Eight-year follow-up after prospectively randomized implantation of different mechanical aortic valves

Objective  The aim of this prospectively randomized study was to evaluate the hemodynamic and functional outcomes after aortic valve replacement with three different bileaflet mechanical valves. Methods  From March 1996 to August 1998, 300 consecutive patients were randomly assigned to receive ATS (n = 100), Carbomedics (n = 100), or St Jude Medical Hemodynamic Plus (n = 100) mechanical aortic valve replacement. There were no significant differences regarding patient age (61 ± 8 years), gender, NYHA, aortic valve pathology, ventricular morphology, ejection fraction and requirement for additional procedures at implant. Mean follow-up extends to 95 ± 21 months at a total of 2,891 patients years and is in 95.3% complete. Results  Implanted valve sizes were comparable at 24 ± 2 mm (ATS), 23.7 ± 1.6 mm (CM), and 23.6 ± 1.9 mm (SJMHP) (NS). Follow-up results were: transvalvular flow velocities 2.3/2.3/2.2 m/s, ejection fraction 64/59/63%, trivial transvalvular incompetence 3/3/2; paravalvular leak 2/3/2; freedom of reoperation 100/99/99%, NYHA functional status 1.5/1.8/1.6, overall survival 86.4/82.8/80.6%, freedom from thrombembolic events 100/96/98%, freedom from hemorrhage 100/100/99%, freedom from all valve related events was 100/96/98%; respectively (NS). There were no episodes of endocarditis. Ninety-four percent of the patients were satisfied with the procedure enjoying an enhanced daily life activity. Conclusions  There are no clinically relevant differences among the tested bileaflet aortic valves. Regardless of valve type, there was a rather low complication rate in this relatively young population. All three bileaflet prostheses are well suited for aortic valve replacement.     

Bone marrow stem cell-based gene transfer in a mouse model for metachromatic leukodystrophy: effects on visceral and nervous system disease manifestations

Arylsulfatase A (ASA) knockout mice represent an animal model for the lysosomal storage disease metachromatic leukodystrophy (MLD). Stem cell gene therapy with bone marrow overexpressing the human ASA cDNA from a retroviral vector resulted in the expression of high enzyme levels in various tissues. Treatment partially reduces sulfatide storage in livers exceeding 18 ng ASA/mg tissue, while complete reduction was observed in livers exceeding 50 ng ASA/mg tissue. This corresponds to about 80% and 200% of normal enzyme activity. Similar values seem to apply for kidney. A partial correction of the lipid metabolism was detectable in the brain where the galactoerebroside/sulfatide ratio, which is diminished in ASA-deficient mice, increased upon treatment. This partial correction was accompanied by amelioration of neuropathology; axonal cross-sectional areas, which are reduced in deficient mice, were significantly increased in the saphenic and sciatic nerve but not in the optic nerve. Behavioral tests suggest some improvement of neuromotor abilities. The gene transfer did not delay the degeneration occurring in the acoustic ganglion of ASA-deficient animals. The limited success of the therapy appears to be due to the requirement of unexpected high levels of ASA for correction of the metabolic defect.     

Erfolgreiche Epilepsiechirurgie bei seit über 20 Jahren therapierefraktärer Temporallappenepilepsie und multiplen Voreingriffen

Epilepsy is a common chronic neurological disease and represents a significant burden for patients and their families. We present a case of a patient, who had a pharmacoresistant epilepsy for more than 20 years and several previous surgeries. He achieved long lasting seizure freedom after an epilepsy surgery. The case illustrates that pharmacoresistant epilepsy should prompt presurgical evaluation in order to influence the course of the illness and to attenuate social consequences.     

Selective transduction of malignant glioma by lentiviral vectors pseudotyped with lymphocytic choriomeningitis virus glycoproteins

Malignant gliomas are the most frequent primary brain tumors and have a dismal prognosis due to their infiltrative growth. Gene therapy using viral vectors represents an attractive alternative to conventional cancer therapies. In a previous study, we established lentiviral vectors pseudotyped with lymphocytic choriomeningitis virus (LCMV) glycoproteins (GPs) and demonstrated transduction of human malignant glioma cells in culture. In the current approach, we compared the transduction efficacy of LCMV-GP- and vesicular stomatitis virus glycoprotein (VSV-G)-pseudotyped lentiviral vectors for malignant glioma cells and normal brain cells in vitro and in vivo. LCMV-GP pseudotypes transduced almost exclusively astrocytes, whereas VSV-G pseudotypes infected neurons as well as astrocytes. LCMV-GP pseudotypes showed an efficient transduction of solid glioma parts and specific transduction of infiltrating tumor cells. In contrast, VSV-G-pseudotyped lentiviral vectors transduced only a few tumor cells in solid tumor parts and infected mostly normal brain cells in infiltrating tumor areas. In conclusion, lentiviral vectors pseudotyped with LCMV glycoproteins represent an attractive option for gene therapy of malignant glioma.     

In vitro fabrication of autologous living tissue‐engineered vascular grafts based on prenatally harvested ovine amniotic fluid‐derived stem cells

Amniotic fluid cells (AFCs) have been proposed as a valuable source for tissue engineering and regenerative medicine. However, before clinical implementation, rigorous evaluation of this cell source in clinically relevant animal models accepted by regulatory authorities is indispensable. Today, the ovine model represents one of the most accepted preclinical animal models, in particular for cardiovascular applications. Here, we investigate the isolation and use of autologous ovine AFCs as cell source for cardiovascular tissue engineering applications. Fetal fluids were aspirated in vivo from pregnant ewes (n = 9) and from explanted uteri post mortem at different gestational ages (n = 91). Amniotic non‐allantoic fluid nature was evaluated biochemically and in vivo samples were compared with post mortem reference samples. Isolated cells revealed an immunohistochemical phenotype similar to ovine bone marrow‐derived mesenchymal stem cells (MSCs) and showed expression of stem cell factors described for embryonic stem cells, such as NANOG and STAT‐3. Isolated ovine amniotic fluid‐derived MSCs were screened for numeric chromosomal aberrations and successfully differentiated into several mesodermal phenotypes. Myofibroblastic ovine AFC lineages were then successfully used for the in vitro fabrication of small‐ and large‐diameter tissue‐engineered vascular grafts (n = 10) and cardiovascular patches (n = 34), laying the foundation for the use of this relevant pre‐clinical in vivo assessment model for future amniotic fluid cell‐based therapeutic applications. Copyright © 2013 John Wiley & Sons, Ltd.     

Comparison of microarray-based RNA expression with ELISA-based protein determination of HER2, uPA and PAI-1 in tumour tissue of patients with breast cancer and relation to outcome

Purpose  

Prognostic and predictive markers in breast cancer are currently determined by single analysis of protein amounts. If RNA-based multi-gene analyses enter clinical practice, simultaneous determination of currently established markers like human epidermal growth factor receptor 2 (HER2), urokinase plasminogen activator (uPA) and its inhibitor (PAI-1) would represent an elegant simplification. To investigate the correlation between RNA and protein levels, we assessed HER2, uPA and PAI-1 in patients with breast cancer. In addition, we evaluated the influence of these factors on patient outcome.     

From Serendipity to Mitochondria-Targeted Nanocarriers

This review illustrates how a random observation at the laboratory bench has helped pave the way towards the development of organelle-targeted pharmaceutical nanocarriers. A fortuitous discovery in the mid 1990s involving the self-assembly of a molecule, known to accumulate inside mitochondria, has lead to the development of subcellular nanocarriers suited for the selective delivery of biologically active molecules to mitochondria inside living mammalian cells. Applications for mitochondria-specific drug and DNA delivery are described, the current state-of-the-art of mitochondrial drug targeting technology is reviewed, and its future perspectives are discussed.