Divergent proarrhythmic potential of macrolide antibiotics despite similar QT prolongation: fast phase 3 repolarization prevents early afterdepolarizations and torsade de pointes

Macrolide antibiotics are known to have a different proarrhythmic potential in the presence of comparable QT prolongation in the surface ECG. Because the extent of QT prolongation has been used as a surrogate marker for cardiotoxicity, we aimed to study the different electrophysiological effects of the macrolide antibiotics erythromycin, clarithromycin, and azithromycin in a previously developed experimental model of proarrhythmia. In 37 Langendorff-perfused rabbit hearts, erythromycin (150-300 microM, n = 13) clarithromycin (150-300 microM, n = 13), and azithromycin (150-300 microM, n = 11) led to similar increases in QT interval and monophasic action potential (MAP) duration. In bradycardic (atrioventricular-blocked) hearts, eight simultaneously recorded epi- and endocardial MAPs demonstrated increased dispersion of repolarization in the presence of all three antibiotics. Erythromycin and clarithromycin led to early afterdepolarizations (EADs) and torsade de pointes (TdP) after lowering of potassium concentration. In the presence of azithromycin, no EAD or TdP occurred. Erythromycin and clarithromycin changed the MAP configuration to a triangular pattern, whereas azithromycin caused a rectangular pattern of MAP prolongation. In 13 additional hearts, 150 microM azithromycin was administered after previous treatment with 300 microM erythromycin and suppressed TdP provoked by erythromycin. In conclusion, macrolide antibiotics lead to similar prolongation of repolarization but show a different proarrhythmic potential (erythromycin > clarithromycin > azithromycin). In the presence of azithromycin, neither EAD nor TdP occur. This effect may be related to a rectangular pattern of action potential prolongation, whereas erythromycin and clarithromycin cause triangular action potential prolongation and induce TdP.     

Urodynamic changes induced by the intravaginal electrode during pelvic floor electrical stimulation

AIMS: The goal of this study was to evaluate whether the intravaginal electrode used to perform vaginal electrical stimulation could induce acute changes on the cystometrograms and urethral pressure profiles (UPP) recordings. METHODS: Three consecutive urodynamic examinations were performed on 30 women with stress urinary incontinence (SUI) symptoms. The first exam was performed without the electrode, the second with the electrode inserted into the vagina, but with the stimulator switched off and the third with the stimulator turned on. We used the INNOVA (Empi) stimulator with electrical parameters set at 50 Hz and 60 mA and on an intermittent cycle during the cystometries and a continuous stimulation during the UPP. The data of functional profile length (FPL), maximum urethral closure pressure (MUCP), and area of the resting UPP, as well as the filling sensations and its respective bladder volumes during the cystometries, were compared. With regard to the cystometries. RESULTS: No effect of the electrode was observed on cystometry. However, the simple presence of the electrode improved the FPL, MUCP, and areas of the UPP similar to those when the stimulation was applied. CONCLUSIONS: We conclude that, the presence of the intravaginal electrode induces changes in the UPP not related to the stimulation itself. The physiotherapeutic effect of the electrode itself is still to be evaluated.     

Priming characteristics of peptide mimotopes of carbohydrate antigens

Immunization with peptide mimetics of carbohydrate antigens can induce functional carbohydrate-reactive antibodies. Here, we examine the immune characteristics of alternative approaches in prime and boost strategies using glycosylated HIV-1 envelope protein and model tumor associated carbohydrate antigens. Our results indicate that peptide mimotopes either in a DNA or carrier-conjugated format can induce comparable levels of IgM and IgG. Carbohydrate boosting of peptide-primed animals does not affect end-point titer, however, boosting mediates a stable long lasting carbohydrate reactive IgM response, not achievable by carbohydrate immunization alone. Boosting with carbohydrate in animals primed with DNA- or peptide-conjugate, facilitates the induction of detectable IgG with a dominant IgG2a isotype. Immunization with HIV-1 envelope glycoprotein of peptide-primed animals induces different IgG isotype profiles with a dominant IgG1 antibody. We observed that HIV-1 envelope glycoprotein immunization of peptide primed mice induces a cross-reactive cellular response, as detected by cytokine secretion, which lends to IFN-gamma production upon splenocyte stimulation and CTL activity against recombinant vaccinia virus infected cells after in vitro stimulation. DNA immunization with mimotope, inclusion of a T-cell epitope from the HIV-1 envelope protein in the expression cassette and co-administration with IL-12 or GM-CSF encoding plasmids activate a cellular response to the HIV-1 envelope protein.     

Peyronie's disease: a review

PURPOSE: We provide a current review of Peyronie's disease. MATERIALS AND METHODS: We reviewed the world peer reviewed literature on the pathology, pathogenesis, diagnosis and treatment of Peyronie's disease. RESULTS: The incidence of Peyronie's disease has continuously increased during the last 30 years. However, fewer patients need prosthesis surgery as the sole treatment option because of earlier diagnosis, improved medical therapy, refinement in surgical technique and better understanding of the basic sciences of the disease. CONCLUSIONS: Currently patients with Peyronie's disease have had improvements in prognosis and experienced an expansion of the available therapeutic options.     

MRI-guided access to the retropharynx

PURPOSE: To describe MR-guided access to the retropharynx for precise fine-needle aspiration cytology (FNAC), and other indications for needle placement. MATERIALS AND METHODS: A retrospective review was made of 15 procedures that had been performed on 14 patients. These patients had a retropharyngeal mass on MRI and had undergone MR-guided minimally invasive access to the retropharynx for either diagnostic or therapeutic intervention in the period of October 1989 to January 2000. RESULTS: All 14 patients underwent MR-guided access to the retropharynx for FNAC without immediate or delayed complications. MRI confirmed that the biopsy needle was within the retropharyngeal mass in all patients. MR-guided FNAC revealed five true-positive, five true-negative, four indeterminate, and no false-positive cases. Ten of the 14 patients (71%) had diagnostic aspirations. In one patient with retropharyngeal extension of carcinoma, an MR-guided approach was used for the experimental interstitial laser therapy (ILT). CONCLUSION: The results suggest that an MR-guided retromandibular approach to biopsy of retropharyngeal mass is minimally invasive and safe.     

Biological behavior of polypropylene meshes suitable for intra-abdominal implantation in animal model

The expected incisional hernia rate is between 11-20% after laparotomy. Using mesh repair the results of the hernioplasty have recently improved. However the complication of mesh implants--especially in intraperitoneal position--can be life threatening. Additionally the appropriate mesh is expensive. We tried to create a mesh, which can be used intraperitoneally and generates adhesion in the abdominal wall, but keeps the intraabdominal organs adhesion free. Our experiments were divided into four groups. In the first we used different materials to cover the intraperitoneal side of polypropylene mesh. In the second phase three different pore-sized meshes were compared. In the third part the biological behavior of three different material-reduced meshes were investigated. Based on our previous results in the last session we used only silicone membrane protected material-reduced polypropylene meshes to cover the abdominal defects. Our experiments have shown that intraperitoneal implant with silicone-covered Vypro (Ethicon)/Premilene (B. Braun Medical) mesh significantly decreases the formations of adhesion.     

Lifetime exposure to a soluble TGF-beta antagonist protects mice against metastasis without adverse side effects

TGF-betas play diverse and complex roles in many biological processes. In tumorigenesis, they can function either as tumor suppressors or as pro-oncogenic factors, depending on the stage of the disease. We have developed transgenic mice expressing a TGF-beta antagonist of the soluble type II TGF-beta receptor:Fc fusion protein class, under the regulation of the mammary-selective MMTV-LTR promoter/enhancer. Biologically significant levels of antagonist were detectable in the serum and most tissues of this mouse line. The mice were resistant to the development of metastases at multiple organ sites when compared with wild-type controls, both in a tail vein metastasis assay using isogenic melanoma cells and in crosses with the MMTV-neu transgenic mouse model of metastatic breast cancer. Importantly, metastasis from endogenous mammary tumors was suppressed without any enhancement of primary tumorigenesis. Furthermore, aged transgenic mice did not exhibit the severe pathology characteristic of TGF-beta null mice, despite lifetime exposure to the antagonist. The data suggest that in vivo the antagonist may selectively neutralize the undesirable TGF-beta associated with metastasis, while sparing the regulatory roles of TGF-betas in normal tissues. Thus this soluble TGF-beta antagonist has potential for long-term clinical use in the prevention of metastasis.     

Resection of abdominal solid organs using high-intensity focused ultrasound

Our objective was to evaluate high-intensity focused ultrasound (HIFU) for minimizing blood loss during surgery by hemodynamically isolating large portions of solid organs before their resection. A high-power HIFU device (in situ intensity of 9000 W/cm(2), frequency of 3.3 MHz) was used to produce a wall of cautery for sealing of blood vessels along the resection line in surgically exposed solid organs (liver lobes, spleen and kidneys) of eight adult pigs. Following HIFU application, the distal portion of the organ was excised using a scalpel. If any blood vessels were still bleeding, additional HIFU application was used to stop the bleeding. The resection was achieved in 6.0 +/- 1.5 min (liver), 3.6 +/- 1.1 min (spleen) and 2.8 +/- 0.6 min (kidneys) of HIFU treatment time, with no occurrence of bleeding for up to 4 h (until sacrifice). The coagulated region at the resection line had average width of 3 cm and extended through the whole thickness of the organ (up to 4 cm). Blood vessels of up to 1 cm in size were occluded. This method holds promise for future clinical applications in resection of solid tumors and hemorrhage control from high-grade organ injuries.