The role of long-term mechanical circulatory support in patients with advanced heart failure

In patients with end-stage heart failure, advanced therapies such as heart transplantation and long-term mechanical circulatory support (MCS) with a left ventricular assist device (LVAD) have to be considered. LVADs can be implanted as a bridge to transplantation or as an alternative to heart transplantation: destination therapy. In the Netherlands, long-term LVAD therapy is gaining importance as a result of increased prevalence of heart failure together with a low number of heart transplantations due to shortage of donor hearts. As a result, the difference between bridge to transplantation and destination therapy is becoming more artificial since, at present, most patients initially implanted as bridge to transplantation end up receiving extended LVAD therapy. Following LVAD implantation, survival after 1, 2 and 3 years is 83%, 76% and 70%, respectively. Quality of life improves substantially despite important adverse events such as device-related infection, stroke, major bleeding and right heart failure. Early referral of potential candidates for long-term MCS is of utmost importance and positively influences outcome. In this review, an overview of the indications, contraindications, patient selection, clinical outcome and optimal time of referral for long-term MCS is given

RDE-2 interacts with MUT-7 to mediate RNA interference in Caenorhabditis elegans

In Caenorhabditis elegans, the activity of transposable elements is repressed in the germline. One of the mechanisms involved in this repression is RNA interference (RNAi), a process in which dsRNA targets cleavage of mRNAs in a sequence-specific manner. The first gene found to be involved in RNAi and transposon silencing in C.elegans is mut-7, a gene encoding a putative exoribonuclease. Here, we show that the MUT-7 protein resides in complexes of ∼250 kDa in the nucleus and in the cytosol. In addition, we find that upon triggering of RNAi the cytosolic MUT-7 complex increases in size. This increase is independent of the presence of target RNA, but does depend on the presence of RDE-1 and RDE-4, two proteins involved in small interfering RNA (siRNA) production. Finally, using a yeast two-hybrid screen, we identified RDE-2/MUT-8 as one of the other components of this complex. This protein is encoded by the rde-2/mut-8 locus, previously implicated in RNAi and transposon silencing. Using genetic complementation analysis, we show that the interaction between these two proteins is required for efficient RNAi in vivo. Together these data support a role for the MUT-7/RDE-2 complex downstream of siRNA formation, but upstream of siRNA mediated target RNA recognition, possibly indicating a role in the siRNA amplification step

Cardiac computed tomography: indications, applications, limitations, and training requirements: Report of a Writing Group deployed by the Working Group Nuclear Cardiology and Cardiac CT of the European Society of Cardiology and the European Council of Nuclear Cardiology

As a consequence of improved technology, there is growing clinical interest in the use of multi-detector row computed tomography (MDCT) for non-invasive coronary angiography. Indeed, the accuracy of MDCT to detect or exclude coronary artery stenoses has been high in many published studies. This report of a Writing Group deployed by the Working Group Nuclear Cardiology and Cardiac CT (WG 5) of the European Society of Cardiology and the European Council of Nuclear Cardiology summarizes the present state of cardiac CT technology, as well as the currently available data concerning its accuracy and applicability in certain clinical situations. Besides coronary CT angiography, the use of CT for the assessment of cardiac morphology and function, evaluation of perfusion and viability, and analysis of heart valves is discussed. In addition, recommendations for clinical applications of cardiac CT imaging are given and limitations of the technique are describe

Noninvasive Evaluation of the Aortic Root With Multislice Computed Tomography Implications for Transcatheter Aortic Valve Replacement

ObjectivesIn the present study, the anatomy of the aortic root was assessed noninvasively with multislice computed tomography (MSCT).BackgroundTranscatheter aortic valve replacement has been proposed as an alternative to surgery in high-risk patients with severe aortic stenosis. For this procedure, detailed knowledge of aortic annulus diameters and the relation between the annulus and the coronary arteries is needed.MethodsIn 169 patients (111 men, age 54 ± 11 years), a 64-slice MSCT scan was performed for evaluation of coronary artery disease. Of these, 150 patients had no or mild aortic stenosis, and 19 patients had moderate to severe aortic stenosis. Reconstructed coronal and sagittal views were used for assessment of the aortic annulus diameter in 2 directions. In addition, the distance between the annulus and the ostium of the right and left coronary arteries and the length of the coronary leaflets were assessed. The LV outflow tract and interventricular septum were analyzed on the single oblique sagittal view at end-diastole.ResultsThe diameter of the aortic annulus was 26.3 ± 2.8 mm on the coronal view, and 23.5 ± 2.7 mm on the sagittal view. Mean difference between the 2 diameters was 2.9 ± 1.8 mm, indicating an oval shape of the aortic annulus. Mean distance between the aortic annulus and the ostium of the right coronary artery was 17.2 ± 3.3 mm, and mean distance between the annulus and the ostium of the left coronary artery was 14.4 ± 2.9 mm. In 82 patients (49%), the length of the left coronary leaflet exceeded the distance between the annulus and the ostium of the left coronary artery. There were no significant differences in the diameter of annulus, diameter of sinus of Valsalva, or the distance between the annulus, left coronary leaflet, and the ostium of the left coronary artery, between the patient with and without severe aortic stenosis.ConclusionsThe MSCT can provide detailed information on the shape of the aortic annulus and the relation between the annulus and the ostia of the coronary arteries. Thereby, MSCT may be helpful for avoiding paravalvular leakage and coronary occlusion and may facilitate the selection of candidates for transcatheter aortic valve replacement

Declining detection rates for APC and biallelic MUTYH variants in polyposis patients, implications for DNA testing policy

This study aimed to determine the prevalence of APC-associated familial adenomatous polyposis (FAP) and MUTYH-associated polyposis (MAP) in a large cohort, taking into account factors as adenoma count and year of diagnosis. All application forms used to send patients in for APC and MUTYH variant analysis between 1992 and 2017 were collected (n = 2082). Using the data provided on the application form, the APC and biallelic MUTYH prevalence was determined and possible predictive factors were examined using multivariate multinomial logistic regression analysis in SPSS. The prevalence of disease causing variants in the APC gene significantly increases with adenoma count while MAP shows a peak prevalence in individuals with 50–99 adenomas. Logistic regression analysis shows significant odds ratios for adenoma count, age at diagnosis, and, interestingly, a decline in the chance of finding a variant in either gene over time. Moreover, in 22% (43/200) of patients with FAP-related extracolonic manifestations a variant was identified. The overall detection rates are above 10% for patients with >10 adenomas aged 20 adenomas aged T variant in the tumor or a first-degree relative with >10 adenomas. Therefore, APC and MUTYH testing in patients with >10 adenomas aged 20 adenomas aged <70 is advised. Almost all FAP and MAP patients not meeting these criteria showed other characteristics that can be used as an indication to prompt genetic testing

The possibility of evidence-based psychiatry: depression as a case

Considering psychiatry as a medical discipline, a diagnosis identifying a disorder should lead to an effective therapy. Such presumed causality is the basis of evidence-based psychiatry. We examined the strengths and weaknesses of research onto the causality of relationship between diagnosis and therapy of major depressive disorder and suggest what could be done to strengthen eventual claims on causality. Four obstacles for a rational evidence-based psychiatry were recognised. First, current classification systems are scientifically nonfalsifiable. Second, cerebral processes are—at least to some extent—nondeterministic, i.e. they are random, stochastic and/or chaotic. Third, the vague or lack of relationship between therapeutic regimens and suspected pathogenesis. Fourth, the inadequacy of tools to diagnose and delineate a functional disorder. We suggest a strategy to identify diagnostic prototypes that are characterised by a limited number of parameters (symptoms, markers and other characteristics). A prototypical diagnosis that may either support or reject particular elements of current diagnostic systems. Nevertheless, one faces the possibility that psychiatry will remain a relatively weak evidence-based medical discipline

The CHEK2 1100delC mutation identifies families with a hereditary breast and colorectal cancer phenotype

Because of genetic heterogeneity, the identification of breast cancer-susceptibility genes has proven to be exceedingly difficult. Here, we define a new subset of families with breast cancer characterized by the presence of colorectal cancer cases. The 1100delC variant of the cell cycle checkpoint kinase CHEK2 gene was present in 18% of 55 families with hereditary breast and colorectal cancer (HBCC) as compared with 4% of 380 families with non-HBCC (P<.001), thus providing genetic evidence for the HBCC phenotype. The CHEK2 1100delC mutation was, however, not the major predisposing factor for the HBCC phenotype but appeared to act in synergy with another, as-yet-unknown susceptibility gene(s). The unequivocal definition of the HBCC phenotype opens new avenues to search for thi

Whole Gene Capture Analysis of 15 CRC Susceptibility Genes in Suspected Lynch Syndrome Patients

Background and Aims Lynch Syndrome (LS) is caused by pathogenic germline variants in one of the mismatch repair (MMR) genes. However, up to 60% of MMR-deficient colorectal cancer cases are categorized as suspected Lynch Syndrome (sLS) because no pathogenic MMR germline variant can be identified, which leads to difficulties in clinical management. We therefore analyzed the genomic regions of 15 CRC susceptibility genes in leukocyte DNA of 34 unrelated sLS patients and 11 patients with MLH1 hypermethylated tumors with a clear family history. Methods Using targeted next-generation sequencing, we analyzed the entire non-repetitive genomic sequence, including intronic and regulatory sequences, of 15 CRC susceptibility genes. In addition, tumor DNA from 28 sLS patients was analyzed for somatic MMR variants. Results Of 1979 germline variants found in the leukocyte DNA of 34 sLS patients, one was a pathogenic variant (MLH1 c.1667+1delG). Leukocyte DNA of 11 patients with MLH1 hypermethylated tumors was negative for pathogenic germline variants in the tested CRC susceptibility genes and for germline MLH1 hypermethylation. Somatic DNA analysis of 28 sLS tumors identified eight (29%) cases with two pathogenic somatic variants, one with a VUS predicted to pathogenic and LOH, and nine cases (32%) with one pathogenic somatic variant (n = 8) or one VUS predicted to be pathogenic (n = 1). Conclusions This is the first study in sLS patients to include the entire genomic sequence of CRC susceptibility genes. An underlying somatic or germline MMR gene defect was identified in ten of 34 sLS patients (29%). In the remaining sLS patients, the underlying genetic defect explaining the MMRdeficiency in their tumors might be found outside the genomic regions harboring the MMR and other known CRC susceptibility genes