Pharmacoepigenetics of depression: no major influence of MAO-A DNA methylation on treatment response.

The monoamine oxidase A (MAO-A) gene has been suggested to be involved in the pathogenesis as well as the pharmacological treatment of major depressive disorder. In the present analysis, for the first time a pharmacoepigenetic approach was applied investigating the influence of DNA methylation patterns in the MAO-A regulatory and exon1/intron1 region on antidepressant treatment response. 94 patients of Caucasian descent with major depressive disorder (f = 61; DSM-IV) were analyzed for DNA methylation status at 43 MAO-A CpG sites via direct sequencing of sodium bisulfite treated DNA extracted from blood cells.

Serotonin transporter gene hypomethylation predicts impaired antidepressant treatment response.

Variation in the serotonin transporter gene (5-HTT; SERT; SLC6A4) has been suggested to pharmacogenetically drive interindividual differences in antidepressant treatment response. In the present analysis, a 'pharmaco-epigenetic' approach was applied by investigating the influence of DNA methylation patterns in the 5-HTT transcriptional control region on antidepressant treatment response. Ninety-four patients of Caucasian descent with major depressive disorder (MDD) (f = 61) were analysed for DNA methylation status at nine CpG sites in the 5-HTT transcriptional control region upstream of exon 1A via direct sequencing of sodium bisulfite treated DNA extracted from blood cells.

Medial prefrontal cortex stimulation modulates the processing of conditioned fear.

The extinction of conditioned fear depends on an efficient interplay between the amygdala and the medial prefrontal cortex (mPFC). In rats, high-frequency electrical mPFC stimulation has been shown to improve extinction by means of a reduction of amygdala activity. However, so far it is unclear whether stimulation of homologues regions in humans might have similar beneficial effects.

Neural correlates of a standardized version of the trail making test in young and elderly adults: a functional near-infrared spectroscopy study.

The trail making test (TMT) is a widely applied diagnostic tool measuring executive functioning in order to discriminate between healthy and pathological aging processes. However, due to its paper-and-pencil nature it is difficult to adapt for functional brain imaging. Related neural underpinnings even in healthy aging are mostly unknown since no consistent administration for imaging is available.

Mass spectrometry-based relative quantification of proteins in precatalytic and catalytically active spliceosomes by metabolic labeling (SILAC), chemical labeling (iTRAQ), and label-free spectral count.

The spliceosome undergoes major changes in protein and RNA composition during pre-mRNA splicing. Knowing the proteins-and their respective quantities-at each spliceosomal assembly stage is critical for understanding the molecular mechanisms and regulation of splicing. Here, we applied three independent mass spectrometry (MS)-based approaches for quantification of these proteins: (1) metabolic labeling by SILAC, (2) chemical labeling by iTRAQ, and (3) label-free spectral count for quantification of the protein composition of the human spliceosomal precatalytic B and catalytic C complexes.

The CD37-targeted antibody-drug conjugate IMGN529 is highly active against human CLL and in a novel CD37 transgenic murine leukemia model.

Therapeutic regimens for chronic lymphocytic leukemia (CLL) have increasingly utilized monoclonal antibodies since the chimeric anti-CD20 antibody rituximab was introduced. Despite improved clinical outcomes, current CLL therapies are not curative. Therefore, antibodies with greater efficacy and novel targets are desirable.

Investigation of association of serotonin transporter and monoamine oxidase-A genes with Alzheimer's disease and depression in the VITA study cohort: a 90-month longitudinal study.

Alzheimer's disease (AD) and depression (DE) are common psychiatric disorders strongly intertwined with one another. Nevertheless, etiology and early diagnosis of the disorders are still elusive. Several genetic variations have been suggested to associate with AD and DE, particularly in genes involved in the serotonergic system such as the serotonin transporter (SERT/SLC6A4), responsible for the removal from the synaptic cleft, and the monoamine-oxidase-A (MAOA), responsible for the presynaptic degradation of serotonin.

Gender-specific association of variants in the AKR1C1 gene with dimensional anxiety in patients with panic disorder: additional evidence for the importance of neurosteroids in anxiety?

Background: Neurosteroids are synthesized both in brain and peripheral steroidogenic tissue from cholesterol or steroidal precursors. Neurosteroids have been shown to be implicated in neural proliferation, differentiation, and activity. Preclinical and clinical studies also suggest a modulatory role of neurosteroids in anxiety-related phenotypes.

Interaction of valproic acid and the antidepressant drugs doxepin and venlafaxine: analysis of therapeutic drug monitoring data under naturalistic conditions.

Valproic acid and the antidepressants doxepin and venlafaxine are frequently used psychotropic drugs. In the literature, an influence of valproic acid on serum levels of antidepressants has been described, although studies have focused on amitriptyline. The authors assessed their therapeutic drug monitoring (TDM) database for patients receiving a combination of doxepin or venlafaxine and valproic acid and compared these samples with matched controls without valproic acid comedication in terms of the serum concentration of antidepressants.

The comparison of brand-name and generic formulations of venlafaxine: a therapeutic drug monitoring analysis.

Objective: Venlafaxine (VEN) is a widely used antidepressant drug, which is available in both brand-name and generic formulations. Bioequivalence studies indicate some pharmacokinetic variability. However, naturalistic therapeutic drug monitoring studies of different generic formulations are lacking.

Neuron-specific alterations in signal transduction pathways associated with Alzheimer's disease.

The hallmarks of sporadic Alzheimer's disease (AD) are extracellular amyloid deposits, intracellular neurofibrillary tangles (NFTs), and neuronal death. Hyperphosphorylation of tau is a key factor in the generation of NFTs. Mitogen activated protein kinase 1 (MAPK1) and protein kinase C beta (PRKCB) are thought to play a role in hyperphosphorylation, and PRCKB is thought to be involved in hypoxic stress and vascular dysfunction, and to trigger MAPK phosphorylation pathways.

The BDNF Val66Met polymorphism modulates the generalization of cued fear responses to a novel context.

Brain-derived neurotrophic factor (BDNF) has a crucial role in activity-dependent synaptic plasticity and learning and memory. The human functional single-nucleotide BDNF rs6265 (Val66Met) polymorphism has been found to be associated with alteration in neural BDNF release and function correlating with altered emotional behavior. Here, we investigated for the first time the hypothesis that this polymorphism in humans modulates the context dependency of conditioned fear responses.

Timing matters: change depends on the stage of treatment in cognitive behavioral therapy for panic disorder with agoraphobia.

Objective: The mechanisms of action underlying treatment are inadequately understood. This study examined 5 variables implicated in the treatment of panic disorder with agoraphobia (PD/AG): catastrophic agoraphobic cognitions, anxiety about bodily sensations, agoraphobic avoidance, anxiety sensitivity, and psychological flexibility. The relative importance of these process variables was examined across treatment phases: (a) psychoeducation/interoceptive exposure, (b) in situ exposure, and (c) generalization/follow-up.

Neuron-specific mitochondrial DNA deletion levels in sporadic Alzheimer's disease.

Oxidative stress is implicated in the pathogenesis of neurodegenerative diseases, including sporadic Alzheimer´s disease (AD). Mitochondrial DNA (mtDNA) deletions are markers of oxidative damage and increase with age. To unravel the impact of mtDNA damage on AD development, we analyzed mtDNA deletion levels in diverse neuronal cell types of four brain regions (hippocampal CA1 and CA2 regions, nucleus tractus spinalis nervi trigemini, and the cerebellum) that exhibit differing levels of vulnerability to AD related changes at progressive Braak stages compared with age-matched controls.

The interaction of early life experiences with COMT val158met affects anxiety sensitivity.

The pathogenesis of anxiety disorders is considered to be multifactorial with a complex interaction of genetic factors and individual environmental factors. Therefore, the aim of this study was to examine gene-by-environment interactions of the genes coding for catechol-O-methyltransferase (COMT) and monoamine oxidase A (MAOA) with life events on measures related to anxiety. A sample of healthy subjects (N = 782; thereof 531 women; mean age M = 24.

Nitric oxide mediates Cd-dependent induction of signaling- associated genes.

The first reaction of plants to stress factors, including cadmium, is activation of signal transduction pathways leading to the mobilization of defense mechanisms. In a recent study we have demonstrated that cadmium causes a rapid induction of several genes associated with cellular signaling in soybean seedlings. Here we show that nitric oxide can be an important signaling molecule mediating observed increase in genes expression under short-term cadmium stress.

Effects of transcranial direct current stimulation on consolidation of fear memory.

It has been shown that applying transcranial direct current stimulation (tDCS) over the dorsolateral prefrontal cortex (DLPFC) influences declarative memory processes. This study investigates the efficacy of tDCS on emotional memory consolidation, especially experimental fear conditioning. We applied an auditory fear-conditioning paradigm, in which two differently colored squares (blue and yellow) were presented as conditioned stimuli (CS) and an auditory stimulus as unconditioned stimulus (UCS).

[Differences between patients in consultation psychiatry and psychiatric inpatients].

Objective: To optimize psychiatric consultation service epidemiological information is needed.

Methods: We compared data on gender, age and diagnoses of patients in the consultation service to psychiatric inpatients.

Results: In psychiatric consultation service patients are older (56.

A novel anti-CD37 antibody-drug conjugate with multiple anti-tumor mechanisms for the treatment of B-cell malignancies.

CD37 has gathered renewed interest as a therapeutic target in non-Hodgkin lymphoma (NHL) and chronic lymphocytic leukemia (CLL); however, CD37-directed antibody-drug conjugates (ADCs) have not been explored. Here, we identified a novel anti-CD37 antibody, K7153A, with potent in vitro activity against B-cell lines through multiple mechanisms including apoptosis induction, antibody-dependent cellular cytotoxicity, antibody-dependent cellular phagocytosis, and complement-dependent cytotoxicity. The antibody was conjugated to the maytansinoid, DM1, a potent antimicrotubule agent, via the thioether linker, N-succinimidyl-4-(N-maleimidomethyl)cyclohexane-1-carboxylate (SMCC), and the resulting ADC, IMGN529, retained the intrinsic antibody activities and showed enhanced cytotoxic activity from targeted payload delivery.

The toxic Doppelganger: on the ionic and molecular mimicry of cadmium.

Cadmium is a toxic heavy metal which can cause numerous alterations in cell functioning. Exposure to cadmium leads to generation of reactive oxygen species, disorders in membrane structure and functioning, inhibition of respiration, disturbances in ion homeostasis, perturbations in cell division, and initiation of apoptosis and necrosis. This heavy metal is considered a carcinogen by the Agency for Toxic Substances and Disease Registry.

Short term signaling responses in roots of young soybean seedlings exposed to cadmium stress.

In the present study, the expression of fourteen genes involved in various signal transduction pathways was examined in young soybean (Glycine max) seedlings exposed to cadmium at two concentrations (10 mg L(-1) and 25 mg L(-1)) for short time periods (3, 6 and 24 h). The results show that cadmium causes induction of genes encoding proteins involved in ethylene and polyamines metabolism, nitric oxide generation, MAPK cascades and regulation of other genes' expression. The bioinformatic analysis of promoter sequences of Cd-inducible genes revealed that their promoters possess several regulative motifs associated with the plant response to stress factors and abscisic acid and ethylene signaling.

Epigenetic signature of panic disorder: a role of glutamate decarboxylase 1 (GAD1) DNA hypomethylation?

Glutamate decarboxylases (GAD67/65; GAD1/GAD2) are crucially involved in gamma-aminobutyric acid (GABA) synthesis and thus were repeatedly suggested to play an important role in the pathogenesis of anxiety disorders. In the present study, DNA methylation patterns in the GAD1 and GAD2 promoter and GAD1 intron 2 regions were investigated for association with panic disorder, with particular attention to possible effects of environmental factors. Sixty-five patients with panic disorder (f=44, m=21) and 65 matched healthy controls were analyzed for DNA methylation status at 38 GAD1 promoter/intron2 and 10 GAD2 promoter CpG sites via direct sequencing of sodium bisulfate treated DNA extracted from blood cells.

Interaction of valproic acid and amitriptyline: analysis of therapeutic drug monitoring data under naturalistic conditions.

Amitriptyline (AMI) and valproic acid (VPA) are common psychotropic drugs which are frequently used in psychiatry and also administered in neurology or anesthesia in the absence of a psychiatric indication. On the basis of the case of a 73-year-old man with therapy-resistant major depressive episode who experienced anticholinergic delirium after adding VPA to AMI, we retrospectively analyzed therapeutic drug monitoring data of the years 2008 to 2010. We assessed cases receiving a combination of AMI and VPA, and obtained a control sample of AMI patients without VPA which were matched for sex, age, daily dose, and comedication.

Vagus somatosensory evoked potentials are delayed in Alzheimer's disease, but not in major depression.

In Alzheimer's disease (AD), the degeneration of brainstem nuclei is different from major depression (MD). Thus, vagus somatosensory evoked potentials (VSEP) proposed for the functional assessment of brainstem nuclei should show prolonged latencies in AD but not in MD. In 55 AD patients, 57 MD patients and two age-matched control groups evoked potentials were recorded upon stimulation of the auricular branch of the vagus nerve.

Contextual fear conditioning in virtual reality is affected by 5HTTLPR and NPSR1 polymorphisms: effects on fear-potentiated startle.

The serotonin (5-HT) and neuropeptide S (NPS) systems are discussed as important genetic modulators of fear and sustained anxiety contributing to the etiology of anxiety disorders. Sustained anxiety is a crucial characteristic of most anxiety disorders which likely develops through contextual fear conditioning. This study investigated if and how genetic alterations of the 5-HT and the NPS systems as well as their interaction modulate contextual fear conditioning; specifically, function polymorphic variants in the genes coding for the 5-HT transporter (5HTT) and the NPS receptor (NPSR1) were studied.