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Karmar R.T.,Karolinska Institutet | Holtback U.,Karolinska Institutet | Anita Bergh A.,Karolinska Institutet | Svensson E.,Karolinska Institutet | Wuhl E.,Center for Pediatrics and Adolescent Medicine
American Journal of Hypertension | Year: 2015

BACKGROUND: Casual blood pressure (CBP) is considered a reliable proxy for cardiovascular health. Although the auscultatory technique is the reference standard method for measuring CBP, oscillometric devices are increasingly being used in children. We sought to establish oscillometric CBP normative standards for Swedish children. METHODS: Cross-sectional oscillometric CBP readings were obtained by the Welch Allyn Spot Vital Signs 420 monitor and measured according to the International Guidelines' recommendations. Participants with elevated oscillometric CBP levels underwent verification by the auscultatory method. Ambulatory blood pressure monitoring (ABPM) was used to exclude casual hypertension. Data on 1,470 (772 males) apparently healthy Swedish schoolchildren aged 6-16 years were analyzed and sex-specific reference charts normalized to age or height were constructed. RESULTS: Systolic and diastolic CBP values were significantly higher with age, height, height standard deviation score (SDS), body mass index (BMI), and BMI SDS. Gender differences for systolic CBP were present starting from age of 15 years and revealed significantly higher values in boys than in girls, whereas for diastolic CBP, the differences were apparent at the age of 12 years, with higher values in girls. Increased BMI and BMI SDS were positively associated with CBP levels. Positive parental history of hypertension turned out to be a risk factor for higher systolic and diastolic CBP across all ages. CONCLUSIONS: Our normative standard for CBP can be used for blood pressure screening and control programs in Swedish children. The use of ABPM should be considered to confirm the diagnosis of casual hypertension. © 2014 © American Journal of Hypertension, Ltd 2014. All rights reserved. Source

Ozaltin F.,Hacettepe University | Ibsirlioglu T.,Hacettepe University | Taskiran E.Z.,Hacettepe University | Baydar D.E.,Hacettepe University | And 10 more authors.
American Journal of Human Genetics | Year: 2011

Idiopathic nephrotic syndrome (INS) is a genetically heterogeneous group of disorders characterized by proteinuria, hypoalbuminemia, and edema. Because it typically results in end-stage kidney disease, the steroid-resistant subtype (SRNS) of INS is especially important when it occurs in children. The present study included 29 affected and 22 normal individuals from 17 SRNS families; genome-wide analysis was performed with Affymetrix 250K SNP arrays followed by homozygosity mapping. A large homozygous stretch on chromosomal region 12p12 was identified in one consanguineous family with two affected siblings. Direct sequencing of protein tyrosine phosphatase receptor type O (PTPRO; also known as glomerular epithelial protein-1 [GLEPP1]) showed homozygous c.2627+1G>T donor splice-site mutation. This mutation causes skipping of the evolutionarily conserved exon 16 (p.Glu854-Trp876del) at the RNA level. Immunohistochemistry with GLEPP1 antibody showed a similar staining pattern in the podocytes of the diseased and control kidney tissues. We used a highly polymorphic intragenic DNA marker-D12S1303-to search for homozygosity in 120 Turkish and 13 non-Turkish individuals in the PodoNet registry. This analysis yielded 17 candidate families, and a distinct homozygous c.2745+1G>A donor splice-site mutation in PTPRO was further identified via DNA sequencing in a second Turkish family. This mutation causes skipping of exon 19, and this introduces a premature stop codon at the very beginning of exon 20 (p.Asn888Lysfs*3) and causes degradation of mRNA via nonsense-mediated decay. Immunohistochemical analysis showed complete absence of immunoreactive PTPRO. Ultrastructural alterations, such as diffuse foot process fusion and extensive microvillus transformation of podocytes, were observed via electron microscopy in both families. The present study introduces mutations in PTPRO as another cause of autosomal-recessive nephrotic syndrome. © 2011 by The American Society of Human Genetics. All rights reserved. Source

Schaefer F.,Center for Pediatrics and Adolescent Medicine | Warady B.A.,Section of Pediatric Nephrology
Nature Reviews Nephrology | Year: 2011

Peritoneal dialysis is the preferred chronic dialysis modality for most children owing to its almost universal applicability and superior compatibility with lifestyle over other modalities. Although technological advances and increasing clinical experience have impacted favorably on patient and technique survival, clinical research in pediatric peritoneal dialysis has been hampered by the low incidence of end-stage renal disease (ESRD) in the pediatric population. To overcome this limitation, several international registries have emerged in the past few years to complement other long-standing registries, which together have provided useful information regarding technique-specific complications and comorbidities associated with ESRD in children undergoing chronic peritoneal dialysis. In this Review, we summarize the most relevant findings from these studies, highlighting the substantial variation in patient conditions, peritoneal dialysis practices and management of comorbidities encountered in different parts of the world. © 2011 Macmillan Publishers Limited. All rights reserved. Source

Rohrer T.R.,Saarland University | Wolf J.,St. Vincenz Hospital | Liptay S.,TU Munich | Zimmer K.-P.,Justus Liebig University | And 8 more authors.
Diabetes Care | Year: 2015

OBJECTIVE: To investigate whether celiac disease (CD) associated with type 1 diabetes increases the risk of microvascular complications. RESEARCH DESIGN AND METHODS: Patients (n = 56,514) aged >10 years with diabetes duration <20 years from 392 centers in Germany and Austria were assigned to one of three categories (n): no CD (50,933), biopsy-confirmed CD (812), or suspected CD (4,769; clinical diagnosis or positive antibodies). The confirmed and suspected groups were combined and analyzed for retinopathy or nephropathy. Cox proportional hazards regression was used to adjust for potential confounders (glycated hemoglobin [HbA1c], age at diabetes onset, sex, smoking, dyslipidemia, and hypertension). RESULTS: Kaplan-Meier analysis revealed that retinopathy and nephropathy occurred earlier in the presence versus absence of CD: retinopathy at age 26.7 years (95% CI 23.7-30.2) in 25% of patients with CD vs. age 33.7 years (33.2-34.4) in 25% without CD and microalbuminuria at age 32.8 years (29.7-42.5) vs. 42.4 years (41.4-43.3). The adjusted risk for both retinopathy (hazard ratio 1.263 [95% CI 1.078-1.481]) and nephropathy (1.359 [1.228-1.504]) was higher in patients with diabetes and CD versus those without CD. Cox regression revealed CD as an independent risk factor for microvascular complications after adjustment for confounders. CONCLUSIONS: CD is an independent risk factor for retinopathy and nephropathy in patients with type 1 diabetes. Our study therefore supports the recommendation for regular serologic testing for CD, even in the absence of clinical CD. Further prospective studies are required to investigate whether a gluten-free diet might reduce the risk of microvascular disorders in patients with diabetes and CD. © 2015 by the American Diabetes Association. Source

Mele C.,Mario Negri Institute for Pharmacological Research | Iatropoulos P.,Mario Negri Institute for Pharmacological Research | Donadelli R.,Mario Negri Institute for Pharmacological Research | Calabria A.,University of Milan | And 23 more authors.
New England Journal of Medicine | Year: 2011

BACKGROUND: Focal segmental glomerulosclerosis is a kidney disease that is manifested as the nephrotic syndrome. It is often resistant to glucocorticoid therapy and progresses to end-stage renal disease in 50 to 70% of patients. Genetic studies have shown that familial focal segmental glomerulosclerosis is a disease of the podocytes, which are major components of the glomerular filtration barrier. However, the molecular cause in over half the cases of primary focal segmental glomerulosclerosis is unknown, and effective treatments have been elusive. METHODS: We performed whole-genome linkage analysis followed by high-throughput sequencing of the positive-linkage area in a family with autosomal recessive focal segmental glomerulosclerosis (index family) and sequenced a newly discovered gene in 52 unrelated patients with focal segmental glomerulosclerosis. Immunohistochemical studies were performed on human kidney-biopsy specimens and cultured podocytes. Expression studies in vitro were performed to characterize the functional consequences of the mutations identified. RESULTS: We identified two mutations (A159P and Y695X) in MYO1E, which encodes a non-muscle class I myosin, myosin 1E (Myo1E). The mutations in MYO1E segregated with focal segmental glomerulosclerosis in two independent pedigrees (the index family and Family 2). Patients were homozygous for the mutations and did not have a response to glucocorticoid therapy. Electron microscopy showed thickening and dis-organization of the glomerular basement membrane. Normal expression of Myo1E was documented in control human kidney-biopsy specimens in vivo and in glomerular podocytes in vitro. Transfection studies revealed abnormal subcellular localization and function of the A159P-Myo1E mutant. The Y695X mutation causes loss of calmodulin binding and of the tail domains of Myo1E. CONCLUSIONS: MYO1E mutations are associated with childhood-onset, glucocorticoid-resistant focal segmental glomerulosclerosis. Our data provide evidence of a role of Myo1E in podocyte function and the consequent integrity of the glomerular filtration barrier. Copyright © 2011 Massachusetts Medical Society. All rights reserved. Source

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