Osteoarthritis development related to cartilage quality-the prognostic value of dGEMRIC after anterior cruciate ligament injury.

OBJECTIVE: Rupture of the anterior cruciate ligament (ACL) increases the risk of developing osteoarthritis (OA). Delayed Gadolinium enhanced magnetic resonance imaging (MRI) of cartilage (dGEMRIC) investigates cartilage integrity through T1-analysis after intravenous contrast injection. A high dGEMRIC index represents good cartilage quality. The main purpose of this prospective cohort study was to investigate the prognostic value of the dGEMRIC index regarding future knee OA. METHOD: 31 patients with ACL injury (mean age 27 ± 6.7 (±SD) years, 19 males) were examined after 2 years with 1.5T dGEMRIC of femoral cartilage. Re-examination 14 years post-injury included weight-bearing knee radiographs, Lysholm and Knee Osteoarthritis Outcome Score (KOOS). RESULTS: At the 14-year follow up radiographic OA (ROA) was present in 68% and OA symptoms (SOA) in 42% of the injured knees. The dGEMRIC index of the medial compartment was lower in knees that developed medial ROA, 325 ± 68 (ms±SD) vs 376 ± 47 (51 (7-94)) (difference of means (95% confidence interval (CI))), in patients that developed symptomatic OA (SOA), 327 ± 61 vs 399 ± 42 (52 (11-93)), and poor knee function 337 ± 54 vs 381 ± 52 (48 (7-89)) compared to those that did not develop ROA, SOA or poor function. The dGEMRIC index correlated negatively with the OARSI osteophyte score in medial (r = -0.44, P = 0.01) and lateral (r = -0.38, P = 0.03) compartments. CONCLUSION: The associations between a low dGEMRIC index and future ROA, as well as SOA, are in agreement with previous studies and indicate that dGEMRIC has a prognostic value for future knee OA.

Effect of late prophylaxis in hemophilia on joint status: a randomized trial.

Essentials High-quality data are lacking on use of prophylaxis in adults with hemophilia and arthropathy. SPINART was a 3-year randomized clinical trial of late/tertiary prophylaxis vs on-demand therapy. Prophylaxis improved function, quality of life, activity and pain but not joint structure by MRI. Prophylaxis improves function but must start before joint bleeding onset to prevent arthropathy. SUMMARY: Background Limited data exist on the impact of prophylaxis on adults with severe hemophilia A and pre-existing joint disease. Objectives To describe 3-year bleeding, joint health and structure, health-related quality-of-life (HRQoL) and other outcomes from the open-label, randomized, multinational SPINART study. Patients/Methods Males aged 12-50 years with severe hemophilia A, ≥ 150 factor VIII exposure days, no inhibitors and no prophylaxis for > 12 consecutive months in the past 5 years were randomized to sucrose-formulated recombinant FVIII prophylaxis or on-demand therapy (OD). Data collected included total and joint bleeding events (BEs), joint structure (magnetic resonance imaging [MRI]), joint health (Colorado Adult Joint Assessment Scale [CAJAS]), HRQoL, pain, healthcare resource utilization (HRU), activity, and treatment satisfaction. Results Following 3 years of prophylaxis, adults maintained excellent adherence, with a 94% reduction in BEs despite severe pre-existing arthropathy; 35.7% and 76.2% of prophylaxis participants were bleed-free or had fewer than two BEs per year, respectively. As compared with OD, prophylaxis was associated with improved CAJAS scores (least squares [LS] mean, - 0.31 [n = 42] versus + 0.63 [n = 42]) and HAEMO-QoL-A scores (LS mean, + 3.98 [n = 41] versus - 6.00 [n = 42]), less chronic pain (50% decrease), and approximately two-fold less HRU; activity, Euro QoL-5D-3L (EQ-5D-3L) scores and satisfaction scores also favored prophylaxis. However, MRI score changes were not different for prophylaxis versus OD (LS mean, + 0.79 [n = 41] versus + 0.96 [n = 38]). Conclusions Over a period of 3 years, prophylaxis versus OD in adults with severe hemophilia A and arthropathy led to decreased bleeding, pain, and HRU, better joint health, activity, satisfaction, and HRQoL, but no reduction in structural arthropathy progression, suggesting that pre-existing joint arthropathy may be irreversible.

SPINART study: validation of the extended magnetic resonance imaging scale for evaluation of joint status in adult patients with severe haemophilia A using baseline data.

INTRODUCTION: Most previous joint imaging scales for haemophilia have focused on earlier disease stages observed in younger patients. AIM: We sought to demonstrate that the 45-item extended magnetic resonance imaging (eMRI) scale is a valid instrument for measuring joint status in adults with severe haemophilia A. METHODS: Six scale categories (effusion/haemarthrosis, synovial hypertrophy, hemosiderin, erosion, subchondral cysts and cartilage loss) in two domains (soft tissue [range = 0-9] and osteochondral [range = 0-36]) were evaluated for each joint. eMRI scores were derived using baseline data from a randomized, controlled, parallel-group clinical trial (SPINART). Quantitative analysis of linearity included assessments of the relationship between scores derived from the eMRI scale vs. the 17-point International Prophylaxis Study Group (IPSG) MRI scale and Colorado Adult Joint Assessment Scale (CAJAS). RESULTS: Patient eMRI scores correlated with age (r = 0.58), consistent with the expectation of arthropathy progression and more severe joint changes in older patients. eMRI scores demonstrated excellent between-reader agreement for overall patient score (intraclass correlation coefficient [ICC] = 0.88) and outstanding agreement for knee evaluations (ICC = 0.95). There was a strong linear relationship of the eMRI score with the CAJAS (r = 0.7). Adding individual bone evaluations for each joint increased the sensitivity of the instrument to detect change at low scores. There was minimal ceiling effect (5% maximum scores for all evaluated joints) compared with the IPSG MRI scale (20%). Internal reliability was good (overall Cronbach's alpha = 0.75). CONCLUSIONS: Overall, the eMRI scale represents a valid and reliable measure of joint status in adolescents and adults with severe haemophilia A.

Potential biomarkers of haemophilic arthropathy: correlations with compatible additive magnetic resonance imaging scores.

INTRODUCTION: Although biomarkers are useful diagnostic tools to assess joint damage in osteoarthritis and rheumatoid arthritis, few data exist for biomarkers of haemophilic arthropathy. AIM: To evaluate the association between biomarkers and compatible additive magnetic resonance imaging (MRI) scores in patients with severe haemophilia A. METHODS: Patients aged 12-35 years with no history of factor VIII (FVIII) inhibitors were enrolled in a controlled, cross-sectional, multinational investigation. Patients received primary or secondary prophylaxis or on-demand treatment with FVIII and underwent MRI on four joints (two ankles, two knees). Soluble biomarkers of cartilage and bone degradation, inflammation, and angiogenesis were assessed (serum levels of C-terminal telopeptides of type I collagen [CTX-I], cartilage oligomeric matrix protein [COMP], chondroitin-sulphate aggrecan turnover 846 epitope [CS846], tissue inhibitor of metalloproteinase 1 [TIMP-1]; plasma levels of vascular endothelial growth factor [VEGF], matrix metalloproteinases 3 and 9 [MMP3, MMP9]). Relationships between biomarkers and MRI scores were evaluated using Spearman rank correlation. RESULTS: Biomarkers were assessed in 117 of 118 per-protocol patients. Mean and median CTX-I, COMP, TIMP-1, MMP3, MMP9, and VEGF values were within normal ranges (reference range not available for CS846 in healthy volunteers). No correlations between biomarkers and MRI scores were found, with the exception of CS846, which showed significant correlation in a subgroup of 22 on-demand patients (r = 0.436; P = 0.04). CONCLUSIONS: Compatible additive MRI scores showed no clear correlations with any of the potential biomarkers for haemophilic arthropathy in the overall population. CS846 levels were significantly correlated with MRI scores in patients treated on demand.

Controlled, cross-sectional MRI evaluation of joint status in severe haemophilia A patients treated with prophylaxis vs. on demand.

In patients with haemophilia A, factor VIII (FVIII) prophylaxis reduces bleeding frequency and joint damage compared with on-demand therapy. To assess the effect of prophylaxis initiation age, magnetic resonance imaging (MRI) was used to evaluate bone and cartilage damage in patients with severe haemophilia A. In this cross-sectional, multinational investigation, patients aged 12-35 years were assigned to 1 of 5 groups: primary prophylaxis started at age <2 years (group 1); secondary prophylaxis started at age 2 to <6 years (group 2), 6 to <12 years (group 3), or 12-18 years (group 4); or on-demand treatment (group 5). Joint status at ankles and knees was assessed using Compatible Additive MRI scoring (maximum and mean ankle; maximum and mean of all 4 joints) and Gilbert scores in the per-protocol population (n = 118). All prophylaxis groups had better MRI joint scores than the on-demand group. MRI scores generally increased with current patient age and later start of prophylaxis. Ankles were the most affected joints. In group 1 patients currently aged 27-35 years, the median of maximum ankle scores was 0.0; corresponding values in groups 4 and 5 were 17.0 and 18.0, respectively [medians of mean index joint scores: 0.0 (group 1), 8.1 (group 2) and 13.8 (group 4)]. Gilbert scores revealed outcomes less pronounced than MRI scores. MRI scores identified pathologic joint status with high sensitivity. Prophylaxis groups had lower annualized joint bleeds and MRI scores vs. the on-demand group. Primary prophylaxis demonstrated protective effects against joint deterioration compared with secondary prophylaxis.

DC-LAMP+ dendritic cells are recruited to gastric lymphoid follicles in Helicobacter pylori-infected individuals.

Infection with Helicobacter pylori is associated with development of ulcer disease and gastrointestinal adenocarcinoma. The infection leads to a large infiltration of immune cells and the formation of organized lymphoid follicles in the human gastric mucosa. Still, the immune system fails to eradicate the bacteria, and the substantial regulatory T cell (Treg) response elicited is probably a major factor permitting bacterial persistence. Dendritic cells (DCs) are professional antigen-presenting cells that can activate naive T cells, and maturation of DCs is crucial for the initiation of primary immune responses. The aim of this study was to investigate the presence and localization of mature human DCs in H. pylori-infected gastric mucosa. Gastric antral biopsy specimens were collected from patients with H. pylori-associated gastritis and healthy volunteers, and antrum tissue was collected from patients undergoing gastric resection. Immunohistochemistry and flow cytometry showed that DCs expressing the maturation marker dendritic cell lysosome-associated membrane glycoprotein (DC-LAMP; CD208) are enriched in the H. pylori-infected gastric mucosa and that these DCs are specifically localized within or close to lymphoid follicles. Gastric DC-LAMP-positive (DC-LAMP(+)) DCs express CD11c and high levels of HLA-DR but little CD80, CD83, and CD86. Furthermore, immunofluorescence analyses demonstrated that DC-LAMP(+) DCs are in the same location as FoxP3-positive putative Tregs in the follicles. In conclusion, we show that DC-LAMP(+) DCs with low costimulatory capacity accumulate in the lymphoid follicles in human H. pylori-infected gastric tissue, and our results suggest that Treg-DC interactions may promote chronic infection by rendering gastric DCs tolerogenic.

An MRI scale for assessment of haemophilic arthropathy from the International Prophylaxis Study Group.

Evaluation of prophylactic treatment of haemophilia requires sensitive methods. To design and test a new magnetic resonance imaging (MRI) scale for haemophilic arthropathy, two scales of a combined MRI scoring scheme were merged into a single scale which includes soft tissue and osteochondral subscores. Sixty-one joint MRI's of 46 patients with haemophilia were evaluated by four radiologists using the new and older scales. Forty-six of the joints were evaluated using two X-ray scales. For all MRI scores, interreader agreement and correlations with X-ray scores and lifetime number of haemarthroses were analysed. The interreader agreement intraclass correlation coefficient was 0.82, 0.89 and 0.88 for the soft tissue and osteochondral subscores and the total score, as evaluated according to the new MRI scale, compared to 0.80 and 0.89 as for the older scales. The total score and osteochondral subscore according to the new scale, as well as scores according to the older scales were correlated (P < 0.01) with number of haemarthroses (Spearman correlation 0.35-0.68) and with the X-ray scores (Spearman correlation 0.40-0.76), but no correlation (P > 0.05) was found between the soft tissue subscore of the new MRI scale and the X-ray scores. The new MRI scale is simpler to apply than the older and has similar reader reliability and correlation with lifetime number of haemarthroses, and by separating soft tissue and osteochondral changes it gives additional information. The new scale is useful for analyses of early and moderate stages of arthropathy, and may help to evaluate prophylactic haemophilia treatment.

A randomized clinical trial of prophylaxis in children with hemophilia A (the ESPRIT Study).

BACKGROUND: Prevention of arthropathy is a major goal of hemophilia treatment. While studies in adults have demonstrated an impact of prophylaxis on the incidence of joint bleeds and patients' well-being in terms of improved quality of life (QoL), it is unclear whether or not prophylaxis influences the outcome and perception of well- of children with hemophilia. OBJECTIVE: This randomized controlled study compared the efficacy of prophylaxis with episodic therapy in preventing hemarthroses and image-proven joint damage in children with severe hemophilia A (factor VIII <1%) over a 10-year time period. METHODS: Forty-five children with severe hemophilia A, aged 1-7 years (median 4), with negative clinical-radiologic joint score at entry and at least one bleed during the previous 6 months, were consecutively randomized to prophylaxis with recombinant factor VIII (25 IU kg(-1) 3 × week) or episodic therapy with ≥25 IU kg(-1) every 12-24 h until complete clinical bleeding resolution. Safety, feasibility, direct costs and QoL were also evaluated. RESULTS: Twenty-one children were assigned to prophylaxis, 19 to episodic treatment. Children on prophylaxis had fewer hemarthroses than children on episodic therapy: 0.20 vs. 0.52 events per patient per month (P < 0.02). Plain-film radiology showed signs of arthropathy in six patients on prophylaxis (29%) vs. 14 on episodic treatment (74%) (P < 0.05). Prophylaxis was more effective when started early (≤36 months), with patients having fewer joint bleeds (0.12 joint bleeds per patient per month) and no radiologic signs of arthropathy. CONCLUSION: This randomized trial confirms the efficacy of prophylaxis in preventing bleeds and arthropathy in children with hemophilia, particularly when it is initiated early in life.

FOXP3-expressing CD4(+) T-cell numbers increase in areas of duodenal gastric metaplasia and are associated to CD4(+) T-cell aggregates in the duodenum of Helicobacter pylori-infected duodenal ulcer patients.

BACKGROUND: We have previously demonstrated that Helicobacter pylori infection is associated with an increased number of CD4(+)CD25(high) regulatory T cells in the gastric and duodenal mucosa. In this study, we determined the number and localization of CD4(+) cells expressing the regulatory T-cell-specific transcription factor FOXP3 in the antrum and duodenum of duodenal ulcer patients, asymptomatic carriers, and uninfected individuals. We also determined gene expression levels of FOXP3 as well as anti- and proinflammatory cytokines before and after H. pylori eradication. METHODS: Cellular FOXP3 expression was studied by immunofluorescence and flow cytometry, and transcription levels of FOXP3, interleukin (IL)-10, transforming growth factor-beta, CD4, and interferon-gamma were analyzed by real-time reverse transcription-polymerase chain reaction. RESULTS: We found an increased (6-fold) frequency of CD4(+)FOXP3(+) T cells in H. pylori-infected gastric mucosa; interestingly 26% of these cells did not co-express CD25. The increase of FOXP3-expressing T cells in the antrum of infected individuals was dependent on the presence of H. pylori, since eradication therapy resulted in 4-fold lower levels of FOXP3 and IL-10 mRNA in the antrum. Furthermore, higher numbers of CD4(+)FOXP3(+) T cells were found in areas of duodenal gastric metaplasia in the duodenum of duodenal ulcer patients compared to duodenal gastric metaplasia of asymptomatic individuals and healthy mucosa in both patient groups. In duodenal ulcer patients, the CD4(+)FOXP3(+) T cells were more highly associated to aggregates in the duodenal mucosa. CONCLUSION: The numbers of CD4(+)FOXP3(+) T cells are increased and localized in CD4(+) T-cell aggregates in areas of duodenal gastric metaplasia in duodenal ulcer patients.

Digital scoring of haemophilic arthropathy using radiographs is feasible.

Radiographs are important tools to evaluate structural changes in many joint diseases. In the case of haemophilic arthropathy (HA), the Pettersson score is widely used. The rising of digital radiography enables evaluation of these changes in a more quantitative and detailed manner, potentially improving diagnosis and follow-up. The aim of this study was to evaluate whether digital image analysis in the case of HA is feasible, using a presently available method for radiographic changes in knee osteoarthritis (OA), knee image digital analysis (KIDA). Sixty-two knee radiographs were scored according to Pettersson and with KIDA, each by two independent observers. Inter-observer variation and correlations between the two scoring methods were determined. The inter-observer variation was smaller for KIDA than for Pettersson and for KIDA not significantly different from evaluation of OA joints. Good correlations were found for the two methods where comparison of parameters was appropriate. Importantly, for each of the parameters within one point in the ordinal Pettersson score, a large window still existed in the continuous KIDA grading. Digital analysis of radiographs to quantify joint damage in HA is feasible. The use of continuous variables, as used in a digital method such as KIDA has the advantage that it enables objective and much more sensitive detection of small changes than by use of an ordinal analogue method such as the Pettersson score. Based on the present results, it would be worthwhile to adapt the KIDA method for the specific characteristics of HA and to extend the method to elbow and ankle radiographs.

Reliability and construct validity of the compatible MRI scoring system for evaluation of elbows in haemophilic children.

We assessed the reliability and construct validity of the Compatible MRI scale for evaluation of elbows, and compared the diagnostic performance of MRI and radiographs for assessment of these joints. Twenty-nine MR examinations of elbows from 27 boys with haemophilia A and B [age range, 5-17 years (mean, 11.5)] were independently read by four blinded radiologists on two occasions. Three centres participated in the study: (Toronto, n = 24 examinations; Atlanta, n = 3; Cuiaba, n = 2). The number of previous joint bleeds and severity of haemophilia were reference standard measures. The inter-reader reliability of MRI scores was substantial (ICC = 0.73) for the additive (A)-scale and excellent (ICC = 0.83) for the progressive (P)-scale. The intrareader reliability was excellent for both P-scores (ICC = 0.91) and A-scores (ICC = 0.93). The total P- and A-scores correlated poorly (r = 0.36) or moderately (r = 0.54), but positively, with clinical-laboratory measurements. The total MRI scores demonstrated high accuracy for discrimination of presence or absence of arthropathy [P-scale, area-under-the-curve (AUC) = 0.94 +/- 0.05; A-scale, AUC = 0.89 +/- 0.06], as did the soft tissue scores of both scales (P-scale, AUC = 0.90 +/- 0.06; A-scale, AUC = 0.86 +/- 0.06). Areas-under-the-curve used to discriminate severe disease demonstrated high accuracy for both P-MRI scores (AUC = 0.83 +/- 0.09) and A-MRI scores (AUC = 0.87 +/- 0.09), but non-diagnostic ability to discriminate mild disease. Similar results were noted for radiographic scales. In conclusion, both MRI scales demonstrated substantial to excellent reliability and accuracy for discrimination of presence/absence of arthropathy, and severe/non-severe disease, but poor to moderate convergent validity for total scores and non-diagnostic discriminant validity for mild/non-mild disease. Compared with radiographic scores, MRI scales did not perform better for discrimination of severity of arthropathy.

The local and systemic T-cell response to Helicobacter pylori in gastric cancer patients is characterised by production of interleukin-10.

Helicobacter pylori causes a life-long infection that may lead to development of gastric adenocarcinoma (GC) and thereby cause major worldwide health problems. The present study was designed to study whether those that develop GC have an altered immune response to H. pylori compared to individuals that remain asymptomatic. When stimulated with H. pylori antigens, T cells from both peripheral blood and gastric mucosa of H. pylori-infected GC patients produced high amounts of IL-10, while the IL-10 production from blood T cells of H. pylori-infected asymptomatic subjects was low. Furthermore, mRNA levels of IL-10 were increased in the gastric mucosa of GC patients. In addition, the frequency of activated CD8(+) T cells was markedly reduced in stomach mucosa of patients with GC compared to asymptomatic individuals. We propose that the increased production of the suppressive cytokine IL-10 in H. pylori-infected GC patients leads to a diminished cytotoxic anti-tumour T-cell response in the stomach, which may contribute to tumour progression in subjects suffering from GC.

Gadolinium contrast agent is of limited value for magnetic resonance imaging assessment of synovial hypertrophy in hemophiliacs.

PURPOSE: To examine the influence of different doses of gadolinium contrast agent on synovial enhancement, to compare magnetic resonance imaging (MRI) findings of synovial hypertrophy and radiographic joint changes in hemophiliacs, and to investigate the value of gadolinium in MRI assessment of synovial hypertrophy in hemophiliacs using dynamic MRI and MRI scoring. MATERIAL AND METHODS: Twenty-one hemophiliacs on prophylactic factor treatment without recent bleeds were subjected to radiography and gadolinium contrast-enhanced dynamic and static MRI of the knee using a standard dose of 0.1 mmol/kg b.w. gadoteridol. In 17 of the patients, the MRI procedure was repeated after a triple dose of gadoteridol. RESULTS: MRI findings of synovial hypertrophy were significantly correlated with Pettersson radiographic scores. In 19 of the 21 MRI investigated joints, administration of contrast agent did not alter the result of the evaluation of synovial hypertrophy. CONCLUSION: The optimal time interval for volume assessment of synovial hypertrophy after injection of gadolinium contrast agent is dose dependent. Hemophiliacs without recent bleeds have minor to abundant synovial hypertrophy in joints with pronounced radiographic changes. Dynamic MRI is not useful for evaluating hemophilic arthropathy, and gadolinium contrast agent is not routinely indicated for MRI scoring of joints in hemophiliacs.

CD4+ CD25high regulatory T cells reduce T cell transendothelial migration in cancer patients.

Cell-mediated immunity is thought to be the main mechanism of anti-tumour responses of the host, but it is not known if cancer disease affects T cell recruitment from blood to tissues. Therefore, we compared Heliobacter pylori-induced T cell transendothelial migration (TEM) in H. pylori-infected gastric carcinoma patients, colon and lung carcinoma patients and healthy volunteers. H. pylori induced significant T cell migration from all groups. However, there was a dramatic reduction of T cell TEM in gastric carcinoma patients (80%) compared to healthy individuals. A similarly reduced transmigration was also seen in colon and lung carcinoma patients. We found significantly increased frequencies of T(reg) cells in the blood of gastric carcinoma patients compared to healthy individuals, and depletion of T(reg) cells from the blood of these patients prior to TEM restored T cell migration. The effect of T(reg) cells was largely dependent on cell-cell contact, but not on IL-10 or TGF-beta. In addition, the presence of T(reg) cells led to reduced T cell attachment to endothelium and decreased production of T cell-recruiting chemokines during TEM. In conclusion, T(reg) cell-mediated reduction of T cell TEM may reduce T cell recruitment in patients with epithelial malignancies, thereby hampering anti-tumour responses.

Reliability and construct validity of the compatible MRI scoring system for evaluation of haemophilic knees and ankles of haemophilic children. Expert MRI working group of the international prophylaxis study group.

We tested the reliability and construct validity of the Compatible magnetic resonance imaging (MRI) scale for the evaluation of haemophilic knees and ankles and compared the diagnostic performance of MRI and plain film radiographs. Sagittal and coronal gradient-echo 1.5-T MR images of knees (n=22) and ankles (n=23) were obtained from boys (age range 4-16 years; mean 11 years) in two centres (Toronto, n=26; Europe, n=19). The MR images were independently read by four blinded radiologists on two occasions. Number of previous joint bleedings and laboratory level of severity of haemophilia were the reference standards for imaging assessment. Both components of the MRI scale demonstrated high inter- and intrareader intraclass correlation coefficients (progressive (P) scale, 0.91 and 0.94; additive (A) scale, 0.81 and 0.92 respectively). The correlation between the osteochondral domain of the MRI scale and patient's age was moderate. Otherwise, correlations between A- and P-scales and clinical laboratory measurements were weak. The areas under the curve (AUCs) used for discrimination of disease severity were similar for the A- and P-scales (AUCs used for mild disease, A-scale, 0.72+/-0.07; P-scale, 0.69+/-0.08; P=0.23; AUCs for severe disease, A-scale, 0.93+/-0.05; P-scale, 0.87+/-0.08; P=0.05). No differences were noted between the AUCs of the MRI and radiographic scales used for discrimination of late osteoarticular changes; MRI scales performed better for discrimination of early changes. In conclusion, both MRI scales demonstrated excellent reliability, poor convergent validity, and moderate and excellent validity for discrimination of mild and severe diseases respectively. Compared with radiographic scores, the MRI scales performed better for discrimination of early osteoarticular changes.

Function and recruitment of mucosal regulatory T cells in human chronic Helicobacter pylori infection and gastric adenocarcinoma.

CD4(+)CD25(high) FOXP3-expressing regulatory T cells (Treg) can suppress immune responses to infections and tumors, thereby promoting microbial persistence and tumor progression. However, little is known about the phenotype and function of human mucosal Treg. Therefore, we analyzed the suppressive activity and homing phenotype of Treg in gastric mucosa of Helicobacter pylori-infected gastric adenocarcinoma patients. We found increased numbers of CD4(+)FOXP3(+) Treg in the tumor compared to tumor-free gastric mucosa. Gastric Treg cells were able to suppress H. pylori-induced T cell proliferation and IFN-gamma production. Furthermore, gastric Treg expressed increased levels of l-selectin and CCR4, compared to non-Treg cells, suggesting that these receptors contribute to Treg recruitment. The presence of functional antigen-specific Treg in H. pylori-infected gastric mucosa supports an important role for these cells in suppression of mucosal effector T cell responses, which probably contribute to bacterial persistence and possibly also to gastric tumor progression.

Identification of protein expression signatures associated with Helicobacter pylori infection and gastric adenocarcinoma using recombinant antibody microarrays.

Antibody microarray based technology is a powerful emerging tool in proteomics, target discovery, and differential analysis. Here, we report the first study where recombinant antibody fragments have been used to construct large scale antibody microarrays, composed of 127 different antibodies against mostly immunoregulatory antigens. The arrays were based on single framework recombinant antibody fragments (SinFabs) designed for high on-chip stability and functionality and were used for the analysis of malignant and normal stomach tissue samples from Helicobacter pylori-positive and -negative patients. Our results demonstrate that distinct tumor- as well as infection-associated protein expression signatures could be identified from these complex tissue proteomes, as well as biomarkers such as IL-9, IL-11, and MCP-4, previously not found in these diseases. In a longer perspective, this study may improve the understanding of H. pylori-induced stomach cancer and lead to development of improved diagnostics.

Recent developments in clinimetric instruments.

Assessment of impairment and function is essential in order to monitor joint status and evaluate therapeutic interventions in patients with haemophilia. The improvements in the treatment of haemophilia have required the development of more sensitive tools to detect the more minor dysfunctions that may now be apparent. This paper outlines some of the recent developments in this field. The Haemophilia Joint Health Score (HJHS) provides a systematic and robust measure of joint impairment. The MRI Scoring System has been designed to provide a comprehensive scoring system combining both progressive and additive scales. The Functional Independence Score for Haemophilia (FISH) has been developed to assess performance of functional activities and can be used in conjunction with the Haemophilia Activities List (HAL) which provides a self report measure of function. It is recommended that both measures are evaluated as these tools measure different constructs. Further refinement and testing of the psychometric properties of all of these tools is in progress. More widespread use of these tools will enable the sharing of data across the world so promoting best practice and ultimately enhancing patient care.