Rilonacept in the treatment of acute gouty arthritis: a randomized,controlled clinical trial using indomethacin as the active comparator

Introduction

In phase-3 clinical trials, the interleukin (IL-1) blocker, rilonacept (IL-1 Trap), demonstrated efficacy for gout flare prevention during initiation of urate-lowering therapy. This trial evaluated rilonacept added to a standard-of-care, indomethacin, for treatment of acute gout flares.

Methods

Adults, aged 18-70 years, with gout presenting within 48 hours of flare onset and having at least moderate pain as well as swelling and tenderness in the index joint were randomized to subcutaneous (SC) rilonacept 320 mg at baseline plus oral indomethacin 50 mg TID for 3 days followed by 25 mg TID for up to 9 days (n = 74); SC placebo at baseline plus oral indomethacin as above (n = 76); or SC rilonacept 320 mg at baseline plus oral placebo (n = 75). The primary efficacy endpoint was change in pain in the index joint (patient-reported using a Likert scale (0 = none; 4 = extreme)) from baseline to the average of values at 24, 48 and 72 hours (composite time point) for rilonacept plus indomethacin versus indomethacin alone. Comparison of rilonacept monotherapy with indomethacin monotherapy was dependent on demonstration of significance for the primary endpoint. Safety evaluation included clinical laboratory and adverse event (AE) assessments.

Results

Patient characteristics were comparable among the groups; the population was predominantly male (94.1%), white (75.7%), with mean ± SD age of 50.3 ± 10.6 years. All treatment groups reported within-group pain reductions from baseline (P < 0.0001). Although primary endpoint pain reduction was greater with rilonacept plus indomethacin (-1.55 ± 0.92) relative to indomethacin alone (-1.40 ± 0.96), the difference was not statistically significant (P = 0.33), so formal comparison between monotherapy groups was not performed. Pain reduction over the 72-hour period with rilonacept alone (-0.69 ± 0.97) was less than that in the other groups, but pain reduction was similar among groups at 72 hours. Treatment with rilonacept was well-tolerated with no reported serious AEs related to rilonacept. Across all groups, the most frequent AEs were headache and dizziness.

Conclusions

Although generally well-tolerated, rilonacept in combination with indomethacin and rilonacept alone did not provide additional pain relief over 72 hours relative to indomethacin alone in patients with acute gout flare.

Trial registration

ClinicalTrials.gov registration number {"type":"clinical-trial","attrs":{"text":"NCT00855920","term_id":"NCT00855920"}}NCT00855920.     

Obesity and Association with Area of Residence,Gender and Socio-Economic Factors in Algerian and Tunisian Adults

Introduction

The epidemiological transition has resulted in a major increase in the prevalence of obesity in North Africa. This study investigated differences in obesity and its association with area of residence, gender and socio-economic position among adults in Algeria and Tunisia, two countries with socio-economic and socio-cultural similarities.

Methods

Cross-sectional studies used stratified, three-level, clustered samples of 35–70 year old adults in Algeria, (women n = 2741, men n = 2004) and Tunisia (women n = 2964, men n = 2379). Thinness was defined as Body Mass Index (BMI) = weight/height <18.5 kg/m², obesity as BMI ≥30, and abdominal obesity as waist circumference/height ≥0.6. Associations with area of residence, gender, age, education, profession and household welfare were assessed.

Results

Prevalence of thinness was very low except among men in Algeria (7.3% C.I.[5.9–8.7]). Prevalence of obesity among women was high in Algeria (30.1% C.I.[27.8–32.4]) and Tunisia (37.0% C.I.[34.4–39.6]). It was less so among men (9.1% C.I.[7.1–11.0] and 13.3% C.I.[11.2–15.4]).The results were similar for abdominal obesity. In both countries women were much more obesity-prone than men: the women versus men obesity Odds-Ratio was 4.3 C.I.[3.4–5.5] in Algeria and 3.8 C.I.[3.1–4.7] in Tunisia. Obesity was more prevalent in urban versus rural areas in Tunisia, but not in Algeria (e.g. for women, urban versus rural Odds-Ratio was 2.4 C.I.[1.9–3.1] in Tunisia and only 1.2 C.I.[1.0–5.5] in Algeria). Obesity increased with household welfare, but more markedly in Tunisia, especially among women. Nevertheless, in both countries, even in the lowest quintile of welfare, a fifth of the women were obese.

Conclusion

The prevention of obesity, especially in women, is a public health issue in both countries, but there were differences in the patterning of obesity according to area of residence and socio-economic position. These specificities must be taken into account in the management of obesity inequalities.     

Combining ecosystem indicators and life cycle assessment for environmental assessment of demersal trawling in Tunisia

The International Journal of Life Cycle Assessment - The present study assesses environmental performance of seafood production by demersal trawling in Tunisia (Gulf of Gabes) in order to analyze...     

Competition for nodule formation between introduced strains of <Emphasis Type="Italic">Mesorhizobium ciceri</Emphasis> and the native populations of rhizobia nodulating chickpea (<Emphasis Type="Italic">Cicer arietinum</Emphasis>) in Tunisia

Chickpea is the most cultivated grain legume in the world and it shares the first rank with faba bean in Tunisia. However, the yield remains low, mainly due to the limited availability of N and P, and to the severe bioclimatic conditions. No inoculation trials had been conducted on chickpea in the Tunisian soils. This paper reports the yield response to inoculation by two different strains of Mesorhizobium ciceri, an exogenous type strain (UPMCa7^T) and a selected local strain (CMG6). Field experiments were conducted in different sites in the north of Tunisia using three chickpea cultivars (cvs. Amdoun I, Chetoui and Kasseb). Rhizobia occupying field nodules were isolated and identified using 16S rDNA typing for both inoculated and non-inoculated plots. In contrast to the exogenous strain, the local strain gave a significant increase in nodule number and shoot dry yield in all the experimental fields for the three cultivars used. Monitoring of the nodule occupancy showed that the local strain competed well the native populations of rhizobia. The usefulness and the persistence of this strain in the different soils where it was introduced will be assessed further during the next years.     

Founder mutations in Tunisia: implications for diagnosis in North Africa and Middle East

ABSTRACT: Background Tunisia is a North African country of 10 million inhabitants. The native background population is Berber. However, throughout its history, Tunisia has been the site of invasions and migratory waves of allogenic populations and ethnic groups such as Phoenicians, Romans, Vandals, Arabs, Ottomans and French. Like neighbouring and Middle Eastern countries, the Tunisian population shows a relatively high rate of consanguinity and endogamy that favor expression of recessive genetic disorders at relatively high rates. Many factors could contribute to the recurrence of monogenic morbid trait expression. Among them, founder mutations that arise in one ancestral individual and diffuse through generations in isolated communities. Method We report here on founder mutations in the Tunisian population by a systematic review of all available data from PubMed, other sources of the scientific literature as well as unpublished data from our research laboratory. Results We identified two different classes of founder mutations. The first includes founder mutations so far reported only among Tunisians that are responsible for 30 genetic diseases. The second group represents founder haplotypes described in 51 inherited conditions that occur among Tunisians and are also shared with other North African and Middle Eastern countries. Several heavily disabilitating diseases are caused by recessive founder mutations. They include, among others, neuromuscular diseases such as congenital muscular dystrophy and spastic paraglegia and also severe genodermatoses such as dystrophic epidermolysis bullosa and xeroderma pigmentosa. Conclusion This report provides informations on founder mutations for 73 genetic diseases either specific to Tunisians or shared by other populations. Taking into account the relatively high number and frequency of genetic diseases in the region and the limited resources, screening for these founder mutations should provide a rapid and cost effective tool for molecular diagnosis. Indeed, our report should help designing appropriate measures for carrier screening, better evaluation of diseases burden and setting up of preventive measures at the regional level.     

COPI–TRAPPII activates Rab18 and regulates its lipid droplet association

The transport protein particle (TRAPP) was initially identified as a vesicle tethering factor in yeast and as a guanine nucleotide exchange factor (GEF) for Ypt1/Rab1. In mammals, structures and functions of various TRAPP complexes are beginning to be understood. We found that mammalian TRAPPII was a GEF for both Rab18 and Rab1. Inactivation of TRAPPII‐specific subunits by various methods including siRNA depletion and CRISPR–Cas9‐mediated deletion reduced lipolysis and resulted in aberrantly large lipid droplets. Recruitment of Rab18 onto lipid droplet (LD) surface was defective in TRAPPII‐deleted cells, but the localization of Rab1 on Golgi was not affected. COPI regulates LD homeostasis. We found that the previously documented interaction between TRAPPII and COPI was also required for the recruitment of Rab18 to the LD. We hypothesize that the interaction between COPI and TRAPPII helps bring TRAPPII onto LD surface, and TRAPPII, in turn, activates Rab18 and recruits it on the LD surface to facilitate its functions in LD homeostasis.     

Evidence for independent recruitment of zeta-crystallin/quinone reductase (CRYZ) as a crystallin in camelids and hystricomorph rodents

Zeta-crystallin/quinone reductase (CRYZ) is an NADPH oxidoreductase expressed at very high levels in the lenses of two groups of mammals: camelids and some hystricomorph rodents. It is also expressed at very low levels in all other species tested. Comparative analysis of the mechanisms mediating the high expression of this enzyme/crystallin in the lens of the Ilama (Lama guanacoe) and the guinea pig (Cavia porcellus) provided evidence for independent recruitment of this enzyme as a lens crystallin in both species and allowed us to elucidate for the first time the mechanism of lens recruitment of an enzyme- crystallin. The data presented here show that in both species such recruitment most likely occurred through the generation of new lens promoters from nonfunctional intron sequences by the accumulation of point mutations and/or small deletions and insertions. These results further support the idea that recruitment of CRYZ resulted from an adaptive process in which the high expression of CRYZ in the lens provides some selective advantage rather than from a purely neutral evolutionary process.      

Evidence of independent gene duplications during the evolution of archaeal and eukaryotic family B DNA polymerases

Eukaryotes and archaea both possess multiple genes coding for family B DNA polymerases. In animals and fungi, three family B DNA polymerases, alpha, delta, and epsilon, are responsible for replication of nuclear DNA. We used a PCR-based approach to amplify and sequence phylogenetically conserved regions of these three DNA polymerases from Giardia intestinalis and Trichomonas vaginalis, representatives of early-diverging eukaryotic lineages. Phylogenetic analysis of eukaryotic and archaeal paralogs suggests that the gene duplications that gave rise to the three replicative paralogs occurred before the divergence of the earliest eukaryotic lineages, and that all eukaryotes are likely to possess these paralogs. One eukaryotic paralog, epsilon, consistently branches within archaeal sequences to the exclusion of other eukaryotic paralogs, suggesting that an epsilon-like family B DNA polymerase was ancestral to both archaea and eukaryotes. Because crenarchaeote and euryarchaeote paralogs do not form monophyletic groups in phylogenetic analysis, it is possible that archaeal family B paralogs themselves evolved by a series of gene duplications independent of the gene duplications that gave rise to eukaryotic paralogs.      

Esthesioneuroblastoma metastatic to the breast in a young woman

BACKGROUND: Metastases to the breast are rare and can be missed without knowledge of the clinical history. We report an unusual breast metastasis originating in an olfactory neuroblastoma. CASE: A breast metastasis from esthesioneuroblastoma occurred in a 20-year-old woman 2 years after the onset of the disease. The aspirates were hypercellular and composed of cellular aggregates and single cells with a monomorphic appearance. The cytoplasm was scanty and inconspicuous. The nucleus was large, with granular, hyperchromatic chromatin. Mitoses and apoptotic bodies were numerous. Because we were unaware of the past history at the time of the cytologic analysis, a definitive diagnosis was made only after pathologic study. CONCLUSION: Esthesioneuroblastoma metastatic to the breast must be considered in the differential diagnosis of breast metastases. Fine needle aspiration, in conjunction with clinical information, can be effective in the diagnosis of esthesioneuroblastoma metastatic to the breast.