Clinical and angiographic results with the ACS MULTI-LINK DUET trade mark Coronary Stent System - the DUET Study

BACKGROUND: The DUET Study is a multicenter prospective efficacy and safety evaluation of the ACS MULTI-LINK DUET coronary stainless steel balloon-expandable stent. AIMS: The primary objective was to determine the one-month incidence of MACE (major adverse cardiac events). The secondary objectives were the acute success rate, the restenosis and reocclusion rates (assessed by quantitative coronary angiography (QCA)) at six months and the occurrence of MACE in hospital and at six months. METHODS: Two hundred and ten patients were enrolled between February and June 1998 in 18 European centers. Successful stent placement was achieved in 209 patients. All patients were treated with ticlopidine 500 mg/day for one month and with aspirin >/=100 mg/day. To allow the investigators to gain familiarity with the stent system, the first one to three patients per center formed a separate lead-in population leaving an intention-to-treat population of 157 patients. The majority of the intention-to-treat population were male (79%); 28% had unstable angina, 69% had stable angina, 44% had had a previous myocardial infarction, 15% had had a previous percutaneous transluminal coronary angioplasty, and 3% had a history of stroke. The target vessel was 38.5% left anterior descending artery, 20.5% left circumflex artery and 41.0% right coronary artery. RESULTS: All but one of the intention-to-treat patients were effectively stented (17 required multiple stents). Six-month angiographic follow-up was available in 90% of the intention-to-treat population. Minimal lumen diameter (MLD) postprocedure was 2.61 +/- 0.33 mm, with a residual diameter stenosis of 16%. Six-month follow-up data showed an MLD of 1.87 +/- 0.56 mm with a residual diameter stenosis of 36%. The binary restenosis rate (>/=50% residual stenosis) was 15.6%. Up to one month following the procedure 94.9% of the population was MACE-free, with two subacute occlusions. At six months all patients were alive, of whom 82.8% were MACE-free, and 73% were free of anginal complaints. CONCLUSION: The results observed in the current DUET registry are comparable to data of other balloon-expandable-stent trials, with a low incidence of clinical events at follow-up.     

The variability of the hepatitis B virus genome: statistical analysis and biological implications

A statistical analysis of the nucleotide sequence variability in 14 published hepatitis B virus (HBV) genomes was carried out using parametric and nonparametric methods. A parametric statistical model revealed that the different regions of the genome differed significantly in their variability. The conclusion was supported by a nonparametric kernel-density model of the HBV genome. Genes S, C, and P, region X, the precore region, and the pre-S2/pre-S1 regions were ranked in order of increasing variability. In many instances, conserved regions of the genome identified with sequences of known function in HBV biology. However, other characterized regions (such as pre-S) showed much variability despite the involvement of their encoded peptides in specific functions. Point mutations that may result in the formation of stop codons and amino acid changes may affect the clinical picture of HBV infection and may be reflected in atypical serological patterns.      

Virtual reality 3D echocardiography in the assessment of tricuspid valve function after surgical closure of ventricular septal defect

Background

Chronic right ventricular apical pacing may have detrimental effect on left ventricular function and may promote to heart failure in adult patients with left ventricular dysfunction.

Methods

A group of 99 pediatric patients with previously implanted pacemaker was studied retrospectively. Forty-three patients (21 males) had isolated congenital complete or advanced atrioventricular block. The remaining 56 patients (34 males) had pacing indication in the presence of structural heart disease. Thirty-two of them (21 males) had isolated structural heart disease and the remaining 24 (13 males) had complex congenital heart disease. Patients were followed up for an average of 53 ± 41.4 months with 12-lead electrocardiogram and transthoracic echocardiography. Left ventricular shortening fraction was used as a marker of ventricular function. QRS duration was assessed using leads V₅ or II on standard 12-lead electrocardiogram.

Results

Left ventricular shortening fraction did not change significantly after pacemaker implantation compared to preimplant values overall and in subgroups. In patients with complex congenital heart malformations shortening fraction decreased significantly during the follow up period. (0.45 ± 0.07 vs 0.35 ± 0.06, p = 0.015). The correlation between the change in left ventricular shortening fraction and the mean increase of paced QRS duration was not significant. Six patients developed dilated cardiomyopathy, which was diagnosed 2 months to 9 years after pacemaker implantation.

Conclusion

Chronic right ventricular pacing in pediatric patients with or without structural heart disease does not necessarily result in decline of left ventricular function. In patients with complex congenital heart malformations left ventricular shortening fraction shows significant decrease.     

A novel tetravalent bispecific TandAb (CD30/CD16A) efficiently recruits NK cells for the lysis of CD30+ tumor cells

To improve recruitment and activation of natural killer (NK) cells to lyse tumor cells, we isolated a human anti-CD16A antibody with similar affinity for the CD16A 158F/V allotypes, but no binding to the CD16B isoform. Using CD16A-targeting Fv domains, we constructed a tetravalent bispecific CD30/CD16A tandem diabody (TandAb®) consisting solely of Fv domains. This TandAb has two binding sites for CD16A and two for CD30, the antigen identifying Hodgkin lymphoma cells. The binding and cytotoxicity of the TandAb were compared with antibodies with identical anti-CD30 domains: (1) a native IgG, (2) an IgG optimized for binding to Fc receptors, and (3) a bivalent bispecific CD30/CD16A diabody. Due to its CD16A-bivalency and reduced k_off, the TandAb was retained longer on the surface of NK cells than the IgGs or the diabody. This contributed to the higher potency and efficacy of the TandAb relative to those of the other anti-CD30 antibodies. TandAb cytotoxicity was independent of the CD16A allotype, whereas the anti-CD30 IgGs were substantially less cytotoxic when NK cells with low affinity CD16A allotype were employed. TandAb activation of NK cells was strictly dependent on the presence of CD30⁺ target cells. Therefore, the CD30/CD16A TandAb may represent a promising therapeutic for the treatment of Hodgkin’s lymphoma; further, anti-CD16A TandAbs may function as potent immunotherapeutics that specifically recruit NK cells to destroy cancer cells.     

The efficiency of designs for fine-mapping of quantitative trait loci using combined linkage disequilibrium and linkage

In a simulation study, different designs were compared for efficiency of fine-mapping of QTL. The variance component method for fine-mapping of QTL was used to estimate QTL position and variance components. The design of many families with small size gave a higher mapping resolution than a design with few families of large size. However, the difference is small in half sib designs. The proportion of replicates with the QTL positioned within 3 cM of the true position is 0.71 in the best design, and 0.68 in the worst design applied to 128 animals with a phenotypic record and a QTL explaining 25% of the phenotypic variance. The design of two half sib families each of size 64 was further investigated for a hypothetical population with effective size of 1000 simulated for 6000 generations with a marker density of 0.25 cM and with marker mutation rate 4 × 10^-4 per generation. In mapping using bi-allelic markers, 42~55% of replicated simulations could position QTL within 0.75 cM of the true position whereas this was higher for multi allelic markers (48~76%). The accuracy was lowest (48%) when mutation age was 100 generations and increased to 68% and 76% for mutation ages of 200 and 500 generations, respectively, after which it was about 70% for mutation ages of 1000 generations and older. When effective size was linearly decreasing in the last 50 generations, the accuracy was decreased (56 to 70%). We show that half sib designs that have often been used for linkage mapping can have sufficient information for fine-mapping of QTL. It is suggested that the same design with the same animals for linkage mapping should be used for fine-mapping so gene mapping can be cost effective in livestock populations.     

Accuracy of pedigree and genomic predictions of carcass and novel meat quality traits in multi-breed sheep data assessed by cross-validation

Background

Genomic predictions can be applied early in life without impacting selection candidates. This is especially useful for meat quality traits in sheep. Carcass and novel meat quality traits were predicted in a multi-breed sheep population that included Merino, Border Leicester, Polled Dorset and White Suffolk sheep and their crosses.

Methods

Prediction of breeding values by best linear unbiased prediction (BLUP) based on pedigree information was compared to prediction based on genomic BLUP (GBLUP) and a Bayesian prediction method (BayesR). Cross-validation of predictions across sire families was used to evaluate the accuracy of predictions based on the correlation of predicted and observed values and the regression of observed on predicted values was used to evaluate bias of methods. Accuracies and regression coefficients were calculated using either phenotypes or adjusted phenotypes as observed variables.

Results and conclusions

Genomic methods increased the accuracy of predicted breeding values to on average 0.2 across traits (range 0.07 to 0.31), compared to an average accuracy of 0.09 for pedigree-based BLUP. However, for some traits with smaller reference population size, there was no increase in accuracy or it was small. No clear differences in accuracy were observed between GBLUP and BayesR. The regression of phenotypes on breeding values was close to 1 for all methods, indicating little bias, except for GBLUP and adjusted phenotypes (regression = 0.78). Accuracies calculated with adjusted (for fixed effects) phenotypes were less variable than accuracies based on unadjusted phenotypes, indicating that fixed effects influence the latter. Increasing the reference population size increased accuracy, indicating that adding more records will be beneficial. For the Merino, Polled Dorset and White Suffolk breeds, accuracies were greater than for the Border Leicester breed due to the smaller sample size and limited across-breed prediction. BayesR detected only a few large marker effects but one region on chromosome 6 was associated with large effects for several traits. Cross-validation produced very similar variability of accuracy and regression coefficients for BLUP, GBLUP and BayesR, showing that this variability is not a property of genomic methods alone. Our results show that genomic selection for novel difficult-to-measure traits is a feasible strategy to achieve increased genetic gain.     

Anti-alpha-fodrin antibodies do not add much to the diagnosis of Sjögren's syndrome

The presence of anti-alpha-fodrin autoantibodies has been reported to be a highly specific and sensitive test for the diagnosis of Sj?gren's syndrome (SjS). We looked (in Nijmegen) for anti-alpha-fodrin, anti-Ro60, and anti-La autoantibodies in a cohort of 51 patients with rheumatic diseases (primary SjS [21], secondary SjS 6, rheumatoid arthritis [RA] 12, systemic lupus erythematosus [SLE] 6, and scleroderma 6) and in 28 healthy subjects, using ELISA, immunoblotting, and immunoprecipitation. The same samples were analyzed with an alternative anti-alpha-fodrin ELISA in Hanover. The Nijmegen ELISA of the sera from primary SjS showed sensitivities of 43% and 48% for IgA- and IgG-type anti-alpha-fodrin antibodies, respectively. The Hanover ELISA showed sensitivities of 38% and 10% for IgA- and IgG-type anti-alpha-fodrin antibodies, respectively. The ELISAs for alpha-fodrin showed six (Nijmegen) and four (Hanover) anti-alpha-fodrin-positive RA sera. IgA and IgG anti-fodrin antibodies were also present in four patients with secondary SjS. The sensitivities of Ro60 and La-antibodies in the Nijmegen ELISA were 67% and 62%, respectively. Unlike anti-alpha-fodrin antibodies, all anti-Ro60 and anti-La positive sera could be confirmed by immunoblotting or RNA immunoprecipitation. Thus, anti-Ro and anti-La autoantibodies were more sensitive than anti-alpha-fodrin autoantibodies in ELISA and were more frequently confirmed by other techniques. Anti-La antibodies appear to be more disease-specific than anti-alpha-fodrin antibodies, which are also found in RA sera. Therefore, the measurement of anti-alpha-fodrin autoantibodies does not add much to the diagnosis of Sj?gren's syndrome.     

A phasing and imputation method for pedigreed populations that results in a single-stage genomic evaluation

Background

Efficient, robust, and accurate genotype imputation algorithms make large-scale application of genomic selection cost effective. An algorithm that imputes alleles or allele probabilities for all animals in the pedigree and for all genotyped single nucleotide polymorphisms (SNP) provides a framework to combine all pedigree, genomic, and phenotypic information into a single-stage genomic evaluation.

Methods

An algorithm was developed for imputation of genotypes in pedigreed populations that allows imputation for completely ungenotyped animals and for low-density genotyped animals, accommodates a wide variety of pedigree structures for genotyped animals, imputes unmapped SNP, and works for large datasets. The method involves simple phasing rules, long-range phasing and haplotype library imputation and segregation analysis.

Results

Imputation accuracy was high and computational cost was feasible for datasets with pedigrees of up to 25 000 animals. The resulting single-stage genomic evaluation increased the accuracy of estimated genomic breeding values compared to a scenario in which phenotypes on relatives that were not genotyped were ignored.

Conclusions

The developed imputation algorithm and software and the resulting single-stage genomic evaluation method provide powerful new ways to exploit imputation and to obtain more accurate genetic evaluations.