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Sepsis affects 25 million children per year globally, leading to 2.9 million deaths and substantial disability in survivors. Extensive characterization of interactions between the host and bacteria in children is required to design novel preventive and therapeutic strategies tailored to this age group. Vγ9Vδ2 T cells are the first T cells generated in humans. These cells are defined by the expression of Vγ9Vδ2 T‐cell receptors (TCRs, using the TRGV9 and TRDV2 gene segments), which react strongly against the prototypical bacterial phosphoantigen HMBPP. We investigated this reactivity by analyzing the TCR δ (TRD) repertoire in the blood of 76 children (0–16 years) with blood culture‐proven bacterial sepsis caused by HMBPP‐positive Escherichia coli or by HMBPP‐negative Staphylococcus aureus or by HMBPP‐negative Streptococcus pneumoniae. Strikingly, we found that S. aureus, and to a lesser extent E. coli but not S. pneumoniae, shaped the TRDV2 repertoire in young children (<2 years) but not in older children or adults. This dichotomy was due to the selective expansion of a fetal TRDV2 repertoire. Thus, young children possess fetal‐derived Vγ9Vδ2 T cells that are highly responsive toward specific bacterial pathogens. [ABSTRACT FROM AUTHOR]

The renin‐angiotensin system (RAS) regulates systemic and cerebral blood flow and is dysregulated in dementia. The major aim of this study was to determine if RAS signalling is dysregulated in vascular dementia. We measured markers of RAS signalling in white matter underlying the frontal and occipital cortex in neuropathologically confirmed cases of vascular dementia (n = 42), Alzheimer's disease (n = 50), mixed AD/VaD (n = 50) and age‐matched controls (n = 50). All cases were stratified according to small vessel disease (SVD) severity across both regions. ACE‐1 and ACE‐2 protein and activity was measured by ELISA and fluorogenic peptide assays respectively, and angiotensin peptide (Ang‐II, Ang‐III and Ang‐(1–7)) levels were measured by ELISA. ACE‐1 protein level and enzyme activity, and Ang‐II and Ang‐III, were elevated in the white matter in vascular dementia in relation to SVD severity. ACE‐1 and Ang‐II protein levels were inversely related to MAG:PLP1 ratio, a biochemical marker of brain tissue oxygenation that when reduced indicates cerebral hypoperfusion, in a subset of cases. ACE‐2 level was elevated in frontal white matter in vascular dementia. Ang‐(1–7) level was elevated across all dementia groups compared to age‐matched controls but was not related to SVD severity. RAS signalling was not altered in the white matter in Alzheimer's disease. In the overlying frontal cortex, ACE‐1 protein was reduced and ACE‐2 protein increased in vascular dementia, whereas angiotensin peptide levels were unchanged. These data indicate that RAS signalling is dysregulated in the white matter in vascular dementia and may contribute to the pathogenesis of small vessel disease. [ABSTRACT FROM AUTHOR]

INTRODUCTION: There remains an urgent need to identify preclinical pathophysiological mechanisms of Alzheimer's disease (AD) development in high‐risk, racially diverse populations. We explored the relationship between cerebrospinal fluid (CSF) markers of vascular injury and neuroinflammation with AD biomarkers in middle‐aged Black/African American (B/AA) and non‐Hispanic White (NHW) participants. METHODS: Adults (45–65 years) with a parental history of AD were enrolled (n = 82). CSF and blood biomarkers were collected at baseline and year 2. RESULTS: CSF total tau (t‐tau), phosphorylated tau (p‐tau), and amyloid beta (Aβ)40 were elevated at year 2 compared to baseline. CSF soluble platelet‐derived growth factor receptor β (sPDGFRβ) levels, a marker of pericyte injury, correlated positively with t‐tau, p‐tau, Aβ40 markers of vascular injury, and cytokines at baseline and year 2. CSF sPDGFRβ and tau were significantly lower in B/AA than NHW. DISCUSSION: Vascular dysfunction and neuroinflammation may precede cognitive decline and disease pathology in the very early preclinical stages of AD, and there are race‐related differences in these relationships. Highlights: Cerebrospinal fluid (CSF) Alzheimer's disease (AD) biomarkers changed over 2 years in high‐risk middle‐aged adults.Markers of vascular dysfunction were associated with the CSF biomarkers amyloid beta and tau.AD biomarkers were lower in Black compared to non‐Hispanic White individuals.Markers of vascular dysfunction were lower among Black individuals. [ABSTRACT FROM AUTHOR]

Background: Vascular dysfunction often occurs concurrently with Alzheimer's disease (AD). Breakdown of the blood–brain barrier (BBB) and vascular injury may be related to amyloid and tau pathology. In preliminary analyses, we examined the relationship between cerebrospinal fluid (CSF) biomarkers of AD, neurodegeneration, and glial activation, and two novel CSF markers of vascular dysfunction: soluble platelet‐derived growth factor receptor beta (sPDGFRβ) a marker of BBB integrity, and angiopoietin‐2 (Ang2), a marker of vascular injury. Method: CSF samples from participants enrolled in the Wisconsin Registry for Alzheimer's Prevention (WRAP) or the Wisconsin Alzheimer's Disease Research Center (WADRC) studies were assayed for markers of AD, neurodegeneration, and gliosis, using Roche NeuroToolKit® immunoassays (Roche Diagnostics International Ltd, Switzerland). A subset of serially sampled participants (N = 209, Nobs = 531) who spanned the AD clinical spectrum (cognitively unimpaired, MCI, dementia) underwent sPDGFRβ measurement (ELISA); a sample of N = 121 (Nobs= 276) was also assayed for Ang2 (ELISA) (Table 1). Pearson correlations were calculated for all CSF biomarkers. Linear mixed‐effects models with random intercepts, age‐at‐lumbar‐puncture as the measure of time, and CSF vascular biomarker as the outcome were used to test associations with tau positivity (>24.8 pg/mL), and cognitive status. Result: sPDGFRβ correlated with all CSF biomarkers (rs range.18 to.45, ps<.001, Figure 1A) except AB42/40. Ang2 correlated with all CSF biomarkers (rs range.21 to.45 ps <.001, Figure 1B) except AB42/40, and S100B. sPDGFRβ and Ang2 correlated most strongly with Aβ40 and biomarkers of synaptic function (neurogranin and α‐synuclein). Tau positivity was associated with sPDGFRβ in the whole sample (estimate = 64.5, p<.001) and excluding participants with MCI/dementia (estimate = 77.7, p<.001). Tau positivity was associated with Ang2 (estimate = 18.1, p =.007), however the association was not significant after excluding participants with MCI/dementia. There was no difference in sPDGFRβ across the AD clinical spectrum. Ang2 was higher among participants with MCI than cognitively unimpaired participants (estimate = 21.0, p =.037, Figure 2). Conclusion: CSF markers of vascular injury were elevated in MCI and were moderately related to tau pathology and markers of neuronal injury and neuroinflammation, but not amyloid pathology, providing insight into the association of of vascular injury to AD related disease [ABSTRACT FROM AUTHOR]

Background: Understanding the health care activity and associated hospital costs of caring for people living with HIV is an important component of assessing the cost effectiveness of new technologies and for budget planning. Methods: Data collected between 2010 and 2017 from an English HIV treatment centre were combined with national reference costs to estimate the rate of hospital attendances and costs per quarter year, according to demographic and clinical factors. The final dataset included records for 1763 people living with HIV, which was analysed using negative binomial regression models and general estimating equations. Results: People living with HIV experienced an unadjusted average of 0.028 (standard deviation [SD] 0.20) inpatient episodes per quarter, equivalent to one every 9 years, and 1.85 (SD 2.30) outpatient visits per quarter. The unadjusted mean quarterly cost per person with HIV (excluding antiretroviral drug costs) was £439 (SD 604). Outpatient appointments and inpatient episodes accounted for 88% and 6% of total costs, respectively. In adjusted models, low CD4 count was the strongest predictor of inpatient stays and outpatient visits. Low CD4 count and new patient status (having a first visit at the Trust in the last 6 months) were the factors that most increased estimated costs. Associations were weaker or less consistent for demographic factors (age, sex/sexual orientation/ethnicity). Sensitivity analyses suggest that the findings were generally robust to alternative parameter and modelling assumptions. Conclusion: A number of factors predicted hospital activity and costs, but CD4 cell count and new patient status were the strongest. The study results can be incorporated into future economic evaluations and budget impact assessments of HIV‐related technologies. [ABSTRACT FROM AUTHOR]

Objectives: The aim of the study was to explore staff views about whether and how service users should be involved in the process of team formulation. Design: This study used Q methodology to explore health care professionals' views about service user involvement in team formulation meetings. Methods: Forty staff members with experience of attending team formulation meetings completed a Q Sort in which they ranked how much they agreed or disagreed with 58 statements about service user inclusion in team formulation. Factor analysis was used to identify viewpoints within the data set. Results: A three‐factor solution accounting for 60% of the variance was considered the best fit for the data. The factors were: 'A safe space for staff', 'Concerns about inclusion and collaboration' and 'Service users might find attendance harmful'. Consensus statements identified areas where all participants agreed. Conclusions: This is an important area for exploration, given the growing practice of team formulation and the professional and ethical issues raised by service user involvement. There are a range of ways to promote inclusion within the practice, and staff should always consider the individual needs of service users. [ABSTRACT FROM AUTHOR]

Cerebrovascular disease underpins vascular dementia (VaD), but structural and functional changes to the cerebral vasculature contribute to disease pathology and cognitive decline in Alzheimer's disease (AD). In this review, we discuss the contribution of cerebral amyloid angiopathy and non‐amyloid small vessel disease in AD, and the accompanying changes to the density, maintenance and remodelling of vessels (including alterations to the composition and function of the cerebrovascular basement membrane). We consider how abnormalities of the constituent cells of the neurovascular unit – particularly of endothelial cells and pericytes – and impairment of the blood‐brain barrier (BBB) impact on the pathogenesis of AD. We also discuss how changes to the cerebral vasculature are likely to impair Aβ clearance – both intra‐periarteriolar drainage (IPAD) and transport of Aβ peptides across the BBB, and how impaired neurovascular coupling and reduced blood flow in relation to metabolic demand increase amyloidogenic processing of APP and the production of Aβ. We review the vasoactive properties of Aβ peptides themselves, and the probable bi‐directional relationship between vascular dysfunction and Aβ accumulation in AD. Lastly, we discuss recent methodological advances in transcriptomics and imaging that have provided novel insights into vascular changes in AD, and recent advances in assessment of the retina that allow in vivo detection of vascular changes in the early stages of AD. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Introduction: Interpersonal spin is an indicator of intraindividual variability in social behavior. Spin is positively related to Neuroticism and is maladaptive, with well‐documented deleterious effects on social functioning. The perceptual processes associated with spin and how spin emerges are less well‐understood. The present research examines the interpersonal perception of individuals with higher spin and tests whether these perceptual processes explain the association of spin with Neuroticism. Method: 267 students participated in a 20‐day event contingent recording procedure, reporting on social interactions via mobile application. Participants' perceptions of others' behavior, their own affect, and their own behavior were measured within and across interactions. Results: We examined the affective and behavioral responses of individuals with higher spin to perceptions of others' behaviors. Individuals with higher spin showed greater affective and behavioral reactivity to perceptions of others' communal (agreeable‐quarrelsome) behavior. Neuroticism predicted greater affective reactivity (i.e., steeper slopes between event‐level perceived communion and negative affect), which in turn predicted higher spin. Conclusions: Individuals with higher spin may have an interpersonal style characterized by greater reactivity to perceptions of others' communal behavior. These individuals' behavioral lability may reflect underlying emotional dysregulation. These processes may ultimately interfere with the formation and maintenance of social bonds. [ABSTRACT FROM AUTHOR]

Objectives: Vaccines that prime Wilms' tumor 1 (WT1)‐specific CD8+ T cells are attractive cancer immunotherapies. However, immunogenicity and clinical response rates may be enhanced by delivering WT1 to CD141+ dendritic cells (DCs). The C‐type lectin‐like receptor CLEC9A is expressed exclusively by CD141+ DCs and regulates CD8+ T‐cell responses. We developed a new vaccine comprising a human anti‐CLEC9A antibody fused to WT1 and investigated its capacity to target human CD141+ DCs and activate naïve and memory WT1‐specific CD8+ T cells. Methods: WT1 was genetically fused to antibodies specific for human CLEC9A, DEC‐205 or β‐galactosidase (untargeted control). Activation of WT1‐specific CD8+ T‐cell lines following cross‐presentation by CD141+ DCs was quantified by IFNγ ELISPOT. Humanised mice reconstituted with human immune cell subsets, including a repertoire of naïve WT1‐specific CD8+ T cells, were used to investigate naïve WT1‐specific CD8+ T‐cell priming. Results: The CLEC9A‐WT1 vaccine promoted cross‐presentation of WT1 epitopes to CD8+ T cells and mediated priming of naïve CD8+ T cells more effectively than the DEC‐205‐WT1 and untargeted control‐WT1 vaccines. Conclusions: Delivery of WT1 to CD141+ DCs via CLEC9A stimulates CD8+ T cells more potently than either untargeted delivery or widespread delivery to all Ag‐presenting cells via DEC‐205, suggesting that cross‐presentation by CD141+ DCs is sufficient for effective CD8+ T‐cell priming in humans. The CLEC9A‐WT1 vaccine is a promising candidate immunotherapy for malignancies that express WT1. [ABSTRACT FROM AUTHOR]

The construction of dams significantly alters flow and sediment regimes with subsequent deleterious effects on the morphological and ecological character of rivers. Effective experimental floods can ameliorate the downstream geomorphic impacts of dams. The traditional view is that large floods are required to perform effective geomorphic work, and the geomorphic outcomes of small floods are often overlooked. Many river restoration frameworks do not consider small floods. Yet, there is evidence that the hydrological characteristics that ameliorate specific geomorphic impacts in a river are unique to each river, and a customised approach to setting the right mix of floods (including small experimental floods) is needed. In this study, we modify an existing flood effectiveness model developed for large floods, for determining the geomorphic effectiveness of small floods in a highly regulated Australian river. Two flood classes were added to the model (medium peak stream power and moderate total energy expenditure), and the flood power characteristics were rescaled to reflect the relative difference in the magnitude of the small floods and the magnitude of the geomorphic work performed. Using a step‐wise approach, this customised model determined the geomorphic effectiveness of small floods. The best flood for ameliorating the geomorphic impacts of flow regulation had medium to long duration (10 to 51 days), high peak unit stream power (77 to 123 Wm−2) and moderate to large total energy expenditure (78,600 to 342,320 × 103 J). This approach to determining flood effectiveness for small floods is applicable to other geomorphically impacted river channels downstream of dams and can be used to inform experimental flood releases for geomorphic outcomes. [ABSTRACT FROM AUTHOR]

Experimental floods, generated downstream of dams, are used to recover specific bio‐geomorphic functions in regulated rivers. Studies of the effects of experimental floods vary in their objective, location, and the hydrological and bio‐geomorphic variables used to quantify recovery. Measurements of geomorphic change are required to guide future release strategies. The focus of this study was to determine if a large experimental flood in the Snowy River Australia, could promote geomorphic recovery of the river channel downstream of Jindabyne Dam following 35 years of flow regulation. The objectives of the release were to deepen, widen, and increase channel capacity and coarsen the riverbed substratum in the Jindabyne Gorge and Dalgety Uplands sections of the Snowy River. Data from the release were compared with that of a natural flood event that occurred after the experimental flow event. Both events showed channel adjustments and a degree of geomorphic recovery, but this varied between the two river sections. Marked channel adjustments occurred in the Dalgety Uplands reach following both the experimental and natural flood event and in the Jindabyne Gorge section following the natural flood event. Geomorphic changes were related to the hydrological character of each flood event. The number of flood peaks, the sequence of peaks, the flood duration, and the total energy expenditure differed markedly between the two events, and these four flood hydrological characteristics explained the greater geomorphic recovery associated with the natural flood event in the Jindabyne Gorge. No clear hydro‐geomorphic relationship was derived for channel change in the Dalgety Uplands where existing morphological constraints limit flood effectiveness. [ABSTRACT FROM AUTHOR]

Background: The renin‐angiotensin system (RAS) is dysregulated in Alzheimer's disease (AD): angiotensin‐converting enzyme (ACE‐1) activity, a rate‐limiting enzyme in the disease‐associated classical RAS (cRAS) pathway, is elevated, whereas ACE‐2 activity, a central mediator of the counter‐regulatory protective pathway (rRAS) (that generates Ang‐(1‐7) from Ang‐II) is defective. Previous meta‐analyses, more recently confirmed in GWAS studies, indicate that ACE1 variants, including an insertion (I)/deletion (D) (indel) polymorphism at intron 16, are risk variants in AD. In this study, we have determined if ACE‐1 and ACE‐2 are dysregulated in AD in relation to ACE1 variant (rs4343) (a proxy marker for the more commonly studied indel polymorphism). Method: We studied brain tissue from the frontal and parietal cortex from 147 dementia cases (AD (n = 94) and vascular dementia n = 20 and mixed AD/VaD (n = 33)) and 104 age‐matched controls from the South West Dementia Brain Bank, University of Bristol. ACE‐1 and ACE‐2 protein levels were measured by ELISA, and enzyme activities were measured using fluorogenic peptide substrate assays. ACE1 (rs4343) polymorphism was genotyped by PCR. Result: ACE‐1 protein level was increased (p<0.0001) and ACE‐2 protein level reduced (p = 0.0103) in AD cases compared to controls in the parietal cortex. In contrast, no significant changes in protein level were observed in the frontal cortex. ACE‐1 enzyme activity was elevated (p<0.0001) as was ACE‐2 enzyme activity in both frontal and parietal cortices (p<0.0001 and p = 0.001 respectively) in AD. Individuals with I/I compared with D/D and I/D genotypes in AD had unchanged ACE‐1 level (p = 0.079), lower ACE‐1 enzyme activity (p = 0.029), higher ACE‐2 level (p = 0.011) and unaltered ACE‐2 enzyme activity (p = 0.085) in the frontal cortex. Conclusion: These data confirm our previous findings showing that RAS is dysregulated in AD. Interestingly, we report regional differences in RAS signalling in AD and a reciprocal relationship between ACE‐2 protein level (reduced) and enzyme activity (increased) in AD that warrants further investigation. RAS appears to be most dysregulated in individuals with an I/I genotype in AD. [ABSTRACT FROM AUTHOR]

Aims: There is evidence that accumulation of α‐synuclein (α‐syn) in Parkinson's disease (PD) and dementia with Lewy bodies (DLB) results from impaired removal of α‐syn rather than its overproduction. Kallikrein‐6 (KLK6), calpain‐1 (CAPN1) and cathepsin‐D (CTSD) are among a small number of proteases that cleave α‐syn and are dysregulated in PD and DLB. Our aim in this study was to determine whether protease activity is altered in another α‐synucleinopathy, multiple system atrophy (MSA), and might thereby modulate the regional distribution of α‐syn accumulation. Methods: mRNA and protein level and/or activity of KLK6, CAPN1 and CTSD were measured and assessed in relation to α‐syn load in multiple brain regions (posterior frontal cortex, caudate nucleus, putamen, occipital cortex, pontine base and cerebellar white matter), in MSA (n = 20) and age‐matched postmortem control tissue (n = 20). Results: CTSD activity was elevated in MSA in the pontine base and cerebellar white matter. KLK6 and CAPN1 levels were elevated in MSA in the putamen and cerebellar white matter. However, the activity or level of these proteolytic enzymes did not correlate with the regional distribution of α‐syn. Conclusions: Accumulation of α‐syn in MSA is not due to reduced activity of the proteases we have studied. We suggest that their upregulation is likely to be a compensatory response to increased α‐syn in MSA. [ABSTRACT FROM AUTHOR]

Abstract: Research suggests that prototypical group members often exert stronger social influence and thus have greater leadership opportunities relative to members of marginalized or underrepresented social categories. This article offers a new model for understanding and promoting leadership diversity by focusing on the mechanisms by which a group or organization coordinates behavior among its members. We predict that means‐focused groups (in which social norms drive coordination) are likely to suppress influence among non‐prototypic members, whereas ends‐focused groups (in which shared goals drive coordination) are more likely to allow for leadership from a diverse set of members. The primary mechanism by which a group coordinates its members—social norms versus shared goals—is thus expected to serve as a critical moderator affecting the likelihood that group‐level diversity will translate into inclusion, innovation, performance, and prosperity. Implications of the model for policy and practice, particularly in organizational settings, are discussed. [ABSTRACT FROM AUTHOR]

Recent advances in the identification and characterization of renal drug transporters and drug-metabolizing enzymes has led to greater understanding of their roles in drug and chemical elimination and in modulation of the intrarenal exposure and response to drugs, nephrotoxic compounds, and physiological mediators. Furthermore, there is increasing awareness of the potential importance of drug-drug interactions (DDIs) arising from inhibition of renal transporters, and regulatory agencies now provide recommendations for the evaluation of transporter-mediated DDIs. Apart from the well-recognized effects of kidney disease on renal drug clearance, there is a growing body of evidence demonstrating that the nonrenal clearances of drugs eliminated by certain transporters and drug-metabolizing enzymes are decreased in patients with chronic kidney disease (CKD). Based on these observations, renal impairment guidance documents of regulatory agencies recommend pharmacokinetic characterization of both renally cleared and nonrenally cleared drugs in CKD patients to inform possible dosage adjustment. [ABSTRACT FROM AUTHOR]

Clusterin, also known as apoJ, is a lipoprotein abundantly expressed within the CNS. It regulates Aβ fibril formation and toxicity and facilitates amyloid-β (Aβ) transport across the blood-brain barrier. Genome-wide association studies have shown variations in the clusterin gene ( CLU) to influence the risk of developing sporadic Alzheimer's disease (AD). To explore whether clusterin modulates the regional deposition of Aβ, we measured levels of soluble (NP40-extracted) and insoluble (guanidine-HCl-extracted) clusterin, Aβ40 and Aβ42 by sandwich ELISA in brain regions with a predilection for amyloid pathology-mid-frontal cortex (MF), cingulate cortex (CC), parahippocampal cortex (PH), and regions with little or no pathology-thalamus (TH) and white matter (WM). Clusterin level was highest in regions with plaque pathology (MF, CC, PH and PC), approximately mirroring the regional distribution of Aβ. It was significantly higher in AD than controls, and correlated positively with Aβ42 and insoluble Aβ40. Soluble clusterin level rose significantly with severity of cerebral amyloid angiopathy, and in MF and PC regions was highest in APOE ɛ4 homozygotes. In the TH and WM (areas with little amyloid pathology) clusterin was unaltered in AD and did not correlate with Aβ level. There was a significant positive correlation between the concentration of clusterin and the regional levels of insoluble Aβ42; however, the molar ratio of clusterin : Aβ42 declined with insoluble Aβ42 level in a region-dependent manner, being lowest in regions with predilection for Aβ plaque pathology. Under physiological conditions, clusterin reduces aggregation and promotes clearance of Aβ. Our findings indicate that in AD, clusterin increases, particularly in regions with most abundant Aβ, but because the increase does not match the rising level of Aβ42, the molar ratio of clusterin : Aβ42 in those regions falls, probably contributing to Aβ deposition within the tissue. [ABSTRACT FROM AUTHOR]

We have examined the roles of the endothelin-converting enzyme-1 and -2 ( ECE-1 and ECE-2) in the homeostasis of α-synuclein (α-syn) and pathogenesis of Lewy body disease. The ECEs are named for their ability to convert inactive big endothelin to the vasoactive peptide endothelin-1 ( EDN1). We have found that ECE-1 and ECE-2 cleave and degrade α-syn in vitro and si RNA-mediated knockdown of ECE-1 and ECE-2 in SH- SY5Y neuroblastoma cells significantly increased α-syn both intracellularly (within the cell lysate) ( p < 0.05 for both ECE-1 and -2) and extracellularly (in the surrounding medium) ( p < 0.05 for ECE-1 and p = 0.07 for ECE-2). Double immunofluorescent labelling showed co-localization of ECE-1 and ECE-2 with α-syn within the endolysosomal system (confirmed by a proximity ligation assay). To assess the possible relevance of these findings to human Lewy body disease, we measured ECE-1 and ECE-2 levels by sandwich ELISA in post-mortem samples of cingulate cortex (a region with a predilection for Lewy body pathology) in dementia with Lewy bodies ( DLB) and age-matched controls. ECE-1 ( p < 0.001) and ECE-2 ( p < 0.01) levels were significantly reduced in DLB and both enzymes correlated inversely with the severity of Lewy body pathology as indicated by the level of α-syn phosphorylated at Ser129 ( r = −0.54, p < 0.01 for ECE-1 and r = −0.49, p < 0.05 for ECE-2). Our novel findings suggest a role for ECEs in the metabolism of α-syn that could contribute to the development and progression of DLB. [ABSTRACT FROM AUTHOR]

Objectives An increasing proportion of people living with HIV are older adults, who may require specialized care. Adverse physical and psychological effects of HIV infection may be greatest among older people or those who have lived longer with HIV. Methods The ASTRA study is a cross-sectional questionnaire study of 3258 HIV-diagnosed adults (2248 men who have sex with men, 373 heterosexual men and 637 women) recruited from UK clinics in 2011-2012. Associations of age group with physical symptom distress (significant distress for at least one of 26 symptoms), depression and anxiety symptoms (scores ≥ 10 on PHQ-9 and GAD-7, respectively), and health-related functional problems (problems on at least one of three domains of the Euroqol 5D-3L)) were assessed, adjusting for time with diagnosed HIV infection, gender/sexual orientation and ethnicity. Results The age distribution of participants was: < 30 years, 5%; 30-39 years, 23%; 40-49 years, 43%; 50-59 years, 22%; and ≥ 60 years, 7%. Overall prevalences were: physical symptom distress, 56%; depression symptoms, 27%; anxiety symptoms, 22%; functional problems, 38%. No trend was found in the prevalence of physical symptom distress with age [adjusted odds ratio ( OR) for trend across age groups, 0.96; 95% confidence interval ( CI) 0.89, 1.04; P = 0.36]. The prevalence of depression and anxiety symptoms decreased with age [adjusted OR 0.86 (95% CI 0.79, 0.94; P = 0.001) and adjusted OR 0.85 (95% CI 0.77, 0.94; P = 0.001), respectively], while that of functional problems increased (adjusted OR 1.28; 95% CI 1.17, 1.39; P < 0.001). In contrast, a longer time with diagnosed HIV infection was strongly and independently associated with a higher prevalence of symptom distress, depression symptoms, anxiety symptoms, and functional problems ( P < 0.001 for trends, adjusted analysis). Conclusions Among people living with HIV, although health-related functional problems were more common with older age, physical symptom distress was not, and mental health was more favourable. These results suggest that a longer time with diagnosed HIV infection, rather than age, is the dominating factor contributing to psychological morbidity and lower quality of life. [ABSTRACT FROM AUTHOR]

The CD8 co‐receptor engages peptide‐major histocompatibility complex class I (pMHCI) molecules at a largely invariant site distinct from the T‐cell receptor (TCR)‐binding platform and enhances the sensitivity of antigen‐driven activation to promote effective CD8+ T‐cell immunity. A small increase in the strength of the pMHCI/CD8 interaction (~1.5‐fold) can disproportionately amplify this effect, boosting antigen sensitivity by up to two orders of magnitude. However, recognition specificity is lost altogether with more substantial increases in pMHCI/CD8 affinity (~10‐fold). In this study, we used a panel of MHCI mutants with altered CD8‐binding properties to show that TCR‐mediated antigen specificity is delimited by a pMHCI/CD8 affinity threshold. Our findings suggest that CD8 can be engineered within certain biophysical parameters to enhance the therapeutic efficacy of adoptive T‐cell transfer irrespective of antigen specificity. [ABSTRACT FROM AUTHOR]

Background: Alzheimer's disease (AD) incidence among Black/African Americans (B/AA) is 64% higher than non‐Hispanic Whites (NHW). Studies show CSF total and phosphorylated tau are lower in cognitively unimpaired middle‐aged B/AAs compared to NHWs. Cognitive changes in B/AA adults are associated with smaller increases in CSF tau. We examined rate of cognitive and CSF AD biomarker change, over two years, in a cognitively unimpaired, racially diverse, middle‐aged cohort with a parental history of AD. Method: Cognitive tests (MOCA, Trails B, Digit Span, Benson Delay, Buschke Delay, and MINT) were collected at baseline (BL), 1 year (Y1), and 2 years (Y2). CSF was collected at BL and Y2 for AD biomarkers (Aβ and tau) and sPDGFRβ, an index of blood brain barrier damage. Analyses controlled for age, sex, race, education, and APOE4. Result: Participants (N=80) were mostly female (69%), highly educated (81% ≥college), and 34% B/AA. B/AAs exhibited lower levels of p‐tau, t‐tau, and sPDGFRβ at BL and Y2 compared to NHWs (p≤0.02). P‐tau increased from BL to Y2 for all participants (p<0.01). NHWs outperformed B/AAs in 7/7 cognitive tests at baseline and 6/7 at Y2. Digit Span improved from BL to Y2 (p=0.014) for all participants. Analyses by race demonstrated improvements for MOCA and Buschke Delay among B/AAs, and improvements for Trails B and Benson Delay among NHWs. There was a difference in rate of change over time by race in Benson Delay (F=8.22, p=0.0055). Linear models showed positive associations between Trails B and p‐tau and sPDGFRβ (p≤0.05). Negative associations were found between Benson Delay and p‐tau and t‐tau (p≤0.04), between MINT and sPDGFRβ, p‐tau, and t‐tau (p=0.04), and between Bushcke Delay and sPDGFRβ (p=0.03). Conclusion: While cognitive scores changed over time, group analyses showed improvements among B/AA participants in verbal memory and global cognition, while NHW participants improved in tests of processing speed and visuospatial memory. CSF p‐tau increased over 2 years. As CSF AD biomarkers were predictive of cognitive function scores, AD pathologic processes may begin earlier in at‐risk adults. Further study of race‐associated differences in AD biomarkers is needed, as these differences may contribute to AD‐related health disparities. [ABSTRACT FROM AUTHOR]

Paracetamol is a commonly used drug in the intensive care unit. There have been reports in the literature of an association with significant hypotension, a potentially important interaction for labile critically ill patients. Route of administration may influence the incidence of hypotension. This single-centre, prospective, open-label, randomised, parallel-arm, active-control trial was designed to determine the incidence of hypotension following the administration of paracetamol to critically ill patients. Fifty adult patients receiving paracetamol for analgesia or pyrexia were randomly assigned to receive either the parenteral or enteral formulation of the drug. Paracetamol concentrations were measured at baseline and at multiple time points over 24 h. The maximal plasma paracetamol concentration was significantly different between routes; 156 vs. 73 micromol.l(-1) [p = 0.0005] following the first dose of parenteral or enteral paracetamol, respectively. Sixteen hypotensive events occurred in 12 patients: parenteral n = 12; enteral n = 4. The incident rate ratio for parenteral vs. enteral paracetamol was 2.94 (95% CI 0.97-8.92; p = 0.06). The incidence of hypotension associated with paracetamol administration is higher than previously reported and tends to be more frequent with parenteral paracetamol. [ABSTRACT FROM AUTHOR]

There is a perfusion deficit in Alzheimer's disease (AD), commencing in the precuneus and spreading to other parts of the cerebral cortex. The deficit anticipates the development of dementia, contributes to brain damage, and is caused by both functional and structural abnormalities of the cerebral vasculature. Most of the abnormalities are probably secondary to the accumulation of Aβ but the consequent hypoperfusion may, in turn, increase Aβ production. In the early stages of disease, abnormalities that cause vasoconstriction predominate. These include cholinergic vascular denervation, inhibition of endothelial nitric oxide synthase, increased production of endothelin-1 production and possibly also of angiotensin II. Patients with AD also have an increased prevalence of structural disease of cerebral microvessels, particularly CAA and capillary damage, and particularly in the later stages of disease these are likely to make an important contribution to the cerebral hypoperfusion. The metabolic abnormalities that cause early vascular dysfunction offer several targets for therapeutic intervention. However, for intervention to be effective it probably needs to be early. Prolonged cerebral hypoperfusion may induce compensatory circulatory changes that are themselves damaging, including hypertension and small vessel disease. This has implications for the use of antihypertensive drugs once there is accumulation of Aβ within the brain. [ABSTRACT FROM AUTHOR]

Adoptive transfer of tumor‐specific cytotoxic T cells is a promising advance in cancer therapy. Similarly, checkpoint inhibition has shown striking clinical results in some patients. Here we combine adoptive cell transfer with ablation of the checkpoint protein Src homology 2‐domain‐containing phosphatase 1 (SHP‐1, Ptpn6). Naturally occurring motheaten mice lack SHP‐1 and do not survive weaning due to extensive immunopathology. To circumvent this limitation, we created a novel SHP‐1null mouse that is viable up to 12 weeks of age by knocking out IL1r1. Using this model, we demonstrate that the absence of SHP‐1 augments the ability of adoptively transferred CD8+ T cells to control tumor growth. This therapeutic effect was only observed in situations where T‐cell numbers were limited, analogous to clinical settings. However, adoptive transfer of non‐CD8+ SHP‐1null hematopoietic cells resulted in lethal motheaten‐like pathology, indicating that systemic inhibition of SHP‐1 could have serious adverse effects. Despite this caveat, our findings support the development of SHP‐1 inhibition strategies in human T cells to complement adoptive transfer therapies in the clinic. [ABSTRACT FROM AUTHOR]

The earliest decline in cerebral perfusion in Alzheimer's disease (AD) is in the medial parietal cortex (precuneus). We have analyzed precuneus in post-mortem tissue from 70 AD and 37 control brains to explore the pathophysiology of the hypoperfusion: the contribution of arteriolosclerotic small vessel disease (SVD) and cerebral amyloid angiopathy (CAA), and of the vasoconstrictors endothelin-1 (EDN1) and angiotensin II (Ang II), and the association with Aβ. The myelin-associated glycoprotein:proteolipid protein-1 ratio (MAG:PLP1) was used as an indicator of oxygenation of the precuneus prior to death. MAG:PLP1 was reduced ∼50% in early AD (Braak stage III-IV). Although MAG:PLP1 remained low in advanced AD (stage V-VI), the reduction was less pronounced, possibly reflecting falling oxygen demand. Reduction in cortical MAG:PLP1 correlated with elevation in vascular endothelial growth factor (VEGF), another marker of hypoperfusion. Cortical MAG:PLP1 declined nonsignificantly with increasing SVD and CAA, but significantly with the concentration of EDN1, which was elevated approximately 75% in AD. In contrast, with reduction in cortical MAG:PLP1, Ang II level and angiotensin-converting enzyme (ACE) activity declined, showing a normal physiological response to hypoperfusion. MAG:PLP1 was reduced in the parietal white matter (WM) in AD but here the decline correlated positively (ie, physiologically) with WM EDN1. However, the decline of MAG:PLP1 in the WM was associated with increasing cortical EDN1 and perhaps reflected vasoconstriction of perforating arterioles, which traverse the cortex to perfuse the WM. EDN1 in the cortex correlated highly significantly with both soluble and insoluble Aβ42, shown previously to upregulate neuronal endothelin-converting enzyme-2 (ECE2), but not with Aβ40. Our findings demonstrate reduced oxygenation of the precuneus in early AD and suggest that elevated EDN1, resulting from Aβ42-mediated upregulation of ECE2, is a contributor. [ABSTRACT FROM AUTHOR]

Haemophilia remains a complex disorder to diagnose and manage, requiring close cooperation between multidisciplinary healthcare professionals. There are still many unmet challenges in haemophilia care. The first Team Haemophilia Education ( THE) meeting, held on 7-8 May 2015 in Amsterdam, The Netherlands, aimed to promote the optimal care of haemophilia patients through education of the multidisciplinary treatment team. This was achieved by reviewing the latest developments in haemophilia management, considering how these can be implemented in the clinic to improve patient care and providing a platform for networking and debate for all haemophilia treatment team members. Haemophilia treatment centres from several countries were asked to complete a premeeting online questionnaire to establish the biggest challenges that they face when managing patients. The concerns expressed were used to develop the agenda, which comprised a combination of formal presentations, case studies and informal workshops covering such topics as pharmacokinetics, laboratory assays and tailoring of treatment to individual patients. This report is a summary of the key developments in haemophilia care presented by various investigators and healthcare professionals at THE meeting 2015. [ABSTRACT FROM AUTHOR]

Aim To determine the scaling factors required for inclusion of renal drug glucuronidation clearance in the prediction of total clearance via glucuronidation (CLUGT). Methods Microsomal protein per gram of kidney (MPPGK) was determined for human 'mixed' kidney ( n = 5) microsomes (MKM). The glucuronidation activities of deferiprone (DEF), propofol (PRO) and zidovudine (AZT) by MKM and paired cortical (KCM) and medullary (KMM) microsomes were measured, along with the UGT 1A6, 1A9 and 2B7 protein contents of each enzyme source. Unbound intrinsic clearances (CLint,u,UGT) for PRO and morphine (MOR; 3- and 6-) glucuronidation by MKM, human liver microsomes (HLM) and recombinant UGT1A9 and 2B7 were additionally determined. Data were scaled using in vitro- in vivo extrapolation (IV-IVE) approaches to assess the influence of renal CLint,u,UGT on the prediction accuracy of the calculated CLUGT values of PRO and MOR. Results MPPGK was 9.3 ± 2.0 mg g−1 (mean ± SD). The respective rates of DEF (UGT1A6), PRO (UGT1A9) and AZT (UGT2B7) glucuronidation by KCM were 1.4-, 5.2- and 10.5-fold higher than those for KMM. UGT 1A6, 1A9 and 2B7 were the only enzymes expressed in kidney. Consistent with the activity data, the abundance of each of these enzymes was greater in KCM than in KMM. The abundance of UGT1A9 in MKM (61.3 pmol mg−1) was 2.7 fold higher than that reported for HLM. Conclusions Scaled renal PRO glucuronidation CLint,u,UGT was double that of liver. Renal CLint,u,UGT should be accounted for in the IV-IVE of UGT1A9 and considered for UGT1A6 and 2B7 substrates. [ABSTRACT FROM AUTHOR]

Background: With the increasing prevalence of Alzheimer's disease (AD), there is an increased need for systematic research targeting preclinical pathophysiologic mechanisms of AD development for high‐risk, racially diverse, populations. Neurovascular dysfunction and blood brain barrier (BBB) breakdown likely occur early in AD pathology, however their relationship to AD biomarkers in preclinical populations are not well known. Soluble platelet derived growth factor receptor‐β (sPDGFRβ), a novel CSF biomarker of BBB‐associated capillary pericyte damage, is shed from injured human pericytes and is associated with AD pathology. Here we tested the hypothesis that sPDGFRβ is related to CSF AD biomarkers and CSF markers of vascular dysfunction in a cohort of Black/African American (B/AA) and non‐Hispanic White (NHW) participants. Method: Cognitively unimpaired, middle‐aged (45‐65 years) adults with a parental history of AD were enrolled. CSF was collected at baseline and 2 years for measurement of sPDGFRβ, AD biomarkers (Aβ and tau), and markers of vascular dysfunction (ACE activity, and VCAM‐1). Result: Participants (N=70) were mostly female (69%), well educated (81% college or greater), and 34% identified as B/AA. Forty‐eight percent were ApoEε4 positive. At both baseline and 2 years sPDGFRβ was positively correlated with P‐tau (r=.380, p=.003; r=.356, p=.008), T‐tau (r=.466, p<.001; r=.485, p<.001), Aβ40 (r=.439, p=.001; r=.454, p=.001), ACE‐1 activity (r=.363, p=.003; r=.272, p=.041), and VCAM‐1 (r=.511, p<.011; r‐=.401, p=.002) and negatively correlated with Aβ42/40 (r=‐.282, p=.024; r=‐.399, p=.002), controlling for age, sex, race, and education. At both time points, AAs had lower sPDGFRβ, P‐tau, T‐tau, and Aβ40 and higher Aβ42/40 compared to NHWs. Conclusion: sPDGFRβ was associated with tau hyperphosphorylation (P‐tau) and neurodegeneration (T‐tau) in a cohort of cognitively unimpaired middle‐aged adults at risk for AD. Pericyte loss may relate to disease pathology early in AD development in at‐risk individuals, providing a potential mechanistic target for early intervention and prevention strategies. sPDGFRβ was associated with ACE‐1 and VCAM‐1, suggesting a potential role for endothelial activation in early BBB breakdown. As we found differences in AD biomarkers by between AA and NHW participants, reference ranges for these biomarkers may vary by race. More research is needed examining pre‐clinical disease pathways in diverse populations. [ABSTRACT FROM AUTHOR]

Basic parameters of the naive antigen (Ag)-specific T-cell repertoire in humans remain poorly defined. Systematic characterization of this 'ground state' immunity in comparison with memory will allow a better understanding of clonal selection during immune challenge. Here, we used high-definition cell isolation from umbilical cord blood samples to establish the baseline frequency, phenotype and T-cell antigen receptor (TCR) repertoire of CD8+ T-cell precursor populations specific for a range of viral and self-derived Ags. Across the board, these precursor populations were phenotypically naive and occurred with hierarchical frequencies clustered by Ag specificity. The corresponding patterns of TCR architecture were highly ordered and displayed partial overlap with adult memory, indicating biased structuring of the T-cell repertoire during Ag-driven selection. Collectively, these results provide new insights into the complex nature and dynamics of the naive T-cell compartment. [ABSTRACT FROM AUTHOR]

Aims Deposition of amyloid beta ( Aβ) in the brain is one of the defining abnormalities of Alzheimer's disease ( AD). Phosphorylation of Aβ at serine 8 (p Aβ) has been implicated in its aggregation in vitro and p Aβ level has been shown to be significantly elevated in AD. We aimed to assess the specificity of p Aβ for AD and have investigated associations of p Aβ with parenchymal and cerebrovascular accumulation of Aβ, disease progression, angiotensin-converting enzyme activity and APOE genotype. Methods The distribution of p Aβ was studied by immunohistochemistry in sporadic and familial AD, pure dementia with Lewy bodies ( DLB), pure vascular dementia ( VaD) and age-matched controls. Soluble and insoluble (guanidine-extractable) p Aβ level was measured by enzyme-linked immunosorbent assay ( ELISA) in the midfrontal and parahippocampal cortex in sporadic AD ( n = 20, 10 with Braak tangle stages of III- IV and 10 of stages V- VI), DLB ( n = 10), VaD ( n = 10) and age-matched controls ( n = 20). Results We found p Aβ to be associated with only a subset of Aβ plaques and vascular deposits in sporadic and familial AD, with absent or minimal immunohistochemically detectable p Aβ in control, DLB and VaD brains. In both brain regions, insoluble p Aβ level was significantly elevated only in advanced AD ( Braak tangle stage of V or VI) and in the parahippocampus soluble and insoluble p Aβ level increased with the number of APOE ε4 alleles. Conclusions These results indicate that p Aβ accumulation in the parenchyma and vasculature is largely restricted to late-stage AD ( Braak tangle stage V- VI). [ABSTRACT FROM AUTHOR]

Neuroimaging has revealed a range of white matter abnormalities that are common in dementia, some that predict cognitive decline. The abnormalities may result from structural diseases of the cerebral vasculature, such as arteriolosclerosis and amyloid angiopathy, but can also be caused by nonstructural vascular abnormalities (eg, of vascular contractility or permeability), neurovascular instability or extracranial cardiac or vascular disease. Conventional histopathological assessment of the white matter has tended to conflate morphological vascular abnormalities with changes that reflect altered interstitial fluid dynamics or white matter ischemic damage, even though the latter may be of extracranial or nonstructural etiology. However, histopathology is being supplemented by biochemical approaches, including the measurement of proteins involved in the molecular responses to brain ischemia, myelin proteins differentially susceptible to ischemic damage, vessel-associated proteins that allow rapid measurement of microvessel density, markers of blood-brain barrier dysfunction and axonal injury, and mediators of white matter damage. By combining neuroimaging with histopathology and biochemical analysis, we can provide reproducible, quantitative data on the severity of white matter damage, and information on its etiology and pathogenesis. Together these have the potential to inform and improve treatment, particularly in forms of dementia to which white matter hypoperfusion makes a significant contribution. [ABSTRACT FROM AUTHOR]

The annual amount of clotting factor used by patients at the Royal Free Haemophilia Centre increased significantly from 4 million iu in 1980 to over 15 million iu by 1994 (P < 0.0001). In order to assess the reasons for this increase, data on concentrate usage over this period were retrospectively collected for patients who had Haemophilia or von Willebrand’s disease. Only patients who were registered exclusively at the Centre were included in the study. In total, 498 patients met the inclusion criterion. The median age of the cohort on 1 January 1980 was 21 (range < 1–69) years. During the period there were 88 births and 45 deaths. The majority of patients had Haemophilia A (55%). The median follow-up period per patient was 2.1 (range 0–14.8) years. Despite adjusting for increases in the number of patients and changes in body weight, statistically significant increases in clotting factor usage were detected for some subgroups of patients, in particularly for those with severe Haemophilia A and B and from the late 1980s onwards, for patients with von Willebrand’s disease. Two reasons for this increase in clotting factor usage were identified as being the introduction of improved products and prophylaxis. However, the increased cost of clotting factor provision that has resulted from these changes in treatment policy should not be analysed in isolation but should be balanced off against cost decreases in other areas and against increases in the effectiveness of treatment. [ABSTRACT FROM AUTHOR]

summary Hepatitis C ( HCV) infection can cause cirrhosis, liver cancer and death in the absence of treatment. Many people living in the UK but born overseas are believed to be infected with HCV although many are unlikely to know they are infected. The aim of this study is to assess the potential for a case-finding approach to be cost-effective and to estimate the value of further research. An economic evaluation and value of information analysis was undertaken by developing a model of HCV disease progression and by populating it with evidence from the published literature. They were performed from a UK National Health Services cost perspective, and outcomes were expressed in terms of quality-adjusted life-years ( QALYs). The comparator intervention was defined as the background rate of testing (i.e. no intervention). The base case results generated an incremental cost-effectiveness ratio ( ICER) of about £23 200 per additional QALY. However, the ICER was shown to be particularly sensitive to HCV seroprevalence, the intervention effect / cost and the probability of treatment uptake. The value of information analysis suggested that approximately £4 million should be spent on further research. This evaluation demonstrates that testing UK migrants for HCV could be cost-effective. However, further research, particularly to refine estimates of the probability of treatment uptake once identified, the utility associated with sustained virological response and the cost of the intervention, would help to increase the robustness of this conclusion. [ABSTRACT FROM AUTHOR]

Most rebels have a cause, and the expression of internal criticism and dissent is vital for healthy civic and collective functioning. Here, we review the normative conflict model (NCM), which posits that social identities are key to understanding conformity and deviance in group contexts. The NCM hypothesizes that strongly identified group members are willing to articulate critical and dissenting opinions when they believe that doing so is in the interest of the collective. In this paper, we conceptually advance the NCM by exploring how responses to group norms can be understood from a goal system perspective, conceptualizing dissent decisions as often involving choices between conflicting goals. We review the evidence for this approach to dissent and outline a range of future directions. [ABSTRACT FROM AUTHOR]

In dementia with Lewy bodies ( DLB), blood flow tends to be reduced in the occipital cortex. We previously showed elevated activity of the endothelin and angiotensin pathways in Alzheimer's disease ( AD). We have measured endothelin-1 ( ET-1) level and angiotensin-converting enzyme ( ACE) activity in the occipital cortex in DLB and control brains. We also measured vascular endothelial growth factor ( VEGF); factor VIII-related antigen ( FVIIIRA) to indicate microvessel density; myelin-associated glycoprotein ( MAG), a marker of ante-mortem hypoperfusion; total α-synuclein (α-syn) and α-synuclein phosphorylated at Ser129 (α-syn-p129). In contrast to findings in AD, ACE activity and ET-1 level were unchanged in DLB compared with controls. VEGF and FVIIIRA levels were, however, significantly lower in DLB. VEGF correlated positively with MAG concentration (in keeping with a relationship between reduction in VEGF and hypoperfusion), and negatively with α-syn and α-syn-p129 levels. Both α-syn and α-syn-p129 levels increased in human SH- SY5 Y neuroblastoma cells after oxygen-glucose deprivation ( OGD), and VEGF level was reduced in SH- SY5 Y cells overexpressing α-syn. Taken together, our findings suggest that reduced microvessel density rather than vasoconstriction is responsible for lower occipital blood flow in DLB, and that the loss of microvessels may result from VEGF deficiency, possible secondary to the accumulation of α-syn. [ABSTRACT FROM AUTHOR]

Although knowledge of human renal cytochrome P450 ( CYP) and UDP-glucuronosyltransferase ( UGT) enzymes and their role in xenobiotic and endobiotic metabolism is limited compared with hepatic drug and chemical metabolism, accumulating evidence indicates that human kidney has significant metabolic capacity. Of the drug metabolizing P450s in families 1 to 3, there is definitive evidence for only CYP 2B6 and 3A5 expression in human kidney. CYP 1A1, 1A2, 1B1, 2A6, 2C19, 2D6 and 2E1 are not expressed in human kidney, while data for CYP 2C8, 2C9 and 3A4 expression are equivocal. It is further known that several P450 enzymes involved in the metabolism of arachidonic acid and eicosanoids are expressed in human kidney, CYP 4A11, 4F2, 4F8, 4F11 and 4F12. With the current limited evidence of drug substrates for human renal P450s drug-endobiotic interactions arising from inhibition of renal P450s, particularly effects on arachidonic acid metabolism, appear unlikely. With respect to the UGTs, 1A5, 1A6, 1A7, 1A9, 2B4, 2B7 and 2B17 are expressed in human kidney, whereas UGT 1A1, 1A3, 1A4, 1A8, 1A10, 2B10, 2B11 and 2B15 are not. The most abundantly expressed renal UGTs are 1A9 and 2B7, which play a significant role in the glucuronidation of drugs, arachidonic acid, prostaglandins, leukotrienes and P450 derived arachidonic acid metabolites. Modulation by drug substrates (e.g. NSAIDs) of the intrarenal activity of UGT1A9 and UGT2B7 has the potential to perturb the metabolism of renal mediators including aldosterone, prostaglandins and 20-hydroxyeicosatetraenoic acid, thus disrupting renal homeostasis. [ABSTRACT FROM AUTHOR]

A number of studies examining the cost effectiveness of haemophilia prophylaxis have been published, but they report a wide range of results. The aim of this study was to explain why the results from existing economic evaluations of prophylaxis with clotting factor vary so much and to suggest areas of further research that will help to generate stronger economic evidence. Results from a previous systematic review were updated using a textword search of a number of electronic databases. Eleven economic evaluations were identified. They reported incremental cost-effectiveness ratios for prophylaxis ranging from 'cost saving and clinically beneficial' (i.e. 'dominant') to over €1 million per additional quality-adjusted life year ( QALY) if prophylaxis replaces treatment following a bleed. A number of reasons are likely to explain this breadth of results, most notably differences in choice of time horizon, estimates of treatment effect, clotting factor unit cost, discount rates and definitions of prophylaxis. Although the existing cost-effectiveness literature for haemophilia prophylaxis appears to report a wide range of results, closer inspection suggests that differences are largely explained by a number of design features. Some are likely to reflect local economic conditions and should be expected. However, others, such as differences in the choice of appropriate time horizon, are more concerning as they reflect differences in opinion over appropriate methodology. A number of studies to help address these evidence gaps are suggested: however, it is also recommended that analysts continue to adhere to established conventions when conducting and reporting economic evaluations. [ABSTRACT FROM AUTHOR]

. Long-term, continuous prophylaxis for haemophilia began at a modest scale during the 1950s and 1960s in Sweden and The Netherlands. In the face of high cost and impediments to the performance of longitudinal, well-designed studies, it was decades before prophylaxis was considered to be the best practice in countries that could afford the cost. In 2007 and 2011, the only prospective randomized studies ever performed confirmed what large cohort studies in Europe had long since shown. Today, focus is on when to start prophylaxis, dosing and when/if to stop. Retrospective comparisons of the Swedish and Dutch cohorts, where different strategies have been used, indicate that a costly, high-dose regimen improves outcome, but not dramatically. A prospective comparison is now underway. Treatment, clinical outcome, clotting factor consumption and socioeconomic parameters will be compared between the two strategies. Results are expected to provide greater insight into the long-term consequences of the different prophylactic treatment strategies. The economic justification for prophylaxis has been addressed in several studies with varying results. While the majority (implicitly) suggest that prophylaxis is not cost effective at conventional willingness to pay for additional units in health thresholds, their results vary markedly. Closer inspection suggests that the primary reasons results differ include different definitions of prophylaxis, clotting factor price, discount rates, choice of outcome measures and time horizon. [ABSTRACT FROM AUTHOR]

Neprilysin (NEP), which degrades amyloid-β (Aβ), is expressed by neurons and cerebrovascular smooth muscle cells (CVSMCs). NEP immunolabeling is reduced within cerebral blood vessels of Alzheimer's disease (AD) patients with cerebral amyloid angiopathy (CAA). We have now measured NEP enzyme activity in leptomeningeal and purified cerebral cortical blood vessel preparations from control and AD patients with and without CAA. Measurements were adjusted for smooth muscle actin (SMA) to control for variations in CVSMC content. NEP activity was reduced in CAA, in both controls and AD. In leptomeningeal vessels, NEP activity was related to APOE genotype, being highest in ε2-positive and lowest in ε4-positive brains. To assess the role of NEP in protecting CVSMCs from Aβ toxicity, we measured cell death in primary human adult CVSMCs exposed to Aβ1-40, Aβ1-42 or Aβ1-40(Dutch variant). Aβ1-42 was most cytotoxic to CVSMCs. Aβ1-42-mediated cell death was increased following siRNA-mediated knockdown or thiorphan-mediated inhibition of NEP activity; conversely Aβ1-42-mediated cytotoxicity was reduced by the addition of somatostatin and NEP over-expression following transfection with NEP cDNA. Our findings suggest that NEP protects CVSMCs from Aβ toxicity and protects cerebral blood vessels from the development and complications of CAA. [ABSTRACT FROM AUTHOR]

• Many drugs inhibit or induce cytochrome P450 enzymes (CYP) to cause clinically significant changes in the concentrations of other drugs, i.e. 'perpetrate' pharmacokinetic drug-drug interactions (PK-DDIs). • Tables that list the substrates, inhibitors and inducers of CYP are common, but they lack consistency and are constructed from evidence of variable quality. • This is the first study to catalogue important perpetrators of PK-DDIs using objective criteria and clinical pharmacokinetic drug interaction studies. This information is intended to inform clinical decisions on PK-DDIs. • Existing tables of CYP inhibitors and inducers have low sensitivity and low positive predictive value in identifying the major perpetrators of PK-DDIs. • Several drugs were identified which potentially perpetrate CYP-mediated PK-DDIs, but quality clinical pharmacokinetic interaction studies are lacking. This information may be used to inform future research. To catalogue the perpetrators of CYP-mediated pharmacokinetic drug-drug interactions (PK-DDIs) using clinically relevant criteria, and to compare this with an analogous catalogue. Candidate inhibitors and inducers of CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A ('perpetrators') were evaluated using published clinical pharmacokinetic interaction studies. Studies were selected on the basis of ≥six human subjects, use of a validated in vivo probe substrate for the CYP enzyme, and clinically relevant dosing. Inhibitors were described according to the FDA classifications of strong, moderate or weak, whereas inducers were classified as major (≥twofold decrease in AUC) or weak (

We recently found that insoluble Aβ increases, but soluble Aβ decreases with age in normal brains. We now report the changes in activities of β-secretase (BACE-1) and Aβ-degrading enzymes with age, and their relationships to concentrations of soluble and insoluble Aβ. We measured BACE-1 activity and the levels and activities of neprilysin (NEP), insulin-degrading enzyme (IDE) and angiotensin-converting enzyme (ACE) in normal control brains (16 years–95 years). We also compared the measurements to those in AD. BACE-1 activity correlated closely with age in controls and was significantly higher in AD. In controls, NEP and IDE activities (but not protein levels) increased with age but ACE activity and level did not. BACE-1 activity correlated directly with insoluble but inversely with soluble Aβ. IDE activity correlated directly with insoluble Aβ and NEP activity was inversely related to soluble Aβ. ACE level correlated directly with insoluble and inversely with soluble Aβ in controls but not AD. Both Aβ-synthesizing and -degrading enzyme activities increase with age, coinciding with declining soluble Aβ and increasing insoluble Aβ. Further research is needed to establish whether these changes in enzyme activity and Aβ levels are causally related and if so how. [ABSTRACT FROM AUTHOR]

Little is known about the relationship between soluble amyloid β (Aβ) and age. We have measured soluble and insoluble Aβ by enzyme-linked immunosorbent assay (ELISA) in post-mortem frontal cortex in normal brains (16–95 years) and AD. Insoluble Aβ increased with age, and was significantly higher in Alzheimer's disease (AD) than age-matched controls. However, levels of soluble Aβ declined with age and were significantly greater in younger adults than older adults with or without AD. In AD, insoluble : soluble Aβ ratio was much higher than in age-matched controls. The high levels of soluble Aβ in young adults included oligomeric species of Aβ1-42. These observations do not preclude Aβ oligomers as neurotoxic mediators of AD but suggest that if they are, the toxicity may be restricted to certain species (eg, β-pleated protofibrillar species not detected by our assay) or takes decades to manifest. The dramatically increased insoluble : soluble Aβ in AD points to an altered dynamic equilibrium of Aβ in AD, reflecting both enhanced aggregation and continued overproduction or impaired removal of the soluble peptide in older age, when the concentration of this peptide should be declining. [ABSTRACT FROM AUTHOR]

Despite accumulating evidence of a central role for oligomeric amyloid β (Aβ) in the pathogenesis of Alzheimer's Disease (AD), there is scant information on the relationship between the levels and distribution of oligomeric Aβ and those of other neurodegenerative abnormalities in AD. In the present study, we have found oligomeric Aβ to be associated with both diffuse and neuritic plaques (mostly co-localized with Aβ1–42) and with cerebrovascular deposits of Aβ in paraffin sections of formalin-fixed human brain tissue. The amount of oligomeric Aβ that was labeled in the sections correlated with total Aβ plaque load, but not phospho-tau load, cerebral amyloid angiopathy (CAA) severity or APOE genotype. Although soluble, oligomeric and insoluble Aβ levels were all significantly increased in AD brain homogenates, case-to-case variation and overlap between AD and controls were considerable. Over the age-range studied (43–98 years), the levels of soluble Aβ, oligomeric Aβ42, oligomeric Aβ40 and insoluble Aβ did not vary significantly with age. Oligomeric Aβ1–42 and insoluble Aβ levels were significantly higher in women. Overall, the level of insoluble Aβ, but neither oligomeric nor soluble Aβ, was associated with Braak stage, CAA severity and APOEε4 frequency, raising questions as to the role of soluble and oligomeric Aβ in the progression of AD. [ABSTRACT FROM AUTHOR]

By using Fink's taxonomy to shape new learning goals and creating new learning and assessment activities, two teachers succeeded in raising students' awareness of the value of their courses and enabled them to become more reflective learners in the process. [ABSTRACT FROM AUTHOR]

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Carboxylic acid NSAIDs are extensively glucuronidated as either the parent drug or hydroxylated metabolites and UGT2B7 is ranked highest in terms of NSAID-glucuronidation activity. • NSAIDs cause adverse renal effects including sodium and water retention and hyperkalaemia. • In human kidney the mineralocorticoid aldosterone is glucuronidated directly to form aldosterone 18β-glucuronide. WHAT THIS STUDY ADDS • Human liver and kidney microsomes and UGT1A10 and UGT2B7 catalyze aldosterone18β-glucuronidation. • Non-selective NSAIDs inhibit renal and hepatic aldosterone18β-glucuronidation and in vivo this may lead to elevated intra-renal concentrations of this hormone. • Common involvement of UGT2B7 in NSAID and aldosterone glucuronidation predicates an intra-renal NSAID-aldosterone interaction that may explain in part the clinical observations of variable effects of NSAIDs on electrolytes, fluid retention and blood pressure. AIMS To characterize: i) the kinetics of aldosterone (ALDO) 18β-glucuronidation using human liver and human kidney microsomes and identify the human UGT enzyme(s) responsible for ALDO 18β-glucuronidation and ii) the inhibition of ALDO 18β-glucuronidation by non-selective NSAIDs. METHODS Using HPLC and LC-MS methods, ALDO 18β-glucuronidation was characterized using human liver ( n= 6), human kidney microsomes ( n= 5) and recombinant human UGT 1A1, 1A3, 1A4, 1A5, 1A6, 1A7, 1A8, 1A9, 1A10, 2B4, 2B7, 2B10, 2B15, 2B17 and 2B28 as the enzyme sources. Inhibition of ALDO 18β-glucuronidation was investigated using alclofenac, cicloprofen, diclofenac, diflunisal, fenoprofen, R- and S-ibuprofen, indomethacin, ketoprofen, ketorolac, meclofenamic acid, mefenamic acid, S-naproxen, pirprofen and tiaprofenic acid. A rank order of inhibition (I C50) was established and the mechanism of inhibition investigated using diclofenac, S-ibuprofen, indomethacin, mefenamic acid and S-naproxen. RESULTS ALDO 18β-glucuronidation by hepatic and renal microsomes exhibited Michaelis-Menten kinetics. Mean (±SD) Km, Vmax and CLint values for HLM and HKCM were 509 ± 137 and 367 ± 170 µm, 1075 ± 429 and 1110 ± 522 pmol min−1 mg−1, and 2.36 ± 1.12 and 3.91 ± 2.35 µl min−1 mg−1, respectively. Of the UGT proteins, only UGT1A10 and UGT2B7 converted ALDO to its 18β-glucuronide. All NSAIDs investigated inhibited ALDO 18β-G formation by HLM, HKCM and UGT2B7. The rank order of inhibition (I C50) of renal and hepatic ALDO 18β-glucuronidation followed the general trend: fenamates > diclofenac > arylpropionates. CONCLUSION A NSAID-ALDO interaction in vivo may result in elevated intra-renal concentrations of ALDO that may contribute to the adverse renal effects of NSAIDs and their effects on antihypertensive drug response. [ABSTRACT FROM AUTHOR]

Severe haemophilia A is a lifelong condition that requires treatment with exogenous clotting factor. While primary prophylaxis is the clinically preferred method of delivering treatment, its provision is costly. A 2002 evaluation of primary prophylaxis suggested an incremental cost-effectiveness of approximately £50 000 per additional quality-adjusted life-year (QALY). However, since this time, preferable evaluative methods have been developed and means of assessing the value of future research also now exist. Thus, the primary aims of this study were to update a previously published cost-effectiveness analysis of primary prophylaxis vs. treating on-demand in terms of methods and to estimate the value of undertaking further primary research. The base case incremental cost-effectiveness ratio was shown to be approximately £37 000, £10 000 lower than the value published in 2002. The main reason for this difference was the use of different structural assumptions and methods to fit the various model parameters. At a willingness to pay per additional QALY threshold of £30 000, the probability prophylaxis is cost-effective was 13%. However, this increased to over 90% when alternative structural assumptions were employed, such as the rate at which future QALYs are discounted. The value of further research to increase the precision of this newly calculated cost-effectiveness estimate was high at a threshold willingness to pay values of £30 000–£40 000 per QALY, particularly for the utilities associated with the health states. Thus, there is considerable value in conducting further primary research related to economic aspects of primary prophylaxis. [ABSTRACT FROM AUTHOR]