• Users Online: 142
  • Home
  • Print this page
  • Email this page
Home About us Editorial board Ahead of print Current issue Search Archives Submit article Instructions Subscribe Contacts Login 


 
 Table of Contents  
REVIEW ARTICLE
Year : 2019  |  Volume : 4  |  Issue : 1  |  Page : 13-16

Surgical Treatment for perianal Crohn's disease


Department of Coloproctology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of T.C.M., Shanghai, China

Date of Submission28-Dec-2018
Date of Acceptance20-Mar-2019
Date of Web Publication8-May-2019

Correspondence Address:
Dr. Zhen-Yi Wang
Department of Coloproctology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of T.C.M, NO. 110 Ganhe Road, Shanghai 200437
China
Login to access the Email id

Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ts.ts_19_18

Rights and Permissions
  Abstract 


Crohn's disease (CD) is an inflammatory disease that occurs in unexplained gastrointestinal mucosa. Anal fistula is a common complication of CD. Anal fistula accounts for 15% of patients with ileocolonic CD, and 92% of CD patients with colon and rectum involvement have anal fistula. Although perianal CD is an anorectal benign disease, it significantly affects the patients' quality of life. Medical and surgical management are two major treatment approaches for Crohn's anal fistula. Drug treatment includes antibiotics, immunological agents, and biological agents. Nearly 30% of patients with CD anal fistula can be cured by standard medical treatment, and 70% need surgical intervention. The purpose of the current surgical treatment is to alleviate local symptoms and protect the anal sphincter function. The surgical treatment of Crohn's anal fistula depends largely on the type of anal fistula, the relationship with the sphincter, and whether it is in the remission of CD.

Keywords: Anal fistula, Crohn's disease, surgery


How to cite this article:
Gan D, Jin W, Li Y, Han CP, Wang ZY. Surgical Treatment for perianal Crohn's disease. Transl Surg 2019;4:13-6

How to cite this URL:
Gan D, Jin W, Li Y, Han CP, Wang ZY. Surgical Treatment for perianal Crohn's disease. Transl Surg [serial online] 2019 [cited 2019 Nov 15];4:13-6. Available from: http://www.translsurg.com/text.asp?2019/4/1/13/257801




  Introduction Top


Crohn's disease (CD) is an inflammatory disease that may affect any part of the gastrointestinal mucosa. Anal fistula is one of the complications of CD, with an incidence rate of about 5%–40%, associated with severe diarrhea and inflammation of the colon and rectum.[1],[2],[3],[4] Anal fistula accounts for 12%–14% of patients with ileocolonic CD and 92% of colonic CD with rectal involvement.[4],[5],[6] The frequency of perianal fistulas in CD was reported as 12% at 1 year, 15% at 5 years, 21% at 10 years, and 26% at 20 years.[4] Although perianal CD (PCD) is an anorectal benign disease, it significantly affects the patients' quality of life. Medical and surgical management are two major treatment approaches for Crohn's anal fistula. Medical management includes the use of antibiotics and immunological and biological agents. In nearly 30% of patients with CD, anal fistula can be cured by standard medical treatment, while 70% need surgical intervention.[7] Challenges involved, however, are early age of onset, use of multiple antibiotics, poor prognosis, and repeated surgical procedures.[8] The purpose of the current surgical treatment is to alleviate local symptoms and to protect the anal sphincter function while[9] choosing appropriate timing for surgery.[10] The surgical management of Crohn's anal fistula depends mainly on the type of anal fistula, the relationship with the sphincter, and whether it is in the remission phase of CD.


  Fistulotomy Top


Fistulotomy is a safe surgical method for symptomatic, superficial, low-intersphincteric, and low-transsphincteric anal fistula.[11] It does not cause anal incontinence and heal faster with low recurrence rate.[12],[13] However, fistulotomy can have prolonged healing time and increased chance of anal incontinence in high-transsphincteric, upper sphincteric, and external sphincteric anal fistula.


  Mucosal Advancement Flap Top


Mucosal advancement flap (MAF) is a surgical method to close the internal orifice of a fistula where the valve of the rectal mucosa covers the primary opening of the fistula. Closing the fistula distal to the high-pressure zone does not affect the sphincter complex; however, the outer fistula is expected to dry out over time. In a systematic review that included 35 studies with an average follow-up of 28.9 months, the success rate of MAFs for CD anal fistula was 64%, and the rate of anal incontinence was 9.4% with reintervention in 50% of patients.[14] MAF is the most commonly used surgical method with a success rate of 50%–80% and the outcome depends on the blood supply to the rectal mucosal flap, tension-free suture, and absence of acute inflammation and abscess.[15]


  Biologic Patch Top


Biologic patch, made up of collagen or more often from the submucosal tissue of the small intestine, is inserted into the fistula tract through the internal orifice of the fistula without altering the sphincter structure. A retrospective cohort study and an open-label study showed a success rate of 24%–88% (median follow-up of 6–15 months), while another study reported 22% of failures due to the displacement of the patch. However, the closure rate of fistulas was excellent (87%) when treated with sutured biopsy. In a similar study on the efficacy of fibrin glue (FG) in PCD patients, 71% of patients were relieved of symptoms and 7% had decreased perianal discharge after 3 months of injection of FG.[16],[17] Hence, preventing patch displacement and use of preoperative antibiotics may increase the success rate of biologic patch, making it the first line of surgical treatment. However, the major issue is related to its cost.[14]


  Ligation of Intersphincteric Fistula Tract Top


Ligation of intersphincteric fistula tract (LIFT) technique was first proposed by a Thai scholar Rojanasakul in 2007,[18] which can be used when the sphincter fistula has formed a granulation tissue fibrosis conduit for ligation and transection. In this method, closure of the internal orifice is achieved through the intersphincter plane with removal of the infected tissue. A single-center study, with small sample size (forty cases), reported success rate of 94%, while another recent study showed moderate efficacy (a cure rate of 56% after 1 year) and relapse cases within 2 months after surgery.[14] Gingold et al.[19],[20] reported healing rate of 67% at 12 months with no reports of incontinence; a similar study by Kamiński et al.[21] reported healing rate of 75% at <12-month follow-up and 33% with more than 1-year follow-up. LIFT technique is suitable for intersphincteric and transsphincteric fistula without inflammation and infection of cavity gap; in contrast, it is difficult for anal fistula above the sphincter and outside the sphincter. Meanwhile, a large prospective study with outcome of the treatment of CD has not been published.


  Fiber Glue Top


FG consists of fibrinogen and thrombin; it can promote wound healing by inducing angiogenesis and fibroblast growth. In many studies due to differences in the source of fistulas and the heterogeneity of follow-up, the success rate of closure of fistulas is quite different, with healing rate ranging between 30% and 80%.[3],[4],[22] A meta-analysis showed that the recurrence rate and defecation incontinence rate of FG are similar to those of the traditional surgical treatment,[14] and FG is safe in the treatment of anal incontinence. Meanwhile, it is believed that[23] it is necessary to loosen the cord and drain before FG tamponade along with thoroughly clearing the dead tissue from the fistula.


  Stem Cell Therapy Top


Stem cell therapy was widely used as a treatment modality for inflammatory bowel disease in the last decade. In 2005, the first case of stem cell transplantation for anal fistula CD was reported.[24] Stem cell therapy is based on the ability of stem cells derived from mesenchymal tissue to have high plasticity and to regulate immune cells. Hematopoietic and mesenchymal stem cells, whether allogeneic or autologous, are safe and feasible to inject autologous adipose stem cells or bone marrow stem cells into the fistula.[25],[26] Earlier studies[14] have shown that stem cells combined with FG can close the fistulas in 56%–82% of patients, and their 1- and 3-year sustained remission rates were 53% and 30%, respectively. Even though stem cell therapy seems to be promising, it needs long-term, randomized, placebo-controlled clinical trials on CD anal fistula.


  Anal Fistula Plug Top


Anal fistula surgery has got the advantages of causing less trauma, ensuring quicker recovery, shorter duration of treatment, and no impairment of anal function and appearance, with a reported success rate of 24%–88%.[27] Johnson et al.[28] reported for the first time the efficacy of anal fistula embolization for the treatment of anal fistula in 2006. In a study conducted by Cintron et al.,[29] 73 cases of anal fistulas including 8 cases of CD excluding rectovaginal fistula showed total surgical success rate of 38% and for CD 50%. Less number of cases and short follow-up time are certain limitations in the studies. The failing reason for anal plug is usually associated with plug extrusion,[30],[31] and further studies are needed to confirm the conclusion.


  Video-Assisted Anal Fistula Treatment Top


Meinero and Mori[32] developed a new technique of video-assisted anal fistula treatment (VAAFT) and conducted a study which showed 74% of first-stage healing rate, with no complications within 6 months after the operation, and demonstrated a recovery rate of 87%. It was observed that the accuracy of finding the inner mouth during the treatment of anal fistula with VAAFT was 83%.[33],[34] VAAFT is a minimally invasive surgery performed under direct visualization, and it can identify the location of internal mouth, branch fistula, and the abscess cavity. Schwandner[34] conducted a feasibility and preliminary study of VAAFT combined with mucosal flap truss in the treatment of patients with complicated anal fistula with CD, which demonstrated a higher possibility of identifying hidden branch fistulas and a satisfactory short-term cure rate in the treatment of CD-related fistula. As of now, VAAFT surgery is still in its infancy with requirement of relatively expensive equipment.


  Filac™ Top


FiLaC™ was first proposed and used by Wilhelm A in Germany. In 2014, Giamundo et al.[35] conducted a study on 35 cases of anal fistula who received FiLaC™ surgery; the results/observations of the study include a median operation time of 20 min (range: 6–35 min) and a median follow-up time of 20 months (range: 3–36 months), with healing achieved in 25 patients (71.4%), eight patients failed to heal (23%), and two recurrences were observed at 3 and 6 months after surgery with nil anal incontinence postoperatively. Oztürk and Gülcü[36] conducted a similar study on fifty patients, consisting of 37 males and 13 females, with a median age of 41 years (range: 23–83 years). The study population included ten cases of sphincter anal fistula and six cases of high transsphincteric anal fistula and was conducted using a 15-W probe, emitting 1470-nm wavelength laser, generating 100–120 J/cm of energy, under general anesthesia. Short-term outcome indicators such as the success rate of surgery, complications, pain scores, and the time to resume daily activities were evaluated. Meanwhile, patients without any complaints was considered as the criterion for successful treatment. The results showed 82% success rate with no requirement of parenteral analgesics, and a median of 7 days (5–17) was required to return to daily activities. The median follow-up time was 12 months (range: 2–18 months), and laser treatment failed in nine cases, and hence they were switched over to traditional surgical treatment later. To conclude, laser fistula ablation is a safe and effective method for preserving the anal sphincter, and can be operated by the surgeon. FiLaC™ does not injure the internal or external anal sphincter, and it does not affect the anal function. It applies to all types of anal fistula with 71%–89% of healing rate,[37] and the main advantage observed is the sphincter remains intact, causing less tissue damage, and at the same time, leaving a small postoperative wound. It does not affect future surgeries once the recurrence occurs. With the advancement of minimally invasive technique and the deep understanding of perianal tissue anatomy, FiLaC™ will greatly improve the cure rate of anal fistula and improve the quality of life of patients. Patients can keep it as an option because multicentric FiLaC™ clinical studies of anal fistula still need long-term follow-up data.


  Fecal Diversion Top


The method of preserving function is considered for complicated and refractory perianal diseases. A retrospective study[14] showed that early remission rate was high (81%), while only 26%–50% of patients could receive sustained remission. Many patients who undergo the procedure eventually require rectal resection, whereas in few patients, the continuity of the small intestine can be restored. Statistical analysis showed that CD colostomy surgery accounts for 19% of the total CD surgery, and other large sample studies showed similar results. The probability of colostomy surgeries after 20 years with CD would be 40%.[38],[39],[40],[41] A systematic review of the long-term efficacy of fecal diversion in patients with PCD revealed that 63.8% of patients had early clinical response, and an attempt was made to restore intestinal continuity in 34.5%, but it was successful only in 16.6%, and 41.6% needed complete rectal resection.[42]


  Conclusions Top


There is no gold-standard treatment currently for perianal fistulas, but there is value in a therapeutic relationship between gastroenterologists, endoscopists, and colorectal surgeons.[43] Multidisciplinary approach is the best treatment choice for anal fistula in CD.[44].[45],[46] The combination of multiple examination techniques, such as magnetic resonance imaging, can often improve the accuracy of diagnosis.[47] The risk score system may be a useful clinical tool for clinicians to evaluate the prognosis and amend the treatment of CD.[5] Currently, combined surgical treatment of CD anal fistula with biologic agents such as infliximab and alemtuzumab may improve the efficacy and alleviate the clinical symptoms of patients. The management of PCD remains a clinical challenge, and the combination of medical and surgical management does offer hope for many, but still lacks high-quality randomized controlled trials, and hence further research on the pathogenesis of CD anal fistula is needed. Thus, interdisciplinary co-operation is needed to make a breakthrough progress in the management of PCD.

Financial support and sponsorship

This study was financially supported by the National Natural Science Foundation of China (youth), No. 81403399; the National Natural Science Foundation of China (youth), No. 81603633; Shanghai Science and Technology Commission Scientific Research Project, No. 16401971400; and Shanghai Municipal Commission of Health and Family Planning Project, No. zyjx-2017008.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Safar B, Sands D. Perianal Crohn's disease. Clin Colon Rectal Surg 2007;20 (4):282-93.  Back to cited text no. 1
    
2.
Kotze PG, Shen B, Lightner A, Yamamoto T, Spinelli A, Ghosh S, Panaccione R. Modern management of perianal fistulas in Crohn's disease: Future directions. Gut 2018;67 (6):1181-94.  Back to cited text no. 2
    
3.
Sica GS, Di Carlo S, Tema G. Treatment of peri-anal fistula in Crohn's disease. World J Gastroenterol 2014;20 (37):13205-10.  Back to cited text no. 3
    
4.
Schwartz DA, Loftus EV Jr., Tremaine WJ. The natural history of fistulizing Crohn's disease in Olmsted county, Minnesota. Gastroenterology 2002;122 (4):875-80.  Back to cited text no. 4
    
5.
Pallotta N, Vincoli G, Pezzotti P. A risk score system to timely manage treatment in Crohn's disease: A cohort study. BMC Gastroenterol 2018;18 (1):164.  Back to cited text no. 5
    
6.
Yamamoto T, Kotze PG, Spinelli A, Panaccione R. Fistula-associated anal carcinoma in Crohn's disease. Expert Rev Gastroenterol Hepatol 2018;12 (9):917-25.  Back to cited text no. 6
    
7.
Peng JS, Zhou ZY, Gao X. Imaging diagnosis technique and perioperative management for complex anal fistula in patients with Crohn's disease. Chin J Pract Surg 2013;33 (7):563-5.  Back to cited text no. 7
    
8.
Mak WY, Mak OS, Lee CK. Significant medical and surgical morbidity in perianal Crohn's disease: Results from a territory-wide study. J Crohns Colitis 2018;12 (12):1392-8.  Back to cited text no. 8
    
9.
Vogel JD, Johnson EK, Morris AM. Clinical practice guideline for the management of anorectal abscess, fistula-in-ano, and rectovaginal fistula. Dis Colon Rectum 2016;59 (12):1117-33.  Back to cited text no. 9
    
10.
Koganei K, Tatsumi K, Futatsuki R. Surgical treatment for Crohn's disease. Nihon Rinsho 2017;75 (3):426-32.  Back to cited text no. 10
    
11.
Yun-Fei GU. Surgical management of perianal Crohn's disease. Chin J Pract Surg 2013;33:560-3.  Back to cited text no. 11
    
12.
Marzo M, Felice C, Pugliese D. Management of perianal fistulas in Crohn's disease: An up-to-date review. World J Gastroenterol 2015;21 (5):1394-403.  Back to cited text no. 12
    
13.
Sandborn WJ, Fazio VW, Feagan BG, Hanauer SB; American Gastroentero logical Association Clinical Practice Committee. AGA technical review on perianal Crohn's disease. Gastroenterology 2003;125 (5):1508-30.  Back to cited text no. 13
    
14.
You-Ran L, Yun-Fei GU, Lian L. World gastroenterology organization Crohn's disease anal fistula expert consensus. Chin J Gastrointest Surg 2015;18 (7):726-9.  Back to cited text no. 14
    
15.
Mizrahi N, Wexner SD, Zmora O. Endorectal advancement flap: Are there predictors of failure? Dis Colon Rectum 2002;45 (12):1616-21.  Back to cited text no. 15
    
16.
Vitton V, Gasmi M, Barthet M, Desjeux A, Orsoni P, Grimaud JC. Long-term healing of Crohn's anal fistulas with fibrin glue injection. Aliment Pharmacol Ther 2005;21 (12):1453-7.  Back to cited text no. 16
    
17.
Adegbola SO, Pisani A, Sahnan K, Tozer P, Ellul P, Warusavitarne J. Medical and surgical management of perianal Crohn's disease. Ann Gastroenterol 2018;31 (2):129-39.  Back to cited text no. 17
    
18.
Rojanasakul A, Pattanaarun J, Sahakitrungruang C, Tantiphlachiva K. Total Anal sphincter saving technique for fistula-in-ano: The ligation of intersphincteric fistula tract. J Med Assoc Thai 2007;90 (3):581-6.  Back to cited text no. 18
    
19.
Pellino G, Selvaggi F. Surgical treatment of perianal fistulizing Crohn's disease: From lay-open to cell-based therapy – An over complex anal fistula in patients with Crohn's disease. ScientificWorldJournal 2014;2014:146281.  Back to cited text no. 19
    
20.
Gingold DS, Murrell ZA, Fleshner PR. A prospective evaluation of the ligation of the intersphincteric tract procedure for complex anal fistula in patients with Crohn's disease. Ann Surg 2014;260 (6):1057-61.  Back to cited text no. 20
    
21.
Kamiński JP, Zaghiyan K, Fleshner P. Increasing experience of LIFT procedure for patients with Crohn's disease: What have we learned? Colorectal Dis 2017;19:750-5.  Back to cited text no. 21
    
22.
Kotze PG, Shen B, Lightner A. Modern management of perianal fistulas in Crohn's disease: Future directions. Gut 2018;67 (6):1181-94.  Back to cited text no. 22
    
23.
Senejoux A. Traiter une fistula anal parallel biologique: How to treat anal fistula with fibrin glue? Colon Rectum 2010;4 (1):57-9.  Back to cited text no. 23
    
24.
Garcia-Olmo D, Garcia-Arranz M, Herreros D. A phase I clinical trail of the treatment of Crohn's fistula by adipose mesenchymal stem cell transplantation. Dis Colon Rectum 2005;48 (7):141623.  Back to cited text no. 24
    
25.
Turse EP, Dailey FE, Naseer M. Stem cells for luminal, fistulizing, and perianal inflammatory bowel disease: A comprehensive updated review of the literature. Stem Cells Cloning 2018;11:95-113.  Back to cited text no. 25
    
26.
Gold SL, Cohen-Mekelburg S, Schneider Y. Perianal fistulas in patients with Crohn's disease, Part 1: Current medical management. Gastroenterol Hepatol 2018;14 (8):470-81.  Back to cited text no. 26
    
27.
Limura E, Giordano P. Modern management of anal fistula. World J Gastroenterol 2015;21 (1):12-20.  Back to cited text no. 27
    
28.
Johnson EK, Gaw JU, Armstrong DN. Efficacy of anal fistula plug vs. fibrin glue in closure of anorectal fistulas. Dis Colon Rectum 2006;49 (3):371-6.  Back to cited text no. 28
    
29.
Cintron JR, Abcarian H, Chaudhry V. Treatment of fistula-in-ano using a porcine small intestinal submucosa anal fistula plug. Tech Coloproctol 2013;17 (2):187-91.  Back to cited text no. 29
    
30.
O'Riordan JM, Datta I, Johnston C, Baxter NN. A systematic review of the anal fistula plug for patients with Crohn's and non-Crohn's related fistula-in-ano. Dis Colon Rectum 2012;55 (3):351-8.  Back to cited text no. 30
    
31.
Al-Maawali AK, Nguyen P, Phang PT. Modern treatments and stem cell therapies for perianal Crohn's fistulas. Can J Gastroenterol Hepatol 2016;2016:1651570.  Back to cited text no. 31
    
32.
Meinero P, Mori L. Video-assisted anal fistula treatment (VAAFT): A novel sphincter-saving procedure for treating complex anal fistulas. Tech Coloproctol 2011;15 (4):417-22.  Back to cited text no. 32
    
33.
Grolich T, Skricka T, Robek O, Kala Z, Hemmelová B, Hrivnák R. Role of video-assisted anal fistula treatment in our management of fistula-in-ano. Acta Chir Iugosl 2014;61 (2):83-5.  Back to cited text no. 33
    
34.
Schwandner O. Video-assisted anal fistula treatment (VAAFT) combined with advancement flap repair in Crohn's disease. Tech Coloproctol 2013;17 (2):221-5.  Back to cited text no. 34
    
35.
Giamundo P, Geraci M, Tibaldi L. Closure of fistula-in-ano with laser–FiLaC™: An effective novel sphincter-saving procedure for complex disease. Colorectal Dis 2014;16 (2):110-5.  Back to cited text no. 35
    
36.
Oztürk E, Gülcü B. Laser ablation of fistula tract: A sphincter-preserving method for treating fistula-in-ano. Dis Colon Rectum 2014;57 (3):360-4.  Back to cited text no. 36
    
37.
Wilhelm A. A new technique for sphincter-preserving anal fistula repair using a novel radial emitting laser probe. Tech Coloproctol 2011;15 (4):445.  Back to cited text no. 37
    
38.
Geltzeiler CB, Hart KD, Lu KC. Trends in the surgical management of Crohn's disease. J Gastro Surg 2015;19 (10):1862-8.  Back to cited text no. 38
    
39.
Post S, Herfarth CH, Schumacher H. Experience with ileostomy and colostomy in Crohn's disease. Br J Surg 1995;82 (12):1629-33.  Back to cited text no. 39
    
40.
Peyrin-Biroulet L, Oussalah A, Williet N. Impact of azathioprine and tumour necrosis factor antagonists on the need for surgery in newly diagnosed Crohn's disease. Gut 2011;60 (7):930-6.  Back to cited text no. 40
    
41.
Fumery M, Seksik P, Auzolle C. Postoperative complications after ileocecal resection in Crohn's disease: A prospective study from the REMIND group. J Gastroenterol 2017;112 (2):337-45.  Back to cited text no. 41
    
42.
Singh S, Ding NS, Mathis KL. Systematic review with meta-analysis: Fecal diversion for management of perianal Crohn's disease. Aliment Pharmacol Ther 2015;42 (7):783-92.  Back to cited text no. 42
    
43.
Gold SL, Cohen-Mekelburg S. Perianal fistulas in patients with Crohn's disease, part 2: Surgical, endoscopic, and future therapies. Gastroenterol Hepatol 2018;14 (9):521-8.  Back to cited text no. 43
    
44.
Zhan-Ju LI. Prevention and therapy of postoperative occurrence in Crohn's disease. Chin J Digestion 2010;30 (8):505-6.  Back to cited text no. 44
    
45.
Sebastian S, Black C, Pugliese D. The role of multimodal treatment in Crohn's disease patients with perianal fistula: A multicentre retrospective cohort study. Aliment Pharmacol Ther 2018;48 (9):941-50.  Back to cited text no. 45
    
46.
Atasoy D, Aghayeva A, Aytaç E, Erenler L, Celik AF, Baca B, Karahasanoglu T, Hamzaoglu L. Surgery for intestinal Crohn's disease: Results of a multidisciplinary approach. Turk J Surg 2018;34 (3):225-8.  Back to cited text no. 46
    
47.
Ilias A, Lovasz BD, Gonczi L, Kurti Z, Vegh Z, Sumegi LD, Golovics PA, Rudas G, Lakatos PL. Optimizing patient management in Crohn's disease in a tertiary referral center: The impact of fast-track MRI on patient management and outcomes. J Gastrointestin Liver Dis 2018;27 (4):391-7.  Back to cited text no. 47
    




 

Top
 
 
  Search
 
Similar in PUBMED
   Search Pubmed for
   Search in Google Scholar for
 Related articles
Access Statistics
Email Alert *
Add to My List *
* Registration required (free)

 
  In this article
Abstract
Introduction
Fistulotomy
Mucosal Advancem...
Biologic Patch
Ligation of Inte...
Fiber Glue
Stem Cell Therapy
Anal Fistula Plug
Video-Assisted A...
Filac™
Fecal Diversion
Conclusions
References

 Article Access Statistics
    Viewed956    
    Printed97    
    Emailed0    
    PDF Downloaded115    
    Comments [Add]    

Recommend this journal


[TAG2]
[TAG3]
[TAG4]