen der einzelnen Nukleotidpolymorphismen zwischen den beiden Versuchsgruppen zu ermitteln. Ergebnisse: Bei einem Vergleich der beiden Gruppen miteinander konnten keine maβgeblichen Unterschiede in der Verteilung der Allelen und Genotypen der beiden Polymorphismen festgestellt werden. Schlussfolgerung: Die Ergebnisse weisen aus, dass Polymorphismen in den Genen des Typs IL-2 (T-330G) sowie IL-6 (G-174C) nicht mit einem frühzeitigen Versagen von Implantaten in Verbindung stehen, und lassen damit den Schluss zu, dass das Vorhandensein solcher einzelnen Nukleotidpolymorphismen bei den untersuchten Gruppen an sich kein genetisches Risiko für einen Implantatverlust darstellt.

SCHLÜSSELWÖRTER: Interleukin-2, Interleukin-6, Genpolymorphismus, Implantatversagen, Knochengewebsintegration

AUTOR(ES): Maria Isabela Guimaraes Campos, MS*, Maria Cristina Leme Godoy dos Santos, MS**, Paula Cristina Trevilatto, PhD***, Raquel Mantuaneli Scarel-Caminaga, PhD****, Fabio Jose Bezerra*****, Sergio Roberto Peres Line PhD******. 4 *Departamentos de Morfología, Facultad de Odontología de Piracicaba, Universidad Estatal de Campinas, Piracicaba, SP, Brasil. **Departamentos de Morfología, Facultad de Odontología de Piracicaba, Universidad Estatal de Campinas, Piracicaba, SP, Brasil. ***Facultad de Odontología, Universidad Católica Pontífica de Paraná (PUC-PR), Curitiba, PR, Brasil. ****Departamento de Morfología, Facultad de Odontología, Universidad del Estado de San Pablo, UNESP, Araraquara, SP, Brasil. *****Práctica Privada en Periodóntica, Salvador, BA, Brasil. ******Departamentos de Morfología, Facultad de Odontología de Piracicaba, Universidad Estatal de Campinas, Piracicaba, SP, Brasil. Correspondencia a: Sergio Roberto Peres Line PhD, Faculdade de Odontologia de Piracicaba/UNICAMP, Departamento de Morfologia, Av. Limeira 901, CP 52, CEP 13414-903, Piracicaba, SP, Brazil. 4 Teléfono: +55-019-34125333, Fax: +55-019-34125218, Correo electrónico:serglim@fop.unicamp.br

Polimorfismos promotores de los genes IL-2 y IL-6 y la falla temprana de implantes dentales

ABSTRACTO: Antecedentes: Los polimorfismos con un solo nucleótido (SNP) en la región promotora de los genes humanos IL-2 (T 330G) y IL-6 (G-174C) han demostrado que modifican la actividad transcripcional de estas citocinas y están asociados con varias enfermedades. El objetivo de este estudio fue investigar la posible relación entre estos SNP y una falla temprana de implantes. Métodos: Se dividió una muestra de 74 no fumadores en dos grupos: el grupo de prueba estaba compuesto por 34 pacientes (edad media de 49,3) con uno o más implantes fallados y el grupo de control compuesto por 40 pacientes (edad media de 43,8) con uno o más implantes saludables. El DNA genómico de la mucosa oral se amplificó usando una reacción en cadena de polimerasa (PCR) y analizado a través del polimorfismo restringido de longitud de fragmento (RFLP). Las diferencias en los alelos y las frecuencias de los genotipos de los SNP entre los dos grupos se evaluaron a través de las simulaciones de Monte Carlo (p < 0.05). Resultados: No se observaron diferencias significativas en la distribución de los alelos y genotipos de ambos polimorfismos cuando se compararon a los dos grupos. Conclusión: Los resultados indican que los polimorfismos en los genos IL-2 (T-330G) e IL-6 (G-174C) no están asociados con una falla temprana del implante, sugiriendo que la presencia de dichos SNP no constituye un factor de riesgo genético para la pérdida del implante en la población estudiada.

PALABRAS CLAVES: interleukin-2; interleukin -6, polimorfismo del gen; falla del implante; oseointegración.

AUTOR(ES): Maria Isabela Guimarães Campos, Mestre em Ciência*, Maria Cristina Leme Godoy dos Santos, Mestre em Ciência**, Paula Cristina Trevilatto, PhD***, Raquel Mantuaneli Scarel-Caminaga, PhD****, Fábio José Bezerra*****, Sérgio Roberto Peres Line, PhD******. *Departamentos de Morfologia, Faculdade de Odontologia de Piracicaba, Universidade Estadual de Campinas, Piracicaba, SP, Brasil. **Departamentos de Morfologia, Faculdade de Odontologia de Piracicaba, Universidade Estadual de Campinas, Piracicaba, SP, Brasil. ***Faculdade de Odontologia, Pontifícia Universidade Católica do Paraná (PUC-PR), Curitiba, PR, Brasil. ****Departamento de Morfologia, Faculdade de Odontologia, Universidade Estadual Paulista, UNESP, Araraquara, SP, Brasil. *****Clínica Particular em Periodontia, Salvador, BA, Brasil. ******Departamentos de Morfologia, Faculdade de Odontologia de Piracicaba, Universidade Estadual de Campinas, Piracicaba, SP, Brasil. Correspondência para: Sérgio Roberto Peres Line, PhD, Faculdade de Odontologia de Piracicaba/UNICAMP, Departamento de Morfologia, Av. Limeira, 901, CP 52, CEP 13414-903, Piracicaba-SP, Brasil. Telefone: +55-019-34125333, Fax: +55-019-34125218, E-mail:serglin@fop.unicamp.br

Polimorfismos do Promotor dos Genes IL-2 e IL-6 e Falha Precoce de Implantes Dentários

RESUMO: Antecedentes: Polimorfismos de nucleotídeo único (SNPs) na região promotora dos genes IL-2 (T-330G) e IL-6 (G-174C) humanos demonstraram modificar a atividade transcripcional destas citoquinas e estão associados a várias doenças. O objetivo deste estudo foi investigar o possível relacionamento entre estes SNPs e falha precoce no implante. Métodos: Uma amostra de 74 não-fumantes foi dividida em dois grupos: o grupo de teste compreendendo 34 pacientes (idade média 49,3) com um ou mais implantes falhos e o grupo de controle consistindo em 40 pacientes (idade média 43,8) com ou mais implantes saudáveis. O DNA genômico da mucosa oral foi amplificado por reação em cadeia de polimerase (PCR) e analisado por polimorfismo de comprimento por fragmento de restrição (RFLP). Diferenças nas freqüências de alelos e genótipos dos SNPs entre os dois grupos foram avaliadas por simulações de Monte Carlo (p < 0.05). Resultados: Nenhuma diferença significativa foi observada na distribuição de alelos e genótipos de ambos os polimorfismos quando os dois grupos foram comparados. Conclusão: Os resultados indicam que os polimorfismos nos genes IL-2 (T-330G) e IL-6 (G-174C) não estão associados a falha precoce no implante, sugerindo que a presença destes SNPs não constitui um fator de risco genético para perda de implante na população estudada.

PALAVRAS-CHAVE: interleucina-2; interleucina-6; polimorfismo de genes; falha no implante; osseointegração.

Figure
Figure:
No Caption available.
Keywords:

interleukin-2; interleukin-6; gene polymorphism; implant failure; osseointegration

© 2005 Lippincott Williams & Wilkins, Inc.