Volume 93, Issue 4
  • ISSN: 0002-9637
  • E-ISSN: 1476-1645



ssp. (TPA) causes over 10 million new cases of syphilis worldwide whereas ssp. (TPE), the causative agent of yaws, affects about 2.5 million people. Although penicillin remains the drug of choice in the treatment of syphilis, in penicillin-allergic patients, macrolides have been used in this indication since the 1950s. Failures of macrolides in syphilis treatment have been well documented in the literature and since 2000, there has been a dramatic increase in a number of clinical samples with macrolide-resistant TPA. Scarce data regarding the genetics of macrolide-resistant mutations in TPA suggest that although macrolide-resistance mutations have emerged independently several times, the increase in the proportion of TPA strains resistant to macrolides is mainly due to the spread of resistant strains, especially in developed countries. The emergence of macrolide resistance in TPA appears to require a two-step process including either A2058G or A2059G mutation in one copy of the 23S rRNA gene and a subsequent gene conversion unification of both rRNA genes. Given the enormous genetic similarity that was recently revealed between TPA and TPE strains, there is a low but reasonable risk of emergence and spread of macrolide-resistant yaws strains following azithromycin treatment.


Article metrics loading...

The graphs shown below represent data from March 2017
Loading full text...

Full text loading...



  1. Čejková D, Zobaníková M, Chen L, Pospíšilová P, Strouhal M, Qin X, Mikalová L, Norris SJ, Muzny DM, Gibbs RA, Fulton LL, Sodergren E, Weinstock GM, Šmajs D, , 2012. Whole genome sequences of three Treponema pallidum ssp. pertenue strains: yaws and syphilis treponemes differ in less than 0.2% of the genome sequence. PLoS Negl Trop Dis 6: e1471. [Google Scholar]
  2. Centers for Disease Control and Prevention, 1982. Sexually transmitted diseases treatment guidelines 1982. MMWR Morb Mortal Wkly Rep 31 (Suppl 2): 33S60S. [Google Scholar]
  3. Mitjà O, Hays R, Rinaldi AC, McDermott R, Bassat Q, , 2012. New treatment schemes for yaws: the path toward eradication. Clin Infect Dis 55: 406412. [Google Scholar]
  4. WHO, 2012. Summary Report of the Consultative Meeting on Eradication of Yaws, 5–7 March 2012, Morges, Switzerland. Available at: http://apps.who.int/iris/bitstream/10665/75528/1/WHO_HTM_NTD_IDM_2012.2_eng.pdf. Accessed April 21, 2015. [Google Scholar]
  5. Stamm LV, , 2010. Global challenge of antibiotic-resistant Treponema pallidum. Antimicrob Agents Chemother 54: 583589. [Google Scholar]
  6. Stamm LV, , 2015. Syphilis: antibiotic treatment and resistance. Epidemiol Infect 143: 15671574. [Google Scholar]
  7. Pfister P, Jenni S, Poehlsgaard J, Thomas A, Douthwaite S, Ban N, Böttger EC, , 2004. The structural basis of macrolide-ribosome binding assessed using mutagenesis of 23S rRNA positions 2058 and 2059. J Mol Biol 342: 15691581. [Google Scholar]
  8. Hashisaki P, Wertzberger GG, Conrad GL, Nichols CR, , 1983. Erythromycin failure in the treatment of syphilis in a pregnant woman. Sex Transm Dis 10: 3638. [Google Scholar]
  9. Stapleton JT, Stamm LV, Bassford PJ, Jr, 1985. Potential for development of antibiotic resistance in pathogenic treponemes. Rev Infect Dis 7 (Suppl 2): S314S317. [Google Scholar]
  10. Stamm LV, Stapleton JT, Bassford PJ, Jr, 1988. In vitro assay to demonstrate high-level erythromycin resistance of a clinical isolate of Treponema pallidum. Antimicrob Agents Chemother 32: 164169. [Google Scholar]
  11. Duncan WC, , 1988. Failure of erythromycin to cure secondary syphilis in a patient infected with the human immunodeficiency virus. Arch Dermatol 125: 8284. [Google Scholar]
  12. Sands M, Markus A, , 1995. Lues maligna, or ulceronodular syphilis, in man infected with human immunodeficiency virus: case report and review. Clin Infect Dis 20: 387390. [Google Scholar]
  13. Klausner JD, Kohn RP, Kent CK, , 2006. Azithromycin versus penicillin for early syphilis. N Engl J Med 354: 203205. [Google Scholar]
  14. Lukehart SA, Godornes C, Molini BJ, Sonnett P, Hopkins S, Mulcahy F, Engelman J, Mitchell SJ, Rompalo AM, Marra CM, Klausner JD, , 2004. Macrolide resistance in Treponema pallidum in the United States and Ireland. N Engl J Med 351: 154158. [Google Scholar]
  15. Mitchell SJ, Engelman J, Kent CK, Lukehart SA, Godornes C, Klausner JD, , 2006. Azithromycin-resistant syphilis infection: San Francisco, California, 2000–2004. Clin Infect Dis 42: 337345. [Google Scholar]
  16. Matějková P, Flasarová M, Zákoucká H, Bořek M, Křemenová S, Arenberger P, Woznicová V, Weinstock GM, Šmajs D, , 2009. Macrolide treatment failure in a case of secondary syphilis: a novel A2059G mutation in the 23S rRNA gene of Treponema pallidum subsp. pallidum. J Med Microbiol 58: 832836. [Google Scholar]
  17. Zhou P, Li K, Lu H, Qian Y, Gu X, Gong W, Tucker JD, Cohen MS, , 2010. Azithromycin treatment failure among primary and secondary syphilis patients in Shanghai. Sex Transm Dis 37: 726729. [Google Scholar]
  18. Woznicová V, Matějková P, Flasarová M, Zákoucká H, Vališová Z, Šmajs D, Dastychová E, , 2010. Clarithromycin treatment failure due to macrolide resistance in Treponema pallidum in a patient with primary syphilis. Acta Derm Venereol 90: 206207. [Google Scholar]
  19. Ayove T, Houniei W, Wangnapi R, Bieb SV, Kazadi W, Luke LN, Manineng C, Moses P, Paru R, Esfandiari J, Alonso PL, de Lazzari E, Bassat Q, Mabey D, Mitjà O, , 2014. Sensitivity and specificity of a rapid point-of-care test for active yaws: a comparative study. Lancet Glob Health 2: e415e421. [Google Scholar]
  20. Mitjà O, Houinei W, Moses P, Kapa A, Paru R, Hays R, Lukehart S, Godornes C, Bieb SV, Grice T, Siba P, Mabey D, Sanz S, Alonso PL, Asiedu K, Bassat Q, , 2015. Mass treatment with single-dose azithromycin for yaws. N Engl J Med 372: 703710. [Google Scholar]
  21. Chi KH, Danavall D, Taleo F, Pillay A, Ye T, Nachamkin E, Kool JL, Fegan D, Asiedu K, Vestergaard LS, Ballard RC, Chen CY, , 2015. Molecular differentiation of Treponema pallidum subspecies in skin ulceration clinically suspected as yaws in Vanuatu using real-time multiplex PCR and serological methods. Am J Trop Med Hyg 92: 134138. [Google Scholar]
  22. Stamm LV, Bergen HL, , 2000. A point mutation associated with bacterial macrolide resistance is present in both 23S rRNA genes of an erythromycin-resistant Treponema pallidum clinical isolate. Antimicrob Agents Chemother 44: 806807. [Google Scholar]
  23. Sander P, Prammananan T, Meier A, Frischkorn K, Böttger EC, , 1997. The role of ribosomal RNAs in macrolide resistance. Mol Microbiol 26: 469480. [Google Scholar]
  24. Heifets L, Mor N, Vanderkolk J, , 1993. Mycobacterium avium strains resistant to clarithromycin and azithromycin. Antimicrob Agents Chemother 37: 23642370. [Google Scholar]
  25. Lee SY, Ning Y, Fenno JC, , 2002. 23S rRNA point mutation associated with erythromycin resistance in Treponema denticola. FEMS Microbiol Lett 207: 3942. [Google Scholar]
  26. Drake JW, , 1991. A constant rate of spontaneous mutation in DNA-based microbes. Proc Natl Acad Sci USA 88: 71607164. [Google Scholar]
  27. Drake JW, Charlesworth B, Charlesworth D, Crow JF, , 1998. Rates of spontaneous mutation. Genetics 148: 16671686. [Google Scholar]
  28. Agampodi SB, Moreno AC, Vinetz JM, Matthias MA, , 2013. Utility and limitations of direct multi-locus sequence typing on qPCR-positive blood to determine infecting Leptospira strain. Am J Trop Med Hyg 88: 184185. [Google Scholar]
  29. Liveris D, Schwartz I, McKenna D, Nowakowski J, Nadelman RB, DeMarco J, Iyer R, Cox ME, Holmgren D, Wormser GP, , 2012. Quantitation of cell-associated borrelial DNA in the blood of Lyme disease patients with erythema migrans. Eur J Clin Microbiol Infect Dis 31: 791795. [Google Scholar]
  30. Tipple C, Hanna MO, Hill S, Daniel J, Goldmeier D, McClure MO, Taylor GP, , 2011. Getting the measure of syphilis: qPCR to better understand early infection. Sex Transm Infect 87: 479485. [Google Scholar]
  31. Gayet-Ageron A, Ninet B, Toutous-Trellu L, Lautenschlager S, Furrer H, Piguet V, Schrenzel J, Hirschel B, , 2009. Assessment of a real-time PCR test to diagnose syphilis from diverse biological samples. Sex Transm Infect 85: 264269. [Google Scholar]
  32. Fraser CM, Norris SJ, Weinstock GM, White O, Sutton GG, Dodson R, Gwinn M, Hickey EK, Clayton R, Ketchum KA, Sodergren E, Hardham JM, McLeod MP, Salzberg S, Peterson J, Khalak H, Richardson D, Howell JK, Chidambaram M, Utterback T, McDonald L, Artiach P, Bowman C, Cotton MD, Fujii C, Garland S, Hatch B, Horst K, Roberts K, Sandusky M, Weidman J, Smith HO, Venter JC, , 1998. Complete genome sequence of Treponema pallidum, the syphilis spirochete. Science 281: 375388. [Google Scholar]
  33. Matějková P, Strouhal M, Šmajs D, Norris SJ, Palzkill T, Petrosino JF, Sodergren E, Norton JE, Singh J, Richmond TA, Molla MN, Albert TJ, Weinstock GM, , 2008. Complete genome sequence of Treponema pallidum ssp. pallidum strain SS14 determined with oligonucleotide arrays. BMC Microbiol 8: 76. [Google Scholar]
  34. Giacani L, Jeffrey BM, Molini BJ, Le HT, Lukehart SA, Centurion-Lara A, Rockey DD, , 2010. Complete genome sequence and annotation of the Treponema pallidum subsp. pallidum Chicago strain. J Bacteriol 192: 26452646. [Google Scholar]
  35. Šmajs D, Zobaníková M, Strouhal M, Čejková D, Dugan-Rocha S, Pospíšilová P, Norris SJ, Albert T, Qin X, Hallsworth-Pepin K, Buhay C, Muzny DM, Chen L, Gibbs RA, Weinstock GM, , 2011. Complete genome sequence of Treponema paraluiscuniculi, strain Cuniculi A: the loss of infectivity to humans is associated with genome decay. PLoS One 6: e20415. [Google Scholar]
  36. Pětrošová H, Zobaníková M, Čejková D, Mikalová L, Pospíšilová P, Strouhal M, Chen L, Qin X, Muzny DM, Weinstock GM, Šmajs D, , 2012. Whole genome sequence of Treponema pallidum ssp. pallidum, strain Mexico A, suggests recombination between yaws and syphilis strains. PLoS Negl Trop Dis 6: e1832. [Google Scholar]
  37. Zobaníková M, Mikolka P, Čejková D, Pospíšilová P, Chen L, Strouhal M, Qin X, Weinstock GM, Šmajs D, , 2012. Complete genome sequence of Treponema pallidum strain DAL-1. Stand Genomic Sci 7: 2615838. [Google Scholar]
  38. Pětrošová H, Pospíšilová P, Strouhal M, Čejková D, Zobaníková M, Mikalová L, Sodergren E, Weinstock GM, Šmajs D, , 2013. Resequencing of Treponema pallidum ssp. pallidum strains Nichols and SS14: correction of sequencing errors resulted in increased separation of syphilis Treponema subclusters. PLoS One 8: e74319. [Google Scholar]
  39. Zobaníková M, Strouhal M, Mikalová L, Čejková D, Ambrožová L, Pospíšilová P, Fulton LL, Chen L, Sodergren E, Weinstock GM, Šmajs D, , 2013. Whole genome sequence of the Treponema Fribourg-blanc: unspecified simian isolate is highly similar to the yaws subspecies. PLoS Negl Trop Dis 7: e2172. [Google Scholar]
  40. Giacani L, Iverson-Cabral SL, King JC, Molini BJ, Lukehart SA, Centurion-Lara A, , 2014. Complete genome sequence of the Treponema pallidum subsp. pallidum Sea81-4 strain. Genome Announc 2: e00333-14. [Google Scholar]
  41. Štaudová B, Strouhal M, Zobaníková M, Čejková D, Fulton LL, Chen L, Giacani L, Centurion-Lara A, Bruisten SM, Sodergren E, Weinstock GM, Šmajs D, , 2014. Whole genome sequence of the Treponema pallidum subsp. endemicum strain Bosnia A: the genome is related to yaws treponemes but contains few loci similar to syphilis treponemes. PLoS Negl Trop Dis 8: e3261. [Google Scholar]
  42. Čejková D, Zobaníková M, Pospíšilová P, Strouhal M, Mikalová L, Weinstock GM, Šmajs D, , 2013. Structure of rrn operons in pathogenic non-cultivable treponemes: sequence but not genomic position of intergenic spacers correlates with classification of Treponema pallidum and Treponema paraluiscuniculi strains. J Med Microbiol 62: 196207. [Google Scholar]
  43. Liao D, , 2000. Gene conversion drives within genic sequences: concerted evolution of ribosomal RNA genes in bacteria and archaea. J Mol Evol 51: 305317. [Google Scholar]
  44. Flasarová M, Pospíšilová P, Mikalová L, Vališová Z, Dastychová E, Strnadel R, Kuklová I, Woznicová V, Zákoucká H, Šmajs D, , 2012. Sequencing-based molecular typing of Treponema pallidum strains in the Czech Republic: all identified genotypes are related to the sequence of the SS14 strain. Acta Derm Venereol 92: 669674. [Google Scholar]
  45. Grillová L, Pětrošová H, Mikalová L, Strnadel R, Dastychová E, Kuklová I, Kojanová M, Kreidlová M, Vaňousová D, Hercogová J, Procházka P, Zákoucká H, Krchňáková A, Vašků V, Šmajs D, , 2014. Molecular typing of Treponema pallidum in the Czech Republic during 2011 to 2013: increased prevalence of identified genotypes and of isolates with macrolide resistance. J Clin Microbiol 52: 36933700. [Google Scholar]
  46. Read P, Jeoffreys N, Tagg K, Guy RJ, Gilbert GL, Donovan B, , 2014. Azithromycin resistant syphilis-causing strains in Sydney: prevalence and risk factors. J Clin Microbiol 52: 27762781. [Google Scholar]
  47. Morshed MG, Jones HD, , 2006. Treponema pallidum macrolide resistance in BC. CMAJ 174: 349. [Google Scholar]
  48. Martin IE, Tsang RSW, Sutherland K, Tilley P, Read R, Anderson B, Roy C, Singh AE, , 2009. Molecular characterization of syphilis in patients in Canada: azitromycin resistance and detection of Treponema pallidum DNA in whole-blood samples versus ulcerative swabs. J Clin Microbiol 47: 16681673. [Google Scholar]
  49. Martin IE, Tsang RSW, Sutherland K, Anderson B, Read R, Roy C, Yanow S, Fonseca K, White W, Kandola K, Kouadjo E, Singh AE, , 2010. Molecular typing of Treponema pallidum strains in western Canada: predominance of 14d subtypes. Sex Transm Dis 37: 544548. [Google Scholar]
  50. Martin IE, Gu W, Yang Y, Tsang RS, , 2009. Macrolide resistance and molecular types of Treponema pallidum causing primary syphilis in Shanghai, China. Clin Infect Dis 49: 515521. [Google Scholar]
  51. Chen XS, Yin YP, Wei WH, Wang HC, Peng RR, Zheng HP, Zhang JP, Zhu BY, Liu QZ, Huang SJ, , 2012. High prevalence of azithromycin resistance to Treponema pallidum in geographically different areas in China. Clin Microbiol Infect 19: 975979. [Google Scholar]
  52. Li Z, Hou J, Zheng R, Li Z, Wen J, Liu D, Liu R, Chu T, Liu B, Yu G, Tian H, Zhang F, , 2013. Two mutations associated with macrolide resistance in Treponema pallidum in Shandong, China. J Clin Microbiol 51: 42704271. [Google Scholar]
  53. Tipple C, McClure MO, Taylor GP, , 2011. High prevalence of macrolide resistant Treponema pallidum strains in a London centre. Sex Transm Infect 87: 486488. [Google Scholar]
  54. Lukehart SA, Godornes C, Molini BJ, Sonnett P, Hopkins S, Mulcahy F, Engelman J, Mitchell SJ, Rompalo AM, Marra CM, Klausner JD, , 2004. Macrolide resistance in Treponema pallidum in the United States and Ireland. N Engl J Med 351: 154158. [Google Scholar]
  55. Muldoon EG, Walsh A, Crowley B, Mulcahy F, , 2012. Treponema pallidum azithromycin resistance in Dublin, Ireland. Sex Transm Dis 39: 784786. [Google Scholar]
  56. Grimes M, Sahi SK, Godornes BC, Tantalo LC, Roberts N, Bostick D, Marra CM, Lukehart SA, , 2012. Two mutations associated with macrolide resistance in Treponema pallidum: increasing prevalence and correlation with molecular strain type in Seattle, Washington. Sex Transm Dis 39: 954958. [Google Scholar]
  57. Van Damme K, Behets F, Ravelomanana N, Godornes C, Khan M, Randrianasolo B, Rabenja NL, Lukehart S, Cohen M, Hook E, , 2009. Evaluation of azithromycin resistance in Treponema pallidum specimens from Madagascar. Sex Transm Dis 36: 775776. [Google Scholar]
  58. Tipple C, Taylor GP, , 2015. Syphilis testing, typing, and treatment follow-up: a new era for an old disease. Curr Opin Infect Dis 28: 5360. [Google Scholar]
  59. Müller EE, Paz-Bailey G, Lewis DA, , 2012. Macrolide resistance testing and molecular subtyping of Treponema pallidum strains from southern Africa. Sex Transm Infect 88: 470474. [Google Scholar]
  60. Wu H, Chang SY, Lee NY, Huang WC, Wu BR, Yang CJ, Liang SH, Lee CH, Ko WC, Lin HH, Chen YH, Liu WC, Su YC, Hsieh CY, Wu PY, Hung CC, , 2012. Evaluation of macrolide resistance and enhanced molecular typing of Treponema pallidum in patients with syphilis in Taiwan: a prospective multicenter study. J Clin Microbiol 50: 22992304. [Google Scholar]
  61. Wu BR, Yang CJ, Tsai MS, Lee KY, Lee NY, Huang WC, Wu H, Lee CH, Chen TC, Ko WC, Lin HH, Lu PL, Chen YH, Liu WC, Yang SP, Wu PY, Su YC, Hung CC, Chang SY, , 2014. Multicentre surveillance of prevalence of the 23S rRNA A2058G and A2059G point mutations and molecular subtypes of Treponema pallidum in Taiwan, 2009–2013. Clin Microbiol Infect 20: 802807. [Google Scholar]
  62. Katz KA, Pillay A, Ahrens K, Kohn RP, Hermanstyne K, Bernstein KT, Ballard RC, Klausner JD, , 2010. Molecular epidemiology of syphilis – San Francisco, 2004–2007. Sex Transm Dis 37: 660663. [Google Scholar]
  63. Marra CM, Colina AP, Godornes C, Tantalo LC, Puray M, Centurion-Lara A, Lukehart SA, , 2006. Antibiotic selection may contribute to increases in macrolide-resistant Treponema pallidum. J Infect Dis 194: 17711773. [Google Scholar]
  64. Su JR, Pillay A, Hook EW, Ghanem KG, Wong W, Jackson D, Smith LD, Pierce E, Philip SS, Wilson S, Golden MR, Workowski KA, Chi KH, Parrish DD, Chen CY, Weinstock HS, A2058G Prevalence Workgroup, , 2012. Prevalence of the 23S rRNA A2058G point mutation and molecular subtypes in Treponema pallidum in the United States, 2007 to 2009. Sex Transm Dis 39: 794798. [Google Scholar]
  65. Chen CY, Chi KH, Pillay A, Nachamkin E, Su JR, Ballard RC, , 2013. Detection of the A2058G and A2059G 23S rRNA gene point mutations associated with azithromycin resistance in Treponema pallidum by use of a TaqMan real-time multiplex PCR assay. J Clin Microbiol 51: 908913. [Google Scholar]
  66. Pei A, Nossa CW, Chokshi P, Blaser MJ, Yang L, Rosmarin DM, Pei Z, , 2009. Diversity of 23S rRNA genes within individual prokaryotic genomes. PLoS One 4: e5437. [Google Scholar]
  67. Harvey S, Hill CW, , 1990. Exchange of spacer regions between rRNA operons in Escherichia coli. Genetics 125: 683690. [Google Scholar]
  68. Marra C, Sahi S, Tantalo L, Godomes C, Reid T, Behets F, Rompalo A, Klausner JD, Yin Y, Mulcahy F, Golden MR, Centurion-Lara A, Lukehart SA, , 2010. Enhanced molecular typing of Treponema pallidum: geographical distribution of strain types and association with neurosyphilis. J Infect Dis 202: 13801388. [Google Scholar]
  69. Pillay A, Liu H, Chen CY, Holloway B, Sturm AW, Steiner B, Morse SA, , 1998. Molecular subtyping of Treponema pallidum subspecies pallidum. Sex Transm Dis 25: 408414. [Google Scholar]
  70. Riedner G, Rusizoka M, Todd J, Maboko L, Hoelscher M, Mmbando D, Samky E, Lyamuya E, Mabey D, Grosskurth H, Hayes R, , 2005. Single-dose azithromycin versus penicillin G benzathine for the treatment of early syphilis. N Engl J Med 353: 12361244. [Google Scholar]
  71. Kiddugavu MG, Kiwanuka N, Wawer MJ, Serwadda D, Sewankambo NK, Wabwire-Mangen F, Makumbi F, Li X, Reynolds SJ, Quinn TC, Gray RH, Rakai Study Group, , 2005. Effectiveness of syphilis treatment using azithromycin and/or benzathine penicillin in Rakai, Uganda. Sex Transm Dis 32: 16. [Google Scholar]
  72. Hook EW, 3rd Stephens J, Ennis DM, , 1999. Azithromycin compared with penicillin G benzathine for treatment of incubating syphilis. Ann Intern Med 131: 434437. [Google Scholar]
  73. Hook EW, 3rd Martin DH, Stephens J, Smith BS, Smith K, , 2002. A randomized, comparative pilot study of azithromycin versus benzathine penicillin G for treatment of early syphilis. Sex Transm Dis 29: 486490. [Google Scholar]
  74. Mitjà O, Hays R, Ipai A, Penias M, Paru R, Fagaho D, de Lazzari E, Bassat Q, , 2012. Single-dose azithromycin versus benzathine benzylpenicillin for treatment of yaws in children in Papua New Guinea: an open-label, non-inferiority, randomised trial. Lancet 379: 342347. [Google Scholar]
  75. Ghinai R, El-Duah P, Chi KH, Pillay A, Solomon AW, Bailey RL, Agana N, Mabey DC, Chen CY, Adu-Sarkodie Y, Marks M, , 2015. A cross-sectional study of ‘yaws’ in districts of Ghana which have previously undertaken azithromycin mass drug administration for trachoma control. PLoS Negl Trop Dis 9: e0003496. [Google Scholar]
  76. Weigel LM, Radolf JD, Norgard MV, , 1994. The 47-kDa major lipoprotein immunogen of Treponema pallidum is a penicillin-binding protein with carboxypeptidase activity. Proc Natl Acad Sci USA 91: 1161111615. [Google Scholar]
  77. Cha JY, Ishiwata A, Mobashery S, , 2004. A novel beta-lactamase activity from a penicillin-binding protein of Treponema pallidum and why syphilis is still treatable with penicillin. J Biol Chem 279: 1491714921. [Google Scholar]
  78. Hicks LA, Taylor TH, Jr Hunkler RJ, , 2013. More on U.S. outpatient antibiotic prescribing, 2010. N Engl J Med 369: 11751176. [Google Scholar]

Data & Media loading...

  • Received : 29 Apr 2015
  • Accepted : 05 Jun 2015
  • Published online : 07 Oct 2015

Most Cited This Month

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error