Outcomes of Ceramic-On-Ceramic Bearing Total Hip Arthroplasty: A Minimum 10-Year Follow-Up Study.

BACKGROUND: Although the fourth generation of ceramics has demonstrated excellent clinical results 5 to 6 years postoperatively, concerns over ceramic fracture and squeaking persist and longer-term follow-up (minimum 10 years) studies are warranted. Our study aimed to evaluate the minimum 10-year clinical outcomes and bearing-specific complications of ceramic-on-ceramic (CoC) total hip arthroplasties. METHODS: We retrospectively evaluated all patients who underwent primary delta CoC total hip arthroplasty in our institution between January 2004 and February 2013. Demographics, surgical techniques, complications, patient-reported outcomes, and radiographic outcomes were collected and analyzed. For continuous variables, the comparison between groups was conducted using a one-way analysis of variance. Of all 235 patients included in the study, 70.5% were women (190 hips). The mean follow-up period was 12 years (range, 10 to 18). The femoral head sizes of 28- mm, 32 mm, and 36 mm were used in 50, 26, and 197 cases, respectively. Mean acetabular inclination and anteversion angles were 39.2 ± 7.1° and 14.9 ± 3.5°. RESULTS: There were 5 hips revised at a mean 4.6 years (range, 0.1 to 7.1). One revision was squeaking-related. Squeaking was also reported by 8 other patients, but did not require revision. Other reasons for revision were early infection in 2 cases, stem loosening in 1 case, and stem fracture in 2 cases. The survival analysis for any causes for revision as an endpoint was 96.7% (95% confidence interval 0.313%-2.57%). CONCLUSION: We report excellent mean 12-year follow-up results regarding the complications and survivorship of the fourth generation CoC bearings.

Carvedilol Among Patients With Heart Failure With a Cocaine-Use Disorder.

OBJECTIVES: This study sought to assess the safety of carvedilol therapy among heart failure (HF) patients with a cocaine-use disorder (CUD). BACKGROUND: Although carvedilol therapy is recommended among certain patients with HF, the safety and efficacy of carvedilol among HF patients with a CUD is unknown. METHODS: This was a single-center study of hospitalized patients with HF. Cocaine use was self-reported or defined as having a positive urine toxicology. Patients were divided by carvedilol prescription. Subgroup analyses were performed by strata of ejection fraction (EF) ≤40%, 41% to 49%, or ≥50%. Major adverse cardiovascular events (MACE) were defined as cardiovascular mortality and 30-day HF readmission. RESULTS: From a cohort of 2,578 patients hospitalized with HF in 2011, 503 patients with a CUD were identified, among whom 404 (80%) were prescribed carvedilol, and 99 (20%) were not. Both groups had similar characteristics; however, those prescribed carvedilol had a lower LVEF, heart rate, and N-terminal pro-B-type natriuretic peptide concentrations at admission and on discharge, and more coronary artery disease. Over a median follow-up of 19 months, there were 169 MACEs. The MACE rates were similar between the carvedilol and the non-carvedilol groups (32% vs. 38%, respectively; p = 0.16) and between those with a preserved EF (30% vs. 33%, respectively; p = 0.48) and were lower in patients with a reduced EF taking carvedilol (34% vs. 58%, respectively; p = 0.02). In a multivariate model, carvedilol therapy was associated with lower MACE among patients with HF with a CUD (hazard ratio: 0.67; 95% confidence interval; 0.481 to 0.863). CONCLUSIONS: Our findings suggest that carvedilol therapy is safe for patients with HF with a CUD and may be effective among those with a reduced EF.

The Risk for Sudden Cardiac Death Among Patients Living With Heart Failure and Human Immunodeficiency Virus.

OBJECTIVES: The aim of this study was to determine the incidence of sudden cardiac death (SCD) among persons living with human immunodeficiency virus infection (PHIV) with heart failure (HF), who were hospitalized for HF, and the risk factors associated with it. BACKGROUND: HF is associated with an increased risk for SCD. PHIV are at heightened risk for HF. METHODS: This was a retrospective study of 2,578 patients hospitalized with HF from a single academic center, of whom 344 were PHIV. The outcome of interest was SCD. Subgroup analyses were performed by strata of viral load (VL) and left ventricular ejection fraction (LVEF) <35%, 35% to 49%, and ≥50%. RESULTS: Of 2,578 patients with HF, 2,149 (86%) did not have implantable cardioverter-defibrillators; of these, there were 344 PHIV and 1,805 uninfected control subjects. Among PHIV with HF, 313 (91%) were prescribed antiretroviral therapy and 64% were virally suppressed. There were 191 SCDs over a median follow-up period of 19 months. Compared with control subjects, PHIV had a 3-fold increase in SCD (21.0% vs. 6.4%; adjusted odds ratio: 3.0; 95% confidence interval: 1.78 to 4.24). Among PHIV, cocaine use, lower LVEF, absence of beta-blocker prescription, and VL were predictors of SCD. The SCD rate among PHIV with undetectable VL was similar to the rate among uninfected subjects. Similar findings were observed by LVEF strata. Among PHIV with HF without conventional indications for an implantable cardioverter-defibrillator, the rate of SCD was 10% per year. CONCLUSIONS: PHIV hospitalized with HF are at a markedly increased risk for SCD. SCD risk was increased in patients with lower LVEFs, lower CD4 counts, and higher VL.

Determination of the equilibrium charge distribution for polyampholytes of different compactness in a single computer experiment.

The conformational properties of charge-balanced polyampholytes described by the end-to-end distance or radius of gyration depend on parameters such as the temperature and pH as well as on the detailed charge distribution along the backbone. In this work we present a method to determine the charge distribution along a semi-stiff polyampholyte backbone which will result in a thermodynamically stable structure for the compactness of interest, from several loops to an uncoiled structure, performed in a single computer experiment.

Method for sampling compact configurations for semistiff polymers.

The sampling of compact configurations is crucial when investigating structural properties of semistiff polymers, like proteins and DNA, using Monte Carlo methods. A sampling scheme for a continuous model based on configuration biasing is introduced, tested, and compared with conventional methods. The proposed configuration biased Monte Carlo method, used together with the Wang-Landau sampling scheme, enables us to obtain any thermodynamic property within the statistical ensemble in use. Using the proposed method, it is possible to collect statistical data of interest for a wide range of compactions (from stretched up to several toroid loops) in a single computer experiment. A second-order-like stretched-toroid phase transition is observed for a semistiff polymer, and the critical temperature is estimated.

Decreased osmotic pressure via interfacial charge clustering.

Behaviors of a model interfacial system featuring the clustering of discrete, mobile wall charges and a counterion solution are investigated. The results demonstrate that even very small localized charge clusters produce significant effects for the osmotic pressure, effects that are not adequately represented in common colloidal models. We observe a pronounced decrease in osmotic pressure where a certain level of clustering is attained, with potentially significant implications for theories of colloidal stability and biochemical processes at microscopic length scales. The stable level of wall charge clustering, and thus the osmotic pressure, is found to be variable in the addition of an attractive potential, as measured via the excess free energy of clustering.

Interaction between charged surfaces mediated by rodlike counterions: the influence of discrete charge distribution in the solution and on the surfaces.

The interaction between two charged surfaces, with discrete or uniform charge distributions, embedded in a solution of rodlike counterions has been studied. Monte Carlo simulations and density functional theory have been applied to study the concentration profiles of counterions and the force between the charged surfaces. We show that for low surface charge densities the repulsive force between like-charged surfaces is observed regardless of the rod length. Where high surface charge densities are present, attractive forces at surface separations related to the rod length are observed.

Effects of Discrete Charge Clustering in Simulations of Charged Interfaces.

A system of counterions between charged surfaces is investigated, with the surfaces represented by uniform charged planes and three different arrangements of discrete surface charges - an equispaced grid and two different clustered arrangements. The behaviors of a series of systems with identical net surface charge density are examined, with particular emphasis placed on the long ranged corrections via the method of "charged slabs" and the effects of the simulation cell size. Marked differences are observed in counterion distributions and the osmotic pressure dependent on the particular representation of the charged surfaces; the uniformly charged surfaces and equispaced grids of discrete charge behave in a broadly similar manner, but the clustered systems display a pronounced decrease in osmotic pressure as the simulation size is increased. The influence of the long ranged correction is shown to be minimal for all but the very smallest of system sizes.

Identification of differentially expressed genes in spontaneously regressing melanoma using the MeLiM swine model.

Partial and some few cases of complete spontaneous regression have been observed in cutaneous melanoma patients but little is known about the molecular mechanisms involved. The Melanoblastoma-bearing Libechov Minipig (MeLiM) is a suitable animal model to study the phenomenon of spontaneous regression because MeLiM pigs exhibit naturally occurring melanomas which regress completely 6 months after birth. In this study, we used suppression subtractive hybridization (SSH) to identify molecular determinants of melanoma regression within swine melanoma tissues and melanoma cell cultures. Several markers involved in cell-adhesion, -communication, -motility, signal transduction, negative regulation of cell proliferation, transport and immune response were identified that correlated with melanoma regression whereas the main genes involved in melanin synthesis showed a strong downregulation. For the most differentially expressed genes, we validated the results obtained by SSH with qRT-PCR and with immunohistochemistry for some of them (CD9, MITF, RARRES1). Most notable, for the first time in melanoma, we identified the retinoic acid responder 1 gene (RARRES1) as a main actor of the regression process in melanoma. This first gene expression study in swine melanoma regression, may contribute to the finding of new therapeutic targets for human melanoma treatment.

The influence of discrete surface charges on the force between charged surfaces.

The force between two parallel charged flat surfaces, with discrete surface charges, has been calculated with Monte Carlo simulations for different values of the electrostatic coupling. For low electrostatic coupling (small counterion valence, small surface charge, high dielectric constant, and high temperature) the total force is dominated by the entropic contribution and can be described by mean field theory, independent of the character of the surface charges. For moderate electrostatic coupling, counterion correlation effects lead to a smaller repulsion than predicted by mean field theory. This correlation effect is strengthened by discrete surface charges and the repulsive force is further reduced. For large electrostatic coupling the total force for smeared out surface charges is known to be attractive due to counterion correlations. If discrete surface charges are considered the attractive force is weakened and can even be turned into a repulsive force. This is due to the counterions being strongly correlated to the discrete surface charges forming effective, oppositely directed, dipoles on the two walls.

Immune characterization of the Lewis rats inoculated with K2 sarcoma cell line and newly derived R5-28 malignant cells.

Sarcoma is a relatively rare malignant disease with high mortality, bad prognosis and response to conventional therapy. Two possible models of this disease were tested: the K2 rat sarcoma cell line, which was described previously, and the new rat R5-28 cell line derived from a spontaneously growing rat neoplasm with sarcoma morphology. While all rats inoculated with K2 cells developed tumours at 22th-25th day after inoculation (D = 22-25), only 60%-75% of R5-28-inoculated rats were affected by tumours. The frequency and progress of the disease depended on the number of inoculated cells. No metastases were detected in both cases. All affected animals showed large splenomegaly. A possible response of some immune system components to tumours was tested. No tumour-infiltrating lymphocytes were revealed in the tumour tissue. Anti-tumour antibodies were not found in tumour-bearing animal sera. Appropriate changes in peripheral blood lymphocyte subsets were explored. While the relative numbers of both NK cells and Tc were impaired, no changes were noted in numbers of CD4+CD8- T helper cells. Leukocytosis with highly increased numbers of CD11b+ myeloid cells displaying variable expression of CD4 was detected in terminal stages of the disease.

A scalable parallel Monte Carlo method for free energy simulations of molecular systems.

We present a method of parallelizing flat histogram Monte Carlo simulations, which give the free energy of a molecular system as an output. In the serial version, a constant probability distribution, as a function of any system parameter, is calculated by updating an external potential that is added to the system Hamiltonian. This external potential is related to the free energy. In the parallel implementation, the simulation is distributed on to different processors. With regular intervals the modifying potential is summed over all processors and distributed back to every processor, thus spreading the information of which parts of parameter space have been explored. This implementation is shown to decrease the execution time linearly with added number of processors.

Differential expression of rat frizzled-related frzb-1 and frizzled receptor fz1 and fz2 genes in the rat aorta after balloon injury.

Frzb-1 is a secreted protein, presenting similarity with the Wnt-binding domain of the frizzled family of receptors, which acts as an antagonist of Wnt signaling. Using mRNA differential display in the rat aorta balloon injury model, we identified overexpression of Frzb-1 mRNA and determined its cDNA sequence. By quantitative reverse transcription-polymerase chain reaction and RNase protection assay, a biphasic upregulation of rFrzb-1 expression was observed, with significant peaks of a 1.7-fold increase at 4 days and a 1. 5-fold increase at 3 weeks after aortic injury in vivo. In contrast, expression of the rat frizzled receptor genes rfz1 and rfz2 were transiently downregulated at 1 and 4 hours after balloon injury. rFrzb-1 was expressed predominantly in rat aortic smooth muscle cells (RASMCs) and barely in aortic fibroblasts and endothelial cells (RAECs), whereas rfz1 and rfz2 were expressed in all of these cells when stimulated with serum. Transient downregulation of rfz1 and rfz2 expression was reproduced by stimulation of quiescent RASMCs with serum, platelet-derived growth factor-BB, or fibroblast growth factor-2. In contrast, rFrzb-1 expression diminished slowly, to reach a 2-fold decrease 24 hours after growth factor stimulation, implying that quiescent RASMCs expressed higher levels of rFrzb-1 mRNA than did proliferative ones. Overexpression of rFrzb-1 in the aorta seemed to coincide with the arrest of RASMC proliferation occurring in the media 4 days and in the neointima 3 weeks after balloon injury. Our results demonstrate that rfrzb-1, rfz1, and rfz2 are differentially regulated in response to arterial injury and that this modulation seems to follow the proliferative state of RASMCs, suggesting that these Wnt-signaling components may be involved in intimal vascular disease.

Plant mitochondrial RNA editing.

RNA editing affects messenger RNAs and transfer RNAs in plant mitochondria by site-specific exchange of cytidine and uridine bases in both seed and nonseed plants. Distribution of the phenomenon among bryophytes has been unclear since RNA editing has been detected in some but not all liverworts and mosses. A more detailed understanding of RNA editing in plants required extended data sets for taxa and sequences investigated. Toward this aim an internal region of the mitochondrial nad5 gene (1104 nt) was analyzed in a large collection of bryophytes and green algae (Charles). The genomic nad5 sequences predict editing in 30 mosses, 2 hornworts, and 7 simple thalloid and leafy liverworts (Jungermanniidae). No editing is, however, required in seven species of the complex thalloid liverworts (Marchantiidae) and the algae. RNA editing among the Jungermanniidae, on the other hand, reaches frequencies of up to 6% of codons being modified. Predictability of RNA editing from the genomic sequences was confirmed by cDNA analysis in the mosses Schistostega pennata and Rhodobryum roseum, the hornworts Anthoceros husnotii and A. punctatus, and the liverworts Metzgeria conjugata and Moerckia flotoviana. All C-to-U nucleotide exchanges predicted to reestablish conserved codons were confirmed. Editing in the hornworts includes the removal of genomic stop codons by frequent reverse U-to-C edits. Expectedly, no RNA editing events were identified by cDNA analysis in the marchantiid liverworts Ricciocarpos natans, Corsinia coriandra, and Lunularia cruciata. The findings are discussed in relation to models on the phylogeny of land plants.

Trans-splicing group II introns in plant mitochondria: the complete set of cis-arranged homologs in ferns, fern allies, and a hornwort.

The fragmentation of group II introns without concomitant loss of splicing competence is illustrated by extraordinary gene arrangements in plant mitochondrial genomes. The mitochondrial genes nad1, nad2, and nad5, all encoding subunits of the NADH dehydrogenase, require trans-splicing for functional assembly of their mRNAs in flowering plants. Tracing the origins of trans-splicing group II introns shows that they have evolved from formerly cis-arranged homologs whose descendants can still be identified in lineages of early branching land plants. In this contribution we present the full set of ancestor introns for all five conserved mitochondrial trans-splicing positions. These introns are strikingly small in the quillwort Isoetes lacustris, the continuous nad2 gene intron in this species representing the smallest (389 nt) land plant group II intron yet identified. cDNA analysis shows correct splicing of the introns in vivo and also identifies frequent RNA editing events in the flanking nad gene exons. Other representatives of the ancestral cis-arranged introns are identified in the fern Osmunda regalis, the horsetail Equisetum telmateia, and the hornwort Anthoceros crispulus. Only the now identified intron in Osmunda carries significant traces of a former maturase reading frame. The identification of a continuous homolog in Anthoceros demonstrates that intron invasion into the affected genes in some cases predated the split of vascular and nonvascular plants more than 400 million years ago. As an alternative to disruption after size increase, the respective introns can get secondarily lost in certain lineages.

Evolution of trans-splicing plant mitochondrial introns in pre-Permian times.

Trans-splicing in angiosperm plant mitochondria connects exons from independent RNA molecules by means of group II intron fragments. Homologues of trans-splicing introns in the angiosperm mitochondrial nad2 and nad5 genes are now identified as uninterrupted group II introns in the ferns Asplenium nidus and Marsilea drummondii. These fern introns are correctly spliced from the pre-mRNA at the sites predicted from their well-conserved secondary structures. The flanking exon sequences of the nad2 and nad5 genes in the ferns require RNA editing, including the removal of in-frame stop codons by U-to-C changes for correct expression of the genetic information. We conclude that cis-splicing introns like the ones now identified in ferns are the ancestors of trans-splicing introns in angiosperm mitochondria. Intron disruption is apparently due to a size increase of the structurally variable group II intron domain IV followed by DNA recombination in the plant mitochondrial genome.

RNA editing in the cox3 mRNA of Magnolia is more extensive than in other dicot or monocot plants.

The Magnoliaceae are discussed as one of the key species at the root of the flowering plants. To obtain molecular information for one of these phylogenetically interesting plant species, we determined genomic and cDNA sequences of the mitochondrial cox3 gene in Magnolia grandiflora. Twenty-two RNA editing events are identified to alter cytidines in the mRNA to uridines, all but one of which change the encoded amino acid identity. RNA editing in the cox3 coding region is thus more frequent in Magnolia than in other dicot or monocot plants investigated and almost as predominant as in some gymnosperms. The cox3 RNA editing frequency in Magnolia thus occupies an intermediate position between angiosperms and gymnosperms consistent with the phylogenetic position of the Magnoliales.

RNA editing in bryophytes and a molecular phylogeny of land plants.

RNA editing has been observed to date in all groups of vascular plants, but not in bryophytes. Its occurrence was therefore assumed to correlate with the evolution of tracheophytes. To gain more insight into both the phylogeny of early land plants and the evolution of mitochondrial RNA editing we have investigated a number of vascular and non-vascular plant species. Contrary to the belief that editing is absent from bryophytes, here we report mitochondrial RNA editing in cox3 mRNA of the liverwort Pellia epiphylla, the mosses Tetraphis pellucida and Ceratodon purpureus and the hornwort Anthroceros crispulus. RNA editing in plants consequently predates the evolution of tracheophytes. Editing is also found in the eusporangiate ferns Ophioglossum petiolatum and Angiopteris palmiformis, the whisk fern Tmesipteris elongata and the gnetopsid Ephedra gerardiana, but was not detected in Gnetum gnemon.cox3 mRNA of the lycopsid Isoetes lacustris shows the highest frequency of RNA editing ever observed in a plant, with 39% of all cytidine residues converted to uridines. The frequency of RNA editing correlates with the genomic GC content rather than with the phylogenetic position of a species. Phylogenetic trees derived from the slowly evolving mitochondrial sequences find external support from the assessments of classical systematics.