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[br/][b]Background[/b][br/]Juvenile hormone (JH) plays an important role in honeybee development and the regulation of age-related division of labor. However, honeybees can be exposed to insect growth regulators (IGRs), such as JH analogs developed for insect pest and vector control. Although their side effects as endocrine disruptors on honeybee larval or adult stages have been studied, little is known about the subsequent effects on adults of a sublethal larval exposure. We therefore studied the impact of the JH analog pyriproxyfen on larvae and resulting adults within a colony under semi-field conditions by combining recent laboratory larval tests with chemical analysis and behavioral observations. Oral and chronic larval exposure at cumulative doses of 23 or 57 ng per larva were tested.[br/][br/][b]Results[/b][br/]Pyriproxyfen-treated bees emerged earlier than control bees and the highest dose led to a significant rate of malformed adults (atrophied wings). Young pyriproxyfen-treated bees were more frequently rejected by nestmates from the colony, inducing a shorter life span. This could be linked to differences in cuticular hydrocarbon (CHC) profiles between control and pyriproxyfen-treated bees. Finally, pyriproxyfen-treated bees exhibited fewer social behaviors (ventilation, brood care, contacts with nestmates or food stocks) than control bees.[br/][br/][b]Conclusion[/b][br/]Larval exposure to sublethal doses of pyriproxyfen affected several life history traits of the honeybees. Our results especially showed changes in social integration (acceptance by nestmates and social behaviors performance) that could potentially affect population growth and balance of the colony.

Recent studies have demonstrated that insect growth regulating insecticides are able to affect reproductive endpoints in zooplankton species at very low levels. For the cyclic parthenogenetic water flea Daphnia, most of this research has focused on the asexual part of the life cycle and induction of male offspring. Even though Daphnia and many other aquatic invertebrates rely on sexual reproduction and subsequent production of dormant eggs to recover from environmentally harsh conditions, much less is known about the effects of toxicants on the sexual reproductive phase. Using fenoxycarb as a model pesticide, we exposed male and female neonate Daphnia magna, under conditions inducing a switch to sexual reproduction, and tested for effects on dormant egg (ephippia) production and sex ratio of parthenogenetic offspring. Subsequently, we assessed whether fenoxycarb exposure affected the quality of the produced dormant eggs and viability of the hatchlings. Our results showed that exposure to sub-lethal concentrations of fenoxycarb caused a sharp decrease in parthenogenetic reproduction, while inducing male offspring. Dormant egg production was marginally negatively affected, but survival and fitness of the hatched individuals were not significantly affected. This indicates that under pesticide stress, surviving adult females invested in sexual reproduction at the expense of parthenogenetic reproduction. Exposure to toxicants during the sexual reproductive phase, could affect the active aquatic phase as well as the dormant phase in natural zooplankton populations. This indicates the need for further ecotoxicological research and development of test protocols taking into account the full life cycle of zooplankton species.

The risk of herpes zoster among patients with juvenile idiopathic arthritis (JIA) exposed to biologics has not been evaluated. We determined incidence rates of herpes zoster among children with JIA in correlation with medication at time of occurrence and total drug exposure. The German biologics register database was used to identify patients with herpes zoster. Crude infection rates and incidence ratios (IRR) were compared to published rates. Demographics and overall exposure and particular exposure time to corticosteroids, immunosuppressive drugs and biologics were analyzed. The JIA cohort included 3,042 patients with 5,557.9 person-years of follow-up; 1,628 have used corticosteroids, 2,930 methotrexate and 1,685 etanercept. In total, 17 herpes zoster events have been documented [6/1,000 patients (3.5–9.0); 3.1/1,000 patient-years (1.9–4.9)]. Thus, the incidence rate in JIA patients was higher than expected [IRR 2.9 (1.8–4.5), p  < 0.001]. In all patients, the event resolved completely. There were two complications, one patient developed intercostal neuralgia, and one had a recurrent herpes zoster. Compared to the healthy population, a significant higher IRR is observed in JIA patients who received a monotherapy with etanercept or in combination with steroids and methotrexate, but not in JIA patients exposed to methotrexate without biologics. In comparison with our control group of patients treated with methotrexate, the IRR was higher for exposure to etanercept monotherapy and combination of etanercept and corticosteroids irrespective of methotrexate use. A generally higher incidence rate in JIA patients treated with etanercept was observed. No serious or refractory manifestations occurred.

ObjectivesGiven the limited tocilizumab (TCZ) treatment data for systemic juvenile idiopathic arthritis (sJIA) in China, we evaluated the long-term efficacy and safety of TCZ in Chinese patients with sJIA.MethodIn this multicentre, interventional Phase IV study, patients with sJIA and inadequate clinical response to non-steroidal anti-inflammatory drugs/corticosteroids received TCZ infusions every 2 weeks based on body weight (< 30 kg, 12 mg/kg; ≥ 30 kg, 8 mg/kg), over a 52-week open-label period and an 8-week safety follow-up period. The primary endpoint was the proportion of patients with a JIA American College of Rheumatology (ACR) 30 response and absence of fever at Week 12.ResultsSixty-two patients were enrolled and treated (12-mg/kg group, 34; 8-mg/kg group, 28). At Week 12, 87.1% (95% confidence interval 78.8%–95.4%) of patients had JIA ACR 30 response and absence of fever; Week 52 results were similar. The proportion of JIA ACR 30/50/70/90 responders rapidly increased at Week 12, up to Week 52. High-sensitivity C-reactive protein (hsCRP) levels decreased within 4 weeks; 44/58 patients (75.9%) with elevated baseline hsCRP recovered at Week 52. Childhood Health Assessment Questionnaire pain scores, disability index scores, and mean corticosteroid dose decreased over time. Height standard deviation score changes at Week 52 indicated catch-up growth. Most adverse events (AEs) were mild (serious AE incidence, 17.7%). No deaths or macrophage activation syndrome occurred.ConclusionThis is the first multicentre trial to report the efficacy and safety of TCZ in Chinese patients with sJIA at 52 weeks. No new safety concerns were found.Key points• This is the first multicentre trial providing strong evidence for tocilizumab (TCZ) treatment for systemic juvenile idiopathic arthritis (sJIA) in China.• The study reported TCZ had good efficacy and favourable safety profiles in Chinese sJIA patients in the long term (52 weeks).• TCZ treatment showed rapid disease control, which was maintained over time, catch-up growth benefits in patients, tapering and discontinuation of corticosteroids, and improved quality of life.

ContextGrowth hormone (GH) therapy may improve statural growth outcomes in patients with severe juvenile idiopathic arthritis (JIA).ObjectivesTo evaluate the effect of GH treatment on adult height and to identify determinants of growth outcomes in JIA.Design and PatientsData from 58 patients with JIA, including 53 receiving GH, enrolled in three prospective clinical trials between 1997 and 2002 were analyzed.InterventionGH (0.056 mg/kg/d [interquartile range (IQR), 0.050 to 0.062]) for a median duration of 6.5 years (IQR, 4.7 to 7.9 years).Main Outcome MeasuresFactors associated with a favorable growth outcome (adult height − target height ≤ −1.5 standard deviations) were identified by multivariate logistic regression.ResultsAdult height was available for 48 patients 8.6 years after GH initiation (IQR, 6.0 to 10.2 years). Height standard deviation score (SDS) increased from −2.9 (IQR, −4.4 to −1.6) at baseline to −1.7 (IQR, −3.9 to −0.1) in adulthood (P < 0.001). Median adult height was below target height [SDS, −0.2 (IQR, −1.4 to 0.4); P < 0.001]. Corrected adult height SDS was −1.3 (IQR, −3.0 to −0.2). Growth outcome was favorable in 24 (52.2%) patients. Significant independent determinants of growth outcome were age at GH initiation [adjusted odds ratio (aOR), 0.68 per additional year; 95% confidence interval (CI), 0.47 to 0.99], height at GH initiation (aOR, 2.6 per additional SDS; 95% CI, 1.15 to 5.9), and mean C-reactive protein levels during follow up (aOR, 0.51 per additional 10 mg/L; 95% CI, 0.28 to 0.92).ConclusionLong-term GH treatment significantly increased growth in patients with JIA but did not fully restore the genetic growth potential. The response showed marked interindividual variability and was weaker in patients with severe inflammation.This study of the effects of GH therapy in children with JIA receiving corticosteroids found that GH treatment improved growth when started early in patients with good inflammation control.

ObjectivesThis study aimed to assess the prevalence and identify predictors of hepatic steatosis and fibrosis in patients with juvenile idiopathic arthritis (JIA) during methotrexate treatment.MethodThis cross-sectional study included JIA patients who had received methotrexate for > 1 year. Laboratory data including liver chemistry and lipid profiles were collected. Liver stiffness measurements (LSM) and controlled attenuation parameters (CAP) were determined by transient elastography. Significant hepatic fibrosis was defined as LSM > 7 kilopascal (kPa), and hepatic steatosis was defined as CAP > 225 decibel/meter (dB/m). Logistic regression analysis was performed to identify predictors associated with hepatic steatosis and fibrosis.ResultsOf 60 patients, 66.7% were female, and the median age (IQR) was 12.8 (10.6–15.0) years. The median duration of methotrexate usage (IQR) was 45 (22–85) months, and the median cumulative dose of methotrexate (IQR) was 3768 (1806–6466) mg. The median LSM (IQR) and CAP (IQR) were 4.1 (3.4–4.6) kPa and 191.0 (170.3–223.8) dB/m, respectively. No patients had transient elastography-defined hepatic fibrosis, whereas 21.7% had hepatic steatosis. A body mass index Z-score > 1 (OR 5.71 [95%CI 1.31–24.98], p = 0.021) and higher cumulative dose of methotrexate (OR 1.02 [95%CI 1.00–1.04], p = 0.041) were associated with hepatic steatosis, whereas the cumulative dose of steroids was not (OR 1.00 [95%CI 1.00–1.01], p = 0.097).ConclusionsHepatic steatosis is common among JIA patients receiving methotrexate, but none had transient elastography-defined hepatic fibrosis. Overweight/obese JIA adolescents and patients with a high cumulative dose of methotrexate are at risk for hepatic steatosis.Key Points•Long-term low-dose methotrexate usage and the concomitant use of other DMARDs did not increase the risk of hepatic fibrosis in JIA patients.•The prevalence of hepatic steatosis in JIA patients receiving methotrexate was higher than in a healthy pediatric population.•Overweight/obesity and a higher cumulative dose of methotrexate were predictors of hepatic steatosis.

Uveitis in children accounts for 5–10% of all cases. The causes vary considerably. Classically, uveitis is distinguished according to its infectious or inflammatory origin and whether it is part of a systemic disease or represents an isolated ocular disease. It is important to highlight the specificity of certain etiologies among children such as juvenile idiopathic arthritis. The development of visual function can potentially be hindered by amblyopia (children aged < 7 years), in addition to the usual complications (synechiae, macular edema) seen in adult patients. Moreover, the presentation of uveitis in children is often “silent” with few warning signs and few functional complaints from young children, which frequently leads to a substantial diagnostic delay. The diagnostic approach is guided by the presentation of the uveitis, which can be characterized by its location, and corresponds to the initial and main site of intraocular inflammation; its presentation, whether acute or chronic, granulomatous or not; and the response to treatment. Pediatricians have an important role to play and must be aware of the various presentations and etiologies of uveitis in children. Juvenile idiopathic arthritis is the most common etiology of pediatric non-infectious uveitis, but other causes must be recognized. Promptly initiated treatment before complications arise requires early diagnosis, recognition, and treatment. Any dependence on prolonged local corticosteroid therapy justifies discussing the introduction of a corticosteroid-sparing treatment considering the risk to develop corticoid-induced glaucoma and cataracts. Systemic corticosteroid therapy can be required for urgent control of inflammation in the case of severe uveitis. Long-lasting immunosuppressive treatment and biotherapies are most often prescribed at the same time to reinforce treatment efficacy and to prevent relapse and corticosteroid dependency. We review the different causes of uveitis, excluding infection, and the diagnostic and therapeutic management aimed at limiting the risk of irreversible sequelae.

Agrochemical research over the last two decades has resulted in the discovery of chemically novel insecticides that mimic the action of the two insect growth and developmental hormones, the steroidal 20-hydroxyecdysone (20E) and the sesquiterpenoid juvenile hormone (JH). Bisacylhydrazines are non-steroidal agonists of 20E and exhibit their insecticidal activity via interaction with the ecdysteroid receptor proteins. Interestingly, two of the bisacylhydrazine (tebufenozide and RH-2485) insecticides are very selectively toxic to lepidopteran pests. These insecticides are safe to beneficial insects and have a benign ecotoxicological profile. Aromatic non-terpenoidal insecticides (fenoxycarb and pyriproxyfen) mimic the action of JHs. However, like the JHs, their exact mode of action is not well understood. These insecticides are toxic to a broad spectrum of insects during their embryonic, last larval, or reproductive stages. The insecticidal, ecotoxicological properties and the mode of action of the two groups of insecticides are reviewed in this article.

Early life exposure to Bisphenol A (BPA), a component of polycarbonate plastics and epoxy resins, alters sociosexual behavior in numerous species including humans. The present study focused on the ontogeny of these behavioral effects beginning in adolescence and assessed the underlying molecular changes in the amygdala. We also explored the mitigating potential of a soy-rich diet on these endpoints. Wistar rats were exposed to BPA via drinking water (1 mg/L) from gestation through puberty, and reared on a soy-based or soy-free diet. A group exposed to ethinyl estradiol (50 µg/L) and a soy-free diet was used as a positive estrogenic control. Animals were tested as juveniles or adults for anxiety-like and exploratory behavior. Assessment of serum BPA and genistein (GEN), a soy phytoestrogen, confirmed that internal dose was within a human-relevant range. BPA induced anxiogenic behavior in juveniles and loss of sexual dimorphisms in adult exploratory behavior, but only in the animals reared on the soy-free diet. Expression analysis revealed a suite of genes, including a subset known to mediate sociosexual behavior, associated with BPA-induced juvenile anxiety. Notably, expression of estrogen receptor beta (Esr2) and two melanocortin receptors (Mc3r, Mc4r) were downregulated. Collectively, these results show that behavioral impacts of BPA can manifest during adolescence, but wane in adulthood, and may be mitigated by diet. These data also reveal that, because ERβ and melanocortin receptors are crucial to their function, oxytocin/vasopressin signaling pathways, which have previously been linked to human affective disorders, may underlie these behavioral outcomes.

Prenatal stress (PS) is a major risk factor for the development of emotional disorders in adulthood that may be mediated by an altered hypothalamic–pituitary–adrenal axis response to stress. Although the early onset of stress-related disorders is recognized as a major public health problem, to date, there are relatively few studies that have examined the incidence of early-life stressors in younger individuals. In this study, we assessed PS impact on the stress-coping response of juvenile offspring in behavioral tests and in the induced molecular changes in the hippocampus. Furthermore, we assessed if pregnancy stress could be driving changes in patterns of maternal behavior during early lactation. We found that PS modified stress-coping abilities of both sex offspring. In the hippocampus, PS increased the expression of bdnf- IV and crfr1 and induced sex difference changes on glucocorticoids and BDNF mRNA receptor levels. PS changed the hippocampal epigenetic landscape mainly in male offspring. Stress during pregnancy enhanced pup-directed behavior of stressed dams. Our study indicates that exposure to PS, in addition to enhanced maternal behavior, induces dynamic neurobehavioral variations at juvenile ages of the offspring that should be considered adaptive or maladaptive, depending on the characteristics of the confronting environment. Our present results highlight the importance to further explore risk factors that appear early in life that will be important to allow timely prevention strategies to later vulnerability to stress-related disorders.