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Abstract: As part of a broad-based SAR investigation of E-resveratrol (strong sirtuin activator and antineoplastic) and the anticancer vascular-targeting combretastatin-type stilbenes, a series of twenty-three β-E-nitrostyrenes was synthesized in order to evaluate potential antineoplastic, antitubulin, and antimicrobial activities. The β-E-nitrostyrenes evaluated ranged from monosubstituted phenols to trimethoxy and 3-methoxy-4,5-methylenedioxy derivatives. Two of the β-nitrostyrenes were synthesized as water-soluble sodium phosphate derivatives (4t, 4v). All except four (4r, 4s, 4t, 4u) of the series significantly inhibited a minipanel of human cancer cell lines. All but eight led to an IC50 of <10μM for inhibition of tubulin polymerization, and all except three (4l, 4t, 4v) displayed antimicrobial activity. [Copyright &y& Elsevier]

Abstract: 59122 is a transgenic maize line containing event DAS-59122-7 that expresses the corn rootworm (CRW) specific pesticidal Cry34Ab1 and Cry35Ab1 proteins from Bacillus thuringiensis (Bt) Berliner strain PS149B1 and the phosphinothricin-N-acetyltransferase (PAT) protein from Streptomyces viridochromogenes for tolerance to the herbicidal ingredient glufosinate-ammonium. For the current study, 59122 maize grain, non-transgenic near-isogenic maize grain (091), and a commercially available non-transgenic reference maize grain (33R77) were grown under conditions simulating commercial farming practices. Adult Sprague-Dawley rats (12/sex/group) were fed diets formulated with 35% maize grain from either 59122, 091, or 33R77, or one of two separate lots of commercially available rodent chow prepared with commercially available corn (35%) in accordance with the standards of Purina Mills Labdiet® 5002 for approximately 90 days. All diets possessed similar nutritional and contaminant profiles. The transgenic proteins were detected only in diets prepared with 59122 maize grain and were stable over the course of the study. Compared to control groups, no adverse diet-related differences were observed in rats fed diets formulated with 59122 maize grain with respect to body weight/gain, food consumption/efficiency, clinical signs of toxicity, mortality, ophthalmology, neurobehavioral (FOB and motor activity) assessments, clinical pathology (hematology, clinical chemistry, coagulation, and urinalysis), and pathology (organ weights and gross and microscopic pathology). Results from this study indicate that 59122 maize grain is nutritionally equivalent to and as safe as conventional maize grain. [Copyright &y& Elsevier]

Adult-onset Still's disease (AOSD) is a rare inflammatory disease that may be life-threatening if complicated by cardiac problems. We performed a retrospective multicenter study to describe the manifestations, treatments and outcomes of cardiac involvement in AOSD. We reviewed the medical databases of eight centers. All AOSD patients identified as fulfilling Yamagushi's or Fautrel's criteria were included in the study. Cardiac involvement, clinical manifestations, laboratory features, the course of the disease and treatments were evaluated. We included 96 AOSD patients in this study: 28 (29%) had documented cardiac involvement (AOSD + C group) and 68 (71%) had no cardiac involvement (control group). Cardiac complications were observed at diagnosis in 89% of cases. It were pericarditis (n = 17), tamponade (n = 5), myocarditis (n = 5) and non-infectious endocarditis (n = 1). Levels of leukocytes, neutrophils and C-reactive protein were significantly higher (p = 0.02, p = 0.02 and p = 0.002, respectively in the AOSD + C group than in the control group. Admission to intensive care, and the use of biotherapy were more frequent during follow-up in the AOSD + C group than the control group (p = 0.0001 and p = 0.03 respectively). Cardiac involvement was associated with refractory form in multivariate analyzed (p = 0.01). Corticosteroids were effective with or without methotrexate in 71% of patients but not in severe involvement as myocarditis or tamponade. Cardiac complications are frequent, inaugural, can be life-threatening and predictive of a refractory course in patients with AOSD. Systematic cardiac screening should be proposed at diagnosis and biotherapy early use should be considered especially in myocarditis. • About 30% of Adult onset Still's disease developed cardiac involvement. • AAdmission to intensive care and use of biotherapy were more frequent during follow-up in AOSD + C group than control group. • Cardiac involvement was associated with refractory form in multivariate analyzed. [ABSTRACT FROM AUTHOR]

Background: Sjögren's disease is the autoimmune disease with the highest risk of lymphoma development. There is no consensus on the optimal way to manage Sjögren's disease complicated by lymphoma. We aimed to describe characteristics, therapeutic strategies, and outcomes of non-Hodgkin lymphoma associated with Sjögren's disease, and their effect on lymphoma and Sjögren's disease prognoses., Methods: We did a multicentre, retrospective, observational study including patients with Sjögren's disease according to the 2016 American College of Rheumatology-European League Against Rheumatism criteria who did not fulfil diagnostic criteria for other connective tissue diseases. We included patients with a lymphoma diagnosis made before Jan 1, 2020, from two expert centres in Paris (France); from the French, multicentre, prospective Assessment of Systemic Signs and Evolution of Sjögren's Syndrome cohort; and via practitioners registered with the Club Rhumatismes et Inflammation. Using inverse probability of treatment weighting, the effect of lymphoma treatment was compared in relation to three endpoints: lymphoma progression-free survival, new Sjögren's disease systemic activity, and overall survival. Exploratory analyses also aimed to identify factors associated with lymphoma relapse, new Sjögren's disease systemic activity, and overall survival. People with lived experience were not involved in this research., Findings: 106 patients with Sjögren's disease who developed lymphoma were included in the study. The most frequent histological subtype was mucosa-associated lymphoid tissue lymphoma (68 [64%] of 106 patients), followed by other marginal zone subtypes (14 [13%] of 106 patients) and diffuse large B-cell lymphoma (14 [13%] of 106 patients). Among the 82 patients with marginal zone lymphoma (72 [88%] women and ten (12%) men; mean age at lymphoma diagnosis 57·5 years [SD 14·8]), multivariable analysis showed that pulmonary localisation was associated with mortality (hazard ratio [HR] 7·92 [95% CI 1·70-37·0]). A watch and wait approach was proposed in 19 (23%) of 82 patients with marginal zone lymphoma, 13 (16%) had first-line localised treatment (surgery or radiotherapy), and 50 (61%) had first-line systemic treatment. After a median follow-up of 7 years, 26 patients (32%) had lymphoma relapse, nine (11%) died, and 27 (33%) had new Sjögren's disease systemic activity. After inverse probability of treatment weighting, patients with systemic treatment at lymphoma diagnosis had a reduced risk of new Sjögren's disease activity (HR 0·43 [95% CI 0·21-0·90]). When comparing patients treated with a combination of chemotherapy and anti-CD20 therapy (n=32) with patients treated with monotherapy (n=18) as a first-line therapy for lymphoma, lymphoma-progression-free survival was improved in patients treated with combination therapy (HR 0·36 [95% CI 0·14-0·94]). The were no differences in new Sjögren's disease systemic activity or overall survival according to combination therapy or monotherapy., Interpretation: A systemic treatment strategy for Sjögren's disease-associated lymphoma, rather than localised treatment or a watch and wait strategy, reduces the risk of new Sjögren's disease systemic activity and combination therapy is associated with decreased risk of lymphoma relapse., Funding: None., Competing Interests: Declaration of interests VLG received consulting fees from Novartis; honoraria from Novartis and Bristol Myers Squibb; and travel fees from AstraZeneca and Novartis. MC received honoraria from Lilly and travel fees from Novartis, Janssen, UCB, and Pfizer. XM received consulting fees from AstraZeneca, Bristol Myers Squibb, Galapagos, GSK, Novartis, and Pfizer. RS received consulting fees from GSK, Bristol Myers Squibb, Boehringer, and Janssen; honoraria from GSK, Bristol Myers Squibb, Boehringer, Amgen, Pfizer, and Roche; and travel fees from Amgen and GSK. GN received honoraria from Novartis, Boehringer, AbbVie, and Galapagos SASU and travel fees from Amgen, AbbVie, and UCB. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Biomedical graduate students receive intensive training in their scientific area of interest yet need additional skills for successful scientific careers. Our aim was to promote team building, improve collaborations and enhance communication skills. An off-site yearly retreat was organized for the graduate students in our NIH-funded Research Initiative for Scientific Enhancement (RISE) graduate training program. Retreat themes were addressed through short presentations, case studies, live podcasts, webinars, focus groups, role-play, and breakout sessions with various team building exercises to practice communication skills and identify abilities, knowledge, values, and behaviors. Trainees gave short presentations and served as discussion leaders on topics related to the central theme. Expert guest speakers participated in discussion sessions with the trainees. Trainees evaluated the retreats at the end. A total of 48 trainees, 12 RISE Program faculty and staff, and 26 external speakers from industry, academia, media/journalism, the arts, psychology, and holistic medical fields participated over 9 years. The overall average benefit of the in-person retreats was rated 4.80 on a Likert scale of 1-5 by trainees. Trainees particularly enjoyed the informal interactions with program faculty, staff, and fellow trainees. They appreciated the opportunity to learn soft skills, such as interpersonal communication, conflict resolution, and leadership. Two additional retreats conducted virtually because of the COVID-19 pandemic were perceived as less beneficial. We conclude that off-site interactive retreats are a valuable tool for enhancing soft skills and a sense of team identity in a biomedical sciences graduate program, while covering important issues related to scientific careers. NEW & NOTEWORTHY Off-site interactive science-related retreats are a valuable tool for enhancing soft skills and sense of team identity in a biomedical sciences graduate program, while covering important issues related to pursuing a career in science. There are many perceived benefits, so we encourage other training programs to include a similar type of regular activity in students' training with the goal of improving trainee well-being and supporting their academic and research productivity.

Background: Cardiac uptake on technetium-99m whole-body scintigraphy (WBS) is almost pathognomonic of transthyretin cardiac amyloidosis. The rare false positives are often related to light-chain cardiac amyloidosis. However, this scintigraphic feature remains largely unknown, leading to misdiagnosis despite characteristic images. A retrospective review of all WBSs in a hospital database to detect those with cardiac uptake may allow the identification of undiagnosed patients., Objectives: The authors sought to develop and validate a deep learning-based model that automatically detects significant cardiac uptake (Perugini grade ≥2) on WBS from large hospital databases in order to retrieve patients at risk of cardiac amyloidosis., Methods: The model is based on a convolutional neural network with image-level labels. The performance evaluation was performed with C-statistics using a 5-fold cross-validation scheme stratified so that the proportion of positive and negative WBSs remained constant across folds and using an external validation data set., Results: The training data set consisted of 3,048 images: 281 positives (Perugini grade ≥2) and 2,767 negatives. The external validation data set consisted of 1,633 images: 102 positives and 1,531 negatives. The performance of the 5-fold cross-validation and external validation was as follows: 98.9% (± 1.0) and 96.1% for sensitivity, 99.5% (± 0.4) and 99.5% for specificity, and 0.999 (SD = 0.000) and 0.999 for the area under the curve of the receiver-operating characteristic curves. Sex, age <90 years, body mass index, injection-acquisition delay, radionuclides, and the indication of WBS only slightly affected performances., Conclusions: The authors' detection model is effective at identifying patients with cardiac uptake Perugini grade ≥2 on WBS and may help in the diagnosis of patients with cardiac amyloidosis., Competing Interests: Funding Support and Author Disclosures This work was financed by a research grant from Pfizer France. Its initiative, conception and realization were independent. The authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: To evaluate the usefulness of positron emission tomography (PET) coupled with computed tomography (CT) in the diagnostic workup for inflammatory syndrome of undetermined origin (IUO) and to determine the diagnostic delay in an internal medicine department., Patients and Methods: We retrospectively studied a cohort of patients for whom a PET/CT scan had been prescribed in an indication of IUO in an internal medicine department (Amiens University Medical Center, Amiens, France) between October 2004 and April 2017. The patients were grouped according to the PET/CT findings: very useful (enabling an immediate diagnosis), useful, not useful, and misleading., Results: We analyzed 144 patients. The median (interquartile range) age was 67.7 years (55.8-75.8 years). The final diagnosis was an infectious disease in 19 patients (13.2%), cancer in 23 (16%), inflammatory disease in 48 (33%), and miscellaneous diseases in 12 (8.3%). No diagnosis was made in 29.2% of the cases; half of the remaining had a spontaneously favorable outcome. Fever was observed in 63 patients (43%). Positron emission tomography coupled with CT was determined to be very useful in 19 patients (13.2%), useful in 37 (25.7%), not useful in 63 (43.7%), and misleading in 25 (17.4%). The median diagnostic delay (ie, the time interval between the first admission and a confirmed diagnosis) was significantly shorter in the useful (71 days [38-170 days]) and very useful (55 days [13-79 days]) groups than that in the not useful group (175 days [51-390 days]; P<.001). The median time interval between the PET/CT scan and the diagnosis was twice as long in the not useful group than that in the pooled misleading, useful, or very useful groups (P=.03). In a univariate analysis, the poor overall condition (P=.007) and the absence of fever (P=.005) were predictive of usefulness of PET/CT., Conclusion: Positron emission tomography coupled with CT seems to be useful in the diagnosis of IUO and might shorten the diagnostic delay., Competing Interests: The authors report no competing interests., (© 2023 The Authors.)

Background: Patients with inflammatory rheumatic and musculoskeletal diseases (iRMD) receiving mycophenolic acid (MPA) may have a less favourable outcome from COVID-19 infection. Our aim was to investigate whether MPA treatment is associated with severe infection and/or death., Methods: IRMD patients with and without MPA treatment with highly suspected/confirmed COVID-19 were included in this observational multicentre study. The primary outcome was death rate from COVID-19 with secondary objectives to determine the severity of infection and length of hospital stay. Outcome comparisons were made using regression models with and without adjustment on prespecified confounding factors. ORs, sub-HR (sHR) and 95% CIs were calculated using patients not treated with MPA as a reference group., Results: Of the 1977 patients, 1928 were not treated with MPA (393 were MPA eligible), and 49 patients were treated with MPA. MPA-treated patients had more severe disease, longer hospital stays and higher death rate from COVID-19 than non-MPA patients (OR 8.02 (95% CI 3.35 to 19.20), p<0.001; sHR 0.57 (95% CI 0.33 to 0.98), p=0.040; OR 11.58 (95% CI 4.10 to 32.69), p<0.001). In adjusted analyses, however, no outcome was independently associated with MPA treatment. Death rate, severity and length of hospital stay of MPA-treated patients were not significantly different from those of not treated but MPA-eligible patients., Conclusion: MPA therapy is not associated with a more severe COVID-19 infection. However, due to increased vulnerability of developing a severe form of COVID-19, careful consideration should be taken with iRMD patients likely to be treated with MPA., Trial Registration Number: NCT04353609., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: Myelodysplastic syndromes (MDS) and chronic myelomonocytic leukaemia (CMML) are associated with systemic inflammatory and autoimmune diseases (SIADs) in 10-30% of cases. The aims of this study were (i) to evaluate the prevalence of venous thromboembolism VTE in patients presenting with both MDS/CMML and SIADs, (ii) to describe risk factors associated with thrombosis, and (iii) to analyse the impact of VTE on overall survival and transformation to acute myeloid leukaemia in comparison to patients with MDS/CMML-associated SIADs without VTE., Methods: This retrospective multicentre case-control study was conducted among patients with MDS/CMML and dysimmune disorders and featured in the French retrospective database of the French Network of Dysimmune Disorders Associated with Hemopathies (MINHEMON), diagnosed with MDS/CMML and dysimmune disorders., Results: During a median follow-up of 16 months (5-48) VTE occurred in 35 patients (21.6 %) whereas 127 patients did not. Among those with VTE, 8 patients (22.9%) experienced two or more VTE. Common prothrombotic risk factors were not significantly different in patients with or without VTE. CMML was more frequent in patients without VTE (37 % vs. 14.3%, p=0.01), whereas myelodysplasic/myeloproliferative neoplasm (MDS/MPN) was higher in VTE patients (20 % vs. 5.5 %, p=0.01). In a multivariate analysis, only MDS/CMML progression at the time of VTE (odds ratio 28.82, 95 % CI (5.52-530.70) was significantly associated with VTE. When treated with an anticoagulation therapy, bleeding occurred in 19.4% of cases (6/31). Overall survival was not significantly different between patients with and without VTE (p=0.68). Leukaemia-free survival between groups was not significantly different (p=0.83)., Conclusions: VTE is a common complication in MDS/CMML-associated SIADSs with an increased risk of bleeding when treated by anticoagulants. In the MDS/CMML subgroup, SIADS flares and MDS/CMML progression seem to be prothrombotic risk factors.

Objective: A new adult-onset autoinflammatory syndrome has been described, named VEXAS (Vacuoles, E1 Enzyme, X-linked, Autoinflammatory, Somatic). We aimed to compare the clinical characteristics, the laboratory features and the outcomes between idiopathic-relapsing polychondritis (I-RP) and VEXAS-relapsing polychondritis (VEXAS-RP)., Methods: Patients from French retrospective multicentre cohort of RP were separated into two groups: a VEXAS-RP and an I-RP., Results: Compared with patients with I-RP (n=40), patients with VEXAS-RP (n=55) were men (96% vs 30%, p<0.001) and were older at diagnosis (66 vs 44 years, p<0.001). They had a greater prevalence of fever (60% vs 10%, p<0.001), of skin lesions (82% vs 20%, p<0.001), of ocular involvement (57% vs 28%, p=0.01), of pulmonary infiltrates (46% vs 0%, p<0.001), of heart involvement (11% vs 0%, p=0.0336) and with higher median C-reactive protein levels (64 mg/L vs 10 mg/L, p<0.001). Seventy-five per cent of the patients with VEXAS-RP had myelodysplastic syndrome (MDS) versus none in I-RP group. The glucocorticoids use, and the number of steroid sparing agents were similar in both groups, but patients with VEXAS-RP had more frequent refractory disease (remission obtained in 27% vs 90%, p<0001). VEXAS-RP was associated with higher risk of death: six patients (11%) died in the VEXAS-RP group after a median follow-up of 37 months and none in the I-RP group after a median follow-up of 92 months (p<0.05)., Conclusion: We report the largest cohort of VEXAS-RP, characterised by high prevalence of male sex, fever, skin lesion, ocular involvement, pulmonary infiltration, heart involvement, older age and MDS association., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: To determine whether the use of disease-modifying antirheumatic drugs (DMARDs) is linked to the risk of COVID-19 among patients with inflammatory rheumatic diseases (IRDs)., Methods: We performed a disproportionality analysis of the World Health Organization pharmacovigilance database between January 1, 2020, and June 10, 2020. The frequency of COVID-19 reports for all DMARD classes identified was compared with that for all other reports for all other drugs and quoted as the reporting odds ratio (ROR) (95% confidence interval [CI])., Results: Among 980,446 individual case-safety reports voluntarily recorded in the database, 398 identified COVID-19 in DMARD-treated patients with IRDs. There were 177 (44.5%) patients with rheumatoid arthritis (RA), 120 (30.1%) with ankylosing spondylitis (AS), 93 (23.4%) with psoriatic arthritis (PsA), and 8 (2.0%) with juvenile idiopathic arthritis. Most of the cases of COVID-19 occurred in patients taking anti-TNF agents (84.2%), resulting in a significant disproportionality signal (ROR [95% CI]: 8.31 [7.48-9.23]) - particularly in patients with RA, AS or PsA. A significant inverse disproportionality was found for the anti-IL-6 agent tocilizumab (ROR [95% CI]: 0.12 [0.02-0.88]) and JAK inhibitors (ROR [95% CI]: 0.33 [0.19-0.58]) in patients with RA - suggesting that these two drug classes are safer in the context of RA., Conclusion: Our results are in line with the literature on a potentially better safety profile for anti-IL-6 agents and JAK inhibitors. The WHO pharmacovigilance data suggest that COVID-19 is significantly more frequent in patients with IRDs treated with TNF inhibitors., (© 2021 Société Française de Pharmacologie et de Thérapeutique.)

Background/aim: Multiple myeloma (MM) is characterized by high production of immunoglobulins resulting in a constant source of endoplasmic reticulum (ER)-stress. Mesencephalic astrocyte-derived neurotrophic factor (MANF) was identified as a possible circulating biomarker that could help in monitoring ER-stress mediated diseases., Materials and Methods: To assess the relevance of MANF in MM, we performed in silico and in vitro analysis in malignant cell lines including the myeloma cell line RPMI 8226. Serum MANF concentration was compared between healthy subjects (n=60), patients with MM (n=68), or those with monoclonal gammopathy of undetermined significance (MGUS) (n=73)., Results: MANF mRNA expression was upregulated in the RPMI 8226 cell line, and higher secretion of MANF was measured in RPMI 8226 supernatant. Serum MANF levels were not significantly different between MM or MGUS patients and those in age- and sex-matched healthy controls., Conclusion: MANF was not validated as a biomarker of interest in MM patients. Its potential implication in myeloma pathogenesis should be investigated., (Copyright © 2021 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

The ZMM28 protein encoded by the zmm28 gene is endogenous to maize. DP202216 maize was genetically modified to increase and extend expression of the zmm28 gene relative to native zmm28 gene expression, resulting in plants with enhanced grain yield potential. Evaluation of the history of safe use (HOSU) is one component of the safety assessment framework for a newly expressed protein in a GM crop. The deduced amino acid sequence of the introduced ZMM28 protein in DP202216 maize is identical to the ZMM28 protein in nonmodified conventional maize. The ZMM28 protein has also been found in selected varieties of sweet corn kernels, and closely related proteins are found in other commonly consumed food crops. Concentrations of the ZMM28 protein in event DP202216 maize, conventional maize, and sweet corn are reported. This information supports, in part, the evaluation of HOSU, which can be leveraged in the safety assessment of the ZMM28 protein. Additional studies will be considered in the food and feed safety assessment of the DP202216 maize event.

Genetically modified (GM) crops undergo large scale multi-location field trials to characterize agronomics, composition, and the concentration of newly expressed protein(s) [herein referred to as transgenic protein(s)]. The concentration of transgenic proteins in different plant tissues and across the developmental stages of the plant is considered in the safety assessment of GM crops. Reference or housekeeping proteins are expected to maintain a relatively stable expression pattern in healthy plants given their role in cellular functions. Understanding the effects of genotype, growth stage and location on the concentration of endogenous housekeeping proteins may provide insight into the contribution these factors could have on transgenic protein concentrations in GM crops. The concentrations of three endogenous proteins (actin, elongation factor 1-alpha, and glyceraldehyde 3-phosphate dehydrogenase) were measured in several different maize hybrids grown across multiple field locations over 2 years. Leaf samples were collected from healthy plants at three developmental stages across the growing seasons, and protein concentrations were quantified by indirect enzyme-linked immunosorbent assay (ELISA) for each protein. In general, the concentrations of these three endogenous proteins were relatively consistent across hybrid backgrounds, when compared within one growth stage and location (2-26%CV), whereas the concentrations of proteins in the same hybrid and growth stage across different locations were more variable (12-64%CV). In general, the protein concentrations in 2013 and 2014 show similar trends in variability. Some degree of variability in protein concentrations should be expected for both transgenic and endogenous plant-expressed proteins. In the case of GM crops, the potential variation in protein concentrations due to location effects is captured in the current model of multi-location field testing.

Objectives: To evaluate cardiopulmonary (CP) involvement in patients with Takayasu's arteritis (TAK) and assess the impact on disease outcomes., Methods: A retrospective cohort of patients with newly diagnosed TAK from 1984 to 2009 was assembled. Demographics, baseline disease characteristics, relapse events, surgeries and mortality were abstracted from direct medical record review. Angiograms, advanced imaging and cardiac studies were reviewed for evidence of CP involvement. Cox models with time-dependent covariates were used to assess the association between CP involvement and outcomes., Results: A total of 124 patients with TAK were identified. Forty-five (36%) patients had at least one objective CP abnormality observed within 6 months of TAK diagnosis. Age at diagnosis was higher in those with CP involvement than those without (34.6 vs 30.1 yrs; p=0.04). Baseline characteristics and symptoms were similar, except shortness of breath, which was more frequently observed at TAK diagnosis in patients with CP involvement compared to those without (53% vs 21%; p=0.001). Composite CP involvement was not associated with risk of first surgery [Hazard ratio (95% CI): 1.21 (0.64-2.30); p=0.56]. However, pulmonary hypertension (PH) on echocardiogram was significantly associated with risk of first surgery [HR (95% CI): 12.9 (1.86- 89.14); p=0.01]. CP involvement was not significantly associated with mortality [HR (95% CI): 2.51 (0.45- 14.02); p=0.29]., Conclusions: Cardiopulmonary abnormalities in TAK are common at the time of initial presentation. In this population, the presence of PH predicted a 13-fold increased risk for vascular or valvular surgery. In this cohort, the presence of CP involvement did not increase mortality.

Objective: To compare clinical and imaging characteristics of patients with giant cell arteritis (GCA) and upper extremity (UE) arterial involvement to patients with Takayasu arteritis (TAK)., Methods: A cohort of patients seen at the Mayo Clinic with TAK diagnosed between 1984 and 2009 and a cohort of patients with GCA and UE arterial involvement diagnosed between 1999 and 2008 were studied., Results: The TAK cohort consisted of 125 patients (91% female); the mean age (±SD) at diagnosis was 30.9 (±10) years. The cohort of patients with GCA and UE involvement comprised of 120 patients (80% female); the mean age (±SD) at diagnosis was 67.8 (±7.5) years. The mean time from onset of symptoms to diagnosis was significantly longer in TAK (3.2 years) than GCA (0.5 years), p < 0.001. UE claudication was reported in 40% with TAK and 53% with GCA, p = 0.04. UE blood pressure discrepancy was present in 65% with TAK versus 28% with GCA, p < 0.001. Involvement of the thoracic aorta, abdominal aorta, carotid arteries, innominate artery, mesenteric artery, and left renal artery was more frequently observed in TAK (p < 0.05). Among patients with luminal changes of the thoracic aorta, stenotic/occlusive lesions were predominant in TAK (81% compared to 0% in GCA), whereas aneurysmal disease was more common in GCA (100% compared with 19% in TAK, p < 0.001)., Conclusion: Patients with GCA and UE involvement differ from patients with TAK in clinical and imaging characteristics. Aortic aneurysms were more common in GCA, while stenotic changes of the aorta were more common in TAK, suggesting different pathophysiologic mechanisms or vascular response to injury., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Objective: To describe the clinical features, treatment, and outcomes in a longitudinal cohort of patients with Takayasu arteritis (TAK)., Patients and Methods: We retrospectively studied patients with newly diagnosed TAK evaluated from January 1, 1984, through December 31, 2009., Results: The cohort included 126 patients who were predominantly white (85/103; 82.5%) and female (115/126; 91%). The median age at diagnosis was 31.6 years (interquartile range, 22.9-39.8 years). Median delay in diagnosis was 17.5 months (interquartile range, 7-41.8 months). Thirty-one patients (25%) were 40 years or older at diagnosis. Median delay in diagnosis for patients 40 years or older was 44.8 months compared with 28.3 months for those younger than 40 years (P<.001). Limb claudication was the presenting symptom in 64 of 123 patients (52%). Hata type V arteriographic abnormalities were the most common (57/100; 57%). Renal artery abnormalities were observed in 24 of 41 patients (58%) with new-onset hypertension. Inflammatory markers were elevated at diagnosis in 85 of 119 patients (71%). Vascular interventions were performed in 69 patients (55%). Seventy-nine patients (63%) were followed up for more than 1 year (median follow-up, 5.5 years; interquartile range, 2.9-10.0 years). In this subset, treatment consisted of corticosteroids in 73 patients (92%) and additional immunosuppressants in 52 patients (66%). At 5 years, 96% experienced at least one remission of any duration. The overall survival was 97% at 10 years and 86% at 15 years. Mortality was increased compared with the general population (standardized mortality ratio, 3.0; 95% CI, 1.0-8.9)., Conclusion: There continues to be an unacceptably long delay in the diagnosis of TAK. Awareness of TAK in patients older than 40 years is needed. Morbidity was high despite immunosuppressive treatment. Survival was decreased in this cohort., (Copyright © 2013 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. All rights reserved.)

Giant cell arteritis (GCA) is an inflammatory vasculopathy that involves large- and medium-sized arteries and can cause vision loss, stroke and aneurysms. GCA occurs in people aged >50 years and is more common in women. A higher incidence of the disease is observed in populations from Northern European countries. Polymyalgia rheumatica (PMR) is a periarticular inflammatory process manifesting as pain and stiffness in the neck, shoulders and pelvic girdle. PMR shares the same pattern of age and sex distribution as GCA. The pathophysiology of PMR and GCA is not completely understood, but the two conditions may be related and often occur concurrently. A delay in the diagnosis should be avoided because of the risk of vascular ischaemic complications due to GCA. The diagnosis should be considered in patients aged >50 years presenting with symptoms such as new headache, visual disturbances, jaw claudication or symptoms of PMR. GCA can also present as a systemic inflammatory syndrome with fever of unknown origin. Marked elevation of acute-phase reactants, recognizable in higher erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) levels, is often seen in both PMR and GCA. However, some patients can present with a normal ESR. Confirmation of the diagnosis of GCA by temporal artery biopsy is important because clinical findings and laboratory tests are not specific, and because a diagnosis of GCA commits patients to long-term treatment with corticosteroids. The role of imaging techniques for the diagnosis of GCA remains unclear, but these modalities can be helpful in assessing the extent of vascular involvement, especially when extra-cranial disease is present. In PMR, subdeltoid and subacromial bursitis can be identified by imaging techniques, especially ultrasound or MRI. The clinical manifestations of GCA and PMR respond dramatically within 12-48 hours of starting corticosteroid treatment. The initial corticosteroid dosage commonly used in GCA is oral prednisone 40-60 mg/day, and for patients with PMR a dosage of 15-20 mg/day is often sufficient. A prolonged course of treatment is necessary, and corticosteroids are gradually tapered, guided by regular clinical evaluation and ESR (and/or CRP) measurement. Methotrexate is the best studied corticosteroid-sparing agent in GCA, and may be useful for patients with frequent disease relapses and/or corticosteroid-related toxicity. Retrospective studies favour aspirin (acetylsalicylic acid) as an effective adjuvant treatment for reducing the ischaemic complications of GCA. The long-term course of corticosteroid therapy frequently exposes elderly patients with PMR/GCA to various adverse effects, which can be attenuated with appropriate prophylactic measures. Co-morbid diseases and polypharmacy can pose particular challenges in the geriatric population. In general, the life expectancy of patients with GCA does not appear to be shortened, whereas the morbidity associated with the disease and its treatment is well recognized.

Backgrounds: Among anti-double-strand (ds)DNA antibody assays, Farr radioimmunoassay is decreasingly used because it requires radioactive material and is labor intensive. We evaluated the performance of Farr, three commercial enzyme immunoassays (EIAs) and the Crithidia luciliae immunofluorescence test (CLIFT) in systemic lupus erythematosus (SLE)., Methods: Anti-dsDNA antibodies were determined in 99 SLE patients, 101 healthy subjects, and 53 patients with autoimmune rheumatic diseases., Results: Farr performed better than the 3 EIAs and CLIFT for the diagnosis of SLE at the manufacturer's cut off and at the cut off set to achieve a specificity of 95%. To achieve a similar level of specificity, some EIAs had a decrease in sensitivity which was dramatic for some tests. Farr was also the best at distinguishing patients with quiescent to mildly active disease from patients with more active disease at the cut off value of 93 IU/ml. Using manufacturer's cut off did not allow distinguishing between patients with quiescent and active SLE., Conclusions: Farr was the best global test to assess the level of anti-dsDNA antibodies for both diagnosis and disease activity evaluation in SLE with adequately determined cut off values. Some EIA had low performances limiting their use in decision-making regarding diagnosis and/or treatment., (Copyright 2010 Elsevier B.V. All rights reserved.)

The glyphosate acetyltransferase (gat) gene from Bacillus licheniformis was subjected to multiple rounds of gene shuffling to optimize kinetics of corresponding GAT proteins to acetylate the herbicide active ingredient glyphosate. Genetically modified soybeans expressing the gat4601 gene (356043 soybeans) are tolerant to the application of glyphosate. The current manuscript reports the outcome of the allergenicity and toxicity assessment for the GAT4601 protein. Bioinformatic comparison of the amino acid sequence of GAT4601 did not identify similarities to known allergenic or toxic proteins. In vitro studies conducted with heterologously produced GAT4601 protein demonstrated that it was rapidly degraded in simulated gastric fluid containing pepsin (< 30 s) and in simulated intestinal fluid containing pancreatin (< 2 min) and completely inactivated at temperatures above 56 degrees C. The GAT4601 protein expressed in planta is not glycosylated and similar protein profiles were observed in flour extracts from 356043 soybeans and nontransgenic near isoline comparator soybeans (Jack) using serum from soy allergic persons. No evidence of adverse effects was observed in mice following acute oral exposure to 2000 mg/kg of GAT4601 protein or in a repeated dose dietary exposure study at doses of 800-1000 mg/kg/day. This comprehensive assessment demonstrates that the GAT4601 protein does not present a risk for adverse effects in humans when used in the context of agricultural biotechnology.

Community-based health insurance schemes were introduced in Rwanda in 1999 and now cover 27% of the population. Due to widespread poverty, it remains unclear to what degree poorer population strata can be anticipated to pay into the system. This study investigates the extent to which the Rwandan population can financially contribute to obtain health insurance. More specifically, researchers explored the relationship between resource mobilization for the health system and the ability to provide community-based health insurance across socio-economic strata. Data from six household surveys are analysed revealing a consistent pattern: the goals of maximizing health revenue and maximizing participation in community-based health insurance are mutually exclusive. However, the upper three quartiles of the Rwandan population are able to contribute 1 US dollar per capita per year. In order to extend coverage to the poorest quartile, a corresponding subsidy for the coming years has to be considered.

The bark of the giant neem tree Melia dubia was found to contain 11 euphane-type triterpenes. Five new compounds, meliastatins 1-5 (1-5), proved to inhibit growth of the P388 lymphocytic leukemia cell line (ED(50) 1.7-5.6 microg/mL). Four of the others, the previously known methyl kulonate (8), kulinone (9), 16-hydroxybutyrospermol (10), and kulactone (11), were also found to inhibit (ED(50) 2.5-6.2 microg/mL) the P388 cancer cell line. In addition, two new euphane triterpenes were isolated and named dubione A (6) and dubione B (7). Structures for each of the 11 euphane triterpenes were established by spectral techniques that included HRMS and 2D NMR.

As an extension of structure/activity investigations of resveratrol (1), phenstatin (2c), and the cancer antiangiogenesis drug sodium combretastatin A-4 phosphate (2b), syntheses of certain related stilbenes (14) and benzophenones (16) were undertaken. The trimethyl ether derivative of (Z)-resveratrol (4a) exhibited the strongest activity (GI(50) = 0.01-0.001 microg/mL) against a minipanel of human cancer cell lines. A monodemethylated derivative (14c) was converted to prodrug 14n (sodium resverastatin phosphate) for further biological evaluation. The antitubulin and antimicrobial activities of selected compounds were also evaluated.