Canakinumab for the treatment of acute flares in difficult-to-treat gouty arthritis: Results of a multicenter, phase II, dose-ranging study.

OBJECTIVE: To assess the efficacy and tolerability of canakinumab, a fully human anti-interleukin-1β monoclonal antibody, for the treatment of acute gouty arthritis. METHODS: In this 8-week, single-blind, double-dummy, dose-ranging study, patients with acute gouty arthritis whose disease was refractory to or who had contraindications to nonsteroidal antiinflammatory drugs and/or colchicine were randomized to receive a single subcutaneous dose of canakinumab (10, 25, 50, 90, or 150 mg; n = 143) or an intramuscular dose of triamcinolone acetonide (40 mg; n = 57). Patients assessed pain using a 100-mm visual analog scale. RESULTS: Seventy-two hours after treatment, a statistically significant dose response was observed for canakinumab. All canakinumab doses were associated with numerically less pain than triamcinolone acetonide; thus, a dose with equivalent efficacy to triamcinolone acetonide 72 hours after treatment could not be determined. The reduction from baseline in pain intensity with canakinumab 150 mg was greater than with triamcinolone acetonide 24, 48, and 72 hours after treatment (differences of -11.5 mm [P = 0.04], -18.2 mm [P = 0.002], and -19.2 mm [P < 0.001], respectively), and 4, 5, and 7 days after treatment (all P < 0.05). Canakinumab significantly reduced the risk of recurrent flares versus triamcinolone acetonide (P ≤ 0.01 for all doses) (relative risk reduction 94% for canakinumab 150 mg versus triamcinolone acetonide). The overall incidence of adverse events was similar for canakinumab (41%) and triamcinolone acetonide (42%); most were mild or moderate in severity. CONCLUSION: Our findings indicate that canakinumab 150 mg provides rapid and sustained pain relief in patients with acute gouty arthritis, and significantly reduces the risk of recurrent flares compared with triamcinolone acetonide.

Diet and the risk of head and neck cancer: a pooled analysis in the INHANCE consortium.

We investigated the association between diet and head and neck cancer (HNC) risk using data from the International Head and Neck Cancer Epidemiology (INHANCE) consortium. The INHANCE pooled data included 22 case-control studies with 14,520 cases and 22,737 controls. Center-specific quartiles among the controls were used for food groups, and frequencies per week were used for single food items. A dietary pattern score combining high fruit and vegetable intake and low red meat intake was created. Odds ratios (OR) and 95% confidence intervals (CI) for the dietary items on the risk of HNC were estimated with a two-stage random-effects logistic regression model. An inverse association was observed for higher-frequency intake of fruit (4th vs. 1st quartile OR = 0.52, 95% CI = 0.43-0.62, p (trend) < 0.01) and vegetables (OR = 0.66, 95% CI = 0.49-0.90, p (trend) = 0.01). Intake of red meat (OR = 1.40, 95% CI = 1.13-1.74, p p (trend) < 0.01) was positively associated with HNC risk. Higher dietary pattern scores, reflecting high fruit/vegetable and low red meat intake, were associated with reduced HNC risk (per score increment OR = 0.90, 95% CI = 0.84-0.97).

EULAR recommendations for the management of large-vessel vasculitis.

Objectives: To develop European League Against Rheumatism (EULAR) recommendations for the management of large vessel vasculitis. Methods: An expert group (10 rheumatologists, 3 nephrologists, 2 immunolgists, 2 internists representing 8 European countries and the USA, a clinical epidemiologist and a representative from a drug regulatory agency) identified 10 topics for a systematic literature search through a modified Delphi technique. In accordance with standardised EULAR operating procedures, recommendations were derived for the management of large vessel vasculitis. In the absence of evidence, recommendations were formulated on the basis of a consensus opinion. Results: Seven recommendations were made relating to the assessment, investigation and treatment of patients with large vessel vasculitis. The strength of recommendations was restricted by the low level of evidence and EULAR standardised operating procedures. Conclusions: On the basis of evidence and expert consensus, management recommendations for large vessel vasculitis have been formulated and are commended for use in everyday clinical practice.

EULAR recommendations for the management of primary small and medium vessel vasculitis.

Objectives: To develop European League Against Rheumatism (EULAR) recommendations for the management of small and medium vessel vasculitis. Methods: An expert group (consisting of 10 rheumatologists, 3 nephrologists, 2 immunologists, 2 internists representing 8 European countries and the USA, a clinical epidemiologist and a representative from a drug regulatory agency) identified 10 topics for a systematic literature search using a modified Delphi technique. In accordance with standardised EULAR operating procedures, recommendations were derived for the management of small and medium vessel vasculitis. In the absence of evidence, recommendations were formulated on the basis of a consensus opinion. Results: In all, 15 recommendations were made for the management of small and medium vessel vasculitis. The strength of recommendations was restricted by low quality of evidence and by EULAR standardised operating procedures. Conclusions: On the basis of evidence and expert consensus, recommendations have been made for the evaluation, investigation, treatment and monitoring of patients with small and medium vessel vasculitis for use in everyday clinical practice.

Efficacy Of Canakinumab (Acz885), A Fully Human Anti-Interleukin (Il)-1beta Monoclonal Antibody, In The Prevention Of Flares In Gout Patients Initiating Allopurinol Therapy

Background: Gout patients initiating urate lowering therapy have an increased risk of flares. Inflammation in gouty arthritis is induced by IL-1b. Canakinumab targets and inhibits IL-1b effectively in clinical studies. This study compared different doses of canakinumab vs colchicine in preventing flares in gout patients initiating allopurinol therapy.Methods: In this 24 week double blind study, gout patients (20-79 years) initiating allopurinol were randomized (1:1:1:1:1:1:2) to canakinumab s.c. single doses of 25, 50, 100, 200, 300 mg, or 150 mg divided in doses every 4 weeks (50+50+25+25 mg [q4wk]) or colchicine 0.5 mg p.o. daily for 16 weeks. Primary outcome was to determine the canakinumab dose giving comparable efficacy to colchicine with respect to the number of gout flares occurring during first 16 weeks. Secondary outcomes included number of patients with gout flares and C-reactive protein (CRP) levels during the first 16 weeks.Results: 432 patients were randomized and 391 (91%) completed the study. All canakinumab doses were better than colchicine in preventing flares and therefore, a canakinumab dose comparable to colchicine could not be determined. Based on a negative binomial model, all canakinumab groups, except 25 mg, reduced the flare rate ratio per patient significantly compared to colchicine group (rate ratio estimates 25 mg 0.60, 50 mg 0.34, 100 mg 0.28, 200 mg 0.37, 300 mg 0.29, q4wk 0.38; p<=0.05). The percentage of patients with flares was lower for all canakinumab groups (25 mg 27.3%, 50 mg 16.7%, 100 mg 14.8%, 200 mg 18.5%, 300 mg 15.1%, q4wk 16.7%) compared to colchicine group (44.4%). All patients taking canakinumab were significantly less likely to experience at least one gout flare than patients taking colchicine (odds ratio range [0.22 - 0.47]; p<=0.05 for all). The median baseline CRP levels were 2.86 mg/L for 25 mg, 3.42 mg/L for 50 mg, 1.76 mg/L for 100 mg, 3.66 mg/L for 200 mg, 3.21 mg/L for 300 mg, 3.23 mg/L for q4wk canakinumab groups and 2.69 mg/L for colchicine group. In all canakinumab groups with median CRP levels above the normal range at baseline, median levels declined within 15 days of treatment and were maintained at normal levels (ULN=3 mg/L) throughout the 16 week period. Adverse events (AEs) occurred in 52.7% (25 mg), 55.6% (50 mg), 51.9% (100 mg), 51.9% (200 mg), 54.7% (300 mg), and 58.5% (q4wk) of patients on canakinumab vs 53.7% of patients on colchicine. Serious AEs (SAE) were reported in 2 (3.6%; 25 mg), 2 (3.7%, 50 mg), 3 (5.6%, 100 mg), 3 (5.6%, 200 mg), 3 (5.7%, 300 mg) and 1 (1.9%, q4wk) patients on canakinumab and in 5 (4.6%) patients on colchicine. One fatal SAE (myocardial infarction, not related to study drug) occurred in colchicine group.Conclusion: In this large randomized, double-blind active controlled study of flare prevention in gout patients initiating allopurinol therapy, treatment with canakinumab led to a statistically significant reduction in flares compared with colchicine (standard of care), and was well tolerated.

Corrosion of Steel in CRCP, HR-1004, 1975

The Materials and Research Departments cooperated in planning and performing Research Project HR-1004 during the summer of 1974. The Research Department agreed to accept responsibility for the final report; it has been delayed because of our efforts to obtain a maximum amount of information from the data by means of various statistical analyses. This memorandum contains all of the data, hopefully in a manner that will permit you to proceed with your consideration of an experimental project using cathodic protection for the CRCP steel. A more detailed report will be prepared at a later date.

Evaluation of Corrosion Resistance of Different Steel Reinforcement Types, 2006

The corrosion of steel reinforcement in an aging highway infrastructure is a major problem currently facing the transportation engineering community. In the United States alone, maintenance and replacement costs for deficient bridges are measured in billions of dollars. The application of corrosion-resistant steel reinforcement as an alternative reinforcement to existing mild steel reinforced concrete bridge decks has potential to mitigate corrosion problems, due to the fundamental properties associated with the materials. To investigate corrosion prevention through the use of corrosion-resistant alloys, the performance of corrosion resistance of MMFX microcomposite steel reinforcement, a high-strength, high-chromium steel reinforcement, was evaluated. The study consisted of both field and laboratory components conducted at the Iowa State University Bridge Engineering Center to determine whether MMFX reinforcement provides superior corrosion resistance to epoxy-coated mild steel reinforcement in bridge decks. Because definitive field evidence of the corrosion resistance of MMFX reinforcement may require several years of monitoring, strict attention was given to investigating reinforcement under accelerated conditions in the laboratory, based on typical ASTM and Rapid Macrocell accelerated corrosion tests. After 40 weeks of laboratory testing, the ASTM ACT corrosion potentials indicate that corrosion had not initiated for either MMFX or the as-delivered epoxy-coated reinforcement. Conversely, uncoated mild steel specimens underwent corrosion within the fifth week, while epoxy-coated reinforcement specimens with induced holidays underwent corrosion between 15 and 30 weeks. Within the fifth week of testing, the Rapid Macrocell ACT produced corrosion risk potentials that indicate active corrosion for all reinforcement types tested. While the limited results from the 40 weeks of laboratory testing may not constitute a prediction of life expectancy and life-cycle cost, a procedure is presented herein to determine life expectancy and associated life-cycle costs.

Transcriptome analyses of primitively eusocial wasps reveal novel insights into the evolution of sociality and the origin of alternative phenotypes

BACKGROUND: Understanding how alternative phenotypes arise from the same genome is a major challenge in modern biology. Eusociality in insects requires the evolution of two alternative phenotypes - workers, who sacrifice personal reproduction, and queens, who realize that reproduction. Extensive work on honeybees and ants has revealed the molecular basis of derived queen and worker phenotypes in highly eusocial lineages, but we lack equivalent deep-level analyses of wasps and of primitively eusocial species, the latter of which can reveal how phenotypic decoupling first occurs in the early stages of eusocial evolution. RESULTS: We sequenced 20 Gbp of transcriptomes derived from brains of different behavioral castes of the primitively eusocial tropical paper wasp Polistes canadensis. Surprisingly, 75% of the 2,442 genes differentially expressed between phenotypes were novel, having no significant homology with described sequences. Moreover, 90% of these novel genes were significantly upregulated in workers relative to queens. Differential expression of novel genes in the early stages of sociality may be important in facilitating the evolution of worker behavioral complexity in eusocial evolution. We also found surprisingly low correlation in the identity and direction of expression of differentially expressed genes across similar phenotypes in different social lineages, supporting the idea that social evolution in different lineages requires substantial de novo rewiring of molecular pathways. CONCLUSIONS: These genomic resources for aculeate wasps and first transcriptome-wide insights into the origin of castes bring us closer to a more general understanding of eusocial evolution and how phenotypic diversity arises from the same genome.

PAX5 activates the transcription of the human telomerase reverse transcriptase gene in B cells.

Telomerase is an RNA-dependent DNA polymerase that synthesizes telomeric DNA. Its activity is not detectable in most somatic cells but it is reactivated during tumorigenesis. In most cancers, the combination of hTERT hypermethylation and hypomethylation of a short promoter region is permissive for low-level hTERT transcription. Activated and malignant lymphocytes express high telomerase activity, through a mechanism that seems methylation-independent. The aim of this study was to determine which mechanism is involved in the enhanced expression of hTERT in lymphoid cells. Our data confirm that in B cells, some T cell lymphomas and non-neoplastic lymph nodes, the hTERT promoter is unmethylated. Binding sites for the B cell-specific transcription factor PAX5 were identified downstream of the ATG translational start site through EMSA and ChIP experiments. ChIP assays indicated that the transcriptional activation of hTERT by PAX5 does not involve repression of CTCF binding. In a B cell lymphoma cell line, siRNA-induced knockdown of PAX5 expression repressed hTERT transcription. Moreover, ectopic expression of PAX5 in a telomerase-negative normal fibroblast cell line was found to be sufficient to activate hTERT expression. These data show that activation of hTERT in telomerase-positive B cells is due to a methylation-independent mechanism in which PAX5 plays an important role.

The genome of the recently domesticated crop plant sugar beet (Beta vulgaris)

Sugar beet (Beta vulgaris ssp. vulgaris) is an important crop of temperate climates which provides nearly 30% of the world's annual sugar production and is a source for bioethanol and animal feed. The species belongs to the order of Caryophylalles, is diploid with 2n = 18 chromosomes, has an estimated genome size of 714-758 megabases and shares an ancient genome triplication with other eudicot plants. Leafy beets have been cultivated since Roman times, but sugar beet is one of the most recently domesticated crops. It arose in the late eighteenth century when lines accumulating sugar in the storage root were selected from crosses made with chard and fodder beet. Here we present a reference genome sequence for sugar beet as the first non-rosid, non-asterid eudicot genome, advancing comparative genomics and phylogenetic reconstructions. The genome sequence comprises 567 megabases, of which 85% could be assigned to chromosomes. The assembly covers a large proportion of the repetitive sequence content that was estimated to be 63%. We predicted 27,421 protein-coding genes supported by transcript data and annotated them on the basis of sequence homology. Phylogenetic analyses provided evidence for the separation of Caryophyllales before the split of asterids and rosids, and revealed lineage-specific gene family expansions and losses. We sequenced spinach (Spinacia oleracea), another Caryophyllales species, and validated features that separate this clade from rosids and asterids. Intraspecific genomic variation was analysed based on the genome sequences of sea beet (Beta vulgaris ssp. maritima; progenitor of all beet crops) and four additional sugar beet accessions. We identified seven million variant positions in the reference genome, and also large regions of low variability, indicating artificial selection. The sugar beet genome sequence enables the identification of genes affecting agronomically relevant traits, supports molecular breeding and maximizes the plant's potential in energy biotechnology.

The Effect of Load Follow Operation on Fuel Behaviour in Loviisa NPP

Työn tarkoituksena oli analysoida polttoainesauvojen käyttäytymistä Loviisan ydinvoimalaitoksen tehonsäätöajossa. Sähkömarkkinoiden vapautuminen Pohjoismaissa sekä tämän seurauksena vaihteleva sähkön markkinahinta ovat ajaneet sähkötuottajat tilanteeseen, jossa tuotanto aiempaa enemmän mukautuu markkinatilanteeseen. Näin ollen myös Loviisan ydinvoimalaitoksen osallistuminen sähkön tuotannon säätelyyn saattaa tulevaisuudessa olla ajankohtaista. Ennen kuin reaktorin tehonsäätöajoa voidaan alkaa toteuttaa, tulee varmistua siitä, että polttoainesauvassa tehonsäätöjen seurauksena tapahtuvat muutokset eivät aiheuta epäsuotuisia käyttäytymisilmiöitä. Työssä tarkastellaan kahden Loviisan ydinvoimalaitoksen polttoainetoimittajan, British Nuclear Fuels plc:n ja venäläisen TVEL:n ensinippujen polttoainesauvan käyttäytymistä tehonsäätötapauksissa. Työssä tarkastellut tehonsäätötapaukset on pyritty valitsemaan niin, että ne kuvaisivat tulevaisuudessa mahdollisesti toteutettavia tehonsäätöjä. Laskentatapauksien sauvatehohistoriat on generoitu HEXBU-3D sydänsimulaattoriohjelmalla lasketun nelivuotisen perustehohistorian pohjalta lisäämällä säätösauvan aiheuttama reaktoritehon muutos, säätösauvan viereisen polttoainenipun aksiaalitehon muutos sekä säätösauvan rakenteen aiheuttama paikallinen tehopiikki säätösauvan vieressä. Työssä tarkastellaan tehonsäätöjen toteuttamista eri tehotasoille ja vaihtelevilla määrillä tehonsäätösyklejä. Työssä käsitellyt laskentatapaukset on jaoteltu reaktorin ajotavan mukaan seuraavasti: peruskuorma-ajo, viikonloppusäätö ja päiväsäätö. Laskenta suoritettiin ydinpolttoaineen käyttäytymistä kuvaavaa ENIGMA-B 7.3.0 ohjelmaa apuna käyttäen. Laskelmien tulokset osoittavat, että molempien polttoainetoimittajien ensinippujen sauvat kestävät reaktorin tehonsäätöajoa rajoituksetta tarkastelluissa laskentatapauksissa. ENIGMA-ohjelman sisältämät mallit, jotka ennustavat polttoainesauvan suojakuoren vaurioitumistodennäköisyyden jännityskorroosion tai väsymismurtuman kautta, eivät näytä mitään merkkejä vaurioitumisesta. BNFL:n polttoainesauva saavuttaa kuitenkin suurempia väsymismurtumatodennäköisyyden arvoja. Tämä johtuu siitä, että polttoainepelletin ja suojakuoren välinen mekaaninen vuorovaikutus syntyy BNFL:n sauvassa aikaisemmin, joka taas johtaa suurempaan määrään sauvaa rasittavia muodonmuutoksia tehonnostotilanteissa. TVEL:n Zr1%Nb -materiaalista valmistetun suojakuoren käyttäytymistä ei voida kuitenkaan suoraan näiden laskujen perusteella arvioida, sillä ENIGMA-ohjelman mallit perustuvat Zircaloy-suojakuorimateriaaleilla suoritettuihin kokeisiin.

The structure of human tRNALys3 anticodon bound to HIV genome is stabilized by modified nucleosides and adjacent mismatch base pairs

Replication of human immunodeficiency virus (HIV) requires base pairing of the reverse transcriptase primer, human tRNA(Lys3), to the viral RNA. Although the major complementary base pairing occurs between the HIV primer binding sequence (PBS) and the tRNA's 3'-terminus, an important discriminatory, secondary contact occurs between the viral A-rich Loop I, 5'-adjacent to the PBS, and the modified, U-rich anticodon domain of tRNA(Lys3). The importance of individual and combined anticodon modifications to the tRNA/HIV-1 Loop I RNA's interaction was determined. The thermal stabilities of variously modified tRNA anticodon region sequences bound to the Loop I of viral sub(sero)types G and B were analyzed and the structure of one duplex containing two modified nucleosides was determined using NMR spectroscopy and restrained molecular dynamics. The modifications 2-thiouridine, s(2)U(34), and pseudouridine, Psi(39), appreciably stabilized the interaction of the anticodon region with the viral subtype G and B RNAs. The structure of the duplex results in two coaxially stacked A-form RNA stems separated by two mismatched base pairs, U(162)*Psi(39) and G(163)*A(38), that maintained a reasonable A-form helix diameter. The tRNA's s(2)U(34) stabilized the interaction between the A-rich HIV Loop I sequence and the U-rich anticodon, whereas the tRNA's Psi(39) stabilized the adjacent mismatched pairs.

The determinants of contractual choice for private involvement in infrastructure projects in the United States

Reliance on private partners to help provide infrastructure investment and service delivery is increasing in the United States. Numerous studies have examined the determinants of the degree of private participation in infrastructure projects as governed by contract type. We depart from this simple public/private dichotomy by examining a rich set of contractual arrangements. We utilize both municipal and state-level data on 472 projects of various types completed between 1985 and 2008. Our estimates indicate that infrastructure characteristics, particularly those that reflect stand alone versus network characteristics, are key factors influencing the extent of private participation. Fiscal variables, such as a jurisdiction’s relative debt level, and basic controls, such as population and locality of government, increase the degree of private participation, while a greater tax burden reduces private participation.

Impact of 18F-FDG PET scan on the prevalence of benign thoracic lesions at surgical resection

OBJECTIVE: The main utility of 18-fluorodeoxyglucose positron emission tomography (FDG-PET) lies in the staging of lung cancer. However, it can also be used to differentiate indeterminate pulmonary lesions, but its impact on the resection of benign lesions at surgery is unknown. The aim of this study was to compare the prevalence of benign lesions at thoracotomy carried out for suspected lung cancer, before and after the introduction of PET scanning in a large thoracic surgical centre. MATERIALS AND METHODS: We reviewed our prospectively recorded surgical database for all consecutive patients undergoing thoracotomy for suspected or proven lung cancer and compared the prevalence of benign lesions in 2 consecutive 2-year groups, before (group I) and after (group II) the introduction of FDG-PET scan respectively. RESULTS: Surgical resection was performed on 1233 patients during the study period. The prevalence of benign lesions at surgery in groups I and II was similar (44/626 and 41/607, both 7%), and also in group II between those who underwent FDG-PET scan and the remainder (21/301 and 20/306 respectively, both 7%). In group II, of the 21 patients with benign lesions, who underwent FDG-PET, 19 had a false positive scan (mean standardised uptake value 5.3 [range 2.6-12.7]). Of these, 13 and 4 patients respectively had non-diagnostic bronchoscopy and percutaneous transthoracic lung biopsy pre thoracotomy. There was no difference in the proportion of different benign lesions resected between group I and those with FDG-PET in group II. CONCLUSION: The introduction of FDG-PET scanning has not altered the proportion of patients undergoing thoracotomy for ultimately benign lesions, mainly due to the avidity for the isotope of some non-malignant lesions. Such false positive results need to be considered when patients with unconfirmed lung cancer are contemplated for surgical resection.