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6. Enzymatic synthesis of glycosides and oligosaccharides

Author

MacManus, D. A.

Subjects
547, QD Chemistry
Abstract

The β-D-galactosidase of Escherichia coli catalysed galactosyl transfer to a variety of acceptor substrates. Transfers to simple alcohols were followed by transfers to chiral alcohols, chiral diols (bearing primary and secondary hydroxyl groups) and to a me so- diol. In particular, the regio- and stereoselective aspects of the reactions were investigated. In general, transfer to primary hydroxyl groups was favoured over transfer to secondary hydroxyl groups, but little or no preference for the transfer to specific enantiomers in a racemic mixture was observed. The results for propane-1,2-diol and butane- 1,3-diol are interpreted in terms of the possible conformations which might be adopted at the active site of the enzyme. Transfer to cii-cyclohexa-3,5-diene- 1,2-diol gave rise to two diastereoisomers. During the early stages of the reaction, a diastereoisomeric excess of ca. 80% was observed; this was reduced to ca. 20% as the yields of product reached their maximum values. Assignment of the structures of the products was based on a combination of the techniques of nuclear Overhauser enhancement and molecular modelling. α-Galactosyl transfers to lactose and cellobiose using Mortierella vinacea a-D-galactosidase were also studied. In both cases, a single trisaccharide was isolated. Spectroscopic evidence indicated that a (1-6) linkages had been formed in both cases. An acrylamide/acrylic acid polymer intended for use in enzymatic oligosaccharide synthesis was developed. The polymer was high swelling so as to allow permeation by the enzyme and could be easily stored. An attempt to introduce chiral cavities specific for certain monosaccharides was made by substituting part of the acrylamide for a boronate-containing acrylamide and carrying out the polymerisation in the presence of the monosaccharide. The success of the imprinting procedure was measured by the ability of the polymer to separate the components of a racemic mixture of the monosaccharide. The application of such "molecular imprinting" as an aid to oligosaccharide synthesis is discussed.

Published
1991

8. Mental health disorders and alcohol misuse among UK military veterans and the general population:a comparison study

Author

Rhead, R, MacManus, D, Jones, M, Greenberg, N, Fear, NT, Goodwin, L, Rhead, R, MacManus, D, Jones, M, Greenberg, N, Fear, NT, and Goodwin, L

Abstract

Background For a small minority of personnel, military service can have a negative impact on their mental health. Yet no studies have assessed how the mental health of UK veterans (who served during the recent operations in Afghanistan or Iraq) compares to non-veterans, to determine if they are at a disadvantage. We examine the prevalence of mental disorders and alcohol misuse in UK veterans compared to non-veterans. Methods Veteran data were taken from the third phase of the King's Centre for Military Health Research cohort study (n = 2917). These data were compared with data on non-veterans taken from two large general population surveys: 2014 Adult Psychiatric Morbidity Survey (n = 5871) and wave 6 of the UK Household Longitudinal Study (UKHLS, n = 22 760). Results We found that, overall, UK veterans who served at the time of recent military operations were more likely to report a significantly higher prevalence of common mental disorders (CMD) (23% v. 16%), post-traumatic stress disorder (PTSD) (8% v. 5%) and alcohol misuse (11% v. 6%) than non-veterans. Stratifying by gender showed that the negative impact of being a veteran on mental health and alcohol misuse was restricted to male veterans. Being ill or disabled was associated with a higher prevalence of CMD and PTSD for both veterans and non-veterans. Conclusion Whilst the same sociodemographic groups within the veteran and non-veteran populations seemed to have an increased risk of mental health problems (e.g. those who were unemployed), male veterans, in particular, appear to be at a distinct disadvantage compared to those who have never served.

Published
2022

9. Mental health disorders and alcohol misuse among UK military veterans and the general population : a comparison study

Author

Rhead, R, MacManus, D, Jones, M, Greenberg, N, Fear, NT, Goodwin, L, Rhead, R, MacManus, D, Jones, M, Greenberg, N, Fear, NT, and Goodwin, L

Abstract

Background For a small minority of personnel, military service can have a negative impact on their mental health. Yet no studies have assessed how the mental health of UK veterans (who served during the recent operations in Afghanistan or Iraq) compares to non-veterans, to determine if they are at a disadvantage. We examine the prevalence of mental disorders and alcohol misuse in UK veterans compared to non-veterans. Methods Veteran data were taken from the third phase of the King's Centre for Military Health Research cohort study (n = 2917). These data were compared with data on non-veterans taken from two large general population surveys: 2014 Adult Psychiatric Morbidity Survey (n = 5871) and wave 6 of the UK Household Longitudinal Study (UKHLS, n = 22 760). Results We found that, overall, UK veterans who served at the time of recent military operations were more likely to report a significantly higher prevalence of common mental disorders (CMD) (23% v. 16%), post-traumatic stress disorder (PTSD) (8% v. 5%) and alcohol misuse (11% v. 6%) than non-veterans. Stratifying by gender showed that the negative impact of being a veteran on mental health and alcohol misuse was restricted to male veterans. Being ill or disabled was associated with a higher prevalence of CMD and PTSD for both veterans and non-veterans. Conclusion Whilst the same sociodemographic groups within the veteran and non-veteran populations seemed to have an increased risk of mental health problems (e.g. those who were unemployed), male veterans, in particular, appear to be at a distinct disadvantage compared to those who have never served.

Published
2022

21. Spinal cord MRI in clinically isolated optic neuritis

Author

Dalton, C. M., Brex, P. A., Miszkiel, K A., Fernando, K, MacManus, D G., Plant, G T., Thompson, A. J., and Miller, D.H.

Subjects
Spinal cord -- Evaluation -- Usage, Optic neuritis -- Diagnosis, Magnetic resonance imaging -- Usage, Statistics -- Usage, Health, Psychology and mental health, Diagnosis, Evaluation, Usage
Abstract

J Neurol Neurosurg Psychiatry 2003;74: 1577-1580 Background/methods: One hundred and fifteen patients with clinically isolated optic neuritis underwent magnetic resonance imaging (MRI) of the brain and spinal cord within 3 [...]

Published
2003

39. Do serving and ex-serving personnel of the UK armed forces seek help for perceived stress, emotional or mental health problems?

Author

Stevelink, SAM, Jones, N, Jones, M, Dyball, D, Khera, CK, Pernet, D, MacCrimmon, S, Murphy, D, Hull, L, Greenberg, N, MacManus, D, Goodwin, L, Sharp, ML, Fear, NT, Stevelink, SAM, Jones, N, Jones, M, Dyball, D, Khera, CK, Pernet, D, MacCrimmon, S, Murphy, D, Hull, L, Greenberg, N, MacManus, D, Goodwin, L, Sharp, ML, and Fear, NT

Abstract

Background: UK armed forces personnel are at risk of occupational psychological injury; they are often reluctant to seek help for such problems. Objective: We aimed to examine and describe sources of support, prevalence and associates of help-seeking among UK serving and ex-serving personnel. Method: A total of 1450 participants who self-reported a stress, emotional or mental health problem in the past 3 years were sampled from a health and wellbeing study and subsequently completed a telephone interview comprising measures of mental disorder symptoms, alcohol misuse and help-seeking behaviour. Results: Seven per cent of participants had not sought any help, 55% had accessed medical sources of support (general practitioner or mental health specialist), 46% had received formal non-medical (welfare) support and 86% had used informal support. Gender, age, perceived health, functional impairment, social support, deployment, alcohol and comorbidity impacted upon the choice of help source. Conclusions: This study found that the majority of those with perceived mental health problems sought some form of help, with over half using formal medical sources of support.

Published
2019

49. Multiple Sclerosis-Secondary Progressive Multi-Arm Randomisation Trial (MS-SMART).:a multiarm phase IIb randomised, double-blind, placebo-controlled clinical trial comparing the efficacy of three neuroprotective drugs in secondary progressive multiple sclerosis

Author

Connick, P, De Angelis, F, Parker, Ra, Plantone, D, Doshi, A, John, N, Stutters, J, Macmanus, D, Prados Carrasco, F, Barkhof, F, Ourselin, S, Braisher, M, Ross, M, Cranswick, G, Pavitt, Sh, Giovannoni, G, Gandini Wheeler-Kingshott CA, Hawkins, C, Sharrack, B, Bastow, R, Weir, Cj, Stallard, N, Chandran, S, Chataway, J, UK Multiple Sclerosis Society Clinical Trials, Network., Radiology and nuclear medicine, and Amsterdam Neuroscience - Neuroinfection & -inflammation

Subjects
Adult, Male, 0301 basic medicine, medicine.medical_specialty, Serotonin reuptake inhibitor, Placebo, Amiloride, 03 medical and health sciences, 0302 clinical medicine, Atrophy, Double-Blind Method, Fluoxetine, Internal medicine, Statistical significance, Protocol, medicine, Humans, Riluzole, drug repurposing, business.industry, Multiple sclerosis, clinical trial, General Medicine, Middle Aged, Multiple Sclerosis, Chronic Progressive, RC346, mechanistic evaluation, medicine.disease, 3. Good health, Clinical trial, progressive multiple sclerosis, Neuroprotective Agents, Treatment Outcome, 030104 developmental biology, Neurology, neuroprotection, Female, business, 030217 neurology & neurosurgery, medicine.drug
Abstract

IntroductionThe major unmet need in multiple sclerosis (MS) is for neuroprotective therapies that can slow (or ideally stop) the rate of disease progression. The UK MS Society Clinical Trials Network (CTN) was initiated in 2007 with the purpose of developing a national, efficient, multiarm trial of repurposed drugs. Key underpinning work was commissioned by the CTN to inform the design, outcome selection and drug choice including animal models and a systematic review. This identified seven leading oral agents for repurposing as neuroprotective therapies in secondary progressive MS (SPMS). The purpose of the Multiple Sclerosis-Secondary Progressive Multi-Arm Randomisation Trial (MS-SMART) will be to evaluate the neuroprotective efficacy of three of these drugs, selected with distinct mechanistic actions and previous evidence of likely efficacy, against a common placebo arm. The interventions chosen were: amiloride (acid-sensing ion channel antagonist); fluoxetine (selective serotonin reuptake inhibitor) and riluzole (glutamate antagonist).Methods and analysisPatients with progressing SPMS will be randomised 1:1:1:1 to amiloride, fluoxetine, riluzole or matched placebo and followed for 96 weeks. The primary outcome will be the percentage brain volume change (PBVC) between baseline and 96 weeks, derived from structural MR brain imaging data using the Structural Image Evaluation, using Normalisation, of Atrophy method. With a sample size of 90 per arm, this will give 90% power to detect a 40% reduction in PBVC in any active arm compared with placebo and 80% power to detect a 35% reduction (analysing by analysis of covariance and with adjustment for multiple comparisons of three 1.67% two-sided tests), giving a 5% overall two-sided significance level. MS-SMART is not powered to detect differences between the three active treatment arms. Allowing for a 20% dropout rate, 110 patients per arm will be randomised. The study will take place at Neuroscience centres in England and Scotland.Ethics and disseminationMS-SMART was approved by the Scotland A Research Ethics Committee on 13 January 2013 (REC reference: 13/SS/0007). Results of the study will be submitted for publication in a peer-reviewed journal.Trial registration numbersNCT01910259; 2012-005394-31;ISRCTN28440672.

Published
2018

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