Carboxylic acid mediated antimicrobial activity of silicone elastomers.

Due to their high biocompatibility silicone elastomers are the material of choice in many sensitive health care applications. However, the inherent hydrophobicity of the polymer makes silicones more susceptible to spontaneous protein adsorption and subsequent biofilm formation than more hydrophilic abiotic materials. Hence, the development of antimicrobial silicone elastomers could help to reduce potential biofilm-associated infections when using silicone based medical devices. In this study, we describe carboxylic-acid-modified silicone elastomers that are biocompatible and exhibit a specific antimicrobial activity against clinically relevant pathogens even after being stored in common packaging materials.

Thrombosis, fracture, and percutaneous removal of a patent foramen ovale closure device 1 month after successful deployment.

Several different devices have been developed for the percutaneous closure of interatrial defects and patent foramen ovale. Although the implantation of these devices is both safe and effective, a number of complications, both in the early and the late follow-up, may occur. We describe a case of device fracture manifested early (1 month after implantation) with the formation of massive thrombosis on the right atrial disc. The patient was treated with anticoagulants and the device was percutaneously retrieved. Our images allowed early noninvasive therapy and emphasize the need for echocardiographic follow-up early after implantation.

Small Molecule Subgraph Detector (SMSD) toolkit.

BACKGROUND: Finding one small molecule (query) in a large target library is a challenging task in computational chemistry. Although several heuristic approaches are available using fragment-based chemical similarity searches, they fail to identify exact atom-bond equivalence between the query and target molecules and thus cannot be applied to complex chemical similarity searches, such as searching a complete or partial metabolic pathway.In this paper we present a new Maximum Common Subgraph (MCS) tool: SMSD (Small Molecule Subgraph Detector) to overcome the issues with current heuristic approaches to small molecule similarity searches. The MCS search implemented in SMSD incorporates chemical knowledge (atom type match with bond sensitive and insensitive information) while searching molecular similarity. We also propose a novel method by which solutions obtained by each MCS run can be ranked using chemical filters such as stereochemistry, bond energy, etc. RESULTS: In order to benchmark and test the tool, we performed a 50,000 pair-wise comparison between KEGG ligands and PDB HET Group atoms. In both cases the SMSD was shown to be more efficient than the widely used MCS module implemented in the Chemistry Development Kit (CDK) in generating MCS solutions from our test cases. CONCLUSION: Presently this tool can be applied to various areas of bioinformatics and chemo-informatics for finding exhaustive MCS matches. For example, it can be used to analyse metabolic networks by mapping the atoms between reactants and products involved in reactions. It can also be used to detect the MCS/substructure searches in small molecules reported by metabolome experiments, as well as in the screening of drug-like compounds with similar substructures.Thus, we present a robust tool that can be used for multiple applications, including the discovery of new drug molecules. This tool is freely available on http://www.ebi.ac.uk/thornton-srv/software/SMSD/

Recurrent events following patent foramen ovale closure in patients above 55 years of age with presumed paradoxical embolism.

OBJECTIVES: The aim of this article is to summarize our experience of patent foramen ovale (PFO) closure in patients above the age of 55 years. BACKGROUND: PFO is associated with cryptogenic thromboembolic events (TEs) in patients younger than 55 years. Little is known about the recurrence rate of TE in patients above the age of 55 years undergoing PFO closure for presumed paradoxical embolism. METHODS: PFO closure was performed in 1,055 patients, 423 of whom were above 55 years of age. Implantation of the device was guided by fluoroscopy and transesophageal or intracardiac echocardiography. RESULTS: A PFO occluding device was implanted successfully in all patients. Residual shunt was documented in 10% of patients above 55 years of age and in 8.4% of patients aged 55 years or younger (P = 0.325). During a median follow-up period of 18 months (range, 0-162 months) the annual incidence of recurrent TE in patients above 55 years was 1.8% while patients aged 55 or below had an annual incidence of recurrent TE of 1.3%. TE-free survival was similar in patients above 55 years of age compared with those aged 55 years and below. CONCLUSIONS: PFO closure in older patients is as efficient and seems comparable to those under the age of 55. Although traditional cardiovascular risk factors may be more frequent in the older age group compared with those younger than 55 years, PFO closure should not be withheld as a possible therapeutic option in this age group.

Comparison of contemporary devices used for transcatheter patent foramen ovale closure.

BACKGROUND: Transcatheter patent foramen ovale (PFO) closure can be performed with various devices. However, their handling, safety, presence of residual shunt and impact on recurrent thromboembolic events (TEs) are rarely compared with one another. Our goal was to compare the clinical performance of contemporary devices designed for PFO closure. METHODS: PFO closure with the Cardia PFO occluder (n = 405), Intrasept (n = 301) and Amplatzer PFO occluder (n = 89) was attempted in 795 patients with presumed paradoxical embolism. RESULTS: The procedure was successful in all patients. The periprocedural complication rate of 1.8% was comparable among the three groups. Residual shunting immediately following the procedure was higher in patients treated with the Cardia PFO occluder (24% vs. 14% [Intrasept] and 16% [Amplatzer]; p = 0.004). After a mean follow-up period of 26 months, no difference in residual shunting was seen (8% [Cardia] vs. 7% [Intrasept] vs. 8% [Amplatzer]; p = 0.736). The annual incidence of recurrent TE was 1.4%, which was not affected by the presence of a residual shunt or the type of device used. New-onset atrial fibrillation (AF) following PFO closure was the only predictor of recurrent TE and was more common in patients treated with the Amplatzer (10% vs. 5% [Cardia]) and 5% [Intrasept]; p = 0.057). CONCLUSIONS: The clinical performance of the three PFO occluders evaluated in this study seems comparable. Device design does not seem to impact the success of the PFO closure procedure. AF was the only predictor of recurrent TEs, underscoring the importance of aggressive therapy for atrial arrhythmias early following PFO closure.

Incidence of atrial fibrillation following transcatheter closure of atrial septal defects in adults.

Transcatheter closure of secundum atrial septal defect (ASD) and patent foramen ovale (PFO) has become a routine procedure. Little is known about the effect of atrial septal device implantation on the occurrence of atrial fibrillation (AF). We evaluated the frequency of AF occurring after transcatheter PFO and ASD closure in a large population. From 1994 until 2007 a total of 1,062 patients underwent transcatheter closure of an interatrial communication. New-onset AF was defined by 12-lead electrocardiogram or Holter monitoring in patients without a history of AF at baseline. Of the 1,062 patients, 822 had a PFO and 240 had an ASD. During a median follow up of 20 months, new-onset AF was documented in 8% of patients. New-onset AF occurred in 7% of patients after PFO closure and in 12% of patients with underlying ASD. The annual incidence of new-onset AF was 2.5% and 4.1% in patients with PFO and ASD, respectively. Generally, patients with new-onset AF were older than those without AF. Device type or size did not influence the occurrence of AF. In the group of patients with PFO, residual shunt was more common in patients with AF compared with the non-AF group. In conclusion, AF is more common after PFO and ASD closure compared with the general population; although device type or size did not impact the occurrence of AF, residual shunt may influence the occurrence of AF after intervention in patients with underlying PFO.

Outcome after percutaneous closure of a patent foramen ovale using the Intrasept device: a multi-centre study.

OBJECTIVES: This multi-centre study reports safety and efficacy of percutaneous patent foramen ovale (PFO) closure, using the fourth generation Intrasept device. BACKGROUND: PFO has been associated with paradoxical embolism and cryptogenic stroke. Percutaneous PFO closure seems to reduce the risk for recurrent paradoxical thrombo-embolism. Currently, different devices are used for PFO closure. METHODS: Patients, who underwent a PFO closure with the Intrasept device (Cardia, Eagan, MN) between July 2002 and September 2006, were included in the study. The primary endpoint was defined as reoccurrence of stroke, transient ischemic attack (TIA), or peripheral thrombo-embolism. Peri-procedural and mid-term complications were reported. RESULTS: Four-hundred thirty patients (mean age 50.7 +/- 13.0 years, 231 men) underwent closure. The indications were cryptogenic stroke (69.8%), TIA (23.5%), peripheral embolism (3.3%), and other (3.5%). The median follow-up time was 0.8 years, range 3.9 years. The primary endpoint occurred in 0.5% for stroke, in 2.5% for TIA, and in none for peripheral embolism. Peri-procedural complications were reported in 11.5% of cases, from which 0.2% was defined as major. No severe complications occurred during mid-term follow-up. A residual shunt was present in 12.5% of patients who did not suffer from a recurrent event, compared to 36.4% of patients who reached the primary endpoint (P = 0.04). CONCLUSION: This multi-centre study suggests that percutaneous closure of a symptomatic PFO with the fourth generation Intrasept device is safe and might be effective to prevent the recurrence of paradoxical thrombo-embolic events.

Identifying genes of gene regulatory networks using formal concept analysis.

In order to understand the behavior of a gene regulatory network, it is essential to know the genes that belong to it. Identifying the correct members (e.g., in order to build a model) is a difficult task even for small subnetworks. Usually only few members of a network are known and one needs to guess the missing members based on experience or informed speculation. It is beneficial if one can additionally rely on experimental data to support this guess. In this work we present a new method based on formal concept analysis to detect unknown members of a gene regulatory network from gene expression time series data. We show that formal concept analysis is able to find a list of candidate genes for inclusion into a partially known basic network. This list can then be reduced by a statistical analysis so that the resulting genes interact strongly with the basic network and therefore should be included when modeling the network. The method has been applied to the DNA repair system of Mycobacterium tuberculosis. In this application, our method produces comparable results to an already existing method of component selection while it is applicable to a broader range of problems.

Patent foramen ovale closure with the Intrasept occluder: Complete 6-56 months follow-up of 247 patients after presumed paradoxical embolism.

OBJECTIVE: We report our experience of transcatheter patent foramen ovale (PFO) closure with the new Intrasept occluder. BACKGROUND: The Intrasept device is the fourth generation of the Cardia occluder family. Developed for transcatheter closure of PFO, the main difference between the Intrasept and prior generations of the Cardia occluder is its articulating center post. This modification allows better alignment of the umbrellas on both sides of the atrial septum. We report our experience with this new PFO occluder. METHODS: From July 2002 until October 2006, PFO closure with the Intrasept occluder was attempted in 247 patients with presumed paradoxical embolism. Prior to PFO closure, a total of 269 cerebrovascular thromboembolic events (TEs) had occurred. Implantation of the device was guided by fluoroscopy and transesophageal echocardiography with conscious sedation. RESULTS: Median age was 53 years (range, 21-77). One hundred twenty-seven (51%) patients had an atrial septal aneurysm. The device was implanted successfully in all cases. Acute complications occurred in 4 (1.6%) patients (air embolism = 2, pericardial effusion = 1, supraventricular tachycardia = 1). Follow-up information is available for all 247 (100%) patients. Median follow-up time was 14 months (range 6-56). Residual shunt at 6 months follow-up was 13%. After 1 year, the presence of residual shunt rate decreased to 10%. Following PFO closure, seven recurrent TEs (TIA = 4, CVA = 3) were observed in 6 patients. No wire fractures or device-associated thrombi were seen. CONCLUSIONS: PFO closure with the Intrasept occluder is safe and efficient. Rates of residual shunt and recurrent TE compare favorably with other contemporary devices.

Modeling feedback loops in the H-NS-mediated regulation of the Escherichia coli bgl operon.

The histone-like nucleoid-associated protein H-NS is a global transcriptional repressor that controls approximately 5% of all genes in Escherichia coli and other enterobacteria. H-NS binds to DNA with low specificity. Nonetheless, repression of some loci is exceptionally specific. Experimental data for the E. coli bgl operon suggest that highly specific repression is caused by regulatory feedback loops. To analyze whether such feedback loops can account for the observed specificity of repression, here a model was built based on expression data. The model includes several regulatory interactions, which are synergy of repression by binding of H-NS to two regulatory elements, an inverse correlation of the rate of repression by H-NS and transcription, and a threshold for positive regulation by anti-terminator BglG, which is encoded within the operon. The latter two regulatory interactions represent feedback loops in the model. The resulting system of equations was solved for the expression level of the operon and analyzed with respect to different promoter activities. This analysis demonstrates that a small (3-fold) increase of the bgl promoter activity results in a strong (80-fold) enhancement of bgl operon expression. Thus, the parameters included into the model are sufficient to simulate specific repression by H-NS.

A modified Cook sheath for closure of a large secundum atrial septal defect.

Transcatheter closure of large secundum atrial septal defects with deficient rims is difficult. Several techniques have been described to improve delivery of the occluder in anatomically challenging cases. Among these is a recently described technique using a modified delivery sheath with the creation of a bevel. However, the initial case report was complicated by malfunction and longitudinal splitting of the sheath. We describe the successful use of a modified delivery sheath for closure of a large atrial septal defect with a deficient rim.

Transcatheter closure of secundum atrial septal defects in adults with the Amplatzer septal occluder: intermediate and long-term results.

AIMS: Transcatheter closure of secundum atrial septal defects (ASD) with the Amplatzer septal occluder (ASO) has become a standard procedure in most pediatric and adult patients. However, data addressing success rates and outcome in adults is limited. We sought to define the safety profile of the ASO in the community setting and identify the percentage of adults with ASD amenable to percutaneous closure with the ASO. METHODS: We performed a retrospective analysis of patients' records referred for transcatheter ASD closure from 1999 through 2005 at a single institution. Patients were evaluated with right heart catheterization and underwent closure of the ASD according to standard indications under transesophageal and fluoroscopic guidance. RESULTS: Two hundred and seven consecutive patients were taken to the catheterization laboratory for hemodynamic evaluation and possible interventional closure of an ASD. Of those patients, 18 were excluded because the defect and the left-to-right shunt were hemodynamically insignificant (n = 7) or because there was no distinct defect, but instead a multi-perforated septum (n = 11). Nineteen cases were excluded for anatomic reasons. Of the remaining 170 patients, ASO implantation was attempted and successfully performed in 166 (83% of 200 patients with hemodynamically significant ASD). Complications occurred in 11 cases (6.5%) (device dislocation = 4, transient ST-segment elevation = 4, TIA = 1, hemoptysis = 1, pericardial effusion = 1); none of these events were associated with long-term sequelae. During a median follow-up period of 13 months (range 6-80) there were no major clinical events. CONCLUSIONS: More than 80% of adults with a distinct, hemodynamically significant secundum ASD can be successfully treated with the ASO. The immediate success rates are excellent and follow-up data suggest that the ASO is a safe device well suited for transcatheter ASD closure.

Transcatheter closure of patent foramen ovale in patients with migraine headache.

Our objective is to review the epidemiology and pathophysiology of migraine headache, its association with patent foramen ovale (PFO), and the impact of PFO closure on migraine. Upon reviewing English-language publications listed in MEDLINE relating to migraine headache, PFO, and transcatheter closure of PFO, we selected case series, retrospective and prospective studies relevant to the topic. Primarily retrospective case-control studies demonstrate a link between PFO closure and improvement of migraine headache. Few prospective data confirm the initial results. However, the only randomized, controlled trial finished to date analyzing the effect of PFO closure on migraine failed to reach its primary outcome of resolution of migraine following the intervention. The evidence of a benefit on migraine headache following PFO closure is not convincing, but certainly intriguing. With currently ongoing trials, more information related to this topic can be expected.

Temperature-sensitive eIF5A mutant accumulates transcripts targeted to the nonsense-mediated decay pathway.

The highly conserved protein eIF5A found in Archaea and all eukaryotes uniquely contains the posttranslationally formed amino acid hypusine. Despite being essential the functions of this protein and its modification remain unclear. To gain more insight into these functions temperature-sensitive mutants of the human EIF5A1 were characterized in the yeast Saccharomyces cerevisiae. Expression of the point mutated form V81G in a DeltaeIF5A strain of yeast led to a strongly temperature-sensitive phenotype and to a significantly reduced protein level at restrictive temperature. The mutant showed accumulation of a subset of mRNAs that was also observed in nonsense-mediated decay (NMD)-deficient yeast strains. After short incubation at restrictive temperature the mutant exhibited increased half-lives of the intron containing CYH2 pre-mRNA and mature transcripts of NMD-dependent genes. Reduced telomere silencing and shortening was detected in the V81G mutant further supporting similarities to NMD-deficient strains. Our data suggest that eIF5A mediates important cellular processes like cell viability and senescence through its effects on the stability of certain mRNAs.

CASPAR: a hierarchical bayesian approach to predict survival times in cancer from gene expression data.

MOTIVATION: DNA microarrays allow the simultaneous measurement of thousands of gene expression levels in any given patient sample. Gene expression data have been shown to correlate with survival in several cancers, however, analysis of the data is difficult, since typically at most a few hundred patients are available, resulting in severely underdetermined regression or classification models. Several approaches exist to classify patients in different risk classes, however, relatively little has been done with respect to the prediction of actual survival times. We introduce CASPAR, a novel method to predict true survival times for the individual patient based on microarray measurements. CASPAR is based on a multivariate Cox regression model that is embedded in a Bayesian framework. A hierarchical prior distribution on the regression parameters is specifically designed to deal with high dimensionality (large number of genes) and low sample size settings, that are typical for microarray measurements. This enables CASPAR to automatically select small, most informative subsets of genes for prediction. RESULTS: Validity of the method is demonstrated on two publicly available datasets on diffuse large B-cell lymphoma (DLBCL) and on adenocarcinoma of the lung. The method successfully identifies long and short survivors, with high sensitivity and specificity. We compare our method with two alternative methods from the literature, demonstrating superior results of our approach. In addition, we show that CASPAR can further refine predictions made using clinical scoring systems such as the International Prognostic Index (IPI) for DLBCL and clinical staging for lung cancer, thus providing an additional tool for the clinician. An analysis of the genes identified confirms previously published results, and furthermore, new candidate genes correlated with survival are identified.

Contrast material-induced renal failure: an overview.

The administration of iodinated contrast media (CM) is integral to many cardiovascular procedures. While it is clear that CM provide significant diagnostic benefit, there is some risk of contrast medium-related adverse events in a small percentage of patients. Potentially the most serious complication associated with the use of iodinated contrast agents is contrast-induced nephropathy (CIN). Most patients undergoing contrast-enhanced radiographic procedures are not at risk for CIN, however subjects with pre-existing renal insufficiency, diabetes mellitus, or cardiovascular disease receiving intra-arterial administrations of contrast material are at increased risk. Typically, patients with CIN will experience changes in serum creatinine 1-5 days following contrast exposure. While decrements in renal function are generally small and transient, some patients experience a more prolonged decrease and, in rare cases, require dialysis. More importantly, there is substantial literature documenting that patients with CIN after cardiac intervention experience greater morbidity (including prolonged hospitalization) and acute and 1-year mortality. The present article aims to briefly review the pathogenesis of CIN and reviews current opinion on how best to prevent CIN and manage at-risk patients.

A fractional programming approach to efficient DNA melting temperature calculation.

MOTIVATION: In a wide range of experimental techniques in biology, there is a need for an efficient method to calculate the melting temperature of pairings of two single DNA strands. Avoiding cross-hybridization when choosing primers for the polymerase chain reaction or selecting probes for large-scale DNA assays are examples where the exact determination of melting temperatures is important. Beyond being exact, the method has to be efficient, as these techniques often require the simultaneous calculation of melting temperatures of up to millions of possible pairings. The problem is to simultaneously determine the most stable alignment of two sequences, including potential loops and bulges, and calculate the corresponding melting temperature. RESULTS: As the melting temperature can be expressed as a fraction in terms of enthalpy and entropy differences of the corresponding annealing reaction, we propose to use a fractional programming algorithm, the Dinkelbach algorithm, to solve the problem. To calculate the required differences of enthalpy and entropy, the Nearest Neighbor model is applied. Using this model, the substeps of the Dinkelbach algorithm in our problem setting turn out to be calculations of alignments which optimize an additive score function. Thus, the usual dynamic programming techniques can be applied. The result is an efficient algorithm to determine melting temperatures of two DNA strands, suitable for large-scale applications such as primer or probe design. AVAILABILITY: The software is available for academic purposes from the authors. A web interface is provided at http://www.zaik.uni-koeln.de/bioinformatik/fptm.html

Transcatheter closure of a 22 mm patent ductus arteriosus with an Amplatzer atrial septal occluder.

Transcatheter techniques for closure of patent ductus arteriosus (PDA) have been used for almost 40 years. We report a case of a 24-year-old female with a 22 mm PDA, congestive heart failure, and atrial fibrillation. She underwent transcatheter PDA closure with an Amplatzer atrial septal occluder (ASO). Following the procedure, she developed hemolysis due to a large residual shunt. However, the shunt gradually resolved until complete closure was achieved within 8 months. An attempt to restore sinus rhythm with electrical cardioversion was successful and the patient is now, 2 years after procedure, in New York Heart Association functional class I. Off-label use of an ASO for closure of a very large PDA yielded an excellent clinical result.

Diagnosis of patent foramen ovale using contrast-enhanced dynamic MRI: a pilot study.

OBJECTIVE: The aim of this study was to evaluate the feasibility of dynamic contrast-enhanced MRI for detection of patent foramen ovale. SUBJECTS AND METHODS: Fifteen patients with and five patients without patent foramen ovale underwent transesophageal echocardiography and MRI, which were performed during the Valsalva maneuver. Grading results (grade 0, no patent foramen ovale and grades 1-3, minor to major enhancement due to intracardiac shunt) were assessed visually. Signal-intensity curves in the left atrium and in a pulmonary vein served to underline the diagnosis. RESULTS: The diagnoses of all patients with (15/15) and without patent foramen ovale (5/5) were correct compared with the findings of the reference transesophageal echocardiography. In 12 (60%) of 20 patients, the grading scores were identical, and in four (20%) of 20 patients, the scores differed by more than one grade. Overall, there was a good correlation of grading scores (r = 0.7, p < 0.05). Using signal-intensity curves, we found that the patients with patent foramen ovale showed an additional signal peak in the left atrium before the enhancement of the pulmonary vein because of an intracardiac shunt. In three of 15 patients with patent foramen ovale, an atrial septal aneurysm was correctly diagnosed. CONCLUSION: This pilot study shows that MRI is a new noninvasive method to detect patent foramen ovale and atrial septal aneurysm. A grading is possible but warrants further investigation regarding its predictive value and impact on treatment strategies.