Protein C deficiency (McK. No. 176860) is an autosomally inherited disorder that is associated with a high risk of recurrent venous thrombosis. Until recently, the analysis and diagnosis of protein C deficiency has been reliant upon the laboratory measurement of plasma protein C antigen and activity levels. Diagnostic uncertainty ffioy, however, arise due to the overlap between the ranges of values characteristic of the normal and deficiency states. Diagnostic uncertainty may be further increased if the patient is already undergoing ordl anticoagulant therapy with vitamin K antagonists such as Coumarin drugs that block y-carboxylation. Moreover, this type of laboratory analysis provides little or no information as to the nature of the underlying defect or its mode of inheritance. The utility of a molecular genetic approach to the study of protein C deficiency lies in its ability to provide accurate and reliable information both on the specific genetic lesion(s) involved and on the genotypes of the propositae and their relatives. Precise knowledge of the underlying genetic abnormalities may also provide starting points for the structure-function analysis of the protein C gene (the effect of promoter mutations on gene expression) and molecule (protein C variants). With the advent of rapid and efficient techniques for the analysis of DNA at the single nucleotide level, such an approach has become feasible in an increasing number of laboratories. Here, we present an up-todate listing of mutations in the protein C gene so far identified. Only a small proportion of these lesions have been published in any detail. All unreviewed and unpublished data must be regarded as preliminary. Inclusion in the database should not preclude more detailed publication elsewhere. Structure and Function of Protein C Protein C, a vitamin K-dependent glycoprotein and zymogen of a serine protease, plays an important regulatory role in haemostasis (1, 2). Synthesized in the liver as a single-chain polypeptide, it undergoes post-translational modification (B-hydroxylation, y-carboxylation and glycosylation) to give rise
It is widely accepted that the repertoire of Melan-A-specific T cells naturally selected in melanoma patients is diverse and mostly nonoverlapping among different individuals. To date, however, no studies have addressed the TCR profile in different tumor sites and the peripheral blood from the same patient. We compared the TCR usage of Melan-A-specific T cells from different compartments of a single melanoma patient to evaluate possible clonotype expansion or preferential homing over a 4-mo follow-up period. Using HLA-A2 peptide tetramers, CD8+ T cells recognizing the modified Melan-A immunodominant ELAGIGILTV peptide were isolated from four metastatic lesions resected from a single melanoma patient, and their TCR repertoire was studied. A panel of T cell clones was generated by cell cloning of tetramer-positive cells. Analysis of the TCR β-chain V segment and the complementarity-determining region 3 (CDR3) length and sequence revealed a large diversity in the TCR repertoire, with only some of the clones showing a partial conservation in the CDR3. A similar degree of diversity was found by analyzing a number of T cell clones obtained after sorting a Melan-A-specific population derived from PBLs of the same patient after in vitro culture with the immunodominant epitope. Moreover, clonotypes found at one site were not present in another, suggesting the lack of expansion and circulation of one or more clonotypes. Taken together, these results buttress the notion that the CTLs recognizing the immunodominant Ag of Melan-A comprise a high number of different clonotypic TCR, of which only some exhibit common features in the CDR3.
Background No study has evaluated the impact of the additional manipulation demanded by multiple resheathing (MR) in patients undergoing transcatheter aortic valve replacement with repositionable self‐expanding valves. Methods and Results This study included a real‐world, multicenter registry involving 16 centers from Canada, Germany, Latin America, and Spain. All consecutive patients who underwent transcatheter aortic valve replacement with the Evolut R, Evolut PRO, and Portico valves were included. Patients were divided according to the number of resheathing: no resheathing, single resheathing (SR), and MR. The primary end point was device success. Secondary outcomes included procedural complications, early safety events, and 1‐year mortality. In 1026 patients, the proportion who required SR and MR was 23.9% and 9.3%, respectively. MR was predicted by the use of Portico and moderate/severe aortic regurgitation at baseline (both with P <0.01). Patients undergoing MR had less device success (no resheathing=89.9%, SR=89.8%, and MR=80%; P =0.01), driven by more need for a second prosthesis and device embolization. At 30 days, there were no differences in safety events. At 1 year, more deaths occurred with MR (no resheathing=10.5%, SR=8.0%, and MR=18.8%; P =0.014). After adjusting for baseline differences and center experience by annual volume, MR associated with less device success (odds ratio, 0.42; P =0.003) and increased 1‐year mortality (hazard ratio, 2.06; P =0.01). When including only the Evolut R/PRO cases (N=837), MR continued to have less device success ( P <0.001) and a trend toward increased mortality ( P =0.05). Conclusions Repositioning a self‐expanding valve is used in a third of patients, being multiple in ≈10%. MR, but not SR, was associated with more device failure and higher 1‐year mortality, regardless of the type of valve implanted.
T ranscatheter aortic valve replacement (TAVR) is a complex multistep procedure that has been established as a treatment option for patients with severe aortic stenosis, considered to be inoperable or at high surgical risk. 1 In experienced centers, there has been a trend toward a simplification of the procedure, moving from general anesthesia and surgical cutdown for the femoral access, to a more minimalistic approach with conscious sedation, local anesthesia, and a fully percutaneous approach.2 Likewise, during the early days of TAVR, balloon aortic valve predilatation (BAVP) was considered an essential step to prepare the calcified aortic valve for the correct positioning and deployment of bulkier transcatheter heart valves (THV). Nonetheless, in line with this trend of making the procedure more straightforward, together with the greater experience of the operators and improvement of devices and technique, the need for predilatation has been questioned. Background-Direct
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