Publications by authors named "John Lindsay"

74 Publications

Corticotroph aggressive pituitary tumours and carcinomas frequently harbour ATRX mutations.

J Clin Endocrinol Metab 2020 Oct 26. Epub 2020 Oct 26.

Department of Endocrinology, Skåne University Hospital, Malmö, Lund University, Sweden.

Context: Aggressive pituitary tumours (APTs) are characterised by unusually rapid growth and lack of response to standard treatment. About 1-2% develop metastases being classified as pituitary carcinomas (PCs). For unknown reasons, the corticotroph tumours are overrepresented amongst APTs and PCs. Mutations in the ATRX gene, regulating chromatin remodelling and telomere maintenance, have been implicated in the development of several cancer types, including neuroendocrine tumours.

Objective: To study ATRX protein expression and mutational status of the ATRX gene in APTs and PCs.

Design: We investigated ATRX protein expression by using immunohistochemistry in 30 APTs and 18 PCs, mostly of Pit-1 and T-Pit cell lineage. In tumours lacking ATRX immunolabeling, mutational status of the ATRX gene was explored.

Results: Nine of the 48 tumours (19%) demonstrated lack of ATRX immunolabelling with a higher proportion in patients with PCs (5/18 - 28%) than in those with APTs (4/30 - 13%). Lack of ATRX was most common in the corticotroph tumours, 7/22 (32%), vs 2/24 (8%) in the tumours of the Pit-1 lineage. Loss-of-function ATRX mutations were found in all the nine ATRX immuno-negative cases: nonsense mutations (n=4), frameshift deletions (n=4) and large deletions affecting 22-28 of the 36 exons (n=3). More than one ATRX gene defect was identified in two PCs.

Conclusion: ATRX mutations occur in a subset of aggressive pituitary tumours and are more common in corticotroph tumours. The findings provide a rationale for performing ATRX immunohistochemistry to identify patients at risk of developing aggressive and potentially metastatic pituitary tumours.
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http://dx.doi.org/10.1210/clinem/dgaa749DOI Listing
October 2020

Detection of vertebral fracture in an acute hospital setting: an intervention to reduce future fracture risk through fracture liaison service intervention?

Arch Osteoporos 2020 10 10;15(1):160. Epub 2020 Oct 10.

Mater Infirmorum Hospital, Belfast Health & Social Care Trust, Belfast, Northern Ireland.

We introduced a standardised reporting system in the radiology department to highlight vertebral fractures and to signpost fracture prevention services. Our quality improvement project achieved improved fracture reporting, access to the FLS service, bone density assessment and anti-fracture treatment.

Purpose: Identification of vertebral fragility fractures (VF) provides an opportunity to identify individuals at high risk who might benefit from secondary fracture prevention. We sought to standardise VF reporting and to signpost fracture prevention services. Our aim was to improve rates of VF detection and access to our fracture liaison service (FLS).

Methods: We introduced a standardised reporting tool within the radiology department to flag VFs with signposting for referral for bone densitometry (DXA) and osteoporosis assessment in line with Royal Osteoporosis Society guidelines. We monitored uptake of VF reporting during a quality improvement phase and case identification within the FLS service.

Results: Recruitment of individuals with VF to the FLS service increased from a baseline of 63 cases in 2017 (6%) to 95 (8%) in 2018 and 157 (8%) in 2019 and to 102 (12%) in the first 6 months of 2020 (p = 0.001). One hundred fifty-three patients with VFs were identified during the QI period (56 males; 97 females). Use of the terminology 'fracture' increased to 100% (mean age 70 years; SD 13) in computed tomography (n = 110), plain X-ray (n = 37) or magnetic resonance imaging (n = 6) reports within the cohort. Signposting to DXA and osteoporosis assessment was included in all reports (100%). DXA was arranged for 103/153; 12 failed to attend. Diagnostic categories were osteoporosis (31%), osteopenia (36%) or normal bone density (33%). A new prescription for bone protection therapy was issued in 63/153. Twelve of the series died during follow-up.

Conclusions: Standardisation of radiology reporting systems facilitates reporting of prevalent vertebral fractures and supports secondary fracture prevention strategies.
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http://dx.doi.org/10.1007/s11657-020-00832-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7547950PMC
October 2020

Management of pneumothorax in mechanically ventilated COVID-19 patients: early experience.

Interact Cardiovasc Thorac Surg 2020 10;31(4):540-543

Department of Cardiothoracic Surgery, King's College Hospital, London, UK.

A significant proportion of patients infected with the novel coronavirus, now termed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), require intensive care admission and subsequent mechanical ventilation. Pneumothorax, a potential fatal complication of mechanical ventilation, can further complicate the management of COVID-19 patients, whilst chest drain insertion may increase the risk of transmission of attending staff. We present a case series and a suggested best-practice protocol for how to manage and treat pneumothoraces in COVID-19 patients in an intensive care unit setting.
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http://dx.doi.org/10.1093/icvts/ivaa129DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7499637PMC
October 2020

A service evaluation of e-triage in the osteoporosis outpatient clinic-an effective tool to improve patient access?

Arch Osteoporos 2020 03 21;15(1):53. Epub 2020 Mar 21.

Osteoporosis Service, Musgrave Park Hospital, Belfast Health & Social Care Trust, Stockmans Lane, Belfast, BT9 7JB, UK.

We introduced an electronic triage system into our osteoporosis service to actively manage referral demand in a busy outpatient service. Our study demonstrated the effectiveness of e-triage in supporting alternative management pathways, through use of virtual advice and direct to investigation services, to improve patient access.

Purpose: Osteoporosis referrals are increasing with awareness of the potential for prevention of fragility fracture and with complex decision making around management with long-term bisphosphonate therapy. We examined whether active triage of referrals might improve referral management processes and patient access to osteoporosis services.

Methods: We implemented electronic triage (e-triage) of referrals to our osteoporosis service using the Northern Ireland electronic health care record. This included the option of 'advice only', direct to investigation with DXA or face-to-face appointments at the consultant-led complex osteoporosis service. We anticipated that there was scope to manage patient flow direct to investigation, or to provide referring clinicians with clinical advice without the need for a face-to-face assessment, at the consultant-led specialist service.

Results: We reviewed e-triage outcomes of 809 referrals (692 F; 117 M) to osteoporosis specialist services (mean age 65 ± 16.5 years) over a 12-month period. There was a high degree of agreement for the triage category between the referring clinician and specialist services (741/809). 73.3% attended a face-to-face appointment at the consultant-led clinic, while active triage enabled direct to investigation (18.4%) or discharge (8.3%) in the remainder. The mean time between receipt of an electronic referral and e-triage was 3 days over the 12-month period as compared with 2.1 days (median 1.1 days) when annual leave periods were excluded.

Conclusion: E-triage supports effective referral management in a busy osteoporosis service. Efficiency is limited by reliance on a sole clinician and 5 day working at present. There is scope to further improve systems access through multidisciplinary team working, virtual clinics and future information technology developments.
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http://dx.doi.org/10.1007/s11657-020-0703-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7083822PMC
March 2020

Systemic Lupus Erythematosus Presenting with Ischemic Proctitis and Abdominal Compartment Syndrome.

Case Rep Gastrointest Med 2020 13;2020:5723403. Epub 2020 Feb 13.

Department of Medicine, Section of Pulmonary and Critical Care Medicine, West Virginia University, Morgantown, WV, USA.

Ischemic colitis and proctitis is a rare manifestation of systemic lupus erythematosus (SLE) and results from mesenteric vasculitis. Owing to diverse blood supply and presence of multiple collaterals, rectum is the least effected site in SLE enteritis. Ischemic proctocolitis as the presenting feature of SLE is exceedingly rare, with only three cases reported in the published scientific literature. We present the first case of SLE presenting as ischemic proctitis, leading to intraperitoneal hemorrhage and abdominal compartment syndrome. A young lady presented with ischemic proctitis and a hematoma masquerading as a pelvic mass, with subsequent development of massive intraperitoneal hemorrhage, shock, and rectal perforation. The patient required urgent surgery and was initiated on high-dose steroids.
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http://dx.doi.org/10.1155/2020/5723403DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7040385PMC
February 2020

Using a Reconciliation Module Leads to Large Gains in Evolution Acceptance.

CBE Life Sci Educ 2019 12;18(4):ar58

Department of Biology, Monte L. Bean Museum.

Too many students reject the theory of evolution because they view it as incompatible with their religious beliefs. Some have argued that abandoning religious belief is the only way to help religious individuals accept evolution. Conversely, our data support that highlighting faith/evolution compatibility is an effective means to increase student acceptance. We surveyed students enrolled in entry-level biology courses at four religiously affiliated institutions. At each university, teachers gave students a presentation that demonstrated potential compatibility between evolution and faith within the teachings of each university's respective religious affiliation. Students were asked to evaluate their own beliefs about evolution both before and after this instruction. After instruction at each university, students showed significant gains in evolution acceptance without abandoning their religious beliefs. These results demonstrate that giving religious students the opportunity to reconcile their religious beliefs with the theory of evolution under the influence of intentional instruction on the compatibility of belief and evolution can lead to increased evolution acceptance among religious students.
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http://dx.doi.org/10.1187/cbe.19-04-0080DOI Listing
December 2019

GCC Consolidated Feedback to ICH on the 2019 ICH M10 Bioanalytical Method Validation Draft Guideline.

Bioanalysis 2019 Sep 30;11(18s):1-228. Epub 2019 Sep 30.

WuXi Apptec, Shanghai, China.

The 13 GCC Closed Forum for Bioanalysis was held in New Orleans, Louisiana, USA on April 5, 2019. This GCC meeting was organized to discuss the contents of the 2019 ICH M10 Bioanalytical Method Validation Draft Guideline published in February 2019 and consolidate the feedback of the GCC members. In attendance were 63 senior-level participants from eight countries representing 44 bioanalytical CRO companies/sites. This event represented a unique opportunity for CRO bioanalytical experts to share their opinions and concerns regarding the ICH M10 Bioanalytical Method Validation Draft Guideline and to build unified comments to be provided to the ICH.
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http://dx.doi.org/10.4155/bio-2019-0207DOI Listing
September 2019

12th GCC Closed Forum: critical reagents; oligonucleotides; CoA; method transfer; HRMS; flow cytometry; regulatory findings; stability and immunogenicity.

Bioanalysis 2019 Jun 19;11(12):1129-1138. Epub 2019 Jul 19.

WuXi Apptec, Plainsboro, NJ 08536, USA.

The 12th GCC Closed Forum was held in Philadelphia, PA, USA, on 9 April 2018. Representatives from international bioanalytical Contract Research Organizations were in attendance in order to discuss scientific and regulatory issues specific to bioanalysis. The issues discussed at the meeting included: critical reagents; oligonucleotides; certificates of analysis; method transfer; high resolution mass spectrometry; flow cytometry; recent regulatory findings and case studies involving stability and nonclinical immunogenicity. Conclusions and consensus from discussions of these topics are included in this article.
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http://dx.doi.org/10.4155/bio-2019-0131DOI Listing
June 2019

Recommendations for classification of commercial LBA kits for biomarkers in drug development from the GCC for bioanalysis.

Bioanalysis 2019 Apr 17;11(7):645-653. Epub 2019 Apr 17.

WuXi Apptec, Plainsboro, NJ, USA.

Over the last decade, the use of biomarker data has become integral to drug development. Biomarkers are not only utilized for internal decision-making by sponsors; they are increasingly utilized to make critical decisions for drug safety and efficacy. As the regulatory agencies are routinely making decisions based on biomarker data, there has been significant scrutiny on the validation of biomarker methods. Contract research organizations regularly use commercially available immunoassay kits to validate biomarker methods. However, adaptation of such kits in a regulated environment presents significant challenges and was one of the key topics discussed during the 12th Global Contract Research Organization Council for Bioanalysis (GCC) meeting. This White Paper reports the GCC members' opinion on the challenges facing the industry and the GCC recommendations on the classification of commercial kits that can be a win-win for commercial kit vendors and end users.
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http://dx.doi.org/10.4155/bio-2019-0072DOI Listing
April 2019

Remotely Monitored Therapy and Nitric Oxide Suppression Identifies Nonadherence in Severe Asthma.

Am J Respir Crit Care Med 2019 02;199(4):454-464

8 Royal College of Surgeons in Ireland, Dublin, Ireland.

Rationale: Poor adherence is common in difficult-to-control asthma. Distinguishing patients with difficult-to-control asthma who respond to inhaled corticosteroids (ICS) from refractory asthma is an important clinical challenge.

Objectives: Suppression of fractional exhaled nitric oxide (Fe) with directly observed ICS therapy over 7 days can identify nonadherence to ICS treatment in difficult-to-control asthma. We examined the feasibility and utility of Fe suppression testing in routine clinical care within UK severe asthma centers using remote monitoring technologies.

Methods: A web-based interface with integrated remote monitoring technology was developed to deliver Fe suppression testing. We examined the utility of Fe suppression testing to demonstrate ICS responsiveness and clinical benefit on electronically monitored treatment with standard high-dose ICS and long-acting β-agonist treatment.

Measurements And Main Results: Clinical response was assessed using the Asthma Control Questionnaire-5, spirometry, and biomarker measurements (Fe and peripheral blood eosinophil count). Of 250 subjects, 201 completed the test with 130 positive suppression tests. Compared with a negative suppression test, a positive test identified a Fe-low population when adherent with ICS/long-acting β-agonist (median, 26 ppb [interquartile range, 16-36 ppb] vs. 43 ppb [interquartile range, 38-73 ppb]) with significantly greater FEV% (mean, 88.2 ± 16.4 vs. 74.1 ± 20.9; P < 0.01). Asthma Control Questionnaire-5 improved significantly in both groups (positive test: mean difference, -1.2; 95% confidence interval, -0.9 to -1.5; negative test: mean difference, -0.9; 95% confidence interval, -0.4 to -1.3).

Conclusions: Remote Fe suppression testing is an effective means of identifying nonadherence to ICS in subjects with difficult-to-control asthma and the substantial population of subjects who derive important clinical benefits from optimized ICS/long-acting β-agonist treatment.
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http://dx.doi.org/10.1164/rccm.201806-1182OCDOI Listing
February 2019

11th GCC Closed Forum: cumulative stability; matrix stability; immunogenicity assays; laboratory manuals; biosimilars; chiral methods; hybrid LBA/LCMS assays; fit-for-purpose validation; China Food and Drug Administration bioanalytical method validation.

Bioanalysis 2018 Apr 27;10(7):433-444. Epub 2018 Apr 27.

Worldwide Clinical Trials, Austin, TX, USA.

The 11th Global CRO Council Closed Forum was held in Universal City, CA, USA on 3 April 2017. Representatives from international CRO members offering bioanalytical services were in attendance in order to discuss scientific and regulatory issues specific to bioanalysis. The second CRO-Pharma Scientific Interchange Meeting was held on 7 April 2017, which included Pharma representatives' sharing perspectives on the topics discussed earlier in the week with the CRO members. The issues discussed at the meetings included cumulative stability evaluations, matrix stability evaluations, the 2016 US FDA Immunogenicity Guidance and recent and unexpected FDA Form 483s on immunogenicity assays, the bioanalytical laboratory's role in writing PK sample collection instructions, biosimilars, CRO perspectives on the use of chiral versus achiral methods, hybrid LBA/LCMS assays, applications of fit-for-purpose validation and, at the Global CRO Council Closed Forum only, the status and trend of current regulated bioanalytical practice in China under CFDA's new BMV policy. Conclusions from discussions of these topics at both meetings are included in this report.
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http://dx.doi.org/10.4155/bio-2018-0014DOI Listing
April 2018

Diabetes distress, illness perceptions and glycaemic control in adults with type 2 diabetes.

Psychol Health Med 2018 Feb 14;23(2):171-177. Epub 2017 Jun 14.

a School of Psychology , Queen's University Belfast , Belfast , Northern Ireland.

The emotional distress associated with adjusting to and living with diabetes has been termed diabetes distress. Diabetes distress is associated with glycaemic control but interventions to reduce diabetes distress have failed to consistently improve diabetes control. Various illness perceptions have previously been linked with both diabetes distress and glycaemic control but interrelationships between these features have not been previously investigated. We hypothesised that illness perceptions mediate the relationship between diabetes distress and glycaemia. Participants with type 2 diabetes attending diabetes outpatient clinics (n = 84) provided demographic and clinical information and completed the Diabetes Distress Scale-17 and the Brief Illness Perceptions Questionnaire. Using regression analysis we demonstrated that the illness perceptions of personal control, regimen-related distress, socioeconomic status and insulin use were significant contributors in the final model predicting HbA. Higher levels of personal control were associated with better glycaemic control. Conversely, regimen-related distress was associated with hyperglycaemia. Mediation analyses showed that the relationship between regimen-related distress and HbA was mediated by personal control. Our work suggests that psychological interventions designed to reduce diabetes distress may be more efficacious in improving glycaemic control if they address an individual's perception of personal control.
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http://dx.doi.org/10.1080/13548506.2017.1339892DOI Listing
February 2018

Look but don't touch! An alternative to the gold standard?

J Thorac Cardiovasc Surg 2017 08 12;154(2):467-468. Epub 2017 Apr 12.

Cardiac Surgery Department, Kings College Hospital, London, United Kingdom.

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http://dx.doi.org/10.1016/j.jtcvs.2017.04.007DOI Listing
August 2017

The Pyruvate Dehydrogenase Complex and Related Assemblies in Health and Disease.

Subcell Biochem 2017;83:523-550

Institute of Molecular, Cell and Systems Biology, Davidson Building, College of Medicine, Veterinary and Life Sciences, University of Glasgow, Glasgow, G12 8QQ, UK.

The family of 2-oxoacid dehydrogenase complexes (2-OADC), typified by the pyruvate dehydrogenase multi-enzyme complex (PDC) as its most prominent member, are massive molecular machines (M, 4-10 million) controlling key steps in glucose homeostasis (PDC), citric acid cycle flux (OGDC, 2-oxoglutarate dehydrogenase) and the metabolism of the branched-chain amino acids, leucine, isoleucine and valine (BCOADC, branched-chain 2-OADC). These highly organised mitochondrial arrays, composed of multiple copies of three separate enzymes, have been widely studied as paradigms for the analysis of enzyme cooperativity, substrate channelling, protein-protein interactions and the regulation of activity by phosphorylation . This chapter will highlight recent advances in our understanding of the structure-function relationships, the overall organisation and the transport and assembly of PDC in particular, focussing on both native and recombinant forms of the complex and their individual components or constituent domains. Biophysical approaches, including X-ray crystallography (MX), nuclear magnetic resonance spectroscopy (NMR), cryo-EM imaging, analytical ultracentrifugation (AUC) and small angle X-ray and neutron scattering (SAXS and SANS), have all contributed significant new information on PDC subunit organisation, stoichiometry, regulatory mechanisms and mode of assembly. Moreover, the recognition of specific genetic defects linked to PDC deficiency, in combination with the ability to analyse recombinant PDCs housing both novel naturally-occurring and engineered mutations, have all stimulated renewed interest in these classical metabolic assemblies. In addition, the role played by PDC, and its constituent proteins, in certain disease states will be briefly reviewed, focussing on the development of new and exciting areas of medical and immunological research.
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http://dx.doi.org/10.1007/978-3-319-46503-6_19DOI Listing
June 2019

The Peroxiredoxin Family: An Unfolding Story.

Subcell Biochem 2017;83:127-147

Institute of Molecular, Cell and Systems Biology, Davidson Building, College of Medicine, Veterinary and Life Sciences, University of Glasgow, Glasgow, G12 8QQ, UK.

Peroxiredoxins (Prxs) are a large and conserved family of peroxidases that are considered to be the primary cellular guardians against oxidative stress in all living organisms. Prxs share a thioredoxin fold and contain a highly-reactive peroxidatic cysteine in a specialised active-site environment that is able to reduce their peroxide substrates. The minimal functional unit for Prxs are either monomers or dimers, but many dimers assemble into decameric rings. Ring structures can further form a variety of high molecular weight complexes. Many eukaryotic Prxs contain a conserved GGLG and C-terminal YF motif that confer sensitivity to elevated levels of peroxide, leading to hyperoxidation and inactivation. Inactive forms of Prxs can be re-reduced by the enzyme sulfiredoxin, in an ATP-dependent reaction. Cycles of hyperoxidation and reactivation are considered to play an integral role in a variety of HO-mediated cell signalling pathways in both stress and non-stress conditions. Prxs are also considered to exhibit chaperone-like properties when cells are under oxidative or thermal stress. The roles of various types of covalent modifications, e.g. acetylation and phosphorylation are also discussed. The ability of Prxs to assemble into ordered arrays such as nanotubes is currently being exploited in nanotechnology.
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http://dx.doi.org/10.1007/978-3-319-46503-6_5DOI Listing
June 2019

Diabetes distress: understanding the hidden struggles of living with diabetes and exploring intervention strategies.

Postgrad Med J 2015 May 31;91(1075):278-83. Epub 2015 Mar 31.

School of Psychology, Queen's University Belfast, Belfast, UK.

Diabetes distress is a rational emotional response to the threat of a life-changing illness. Distinct from depression, it is conceptually rooted in the demands of diabetes management and is a product of emotional adjustment. Diabetes distress has been found to be significantly associated with glycated haemoglobin (HbA1c) level and the likelihood of an individual adopting self-care behaviours. The lack of perceived support from family, friends and healthcare professionals significantly contributes to elevated diabetes distress, and this issue tends to be overlooked when designing interventions. Pioneering large-scale research, DAWN2, gives voices to the families of those with diabetes and reaffirms the need to consider psychosocial factors in routine diabetes care. Structured diabetes education programmes are the most widely used in helping individuals cope with diabetes, but they tend not to include the psychological or interpersonal aspects of diabetes management in their curricula. The need for health practitioners, irrespective of background, to demonstrate an understanding of diabetes distress and to actively engage in discussion with individuals struggling to cope with diabetes is emphasised.
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http://dx.doi.org/10.1136/postgradmedj-2014-133017DOI Listing
May 2015

Glucocorticoids and mepolizumab in eosinophilic asthma.

N Engl J Med 2014 12;371(25):2433

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http://dx.doi.org/10.1056/NEJMc1412892DOI Listing
December 2014

An unusual headache.

BMJ 2014 Sep 16;349:g5602. Epub 2014 Sep 16.

Department of Diabetes and Endocrinology, Mater Hospital, Belfast BT14 6AB, UK.

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http://dx.doi.org/10.1136/bmj.g5602DOI Listing
September 2014

Non-adherence in difficult asthma and advances in detection.

Expert Rev Respir Med 2013 Dec 29;7(6):607-14. Epub 2013 Oct 29.

Centre for Infection and Immunity, Health Sciences Building, Queens University Belfast, Lisburn Road, Belfast, UK.

Non-adherence to anti-inflammatory therapies is common in patients referred for specialist assessment at difficult-to-treat asthma services. In the difficult asthma setting, non-adherence to treatment is associated with poor baseline asthma control, increased frequency of exacerbations and asthma-related hospitalizations, as well as increased risk of death. Here, we present a review of the current literature surrounding the prevalence and risks of non-adherence in difficult asthma and we report on current methods of measuring treatment adherence and advances in the detection of non-adherence. We will also explore methods by which non-adherence in difficult asthma can be addressed.
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http://dx.doi.org/10.1586/17476348.2013.842129DOI Listing
December 2013

High-throughput bioanalysis of bile acids and their conjugates using UHPLC coupled to HRMS.

Bioanalysis 2013 Oct;5(20):2481-94

Covance Laboratories Inc., 3301 Kinsman Blvd, Madison, WI 53704, USA.

Background: Quantitative assessment of bile acids in biological matrixes is of growing interest, primarily due to hepatic toxicity resulting from drug interactions with the bile salt export pump. Nevertheless, many bile acids demonstrate poor fragmentation in MS, making conventional MS/MS not a good match for their selective quantitation in biological matrices.

Results: The current study was designed to evaluate the feasibility of simultaneous quantitation of 19 bile acids using HRMS coupled to UHPLC separation with minimal instrument optimization. An effective chromatography was developed using an Agilent Zorbax(®) Eclipse XDB-C18 column (1.8 µm, 50 x 2.1 mm internal diameter), achieving separation of 19 compounds in 10 min. Excellent assay reproducibility was demonstrated, with two sets of standard curves, run 42 days apart.

Conclusions: The results show that LC-HRMS is a viable platform for high throughput bioanalysis of bile acids especially in a drug-discovery setting.
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http://dx.doi.org/10.4155/bio.13.215DOI Listing
October 2013

Hypopituitarism as the presenting feature of bronchogenic carcinoma with metastases to the pituitary gland.

Indian J Endocrinol Metab 2013 Jan;17(1):167-9

Department of Endocrinology and Diabetes, Altnagelvin Area Hospital, Londonderry Belfast, United Kingdom.

Tumours metastasizing to the pituitary gland are uncommon. Symptomatic patients with pituitary metastases can present with diabetes insipidus, headache, visual field defects and/or anterior pituitary hormonal dysfunction. Treatment options for pituitary metastases include, surgical resection, cranial or parasellar irradiation and/or chemotherapy, and hormonal replacement if indicated. The overall prognosis of pituitary metastases is poor. We present a case of hypopituitarism as the presenting feature of bronchogenic carcinoma with metastases to the pituitary gland.
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http://dx.doi.org/10.4103/2230-8210.107876DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3659889PMC
January 2013

Nonadherence in difficult asthma - facts, myths, and a time to act.

Patient Prefer Adherence 2013 19;7:329-36. Epub 2013 Apr 19.

Centre for Infection and Immunity, Queens University Belfast, Belfast, UK.

Nonadherence to prescribed treatment is an important cause of difficult asthma. Rates of nonadherence amongst asthmatic patients have been shown to range between 30% and 70%. This is associated with poor health care outcomes and increased health care costs. There is no such thing as a "typical" nonadherent patient. The reasons driving nonadherence are multifactorial. Furthermore, adherence is a variable behavior and not a trait characteristic. Adherence rates can vary between the same individual across treatments for different conditions. There is no consistent link between socioeconomic status and nonadherence, and although some studies have shown that nonadherence is more common amongst females, this is not a universal finding. The commonly held perception that better adherence is driven by greater disease severity has been demonstrated to not be the case, in both pediatric and adult patients. Identification of nonadherence is the first step. If adherence is not checked, it is likely that poor adherence will be labeled as refractory disease. Failure to identify poor adherence may lead to inappropriate escalation of therapy, including the potential introduction of complex biological therapies. Surrogate measures, such as prescription counting, are not infallible. Nonadherence can be difficult to identify in clinical practice, and a systematic approach using a variety of tools is required. Nonadherence can be successfully addressed. Therefore, assessment of adherence is of paramount importance in difficult asthma management, in order to reduce exacerbations and steroid-related side effects as well as hospital and intensive care admissions, health care cost, and inappropriate treatment escalation. In this paper, we present an overview of the literature surrounding nonadherence in difficult asthma. We explore the facts and myths surrounding the factors driving nonadherence as well as how it can be identified and addressed.
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http://dx.doi.org/10.2147/PPA.S38208DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3666590PMC
June 2013

An unusual cause of reversible cardiomyopathy.

Ulster Med J 2012 Sep;81(3):134-5

Department of Endocrinology and Diabetes, Belfast, UK.

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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3632823PMC
September 2012

Extrapleural harvesting of the mammary artery in the costodiaphragmatic sulcus.

Authors:
Lindsay C H John

Heart Lung Circ 2013 Feb 7;22(2):156-7. Epub 2012 Sep 7.

Department of Cardiothoracic Surgery, Kings College Hospital, Denmark Hill, London SE5 9RS, United Kingdom. Electronic address:

In coronary artery bypass surgery the most commonly used conduit for grafting the left anterior descending artery is the left internal mammary artery. In harvesting the internal mammary artery the parietal pleura is frequently breached. This is associated with increased post operative complications. The diaphragm is not in contact with the parietal pleura anteriorly. The risk of opening the pleura is considerably reduced if the costodiaphragmatic sulcus is developed first. If more cardiac surgeons were aware of the potential of the costodiaphragmatic sulcus then some of the complications associated with coronary artery surgery could be reduced.
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http://dx.doi.org/10.1016/j.hlc.2012.08.002DOI Listing
February 2013

Apollo, sudden death, and Homer's "Odyssey": a warning from the past that we may be unable to eradicate coronary artery disease.

Authors:
Lindsay C H John

Perspect Biol Med 2012 ;55(2):230-5

Department of Cardiothoracic Surgery, Kings College Hospital, Denmark Hill, London, SE5 3RS, United Kingdom.

Over recent years there has been a gratifying decrease in the incidence of recorded deaths from coronary artery disease in the Western world. The common view is that coronary artery disease is a recent phenomenon, that we have been subject to an epidemic in the mid-20th century that is now tailing off, and that with appropriate risk modification we may eradicate this disease or make it very rare. However, this article examines the cases of sudden, nontraumatic death described in Homer's Odyssey, which dates from c. 800 BCE. The results suggest that a high incidence of death from coronary artery disease may not be a recent phenomenon. Together with other described evidence, this study casts doubt on the view that coronary artery disease is a modern epidemic that can be eradicated.
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http://dx.doi.org/10.1353/pbm.2012.0015DOI Listing
September 2012

Remote intermittent ischemia before coronary artery bypass graft surgery: a strategy to reduce injury and inflammation?

Basic Res Cardiol 2011 Jun 5;106(4):511-9. Epub 2011 May 5.

Department of Anaesthetics, Intensive Care Medicine and Pain Therapy, King's College Hospital NHS Foundation Trust, Denmark Hill, London, United Kingdom.

Perioperative myocardial ischemia contributes to postoperative morbidity and mortality. Remote intermittent ischemia (RI) has been shown to benefit patients undergoing coronary artery bypass graft (CABG) surgery by decreasing postoperative cardiac troponin levels. In addition, there is evidence that volatile anesthetics may provide myocardial protection. In this prospective randomized controlled trial we tested the hypothesis that RI is cardioprotective under a strict anesthetic regime with volatile anesthesia until cardiopulmonary bypass (CPB). We also assessed whether RI modulates postoperative cytokine and growth factor concentrations. Fifty-four patients referred for elective CABG surgery without concomitant valve or aortic surgery were randomized to three 5-min cycles of left upper limb ischemia by cuff inflation (RI) or placebo without cuff inflation (Plac). All patients received the volatile anesthetic isoflurane (1.15-1.5 vol%) before CPB and the intravenous anesthetic propofol (3-4 mg/kg/h) thereafter until the end of surgery. Cardiac arrest during CPB was induced by intermittent cross-clamp fibrillation, or by blood cardioplegia. We excluded patients older than 85 years, with unstable angina, significant renal disease, and those taking sulfonylureas. Troponin I (cTnI) was measured preoperatively and after 6, 12, 24 and 48 h. In addition, brain natriuretic peptide (BNP), creatine kinase (CKMB) and a panel of cytokines and growth factors were analyzed perioperatively. Although cTnI, BNP and CKMB all increased post-CABG, there were no significant differences between RI and Plac groups; area under the curve for cTnI 189.4 (183.6) ng/mL/48 h and 183.0 (155.2) ng/mL/48 h mean (SD), p = 0.90, respectively, despite a tendency to a shorter (p < 0.07) cross-clamp time in the treatment group. Similarly, there were no differences between groups in the central venous concentrations of numerous cytokines and growth factors. In patients undergoing CABG surgery RI does not provide myocardial protection under a strict anesthetic regime with volatile anesthesia until CPB, and RI was not associated with changes in cytokines.
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http://dx.doi.org/10.1007/s00395-011-0185-9DOI Listing
June 2011

The postoperative basal cortisol and CRH tests for prediction of long-term remission from Cushing's disease after transsphenoidal surgery.

J Clin Endocrinol Metab 2011 Jul 20;96(7):2057-64. Epub 2011 Apr 20.

National Institute of Neurologic Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892, USA.

Context: Selective adenomectomy via transsphenoidal surgery induces remission of Cushing's disease (CD) in most patients. Although an undetectable postoperative serum cortisol (<2 μg/dl) has been advocated as an index of remission, there is no consensus on predictors of recurrence.

Objective: We hypothesized that patients with subnormal cortisol (2-4.9 μg/dl) might achieve long-term remission and that postoperative responses to CRH might predict recurrence.

Design, Setting, And Participants: We prospectively studied CD patients with initial remission after adenomectomy or hemihypophysectomy (n = 14). Long-term recurrence (n = 39) or remission (n = 293) was assigned by laboratory results, glucocorticoid dependence, or patient survey at a mean of 10.6 yr after surgery.

Intervention And Main Outcome Measures: Postoperatively, morning cortisol was measured on d 3-5, and cortisol and ACTH responses to ovine CRH were assessed around d 10.

Results: Follow-up duration was median 11 yr (range 1-22.8 yr). Fewer patients achieved a cortisol nadir below 2 μg/dl (87%) than below 5 μg/dl (98%), yet recurrence rates were similar (<2 μg/dl, 9.5%; <5 μg/dl, 10.4%; 2-4.9 μg/dl, 20%; not significant). CRH-stimulated cortisol (P < 0.002) and ACTH (P = 0.04) values were higher for the recurrence than the remission group. However, no basal or stimulated ACTH or serum or urine cortisol cutoff value predicted all who later recurred.

Conclusions: A postoperative cortisol below 2 μg/dl predicts long-term remission after transsphenoidal surgery in CD. Remission in those with intermediate d 3-5 postoperative cortisol values (2-4.9 μg/dl) suggests that these patients do not require immediate reoperation. However, because no single cortisol cutoff value excludes all patients with recurrence, all require long-term clinical follow-up.
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http://dx.doi.org/10.1210/jc.2011-0456DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3135190PMC
July 2011

Differential expression and localization of 12/15 lipoxygenases in adipose tissue in human obese subjects.

Biochem Biophys Res Commun 2010 Dec 19;403(3-4):485-90. Epub 2010 Nov 19.

Department of Physiological Sciences, Eastern Virginia Medical School, Norfolk, VA 23507, USA.

Adipose tissue inflammation in obesity is a major factor leading to cardiovascular disease and type 2 diabetes.12/15 lipoxygenases (ALOX) play an important role in the generation of inflammatory mediators, insulin resistance and downstream immune activation in animal models of obesity. However, the expression and roles of 12/15ALOX isoforms, and their cellular sources in human subcutaneous (sc) and omental (om) fat in obesity is unknown. The objective of this study was to examine the gene expression and localization of ALOX isoforms and relevant downstream cytokines in subcutaneous (sc) and omental (om) adipose tissue in obese humans. Paired biopsies of sc and om fat were obtained during bariatric surgeries from 24 morbidly obese patients. Gene and protein expression for ALOX15a, ALOX15b and ALOX 12 were measured by real-time PCR and western blotting in adipocytes and stromal vascular fractions (SVF) from om and sc adipose tissue along with the mRNA expression of the downstream cytokines IL-12a, IL-12b, IL-6, IFNγ and the chemokine CXCL10. In a paired analysis, all ALOX isoforms, IL-6, IL-12a and CXCL10 were significantly higher in om vs. sc fat. ALOX15a mRNA and protein expression was found exclusively in om fat. All of the ALOX isoforms were expressed solely in the SVF. Further fractionation of the SVF in CD34+ and CD34- cells indicated that ALOX15a is predominantly expressed in the CD34+ fraction including vascular and progenitor cells, while ALOX15B is mostly expressed in the CD34- cells containing various leucocytes and myeloid cells. This result was confirmed by immunohistochemistry showing exclusive localization of ALOX15a in the om fat and predominantly in the vasculature and non-adipocyte cells. Our finding is identifying selective expression of ALOX15a in human om but not sc fat. This is a study showing a major inflammatory gene exclusively expressed in visceral fat in humans.
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http://dx.doi.org/10.1016/j.bbrc.2010.11.065DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3014727PMC
December 2010

The resonance theory of coronary arterial wall stress as an explanation for the distribution of coronary artery disease.

Authors:
Lindsay C H John

Med Hypotheses 2010 May 30;74(5):820-2. Epub 2009 Dec 30.

Department of Cardiothoracic Surgery, Kings College Hospital, Denmark Hill, London, UK.

The coronary arteries are unique within the arterial system in being subject to a continuous oscillatory displacement. It is hypothesised that oscillatory resonance of the coronary arteries occurs when the heart rate is the same as the arteries' Natural Frequency of oscillation. If resonance were to occur then standing waves would exist along the coronary arteries. The sites of the anti-nodes of such standing waves would be the sites of increased wall stress and therefore be expected to be predisposed to disease. Coronary artery resonance would explain the observed increased incidence of disease in the proximal segments of the arteries. It is proposed that coronary artery resonance is a previously unrecognised aetiological factor for coronary artery disease that contributes to its location. If the hypothesis is true then there are potential important consequences for the diagnosis and treatment of the disease.
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http://dx.doi.org/10.1016/j.mehy.2009.12.005DOI Listing
May 2010

Insulinotropic actions of nateglinide in type 2 diabetic patients and effects on dipeptidyl peptidase-IV activity and glucose-dependent insulinotropic polypeptide degradation.

Eur J Endocrinol 2009 Dec 15;161(6):877-85. Epub 2009 Sep 15.

School of Biomedical Sciences, University of Ulster, Coleraine BT52 1SA, Northern Ireland, UK.

Background: Nateglinide restores early-phase insulin secretion to feeding and reduces postprandial hyperglycaemia in type 2 diabetes. This study evaluated the effects of nateglinide on dipeptidyl peptidase-IV (DPP-IV) activity and glucose-dependent insulinotropic polypeptide (GIP) degradation. Research design and methods Blood samples were collected from type 2 diabetic subjects (n=10, fasting glucose 9.36+/-1.2 mmol/l) following administration of oral nateglinide (120 mg) 10 min prior to a 75 g oral glucose load in a randomised crossover design.

Results: Plasma glucose reached 18.2+/-1.7 and 16.7+/-1.7 mmol/l at 90 min in control and placebo groups (P<0.001). These effects were accompanied by prompt 32% inhibition of DPP-IV activity after 10 min (19.9+/-1.6 nmol/ml per min, P<0.05), reaching a minimum of 1.9+/-0.1 nmol/ml per min at 120 min (P<0.001) after nateglinide. Insulin and C-peptide levels increased significantly compared with placebo, to peak after 90 min at 637.6+/-163.9 pmol/l (P<0.05) and 11.8+/-1.4 mg/l (P<0.01) respectively. DPP-IV-mediated degradation of GIP was significantly less in patients receiving nateglinide compared with placebo. Inhibition of DPP-IV activity corresponded with a time- and concentration-dependent inhibitory effect of nateglinide on DPP-IV-mediated truncation of GIP(1-42) to GIP(3-42) in vitro. Comparison of in vitro inhibition of DPP-IV by nateglinide and vildagliptin revealed IC(50) values of 17.1 and 2.1 microM respectively.

Conclusions: Although considerably less potent than specified DPP-IV inhibitors, the possibility that some of the beneficial actions of nateglinide are indirectly mediated through DPP-IV inhibition and increased bioavailability of GIP and other incretins merits consideration.
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http://dx.doi.org/10.1530/EJE-09-0547DOI Listing
December 2009