The cardiovascular phenotype of adult patients with phenylketonuria

BACKGROUND: Patients with Phenylketonuria (PKU) are exposed to multiple cardiovascular risk factors, but the clinical significance of these abnormalities is yet unknown. The purpose of this study was to characterize the cardiovascular phenotype in adult patients with PKU by clinical and dietary data, measurements of biochemical markers, and non-invasive examination of vascular functions. RESULTS: Twenty-three adult patients with PKU (age: 18-47 y; 30.8 ± 8.4 y) and 28 healthy controls (age: 18-47 y; 30.1 ± 9.1 y) were included in this study. PKU patients had significantly higher systolic and diastolic blood pressure, increased resting heart rate and a higher body mass index. Total cholesterol and non-HDL cholesterol levels were significantly increased in PKU patients, whereas plasma levels of HDL cholesterol and its subfraction HDL2 (but not HDL3) were significantly decreased. The inflammatory markers C-reactive protein and serum amyloid A protein and the serum oxidative stress marker malondialdehyde were significantly higher in patients with PKU. Venous occlusion plethysmography showed marked reduction in post-ischemic blood flow and the carotid to femoral pulse wave velocity was significantly increased demonstrating endothelial dysfunction and increased vascular stiffness. CONCLUSIONS: This study shows that the cardiovascular phenotype of adult PKU patients is characterized by an accumulation of traditional cardiovascular risk factors, high levels of inflammatory and oxidative stress markers, endothelial dysfunction and vascular stiffness. These data indicate the need for early cardiovascular risk reduction in patients with PKU

A Lindera obtusiloba Extract Blocks Calcium-/Phosphate-Induced Transdifferentiation and Calcification of Vascular Smooth Muscle Cells and Interferes with Matrix Metalloproteinase-2 and Metalloproteinase-9 and NF-kB

Vascular calcifications bear the risk for cardiovascular complications and have a high prevalence among patients with chronic kidney disease. Central mediators of vascular calcifications are vascular smooth muscle cells (VSMC). They transdifferentiate into a synthetic/osteoblast-like phenotype, which is induced, for example, by elevated levels of calcium and phosphate (Ca/P) due to a disturbed mineral balance. An aqueous extract from Lindera obtusiloba (LOE) is known to exert antifibrotic and antitumor effects or to interfere with the differentiation of preadipocytes. Using murine and rat VSMC cell lines, we here investigated whether LOE also protects VSMC from Ca/P-induced calcification. Indeed, LOE effectively blocked Ca/P-induced calcification of VSMC as shown by decreased VSMC mineralization and secretion of alkaline phosphatase. In parallel, mRNA expression of the calcification markers osterix and osteocalcin was reduced. Vice versa, the Ca/P-induced loss of the VSMC differentiation markers alpha smooth muscle actin and smooth muscle protein 22-alpha was rescued by LOE. Further, LOE blocked Ca/P-induced mRNA expressions and secretions of matrix metalloproteinases-2/-9 and activation of NF-B, which are known contributors to vascular calcification. In conclusion, LOE interferes with the Ca/P-induced transdifferentiation/calcification of VSMC. Thus, LOE should be further analysed regarding a potential complementary treatment option for cardiovascular diseases including vascular calcifications

Wnt signaling contributes to vascular calcification by induction of matrix metalloproteinases

Background Vascular calcifications such as arteriosclerosis, which is characterized by a calcificiation of the tunica media, represent major comorbidities e.g. in patients with chronic kidney disease (CKD). An essential step during the development of arteriosclerosis is the transdifferentiation/calcification of vascular smooth muscle cells (VSMC) resembling osteogenesis. The matrix metalloproteinases (MMP)-2 and −9 were shown to promote these VSMC calcifications and their inhibition is of therapeutic value to prevent arteriosclerosis in preclinical studies. Aiming for an understanding of the underlying regulatory mechanisms of MMPs we here investigated, if the MMP-mediated VSMC calcification involves altered signaling of the Wnt pathway, which is known to impact osteogenesis. Methods We used an experimental in vitro model of vascular calcification. Transdifferentiation/calcification of murine VSMC was induced by elevated calcium and phosphorus levels. Calcification was assessed by calcium and alkaline phosphatase measurements. Activation/activity of the gelatinases MMP-2 and MMP-9 was assessed by conversion of fluorescence-labelled substrates. Activation of the Wnt pathway was analysed by a reporter gene assay. Results Besides pro-calcifying culture conditions, also activation of Wnt signaling by a specific agonist (under normal culture conditions) stimulated VSMC-calcification accompanied by enhanced expression and secretion of the gelatinases MMP-2 and −9. Vice versa, recombinant MMP-2 and −9 induced a time-delayed activation of Wnt signaling after 72 h in VSMC but showed no direct effects after 24–48 h. These effects were blocked by pharmacological inhibition of MMPs or of Wnt signaling. Conclusions Our study suggests that the pro-calcifying environment in CKD induces Wnt signaling in VSMC which in turn contributes to the induction of MMPs which then foster the development of arteriosclerosis. Thus, besides MMP inhibition, the inhibition of Wnt signaling in VSMC might represent a therapeutic target for the prevention of vascular calcifications

Endothelial dysfunction in children with steroid-resistant nephrotic syndrome

Background: Steroid-resistant nephrotic syndrome (SRNS) is associated with early atherosclerosis because of comorbidities including persistent hyperlipidemia and hypertension. The aim of this study was to determine the incidence of abnormal carotid intima-media thickening (cIMT) as an early sign of atherosclerosis in a small group of children with SRNS. Methods: A total of 8 children with SRNS (mean age, 10.8±4.2 years at recruitment andmeandisease duration, 40.9±20.7 months) were studied; all children were normotensive. B-mode ultrasound was used to measure cIMT, and the results were compared with healthy controls. Results: Children with SRNS had significantly thicker CIMT (0.44±0.04 mm), compared to the controls (0.37±0.59mm)(P < 0.01). A high level of total cholesterol (5.4±2.0 mmol/L; normal < 5.2 mmol/L) was reported in these children, while normal levels of lowdensity lipoprotein, very-low-density lipoprotein, triglyceride, and high-density lipoprotein were found. Also, the mean creatinine level was 45.1±15.0 µmol/L, and the mean urea level was 4.2±1.8 mmol/L. Conclusions: Children with SRNS had an abnormal vascular phenotype with a thicker CIMT, compared to the controls and showed evidence of hypercholesterolemia

Cardiovascular disease in childhood and adolescence: Lessons from children with chronic kidney disease

Children suffering from chronic kidney disease (CKD) have the apparent highest risk for the development of cardiovascular disease (CVD) at a young age. While symptoms of CVD are characteristically absent in childhood and adolescence, remodelling of the myocardium, medium and large-sized arteries and of the microcirculation is clinically significant and can be assessed with non-invasive technology. Kidney disease and its progression are the driver of CVD, mediated by an unparalleled accumulation of risk factors converging on several comorbid conditions including hypertension, anaemia, dyslipidaemia, disturbed mineral metabolism and chronic persistent inflammation. Large prospective paediatric cohorts studies have provided valuable insights into the pathogenesis and the progression of CKD-induced cardiovascular comorbidity and have characterised the cardiovascular phenotype in young patients. They have also provided the rationale for close monitoring of risk factors and have defined therapeutic targets. Recently discovered new biomarkers could help identify the individual risk for CVD. Prevention of CVD by aggressive therapy of modifiable risk factors is essential to enable long-term survival of young patients with CKD

Radioanalytical Investigations of Water Samples from the Vicinity of the Nuclear Power Plants "Chernobyl" and "Fukushima Daiichi"

In this work, the fission products 90Sr, 129I, and 137Cs and reactor nuclides 3H, and 134Cs were analyzed in the compartment water from the immediate vicinity of the Chernobyl and Fukushima NPPs, and the methods were adapted for these measurements. Both, radioanalytical and mass spectrometrical methods were used, such as liquid scintillation counting, gamma spectrometry via high-purity germanium detector, and accelerator mass spectrometry. The optimized methods were subsequently applied to natural water samples from the Chernobyl exclusion zone with large sample volumes. Further adaptations were made for small sample volumes of Fukushima surface water samples, which were sampled only a month after the accident. Finally, both drinking water as well as a variety of surface water samples from sites of the Tokyo 2020 Olympic Games were tested for their radionuclide content to assess potential risks to athletes and visitors

Polarimetric Properties of Flux-Ropes and Sheared Arcades in Coronal Prominence Cavities

The coronal magnetic field is the primary driver of solar dynamic events. Linear and circular polarization signals of certain infrared coronal emission lines contain information about the magnetic field, and to access this information, either a forward or an inversion method must be used. We study three coronal magnetic configurations that are applicable to polar-crown filament cavities by doing forward calculations to produce synthetic polarization data. We analyze these forward data to determine the distinguishing characteristics of each model. We conclude that it is possible to distinguish between cylindrical flux ropes, spheromak flux ropes, and sheared arcades using coronal polarization measurements. If one of these models is found to be consistent with observational measurements, it will mean positive identification of the magnetic morphology that surrounds certain quiescent filaments, which will lead to a greater understanding of how they form and why they erupt.Comment: 22 pages, 8 figures, Solar Physics topical issue: Coronal Magnetis

Estimation of solar prominence magnetic fields based on the reconstructed 3D trajectories of prominence knots

We present an estimation of the lower limits of local magnetic fields in quiescent, activated, and active (surges) promineces, based on reconstructed 3-dimensional (3D) trajectories of individual prominence knots. The 3D trajectories, velocities, tangential and centripetal accelerations of the knots were reconstructed using observational data collected with a single ground-based telescope equipped with a Multi-channel Subtractive Double Pass imaging spectrograph. Lower limits of magnetic fields channeling observed plasma flows were estimated under assumption of the equipartition principle. Assuming approximate electron densities of the plasma n_e = 5*10^{11} cm^{-3} in surges and n_e = 5*10^{10} cm^{-3} in quiescent/activated prominences, we found that the magnetic fields channeling two observed surges range from 16 to 40 Gauss, while in quiescent and activated prominences they were less than 10 Gauss. Our results are consistent with previous detections of weak local magnetic fields in the solar prominences.Comment: 14 pages, 12 figures, 1 tabl

Quantitative Histomorphometry of the Healthy Peritoneum

The peritoneum plays an essential role in preventing abdominal frictions and adhesions and can be utilized as a dialysis membrane. Its physiological ultrastructure, however, has not yet been studied systematically. 106 standardized peritoneal and 69 omental specimens were obtained from 107 patients (0.1–60 years) undergoing surgery for disease not affecting the peritoneum for automated quantitative histomorphometry and immunohistochemistry. The mesothelial cell layer morphology and protein expression pattern is similar across all age groups. Infants below one year have a thinner submesothelium; inflammation, profibrotic activity and mesothelial cell translocation is largely absent in all age groups. Peritoneal blood capillaries, lymphatics and nerve fibers locate in three distinct submesothelial layers. Blood vessel density and endothelial surface area follow a U-shaped curve with highest values in infants below one year and lowest values in children aged 7–12 years. Lymphatic vessel density is much lower, and again highest in infants. Omental blood capillary density correlates with parietal peritoneal findings, whereas only few lymphatic vessels are present. The healthy peritoneum exhibits major thus far unknown particularities, pertaining to functionally relevant structures, and subject to substantial changes with age. The reference ranges established here provide a framework for future histomorphometric analyses and peritoneal transport modeling approaches

Chronic kidney disease induces a systemic microangiopathy, tissue hypoxia and dysfunctional angiogenesis

Chronic kidney disease (CKD) is associated with excessive mortality from cardiovascular disease (CVD). Endothelial dysfunction, an early manifestation of CVD, is consistently observed in CKD patients and might be linked to structural defects of the microcirculation including microvascular rarefaction. However, patterns of microvascular rarefaction in CKD and their relation to functional deficits in perfusion and oxygen delivery are currently unknown. In this in-vivo microscopy study of the cremaster muscle microcirculation in BALB/c mice with moderate to severe uremia, we show in two experimental models (adenine feeding or subtotal nephrectomy), that serum urea levels associate incrementally with a distinct microangiopathy. Structural changes were characterized by a heterogeneous pattern of focal microvascular rarefaction with loss of coherent microvascular networks resulting in large avascular areas. Corresponding microvascular dysfunction was evident by significantly diminished blood flow velocity, vascular tone, and oxygen uptake. Microvascular rarefaction in the cremaster muscle paralleled rarefaction in the myocardium, which was accompanied by a decrease in transcription levels not only of the transcriptional regulator HIF-1 alpha, but also of its target genes Angpt-2, TIE-1 and TIE-2, Flkt-1 and MMP-9, indicating an impaired hypoxia-driven angiogenesis. Thus, experimental uremia in mice associates with systemic microvascular disease with rarefaction, tissue hypoxia and dysfunctional angiogenesis