Haemoglobin causes neuronal damage in vivo which is preventable by haptoglobin

After subarachnoid haemorrhage, prolonged exposure to toxic extracellular haemoglobin occurs in the brain. Here, we investigate the role of haemoglobin neurotoxicity in vivo and its prevention. In humans after subarachnoid haemorrhage, haemoglobin in cerebrospinal fluid was associated with neurofilament light chain, a marker of neuronal damage. Most haemoglobin was not complexed with haptoglobin, an endogenous haemoglobin scavenger present at very low concentration in the brain. Exogenously added haptoglobin bound most uncomplexed haemoglobin, in the first 2 weeks after human subarachnoid haemorrhage, indicating a wide therapeutic window. In mice, the behavioural, vascular, cellular and molecular changes seen after human subarachnoid haemorrhage were recapitulated by modelling a single aspect of subarachnoid haemorrhage: prolonged intrathecal exposure to haemoglobin. Haemoglobin-induced behavioural deficits and astrocytic, microglial and synaptic changes were attenuated by haptoglobin. Haptoglobin treatment did not attenuate large-vessel vasospasm, yet improved clinical outcome by restricting diffusion of haemoglobin into the parenchyma and reducing small-vessel vasospasm. In summary, haemoglobin toxicity is of clinical importance and preventable by haptoglobin, independent of large-vessel vasospasm

Dietary supplementation of cystinotic mice by lysine inhibits the megalin pathway and decreases kidney cystine content.

peer reviewedMegalin/LRP2 is a major receptor supporting apical endocytosis in kidney proximal tubular cells. We have previously reported that kidney-specific perinatal ablation of the megalin gene in cystinotic mice, a model of nephropathic cystinosis, essentially blocks renal cystine accumulation and partially preserves kidney tissue integrity. Here, we examined whether inhibition of the megalin pathway in adult cystinotic mice by dietary supplementation (5x-fold vs control regular diet) with the dibasic amino-acids (dAAs), lysine or arginine, both of which are used to treat patients with other rare metabolic disorders, could also decrease renal cystine accumulation and protect cystinotic kidneys. Using surface plasmon resonance, we first showed that both dAAs compete for protein ligand binding to immobilized megalin in a concentration-dependent manner, with identical inhibition curves by L- and D-stereoisomers. In cystinotic mice, 2-month diets with 5x-L-lysine and 5x-L-arginine were overall well tolerated, while 5x-D-lysine induced strong polyuria but no weight loss. All diets induced a marked increase of dAA urinary excretion, most prominent under 5x-D-lysine, without sign of kidney insufficiency. Renal cystine accumulation was slowed down approx. twofold by L-dAAs, and totally suppressed by D-lysine. We conclude that prolonged dietary manipulation of the megalin pathway in kidneys is feasible, tolerable and can be effective in vivo

Surface Energy Budgets of Arctic Tundra During Growing Season

This study analyzed summer observations of diurnal and seasonal surface energy budgets across several monitoring sites within the Arctic tundra underlain by permafrost. In these areas, latent and sensible heat fluxes have comparable magnitudes, and ground heat flux enters the subsurface during short summer intervals of the growing period, leading to seasonal thaw. The maximum entropy production (MEP) model was tested as an input and parameter parsimonious model of surface heat fluxes for the simulation of energy budgets of these permafrost‐underlain environments. Using net radiation, surface temperature, and a single parameter characterizing the thermal inertia of the heat exchanging surface, the MEP model estimates latent, sensible, and ground heat fluxes that agree closely with observations at five sites for which detailed flux data are available. The MEP potential evapotranspiration model reproduces estimates of the Penman‐Monteith potential evapotranspiration model that requires at least five input meteorological variables (net radiation, ground heat flux, air temperature, air humidity, and wind speed) and empirical parameters of surface resistance. The potential and challenges of MEP model application in sparsely monitored areas of the Arctic are discussed, highlighting the need for accurate measurements and constraints of ground heat flux.Plain Language SummaryGrowing season latent and sensible heat fluxes are nearly equal over the Arctic permafrost tundra regions. Persistent ground heat flux into the subsurface layer leads to seasonal thaw of the top permafrost layer. The maximum energy production model accurately estimates the latent, sensible, and ground heat flux of the surface energy budget of the Arctic permafrost regions.Key PointThe MEP model is parsimonious and well suited to modeling surface energy budget in data‐sparse permafrost environmentsPeer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/150560/1/jgrd55584.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/150560/2/jgrd55584_am.pd

Air temperature variations and gradients along the coast and fjords of western Spitsbergen

Daily temperature measurements from six meteorological stations along the coast and fjords of western Spitsbergen have been digitized and quality controlled in a Norwegian, Russian and Polish collaboration. Complete daily data series have been reconstructed back to 1948 for all of the stations. One of the station’s monthly temperature series has previously been extended back to 1898 and is included in this study. The long-term series show large temperature variability on western Spitsbergen with colder periods in the 1910s and 1960s and warmer periods in the 1930s, 1950s and in the 21st century. The most recent years are the warmest ones in the instrumental records. There is a positive and statistically significant trend in the annual times series for all of the stations; however, the strongest warming is seen in winter and spring. For the period 1979-2015, the linear trends range from 1.0 to 1.38°C/decade for the annual series and from 2.0 to 2.38°C/decade in winter. Threshold statistics demonstrate a decrease in the number of cold days per year and an increase in the number of warm days. A decreasing inter-annual variability is observed. In winter, spring and autumn, the stations in the northernmost areas of west Spitsbergen and in the innermost parts of Isfjorden are the coldest ones. In summer, however, the southernmost station is the coldest one

The RISAP-study: a complex intervention in risk communication and shared decision-making in general practice

General practitioners (GPs) and patients find it difficult to talk about risk of future disease, especially when patients have asymptomatic conditions, and treatment options are unlikely to cause immediate perceptible improvements in well-being. Further studies in risk communication training are needed. Aim:1) to systematically develop, describe and evaluate a complex intervention comprising a training programme for GPs in risk communication and shared decision-making, 2) to evaluate the effect of the training programme on real-life consultations between GPs and patients with high cholesterol levels, and 3) to evaluate patients' reactions during and after the consultations. Methods/Design The effect of the complex intervention, based around a training programme, will be evaluated in a cluster-randomised controlled trial with an intervention group and an active control group with 40 GPs and 280 patients in each group. The GPs will receive a questionnaire at baseline and after 6 months about attitudes towards risk communication and cholesterol-reducing medication. After each consultation with a participating high cholesterol-patient, the GPs will complete a questionnaire about decision satisfaction (Provider Decision Process Assessment Instrument). The patients will receive a questionnaire at baseline and after 3 and 6 months. It includes questions about adherence to chosen treatment (Morisky Compliance Scale), self-rated health (SF-12), enablement (Patient Enablement Instrument), and risk communication and decision-making effectiveness (COMRADE Scale). Prescriptions, contacts to the health services, and cholesterol level will be drawn from the registers. In each group, 12 consultations will be observed and tape-recorded. The patients from these 24 consultations will be interviewed immediately after the consultation and re-interviewed after 6 months. Eight purposefully selected GPs from the intervention group will be interviewed in a focus group 6 months after participation in the training programme. The process and context of the RISAP-study will be investigated in detail using an action research approach, in order to analyse adaptation of the intervention model to the specific context. Discussion This study aims at providing GPs and patients with a firm basis for active deliberation about preventive treatment options, with a view to optimising adherence to chosen treatment. Trial registration ClinicalTrials.gov Protocol Registration System NCT0118705

Impact of renal impairment on atrial fibrillation: ESC-EHRA EORP-AF Long-Term General Registry

Background: Atrial fibrillation (AF) and renal impairment share a bidirectional relationship with important pathophysiological interactions. We evaluated the impact of renal impairment in a contemporary cohort of patients with AF. Methods: We utilised the ESC-EHRA EORP-AF Long-Term General Registry. Outcomes were analysed according to renal function by CKD-EPI equation. The primary endpoint was a composite of thromboembolism, major bleeding, acute coronary syndrome and all-cause death. Secondary endpoints were each of these separately including ischaemic stroke, haemorrhagic event, intracranial haemorrhage, cardiovascular death and hospital admission. Results: A total of 9306 patients were included. The distribution of patients with no, mild, moderate and severe renal impairment at baseline were 16.9%, 49.3%, 30% and 3.8%, respectively. AF patients with impaired renal function were older, more likely to be females, had worse cardiac imaging parameters and multiple comorbidities. Among patients with an indication for anticoagulation, prescription of these agents was reduced in those with severe renal impairment, p <.001. Over 24 months, impaired renal function was associated with significantly greater incidence of the primary composite outcome and all secondary outcomes. Multivariable Cox regression analysis demonstrated an inverse relationship between eGFR and the primary outcome (HR 1.07 [95% CI, 1.01–1.14] per 10 ml/min/1.73 m2 decrease), that was most notable in patients with eGFR <30 ml/min/1.73 m2 (HR 2.21 [95% CI, 1.23–3.99] compared to eGFR ≥90 ml/min/1.73 m2). Conclusion: A significant proportion of patients with AF suffer from concomitant renal impairment which impacts their overall management. Furthermore, renal impairment is an independent predictor of major adverse events including thromboembolism, major bleeding, acute coronary syndrome and all-cause death in patients with AF

Clinical complexity and impact of the ABC (Atrial fibrillation Better Care) pathway in patients with atrial fibrillation: a report from the ESC-EHRA EURObservational Research Programme in AF General Long-Term Registry

Background: Clinical complexity is increasingly prevalent among patients with atrial fibrillation (AF). The ‘Atrial fibrillation Better Care’ (ABC) pathway approach has been proposed to streamline a more holistic and integrated approach to AF care; however, there are limited data on its usefulness among clinically complex patients. We aim to determine the impact of ABC pathway in a contemporary cohort of clinically complex AF patients. Methods: From the ESC-EHRA EORP-AF General Long-Term Registry, we analysed clinically complex AF patients, defined as the presence of frailty, multimorbidity and/or polypharmacy. A K-medoids cluster analysis was performed to identify different groups of clinical complexity. The impact of an ABC-adherent approach on major outcomes was analysed through Cox-regression analyses and delay of event (DoE) analyses. Results: Among 9966 AF patients included, 8289 (83.1%) were clinically complex. Adherence to the ABC pathway in the clinically complex group reduced the risk of all-cause death (adjusted HR [aHR]: 0.72, 95%CI 0.58–0.91), major adverse cardiovascular events (MACEs; aHR: 0.68, 95%CI 0.52–0.87) and composite outcome (aHR: 0.70, 95%CI: 0.58–0.85). Adherence to the ABC pathway was associated with a significant reduction in the risk of death (aHR: 0.74, 95%CI 0.56–0.98) and composite outcome (aHR: 0.76, 95%CI 0.60–0.96) also in the high-complexity cluster; similar trends were observed for MACEs. In DoE analyses, an ABC-adherent approach resulted in significant gains in event-free survival for all the outcomes investigated in clinically complex patients. Based on absolute risk reduction at 1 year of follow-up, the number needed to treat for ABC pathway adherence was 24 for all-cause death, 31 for MACEs and 20 for the composite outcome. Conclusions: An ABC-adherent approach reduces the risk of major outcomes in clinically complex AF patients. Ensuring adherence to the ABC pathway is essential to improve clinical outcomes among clinically complex AF patients