MCID/Low Disease Activity State Workshop: summary,recommendations, and research agenda

The OMERACT 6 Minimal Clinically Important Difference/Low Disease Activity Workshop was organized with the aim of meeting the many challenges that exist in determining a low disease activity in rheumatoid arthritis (RA). This article presents an overview of that workshop, including results of the voting, a summary of associated discussions, recommendations, and a proposed research agenda.     

Mycobacterium tuberculosis Lineage 7 Strains Are Associated with Prolonged Patient Delay in Seeking Treatment for Pulmonary Tuberculosis in Amhara Region,Ethiopia

Recent genotyping studies of Mycobacterium tuberculosis in Ethiopia have reported the identification of a new phylogenetically distinct M. tuberculosis lineage, lineage 7. We therefore investigated the genetic diversity and association of specific M. tuberculosis lineages with sociodemographic and clinical parameters among pulmonary TB patients in the Amhara Region, Ethiopia. DNA was isolated from M. tuberculosis-positive sputum specimens (n = 240) and analyzed by PCR and 24-locus mycobacterial interspersed repetitive unit–variable-number tandem-repeat (MIRU-VNTR) analysis and spoligotyping. Bioinformatic analysis assigned the M. tuberculosis genotypes to global lineages, and associations between patient characteristics and genotype were evaluated using logistic regression analysis. The study revealed a high diversity of modern and premodern M. tuberculosis lineages, among which approximately 25% were not previously reported. Among the M. tuberculosis strains (n = 138) assigned to seven subgroups, the largest cluster belonged to the lineage Central Asian (CAS) (n = 60; 26.0%), the second largest to lineage 7 (n = 36; 15.6%), and the third largest to the lineage Haarlem (n = 35; 15.2%). Four sublineages were new in the MIRU-VNTRplus database, designated NW-ETH3, NW-ETH1, NW-ETH2, and NW-ETH4, which included 24 (10.4%), 18 (7.8%), 8 (3.5%), and 5 (2.2%) isolates, respectively. Notably, patient delay in seeking treatment was significantly longer among patients infected with lineage 7 strains (Mann-Whitney test, P < 0.008) than in patients infected with CAS strains (adjusted odds ratio [AOR], 4.7; 95% confidence interval [CI], 1.6 to 13.5). Lineage 7 strains also grew more slowly than other M. tuberculosis strains. Cases of Haarlem (OR, 2.8; 95% CI, 1.2 to 6.6) and NW-ETH3 (OR, 2.8; 95% CI, 1.0 to 7.3) infection appeared in defined clusters. Intensified active case finding and contact tracing activities in the study region are needed to expedite diagnosis and treatment of TB.     

Improved survival and quality of life in patients undergoing R1 pancreatic resection compared to patients with locally advanced unresectable pancreatic adenocarcinoma

ObjectiveTo prospectively record the clinical consequences of R1 resection of pancreatic adenocarcinoma compared to patients with locally advanced tumours not undergoing surgery.BackgroundSurgery is the only potentially curative treatment of pancreatic cancer, and postoperative safety is increasing. The rate of R1 resections might also increase unintentionally as surgical procedures with curative goal become more comprehensive, and the clinical outcome requires further prospective evaluation.Material and methodsProspective observational cohort study from October 2008 to December 2010. Outcome after R1 resection (group 1, surgery, n = 32) and conservative palliative chemoradiation/endoscopy (group 2, no surgery, n = 56) is compared with survival and longitudinal patient-reported quality of life (QoL) as endpoints. QoL was assessed by the Edmonton Symptom Assessment System (ESAS).ResultsDemographic characteristics and tumour diameters were similar in both groups: 38.0 (31.3, 49.8) mm in group 1 versus 44.0 (39.6, 49.1) mm in group 2 (p = 0.18). Perioperative morbidity was 25% with no mortality. Disease-specific survival was 18.0 (14.5, 23.8) months in group 1 versus 8.1 (4.8, 10.1) months in group 2 (p < 0.0001). Overall survival was 11 (7.8, 14.4) months. Reduction in fatigue was significantly improved in the surgery group 6, 12, and 19 weeks after baseline, whereas reduction in global health was significantly better in group 2.ConclusionRadical removal (R0 resection) is the primary aim of surgery, but also R1 resection seems to improve survival and QoL, compared to outcome in patients with locally advanced tumours not undergoing surgery.     

Longitudinal observation of enterovirus and adenovirus in stool samples from Norwegian infants with the highest genetic risk of type 1 diabetes.

BACKGROUND: Enterovirus and adenovirus are common in infancy, causing mostly asymptomatic infections. However, even an asymptomatic infection may be associated with increased risk of development of certain chronic non-infectious diseases, as has been suggested for enterovirus and type 1 diabetes. Data on occurrence and course of the infections in infancy are therefore important for designing effective approaches towards study of the association. OBJECTIVES: To estimate the frequency of enterovirus and adenovirus infections in Norwegian infants, to evaluate the duration of the infections, to investigate their association with symptoms, and to establish a robust procedure that will be used to study the association between these viruses and the development of auto-immunity leading to type 1 diabetes. STUDY DESIGN: Parents of infants, recruited for a study on environmental triggers of type 1 diabetes, submitted monthly samples of infant faeces, as well as information on symptoms of infection. The samples were analysed for enterovirus and adenovirus using quantitative real-time PCR, and enterovirus-positive samples were sequenced. RESULTS: Enteroviruses were found in 142/1,255 (11.3%), and adenoviruses in 138/1,255 (11.0%) of stool samples. Approximately half of the infants were exposed to these viruses at least once during the first year of observation (period 3-14 months of age). The presence of adenovirus was associated with fever and with symptoms of cold but not with diarrhoea and vomiting. The enterovirus positivity was not associated with any symptoms. CONCLUSIONS: The prevalence of enterovirus and adenovirus in longitudinally obtained faecal samples from infants is sufficiently high to enable studies of their association with chronic diseases. The present protocol for evaluating exposure to these viruses is well suited for large-scale efforts aimed at assessing possible long-term consequences, particularly in relation to type 1 diabetes.     

A study of the association between exercise‐induced wheeze and exercise versus methacholine‐induced bronchoconstriction in adolescents

Among asthmatics, exercise‐induced wheeze (EIW) is a frequent symptom, and 40–77% of asthmatics demonstrate exercise‐induced bronchoconstriction (EIB). In the North‐Trøndelag population‐based survey of 8,571 adolescents (YOUNG‐HUNT), 26% reported wheeze during the previous 12 months (current wheeze). Of those subjects, 50% reported EIW. The aim of the present study was to investigate the association between EIW and EIB in randomly selected adolescents with EIW as the only or predominant asthma‐like symptom, and to relate our findings to results from methacholine bronchoprovocation tests (MT) and measurements of exhaled nitric oxide (ENO). Sixty‐three subjects with current wheeze induced by exercise, but not by allergen exposure, were investigated using a treadmill exercise test (ET) and measurements of ENO. Fifty‐eight subjects completed a MT on a separate study day. EIB was defined as a fall of ≥ 10% in the forced expiratory volume in 1 second (FEV₁) after exercise (ΔFEV₁%_ex). Twenty‐one subjects (33%) had EIB and 33 (57%) had a positive MT. The degree of reported dyspnea during the ET was not correlated to the ΔFEV₁%_ex. The correlation between EIB and methacholine‐induced bronchoconstriction (MIB) was poor, and the ΔFEV₁%_ex was more pronounced in smokers than in non‐smokers. Moreover, ENO was not increased in subjects with positive vs. negative ET. Hence, EIW, when reported as the only or predominant asthma‐like symptom, was linked to EIB in only one‐third of the patients. We conclude that EIW is a poor predictor of EIB in epidemiological studies. The poor correlation between EIB and MIB indicates that these two tests measure different mechanisms of bronchial hyper‐responsiveness.     

Bcl-2, BAX, and apoptosis in endometrial hyperplasia after high dose gestagen therapy: a comparison of responses in patients treated with intrauterine levonorgestrel and systemic medroxyprogesterone

OBJECTIVES: The aim of the study was to investigate apoptosis as a growth regulatory mechanism of gestagen in endometrial precancers and to compare differences in the apoptotic cascade after high and low dose gestagen regimens. METHOD: Pre- and post-treatment paraffin-embedded endometrial hyperplasia specimens from women treated with levonorgestrel intrauterine device (n = 26) and women treated with 10 mg medroxyprogesterone for 10 days per cycle (n = 31) were examined for changes in the expression of Bcl-2 and BAX and the extent of apoptosis after 3 months of treatment. Immunohistochemical expression in tissue specimens for Bcl-2 and BAX was evaluated by H-score. Average number of apoptotic cells per hundred cells within ten different high power field (40 x) was evaluated for each section after in situ apoptosis detection (TUNEL method). A second group of patients with endometrial hyperplasia was examined after 1 week treatment with levonorgestrel IUD (n = 6) or medroxyprogesterone (n = 5) to determine early effects on expression of Bcl-2 and BAX and the extent of apoptosis. RESULTS: All the patients in the IUD group (n = 31) but only about half of the patients in per oral group (16 of 26) responded to treatment. The glandular reduction in Bcl-2 expression was markedly greater for the IUD patients than for the patients who received oral gestagen. The decrease in BAX expression after IUD treatment was less than the reduction of Bcl-2. Decrease in glandular Bcl-2 after 3 months of treatment was coincident with a significant increase in the measurable amount of apoptosis. In stromal cells, the increase in expression of Bcl-2 and BAX was found after gestagen treatment, the response being much more marked for the IUD group. The non- responders to per oral gestagen had no Bcl-2 expression in stroma after 3 months of therapy whereas an increase was observed for the responders. After 1 week, glandular Bcl-2 expression was significantly reduced after treatment in the IUD group. As for the rest, no changes were detected in either of the groups. CONCLUSION: Our results indicate that proteins in the apoptotic cascade are regulated by gestagen therapy in human endometrial precancers. Expression of these proteins is shown to be dependent on administration form and/or type of gestagen. Stromal Bcl-2 expression appears to be a potential biomarker which can separate responders of gestagen treatment from non-responders after oral administration.     

Adolescent respiratory symptoms--girls are at risk: the Young-HUNT study, Norway

The objective was to study sex differences in adolescence regarding prevalence of asthma and current wheeze and to explore the association between respiratory symptoms and hereditary, lifestyle and socioeconomic factors. Young-HUNT included data comprehensive questionnaire on health, disease, lifestyle and social factors from 8817 teenagers 13-19 years conducted in 1995/97 (89% response rate). Questionnaire on respiratory symptoms was based on the International Study of Asthma and Allergy in Childhood (ISAAC). In age groups 13-16 and 17-19 years, current wheeze was reported by 29.0% and 33.5% among girls and 20.4% and 22.1% among boys, whilst the corresponding figures for asthma were 8.5% and 12.2% among girls and 7.1% and 7.0% among boys. Both wheeze and asthma were significantly more prevalent and increased with age in girls compared to boys. Heredity was associated with asthma, but the association was strongest between parents and children of the same sex. Environmental smoking was associated with asthma and wheeze in girls only. Girls reported more asthma and wheeze in association with overweight compared to boys. Girls reported more wheeze and asthma than boys and seemed more susceptible to risk factors such as environmental smoking and overweight than boys. Moreover, girls with mothers having asthma were more likely to be diagnosed as asthmatics themselves.     

Platelet-derived LIGHT induces inflammatory responses in endothelial cells and monocytes

Traditionally, platelets are known to play an important role in hemostasis, thrombosis, and wound healing, but increasing evidence suggests that activated platelets also may promote inflammation. Platelet-induced modulation of inflammation seems to involve platelet expression of ligands in the tumor necrosis factor (TNF) superfamily such as CD40 ligand and Fas ligand. The present study demonstrates that LIGHT, another member of the TNF superfamily, is associated with platelets and is released as a soluble ligand on platelet activation. The release of LIGHT involves GP IIb/IIIa-dependent mechanisms and action of metal-dependent proteases as well as intracellular processes such as actin polymerization. We also report that platelet-derived LIGHT is biologically active and can induce an inflammatory response in monocytes and particularly within endothelial cells measured as up-regulation of adhesion molecules and release of chemokines. Moreover, we demonstrate that thrombus material, obtained at the site of plaque rupture in patients with acute myocardial infarction, contains platelet-associated LIGHT, suggesting that LIGHT-mediated inflammation also is operating in vivo within an inflamed and thrombotic vessel wall. The data may suggest a pathogenic role for platelet-derived LIGHT in atherogenesis and plaque destabilization as well as in other inflammatory disorders involving leukocyte infiltration into the vessel wall.     

Complex rearrangements involving der(8)t(8;20) and der(14)t(8;14)t(11;14), CCND1, and duplication of IgH constant region in acute plasmablastic leukemia

We report on a rapidly fatal case of acute plasmablastic leukemia in a 72-year-old male from The Ukraine, who was 70 km away from Chernobyl at the time of the atomic accident in 1986. Spectral karyotyping and fluorescence in situ hybridization (FISH) studies of a bone marrow sample obtained at diagnosis revealed a hypodiploid karyotype with 45 chromosomes and two novel complex rearrangements, der(8)t(8;20)(p11.2;p?12) and der(14)t(8;14)(p?;p11.2)t(11;14)(q13;q32), with juxtaposition of CH (constant region of IgH) sequences to the oncogene CCND1 (translocated to 14q32). FISH analysis demonstrated that the CH on the der(14) was duplicated.