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Background: The aim of the study was to assess underlying genetic cause(s), clinical features, and response to therapy in catecholaminergic polymorphic ventricular tachycardia (CPVT) probands. Methods and results: We identified 13 missense mutations in the cardiac ryanodine receptor (RYR2) in 12 probands with CPVT. Twelve were new, of which two are de novo mutations. A further 11 patients were silent gene carriers, suggesting that some mutations are associated with low penetrance. A marked resting sinus bradycardia off drugs was observed in all carriers. On β blocker treatment, 98% of the RYR2 mutation carriers remained symptom free with a median follow up of 2 (range: 2–37) years. Conclusion: CPVT patients with RYR2 mutation have bradycardia regardless of the site of the mutation, which could direct molecular diagnosis in (young) patients without structural heart disease presenting with syncopal events and a slow heart rate but with normal QTc at resting ECG. Treatment with β blockers has been very effective in our CPVT patients during initial or short term follow up. Given the risk of sudden death and the efficacy of β blocker therapy, the identification of large numbers of RYR2 mutations thus calls for genetic screening, early diagnosis, and subsequent preventive strategies.

Background The T gene (brachyury gene) is the founding member of the T-box family of transcription factors and is vital for the formation and differentiation of the mesoderm and the axial development of all vertebrates. Results We report here on four patients from three consanguineous families exhibiting sacral agenesis, a persistent notochordal canal and abnormal ossification of the vertebral bodies, and the identification and characterisation of their underlying genetic defect. Given the consanguineous nature and the similarity of the phenotypes between the three families, we performed homozygosity mapping and identified a common 4.1 Mb homozygous region on chromosome 6q27, containing T, brachyury homologue (mouse) or T. Sequencing of T in the affected individuals led to the identification of a homozygous missense mutation, p.H171R, in the highly conserved T-box. The homozygous mutation results in diminished DNA binding, increased cell growth, and interferes with the normal expression of genes involved in ossification, notochord maintenance and axial mesoderm development. Conclusions We have identified a shared homozygous mutation in three families in T and linked it to a novel syndrome consisting of sacral agenesis, a persistent notochordal canal and abnormal ossification of the vertebral bodies. We suggest that screening for the ossification of the vertebrae is warranted in patients with sacral agenesis to evaluate the possible causal involvement of T.

Background: A relationship between post-surgical adhesion formation and peritoneal tumour implantation has been proposed. Hyaluronan (HA)-based agents reduce adhesion formation, but the effect on peritoneal tumour is not established. This study investigated the influence of a HA-containing agent on intraperitoneal tumour in an experimental model. Methods: 66 Balb/c mice underwent laparotomy and damage was inflicted to the parietal peritoneum. The animals were randomized into five groups. Groups 1 and 2 received HA-carboxymethylcellulose bioresorbable membrane and no treatment, respectively. Mice in groups 3–5 were injected intraperitoneally with 10 5 colon 26-B cells after the laparotomy. Treatment consisted of HA membrane, no HA agent and placement of HA membrane on the non-traumatized peritoneal wall, respectively. Animals were killed after 14 days; adhesions were scored in groups 1 and 2, and the tumour mass in groups 3–5. 45 Wag/Rij rats underwent the same procedures and treatment as mice in groups 3–5. In rats, 10 6 CC-531 cells were injected. Rats were killed after 3 weeks and the tumour mass was scored. Results: HA membrane resulted in a significant reduction of adhesions, but had no major effect on the intraperitoneal tumour mass in mice and rats. Conclusion: HA-carboxymethylcellulose bioresorbable membrane has no major effect on intraperitoneal tumour implantation and growth in an experimental model.

The differential diagnosis of unilocular intraabdominal cysts includes ovarian, gastrointestinal, urological, and lymphatic processes. They occur at all ages and can be benign or malignant. We present a case of a 17-year-old female with asymptomatic abdominal distension. Ultrasonography (US) revealed a 20 x 21-cm unilocular cystic mass with smooth surface lining. Paracentesis was performed during diagnostic laparoscopy, recovering more than 7 L of clear fluid. The cyst and left adnex were completely removed laparoscopically and diagnosis of ovarian cystadenoma was made. The patient made a quick and uneventful recovery. In all cases of abdominal distension, US must be performed and a tumor marker profile consisting of AFP, LDH, testosterone, estradiol, and CA-125 must be established in order to differentiate between benign and malignant processes. When the latter is suspected, additional computerized tomographic scanning must be performed. In this case, a normal tumor marker profile and benign ultrasonographic appearance excluded the possibility of malignancy. Conventional treatment in these large cysts is laparotomy. We propose that complete laparoscopic drainage and extirpation should be the treatment of choice, regardless of cystic size.

To follow a candidate gene approach for the involvement of the KCND2 and KCND3 genes (Kv4.2 and Kv4.3) in the pathogenesis of the long QT syndrome (LQTS) and Brugada syndrome, it is necessary to determine the genomic organisation of KCND2 and KCND3. We therefore resolved the intron-exon boundaries and flanking intronic sequences and found that KCND2 consisted of six exons and KCND3 of seven exons. Subsequently, we designed the oligonucleotide primers needed for amplifying the coding exons of both KCND2 and KCND3 and established conditions for polymerase chain reaction amplification of each exon from genomic DNA. Furthermore, the chromosomal localisation of KCND2 and KCND3 was determined as 7q31 and 1p13.2, respectively. This information should facilitate the systematic screening of KCND2 and KCND3 exons for mutations in (inherited) arrhythmia syndromes, such as LQTS and Brugada.

Congenital heart defects (CHDs) occur mostly sporadic, but familial CHD cases have been reported. Mutations in several genes, including NKX2.5, GATA4 and NOTCH1, were identified in families and patients with CHD, but the mechanisms underlying CHD are largely unknown. We performed genome-wide linkage analysis in a large four-generation family with autosomal dominant CHD (including atrial septal defect type I and II, tetralogy of Fallot and persistent left superior vena cava) and low atrial rhythm, a unique phenotype that has not been described before. We obtained phenotypic information including electrocardiography, echocardiography and DNA of 23 family members. Genome-wide linkage analysis on 12 affected, 5 unaffected individuals and 1 obligate carrier demonstrated significant linkage only to chromosome 9q21–33 with a multipoint maximum LOD score of 4.1 at marker D9S1690, between markers D9S167 and D9S1682. This 48-c M critical interval corresponds to 39 Mb and contains 402 genes. Sequence analysis of nine candidate genes in this region ( INVS , TMOD1 , TGFBR1 , KLF4 , IPPK , BARX1 , PTCH1 , MEGF9 and S1PR3 ) revealed no mutations, nor were genomic imbalances detected using array comparative genomic hybridization. In conclusion, we describe a large family with CHD and low atrial rhythm with a significant LOD score to chromosome 9q. The phenotype is representative of a mild form of left atrial isomerism or a developmental defect of the sinus node and surrounding tissue. Because the mechanisms underlying CHD are largely unknown, this study represents an important step towards the discovery of genes implied in cardiogenesis.

Congenital Heart Disease (CHD) affects approximately 7-9 children per 1000 live births. Numerous genetic studies have established a role for rare genomic variants at the copy number variation (CNV) and single nucleotide variant level. In particular, the role of de novo mutations (DNM) has been highlighted in syndromic and non-syndromic CHD. To identify novel haploinsufficient CHD disease genes we performed an integrative analysis of CNVs and DNMs identified in probands with CHD including cases with sporadic thoracic aortic aneurysm (TAA). We assembled CNV data from 7,958 cases and 14,082 controls and performed a gene-wise analysis of the burden of rare genomic deletions in cases versus controls. In addition, we performed mutation rate testing for DNMs identified in 2,489 parent-offspring trios. Our combined analysis revealed 21 genes which were significantly affected by rare genomic deletions and/or constrained non-synonymous de novo mutations in probands. Fourteen of these genes have previously been associated with CHD while the remaining genes (FEZ1, MYO16, ARID1B, NALCN, WAC, KDM5B and WHSC1) have only been associated in singletons and small cases series, or show new associations with CHD. In addition, a systems level analysis revealed shared contribution of CNV deletions and DNMs in CHD probands, affecting protein-protein interaction networks involved in Notch signaling pathway, heart morphogenesis, DNA repair and cilia/centrosome function. Taken together, this approach highlights the importance of re-analyzing existing datasets to strengthen disease association and identify novel disease genes.

Randomized clinical trials (RCTs) and real-world data (RWD) in patients with atrial fibrillation have shown that-compared to vitamin K antagonists (VKAs)-non-VKA oral anticoagulants (NOACs) are at least as effective in the prevention of ischaemic stroke, while decreasing the risk of bleeding. We aim to evaluate the cost-effectiveness of the NOAC apixaban versus other NOACs (dabigatran, edoxaban and rivaroxaban) and VKA, for stroke prevention in patients with atrial fibrillation by including the available data both from RCT and real-world analyses of all NOACs into one integrative previously published model. The model was updated to the current Dutch healthcare situation. The incremental cost-effectiveness ratio was calculated using either efficacy/effectiveness and safety data derived from a network meta-analysis (NMA) synthesizing NOAC RCTs or RWD. We conducted a systematic literature search to identify eligible publication to best inform the RWD-based analysis. Additional sensitivity and scenario analyses were conducted to test the robustness of the outcomes. In the NMA-based analysis, apixaban appeared to be cost-effective compared to VKA (€3,506 per quality adjusted life-year) and dominant (cost-saving and more effective) over dabigatran 110 mg, dabigatran 150 mg, edoxaban and rivaroxaban. In the RWD-based analysis, apixaban was dominant over all other anticoagulants. In the scenario analysis apixaban appeared to be not cost-effective compared to dabigatran 150 mg, when using equal event-unrelated treatment discontinuation rates for each drug. In all other scenarios apixaban is cost-effective or cost-saving compared to VKA and other NOACs. Based on RCTs as well as RWD, we conclude that apixaban is generally cost-effective or even cost-saving (less costly and more effective) compared to VKA and other NOACs in the overall population of patients with atrial fibrillation.

Aim Previously, we showed that sowing density influences root length density (RLD), specific root length (SRL) especially in the topsoil, and shallowness of fine roots of field grown spring barley ( Hordeum vulagre L.). Here, we ask which trait components may explain these observed changes. Method We grew two spring barley cultivars at contrasting sowing densities in both field trials and rhizotrons, and excavated root crowns and imaged root growth. Results In the field, tiller and nodal root numbers per plant decreased with increasing sowing density, however, nodal roots per tiller, seminal roots per plant, and lateral branching frequencies were not affected. Branching angle did not or only slightly declined with increasing sowing density. In rhizotrons, aboveground only tiller number was affected by sowing density. Root growth rates and counts were not (or only slightly) affected. Conclusion Greater RLD at high sowing densities is largely explained by greater main root number per area. The altered seminal to nodal root ratio might explain observed increases in SRL. We conclude that sowing density is a modifier of root system architecture with probable functional consequences, and thereby an important factor to be considered in root studies or the development of root ideotypes for agriculture.

The endothermic state of mammals and birds requires high heart rates to accommodate the high rates of oxygen consumption. These high heart rates are driven by very similar conduction systems consisting of an atrioventricular node that slows the electrical impulse and a His-Purkinje system that efficiently activates the ventricular chambers. While ectothermic vertebrates have similar contraction patterns, they do not possess anatomical evidence for a conduction system. This lack amongst extant ectotherms is surprising because mammals and birds evolved independently from reptile-like ancestors. Using conserved genetic markers, we found that the conduction system design of lizard (Anolis carolinensis and A. sagrei), frog (Xenopus laevis) and zebrafish (Danio rerio) adults is strikingly similar to that of embryos of mammals (mouse Mus musculus, and man) and chicken (Gallus gallus). Thus, in ectothermic adults, the slow conducting atrioventricular canal muscle is present, no fibrous insulating plane is formed, and the spongy ventricle serves the dual purpose of conduction and contraction. Optical mapping showed base-to-apex activation of the ventricles of the ectothermic animals, similar to the activation pattern of mammalian and avian embryonic ventricles and to the His-Purkinje systems of the formed hearts. Mammalian and avian ventricles uniquely develop thick compact walls and septum and, hence, form a discrete ventricular conduction system from the embryonic spongy ventricle. Our study uncovers the evolutionary building plan of heart and indicates that the building blocks of the conduction system of adult ectothermic vertebrates and embryos of endotherms are similar.