Atomoxetine hydrochloride in the treatment of children and adolescents with attention-deficit/hyperactivity disorder and comorbid oppositional defiant disorder: A placebo-controlled Italian study.

Objective: The primary aim of this study was to assess the efficacy of atomoxetine in improving ADHD and ODD symptoms in paediatric patients with ADHD and comorbid oppositional defiant disorder (ODD), non-responders to previous psychological intervention with parent support.

Methods: This was a multicentre, randomised, placebo-controlled trial conducted in patients aged 6-15 years, with ADHD and ODD diagnosed according to the DSM-IV criteria by a structured clinical interview (K-SADS-PL). Only subjects who are non-responders to a 6-week standardized parent training were randomised to atomoxetine (up to 1.

Structural changes common to catalysis in the Tpx peroxiredoxin subfamily.

Thiol peroxidases (Tpxs) are dimeric 2-Cys peroxiredoxins from bacteria that preferentially reduce alkyl hydroperoxides. Catalysis requires two conserved residues, the peroxidatic cysteine and the resolving cysteine, which are located in helix alpha(2) and helix alpha(3), respectively. The partial unraveling of helices alpha(2) and alpha(3) during catalysis allows for the formation of an intramolecular disulfide between these two residues.

Typical 2-Cys peroxiredoxins--structures, mechanisms and functions.

Peroxiredoxins are abundant cellular antioxidant proteins that help to control intracellular peroxide levels. These proteins may also function, in part, through an evolved sensitivity of some peroxiredoxins towards peroxide-mediated inactivation in hydrogen peroxide signaling in eukaryotes. This review summarizes recent progress in our understanding of the catalytic and regulatory mechanisms of 'typical 2-Cys' peroxiredoxins and of the biological roles played by these important enzymes in oxidative stress and nonstress-related cellular signaling.

Redox-dependent dynamics of a dual thioredoxin fold protein: evolution of specialized folds.

An enzyme system protecting bacteria from oxidative stress includes the flavoprotein AhpF and the peroxiredoxin AhpC. The N-terminal domain of AhpF (NTD), with two fused thioredoxin (Trx) folds, belongs to the hyperthermophilic protein disulfide oxidoreductase family. The NTD is distinct in that it contains a redox active a fold with a CxxC sequence and a redox inactive b fold that has lost the CxxC motif.

A clinical evaluation committee assessment of recombinant human tissue factor pathway inhibitor (tifacogin) in patients with severe community-acquired pneumonia.

Introduction: The purpose of this analysis was to determine the potential efficacy of recombinant human tissue factor pathway inhibitor (tifacogin) in a subpopulation of patients with community-acquired pneumonia (CAP) from a phase III study of severe sepsis.

Methods: A retrospective review of patients with suspected pneumonia was conducted by an independent clinical evaluation committee (CEC) blinded to treatment assignment. The CEC reanalyzed data from patients enrolled in an international multicenter clinical trial of sepsis who had a diagnosis of pneumonia as the probable source of sepsis.

A centralized informatics infrastructure for the National Institute on Drug Abuse Clinical Trials Network.

Background: Clinical trial networks (CTNs) were created to provide a sustaining infrastructure for the conduct of multisite clinical trials. As such, they must withstand changes in membership. Centralization of infrastructure including knowledge management, portfolio management, information management, process automation, work policies, and procedures in clinical research networks facilitates consistency and ultimately research.

Redox regulation and trapping sulfenic acid in the peroxide-sensitive human mitochondrial branched chain aminotransferase.

The human branched chain aminotransferase enzymes are key regulators of glutamate metabolism in the brain and are among a growing number of redox-sensitive proteins. Studies that use thiol-specific reagents and electrospray ionization mass spectrometry demonstrate that the mitochondrial BCAT enzyme has a redox-active CXXC center, which on oxidation forms a disulfide bond (RSSR), via a cysteine sulfenic acid intermediate. Mechanistic details of this redox regulation were revealed by the use of mass spectrometry and dimedone modification.

Efficacy and safety of atomoxetine as add-on to psychoeducation in the treatment of attention deficit/hyperactivity disorder: a randomized, double-blind, placebo-controlled study in stimulant-naïve Swedish children and adolescents.

Objective: The primary objective of this study was to assess the impact of atomoxetine in combination with psychoeducation, compared with placebo and psychoeducation, on health-related quality of life (HRQL) in Swedish stimulant-naïve pediatric patients with attention deficit/hyperactivity disorder (ADHD). HRQL results will be presented elsewhere. Here, psychoeducation as well as efficacy and safety of the treatment are described.

Cysteine pK(a) values for the bacterial peroxiredoxin AhpC.

Salmonella typhimurium AhpC is a founding member of the peroxiredoxin family, a ubiquitous group of cysteine-based peroxidases with high reactivity toward hydrogen peroxide, organic hydroperoxides, and peroxynitrite. For all of the peroxiredoxins, the catalytic cysteine, referred to as the peroxidatic cysteine (C(P)), acts as a nucleophile in attacking the peroxide substrate, forming a cysteine sulfenic acid at the active site. Because thiolates are far stronger nucleophiles than thiol groups, it is generally accepted that cysteine-based peroxidases should exhibit pK(a) values lower than an unperturbed value of 8.

Measurement of protein sulfenic acid content.

Protein sulfenic acids are reactive, reversibly oxidized cysteinyl residues with roles in redox catalysis and regulation. Detection and quantification of these species in proteins is accomplished through chemical modification by reagents such as 7-chloro-4-nitrobenzo-2-oxa-1,3-diazole (NBD chloride), 2-nitro-5-thiobenzoate (TNB), dimedone, or derivatives of dimedone, followed by UV-visible spectroscopy or mass spectrometric analysis.

Prevalence of oral disease among adults with primary HIV infection.

Objective: To explore the type and prevalence of oral mucosal lesions among adults with primary HIV infection (PHI) compared with HIV-negative adults at high risk for HIV disease, and in relation to HIV viral load.

Methods: We conducted standardized oral examinations to identify specific oral mucosal lesions among adults with PHI, both pre-seroconversion and post- seroconversion-recently infected, compared with HIV-negative adults. We compared the group with oral lesions to those without oral lesions with respect to HIV-RNA load and CD4 + T-cell count.

Decreasing peroxiredoxin II expression decreases glutathione, alters cell cycle distribution, and sensitizes glioma cells to ionizing radiation and H(2)O(2).

Glioblastomas are notorious for their resistance to ionizing radiation and chemotherapy. We hypothesize that this resistance to ionizing radiation is due, in part, to alterations in antioxidant enzymes. Here, we show that rat and human glioma cells overexpress the antioxidant enzyme peroxiredoxin II (Prx II).

The provision and nature of ADHD services for children/adolescents in the UK: results from a nationwide survey.

The Attention Deficit Hyperactivity Disorder (ADHD) Observational Research in Europe (ADORE) project aims to describe the relationship between prescribed treatment regimen and quality of life in ADHD patients across Europe over a 2-year period. As an adjunct to the ADORE study, a survey was conducted to assess the availability and range of ADHD treatment services in the UK. A questionnaire was developed to assess service provision at 20 UK ADORE sites.

Discovering mechanisms of signaling-mediated cysteine oxidation.

Accumulating evidence reveals hydrogen peroxide as a key player both as a damaging agent and, from emerging evidence over the past decade, as a second messenger in intracellular signaling. This rather mild oxidant acts upon downstream targets within signaling cascades to modulate the activity of a host of enzymes (e.g.

Functional site profiling and electrostatic analysis of cysteines modifiable to cysteine sulfenic acid.

Cysteine sulfenic acid (Cys-SOH), a reversible modification, is a catalytic intermediate at enzyme active sites, a sensor for oxidative stress, a regulator of some transcription factors, and a redox-signaling intermediate. This post-translational modification is not random: specific features near the cysteine control its reactivity. To identify features responsible for the propensity of cysteines to be modified to sulfenic acid, a list of 47 proteins (containing 49 known Cys-SOH sites) was compiled.

Mutant AhpC peroxiredoxins suppress thiol-disulfide redox deficiencies and acquire deglutathionylating activity.

The bacterial peroxiredoxin AhpC, a cysteine-dependent peroxidase, can be converted through a single amino acid insertion to a disulfide reductase, AhpC*, active in the glutathione and glutaredoxin pathway. Here we show that, whereas AhpC* is inactive as a peroxidase, other point mutants in AhpC can confer the in vivo disulfide reductase activity without abrogating peroxidase activity. Moreover, AhpC* and several point mutants tested in vitro exhibit an enhanced reductase activity toward mixed disulfides between glutathione and glutaredoxin (Grx-S-SG), consistent with the in vivo requirements for these components.

Substrate specificity and redox potential of AhpC, a bacterial peroxiredoxin.

Typical 2-Cys peroxiredoxins (Prxs) are ubiquitous peroxidases that are involved in peroxide scavenging and/or the regulation of peroxide signaling in eukaryotes. Despite their prevalence, very few Prxs have been reliably characterized in terms of their substrate specificity profile and redox potential even though these values are important for gaining insight into physiological function. Here, we present such studies focusing on Salmonella typhimurium alkyl hydroperoxide reductase C component (StAhpC), an enzyme that has proven to be an excellent prototype of this largest and most widespread class of Prxs that includes mammalian Prx I-Prx IV.

Isotope-coded, iodoacetamide-based reagent to determine individual cysteine pK(a) values by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry.

Cysteine reactivity in enzymes is imparted to a large extent by the stabilization of the deprotonated form of the reduced cysteine (i.e., the thiolate) within the active site.

The catalytic mechanism of peroxiredoxins.

Peroxiredoxins carry out the efficient reduction of a typically broad range of peroxide substrates through an absolutely conserved, activated cysteine residue within a highly conserved active site pocket structure. Though details of reductive recycling after cysteine sulfenic acid formation at the active site vary among members of different Prx classes, local unfolding around the active site cysteine is likely generally required in these proteins for disulfide bond formation with a second resolving cysteine and/or for access of the reductant to the oxidized active site. The conformational change associated with the catalytic cycle and the redox-dependent decamer formation occurring in at least some typical 2-Cys Prxs have interesting implications in the interplay between active site loop dynamics, oligomerization state, catalytic efficiency and propensity toward inactivation during turnover in these important antioxidant enzymes.

An audit of the use of the Barthel Index in palliative care.

The Barthel Index (Mahoney and Barthel, 1965) is an objective tool which assesses an individual's ability to perform activities of daily living; for example, personal care, mobility, transfers, bathing and feeding. The purpose of this study was to investigate whether the Index could be used with patients with life-threatening illnesses who are admitted to the inpatient intermediate care unit, to aid clinical practice, establish patients' current level of function, and highlight any progress or deterioration in abilities. The overall aim was to facilitate discharge planning and ensure that patients were managed in their preferred place of care.

Fluorescent and affinity-based tools to detect cysteine sulfenic acid formation in proteins.

Cysteine sulfenic acid formation in proteins results from the oxidative modification of susceptible cysteine residues by hydrogen peroxide, alkyl hydroperoxides, and peroxynitrite. This species represents a biologically significant modification occurring during oxidant signaling or oxidative stress, and it can modulate protein function. Most methods to identify such oxidatively modified proteins rely on monitoring the loss of one or more thiol group(s) or on selective labeling of nascent thiol groups following reduction of oxidized proteins.

The requirement of reversible cysteine sulfenic acid formation for T cell activation and function.

Reactive oxygen intermediates (ROI) generated in response to receptor stimulation play an important role in mediating cellular responses. We have examined the importance of reversible cysteine sulfenic acid formation in naive CD8(+) T cell activation and proliferation. We observed that, within minutes of T cell activation, naive CD8(+) T cells increased ROI levels in a manner dependent upon Ag concentration.

Cysteine reactivity and thiol-disulfide interchange pathways in AhpF and AhpC of the bacterial alkyl hydroperoxide reductase system.

AhpC and AhpF from Salmonella typhimurium undergo a series of electron transfers to catalyze the pyridine nucleotide-dependent reduction of hydroperoxide substrates. AhpC, the peroxide-reducing (peroxiredoxin) component of this alkyl hydroperoxidase system, is an important scavenger of endogenous hydrogen peroxide in bacteria and acts through a reactive, peroxidatic cysteine, Cys46, and a second cysteine, Cys165, that forms an active site disulfide bond. AhpF, a separate disulfide reductase protein, regenerates AhpC every catalytic cycle via electrons from NADH which are transferred to AhpC through a tightly bound flavin and two disulfide centers, Cys345-Cys348 and Cys129-Cys132, through putative large domain movements.

A multi-centre, randomised, open-label study of atomoxetine compared with standard current therapy in UK children and adolescents with attention-deficit/hyperactivity disorder (ADHD).

Objective: To assess the broader efficacy (i.e., improvements in quality of life/functional outcomes) of atomoxetine compared with standard current therapy (SCT) in UK paediatric patients with ADHD and to explore clinician/parent/child perceptions of ADHD.