[Early therapy of axial spondyloarthritis and relevance of radiological progression]. / Frühtherapie bei axialer Spondyloarthritis und Relevanz der radiologischen Progression.

In recent years great achievements have been made in terms of early diagnosis of axial spondyloarthritis (SpA). In addition new classification criteria have been established. An early diagnosis offers the possibility for effective early treatment. For the treatment of axial SpA according to the Assessment of Spondyloarthritis International Society-European League Against Rheumatism (ASAS-EULAR) recommendations non-steroidal anti-inflammatory drugs (NSAIDs) should be used first. In cases of non-response to at least 2 different NSAIDs given for at least 4 weeks, tumor necrosis factor alpha (TNF-α) blocking agents can be used. Data from three clinical trials with TNF-α blockers in early axial SpA showed that clinical remission can be reached in about 50% of cases. Furthermore, it could be shown that during TNF-α blocking treatment acute inflammatory lesions of the sacroiliac joints, the spine and entheses could be effectively reduced in magnetic resonance imaging (MRI). Recently a close interaction between acute inflammation, TNFα blockade and the development of fatty lesions could be shown. This is an important step for understanding the process of radiographic progression in axial SpA. Early treatment might prevent radiographic progression.

Treatment of active ankylosing spondylitis with abatacept: an open-label, 24-week pilot study.

OBJECTIVE: To prospectively explore the short-term efficacy and safety of abatacept in patients with ankylosing spondylitis (AS). METHODS: In this prospective open-label pilot study, abatacept (10 mg/kg) was administered intravenously on days 1, 15, 29 and every 28 days thereafter up to week 24 in 15 tumour necrosis factor α (TNFα)-inhibitor naive patients (group 1) and 15 patients with inadequate response to TNFα inhibitors (group 2) with active AS. The primary end point was the proportion of patients with 40% improvement according to the Assessment of SpondyloArthritis international Society criteria (ASAS40) in both groups at week 24. RESULTS: At week 24, ASAS40 was reached by 13% of group 1 and 0% of group 2; 20% improvement (ASAS20) was reached by 27% and 20%, respectively. There was no significant change of Bath Ankylosing Spondylitis Disease Activity Index score, patient global assessment or C reactive protein. Overall, abatacept was well tolerated. CONCLUSIONS: In this pilot open-label AS study a major response was not observed.

Effects of etanercept versus sulfasalazine in early axial spondyloarthritis on active inflammatory lesions as detected by whole-body MRI (ESTHER): a 48-week randomised controlled trial.

PURPOSE: To evaluate the potential of etanercept versus sulfasalazine to reduce active inflammatory lesions on whole-body MRI in active axial spondyloarthritis with a symptom duration of less than 5 years. METHODS: Patients were randomly assigned to etanercept (n=40) or sulfasalazine (n=36) treatment over 48 weeks. All patients showed active inflammatory lesions (bone marrow oedema) on MRI in either the sacroiliac joints or the spine. MRI was performed at weeks 0, 24 and 48 and was scored for active inflammatory lesions in sacroiliac joints and the spine including posterior segments and peripheral enthesitis by two radiologists, blinded for treatment arm and MRI time point. RESULTS: In the etanercept group, the reduction of the sacroiliac joint score from 7.7 at baseline to 2.0 at week 48 was significantly (p=0.02) larger compared with the sulfasalazine group from 5.4 at baseline to 3.5 at week 48. A similar difference in the reduction of inflammation was found in the spine from 2.2 to 1.0 in the etanercept group versus from 1.4 to 1.3 in the sulfasalazine group between baseline and week 48, respectively (p=0.01). The number of enthesitic sites also improved significantly from 26 to 11 in the etanercept group versus 24 to 26 in the sulfasalazine group (p=0.04 for difference). 50% of patients reached clinical remission in the etanercept group versus 19% in the sulfasalazine group at week 48. CONCLUSION: In patients with early axial spondyloarthritis active inflammatory lesions detected by whole-body MRI improved significantly more in etanercept versus sulfasalazine-treated patients. This effect correlated with a good clinical response in the etanercept group.

Relationship between active inflammatory lesions in the spine and sacroiliac joints and new development of chronic lesions on whole-body MRI in early axial spondyloarthritis: results of the ESTHER trial at week 48.

AIM: To investigate the relationship between active inflammatory lesions on whole-body MRI (wb-MRI) and new development of chronic lesions on T1 MRI in patients with early axial spondyloarthritis (SpA) treated either with etanercept (ETA) or sulfasalazine (SSZ). METHODS: Wb-MRIs of 65 patients treated either with ETA (n=35) or SSZ (n=30) over 1 year were scored for active inflammation, fatty lesions, erosions and ankylosis in the 23 vertebral units (VUs) of the spine and in the sacroiliac joints (SI joints). Scoring was performed by two blinded radiologists. RESULTS: If there was no previous inflammation in the bone no new fatty lesions occurred in SI joint quadrants and only a few (0.6%) in spine VUs. There was a significant relationship between disappearance of inflammation and the appearance of fatty lesions: if baseline inflammation resolved fatty lesions occurred in 10.5% of SI joint quadrants and 17.9% of VUs. If inflammation did not resolve over 1 year, fatty lesions occurred less frequently: 2.4% (SI joint quadrants) and 7.2% (VUs). There was a significantly higher increase of the mean fatty lesion score between baseline and week 48 in the ETA (4.0 vs 4.8 for the SI joints and 1.9 vs 2.7 for the spine) compared to the SSZ (3.0 vs 3.2 for the SI joints and 1.1 vs 1.2 for the spine, respectively) group (p=0.001 and p=0.020 for the differences). No significant changes in the erosion or ankylosis score were observed in any of the two groups during this time. CONCLUSIONS: These data indicate that there is a close interaction between inflammation, tumour necrosis factor blockade and the development of fatty lesions in subchondral bone marrow of patients with axial SpA.

Different response to rituximab in tumor necrosis factor blocker-naive patients with active ankylosing spondylitis and in patients in whom tumor necrosis factor blockers have failed: a twenty-four-week clinical trial.

OBJECTIVE: Histologic studies have shown B cell clusters in the subchondral bone marrow of the spine of patients with ankylosing spondylitis (AS). An immunotherapy targeting B cells in AS is therefore of interest. We undertook this study to examine the efficacy and safety of rituximab in patients with AS refractory to nonsteroidal antiinflammatory drugs in whom previous treatment with tumor necrosis factor alpha (TNFalpha) blockers either had not been tried or had failed. METHODS: In this phase II clinical trial, 1,000 mg rituximab was administered intravenously at baseline and at week 2 in 20 patients with active AS. Ten of these patients had never received TNF blockers, and treatment with TNF blockers had failed in the other 10 patients. The primary end point was a 20% improvement in disease activity at week 24 according to the criteria of the Assessment of SpondyloArthritis international Society (an ASAS20 response). RESULTS: Seventy-five percent of the patients were male, 90% were HLA-B27 positive, their mean age was 39.7 years, and their mean disease duration was 16.8 years. Patients had active disease, defined as a Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) score >or=4. While there was no clear response at week 24 in the group in whom TNF blockers had failed (30% had achieved an ASAS20 response, 10% had achieved an ASAS40 response, none had achieved partial remission according to the ASAS criteria, and none had achieved 50% improvement on the BASDAI [a BASDAI50 response] beyond an expected placebo response), we observed a good improvement in the TNF blocker-naive group at week 24 (50% had achieved an ASAS20 response, 40% had achieved an ASAS40 response, 30% had achieved partial remission according to the ASAS criteria, and 50% had achieved a BASDAI50 response). CONCLUSION: Although rituximab does not seem to be effective in patients with AS that does not respond to TNF blockers, it had significant efficacy in TNF blocker-naive patients. Therefore, further controlled trials with B cell-directed therapies should be performed in TNF blocker-naive AS patients in the future.

[Advice for patients diagnosed with ankylosing spondylitis: results of a representative patient survey in Germany]. / Hinweise für Patienten mit der Diagnose Ankylosierende Spondylitis: Ergebnisse einer Repräsentativbefragung der Deutschen Vereinigung Morbus Bechterew e.V.

BACKGROUND: Following the diagnosis of a chronic disease like ankylosing spondylitis (AS), patients need extensive information on what to expect, how to behave and what they need to be aware of in particular in order to contribute to a favourable disease outcome. METHODS: A questionnaire consisting of 82 questions regarding demographics, diagnosis, information received with the diagnosis, disease activity, function, quality of life, treatment, ability to work, smoking etc. was distributed to AS patients by rheumatologists in 51 hospitals and/or private practices. In addition, the questionnaire was sent to 3400 randomly selected members out of the 14,000 patient members of the German Ankylosing Spondylitis Society (Deutsche Vereinigung Morbus Bechterew, DVMB). RESULTS: In all, 1068 DVMB members and 205 non-members responded to the survey. Almost all of these indicated that they had received at least one piece of information regarding what they should be particularly aware of, at the time of diagnosis. A total of 69% were informed about the need for daily exercise, 51% about the value of individual physiotherapy, 38% about the value of group physiotherapy, 37% about the need to maintain an upright posture, and 33% were recommended 3 weeks in a rehabilitation centre. Less than 30% were informed about appropriate sports, appropriate working conditions, suitable chairs, mattress, pillows etc., about the value of radon therapy or about joining a disease-specific patient organisation. To the question regarding what patients meanwhile consider as most important, daily exercise (50%) and sufficient movement at work and leisure (55%) were reported most frequently. Other aspects regarded as important to patients included a flat, firm mattress (53%), avoiding large pillows (42%), keeping an upright posture at work (38%), appropriate sports (36%), and an upright posture also when not at work (34%). Of the DVMB members, 46% had participated in disease-specific standardised patient education, compared with only 31% of non-members (p<0.001).

The ASAS-OMERACT core domain set for axial spondyloarthritis.

BACKGROUND: The current core outcome set for ankylosing spondylitis (AS) has had only minor adaptations since its development 20 years ago. Considering the significant advances in this field during the preceding decades, an update of this core set is necessary. OBJECTIVE: To update the ASAS-OMERACT core outcome set for AS into the ASAS-OMERACT core outcome set for axial spondyloarthritis (axSpA). METHODS: Following OMERACT and COMET guidelines, an international working group representing key stakeholders (patients, rheumatologists, health professionals, pharmaceutical industry and drug regulatory agency representatives) defined the core domain set for axSpA. The development process consisted of: i) Identifying candidate domains using a systematic literature review and qualitative studies; ii) Selection of the most relevant domains for different stakeholders through a 3-round Delphi survey involving axSpA patients and axSpA experts; iii) Consensus and voting by ASAS; iv) Endorsement by OMERACT. Two scenarios are considered based on the type of therapy investigated in the trial: symptom modifying therapies and disease modifying therapies. RESULTS: The updated core outcome set for axSpA includes 7 mandatory domains for all trials (disease activity, pain, morning stiffness, fatigue, physical function, overall functioning and health, and adverse events including death). There are 3 additional domains (extra-musculoskeletal manifestations, peripheral manifestations and structural damage) that are mandatory for disease modifying therapies and important but optional for symptom modifying therapies. Finally, 3 other domains (spinal mobility, sleep, and work and employment) are defined as important but optional domains for all trials. CONCLUSION: The ASAS-OMERACT core domain set for AS has been updated into the ASAS-OMERACT core domain set for axSpA. The next step is the selection of instruments for each domain.

Comparison of the Bath Ankylosing Spondylitis Disease Activity Index and a modified version of the index in assessing disease activity in patients with ankylosing spondylitis without peripheral manifestations.

OBJECTIVE: To compare the original Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) with a modified BASDAI without questions about peripheral arthritis (question 3) and enthesitis (question 4), here termed the mini-BASDAI, as an instrument to assess disease activity in patients with ankylosing spondylitis (AS) without peripheral manifestations. METHODS: The mini-BASDAI was calculated by omitting questions 3 and 4. The correlation of the original BASDAI and the mini-BASDAI with patient global and other disease parameters was assessed in a total of 692 patients from three AS cohorts including one observational AS cohort and two clinical trial populations treated with non-steroidal anti-inflammatory drugs and tumour necrosis factor alpha inhibitors. Sensitivity to change was assessed by calculating effect sizes. RESULTS: Up to 70% of AS patients did not have peripheral involvement. Patients with peripheral involvement had higher disease activity in all activity parameters. The mini-BASDAI had higher values compared with the original BASDAI, also in the subgroup with peripheral manifestations. However, the mini-BASDAI did not correlate better with other markers of disease activity compared with the original BASDAI. Furthermore, effect sizes of the original BASDAI and mini-BASDAI were comparable in the treatment trials. Interestingly, approximately 5% of active AS patients with pure axial disease manifestation were identified whose disease activity was underestimated by the original BASDAI. CONCLUSION: On a group level using the mini-BASDAI did not result in an advantage to assess disease activity or in the subgroup without peripheral involvement. In only approximately 5% of AS patients was the mini-BASDAI superior to the original BASDAI.

Contrast-enhanced ultrasound in monitoring the efficacy of a bradykinin receptor 2 antagonist in painful knee osteoarthritis compared with MRI.

OBJECTIVES: To evaluate contrast-enhanced ultrasound (CE-US) as a monitoring tool to assess hypervascularisation of synovial processes in knee osteoarthritis (OA) treated with intra-articular injections of the bradykinin-receptor 2 antagonist icatibant compared to contrast-enhanced magnetic resonance imaging (CE-MRI). PATIENTS AND METHODS: In a randomised, double-blind, placebo-controlled trial, 41 patients with painful knee OA underwent US (12.5 MHz for B-mode and 3-8 MHz for CE-US), and 36 of the patients underwent additional MRI (0.2T) at baseline and after 3 injections of the study drug (after a mean of 22.2 days). A total of 15 patients received placebo (group A), 12 patients 500 microg icatibant (group B) and 14 patients 2000 microg icatibant (group C). Pain and the synovial process (B-mode, power Doppler US (PD-US), CE-US, CE-MRI) were assessed at both time points. RESULTS: At baseline, the placebo group showed more activity in terms of effusion in the superior and lateral recess in ultrasound as well as in PD-US in the lateral recess. Pain improved significantly in all subgroups. Effect sizes were 0.43 (pain at rest) and 0.52 (pain during activity) in group B vs 0.48 and 1.11 in group C. There was no change of US and MRI parameters. We found moderate to good correlation (r) and kappa values (kappa) for effusion in the superior recess (r = 0.591, k = 0.453), effusion in the lateral recess (r = 0.304, k = 0.440) and contrast enhancement (r = 0.601, k = 0.242) between US and MRI. CONCLUSIONS: Our results show that CE-US and CE-MRI have good agreement in assessing inflammatory changes in knee OA. For the 41 patients with OA, an analgesic effect of icatibant could clearly be shown, especially for pain during activity in the high dose icatibant group. However, we could not find an anti-inflammatory effect of icatibant by CE-US compared to CE-MRI.

A systematic comparison of rheumatoid arthritis and ankylosing spondylitis: non-steroidal anti-inflammatory drugs.

Non-steroidal anti-inflammatory drugs (NSAIDs) play different roles in the management of patients with rheumatoid arthritis (RA) and ankylosing spondylitis (AS). In RA there is minimal evidence that NSAIDs are able to alter the course of disease or prevent joint destruction and, therefore, they should mostly be used as a short-term bridging therapy. In contrast to RA, in AS NSAIDs are considered as a cornerstone of the treatment not only because of a high symptomatic efficacy, but also because they might even retard osteoproliferation and radiographic progression. Considering younger age of AS patients and lower prevalence of comorbidities, they are probably at lower risk for cardiovascular and gastrointestinal side effects of short- and long-term NSAID therapy in comparison to RA.

The diagnostic value of scintigraphy in assessing sacroiliitis in ankylosing spondylitis: a systematic literature research.

BACKGROUND: The diagnostic value of scintigraphy in detecting sacroiliitis in patients with spondyloarthritis is not clear. OBJECTIVE: To assess the diagnostic value of scintigraphy in detecting sacroiliitis in ankylosing spondylitis (AS) and in patients with clinically probable sacroiliitis without x-ray changes. MATERIALS AND METHODS: A systematic literature research was performed in the Pubmed and Medline database up to August 2007. Articles in English and German on patients with established AS and clinically probable sacroiliitis without x-ray changes were selected. In addition, studies including patients with mechanical low back pain as a control group were searched. Pooled sensitivity, specificity and positive and negative likelihood ratios were calculated. RESULTS: In total 99 articles about scintigraphy were found. 25 articles were included into the analysis. Overall sensitivity for scintigraphy to detect sacroiliitis was 51.8% for patients with established AS (n = 361) and 49.4% for patients with probable sacroiliitis (n = 255). Sensitivity of scintigraphy in patients with AS with inflammatory back pain (indicating ongoing inflammation) was 52.7% (n = 112) and in patients with AS and suspected sacroiliitis with magnetic resonance imaging showing acute sacroiliitis (as a gold standard) was 53.2% (n = 62). In controls with mechanical low back pain specificity was 78.3% (n = 60) resulting in likelihood ratios not higher than 2.5-3.0. CONCLUSION: These data as a result of a literature research suggest that scintigraphy of the sacroiliac joints is at most of limited diagnostic value for the diagnosis of established AS, including the early diagnosis of probable/suspected sacroiliitis.

Knee osteoarthritis. Efficacy of a new method of contrast-enhanced musculoskeletal ultrasonography in detection of synovitis in patients with knee osteoarthritis in comparison with magnetic resonance imaging.

OBJECTIVE: To develop a new method of digital synovial vascularisation quantification by using contrast-enhanced musculoskeletal ultrasonography (MUS) in detecting synovitis in patients with knee osteoarthritis (OA) compared with healthy subjects and MRI. METHODS: Evaluation of 41 patients with painful knee OA and 6 healthy subjects. The severity of knee pain was evaluated. All patients and all 6 healthy subjects underwent contrast medium-enhanced (CE)-MUS with SonoVue, and 36 patients additionally underwent CEMRI with Magnevist. Joint effusion, synovial thickening and pain were assessed and compared with B-mode and Power Doppler sonography (PDS) as well as contrast medium enhancement. RESULTS: Pain evaluated by the visual analogue scale(VAS) hardly correlated with other markers of disease activity measured by ultrasound (US) in B-mode or MRI. US of the superior recess revealed an effusion or synovial thickening in 58%. PDS findings were positive in 63%, and CE-MUS in the superior knee recess was positive in 95%. MRI showed effusion in the superior recess in 61% and showed positive findings in 82% when using contrast medium. The kappa value was 0.48 between US and MRI with regard to the effusion in the superior recess, and 0.53 between PD signal in the superior recess and effusion in the superior recess by US. Using MRI as the reference standard, there was a sensitivity of 72% for assessing effusion in the superior recess and 81% for assessing effusion in the lateral recess. CONCLUSION: Assessment of disease activity (synovitis) in knee OA by VAS is not sufficient. US PDS was more sensitive than B-mode, and CE-MUS was more sensitive than PDS and CE-MRI in detecting synovitis in patients with painful knee OA. Also, CE-MRI was more sensitive in detecting inflammatory changes in the superior recess than without contrast medium. Using CE-MUS and performing time/intensity analysis has shown to be a good model for evaluation of an inflammatory process in the setting of knee OA in the superior recess.

Evidence-based recommendations for the management of ankylosing spondylitis: systematic literature search of the 3E Initiative in Rheumatology involving a broad panel of experts and practising rheumatologists.

OBJECTIVE: Recommendations and/or guidelines represent a popular way of integrating evidence-based medicine into clinical practice. The 3E Initiatives is a multi-national effort to develop recommendations for the management of rheumatic diseases, which involves a large number of experts combined with practising rheumatologists addressing specific questions relevant to clinical practice. METHODS: Ten countries participated in three rounds of discussions and votes concerning the management of AS. A set of nine questions was formulated in the domains of diagnosis, monitoring and treatment, after a Delphi procedure. A literature search in MedLine was conducted. Predefined outcome parameters for the domains of diagnosis, monitoring and treatment were assessed. The evidence to support each proposition was evaluated and scored. After discussion and votes, the final recommendations were presented using brief statements by each national group, following which the final international recommendations were formulated. RESULTS: A total of 2699 papers were found and 467 were selected for analysis. Twelve key recommendations were developed: three in the domain of diagnosis addressing general diagnostic considerations, early AS diagnosis and general practitioners' referral recommendations; three concerning monitoring of AS disease activity, severity and prognosis; six concerning pharmacological treatment (except biologics): non-steroidal anti-inflammatory drugs/COX-II inhibitors, bisphosphonates and treatment of enthesitis. The compiled agreement among experts ranged from 72% to 93%. CONCLUSION: Recommendations for the management of AS were developed using an evidence-based approach followed by expert/physician consensus with high level of agreement. Involvement of a larger and more representative group of rheumatologists may improve their dissemination and implementation in daily clinical practice.

Multicenter open-label study with infliximab in active ankylosing spondylitis over 28 weeks in daily practice.

OBJECTIVE: The aim of this study was to prospectively investigate the therapeutic efficacy and safety of infliximab therapy in NSAID-refractory AS patients, with special emphasis on impact on quality of life in daily practice. PATIENTS AND METHODS: 101 AS patients with active disease (mean Bath ankylosing spondylitis activity index (BASDAI) 6.3, range 4.0-9.8) were enrolled in an open label study. Infliximab 5 mg/kg body weight was administered intravenously at week 0, 2, 6, 12, 18 and 24 followed by a final assessment at week 28. Clinical assessments included quality of life (SF-36, primary endpoint), disease activity (BASDAI), function (BASFI), metrology (BASMI), patients' and physicians' global, pain, work productivity (WPAI) and CRP. RESULTS: Using an intention to treat (ITT) analysis, the mean SF-36 physical health component improved from 27.6 at baseline to 40.9 at study end (p<0.001), the mean SF-36 mental health component improved from 44.4 at study entry to 53.0 at final assessment (p<0.001). The Assessment of AS (ASAS-) 20 short-term improvement criteria were reached by 80.2% of patients, ASAS 40 by 60.4% and the ASAS criteria for partial remission were reached by 27.7% of patients. A BASDAI 50% improvement was found in 66.3% of patients. Comparable significant improvements were found for mean BASDAI; BASFI, BASMI, patients' and physicians' global, general pain, CRP and WPAI. 11.8% of patients stopped therapy because of side effects. CONCLUSIONS: Infliximab showed high efficacy and safety when used by non-specialised rheumatologists in daily practice.

Chronic hepatitis B in hepatocarcinogenesis.

Hepatocellular carcinoma (HCC) is the fifth most common cancer in the world, and has a wide geographical variation. Eighty per cent of HCC is attributed to hepatitis B virus (HBV). The predominant carcinogenic mechanism of HBV associated HCC is through the process of liver cirrhosis, but direct oncogenic effects of HBV may also contribute. Prevention of HBV infections as well as effective treatment of chronic hepatitis B is still needed for the global control of HBV associated HCC. Continued investigation of the mechanisms of hepatocarcinogenesis will refine our current understanding of the molecular and cellular basis for neoplastic transformation in the liver.

Inhibition of pulmonary cancer progression by epidermal growth factor receptor-targeted transfection with Bcl-2 and survivin siRNAs.

Clinical application of small interfering RNA (siRNA) in cancer therapy has been limited by the lack of an efficient systemic siRNA delivery system. In this report we describe an efficient siRNA delivery system directed to metastasized tumors, especially in the lungs. Anticancer siRNA was condensed in the presence of 9-arginine peptides (9Arg) and then complexed with cationic O,O'-dimyristyl-N-lysyl glutamate liposomes conjugated to antibodies against the epidermal growth factor receptor (EGFR). The ternary complex of optimized anti-EGFR-9Arg-lipoplexes exhibited efficient siRNA transfection of LS174T-Luc cancer cells grown in culture or orthotopically in mouse lungs. Anti-tumor Bcl-2/survivin siRNAs loaded in the anti-EGFR-9Arg-lipoplexes effectively suppressed transcription of their target genes, resulting in an efficient cancer cell death. Repeated intravenous administrations of the anti-EGFR-9Arg-lipoplexes effectively inhibited tumor growth in the mouse lungs and prolonged survival of the mice compared with nontargeted lipoplexes. These results suggest that the ternary complexes of anti-EGFR-9Arg-lipoplexes might have clinical applications in RNA interference cancer therapy.

Effect of modified atmosphere packaging and irradiation in combination on content of nitrosamines in cooked pork sausage.

The effect of modified atmosphere packaging and irradiation in combination on nitrosodimethylamine (NDMA) and nitrosopyrrolidine (NPYR) levels in pork sausage was studied. Emulsion-type cooked pork sausage was manufactured and packaged in aerobic, CO2 (100%), N2 (100%), and CO2/N2 (25%/75%) environments, respectively, and irradiated at 0, 5, 10, and 20 kGy with gamma irradiation. The nitrosamine contents were significantly reduced by irradiation, and the reduction of nitrosamines was more extensive with modified atmosphere packaging than with aerobic packaging. The correlation coefficient between irradiation dose and nitrosamine content indicated that irradiation can reduce the levels of nitrosamines. The combination of irradiation and modified atmosphere packaging is effective in enhancing the chemical safety of sausage by reducing nitrosamines, if present, as well as enhancing the microbial safety of cooked pork sausage.

Mitomycin C-induced apoptosis in cultured human Tenon's capsule fibroblasts.

To investigate the mitomycin C-induced apoptotic cell death of fibroblasts, the primarily cultured human Tenon's capsule fibroblasts were exposed to a clinically used dosage of 0.4 mg/ml of mitomycin C for 5 minutes. TUNEL (TdT-mediated dUTP-biotin nick end labeling) assay and electron microscopic studies were performed to determine the extent of mitomycin C-induced apoptosis. A flow cytometric study was performed to quantify the apoptotic cell population over time. The TUNEL stains were positive and electron microscopy showed features of apoptotic cell death in some fibroblasts 3 and 5 days after treatment. Flow cytometric analysis using Annexin V-propidium iodide double staining detected apoptotic cells 3 days after treatment. These apoptotic cell populations increased at 4 days and were sustained for one week. This study revealed that the clinical effects of mitomycin C on fibroblasts may be mediated not only by antiproliferative but also apoptotic cell death to some degree. Therefore, the apoptotic cell death of fibroblasts induced by mitomycin C should be considered to properly understand the mechanism of wound healing after trabeculectomy with adjunctive mitomycin C.

Therapeutic controversies: tumor necrosis factor α inhibitors in ankylosing spondylitis.

Tumor necrosis factor α inhibitors (TNF blockers) have revolutionized the treatment of patients with anklyosing spondylitis. Despite clinical efficacy, there are questions and controversies treating rheumatologists face, which this review discusses: whether there are specific indications for specific TNF blockers; whether the dose of TNF blockers can be decreased; whether immunogenicity plays a role; what the role of residual active inflammation MRI might be; and whether there is a window of opportunity to treat patients with anklyosing spondylitis and prevent radiographic progression. This article summarizes evidence for switching between TNF blockers and addresses the question of malignancies.