Saudi Journal of Gastroenterology
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ORIGINAL ARTICLE Table of Contents   
Year : 2006  |  Volume : 12  |  Issue : 1  |  Page : 16-20
Importance of Helicobacter pylori eradcation for maintenance of remission of drug associated peptic ulcer disease


PO Box 6328, Sharjah, United Arab Emirates

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Date of Submission13-Mar-2005
Date of Acceptance13-Oct-2005
 

   Abstract 

Background: The role of Helicobacter pylori (H. pylori) eradication in non-steroidal anti inflammatory drug (NSAID) users with peptic ulcer disease is controversial especially in countries with a high prevalence of the infection. Furthermore the value of low dose omeprazole for maintenance of remission is not yet known. Patients and methods: 138 symptomatic out-patients receiving continuous COX 1 NSAID therapy, were treated with omeprazole 40mg/day upon endoscopic confirmation of gastro-duodenal ulceration or erosions while those infected with H. pylori received in addition clarithromycin 500 mg and amoxycillin 1000 mg twice daily during the first week of treatment. After endoscopic confirmation of healing at the end of week 5, the patients were randomized to receive omeprazole 10 mg (n=50) or 20 mg once daily (n=66) and endoscopy repeated after 20 weeks. Results: The overall healing rate (per protocol) at five weeks (116/128) was 90.6% while in 85.5% (65/76) eradication was successful. The healing rate for the H. pylori eradicated patients (58/65) was 89.2%. For those who failed eradication (8/11) it was 72.7% (NS), while for patients not infected with H. pylori at entry to the study (50/52) it was 96.2% (NS). An intention to treat analysis showed that after 20 weeks of omeprazole prophylaxis with the 10mg dose 86% (43/50) had maintained healing while for the 20mg dose a similar figure was observed (87.9; 58/66). Only three patients in the two groups (pp) had persistent H. pylori infection, all of whom relapsed. No patients discontinued treatment because of adverse effects of the drugs. Conclusion: H. pylori eradication was not associated with impaired ulcer healing in a Middle Eastern population with symptomatic NSAID induced gastro/duodenal lesions, when a high healing dose of omeprazole (40 mg) was used. After eradication, omeprazole 10 or 20 mg per day were highly and equally effective for maintenance of gastroduodenal mucosal integrity during continued NSAID use. H. pylori should be eradicated from symptomatic Middle Eastern NSAID users with peptic ulcer disease.

Keywords: NSAID, Peptic Ulcer, H. pylori, Omeprazole

How to cite this article:
Dajani A, Dham R, El-Sahhar M, Subeih S, El Sheikh S, Mansour A, El-Ebeidi G, Mohammed S, El Horaibi M, Al Gawli A, Al-Anzi A, Gautham S, Ahmed O, Hammour A, Nounou M, Al-Mardini H. Importance of Helicobacter pylori eradcation for maintenance of remission of drug associated peptic ulcer disease. Saudi J Gastroenterol 2006;12:16-20

How to cite this URL:
Dajani A, Dham R, El-Sahhar M, Subeih S, El Sheikh S, Mansour A, El-Ebeidi G, Mohammed S, El Horaibi M, Al Gawli A, Al-Anzi A, Gautham S, Ahmed O, Hammour A, Nounou M, Al-Mardini H. Importance of Helicobacter pylori eradcation for maintenance of remission of drug associated peptic ulcer disease. Saudi J Gastroenterol [serial online] 2006 [cited 2019 Nov 20];12:16-20. Available from: http://www.saudijgastro.com/text.asp?2006/12/1/16/27739


Inspite of their gastrointestinal side effects, non-steroidal anti-inflammatory drugs (NSAIDs) are the most widely prescribed drugs for arthritic and musculoskeletal disorders world wide [1]. Elderly patients with a history of gastrointestinal events and those who receive concomitant steroids have an increased relative risk of further events [2]. The prevalence of NSAID induced gastroduodenal damage is greatest in the first three months of exposure [3]. Symptoms are poor predictors of serious lesions and complications [3] and the risk of bleeding in the non aspirin NSAID users is increased (odds ratio 4.5; 3.1-5.6) [4]. Until recently, the best practice was to shift NSAIDs users with gastric complications into COX2 inhibitors [5]. This is no more the case with the withdrawal of rofecoxib and valdecoxib and the doubt cast on the other COX2 inhibitors. Alternative measures available include minimizing accompanying risks factors [3] or addition of prophylactic medications. For the short-term prevention of NSAID induced duodenal ulcer, H2 receptor antagonists are ineffective but for long-term management there may be some benefit [6]. Several studies now confirm the efficacy of proton pump inhibitors for the prevention of NSAID-induced upper gastrointestinal injury [7],[8]. The recent ASTRONAUT study [9], documented the greater prophylactic efficacy of omeprazole over ranitidine at standard dosages for 6 months, while the OMNIUM study showed omeprazole to be slightly more effective overall than misoprostol with better tolerability [10].

H. pylori infection and NSAIDs are the two most important causal factors in gastroduodenal ulcer disease. The contribution of concomitant H. pylori infection to NSAID ulcer pathogenesis is controversial [3]. Some authors believe that H. pylori infection appears to have little effect on gastroduodenal mucosal injury associated with long-term NSAID administration [11] while others have observed a negative, although insignificant, interaction and concluded that H. pylori infection increases the risk of peptic ulcer bleeding but may play a protective role in NSAID users [12]. This beneficial effect could be related to the stimulation of endogenous gastric prostaglandins by H. pylori [13]. Conversely meta-analysis has shown a 3.5 fold increased risk of peptic ulcer in NSAID users who are also H. pylori positive [14] while in NSAID users 16% of bleeding peptic ulcers can be attributed to concurrent H. pylori infection [15].

Previous studies (9, 10) have used the standard 20 mg dose of omeprazole for maintenance of remission but the efficacy of 10 mg is not as yet known.

We therefore conducted an open label, multi-center, endoscopically controlled comparative study aimed at evaluating the efficacy of omeprazole 10 or 20 mg in maintaining healing of NSAID induced gastric and duodenal ulcers or erosions during continued NSAID use after H. pylori eradication.


   Patients and methods Top


Out-patients who were on continuous therapy with COX 1 NSAIDs for variable reasons were recruited to the study when they were shown to have a gastro-duodenal mucosal break (5 mm upon endoscopy undertaken) because of gastrointestinal symptoms. Patients who were found to be infected with H. pylori at initial recruitment were first treated for one week with omeprazole (Risek) 20 mg, amoxycillin (Julphamox) 1000 mg and clarithromycin (Klacid) 500 mg twice daily to eradicate the bacteria. Uninfected subjects were given omeprazole (Risek) 20 mg, twice daily for the same period (Phase 1). Both groups then entered phase II where healing of the detected lesions was induced by omeprazole (Risek) 40 mg taken once daily in a single dosage in the morning for a period of four weeks. Only those who proved to have their lesion healed at a second endoscopy at week 5 were enrolled into phase III of the study when they were randomly allocated to take omeprazole (Risek)10 mg or 20 mg once daily in the morning for a further 20 weeks. Endoscopy was repeated at the termination of the trial. During this phase patients were reviewed on three occasions at 6-8 week intervals. The primary end points were: for phases I and ll, strict compliance with the protocol, CLO test done at the end of week 5 and an endoscopically proven complete re-epithelization of the gastric and duodenal mucosa at the end of week 5, while for phase III, it was an endoscopically confirmed absence of mucosal lesions at the end of week 25. Compliance with the study medication was assured by the issue of new medication at each visit and tablet counting. H. pylori colonization of the gastric mucosa was verified by the rapid CLO urease test (CLO-test, Delta West Ltd., Bently, Western Australia) at week 5. Healing and eradication rates were determined in the patients who completed the efficacy analysis per protocol.

A safety analysis (Intention-To-Treat) has been included for the maintenance of remissions (phase III). The study was carried out in accordance with Good Clinical Practice and the Declaration of Helsinki. All patients participating gave informed consent. The protocol was approved by the Ethics Committee of the Ministry of Health, UAE.


   Statistical Analysis Top


Data entry and analysis were carried out using the statistical software package SPSS. Data analysis was performed using the non-parametric Pearson Chi-Square test or Fisher's Exact test. We estimated from previous studies that if prophylaxis was 80% successful, to show a clinically important difference of 30% in relapse rates between the two treatments with a power of 80%, 45 patients in each group would be required.


   Resuls Top


Fourteen secondary care medical centers in five Middle Eastern countries participated in the study. In Phase I, 138 consecutive patients were initially recruited to the study between November 1999 and June 2000. Eight dropped out, two because they were on rofecoxib, three were lost to follow up, two due to stopping their NSAID treatment and one developed an elevation of liver enzymes due to Hepatitis C virus infection. Thus, the number of per protocol patients at end of Phase I was 130. In Phase II, 116 subjects had successful healing of their gastroduodenal lesions (2 dropped out, 12 failed healing) and were enrolled into Phase III irrespective of the success of H. pylori eradication [Figure 1].

Demographic Characteristics

The patient population (138) was a predominantly Arab cohort with 26% (36) from the gulf area, 17% (23) from Yemen, 37% (51) from North African countries (Egypt and Sudan), 11% (16) from other Middle Eastern countries while 9% (12) belonged to a miscellaneous group mainly from the Indian subcontinent. Males and females were almost equal in numbers, with a mean age of 50.6 years (12), height of 164 (9) cm and weight of 74 kg (14).

Thirty one patients were smokers (23%) and 8 (6%) were regular non-excessive consumers of alcohol. None of the study population were using narcotic drugs, tranquilizers or any psychotropic agents. The details of the groups entering phase III are shown in [Table - 1][Table - 2], which shows that the two groups were well matched for personal details, medical history, and the NSAID used.

Clinical diagnosis

Long term NSAID therapy was required for the following arthritic conditions: osteoarthritis (60 patients; 43%); rheumatoid arthritis (48 patients; 35%) and spinal problems; prolapsed intervertebral disc, chronic back pain, vertebral injury and ankylosing spondylitis (25 patients; 18%). Five patients (4%) had a collagenosis as the sole reason for prolonged NSAID use. Fifty-one (37%) of the 138 patients had other diseases necessitating treatment including diabetes mellitus, hypertension and IHD.

Patients presented with ulcer like dyspepsia, dismotility like dyspepsia or symptomatic reflux. Overlapping symptoms included epigastric pain as the most prevalent (127; 92%) and was reported to last for a mean period of 1.5 years followed by flatulence and bloating (69; 50%) for a mean period of 1.3 years and symptomatic reflux (44; 32%) for a mean period of 0.6 years. Other less common gastrointestinal symptoms included constipation, nausea and vomiting, abdominal colic and diarrhoea. Previous history of haematemesis was reported by two patients and of melaena by another two.

Diagnostic tests

Gastroduodenal mucosal injuries in patients admitted to the study were gastric ulcers and/or erosions and duodenal ulcers and/or erosions. Endoscopic findings are summarized in [Table - 3]. A CLO test was done with the first and second endoscopy. H. pylori was detected in 80 patients of the ITT population (58%). Eradication of H. pylori was concluded from a negative CLO test at the second endoscopy done after 4 weeks of stopping the antibiotics treatment to avoid detecting a false suppression of the bacteria. Baseline laboratory tests indicated normal findings for all tested parameters including full blood count and biochemical analysis of renal and hepatic function.

Response to treatment

1. Adverse effects

Adverse events were reported in 28 patients (22%) during phase I. All were mild and none necessitated stopping the treatment or withdrawal from the study. Twenty-four of these patients were CLO positive and received antibiotic treatment for eradication. Four patients of the uninfected group reported minor side effects.

Seventeen patients reported adverse events in phase II but none necessitated discontinuation of treatment.

2. Healing of gastroduodenal lesions

One hundred and sixteen patients had complete healing of their lesions [Table - 4]. The healing rate for the patients completing the trial per protocol (116/128) was 90.6% while the eradication rate of H. pylori infected patients (65/76) was 85.5% regardless of their endoscopic diagnosis being duodenal ulcers, gastric ulcers, or duodenal and gastric erosions. The healing rate for H. pylori infected patients (58/65) was 89.2% when the bacterium was successfully eradicated and 72.7% when eradication failed (8/11). Although this difference was not statistically significant (p=0.153), only a small number of patients failed H. pylori eradication and thus a type II error cannot be excluded. For the patients who were not infected with H. pylori at entry to the study, the healing rate was 96.2% (50/52). When compared with eradicated patients, this difference was not statistically significant (p=0.163).

Maintenance of remission (Phase III; Weeks 6-25) [Table5]: One hundred and sixteen subjects who had complete re-epithelization of their lesions at the end of phase II were available but only 107 completed phase III, three of whom had persisting H. pylori infection. Adverse events were very rare. None were related to the study medicine (omeprazole) but were more related to the NSAID or an intervening illness. They did not necessitate stopping the medicine or withdrawal from the study. For the omeprazole 10 mg group (n=50) maintenance of endoscopic healing was found in 43 of 47 patients completing the protocol (91.5%). Four patients showed a relapse with one developing a recurrent duodenal ulcer and three gastric erosions. Three patients were lost to follow up. For the omeprazole 20 mg group patients (n=66), endoscopic healing was maintained in 58 of the 60 patients completing the protocol (96.7%).

Two patients showed relapse with re-appearance of gastric erosions. Six patients were lost to follow up. No statistically significant difference was observed between the 10 and 20 mg dosage groups using the per protocol or intention to treat analysis [Table - 5]. Smoking, alcohol or type of NSAID taken did not have any significant effect upon the results.

In the present trial of symptomatic patients, because of the high incidence of H. pylori in the study population and associated peptic ulcer disease, it was not felt justifiable to withhold H. pylori eradication. In asymptomatic patients screened for peptic ulcer or more than ten erosions, there is a slightly lower overall incidence of healing with omeprazole in H. pylori negative patients compared to those who are H. pylori positive [9],[10], possibly because of increased efficacy of acid suppression in H. pylori infected patients when given omeprazole [16]. This difference was significant only for gastric ulcer patients [17],[18].

In order to overcome this problem and achieve a high healing rate we therefore chose double the standard dose of omeprazole i.e., 40 mg during not only the first week for H. pylori eradication but the whole five-week healing phase.

Using this study design, a healing rate of 90.6% was achieved while the H. pylori eradication rate (85.5%) was slightly lower than expected in western populations with clarithromycin/omeprazole based regimes (19). In the present study in symptomatic Middle Eastern NSAID users the healing rate for H. pylori eradicated patients was 89.2% while, for those who had failed eradication and remained positive it was 72.7%. This result does not justify withholding H. pylori eradication as has been suggested for asymptomatic western populations.

In the maintenance phase omeprazole 10 mg once daily and 20 mg once daily were found to be of similar efficacy. Most of the patients who were included in phase III were either cured from H. pylori in the healing phase or were not infected from the beginning and in only three patients (pp) was the infection persisting, all of whom relapsed. Thus, unlike other studies, 97% of the population completing the maintenance phase (104/107) were H. pylori negative. The low relapse rate in the present study was consistent with the primary prophylaxis trials of Chan et al [20],[21] who found a lower de novo incidence of peptic ulcer in patients treated with naproxen or diclofenac that had previously received H. pylori eradication compared to those not eradicated. In the HELP study [18] H. pylori positive patients on NSAID were randomized double-blind to eradication or no eradication and ulcer free patients or those with only mild dyspepsia continuing NSAIDs were followed up with endoscopies at 1, 3 and 6 months. Unlike the present study, only 26-32% of recruited patients had an ulcer at entry although the remainder gave a history of previous ulcers in the past five years or severe dyspepsia. In the absence of prophylactic acid suppressive therapy, just over 50% of patients remained ulcer free at the end of the study in both the H. pylori eradicated and control groups. The high relapse rates observed indicate the need for additional measures to prevent ulcer relapse in both H. pylori positive and negative patients.

In the present study using H. pylori eradication and prophylactic omeprazole, the intention to treat remission rate with the 20 mg dose was 87.9% (per protocol 96.7%). The figure is higher than seen in previous studies in asymptomatic patients using 20 mg of omeprazole where 61% [10] or 72% (9) of the study population maintained healing compared to 27% given placebo [10]. In these studies, H. pylori eradication was not undertaken and 42% and 53% of patients respectively were positive during the maintenance phase.

The benefit of omeprazole prophylaxis over other therapies in asymptomatic screened patients was especially evident in those who were H. pylori positive [22]. In such patients the NSAID may be having a greater effect upon the gastroduodenal mucosa than in symptomatic patients where the effect of H. pylori may be considerably greater. We therefore suggest that the favorable results in symptomatic patients observed in the present study during the maintenance phase is due to the low level of H. pylori infection (3%) in our study population. Indeed, in a recent meta-analysis it was shown that in case control studies NSAID takers with H. pylori infection were 61 times more likely to have a peptic ulcer than non-infected non-takers and that either factor alone increased the risk twenty-fold [14],[23].

It is therefore concluded from this work that after H. pylori eradication, 10 or 20 mg per day of omeprazole are highly efficacious and equally effective in preventing recurrence of NSAID induced gastroduodenal injury during a 20 week follow up period. We believe that H. pylori eradication is an

important aspect of the treatment of NSAID induced ulcers, especially for patients whose ulcers are complicated by bleeding [24].

 
   References Top

1.Fries JF, Miller SR, Spitz PW, Williams CA, Herbert HB, Block DA. Toward an pidemiology of gastropathy associated with non-steroidal anti-inflammatory drug use. Gastroenterology 1989;96:647-655.  Back to cited text no. 1    
2.Gabreil SE, Jaakimainen L, Bombardier C. Risk of serious gastrointestinal complications related to use of non-steroidal anti-inflammatory drugs. A meta-analysis. Ann Int Med 1991; 115:787-796.  Back to cited text no. 2    
3.Lanes A and Hirschowitz BI. Toxicity of NSAIDs in stomach and duodenum. E J Gastroenterol Hepatol 1999; 11: 325-381.  Back to cited text no. 3    
4.Langman MJS, Weil J, Wainwright P, Lawson DH, Rawlins MO, Logan RF. Risks of bleeding peptic ulcer associated with individual non-steroidal anti-inflammatory drugs. Lancet 1994; 343: 1075-1079.  Back to cited text no. 4    
5.Wallace JL; Reuter BK; McKnight W; Bak A. Selective inhibitors of cyclooxygenase-2: are they really effective, selective, and GI safe? J Clin Gastroenterol 1998; 27: S28-S34.  Back to cited text no. 5    
6.Koch M; Dezi A; Ferrario F; Capurso I. Prevention of nonsteroidal anti-inflammatory drug-induced gastrointestinal mucosal injury. A meta-analysis of randomized controlled clinical trials. Arch Intern Med 1996; 156: 2321-32.  Back to cited text no. 6    
7.Brown GJ; Yeomans ND. Prevention of the gastrointestinal adverse effects of nonsteroidal anti-inflammatory drugs: the role of proton pump inhibitors. Drug Saf 1999; 6: 503-512.  Back to cited text no. 7    
8.Ekstrom P, Carling L, Wetterhus S, Wingren PE, Anker-Hansen O, Lundegardh G et al. Prevention of peptic ulcer with Omeprazole in patients receiving continuous Non-steroidal anti-inflammatory drug therapy. A Nordic multicenter study. Scand J Gastroenterol 1996; 31: 753-758.  Back to cited text no. 8    
9.Yeomans ND, Tulassay Z, Juhasz L, Racz I, Howard JM, Van Rensburg CJ et al. A comparison of Omeprazole with Ranitidine for ulcers associated with Non-steroidal anti- inflammatory drugs. N Engl J Med 1998;338:719-726.  Back to cited text no. 9    
10.Hawkey C, Karrasch JA, Szczepanski L, Walker DG, Barkun A, Swallell AJ et al. Omeprazole compared with Misoprostil for ulcers associated with Nonsteroidal anti-inflammatory drugs. N Engl J Med 1998; 338: 727-734.  Back to cited text no. 10    
11.Mizokami Y, Tamura K, Fukuda Y, Yamamoto I, Shimoyama T. Non-steroidal anti-inflammatory drugs associated with gastroduodenal injury and Helicobacter pylori. E J Gastroenterol Hepatol 1994; 6: S109-S112.  Back to cited text no. 11  [PUBMED]  
12.Wu CY; Poon SK; Chen GH; Chang CS; Yeh HZ .Interaction between Helicobacter pylori and non-steroidal anti-inflammatory drugs in peptic ulcer bleeding. Scand J Gastroenterol 1999: 34: 234-237.  Back to cited text no. 12    
13.Chan FKL, Sung JJY. How does Helicobacter pylori infection interact with non-steroidal anti-inflammatory changes. Clin Gastroenterol 2000; 14: 161-172.  Back to cited text no. 13    
14.Huang JQ, Sridhar S, Hunt R. Role of H. pylori infection and non-steroidal anti-inflammatory drug in peptic ulcer disease: A meta-analysis. Lancet 2002; 359: 14-22.  Back to cited text no. 14    
15.Aalykke C, Lauritsen JM, Hallas J, Reinholdt S, Krogfelt K, Lauritsen K. Helicobacter pylori and risk of ulcer bleeding among users of non-steroidal anti-inflammatory drugs: a case-control study. Gastroenterology 1999; 116: 1305-1309.  Back to cited text no. 15  [PUBMED]  [FULLTEXT]
16.Gillen D, Wirz AA, Neithercut WD, Ardill JES, McColl KEL. Helicobacter pylori infection potentiates the inhibition of gastric acid secretion by Omeprazole. Gut 1999; 44: 468-475.  Back to cited text no. 16    
17.Hawkey CJ, Wilson I, Naesdal J, Langstrom G, Swannell AJ, Yeomans ND. Influence of sex and Helicobacter pylori on development and healing of gastroduodenal lesions in non-steroidal anti-inflammatory drug users. Gut 2002; 51: 344-350.  Back to cited text no. 17  [PUBMED]  [FULLTEXT]
18.Hawkey CJ, Tulassay Z, Szczepanski L, Van Rensburg CJ, Filipowics-Sosnowska A, Lanas A et al. Randomized controlled trial of Helicobacter pylori eradication in patients on non-steroidal anti-inflammatory drugs: HELP NSAIDs study. Lancet 1998; 352: 1016-1021.  Back to cited text no. 18    
19.Lind T, Megraud F, Unge P, Bayerdorffer E, O'Morain C, Spiller R et al. The MACH2 Study: Role of Omeprazole in eradication of Helicobacter pylori with 1-week triple therapies. Gastroenterology 1999; 116: 248-253.  Back to cited text no. 19    
20.Chan FKL, Sung JJY, Chung SCS, To KF, Yung MY, Leung Vet al. Randomized trial of eradication of Helicobacter pylori before non-steroidal anti-inflammatory drug therapy to prevent peptic ulcers. Lancet 1997; 350: 975-979.  Back to cited text no. 20    
21.Chan FKL, To KF, Wu JCY, Yung MY, Leung WK, Kovok T et al. Does eradication of helicobacter pylori before non-steroidal anti-inflammatory drug therapy reduce the long-term risk of ulcers? A double-blinded randomized trial. Lancet 2002; 359: 9-13.  Back to cited text no. 21    
22.Hawkey CJ, Naesdal J, Wilson I, Langstrom G, Swannell AJ, Peacock RA et al. Relative contribution of mucosal injury and Helicobacter pylori in the development of gastroduodenal lesions in patients taking non-steroidal anti-inflammatory drugs. Gut 2002; 51: 336-343.  Back to cited text no. 22    
23.Pounder RE. Helicobacter pylori and NSAIDs - the end of the debate. Lancet 2002; 359: 3-4.  Back to cited text no. 23  [PUBMED]  [FULLTEXT]
24.Chan FKL, Chung SCS, Suen BY, Lee YT, Leung WK, Leung VKS et al. Preventing recurrent upper gastrointestinal bleeding in patients with helicobacter pylori infection who are taking low-dose Aspirin or Naproxen. N Engl J Med 2001; 344: 967-973.  Back to cited text no. 24    

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Correspondence Address:
A Dajani
PO Box 6328, Sharjah
United Arab Emirates
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/1319-3767.27739

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    Tables

[Table - 1], [Table - 2], [Table - 3], [Table - 4], [Table - 5]



 

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