IκB-ζ controls the constitutive NF-κB target gene network and survival of ABC DLBCL.

Constitutive activation of the nuclear factor-κ B (NF-κB) pathway is a hallmark of the activated B-cell-like (ABC) subtype of diffuse large B-cell lymphoma (DLBCL). Recurrent mutations of NF-κB regulators that cause constitutive activity of this oncogenic pathway have been identified. However, it remains unclear how specific target genes are regulated. We identified the atypical nuclear IκB protein IκB-ζ to be upregulated in ABC compared with germinal center B-cell-like (GCB) DLBCL primary patient samples. Knockdown of IκB-ζ by RNA interference was toxic to ABC but not to GCB DLBCL cell lines. Gene expression profiling after IκB-ζ knockdown demonstrated a significant downregulation of a large number of known NF-κB target genes, indicating an essential role of IκB-ζ in regulating a specific set of NF-κB target genes. To further investigate how IκB-ζ mediates NF-κB activity, we performed immunoprecipitations and detected a physical interaction of IκB-ζ with both p50 and p52 NF-κB subunits, indicating that IκB-ζ interacts with components of both the canonical and the noncanonical NF-κB pathway in ABC DLBCL. Collectively, our data demonstrate that IκB-ζ is essential for nuclear NF-κB activity in ABC DLBCL, and thus might represent a promising molecular target for future therapies.

Topical retinoids exposure during pregnancy.

Concerns have been raised with the topical use of retinoids since the publication of occasional cases associated with characteristic retinoid embryopathy, originally described after oral use. Epidemiological data are still scant. A collaborative study was carried out to evaluate the rate of congenital malformations following 1st trimester topical retinoid exposure. Using a standardized protocol exposed pregnancies and non exposed controls were prospectively recorded by the European Network of Teratology Information Services (ENTIS). A population of 222 pregnant women exposed to topical retinoids (median age [range]: 30 [21 - 42] years; gestational week at call: 7 [3 - 35]) were compared to 444 women not exposed (median age [range]: 32 [17 - 48] years; gestational week at call: 8 [2 - 39]). The following retinoids were identified: adapalene: 22; retinoic acid: 10; tretinoin: 135; isotretinoin:49, others: 6. The exposed and non-exposed groups did not differ in maternal alcohol and tobacco use, gestational duration, birth weight and length. There were no Abstracts: Clinical Pharmacology and Therapeutics IXth World Congress -2008 significant differences between groups in the rate of pregnancies ending in spontaneous abortion (8.7% in exposed vs. 5.9% in unexposed; P=0.18) or in infants with minor malformations (3.7% in exposed vs. 2.9% in unexposed; P=0.61) and major malformations (3.7% in exposed vs. 2.2% in unexposed; P=0.29). No child showed features of retinoid embryopathy. In conclusion, these results bring reassurance in cases of fortuitous topical retinoid exposure. However, according to the current knowledge, topical retinoids can not be recommended for use during pregnancy, as the risk/benefit ratio remains questionable.

Pregnancy outcome following maternal exposure to statins: a multicentre prospective study.

OBJECTIVE: This contribution addresses the risk associated with exposure to statins during pregnancy. DESIGN: Multicentre observational prospective controlled study. SETTING: European Network of Teratology Information Services. POPULATION: Pregnant women who contacted one of 11 participating centres, seeking advice about exposure to statins during pregnancy, or to agents known to be nonteratogenic. METHODS: Pregnancies exposed during first trimester to statins were followed up prospectively, and their outcomes were compared with a matched control group. MAIN OUTCOME MEASURES: Rates of major birth defects, live births, miscarriages, elective terminations, preterm deliveries and gestational age and birthweight at delivery. RESULTS: We collected observations from 249 exposed pregnancies and 249 controls. The difference in the rate of major birth defects between the statin-exposed and the control groups was small and statistically nonsignificant (4.1% versus 2.7% odds ratio [OR] 1.5; 95% confidence interval [95% CI] 0.5-4.5, P = 0.43). In an adjusted Cox model, the difference between miscarriage rates was also small and not significant (hazard ratio 1.36, 95% CI 0.63-2.93, P = 0.43). Premature birth was more frequent in exposed pregnancies (16.1% versus 8.5%; OR 2.1, 95% CI 1.1-3.8, P = 0.019). Nonetheless, median gestational age at birth (39 weeks, interquartile range [IQR] 37-40 versus 39 weeks, IQR 38-40, P = 0.27) and birth weight (3280 g, IQR 2835-3590 versus 3250 g, IQR 2880-3630, P = 0.95) did not differ between exposed and non-exposed pregnancies. CONCLUSIONS: This study did not detect a teratogenic effect of statins. Its statistical power remains insufficient to challenge current recommendations of treatment discontinuation during pregnancy.

Glutamate exocytosis from astrocytes controls synaptic strength.

The release of transmitters from glia influences synaptic functions. The modalities and physiological functions of glial release are poorly understood. Here we show that glutamate exocytosis from astrocytes of the rat hippocampal dentate molecular layer enhances synaptic strength at excitatory synapses between perforant path afferents and granule cells. The effect is mediated by ifenprodil-sensitive NMDA ionotropic glutamate receptors and involves an increase of transmitter release at the synapse. Correspondingly, we identify NMDA receptor 2B subunits on the extrasynaptic portion of excitatory nerve terminals. The receptor distribution is spatially related to glutamate-containing synaptic-like microvesicles in the apposed astrocytic processes. This glial regulatory pathway is endogenously activated by neuronal activity-dependent stimulation of purinergic P2Y1 receptors on the astrocytes. Thus, we provide the first combined functional and ultrastructural evidence for a physiological control of synaptic activity via exocytosis of glutamate from astrocytes.

Profile of male adolescents with conduct disorder on intellectual efficacy, cognitive flexibility, cognitive coping, impulsivity and alexithymia: a comparison with high-risk controls

Background and Objectives: To specify which of the documented cognitive and emotional deficits characterize adolescents with conduct disorder (CD) compared with high-risk controls. Methods: High-risk adolescent males with and without CD were compared on intellectual efficiency, cognitive flexibility, impulsivity, alexithymia, and cognitive coping strategies. Substance use was controlled for in analyses. Results: Both groups showed normal intellectual efficiency and cognitive flexibility, as weil as heightened alexithymia and bebavioral impulsivity. Youths with CD evidenced more self-defeating and black-and-white tbinking under stress, and more acting-out under negative affect, than those without CD. Conclusions: Deficits specifie to CD resided in facets of emotional functioning and cognitive coping that might be targeted by a coping skills intervention.

Resting metabolic rate in six- to ten-year-old obese and nonobese children.

The resting metabolic rate (RMR) and body composition of 130 obese and nonobese prepubertal children, aged 6 to 10 years, were assessed by indirect calorimetry and skin-fold thickness, respectively. The mean (+/- SD) RMR was 4619 +/- 449 kJ.day-1 (164 +/- 31 kJ.kg body weight-1 x day-1) in the 62 boys and 4449 +/- 520 kJ.day-1 (147 +/- 32 kJ.kg body weight-1 x day-1) in the 68 girls. Fat-free mass was the best single predictor of RMR (R2 = 0.64; p < 0.001). Step-down multiple regression analysis, with independent variables such as age, gender, weight, and height, allowed several RMR predictive equations to be developed. An equation for boys is as follows: RMR (kJ.day-1) = 1287 + 28.6 x Weight(kg) + 23.6 x Height(cm) - 69.1 x Age(yr) (R2 = 0.58; p < 0.001). An equation for girls is as follows: RMR (kJ.day-1 = 1552 + 35.8 x Weight (kg) + 15.6 x Height (cm) - 36.3 x Age (yr) (R2 = 0.69; p < 0.001). Comparison between the measured RMR and that predicted by currently used formulas showed that most of these equations tended to overestimate the RMR of both genders, especially in overweight children.

The effect of treatment with calcitonin on vertebral fracture rate in osteoporosis.

The efficacy of treatments for osteoporosis does not become evident when evaluated by fracture incidence (FI). Vertebral FI decreased in all controlled studies on calcitonin, but not significantly. Small sample sizes and short periods of treatment may have masked a possible therapeutic benefit, but longer, controlled studies with sodium fluoride or etidronate in larger groups of patients also failed to show a decrease in FI. The present analysis of nine published, therapeutic studies which indicate the FI per year and the initial prevalence of vertebral fractures, examines the question of whether the initial prevalence of fractures has an effect on the subsequent incidence of new fractures and whether the therapeutic effects have to be evaluated as a function of the initial prevalence of fractures. Bearing in mind the differences in roentgenological evaluation and in the size and quality of the various studies, the analysis revealed (1) that in the control groups there was a higher FI in patients with more than three vertebral fractures at baseline (estimated odds ratio (OR) = 49, p = 0.011); (2) that a similar trend, although not statistically significant, was observed in treated patients; (3) that the groups of control patients treated for more than 1 year showed in general an increase in FI beyond the first year and that the reverse was true in treated patients. In conclusion, failure to allow for the initial prevalence of vertebral fractures at the individual level in therapeutic trials of calcitonin to treat osteoporosis and prevent new fractures might have contributed to the absence of a demonstrable benefit of the treatment in those studies.

The rate-limiting step for glucose transport into the hypothalamus is across the blood-hypothalamus interface.

Specialized glucosensing neurons are present in the hypothalamus, some of which neighbor the median eminence, where the blood-brain barrier has been reported leaky. A leaky blood-brain barrier implies high tissue glucose levels and obviates a role for endothelial glucose transporters in the control of hypothalamic glucose concentration, important in understanding the mechanisms of glucose sensing We therefore addressed the question of blood-brain barrier integrity at the hypothalamus for glucose transport by examining the brain tissue-to-plasma glucose ratio in the hypothalamus relative to other brain regions. We also examined glycogenolysis in hypothalamus because its occurrence is unlikely in the potential absence of a hypothalamus-blood interface. Across all regions the concentration of glucose was comparable at a given plasma glucose concentration and was a near linear function of plasma glucose. At steady-state, hypothalamic glucose concentration was similar to the extracellular hypothalamic glucose concentration reported by others. Hypothalamic glycogen fell at a rate of approximately 1.5 micromol/g/h and remained present in substantial amounts. We conclude for the hypothalamus, a putative primary site of brain glucose sensing that: the rate-limiting step for glucose transport into brain cells is at the blood-hypothalamus interface, and that glycogenolysis is consistent with a substantial blood -to- intracellular glucose concentration gradient.

Self-paced Movement Intention Detection from Human Brain Signals: Invasive and Non-invasive EEG

Neural signatures of humans' movement intention can be exploited by future neuroprosthesis. We propose a method for detecting self-paced upper limb movement intention from brain signals acquired with both invasive and noninvasive methods. In the first study with scalp electroencephalograph (EEG) signals from healthy controls, we report single trial detection of movement intention using movement related potentials (MRPs) in a frequency range between 0.1 to 1 Hz. Movement intention can be detected above chance level (p<0.05) on average 460 ms before the movement onset with low detection rate during the on-movement intention period. Using intracranial EEG (iEEG) from one epileptic subject, we detect movement intention as early as 1500 ms before movement onset with accuracy above 90% using electrodes implanted in the bilateral supplementary motor area (SMA). The coherent results obtained with non-invasive and invasive method and its generalization capabilities across different days of recording, strengthened the theory that self-paced movement intention can be detected before movement initiation for the advancement in robot-assisted neurorehabilitation.

Protonation controls ASIC1a activity via coordinated movements in multiple domains.

Acid-sensing ion channels (ASICs) are neuronal Na(+)-conducting channels activated by extracellular acidification. ASICs are involved in pain sensation, expression of fear, and neurodegeneration after ischemic stroke. Functional ASICs are composed of three identical or homologous subunits, whose extracellular part has a handlike structure. Currently, it is unclear how protonation of residues in extracellular domains controls ASIC activity. Knowledge of these mechanisms would allow a rational development of drugs acting on ASICs. Protonation may induce conformational changes that control the position of the channel gate. We used voltage-clamp fluorometry with fluorophores attached to residues in different domains of ASIC1a to detect conformational changes. Comparison of the timing of fluorescence and current signals identified residues involved in movements that preceded desensitization and may therefore be associated with channel opening or early steps leading to desensitization. Other residues participated in movements intimately linked to desensitization and recovery from desensitization. Fluorescence signals of all mutants were detected at more alkaline pH than ionic currents. Their midpoint of pH dependence was close to that of steady-state desensitization, whereas the steepness of the pH fluorescence relationship was closer to that of current activation. A sequence of movements was observed upon acidification, and its backward movements during recovery from desensitization occurred in the reverse order, indicating that the individual steps are interdependent. Furthermore, the fluorescence signal of some labeled residues in the finger domain was strongly quenched by a Trp residue in the neighboring β-ball domain. Upon channel activation, their fluorescence intensity increased, indicating that the finger moved away from the β ball. This extensive analysis of activity-dependent conformational changes in ASICs sheds new light on the mechanisms by which protonation controls ASIC activity.

Efficacy of garenoxacin in treatment of experimental endocarditis due to Staphylococcus aureus or viridans group streptococci.

The activity of garenoxacin was investigated in rats with experimental endocarditis due to staphylococci and viridans group streptococci (VGS). The staphylococci tested comprised one ciprofloxacin-susceptible and methicillin-susceptible Staphylococcus aureus (MSSA) isolate (isolate 1112), one ciprofloxacin-susceptible but methicillin-resistant S. aureus (MRSA) isolate (isolate P8), and one ciprofloxacin-resistant mutant (grlA) of P8 (isolate P8-4). The VGS tested comprised one penicillin-susceptible isolate and one penicillin-resistant isolate (Streptococcus oralis 226 and Streptococcus mitis 531, respectively). To simulate the kinetics of drugs in humans, rats were infused intravenously with garenoxacin every 24 h (peak and trough levels in serum, 6.1 and 1.0 mg/liter, respectively; area under the concentration-time curve [AUC], 63.4 mg. h/liter) or levofloxacin every 12 h (peak and trough levels in serum, 7.3 and 1.5 mg/liter, respectively; AUC, 55.6 mg. h/liter) for 3 or 5 days. Flucloxacillin, vancomycin, and ceftriaxone were used as control drugs. Garenoxacin, levofloxacin, flucloxacillin, and vancomycin sterilized >/=70% of the vegetations infected with both ciprofloxacin-susceptible staphylococcal isolates (P < 0.05 versus the results for the controls). Garenoxacin and vancomycin also sterilized 70% of the vegetations infected with ciprofloxacin-resistant MRSA isolate P8-4, whereas treatment with levofloxacin failed against this organism (cure rate, 0%; P < 0.05 versus the results obtained with the comparator drugs). Garenoxacin did not select for resistant derivatives in vivo. In contrast, levofloxacin selected for resistant variants in four of six rats infected with MRSA isolate P8-4. Garenoxacin sterilized 90% of the vegetations infected with both penicillin-susceptible and penicillin-resistant isolates of VGS. Levofloxacin sterilized only 22 and 40% of the vegetations infected with penicillin-susceptible S. oralis 226 and penicillin-resistant S. mitis 531, respectively. Ceftriaxone sterilized only 40% of those infected with penicillin-resistant S. mitis 531 (P < 0.05 versus the results obtained with garenoxacin). No quinolone-resistant VGS were detected. In all the experiments successful quinolone treatment was predicted by specific pharmacodynamic criteria (D. R. Andes and W. A. Craig, Clin. Infect. Dis. 27:47-50, 1998). The fact that the activity of garenoxacin was equal or superior to those of the standard comparators against staphylococci and VGS indicates that it is a potential alternative for the treatment of infections caused by such bacteria.

Long-term treatment of eosinophilic esophagitis esophagitis with budesonide

BACKGROUND: Eosinophilic esophagitis (EoE) is a chronic-inflammatory disease of the esophagus, characterized by esophagus-related symptoms and a dense tissue eosinophilia, both refractory to proton pump inhibitors. Topical corticosteroids have proven effective in inducing clinical and histologic remission. However, a long-term strategy for the management of this chronic disease is not yet defined. METHODS: In a randomized, double-blind, placebocontrolled, long-term trial, we evaluated the efficacy of twice-daily 0.25 mg swallowed budesonide in maintaining a remission in adult EoE with prior response to induction therapy. Pre- and post-treatment disease activity was assessed clinically, endoscopically, histologically, by immunofluorescence and by high-resolution endosonography. The primary end point was the ability to maintain histologic remission (<5 eos/hpf) of EoE in. Secondary end points were the efficacy on symptom control and on tissue remodeling as well as the determination of the safety of long-term esophageal administration of topical corticosteroids. RESULTS: During a 50-week therapy of quiescent EoE with low-dose budesonide the esophageal eosinophil load (ECP staining) increased from 1.1 to 29.9 eos/hpf, but under placebo the increase was significantly larger (0.5 to 51.1 eos/hpf; p=0.01). At the end of the studyperiod, 35.7% (5/14) of the budesonide patients were in complete and 14.3% (2/14) in partial histologic remission; with placebo no patient was in complete and 28.6% (4/14) were in partial remission (p=0.0647). The increase of the symptom score was markedly lower in budesonide- (0.79 to 2.29 points) than in placebo-patients (0.71 to 4.00 points; p=0.0875). The median time to relapse of symptoms was >125 days in the budesonide and 95 days in the placebo group (p = 0.14). Measured by high-resolution endosonography, all EoE patients had pre-treatment a highly thickened esophageal wall compared with healthy controls (3.05±1.08 mm vs. 2.18±0.35 mm; p<0.0001). Long-term topical budesonide reduced mainly the thickness of the superficial wall layers (mucosa, 0.75 mm to 0.45 mm; p=0.025) whereas the response of the deeper layers was less pronounced (submucosa 1.31 to 1.08 mm; p=0.19 and muscularis 0.82 to 0.76 mm; p=0.72). Budesonide did not evoke any mucosal atrophy. CONCLUSIONS: This study clearly demonstrates that 1) Untreated eosinophil inflammation results in an impressive remodeling of the esophagus; 2) A therapy is therefore needed; 3) The high relapse rate after short-term therapy requires a long-term management and 4) Maintenance treatment with budesonide is well tolerated and keeps half of the patients in remission.

Extra burden of psychosomatic complaints among adolescents suffering from chronic conditions.

OBJECTIVE:: To determine whether there are differences in health perception and health care use among adolescents with psychosomatic symptoms (PS), with chronic conditions (CCs), and with both conditions compared with healthy controls. METHODS:: By using the SMASH02 database, 4 groups were created: youths with PS but no CCs (N = 1010); youths with CCs but no PS (N = 497); youths with both psychosomatic symptoms and chronic conditions (PSCC, N = 213); and youths with neither PS nor CC (control, N = 5709). We used χ tests and analysis of variance to compare each variable between the 4 groups. In a second step, all health and health care use variables were included in a multinomial regression analysis controlling for significant (p < .05) background variables and using the control group as the reference. RESULTS:: Overall, PS and PSCC youths were significantly more likely to rate their health as poor, to be depressed, and to have consulted several times their primary health care provider or a mental health professional than their healthy peers. With the exception of being depressed, PSCC adolescents reported worse health perception and higher health care use than CC and PS. CONCLUSIONS:: Although PS youths do not define PS as a CC, it should be considered as one. Moreover, having PS represents an additional burden to chronically ill adolescents. Health professionals dealing with adolescents must be aware of the deleterious health effects that PS can have on adolescents and have this diagnosis in mind to better target the treatment and improve their management.

Postprandial thermogenesis in obese children before and after weight reduction.

The thermic effect of a meal (TEM) was measured in a group of 10 prepubertal obese children before (OB) and after (OA) weight reduction, and in a group of 10 age-matched control children (C) of normal body weight. Following a hypocaloric balanced diet for 6 +/- 1 months, the obese children lost 5.2 +/- 1.3 kg i.e. 11% of their initial body weight. The thermic response to the mixed liquid meal - fed at an energy level corresponding to 30% of the 24 h premeal resting metabolic rate - was found to be significantly lower in OB than in C children (61 +/- 25 kJ.3h-1 vs 79 +/- 21 kJ.3h-1, P less than 0.05), despite their higher test meal energy. After slimming, the TEM of obese children increased towards the controls' values (73 +/- 30 kJ.3h-1). These results support the hypothesis of the existence of a moderate thermogenic defect in some obese children which represents a consequence rather than an aetiological factor of obesity.

PIDD death-domain phosphorylation by ATM controls prodeath versus prosurvival PIDDosome signaling.

Biochemical evidence implicates the death-domain (DD) protein PIDD as a molecular switch capable of signaling cell survival or death in response to genotoxic stress. PIDD activity is determined by binding-partner selection at its DD: whereas recruitment of RIP1 triggers prosurvival NF-κB signaling, recruitment of RAIDD activates proapoptotic caspase-2 via PIDDosome formation. However, it remains unclear how interactor selection, and thus fate decision, is regulated at the PIDD platform. We show that the PIDDosome functions in the "Chk1-suppressed" apoptotic response to DNA damage, a conserved ATM/ATR-caspase-2 pathway antagonized by Chk1. In this pathway, ATM phosphorylates PIDD on Thr788 within the DD. This phosphorylation is necessary and sufficient for RAIDD binding and caspase-2 activation. Conversely, nonphosphorylatable PIDD fails to bind RAIDD or activate caspase-2, and engages prosurvival RIP1 instead. Thus, ATM phosphorylation of the PIDD DD enables a binary switch through which cells elect to survive or die upon DNA injury.