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

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

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

Publisher Correction to: Chlormethine Gel for Patients with Mycosis Fungoides Cutaneous T Cell Lymphoma: A Review of Efficacy and Safety in Clinical Trial and Real-World Settings

A plain language summary was retrospectively added to this publication

Chlormethine Gel for Patients with Mycosis Fungoides Cutaneous T Cell Lymphoma: A Review of Efficacy and Safety in Clinical Trial and Real-World Settings

Mycosis fungoides (MF) is a rare disease and is the most common form of cutaneous T cell lymphoma. Topical chlormethine (CL) gel is the first cytotoxic chemotherapy gel that was specifically developed for treatment of MF. In this review, we provide an overview of all available data on the use of CL gel for treatment of patients with MF. On the basis of the current data collected, CL gel is highly effective, with good response rates observed both in clinical trial and real-world settings. While the gel is approved for monotherapy, it is also used in combination with concomitant skin-directed or systemic therapies in clinical practice. Responses to CL gel treatment can be rapid, but they also frequently occur with a delayed onset of up to 6 months. This indicates that continued treatment with CL gel is important. CL gel has a manageable safety profile, with most adverse events being mild and skin related. Contact dermatitis is one of the more common skin-related adverse events to occur with CL gel treatment that can potentially lead to treatment discontinuation. The data from the literature indicate that patients being treated with CL gel should be monitored carefully, and that dermatitis must be managed effectively to allow patients to continue treatment and achieve the best possible response to treatment

Uraemic extracellular vesicles augment osteogenic transdifferentiation of vascular smooth muscle cells via enhanced AKT signalling and PiT‐1 expression

Extracellular vesicles (EV) function as messengers between endothelial cells (EC) and vascular smooth muscle cells (VSMC). Since chronic kidney disease (CKD) increases the risk for vascular calcifications, we investigated whether EV derived from uraemic milieu-stimulated EC and derived from uraemic rats impact the osteogenic transdifferentiation/calcification of VSMC. For that purpose, human EC were treated with urea and indoxyl sulphate or left untreated. Experimental uraemia in rats was induced by adenine feeding. 'Uraemic' and control EV (EVUR; EVCTRL) were isolated from supernatants and plasma by using an exosome isolation reagent. Rat VSMC were treated with a pro-calcifying medium (CM) with or without EV supplementation. Gene expressions, miRNA contents and protein expressions were determined by qPCR and Western blots, respectively. Calcifications were determined by colorimetric assays. Delivery of miRNA inhibitors/mimics to EV and siRNA to VSMC was achieved via transfection. EVCTRL and EVUR differed in size and miRNA contents. Contrary to EVCTRL, EC- and plasma-derived EVUR significantly increased the pro-calcifying effects of CM, including altered gene expressions of osterix, runx2, osteocalcin and SM22 alpha. Further, EVUR enhanced the protein expression of the phosphate transporter PiT-1 in VSMC and induced a phosphorylation of AKT and ERK. Knock down of PiT-1 and individual inhibition of AKT and ERK signalling in VSMC blocked the pro-calcifying effects of EVUR. Similar effects were achieved by inhibition of miR-221/-222 and mimicking of miR-143/-145 in EVUR. In conclusion, EVUR might represent an additional puzzle piece of the complex pathophysiology of vascular calcifications in CKD

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