The histone lysine acetyltransferase HBO1 (KAT7) regulates hematopoietic stem cell quiescence and self-renewal.

The histone acetyltransferase HBO1 (MYST2, KAT7) is indispensable for postgastrulation development, histone H3 lysine 14 acetylation (H3K14Ac), and the expression of embryonic patterning genes. In this study, we report the role of HBO1 in regulating hematopoietic stem cell function in adult hematopoiesis. We used 2 complementary cre-recombinase transgenes to conditionally delete Hbo1 (Mx1-Cre and Rosa26-CreERT2). Hbo1-null mice became moribund due to hematopoietic failure with pancytopenia in the blood and bone marrow 2 to 6 weeks after Hbo1 deletion. Hbo1-deleted bone marrow cells failed to repopulate hemoablated recipients in competitive transplantation experiments. Hbo1 deletion caused a rapid loss of hematopoietic progenitors. The numbers of lineage-restricted progenitors for the erythroid, myeloid, B-, and T-cell lineages were reduced. Loss of HBO1 resulted in an abnormally high rate of recruitment of quiescent hematopoietic stem cells (HSCs) into the cell cycle. Cycling HSCs produced progenitors at the expense of self-renewal, which led to the exhaustion of the HSC pool. Mechanistically, genes important for HSC functions were downregulated in HSC-enriched cell populations after Hbo1 deletion, including genes essential for HSC quiescence and self-renewal, such as Mpl, Tek(Tie-2), Gfi1b, Egr1, Tal1(Scl), Gata2, Erg, Pbx1, Meis1, and Hox9, as well as genes important for multipotent progenitor cells and lineage-specific progenitor cells, such as Gata1. HBO1 was required for H3K14Ac through the genome and particularly at gene loci required for HSC quiescence and self-renewal. Our data indicate that HBO1 promotes the expression of a transcription factor network essential for HSC maintenance and self-renewal in adult hematopoiesis.

Efficacy of risankizumab in patients with moderate-to-severe plaque psoriasis by baseline demographics, disease characteristics and prior biologic therapy: an integrated analysis of the phase III UltIMMa-1 and UltIMMa-2 studies.

BACKGROUND: Risankizumab is a humanized IgG monoclonal antibody that selectively inhibits interleukin-23 through binding the p19 subunit. In Phase 3 trials, risankizumab demonstrated superior efficacy compared with adalimumab and ustekinumab in patients with moderate-to-severe plaque psoriasis. Here, we evaluated the impact of baseline characteristics on efficacy of risankizumab compared with ustekinumab in patients with moderate-to-severe plaque psoriasis. METHODS: This analysis included all patients initially randomized to risankizumab or ustekinumab from the replicate, double-blinded, randomized, placebo-controlled phase 3 trials, UltIMMa-1 (NCT02684370) and UltIMMa-2 (NCT02684357). Patients received either risankizumab (150 mg) or ustekinumab (weight-based; 45 or 90 mg per label) at weeks 0, 4, 16, 28 and 40. Efficacy was assessed as the proportion of patients achieving ≥90% improvement in Psoriasis Area and Severity Index (PASI 90) at weeks 16 and 52 by baseline patient demographics, disease characteristics and prior biologic exposure. Mean per cent improvement in PASI was calculated by body weight and body mass index at week 52. Missing efficacy data were imputed as non-responders for categorical variables and last observation carried forward for continuous variables. Logistic regression analyses assessed for interactions between treatment and five independent variables (age, sex, weight, baseline PASI score and presence of psoriatic arthritis) at both weeks 16 and 52. RESULTS: Baseline patient demographics, disease characteristics and prior biologic exposure were similar between patients randomized to risankizumab (n = 598) and ustekinumab (n = 199). At weeks 16 and 52, risankizumab demonstrated superior efficacy compared with ustekinumab across these patient characteristics (P < 0.01). Logistic regression analyses demonstrated that risankizumab was superior to ustekinumab at weeks 16 and 52 in all models tested (P < 0.0001 for all). CONCLUSIONS: Risankizumab demonstrated consistent and superior efficacy compared with ustekinumab regardless of patient demographics, disease characteristics or prior biologic exposure.

Stimulation parameters differ between current anti-modiolar and peri-modiolar electrode arrays implanted within the same child.

OBJECTIVE: To compare stimulation parameters of peri-modiolar and anti-modiolar electrode arrays using two surgical approaches. METHODS: Impedance, stimulation thresholds, comfortably loud current levels, electrically evoked compound action potential thresholds and electrically evoked stapedial reflex thresholds were compared between 2 arrays implanted in the same child at 5 time points: surgery, activation/day 1, week 1, and months 1 and 3. The peri-modiolar array was implanted via cochleostomy in all children (n = 64), while the anti-modiolar array was inserted via a cochleostomy in 43 children and via the round window in 21 children. RESULTS: The anti-modiolar array had significantly lower impedance, but required higher current levels to elicit thresholds, comfort, electrically evoked compound action potential thresholds and electrically evoked stapedial reflex thresholds than the peri-modiolar array across all time points, particularly in basal electrodes (p < 0.05). The prevalence of open electrodes was similar in anti-modiolar (n = 5) and peri-modiolar (n = 3) arrays. CONCLUSION: Significant but clinically acceptable differences in stimulation parameters between peri-modiolar and anti-modiolar arrays persisted four months after surgery in children using bilateral cochlear implants. The surgical approach used to insert the anti-modiolar array had no overall effect on outcomes.

Sex-specific transcriptional responses of the zebrafish (Danio rerio) brain selenoproteome to acute sodium selenite supplementation.

The potential benefits of selenium (Se) supplementation are currently under investigation for prevention of certain cancers and treatment of neurological disorders. However, little is known concerning the response of the brain to increased dietary Se under conditions of Se sufficiency, despite the majority of Se supplementation trials occurring in healthy, Se sufficient subjects. We evaluated the transcriptional response of Se-dependent genes, selenoproteins and the genes necessary for their synthesis (the selenoproteome), in the zebrafish (Danio rerio) brain to supplementation with nutritionally relevant levels of dietary Se (sodium selenite) during conditions of assumed Se sufficiency. We first used a microarray approach to analyze the response of the brain selenoproteome to dietary Se supplementation for 14 days and then assessed the immediacy and time-scale transcriptional response of the brain selenoproteome to 1, 7, and 14 days of Se supplementation by quantitative real-time PCR (qRT-PCR). The microarray approach did not indicate large-scale influences of Se on the brain transcriptome as a whole or the selenoproteome specifically; only one nonselenoproteome gene (si:ch73-44m9.2) was significantly differentially expressed. Our qRT-PCR results, however, indicate that increases of dietary Se cause small, but significant transcriptional changes within the brain selenoproteome, even after only 1 day of supplementation. These responses were dynamic over a short period of supplementation in a manner highly dependent on sex and the duration of Se supplementation. In nutritional intervention studies, it may be necessary to utilize methods such as qRT-PCR, which allow larger sample sizes, for detecting subtle transcriptional changes in the brain.

[The effectiveness of the spa and health resort treatment for the pre-gravid preparation of the women at high risk of obstetric and perinatal pathology].

Chronic recurrent inflammatory diseases of the small pelvis are known to be responsible for the development of the adhesive process and infertility. Therefore, they require surgical treatment and increase the risk of obstetric and perinatal pathology. The present study was focused on the assessment of therapeutic and prophylactic effectiveness of the application of natural and preformed physical factors for the pre-gravid preparation of the patients presenting with gynecological problems and pregnant women at high risk of obstetric and perinatal pathology based at the spa and health resort facilities of the Krasnodar Krai (region). The treatment included aero-, helio-, and thalassotherapy, transcranial electroneural stimulation, UHF therapy, hydrogen sulfide or iodine-bromine therapy. A total of 267 women were included in the study. Pregnancy was documented in 52% of the 144 patients who comprised the main group and underwent a course of rehabilitative treatment; it developed within 3-5 months after therapeutic and prophylactic laparoscopic procedures. The frequency of obstetric and perinatal pathology in this group significantly decreased in comparison with that among the control patients which allowed to greatly reduce material and financial expenditures.

[The use of restorative medicine technologies for the rehabilitation of the patients presenting with endometriosis of external genitalia].

This paper reports the results of analysis of the psycho-emotional status and pain syndrome in the women presenting with endometriosis of external genitalia treated with a combination of hormonal preparations and balneotherapy. A total of 216 infertile patients were involved in the study. The duration of the infertility period varied from 1.5 to 19 years. All the patients underwent surgical intervention. The influence of rehabilitative therapy on the quantitative vital indices (psycho-emotional adaptation to the social environment and pain intensity) was estimated before and after the treatment. The patients were divided into 3 groups. Those of group 1 received an oral contraceptive (30 mcg of ethinylestradiol plus 2 mg dienogest) as a continuous three-cycle course (63 tablets) followed by its discontinuation for the 7 day menstrual period and the final three-cycle course (total duration of therapy 6 months). The patients of group 2 were treated with injections of agonists of gonadotropin releasing hormone (GnRH) at a dose of 3.75 mg once every 4 weeks (total duration 6 months). In group 3, the injections of GnRH agonists (3.75 mg once every 4 weeks, total duration 6 months) were combined with a course of balneotherapy using radon. All the three rehabilitative modalities produced a well-apparent positive effect. Chronic pelvic pain before treatment was reported by 90,3% of the patients. After the treatment, the number of such women in groups 1, 2, and 3 decreased to 20,8%, 12,5%, and 30,6% respectively Dyspareunia in the pre-treatment period was diagnosed in 66,7% of the patients. After treatment, this pathology persisted only in 23,6%, 18,1%, and 31,9% of the patients in groups 1, 2, and 3 respectively. Psycho-emotional disorders before treatment were documented in 90,3% of the patients compared with 27,8%, 25%, and 30,6% after therapy. It is concluded that all the three therapeutic modalities markedly improved health conditions of the patients presenting with endometriosis of external genitalia, but the combination of GnRH agonists with radon therapy produced the most pronounced clinical effect.

Is behavioral variation along the bold-shy continuum associated with variation in the stress axis in zebrafish?

We tested whether boldness is associated with attenuation of the physiological stress response in behaviorally selected lines of zebrafish Danio rerio. We measured three component behaviors of boldness: cortisol levels under control and stressed conditions, growth rate, and expression of key genes linked to the hypothalamic-pituitary-interrenal axis in the brain. Surprisingly, bold animals did not differ from shy animals with respect to cortisol levels. However, significant differences between these animals in the expression of glucocorticoid receptors and genes that regulate production of stress hormones indicate that there may still be a relationship between bold behavior and the stress axis. Perhaps the most surprising result of this study was the degree of sexual dimorphism: female zebrafish were bolder than male zebrafish, had significantly lower levels of cortisol, and differed significantly in the expression of several genes in the brain. Our data indicate that a bold behavioral type is associated with transcriptional attenuation of stress axis genes, but we do not yet know whether evolution along the bold-shy continuum is attributable to genetic changes in the stress axis. The bold and shy zebrafish lines will be valuable tools for additional research into the relationship between stress and behavior and the mechanisms regulating sexual dimorphism in these traits.

Glutamine supplementation improves intestinal barrier function in a weaned piglet model of Escherichia coli infection.

The weaning period is associated with an increased prevalence of gastrointestinal infection in many species. Glutamine (Gln) has been shown to improve intestinal barrier function and immune function in both in vivo and in vitro models. The objective of the present study was to determine the effect of dietary Gln supplementation on intestinal barrier function and intestinal cytokines in a model of Escherichia coli infection. We randomised 21-d-old piglets (n 20) to nutritionally complete isonitrogenous diets with or without Gln (4·4 %, w/w) for 2 weeks. Intestinal loops were isolated from anaesthetised pigs and inoculated with either saline or one of the two E. coli (K88AC or K88 wild-type)-containing solutions. Intestinal tissue was studied for permeability, cytokine expression, fluid secretion and tight-junction protein expression. Animals receiving Gln supplementation had decreased potential difference (PD) and short-circuit current (I(sc)) in E. coli-inoculated intestinal loops (PD 0·628 (SEM 0·151) mV; I(sc) 13·0 (SEM 3·07) µA/cm(2)) compared with control-fed animals (PD 1·36 (SEM 0·227) mV; I(sc) 22·4 (SEM 2·24) µA/cm(2)). Intestinal tissue from control, but not from Gln-supplemented, animals responded to E. coli with a significant increase in mucosal cytokine mRNA (IL-1ß, IL-6, transforming growth factor-ß and IL-10). Tight-junction protein expression (claudin-1 and occludin) was reduced with exposure to E. coli in control-fed animals and was not influenced in Gln-supplemented piglets. Gln supplementation may be useful in reducing the severity of weaning-related gastrointestinal infections, by reducing the mucosal cytokine response and altering intestinal barrier function.

Identifying emotions in music through electrical hearing in deaf children using cochlear implants.

OBJECTIVE: Cochlear implant (CI) devices are the choice of treatment for individuals with severe to profound hearing loss. The CI devices provide the opportunity for children who are deaf to perceive sound by electrical stimulation of the auditory nerve, with the goal of optimizing oral communication. A natural benefit of acquiring hearing using CIs is the ability to hear, and perhaps enjoy, music. Music is a non-verbal auditory stimulus and a powerful tool for transmitting emotion. Identifying emotional cues is an important part of normal social development and communication and thus music may play an important role in establishing these skills during development. To date, it is not known whether children who use cochlear implants to hear can identify the emotional content carried in music. Our objective in the present study was to determine whether children who have been deaf from infancy and are experienced CI users have acquired the ability to identify emotion in musical phrases. METHOD: Study participants were 18 CI users (ages 7-13 years) who received right unilateral CIs (mean age at CI activation of 2.9 years) and 18 age-and gender-matched controls. Participants were asked to judge 32 brief musical excerpts as happy or sad by pointing to simple graphics of a smiling or frowning face. RESULTS: Children using CIs were able to correctly distinguish happy versus sad music well above chance levels, but performed more poorly on this task than their peers with typical hearing. Age at CI activation and time since CI activation were both uncorrelated with outcome measures. CONCLUSION: Children with CIs show the ability to perceive emotion in music but do so less accurately than typically hearing peers.

Factors contributing to the efficacy of concurrent-adjuvant chemotherapy for locoregionally advanced nasopharyngeal carcinoma: combined analyses of NPC-9901 and NPC-9902 Trials.

BACKGROUND: The current standard treatment for locoregionally advanced nasopharyngeal carcinoma (NPC) was conventional-fractionation radiotherapy plus concurrent-adjuvant chemotherapy as recommended by the Intergroup-0099 Study. This combined analysis of the NPC-9901 and the NPC-9902 Trials aims to provide more comprehensive data to evaluate the efficacy of the Intergroup-0099 regimen and the contributing factors. METHODS: Eligible patients with stage III-IVB non-keratinizing NPC were randomly assigned to radiotherapy-alone (RT(i) group: 218 patients) or chemoradiotherapy (CRT(i) group: 223 patients) using cisplatin (100mg/m(2)) for three cycles in concurrence with radiotherapy, followed by cisplatin (80 mg/m(2)) plus fluorouracil (1000 mg/m(2)/day for 4 days) for three cycles. The median follow-up was 6.1 years. FINDINGS: Comparison by intention-to-treat showed that the CRT(i) group achieved significant improvement in overall failure-free rate (FFR), locoregional-FFR and cancer-specific survival (p ≤ 0.019); but the improvements for distant-FFR and overall survival (OS) were statistically insignificant (p ≥ 0.14). Further exploratory studies based on actual treatment showed that an additional improvement achieved was a significant gain in OS (CRT(a) versus RT(a) group: 72% versus 63% at 5-year, p=0.037). Multivariate analyses showed that the dose of cisplatin during the concurrent phase had significant impact on locoregional-FFR and OS, while that of fluorouracil during the adjuvant phase was significant for distant-FFR. The 5-year locoregional-FFR for patients who received 0-1, 2 and 3 concurrent cycles were 79%, 88% and 88%, respectively; the corresponding distant-FFR by adjuvant cycles were 68%, 78% and 77%, respectively. INTERPRETATION: Our results support the current practice of adding concurrent cisplatin plus adjuvant cisplatin-fluorouracil to radiotherapy for treating patients with locoregionally advanced NPC. The concurrent phase is important for locoregional control and survival, cisplatin 200mg/m(2) in two concurrent cycles might be adequate. Additional chemotherapy using fluorouracil-containing combination contributed to improving distant control.

A randomized trial on addition of concurrent-adjuvant chemotherapy and/or accelerated fractionation for locally-advanced nasopharyngeal carcinoma.

BACKGROUND AND PURPOSE: To evaluate the therapeutic benefits by adding chemotherapy (+C) and/or accelerated-fractionation (AF) for patients with T3-4N0-1M0 nasopharyngeal carcinoma. MATERIALS AND METHODS: From 1999 to 2004, 189 eligible patients were randomized to one of four treatment groups (CF/CF+C/AF/AF+C). The number of fractions/week was 5 for the CF groups and 6 for the AF groups. Patients in the +C groups were given concurrent cisplatin plus adjuvant cisplatin and fluorouracil. RESULTS: The AF+C group achieved significantly higher failure-free rate (88% at 5-year) than the CF group (63%; p=0.013), the AF group (56%; p=0.001) and the CF+C group (65%; p=0.027). As compared with CF alone, the increase in late toxicity was statistically insignificant (36% vs. 20%; p=0.25). Deaths due to cancer progression decreased (7% vs. 33%; p=0.011) but deaths due to incidental causes increased (9% vs. 2%; p=0.62). Improvement in overall survival reached borderline significance (85% vs. 66%; p=0.058). CONCLUSIONS: Concurrent-adjuvant chemotherapy combined with AF significantly reduced failure and cancer-specific deaths. Although the increase in major late toxicity and incidental deaths were statistically insignificant, a subtle increase in non-cancer deaths narrowed the overall survival gain.

[Non-medicamental correction of the hormonal and psycho-autonomic status in women with pathology of the reproductive system treated at health resort of the Krasnodar Krai (region)].

The authors report the results of the study on the hormonal and psychovegetative status, functional activity of the vegetative nervous system, the level of activity of the protective and adaptive hemostatic mechanisms, and the clinical features of concomitant extragenital pathology in 90 adolescent girls suffering uterine bleeding. All the patients had gone through in-patient and out-patient phases of therapy, sixty of them were selected for the spa and resort rehabilitative treatment. The use of rehabilitative technologies on an individual basis at a spa and resort facility made it possible to ensure rather high efficacy of the combined therapeutic and preventive treatment of reproductive system pathology and concomitant psycho-vegetative disorders. It helped to decrease the frequency of relapses of uterine bleeding and exacerbation of the accompanying extragenital diseases.

Randomized trial of radiotherapy plus concurrent-adjuvant chemotherapy vs radiotherapy alone for regionally advanced nasopharyngeal carcinoma.

BACKGROUND: Current practice of adding concurrent-adjuvant chemotherapy to radiotherapy (CRT) for treating advanced nasopharyngeal carcinoma is based on the Intergroup-0099 Study published in 1998. However, the outcome for the radiotherapy-alone (RT) group in that trial was substantially poorer than those in other trials, and there were no data on late toxicities. Verification of the long-term therapeutic index of this regimen is needed. METHODS: Patients with nonkeratinizing nasopharyngeal carcinoma staged T1-4N2-3M0 were randomly assigned to RT (176 patients) or to CRT (172 patients) using cisplatin (100 mg/m(2)) every 3 weeks for three cycles in concurrence with radiotherapy, followed by cisplatin (80 mg/m(2)) plus fluorouracil (1000 mg per m(2) per day for 4 days) every 4 weeks for three cycles. Primary endpoints included overall failure-free rate (FFR) (the time to first failure at any site) and progression-free survival. Secondary endpoints included overall survival, locoregional FFR, distant FFR, and acute and late toxicity rates. All statistical tests were two-sided. RESULTS: The two treatment groups were well balanced in all patient characteristics, tumor factors, and radiotherapy parameters. Adding chemotherapy statistically significantly improved the 5-year FFR (CRT vs RT: 67% vs 55%; P = .014) and 5-year progression-free survival (CRT vs RT: 62% vs 53%; P = .035). Cumulative incidence of acute toxicity increased with chemotherapy by 30% (CRT vs RT: 83% vs 53%; P < .001), but the 5-year late toxicity rate did not increase statistically significantly (CRT vs RT: 30% vs 24%; P = .30). Deaths because of disease progression were reduced statistically significantly by 14% (CRT vs RT: 38% vs 24%; P = .008), but 5-year overall survival was similar (CRT vs RT: 68% vs 64%; P = .22; hazard ratio of CRT = 0.81, 95% confidence interval = 0.58 to 1.13) because deaths due to toxicity or incidental causes increased by 7% (CRT vs RT: 1.7% vs 0, and 8.1% vs 3.4%, respectively; P = .015). CONCLUSIONS: Adding concurrent-adjuvant chemotherapy statistically significantly reduced failure and cancer-specific deaths when compared with radiotherapy alone. Although there was no statistically significant increase in major late toxicity, increase in noncancer deaths narrowed the resultant gain in overall survival.

Transcriptional profiling by deep sequencing identifies differences in mRNA transcript abundance in in vivo-derived versus in vitro-cultured porcine blastocyst stage embryos.

In vitro embryo culture systems promote development at rates lower than in vivo systems. The goal of this project was to discover transcripts that may be responsible for a decrease of embryo competency in blastocyst-stage embryos cultured in vitro. Gilts were artificially inseminated on the first day of estrus, and on Day 2, one oviduct and the tip of a uterine horn were flushed and the recovered embryos were cultured in porcine zygote medium 3 for 4 days. On Day 6, the gilts were euthanized and the contralateral horn was flushed to obtain in vivo derived embryos. Total RNA was extracted from three pools of 10 blastocysts from each treatment. First and second strand cDNA was synthesized and sequenced using Illumina sequencing. The reads generated were aligned to a custom-built database designed to represent the known porcine transcriptome. A total of 1170 database members were different between the two groups (P < 0.05), and 588 of those had at least a 2-fold difference. Eleven transcripts were subjected to real-time PCR that validated the sequencing. There was an overall decrease in inner cell mass (ICM) and trophectodermal (TE) cell numbers in embryos cultured in vitro; however, no difference in the ICM:TE ratio was found. Interestingly, the transcript SLC7A1 was higher in the in vitro cultured group. This difference disappeared after addition of arginine to the 4-day culture. Illumina sequencing and alignment to a custom transcriptome identified a large number of genes that yield clues on ways to manipulate the culture media to mimic the in vivo environment.

Raman spectroscopic quantification of milk powder constituents.

Raman spectroscopy has significant potential for the quantification of food products. Milk powder is an important foodstuff and ingredient that is produced on large scale (over 20 million tonnes per annum). Raman spectroscopy, unlike near- and mid-infrared spectroscopies, has not been used extensively to quantify milk powder constituents. The effect of sample presentation on spectroscopic calibrations of protein and fat for 136 New Zealand milk powders was assessed using Raman spectroscopy. Prediction models were produced to quantify a protein concentration range of 32.19-37.65% w/w for skim milk powder, and a protein concentration range of 23.34-25.02% w/w and a fat concentration range of 26.26-29.68% w/w for whole milk powder (where ratios of prediction to deviation exceeded 2.6 with one exception). The resultant calibrations were not influenced by sample orientation; the sample temperature during data collection did affect the calibrations. Calcium fortification in the form of calcium carbonate was identified within a sub-set of samples, reinforcing the efficacy of Raman spectroscopy for identifying both crystalline and non-crystalline constituents within milk powder.

Opposing roles of polycomb repressive complexes in hematopoietic stem and progenitor cells.

Polycomb group (PcG) proteins are transcriptional repressors with a central role in the establishment and maintenance of gene expression patterns during development. We have investigated the role of polycomb repressive complexes (PRCs) in hematopoietic stem cells (HSCs) and progenitor populations. We show that mice with loss of function mutations in PRC2 components display enhanced HSC/progenitor population activity, whereas mutations that disrupt PRC1 or pleiohomeotic repressive complex are associated with HSC/progenitor cell defects. Because the hierarchical model of PRC action would predict synergistic effects of PRC1 and PRC2 mutation, these opposing effects suggest this model does not hold true in HSC/progenitor cells. To investigate the molecular targets of each complex in HSC/progenitor cells, we measured genome-wide expression changes associated with PRC deficiency, and identified transcriptional networks that are differentially regulated by PRC1 and PRC2. These studies provide new insights into the mechanistic interplay between distinct PRCs and have important implications for approaching PcG proteins as therapeutic targets.

Adalimumab safety and mortality rates from global clinical trials of six immune-mediated inflammatory diseases.

OBJECTIVES: Clinical trials of tumour necrosis factor antagonists have raised questions about the potential risk of certain serious adverse events (SAE). To assess the safety of adalimumab in rheumatoid arthritis (RA) over time and across five other immune-mediated inflammatory diseases and to compare adalimumab malignancy and mortality rates with data on the general population. METHODS: This analysis included 19,041 patients exposed to adalimumab in 36 global clinical trials in RA, psoriatic arthritis (PsA), ankylosing spondylitis (AS), Crohn's disease (CD), psoriasis and juvenile idiopathic arthritis (JIA) to 15 April 2007. Events per 100 patient-years were calculated using SAE reported after the first dose to 70 days after the last dose. Standardised incidence rates were calculated for malignancies using national and state-specific databases. Standardised mortality rates (SMR) were calculated for each disease using data from the World Health Organization. RESULTS: Cumulative rates of SAE of interest in RA have remained stable over time. Rates of SAE of interest for PsA, AS, CD, psoriasis and JIA were similar to or lower than rates for RA. Overall malignancy rates for adalimumab-treated patients were as expected for the general population. SMR across all six diseases indicated that no more deaths occurred with adalimumab than expected in the general population. CONCLUSIONS: Based on 10 years of clinical trial experience across six diseases, this safety report and the established efficacy of adalimumab in these diseases provide the foundation for a better understanding of its benefit-risk profile.

Characterizing responses from auditory cortex in young people with several years of cochlear implant experience.

OBJECTIVE: To determine if cortical responses evoked by a cochlear implant in children who are deaf differ from normal and to characterize these differences in children who achieve good versus fair speech perception outcomes post-implantation. METHODS: Late latency-evoked potential responses were recorded at 28 scalp locations in 16 children who were deaf from infancy and experienced cochlear implant users. Speech perception measures indicated that 8 had good scores and 8 had fair scores. In each child, responses were evoked by 36ms electrical pulse trains delivered from a single-implant electrode at the apical and basal ends of the array and by 36ms tone bursts (0.5, 2, and 6kHz). Responses to the tone bursts were also recorded in 14 age-matched children with normal hearing. RESULTS: We found (1) a dominant positive wave in all implant users and (2) a larger than normal negative amplitude peak in users with fair speech perception scores which had similar scalp topography to N1 but did not show the expected changes in amplitude with stimulus frequency. CONCLUSIONS: Late latency-evoked potential responses in children using cochlear implants reflect abnormal and/or immature patterns of cortical activity. SIGNIFICANCE: Limitations in auditory skills with a cochlear implant in children may be due to developmental processes in the cortex which are either slow to mature or which mature abnormally.