Synthesis of Histidine Derivatives Present in Cardiac Muscle

N-Acyl-L-histidine derivatives, a number of N-acyldipeptides containing L-histidine (A), and dipeptides containing 1-methyl-L-histidine (B) or 3-methyl-L-histidine (C) are thought to be present in cardiac muscle. These compounds are believed to play an important role in the healthy functioning of the heart. The work presented in this thesis investigates the synthesis of optically active forms of some of these L-histidine derivatives. The results obtained when these compounds were tested by the physiologists for their individual effects on cardiac muscle are presented. (A). N-Acyl-L-histidine Derivatives and N-Acyldipeptides Containing L-Histidine N-Acetyl-L-histidine and A-propionyl-L-histidine were successfully synthesised in good yield and high optical purity by the direct acylation of L-histidine with acetic or propionic anhydride. Two routes aimed at providing a range of N- acyldipeptides containing L-histidine in chemically and optically pure form were studied. A series of N-acylamino acids were coupled to L-histidine protected on the carboxyl function. The first route used the benzyl ester of L-histidine but a number of problems were encountered which made this route unattractive. The second route involved L-histidine protected as a metal salt. The mixed anhydride method of peptide coupling was employed to produce the compounds in chemically pure form. A number of methods were used in an attempt to determine the optical purities of the histidine derivatives synthesised. The most promising method involved the coupling of (R)-a-methylbenzylamine to the carboxyl function of the N-acyldipeptides. The diastereoisomeric mixtures formed were then analysed using reverse-phase high performance liquid chromatography (HPLC). The solvent mixture used to elute the column was adjusted to find a composition which would allow the separation of the diastereoisomers. The areas under the peaks were then used to estimate the optical purities of the compounds under investigation. The L-histidine derivatives were examined by physiologists at Glasgow University. They discovered, using HPLC techniques, that N-acetyl-L-histidine, N-acetyl-L-carnosine and N-acetyl-L-homocarnosine were present in cardiac muscle. The N-propionyl derivatives synthesised had an adverse effect on the Ca-sensitising apparatus of cardiac muscle. N-Acetyl-L-histidine, N-acetyl-L-alanyl-L-histidine and N-acetyl-D-alanyl-L-histidine were weak Ca-sensitisers. N-Acetylglycyl-L-histidine, N-acetyl-L-carnosine and N-acetyl-L-homocarnosine produced more positive action on the Ca-sensitising apparatus of the heart muscle. (B). 1-Methyl-L-histidine. 3-Methyl-L-histidine and Dipeptides Containing L-Histidine Methylated on the Imidazole Ring Because the imidazole function of L-histidine has two possible sites for N-alkylation to take place, routes were developed to obtain selectively the desired N-methylated histidine derivatives as pure isomers. A synthesis of 1-methyl-L-histidine, reported in the literature, was attempted. Problems were encountered in introducing the protecting group onto the 3-position of the imidazole ring. This could not be achieved in the manner described in the literature, thus an alternative route was studied. N(a),3-bis(t-Butoxycarbonyl)-L-histidine methyl ester was alkylated using methyl iodide. The residue obtained from the reaction was found to be a mixture of the desired 1-methyl compound and the 1,3-dimethyl compound. This mixture was successfully separated. The final stage was to remove the protecting groups. A number of different methods were used. Each procedure removed the protecting groups without any difficulties but each attempt yielded 1-methylhistidine which was not optically active. The synthesis of 3-methyl-L-histidine, reported in the literature, was attempted. The synthetic sequence was successful until the final deprotection stage which yielded 3-methylhistidine in chemically pure form, but contrary to the data published, the product was not optically active. An alternative route was investigated. N(a)-t-Butoxy carbonyl-1-benzoxy methyl-3-methyl- L-histidinium methyl ester iodide was synthesised. 3-Methyl-L-histidine should then be obtained upon removal of the protecting groups. The removal of the methyl ester resulted in a racemic product. Attempts to remove the benzoxymethyl group were consistently unsuccessful. 3-Methylhistidine could not be obtained in chemically or optically pure form from this route. A route to dipeptides containing 1-methylhistidine was established. 1-Methylglycylhistidine, 1-methylcarnosine and 1-methylhomocarnosine were synthesised in chemically pure form. The intermediates in this route all possessed some degree of optical purity but the hydrolysis of the methyl esters at the end of the route resulted in racemic products. The route established for the synthesis of dipeptides containing 3-methylglycylhistidine and 3-methylcarnosine produced these compounds as pure isomers. Problems in removing the methyl esters in the final stage resulted in the products being racemic

Relationship Between Balance and Cognitive Performance in Older People

We investigated the relationship between balance and cognitive level in a group of 70 women with no definite Alzheimer’s disease or mild cognitive impairment diagnosis and no impairment of daily activity. Static stabilometry and the Montreal Cognitive Assessment (MoCA) test were performed. The antero-posterior sway component was demonstrated to be the best predictor of the MoCA overall score. As visual and proprioceptive components of balance could safely be excluded in our assessments, the vestibular system is to be considered as a putative link between balance and cognitive impairment

Getting podiatry research off the ground

Few studies have investigated the outcomes of chiropody treatment, especially in a large community sample. There is an increasing need for research in this field. Podiatrists and other professionals allied to medicine need the evidence from research to back up their opinions within health care. Collaboration between clinicians and higher education is critical for success

Anticholinergic Exposure During Rehabilitation: Cognitive and Physical Function Outcomes in Patients with Delirium Superimposed on Dementia

OBJECTIVES: We examined the association between anticholinergic medication exposure and subsequent cognitive and physical function in patients with delirium superimposed on dementia during rehabilitation. We also examined length of stay and discharge disposition by anticholinergic medication exposure. DESIGN: In this secondary analysis we used control group data from an ongoing randomized clinical trial. SETTING/PARTICIPANTS: Participants with delirium and dementia were enrolled at admission to post-acute care. These 99 participants had a mean age of 86.11 (±6.83) years; 67.6% were women; 98% were Caucasian; and 33% were positive for at least one APOE e4 allele. MEASURES: We obtained daily measures of cognitive and physical function using: Digit Span; memory, orientation and attention items from the Montreal Cognitive Assessment; CLOX; the Confusion Assessment Method; and the Barthel Index. Anticholinergic medication exposure was measured weekly using the Anticholinergic Cognitive Burden Scale. RESULTS: Using multilevel models for time we found that greater use of clinically relevant anticholinergic medications in the previous week reduced cognitive and physical function, as measured by Digit Span Backwards and the Barthel index, in the current week. There was no effect of anticholinergic medication use on delirium severity, and APOE status did not moderate any outcomes. Greater use of clinically relevant anticholinergic medications was related to longer length of stay but not discharge disposition. CONCLUSIONS: For vulnerable older adults, anticholinergic exposure represents a potentially modifiable risk factor for poor attention, working memory, physical function, and greater length of stay during rehabilitation

Genetic association study of QT interval highlights role for calcium signaling pathways in myocardial repolarization.

The QT interval, an electrocardiographic measure reflecting myocardial repolarization, is a heritable trait. QT prolongation is a risk factor for ventricular arrhythmias and sudden cardiac death (SCD) and could indicate the presence of the potentially lethal mendelian long-QT syndrome (LQTS). Using a genome-wide association and replication study in up to 100,000 individuals, we identified 35 common variant loci associated with QT interval that collectively explain ∼8-10% of QT-interval variation and highlight the importance of calcium regulation in myocardial repolarization. Rare variant analysis of 6 new QT interval-associated loci in 298 unrelated probands with LQTS identified coding variants not found in controls but of uncertain causality and therefore requiring validation. Several newly identified loci encode proteins that physically interact with other recognized repolarization proteins. Our integration of common variant association, expression and orthogonal protein-protein interaction screens provides new insights into cardiac electrophysiology and identifies new candidate genes for ventricular arrhythmias, LQTS and SCD

Effects of antiplatelet therapy on stroke risk by brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases: subgroup analyses of the RESTART randomised, open-label trial

Background Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy

BHPR research: qualitative1. Complex reasoning determines patients' perception of outcome following foot surgery in rheumatoid arhtritis

Background: Foot surgery is common in patients with RA but research into surgical outcomes is limited and conceptually flawed as current outcome measures lack face validity: to date no one has asked patients what is important to them. This study aimed to determine which factors are important to patients when evaluating the success of foot surgery in RA Methods: Semi structured interviews of RA patients who had undergone foot surgery were conducted and transcribed verbatim. Thematic analysis of interviews was conducted to explore issues that were important to patients. Results: 11 RA patients (9 ♂, mean age 59, dis dur = 22yrs, mean of 3 yrs post op) with mixed experiences of foot surgery were interviewed. Patients interpreted outcome in respect to a multitude of factors, frequently positive change in one aspect contrasted with negative opinions about another. Overall, four major themes emerged. Function: Functional ability & participation in valued activities were very important to patients. Walking ability was a key concern but patients interpreted levels of activity in light of other aspects of their disease, reflecting on change in functional ability more than overall level. Positive feelings of improved mobility were often moderated by negative self perception ("I mean, I still walk like a waddling duck”). Appearance: Appearance was important to almost all patients but perhaps the most complex theme of all. Physical appearance, foot shape, and footwear were closely interlinked, yet patients saw these as distinct separate concepts. Patients need to legitimize these feelings was clear and they frequently entered into a defensive repertoire ("it's not cosmetic surgery; it's something that's more important than that, you know?”). Clinician opinion: Surgeons' post operative evaluation of the procedure was very influential. The impact of this appraisal continued to affect patients' lasting impression irrespective of how the outcome compared to their initial goals ("when he'd done it ... he said that hasn't worked as good as he'd wanted to ... but the pain has gone”). Pain: Whilst pain was important to almost all patients, it appeared to be less important than the other themes. Pain was predominately raised when it influenced other themes, such as function; many still felt the need to legitimize their foot pain in order for health professionals to take it seriously ("in the end I went to my GP because it had happened a few times and I went to an orthopaedic surgeon who was quite dismissive of it, it was like what are you complaining about”). Conclusions: Patients interpret the outcome of foot surgery using a multitude of interrelated factors, particularly functional ability, appearance and surgeons' appraisal of the procedure. While pain was often noted, this appeared less important than other factors in the overall outcome of the surgery. Future research into foot surgery should incorporate the complexity of how patients determine their outcome Disclosure statement: All authors have declared no conflicts of interes

Shared heritability and functional enrichment across six solid cancers

Correction: Nature Communications 10 (2019): art. 4386 DOI: 10.1038/s41467-019-12095-8Quantifying the genetic correlation between cancers can provide important insights into the mechanisms driving cancer etiology. Using genome-wide association study summary statistics across six cancer types based on a total of 296,215 cases and 301,319 controls of European ancestry, here we estimate the pair-wise genetic correlations between breast, colorectal, head/neck, lung, ovary and prostate cancer, and between cancers and 38 other diseases. We observed statistically significant genetic correlations between lung and head/neck cancer (r(g) = 0.57, p = 4.6 x 10(-8)), breast and ovarian cancer (r(g) = 0.24, p = 7 x 10(-5)), breast and lung cancer (r(g) = 0.18, p = 1.5 x 10(-6)) and breast and colorectal cancer (r(g) = 0.15, p = 1.1 x 10(-4)). We also found that multiple cancers are genetically correlated with non-cancer traits including smoking, psychiatric diseases and metabolic characteristics. Functional enrichment analysis revealed a significant excess contribution of conserved and regulatory regions to cancer heritability. Our comprehensive analysis of cross-cancer heritability suggests that solid tumors arising across tissues share in part a common germline genetic basis.Peer reviewe