Design and baseline characteristics of the finerenone in reducing cardiovascular mortality and morbidity in diabetic kidney disease trial

Background: Among people with diabetes, those with kidney disease have exceptionally high rates of cardiovascular (CV) morbidity and mortality and progression of their underlying kidney disease. Finerenone is a novel, nonsteroidal, selective mineralocorticoid receptor antagonist that has shown to reduce albuminuria in type 2 diabetes (T2D) patients with chronic kidney disease (CKD) while revealing only a low risk of hyperkalemia. However, the effect of finerenone on CV and renal outcomes has not yet been investigated in long-term trials. Patients and Methods: The Finerenone in Reducing CV Mortality and Morbidity in Diabetic Kidney Disease (FIGARO-DKD) trial aims to assess the efficacy and safety of finerenone compared to placebo at reducing clinically important CV and renal outcomes in T2D patients with CKD. FIGARO-DKD is a randomized, double-blind, placebo-controlled, parallel-group, event-driven trial running in 47 countries with an expected duration of approximately 6 years. FIGARO-DKD randomized 7,437 patients with an estimated glomerular filtration rate >= 25 mL/min/1.73 m(2) and albuminuria (urinary albumin-to-creatinine ratio >= 30 to <= 5,000 mg/g). The study has at least 90% power to detect a 20% reduction in the risk of the primary outcome (overall two-sided significance level alpha = 0.05), the composite of time to first occurrence of CV death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure. Conclusions: FIGARO-DKD will determine whether an optimally treated cohort of T2D patients with CKD at high risk of CV and renal events will experience cardiorenal benefits with the addition of finerenone to their treatment regimen. Trial Registration: EudraCT number: 2015-000950-39; ClinicalTrials.gov identifier: NCT02545049

Early-infantile onset epilepsy and developmental delay caused by bi-allelic GAD1 variants.

Gamma-aminobutyric acid (GABA) and glutamate are the most abundant amino acid neurotransmitters in the brain. GABA, an inhibitory neurotransmitter, is synthesized by glutamic acid decarboxylase (GAD). Its predominant isoform GAD67, contributes up to ∼90% of base-level GABA in the CNS, and is encoded by the GAD1 gene. Disruption of GAD1 results in an imbalance of inhibitory and excitatory neurotransmitters, and as Gad1-/- mice die neonatally of severe cleft palate, it has not been possible to determine any potential neurological dysfunction. Furthermore, little is known about the consequence of GAD1 disruption in humans. Here we present six affected individuals from six unrelated families, carrying bi-allelic GAD1 variants, presenting with developmental and epileptic encephalopathy, characterized by early-infantile onset epilepsy and hypotonia with additional variable non-CNS manifestations such as skeletal abnormalities, dysmorphic features and cleft palate. Our findings highlight an important role for GAD1 in seizure induction, neuronal and extraneuronal development, and introduce GAD1 as a new gene associated with developmental and epileptic encephalopathy

Mandibuloacral dysplasia and LMNA A529V mutation in Turkish patients with severe skeletal changes and absent breast development

WOS: 000378613800001PubMed ID: 27100822Mandibuloacral dysplasia (MAD) is an autosomal recessive disorder characterized by acroosteolysis (resorption of terminal phalanges), skin changes (hyperpigmentation), clavicular hypoplasia, craniofascial anomalies, a hook nose and prominent eyes, delayed closures of the cranial sutures, lipodystrophy, alopecia, and skeletal anomalies. MAD patients are classified according to lipodystrophy patterns: type A and type B. The vast majority of MAD cases are caused by LMNA gene mutations. MAD patients with type A lipodystrophy (MADA) have been reported to have LMNA R527H, A529V, or A529T mutations. In this report, we describe two MADA patients with progressive skeletal changes, absent breast development, and cataract in addition to the classical MAD phenotype. Both patients were found to be homozygous for the Ala529Val mutation of the LMNA gene. Our female patient is the oldest MADA patient (59 years old) who has ever been reported with the LMNA mutation and also the LMNA Ala529Val mutation. This study is the second report on MADA patients with a homozygous Ala529Val mutation

Novel Mutations in Obesity-related Genes in Turkish Children with Non-syndromic Early Onset Severe Obesity: A Multicentre Study

Objective: Non syndromic monogenic obesity is a rare cause of early onset severe obesity in the childhood period. This form may not be distinguishable from other forms of severe obesity without genetic analysis, particularly if patients do not exibit any physical abnormalities or developmental delay. The aim of this study was to screen 41 different obesity-related genes in children with nonsyndromic early onset severe obesity. Methods: Children with severe (body mass index-standard deviation score >3) and early onset (<7 years) obesity were screened by next-generation sequencing based, targeted DNA custom panel for 41 known-obesity-related genes and the results were confirmed by Sanger technique. Results: Six novel variants were identified in five candidate genes in seven out of 105 children with severe obesity; two in SIM1 (p.W306C and p.Q36X), one in POMC (p.Y160H), one in PCSK1 (p.W130G fs Ter8), two in MC4R (p.D126E) and one in LEPR (p.Q4H). Additionally, two previously known variations in MC4R were identified in four patients (p.R165W in three, and p.V166I in one). Conclusion: We identified six novel and four previously described variants in six obesity-related genes in 11 out of 105 childrens with early onset severe obesity. The prevalence of monogenic obesity was 10.4% in our cohort.Inonu University Research Fundation, Malatya, TurkeyInonu University [TSG-2018-1137]This project was supported by Inonu University Research Fundation, Malatya, Turkey, project number: TSG-2018-1137

First successful preimplantation genetic diagnosis of epidermolysis bullosa with pyloric atresia: Case study of a novel c.4505-4508insACTC mutation

WOS: 000302070800013PubMed ID: 22354727

The expression levels of miRNA-15a and miRNA-16-1 in circulating tumor cells of patients with diffuse large B-cell lymphoma.

MicroRNAs (miRNAs) have major roles in nearly all cellular process including gene expression, and may behave as oncogene or tumor suppressor gene by binding to complementary sequences in the target mRNA. The circulating microRNA-15a (miRNA-15a) and microRNA-16-1 (miRNA-16-1) of 15 healthy adults and of 40 untreated patients diagnosed with diffuse large B-cell lymphoma (DLBC) were recruited to investigate the expression levels. The expression levels of miRNA-15a, and miRNA-16-1 genes of the untreated DLBCL patients, and healthy individuals with matched age, sex and ethnicity were examined. MicroRNA expression profiles obtained from peripheral blood were investigated. The samples were collected from 40 patients diagnosed with DLBC patients, and from 15 healthy controls. Two miRNAs were selected, and expression profile was examined using a quantitative real-time polymerase chain reaction (qPCR) based on the previous studies. Statistically significant expression level differences (p0.05). On the contrary to the literature, miRNA-16-1 expression level was suppressed in DLBCL group in our study, however no whole gene silencing was performed. MicroRNA-16-1 might be suggested to behave as a tumor suppressor in DLBCL in our study

Aspirynooporność u chorych z niewydolnością nerek

Background: Cardiovascular diseases (CVD) are the leading cause of death in patients with chronic kidney diseases (CKD). Aspirin resistance (AR) worsens prognosis in CVD.Aim: The aim of this study was to detect AR prevalence in this patient group.Methods: The 203 patients (mean age 61.84 ± 11.51 years, 128 [63.1%] male) with stable coronary artery disease included in the study were grouped into four study groups according to their estimated glomerular filtration rate (eGFR) values. Multiplatetest was used to determine AR. Platelet aggregation results were presented as aggregation unit (AU) × min and valuesover 300 AU × min were accepted as AR.Results: 61 (30.04%) patients in the whole study population were found to have AR. Differences were detected between AR ratios and multiplate values of the patient groups (p = 0.006 and p = 0.002). AR ratio was highest in patient group 4 (eGFR &lt; 30 mL/min/1.73 m2) and/or on chronic haemodialysis therapy, whereas there was little difference amongthe other three groups. In multivariate analysis, while AR status was independently related to female sex (OR = 2.31,CI 1.14–4.65, p = 0.019) and mean platelet volume (MPV) (OR = 1.68, CI 1.21–2.33, p = 0.002), multiplate test results were independently related to MPV (b = 0.265, p &lt; 0.0001) and eGFR (b = –0.165, p = 0.025).Conclusions: The AR ratio was found to be high in severe CKD patients, especially haemodialysis patients, but not in mild and moderate CKD patients. This increased AR ratio in severe CKD patients may affect the prognosis in patients who already have an increased risk for cardiovascular complications. Wstęp: Choroby układu sercowo-naczyniowego są główną przyczyną zgonów u pacjentów z przewlekłą chorobą nerek (CKD). Aspirynooporność (AR) pogarsza rokowanie w chorobie układu sercowo-naczyniowego.Cel: Badanie przeprowadzono w celu ustalenia częstości występowania AR w tej grupie chorych.Metody: Dwustu trzech chorych (średnia wieku 61,84 ± 11,51 roku; 128 [63,1%] mężczyzn) ze stabilną chorobą wieńcową, włączonych do badania, podzielono na 4 grupy w zależności od oszacowanej filtracji kłębuszkowej (eGFR). W celu określenia AR zastosowano metodę testów wielokrotnych. Wyniki oceny agregacji płytek przedstawiono w jednostkach agregacji (AU) × min, a wartości większe niż 300 AU × min uznano za wskazujące na obecność AR.Wyniki: U 61 (30,04%) chorych z całej badanej grupy wykryto AR. Stwierdzono różnice w częstości występowania AR i wyników testów wielokrotnych między poszczególnymi grupami pacjentów (p = 0,006 i p = 0,002). Częstość występowania AR była największa u osób z grupy 4 (eGFR &lt; 30 ml/min/1,73 m2) i/lub stosujących długotrwale hemodializę, natomiast różnice między pozostałymi trzema grupami były niewielkie. W analizie wieloczynnikowej częstość występowania AR była niezależnie związana z płcią żeńską (OR = 2,31; CI 1,14–4,65; p = 0,019) i średnią objętością krwinek (MPV) (OR = 1,68;CI 1,21–2,33; p = 0,002), natomiast wyniki testów wielokrotnych były niezależnie związane z MPV (b = 0,265; p &lt; 0,0001)i eGFR (b = –0,165; p = 0,025).Wnioski: Częstość występowania AR była większa w grupie pacjentów z CKD, zwłaszcza u osób hemodializowanych, natomiast nie była zwiększona u pacjentów z łagodną lub umiarkowaną CKD. Zwiększenie częstości AR u chorych z ciężką CKD może wpływać na rokowanie u osób, u których ryzyko powikłań sercowo-naczyniowych było już wcześniej zwiększone.