Treatment of Obsessive Compulsive Disorder and excessive reassurance seeking in an older adult: a single case quasi-experimental design

Background: Cognitive behavioural interventions for excessive reassurance seeking (ERS) typically focus on encouraging individuals to refrain from seeking any reassurance and in some cases banning caregivers (e.g. family members) from providing it. However, this blanket consideration that reassurance is a bad thing that should simply be stopped may not always be appropriate or helpful. Cognitive behavioural treatment (CBT) targeting ERS by helping the sufferer to shift from seeking reassurance to seeking support may be a promising treatment intervention. Aims: This study aims to examine the targeted treatment of ERS in an older adult who has been suffering from severe obsessive compulsive disorder (OCD) for seven decades. Method: Using a single case quasi-experimental design (ABCD), the frequency of reassurance seeking, urges to seek reassurance, OCD beliefs and anxiety were measured daily for almost a year in addition to standard symptom measures. Results: At the end of treatment, visual inspection showed that reassurance seeking was no longer considered excessive and OCD severity fell from the severe to non-clinical range across the treatment sessions. All treatment gains were maintained at follow-up. Conclusions: This study illustrates how CBT can be successfully applied to treat long-standing OCD and ERS in an older adult. Engendering support as an alternative to reassurance seeking in CBT may be a particularly promising intervention for ERS.Aims: This study aims to examine the targeted treatment of ERS in an older adult who has been suffering from severe Obsessive Compulsive Disorder (OCD) for seven decades Method: Using a single case quasi-experimental design (ABCD), the frequency of reassurance seeking, urges to seek reassurance, OCD beliefs and anxiety were measured daily for almost a year in addition to standard symptom measures. Results: At the end of treatment, visual inspection showed that reassurance seeking was no longer considered excessive and OCD severity fell from the severe to non-clinical range across the treatment sessions. All treatment gains were maintained at follow-up. Conclusions: This study illustrates how CBT can be successfully applied to treat long standing OCD and ERS in an older adult. Engendering support as an alternative to reassurance seeking in CBT may be a particularly promising intervention for ERS

Far-UV FUSE spectroscopy of the OVI resonance doublet in Sand2 (WO)

We present Far-Ultraviolet Spectroscopic Explorer (FUSE) spectroscopy of Sand 2, a LMC WO-type Wolf-Rayet star, revealing the OVI resonance P Cygni doublet at 1032-38A. These data are combined with HST/FOS ultraviolet and Mt Stromlo 2.3m optical spectroscopy, and analysed using a spherical, non-LTE, line-blanketed code. Our study reveals exceptional stellar parameters: T*=150,000K, v_inf=4100 km/s, log (L/Lo)=5.3, and Mdot=10^-5 Mo/yr if we adopt a volume filling factor of 10%. Elemental abundances of C/He=0.7+-0.2 and O/He=0.15(-0.05+0.10) by number qualitatively support previous recombination line studies. We confirm that Sand 2 is more chemically enriched in carbon than LMC WC stars, and is expected to undergo a supernova explosion within the next 50,000 yr.Comment: 17 pages, 4 figures, AASTeX preprint format. This paper will appear in a special issue of ApJ Letters devoted to the first scientific results from the FUSE missio

Protecting noncommunicable disease prevention policy in trade and investment agreements

Preventing noncommunicable diseases is a global priority, for which the World Health Organization has recommended policies to reduce the consumption of tobacco products, alcohol and unhealthy foods. However, regulation has been strongly opposed by affected industries, who have invoked the provisions of legally binding trade and investment agreements. The aim of this analysis of the legal, economic and public health literature was to present a short primer on the relationship between noncommunicable disease prevention policy and trade and investment agreements to help public health policy-makers safeguard public health policies. The analysis identified opportunities for protecting, and even promoting, public health in trade and investment agreements, including: (i) ensuring exceptions for public health measures are included in agreements; (ii) committing to good regulatory practice that balances transparency and cooperation with the need for governments to limit the influence of vested interests; (iii) ensuring trade and investment agreement preambles acknowledge the importance of public health; (iv) excluding investor–state dispute settlement mechanisms from agreements; and (v) limiting the scope and definition of key provisions on investor protection to reduce the risk of investment disputes. This synthesis of the multidisciplinary literature also provides support for greater strategic and informed engagement between the health and trade policy sectors. In addition, ensuring a high level of health protection in trade and investment agreements requires cooperation between disciplines, engagement with experts in law, economics and public health policy, and fully transparent policy processes and governance structures

An evaluation of the complement-regulating activities of human complement factor H (FH) variants associated with age-related macular degeneration

PURPOSE: Factor H (FH, encoded by CFH) prevents activation of the complement system's alternative pathway (AP) on host tissues. FH impedes C3 convertase (C3bBb) formation, accelerates C3bBb decay, and is a cofactor for factor I (FI)–catalyzed C3b cleavage. Numerous CFH variants are associated with age-related macular degeneration (AMD), but their functional consequences frequently remain undetermined. Here, we conduct functional comparisons between a control version of FH (not AMD linked) and 21 AMD-linked FH variants. METHODS: Recombinantly produced, untagged, full-length FH versions were assayed for binding to C3b and decay acceleration of C3bBb using surface-plasmon resonance, FI-cofactor activity using a fluorescent probe of C3b integrity, suppression of C5b-9 assembly on an AP-activating surface, and inhibition of human AP-mediated lysis of sheep erythrocytes. RESULTS: All versions were successfully purified despite below-average yields for Arg2Thr, Arg53Cys, Arg175Pro, Arg175Gln, Ile221Val, Tyr402His, Pro503Ala, Arg567Gly, Gly1194Asp, and Arg1210Cys. Compared to control FH, Arg2Thr, Leu3Val, Ser58Ala, Asp90Gly, Asp130Asn, Gln400Lys, Tyr402His, Gly650Val, Ser890Ile, and Thr965Met showed minimal functional differences. Arg1210C, Arg53His, Arg175Gln, Gly1194Asp, Pro503Ala, Arg53Cys, Arg576Gly, and Arg175Pro (in order of decreasing efficacy) underperformed, while Ile221Val, Arg303Gln, and Arg303Trp were “marginal.” We newly identified variants toward the center of the molecule, Pro503Ala and Arg567Gly, as potentially pathogenic. CONCLUSIONS: Our approach could be extended to other variants of uncertain significance and to assays for noncanonical FH activities, aiming to facilitate selection of cohorts most likely to benefit from therapeutic FH. This is timely as recombinant therapeutic FH is in development for intravitreal treatment of AMD in patients with reduced FH functionality

Structural Models of Human eEF1A1 and eEF1A2 Reveal Two Distinct Surface Clusters of Sequence Variation and Potential Differences in Phosphorylation

BACKGROUND:Despite sharing 92% sequence identity, paralogous human translation elongation factor 1 alpha-1 (eEF1A1) and elongation factor 1 alpha-2 (eEF1A2) have different but overlapping functional profiles. This may reflect the differential requirements of the cell-types in which they are expressed and is consistent with complex roles for these proteins that extend beyond delivery of tRNA to the ribosome. METHODOLOGY/PRINCIPAL FINDINGS:To investigate the structural basis of these functional differences, we created and validated comparative three-dimensional (3-D) models of eEF1A1 and eEF1A2 on the basis of the crystal structure of homologous eEF1A from yeast. The spatial location of amino acid residues that vary between the two proteins was thereby pinpointed, and their surface electrostatic and lipophilic properties were compared. None of the variations amongst buried amino acid residues are judged likely to have a major structural effect on the protein fold, or to affect domain-domain interactions. Nearly all the variant surface-exposed amino acid residues lie on one face of the protein, in two proximal but distinct sub-clusters. The result of previously performed mutagenesis in yeast may be interpreted as confirming the importance of one of these clusters in actin-bundling and filament disorganization. Interestingly, some variant residues lie in close proximity to, and in a few cases show differences in interactions with, residues previously inferred to be directly involved in binding GTP/GDP, eEF1Balpha and aminoacyl-tRNA. Additional sequence-based predictions, in conjunction with the 3-D models, reveal likely differences in phosphorylation sites that could reconcile some of the functional differences between the two proteins. CONCLUSIONS:The revelation and putative functional assignment of two distinct sub-clusters on the surface of the protein models should enable rational site-directed mutagenesis, including homologous reverse-substitution experiments, to map surface binding patches onto these proteins. The predicted variant-specific phosphorylation sites also provide a basis for experimental verification by mutagenesis. The models provide a structural framework for interpretation of the resulting functional analysis

Structural basis for complement factor H-linked age-related macular degeneration

This is the final version of the article. Available from the publisher via the DOI in this record.Nearly 50 million people worldwide suffer from age-related macular degeneration (AMD), which causes severe loss of central vision. A single-nucleotide polymorphism in the gene for the complement regulator factor H (FH), which causes a Tyr-to-His substitution at position 402, is linked to approximately 50% of attributable risks for AMD. We present the crystal structure of the region of FH containing the polymorphic amino acid His402 in complex with an analogue of the glycosaminoglycans (GAGs) that localize the complement regulator on the cell surface. The structure demonstrates direct coordination of ligand by the disease-associated polymorphic residue, providing a molecular explanation of the genetic observation. This glycan-binding site occupies the center of an extended interaction groove on the regulator's surface, implying multivalent binding of sulfated GAGs. This finding is confirmed by structure-based site-directed mutagenesis, nuclear magnetic resonance-monitored binding experiments performed for both H402 and Y402 variants with this and another model GAG, and analysis of an extended GAG-FH complex.B. Prosser is funded by the Wellcome Trust Structural Biology Training Program (075415/Z/04/Z). S. Johnson and P. Roversi were funded by grants to S.M. Lea from the Medical Research Council (MRC) of the United Kingdom (grants G0400389 and G0400775). D. Uhrin and P.N. Barlow were funded by the Wellcome Trust (078780/ Z/05/Z). S.J. Clark was funded by an MRC Doctoral Training Account (G78/7925), and R.B. Sim and A.J. Day were funded by MRC core funding to the MRC Immunochemistry Unit

Interactions Between Autophagy and the Unfolded Protein Response: Implications for Inflammatory Bowel Disease

Inflammatory Bowel Disease (IBD), which includes Crohn's disease (CD) and ulcerative colitis, is characterised by chronic inflammation of the gastrointestinal tract. Aetiology involves a combination of genetic and environmental factors resulting in abnormal immune responses to intestinal microbiota. Genetic studies have strongly linked genes involved in autophagy to CD, and genes involved in the unfolded protein response (UPR) to IBD. The UPR is triggered in response to accumulation of misfolded proteins in the endoplasmic reticulum (ER) and autophagy plays a key role to relieve ER-stress and restore homeostasis. This review summarises the known interactions between autophagy and the UPR and discusses the impact of these converging pathways on IBD pathogenesis. With a paucity of effective long-term treatments for IBD, targeting of synergistic pathways may provide novel and more effective therapeutic options

Inflammatory Bowel Disease Drugs: A Focus on Autophagy

Inflammatory bowel disease [IBD] is characterized by chronic inflammation of the gastrointestinal tract. Medications such as corticosteroids, thiopurines, immunomodulators and biologic agents are used to induce and maintain remission; however, response to these drugs is variable and can diminish over time. Defective autophagy has been strongly linked to IBD pathogenesis, with evidence showing that enhancing autophagy may be therapeutically beneficial by regulating inflammation and clearing intestinal pathogens. It is plausible that the therapeutic effects of some IBD drugs are mediated in part through modulation of the autophagy pathway, with studies investigating a wide range of diseases and cell types demonstrating autophagy pathway regulation by these agents.This review will highlight the current evidence, both in vitro and in vivo, for the modulation of autophagy by drugs routinely used in IBD. A clearer understanding of their mechanisms of action will be invaluable to utilize these drugs in a more targeted and personalized manner in this diverse and often complex group of patients