Estimating life expectancy and years of life lost for autistic people in the UK: a matched cohort study.

Background: Previous research has shown that people who have been diagnosed autistic are more likely to die prematurely than the general population. However, statistics on premature mortality in autistic people have often been misinterpreted. In this study we aimed to estimate the life expectancy and years of life lost experienced by autistic people living in the UK. Methods: We studied people in the IQVIA Medical Research Database with an autism diagnosis between January 1, 1989 and January 16, 2019. For each participant diagnosed autistic, we included ten comparison participants without an autism diagnosis, matched by age, sex, and primary care practice. We calculated age- and sex-standardised mortality ratios comparing people diagnosed autistic to the reference group. We used Poisson regression to estimate age-specific mortality rates, and life tables to estimate life expectancy at age 18 and years of life lost. We analysed the data separately by sex, and for people with and without a record of intellectual disability. We discuss the findings in the light of the prevalence of recorded diagnosis of autism in primary care compared to community estimates. Findings: From a cohort of nearly 10 million people, we identified 17,130 participants diagnosed autistic without an intellectual disability (matched with 171,300 comparison participants), and 6450 participants diagnosed autistic with an intellectual disability (matched with 64,500 comparison participants). The apparent estimates indicated that people diagnosed with autism but not intellectual disability had 1.71 (95% CI: 1.39-2.11) times the mortality rate of people without these diagnoses. People diagnosed with autism and intellectual disability had 2.83 (95% CI: 2.33-3.43) times the mortality rate of people without these diagnoses. Likewise, the apparent reduction in life expectancy for people diagnosed with autism but not intellectual disability was 6.14 years (95% CI: 2.84-9.07) for men and 6.45 years (95% CI: 1.37-11.58 years) for women. The apparent reduction in life expectancy for people diagnosed with autism and intellectual disability was 7.28 years (95% CI: 3.78-10.27) for men and 14.59 years (95% CI: 9.45-19.02 years) for women. However, these findings are likely to be subject to exposure misclassification biases: very few autistic adults and older-adults have been diagnosed, meaning that we could only study a fraction of the total autistic population. Those who have been diagnosed may well be those with greater support needs and more co-occurring health conditions than autistic people on average. Interpretation: The findings indicate that there is a group of autistic people who experience premature mortality, which is of significant concern. There is an urgent need for investigation into the reasons behind this. However, our estimates suggest that the widely reported statistic that autistic people live 16-years less on average is likely incorrect. Nine out of 10 autistic people may have been undiagnosed across the time-period studied. Hence, the results of our study do not generalise to all autistic people. Diagnosed autistic adults, and particularly older adults, are likely those with greater-than-average support needs. Therefore, we may have over-estimated the reduction in life expectancy experienced by autistic people on average. The larger reduction in life expectancy for women diagnosed with autism and intellectual disability vs. men may in part reflect disproportionate underdiagnosis of autism and/or intellectual disability in women. Funding: Dunhill Medical Trust, Medical Research Council, National Institute for Health and Care Research, and the Royal College of Psychiatrists.

Attention-deficit hyperactivity disorder diagnoses and prescriptions in UK primary care, 2000-2018: population-based cohort study.

BACKGROUND: Rates of diagnosed attention-deficit hyperactivity disorder (ADHD) may be increasing in the UK. AIMS: Estimate incidence and prevalence of ADHD diagnoses and ADHD prescriptions in UK adults and children in primary care. METHOD: We conducted a cohort study using IQVIA Medical Research Data, a UK primary care database. Rates of ADHD diagnoses and ADHD prescriptions were calculated between 2000 and 2018 for individuals aged 3-99 years, analysed by age, gender, social deprivation status and calendar year. RESULTS: Of 7 655 931 individuals, 35 877 (0.5%) had ADHD diagnoses; 18 518 (0.2%) received ADHD medication prescriptions. Diagnoses and prescription rates were greater in men versus women, children versus adults, and deprivation status (nearly double in most deprived versus least deprived quintile). By 2018, the proportion of ADHD diagnoses was 255 per 10 000 (95% CI 247-263) in boys and 67.7 per 10 000 (95% CI 63.5-71.9) in girls; for adults, it was 74.3 per 10 000 (95% CI 72.3-76.2) in men and 20 per 10 000 (95%CI 19.0-21.0) in women. Corresponding figures for prescriptions were 156 per 10 000 (95% CI 150-163) in boys, 36.8 per 10 000 (95% CI 33.8-40.0) in girls, 13.3 per 10 000 (95% CI 12.5-14.1) in men and 4.5 per 10 000 (95% CI 4.1-5.0) in women. Except among 3- to 5-year-olds, the incidence and prevalence of ADHD diagnoses and prescriptions have increased from 2000 to 2018 in all age groups. The absolute increase was highest in children, but the relative increase was largest among adults (e.g. among men aged 18-29 years, approximately 20-fold and nearly 50-fold increases in diagnoses and prescriptions, respectively). CONCLUSIONS: The incidence and prevalence of both ADHD diagnoses and medication are highest among children. Proportionally, rates increased most among adults during 2000-2018. ADHD diagnoses and prescriptions are associated with socioeconomic deprivation.

Developing a career as a GP educationalist: contemporary challenges and workforce solutions.

GP educationalists are crucial in training the future medical workforce and in developing and advancing the field of primary care medical education, yet opportunities in the UK are patchy and varied. In this article, a group of GP educationalists summarise the challenges facing the sustainability of this particular group of clinical academics and outline opportunities available at each career stage, from medical students through to senior GP educationalists. Recommendations to support the growth of this workforce include the development of a nationally recognised framework for GP educationalist careers, collaboration with professional and educational bodies and taking steps to level out opportunities in order to reduce existing inequity.

Sources of funding for research articles in medical education journals from 1999 to 2019.

BACKGROUND: Prior studies report that most published medical education research is unfunded. We sought to determine the extent and sources of funding for medical education research articles published in leading journals, and how these have changed in the last two decades. METHODS: All research articles published in Academic Medicine, Advances in Health Sciences Education, Medical Education and Medical Teacher in 1999, 2004, 2009, 2014, and 2019 were reviewed for funding declarations. Funding sources were categorised as: government; university; healthcare organisation; private not-for-profit organisation; and for-profit company. Time trends were analysed using the Cochran-Armitage test. RESULTS: 1822 articles were analysed. Over the aggregate 20-year period, 44% of all articles reported funding, with the proportion increasing from 30% in 1999 to 50% in 2019 (p < .001). The proportion of articles with government (10% to 16%, p = .049), university (6% to 17% p < .001), and not-for-profit funding sources (15% to 20%, p = .04) increased. Proportions of healthcare (3% to 4%, p = .45) and for-profit funding (2% to 1%, p = .25) did not significantly change with time. CONCLUSIONS: Over the last 20 years, the proportion of funded published medical education research has significantly increased, as has funding from government, universities, and not-for-profit sources. This may assist researchers in identifying funders with a track record of supporting medical education research, and enhances transparency of where research funding in the field originates.

Medical and pharmacy students' perspectives of remote synchronous interprofessional education sessions.

BACKGROUND: Interprofessional education (IPE) at university level is an essential component of undergraduate healthcare curricula, as well as being a requirement of many associated regulatory bodies. In this study, the perception of pharmacy and medical students' of remote IPE was evaluated. METHODS: A series of IPE sessions took place via Zoom and students' feedback was collected after each session. Both qualitative and quantitative data were collected and analysed. RESULTS: 72% (23/32) of medical students strongly agreed that the sessions had helped to improve their appreciation of the role of pharmacists, whereas 37% (22/59) of pharmacy students strongly agreed, reporting a median response of 'somewhat agreeing', that their appreciation of the role of general practitioners had improved. This difference was found to be statistically significant (p = 0.0143). Amongst students who responded, 55% (53/97) identified remote teaching as their preferred mode of delivery for an IPE session. CONCLUSIONS: The survey demonstrated that the students valued the development of their prescribing skills as well as the ancillary skills gained, such as communication and teamwork. Remote IPE can be a practical means of improving medical and pharmacy students' understanding of each other's professional roles, as well as improving the skills required for prescribing.

Associations between inflammation, coagulation, cardiac strain and injury, and subclinical vascular disease with frailty in older men: a cross-sectional study.

BACKGROUND: Inflammation, coagulation activation, endothelial dysfunction and subclinical vascular disease are cross-sectionally associated with frailty. Cardiac-specific biomarkers are less-well characterised. We assessed associations between these and frailty, in men with, and without, cardiovascular disease (CVD). METHODS: Cross-sectional analysis of 1096 men without, and 303 with, CVD, aged 71-92, from the British Regional Heart Study. Multinominal logistic regression was performed to examine the associations between frailty status (robust/pre-frail/frail) and, separately, C-reactive protein (CRP), interleukin-6 (IL-6), tissue plasminogen activator (tPA), D-dimer, von Willebrand factor (vWF), high-sensitivity cardiac troponin-T (hs-cTnT), N-terminal pro B-type natriuretic peptide (NT-proBNP) (all natural log-transformed), and, in men without CVD, carotid intima-media thickness (CIMT), carotid-femoral pulse wave velocity (cfPWV), carotid distensibility coefficient (DC), and ankle-brachial pressure index (ABPI), adjusted for age, renal function, BMI, social class, smoking, polypharmacy, cognition, multimorbidity and systolic blood pressure. Explanatory variables with p < 0.05 were carried forward into mutually-adjusted analysis. RESULTS: In men without CVD, higher CRP, IL-6, vWF, tPA, hs-cTnT, NT-proBNP, cfPWV, and lower DC were significantly associated with frailty; mutually-adjusted, log IL-6 (OR for frailty = 2.02, 95%CI 1.38-2.95), log hs-cTnT (OR = 1.95, 95%CI 1.24-3.05) and DC (OR = 0.92, 95%CI 0.86-0.99) retained associations. In men with CVD, higher CRP, IL-6, and hs-cTnT, but not vWF, tPA, NT-proBNP or D-dimer, were significantly associated with frailty; mutually-adjusted, log hs-cTnT (OR 3.82, 95%CI 1.84-7.95) retained a significant association. CONCLUSIONS: In older men, biomarkers of myocardial injury are associated with frailty. Inflammation is associated with frailty in men without CVD. Carotid artery stiffness is associated with frailty in men without CVD, independently of these biomarkers.

Subclinical cardiovascular disease and risk of incident frailty: The British Regional Heart Study.

BACKGROUND/OBJECTIVES: Subclinical cardiovascular disease (CVD) is cross-sectionally associated with frailty, but the relationship between subclinical CVD and incident frailty has not been reported. We aimed to assess this prospective association. DESIGN: Longitudinal analysis of data from the British Regional Heart Study, a prospective cohort study. PARTICIPANTS: 1057 men, aged 71-92 years, robust or pre-frail at baseline, and without a clinical diagnosis of CVD. MEASUREMENTS: Participants underwent baseline measurement of carotid-femoral pulse wave velocity (cfPWV), carotid intima-media thickness (CIMT), carotid distensibility coefficient (DC), and ankle-brachial pressure index (ABPI), and had questionnaire-based frailty assessment after three years. Frailty status was based on the Fried phenotype. Multivariate logistic regressions examined associations between incident frailty and tertile of cfPWV, CIMT, DC, and ABPI group (<0.9, 0.9-1.4, ≥1.4). RESULTS: 865 men were examined and completed the 3 year follow-up questionnaire, of whom 78 became frail. Adjusted for age, prefrailty, body mass index, diabetes, smoking, atrial fibrillation, blood pressure, renal function, and incident CVD, higher CIMT was associated with greater odds of incident frailty (2nd tertile OR 1.62, 95% CI 0.78-3.35, 3rd tertile OR 2.61, 95% CI 1.30-5.23, p = 0.007, trend p = 0.006). cfPWV showed a weaker, non-significant association (2nd tertile OR 1.79, 95% CI 0.85-3.78, 3rd tertile OR 1.73, OR 0.81-3.72, p = 0.16, trend p = 0.20). There was no clear association between incident frailty and DC or ABPI. In subgroup analyses, CIMT was significantly associated with incident frailty in men ≥80 years (3rd tertile OR 6.99, 95%CI 1.42-34.5), but not in men aged 75-80 or < 75 years. CONCLUSION: Subclinical CVD, as measured by CIMT, is associated with greater risk of incident frailty in older men over three year follow-up, independent of the development of clinically-apparent stroke, heart failure, or myocardial infarction, and may be a modifiable risk factor for frailty. This association may be stronger in very old age.

Associations between inflammation, cardiovascular biomarkers and incident frailty: the British Regional Heart Study.

INTRODUCTION: cardiovascular disease (CVD) and chronic inflammation are implicated in the development of frailty. Longitudinal analyses of inflammatory markers, biomarkers of cardiac dysfunction and incidence of frailty are limited. METHODS: in the British Regional Heart Study, 1,225 robust or pre-frail men aged 71-92 years underwent a baseline examination, with questionnaire-based frailty assessment after 3 years. Frailty definitions were based on the Fried phenotype. Associations between incident frailty and biomarkers of cardiac dysfunction (high-sensitivity cardiac troponin T (hs-cTnT), N-terminal pro B-type natriuretic peptide (NT-proBNP)) and inflammation (C-reactive protein (CRP) and interleukin-6 (IL-6)) were examined, by tertile, with the lowest as reference. RESULTS: follow-up data were available for 981 men. Ninety one became frail. Adjusted for age, pre-frailty, prevalent and incident CVD, comorbidity, polypharmacy and socioeconomic status, IL-6 (third tertile OR 2.36, 95% CI 1.07-5.17) and hs-cTnT (third tertile OR 2.24, 95% CI 1.03-4.90) were associated with increased odds of frailty. CRP (third tertile OR 1.83, 95% CI 0.97-4.08) and NT-proBNP (second tertile OR 0.48, 95% CI 0.23-1.01) showed no significant association with incident frailty. The top tertiles of CRP, IL-6, hscTnT and NT-proBNP were strongly associated with mortality prior to follow-up. CONCLUSION: IL-6 is associated with incident frailty, supporting the prevailing argument that inflammation is involved in the pathogenesis of frailty. Cardiomyocyte injury may be associated with frailty risk. Associations between elevated CRP and frailty cannot be fully discounted; NT-proBNP may have a non-linear relationship with incident frailty. CRP, IL-6, hs-cTnT and NT-proBNP are vulnerable to survivorship bias.

No such thing as a free lunch?

BACKGROUND: High-quality, out-of-classroom interactions between students and teachers help to develop communities of learning. In medicine, they contribute to the professionalisation of students. METHODS: We designed a novel student-faculty member lunch scheme for first-year medical students at our institution. Students received a free lunch in groups of six with a faculty member 'hosting' and paying for lunch, with the cost reimbursed by the medical school. Focus groups with students were used to evaluate the impact of the intervention. RESULTS: Approximately half of all Year-1 students signed up for the scheme (n = 153). Twenty faculty members hosted one or more lunches. Focus group analysis revealed that attendees felt more positively about individual faculty members and the institution as a result of participation, and that it helped the process of induction and transition into medical school, but that it suffered from a lack of continuing contact. Out-of-classroom interactions between students and teachers help to develop communities of learning CONCLUSIONS: This intervention encouraged positive student-faculty member interactions, albeit with a relatively small group of students. It did not seem to encourage longitudinal staff-student relationships, however, which is a key limitation.

The utility of the FIPI score in predicting long-term clinical outcomes in patients with Fabry disease receiving enzyme replacement therapy with agalsidase alfa.

Fabry disease is a rare X-linked lysosomal storage disorder in which there is deficiency of alpha galactosidase A. Enzyme replacement therapy (ERT) is commercially available and has been demonstrated to improve cardiac and renal outcomes. Predictive scores, such as the Fabry International Prognostic Index (FIPI), have been developed to stratify disease severity; however, these have not been validated to predict outcomes in patients receiving ERT. We show that the FIPI score at baseline can predict outcomes in a group of patients on long-term ERT.

Competition between geometrically induced and density-driven segregation mechanisms in vibrofluidized granular systems.

The behaviors of granular systems are sensitive to a wide variety of particle properties, including size, density, elasticity, and shape. Differences in any of these properties between particles in a granular mixture may lead to segregation, or "demixing," a process of great industrial relevance. Despite the known influence of particle geometry in granular systems, a considerable fraction of research into these systems concerns only uniformly spherical particles. We address, for the case of vertically vibrated granular systems, the important question of whether the introduction of differing particle geometries entirely invalidates our existing knowledge based on purely spherical granulates, or whether current models may simply be adapted to account for the effects of particle shape. We demonstrate that while shape effects can indeed influence the dynamical and segregative behaviors of a granular system, the segregative mechanisms associated with particle geometry are decidedly secondary to those related to particle density. The relevant control parameters determining the extent of geometrically induced segregation are established. Finally, a manner in which shape effects may be accounted for in simulations utilizing purely spherical particles is proposed.

Origin of electrochromism in high-performing nanocomposite nickel oxide.

Electrochromic effects of transition metal oxides provide a great platform for studying lithium intercalation chemistry in solids. Herein, we report on an electronically modified nanocomposite nickel oxide (i.e., Li2.34NiZr0.28Ox) that exhibits significantly improved electrochromic performance relative to the state-of-the-art inorganic electrochromic metal oxides in terms of charge/discharge kinetics, bleached-state transparency, and optical modulation. The knowledge obtained from O K-edge X-ray absorption spectroscopy (XAS) and X-ray photoelectron spectroscopy (XPS) suggests that the internally grown lithium peroxide (i.e., Li2O2) species plays a major role in facilitating charge transfer thus enabling optimal electrochromic performance. This understanding is relevant to recent theoretical studies concerning conductivity in Li2O2 for lithium-air batteries (as cited in the main text). Furthermore, we elucidate the electrochromism in modified nickel oxide in lithium ion electrolyte with the aid of Ni K-edge XAS and Ni L-edge XAS studies. The electrochromism in the nickel oxide materials arises from the reversible formation of hole states on the NiO6 units, which then impacts the Ni oxidation state through the Ni3d-O2p hybridization states. This study sheds light on the lithium intercalation chemistry for general energy storage and semiconductor applications.

RSD931, a novel anti-tussive agent acting on airway sensory nerves.

1 The anti-tussive effects, of the local anaesthetic, lidocaine and carcainium chloride (RSD931) have been investigated in guinea-pigs and rabbits. 2 Pre-treatment of guinea-pigs with aerosols of lidocaine or RSD931 at 0.1, 1.0 and 10 mg ml(-1) reduced the number of citric acid-induced coughs by 9.3, 32.6 and 40.9% (P>0.05) for lidocaine and by 25.3% (P>0.05), 40.4% (P>0.05) and 97.6% (P<0.01) for RSD931, respectively and increased the latency to onset of cough at 10.0 mg ml(-1) only. In addition, RSD931 at 10 mg ml(-1) reduced citric acid-evoked cough responses in rabbits (with prior exposure to ozone at 3 p.p.m. for 1 h) from 22.1+/-5.1 to 2.7+/-0.9 coughs (P<0.01). 3 Acute pre-treatment of guinea-pigs with aerosols of lidocaine or RSD931 at 10.0 and 30.0 mg ml(-1) reduced the number of capsaicin-evoked coughs by 42.2 and 10.3% (P>0.05) (lidocaine) and by 25% (P>0.05) and 76.9% (P<0.01) (RSD931), respectively. Lidocaine had little effect on the latency of cough onset at either 10.0 or 30.0 mg ml(-1), however, RSD at 30.0 mg ml(-1) significantly (P<0.05) prolonged the latency of cough onset. 4 RSD931 (10.0 mg ml(-1)) significantly (P<0.05-<0.01) reduced the spontaneous and histamine-evoked discharges in Adelta-fibres originating from airway, rapidly adapting stretch receptors (RARs) without affecting histamine-evoked bronchoconstriction. Lidocaine at 10.0 mg ml(-1) also significantly (P<0.05) inhibited the spontaneous and histamine-induced discharges of RARs without affecting histamine-evoked bronchoconstriction. 5 Aerosols of RSD931 (10.0 mg ml(-1)) caused a transient, but significant (P<0.05), activation of pulmonary C-fibre endings 2.5 min after administration started. RSD931 had no significant (P>0.05) effects on discharges in bronchial C-fibres originating from bronchial C-fibre endings, capsaicin-evoked discharges of either pulmonary or bronchial C-fibre endings or on capsaicin-evoked bronchoconstriction. In contrast, lidocaine (10.0 mg ml(-1)) significantly (P<0.05) inhibited spontaneous and capsaicin-induced discharges in both pulmonary and bronchial C-fibres respectively. Lidocaine also significantly (P<0.05) reduced capsaicin-evoked bronchoconstriction. 6 These studies suggest that the anti-tussive actions of RSD931 are mediated via inhibition of discharges in Adelta-fibres originating from airway RARs. The mechanism of action of RSD931 is distinct from that of the local anaesthetic lidocaine and RSD931 may represent a novel class of anti-tussive agent.

Relationship of airway responsiveness with airway morphometry in normal and immunized rabbits.

Airway responses to chemical stimuli occur over a wide range of concentrations, with overlap between severe, moderate and mild asthmatic groups and with normal healthy individuals. Mathematical modelling has suggested that relative thickness of the airway wall may account for this range of responsiveness. We have investigated whether in vivo airway responsiveness varies as a function of airway wall thickness in terms of airway smooth muscle area in normal and immunized New Zealand White (NZW) rabbits. Airway responsiveness to inhaled methacholine (MCh) was determined in vivo under neuroleptanalgesia. Subsequently, ex vivo responsiveness to MCh (pD(2)=-log EC(50)) of isolated bronchi from the same animal was established. Smooth muscle area per mm basement membrane (SM/mmBM) was also measured morphometrically in the tested bronchi and the findings related to in vivo and ex vivo responsiveness. We found no relationship between airway responsiveness in vivo and pD(2)values in either immunized or control rabbits. In both control and immunized rabbits, no correlation was found between SM/mmBM and in vivo airway responsiveness. Only in immunized animals with a PCA titre >0, was there a significant correlation (=-0.5986, P<0.05) between SM/mmBM and pD(2). We conclude that airway smooth muscle area per se is not the sole contributor of airway responsiveness in vivo in normal rabbits.

Effect of antagonists for NK(2)and B(2) receptors on antigen-induced airway responses in allergic rabbits.

The effects of the tachykinin NK(2)receptor antagonist, MEN 11420 (300 nmol/kg) and the bradykinin B(2)receptor antagonist, CP 0597 (17.2 and 172 nmol/kg) were studied in a rabbit model of antigen-induced airway responses. Antigen inhalation induced acute bronchoconstriction, airway hyperresponsiveness to histamine, and pulmonary eosinophil infiltration in 3-month-old rabbits immunized with Alternaria tenuis antigen within 24 h of birth. Treatment with MEN 11420 significantly reduced the acute bronchoconstriction induced by antigen, in terms of lung resistance. Antigen-induced changes in dynamic compliance were unaffected. CP 0597 had no effect on antigen-induced changes in lung function. Neither MEN 11420 nor CP 0597 had a significant effect on the antigen-induced increase in airway responsiveness to inhaled histamine or the pulmonary eosinophil infiltration 24 h after antigen challenge. We conclude that blockade of the NK(2)receptor can alter acute airway responses to antigen, but not antigen-induced eosinophilia or hyperresponsiveness to histamine. We also conclude that bradykinin B(2)receptor-mediated responses do not play a role in airway responses to antigen.

Antigen-induced bronchial hyperresponsiveness in the rabbit is not dependent on M(2)-receptor dysfunction.

We have assessed the effect of sensitization to allergen on airway smooth muscle responsiveness and acetylcholine (ACh) release from cholinergic nerves in tracheal preparations from rabbits immunized at birth to Alternaria tenuis and littermate control rabbits injected with saline. ACh release induced by EFS was significantly greater in tracheal preparations obtained from immunized rabbits compared with littermate controls. The ability of the muscarinic-receptor agonist, oxotremorine, to inhibit ACh release to EFS (4 Hz) was not altered by immunization. The contractile response evoked by electrical field stimulation (EFS), ACh and 5-hydroxytryptamine (5-HT) was not significantly altered in tracheal preparations from antigen immunized rabbits compared with littermate controls. Antigen challenge of immunized rabbits did not affect the release of ACh from isolated trachea following EFS, or the ability of oxotremorine to inhibit ACh release. Furthermore, antigen challenge of immunized rabbits failed to alter the contractile response to EFS or ACh, but reduced the contractile potency of 5-HT. These results demonstrate increased ACh release in tracheal preparations following immunization which had no functional consequence on airway smooth muscle responsiveness. Moreover, the increased release in ACh was not associated with an alteration in M(2)-receptor function. Thus, antigen-induced bronchial hyperresponsiveness in the rabbit does not appear to depend upon M(2)-receptor dysfunction.

The effect of 15-HPETE on airway responsiveness and pulmonary cell recruitment in rabbits.

1. In the present study we have investigated the effect of 15-hydroperoxyeicosatetraenoic acid (15-HPETE) and 15-hydroxyeicosatetraenoic acid (15-HETE) on airway responsiveness to inhaled histamine in rabbits in vivo. 2. 15-HPETE increased airway responsiveness to histamine 24 h after tracheal instillation and this was associated with a cellular infiltration consisting mainly of neutrophils, as measured by bronchoalveolar lavage. The airway hyperresponsiveness induced by 15-HPETE was still present 72 h after tracheal instillation of 15-HPETE, but had returned to baseline values one week post challenge. The number of neutrophils in bronchoalveolar lavage remained significantly elevated compared to pre-challenge levels. In contrast to 15-HPETE, the major metabolite 15-HETE, failed to alter airway hyperresponsiveness to histamine despite the recruitment of neutrophils into the lung, suggesting that the effect of 15-HPETE was not secondary to the generation of this metabolite nor dependent on the influx of neutrophils. 3. Both capsaicin and atropine but not the peripherally acting mu-opioid receptor agonist, BW443C (H-Tyr-D-Arg-Gly-Phe(4-NO2)-Pro-NH4), attenuated 15-HPETE-induced hyperresponsiveness. The increased cellular infiltration induced by 15-HPETE was only attenuated by capsaicin. 4. The results of the present study suggest that the release of 15-HPETE into the airways could contribute to sensitization of afferent nerve endings analogous to the hyperalgesia induced by this mediator in skin.

A study on rat platelet responsiveness following intravenous endotoxin administration.

The aim of the present study was to evaluate platelet responsiveness in rats following E.coli endotoxin administration. Injection of E.coli to rats caused a reduction in ADP-induced pulmonary 111In labelled platelet accumulation four hours later. Similarly, when platelet aggregation was evaluated on PRP obtained from rats four hours after endotoxin administration, we found that platelet response to both ADP and collagen was significantly reduced. When platelets obtained from endotoxemic rats were suspended in normal plasma, the aggregating response to ADP and collagen was not different from that obtained with control platelets. Similarly, platelets from control rats suspended in plasma from endotoxemic rats showed hyporesponsiveness to ADP and collagen. There was no difference in the aggregatory response to collagen or to thrombin of washed platelet suspension (WPS) obtained from endotoxemic and normal rats. In conclusion, by using an in vivo minimally invasive technique and an ex vivo platelet aggregation test we demonstrate that during endotoxemia platelet are functionally unaltered and the platelet hyporesponsiveness is only observed in presence of plasma.