JCM Figure table search 04
Home Help [Feedback] [For Subscribers] [Archive] [Search] [Contents]
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Other Versions of this Article:
JCM.02483-07v1
46/5/1602    most recent
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Grisaru, D.
Right arrow Articles by Giladi, M.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Grisaru, D.
Right arrow Articles by Giladi, M.

 Previous Article  |  Next Article 

Journal of Clinical Microbiology, May 2008, p. 1602-1605, Vol. 46, No. 5
0095-1137/08/$08.00+0     doi:10.1128/JCM.02483-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Pilot Study of Prevalence of High-Risk Human Papillomavirus Genotypes in Israeli Jewish Women Referred for Colposcopic Examination{triangledown}

Dan Grisaru,1,{dagger}* Boaz Avidor,2,{dagger} Jacob Niv,1 Silvia Marmor,3 Benjamin Almog,1 Cecilia Leibowitz,2 Merav Graidy,2 and Michael Giladi4

Department of Obstetrics and Gynecology,1 Laboratory for Viruses and Molecular Biology, The Bernard Pridan Laboratory for Molecular Biology of Infectious Diseases,2 The Infectious Disease Unit,4 Department of Pathology, Tel Aviv Sourasky Medical Center, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel3

Received 28 December 2007/ Returned for modification 14 February 2008/ Accepted 23 February 2008


   ABSTRACT
Top
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
The objective of the present study was to determine the prevalence of high-risk (HR) human papillomavirus (HPV) genotypes in a group of Israeli Jewish women referred for colposcopic examination. Scrape specimens were prospectively collected from 84 women referred for colposcopic examination. All the women underwent Papanicolaou (Pap) smears and colposcopies, and some also underwent cervical or loop electrosurgical excision procedure biopsy. HR HPV was detected in scrape specimens (Amplicor HPV test; Roche Molecular Systems), and the individual genotypes in these specimens were identified (HPV GenoArray test kit; Hybribio Ltd., Hong Kong). Forty-one (49%) specimens were positive by the Amplicor HPV test. Sixty-four samples (41 positive and 23 negative by the Amplicor HPV test) were also assayed by use of the HPV GenoArray kit. The overall level of agreement between the two assays was 93.8% (Cohen's kappa = 0.98). HR genotypes were found in 37/41 (90%) HPV-positive samples. The prevalences of the HR HPV genotypes in the 37 HPV-positive samples were 41% of patients for HPV type 16 (HPV-16), 22% for HPV-39, 19% for HPV-52, and 14% for HPV-18. Forty-one percent of these patients were infected with a single HR genotype, whereas 59% were infected with mixtures of HR genotypes. The presence of a relatively high percentage of HPV types 39 and 52 and the relatively high incidence of infections with mixtures of genotypes may be one of the reasons for the low rate of conversion from high-grade squamous intraepithelial lesions to invasive carcinoma in Israeli women. Larger and more comprehensive studies are warranted to investigate this issue in greater detail.


   INTRODUCTION
Top
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
The prevalence of human papillomavirus (HPV) in the general population is estimated to be between 9 and 13 percent worldwide and varies between 1.6 and 25.6 percent by country (2). A significant proportion of HPV infections are attributed to four types (types 6, 11, 16, and 18), with types 16 and 18 causing approximately 70% of all cases of cervical cancer worldwide (11). HPV type 6 (HPV-6) and HPV-11 infections in men and women are responsible for the majority of genital wart cases (16). In a multinational study with young women who reported a lifetime history of four or fewer sexual partners, nearly one-third had serologic or molecular evidence of infection with high-risk (oncogenic) HPV types 16 or 18 or low-risk (nononcogenic) HPV types 6 or 11 (16). The high observed prevalence of HPV types 6, 11, 16, and 18 and their causative association with anogenital cancers, dysplasia, or genital warts led to the development of a prophylactic vaccine that covers these types, which has the potential to substantially reduce the burden of clinical HPV disease in both men and women (16).

Israel was traditionally considered to have the lowest prevalence (age-standardized incidence rate, 3.9) of cervical cancer compared to that in other countries in the Western world (8, 17). A recent study indicated that the incidence rates for premalignant lesions among Israeli Jewish women has become similar to those among women in other Western countries (13); however, the rate of conversion from premalignant cervical lesions to invasive cancer continues to be lower among Israeli Jewish women than among European and North American women. The reasons for this low conversion rate remains to be explored. The Israeli population comprises a high percentage of immigrants from all over the globe. It is therefore important to determine the HPV genotype distribution in Israel in order to study this ethnic uniqueness. A previous study with Israeli Jewish women looked at the presence of HPV types 16 and 18 in small samples of premalignant and malignant cervical pathology specimens and detected HPV DNA in approximately two-thirds of the specimens (9). In the present pilot study, we sought to determine the prevalence of high-risk (HR) HPV genotypes in a selective population of Israeli Jewish women who were referred for colposcopy in Tel Aviv, Israel.

(This study was presented at ESGO, Berlin, Germany, October to November 2007.)


   MATERIALS AND METHODS
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Patients and specimens. This study was conducted in compliance with the institutional ethical board of the Tel Aviv Sourasky Medical Center, Tel Aviv, Israel. The patients enrolled in this study included 84 women referred for colposcopic examination over a period of 3 months (September to November 2005). Most of the women were referred from community clinics. The reasons for referral are summarized in Table 1. All the study patients were examined by colposcopy, and some underwent cervical biopsy or loop electrosurgical excision procedure cone biopsy. Before colposcopy, cervical samples were obtained from all patients by the use of a cervical brush (Cervex-Brush; Rovers Medical Devices B.V., Holland), and a conventional smear was prepared. The sampling head of the brush was then placed into a PreservCyt solution vial (Cytyc Corporation), and the vial was stored at 4°C until it was transferred within 1 to 4 days to the Laboratory for Viruses and Molecular Biology of the Tel Aviv Sourasky Medical Center for HPV DNA detection. The cervical smears and biopsy specimens were analyzed by the Pathology Department of the Tel Aviv Sourasky Medical Center.


View this table:
[in this window]
[in a new window]

  		TABLE 1. Reasons of referral for 84 patients enrolled in the study population

 
Cytology. Papanicolaou (Pap) smear analysis of the cervical smears was carried out by a trained cytopathologist (S. Marmor), who adopted the conventional Bethesda terminology.

Colposcopy. All study participants underwent a colposcopic examination of the cervix, vagina, and vulva. Lesions in the transformation zone (TZ) were assessed by applying 5% acetic acid and iodine solution under x8 to x12 magnification. If the colposcopy findings proved unsatisfactory for a definitive diagnosis, further exploration of the endocervix was systematically carried out under x20 magnification with a Koogan speculum. The international nomenclature (IFCPC) was used to classify the colposcopic patterns.

Biopsy procedures. Some women underwent cervical biopsies, and a loop electrosurgical excision procedure cone biopsy was performed for cases with (i) a Pap test showing high-grade squamous intraepithelial lesions (HSILs) and anal TZ (ATZ) by colposcopy; (ii) a large ATZ (i.e., 50% of the TZ area), regardless of the Pap test result; (iii) an endocervical lesion and unsatisfactory colposcopy findings; or (iv) ATZ and a squamocolumnar junction localized more than 3 mm within the endocervix. One patient refused the biopsy.

Histology. All biopsy specimens were examined in the Tel Aviv Sourasky Medical Center's Pathology Laboratory. Histological assessments were made with the pathologist being unaware of the HPV DNA status. The cervical intraepithelial neoplasia terminology was adopted for classification of the biopsy specimens.

HPV DNA detection. HPV testing was done by the Amplicor HPV test (Roche Molecular Systems), strictly according to the manufacturer's instructions. Specimens were collected and placed into PreservCytR LBC medium (ThinPrep liquid Pap vial; Cytyc Corporation). Specimens that had been collected in PreservCyt medium were transported to the laboratory at 2 to 8°C. The Amplicor HPV test kit contains a pool of HPV-specific primers designed to amplify HPV DNA from 13 HR genotypes (types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, and 68). According to the manufacturer's specification, the Amplicor HPV test detects HPV genotypes 31, 52, 58, and 59 at 240 copies/ml and HPV genotypes 16, 18, 33, 35, 39, 45, 51, 56, and 68 at 100 copies/ml with a positivity rate greater than 95%. All genotypes were detected with a 100% positivity rate at 480 copies/ml.

HPV genotyping. HPV genotyping was performed by using the newly commercially introduced HPV GenoArray test kit (Hybribio Limited, Hong Kong), which makes use of both DNA amplification and HybriBio's proprietary flowthrough hybridization technique to simultaneously identify 21 HPV genotypes, including 5 low-risk types (types 6, 11, 42, 43, and 44), 14 HR types (types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, and 68), and 2 intermediate-risk types (types CP8304 and 53). The test employs a macroarray format with a nylon membrane onto which HPV genotype-specific oligonucleotides probes have been immobilized.


   RESULTS
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Specimens from 84 women (age range, 19 to 51 years) were tested by the Amplicor HPV test during the study period. Forty-one (49%) were HPV positive, indicating the presence of HR HPV genotypes, and 43 (51%) were negative, indicating either the absence of HPV DNA or the presence of low-risk genotypes. Since the Amplicor HPV test gave a dichotomal result for HR HPV and given that our aim was to find specific HPV genotypes, we performed the HPV GenoArray test with a total of 64 samples, 41 of which were positive and 23 of which were negative by the Amplicor HPV test. The results are summarized in Table 2. The overall agreement between the two assays was 93.8% (Cohen's kappa value = 0.98). HR genotypes were found in 37/41 (90%) Amplicor HPV-positive samples, whereas 4 samples were negative for HR genotypes: 2 of them had low-risk HPV genotype 6, and the 2 others were negative for HPV DNA. These women had normal colposcopic examinations, and their Pap smear results indicated low-grade squamous intraepithelial lesions (three samples) or a normal cytology (one sample). The low-risk HPV genotypes which were detected in the 23 HPV-negative samples included genotypes 6 (two samples), 53 (two samples), and 42 (one sample).


View this table:
[in this window]
[in a new window]

  		TABLE 2. Concordance between the results for the 64 samples tested by the Roche Amplicor HPV assay and the HybriBio GenoArray test

 
The distribution of the HR HPV genotypes in the 37 HPV positive samples is summarized in Table 3: HPV types 16, 39, 52, and 18 were the most prevalent genotypes found in this population. It is noteworthy that these four genotypes altogether were detected in 29/37 (74%) of the HR HPV type-infected patients, whereas 8 additional patients were infected with HPV genotypes 31, 33, 45, 53, 56, and 59, in the absence of these four genotypes. Nineteen patients (51.4%) were infected with a single HR HPV genotype, while 12 (32.4%) were infected with a mixture of two HR HPV genotypes and 6 (5.2%) were infected with a mixture of three genotypes. The findings for single and mixed infections with HPV genotypes 16, 39, 52, and 18 are summarized in Table 4.


View this table:
[in this window]
[in a new window]

  		TABLE 3. HR HPV genotypes identifieda

 

View this table:
[in this window]
[in a new window]

  		TABLE 4. Prevalence of single and mixed infections with HPV genotypes 16, 39, 52, and 18

 

   DISCUSSION
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
The close association between HPV infection and cervical neoplasia is well established, but there is a wide disparity between the prevalence of infection and the occurrence of actual neoplasia. It is generally accepted that a small minority of women who are infected with HPV will develop HSILs and still fewer will develop fully evolved carcinoma. In a recent study, Dunne et al. determined the prevalence of HPV among females in the United States (7). The overall HPV prevalence was 26.8% among U.S. females aged 14 to 59 years (n = 1,921), with 15.2% being HR HPV types and HPV types 16 and 18 being 15% of the HR HPV types. Worldwide the prevalence of HR HPV in asymptomatic females aged 15 to 74 years (n = 15,613) was estimated to be 9.2%, with HPV types 16 and 18 being 40% of the HR HPV types (2). In contrast, the prevalence of HR HPV increases to 84 to 90% among patients with high-grade dysplasia and invasive cervical cancer, with HPV types 16 and 18 being present in 50 and 70% of the patients, respectively (4, 5).

In the present study, we evaluated cervical cytology samples from a group of patients referred to a cervical pathology clinic. This is the first study that looked at the distribution of HR HPV genotypes in Israel. Our results showed that 44% (37/84 patients) of the study women were positive for HR HPV type infection. These results reflect the characteristics of our study population, which was a referred group and not the naive general population. Moreover, it is interesting to note that a quarter of the patients were referred because of the presence of condylomata, which are usually related to low-risk HPV types. Interestingly, 20/37 (54%) of our HR HPV type-infected study population had HPV type 16 or 18, resembling the prevalence of these genotypes in women with premalignant lesions (4). Intriguingly, however, is the finding that a high percentage (41%) of our study population had HPV types 39 and 52. In fact, 9/37 (24%) patients were infected with these two genotypes, in the absence of either HPV type 16 or 18 infection. Previous data suggested that infections with HPV types 16 and 18 preferentially progress to cervical cancer more readily than infections with the other HR genotypes (4). Zuna et al. (18) showed that the distribution of infection with HPV types 35, 39, 51, 52, and 59 varied from 15 to 22% for women with moderate HSILs but varied from 4 to 7% for women with severe HSILs and 0 to 2% for women with invasive carcinomas. We may speculate that the high prevalence of HPV types 39 and 52 found in our study population may be one of the reasons for the lower rate of conversion from premalignant cervical lesions to invasive cancer in Israel. Furthermore, Zuna et al. (18) have recently shown that mixed infections with HR HPV genotypes are less likely to progress to cervical cancer than infections with single HR HPV genotypes. The high rate (49%) of mixed infections in our study population may also explain the lower rate of progression to invasive cancer.

Our study, being the first to provide data on the HR HPV genotypes in Israel, may also be relevant in the era of the HPV vaccine, since the vaccine is specifically directed against HPV types 16 and 18. Although the relative distribution of HPV types 16 and 18 in our population is comparable to the distribution in similar populations (2-7), the efficiency of the vaccine in Israel and its cost-effectiveness in light of the low rate of cervical cancer have yet to be seen.

We used the HybriBio GenoArray test for HPV genotyping. This assay is a commercial kit which was only recently introduced into the market. Although it has already been used for some time in China, no literature is available to support its value. Nevertheless, the results of this study show a high level (93.8%) of agreement between the results of that assay and those of the Amplicor HPV test. This high level of concordance is encouraging, since the Amplicor HPV test had gained a good reputation over the past few years as a sensitive, specific, and reliable test for the detection of infections with HR HPV types (1, 10, 12, 14, 15). The discordance in the results between the two assays that emerged in our study is difficult to interpret, but the fact that all four women had normal colposcopic findings and that their Pap smear results were of no pathological concern may suggest that the results of the HPV GenoArray test might have been the correct ones.

In conclusion, the presence of a relative high percentage of HPV types 39 and 52 and the relatively high incidence of mixed infections in the present study population may reflect the low rate of conversion from HSILs to invasive carcinoma in Israeli Jewish women. The HPV GenoArray test is an easy and reliable method for HPV genotyping. Verification by sequencing for HPV-39 and HPV-52 and larger studies are needed to corroborate our findings.


   FOOTNOTES
 
* Corresponding author. Mailing address: Gynecologic Oncology Service, Department of Obstetrics & Gynecology, Tel-Aviv Sourasky Medical Center, 6 Weizmann Street, Tel Aviv 64239, Israel. Phone: 972-3-9625622. Fax: 972-3-9625670. E-mail: grisaro{at}post.tau.ac.il Back

{triangledown} Published ahead of print on 5 March 2008. Back

{dagger} D. Grisaru and B. Avidor contributed equally to the paper. Back


   REFERENCES
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

  1. Carozzi, F., S. Bisanzi, C. Sani, M. Zappa, S. Cecchini, S. Ciatto, and M. Confortini. 2007. Agreement between the Amplicor HPV test and the Hybrid Capture 2 assay in the detection of high-risk human papillomavirus and biopsy-confirmed high-grade cervical disease. J. Clin. Microbiol. 45:364-369.[Abstract/Free Full Text]
  2. Clifford, G. M., S. Gallus, R. Herrero, N. Munoz, P. J. Snijders, S. Vaccarella, P. T. Anh, C. Ferreccio, N. T. Hieu, E. Matos, M. Molano, R. Rajkumar, G. Ronco, S. de Sanjose, H. R. Shin, S. Sukvirach, J. O. Thomas, S. Tunsakul, C. J. Meijer, and S. Franceschi. 2005. Worldwide distribution of human papillomavirus types in cytologically normal women in the International Agency for Research on Cancer HPV prevalence surveys: a pooled analysis. Lancet 366:991.[CrossRef][Medline]
  3. Clifford, G. M., R. K. Rana, S. Franceschi, J. S. Smith, G. Gough, and J. M. Pimenta. 2005. Human papillomavirus genotype distribution in low-grade cervical lesions: comparison by geographic region and with cervical cancer. Cancer Epidemiol. Biomarkers Prev. 14:1157.[Abstract/Free Full Text]
  4. Clifford, G. M., J. S. Smith, T. Aguado, and S. Franceschi. 2003. Comparison of HPV type distribution in high-grade cervical lesions and cervical cancer: a meta-analysis. Br. J. Cancer 89:101.[CrossRef][Medline]
  5. Clifford, G. M., J. S. Smith, M. Plummer, N. Munoz, and S. Franceschi. 2003. Human papillomavirus types in invasive cervical cancer worldwide: a meta-analysis. Br. J. Cancer 88:63.[CrossRef][Medline]
  6. Didelot-Rousseau, M. N., N. Nagot, V. Costes-Martineau, X. Valles, A. Ouedraogo, I. Konate, H. A. Weiss, P. Van de Perre, P. Mayaud, and M. Segondy. 2006. Human papillomavirus genotype distribution and cervical squamous intraepithelial lesions among high-risk women with and without HIV-1 infection in Burkina Faso. Br. J. Cancer 95:355.[CrossRef][Medline]
  7. Dunne, E. F., E. R. Unger, M. Sternberg, G. McQuillan, D. C. Swan, S. S. Patel, and L. E. Markowitz. 2007. Prevalence of HPV infection among females in the United States. JAMA 297:813.[Abstract/Free Full Text]
  8. Glezerman, M., B. Piura, and V. Insler. 1989. Cervical cancer in Jewish women. Am. J. Obstet. Gynecol. 161:1186.[Medline]
  9. Menczer, J., Y. Fintsi, S. Arbel-Alon, L. Tell, E. Friedman, A. Jackman, and L. Sherman. 2000. The presence of HPV 16, 18 and p53 immunohistochemical staining in tumor tissue of Israeli Jewish women with cervical and vulvar neoplasia. Eur. J. Gynaecol. Oncol. 21:30.[Medline]
  10. Monsonego, J., J. M. Bohbot, G. Pollini, C. Krawec, C. Vincent, I. Merignargues, F. Haroun, P. Sednaoui, L. Monfort, R. Dachez, and K. Syrjanen. 2005. Performance of the Roche Amplicor human papillomavirus (HPV) test in prediction of cervical intraepithelial neoplasia (CIN) in women with abnormal Pap smear. Gynecol. Oncol. 99:160.[CrossRef][Medline]
  11. Munoz, N., F. X. Bosch, S. de Sanjose, R. Herrero, X. Castellsague, K. V. Shah, P. J. Snijders, and C. J. Meijer. 2003. Epidemiologic classification of human papillomavirus types associated with cervical cancer. N. Engl. J. Med. 348:518.[Abstract/Free Full Text]
  12. Poljak, M., K. Fujs, K. Seme, B. J. Kocjan, and E. Vrtacnik-Bokal. 2005. Retrospective and prospective evaluation of the Amplicor HPV test for detection of 13 high-risk human papillomavirus genotypes on 862 clinical samples. Acta Dermatovenerol. Alp. Panonica Adriat 14:147.[Medline]
  13. Sadan, O., E. Schejter, S. Ginath, R. Bachar, M. Boaz, J. Menczer, and M. Glezerman. 2004. Premalignant lesions of the uterine cervix in a large cohort of Israeli Jewish women. Arch. Gynecol. Obstet. 269:188.[CrossRef][Medline]
  14. Sandri, M. T., P. Lentati, E. Benini, P. Dell'Orto, L. Zorzino, F. M. Carozzi, P. Maisonneuve, R. Passerini, M. Salvatici, C. Casadio, S. Boveri, and M. Sideri. 2006. Comparison of the Digene HC2 assay and the Roche Amplicor human papillomavirus (HPV) test for detection of high-risk HPV genotypes in cervical samples. J. Clin. Microbiol. 44:2141.[Abstract/Free Full Text]
  15. van Ham, M. A., J. M. Bakkers, G. K. Harbers, W. G. Quint, L. F. Massuger, and W. J. Melchers. 2005. Comparison of two commercial assays for detection of human papillomavirus (HPV) in cervical scrape specimens: validation of the Roche Amplicor HPV test as a means to screen for HPV genotypes associated with a higher risk of cervical disorders. J. Clin. Microbiol. 43:2662.[Abstract/Free Full Text]
  16. Villa, L. L., R. L. Costa, C. A. Petta, R. P. Andrade, J. Paavonen, O. E. Iversen, S. E. Olsson, J. Hoye, M. Steinwall, G. Riis-Johannessen, A. Andersson-Ellstrom, K. Elfgren, G. Krogh, M. Lehtinen, C. Malm, G. M. Tamms, K. Giacoletti, L. Lupinacci, R. Railkar, F. J. Taddeo, J. Bryan, M. T. Esser, H. L. Sings, A. J. Saah, and E. Barr. 2006 High sustained efficacy of a prophylactic quadrivalent human papillomavirus types 6/11/16/18 L1 virus-like particle vaccine through 5 years of follow-up. Br. J. Cancer 95:1459.[CrossRef][Medline]
  17. Vizcaino, A. P., V. Moreno, F. X. Bosch, N. Munoz, X. M. Barros-Dios, J. Borras, and D. M. Parkin. 2000. International trends in incidence of cervical cancer. II. Squamous-cell carcinoma. Int. J. Cancer 86:429.[CrossRef][Medline]
  18. Zuna, R. E., R. A. Allen, W. E. Moore, R. Mattu, and S. T. Dunn. 2004. Comparison of human papillomavirus genotypes in high-grade squamous intraepithelial lesions and invasive cervical carcinoma: evidence for differences in biologic potential of precursor lesions. Mod. Pathol. 17:1314.[CrossRef][Medline]

Journal of Clinical Microbiology, May 2008, p. 1602-1605, Vol. 46, No. 5
0095-1137/08/$08.00+0     doi:10.1128/JCM.02483-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.




This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Other Versions of this Article:
JCM.02483-07v1
46/5/1602    most recent
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Grisaru, D.
Right arrow Articles by Giladi, M.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Grisaru, D.
Right arrow Articles by Giladi, M.

Home Help [Feedback] [For Subscribers] [Archive] [Search] [Contents]
Antimicrob. Agents Chemother. Clin. Microbiol. Rev.
Clin. Vaccine Immunol. ALL ASM JOURNALS