Cohort profile for the STratifying Resilience and Depression Longitudinally (STRADL) study:A depression-focused investigation of Generation Scotland, using detailed clinical, cognitive, and neuroimaging assessments

Grant information: STRADL is supported by the Wellcome Trust through a Strategic Award (104036/Z/14/Z). GS:SFHS received core support from the CSO of the Scottish Government Health Directorates (CZD/16/6) and the Scottish Funding Council (HR03006). ADM is supported by Innovate UK, the European Commission, the Scottish Funding Council via the Scottish Imaging Network SINAPSE, and the CSO. HCW is supported by a JMAS SIM Fellowship from the Royal College of Physicians of Edinburgh, by an ESAT College Fellowship from the University of Edinburgh, and has received previous funding from the Sackler Trust. LR has previously received financial support from Pfizer (formerly Wyeth) in relation to imaging studies of people with schizophrenia and bipolar disorder. JDH is supported by the MRC. DJM is an NRS Clinician, funded by the CSO. RMR is supported by the British Heart Foundation. ISP-V and MRM are supported by the NIHR Biomedical Research Centre at the University Hospitals Bristol NHS Foundation Trust and the University of Bristol. The views expressed in this publication are those of the author(s) and not necessarily those of the NHS, the National Institute for Health Research or the Department of Health; and MRM is also supported by the MRC MC_UU_12013/6). JMW is supported by MRC UK Dementia Research Institute and MRC Centre and project grants, EPSRC, Fondation Leducq, Stroke Association, British Heart Foundation, Alzheimer Society, and the European Union H2020 PHC-03-15 SVDs@Target grant agreement (666881). DJP is supported by Wellcome Trust Longitudinal Population Study funding (216767/Z/19/Z) the Eva Lester bequest to the University of Edinburgh. AMM is additionally supported by the MRC (MC_PC_17209, MC_PC_MR/R01910X/1, MR/S035818/1), The Wellcome Trust (216767/Z/19/Z ), The Sackler Trust, and has previously received research funding from Pfizer, Eli Lilly, and Janssen. Both AMM and IJD are members of The University of Edinburgh Centre for Cognitive Ageing and Cognitive Epidemiology, part of the cross council Lifelong Health and Wellbeing Initiative (MR/K026992/1); funding from the BBSRC and MRC is gratefully acknowledged. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscriptPeer reviewedPublisher PD

An overview of <i>Scheuchzeria palustris</i> in Scotland and a new locality in Westerness (v.c.97)

A new locality for Scheuchzeria palustris L. (Rannoch Rush) in Westerness extends its extant range in Scotland. The characteristics of the site are presented in the context of the known distribution and ecology of S. palustris on and around Rannoch Moor, the only extant populations in the British Isles. An overview of the population dynamics revealed by monitoring since 1988 is given

Effect of the 5-HT4 receptor agonist tegaserod on the expression of GRK2 and GRK6 in the rat gastrointestinal tract

Abstract Objective Tegaserod is a 5-hydroxytryptamine type 4 (5-HT4) receptor agonist, formerly used in treating constipation predominant irritable bowel syndrome, which desensitizes 5-HT4 receptors in rat oesophagus and colon in vitro. Desensitization of 5-HT4 receptors is regulated by G-protein coupled receptor kinases. This study was designed to assess the effect of 5-HT4 receptor activation on the expression of GRK2 and GRK6 in the rat oesophagus and distal colon by acute administration of tegaserod. Results Rats were treated with a single dose of tegaserod (5 mg/kg) and tissue samples of the oesophagus and distal colon were prepared and level of GRK2 and GRK6 protein expression was determined using western blotting. The immunodensity of GRK2 and GRK6 was normalized against the loading control β-actin and compared with control animals. Acute administration of tegaserod for 1, 2, 3, 4, 6, and 8 h did not change significantly the immunodensity of GRK2 or GRK6 in the oesophagus or GRK2 in the distal colon when compared with control animals. This may indicate that the basal level of GRK2 and GRK6 expression is sufficient to regulate the desensitization of 5-HT4 receptors in acute drug treatment

Distribution of 5-HT₃, 5-HT₄, and 5-HT₇ receptors along the human colon

BACKGROUND/AIMS: Several disorders of the gastrointestinal tract are associated with abnormal serotonin (5-HT) signaling or metabolism where the 5-HT(3) and 5-HT(4) receptors are clinically relevant. The aim was to examine the distribution of 5-HT(3), 5-HT(4), and 5-HT(7) receptors in the normal human colon and how this is associated with receptor interacting chaperone 3, G protein coupled receptor kinases, and protein LIN-7 homologs to extend previous observations limited to the sigmoid colon or the upper intestine. METHODS: Samples from ascending, transverse, descending, and sigmoid human colon were dissected into 3 separate layers (mucosa, longitudinal, and circular muscles) and ileum samples were dissected into mucosa and muscle layers (n = 20). Complementary DNA was synthesized by reverse transcription from extracted RNA and expression was determined by quantitative or end point polymerase chain reaction. RESULTS: The 5-HT(3) receptor subunits were found in all tissues throughout the colon and ileum. The A subunit was detected in all samples and the C subunit was expressed at similar levels while the B subunit was expressed at lower levels and less frequently. The 5-HT(3) receptor E subunit was mainly found in the mucosa layers. All splice variants of the 5-HT(4) and 5-HT(7) receptors were expressed throughout the colon although the 5-HT(4) receptor d, g, and i variants were expressed less often. CONCLUSIONS: The major differences in 5-HT receptor distribution within the human colon are in relation to the mucosa and muscular tissue layers where the 5-HT(3) receptor E subunit is predominantly found in the mucosal layer which may be of therapeutic relevance

Characterisation of opioid receptors involved in modulating circular and longitudinal muscle contraction in the rat ileum

1. The aim of the present investigation was to characterise the opioid receptor subtypes present in the rat ileum using a method that detects drug action on the enteric nerves innervating the circular and longitudinal muscles. 2. Neurogenic contractions were reversibly inhibited by morphine (circular muscle pEC(50), 6.43±0.17, E(max) 81.7±5.0%; longitudinal muscle pEC(50), 6.65±0.27, E(max) 59.7±7.8%), the μ-opioid receptor-selective agonist, DAMGO ([D-Ala(2),N-Me-Phe(4),Gly(5)-ol]enkephalin acetate) (circular pEC(50), 7.85±0.04, E(max) 97.8±3.6%; longitudinal pEC(50), 7.35±0.09, E(max) 56.0±6.1%), the δ-selective agonist DADLE ([D-Ala(2),D-Leu(5)]enkephalin acetate) (circular pEC(50), 7.41±0.17, E(max), 93.3±8.4%; longitudinal pEC(50), 6.31±0.07, E(max) 66.5±5.2%) and the κ-selective agonist U 50488H (trans-(±)-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]benzeneacetamide methanesulphonate) (circular pEC(50), 5.91±0.41, E(max), 83.5±26.8%; longitudinal pEC(50), 5.60±0.08, E(max) 74.3±7.2%). Agonist potencies were generally within expected ranges for activity at the subtype for which they are selective, except for U 50488H, which was less potent than expected. 3. The μ and δ receptor-selective antagonists, CTAP (H-D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH(2)) and naltrindole, caused progressive, parallel rightward shifts in the DAMGO and DADLE curves, respectively. Analysis indicated conformity to theoretical simple competitive antagonist behaviour. U 50488H effects were insensitive to the κ-selective antagonist, n-BNI. A high concentration (1 μM) of naltrexone caused apparent potentiation of U 50488H effects. 4. CTAP pK(B) estimates were consistent with previously reported values for μ receptor antagonism (circular 7.84±0.17, longitudinal 7.64±0.35). However, the naltrindole pK(B) estimates indicated lower antagonist potency than expected (circular 8.22±0.23, longitudinal 8.53±0.35). 5. It is concluded that μ and possibly atypical δ receptors (but not κ receptors) mediate inhibition of contraction in this model. Nonopioid actions of U 50488H are probably responsible for the inhibitory effects seen with this compound

Role of α(2)-adrenoceptors in the regulation of intestinal water transport

1. The influence of the sympathetic nervous system on intestinal fluid transport by the jejunum and ileum of the anaesthetized rat was investigated under basal conditions and during active secretion induced by intra-arterial infusion of vasoactive intestinal peptide (VIP). 2. Intra-arterial infusion of noradrenaline (3, 10, 30 nmol min(−1), i.a.) and i.v. injection of the selective α(2)-adrenoceptor agonist UK 14,304 (1 μmol kg(−1), i.v.) increased the rate of basal fluid absorption. The effect of UK 14,304 was blocked by yohimbine (10 μmol kg(−1), i.v). However, the selective α(1)-adrenoceptor agonist phenylephrine (5 μmol kg(−1), i.v.) did not alter either the jejunal or ileal absorption rate. 3. The α(2)-adrenoceptor antagonists yohimbine (0.3, 1.0, 3 and 10 μmol kg(−1), i.v.) and rauwolscine (10 μmol kg(−1), i.v.) decreased the basal absorption rate, while the α(1)-adrenoceptor antagonist prazosin (3 μmol kg(−1), i.v.) was without effect. Intracerebroventricular injection of yohimbine (3 μmol kg(−1)) caused a significant antiabsorptive effect in the jejunum but not ileum. 4. Peripheral chemical sympathectomy induced by pretreating animals with 6-hydroxydopamine (150 mg kg(−1), i.p., total dose) induced a trend towards impaired absorption in the jejunum and ileum. 5. The findings provide evidence that the sympathetic nervous system exerts tonic control on intestinal fluid transport and that the effect is mainly through peripheral α(2)-adrenoceptors. 6. The subtype determination of α(2)-adrenoceptors in modulating intestinal fluid transport was assessed by determining the effects of α(2)-adrenoceptor agents on intestinal fluid secretion induced by i.a. infusion of VIP (0.8 μg min(−1)). 7. Intravenous administration of UK 14,304 caused a dose-dependent reversal of the secretory phase of the VIP-induced response, but failed to restore fluid transport to the control level of net absorption. EC(50) values were 0.17 μmol kg(−1) in the jejunum and 0.22 μmol kg(−1) in the ileum. 8. The effect of UK 14,304 was blocked by the selective α(2A/D) antagonist BRL 44408 and the non-selective α(2) antagonist yohimbine (each 10 μmol kg(−1)). The selective α(2B/C) antagonist ARC 239 (10 μmol kg(−1)) did not affect the antisecretory action of UK 14,304. It is suggested that the α(2)-adrenoceptors in the rat intestinal epithelium are the α(2D) or α(2A)-like subtype

Subtype AE HIV-1 DNA and recombinant Fowlpoxvirus vaccines encoding five shared HIV-1 genes: safety and T cell immunogenicity in macaques

To induce broad T cell immunity to HIV-1, we evaluated the safety, immunogenicity and dose–response relationship of DNA and recombinant Fowlpoxvirus (rFPV) vaccines encoding five shared HIV subtype AE genes (Gag, Pol, Env, Tat, Rev) in pigtail macaques. The DNA (three doses of either 1 mg or 4.5 mg) and rFPV (a single boost of either 5 × 107 or 2 × 108 plaque forming units) vaccines were administered intramuscularly without adjuvants. Broadly reactive HIV-specific T cell immunity was stimulated by all doses of the vaccines administered, without significant differences between the high and low doses studied. The vaccines induced both CD4 and CD8 T cell responses to Gag, Pol, Env and Tat/Rev proteins, with CD4 T cell responses being greater in magnitude than CD8 T cell responses. The vaccine-induced T cell responses had significant cross-recognition of heterologous HIV-1 proteins from non-AE HIV-1 subtypes. In conclusion, these subtype AE HIV-1 DNA and rFPV vaccines were safe, induced broad T-cell immunity in macaques, and are suitable for progression into clinical trials