VLA-2 blockade in vivo by vatelizumab induces CD4+FoxP3+ regulatory T cells.

Integrin α2β1, also known as very late antigen (VLA)-2, is a collagen-binding molecule expressed constitutively on platelets. Vatelizumab, a monoclonal antibody targeting the α2 subunit (CD49b) of VLA-2, was recently investigated for its safety and efficacy during a Phase 2 clinical study in multiple sclerosis patients, as integrin-mediated collagen binding at the site of inflammation is central to a number of downstream pro-inflammatory events. In the course of this study, we could show that VLA-2 is expressed ex vivo on platelets, platelet-T-cell aggregates, as well as a small population of highly activated memory T cells.

Study of stacking interactions between two neutral tetrathiafulvalene molecules in Cambridge Structural Database crystal structures and by quantum chemical calculations.

Tetrathiafulvalene (TTF) and its derivatives are very well known as electron donors with widespread use in the field of organic conductors and superconductors. Stacking interactions between two neutral TTF fragments were studied by analysing data from Cambridge Structural Database crystal structures and by quantum chemical calculations. Analysis of the contacts found in crystal structures shows high occurrence of parallel displaced orientations of TTF molecules.

Influence of hydrogen bonds on edge-to-face interactions between pyridine molecules.

Edge-to-face interactions between two pyridine molecules and the influence of simultaneous hydrogen bonding of one or both of the pyridines to water on those interactions were studied by analyzing data from ab initio calculations. The results show that the edge-to-face interactions of pyridine dimers that are hydrogen bonded to water are generally stronger than those of non-H-bonded pyridine dimers, especially when the donor pyridine forms a hydrogen bond. The binding energy of the most stable edge-to-face interacting H-bonded pyridine dimer is -5.

Gene expression profiles in relation to tension and dissociation in borderline personality disorder.

The biological underpinnings of borderline personality disorder (BPD) and its psychopathology including states of aversive tension and dissociation is poorly understood. Our goal was to examine transcriptional changes associated with states of tension or dissociation within individual patients in a pilot study. Dissociation is not only a critical symptom of BPD but has also been associated with higher risk for self-mutilation and depression.

Influence of COX-2 and OXTR polymorphisms on treatment outcome in treatment resistant depression.

Inflammatory pathways play a crucial role in the pathomechanisms of antidepressant efficacy. The aim of this study was to investigate whether a set of single nucleotide polymorphisms (SNPs) within cyclooxygenase-2 (COX-2, rs5275 and rs20417) and oxytocin receptor (OXTR, rs53576 and rs2254298) genes was associated with antidepressant treatment resistance, response or remission. Three hundred seventy-two patients were recruited in the context of a multicenter resistant depression study.

Failure to replicate influence of GRIK4 and GNB3 polymorphisms on treatment outcome in major depression.

In the present study, we aimed to confirm the previous finding of an association between GRIK4 and GNB3 variants (rs195478 and rs5443) and remission and treatment resistance in major depression, using a multicenter sample of 223 patients. We did not find any supporting evidence for such associations. These conflicting data may result from difficulties in the replication of candidate gene association studies.

COMT and age at onset in mood disorders: a replication and extension study.

Our study aims at replicating our previous finding of an association between COMT rs4680 G/A polymorphism and early onset major depression (MD). We included 462 MD, 147 bipolar disorders (BD) subjects and 295 healthy controls. We could partially replicate previous findings.

Brain-derived neurotrophic factor gene polymorphisms: influence on treatment response phenotypes of major depressive disorder.

Brain-derived neurotrophic factor (BDNF), a member of the nerve growth factor family of neurotrophins, has pivotal roles in neuronal survival, proliferation, and synaptic plasticity in the brain. Both clinical and pharmacological studies have implicated the common single nucleotide polymorphism (SNP) at position 196, Val66Met in the pathophysiology of major depressive disorder (MDD), and antidepressant response. However, inconsistent results were found between Val66Met (rs6265) polymorphism and treatment response phenotypes in genetic association studies.

No influence of PTGS2 polymorphisms on response and remission to antidepressants in major depression.

In the present study, aimed at investigating whether a set of single nucleotide polymorphisms (SNPs) within PTGS2 gene (rs4648276, rs2066826 and rs689466) could be associated with antidepressant response, remission and treatment resistance in a sample of major depression patients, we did not find evidence supporting any of such associations.

Dysbindin gene (DTNBP1) in major depressive disorder (MDD) patients: lack of association with clinical phenotypes.

Objectives: Dystrobrevin binding protein 1 (Dysbindin) is a plausible candidate gene for major depressive disorders (MDD) due to its involvement in synaptic signaling, plasticity and localization in the brain.

Methods: Two intronic SNPs of DTNBP1; rs760761 (P1320) and rs2619522 (P1763) were analyzed in 206 patients with DSM-IV MDD to investigate the functional impact of genotypes on susceptibility for depression and some clinical phenotypes. The Sequenom iPLEX assay (Sequenom, Cambridge, MA) was used for genotyping.

A preliminary investigation of the influence of CREB1 gene on treatment resistance in major depression.

Background: The transcription factor Cyclic adenosine monophosphate Response Element Binding (CREB) protein has been repeatedly involved in the aetiology and pharmacotherapy of major depression (MD). The aim of this study was to investigate the potential association of a set of single nucleotide polymorphisms (SNPs) in CREB1 gene and both MD and response, remission and treatment resistance to antidepressants.

Methods: One hundred-ninety MD patients collected in the context of a resistant depression study and treated with antidepressants for at least 4weeks were genotyped for 5 CREB1 SNPs (rs2709376, rs2253206, rs7569963, rs7594560, and rs4675690).

5HT1A and 5HT2A receptor genes in treatment response phenotypes in major depressive disorder.

The 5HT2A (5HTR2A) and 5HT1A receptor (5HTR1A) genes are plausible candidate genes for major depressive disorders. Two single nucleotide polymorphisms, the rs7997012 in 5HTR2A and the -1019C/G in 5HTR1A, were analyzed in 206 patients with Diagnostic and Statistical Manual of Mental Disorders, fourth edition major depressive disorder. Patients were retrospectively characterized for clinical response to antidepressant treatment.

Obstacles in the diagnostics and therapy of heparin-induced thrombocytopenia.

An immune-mediated, severe, acquired prothrombotic disorder, heparin-induced thrombocytopenia type II (HIT II) occurs in 0.5-5% of patients exposed to unfractionated heparin longer than 5-7 days. Arterial and venous thromboses are induced by HIT II in about 35-50% of patients.

Neurogenesis-dependent and -independent effects of fluoxetine in an animal model of anxiety/depression.

Understanding the physiopathology of affective disorders and their treatment relies on the availability of experimental models that accurately mimic aspects of the disease. Here we describe a mouse model of an anxiety/depressive-like state induced by chronic corticosterone treatment. Furthermore, chronic antidepressant treatment reversed the behavioral dysfunctions and the inhibition of hippocampal neurogenesis induced by corticosterone treatment.

HPA axis and sleep: identifying subtypes of major depression.

It is increasingly acknowledged that the diagnosis of major depression encompasses patients who do not necessarily share the same disease biology. Though the diagnostic criteria allow the specification of different subtypes, e.g.

Pituitary adenylate cyclase-activating peptide affects homeostatic sleep regulation in healthy young men.

Pituitary adenylate cyclase-activating peptide (PACAP) is involved in autonomous regulation, including timekeeping, by its action on the suprachiasmatic nucleus and on neuroendocrine secretion, energy metabolism, and transmitter release. In particular, the interactions between PACAP and the glutamatergic system are well recognized. We compared the effect of intravenously administered PACAP to that of placebo in eight healthy male subjects.

Safety and tolerability of interferon beta-1b in pediatric multiple sclerosis.

Background: Immunomodulatory therapies are widely used in adults with multiple sclerosis (MS) and safety and tolerability is well-established. Although at least 5% of all patients with MS experience the clinical onset of their disease prior to age 18 years, the available literature on safety and tolerability of immunomodulatory therapies for pediatric-onset MS is limited.

Methods: The authors retrospectively reviewed safety and tolerability of interferon beta-1b (IFNbeta-1b) in a cohort of 43 children and adolescents treated for a mean of 29.

Renin-angiotensin-aldosterone system, HPA-axis and sleep-EEG changes in unmedicated patients with depression after total sleep deprivation.

Background: Changes in the activity of the renin-angiontensin-aldosterone system (RAAS) in depression have recently been reported. Renin and aldosterone secretion are coupled to sleep in healthy subjects. As total sleep deprivation (TSD) leads to a rapid mood improvement in patients with depression, it is of interest to investigate its effect on the response of the RAAS in the recovery night in this population as a possible probe for the neurobiological effects of TSD and potentially other rapid acting antidepressive interventions.

Neuropeptide Y (NPY) shortens sleep latency but does not suppress ACTH and cortisol in depressed patients and normal controls.

Preclinical and clinical studies suggest that neuropeptide Y (NPY) exerts functional corticotropin-releasing hormone (CRH) antagonistic effects. NPY activity appears to be blunted in depression. Recently, we have found in young normal male controls after repetitive administration of NPY a shortened sleep latency and a decrease of time awake and, in the second half of the night, EEG delta-power; cortisol and ACTH levels were blunted.

Alpha-helical CRH exerts CRH agonistic effects on sleep-endocrine activity in humans.

CRH is known to enhance wakefulness and to reduce SWS. In addition, some but not all, studies suggest that CRH promotes REM sleep. Alpha-helical CRH exerts CRH-antagonistic effects in various studies.

Depressive disorders -- is it time to endorse different pathophysiologies?

Enhanced activity of the hypothalamic-pituitary-adrenal (HPA) axis, involving elevated secretion of corticotropin-releasing hormone (CRH), is considered a key neurobiological alteration in major depression. Enhanced CRH secretion is also believed to contribute to the typical sleep alterations and the clinical presentation of major depression. While it is acknowledged that HPA overdrive and hypernoradrenergic function is associated with melancholic depression, there is growing evidence that hypoactivity of the HPA axis and afferent noradrenergic pathways is present in patients with atypical features of depression.

Changes in sleep electroencephalogram and nocturnal hormone secretion after administration of the antidyskinetic agent sarizotan in healthy young male volunteers.

Rationale: Sarizotan is a 5-HT(1A) agonist with high affinity to D(3) and D(4) receptors. In animal experiments, the drug shows a strong anti-cataleptic effect and suppresses effectively dyskinesias in animal models of L: -dopa-induced dyskinesia and of tardive dyskinesia. Data from an open pilot study in patients with Parkinson's disease show clear indication of a treatment effect against L: -dopa-induced dyskinesia.

Hexarelin decreases slow-wave sleep and stimulates the secretion of GH, ACTH, cortisol and prolactin during sleep in healthy volunteers.

Ghrelin, the endogenous ligand of the growth hormone (GH) secretagogue (GHS) receptor and some GHSs exert different effects on sleep electroencephalogram (EEG) and sleep-related hormone secretion in humans. Similar to GH-releasing hormone (GHRH) ghrelin promotes slow-wave sleep in humans, whereas GH-releasing peptide-6 (GHRP-6) enhances stage 2 nonrapid-eye movement sleep (NREMS). As GHRP-6, hexarelin is a synthetic GHS.

The somatostatin analogue octreotide impairs sleep and decreases EEG sigma power in young male subjects.

The long-acting somatostatin (SRIF) analogue octreotide decreased nonrapid eye movement sleep (NREMS) in the rat. This effect is opposite to the promotion of sleep after growth hormone (GH)-releasing hormone (GHRH) in various species including humans. Therefore, it appears likely that GHRH and SRIF, besides their opposite action on pituitary GH release, interact reciprocally in sleep regulation.

Depression-like changes of the sleep-EEG during high dose corticosteroid treatment in patients with multiple sclerosis.

Acute exacerbations of multiple sclerosis (MS) are commonly treated with high doses of corticosteroids that can influence sleep regulation and hypothalamo-pituitary-adrenal (HPA) activity. We examined the sleep-EEG (including conventional and spectral EEG analysis) in 9 female patients with relapsing-remitting MS (and no psychiatric disorder) just prior to and on days 2 and 10 of high dose corticosteroid treatment (500 mg/day methylprednisolone given IV for 5 days, then PO taper down) and age-matched healthy female controls. Before treatment with corticosteroids, MS patients compared to controls showed few changes of the sleep EEG, namely a significant increase in slow wave sleep (SWS) and a decrease in stage 2 sleep.