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Ana Sayfa : Recent BD News : Review of published papers : Nonclinical - Scientific : Listed during October 2006 – March 2007

Listed during October 2006 – March 2007

REVIEW OF PUBLISHED PAPERS: NONCLINICAL SCIENTIFIC
Lısted during: October 2006 – March 2007
Prepared by: G. Wallace (UK) E-mail: g.r.wallace@bham.ac.uk

1-3 - Reviews
 
4-14 - Genetics
 
15-25 – Immunology
 
26-32 – Thrombophilia
 
33-34 - Letters
 

Reviews
 

1: An update on Behcet's disease
 . 
Kalayciyan A, Zouboulis C.
 J Eur Acad Dermatol Venereol. 2007 Jan;21(1):1-10. 
Behcet's disease (Adamantiades-Behcet's disease, ABD) is a multisystemic inflammatory disease, the pathogenesis of which is still a mystery. Many questions are still to be answered and the available diverse data need to be brought together to be compared and analysed. There is at least consensus on the effect of possible, but currently unknown, environmental triggering factor(s) against a background of genetic susceptibility. The possible aetiological factors form a broad spectrum, with infectious agents being the most probable ones. Whatever the stimulus is, the target tissue seems to be the small blood vessels, with various consequences of either vasculitis and/or thrombosis in many organ systems. The endothelium seems to be the primary target in this disease; however, it may just be the subject of the bizarre behaviour of the immune system. The diverse existing data could be interpreted in favour of either explanation. A similar confusion exists about the thrombotic tendency in Adamantiades-Behcet's disease, in terms of whether a primary hypercoagulability is present or whether it is secondary to inflammation. Recent interesting immunological data promise a way out of the existing dilemma. These findings will be outlined within the context of possible hypotheses and attention will be paid to further investigations that are needed. 

2. Immunopathogenesis of Behcet's disease with special emphasize on the possible
 role of antigen presenting cells.
Pay S, Simsek I, Erdem H, Dinc A.
 Rheumatol Int. 2006 Dec 14; [Epub ahead of print] 
Behcet's disease (BD) is a systemic vasculitis with unclear etiology and pathogenesis. Although several viral and bacterial causes have been investigated in detail for several years, of late it is widely accepted that microorganisms may play a role as a trigger, or as a cross-reactive antigens that interfere with self-antigens, such as heat-shock proteins. Genes such as HLA-B51, MICA and TNF, considered to play a crucial role in the pathogenesis of BD, are located in the major histocompatibility complex (MHC). However, it has been accepted that, only HLA-B51 is directly related with pathogenesis of the disease, and others have strong linkage disequilibrium with HLA-B51. Some other genes such as IL1, Factor V and ICAM-1, KIR and eNOS assumed to take a part in the pathogenesis are settled out of the MHC region. In patients with BD, several abnormalities in innate and acquired immunity were detected. Mainly, the hypersensitivity of T lymphocytes to different types of antigens plays a critical role in the pathogenesis. However, it is not clear that whether defective signal transduction or antigen presenting cell (APC) dysfunction is responsible for T cell hypersensitivity. Cytokines and chemokines secreted from APCs and T cells are suggested to cause the neutrophil hyperactivation. Activated neutrophils secrete some cytokines, which prime themselves and also stimulate Th1 cells. These relationships among APCs, Th1 lymphocytes and neutrophils constitute the basis of immune responses in BD. In this review, we focus on the possible role of APC in the pathogenesis of BD with an attempt to take attention of researchers in this field to these cells at the crossroads of innate and adaptive immunity, and discuss other potential contributors including cells of the immune system and mediators.

3: Behcet's disease: general concepts and recent advances.
 
Okada AA.
 
Curr Opin Ophthalmol. 2006 Dec;17(6):551-6. 
PURPOSE OF REVIEW: To summarize general concepts of Behcet's disease, as well as present recent scientific developments in delineating the pathogenesis and treatment of this disorder. RECENT FINDINGS: Large, long-term follow-up studies on patients with Behcet's disease have shown improved visual outcomes in recent years when compared with decades ago, presumably due to the more aggressive use of immunosuppressive agents. Increased T-helper cell type 1 activity and increased hypercoagulability continue to be a focus of research into the pathogenesis of the disease. Advanced oxidation protein products and a Behcet's disease activity index may be useful tools for following disease activity. Finally, studies of new treatment modalities, particularly infliximab, interferon-alpha and granulocytapheresis, have reported encouraging results. SUMMARY: Historically a scourge among uveitic disorders, there is new hope for improved long-term visual outcomes in patients with Behcet's disease based on recent scientific advances. 

Genetics 
4: Tumor Necrosis Factor Gene Polymorphisms in Tunisian Patients With Behcet's
 Disease. 
Kamoun M, Chelbi H, Houman MH, Lacheb J, Hamzaoui K. 
Hum Immunol. 2007 Mar;68(3):201-5. Epub 2007 Jan 5. 
Behcet's disease (BD) is an inflammatory disorder that is mainly characterized by recurrent oral and genital ulcers, skin lesions, and uveitis. Recent reports focused on the genetic factors of susceptibility to this disease and especially the TNF in view of the major role played by this proinflammatory cytokine in the lesional process of Behcet's disease. In this report, we investigated the possible association between Behcet's disease and the TNF-alpha gene promoter polymorphisms -1031T/C, -308A/G, and the TNF-beta polymorphism +252A/G in Tunisian population. We compared the distribution of these polymorphisms between 89 BD patients and 157 healthy controls using polymerase chain reaction restriction fragment length-polymorphism (PCR-RFLP) analysis. The frequency of the TNF-alpha -1031C allele was significantly higher in Behcet's patients than in healthy controls (p = 0.015; chi(2) = 5.84; OR = 1.65; 95% CI = 1.08-2.54), whereas the frequencies of the TNF-alpha -308G and the TNF-beta +252G alleles were similar in the two compared groups. These results suggest that the variability of the TNF-alpha -1031T/C polymorphism can be associated with the susceptibility to Behcet's disease in our study group. Therefore, the TNF molecule may have an important genetically and/or functionally implication in the pathogenesis of BD in the Tunisian population. 

5: IL-10 genotype analysis in patients with Behcet's disease.
 
Wallace GR, Kondeatis E, Vaughan RW, Verity DH, Chen Y, Fortune F, Madanat W, Kanawati CA, Graham EM, Stanford MR. 
Hum Immunol. 2007 Mar;68(3):201-5. Epub 2007 Jan 5. 
Behcet's disease (BD) is a multisystem inflammatory disease characterized by recurrent orogenital ulceration, ocular inflammation, and skin lesions. The etiology of the disease is currently unknown but evidence suggests that there is a strong genetic component mediating the chronicity of the disorder. We have examined the association between polymorphisms at position -1082, and -819 in the promoter region of the gene encoding IL-10 in patients with Behcet's disease from two distinct patient populations. The IL-10 -1082AA genotype was weakly associated with BD when all patients were analyzed as a group (pc = 0.04, OR 1.4, 95% CI 1.1-1.9), but not in the UK or Middle Eastern (ME) cohorts of patients alone compared to local controls. An association with IL-10 -819T was evident in all BD patients, (pc = 0.02, OR 1.5, 95% CI 1.1-2.0), and this was because of an association in the UK but not ME patients (pc = 0.0004, OR 2.1, 95% CI 1.4-3.3). The -1082A/-819T haplotype, which is linked to low production of this cytokine, was not significantly associated with Behcet's disease. This link between BD, a chronic, relapsing, autoinflammatory condition, and a genotype associated with low IL-10 production provides evidence that abnormalities in the genetic control of cytokine levels may be relevant in influencing the immune response in Behcet's disease in some patient groups. 

6: Nitric oxide synthase and superoxide dismutase gene polymorphisms in Behcet disease.
Nakao K, Isashiki Y, Sonoda S, Uchino E, Shimonagano Y, Sakamoto T.
 
Arch Ophthalmol. 2007 Feb;125(2):246-51. 
OBJECTIVE: To investigate the association of endothelial nitric oxide synthase (NOS), inducible NOS, manganese superoxide dismutase (SOD), and extracellular SOD gene polymorphisms with susceptibility to Behcet disease (BD) in Japan. METHODS: Seventy-eight consecutive Japanese patients with BD and 107 healthy control subjects were genotyped by polymerase chain reaction or polymerase chain reaction-restriction fragment length polymorphism methods for endothelial NOS polymorphisms in intron 4, exon 7, and promoter region; inducible NOS polymorphisms in exon 16 and promoter region; manganese SOD Ala16Val polymorphism; and extracellular SOD Arg213Gly polymorphism. HLA-B*51 alleles, which have been found to be associated with BD, were also determined. RESULTS: The frequencies of manganese SOD Val16 increased significantly in patients with BD. The manganese SOD-Val/Val genotype and HLA-B*5101 had a synergistic role in controlling susceptibility to BD. There was no significant difference in the frequencies of endothelial NOS, inducible NOS, and extracellular SOD gene polymorphisms between patients with BD and control subjects. CONCLUSION: The manganese SOD Val16 allele is associated with the development of BD in Japan. Extracellular SOD, endothelial NOS, and inducible NOS gene polymorphisms do not constitute a risk factor for developing BD in Japan. CLINICAL RELEVANCE: The manganese SOD gene polymorphism seems to contribute to BD. 

7: Analysis of CD28 and CTLA-4 gene polymorphisms in Turkish patients with Behcet's
disease. 
Gunesacar R, Erken E, Bozkurt B, Ozer HT, Dinkci S, Erken EG, Ozbalkan Z.
 Int J Immunogenet. 2007 Feb;34(1):45-9. 
In this study we aimed to investigate IVS3 +17T/C single nucleotide polymorphism (SNP) of CD28 gene, +49A/G and -318C/T SNPs of CTLA-4 gene in patients with Behcet's disease (BD) and their potential association to the main clinical features of the disease. These polymorphisms were investigated in a Turkish population of 123 patients with BD and 179 healthy controls, by using PCR-RFLP technique. HLA-B*51 genotype was also studied in both groups by using PCR-SSP. The frequency of IVS3 +17TC genotype of the CD28 gene was significantly increased in BD patients compared to controls (43.6% vs. 31.2%, OR = 1.663, 95% CI = 1.033-2.679, P = 0.039). CTLA-4 +49GG genotype frequency was found to be significantly lower in patients with BD than those of healthy controls (4% vs. 10.6%, OR = 0.357, 95% CI = 0.130-0.983, P = 0.05). Genotype and allele frequencies of the CTLA-4-318C/T polymorphism between the BD and healthy control groups were not significantly different (12.2% vs. 10.6%, OR = 1.170, 95% CI = 0.570-2.402, P = 0.713). There were no associations between the studied polymorphisms and the main clinical features of BD. The frequencies of HLA-B*51 were 60.3% and 30.7% in BD and control groups, respectively (OR = 3.429, 95% CI = 2.115-5.559, P = 0.0001). Association between HLA-B*51 and each studied polymorphism did not reach to significant levels (OR = 0.479, 95% CI = 0.228-1.004, P = 0.064 for CD28 IVS3 +17TT genotype; OR = 2.180, 95% CI = 1.025-4.639, P = 0.061 for TC genotype; OR = 1.570, 95% CI = 0.870-2.836, P = 0.146 for C allele). These results may suggest that CD28 IVS3 +17TC genotype may be a risk factor for the development of BD, on the contrary CTLA-4 +49GG genotype may be protective in the studied Turkish population. 

9: Cytochrome P450 polymorphisms in patients with Behcet's disease.
 
Tursen U, Tamer L, Api H, Yildirim H, Baz K, Ikizoglu G, Atik U.
 Int J Immunogenet. 2007 Feb;34(1):45-9. 
OBJECTIVES: Although the etiopathogenesis of Behcet's disease (BD) remains unknown, increased neutrophil functions such as chemotaxis, phagocytosis and excessive production of reactive oxygen species, including superoxide anion, may be responsible for the oxidative tissue damage observed in BD. Cytochrome P-450 are a multigene family of enzymes involved in the detoxification and occasional activation of a wide variety of chemicals. Our aim was to investigate CYP2C9 and CYP2C19 polymorphisms in patients with BD. METHODS: Sixty-two subjects with BD and 107 healthy control subjects were enrolled in the study. Polymorphisms of CYP2C9 and CYP2C19 were performed by real-time PCR with a LightCycler instrument. We researched associations between CYP polymorphisms and BD. RESULTS: The frequencies of wild-type and heterozygous CYP2C19*2 genotypes were 66.1% and 33.9% in the patients and 83.2% and 16.8% in the controls, respectively. There was a 2.53-fold increased risk of Behcet's disease in individuals with the CYP2C19*2 heterozygous genotype (OR = 2.53; 95% CI, 1.22-5.25) when compared with the control group. But the CYP2C9*2, CYP2C9*3 and CYP2C19*3 gene polymorphisms were not related to an increased risk of developing BD. CONCLUSIONS: We observed that patients with BD presented with a higher prevalence of the heterozygous CYP2C19*2 genotype. Hereditary deficiencies of this enzyme activity may lead to an imbalance between pro- and antioxidant systems, resulting in the formation of excessive reactive oxygen species. 

10: HLA-E*0101 and HLA-G*010101 reduce the risk of Behcet's disease.
 
Park KS, Park JS, Nam JH, Bang D, Sohn S, Lee ES.
 Tissue Antigens. 2007 Feb;69(2):139-44. 
The nonclassical human leukocyte antigen (HLA)-E and -G molecules have previously been shown to inhibit natural killer- and cytotoxic T-lymphocyte-mediated cell lysis and have also been shown to prevent the proliferation of CD4 T cells and secrete cytokines that appear to be important in the modulation of the Behcet's disease (BD) immune systems. Polymorphisms in the HLA-E and HLA-G genes have been associated with differential expression and function. Thus, we conducted an analysis of the HLA-E and HLA-G alleles using Amplification Refractory Mutation System-polymerase chain reaction (PCR) and PCR-restriction fragment length polymorphism techniques in a study comprising 312 patients with BD and 486 controls. The HLA-E*0101 and HLA-G*010101 alleles were associated with a reduced risk of BD (P = 0.0002, odds ratio (OR) = 0.7 and P = 0.002, OR = 0.7, respectively). By way of contrast, the variants HLA-E*010302, HLA-G*010102, G*0105N alleles and 3741_3754ins14bp were all associated with an increased risk of BD (P < 0.0001, OR = 1.6; P = 0.002, OR = 1.8; P = 0.024, OR = 2.0 and P = 0.003, OR = 1.4, respectively). Individuals carrying both the HLA-E*0101 and the HLA-G*010101 alleles evidenced significantly lower frequency in the patients than in the controls (35.6% vs 49.6%; P < 0.0001, OR = 0.6). These results indicate that variant HLA-E and HLA-G molecules appear to function independently and synergistically, increasing the risk of BD, and may result in an imbalance of lymphocytic functions, which may culminate in the development of BD. 

11: Haplotype association of IL-8 gene with Behcet's disease.
 
Lee EB, Kim JY, Zhao J, Park MH, Song YW.
 Tissue Antigens. 2007 Feb;69(2):128-32. 
Interleukin-8 (IL-8), a CXC chemokine that recruits and activates inflammatory cells, plays a critical role in the pathogenesis of Behcet's disease (BD). To investigate the association of the genetic polymorphism of IL-8 and BD, we genotyped IL-8 -845 T/C, -738 T/A, -353 A/T, -251 A/T, +293 G/T, +678 T/C and receptors CXCR-1 +2607 G/C and CXCR-2 +785 C/T polymorphisms in 119 Korean patients with BD and 119 age- and sex-matched healthy blood donors. Then, single nucleotide polymorphisms (SNPs) and haplotypes were analyzed between patients and controls. There were no SNPs associated with BD. However, the frequency of haplotype TAT inferred from SNPs, IL-8 -353 A/T, -251 A/T and +678 T/C, was significantly higher in patients with BD than controls (5.9 vs 0.0%, P = 0.0001), as was haplotype ATC (6.7 vs 0.0%, P < 0.0001). The haplotype difference was still valid in human leukocyte antigen-B51-negative subjects. In conclusion, we found a significant difference in the distribution of IL-8 gene haplotypes between patients with BD and healthy controls. These results suggest that the genetic polymorphisms of proinflammatory chemokine IL-8 can contribute to the pathogenesis of BD. 

12: Autoinflammatory gene mutations in Behcet's disease.
 
Kone-Paut I, Sanchez E, Le Quellec A, Manna R, Touitou I.
 Ann Rheum Dis. 2007 Jan 9; [Epub ahead of print] 
Introduction:Behcet's disease [BD] shares clinical features with well-recognized auto-inflammatory disorders. In addition, mutations in genes for Familial Mediterranean fever and TNF receptor-associated periodic syndrome have been reported to be increased in BD patients. PATIENTS AND METHODS: We analyzed DNA samples from 97 BD patients and 51 matched healthy controls for the MVK, CIAS1, and PSTPIP1 genes, responsible for MKD (mevalonate kinase deficiency), CAPS (cryopyrin associated periodic syndromes), and PAPA syndrome (pyogenic sterile arthritis, pyoderma gangrenosum and acne), respectively. Over 90% of known mutations were screened using Restriction Fragment Length Polymorphism analysis and/or sequencing. RESULTS: Two patients had paired mutations in the MVK gene (genotypes: V377I/V377I, V377I/S135L) and displayed typical BD and MKD features. Another was heterozygous for V377I. The V198M mutation in the CIAS1 gene was identified in one patient with typical BD but no symptoms of CAPS. No mutations were identified in the control group. PSTPIP1 analysis revealed a novel exon 10 insertion variant (c.741+33_741+34insGT) in 2/97 patients and in 1/51 controls (p>0.05), indicating that it is a polymorphism rather than a true mutation. Discussion: This study could not demonstrate any significant increases in MVK, CIAS1, or PSTPIP1 mutations in BD patients as compared to controls. 

13: T helper 1 type cytokines polymorphisms: association with susceptibility to Behcet's disease. 
Alayli G, Aydin F, Coban AY, Sullu Y, Canturk F, Bek Y, Durupinar B, Canturk T.
 Clin Rheumatol. 2007 Jan 9; [Epub ahead of print] 
The pathogenesis of Behcet's disease (BD) is not fully understood and immunological abnormalities and genetic factors have been investigated. Because serum concentrations of mainly T helper 1 (Th1) type cells have been reported to be increased in BD, we aimed to investigate whether certain cytokine polymorphisms might represent a risk factor for developing BD. We genotyped 80 patients with BD and 105 healthy controls for interleukin (IL)-1 alpha (T/C -889), IL-1 beta (C/T -511, T/C +3962), IL-1R (C/T pst11970), IL-1RA (T/C mspa111100), IL-2 (T/G -330), IL-12 (C/A -1188), interferon (IFN)-gamma (A/T UTR 5644), and TNF-alpha (G/A -238) polymorphisms. Analyses of cytokine polymorphisms were performed with PCR-SSP. The genotype and allele frequencies of the patients and controls were compared and the association between the polymorphisms of the cytokines with the clinical findings was investigated. Genotype distribution showed significant differences between the patients and the controls for the IL-1 alpha -889, IL-1 beta -511, IL-1 beta +3962, IL-1R, IL-12, IFN- gamma, and TNF-alpha cytokines. We didn't observe significant difference in genotypic frequencies of IL-1RA and IL-2 in our study. Comparison of the IL-1 alpha -889, IL 1 beta -511, and IL 1 beta +3962 genotype frequencies showed significant increase in CC genotype between the patients and the controls. The individuals with IL-1R TT polymorphism had a higher risk for BD compared to patients with CT/CC polymorphism. Comparison of IL-12, IFN- gamma, and TNF-alpha, genotype frequencies showed significant increase in CA, AA, and AA genotypes between the patients and controls, respectively. The frequencies of genotypes according to the clinical features of the patients with BD did not show a significant difference (p>0.05). Our study suggests that development of BD might be determined by various cytokine gene polymorphisms. However, further studies on larger numbers of cases are needed before definite conclusions can be drawn. 

14: Lack of association between leptin G2548A gene polymorphism and Behcet's disease. 
Aydin F, Kara N, Senturk N, Gunes S, Canturk MT, Bagci H, Bek Y, Turanli AY.
 J Eur Acad Dermatol Venereol. 2007 Jan;21(1):68-71. 
BACKGROUND: Behcet's disease is a chronic, multisystem, inflammatory disease characterized by the predominance of T-helper 1 cytokines. The disease is also characterized by infiltration of lymphocytes and neutrophils into the affected tissues. Because cytokines are involved in the regulation of lymphocyte and phagocyte functions, they may play an important role in the pathogenesis of Behcet's disease. Leptin, a member of the gp 130 family of cytokines, induces a strong T-helper 1 response and is regarded as a proinflammatory inducer. Recent studies have shown that serum leptin concentration was increased in patients with Behcet's disease and correlated with disease activity. OBJECTIVES: We aimed to investigate the role of G2548A polymorphism of leptin gene in patients with Behcet's disease and compare the results with healthy controls. PATIENTS AND METHODS: A total of 93 subjects with Behcet's disease and 125 healthy controls were included in this study. Analyses of G-2548A polymorphism of the LEP gene were performed using the PCR-restriction fragment length polymorphism technique. The genotypes (GG, GA, and AA of leptin G2548A) and alleles (G and A of leptin 2548) were scored and the frequency was estimated. The frequencies of the alleles and genotypes in patients and controls were compared. We analysed the correlation between leptin gene polymorphism and the clinical features of BD. RESULTS: Both genotype and allele frequencies were not significantly different between controls and Behcet's disease patients [OR=0.67, 95% CI (0.35-1.29), P=0.197 and OR=0.77, 95% CI (0.52-1.15), P=0.184]. We did not find any significant relationship between leptin gene polymorphism and the clinical features of BD (P>0.05). CONCLUSION: In the present case-control study, we found no evidence of an association between the G-2548A variant of the leptin gene and BD among Turks. Further studies are needed to investigate serum leptin level to explain the mechanisms behind the lack of association between leptin G2548A gene polymorphism and BD. 

Immunology

15: Proteomic surveillance of autoimmunity in Behcet's disease with uveitis:
 Selenium binding protein is a novel autoantigen in Behcet's disease. 
Okunuki Y, Usui Y, Takeuchi M, Kezuka T, Hattori T, Masuko K, Nakamura H, Yudoh
 K, Usui M, Nishioka K, Kato T. Exp Eye Res. 2007 Jan 20; [Epub ahead of print] 
Autoimmune response to retinal antigens is considered to be one of the pathogenesis of uveitis in Behcet's disease (BD). In the present study, we comprehensively compared retinal autoantigens recognized by sera from BD patients with uveitis or healthy donors using proteomic technique, 2-dimensional electrophoresis (2DE) followed by Western blotting (WB). Six protein spots showing high reactivity with the serum from the BD patients were detected as candidate retinal autoantigens, and three of them were identified by mass spectrometry. Two of them were previously reported BD autoantigens, S-antigen and alpha-enolase, whereas the third one was selenium binding protein (SBP), a new candidate retinal autoantigen. Autoantigenicity of SBP was examined by WB and enzyme-linked immunosorbent assay (ELISA) using a recombinant protein. We found that 20 and 16% of the BD patients with uveitis were positive for the anti-SBP antibody by WB and ELISA, respectively. Comparison of clinical parameters between anti-SBP antibody-positive and -negative patients revealed that the anti-SBP antibody-positive patient group showed more frequent ocular inflammation than the antibody-negative patient group. Autoimmunity against the retinal SBP may contribute to the pathogenesis of uveitis in BD patients. 

16: Lymphocyte ceruloplasmin and Behcet's disease.
 
Oliveira R, Banha J, Martins F, Paixao E, Pereira D, Barcelos F, Teixeira A,
 Patto JV, Costa L.Exp Eye Res. 2007 Jan 20; [Epub ahead of print] 
INTRODUCTION: Behcet's disease (BD) is a rare chronic inflammatory disorder of unknown aetiology. However, it has been postulated that a dysregulation of the prooxidant/antioxidant balance may be important to its pathogenesis. Ceruloplasmin (CP) is an acute phase protein expressed at the surface of peripheral blood lymphocytes (PBL) with antioxidant properties and with a relevant role in iron (Fe) metabolism. OBJECTIVES: To study CP expression at the surface of PBL (PBLCP) in patients with BD. MATERIAL AND METHODS: We measured serum CP and PBLCP obtained from BD patients (n=10) and respective controls (n=10) using nephelometry and flow cytometry techniques, respectively. Additionally, haematological parameters, biochemical Fe metabolism markers [serum Fe, serum ferritin, serum transferrin, total Fe binding capacity (TIBC), transferrin saturation] and non-specific markers of inflammation [serum C reactive protein (CRP), beta2-microglobulin] were measured in all individuals. RESULTS: Despite the absence of significant differences between the two study groups when comparing serum CP, a significant difference in PBLCP was found in BD patients mainly due to a significant decrease of CP expression at the surface of CD3-CD56+ lymphocytes. Also, a significant decrease of PBLCP was observed in patients treated with azathioprine compared to patients that were not being treated with this drug. CONCLUSIONS: According to this study, we suggest that the significant decrease of PBLCP observed in BD patients might be due to azathioprine treatment and not directly related to the pathophysiology of BD. 

17: Expression of cytokines, chemokines, and chemokine receptors in oral ulcers of
patients with Behcet's disease (BD) and recurrent aphthous stomatitis is Th1-associated, although Th2-association is also observed in patients with BD. 
Dalghous AM, Freysdottir J, Fortune F.
 Scand J Rheumatol. 2006 Nov-Dec;35(6):472-5. 
OBJECTIVE: Although the pathogenesis of Behcet's disease (BD) is unknown, immune dysfunction appears to be involved. To improve understanding of the role of T cells and cytokines in BD, the current study analysed the localization and extent of expression of T cell subsets, cytokines, chemokines, and chemokine receptors in oral ulcers from BD patients and for comparison in oral ulcers from patients with recurrent aphthous stomatitis (RAS), as well as in healthy oral mucosa. METHODS: Biopsies from oral ulcers of 25 BD patients and 19 RAS patients and oral mucosa from six healthy volunteers were immunoperoxidase stained. RESULTS: Both CD4- and CD8-positive T cells were present in the oral ulcers of BD and RAS patients. The T helper (Th)1 cytokines interleukin (IL)-12, interferon (IFN)-gamma, and tumour necrosis factor (TNF)alpha and the Th1-associated chemokine receptors CCR5 and CXCR3 were increased in both patient groups as compared to normal controls, indicating the involvement of a Th1 immune response in the immunopathology of both BD and RAS. However, the Th2 cytokine IL-4 was only observed in oral ulcers of BD patients but not in RAS patients. CONCLUSION: This is the first study that shows the presence of pro-inflammatory cytokines, as well as Th1-associated chemokine receptors, in the oral ulcers of BD patients, as well as RAS patients, at a protein level. However, the expression of the Th2 cytokine IL-4 within the oral lesions of only BD patients is suggestive of a more complex antigenic stimuli in BD patients compared with RAS patients. 

18: Synovial angiostatic non-ELR CXC chemokines in inflammatory arthritides: does CXCL4 designate chronicity of synovitis? 
Erdem H, Pay S, Musabak U, Simsek I, Dinc A, Pekel A, Sengul A.
 Rheumatol Int. 2007 Jan 31; [Epub ahead of print] 
In our previous studies, we found higher synovial fluid (SF) levels of angiogenic ELR(+) CXC chemokines such as CXCL1, CXCL5, CXCL6 and CXCL8, which play an important role in neutrophil migration and angiogenesis, and more abundant synovial CXCR2 chemokine receptor expression in patients with rheumatoid arthritis (RA) than those with Behcet's disease (BD), familial Mediterranean fever and osteoarthritis (OA). As a continuation of our previous studies, we investigated synovial levels of angiostatic non-ELR CXC chemokines (CXCL4, CXCL9 and CXCL10) in patients with RA, BD, spondyloarthritis (SpA), and OA. Seventy (17 RA, 15 BD, 19 SpA, and 19 OA) patients were enrolled in the study. The levels of CXCL4, CXCL9, and CXCL10 were measured by ELISA. The SF levels of CXCL4 in patients with RA were higher than those of the patients with BD, SpA, and OA (P = 0.007, P = 0.022, and P = 0.017, respectively). No difference was found with respect to CXCL4 levels among the BD, SpA, and OA patients. The synovial CXCL9 levels of patients with RA and SpA were found to be higher than those of the patients with OA (P = 0.002 and P = 0.005, respectively), while no statistically significant difference was detected among the other groups. With regard to SF CXCL10 levels, patients with RA had higher levels as compared to patients with OA (P = 0.002), but no significant difference was found among the other groups. CXCL9 correlated with CXCL4 and CXCL10 (P < 0.05 for both) in patients with RA. No correlation was found in other parameters. The angiostatic non-ELR CXC chemokines were expressed in synovial inflammation. We proposed that angiostatic non-ELR CXC chemokines may increase to balance angiogenic ELR (+) CXC chemokines in which increased levels were shown in patients with inflammatory arthritides and CXCL4 may contribute to designate the chronicity of synovitis in patients with RA. In addition, as CXCL-9 and CXCL-10 play crucial role in inflammation characterized by Th1 polarization, we suggested that they may contribute to the commencement and the perpetuation of synovitis seen in these groups of arthritides. 

19: Increased proportion of CD3+CD4-CD8- double-negative T cells in peripheral blood
 of children with Behcet's disease. 
Ling E, Shubinsky G, Press J.
 Autoimmun Rev. 2007 Mar;6(4):237-40. Epub 2006 Aug 28. 
INTRODUCTION: Behcet's disease (BD) is a multi-system inflammatory disorder of poorly understood pathogenesis, which is characterized by oral aphtosis, genital ulcers and uveitis. OBJECTIVE: To assess the role of CD3+CD4-CD8- double negative (DN) T cells in pathogenesis of Behcet's disease. PATIENTS: Ten BD patients (age 12.2+/-2.2 years, 7 in remission, 3 in exacerbation state) treated at the Pediatric Rheumatology unit of Soroka University Medical Center and 3 age-matched controls participated in the study. METHODS: Peripheral blood lymphocytes of study subjects were isolated and stained with fluorescein-labeled anti-CD45, CD3, CD4, CD8 antibodies and analyzed by FACS assay. RESULTS: Proportion of CD4-CD8- DN T cells was significantly increased in BD patients (n=10) as compared to healthy controls (6.2+/-3.4% vs. 3.2+/-1.1% of total CD3+ cells, p<0.05), this cell group was additionally enhanced in BD exacerbation, compared to patients in remission (10+/-4.1% vs. 4.7+/-1.2%, p<0.05, respectively). DN T cells were significantly increased in BD patients in remission, compared to healthy controls (4.7+1.2% vs. 3.2+1.1% of total CD3+ cells, p<0.05, respectively). CONCLUSIONS: Behcet's disease is characterized by increased proportion of CD3+CD4-CD8- double negative T cells in peripheral blood. Further studies, that include additional immunophenotyping and analysis of gene expression, aimed at characterization of these cells are currently underway. 

20: Sampling of major histocompatibility complex class I-associated peptidome suggests relatively looser global association of HLA-B*5101 with peptides.
Gebreselassie D, Spiegel H, Vukmanovic S. Hum Immunol. 2006 Nov;67(11):894-906. Epub 2006 Sep 20. 
We have analyzed peptides associated with six human major histocompatibility complex (MHC) class I allomorphs expressed by the U937 cell line. Peptides were isolated by mild acid elution or by MHC class I immunoprecipitation by using W6/32 monoclonal antibody. Eighty-five peptides were sequenced by mass spectrometry, and their putative binding alleles were assigned using bioinformatic tools. Only three peptides isolated by the two approaches were identical, suggesting that the approaches may yield distinct partially overlapping peptide populations. Mild acid treatment-derived peptides manifested overall characteristics suggestive of relatively lower affinity of binding for MHC class I. Interestingly, a large proportion of putative HLA-B*5101-binding peptides was evident among the mild acid treatment-eluted peptides, and to a lesser degree in the affinity-purified peptide pool. These results suggest that HLA-B*5101 may bind a potentially large pool of peptides with relatively lower affinity. We suggest that lower affinity of peptide binding may be the basis for inefficient tolerance to HLA-B*5101-binding self-peptides, a predisposing factor for the development of Behcet disease. 

21: Levels of IL-15 in serum and cerebrospinal fluid of patients with Behcet's
 disease. 
Hamzaoui K, Hamzaoui A, Ghorbel I, Khanfir M, Houman H.
 Scand J Immunol. 2006 Dec;64(6):655-60. 
Interleukin-15 (IL-15) is a novel proinflammatory cytokine, involved in the pathogenesis of inflammatory/autoimmune disease. The objective of our study was to measure serum and cerebrospinal fluid (CSF) IL-15 levels in patients with Behcet's disease (BD). CSF/serum IL-15 ratio was introduced to assess the origin of elevated IL-15 levels. We measured serum and CSF-IL-15 levels in 40 patients with BD (20 patients in active stage). Inflammatory and non-inflammatory neurological disease patients acted as controls. Active BD patients have significantly higher serum IL-15 levels (median 10.4 pg/ml; range 5.3-17.4) compared with BD in remission (6.05 pg/ml; 4-10.4) and healthy controls (4.65 pg/ml; 3.9-6.2). Similar serum IL-15 levels were found in active neuro-BD and inflammatory neurological disease (9.5 pg/ml; 5-13). Elevated levels of IL-15 were observed in CSF samples from neuro-BD patients (11 pg/ml; 8.5-15) and inflammatory neurological disease patients (10 pg/ml; 6.5-14) compared with patients with non-inflammatory neurological disease (4 pg/ml; 4-5.5; P < 0.001). Vascular cerebral BD lesions were associated with high CSF/serum IL-15 ratio. Our findings suggest that IL-15 is involved in BD inflammatory process, particularly in vasculitis foci, as an elevated CSF/serum IL-15 ratio characterizes vascular cerebral lesions. 

22:
 Expression of CXCR-1 and CXCR-2 chemokine receptors on synovial neutrophils ininflammatory arthritides: does persistent or increasing expression of CXCR-2 contribute to the chronic inflammation or erosive changes? 
Pay S, Musabak U, Simsek I, Pekel A, Erdem H, Dinc A, Sengul A.
 Joint Bone Spine. 2006 Dec;73(6):691-6. Epub 2006 Jul 18. 
OBJECTIVE: To analyze the CXCR-1 and CXCR-2 chemokine receptor expression on peripheral blood neutrophils (PBN) and synovial fluid neutrophils (SFN) of patients with rheumatoid arthritis (RA) and Behcet's disease (BD) (characterized by erosive and non-erosive arthritis, respectively), and to compare them with those of patients with osteoarthritis (OA). METHODS: We used flow cytometry to investigate the expression of CXCR-1 and CXCR-2 chemokine receptors on PBN and SFN of fifty-five (22 RA, 22 BD and 11 OA) age and sex-matched patients. RESULTS: In respect to chemokine receptor expression on neutrophils isolated from patients with RA, mean fluorescein intensity (MFI) of CXCR-1 chemokine receptors on PBN from active and inactive RA patients, and SFN from patients with RA were 151 (90-395), 129 (81-539) and 136 (64-220), respectively, and there were not statistically significant difference each other. But MFI of CXCR-2 chemokine receptors on SFN of patients with RA was 18 (10-32), and significantly higher than PBN of active and inactive RA patients (MFI: 10 (6-15) and 12 (7-16), P=0.002 and 0.037, respectively). In respect to chemokine receptor expression on neutrophils isolated from patients with BD, MFI of CXCR-1 chemokine receptors on PBN of active BD patients was 245 (97-844), and higher than PBN of active RA patients and SFN of BD patients (MFI: 151 (90-395) and 134 (61-231), P=0.047 and 0.017, respectively). MFI of CXCR-2 chemokine receptors on PBN of active and inactive BD patients, and SFN of patients BD were 10 (6-14), 10 (2-16), and 12 (8-24), respectively, there were not statistically significant difference each other. MFI of CXCR-1 chemokine receptors on SFN from patients with RA, BD, and OA were 136 (64-220), 134 (61-231), and 114 (60-180), respectively, and there was no difference between the study groups. MFI of CXCR-2 chemokine receptors on SFN of patients with RA was 18 (10-32), and higher than patients with BD and OA (MFI: 12 (8-24) and 11 (9-18), P=0.037 and 0.005, respectively), though there was no difference between last two groups. CONCLUSION: Our study points that CXCR-1 and CXCR-2 chemokine receptors of SFN may have diverse functions in the course of inflammatory arthritides. These results indicate that CXCR-2 chemokine receptor might play more critical role in long lasting accumulation of neutrophils within the synovial fluid of patients with RA. 

23 : Immunoglobulin E: a new diagnostic clue for Behcet's disease? IgE and Behcet's
disease. 
Onat AM, Buyukhatipoglu H, Yilmaz M, Geyik R, Celik A, Ozturk MA.
 Clin Rheumatol. 2007 Jan;26(1):81-3. Epub 2006 May 31. 
Behcet's disease (BD) is a multisystemic inflammatory disorder of unknown etiology. Hyperimmunoglobulinemia has been demonstrated in BD; however, its clinical importance has not yet been discovered. In a few reports, an association between BD and plasma immunoglobulin E (IgE) has been noted. In this study, we had three objectives: (1) to investigate plasma levels of IgE and their association with levels of acute phase reactants, (2) to determine whether treatment has any effect upon IgE levels, and (3) to assess whether higher serum levels of IgE provide a clue for the diagnosis of BD. Fifty-two patients with BD, without any accompanying disease or condition that might lead to a rise in IgE, were compared with 51 age-matched healthy controls. Plasma levels of IgE, IgA, IgG, and IgM were analyzed by means of nephelometric analysis. Results showed that among the 52 patients, 23 (44%) had IgE levels that were higher than the upper limits of normal. IgE was not correlated with age, erythrocyte sedimentation rate, or C-reactive protein (p=0.59, p=0.57, and p=0.757, respectively). These relationships remained nonsignificant when multiple regression analysis was performed, with R (2) of 0.187 and p=0.057. Moreover, treatment of patients with elevated IgE did not produce any predictable IgE response. We conclude that Behcet's patients commonly exhibit elevated plasma IgE levels. However, elevated IgE levels are not correlated with levels of acute phase reactants or disease activity. We suggest that IgE levels might be an independent diagnostic clue in Behcet's patients. 

24: Serum-soluble selectin levels in patients with Behcet's disease.
 
Ates A, Tiryaki OA, Olmez U, Tutkak H.
 Clin Rheumatol. 2007 Mar;26(3):411-7. Epub 2007 Jan 6. 
Soluble forms of selectins may play a regulatory role in inflammatory responses. The aim of this study was to examine the levels of serum-soluble (s) selectins in Behcet's disease (BD) patients and to evaluate the associations of these molecules to disease activity, clinical findings, and drugs taken for BD, mainly colchicine. Serum sE-, sL-, and sP-selectins levels were measured by sandwich enzyme-linked immunosorbent assay in 28 BD patients and 22 healthy subjects. The BD patients were classified according to the disease activity, clinical findings, and therapy. Ten patients were newly diagnosed and were not taking any therapy. Remainder were on colchicine (n = 18) and immunosuppressive drugs (n = 5). In BD patients, the levels of sL- and sP-selectins were significantly lower than those of healthy controls, but sE-selectin level was similar to that of the controls. The patients on the therapy had significantly lower levels of sE- and sL-selectins and insignificantly lower level of sP-selectin than the patients not receiving therapy. The BD patients with active disease had significantly higher levels of sE-, sL-, and sP-selectins compared with the patients with inactive disease. There were no significant differences in the levels of selectins between the treated active patients and inactive patients. However, the untreated patients with active disease had significantly higher selectin levels than the inactive patients. There were no significant differences in all selectin levels between the patients with or without vascular involvement. Serum sL-selectin was found to be significantly higher in patients with erythema nodosum. In conclusion, our findings suggest that the levels of soluble selectin molecules in BD patients seem to be modified by the drugs taken for BD. The colchicine therapy is associated with lower selectin levels. 

25: Interferon-beta and adhesion molecules (E-selectin and s-intracellular adhesion
molecule-1) are detected in sera from patients with retinal vasculitis and are induced in retinal vascular endothelial cells by Toll-like receptor 3 signalling. 
Lee MT, Hooper LC, Kump L, Hayashi K, Nussenblatt R, Hooks JJ, Detrick B.
 Clin Rheumatol. 2007 Mar;26(3):411-7. Epub 2007 Jan 6. 
Retinal vasculitis is a major component of ocular inflammation that plays a role in retinal tissue damage in patients with idiopathic uveitis and Behcet's disease. Here we show that type 1 interferons (IFN alpha/beta) were not detected in sera from normal individuals but were identified in up to 46% of the sera from retinal vasculitis patients. The predominant form of IFN observed was IFN-beta, which was detected in 39% of Behcet's disease patients and 47% of idiopathic uveitis patients. Seven patients whose sera contained IFN-beta were monitored prospectively. IFN-beta was shown to be present for 6-12 months in all seven of the sera samples tested. Furthermore, the adhesion molecule profile identified in this study was strikingly different when Behcet's and uveitis patient sera were compared to sera from normal controls. Sera from Behcet's disease patients contained significantly elevated levels of the soluble adhesion molecules, sE-selectin and s-intracellular adhesion molecule-1 (sICAM-1), whereas sera from patients with idiopathic uveitis contained significantly increased sE-selectin. In vitro studies evaluating the cell source of these cytokines revealed that polyriboinosinic polyribocytidylic acid (poly I:C) activated retinal vascular endothelial cells produce sE-selectin, sICAM-1 and IFN-beta. Production of these molecules was inhibited by pretreatment with anti-Toll-like receptor 3 (TLR-3) antibody. In conclusion, IFN-beta, sE-selectin and sICAM-1 are elevated in patients with retinal vasculitis and are induced in retinal vascular endothelial cells in vitro by activating the innate immune system through TLR-3. Further analysis of innate immune signalling may prove to be a novel target for future studies on pathogenic mechanisms and therapeutic approaches in retinal vasculitis. 

Thrombophilia 
26: Caspase-9 expression is increased in endothelial cells of active Behcet's
 disease patients. 
Oztas P, Lortlar N, Polat M, Alli N, Omeroglu S, Basman A.
 Int J Dermatol. 2007 Feb;46(2):172-6.
BACKGROUND: Behcet's disease is a multisystem disease of unknown etiology. Caspase-9 is responsible for initiating the caspase activation cascade during apoptosis. The aim of this study was to examine caspase-9 expression in both endothelial and perivascular infiltrates of patients with active Behcet's disease. METHODS: Fifteen patients with active Behcet's disease, attending the First Dermatology Department, Ankara Numune Hospital, Ankara, Turkey between June 2003 and December 2005, were included in the study. Oral biopsy specimens from nine healthy volunteers were taken as the healthy control group, and skin biopsies from 18 psoriasis patients were used as the inflammatory control group. The specimens were examined with caspase-9 primary antibody. Statistical analyses were performed using SPSS 11.5. RESULTS: The mean caspase-9-positive endothelial cell counts were 7.17 +/- 2.45 in active Behcet's disease, 4.81 +/- 0.76 in healthy controls, and 4.35 +/- 1.34 in inflammatory controls. The difference between Behcet's disease and healthy controls was statistically significant, with increased endothelial staining in active Behcet's disease (P = 0.049). The difference between Behcet's disease and inflammatory controls was also statistically significant; the rate of staining was higher in Behcet's disease (P = 0.006). The mean caspase-9-positive dermal perivascular cell counts were 5.15 +/- 2.32 in Behcet's disease, 3.32 +/- 0.82 in healthy controls, and 5.54 +/- 4.95 in inflammatory controls. These values did not show any statistically significant difference (P = 0.407). CONCLUSION: Endothelial cells are one of the key cells in Behcet's disease, and our findings support the role of endothelial cells in the etiopathogenesis of Behcet's disease. 

27: Assessment of homocysteine, neopterin and nitric oxide levels in Behcet's
 disease. 
Ozkan Y, Yardim-Akaydin S, Sepici A, Engin B, Sepici V, Simsek B.
 Clin Chem Lab Med. 2007;45(1):73-7. 
BACKGROUND: Behcet's disease is a multisystemic immunoinflammatory disease with a wide variety of clinical manifestations, whereas recurrent aphthous stomatitis is a local oral disease. The aim of this study was to examine the distribution of homocysteine levels in patients with active Behcet's disease, possible association of homocysteine with nitric oxide and neopterin levels, and to characterize the differences between patients with Behcet's disease and those with recurrent aphthous stomatitis in terms of these parameters compared with healthy controls. METHODS: A total of 23 patients with active Behcet's disease, 25 patients with recurrent aphthous stomatitis as positive controls, and 21 healthy subjects were included in this study. Serum homocysteine and neopterin levels were measured flourimetrically by HPLC. Serum nitric oxide production was assayed by measuring total nitrite levels with Griess reagent. RESULTS: Significantly higher homocysteine (12.9+/-3.3 micromol/L) and lower nitric oxide (41.5+/-10.9 micromol/L) and neopterin (6.4+/-1.0 nmol/L) levels were observed in patients with Behcet's disease compared with healthy controls (10.7+/-2.0 micromol/L, 49.7+/-16.2 micromol/L, 8.7+/-2.2 nmol/L, respectively) (p&lt;0.03 for neopterin, p&lt;0.04 for homocysteine and nitric oxide). However, homocysteine, nitric oxide, biopterin and neopterin levels and the neopterin/biopterin ratio for recurrent aphthous stomatitis patients were not significantly different compared to healthy controls. A significant positive correlation was observed between serum homocysteine and serum neopterin/biopterin ratio in patients with Behcet's disease (r=0.975, p&lt;0.005). CONCLUSIONS: In contrast to recurrent aphthous stomatitis, there is a higher prevalence of hyperhomocysteinemia in Behcet's disease. Homocysteine may have deleterious effects on the pathology of Behcet's disease by decreasing nitric oxide levels and interfering with the immune system. 

28: Expressions of vascular endothelial growth factor and CD34 in oral aphthous lesions of Behcet's disease. 
Yalcin B, Arda N, Tezel GG, Erman M, Alli N.
 Anal Quant Cytol Histol. 2006 Dec;28(6):303-6. 
OBJECTIVE: Behcet's disease (BD) is an immunoin-flammatory vasculitis with an unknown etiopathogenesis. Vascular endothelial growth factor (VEGF) is a cytokine-stimulating angiogenesis. It has been suggested to play a role in inflammation and pathogenesis of vasculitic processes. STUDY DESIGN: VEGF and CD34 expressions were assessed in samples taken from oral aphthous lesions. The patients were evaluated for disease activity, duration of lesions, serum C-reactive protein (CRP) levels and erythrocyte sedimentation rate (ESR). RESULTS: Twenty-six patients were included. Fourteen (53.9%) had increased CRP levels and 12 (46.1%) had increased ESR levels. Positive VEGF and CD34 staining were detected in 46.2% and 69.2% of biopsy samples, respectively. There was good positive correlation between them. The frequency of positive VEGF and CD34 staining was statistically higher in lesions with a duration of more than 6 days. No correlation was found between positive VEGF staining and serum CRP level, ESR and disease activity. CONCLUSION: Increased VEGF expression in correlation with CD34 positivity in oral aphthous lesions may show the role of VEGF in pathogenesis of these vasculitic lesions. We have concluded that VEGF may play a role during the course of oral aphthous lesions in BD. 

29: Endothelial functions are more severely impaired during active disease period in
patients with Behcet's disease. 
Caliskan M, Yilmaz S, Yildirim E, Gullu H, Erdogan D, Ciftci O, Kaynar G, Yucel E, Muderrisoglu H. Clin Rheumatol. 2006 Nov 7; [Epub ahead of print] 
Oral apthous ulcers and skin lesions are the primary symptoms of Behcet's disease (BD). To date, there is no study to investigate possible associations between these lesions and endothelial functions. We have hypothesized that active BD period with oral and skin lesions might have more deteriorating effect on endothelial functions. Thirty-five patients with BD were registered for the study. Each subject was evaluated two times in both active and inactive disease periods. The subject with at least 30 days of lesion-free period was regarded in the inactive disease period, and the subject with any oral and/or skin lesions was regarded in the active disease period. For the control group, 35 healthy age- and sex-matched subjects were registered. In each subject, flow-mediated dilation (FMD) of the brachial artery after transient ischemia was evaluated in both active and inactive disease periods. High-sensitivity C-reactive protein (hsCRP) values (3.30 +/- 5.76 vs 14.19 +/- 13.55 vs 1.82 +/- 1.31, P < 0.001) and FMD values (13.89 +/- 5.57 vs 8.53 +/- 4.78 vs 15.83 +/- 5.29, P < 0.001) were significantly different among the BD patients in inactive and active disease periods and among control subjects. FMD values in inactive and active disease periods modestly correlated to hsCRP and low-density lipoprotein cholesterol values. Brachial FMD is more prominently impaired in BD patients within the active disease period. BD patients are possibly more vulnerable to cardiovascular manifestations when they are in the active disease period. 

30: Decreased protein S activity is related to the disease activity of Behcet's
 disease. 
Kwon SR, Lim MJ, Park SG, Moon YS, Park W.
 Rheumatol Int. 2006 Nov;27(1):39-43. Epub 2006 Sep 13. 
We wanted to see whether the active inflammation in Behcet's disease (BD) can cause a thrombotic disorder by decreasing the protein S (PS) activity, and we evaluated the relationship between the decreased PS activity and the disease activity of BD. We included 122 patients with BD whose PS activity levels were measured. In 51 patients, the PS activity was measured again when there were changes in the number of items of "The Behcet's Disease Current Activity Form (BDCAF)". The thrombosis rate was 2.5% (3/122), and the PS activity was low in all three of the patients with thrombosis. The incidence of low PS activity in the total 122 BD patients was 27% (33/122). The incidence of the low PS activity in the active BD patients was 33.7% (31/92), and this was significantly more frequent than in the inactive BD patients, (6.7%, 2/30) (chi(2)-test, P value = 0.0038). The decrease of PS activity had good correlation with the increase of the number of BDCAF items (r = -0.351, P value = 0.012). The PS activity decrease is related to the BD activity. The low PS activity can be the risk factor for thrombotic disorder and also the activity marker for BD and other inflammatory diseases. 

31: Decreased nitric oxide and increased platelet aggregation levels in patients
 with Behcet's disease. 
Yapislar H, Aydogan S, Borlu M, Ascioglu O.
 Thromb Res. 2007;119(4):461-5. Epub 2006 Jun 27. 

32: Homocysteine: an activity marker in Behcet's disease?
 
Sarican T, Ayabakan H, Turkmen S, Kalaslioglu V, Baran F, Yenice N.
 J Dermatol Sci. 2007 Feb;45(2):121-6. Epub 2006 Dec 19. 
BACKGROUND: Behcet's disease (BD) is a chronic multisystem inflammatory disorder commonly complicated by vascular thrombosis. OBJECTIVE: In this study, we investigated whether hyperhomocysteinaemia, being a well known risk factor for atherothrombogenesis, is also a contributive risk factor for the pathogenesis and the activation of Behcet's disease. METHODS: Sixty-four patients fulfilling the criteria of the International Study Group for Behcet's disease (48 males, 16 females, 33+/-8 years) were enrolled. They were separated into two groups with respect to activation features of Behcet's disease. Additionally, we collected the blood samples from 13 patients with BD in both active stage and in inactive stage. Twenty-six healthy individuals were included as a negative control group. Serum total homocysteine (Hcy) levels were determined by chemiluminescence immunoassay. RESULTS: Mean serum homocysteine concentrations in total BD patients were significantly higher than in the healthy controls (11.7+/-4.6 versus 8.7+/-2.8micromol/L, p<0.01). Mean serum homocysteine concentrations in the active patients were significantly higher than in the inactive patients and the healthy controls (13.3+/-3.6; 10.8+/-5.0; 8.7+/-2.8micromol/L, respectively) (p<0.05 and p<0.001, respectively). There was no significant difference between the patients with inactive disease and the healthy controls. When the active and the inactive stage of 13 patients with BD were compared, we found that mean serum total homocysteine levels were higher in the active stage than in the inactive stage (p<0.05). CONCLUSION: Hyperhomocysteinaemia may be responsible for the endothelial damage in BD and assumed to be a risk factor and a marker for activation of BD. 

Letters
 

33: HLA-B51 and cigarette smoking as risk factors for chronic progressive
 neurological manifestations in Behcet's disease. 
Aramaki K, Kikuchi H, Hirohata S.
 Mod Rheumatol. 2007;17 (1):81-2. Epub 2007 Feb 20. 

34: Association between K469E polymorphism of intracellular adhesion molecules-1
 ICAM-1 and Behcet's disease. 
Saadat M.
 Saudi Med J. 2006 Dec;27(12):1934.

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