Teck K Khong

Expression and function of the K+ channel KCNQ genes in human arteries

BACKGROUND AND PURPOSE KCNQ‐encoded voltage‐gated potassium channels (Kv7) have recently been identified as important anti‐constrictor elements in rodent blood vessels but the role of these channels and the effects of their modulation in human arteries remain unknown. Here, we have assessed KCNQ gene expression and function in human arteries ex vivo.

Home blood pressure monitoring with nurse-led telephone support among patients with hypertension and a history of stroke: a community-based randomized controlled trial

Background: Adequate control of blood pressure reduces the risk of recurrent stroke. We conducted a randomized controlled study to determine whether home blood pressure monitoring with nurse-led telephone support would reduce blood pressure in patients with hypertension and a history of stroke. Methods: We recruited 381 participants (mean age 72 years) from outpatient and inpatient stroke clinics between Mar. 1, 2007, and Aug. 31, 2009. Nearly half (45%, 170) of the participants had some disability due to stroke. Participants were visited at home for a baseline assessment and randomly allocated to home blood pressure monitoring (n = 187) or usual care (n = 194). Those in the intervention group were given a monitor, brief training and telephone support. Participants who had home blood pressure readings consistently over target (target < 130/80 mm Hg) were advised to consult their family physician. The main outcome measure was a fall in systolic blood pressure after 12 months, measured by an independent researcher unaware of group allocation. Results: Despite more patients in the intervention group than in the control group having changes to antihypertensive treatment during the trial period (60.1% [98/163] v. 47.6% [78/164], p = 0.02), the fall in systolic blood pressure from baseline did not differ significantly between the groups (adjusted mean difference 0.3 mm Hg, 95% confidence interval –3.6 to 4.2 mm Hg). Subgroup analysis showed significant interaction with disability due to stroke (p = 0.03 at 6 months) and baseline blood pressure (p = 0.03 at 12 months). Interpretation: Overall, home monitoring did not improve blood pressure control in patients with hypertension and a history of stroke. It was associated with a fall in systolic pressure in patients who had uncontrolled blood pressure at baseline and those without disability due to stroke. Trial registration: ClinicalTrials.gov registration NCT00514800

Adverse drug reactions: current issues and strategies for prevention and management

Adverse drug reactions (ADRs) are common, frequently serious and cause considerable morbidity and mortality. In addition to human costs, ADRs place considerable economic burden on society and already-stretched healthcare systems. Much work has been done to determine potential causes, commonly responsible drugs and susceptible patient groups. To this end, various national pharmacovigilance schemes exist to collate information about ADRs. Despite this, levels of ADR reporting are universally poor, with ADRs remaining a significant clinical problem. Therefore, more effective dissemination and implementation of available knowledge is needed, together with better use of the systems already in place. Local ADR centres and teams, in close liaison with national centres, appear to be an important part of this process and need to be developed within healthcare systems. In addition, there is now evidence to suggest that better use of informatics will help to facilitate this, together with wider availability of electronic notes and greater use of computer-prescribing. Although advancing technology may help to make the use of medicines safer, more effective and more specific in the future, investment to develop informatics infrastructure and local ADR teams is now needed in our healthcare systems.

Making medicines evergreen.

Andrew Hitchings, Emma Baker, and Teck Khong examine how drug companies maximise profits after patents expire and show why regulatory agencies, policy makers, and prescribers need to be alert to the use of these techniques

Resident phenotypically modulated vascular smooth muscle cells in healthy human arteries

Vascular interstitial cells (VICs) are non‐contractile cells with filopodia previously described in healthy blood vessels of rodents and their function remains unknown. The objective of this study was to identify VICs in human arteries and to ascertain their role. VICs were identified in the wall of human gastro‐omental arteries using transmission electron microscopy. Isolated VICs showed ability to form new and elongate existing filopodia and actively change body shape. Most importantly sprouting VICs were also observed in cell dispersal. RT‐PCR performed on separately collected contractile vascular smooth muscle cells (VSMCs) and VICs showed that both cell types expressed the gene for smooth muscle myosin heavy chain (SM‐MHC). Immunofluorescent labelling showed that both VSMCs and VICs had similar fluorescence for SM‐MHC and αSM‐actin, VICs, however, had significantly lower fluorescence for smoothelin, myosin light chain kinase, h‐calponin and SM22α. It was also found that VICs do not have cytoskeleton as rigid as in contractile VSMCs. VICs express number of VSMC‐specific proteins and display features of phenotypically modulated VSMCs with increased migratory abilities. VICs, therefore represent resident phenotypically modulated VSMCs that are present in human arteries under normal physiological conditions.

In-vivo intracellular pH at rest and during exercise in patients with essential hypertension.

Background Several studies in isolated cells have reported that intracellular pH (pHi) in individuals with essential hypertension may be relatively alkaline compared to normotensive individuals. Such an abnormality of pHi in hypertension would be consistent with enhanced sodium–hydrogen exchanger activity and may provide potential mechanisms by which hypertension and its complications could develop. Objectives To determine in-vivo intracellular pH of skeletal muscle at rest and during recovery from exercise-induced acidosis in hypertensive and normotensive subjects. Methods Using 31-phosphorus magnetic resonance spectroscopy, pHi of the dominant flexor digitorum superficialis was measured in 20 Caucasian subjects (14 male) with essential hypertension and 20 normotensive controls matched for gender, age, race and body mass index. Measurements were made at rest and during the exercise and recovery periods of a stepped incremental maximal exercise protocol. The rate of pHi recovery from exercise-induced acidosis was calculated by linear regression over the first 210 s of recovery from the pHi time plots of respective subjects. Results Mean resting pHi in the hypertensive (7.05 ± 0.04) and normotensive groups (7.06 ± 0.04) were not significantly different. There was a significant effect of gender on pHi: mean pHi was 7.07 ± 0.03 in males and 7.02 ± 0.03 in females, respectively (P < 0.0005). The mean intracellular pH achieved by exercise was 6.74 ± 0.31 in hypertensive individuals and not significantly different in normotensive individuals (6.68 ± 0.19;P = 0.4). The mean rate of pHi recovery in the hypertensives was 0.08 ± 0.03 pH units/min and not significantly different in normotensives (0.08 ± 0.02;P = 0.4). Conclusions These results contrast with previously documented abnormalities in the control of pHi in hypertension and demonstrate the absence of major in-vivo disturbances of pHi in skeletal muscle, both at rest and during recovery from exercise-induced acidosis, in essential hypertension. Therefore, it is possible that previously documented abnormalities of pHi and activity of the exchanger may be either specific to cell type or not present under in-vivo conditions.

Anxiety and depression related to elevated dopamine in a patient with multiple mediastinal paragangliomas

Paragangliomas are rare neuroendocrine tumors. Occasionally they secrete catecholamines in sufficient quantities to cause symptoms. These may include psychiatric symptoms such as anxiety and depression. We describe a patient with multiple mediastinal paragangliomas and persistently elevated dopamine levels who presented with anxiety and depression. She later went on to develop paranoid schizophrenia, which we feel was coincidental. This case illustrates anxiety and depressive symptoms associated with elevated dopamine and the importance of awareness of psychiatric manifestations of neuroendocrine tumors among psychiatrists and physicians.

A randomized controlled crossover trial evaluating differential responses to antihypertensive drugs (used as mono- or dual therapy) on the basis of ethnicity: The comparIsoN oF Optimal Hypertension RegiMens; part of the Ancestry Informative Markers in HYpertension program-AIM-HY INFORM trial.

Background: Ethnicity, along with a variety of genetic and environmental factors, is thought to influence the efficacy of antihypertensive therapies. Current UK guidelines use a “black versus white” approach; in doing so, they ignore the United Kingdoms largest ethnic minority: Asians from South Asia. Study design: The primary purpose of the AIM‐HY INFORM trial is to identify potential differences in response to antihypertensive drugs used as mono‐ or dual therapy on the basis of self‐defined ethnicity. A multicenter, prospective, open‐label, randomized study with 2 parallel, independent trial arms (mono‐ and dual therapy), AIM‐HY INFORM plans to enroll a total of 1,320 patients from across the United Kingdom. Those receiving monotherapy (n = 660) will enter a 3‐treatment (amlodipine 10 mg od; lisinopril 20 mg od; chlorthalidone 25 mg od), 3‐period crossover, lasting 24 weeks, whereas those receiving dual therapy (n = 660) will enter a 4‐treatment (amlodipine 5 mg od and lisinopril 20 mg od; amlodipine 5 mg od and chlorthalidone 25 mg od; lisinopril 20 mg od and chlorthalidone 25 mg od; amiloride 10 mg od and chlorthalidone 25 mg od), 4‐period crossover, lasting 32 weeks. Equal numbers of 3 ethnic groups (white, black/black British, and Asian/Asian British) will ultimately be recruited to each of the trial arms (ie, 220 participants per ethnic group per arm). Seated, automated, unattended, office, systolic blood pressure measured 8 weeks after each treatment period begins will serve as the primary outcome measure. Conclusion: AIM‐HY INFORM is a prospective, open‐label, randomized trial which aims to evaluate first‐ and second‐line antihypertensive therapies for multiethnic populations.

S78 Electronic cigarette advertising impacts adversely on smoking behaviour within a London student cohort: a cross-sectional survey

Introduction In contrast to tobacco smoking, electronic cigarette (“vaping”) advertisement has been approved in the UK since January 2013. Currently, there are 2.6 million e-cigarette users in the UK. The impact of e-cigarette advertisement on tobacco use has not been studied in detail. We hypothesised that e-cigarette advertisement impacts on smoking behaviour. Methods A structured survey was constructed to assess the impact of e-cigarette advertising on the perceived social acceptability of cigarette smoking; and, on trying both cigarettes and e-cigarettes (on a scale of 1 to 5/‘not at all’ to ‘a great deal’). The survey was administered between January to March 2015 to London university students, before and after viewing 5 UK adverts including a TV commercial. Results Data were collected from 106 participants (22 ± 2 years, 66%male), comprising 34 current cigarette-smokers, 57 non-smokers and 15 ex-smokers. There were 17 vapers, 82 non-vapers and 7 ex-vapers. After viewing the adverts, both smokers (2.6 ± 1.0 vs 3.8 ± 1.1, p = 0.0002) and non-smokers (3.2 ± 0.7 vs 3.7 ± 0.8, p = 0.004) felt e-cigarette advertising increased the social acceptability of smoking; and, both smokers and non-smokers were more likely to try e-cigarettes (3.6 ± 1.0 and 2.6 ± 1.0 respectively, p < 0.0001) as well as conventional cigarettes (3.4 ± 1.0 and 1.5 ± 0.9 respectively, p < 0.0001). Additionally after viewing, vapers felt e-cigarettes were ‘less effective’ at helping people stop smoking compared to before (3.6 ± 0.7 vs 4.0 ± 0.6, p = 0.004). Conclusion E-cigarette advertising encourages e-cigarette and conventional cigarette use in young smokers and non-smokers. The adverts impact on the social acceptability of smoking without regarding the importance of smoking cessation.

Generalisability of trials of home blood pressure monitoring; a comparison of two UK primary care trials.

Objective Blood pressure (BP) monitors are widely available and easy for patients to use. Systematic reviews [1-3] show that home monitoring of BP improves BP control but there is significant heterogeneity between studies, and meta regression has only been able to explain part of the heterogeneity, with concomitant interventions being a possible factor. Most evidence comes from trials of patients who have poorly controlled blood pressure at baseline, although not usually explicitly stated in trial or review title. However many hypertensive patients using home monitors may have BP below the recommended target Two large recent UK RCTs [4,5] have been carried out with very different inclusion criteria and interventions. The objective is to compare the main findings of these trials and assess how far difference between the trial populations might explain the apparent difference in the efficacy of the intervention between the two trials.