Investigation of the safety and feasibility of AAV1/SERCA2a gene transfer in patients with chronic heart failure supported with a left ventricular assist device - the SERCA-LVAD TRIAL.

The SERCA-LVAD trial was a phase 2a trial assessing the safety and feasibility of delivering an adeno-associated vector 1 carrying the cardiac isoform of the sarcoplasmic reticulum calcium ATPase (AAV1/SERCA2a) to adult chronic heart failure patients implanted with a left ventricular assist device. The SERCA-LVAD trial was one of a program of AAV1/SERCA2a cardiac gene therapy trials including CUPID1, CUPID 2 and AGENT trials. Enroled subjects were randomised to receive a single intracoronary infusion of 1 × 1013 DNase-resistant AAV1/SERCA2a particles or a placebo solution in a double-blinded design, stratified by presence of neutralising antibodies to AAV. Elective endomyocardial biopsy was performed at 6 months unless the subject had undergone cardiac transplantation, with myocardial samples assessed for the presence of exogenous viral DNA from the treatment vector. Safety assessments including ELISPOT were serially performed. Although designed as a 24 subject trial, recruitment was stopped after five subjects had been randomised and received infusion due to the neutral result from the CUPID 2 trial. Here we describe the results from the 5 patients at 3 years follow up, which confirmed that viral DNA was delivered to the failing human heart in 2 patients receiving gene therapy with vector detectable at follow up endomyocardial biopsy or cardiac transplantation. Absolute levels of detectable transgene DNA were low, and no functional benefit was observed. There were no safety concerns in this small cohort. This trial identified some of the challenges of performing gene therapy trials in this LVAD patient cohort which may help guide future trial design.

Factors derived from adrenals are required for activation of cardiac gene expression in angiotensin II-induced hypertension.

The mechanisms mediating the activation of cardiac gene expression during pressure overload are not fully understood. We examined whether angiotensin II-induced activation of ventricular gene expression is related to blood pressure and ventricular mass or requires other factors by infusing angiotensin II in sham-operated and adrenalectomized rats. In sham-operated rats, angiotensin II (33 microg/kg x h, sc) produced a significant increase in mean arterial pressure (measured by telemetry) within 3 h. Mean arterial pressure (up to 45 h) and the increase in left ventricular hypertrophy in adrenalectomized rats during angiotensin II infusion were similar to those in sham-operated rats. Angiotensin II produced 3.6-fold (P < 0.01) and 20.4-fold (P < 0.001) increases in ventricular atrial natriuretic peptide mRNA levels at 12 and 72 h, respectively. Angiotensin II infusion for 12 h also significantly increased the ventricular mRNA levels of B-type natriuretic peptide (5.2-fold) and adrenomedullin (1.4-fold). Adrenalectomy either abolished (atrial natriuretic peptide and adrenomedullin) or blunted (B-type natriuretic peptide) the early activation of ventricular gene expression by angiotensin II. The baseline synthesis of atrial natriuretic peptide, B-type natriuretic peptide, and adrenomedullin in the ventricle remained unchanged in adrenalectomized rats. In conclusion, our results indicate that factors derived from the adrenals are required for angiotensin II-induced early activation of cardiac gene expression.

Distribution, metabolism and biological activity of deoxycorticosterone in the central nervous system.

Intravenously injected [1,2-3H]deoxycorticosterone (DOC) readily enters all parts of the central nervous system. In intact and eviscerated rats the highest concentration of radioactive label was recovered from areas corresponding to the reticular formation from the brain stem. In addrenalectomized animals, in addition to high brain stem concentration, there was also a marked increase in the uptake of radioactivity in the septum, hippocampus and pituitary. Data from the eviscerated rat point to a uniform distribution of [1,2-3H]DOC in neural tissues and suggest that the higher levels of radioactivity found in the brain stem may be due to a DOC metabolite with the chromatographic characteristics of allo-tetrahydro-DOC, an anaesthetic-type steroid. A decrease in the amplitude of evoked sciatic potentials in brain stem sites but not in the thalamic relay nucleus was observed in 52% of the cases studied, following the i.v. injection of 100-150 mug DOC.

[Septic arthritis associated with childhood salmonellosis]. / Gyermekkori salmonellosishoz társuló septikus arthritis.

A 4 year old girl was admitted with septic arthritis due to Salmonella panama. The treatment with antibiotics and steroids was successful. In this review the authors discuss the ethological factors, the mechanism that might cause the disease, and the possible ways of treatment, and want to point out the association of the disease with the HLA system and other predisposible factors.

[Experience with the first thousand cases of short-term postpartum hospital stay in Hungary]. / Rövid gyermekágyi ápolás elsö ezer esetének hazai tapasztalatai.

There is an international trend shortening postpartum hospital stay. While less than 2 days care initiated harsh response in the USA, questions and anxiety were provoked here by reducing puerperal hospital stay from 5-7 to 2 days. Thousand cases out of 7,277 deliveries were discharged early following appropriate education and normal pregnancy. Response from the affected patients and local doctors are discussed. Maternal and neonatal readmission rate call for careful decision making concerning early discharge. Social motivation has to enjoy priority over economic measures.