Selective serotonin reuptake inhibitors in the treatment of generalized anxiety disorder

Selective serotonin reuptake inhibitors have proven efficacy in the treatment of panic disorder, obsessive–compulsive disorder, post-traumatic stress disorder and social anxiety disorder. Accumulating data shows that selective serotonin reuptake inhibitor treatment can also be efficacious in patients with generalized anxiety disorder. This review summarizes the findings of randomized controlled trials of selective serotonin reuptake inhibitor treatment for generalized anxiety disorder, examines the strengths and weaknesses of other therapeutic approaches and considers potential new treatments for patients with this chronic and disabling anxiety disorder

Inhalation of the Rho-kinase inhibitor Y-27632 reverses allergen-induced airway hyperresponsiveness after the early and late asthmatic reaction

BACKGROUND: In guinea pigs, we have previously demonstrated that the contribution of Rho-kinase to airway responsiveness in vivo and ex vivo is enhanced after active sensitization with ovalbumin (OA). Using conscious, unrestrained OA-sensitized guina pigs, we now investigated the role of Rho-kinase in the development of airway hyperresponsiveness (AHR) after the allergen-induced early (EAR) and late asthmatic reaction (LAR) in vivo. METHODS: Histamine and PGF(2α )PC(100)-values (provocation concentrations causing 100% increase in pleural pressure) were assessed before OA-challenge (basal airway responsiveness) and after the OA-induced EAR (5 h after challenge) and LAR (23 h after challenge). Thirty minutes later, saline or the specific Rho-kinase inhibitor Y-27632 (5 mM, nebulizer concentration) were nebulized, after which PC(100)-values were reassessed. RESULTS: In contrast to saline, Y-27632 inhalation significantly decreased the basal responsiveness toward histamine and PGF(2α )before OA-challenge, as indicated by increased PC(100 )-values. Both after the allergen-induced EAR and LAR, AHR to histamine and PGF(2α )was present, which was reversed by Y-27632 inhalation. Moreover, there was an increased effectiveness of Y-27632 to reduce airway responsiveness to histamine and PGF(2α )after the EAR and LAR as compared to pre-challenge conditions. Saline inhalations did not affect histamine or PGF(2α )PC(100)-values at all. Interestingly, under all conditions Y-27632 was significantly more effective in reducing airway responsiveness to PGF(2α )as compared to histamine. Also, there was a clear tendency (P = 0.08) to a more pronounced degree of AHR after the EAR for PGF(2α )than for histamine. CONCLUSION: The results indicate that inhalation of the Rho-kinase inhibitor Y-27632 causes a considerable bronchoprotection to both histamine and PGF(2α). Moreover, the results are indicative of a differential involvement of Rho-kinase in the agonist-induced airway obstruction in vivo. Increased Rho-kinase activity contributes to the allergen-induced AHR to histamine and PGF(2α )after both the EAR and the LAR, which is effectively reversed by inhalation of Y-27632. Therefore, Rho-kinase can be considered as a potential pharmacotherapeutical target in allergic asthma

Early efficacy of CABG care delivery in a low procedure-volume community hospital: operative and midterm results

BACKGROUND: The Leapfrog Group recommended that coronary artery bypass grafting (CABG) surgery should be done at high volume hospitals (>450 per year) without corresponding surgeon-volume criteria. The latter confounds procedure-volume effects substantially, and it is suggested that high surgeon-volume (>125 per year) rather than hospital-volume may be a more appropriate indicator of CABG quality. METHODS: We assessed 3-year isolated CABG morbidity and mortality outcomes at a low-volume hospital (LVH: 504 cases) and compared them to the corresponding Society of Thoracic Surgeons (STS) national data over the same period (2001–2003). All CABGs were performed by 5 high-volume surgeons (161–285 per year). "Best practice" care at LVH – including effective practice guidelines, protocols, data acquisition capabilities, case review process, dedicated facilities and support personnel – were closely modeled after a high-volume hospital served by the same surgeon-team. RESULTS: Operative mortality was similar for LVH and STS (OM: 2.38% vs. 2.53%), and the corresponding LVH observed-to-expected mortality (O/E = 0.81) indicated good quality relative to the STS risk model (O/E<1). Also, these results were consistent irrespective of risk category: O/E was 0, 0.9 and 1.03 for very-low risk (<1%), low risk (1–3%) and moderate-to-high risk category (>3%), respectively. Postoperative leg wound infections, ventilator hours, renal dysfunction (no dialysis), and atrial fibrillation were higher for LVH, but hospital stay was not. The unadjusted Kaplan-Meier survival for the LVH cohort was 96%, 94%, and 92% at one, two, and three years, respectively. CONCLUSION: Our results demonstrated that high quality CABG care can be achieved at LVH programs if 1) served by high volume surgeons and 2) patient care procedures similar to those of large programs are implemented. This approach may prove a useful paradigm to ensure high quality CABG care and early efficacy at low volume institutions that wish to comply with the Leapfrog standards

Tracking Antigen-Specific T-Cells during Clinical Tolerance Induction in Humans

Allergen immunotherapy presents an opportunity to define mechanisms of induction of clinical tolerance in humans. Significant progress has been made in our understanding of changes in T cell responses during immunotherapy, but existing work has largely been based on functional T cell assays. HLA-peptide-tetrameric complexes allow the tracking of antigen-specific T-cell populations based on the presence of specific T-cell receptors and when combined with functional assays allow a closer assessment of the potential roles of T-cell anergy and clonotype evolution. We sought to develop tools to facilitate tracking of antigen-specific T-cell populations during wasp-venom immunotherapy in people with wasp-venom allergy. We first defined dominant immunogenic regions within Ves v 5, a constituent of wasp venom that is known to represent a target antigen for T-cells. We next identified HLA-DRB1*1501 restricted epitopes and used HLA class II tetrameric complexes alongside cytokine responses to Ves v 5 to track T-cell responses during immunotherapy. In contrast to previous reports, we show that there was a significant initial induction of IL-4 producing antigen-specific T-cells within the first 3–5 weeks of immunotherapy which was followed by reduction of circulating effector antigen-specific T-cells despite escalation of wasp-venom dosage. However, there was sustained induction of IL-10-producing and FOXP3 positive antigen-specific T cells. We observed that these IL-10 producing cells could share a common precursor with IL-4-producing T cells specific for the same epitope. Clinical tolerance induction in humans is associated with dynamic changes in frequencies of antigen-specific T-cells, with a marked loss of IL-4-producing T-cells and the acquisition of IL-10-producing and FOXP3-positive antigen-specific CD4+ T-cells that can derive from a common shared precursor to pre-treatment effector T-cells. The development of new approaches to track antigen specific T-cell responses during immunotherapy can provide novel insights into mechanisms of tolerance induction in humans and identify new potential treatment targets

The RNA Chaperone Hfq Is Important for Growth and Stress Tolerance in Francisella novicida

The RNA-binding protein Hfq is recognized as an important regulatory factor in a variety of cellular processes, including stress resistance and pathogenesis. Hfq has been shown in several bacteria to interact with small regulatory RNAs and act as a post-transcriptional regulator of mRNA stability and translation. Here we examined the impact of Hfq on growth, stress tolerance, and gene expression in the intracellular pathogen Francisella novicida. We present evidence of Hfq involvement in the ability of F. novicida to tolerate several cellular stresses, including heat-shock and oxidative stresses, and alterations in hfq gene expression under these conditions. Furthermore, expression of numerous genes, including several associated with virulence, is altered in a hfq mutant strain suggesting they are regulated directly or indirectly by Hfq. Strikingly, we observed a delayed entry into stationary phase and increased biofilm formation in the hfq mutant. Together, these data demonstrate a critical role for Hfq in F. novicida growth and survival

Homo-PROTACs:bivalent small-molecule dimerizers of the VHL E3 ubiquitin ligase to induce self-degradation

E3 ubiquitin ligases are key enzymes within the ubiquitin proteasome system which catalyze the ubiquitination of proteins, targeting them for proteasomal degradation. E3 ligases are gaining importance as targets to small molecules, both for direct inhibition and to be hijacked to induce the degradation of non-native neo-substrates using bivalent compounds known as PROTACs (for 'proteolysis-targeting chimeras'). We describe Homo-PROTACs as an approach to dimerize an E3 ligase to trigger its suicide-type chemical knockdown inside cells. We provide proof-of-concept of Homo-PROTACs using diverse molecules composed of two instances of a ligand for the von Hippel-Lindau (VHL) E3 ligase. The most active compound, CM11, dimerizes VHL with high avidity in vitro and induces potent, rapid and proteasome-dependent self-degradation of VHL in different cell lines, in a highly isoform-selective fashion and without triggering a hypoxic response. This approach offers a novel chemical probe for selective VHL knockdown, and demonstrates the potential for a new modality of chemical intervention on E3 ligases.Targeting the ubiquitin proteasome system to modulate protein homeostasis using small molecules has promising therapeutic potential. Here the authors describe Homo-PROTACS: small molecules that can induce the homo-dimerization of E3 ubiquitin ligases and cause their proteasome-dependent degradation

Metabolism before, during and after anaesthesia in colic and healthy horses

<p>Abstract</p> <p>Background</p> <p>Many colic horses are compromised due to the disease state and from hours of starvation and sometimes long trailer rides. This could influence their muscle energy reserves and affect the horses' ability to recover. The principal aim was to follow metabolic parameter before, during, and up to 7 days after anaesthesia in healthy horses and in horses undergoing abdominal surgery due to colic.</p> <p>Methods</p> <p>20 healthy horses given anaesthesia alone and 20 colic horses subjected to emergency abdominal surgery were anaesthetised for a mean of 228 minutes and 183 minutes respectively. Blood for analysis of haematology, electrolytes, cortisol, creatine kinase (CK), free fatty acids (FFA), glycerol, glucose and lactate was sampled before, during, and up to 7 days after anaesthesia. Arterial and venous blood gases were obtained before, during and up to 8 hours after recovery. Gluteal muscle biopsy specimens for biochemical analysis of muscle metabolites were obtained at start and end of anaesthesia and 1 h and 1 day after recovery.</p> <p>Results</p> <p>Plasma cortisol, FFA, glycerol, glucose, lactate and CK were elevated and serum phosphate and potassium were lower in colic horses before anaesthesia. Muscle adenosine triphosphate (ATP) content was low in several colic horses. Anaesthesia and surgery resulted in a decrease in plasma FFA and glycerol in colic horses whereas levels increased in healthy horses. During anaesthesia muscle and plasma lactate and plasma phosphate increased in both groups. In the colic horses plasma lactate increased further after recovery. Plasma FFA and glycerol increased 8 h after standing in the colic horses. In both groups, plasma concentrations of CK increased and serum phosphate decreased post-anaesthesia. On Day 7 most parameters were not different between groups. Colic horses lost on average 8% of their initial weight. Eleven colic horses completed the study.</p> <p>Conclusion</p> <p>Colic horses entered anaesthesia with altered metabolism and in a negative oxygen balance. Muscle oxygenation was insufficient during anaesthesia in both groups, although to a lesser extent in the healthy horses. The post-anaesthetic period was associated with increased lipolysis and weight loss in the colic horses, indicating a negative energy balance during the first week post-operatively.</p

Social and occupational factors associated with psychological distress and disorder among disaster responders: a systematic review

BACKGROUND: When disasters occur, there are many different occupational groups involved in rescue, recovery and support efforts. This study aimed to conduct a systematic literature review to identify social and occupational factors affecting the psychological impact of disasters on responders. METHODS: Four electronic literature databases (MEDLINE®, Embase, PsycINFO® and Web of Science) were searched and hand searches of reference lists were carried out. Papers were screened against specific inclusion criteria (e.g. published in peer-reviewed journal in English; included a quantitative measure of wellbeing; participants were disaster responders). Data was extracted from relevant papers and thematic analysis was used to develop a list of key factors affecting the wellbeing of disaster responders. RESULTS: Eighteen thousand five papers were found and 111 included in the review. The psychological impact of disasters on responders appeared associated with pre-disaster factors (occupational factors; specialised training and preparedness; life events and health), during-disaster factors (exposure; duration on site and arrival time; emotional involvement; peri-traumatic distress/dissociation; role-related stressors; perceptions of safety, threat and risk; harm to self or close others; social support; professional support) and post-disaster factors (professional support; impact on life; life events; media; coping strategies). CONCLUSIONS: There are steps that can be taken at all stages of a disaster (before, during and after) which may minimise risks to responders and enhance resilience. Preparedness (for the demands of the role and the potential psychological impact) and support (particularly from the organisation) are essential. The findings of this review could potentially be used to develop training workshops for professionals involved in disaster response. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s40359-016-0120-9) contains supplementary material, which is available to authorized users

Current and prospective pharmacological targets in relation to antimigraine action

Migraine is a recurrent incapacitating neurovascular disorder characterized by unilateral and throbbing headaches associated with photophobia, phonophobia, nausea, and vomiting. Current specific drugs used in the acute treatment of migraine interact with vascular receptors, a fact that has raised concerns about their cardiovascular safety. In the past, α-adrenoceptor agonists (ergotamine, dihydroergotamine, isometheptene) were used. The last two decades have witnessed the advent of 5-HT1B/1D receptor agonists (sumatriptan and second-generation triptans), which have a well-established efficacy in the acute treatment of migraine. Moreover, current prophylactic treatments of migraine include 5-HT2 receptor antagonists, Ca2+ channel blockers, and β-adrenoceptor antagonists. Despite the progress in migraine research and in view of its complex etiology, this disease still remains underdiagnosed, and available therapies are underused. In this review, we have discussed pharmacological targets in migraine, with special emphasis on compounds acting on 5-HT (5-HT1-7), adrenergic (α1, α2, and β), calcitonin gene-related peptide (CGRP 1 and CGRP2), adenosine (A1, A2, and A3), glutamate (NMDA, AMPA, kainate, and metabotropic), dopamine, endothelin, and female hormone (estrogen and progesterone) receptors. In addition, we have considered some other targets, including gamma-aminobutyric acid, angiotensin, bradykinin, histamine, and ionotropic receptors, in relation to antimigraine therapy. Finally, the cardiovascular safety of current and prospective antimigraine therapies is touched upon