Critical function of AP-2gamma/TCFAP2C in mouse embryonic germ cell maintenance

Formation of the germ cell lineage involves multiple processes, including repression of somatic differentiation and reacquisition of pluripotency as well as a unique epigenetic constitution. The transcriptional regulator Prdm1 has been identified as a main coordinator of this process, controlling epigenetic modification and gene expression. Here we report on the expression pattern of the transcription factor Tcfap2c, a putative downstream target of Prdm1, during normal mouse embryogenesis and the consequences of its specific loss in primordial germ cells (PGCs) and their derivatives. Tcfap2c is expressed in PGCs from Embryonic Day 7.25 (E 7.25) up to E 12.5, and targeted disruption resulted in sterile animals, both male and female. In the mutant animals, PGCs were specified but were lost around E 8.0. PGCs generated in vitro from embryonic stem cells lacking TCFAP2C displayed induction of Prdm1 and Dppa3. Upregulation of Hoxa1, Hoxb1, and T together with lack of expression of germ cell markers such Nanos3, Dazl, and Mutyh suggested that the somatic gene program is induced in TCFAP2C-deficient PGCs. Repression of TCFAP2C in TCam-2, a human PGC-resembling seminoma cell line, resulted in specific upregulation of HOXA1, HOXB1, MYOD1, and HAND1, indicative of mesodermal differentiation. Expression of genes indicative of ectodermal, endodermal, or extraembryonic differentiation, as well as the finding of no change to epigenetic modifications, suggested control by other factors. Our results implicate Tcfap2c as an important effector of Prdml activity that is required for PGC maintenance, most likely mediating Prdm1-induced suppression of mesodermal differentiation

Heart transplantation as salvage therapy for progressive prosthetic valve endocarditis due to methicillin-resistant Staphylococcus epidermidis (MRSE)

Background: Prosthetic valve endocarditis (PVE) has the highest in-hospital mortality among all cases of infective endocarditis (IE), it is estimated at about 40 %. Orthotopic heart transplantation (OHT) as a measure of last resort, may be considered in selected cases where repeated surgical procedures and conservative efforts have failed to eradicate persistent or recurrent IE. Only few clinical data are available regarding this rare indication for OHT, since active IE has traditionally been considered as a contraindication for OHT. Case presentation: We report on a 55 year old male patient who underwent prosthetic valve replacement with a mechanical valved conduit ten years ago and developed now persistent PVE with severe complications due to methicillin-resistant Staphylococcus epidermidis (MRSE). Repeated surgical procedures and conservative efforts have failed to eradicate the pathogen. Regarding the lack of curative options, salvage OHT was discussed as a measure of last resort. 28 months after the first diagnosis of PVE, the patient was successfully transplanted and is now doing well under close follow-up (6 months post-OHT). Conclusions: PVE remains a challenging condition regarding diagnosis and treatment. The presented case underscores the urgent need for an integrated and multidisciplinary approach to patients with suspected and definitive IE - especially in PVE. OHT might be a feasible measure of last resort in selected patients with IE. Our case report adds published clinical experience to this rarely performed procedure and consolidates previous findings

Adverse events in families with hypertrophic or dilated cardiomyopathy and mutations in the MYBPC3 gene

<p>Abstract</p> <p>Background</p> <p>Mutations in <it>MYBPC3 </it>encoding myosin binding protein C belong to the most frequent causes of hypertrophic cardiomyopathy (HCM) and may also lead to dilated cardiomyopathy (DCM). <it>MYBPC3 </it>mutations initially were considered to cause a benign form of HCM. The aim of this study was to examine the clinical outcome of patients and their relatives with 18 different <it>MYBPC3 </it>mutations.</p> <p>Methods</p> <p>87 patients with HCM and 71 patients with DCM were screened for <it>MYBPC3 </it>mutations by denaturing gradient gel electrophoresis and sequencing. Close relatives of mutation carriers were genotyped for the respective mutation. Relatives with mutation were then evaluated by echocardiography and magnetic resonance imaging. A detailed family history regarding adverse clinical events was recorded.</p> <p>Results</p> <p>In 16 HCM (18.4%) and two DCM (2.8%) index patients a mutation was detected. Seven mutations were novel. Mutation carriers exhibited no additional mutations in genes <it>MYH7</it>, <it>TNNT2</it>, <it>TNNI3</it>, <it>ACTC </it>and <it>TPM1</it>. Including relatives of twelve families, a total number of 42 mutation carriers was identified of which eleven (26.2%) had at least one adverse event. Considering the twelve families and six single patients with mutations, 45 individuals with cardiomyopathy and nine with borderline phenotype were identified. Among the 45 patients, 23 (51.1%) suffered from an adverse event. In eleven patients of seven families an unexplained sudden death was reported at the age between 13 and 67 years. Stroke or a transient ischemic attack occurred in six patients of five families. At least one adverse event occurred in eleven of twelve families.</p> <p>Conclusion</p> <p><it>MYBPC3 </it>mutations can be associated with cardiac events such as progressive heart failure, stroke and sudden death even at younger age. Therefore, patients with <it>MYBPC3 </it>mutations require thorough clinical risk assessment.</p

The Future of International Investment Regulation: Towards a World Investment Organisation?

With growth in foreign investment and in the number of companies investing in foreign countries, the application of general principles of public international law has not been deemed adequate to regulate foreign investment and there is, as yet, no comprehensive international treaty on the regulation of foreign investment. Consequently, states have resorted to bilateral investment treaties (BITs), regional trade and international investment agreements (IIAs) and free trade agreements (FTAs) to supplement and complement the regime of protection for foreign investors. In the absence of an international investment court, states hosting foreign investment or investor states have opted for investor-state dispute settlement mechanism (ISDS). This mechanism has brought about its own challenges to the international law of foreign investment due to inconsistency in the application and interpretation of the key principles of international investment law by such arbitration tribunals, and further, there is no appellate mechanism to bring about some cohesion and consistency in jurisprudence. Therefore, there are various proposals mooted by scholars to address these challenges and they range from tweaks to BITs and IIAs, the creation of an appellate mechanism and the negotiation of a multilateral treaty to proposals for reform of ISDS only. After assessing the merits and demerits of such proposals, this study goes further, arguing for the creation of a World Investment Organisation (WIO) with a standing mechanism for settlement of investment disputes in order to ensure legal certainty, predictability and the promotion of the flow of foreign investment in a sustainable and responsible manner

Left ventricular long axis strain: a new prognosticator in non-ischemic dilated cardiomyopathy?

Background: Long axis strain (LAS) has been shown to be a fast assessable parameter representing global left ventricular (LV) longitudinal function in cardiovascular magnetic resonance (CMR). However, the prognostic value of LAS in cardiomyopathies with reduced left ventricular ejection fraction (LVEF) has not been evaluated yet. Methods and results: In 146 subjects with non-ischemic dilated cardiomyopathy (NIDCM, LVEF ≤45 %) LAS was assessed retrospectively from standard non-contrast SSFP cine sequences by measuring the distance between the epicardial border of the left ventricular apex and the midpoint of a line connecting the origins of the mitral valve leaflets in end-systole and end-diastole. The final values were calculated according to the strain formula. The primary endpoint of the study was defined as a combination of cardiac death, heart transplantation or aborted sudden cardiac death and occurred in 24 subjects during follow-up. Patients with LAS values > −5 % showed a significant higher rate of cardiac events independent of the presence of late gadolinium enhancement (LGE). The multivariate Cox regression analysis revealed that LVEDV/BSA (HR: 1.01, p  −10 % and the presence of LGE, patients with 3 points had a significantly higher risk for cardiac events than those with 2 or less points. Conclusion: Assessment of long axis function with LAS offers significant incremental information for the prediction of cardiac events in NIDCM and improves risk stratification beyond established CMR parameters

Screening mutations in myosin binding protein C3 gene in a cohort of patients with Hypertrophic Cardiomyopathy

<p>Abstract</p> <p>Background</p> <p><it>MyBPC3 </it>mutations are amongst the most frequent causes of hypertrophic cardiomyopathy, however, its prevalence varies between populations. They have been associated with mild and late onset disease expression. Our objectives were to establish the prevalence of <it>MyBPC3 </it>mutations and determine their associated clinical characteristics in our patients.</p> <p>Methods</p> <p>Screening by Single Strand Conformation Polymorphisms (SSCP) and sequencing of the fragments with abnormal motility of the <it>MyBPC3 </it>gene in 130 unrelated consecutive HCM index cases. Genotype-Phenotype correlation studies were done in positive families.</p> <p>Results</p> <p>16 mutations were found in 20 index cases (15%): 5 novel [D75N, V471E, Q327fs, IVS6+5G>A (homozygous), and IVS11-9G>A] and 11 previously described [A216T, R495W, R502Q (2 families), E542Q (3 families), T957S, R1022P (2 families), E1179K, K504del, K600fs, P955fs and IVS29+5G>A]. Maximum wall thickness and age at time of diagnosis were similar to patients with <it>MYH7 </it>mutations [25(7) vs. 27(8), p = 0.16], [46(16) vs. 44(19), p = 0.9].</p> <p>Conclusions</p> <p>Mutations in <it>MyBPC3 </it>are present in 15% of our hypertrophic cardiomyopathy families. Severe hypertrophy and early expression are compatible with the presence of <it>MyBPC3 </it>mutations. The genetic diagnosis not only allows avoiding clinical follow up of non carriers but it opens new possibilities that includes: to take preventive clinical decisions in mutation carriers than have not developed the disease yet, the establishment of genotype-phenotype relationship, and to establish a genetic diagnosis routine in patients with familial HCM.</p

S100A1: A Multifaceted Therapeutic Target in Cardiovascular Disease

Cardiovascular disease is the leading cause of death worldwide, showing a dramatically growing prevalence. It is still associated with a poor clinical prognosis, indicating insufficient long-term treatment success of currently available therapeutic strategies. Investigations of the pathomechanisms underlying cardiovascular disorders uncovered the Ca2+ binding protein S100A1 as a critical regulator of both cardiac performance and vascular biology. In cardiomyocytes, S100A1 was found to interact with both the sarcoplasmic reticulum ATPase (SERCA2a) and the ryanodine receptor 2 (RyR2), resulting in substantially improved Ca2+ handling and contractile performance. Additionally, S100A1 has been described to target the cardiac sarcomere and mitochondria, leading to reduced pre-contractile passive tension as well as enhanced oxidative energy generation. In endothelial cells, molecular analyses revealed a stimulatory effect of S100A1 on endothelial NO production by increasing endothelial nitric oxide synthase activity. Emphasizing the pathophysiological relevance of S100A1, myocardial infarction in S100A1 knockout mice resulted in accelerated transition towards heart failure and excessive mortality in comparison with wild-type controls. Mice lacking S100A1 furthermore displayed significantly elevated blood pressure values with abrogated responsiveness to bradykinin. On the other hand, numerous studies in small and large animal heart failure models showed that S100A1 overexpression results in reversed maladaptive myocardial remodeling, long-term rescue of contractile performance, and superior survival in response to myocardial infarction, indicating the potential of S100A1-based therapeutic interventions. In summary, elaborate basic and translational research established S100A1 as a multifaceted therapeutic target in cardiovascular disease, providing a promising novel therapeutic strategy to future cardiologists

Atlas of the clinical genetics of human dilated cardiomyopathy

AIM: Numerous genes are known to cause dilated cardiomyopathy (DCM). However, until now technological limitations have hindered elucidation of the contribution of all clinically relevant disease genes to DCM phenotypes in larger cohorts. We now utilized next-generation sequencing to overcome these limitations and screened all DCM disease genes in a large cohort. METHODS AND RESULTS: In this multi-centre, multi-national study, we have enrolled 639 patients with sporadic or familial DCM. To all samples, we applied a standardized protocol for ultra-high coverage next-generation sequencing of 84 genes, leading to 99.1% coverage of the target region with at least 50-fold and a mean read depth of 2415. In this well characterized cohort, we find the highest number of known cardiomyopathy mutations in plakophilin-2, myosin-binding protein C-3, and desmoplakin. When we include yet unknown but predicted disease variants, we find titin, plakophilin-2, myosin-binding protein-C 3, desmoplakin, ryanodine receptor 2, desmocollin-2, desmoglein-2, and SCN5A variants among the most commonly mutated genes. The overlap between DCM, hypertrophic cardiomyopathy (HCM), and channelopathy causing mutations is considerably high. Of note, we find that >38% of patients have compound or combined mutations and 12.8% have three or even more mutations. When comparing patients recruited in the eight participating European countries we find remarkably little differences in mutation frequencies and affected genes. CONCLUSIONS: This is to our knowledge, the first study that comprehensively investigated the genetics of DCM in a large-scale cohort and across a broad gene panel of the known DCM genes. Our results underline the high analytical quality and feasibility of Next-Generation Sequencing in clinical genetic diagnostics and provide a sound database of the genetic causes of DCM