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In vascular dementia (VaD) and Alzheimer’s disease (AD), cerebral hypoperfusion and blood‐brain barrier (BBB) leakiness contribute to brain damage. In this study, we have measured biochemical markers and mediators of cerebral hypoperfusion and BBB in the frontal (BA6) and parietal (BA7) cortex and underlying white matter, to investigate the pathophysiology of vascular dysfunction in AD, VaD and mixed dementia. The ratio of myelin‐associated glycoprotein to proteolipid protein‐1 (MAG:PLP1), a post‐mortem biochemical indicator of the adequacy of ante‐mortem cerebral perfusion; the concentration of fibrinogen adjusted for haemoglobin level, a marker of blood‐brain barrier (BBB) leakiness; the level of vascular endothelial growth factor‐A (VEGF), a marker of tissue hypoxia; and endothelin‐1 (EDN1), a potent vasoconstrictor, were measured by ELISA in the frontal and parietal cortex and underlying white matter in 94 AD, 20 VaD, 33 mixed dementia cases and 58 age‐matched controls. All cases were assessed neuropathologically for small vessel disease (SVD), cerebral amyloid angiopathy (CAA) severity, Aβ and phospho‐tau parenchymal load, and Braak tangle stage. Aβ40 and Aβ42 were measured by ELISA in guanidine‐HCl tissue extracts. We found biochemical evidence of cerebral hypoperfusion in AD, VaD and mixed dementia to be associated with SVD, Aβ level, plaque load, EDN1 level and Braak tangle stage, and to be most widespread in mixed dementia. There was evidence of BBB leakiness in AD—limited to the cerebral cortex and related to EDN1 level. In conclusion, abnormalities of cerebral perfusion and BBB function in common types of dementia can largely be explained by a combination of arteriolosclerosis, and Aβ‐, tau‐ and endothelin‐related vascular dysfunction. The relative contributions of these processes vary considerably both between and within the diseases. Tayler et al. used post‐mortem biochemical methods to determine the severity of chronic and acute hypoperfusion of the cerebral cortex and white matter in Alzheimer's disease (AD), vascular dementia (VaD) and mixed dementia (Mixed). The two myelin proteins myelin‐associated protein (MAG) and proteolipid protein‐1 (PLP‐1), which have a similar slow turnover in vivo, are differentially susceptible to changes in tissue oxygenation such that a fall in the ratio of these proteins indicates reduced perfusion of the tissue over a period of several months prior to death. In contrast, vascular endothelial growth factor‐A (VEGF‐A) is upregulated acutely in response to tissue hypoxia. By measuring these proteins, the authors showed the severity of cerebral hypoperfusion in AD, VaD and mixed dementia to be associated with multiple factors (small vessel disease severity, Aβ level, plaque load, endothelin‐1 level and Braak tangle stage) and to be most widespread in mixed dementia.

Overactivity of the renin-angiotensin system (RAS), both systemically and within organs, is associated with ageing and cardiovascular diseases. Localised brain RAS is dysregulated in Alzheimer's disease (AD). In this thesis, I investigated brain RAS signalling in normal ageing and AD in transgenic mouse models and human post-mortem brain tissue. In mice, ACE-1, ACE-2, (ELISA) and enzyme activity (FRET-based activity assay), and Ang-II and Ang-(1-7) levels (ELISA), were measured at different ages corresponding to the onset of pathology and cognitive decline. In humans, RAS gene (RT-PCR), protein, and enzyme activities were measured in the frontal and temporal cortex in a normal ageing cohort (n=101, 19-80y) and an AD cohort (n=60), stratified according to Braak tangle stage (BS), as a proxy of disease stage. In mice, ACE-2 declined with normal ageing across all four APP-transgenic models. Surprisingly, RAS markers were similar between transgenic and wild-type mice and were not exacerbated in-line with the onset of disease or cognitive decline (except for elevated ACE-2 activity and Ang-II levels at a younger age in the aggressive 5xFAD model). In humans, an age- and disease-related dysregulation of RAS signalling was observed. The age-related imbalance was driven by cRAS overactivation and differed from RAS dysregulation in AD. Notably in AD, ACE-1 enzyme activity was induced in the early stages of disease (BS III-IV) and MAS1 and IRAP's expressions (mediators of regulatory RAS signalling) were reduced. In conclusion, (i) age-related changes in brain RAS differ between mice and humans, (ii) age-related changes in human brain RAS are driven by cRAS signalling (iii) AD-related changes in RAS include early induction of ACE-1 activity and a reduction in the expression of rRAS genes in late-stage AD. Overall, RAS in normal ageing differs from dysregulated RAS in AD, offering a potential novel therapeutic target in the early stages of AD.

It's difficult enough having a \"real\" conversation with employees about their performance over the past year, their development needs and career aspirations, even at the best of times. But when the business strategy is retrenchment, when training budgets have been pruned and career paths blocked because nobody moves on any more, those set-piece discussions can easily be de-motivating and confusing. The latest \"Employee Outlook\" survey from the Chartered Institute of Personnel & Development, taking the pulse of the UK workforce in summer 2012, found that only 46% of employees received feedback on their performance from their line manager, only 39% had discussions about their training and development needs with their boss, and only 30% had been coached on the job by him or her. Clearly, the reality has fallen far short of the ideal.

Opioids are the most common drugs associated with unintentional drug overdose. Death results from respiratory depression. Prolonged use of opioids results in the development of tolerance but the degree of tolerance is thought to vary between different effects of the drugs. Many opioid addicts regularly consume alcohol (ethanol), and post-mortem analyses of opioid overdose deaths have revealed an inverse correlation between blood morphine and ethanol levels. In the present study, we determined whether ethanol reduced tolerance to the respiratory depressant effects of opioids. Mice were treated with opioids (morphine, methadone, or buprenorphine) for up to 6 days. Respiration was measured in freely moving animals breathing 5% CO2 in air in plethysmograph chambers. Antinociception (analgesia) was measured as the latency to remove the tail from a thermal stimulus. Opioid tolerance was assessed by measuring the response to a challenge dose of morphine (10 mg/kg i.p.). Tolerance developed to the respiratory depressant effect of morphine but at a slower rate than tolerance to its antinociceptive effect. A low dose of ethanol (0.3 mg/kg) alone did not depress respiration but in prolonged morphine-treated animals respiratory depression was observed when ethanol was co-administered with the morphine challenge. Ethanol did not alter the brain levels of morphine. In contrast, in methadone- or buprenorphine-treated animals no respiratory depression was observed when ethanol was co-administered along with the morphine challenge. As heroin is converted to morphine in man, selective reversal of morphine tolerance by ethanol may be a contributory factor in heroin overdose deaths.

BackgroundIdentification of athletes with cardiac inflammation following COVID-19 can prevent exercise fatalities. The efficacy of pre and post COVID-19 infection electrocardiograms (ECGs) for detecting athletes with myopericarditis has never been reported.PurposeTo assess the prevalence and diagnostic significance of novel 12-lead ECG patterns following COVID-19 infection in elite soccer players.MethodsWe conducted a multicentre study over a 2-year period involving 5 centres and 34 clubs and compared pre COVID and post COVID ECG changes in 455 consecutive athletes who were infected. ECGs were reported in accordance with the International recommendations for ECG interpretation in athletes. The following patterns were also considered abnormal if they were not detected on the pre COVID-19 infection ECG: (a) biphasic T waves; (b) reduction in T wave amplitude by 50% in contiguous leads; (c) ST segment depression; (d) J-point and ST segment elevation > 0.2 mV in the precordial leads and >0.1 mV in the limb leads; (e) tall T waves ≥ 1.0 mV (f) low QRS amplitude in > 3 limb leads and (g) complete right bundle branch block. Athletes exhibiting novel ECG changes underwent cardiovascular magnetic resonance (CMR) scans. One club mandated CMR scans for all 28 (6%) athletes, despite the absence of cardiac symptoms or ECG changes.ResultsAthletes were aged 22 ± 5 years, 89% were male and 57% were white. 65 (14%) athletes reported cardiac symptoms. The mean duration of illness was 3 ± 4 days. The post COVID ECG was performed 14 ± 16 days following a positive PCR test. 440 (97%) athletes had an unchanged post COVID-19 ECG. Of these, 3 (0.6%) had cardiac symptoms and CMRs resulted in a diagnosis of pericarditis. 15 (3%) athletes demonstrated novel ECG changes following COVID-19 infection. Among athletes who demonstrated novel ECG changes, 10 (67%) reported cardiac symptoms. 13 (87%) athletes with novel ECG changes were diagnosed with inflammatory cardiac sequelae; pericarditis (n=6), healed myocarditis (n=3), definitive myocarditis (n=2), and possible/probable myocarditis (n=2). The overall prevalence of inflammatory cardiac sequelae in the cohort based on novel ECG changes was 2.8%.None of the 28 (6%) athletes, who underwent a CMR, in the absence of cardiac symptoms or novel ECG changes revealed any abnormalities. Athletes revealing novel ECG changes, had a higher prevalence of cardiac symptoms (67% v 12% p<0.0001) and longer symptom duration (8±8 days vs 2±4 days; p<0.0001) compared with athletes without novel ECG changes. Among athletes without cardiac symptoms, the additional yield of novel ECG changes to detect cardiac inflammation was 20% (n=3).Conclusions3% of elite soccer players demonstrated novel ECG changes post COVID-19 infection, of which almost 90% were diagnosed with cardiac inflammation during subsequent investigation. Most athletes with novel ECG changes exhibited cardiac symptoms. Novel ECGs changes contributed to a diagnosis of cardiac inflammation in 20% of athletes without cardiac symptoms.

BackgroundIdentification of athletes with cardiac inflammation following COVID-19 can prevent exercise fatalities. The efficacy of pre and post COVID-19 infection electrocardiograms (ECGs) for detecting athletes with myopericarditis has never been reported.PurposeTo assess the prevalence and diagnostic significance of novel 12-lead ECG patterns following COVID-19 infection in elite soccer players.MethodsWe conducted a multicentre study over a 2-year period involving 5 centres and 34 clubs and compared pre COVID and post COVID ECG changes in 455 consecutive athletes who were infected. ECGs were reported in accordance with the International recommendations for ECG interpretation in athletes. The following patterns were also considered abnormal if they were not detected on the pre COVID-19 infection ECG: (a) biphasic T waves; (b) reduction in T wave amplitude by 50% in contiguous leads; (c) ST segment depression; (d) J-point and ST segment elevation > 0.2 mV in the precordial leads and >0.1 mV in the limb leads; (e) tall T waves ≥ 1.0 mV (f) low QRS amplitude in > 3 limb leads and (g) complete right bundle branch block. Athletes exhibiting novel ECG changes underwent cardiovascular magnetic resonance (CMR) scans. One club mandated CMR scans for all 28 (6%) athletes, despite the absence of cardiac symptoms or ECG changes.ResultsAthletes were aged 22 ± 5 years, 89% were male and 57% were white. 65 (14%) athletes reported cardiac symptoms. The mean duration of illness was 3 ± 4 days. The post COVID ECG was performed 14 ± 16 days following a positive PCR test. 440 (97%) athletes had an unchanged post COVID-19 ECG. Of these, 3 (0.6%) had cardiac symptoms and CMRs resulted in a diagnosis of pericarditis. 15 (3%) athletes demonstrated novel ECG changes following COVID-19 infection. Among athletes who demonstrated novel ECG changes, 10 (67%) reported cardiac symptoms. 13 (87%) athletes with novel ECG changes were diagnosed with inflammatory cardiac sequelae; pericarditis (n=6), healed myocarditis (n=3), definitive myocarditis (n=2), and possible/probable myocarditis (n=2). The overall prevalence of inflammatory cardiac sequelae in the cohort based on novel ECG changes was 2.8%. None of the 28 (6%) athletes, who underwent a CMR, in the absence of cardiac symptoms or novel ECG changes revealed any abnormalities. Athletes revealing novel ECG changes, had a higher prevalence of cardiac symptoms (67% v 12% p<0.0001) and longer symptom duration (8±8 days vs 2±4 days; p<0.0001) compared with athletes without novel ECG changes. Among athletes without cardiac symptoms, the additional yield of novel ECG changes to detect cardiac inflammation was 20% (n=3).Abstract 2 Table 1Clinical Characteristics and CMR and 31P-MRS findings HV n=15 Isolated AS n=63 Diabetes and AS n=25 P value Age, y 71±4 71±12 72±7 0.73 Female, n (%) 6(40) 7(28) 25(40) 0.3 BMI, kg/m2 26±2* 27±4€ 31±4 <0.0001 Systolic BP, mmHg 136±9 132±17 131±20 0.44 HbA1c, mmol/mol 37±3* 37±4€ 56±14 <0.0001 NT- proBNP, ng/L 67[21-112] * 1411[629-2194]† 1376[390-2362] <0.0001 Euro Score II - 1.13 1.14 0.27 Rockwood Score - 2.15 2.22 0.23 CARDIAC STRUCTURAL AND FUNCTIONAL CHANGES LV end-diastolic volume indexed to BSA, mL/m2 78±15 80±22 84±21 0.53 LV end-systolic volume indexed to BSA, ml/m2 28±6 32±22 35±19 0.24 LV mass, g 102±25* 147±41† 164±59 0.0003 LV mass to LV end-diastolic volume, g/mL 0.66±0.11* 0.99±0.26† 0.96±0.25 <0.0001 LV stroke volume, ml 95±22 94±22 100±20 0.42 LV ejection fraction,% 64±3 64±12 60±12 0.25 LV maximal wall thickness, mm 10±1* 14±3† 14±3 <0.0001 RV end-diastolic volume indexed to BSA, mL/m2 83±12 79±18 78±20 0.36 RV end-systolic volume indexed to BSA, ml/m2 32±7 37±14 37±16 0.6 RV stroke volume, ml 97±17† 82±20 84±22 0.03 RV ejection fraction,% 62±5* 55±9† 54±10 0.01 LA biplane end-systolic volumes, mL 72±20 95±50 100±44 0.16 Biplane LA EF,% 59±11* 45±17 39±19 0.008 Global longitudinal strain, (-),% 16±4* 13±4† 11±4 0.001 Peak systolic circumferential strain, (-),% 21±2 19±5 18±5 0.11 Peak longitudinal diastolic strain rate, s-1 0.79±0.2 0.83±0.3 0.65±0.2€ 0.04 Mean native T1, (ms) 1209±79 1232±88 1262±84 0.16 Extra cellular volume, (%) 24±3 24±2 25±4 0.54 LGE, (%) - 3.1±2 3.4±4 0.85 MYOCARDIAL ENERGETICS AND PERFUSION PCr/ATP ratio 2.17±0.5* 1.74±0.4† 1.39±0.25€ <0.0001 Increase in RPP,% 25 23 25 0.5 Stress MBF, ml/min/g 2.14±0.66* 1.68±0.6† 1.24±0.3€ <0.0001 Rest MBF, ml/min/g 0.66±0.11 0.73±0.2 0.68±0.22 0.4 MPR 3.83±1.8* 2.4±0.78† 1.78±0.47€ <0.0001 € signifies p<0.05 between AS DM and AS Control, * signifies p<0.05 between AS DM and HV, † signifies p≤0.05 between AS Control and HV.Values are mean ±standard deviations or percentages. BSA indicates body surface area; LV, Left ventricle; RV, right ventricle; DM, type 2 diabetes mellitus; HCM, hypertrophic cardiomyopathy; LV, left ventricular; LA, left atrial; LA EF, left atrial ejection fraction; PCr, phosphocreatine; ATP, adenosine tri-phosphate; RPP, rate pressure product; MBF, myocardial blood flow; MPR, myocardial perfusion reserve.Abstract 2 Figure 1Cumulative incidence of the clinical events after valve replacement (AVR) is shown in the top row. Differences in myocardial PCr/ATP ratio, global stress myocardial blood flow and global longitudinal strain between healthy volunteers, patients with isolated severe AS and patients with severe AS and DM before the AVR in PCr/ATP ratio; global stress myocardial blood flow (ml/min/g) and global longitudinal strain are shown in the middle row. Changes in energetics, stress MBF and GLS after AVR are shown in the bottom row.Conclusion3% of elite soccer players demonstrated novel ECG changes post COVID-19 infection, of which almost 90% were diagnosed with cardiac inflammation during subsequent investigation. Most athletes with novel ECG changes exhibited cardiac symptoms. Novel ECGs changes contributed to a diagnosis of cardiac inflammation in 20% of athletes without cardiac symptoms.Conflict of InterestNone

Using a wavelet decomposition technique, we have extracted the Hurst exponent for a sample of 46 long and 22 short Gamma-ray bursts (GRBs) detected by the Gamma-ray Burst Monitor (GBM) aboard the Fermi satellite. This exponent is a scaling parameter that provides a measure of long-range behavior in a time series. The mean Hurst exponent for the short GRBs is significantly smaller than that for the long GRBs. The separation may serve as an unbiased criterion for distinguishing short and long GRBs.