VT ablation based on CT imaging substrate visualization: results from a large cohort of ischemic and non-ischemic cardiomyopathy patients.

INTRODUCTION: The eradication of ventricular tachycardia (VT) isthmus sites constitutes the minimal procedural endpoint for VT ablation procedures. Contemporary high-resolution computed tomography (CT) imaging, in combination with computer-assisted analysis and segmentation of CT data, facilitates targeted elimination of VT isthmi. In this context, inHEART offers digitally rendered three-dimensional (3D) cardiac models which allow preoperative planning for VT ablations in ischemic and non-ischemic cardiomyopathies. To date, almost no data have been collected to compare the outcomes of VT ablations utilizing inHEART with those of traditional ablation approaches. METHODS: The presented data are derived from a retrospective analysis of n = 108 patients, with one cohort undergoing VT ablation aided by late-enhancement CT and subsequent analysis and segmentation by inHEART, while the other cohort received ablation through conventional methods like substrate mapping and activation mapping. The ablations were executed utilizing a 3D mapping system (Carto3), with the mapping generated via the CARTO® PENTARAY™ NAV catheter and subsequently merged with the inHEART model, if available. RESULTS: Results showed more successful outcome of ablations for the inHEART group with lower VT recurrence (27% vs. 42%, p < 0.06). Subsequent analyses revealed that patients with ischemic cardiomyopathies appeared to derive a significant benefit from inHEART-assisted VT ablation procedures, with a higher rate of successful ablation (p = 0.05). CONCLUSION: Our findings indicate that inHEART-guided ablation is associated with reduced VT recurrence compared to conventional procedures. This suggests that employing advanced imaging and computational modeling in VT ablation may be valuable for VT recurrences.

Temperature-controlled high-power short-duration ablation with 90 W for 4 s: outcome, safety, biophysical characteristics and cranial MRI findings in patients undergoing pulmonary vein isolation.

BACKGROUND: High-power short-duration (HPSD) radiofrequency ablation (RFA) is highly efficient and safe while reducing procedure and RF time in pulmonary vein isolation (PVI). The QDot™ catheter is a novel contact force ablation catheter that allows automated flow and power adjustments depending on the local tissue temperature to maintain a target temperature during 90 W/4 s lesions. We analysed intraprocedural data and periprocedural safety using the QDot-catheter in patients undergoing PVI for paroxysmal atrial fibrillation (PAF). METHODS: We included n = 48 patients undergoing PVI with the QDot-catheter with a temperature-controlled HPSD ablation mode with 90 W/4 s (TC-HPSD). If focal reconnection occurred besides repeat ablation, the ablation mode was changed to 50 W/15 s (QMode). N = 23 patients underwent cerebral MRI to detect silent cerebral lesions. RESULTS: Mean RF time was 8.1 ± 2.8 min, and procedure duration was 84.5 ± 30 min. The overall maximal measured catheter tip temperature was 52.0 °C ± 4.6 °C, mean overall applied current was 871 mA ± 44 mA and overall applied energy was 316 J ± 47 J. The mean local impedance drop was 12.1 ± 2.4 Ohms. During adenosine challenge, n = 14 (29%) patients showed dormant conduction. A total of n = 24 steam pops were detected in n = 18 patients (39.1%), while no pericardial tamponade occurred. No periprocedural thromboembolic complications occurred, while n = 4 patients (17.4%) showed silent cerebral lesion. CONCLUSIONS: TC-HPSD ablation with 90 W/4 s using the QDot-catheter led to a reduction of procedure and RF time, while no major complications occurred. Despite optimized temperature control and power adjustment, steam pops occurred in a rather high number of patients, while none of them leads to tamponade or to clinical or neurological deficits.

[The authorization of clinical trials by the federal authorities]. / Das Genehmigungsverfahren klinischer Prüfungen von Arzneimitteln bei den Bundesoberbehörden.

Since 2004, clinical trials of medicinal products have to be approved by the federal authorities in Germany. Authorization is necessary in addition to the favorable opinion of the concerned ethics committee. This procedure has undoubtedly resulted in larger expenditures with respect to time and costs of planning and conducting of clinical trials. However, the implementation of Good Clinical Practice has also increased both safety for the trial subjects and validity of the data. The most important laws and regulations, definitions, the procedures for submitting a clinical trial application as well as subsequent amendments are described and further information is provided.

[The community clinical trial system EudraCT at the EMEA for the monitoring of clinical trials in Europe]. / Die EudraCT-Datenbank bei der EMEA zur Erfassung klinischer Prüfungen in Europa.

The GCP-Directive 2001/20/EG has been implemented in Germany by the 12th Amendment to the Drug Law of 6 August 2004 and the GCP-Ordinance of 9 August 2004, introducing new regulations for performing clinical trials. The information and documentation requested by the GCP-Ordinance to apply for the approval of a clinical trial can be partially prepared by using the EudraCT database. Crucial administrative and scientific information on a clinical trial is presented by the applicant to the EU member states in a harmonized manner. After the implementation of the data into the Community Clinical Trial Database System for member states, the clinical trials performed in some member states become comprehensible for the whole of the community. This increased transparency of planned, ongoing or finalized clinical trials will be an advantage for the safety of the participants.

[Approval of clinical trials of immunobiological medicinal products at the Paul Ehrlich Institute]. / Genehmigung der klinischen Prüfung immunbiologischer Arzneimittel am Paul-Ehrlich-Institut.

The GCP Directive 2001/20/EG has been implemented in Germany by the 12th Law Amending the Drug Law of 6 August 2004, thereby introducing new regulations for the performance of clinical trials. The amount of the required documentation has increased, but the assessment and the approval of clinical trials as well as scientific advice procedures (national or by the EMEA) allow the early discussion of many details of the development and the non-clinical and clinical testing of the medicinal product with the experts of the Paul Ehrlich Institute (PEI). This might shorten the times required for later marketing authorisation procedures. To facilitate these new tasks, the PEI has created a new central section "Approval of Clinical Trials", which is responsible for the assessment of the clinical trial applications and will coordinate the procedures within the institute. The main topics of clinical trial applications and the particularities of biological/biotechnological medicinal products such as allergens, blood products, vaccines, sera/mAb and products for cell and gene therapy as well as the differences from chemically defined products are discussed.

The role of NF-Y and IRF-2 in the regulation of human IL-4 gene expression.

Activity of the IL-4 promoter was shown to be regulated by multiple cis-acting elements. In this study, two additional regulatory elements, a CCAAT element and a 15-nucleotide element homologous to the IFN- and virus-stimulation response element (ISRE), were identified in the human promoter region at -195 to -172. The ISRE-homologous sequence was shown to interact with two nuclear proteins, IRF-2, a transcriptional repressor of the IFN genes, and an NF-1-like factor. Mutations of the ISRE site increased overall IL-4 promoter activity twofold, suggesting a possible negative role of IRF-2 in the regulation of IL-4 transcription. The CCAAT element was found to interact with NF-Y, a nuclear factor essential for expression of MHC class II genes. Mutations of the CCAAT element at -195 to -172 resulted in a substantial decrease of IL-4 promoter activity. Furthermore, NF-Y was also found to bind to the previously described NF-ATp binding site of the IL-4 promoter (-79 to -62, originally described as "P element"), and the previously described P-binding complex NF-P was shown to contain NF-Y. These findings suggest that NF-Y may play an important role in the regulation of IL-4 gene expression.

A novel enhancer element in the human IL-4 promoter is suppressed by a position-independent silencer.

IL-4 is a pleiotropic cytokine that regulates T cell-dependent immune responses. We identified and characterized a novel enhancer, positive regulatory element I (PRE-I), in the 5' region of the promoter of the human IL-4 gene. The functional core element of PRE-I is -239GTGTAATTTCCTATGC-224. Two novel nuclear proteins, POS-1 and POS-2, were found to specifically bind to the core element and function as transcriptional activators. The function of PRE-I did not require T cell stimulation and was not restricted to T cells. However, mutations in the core element of PRE-I significantly reduced the promoter activity and completely impaired inducibility of the promoter. In the human IL-4 promoter the enhancer function of PRE-I is strongly suppressed. A negative regulatory element (NRE), 45 bp upstream of PRE-I, directly represses PRE-I enhancer activity. Repression of PRE-I by NRE does not require a particular order or arrangement of positive and negative regulatory sequences. The IL-4 NRE may also down-regulate other enhancers, such as the murine sarcoma virus and the SV40 enhancers. Thus, the IL-4 NRE may represent a new type of cis regulatory element that carries the properties of a silencer but down-regulates enhancer instead of basal promoter activity.

Variation of amino acid concentrations in the medium of HU ß-IFN and HU IL-2 producing cell lines.

There are different requirements for the nutrient medium of various mammalian cell lines. We have determined the behaviour of the amino acid concentrations in the medium of two growing cell lines used for producing human interleukin 2 and human interferon ß constitutively. The experiments are based on a fermentation process with a bubble free cell culture aeration system with porous moving membranes, which allows production of high cell densities without foaming. We found interesting alterations in which the actual amino acid ratios are able to trigger consumption and production of a particular component depending on the supply of other possible replacements. Such data indicate the complicated biochemical network of synthesis, conversion and transport phenomena. Finally, we demonstrated the influence of product synthesis upon the amino acid requirements using as an example transformed hu IL-2- and hu ß-IFN-producing mouse L-cells.

Production of human beta-interferon in mouse L-cells.

Mouse L-cells, producing glycosilated human beta-interferon constitutively, were cultivated on microcarriers in bioreactors, equipped with a bubble-free aeration system up to 22 1 scale. Suitable aeration membrane surfaces and medium exchange rates permitted cultivation up to 8 X 10(6) cells/ml with a specific beta-interferon productivity of 2 X 10(4) U/10(6) cells/day. A correlation was found between the number of cell layers on the microcarriers and the specific human beta-interferon productivity.