Malfunction of subpectorally implanted cardiac resynchronization therapy defibrillators due to weakened header bond.

BACKGROUND: Implantable cardioverter defibrillator (ICD) implantation has increased significantly over the last 10 years. Concerns about the safety and reliability of ICD systems have been raised, with premature lead failure and battery malfunctions accounting for the majority of reported adverse events. We describe the unique mode of presentation, diagnosis, and management of cardiac resynchronization therapy defibrillators (CRT-D) malfunctions that were caused by weakened bonding between the generator and header. METHODS AND RESULTS: Between June 2008 and December 2009, 22 Teligen™ ICDs and 24 Cognis™ CRT-Ds were implanted subpectorally at our institution, until a product advisory was issued. Of 24 Cognis™ CRT-D implants, 3 patients presented with CRT-D malfunctions. All our cases presented with initially intermittent and then persisting increases in shock lead impedance, associated with nonphysiological noise in the shock electrogram channels. These issues were rectified by generator change. Postexplant laboratory analysis confirmed inadequate bonding between device header and titanium casing in all cases, resulting in loosening and rocking of the header followed by fatigue-induced fracture of the shock circuitry. CONCLUSION: Weakened bonding between the header and generator casing of subpectorally implanted CRT-Ds can result in fractures and malfunction of the HV circuit. Physicians monitoring patients with devices affected by the product advisory should remain vigilant in order to diagnose and manage similar device malfunction expediently.

Pulmonary venous isolation by antral ablation with a large cryoballoon for treatment of paroxysmal and persistent atrial fibrillation: medium-term outcomes and non-randomised comparison with pulmonary venous isolation by radiofrequency ablation.

BACKGROUND: To prevent atrial fibrillation (AF) recurrence after catheter ablation, pulmonary venous isolation (PVI) at an antral level is more effective than segmental ostial ablation. Cryoablation around the pulmonary venous (PV) ostia for AF therapy is potentially safer compared to radiofrequency ablation (RFA). The aim of this study was to investigate the efficacy of a strategy using a large cryoablation balloon to perform antral cryoablation with 'touch-up' ostial cryoablation for PVI in patients with paroxysmal and persistent AF. METHODS: Paroxysmal and persistent AF patients undergoing their first left atrial ablation were recruited. After cryoballoon therapy, each PV was assessed for isolation and if necessary, treated with focal ostial cryoablation until PVI was achieved. Follow-up with Holter monitoring was performed. Clinical outcomes of the cryoablation protocol were compared, with consecutive patients undergoing PVI by RFA. RESULTS: 124 consecutive patients underwent cryoablation. 77% of paroxysmal and 48% of persistent AF subjects were free from AF at 12 months after a single procedure. Over the same time period, 53 consecutive paroxysmal AF subjects underwent PVI with RFA and at 12 months, 72% were free from AF at 12 months (p=NS). There were too few persistent AF subjects (n=8) undergoing solely PVI by RFA as a comparison group. Procedural and fluoroscopic times during cryoablation were significantly shorter than RFA. CONCLUSIONS: PV isolation can be achieved in less than 2 h by a simple cryoablation protocol with excellent results after a single intervention, particularly for paroxysmal AF.

Schizophrenia and borderline personality disorder: similarities and differences in the experience of auditory hallucinations, paranoia, and childhood trauma.

This study investigated similarities and differences in the experience of auditory hallucinations, paranoia, and childhood trauma in schizophrenia and borderline personality disorder (BPD). Patients with clinical diagnoses of schizophrenia or BPD were interviewed using the Structured Clinical Interviews for DSM-IV. Axes 1 and 2 and auditory hallucinations, paranoia, and childhood trauma were assessed. A total of 111 patients participated; 59 met criteria for schizophrenia, 33 for BPD, and 19 for both. The groups were similar in their experiences of voices, including the perceived location of them, but they differed in frequency of paranoid delusions. Those with a diagnosis of BPD, including those with schizophrenia comorbidity, reported more childhood trauma, especially emotional abuse. BPD and schizophrenia frequently coexist, and this comorbidity has implications for diagnostic classification and treatment. Levels of reported childhood trauma are especially high in those with a BPD diagnosis, whether they have schizophrenia or not, and this requires assessment and appropriate management.

Interactions of Plasmodium falciparum erythrocyte membrane protein 3 with the red blood cell membrane skeleton.

Plasmodium falciparum parasites express and traffick numerous proteins into the red blood cell (RBC), where some associate specifically with the membrane skeleton. Importantly, these interactions underlie the major alterations to the modified structural and functional properties of the parasite-infected RBC. P. falciparum Erythrocyte Membrane Protein 3 (PfEMP3) is one such parasite protein that is found in association with the membrane skeleton. Using recombinant PfEMP3 proteins in vitro, we have identified the region of PfEMP3 that binds to the RBC membrane skeleton, specifically to spectrin and actin. Kinetic studies revealed that residues 38-97 of PfEMP3 bound to purified spectrin with moderately high affinity (K(D(kin))=8.5 x 10(-8) M). Subsequent deletion mapping analysis further defined the binding domain to a 14-residue sequence (IFEIRLKRSLAQVL; K(D(kin))=3.8 x 10(-7) M). Interestingly, this same domain also bound to F-actin in a specific and saturable manner. These interactions are of physiological relevance as evidenced by the binding of this region to the membrane skeleton of inside-out RBCs and when introduced into resealed RBCs. Identification of a 14-residue region of PfEMP3 that binds to both spectrin and actin provides insight into the potential function of PfEMP3 in P. falciparum-infected RBCs.

Nuclear export inhibitors and kinase inhibitors identified using a MAPK-activated protein kinase 2 redistribution screen.

Redistribution (BioImage) A/S, Søborg, Denmark) is a novel high-throughput screening technology that monitors translocation of specific protein components of intracellular signaling pathways within intact mammalian cells, using green fluorescent protein as a tag. A single Redistribution assay can be used to identify multiple classes of compounds that act at, or upstream of, the level of the protein target used in the primary screening assay. Such compounds may include both conventional and allosteric enzyme inhibitors, as well as protein-protein interaction modulators. We have developed a series of Redistribution assays to discover and characterize compounds that inhibit tumor necrosis factor-alpha biosynthesis via modulation of the p38 mitogen-activated protein kinase (MAPK) pathway. A primary assay was designed to identify low-molecular-weight compounds that inhibit the activation-dependent nuclear export of the p38 kinase substrate MAPK-activated protein kinase 2 (MK2). Hits from the primary screen were categorized, using secondary assays, either as direct inhibitors of MK2 nuclear export, or as inhibitors of the upstream p38 MAPK pathway. Activity profiles are presented for a nuclear export inhibitor, and a compound that structurally and functionally resembles a known p38 kinase inhibitor. These results demonstrate the utility of Redistribution technology as a pathway screening method for the identification of diverse and novel compounds that are active within therapeutically important signaling pathways.

Structural characterization of respiratory syncytial virus fusion inhibitor escape mutants: homology model of the F protein and a syncytium formation assay.

Respiratory syncytial virus (RSV) is a ubiquitous human pathogen and the leading cause of lower respiratory tract infections in infants. Infection of cells and subsequent formation of syncytia occur through membrane fusion mediated by the RSV fusion protein (RSV-F). A novel in vitro assay of recombinant RSV-F function has been devised and used to characterize a number of escape mutants for three known inhibitors of RSV-F that have been isolated. Homology modeling of the RSV-F structure has been carried out on the basis of a chimera derived from the crystal structures of the RSV-F core and a fragment from the orthologous fusion protein from Newcastle disease virus (NDV). The structure correlates well with the appearance of RSV-F in electron micrographs, and the residues identified as contributing to specific binding sites for several monoclonal antibodies are arranged in appropriate solvent-accessible clusters. The positions of the characterized resistance mutants in the model structure identify two promising regions for the design of fusion inhibitors.