hrcak mascot   Srce   HID

Stručni rad
https://doi.org/10.15644/asc49/2/9

Uznapredovali generalizirani parodontitis kod pacijenta s aplastičnom anemijom: prikaz petogodišnjeg praćenja

Ivan Puhar ; Zavod za parodontologiju Stomatološkog fakulteta Sveučilišta u Zagrebu, Zagreb, Hrvatska
Darko Božić ; Zavod za parodontologiju Stomatološkog fakulteta Sveučilišta u Zagrebu, Zagreb, Hrvatsk
Domagoj Žabarović ; Zavod za mobilnu protetiku Stomatološkog fakulteta Sveučilišta u Zagrebu, Hrvatska
Damir Jelušić ; Dentalna poliklinika Dr Jelušić, Opatija, Hrvatska
Darije Plančak ; Zavod za parodontologiju Stomatološkog fakulteta Sveučilišta u Zagrebu, Zagreb, Hrvatsk

Puni tekst: hrvatski, pdf (367 KB) str. 151-157 preuzimanja: 213* citiraj
APA 6th Edition
Puhar, I., Božić, D., Žabarović, D., Jelušić, D. i Plančak, D. (2015). Uznapredovali generalizirani parodontitis kod pacijenta s aplastičnom anemijom: prikaz petogodišnjeg praćenja. Acta stomatologica Croatica, 49 (2), 151-157. https://doi.org/10.15644/asc49/2/9
MLA 8th Edition
Puhar, Ivan, et al. "Uznapredovali generalizirani parodontitis kod pacijenta s aplastičnom anemijom: prikaz petogodišnjeg praćenja." Acta stomatologica Croatica, vol. 49, br. 2, 2015, str. 151-157. https://doi.org/10.15644/asc49/2/9. Citirano 18.09.2021.
Chicago 17th Edition
Puhar, Ivan, Darko Božić, Domagoj Žabarović, Damir Jelušić i Darije Plančak. "Uznapredovali generalizirani parodontitis kod pacijenta s aplastičnom anemijom: prikaz petogodišnjeg praćenja." Acta stomatologica Croatica 49, br. 2 (2015): 151-157. https://doi.org/10.15644/asc49/2/9
Harvard
Puhar, I., et al. (2015). 'Uznapredovali generalizirani parodontitis kod pacijenta s aplastičnom anemijom: prikaz petogodišnjeg praćenja', Acta stomatologica Croatica, 49(2), str. 151-157. https://doi.org/10.15644/asc49/2/9
Vancouver
Puhar I, Božić D, Žabarović D, Jelušić D, Plančak D. Uznapredovali generalizirani parodontitis kod pacijenta s aplastičnom anemijom: prikaz petogodišnjeg praćenja. Acta stomatologica Croatica [Internet]. 2015 [pristupljeno 18.09.2021.];49(2):151-157. https://doi.org/10.15644/asc49/2/9
IEEE
I. Puhar, D. Božić, D. Žabarović, D. Jelušić i D. Plančak, "Uznapredovali generalizirani parodontitis kod pacijenta s aplastičnom anemijom: prikaz petogodišnjeg praćenja", Acta stomatologica Croatica, vol.49, br. 2, str. 151-157, 2015. [Online]. https://doi.org/10.15644/asc49/2/9
Puni tekst: engleski, pdf (367 KB) str. 151-157 preuzimanja: 534* citiraj
APA 6th Edition
Puhar, I., Božić, D., Žabarović, D., Jelušić, D. i Plančak, D. (2015). Severe Generalized Periodontitis in a Patient with an Aplastic Anemia: a 5 Year Follow-up Case Report. Acta stomatologica Croatica, 49 (2), 151-157. https://doi.org/10.15644/asc49/2/9
MLA 8th Edition
Puhar, Ivan, et al. "Severe Generalized Periodontitis in a Patient with an Aplastic Anemia: a 5 Year Follow-up Case Report." Acta stomatologica Croatica, vol. 49, br. 2, 2015, str. 151-157. https://doi.org/10.15644/asc49/2/9. Citirano 18.09.2021.
Chicago 17th Edition
Puhar, Ivan, Darko Božić, Domagoj Žabarović, Damir Jelušić i Darije Plančak. "Severe Generalized Periodontitis in a Patient with an Aplastic Anemia: a 5 Year Follow-up Case Report." Acta stomatologica Croatica 49, br. 2 (2015): 151-157. https://doi.org/10.15644/asc49/2/9
Harvard
Puhar, I., et al. (2015). 'Severe Generalized Periodontitis in a Patient with an Aplastic Anemia: a 5 Year Follow-up Case Report', Acta stomatologica Croatica, 49(2), str. 151-157. https://doi.org/10.15644/asc49/2/9
Vancouver
Puhar I, Božić D, Žabarović D, Jelušić D, Plančak D. Severe Generalized Periodontitis in a Patient with an Aplastic Anemia: a 5 Year Follow-up Case Report. Acta stomatologica Croatica [Internet]. 2015 [pristupljeno 18.09.2021.];49(2):151-157. https://doi.org/10.15644/asc49/2/9
IEEE
I. Puhar, D. Božić, D. Žabarović, D. Jelušić i D. Plančak, "Severe Generalized Periodontitis in a Patient with an Aplastic Anemia: a 5 Year Follow-up Case Report", Acta stomatologica Croatica, vol.49, br. 2, str. 151-157, 2015. [Online]. https://doi.org/10.15644/asc49/2/9

Rad u XML formatu

Sažetak
Aplastična anemija hematološka je bolest koju obilježava pancitopenija. U ovom prikazu slučaja opisana je mlada pacijentica s neliječenim parodontitisom povezanim s hematološkim bolestima i ciklosporinskom terapijom. Parodontna terapija provedena je u dva uzastopna dana, a sastojala se od nekirurške i antibiotske terapije uz dodatak antifibrinolitičke terapije. Obavljeni su mikrobiološki PCR testovi i testiranje parodontitis IL-1 polimorfizma. Nakon parodontne terapije upala se povukla te su izrađene mobilne parcijalne proteze. Nakon petogodišnjeg praćenja pacijentica je imala plitke dubine sondiranja unatoč izostanku suradnje tijekom faze održavanja. Aplastična anemija povećava rizik od pojave težih oblika parodontitisa koji dodatno mogu biti komplicirani ciklosporinskom terapijom. Parodontna terapija kod ovakvih pacijenata mora biti dopunjena antibioticima.

Ključne riječi
aplastična anemija; ciklosporin; hiperplazija gingive; parodontitis

Hrčak ID: 139978

URI
https://hrcak.srce.hr/139978

▼ Article Information



Introduction

Red blood-cell disorders have many different entities, but it seems that only few have an impact on periodontal tissues. Severe periodontal destruction has been reported in patients with aplastic anemia, sickle cell anemia, acatalasia and pernicious anemia (1). Aplastic anemia is a rare hematological disorder characterized by hypocellular bone marrow that produces insufficient number of hematopoietic stem cells, resulting in deficient cellular components such as erythrocytes, thrombocytes, and granulocytes (2). According to the definition of pancytopenia, the most severely affected patients present neutrophil counts of <200/μL, platelet counts of <20,000/μL, and reticulocyte counts of <60,000/μL (3). Because of this, a patient with aplastic anemia has a higher risk of infections. That is the reason why in patients with aplastic anemia the most common causes of death are bacterial sepsis and fungal infections (2). Brennan et al. evaluated the prevalence of oral manifestations in 79 patients with aplastic anemia. Intraoral patechiae were found in 27% of patients, spontaneous gingival bleeding and gingival hyperplasia were reported in 16% of the patients (4).

The aim of this case report is to present a 5-year follow-up of periodontal and prosthodontic treatment in a cyclosporine treated aplastic anemia patient.

Case report

A 26-year-old female patient was referred to the Department of Periodontology, School of Dental Medicine, Zagreb due to a painful and swelling gingiva. She had been in therapy for aplastic anemia (Anemia aplastica gravis) from the age of 16, and was hospitalized on several occasions because of the disease remissions. She gets regular check-ups in a hematological clinic, with an occasional supportive transfusion therapy. In an acute phase of anemia she was treated with corticosteroids. She had been taking 100mg of cyclosporine (Ciklosporin, Alkaloid, Skopje, Macedonia) per day, and 1 ampulla of filgrastim (recombinant methionyl human granulocyte colony-stimulating factor, Neupogen, Roche-Pharma AG, Switzerland) twice a week, for 10 years. However, she lacked a comprehensive dental and periodontal treatment for that period of time. Although her last hematological findings revealed a well regulated blood cells count (Table 1), periodontal treatment was planned to be performed with an antibiotic supportive therapy.

Table 1 Hematological status prior to periodontal treatment.
Parametar •
Parameter
Izmjerene vrijednosti •
Measured values
Normalan raspon •
Normal range
Eritrociti •
Erythrocytes
4.33
3.86 – 5.08 x1012/L
Hemoglobin •
Hemoglobin
141
119 - 157 g/L
MCV •
MCV
98
83.0 – 97.2 fL
Trombociti •
Thrombocytes
171
158 - 424 x109/L
Leukociti •
Leucocytes
3,93.4 – 9.7 x109/L

MCV=mean cell volume

During the oral and periodontal examination an exceptionally poor oral hygiene was found; there was a presence of supra- and subgingival calculus, and a hyperplastic gingiva, especially in the upper frontal teeth with spontaneous bleeding (Figure 1). Oral-medical findings were assessed as normal. Pocket probing depth on every tooth was greater than 4 mm, and up to 12 mm in the upper frontal teeth, which were considered the most critical and severely mobile teeth (Table 2). Radiological examination revealed circumscribed radiolucent lesions on several teeth, especially in the upper front (Figure 2). There were also a number of missing teeth (18, 15, 22, 25, 28, 38, 36, 35, 45, 46, 48), without any prosthodontic rehabilitation. The patient stated that the teeth spontaneously exfoliated during her hospitalization periods. On the basis of the periodontal and radiographic findings, a severe periodontitis associated with hematological disorders (aplastic anemia) was diagnosed (5). Cyclosporine therapy also contributed to the periodontal condition. The patient signed consent for the standard periodontal treatment.

Figure 1 Gingival appearance at the first visit - severe gingival hyperplasia.
ASC_49(2)_151-157-f1
Table 2 Periodontal status before and 5 years after periodontal treatment.
Početak •
Baseline
Nakon 5 godina •
After 5 years
Broj zubi •
N teeth
21
17
Krvarenje pri sondiranju (%) •
Bleeding on probing (%)
100
29.4
Indeks plaka (%) •
Plaque index (%)
100
24.6
Udio srednjih dubina sondiranja •
Mean probing depth percentage
<3 mm (%)
25.9
78.5
4-6 mm (%)
51.2
21.5
>7 mm (%)22.80
Figure 2 Panoramic radiograph at first visit - severe alveolar bone loss.
ASC_49(2)_151-157-f2

A commercially available polymerase chain reaction (PCR) test (MicroDent test, Hain Lifescience, Nehren, Germany) was utilized for the detection of five periodontal pathogens: Aggregatibacter actinomycetemcomitans, Prevotella intermedia, Porphyromonas gingivalis, Tannerella forsythia, and Treponema denticola (Table 3). To ascertain if there was a genetic predisposition for periodontitis, a interleukin-1 (IL-1) polymorphism risk test (GenoType PST, Hain Lifescience, Nehren, Germany) for IL1A-889 and IL1B+3953 was also done.

Table 3 PCR analysis of subgingival samples.
Bakterije •
Bacteria
Početak •
Baseline
Nakon 5 godina •
After 5 years
Aggregatibacter actinomycetemcomitans
Neg
Pos (+)
Prevotella intermedia
Pos (+)
Neg
Porphyromonas gingivalis
Pos (++)
Pos (+)
Tannerella forsythia
Pos (++)
Pos (+++)
Treponema denticolaPos (+)Pos (++)

(< 103=neg, 103-104= +, 104-105=++, 105-106=+++)

Severely mobile teeth with deep pockets (12, 11, 21, 23, 24) were assessed as having a poor prognosis, and were extracted the day prior to initial periodontal treatment. According to the concept of full-mouth periodontal therapy, a non-surgical treatment was performed in 2 consecutive days, and was supplemented with an antibiotic therapy (amoxicillin 500 mg (Amoxicilin, Pliva, Zagreb, Croatia) and metronidazole 400 mg (Medazol, Belupo, Koprivnica, Croatia), 3 times a day, for 8 days, and antifibrinolytic therapy (tranexamic acid 500 mg (Cyklokapron, Pfizer, Zagreb, Croatia) 4 times a day, for 5 days. The antifibrinolytic and antibiotic therapy started 2 days prior to extractions and non-surgical therapy. In addition, the patient was given instructions to rinse twice daily with a 0.2% chlorhexidine solution (Corsodyl® mouthrinse, GlaxoSmithKline Consumer Healthcare, Zagreb, Croatia) for 1 minute, until the next control appointment. Following the 3 month re-evaluation (Figure 3), prosthodontic rehabilitation was done with removable partial dentures in both the upper (12-25) and lower jaw (36, 45-46). Although the patient was young, due to her poor financial situation, this type of prosthodontic appliance was primarily fabricated and the fixed prosthodontic appliances or implant borne fixed partial dentures had to be dismissed. Because of the advanced periodontal disease and continuous cyclosporine therapy, the patient was placed on a periodontal supportive program every 2 months but she was not very compliant.

Figure 3 Gingival appearance after extractions and periodontal treatment, prior to prosthodontic rehabilitation.
ASC_49(2)_151-157-f3

Following non-surgical periodontal treatment supplemented with antibiotics and antifibrinolytic regimen, the periodontal conditions greatly improved and were successfully maintained over a period of five years (Table 2). Although the patient was not entirely compliant, she maintained shallow pocket probing depths and radiographically there was no evidence of further bone loss (Figure 4). By evaluating the panoramic radiograph, it could be noted that there was bone gain in the furcation area of tooth 37, and on the mesial and distal aspects of tooth 34. The patient maintained acceptable oral hygiene and was satisfied with the prosthetic solution (Figure 5). There was a concern that the removable partial dentures were going to induce further deterioration of periodontal conditions on abutment teeth, but there was no further loss of periodontal attachment on these teeth exhibited by shallow pocket probing depths.

Figure 4 Panoramic radiograph 5 years after periodontal treatment. Note stable bone levels and resolution of the mesial and distal bony defects on tooth 34, and the furcation defect on tooth 37.
ASC_49(2)_151-157-f4
Figure 5 Gingival appearance and prosthodontic appliance 5 years after periodontal treatment.
ASC_49(2)_151-157-f5

Repeated microbiological PCR test after 5 years still revealed the presence of putative periodontal pathogens: Aggregatibacter actinomycetemcomitans, Porphyromonas gingivalis, Tannerella forsythia, and Treponema denticola (Table 3) in high counts, in spite of the antibiotic regimen putting the patient at risk of further periodontal attachment loss. The periodontitis IL-1 polymorphism risk test showed negative results because of only one positive allele for IL1A-889 and IL1B+3953, respectively (Table 4).

Table 4 Results of the GenoType PST test.
Il-1 A-889
Alel 1 •
Allele 1
IL-1 A-889
Alel 2 •
Allele 2
IL-1 B+3953
Alel 1 •
Allele 1
IL-1 B+3953
Alel 2 •
Allele 2
PosNegPosNeg

Discussion

Over the past decades, a growing body of evidence documented a relationship between periodontal infection and systemic diseases (6). Anemia represents a condition with decreased concentration of oxygen-transporting system in a certain volume of blood. It has been suggested that lower concentration of oxygen available to the tissues could be a modifying factor in the periodontal immune response (7). Cyclosporine is the first choice in the treatment of acquired aplastic anemia in patients which do not need transfusion. Data showed that treatment with cyclosporine leads to the sustained disease remission in 40% of patients with aplastic anemia (8). However, cyclosporine is also the drug that can be associated with hyperplastic gingival overgrowth, which is also reported for phenytoin and calcium channel blockers. These alterations usually start on the labial papillae, and over time adjacent hyperplastic papillae tend to "merge", as recorded in this case. Gingival overgrowth is always limited to the zone of attached gingiva (9). Aimetti et al. evaluated the clinical efficacy of periodontal therapy in patients with transplanted kidneys, liver or heart, who took cyclosporine A and had severe gingival hyperplasia. They found that non-surgical periodontal treatment leads to significant reductions of all clinical parameters, including a degree of gingival overgrowth (10). Similarly to the mentioned study, in our case the causal periodontal treatment was successful in resolving the inflammation, thus eliminating the need for surgical intervention. Kantarci et al. found that almost 60% of patients with gingival hyperplasia induced by cyclosporine have a fibrotic component, but they also managed to avoid the need for surgical procedures in 47% of the patients (11). Several authors published papers describing the response of patients with aplastic anemia to periodontal therapy. Oyaizu et al. described periodontal therapy in severe aplastic anemia, and stressed the importance of appropriate antibiotic prophylaxis and precautions for potential bleeding. It is important to emphasize that the risk of systemic infection is significantly increased in patients with aplastic anemia (12, 13). In our case, subgingival instrumentation was supplemented with amoxicillin and metronidazole. Also, periodontal therapy was performed only after the approval of the hematologist, who suggested the administration of tranexamic acid for 5 days. At the 5 year follow-up, the microbiological status was still unsatisfactory, which can be attributed to inadequate patient compliance during the maintenance phase. Still, periodontal conditions remained stable with no further loss of periodontal support and shallow pocket probing depths.

Considering the periodontal diagnosis and in order to determine the possible hereditary component, the patient was referred to IL-1 gene polymorphism testing, since the IL-1 genotype positive non-smokers have a 19 times higher risk of alveolar bone loss (14). However, findings of genotype PST test were negative.

With the widespread use of dental implants the chosen prosthodontic treatment could be seen as somewhat out of date, and it is a well-known fact that patients with removable dentures tend to have further loss of periodontal support on abutment teeth (15). Although we realized that implant borne restorations in such a patient would be more interesting, the incidence of peri-implantitis in patients with periodontal disease is very high (16), and the repeated microbiological testing in our patient revealed a recurrence of a high count of periodontal pathogens. Bearing in mind that there is a high number of implants harboring periodontal pathogens and Staphylococcus aureus (17), this could pose an even greater threat of infection in patients with aplastic anemia.

Conclusion

On the basis of oral findings, it can be concluded that aplastic anemia is a disease with an increased risk of onset of severe forms of periodontitis, which can be additionally complicated by cyclosporine therapy. In such patients, periodontal therapy must start as soon as possible with mandatory antibiotic supplement. Apart from the regular recall appointments, a close collaboration between the periodontist and the hematologist is necessary. This case report shows that even in patients with such a severe systemic disease, over a period of 5 years, periodontitis can be well controlled without further periodontal support deterioration.

Acknowledgements

This paper was supported by the Ministry of Science, Education and Sports of the Republic of Croatia, Grant No. 065-0650444-0415 (chief investigator Darije Plančak, project “Systemic aspects in the etiology of periodontal diseases”).

Notes

[1] Conflicts of interest The authors deny any conflicts of interest.

References

1 

Salvi GE, Lawrence HP, Offenbacher S, Beck JD. Influence of risk factors on the pathogenesis of periodontitis. Periodontol 2000. 1997 Jun;14:173–201. DOI: http://dx.doi.org/10.1111/j.1600-0757.1997.tb00197.x PubMed: http://www.ncbi.nlm.nih.gov/pubmed/9567971

2 

Young NS. Acquired aplastic anemia. JAMA. 1999 Jul 21;282(3):271–8. DOI: http://dx.doi.org/10.1001/jama.282.3.271 PubMed: http://www.ncbi.nlm.nih.gov/pubmed/10422997

3 

Young NS, Maciejewski J. The pathophysiology of acquired aplastic anemia. N Engl J Med. 1997 May 8;336(19):1365–72. DOI: http://dx.doi.org/10.1056/NEJM199705083361906 PubMed: http://www.ncbi.nlm.nih.gov/pubmed/9134878

4 

Brennan MT, Sankar V, Baccaglini L, Pillemer SR, Kingman A, Nunez O, et al. Oral manifestations in patients with aplastic anemia. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2001 Nov;92(5):503–8. DOI: http://dx.doi.org/10.1067/moe.2001.116506 PubMed: http://www.ncbi.nlm.nih.gov/pubmed/11709685

5 

Armitage GC. Development of a classification system for periodontal disease and conditions. Ann Periodontol. 1999 Dec;4(1):1–6. DOI: http://dx.doi.org/10.1902/annals.1999.4.1.1 PubMed: http://www.ncbi.nlm.nih.gov/pubmed/10863370

6 

Puhar I, Lovrenčić-Huzjan A, Šodec-Šimičević D, Strineka M, Božić D, Plančak D. Carotid Intima-Media Thickness in Patients with Chronic and Aggressive Periodontitis. Acta Stomatol Croat. 2012;46(4):255–62. [NIJE U PUBMEDU]

7 

Lainson PA, Brady PP, Fraleigh CM. Anemia, a systemic cause of periodontal disease? J Periodontol. 1968 Jan;39(1):35–8. DOI: http://dx.doi.org/10.1902/jop.1968.39.1.35 PubMed: http://www.ncbi.nlm.nih.gov/pubmed/5244507

8 

Yamazaki H, Sugimori C, Chuhjo T, Nakao S. Cyclosporine therapy for acquired aplastic anemia: predictive factors for the response and long-term prognosis. Int J Hematol. 2007 Apr;85(3):186–90. DOI: http://dx.doi.org/10.1532/IJH97.06156 PubMed: http://www.ncbi.nlm.nih.gov/pubmed/17483052

9 

Seymour RA, Jacobs DJ. Cyclosporin and the gingival tissues. J Clin Periodontol. 1992 Jan;19(1):1–11. DOI: http://dx.doi.org/10.1111/j.1600-051X.1992.tb01140.x PubMed: http://www.ncbi.nlm.nih.gov/pubmed/1732303

10 

Aimetti M, Romano F, Debernardi C. Effectiveness of periodontal therapy on the severity of cyclosporin A-induced gingival overgrowth. J Clin Periodontol. 2005 Aug;32(8):846–50. DOI: http://dx.doi.org/10.1111/j.1600-051X.2005.00774.x PubMed: http://www.ncbi.nlm.nih.gov/pubmed/15998267

11 

Kantarci A, Cebeci I, Tuncer O, Carin M, Firatli E. Clinical effects of periodontal therapy on the severity of cyclosporin A-induced gingival hyperplasia. J Periodontol. 1999 Jun;70(6):587–93. DOI: http://dx.doi.org/10.1902/jop.1999.70.6.587 PubMed: http://www.ncbi.nlm.nih.gov/pubmed/10397513

12 

Oyaizu K, Mineshiba F, Mineshiba J, Takaya H, Nishimura F, Tanimoto I, et al. Periodontal treatment in severe aplastic anemia. J Periodontol. 2005 Jul;76(7):1211–6. DOI: http://dx.doi.org/10.1902/jop.2005.76.7.1211 PubMed: http://www.ncbi.nlm.nih.gov/pubmed/16018767

13 

Patel MD, Shakir QJ, Shetty A. Interrelationship between chronic periodontitis and anemia: A 6-month follow-up study. J Indian Soc Periodontol. 2014;18(1):19–25. DOI: http://dx.doi.org/10.4103/0972-124X.128194 PubMed: http://www.ncbi.nlm.nih.gov/pubmed/24744539

14 

Kornman KS, Crane A, Wang HY, di Giovine FS, Newman MG, Pirk FW, et al. The interleukin-1 genotype as a severity factor in adult periodontal disease. J Clin Periodontol. 1997 Jan;24(1):72–7. DOI: http://dx.doi.org/10.1111/j.1600-051X.1997.tb01187.x PubMed: http://www.ncbi.nlm.nih.gov/pubmed/9049801

15 

Zlataric DK, Celebic A, Valentic-Peruzovic M. The effect of removable partial dentures on periodontal health of abutment and non-abutment teeth. J Periodontol. 2002 Feb;73(2):137–44. DOI: http://dx.doi.org/10.1902/jop.2002.73.2.137 PubMed: http://www.ncbi.nlm.nih.gov/pubmed/11895277

16 

Zitzmann NU, Berglundh T. Definition and prevalence of peri-implant diseases. J Clin Periodontol. 2008 Sep;35(8) Suppl:286–91. DOI: http://dx.doi.org/10.1111/j.1600-051X.2008.01274.x PubMed: http://www.ncbi.nlm.nih.gov/pubmed/18724856

17 

Salvi GE, Fürst MM, Lang NP, Persson GR. One-year bacterial colonization patterns of Staphylococcus aureus and other bacteria at implants and adjacent teeth. Clin Oral Implants Res. 2008 Mar;19(3):242–8. DOI: http://dx.doi.org/10.1111/j.1600-0501.2007.01470.x PubMed: http://www.ncbi.nlm.nih.gov/pubmed/18177429


This display is generated from NISO JATS XML with jats-html.xsl. The XSLT engine is libxslt.

[engleski]

Posjeta: 1.163 *