Lethal outcome after pelvic salvage radiotherapy in a patient with prostate cancer due to increased radiosensitivity : Case report and literature review.

BACKGROUND: In general, late side effects after salvage radiotherapy (RT) for prostate cancer are below 10%. Patients with impaired DNA repair ability and genetic instability can have significantly increased reactions after RT. CASE, CLINICAL FOLLOW-UP, AND EXAMINATION: We present a patient who experienced severe side effects after additive RT for prostate cancer and died from the complications 25 months after RT. Imaging (MR) is shown as well as three-color fluorescence in situ hybridization. The blood sample testing revealed that radiosensitivity was increased by 35-55%. We undertook a review of the literature to give an overview over the tests established that are currently considered useful. CONCLUSION: This case highlights that the identification of patients with increased radiosensitivity is an important task in radiation protection. Groups of patients who should be screened have to be found and corresponding research facilities have to be set up.

Safety and tolerability of cladribine tablets in multiple sclerosis: the CLARITY (CLAdRIbine Tablets treating multiple sclerosis orallY) study.

BACKGROUND: Cladribine is a synthetic deoxyadenosine analogue in development as an oral multiple sclerosis (MS) therapy. OBJECTIVE: To report in detail the safety findings from the 96-week, phase III, double-blind CLARITY study, which evaluated treatment with cladribine tablets in relapsing-remitting MS. METHODS: A total of 1,326 patients were randomized 1:1:1 to two short-course regimens of cladribine tablets (3.5 or 5.25 mg/kg cumulative dose over 96 weeks) or placebo. Safety assessments included monitoring for adverse events (AEs), routine physical and neurologic examinations and frequent laboratory parameter assessments. RESULTS: Of the randomized patients, 88.6% completed treatment with cladribine tablets versus 86.3% with placebo. Lymphopenia was the most commonly reported AE in patients treated with cladribine tablets and was anticipated based on the mechanism of action. The incidence of infections was 48.3% with cladribine tablets and 42.5% with placebo, with 99.1% and 99.0% rated mild-to-moderate by investigators. Herpes zoster infections developed in 20 (2.3%) cladribine-treated patients; all cases were dermatomal. There were no herpes zoster infections in the placebo group. Nine (1.0%) patients experienced events related to uterine leiomyomas in the cladribine tablets groups versus one (0.2%) with placebo. Three isolated cases of malignancy were reported in cladribine-treated patients during the study; a fourth was reported during post-study surveillance. A pre-malignant cervical carcinoma in situ was also reported. The incidence of malignancies during the study did not exceed the expected rate in a population standardized for country, gender and age. CONCLUSION: The safety and tolerability profile observed in the CLARITY study together with the reported efficacy support the potential for cladribine tablets as an MS therapy.

Effect of glatiramer acetate on conversion to clinically definite multiple sclerosis in patients with clinically isolated syndrome (PreCISe study): a randomised, double-blind, placebo-controlled trial.

BACKGROUND: Glatiramer acetate, approved for the treatment of relapsing-remitting multiple sclerosis, reduces relapses and disease activity and burden monitored by MRI. We assessed the efficacy of early treatment with glatiramer acetate in delaying onset of clinically definite multiple sclerosis. METHODS: In this randomised, double-blind trial, undertaken in 80 sites in 16 countries, 481 patients presenting with a clinically isolated syndrome with unifocal manifestation, and two or more T2-weighted brain lesions measuring 6 mm or more, were randomly assigned to receive either subcutaneous glatiramer acetate 20 mg per day (n=243) or placebo (n=238) for up to 36 months, unless they converted to clinically definite multiple sclerosis. The randomisation scheme used SAS-based blocks stratified by centre, and patients and all personnel were masked to treatment assignment. The primary endpoint was time to clinically definite multiple sclerosis, based on a second clinical attack. Analysis was by intention to treat. A preplanned interim analysis was done for data accumulated from 81% of the 3-year study exposure. This study was registered with ClinicalTrials.gov, number NCT00666224. FINDINGS: All randomly assigned participants were analysed for the primary outcome. Glatiramer acetate reduced the risk of developing clinically definite multiple sclerosis by 45% compared with placebo (hazard ratio 0.55, 95% CI 0.40-0.77; p=0.0005). The time for 25% of patients to convert to clinically definite disease was prolonged by 115%, from 336 days for placebo to 722 days for glatiramer acetate. The most common adverse events in the glatiramer acetate group were injection-site reactions (135 [56%] glatiramer acetate vs 56 [24%] placebo) and immediate post-injection reactions (47 [19%] vs 12 [5%]). INTERPRETATION: Early treatment with glatiramer acetate is efficacious in delaying conversion to clinically definite multiple sclerosis in patients presenting with clinically isolated syndrome and brain lesions detected by MRI. FUNDING: Teva Pharmaceutical Industries, Israel.

The PTPN22gain-of-function+1858T(+) genotypes correlate with low IL-2 expression in thymomas and predispose to myasthenia gravis.

Protein tyrosine phosphatase, non-receptor type 22 (PTPN22) inhibits T-cell activation and interleukin-2 (IL-2) production. The PTPN22(gain-of-function)+1858T(+) genotypes predispose to multiple autoimmune diseases, including early-onset (non-thymomatous) myasthenia gravis (MG). The disease association and the requirement of IL-2/IL-2 receptor signaling for intrathymic, negative T-cell selection have suggested that these genotypes may weaken T-cell receptor (TCR) signaling and impair the deletion of autoreactive T cells. Evidence for this hypothesis is missing. Thymoma-associated MG, which depends on intratumorous generation and export of mature autoreactive CD4(+) T cells, is a model of autoimmunity because of central tolerance failure. Here, we analyzed the PTPN22 +1858C/T single nucleotide polymorphism in 426 German Caucasian individuals, including 125 thymoma patients (79 with MG), and investigated intratumorous IL-2 expression levels. Unlike two previous studies on French and Swedish patients, we found strong association of PTPN22 +1858T(+) genotypes not only with early-onset MG (P=0.00034) but also with thymoma-associated MG (P=0.0028). IL-2 expression in thymomas with PTPN22 +1858T(+) genotypes (P=0.028) was lower, implying weaker TCR signaling. We conclude that the PTPN22(gain-of-function) variant biases towards MG in a subgroup of thymoma patients possibly by impeding central tolerance induction.

Basic and escalating immunomodulatory treatments in multiple sclerosis: current therapeutic recommendations.

This review updates and extends earlier Consensus Reports related to current basic and escalating immunomodulatory treatments in multiple sclerosis (MS). The recent literature has been extracted for new evidence from randomized controlled trials, open treatment studies and reported expert opinion, both in original articles and reviews, and evaluates indications and safety issues based on published data. After data extraction from published full length publications and critically weighing the evidence and potential impact of the data, the review has been drafted and circulated within the National MS Societies and the European MS Platform to reach consensus within a very large group of European experts, combining evidence-based criteria and expert opinion where evidence is still incomplete. The review also outlines a few areas of controversy and delineates the need for future research.

Triggering receptor expressed on myeloid cells-1 (TREM-1) expression on gastric epithelium: implication for a role of TREM-1 in Helicobacter pylori infection.

In Helicobacter pylori gastritis gastric epithelium plays a central role in the innate immunity to H. pylori. However, epithelial receptors interacting with H. pylori have been poorly characterized so far. Recently a new triggering receptor expressed on myeloid cells-1 (TREM-1) has been identified on human neutrophils and monocytes. On these cells TREM-1 triggers innate immunity by stimulating the secretion of interleukin (IL)-8 and tumour necrosis factor (TNF)-alpha and thus amplifies bacterial-induced inflammation. In this study expression and function of TREM-1 in gastric epithelium exposed to H. pylori has been investigated. TREM-1 mRNA and protein were expressed on gastric epithelial cell lines as demonstrated by reverse transcription-polymerase chain reaction (RT-PCR) and fluorescence activated cell sorter analysis. Gastric epithelial TREM-1 expression was up-regulated directly by H. pylori and was independent of epithelial IL-8 induced by H. pylori. Immunohistochemistry and tissue RT-PCR demonstrated significantly stronger TREM-1 expression in H. pylori gastritis compared with the non-inflamed gastric mucosa supporting in vivo that epithelial TREM-1 is up-regulated during H. pylori infection. Stimulation of gastric epithelial TREM-1 receptor resulted in IL-8 up-regulation on mRNA and protein level, as shown by real-time PCR and immunoassay. This is the first study localizing TREM-1 on gastric epithelium. Functional data suggest that TREM-1 expressed on gastric epithelium amplifies inflammation of the underlying gastric mucosa by up-regulation of IL-8.

[Recent advances in the pathogenesis and immunotherapy of multiple sclerosis]. / Fortschritte im Verständnis von Pathogenese und Immuntherapie der Multiplen Sklerose.

In this article recent advances in research on the pathogenesis of multiple sclerosis (MS) are summarized. New evidence from molecular histopathology is discussed focussing on neurodegenerative aspects. In addition findings with a direct effect on therapeutic decisions are presented which have contributed to improved immunotherapy. During the last decade important advances in immunotherapy have proven especially useful for patients with relapsing-remitting MS. Escalating algorithms are available for both relapses and long-term immunotherapy. Novel therapeutic approaches with monoclonal antibodies have increasing importance, yet side effects are not completely understood. The pathogenetic insights presented here may open new avenues for novel immunotherapies and lead to individualized MS therapy in the future. Limitations are given for primary progressive MS due to the lack of suitable tissue specimens and experimental models. Neuroprotective treatment strategies aiming at the protection of glial and neuronal cells are still in early stages of development.

Palliative care in patients with severe multiple sclerosis: two case reports and a survey among German MS neurologists.

Due to its chronic and fluctuating time course, multiple sclerosis (MS), thus far, has not been regarded as a focus of palliative care. However, sometimes we are confronted with severely affected MS patients, who suffer from complex medical, physical and psychosocial problems, which are not fully covered by the current health care services. We present two cases of severely affected MS patients we saw in our outpatient MS clinic, and who, we believe, are candidates for palliative care. The first patient, with primary chronic progressive (pcP) MS for many years (Expanded Disability Status Scale (EDSS): 8.0) presented with complex painful dysaesthesias and a depressive syndrome. He refused any treatment, and finally committed suicide with the help of a euthanasia group in Switzerland. The second patient was also severely affected by a secondary chronic progressive (scP) MS (EDSS: 9.0) and was finally admitted to our palliative care unit due to a complex pain syndrome associated with panic attacks and anxiety. She spent three weeks on the palliative care unit and her symptoms improved gradually after changing and optimising her pain medication. The patient was discharged with home care and is seen regularly on the palliative care unit. Additionally, as a first step, a questionnaire was sent to 53 German MS specialists regarding their general view on the needs for palliative care in MS. Our two cases and the results of the questionnaire demonstrated that MS patients and their caregivers are confronted with a variety of symptoms which are difficult to treat, and are a cause of great suffering for the patients, including ataxia, depression and fatigue. The data of the questionnaire also showed that neurologists usually do not deal with end-of-life care issues in MS.More research is needed to define the role of palliative care in MS and establish appropriate interventions to improve the quality of life in advanced stage MS patients and their relatives.

Deficiency of the autoimmune regulator AIRE in thymomas is insufficient to elicit autoimmune polyendocrinopathy syndrome type 1 (APS-1).

Thymomas are thymic epithelial neoplasms, associated with a variety of autoimmune disorders (especially myasthenia gravis), that apparently result from aberrant intra-tumourous thymopoiesis and export of inefficiently tolerized T-cells to the periphery. The autoimmune regulator (AIRE) drives the expression of self-antigens in the thymic medulla and plays an essential role in 'central' tolerance in both humans and mice. However, while inactivating AIRE mutations result in the 'autoimmune polyendocrinopathy syndrome type 1' (APS-1), its major features are not well reproduced in AIRE-knock-out mice. Therefore, alternative human disease scenarios with concomitant AIRE deficiency may be valuable tools to test conclusions drawn from mouse models. Here we show, in a large series, that approximately 95% of thymoma patients are 'chimeric'; expression of AIRE and major AIRE-related autoantigens (eg insulin) were undetectable in their tumours but maintained in their remnant thymic tissue and lymph nodes. Notably, despite the AIRE-deficient thymopoiesis in thymomas, disorders and autoantibodies typical of APS-1 were distinctly uncommon in these patients. The one striking similarity was in the recently observed neutralizing anti-type I interferon (IFN) antibodies, which are found at diagnosis in 100% of patients with APS-1 and in approximately 60% of patients with thymomas, as we show here. We conclude that APS-1 type autoantigens must be protected from autoimmunity by mechanisms that do not extend to the muscle autoantigens so frequently targeted in thymoma patients but so rarely recognized in APS-1. Thus our findings argue strongly for a tolerogenic function of AIRE beyond its role in negative T-cell selection in human thymopoiesis, and/or for specific autoimmunization against muscle in thymomas.

Safety and feasibility of long-term temozolomide treatment in patients with high-grade glioma.

We surveyed neuro-oncologists regarding patients treated with temozolomide for at least 12 cycles or 12 months. Patients receiving first-line temozolomide for a median 13 cycles had a median progression-free survival (PFS) of 14 months. Patients with recurrent disease receiving a median 14 cycles had a median PFS of 15.5 months. A small percentage of patients experienced grade III to IV toxicity. These results suggest that long-term treatment with temozolomide is feasible and well tolerated.

Analysis of the C/T(-1) single nucleotide polymorphism in the CD40 gene in multiple sclerosis.

The costimulatory CD40-CD40L pathway plays a critical role in the generation and maintenance of adaptive immune responses. Genetic interference of CD40-CD40L interactions strongly influences the onset and course in many autoimmune disease models including experimental autoimmune encephalomyelitis. We analysed the association of a single nucleotide polymorphism of the CD40 gene (C/T(-1)) in 287 patients with multiple sclerosis (MS) and 184 matched controls. No significant differences were found in the frequency of the C/T(-1) polymorphism between the patients with MS and the controls (53% vs 49%) or among different MS subtypes. Cell surface expression of CD40 did not differ within the different genotypes, but carriers of the T allele showed a trend for a lower stimulatory index compared with individuals with the CC genotype. Although these subtle differences indicate functional consequences in the immune stimulatory capabilities related to the CD40 C/T(-1) polymorphism, our population-based study found no association with disease susceptibility or disease course in MS.

Analysis of the monocyte chemoattractant protein 1 -2518 promoter polymorphism in patients with multiple sclerosis.

Cytokines and chemokines like the proinflammatory chemokine, monocytechemoattractant protein 1 (MCP-1) are important for the recruitment of inflammatory cells into multiple sclerosis (MS) lesions. Recently, a nucleotide substitution from adenosine to guanosine (A-->G) at position -2518 of the MCP-1 promoter was shown to be associated with increased MCP-1 expression. We analysed MCP-1 genotypes in 634 MS patients and 405 healthy controls. The allelic frequencies were comparable between both groups. No correlation was found between genotype and disease course, disease severity or age of disease onset. Although statistically no+ significant mRNA expression and MCP-1 secretion were elevated in patients carrying the mutant allele. Thus, our data could not reveal any association between the MCP-1 -2518 polymorphism and susceptibility to or clinical disease course of MS.

Frequent detection of Mycoplasma pneumoniae in Bell's palsy.

The cause of Bell's palsy (BP) remains unknown despite various hints to an infectious etiology. Mycoplasma pneumoniae is a common pathogen of the respiratory tract causing pharyngitis, tracheobronchitis or pneumonia. Neurological complications are the most frequent extrapulmonary manifestation. So far, only a few case reports suggested an association between cranial nerve palsy and M. pneumoniae infection. Patients with a BP who were admitted to the Department of Otorhinolaryngology or Neurology of the University of Wuerzburg between 2000 and 2002 were tested serologically for the presence of antibodies against Borrelia burgdorferi, herpes viruses (HSV-1/2, VZV) and M. pneumoniae. The diagnosis of mycoplasmal infection was made when at least one of the following criteria was met: a threefold rise or more in the titer of antibody of M. pneumoniae in paired sample or a microparticle agglutination assay (MAG) of > or =1:40 and the detection of IgA and/or IgM antibodies in the acute phase serum. Ninety-one consecutive patients could be included. Fifteen patients showed a reactivation of a VZV ( n=12) or of a HSV-1 ( n=3) infection. In six cases the immunoblot revealed specific antibody bands for B. burgdorferi. In 24 patients (26.4%) a seroconversion of M. pneumoniae could be detected. Only two patients complained of mild respiratory symptoms. According to our results, M. pneumoniae is frequently associated with Bell's palsy. Thus, a routine screening for this pathogen, even in the absence of respiratory symptoms, is necessary.

Combination of serum markers related to several mechanisms in Alzheimer's disease.

Alzheimer's disease (AD) probably involves several pathobiochemical mechanisms and this may be reflected by changes in different serum components. The present study investigated whether the combined analysis of serum molecules related to different mechanisms improves the discrimination of AD patients from healthy controls. Serum of patients with AD was analyzed for a broad spectrum of marker molecules, including 11 inflammatory proteins, 12 sterol intermediates and phytosterols, 2 brain-specific proteins and 4 constituents involved in homocysteine homeostasis. The serum molecule concentrations were combined in a logistic regression model, using a forward stepwise inclusion mode. The results showed that the combination of interleukin-6 (IL-6) receptor, protein alpha1 fraction, cysteine and cholesterol concentrations improved the discrimination between AD patients and healthy controls compared to the single markers. In conclusion, the results of this study have shown that the complex pathology in AD is reflected in a pattern of altered serum concentrations of several marker molecules related to several pathobiochemical mechanisms.

Modulation of cytokine mRNA expression by brain-derived neurotrophic factor and nerve growth factor in human immune cells.

Brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) exert various effects on immune cells. Here we studied, whether they influence the cytokine expression pattern in peripheral blood mononuclear cells (PBMCs) or antigen specific T-cells. In PBMCs BDNF and NGF had interindividually variable effects on T helper cell type (Th)1- and Th2-cytokines. However, there was a high correlation between the modulating properties of these neurotrophins (r=0.97) concerning the expression of interleukin (IL) 4, transforming growth factor-beta and tumour necrosis factor-alpha mRNA at a concentration of 100 ng/ml. In myelin basic protein-specific T-cell lines BDNF and NGF increased interferon -gamma mRNA to a moderate extent, but not IL4. No major effects were detected at the cytokine protein level. In conclusion, our results suggest a partial effect of neurotrophins on immune cells, which may be modified by other signals.

Serial analysis of cytokine mRNA profiles in whole blood samples from patients with early multiple sclerosis.

In this pilot study, we serially determined the cytokine messenger RNA (mRNA) expression pattern in whole blood samples from 12 patients with clinical isolated syndrome suggestive of early multiple sclerosis (MS) using a new sensitive quantitative polymerase chain reaction (PCR) method. Significantly higher levels of tumor necrosis factor-alpha (TNF-alpha; x 5.1), interferon-gamma (IFN-gamma; x 4.8) and interleukin-10 (IL-10; x 5.6) mRNA were detected in MS patients at the time of a relapse compared to healthy controls. Treatment with i.v. methylprednisolone (MP) led to an increase of IL-4 mRNA and a significant decrease of IFN-gamma and TNF-alpha mRNA expression. In this cohort of clinically stable patients, proinflammatory cytokines remained low during the 1-year follow-up period. As several indications point to a cytokine dysregulation in MS, quantitative analysis of cytokine mRNA profiles in whole blood samples by real time PCR may be a useful immunological marker to monitor disease activity in future therapeutic trials in MS.

Expression of tumor necrosis factor-alpha and interferon-gamma mRNA in blood cells correlates with depression scores during an acute attack in patients with multiple sclerosis.

Depression is a common problem in multiple sclerosis (MS) and affects about 50% of MS patients. Since a dysregulation of cytokine levels has been implicated in the pathogenesis of MS and alterations in cytokine serum levels have been found in depressive illness, we examined the relationship between depressive symptoms, cytokine mRNA expression levels of Th1-type and Th2-type cytokines and neurological disability among early diagnosed MS patients in a prospective study. Sixteen patients with clinically or laboratory supported MS were assessed using the Beck Depression Inventory (BDI) and the Kurtzke Expanded Disability Status Scale (EDSS). Cytokine mRNA in whole blood was serially determined by a new quantitative polymerase chain reaction (PCR) method. BDI sum scores (2,9 fold) and the expression levels of tumor necrosis factor-alpha (TNF-alpha; 4 fold), interferon-gamma (IFN-gamma; 4,6 fold) and interleukin-10 (IL-10; 6,1 fold) mRNA were increased in MS patients during an acute attack compared to age and sex matched healthy controls. We detected a significant positive correlation between TNF-alpha (r=0.55) and interferon-gamma (r=0.54) mRNA expression and the BDI sum scores during an acute attack in MS patients. At follow-up after 3-6 months, only TNF-alpha mRNA expression was correlated with BDI sum scores (r=0.62 resp. r=0.31). No correlation of the BDI sum scores with Th2-type cytokine mRNA expression for interleukin-4 (IL-4) and interleukin-10 (IL-10) or with the extent of neurological disability was observed. The possible contribution of Th1-type cytokines to the development of depression in MS is discussed.

Effects of oncostatin M on human cerebral endothelial cells and expression in inflammatory brain lesions.

Oncostatin M (OSM) is a member of the interleukin (IL)-6 cytokine family and modulates inflammatory responses. Here we investigated the role of OSM as an immunoregulatory factor for human cerebral endothelial cells (HCEC). Using RT-PCR we detected transcripts of the receptor components involved in OSM signaling, gp130, OSM receptor (OSMR)-beta, and leukemia inhibitory factor receptor (LIFR), in HCEC. A parallel FACS analysis revealed surface expression of gp130 and OSMR-beta, but not of LIFR on these cells. Functionally, OSM upregulated intercellular adhesion molecule-1, but did not induce vascular cell adhesion molecule-1 in HCEC. Further, OSM upregulated IL-6 and monocyte chemoattractant protein (MCP)-1, whereas IL-8 was unaffected. Combined application of tumor necrosis factor (TNF)-alpha and OSM synergistically enhanced IL-6 and MCP-1 production, but downregulated TNF-alpha-induced IL-8. As OSM regulated molecules relevant in inflammatory brain diseases, we investigated its expression in normal and pathological human brains. OSM was detected by immunohistochemistry in brains from multiple sclerosis patients in microglia, reactive astrocytes, and infiltrating leukocytes, whereas in normal brains and noninflammatory neurological diseases. immunoreactivity was absent from the parenchyma. These data suggest that immunoregulatory functions in human cerebral endothelial cells may be a mechanism by which OSM participates in the pathophysiology of inflammatory brain disease.

[Early multiple sclerosis therapy in the effects of public health economics]. / Frühe Multiple-Sklerose-Therapie und ihre gesundheitsökonomischen Auswirkungen.

BACKGROUND: Meanwhile, a number of drugs are available for the course-modifying therapy of multiple sclerosis. Their use depends on the individual indication as well as on the patient's compliance, but also increasingly on the economic considerations of the public health system. For years, the costs of multiple sclerosis and the critically evaluated cost-benefit analyses were based on estimated figures. PATIENTS AND METHODS: For better transparency of the actual costs of the disease, a cross-sectional study of multiple sclerosis patients was performed for the first time in Germany, where the patients answered questionnaires as to their financial resources and quality of life. Within this representative framework of questionnaires, data of 737 patients were evaluated. RESULTS: This study came up with a total cost of DM 65,400.-per patient and year. The complete costs of multiple sclerosis, based on an estimated number of 120,000 patients, thus run up to 7.85 bio. DM a year. Only a small percentage is caused by medication (7%), including the use of new extremely expensive drugs. There is a positive correlation between the severity of the disease and the underlying costs of treatment. CONCLUSION: Due to these results, concrete health-economic goals in the treatment of patients with multiple sclerosis should aim at stabilization on a low disability level at an early stage of the disease.

Genetic polymorphism of the tumor necrosis factor (TNF)-alpha promoter region in families with localized early-onset periodontitis.

Tumor necrosis factor (TNF)-alpha is a potent proinflammatory cytokine that is able to induce tissue destruction and bone resorption. A G-to-A polymorphism at the -308 position of the TNF-alpha promoter region was suggested to influence TNF-alpha production. We had previously shown that monocytes of patients with localized early-onset periodontitis (EOP) secrete high levels of TNF-alpha compared to matched controls. The aim of the present study was to investigate the possible link between the -308 polymorphism in the TNF-alpha gene and EOP. Genomic DNA was extracted from the blood of 64 individuals from 11 nuclear families with EOP. The TNF-alpha polymorphism at -308 was assessed using allele-specific polymerase chain reaction. 77% of the tested adolescents were found to have the G/G genotype, and 23% had the A/G genotype. In the diseased subjects, 81% were with G/G genotype and 19% with A/G genotype. The healthy children had 74% G/G genotype, while 26% had A/G genotype. The differences between the disease group and the healthy group were not statistically significant. In summary, the present results could not demonstrate any link between EOP and genetic polymorphism in the -308 position of the TNF-alpha promoter.