Metformin-associated lactic acidosis reported to the United Kingdom National Poisons Information Service (NPIS) between 2010 and 2019: a ten-year retrospective analysis.

INTRODUCTION: Metformin toxicity following therapeutic use or overdose may result in metabolic acidosis with hyperlactatemia. This study aims to assess the relationship between serum lactate concentration, arterial pH, and ingested dose with severity of poisoning, and to identify if serum lactate concentration is a useful marker of severity in metformin toxicity. METHODS: A retrospective study of telephone enquiries relating to metformin exposures to the National Poisons Information Service between 2010 and 2019 from hospitals in the United Kingdom. RESULTS: Six-hundred and thirty-seven cases were identified; 117 involved metformin only and 520 involved metformin with other drugs. The majority of cases involved acute (87%) and intentional (69%) exposures. There was a statistically significant difference in doses between the Poisoning Severity Scores, as well as between intentional and unintentional or therapeutic error doses (P < 0.0001). The distribution of cases for each Poisoning Severity Score differed between the metformin only and metformin with other drugs cases (P < 0.0001). Lactic acidosis was reported in 232 cases. Serum lactate concentration and arterial pH differed across Poisoning Severity Scores. Arterial pH inversely correlated with ingested dose (r=-0.3, P = 0.003), and serum lactate concentration positively correlated with ingested dose (r = 0.37, P < 0.0001). Serum lactate concentration and arterial pH did not correlate with each other. Twenty-five deaths were recorded, all following intentional overdoses. DISCUSSION: The dataset focuses mostly on acute, intentional overdoses. Increasing ingested metformin dose, a higher serum lactate concentration and worsening arterial pH were all associated with an unfavourable Poisoning Severity Score in patients in both metformin only and metformin with other drugs groups. As serum lactate concentration did not correlate with arterial pH, it represents an independent marker of poisoning severity. CONCLUSIONS: Data from the present study suggest that serum lactate concentration can be used to assess severity of poisoning in patients who have reportedly ingested metformin.

Real-world effectiveness of molnupiravir, nirmatrelvir-ritonavir, and sotrovimab on preventing hospital admission among higher-risk patients with COVID-19 in Wales: A retrospective cohort study.

OBJECTIVE: To compare the effectiveness of molnupiravir, nirmatrelvir-ritonavir, and sotrovimab with no treatment in preventing hospital admission or death in higher-risk patients infected with SARS-CoV-2 in the community. DESIGN: Retrospective cohort study of non-hospitalized adult patients with COVID-19 using the Secure Anonymised Information Linkage (SAIL) Databank. SETTING: A real-world cohort study was conducted within the SAIL Databank (a secure trusted research environment containing anonymised, individual, population-scale electronic health record (EHR) data) for the population of Wales, UK. PARTICIPANTS: Adult patients with COVID-19 in the community, at higher risk of hospitalization and death, testing positive for SARS-CoV-2 between 16th December 2021 and 22nd April 2022. INTERVENTIONS: Molnupiravir, nirmatrelvir-ritonavir, and sotrovimab given in the community by local health boards and the National Antiviral Service in Wales. MAIN OUTCOME MEASURES: All-cause admission to hospital or death within 28 days of a positive test for SARS-CoV-2. STATISTICAL ANALYSIS: Cox proportional hazard model with treatment status (treated/untreated) as a time-dependent covariate and adjusted for age, sex, number of comorbidities, Welsh Index of Multiple Deprivation, and vaccination status. Secondary subgroup analyses were by treatment type, number of comorbidities, and before and on or after 20th February 2022, when omicron BA.1 and omicron BA.2 were the dominant subvariants in Wales. RESULTS: Between 16th December 2021 and 22nd April 2022, 7013 higher-risk patients were eligible for inclusion in the study. Of these, 2040 received treatment with molnupiravir (359, 17.6%), nirmatrelvir-ritonavir (602, 29.5%), or sotrovimab (1079, 52.9%). Patients in the treatment group were younger (mean age 53 vs 57 years), had fewer comorbidities, and a higher proportion had received four or more doses of the COVID-19 vaccine (36.3% vs 17.6%). Within 28 days of a positive test, 628 (9.0%) patients were admitted to hospital or died (84 treated and 544 untreated). The primary analysis indicated a lower risk of hospitalization or death at any point within 28 days in treated participants compared to those not receiving treatment. The adjusted hazard rate was 35% (95% CI: 18-49%) lower in treated than untreated participants. There was no indication of the superiority of one treatment over another and no evidence of a reduction in risk of hospitalization or death within 28 days for patients with no or only one comorbidity. In patients treated with sotrovimab, the event rates before and on or after 20th February 2022 were similar (5.0% vs 4.9%) with no significant difference in the hazard ratios for sotrovimab between the time periods. CONCLUSIONS: In higher-risk adult patients in the community with COVID-19, those who received treatment with molnupiravir, nirmatrelvir-ritonavir, or sotrovimab were at lower risk of hospitalization or death than those not receiving treatment.

Potential cyanide poisoning reported to the UK national poisons information service: 2008-2019.

INTRODUCTION: Cyanide is a prevalent, lethal chemical. Possible sources of exposure include products of combustion, plant material, industry, chemical warfare and terrorism. METHODS: Retrospective review of UK Poisons Information Database of telephone enquiries to the National Poisons Information Service between 1st January 2008 and 31st December 2019 where cyanide poisoning was considered a possibility. Data extracted included demographics, exposure source, clinical features, Poisoning Severity Score, lactate concentration and antidotes given. RESULTS: A total of 1,252 cases of suspected cyanide poisoning were identified, 239 (19%) involved children under 10 years. The commonest sources of exposure were ingestion of plant material (437 cases; 35%) and smoke inhalation (399; 32%). Smoke inhalation caused the majority of severe and fatal cases (139; 71%). Clinical features associated with fatal outcomes were cardiac arrest (OR 36.4; 95% CI 14.4-92.2), hypotension (15.8; 7.0-35.9), coma (10.8; 5.6-21.0) and lactic acidosis (7.8; 4.1-14.8). 110 patients (9%) were given an antidote and 40 patients (3%) died.Lactate concentrations correlate with Poisoning Severity Score category (r = 0.6, p < 0.0001). Serum lactate <2.0 mmol/L was associated with Poisoning Severity Score None or Minor (sensitivity 76%; specificity 86%) and >11.0 mmol/L was associated with fatal outcome (sensitivity 74%; specificity 80%). 61 cases (5%) had severe carboxyhaemoglobin toxicity (COHb >30%). This was associated with a fatal outcome (OR 7.0; 95% CI 1.5-33.7) and there was positive correlation between carboxyhaemoglobin and Poisoning Severity Score, r = 0.57, p < 0.0001. CONCLUSIONS: Most cases of ingestion of plant material involved children under five years and resulted in no or mild symptoms. In adults smoke inhalation was associated with the most severe poisoning. The lactate cut-off values associated with each severity score calculated in this study are lower than the values used by NPIS on TOXBASE. Analytical conformation of cyanide exposure was unavailable in the majority of case, limiting the strength of these conclusions.

The effects of apixaban on clot characteristics in atrial fibrillation: A novel pharmacodynamic biomarker.

Atrial fibrillation (AF) is a major risk factor for stroke. We aim to characterize AF patients and the effects of apixaban therapy in terms of clot microstructure using gel point analysis, a novel biomarker. Seventy-eight patients were included in the study, 50 Stroke with AF (AF-S), and 28 AF without stroke (AF). Pre- and post-anticoagulation samples were collected: gel point (GP) analysis was performed to obtain (i) TGP (the time taken to reach the GP or the clot formation time) and (ii) df, the fractal dimension of the clot, a quantification of clot fibrin microstructure at the GP. At baseline, the AF-S group had a df  = 1.70 (±0.05) and TGP = 306 (±73 s). The AF group had a df = 1.70 ± 0.05 and TGP = 346 ± 78 s, showing a significantly shortened TGP in the stroke group (p = .008). For both groups, apixaban significantly prolonged TGP, p = .005, but resulted in no change in df. Apixaban prolonged clotting time while having no significant impact on the blood's ability to form stable clots (no change in df ). This indicates that apixaban provides protection from the formation of thrombi by reducing clotting kinetics.

Crack Detection and Localisation in Steel-Fibre-Reinforced Self-Compacting Concrete Using Triaxial Accelerometers.

Cracking in concrete structures can significantly affect their structural integrity and eventually lead to catastrophic failure if undetected. Recent advances in sensor technology for structural health monitoring techniques have led to the development of new and improved sensors for real-time detection and monitoring of cracks in various applications, from laboratory tests to large structures. In this study, triaxial accelerometers have been employed to detect and locate micro- and macrocrack formation in plain self-compacting concrete (SCC) and steel-fibre-reinforced SCC (SFRSCC) beams under three-point bending. Experiments were carried out with triaxial accelerometers mounted on the surface of the beams. The experimental results revealed that triaxial accelerometers could be used to identify the locations of cracks and provide a greater quantity of useful data for more accurate measurement and interpretation. The study sheds light on the structural monitoring capability of triaxial acceleration measurements for SFRSCC structural elements that can act as an early warning system for structural failure.

An Intentional Aconite Overdose: A Case Report.

BACKGROUND: Aconite is one of the most toxic known herbs, widely used for centuries as an essential Chinese medicine, but also for deliberate poisoning throughout history. Clinically indicated in herbal medicine for a range of ailments from headaches to muscle spasm, unfortunately the narrow therapeutic window may lead to a range of toxic presentations. The mechanism of action of the pharmacologically active compounds in Aconite relate to the activation of voltage gated sodium channels within a range of tissue including myocardial, neuronal and smooth muscle leading to persistent cellular activity. CASE PRESENTATION: We report on a rare case of a fifty year old male with intentional aconite overdose presenting with refractory cardiovascular instability from persistent life threatening arrhythmias, respiratory failure and seizure activity. CONCLUSION: An overview of Aconite, its history, pharmacological effects, treatment of overdose and outcomes is presented.

The Diagnosis of Sulfated Hemoglobin (SulfHb) Secondary to Sulfur Dioxide Poisoning Using Matrix-Assisted Laser Desorption Time-of-Flight Mass Spectrometry (MALDI-ToF MS)-A Novel Approach to an Unusual Clinical Problem.

Sulfhemoglobinemia is a rare entity caused by irreversible sulfation of the heme moiety in haemoglobin to form sulfated haemoglobin (SulfHb) and has been caused by H2S arising from certain metabolites of drugs and bacterial infection. Clinical presentation is similar to that of methemoglobin (MetHb). Furthermore, it is often difficult to distinguish between the diagnosis of SulfHb from MetHb in arterial blood gas analysers due to the broad overlap in the optical density (OD) absorption spectra-that of SulfHb swamping the more distinct OD absorption shift seen with MetHb. The presence of SulfHb was suspected in a 73-year-old lady with low oxygen saturation (SaO2 ~75%), central cyanosis, and normal arterial oxygen partial pressure (pO2 ~12 kPa). Repeated arterial blood gas analysis on different systems returned error messages for MetHb quantification. There was an improvement in oxygen saturation and cyanosis after an exchange transfusion. A full OD spectrophotometry (500-700 nm) of the patient's whole blood was suggestive of the presence of SulfHb, with a minor peak absorption at 620 nm. Matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-ToF MS) was undertaken on whole blood samples from the patient pre- and post-transfusion, alongside normal controls. These demonstrated the presence of SulfHb in the patient's blood, identifying sulfur, sulfur monoxide, and sulfur dioxide bound to the heme moiety. This gave vital identification as to the cause of Hb sulfation, which was distinct from that previously reported. Levels fell after the exchange transfusion and were completely eradicated after the correct source, an Epsom Salts constipation tonic, was identified. MALDI-ToF mass spectrometry is a new, rapid, specific, and sensitive diagnostic test for rare hematological syndromes such as SulfHb. In addition, it can identify the specific compounds bound to heme. Here, we provide useful diagnostic evidence as to the source of SulfHb, which was via SO2 rather than the previously described H2S.

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 Kingdom's 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.

Influence of vagal control on sex-related differences in left ventricular mechanics and hemodynamics.

Left ventricular (LV) twist mechanics differ between men and women during acute physiological stress, which may be partly mediated by sex differences in autonomic control. While men appear to have greater adrenergic control of LV twist, the potential contribution of vagal modulation to sex differences in LV twist remains unknown. Therefore, the present study examined the role of vagal control on sex differences in LV twist during graded lower body negative pressure (LBNP) and supine cycling. On two separate visits, LV mechanics were assessed using two-dimensional speckle-tracking echocardiography in 18 men (22 ± 2 yr) and 17 women (21 ± 4 yr) during -40- and -60-mmHg LBNP and 25% and 50% of peak supine cycling workload with and without glycopyrrolate (vagal blockade). LV twist was not different at baseline but was greater in women during -60 mmHg in both control (women: 16.0 ± 3.4° and men: 12.9 ± 2.3°, P = 0.004) and glycopyrrolate trials (women: 17.7 ± 5.9° and men: 13.9 ± 3.3°, P < 0.001) due to greater apical rotation during control (women: 11.9 ± 3.6° and men: 7.8 ± 1.5°, P < 0.001) and glycopyrrolate (women: 11.6 ± 4.9° and men: 7.1 ± 3.6°, P = 0.009). These sex differences in LV twist consistently coincided with a greater LV sphericity index (i.e., ellipsoid geometry) in women compared with men. In contrast, LV twist did not differ between the sexes during exercise with or without glycopyrrolate. In conclusion, women have augmented LV twist compared with men during large reductions to preload, even during vagal blockade. As such, differences in vagal control do not appear to contribute to sex differences in the LV twist responses to physiological stress, but they may be related to differences in ventricular geometry. NEW & NOTEWORTHY This is the first study to specifically examine the role of vagal autonomic control on sex-related differences in left ventricular (LV) mechanics. Contrary to our hypothesis, vagal control does not appear to primarily determine sex differences in LV mechanical or hemodynamic responses to acute physiological stress. Instead, differences in LV geometry may be a more important contributor to sex differences in LV mechanics.

Renoprotection by Direct Renin Inhibition: A Systematic Review and Meta- Analysis.

Even mild abnormalities of the renal structure or function can increase the risk of mortality and complications in other organs. Therefore, safe and effective treatments are necessary in order to influence the progression of renal disease. We used 2 methods to assess the renoprotective effects of aliskiren: 1) a statistical analysis of clinical trials that investigated aliskiren-induced renoprotection, in terms of changes in serum creatinine concentration (sCr) or estimated glomerular filtration rate (eGFR), and, 2) clinical trials that investigated the renoprotective effects of aliskiren with respect to changes in albuminuria or proteinuria. In the forest plot, the overall risk ratio (%) for renal impairment with respect to changes in sCr or eGFR was 0.97 (0.88-1.06; overall p=0.48). The tabulation of data from clinical trials included 10 entries for monotherapy with aliskiren and 6 entries for add-on aliskiren. All of the clinical trials, except one, showed a decrease in proteinuria or albuminuria following aliskiren treatment. In conclusion, inhibiting renin and prorenin with aliskiren is a more promising renoprotective treatment compared with blocking the renin/prorenin receptors (RPR). One of the main mechanisms by which aliskiren may confer renoprotection is by decreasing albuminuria and proteinuria. However, it does not seem to change sCr and eGFR in patients at risk of developing renal disease. Furthermore, co-administration of an angiotensinconverting- enzyme inhibitor (ACEI) or an angiotensin II receptor blocker (ARB) and aliskiren was shown to decrease albuminuria and proteinuria to a greater extent compared with monotherapy with these agents.

The management of ventricular dysrhythmia in aconite poisoning.

INTRODUCTION: Aconite poisoning is relatively rare but is frequently complicated by ventricular dysrhythmias, which may be fatal. Molecular basis of aconite alkaloid ventricular arrhythmogenicity: Aconite exerts its toxic effects due to the presence of an admixture of alkaloids present in all parts of the plant. The major target of these aconite alkaloids is the fast voltage-gates sodium channel, where they cause persistent activation. This blockade of the channel in the activated state promotes automaticity within the ventricular myocardium and the generation of ventricular arrhythmias. Aconitine-induced arrhythmias: Aconite alkaloids are known to cause many different types of disturbance of heart rhythm. However, this focused review specifically looks at ventricular rhythm disturbances, namely ventricular ectopy, ventricular tachycardia, torsades des pointes and ventricular fibrillation. OBJECTIVE: The objective of this review was to identify the outcome of anti-dysrhythmic strategies from animal studies and case reports in humans in order to guide the management of ventricular dysrhythmias in aconite poisoning in humans. METHODS: A review of the literature in English was conducted in PubMed and Google Scholar from 1966 to July 2016 using the search terms "aconite/aconitine"; "aconite/aconitine + poisoning" and "aconite/aconitine + dysrhythmia". 168 human case-reports and case-series were identified by these searches, of which 103 were rejected if exposure to aconite did not result in ventricular dysrhythmias, if it was uncertain as to whether aconite had been ingested, if other agents were co-ingested, if there was insufficient information to determine the type of treatments administered or if there was insufficient information to determine outcome. Thus, 65 case reports of probable aconite poisoning that resulted in ventricular dysrhythmias were identified. Toxicokinetic data in aconite poisoning: Data were only available in three papers; the presence of ventricular rhythm disturbances directly correlated with the concentration of aconite alkaloids in the plasma. MANAGEMENT: 54 of 65 cases developed ventricular tachycardia, six developed torsades des pointes, 15 patients developed ventricular fibrillation, 10 developed ventricular ectopics and one developed a broad complex tachycardia not otherwise specified; each dysrhythmia was regarded as separate and patients may have had more than one dysrhythmia. 10 patients died, giving a mortality of 15%. In total, 147 treatments were administered to 65 patients. 46 of the interventions were assessed by the authors as having been associated with successful restoration of sinus rhythm. Flecainide administration was accompanied by dysrhythmia termination in six of seven cases. Mexiletine was connected with correcting dysrhythmias in 3 of 3 cases. Procainamide administration was associated with return to sinus rhythm in 2 of 2 cases. Prolonged cardio-pulmonary resuscitation was administered to 15 patients where it was associated with a return to sinus rhythm in nine of these. Amiodarone was linked to success in correcting dysrhythmias in 11 of 20 cases. Cardiopulmonary bypass use was associated with a return to sinus rhythm in four out of six cases. Epinephrine was documented as being employed on four occasions, and was associated with a restoration of sinus rhythm on two of these. Magnesium sulphate administration was accompanied by dysrhythmia termination in two of nine cases. Direct cardioversion was associated with a return of sinus rhythm in 5 of 30 cases. However, it is not certain whether the drug treatment influenced the course of the dysrhythmia. CONCLUSIONS: Based on the evidence available from human case reports, flecainaide or amiodarone appear to be more associated with a return to sinus rhythm than lidocaine and/or cardioversion, although it is not established whether the administration of treatment caused reversion to normal sinus rhythm. The potential beneficial effects of amiodarone were not observed in animal studies. This may be due to intra-species differences between ion channels or relate to the wider cardiovascular toxicity of aconite that extends beyond arrhythmias. Prolonged cardiopulmonary resuscitation and cardiopulmonary bypass should be considered as an integral part of good clinical care as "time-buying" strategies to allow the body to excrete the toxic alkaloids. There may also be a role for mexiletine, procainamide and magnesium sulphate.

Methoxetamine toxicity reported to the National Poisons Information Service: clinical characteristics and patterns of enquiries (including the period of the introduction of the UK's first Temporary Class Drug Order).

OBJECTIVE: To report the demographic and clinical characteristics of cases of methoxetamine toxicity reported to The National Poisons Information Service (NPIS) by healthcare professionals. To assess the pattern of enquiries from health professionals to the UK NPIS related to methoxetamine, including the period of the making of the UK first Temporary Class Drug Order (TCDO). METHODS: All telephone enquiries to and user sessions for TOXBASE, the NPIS on-line information resource, related to methoxetamine (and synonyms 'MXE', 'mket' and '2-(3-methoxyphenyl)-2-(ethylamino)cyclohexanone') were reviewed from 1 April 2010 to 1 August 2012. Data were compared for the 3 months before and after the TCDO. RESULTS: There were 47 telephone enquiries and 298 TOXBASE sessions regarding methoxetamine during the period of study. Comparing the 3 months before and after the TCDO, TOXBASE sessions for methoxetamine fell by 79% (from 151 to 32) and telephone enquiries by 80% (from 15 to 3). Clinical features reported by enquirers were consistent with case reports of analytically confirmed methoxetamine toxicity and typical toxidromes were of stimulant (36%), reduced consciousness (17%), dissociative (11%) and cerebellar (6.4%) types, but also particularly featured acute disturbances in mental heath (43%). CONCLUSIONS: Structured NPIS data may reveal trends in drugs of abuse use and toxicity when interpreted within their limitations. Since April 2012, there have been fewer enquiries to NPIS from clinicians, indicating reduced presentations with suspected methoxetamine toxicity to healthcare services. It is unclear if this is related to the TCDO made on 5 April 2012.

Snakebite enquiries to the UK National Poisons Information Service: 2004-2010.

OBJECTIVE: To describe trends regarding snakebite enquiries to the UK National Poisons Information Service (NPIS) from 2004 to 2010. METHODS: The NPIS telephone enquiry database, the UK Poisons Information Database, was interrogated for enquiries to the four NPIS units from 2004 to 2010. Search terms used were 'snake' and 'snakebite'. Information from the national dataset was available from Cardiff and Edinburgh units from 2004 onwards, Birmingham from June 2005 and Newcastle from September 2006. RESULTS: Five hundred and ten cases were identified, of which 69% were male and 31% female. Average age of cases was 32 years (±1 95% CI). The snake was identified as follows: British Adder in 52% of cases, an exotic species in 26%, unknown in 18% and another UK snake in 4%. 82% of cases occurred between the months of April and September. Cases peaked during August (19%). Forty-two per cent of enquiries involved features of envenoming. Eighty-five cases were assessed as requiring antivenom. Eighty-four cases received treatment with antivenom. No adverse reactions to the antivenom were reported and resolution of clinical features was reported in all treated cases. Advice to use an antidote was followed in 98.8% of cases. CONCLUSIONS: Snakebites account for one to two NPIS cases per week. Adder bites account for over half of cases. A quarter of cases were due to non-UK snakes kept in captivity within the UK. Envenoming was said to have occurred in just under half of all cases. Advice given by the NPIS appears to closely reflect national practice guidelines.

Sex differences in the systemic response to adrenoreceptor antagonists during sympathetic activation.

BACKGROUND: Sex differences in sensitivity to adrenergic agonists have been described in forearm plethysmography studies. The attenuation in noradrenaline-mediated vasoconstriction is because of enhanced ß(2)-adrenergic stimulation in women. The systemic relevance of these observations is unknown. The aim of this study was to determine sex inequalities in the systemic haemodynamic response to sympathetic activation by isometric forearm contraction in the presence of adrenoreceptor blockade. MATERIALS AND METHODS: Isometric forearm contraction was performed in the presence of isotonic saline, esmolol and phentolamine, respectively, in six men and six premenopausal women. RESULTS: Isometric forearm contraction increased heart rate by 9·5% ± 4·8 CI(95%), P = 0·00001 in both sexes. Mean arterial pressure was also increased in both sexes 13·9% ± 3·2 CI(95%), P = 0·002. Esmolol attenuated the rise in mean arterial pressure in men (5·9% ± 3·6 CI(95%), P = 0·6) but not in women (14·3% ± 3·2 CI(95%), P = 0·007). CONCLUSIONS: This study supports previous findings of sex differences in adrenergic responsiveness and suggests that its consequences are systemically relevant.

(18)FDG PET imaging can quantify increased cellular metabolism in pulmonary arterial hypertension: A proof-of-principle study.

The past decade has seen increased application of 18-flurodeoxyglucose positron emission tomography ((18)FDG-PET) imaging to help diagnose and monitor disease, particularly in oncology, vasculitis and atherosclerosis. Disordered glycolytic metabolism and infiltration of plexiform lesions by inflammatory cells has been described in idiopathic pulmonary arterial hypertension (IPAH). We hypothesized that increased (18)FDG uptake may be present in the lungs, large pulmonary arteries and right ventricle of patients with pulmonary hypertension, and that this uptake would be related to markers of immune activation. We imaged the thorax of 14 patients with pulmonary hypertension (idiopathic and chronic thromboembolic) and six controls by (18)FDG-PET/computed tomography (CT) and measured uptake in the lung parenchyma, large pulmonary arteries and right ventricle. (18)FDG uptake in the lungs and pulmonary arteries was normalized for venous blood activity to give a target-to-background ratio (TBR). Blood was contemporaneously drawn for high-sensitivity CRP - C-reactive protein (CRP) (hsCRP), N-Terminal Probrain natriuteric peptide (NT-ProBNP) and other inflammatory cytokines. IPAH patients had significantly higher lung parenchymal TBR (P=0.034) and right ventricle FDG uptake (P=0.007) than controls. Uptake in the main pulmonary arteries was similar in chronic thromboembolic pulmonary hypertension, IPAH and controls. There were no correlations between (18)FDG uptake and hsCRP or inflammatory cytokine levels. NT-ProBNP correlated with RV uptake in those with pulmonary hypertension (r=0.55, P=0.04). In this pilot study, we found increased (18)FDG uptake in the lung parenchyma and right ventricle of subjects with IPAH. The lung uptake might be useful as a surrogate marker of increased cellular metabolism and immune activation as underlying mechanisms in this disease. Further evaluation of the impact of targeted therapies in treatment-naïve patients and the significance of right ventricular uptake is suggested.

Excessive aortic inflammation in chronic obstructive pulmonary disease: an 18F-FDG PET pilot study.

UNLABELLED: Chronic obstructive pulmonary disease (COPD) patients exhibit increased cardiovascular risk, even after controlling for smoking. Inflammation may underlie this observation. METHODS: We measured vascular inflammation in both COPD patients and controls using (18)F-FDG PET/CT. Aortic inflammation was expressed as the target-to-background ratio (TBR) of the standardized uptake value in 7 COPD patients, 5 metabolic syndrome patients, and 7 ex-smokers. RESULTS: Abdominal aortic mean TBR (+/-SD) was greater in COPD patients than in ex-smoker controls (1.60 +/- 0.13 vs. 1.34 +/- 0.15, P = 0.0001). Aortic arch and abdominal aorta mean TBRs were higher in metabolic syndrome patients than in COPD patients (aortic arch, 1.80 +/- 0.18 vs. 1.53 +/- 0.18, P = 0.001, and abdominal aorta, 1.71 +/- 0.14 vs. 1.60 +/- 0.13, P = 0.001). CONCLUSION: COPD patients exhibited aortic inflammation that fell between the aortic inflammation exhibited by ex-smokers and that by metabolic syndrome patients. This may in part explain the increased risk of cardiovascular disease in COPD patients.

Paracetamol (acetaminophen) attenuates in vitro mast cell and peripheral blood mononucleocyte cell histamine release induced by N-acetylcysteine.

INTRODUCTION: The treatment of acute paracetamol (acetaminophen) poisoning with N-acetylcysteine (NAC) is frequently complicated by an anaphylactoid reaction to the antidote. The mechanism that underlies this reaction is unclear. We used the human mast cell line 1 (HMC-1) and human peripheral blood mononucleocytes (PBMCs) to investigate the effects of NAC and paracetamol on histamine secretion in vitro. METHOD: HMC-1 and human PBMCs were incubated in the presence of increasing concentrations of NAC +/- paracetamol. Cell viability was determined by the Trypan Blue Assay, and histamine secretion was measured by ELISA. RESULTS: NAC was toxic to HMC-1 cells at 100 mg/mL and to PBMCs at 67 mg/mL. NAC increased HMC-1 and PBMC histamine secretion at concentrations of NAC from 20 to 50 mg/mL and 2.5 to 100 mg/mL, respectively. NAC-induced histamine secretion by both cell types was reduced by co-incubation with 2.5 mg/mL of paracetamol. CONCLUSION: Paracetamol (acetaminophen) is capable of modifying histamine secretion in vitro. This may explain the clinical observation of a lower incidence of adverse reactions to NAC in vivo when higher concentrations of paracetamol are present than when paracetamol concentrations are low. Paracetamol (acetaminophen) attenuates in vitro mast cell and PBMC cell histamine release induced by NAC.