Effect of a reduction in glomerular filtration rate after nephrectomy on arterial stiffness and central hemodynamics: rationale and design of the EARNEST study

Background: There is strong evidence of an association between chronic kidney disease (CKD) and cardiovascular disease. To date, however, proof that a reduction in glomerular filtration rate (GFR) is a causative factor in cardiovascular disease is lacking. Kidney donors comprise a highly screened population without risk factors such as diabetes and inflammation, which invariably confound the association between CKD and cardiovascular disease. There is strong evidence that increased arterial stiffness and left ventricular hypertrophy and fibrosis, rather than atherosclerotic disease, mediate the adverse cardiovascular effects of CKD. The expanding practice of live kidney donation provides a unique opportunity to study the cardiovascular effects of an isolated reduction in GFR in a prospective fashion. At the same time, the proposed study will address ongoing safety concerns that persist because most longitudinal outcome studies have been undertaken at single centers and compared donor cohorts with an inappropriately selected control group.<p></p> Hypotheses: The reduction in GFR accompanying uninephrectomy causes (1) a pressure-independent increase in aortic stiffness (aortic pulse wave velocity) and (2) an increase in peripheral and central blood pressure.<p></p> Methods: This is a prospective, multicenter, longitudinal, parallel group study of 440 living kidney donors and 440 healthy controls. All controls will be eligible for living kidney donation using current UK transplant criteria. Investigations will be performed at baseline and repeated at 12 months in the first instance. These include measurement of arterial stiffness using applanation tonometry to determine pulse wave velocity and pulse wave analysis, office blood pressure, 24-hour ambulatory blood pressure monitoring, and a series of biomarkers for cardiovascular and bone mineral disease.<p></p> Conclusions: These data will prove valuable by characterizing the direction of causality between cardiovascular and renal disease. This should help inform whether targeting reduced GFR alongside more traditional cardiovascular risk factors is warranted. In addition, this study will contribute important safety data on living kidney donors by providing a longitudinal assessment of well-validated surrogate markers of cardiovascular disease, namely, blood pressure and arterial stiffness. If any adverse effects are detected, these may be potentially reversed with the early introduction of targeted therapy. This should ensure that kidney donors do not come to long-term harm and thereby preserve the ongoing expansion of the living donor transplant program.<p></p&gt

Rapidly progressive dementia with thalamic degeneration and peculiar cortical prion protein immunoreactivity, but absence of proteinase K resistant PrP: a new disease entity?

BACKGROUND: Human prion diseases are a group of rare fatal neurodegenerative conditions with well-developed clinical and neuropathological diagnostic criteria. Recent observations have expanded the spectrum of prion diseases beyond the classically recognized forms. RESULTS: In the present study we report six patients with a novel, apparently sporadic disease characterised by thalamic degeneration and rapidly progressive dementia (duration of illness 2-12 months; age at death: 55-81 years). Light and electron microscopic immunostaining for the prion protein (PrP) revealed a peculiar intraneuritic distribution in neocortical regions. Proteinase K resistant PrP (PrPres) was undetectable by Western blotting in frontal cortex from the three cases with frozen tissue, even after enrichment for PrPres by centrifugation or by phosphotungstic acid precipitation. Conformation-dependent immunoassay analysis using a range of PK digestion conditions (and no PK digestion) produced only very limited evidence of meaningful D-N (denatured/native) values, indicative of the presence of disease-associated PrP (PrPSc) in these cases, when the results were compared with appropriate negative control groups. CONCLUSIONS: Our observation expands the spectrum of conditions associated with rapidly progressive dementia and may have implications for the understanding of the pathogenesis of prion diseases

Arterial pulse wave modelling and analysis for vascular age studies: a review from VascAgeNet

Arterial pulse waves (PWs) such as blood pressure and photoplethysmogram (PPG) signals contain a wealth of information on the cardiovascular (CV) system that can be exploited to assess vascular age and identify individuals at elevated CV risk. We review the possibilities, limitations, complementarity, and differences of reduced-order, biophysical models of arterial PW propagation, as well as theoretical and empirical methods for analyzing PW signals and extracting clinically relevant information for vascular age assessment. We provide detailed mathematical derivations of these models and theoretical methods, showing how they are related to each other. Finally, we outline directions for future research to realize the potential of modeling and analysis of PW signals for accurate assessment of vascular age in both the clinic and in daily life

Myeloid cell iron uptake pathways and paramagnetic rim formation in multiple sclerosis

In multiple sclerosis (MS), sustained inflammatory activity can be visualized by iron-sensitive magnetic resonance imaging (MRI) at the edges of chronic lesions. These paramagnetic rim lesions (PRLs) are associated with clinical worsening, although the cell type-specific and molecular pathways of iron uptake and metabolism are not well known. We studied two postmortem cohorts: an exploratory formalin-fixed paraffin-embedded (FFPE) tissue cohort of 18 controls and 24 MS cases and a confirmatory snap-frozen cohort of 6 controls and 14 MS cases. Besides myelin and non-heme iron imaging, the haptoglobin-hemoglobin scavenger receptor CD163, the iron-metabolizing markers HMOX1 and HAMP as well as immune-related markers P2RY12, CD68, C1QA and IL10 were visualized in myeloid cell (MC) subtypes at RNA and protein levels across different MS lesion areas. In addition, we studied PRLs in vivo in a cohort of 98 people with MS (pwMS) via iron-sensitive 3 T MRI and haptoglobin genotyping by PCR. CSF samples were available from 38 pwMS for soluble CD163 (sCD163) protein level measurements by ELISA. In postmortem tissues, we observed that iron uptake was linked to rim-associated C1QA-expressing MC subtypes, characterized by upregulation of CD163, HMOX1, HAMP and, conversely, downregulation of P2RY12. We found that pwMS with [Formula: see text] 4 PRLs had higher sCD163 levels in the CSF than pwMS with [Formula: see text] 3 PRLs with sCD163 correlating with the number of PRLs. The number of PRLs was associated with clinical worsening but not with age, sex or haptoglobin genotype of pwMS. However, pwMS with Hp2-1/Hp2-2 haplotypes had higher clinical disability scores than pwMS with Hp1-1. In summary, we observed upregulation of the CD163-HMOX1-HAMP axis in MC subtypes at chronic active lesion rims, suggesting haptoglobin-bound hemoglobin but not transferrin-bound iron as a critical source for MC-associated iron uptake in MS. The correlation of CSF-associated sCD163 with PRL counts in MS highlights the relevance of CD163-mediated iron uptake via haptoglobin-bound hemoglobin. Also, while Hp haplotypes had no noticeable influence on PRL counts, pwMS carriers of a Hp2 allele might have a higher risk to experience clinical worsening

A comparison between left ventricular ejection time measurement methods during physiological changes induced by simulated microgravity

New findings: What is the central question of this study? First, we validated easy-to-use oscillometric left ventricular ejection time (LVET) against echocardiographic LVET. Second, we investigated progression of left ventricular ejection time index (LVETI), pre-ejection period index (PEPI), total electromechanical systole index (QS2I) and PEP/LVET ratio during 60 days of head-down tilt (HDT). What is the main finding and its importance? The LVETosci and LVETecho showed good agreement in effect direction. Hence, LVETosci might be useful to evaluate cardiovascular responses during space flight. Moreover, the approach might be useful for individual follow-up of patients with altered ejection times. Furthermore, significant effects of 60 days of HDT were captured by measurements of LVETI, PEPI, QS2I and PEP/LVET ratio. Abstract: Systolic time intervals that are easy to detect might be used as parameters reflecting cardiovascular deconditioning. We compared left ventricular ejection time (LVET) measured via ultrasound Doppler on the left ventricular outflow tract with oscillometrically measured LVET, measured at the brachialis. Furthermore, we assessed the progression of the left ventricular ejection time index (LVETI), the pre-ejection period index (PEPI), the Weissler index (PEP/LVET) and the total electromechanical systole index (QS2I) during prolonged strict head-down tilt (HDT) bed rest, including 16 male and eight female subjects. Simultaneous oscillometric and echocardiographic LVET measurements showed significant correlation (r = 0.53 with P = 0.0084 before bed rest and r = 0.73 with P < 0.05 on the last day of bed rest). The shortening of LVET during HDT bed rest measured with both approaches was highly concordant in their effect direction, with a concordance rate of 0.96. Our results also demonstrated a significant decrease of LVETI (P < 0.0001) and QS2I (P = 0.0992) and a prolongation of PEPI (P = 0.0049) and PEP/LVET (P = 0.0003) during HDT bed rest over 60 days. Four days after bed rest, LVETI recovered completely to its baseline value. Owing to the relationship between shortening of LVETI and heart failure progression, the easy-to-use oscillometric method might not only be a useful way to evaluate the cardiovascular system during space flights, but could also be of high value in a clinical setting

Hepatic gene expression involved in glucose and lipid metabolism in transition cows: effects of fat mobilization during early lactation in relation to milk performance and metabolic changes.

Insufficient feed intake during early lactation results in elevated body fat mobilization to meet energy demands for milk production. Hepatic energy metabolism is involved by increasing endogenous glucose production and hepatic glucose output for milk synthesis and by adaptation of postcalving fuel oxidation. Given that cows differ in their degree of fat mobilization around parturition, indicated by variable total liver fat concentration (LFC), the study investigated the influence of peripartum fat mobilization on hepatic gene expression involved in gluconeogenesis, fatty acid oxidation, ketogenesis, and cholesterol synthesis, as well as transcriptional factors referring to energy metabolism. German Holstein cows were grouped according to mean total LFC on d 1, 14, and 28 after parturition as low [300 mg of total fat/g of DM; n=7), indicating fat mobilization during early lactation. Cows were fed total mixed rations ad libitum and held under equal conditions. Liver biopsies were taken at d 56 and 15 before and d 1, 14, 28, and 49 after parturition to measure mRNA abundances of pyruvate carboxylase (PC); phosphoenolpyruvate carboxykinase; glucose-6-phosphatase; propionyl-coenzyme A (CoA) carboxylase α; carnitine palmitoyl-transferase 1A (CPT1A); acyl-CoA synthetase, long chain 1 (ASCL1); acyl-CoA dehydrogenase, very long chain; 3-hydroxy-3-methylglutaryl-CoA synthase 1 and 2; sterol regulatory element-binding factor 1; and peroxisome proliferator-activated factor α. Total LFC postpartum differed greatly among cows, and the mRNA abundance of most enzymes and transcription factors changed with time during the experimental period. Abundance of PC mRNA increased at parturition to a greater extent in high- and medium-LFC groups than in the low-LFC group. Significant LFC × time interactions for ACSL1 and CPT1A during the experimental period indicated variable gene expression depending on LFC after parturition. Correlations between hepatic gene expression and performance data and plasma concentrations of metabolites and hormones showed time-specific relations during the transition period. Elevated body fat mobilization during early lactation affected gene expression involved in gluconeogenesis to a greater extent than gene expression involved in lipid metabolism, indicating the dependence of hepatic glucose metabolism on hepatic lipid status and fat mobilization during early lactation

A new oscillometric method for pulse wave analysis: comparison with a common tonometric method

In the European Society of Cardiology–European Society of Hypertension guidelines of the year 2007, the consequences of arterial stiffness and wave reflection on cardiovascular mortality have a major role. But the investigators claimed the poor availability of devices/methods providing easy and widely suitable measuring of arterial wall stiffness or their surrogates like augmentation index (AIx) or aortic systolic blood pressure (aSBP). The aim of this study was the validation of a novel method determining AIx and aSBP based on an oscillometric method using a common cuff (ARCSolver) against a validated tonometric system (SphygmoCor). aSBP and AIx measured with the SphygmoCor and ARCSolver method were compared for 302 subjects. The mean age was 56 years with an s.d. of 20 years. At least two iterations were performed in each session. This resulted in 749 measurements. For aSBP the mean difference was −0.1 mm Hg with an s.d. of 3.1 mm Hg. The mean difference for AIx was 1.2% with an s.d. of 7.9%. There was no significant difference in reproducibility of AIx for both methods. The variation estimate of inter- and intraobserver measurements was 6.3% for ARCSolver and 7.5% for SphygmoCor. The ARCSolver method is a novel method determining AIx and aSBP based on an oscillometric system with a cuff. The results agree with common accepted tonometric measurements. Its application is easy and for widespread use

Twenty-Four-Hour Central (Aortic) Systolic Blood Pressure: Reference Values and Dipping Patterns in Untreated Individuals.

Central (aortic) systolic blood pressure (cSBP) is the pressure seen by the heart, the brain, and the kidneys. If properly measured, cSBP is closer associated with hypertension-mediated organ damage and prognosis, as compared with brachial SBP (bSBP). We investigated 24-hour profiles of bSBP and cSBP, measured simultaneously using Mobilograph devices, in 2423 untreated adults (1275 women; age, 18-94 years), free from overt cardiovascular disease, aiming to develop reference values and to analyze daytime-nighttime variability. Central SBP was assessed, using brachial waveforms, calibrated with mean arterial pressure (MAP)/diastolic BP (cSBPMAP/DBPcal), or bSBP/diastolic blood pressure (cSBPSBP/DBPcal), and a validated transfer function, resulting in 144 509 valid brachial and 130 804 valid central measurements. Averaged 24-hour, daytime, and nighttime brachial BP across all individuals was 124/79, 126/81, and 116/72 mm Hg, respectively. Averaged 24-hour, daytime, and nighttime values for cSBPMAP/DBPcal were 128, 128, and 125 mm Hg and 115, 117, and 107 mm Hg for cSBPSBP/DBPcal, respectively. We pragmatically propose as upper normal limit for 24-hour cSBPMAP/DBPcal 135 mm Hg and for 24-hour cSBPSBP/DBPcal 120 mm Hg. bSBP dipping (nighttime-daytime/daytime SBP) was -10.6 % in young participants and decreased with increasing age. Central SBPSBP/DBPcal dipping was less pronounced (-8.7% in young participants). In contrast, cSBPMAP/DBPcal dipping was completely absent in the youngest age group and less pronounced in all other participants. These data may serve for comparison in various diseases and have potential implications for refining hypertension diagnosis and management. The different dipping behavior of bSBP versus cSBP requires further investigation

Gene expression profiling of the astrocyte transcriptome in multiple sclerosis normal appearing white matter reveals a neuroprotective role

Multiple sclerosis (MS) is a chronic, inflammatory, demyelinating disease of the central nervous system (CNS). White matter lesions in MS are surrounded by areas of non-demyelinated normal appearing white matter (NAWM) with complex pathology, including blood brain barrier dysfunction, axonal damage and glial activation. Astrocytes, the most abundant cell type within the CNS, may respond and/or contribute to lesion pathogenesis. We aimed to characterise the transcriptomic profile of astrocytes in NAWM to determine whether specific glial changes exist in the NAWM which contribute to lesion development or prevent disease progression. Astrocytes were isolated from control and NAWM by laser capture microdissection (LCM), using glial fibrillary acidic protein (GFAP) as a marker, and the astrocyte transcriptome determined using microarray analysis. 452 genes were significantly differentially expressed (208 up-regulated and 244 down-regulated, FC ≥ 1.5 and p-value ≤ 0.05). Within the NAWM, astrocytes were associated with significant upregulation of genes involved in the control of iron homeostasis (including metallothionein-1 and -2, ferritin light chain and transferrin), oxidative stress responses, the immune response and neurotrophic support. These findings suggest a neuroprotective role of astrocytes in the NAWM in M

Critical assessment of the elemental composition of Corning archeological reference glasses by LA-ICP-MS

Corning archeological reference glasses A, B, C, and D have been made to simulate different historic technologies of glass production and are used as standards in historic glass investigations. In this work, nanoseconds (193, 266 nm) and femtosecond (800 nm) laser ablation were used to study the elemental composition of Corning glasses using laser ablation inductively coupled plasma mass spectrometry. The determined concentrations of 26 oxides (Li2O, B2O3, Na2O, MgO, Al2O3, SiO2, P2O5, K2O, CaO, TiO2, V2O5, Cr2O3, MnO, Fe2O3, CoO, NiO, CuO, ZnO, Rb2O, SrO, ZrO2, SnO2, Sb2O5, BaO, PbO, Bi2O3) are compared with values reported in the literature. Results show variable discrepancies between the data, with the largest differences found for Cr2O3 in Corning A; Li2O, B2O3, and Cr2O3 in Corning B; and MnO, Sb2O5, Cr2O3, and Bi2O3 in Corning C. The best agreement between the measured and literature values was found for Corning D. However, even for this reference, glass re-evaluation of the data was necessary and new values for PbO, BaO, and Bi2O3 are proposed