Impact of tapering targeted therapies (bDMARDs or JAKis) on the risk of serious infections and adverse events of special interest in patients with rheumatoid arthritis or spondyloarthritis: a systematic analysis of the literature and meta-analysis.

OBJECTIVES: To systematically review the impact of tapering targeted therapies (bDMARDs or JAKis) on the risk of serious infections and severe adverse events (SAEs) in patients with rheumatoid arthritis (RA) or axial spondyloarthritis (axSpA) in remission or low disease activity (LDA) state. MATERIALS AND METHODS: A meta-analysis based on a systematic review of PubMed, Embase, Cochrane, until August 2019, as well as relevant databases of international conferences, was used to evaluate the risk difference (RD) at 95% confidence interval (95% CI) of incidence density of serious infections, SAEs, malignancies, cardiovascular adverse events (CV AEs), or deaths after tapering (dose reduction or spacing) compared to continuation of targeted therapies. RESULTS: Of the 1957 studies initially identified, 13 controlled trials (9 RA and 4 SpA trials) were included in the meta-analysis. 1174 patient-years were studied in the tapering group (TG) versus 1086 in the usual care group (UC). There were 1.7/100 patient-year (p-y) serious infections in TG versus 2.6/100 p-y in UC (RD (95% CI) 0.01 (0.00 to 0.02), p = 0.13) and 7.4/100 p-y SAEs in TG versus 6.7/100 p-y in UC (RD 0.00 (- 0.02 to 0.02), p = 0.82). The risk of malignancies, CV AEs, or deaths did not differ between the tapering and the usual care groups. Subgroup analysis (RA and SpA) detected no significant differences between the two groups. CONCLUSION: We could not show significant impact of tapering bDMARD or JAKi over continuation concerning the risk of serious infections, SAEs, malignancies, CV AEs, or deaths in RA and SpA patients in remission or LDA state.

Characterisation of four hotdog-fold thioesterases for their implementation in a novel organic acid production system.

With increasing interest in the diverse properties of organic acids and their application in synthetic pathways, developing biological tools for producing known and novel organic acids would be very valuable. In such a system, organic acids may be activated as coenzyme A (CoA) esters, then modified by CoA-dependent enzymes, followed by CoA liberation by a broad-acting thioesterase. This study has focused on the identification of suitable thioesterases (TE) for utilisation in such a pathway. Four recombinant hotdog-fold TEs were screened with a range of CoA esters in order to identify a highly active, broad spectrum TE. The TesB-like TE, RpaL, from Rhodopseudomonas palustris was found to be able to use aromatic, alicyclic and both long and short aliphatic CoA esters. Size exclusion chromatography, revealed RpaL to be a monomer of fused hotdog domains, in contrast to the complex quaternary structures found with similar TesB-like TEs. Nonetheless, sequence alignments showed a conserved catalytic triad despite the variation in quaternary arrangement. Kinetic analysis revealed a preference towards short-branched chain CoA esters with the highest specificity towards DL-ß-hydroxybutyryl CoA (1.6 × 104 M-1 s-1), which was found to decrease as the acyl chain became longer and more functionalised. Substrate inhibition was observed with the fatty acyl n-heptadecanoyl CoA at concentrations exceeding 0.3 mM; however, this was attributed to its micellar aggregation properties. As a result of the broad activity observed with RpaL, it is a strong candidate for implementation in CoA ester pathways to generate modified or novel organic acids.

[Severe forms of chikungunya virus infection in a pediatric intensive care unit on Reunion Island]. / Infections graves a virus chikungunya en réanimation pédiatrique a l'ile de La Réunion.

UNLABELLED: In 2005-2006, an unexpected, massive outbreak of chikungunya occurred on Reunion Island, a French overseas territory in the Indian Ocean. This arboviral infection transmitted by a mosquito of the Aedes genus is usually benign. A surprising feature of the Reunion Island epidemic was the occurrence of rare severe forms involving adults as well as children. OBJECTIVES: The purpose of this report is to describe severe forms of chikungunya observed in children hospitalized in a pediatric intensive care unit. PATIENTS AND METHODS: This retrospective single-center study was conducted from January 1st to April 30th, 2006. Children between 1 month and 15 years admitted to the pediatric intensive care unit with proven chikungunya infection were included. RESULTS: A total of 9 children were included. The main manifestations were extensive skin blisters in 5 cases, neurological symptoms (encephalopathy) in 4, cardiac complications (myocarditis, hemodynamic disorders) in 5 and bleeding in 1. Two children died. The causes of death were circulatory failure associated with coma and massive hemorrhage in one case and post-infectious encephalitis in the other. Three survivors present long-term neurologic or dermatologic sequels. DISCUSSION: Severe cases of chikungunya in children provide a stark reminder of the cardiac and neurological tropism of the virus and its hemorrhagic forms with high potential mortality and morbidity. These cases underline the need for personal protection measures and for research to develop specific antiviral therapy and vaccines to prevent potentially lethal forms of the disease.

Changes in characteristics of hospitalized heart failure patients in ten years: a single-center study.

BACKGROUND: Progress in therapy and the ageing patients hospitalized with heart failure may have impacted the characteristics of this patients. AIMS: We compared epidemiological data of patients admitted with heart failure during two periods separated by a 10 year interval. METHODS: Characteristics of 353 heart failure patients recruited between 2002 and 2004 with those of 304 heart failure patients recruited between 1992 and 1994 were compared retrospectively. RESULTS: There is now a majority of male patients (56.4%) not found ten years ago. The average age is unchanged (75.1+/-11 then 76.4+/-11 years) even though the proportion of patients aged over 70 years has increased (75% versus 70%). Hospital length of stay has fallen from 14+/-9 to 10+/-7 days. Hospital mortality (8%) are identical. The two main etiologies remain coronary and hypertensive heart disease at 29 and 24% respectively but these proportions are lower than ten years ago (42 and 28% respectively). The ejection fraction is more often preserved (56%) than before (44%). Increased prescription of inhibitors of the renin-angiotensin system and beta-blockers is confirmed. Post-hospital and total mortality has fallen by 50 and 30% from 30 to 16% and 35 to 24% respectively at the expense of a 25% increase in the frequency of hospital readmissions from 29 to 38%. CONCLUSION: Even if mortality has declined, heart failure remains a major public health burden with a significant number of hospital readmissions. Other approaches such as therapeutic education must therefore be developed.

Bone texture analysis on direct digital radiographic images: precision study and relationship with bone mineral density at the os calcis.

Assessment of bone microarchitecture in complement to bone mineral density (BMD) exam could improve prediction of osteoporotic fractures. A high-resolution X-ray prototype was developed to assess microarchitecture quality. Images were obtained on os calcis; then, three texture parameters were calculated on the same region of interest (ROI): a fractal parameter, a run-length parameter, and a co-occurrence parameter. This work describes the reproducibility of this method. We also examine the relationship between texture parameters and BMD at a site-matched ROI. Measurements on the left heel were performed on 30 healthy women, on the same day, with repositioning for short-term precision error. An additional measurement was done at 1 week to evaluate mid-term precision error on 14 subjects. Os calcis images from 10 healthy women were used to evaluate both intra- and interobserver reproducibility. Thirty other healthy patients were measured successively on two similar devices for interprototype comparison. BMD and texture analyses of the left heel were obtained from 57 women. Short-term precision errors ranged 1.16-1.24% according to the texture parameter. Mid-term precision error was slightly higher than short-term precision for the mean Hurst exponent parameter. Comparisons of texture parameters and BMD at a site-matched ROI on the os calcis showed no significant relationships. The results also show that the use of this high-resolution digital X-ray device improves the reproducibility of parameter measurement compared to the indirect digitization of radiologic films previously used.

Relationships between serum leptin and bone markers during stable weight, weight reduction and weight regain in male and female judoists.

OBJECTIVE: Despite a preliminary understanding of leptin-skeletal interactions, data in humans are inconsistent and the exact roles of leptin on bone metabolism have not yet been defined. The aim of this study was to examine the possible role of leptin in the regulation of bone metabolism in healthy, physically trained adults. METHODS AND DESIGN: Body composition and bone mass (dual-energy X-ray absorptiometry), anthropometry, serum leptin, insulin, cortisol, osteocalcin, C-terminal telopeptide of type I collagen (CTx) and total plasma proteins were measured in judoists at normal body weight, after weight reduction and after weight regain. Physical training, weight cycling history, menstrual status and nutritional intake using a 7-day food record were assessed. RESULTS: Precompetitive weight loss averaged 4 +/- 0.3% of bodyweight and resulted in a significant decrease in leptin levels of 64% (P < 0.001) and of 31% for insulin (P < 0.0001). CTx and cortisol concentrations rose by 33% (P < 0.0001) and 81% (P < 0.05) respectively. Osteocalcin and total plasma protein remained unaffected by weight loss. A 4 +/- 0.5% weight regain induced a 276% increase in leptin levels (P < 0.001) and an 18% increase in insulin (P < 0.001). CTx and cortisol decreased by 23% (P < 0.0001) and 27% (P < 0.05) respectively. Changes in leptin were significantly correlated with changes in bone resorption marker in response to both weight loss (r = 0.56, P < 0.01) and regain (r = 0.44, P < 0.05). CONCLUSIONS: These findings suggest that leptin is involved in the regulation of bone metabolism in healthy adults and might play a potential role in the prevention of osteoporosis.

Effects of acute salbutamol intake during a Wingate test.

To investigate the impact of acute salbutamol intake on performance and selected hormonal and metabolic variables during supramaximal exercise, 13 recreational male athletes performed two 30-second Wingate tests after either placebo (PLA, lactose) or salbutamol (SAL, 4 mg) oral administration, according to a double-blind and randomized protocol. Blood samples collected at rest, end of the Wingate test, recovery (5, 10, 15 min) were tested for growth hormone (GH), insulin (INS), blood glucose (GLU), and lactate determination. We found the peak and mean power performed significantly increased after SAL vs. PLA (PPSAL: 896 +/- 46; PPPLA: 819 +/- 57 W; MPSAL: 585 +/- 27; MPPLA: 534 +/- 35 W, p < 0.05), whereas no change was observed in the fatigue index. Blood glucose and INS were significantly increased by SAL at rest, at the end of the Wingate test, and during the 5 first minutes of recovery (p < 0.05). Plasma GH was significantly decreased by SAL (p < 0.05) during the recovery whereas end-exercise and recovery blood lactate tended but were not significantly increased after SAL vs. PLA. From these data, acute salbutamol intake at therapeutical dosage did appear to improve peak power and mean power during a supramaximal exercise, but the mechanisms involved need further investigation.

Effects of short-term salbutamol ingestion during a Wingate test.

The effects of a chronic salbutamol intake (SAL, 12 mg/d during 3 weeks) on changes in body composition, metabolic indices and performance during a 30-second Wingate test were determined in 8 strength-trained male athletes (T) and 7 sedentary male (UT) subjects, according to a double-blind, randomized, cross-over protocol. Blood samples were collected both at rest, at the end of the test, and during passive recovery (5 min, 10 min, 15 min) for leptin (at rest), and blood lactate measurements. No significant changes in lean body mass, fat mass, and leptin were observed with SAL treatment in either group during the trial. Peak power was significantly increased (p < 0.05) after SAL intake in all subjects (T: 11.9 %; UT: 8.3 %) with a decrease in time to peak power with SAL compared to placebo (PLA) (p < 0.05). There was no change in total work performed and in fatigue indices with SAL compared to PLA. Blood lactate was significantly increased after SAL vs. PLA during the recovery (p < 0.05) in all subjects. The data demonstrate that the chronic administration of therapeutic levels of salbutamol increases maximal anaerobic power in man, irrespective of the subjects' training status. This study also rules out any implication of an anabolic effect in this improvement in performance during supramaximal exercise. Further studies are necessary to clarify the mechanisms involved.

Cumulative effects of calcium supplementation and physical activity on bone accretion in premenarchal children: a double-blind randomised placebo-controlled trial.

High calcium intake combined with physical activity during childhood have been shown to improve bone mass accrual and bone mineral density. Our aim was to study the combined effect of calcium and exercise on bone gain in children. Two milk-powder products containing either 800 mg of calcium phosphate (calcium) or not (placebo) were randomly allocated to 113 healthy premenarchal girls on a daily basis for 1 year. The group was composed of 63 exercise (7.2 +/- 4 hours of exercise/week) and 50 sedentary (1.2 +/- 0.8 hours of exercise/week) children. The final experiment had 4 groups: exercise/calcium (n = 12), exercise/placebo (n = 42), sedentary/calcium (n = 10), and sedentary/placebo (n = 21). Bone mineral density (BMD) at 6 skeletal sites and body composition were determined by DXA. Bone age was calculated and the daily spontaneous calcium intake was assessed by a frequency questionnaire. All the tests were performed at baseline and 1 year by the same observer. BMD gains were significantly greater in the exercise/calcium group than in other groups at the total body (increase of 6.3 %, p < 0.05), lumbar spine (11 %, p < 0.05), femoral neck (8.2 %, p < 0.02), and Ward's triangle (9.3 %, p < 0.01). There was no difference between the other groups. These data suggest that calcium supplementation increases the effect of physical exercise on bone mineral acquisition in the period preceding puberty, and that calcium supplementation without physical activity does not improve the BMD acquisition during this period. Physical exercise that stimulates bone accretion needs a high calcium intake to be completely effective.

Thicker radial cortex in physically active prepubertal girls compared to controls.

This study was carried out to investigate the effects of physical activity on cortical bone of the radius in a population of prepubertal girls. Forty-nine healthy girls, 17 actives (10.62 +/- 1.56 years) and 32 controls (9.84 +/- 1.23 years) participated in this study. The active group was involved in gymnastics, judo, and dance on average 7.76 +/- 3.94 h/week. Bone mineral content (BMC) and density (BMD) were performed at the distal third of the non-dominant radius using DXA. The lean mass of the non-dominant forearm was derived from the total body analysis performed with DXA. In order to obtain bone cortical thickness, standard radiographs of the non-dominant radius were scanned and computed using a software program based on radiogrammetry. BMD and BMC values were higher in actives than in controls. Cortical thickness at the ulnar side correlated significantly with all the anthropometric and densitometric values as well as the duration of training. In addition, cortical thickness at the ulnar side was significantly higher in the actives compared to the controls. After adjustment for the duration of training per week, cortical thickness of the ulnar side did not differ any more between actives and controls. The same observation was obtained after adjustment for the forearm lean mass. In our active population, physical practice seemed to have induced greater BMC and higher cortical thickness than those observed in the sedentary.

Fractal analysis of bone texture: a screening tool for stress fracture risk?

BACKGROUND: The aim of this study was to identify specific bone characteristics of stress fracture (SF) cases in sportswomen. To date, no tool is able to distinguish individuals who are at risk, limiting preventive measures. MATERIAL AND METHODS: We investigated the skeletal system of sportswomen who did sustain SF in the past (n = 19) and compared it with that of female controls (C) with a similar sporting history but without any fracture history (n = 20). Bone mass and body composition were measured using dual-energy X-ray absorptiometry. Bone micro-architecture was investigated by calcaneal ultrasound and fractal analysis of calcaneus radiographic images. Oestradiol levels were measured by E.I.A, and IGF-1 by R.I.A. Menstrual characteristics, nutrient intake, and training were assessed using questionnaires. RESULTS: The result of the fractal analysis, expressed by the Hmean parameter, was significantly lower in the SF group, reflecting a more complex structure of the trabecular micro-architectural organization (P < 0.005). Body mass index (BMI) at birth was also found to be lower in the SF cases as compared with their C (P < 0.03). Multivariate analysis revealed that the fractal parameter Hmean, bone mineral content (BMC) at Ward's triangle and the BMI at birth correctly assigned 84.85% of the female athletes into their respective SF or C groups (P = 0.001). CONCLUSION: These results suggest that the fractal parameter and the BMI at birth may be able to identify female athletes most at risk for this overuse bone injury, as their low indexes might reflect a greater skeletal sensitivity.

Risk of new vertebral fracture in the year following a fracture.

CONTEXT: Vertebral fractures significantly increase lifetime risk of future fractures, but risk of further vertebral fractures in the period immediately following a vertebral fracture has not been evaluated. OBJECTIVE: To determine the incidence of further vertebral fracture in the year following a vertebral fracture. DESIGN AND SETTING: Analysis of data from 4 large 3-year osteoporosis treatment trials conducted at 373 study centers in North America, Europe, Australia, and New Zealand from November 1993 to April 1998. SUBJECTS: Postmenopausal women who had been randomized to a placebo group and for whom vertebral fracture status was known at entry (n = 2725). MAIN OUTCOME MEASURE: Occurrence of radiographically identified vertebral fracture during the year following an incident vertebral fracture. RESULTS: Subjects were a mean age of 74 years and had a mean of 28 years since menopause. The cumulative incidence of new vertebral fractures in the first year was 6.6%. Presence of 1 or more vertebral fractures at baseline increased risk of sustaining a vertebral fracture by 5-fold during the initial year of the study compared with the incidence in subjects without prevalent vertebral fractures at baseline (relative risk [RR], 5.1; 95% confidence interval [CI], 3.1-8.4; P<.001). Among the 381 participants who developed an incident vertebral fracture, the incidence of a new vertebral fracture in the subsequent year was 19.2% (95% CI, 13.6%-24.8%). This risk was also increased in the presence of prevalent vertebral fractures (RR, 9.3; 95% CI, 1.2-71.6; P =.03). CONCLUSION: Our data indicate that women who develop a vertebral fracture are at substantial risk for additional fracture within the next year.

High-impact loading training induces bone hyperresorption activity in young elite female gymnasts.

The aim of this study was to investigate the effect of intensive exercise on bone turnover (as reflected by bone resorption) in young elite female gymnasts. Forty-five healthy girls including 24 gymnasts (11.9+/-2 yr) and 21 controls (12.3+/-1.4 yr) were studied. Body weight, height, bone age and body composition were measured. Bone mineral density (BMD) was assessed at the whole body, lumbar vertebrae, hip and radius by means of DXA. Volumetric density (BMAD) was calculated. Bone velocity (SOS) and attenuation (BUA) were measured by QUS at the calcaneus. Urinary androstenedione (delta4), dehydroepiandrosterone sulfate (DHEA-S), and CrossLaps (CTx) were measured. BMD and BMAD were significantly greater in the gymnasts at all sites except whole body. SOS was found significantly higher. Delta4 values were significantly lower in the gymnasts. The distribution of the subjects according to Tanner stages was not different between groups. CTx levels were significantly higher in the gymnasts (989.08+/-154.63 microg/mmol Cr.) vs controls (580.25+/-123.99 microg/mmol Cr., p=0.02). CTx values decreased from Tanner stage 1 to stage 4 in each group, the gymnasts' levels always being higher than those of the controls. In conclusion, gymnastics seems to stimulate bone resorption activity in highly-trained young females. The coexistence of bone hyperresorption and higher BMD in gymnasts suggests increased bone turnover resulting in increased bone density in these subjects.

Rotary Ni-Ti profile systems for preparing curved canals in resin blocks: influence of operator on instrument breakage.

AIM: The aim of this study was to determine the incidence of fracture of ProFile 0.4 and 0.6 taper Series 29 nickel-titanium instruments with respect to operator experience. METHODOLOGY: A total of 125 simulated root canals in resin blocks with the same geometrical shape in terms of angle and radius of curvature and coronal and apical orifice diameter were used. Five operators prepared all the specimens using an identical step-down instrument sequence, each one preparing 25 canals. The operators included two endodontists and three general practitioners. Statistical data concerning the incidence of instrument failure was compiled using Statlab and Fisher's partial least square difference analysis of variance. RESULTS: A total of 21 (16.8%) instruments fractured, all had 0.04 tapers. Nine size 25 instruments failed, 9 size 20 instruments failed and 3 size 15. During the study, the Binary Tree analysis of instrument failure revealed two operator populations belonging to two different study periods. The first period, which represented the first 13 root canal preparations, was called the 'learning period', and the second period, which represented the next 12 sample preparations, was called the 'application period'. A greater number of instruments failed during the first period than during the second. In the 'learning period', both groups of operators learned the same way. In the 'application period', two groups could be distinguished; the first group consisted of a general practitioner who produced worse results, and the second group consisted of the other four operators. CONCLUSIONS: The results indicate the necessity of mastering this rotary canal preparation technique, and the importance of improving competence through learning and experience.

Restoration of surface IgM-mediated apoptosis in an anti-IgM-resistant variant of WEHI-231 lymphoma cells by HS1, a protein-tyrosine kinase substrate.

The HS1 protein is one of the major substrates of non-receptor-type protein-tyrosine kinases and is phosphorylated immediately after crosslinking of the surface IgM on B cells. The mouse B-lymphoma cell line WEHI-231 is known to undergo apoptosis upon crosslinking of surface IgM by anti-IgM antibodies. Variants of WEHI-231 that were resistant to anti-IgM-induced apoptosis expressed dramatically reduced levels of HS1 protein. Expression of the human HS1 protein from an expression vector introduced into one of the variant cell lines restored the sensitivity of the cells to apoptosis induced by surface IgM crosslinking. These results suggest that HS1 protein plays a crucial role in the B-cell antigen receptor-mediated signal transduction pathway that leads to apoptosis.

Signaling properties of anti-immunoglobulin--resistant variants of WEHI-231 B lymphoma cells.

Stimulation of the B cell antigen receptor (BCR) of the murine immature WEHI-231 B lymphoma with anti-immunoglobulin antibodies leads to irreversible growth arrest and apoptosis. As in normal B cells, membrane immunoglobulin (mIg) ligation in WEHI-231 cells triggers a series of signaling cascades from the BCR to intracellular compartments. In order to address the role of early signals in mediating the growth arrest of WEHI-231 cells, we have generated two variants resistant to the anti-Ig-mediated inhibitory effect. Some of the properties of these variants have been recently described in terms of bcl-2 and c-myc gene regulation. We report here that these variants can be further distinguished from the wild type on the basis of significant alterations in the early biochemical events which follow mIg ligation. Both Ca2+ signals and patterns of protein tyrosine phosphorylation were affected in these variants, suggesting that alterations in the early signal transduction machinery may have profound effects on the fate of B cells. In addition, we found that expression of the p75HS1 substrate of p53/56lyn was strikingly reduced in both variants as compared to the wild type. These findings support the view that p75HS1 may play a critical role in BCR-dependent signaling cascades.

Signaling of programmed cell death induction in WEHI-231 B lymphoma cells.

The murine WEHI-231 B lymphoma is highly sensitive to membrane immunoglobulin ligation which leads to programmed cell death (PCD) in this cell line. To study the molecular pathways involved in PCD induction in these cells, we derived two variants of WEHI-231 resistant to anti-Ig treatment. The level of bcl-2 mRNA was identical in the wild type and the variants, either untreated or anti-Ig treated, suggesting that PCD is not under the control of bcl-2 in WEHI-231 cells. In contrast, c-myc gene expression was markedly different in the wild type and the variants, both in the unstimulated and anti-Ig-stimulated state. Our findings are interpreted in the context of the dual capacity of c-myc to promote cell growth or cell death, in conjunction with other growth regulatory signals.

Anti-immunoglobulins induce death by apoptosis in WEHI-231 B lymphoma cells.

Anti-membrane immunoglobulin (anti-mIg) antibodies exert inhibitory effects in immature B lymphocytes such as WEHI-231 cells. We show here that anti-mIg treatment causes DNA fragmentation (apoptosis) in these cells. We also report that co-treatment with the protein kinase C activator phorbol 12-myristate 13-acetate prevents apoptosis induced by anti-mIg. These results are in agreement with our initial proposal that sensitivity to the toxic effects of anti-mIg reflects, at least partially, altered signal transduction in immature B lymphocytes. Variations in signal transduction pathways during B lymphocyte ontogeny may, therefore, play a critical role in determining whether B cells should be activated or inhibited via their mIg.

[Study of plasma androgens in women with autoimmune diseases]. / Etude des androgènes plasmatiques chez les femmes atteintes de maladies auto-immunes.

The exact significance of a reported androgen deficiency in women with lupus has not yet been determined. The authors decided to study plasma androgen concentrations not only in lupus, but also in other auto-immune diseases as well as non-auto -immune diseases. 43 patients (rheumatoid arthritis (RA): 10; systemic lupus erythematosus (SLE): 11; multiple sclerosis (MS): 11; patients without auto-immune disease: 11) were compared to 13 normal women. The age and the hormone concentrations of these different groups were compared by analysis of variance and by the Kruskal-Wallis test. A statistically significant reduction in androgen levels was only detected in the women with lupus. It therefore appears that the androgen deficiency is not a non-specific consequence of any disease, that it does not represent a predisposing factor for auto-immune disease in general, but that it is specific for lupus.