Clinical and genetic aspects of bicuspid aortic valve:a proposed model for family screening based on a review of literature

Bicuspid aortic valve (BAV) is the most common congenital cardiac defect causing serious morbidity including valvular dysfunction and thoracic aortic aneurysms (TAA) in around 30% of BAV patients. Cardiological screening of first-degree relatives is advised in recent guidelines given the observed familial clustering of BAV. However, guidelines regarding screening of family members and DNA testing are not unequivocal. The aim of this review is to provide an overview of the literature on echocardiographic screening in first-degree relatives of BAV patients and to propose a model for family screening. In addition, we provide a flowchart for DNA testing. We performed a PubMed search and included studies providing data on echocardiographic screening in asymptomatic relatives of BAV patients. Nine studies were included. In 5.8-47.4% of the families BAV was shown to be familial. Of the screened first-degree relatives 1.8-11% was found to be affected with BAV. Results regarding a potential risk of TAA in first-degree relatives with a tricuspid aortic valve (TAV) were conflicting. The reported familial clustering of BAV underlines the importance of cardiological screening in relatives. After reviewing the available family history, patient characteristics and the results of cardiological screening in relatives, follow-up in relatives with a TAV and/or DNA testing may be advised in a subset of families. In this study we propose a model for the clinical and genetic work-up in BAV families, based on the most extensive literature review on family screening performed until now

Living well to the end:a phenomenological analysis of life in extra care housing

OBJECTIVES: To understand older adults' experiences of moving into extra care housing which offers enrichment activities alongside social and healthcare support. DESIGN: A longitudinal study was conducted which adopted a phenomenological approach to data generation and analysis. METHODS: Semi-structured interviews were conducted in the first 18 months of living in extra care housing. Interpretative phenomenological analysis was used because its commitment to idiography enabled an in-depth analysis of the subjective lived experience of moving into extra care housing. Themes generated inductively were examined against an existential-phenomenological theory of well-being. RESULTS: Learning to live in an extra care community showed negotiating new relationships was not straightforward; maintaining friendships outside the community became more difficult as capacity declined. In springboard for opportunity/confinement, living in extra care provided new opportunities for social engagement and a restored sense of self. Over time horizons began to shrink as incapacities grew. Seeking care illustrated reticence to seek care, due to embarrassment and a sense of duty to one's partner. Becoming aged presented an ontological challenge. Nevertheless, some showed a readiness for death, a sense of homecoming. CONCLUSIONS: An authentic later life was possible but residents required emotional and social support to live through the transition and challenges of becoming aged. Enhancement activities boosted residents' quality of life but the range of activities could be extended to cater better for quieter, smaller scale events within the community; volunteer activity facilitators could be used here. Peer mentoring may help build new relationships and opportunities for interactive stimulation. Acknowledging the importance of feeling-empathic imagination-in caregiving may help staff and residents relate better to each other, thus helping individuals to become ontologically secure and live well to the end

A reversion of an IL2RG mutation in combined immunodeficiency providing competitive advantage to the majority of CD8+ T cells

Mutations in the common gamma chain (γc, CD132, encoded by the IL2RG gene) can lead to B+T-NK-X-linked severe combined immunodeficiency, as a consequence of unresponsiveness to γc-cytokines such as interleukins-2, -7 and -15. Hypomorphic mutations in CD132 may cause combined immunodeficiencies with a variety of clinical presentations. We analyzed peripheral blood mononuclear cells of a 6-year-old boy with normal lymphocyte counts, who suffered from recurrent pneumonia and disseminated mollusca contagiosa. Since proliferative responses of T cells and NK cells to γc -cytokines were severely impaired, we performed IL2RG gene analysis, showing a heterozygous mutation in the presence of a single X-chromosome. Interestingly, an IL2RG reversion to normal predominated in both naïve and antigen-primed CD8+ T cells and increased over time. Only the revertant CD8+T cells showed normal expression of CD132 and the various CD8+T cell populations had a different T-cell receptor repertoire. Finally, a fraction of γδ+T cells and differentiated CD4+CD27-effector-memory T cells carried the reversion, whereas NK or B cells were repeatedly negative. In conclusion, in a patient with a novel IL2RG mutation, gene-reverted CD8+T cells accumulated over time. Our data indicate that selective outgrowth of particular T-cell subsets may occur following reversion at the level of committed T progenitor cells

Losartan therapy in adults with Marfan syndrome: study protocol of the multi-center randomized controlled COMPARE trial

Contains fulltext : 87305.pdf (publisher's version ) (Open Access

Efficient production of multi-modified pigs for xenotransplantation by ‘combineering’, gene stacking and gene editing

Xenotransplantation from pigs could alleviate the shortage of human tissues and organs for transplantation. Means have been identified to overcome hyperacute rejection and acute vascular rejection mechanisms mounted by the recipient. The challenge is to combine multiple genetic modifications to enable normal animal breeding and meet the demand for transplants. We used two methods to colocate xenoprotective transgenes at one locus, sequential targeted transgene placement - ‘gene stacking’, and cointegration of multiple engineered large vectors - ‘combineering’, to generate pigs carrying modifications considered necessary to inhibit short to mid-term xenograft rejection. Pigs were generated by serial nuclear transfer and analysed at intermediate stages. Human complement inhibitors CD46, CD55 and CD59 were abundantly expressed in all tissues examined, human HO1 and human A20 were widely expressed. ZFN or CRISPR/Cas9 mediated homozygous GGTA1 and CMAH knockout abolished α-Gal and Neu5Gc epitopes. Cells from multi-transgenic piglets showed complete protection against human complement-mediated lysis, even before GGTA1 knockout. Blockade of endothelial activation reduced TNFα-induced E-selectin expression, IFNγ-induced MHC class-II upregulation and TNFα/cycloheximide caspase induction. Microbial analysis found no PERV-C, PCMV or 13 other infectious agents. These animals are a major advance towards clinical porcine xenotransplantation and demonstrate that livestock engineering has come of age

Prevalence of congenital heart defects in neuroblastoma patients: a cohort study and systematic review of literature

Data on the prevalence of congenital heart defects (CHD) in neuroblastoma patients are inconsistent. If CHD are more common in neuroblastoma patients than in the general population, cardiac screening might be warranted. In this study we used echocardiography to determine the prevalence of CHD in a single centre cohort of surviving neuroblastoma patients. In addition, we performed a systematic review of the literature. Echocardiography was performed in 119 of 133 patients (89.5%). Only two patients (1.7%) had CHD. The prevalence of CHD was not significantly different from a previously published control group of 192 leukaemia patients examined by echocardiography (P = 0.49). Literature search revealed 17 studies, showing prevalence rates of CHD in neuroblastoma patients ranging from 0 to 20%. Prevalence was less than 3.6% in the majority of studies. Most studies lacked information on validity. We conclude that current evidence does not support standard cardiac screening in all patients with neuroblastoma

Inflammation Aggravates Disease Severity in Marfan Syndrome Patients

BACKGROUND: Marfan syndrome (MFS) is a pleiotropic genetic disorder with major features in cardiovascular, ocular and skeletal systems, associated with large clinical variability. Numerous studies reveal an involvement of TGF-beta signaling. However, the contribution of tissue inflammation is not addressed so far. METHODOLOGY/PRINCIPAL FINDINGS: Here we showed that both TGF-beta and inflammation are up-regulated in patients with MFS. We analyzed transcriptome-wide gene expression in 55 MFS patients using Affymetrix Human Exon 1.0 ST Array and levels of TGF-beta and various cytokines in their plasma. Within our MFS population, increased plasma levels of TGF-beta were found especially in MFS patients with aortic root dilatation (124 pg/ml), when compared to MFS patients with normal aorta (10 pg/ml; p = 8x10(-6), 95% CI: 70-159 pg/ml). Interestingly, our microarray data show that increased expression of inflammatory genes was associated with major clinical features within the MFS patients group; namely severity of the aortic root dilatation (HLA-DRB1 and HLA-DRB5 genes; r = 0.56 for both; False Discovery Rate(FDR) = 0%), ocular lens dislocation (RAET1L, CCL19 and HLA-DQB2; Fold Change (FC) = 1.8; 1.4; 1.5, FDR = 0%) and specific skeletal features (HLA-DRB1, HLA-DRB5, GZMK; FC = 8.8, 7.1, 1.3; FDR = 0%). Patients with progressive aortic disease had higher levels of Macrophage Colony Stimulating Factor (M-CSF) in blood. When comparing MFS aortic root vessel wall with non-MFS aortic root, increased numbers of CD4+ T-cells were found in the media (p = 0.02) and increased number of CD8+ T-cells (p = 0.003) in the adventitia of the MFS patients. CONCLUSION/SIGNIFICANCE: In conclusion, our results imply a modifying role of inflammation in MFS. Inflammation might be a novel therapeutic target in these patients

Ubiquitous LEA29Y Expression Blocks T Cell Co-Stimulation but Permits Sexual Reproduction in Genetically Modified Pigs

We have successfully established and characterized a genetically modified pig line with ubiquitous expression of LEA29Y, a human CTLA4-Ig derivate. LEA29Y binds human B7.1/CD80 and B7.2/CD86 with high affinity and is thus a potent inhibitor of T cell co-stimulation via this pathway. We have characterized the expression pattern and the biological function of the transgene as well as its impact on the porcine immune system and have evaluated the potential of these transgenic pigs to propagate via assisted breeding methods. The analysis of LEA29Y expression in serum and multiple organs of CAG-LEA transgenic pigs revealed that these animals produce a biologically active transgenic product at a considerable level. They present with an immune system affected by transgene expression, but can be maintained until sexual maturity and propagated by assisted reproduction techniques. Based on previous experience with pancreatic islets expressing LEA29Y, tissues from CAG-LEA29Y transgenic pigs should be protected against rejection by human T cells. Furthermore, their immune-compromised phenotype makes CAG-LEA29Y transgenic pigs an interesting large animal model for testing human cell therapies and will provide an important tool for further clarifying the LEA29Y mode of action

Ebstein's anomaly may be caused by mutations in the sarcomere protein gene MYH7

Ebstein's anomaly is a rare congenital heart malformation characterised by adherence of the septal and posterior leaflets of the tricuspid valve to the underlying myocardium. Associated abnormalities of left ventricular morphology and function including left ventricular noncompaction (LVNC) have been observed. An association between Ebstein's anomaly with LVNC and mutations in the sarcomeric protein gene MYH7, encoding β -myosin heavy chain, has been shown by recent studies. This might represent a specific subtype of Ebstein's anomaly with a Mendelian inheritance pattern. In this review we discuss the association of MYH7 mutations with Ebstein's anomaly and LVNC and its implications for the clinical care for patients and their family members