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Biomedical subjects

A Auricchio

Publications and source records attributed to A Auricchio.

At least 19 recordsLinked to original sources
PubMed2006

Volume measurement by CARTO compared with cardiac magnetic resonance.

AIMS: The CARTO electrophysiological mapping system has demonstrated accurate results for end-diastolic ventricular volumes in casts and animals. However, in humans, a comparison with cardiac magnetic resonance (CMR), the non-invasive gold standard for volumetric analysis, has not yet been performed. METHODS AND RESULTS: A total of 34 (29 male) heart failure patients (NYHA class III/IV) underwent an electrophysiological mapping procedure with the CARTO system in the left ventricle (LV) (n = 34) and right ventricle (RV) (n = 12) and CMR for RV and LV end-diastolic volume (RVEDV and LVEDV) measurements another day. Mean LVEDV was comparable between CMR and CARTO (328 +/- 95 and 320 +/- 92 mL, respectively; P = NS), whereas RV volumes measured by CARTO were larger (CMR 140 +/- 48 vs. CARTO 176 +/- 47 mL; P < 0.01). Overall, we found a good correlation between CMR and CARTO measurements for both chambers; however, the Bland-Altman analysis showed a non-interchangeability of these methods. Measurement differences were independent of chamber size, but significantly affected by the number of acquired mapping points. CONCLUSION: Although CMR and CARTO showed a good correlation in the measurement of RVEDV and LVEDV in a group of heart failure patients, the clinical interchangeability of the two methods may be questioned.

Electrophysiologic Techniques, Cardiac↗
PubMed2005

Replacement of a severe chronic post-traumatic aneurysm of the ascending aorta with aortic valve conduit--reconstruction of the anterior mitral valve ring and implantation of A-V sequential/biventricular pacemaker.

We present the case of a 23-year-old African professional footballer who was admitted on April 1, 1999 to the Cardiology Department of the University Hospital in Magdeburg, on an emergency basis, from a regional lung clinic. According to the history, he was involved in a collision with an opposing player during a football match in his country (in Africa). He lost consciousness for a short time, but continued playing to the end of the match. About two months later he was invited by a German football club for a check-up, with the view to ultimately playing for the club. The team did not find him physically fit enough to play professional football, so he decided to go to Paris by bus on March 31, 1999. During the journey he suddenly became cardio-pulmonary decompensated and had to undergo cardio-pulmonary resuscitation (CPR). He was intubated and placed on a respirator and immediately transferred to a nearby lung clinic. From the lung clinic he was transferred to the Intensive Care Unit of the Cardiology Department of the Magdeburg University Hospital, on April 1, 1999 as an emergency case. He was intensively treated with catecholamines, intravenous ACE inhibitors and diuretics. His clinical condition did not improve appreciably. His chest X-ray showed extreme dilatation of the right and left heart as well as extreme pulmonary congestion.

Adult↗
PubMed2003

Efficient trans-splicing in the retina expands the utility of adeno-associated virus as a vector for gene therapy.

Recombinant vectors based on adeno-associated virus (AAV) can efficiently transduce many different cell types, including cells of the retina, resulting in stable gene expression. A major shortcoming of this vector is its small packaging capacity. A trans-splicing approach, which reconstitutes gene expression from two independent AAV vectors, can be used to overcome the vector's packaging limitations. The efficiency of this system to date has been disappointing, and therefore its utility for therapeutic application limited. We demonstrate here that efficiency and cellular specificity of trans-splicing is dependent on selection of the appropriate AAV serotype. Efficiency of transgene expression resulting from trans-splicing in skeletal muscle approaches that obtained when delivering the intact transgene when using AAV2 vectors packaged with AAV5 capsids (AAV2/5). This expands the potential of AAV vectors for retinal gene therapy. The use of AAV2/5 also increases the efficiency of trans-splicing in photoreceptors. Selection of the appropriate AAV serotype is likely to affect efficiency of trans-splicing in other organ systems as well.

Animals↗
PubMed2002

Constitutive and regulated expression of processed insulin following in vivo hepatic gene transfer.

To test whether hepatocytes engineered in vivo can serve as surrogate beta cells by similarly secreting mature insulin in a glucose-sensitive manner, we prepared adenoviral vectors encoding wild-type proinsulin (hIns-wt), a modified proinsulin cleavable by the ubiquitously expressed protease furin (hIns-M3), or each of the two beta cell specific pro-insulin convertases PC2 and PC3. Following a detailed in vitro characterization of the proteins produced by our vectors, we infected the liver and, for comparison, the muscle of a chemically induced murine model of type I diabetes. Insulin expression from the transduced tissues was extensively characterized and showed to be constitutive rather than regulated. To obtain regulated expression, we placed expression of hIns-M3 under the control of the dimerizer-inducible transcription system. Hormone secretion from mouse liver was negligible in the absence of the dimerizer drug rapamycin, was inducible in a dose-dependent manner upon its administration, and reversible following drug withdrawal. These data confirm liver as a promising target for in vivo expression of processed insulin. While suggesting that hepatocytes cannot provide authentic glucose-responsive regulation, these results demonstrate that pharmacological regulation is a promising alternative route to the controlled delivery of insulin following hepatic gene transfer.

Adenoviridae↗
PubMed2001

Effect of resynchronization therapy stimulation site on the systolic function of heart failure patients.

BACKGROUND: Cardiac resynchronization therapy (CRT) improves systolic function in heart failure patients with ventricular conduction delay by stimulating the left ventricle (LV) or both ventricles (biventricular, BV). Optimal LV site selection is of major clinical interest for CRT device implantation; however, the dependence of hemodynamics on LV stimulation site has not been established. Thus, the objective of this study was to compare the hemodynamic response to CRT for 2 LV coronary vein sites: the free wall and anterior wall. Methods and Results- A total of 30 patients (mean NYHA class, 2.7; mean QRS interval, 152 ms; mean PR interval, 194 ms) enrolled in the PATH-CHF-II trial were studied. CRT was administered with LV and BV stimulation in VDD mode at 4 AV delays. LV stimulation was at the lateral free wall or anterior wall, whereas right ventricular stimulation was fixed near the apex. LV+dP/dt(max) and aortic pulse pressure changes from baseline during CRT were compared for LV sites. Free wall sites with LV and BV stimulation yielded significantly larger LV+dP/dt(max) (14% versus 6%, P<0.001 for LV; 12% versus 5%, P<0.001 for BV) and pulse pressure (8% versus 4%, P<0.001 for LV; 9% versus 5%, P<0.001 for BV) compared with anterior sites. In one third of patients, CRT at free wall sites increased LV+dP/dt(max), whereas it decreased at anterior sites over most AV delays. CONCLUSION: CRT with LV free wall stimulation produced significantly better LV systolic performance compared with anterior stimulation. Further studies are warranted to prove the clinical superiority of the LV free wall as a site for long-term CRT.

Aged↗
PubMed2001

Exchange of surface proteins impacts on viral vector cellular specificity and transduction characteristics: the retina as a model.

Recombinant vectors based on adeno-associated virus (AAV) or human immunodeficiency 1 (lentivirus) are promising tools for long term in vivo gene delivery. Their design allows the exchange of capsids or envelopes, respectively, theoretically providing the opportunity to transduce a range of cell types. We constructed AAV vectors encoding enhanced green fluorescent protein (EGFP) within an AAV serotype 2 (AAV2) genome contained in an AAV2, five or one capsid (called AAV2/2, AAV2/5 and AAV2/1, respectively). Similarly we produced lentiviral vectors, encoding the same expression cassette present in the AAV vectors, pseudotyped with proteins from vesicular stomatitis virus glycoprotein (VSVG) or Mokola envelopes. Transduction characteristics of these vectors were evaluated in the murine retina following subretinal or intravitreal administration. The time of onset of transgene expression and the targeted cell types differed between the various recombinants. Onset of transgene expression was 3-4 days for lentiviral vectors and AAV2/1. In contrast, onset was at 2-4 weeks for AAV2/5 and AAV2/2, respectively. After subretinal injection, both lenti-VSVG and AAV2/5 transduced the retinal pigment epithelium (RPE) and photoreceptors efficiently whereas transgene expression was restricted to RPE cells using lenti with the Mokola envelope or AAV2/1. After intravitreal administration, only AAV2/2 and lenti-VSVG transduced the inner retina. Vector-mediated fluorescence was detected in the retina for over 12 weeks for all of the vectors. We conclude that pseudotyping provides a useful means to manipulate viral vector cell targeting specificity as well as retinal transduction characteristics of vectors containing the same genome.

Animals↗
PubMed2001

In vivo detection of gene expression in liver by 31P nuclear magnetic resonance spectroscopy employing creatine kinase as a marker gene.

In vivo assessment of gene expression is desirable to obtain information on the extent and duration of transduction of tissue after gene delivery. We have developed an in vivo, potentially noninvasive, method for detecting virally mediated gene transfer to the liver. The method employs an adenoviral vector carrying the gene for the brain isozyme of murine creatine kinase (CK-B), an ATP-buffering enzyme expressed mainly in muscle and brain but absent from liver, kidney, and pancreas. Gene expression was monitored by (31)P magnetic resonance spectroscopy (MRS) using the product of the CK enzymatic reaction, phosphocreatine, as an indicator of transfection. The vector was administered into nude mice by tail vein injection, and exogenous creatine was administered in the drinking water and by i.p. injection of 2% creatine solution before (31)P MRS examination, which was performed on surgically exposed livers. A phosphocreatine resonance was detected in livers of mice injected with the vector and was absent from livers of control animals. CK expression was confirmed in the injected animals by Western blot analysis, enzymatic assays, and immunofluorescence measurements. We conclude that the syngeneic enzyme CK can be used as a marker gene for in vivo monitoring of gene expression after virally mediated gene transfer to the liver.

Adenoviridae↗
PubMed2001

Isolation of highly infectious and pure adeno-associated virus type 2 vectors with a single-step gravity-flow column.

One of the most promising gene transfer vectors in human clinical trials is AAV2. The quality of the vector preparations is a key element in obtaining reliable and reproducible data in preclinical studies. However, established protocols either result in impure, low infectious virus (CsCl2 gradient centrifugation) or demand a high level of manual and technical skills (CsCl2 gradient centrifugation, iodixanol/heparin or HPLC purification). In this study, we present an easy-to-do single-step column purification (SSCP) of AAV2 by gravity flow based on its affinity to heparin, without ultracentrifugation. Various vector preparations generated by our method reproducibly showed high titers, infectivity, and purity. In vivo, our single-step column-purified AAV2 vectors mediate significantly higher transduction efficiency compared with conventional protocols. Investigators still unsatisfied with previously published techniques or new to the field of AAV production may find in our method an interesting alternative.

Animals↗
PubMed2001

[Pacing therapies for congestive heart failure considering the results of the PATH-CHF study].

Optimized uni- or biventricular pacing therapy improves left ventricular function in 80% of patients (responders) with wide QRS in surface ECG. Immediate improvement could be shown by an increase of LV dP/dt up to 28% and aortic pulse pressure up to 16%. Chronic improvement was documented by prolongation of the 6-minute-walk-test by 60 meters, an improvement of O2 uptake by 23% at exercise, and improvement of quality of life score and NYHA classification. This controlled study has shown for the first time a significant clinical improvement of congestive heart failure by pacing therapy in a selected group of patients. Conventional right ventricular stimulation is insufficient in this group of patients characterized by LBBB. These results support the hypothesis that optimized ventricular stimulation is an effective chronic therapy of congestive heart failure by improvement of left ventricular hemodynamics. Epicardial placement of the left ventricular electrodes in 50 patients was possible without operative and with low (2%) early mortality.

Aged↗
PubMed2001

Impact of cardiac resynchronization therapy using hemodynamically optimized pacing on left ventricular remodeling in patients with congestive heart failure and ventricular conduction disturbances.

OBJECTIVES: We sought to investigate the impact of six months of cardiac resynchronization therapy (CRT) on echocardiographic variables of left ventricular (LV) function. BACKGROUND: Cardiac resynchronization therapy has recently been introduced as a new therapeutic modality in patients with advanced heart failure (HF) and conduction abnormalities. However, most studies have only investigated the early hemodynamic effects of CRT. METHODS: Twenty-five patients (12 women and 13 men; 59.8 +/- 5.1 years old) with advanced HF caused by ischemic (n = 7) or idiopathic dilated cardiomyopathy (n = 18) and a prolonged QRS complex were analyzed. All patients underwent early hemodynamic testing with a randomized testing protocol; echocardiographic measurements were compared before implantation and after six months of CRT. RESULTS: Left ventricular end-diastolic and end-systolic diameters (LVEDD and LVESD, respectively) were significantly reduced after six months (LVEDD from 71 +/- 10 to 68 +/- 11 mm, p = 0.027; LVESD from 63 +/- 11 to 58 +/- 11 mm, p = 0.007), as were LV end-diastolic and end-systolic volumes (LVEDV from 253 +/- 83 to 227 +/- 112 ml, p = 0.017; LVESV from 202 +/- 79 to 174 +/- 101 ml, p = 0.009). Ejection fraction was significantly increased (from 22 +/- 7% to 26 +/- 9%, p = 0.03). "Nonresponders," with regard to LV volume reduction, had significantly higher baseline LVEDV, compared with "responders" (351 +/- 52 vs. 234 +/- 74 ml, p = 0.018). Overall, there was only mild mitral regurgitation at baseline, with a minor reduction by semiquantitative analysis. The results of early hemodynamic testing did not predict the volume response. CONCLUSIONS: Cardiac resynchronization therapy may lead to a reduction in LV volumes in patients with advanced HF and conduction disturbances. Volume nonresponders have significantly higher baseline LVEDV.

Aged↗
PubMed2001

Pharmacologically regulated gene expression in the retina following transduction with viral vectors.

The availability of inducible expression systems makes regulatable control of therapeutic proteins an attainable goal in gene therapy. We delivered tetracycline-inducible transgenes to the subretinal space using recombinant adenoviruses. Upon administration of doxycycline, we demonstrated reversible expression of green fluorescent protein in the retinal pigment epithelium as well as modulation of human growth hormone produced in the retina and secreted in the blood stream. This mode of delivery and regulation offers a unique way to evaluate gene function in the eye and represents a novel method for introducing therapeutic proteins into the retina.

Adenoviridae↗
PubMed2001

Adenoviral vector-mediated insulin gene transfer in the mouse pancreas corrects streptozotocin-induced hyperglycemia.

Therapy for type 1 diabetes consists of tight blood glucose (BG) control to minimize complications. Current treatment relies on multiple insulin injections or an insulin pump placement, beta-cell or whole pancreas transplantation. All approaches have significant limitations and have led to the realization that novel treatment strategies are needed. Pancreatic acinar cells have features that make them a good target for insulin gene transfer. They are not subject to autoimmune attack, a problem with pancreas or islets transplantation, they are avidly transduced by recombinant adenoviral vectors, and capable of exporting a variety of peptides into the portal circulation. Recombinant adenoviral vectors were engineered to express either wild-type or furin-modified human insulin cDNA (AdCMVhInsM). Immunodeficient mice were made diabetic with streptozotocin and injected intrapancreatically with the vectors. BG and blood insulin levels have normalized after administration of AdCMVhInsM. Immunohistochemistry and electron microscopy showed the presence of insulin in acinar cells throughout the pancreas and localization of insulin molecules to acinar cell vesicles. The data clearly establish a relationship between intrapancreatic vector administration, decreased BG and elevated blood insulin levels. The findings support the use of pancreatic acinar cells to express and secrete insulin into the blood stream.

Adenoviridae↗
PubMed2001

Stimulation of the left ventricle through the coronary sinus with a newly developed 'over the wire' lead system--early experiences with lead handling and positioning.

AIMS: This report describes the initial clinical results with a newly designed guiding catheter and an 'over the wire' pacing lead based on angiolasty technology to stimulate the left ventricle using the transvenous route via the coronary sinus (OTW-CV lead). METHODS AND RESULTS: In 75% of the 15 patients (6 males, 9 females, mean age of 53 +/- 9 years) with congestive heart failure, access to coronary sinus required less than 2 min; in one patient. the attempt failed. Mean R wave amplitudes plus or minus the standard deviation, measured at apical, mid-ventricular and basal positions the anterior (11.4 +/- 9.2, 10.8 +/- 6.2, 9.3 +/- 6.3 mV) and lateral or posterior veins (10.1 +/- 10.7, 8.6 +/- 6.4, 7.7 +/- 4.3 mV) showed a trend favouring the apex without statistical significance. Pacing impedance, measured at the same sites and vein tributaries, ranged from 670 +/- 191 to 915 +/- 145 ohms. Pacing thresholds measured at apical and mid ventricular sites were significantly lower than at the base in the anterior vein 2.5 +/- 2.8 and 2.8 +/- 1.8 vs 5.6 +/- 2.7 V at 0.5 ms, P<0.001). Thresholds in the lateral/posterior veins showed a similar trend but did not reach statistical significance (3.0 +/- 1.7, 3.6 +/- 1.4 +/- 1.8 V at 0.5 ms). In patients, in whom thresholds were determined in more than one vein, the 'best' mean threshold was 1.6 +/- 0.7 V. CONCLUSION: The new 'over the wire' lead and guiding catheter system allows uncomplicated access to the coronary sinus and the depth of the coronary vein tributaries. Left ventricular sensing and pacing thresholds are acceptable for chronic use in implanted cardiac rhythm management systems.

Adult↗
PubMed2001

Hybrid vectors based on adeno-associated virus serotypes 2 and 5 for muscle-directed gene transfer.

Vectors based on hybrids consisting of adeno-associated virus types 2 (ITRs and Rep) and 5 (Cap) were evaluated for muscle-directed gene transfer (called AAV2/5). Evaluation in immune-competent mice revealed greater transduction efficacy with AAV2/5 than with AAV2 and no cross-neutralization between AAV2/5 and AAV2. Interestingly, we saw no immunologic evidence of previous exposure to AAV5 capsids in a large population of healthy human subjects.

Animals↗