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Purpose Gene therapy is a promising option for heart failure patients, but there remains a lack of effective delivery mechanisms. The Impella device is a heart pump that can increase coronary flow and pressure, important factors that determines efficacy of gene transduction when using intracoronary delivery. Because it also lends hemodynamic support, the Impella can be coupled with balloon coronary occlusion to increase cardiac vector dwell time. We hypothesized that use of the Impella offers safe and efficient delivery of genes using intracoronary administration of adeno-associated viral (AAV)-6. Methods AAV6 encoding luciferase gene (5.0 × 10E13) was injected into the coronary artery one week after MI induction in Yorkshire pigs. A total of twelve pigs were allocated to one of the following groups: slow antegrade delivery (n=3), slow antegrade delivery with Impella (n=3), delivery during coronary artery occlusion with Impella hemodynamic support (n=3), delivery during coronary artery and sinus occlusions with Impella hemodynamic support (CA + CS, n=3), Four weeks later, tissues were harvested from various heart regions and other organs to assess luciferase expression and viral uptake. Results Impella support offered safe vector delivery during 1-2 minutes of CA and CS occlusion. Impella + coronary artery block enhanced luciferase expression globally in the heart but not in non-cardiac tissues, such as liver, as compared to injection without coronary artery block. Impella with CA + CS block even further increased luciferase expression by increasing viral uptake, as evidenced by increased vector genome in the tissues detected by PCR. At the infarct border zone, an important area for cardiac gene therapy, CA + CS occlusion led to greater than 300-fold increase in luciferase (p=0.005) compared to viral injection alone. Conclusion Impella unloading with CA + CS occlusion dramatically improves AAV gene expression in the heart without increasing off-target expression; it is thus a promising method for clinical application of cardiac gene therapy.

Optical absorption spectra of CuInSe2 single crystals were measured for the samples with −0.150≤x≤0.053, where x represents a degree of nonstoichiometry in the formula Cu1−xIn1+xSe2. The Urbach’s tail was observed for all samples between 90 K and room temperature. The Urbach’s energy, which represents an arbitrary intensity of exciton–phonon interaction, was almost constant for the Cu‐rich samples (x

Idiopathic pulmonary haemosiderosis (IPH) is a rare cause of alveolar haemorrhage. Its management in pregnancy is complicated and little clinical data exist on outcomes or treatment. Two patients with IPH, one with a known diagnosis prior to pregnancy (patient A) and one presenting de novo during pregnancy (patient B) are reported. Both subjects became maximally symptomatic in the third trimester and were treated with corticosteroids. Despite steroid treatment patient A had continued symptoms and was treated with azathioprine. Both patients delivered healthy female infants at 32 weeks and 38 weeks gestation, respectively. Patient B's course was complicated by the development of fatal invasive pulmonary aspergillosis 4 weeks postpartum. With improved care, more patients with IPH survive to childbearing age. Patients become most symptomatic late in pregnancy, underscoring the need for careful third trimester monitoring. These cases demonstrate that steroids are safe and that azathioprine can be used as additional therapy. When considering treatment options it is important to weigh the benefits of these medications against the potential for maternal and foetal harm.

The Pentax-AWS (AWS(®)), a new video laryngoscope, has been shown to be useful in cases of difficult intubation. We hypothesized that the AWS(®) would be more useful in the settings of a narrow upper airway than the Macintosh laryngoscope. We compared each device in simulated scenarios of representative difficulty of tracheal intubation using a manikin. The primary endpoint was the rate of successful intubation.With each device, 23 anesthesiologists performed tracheal intubation in a SimMan(®) manikin in the following scenarios: (1) normal airway, (2) tongue edema, (3) cervical spine rigidity, (4) pharyngeal obstruction, (5) jaw trismus, (6) tongue edema with pharyngeal obstruction. The intubation time and success rate were measured. Each participant was asked to rate the difficulty of intubation (1=very easy; 5=very difficult).In the scenarios of tongue edema and tongue edema with pharyngeal obstruction, the AWS(®) yielded a higher success rate (100% vs. 34.8%; P0.001, 65.2% vs. 21.7%; P=0.006), a shorter intubation time [14.6 (7.0) vs. 33.4 (13.0) s; P0.001, 24.5 (12.0) vs. 37.6 (11.9); P=0.047; mean (standard deviation)], and a lower difficulty score [2 (1-4) vs. 5 (1-5); P0.001, 4 (2-5) vs. 5 (3-5); P0.001; median (range)], compared with the Macintosh laryngoscope.The AWS(®) has an advantage over the Macintosh laryngoscope in simulated tongue edema and tongue edema with pharyngeal obstruction. Further studies in a clinical setting are necessary to confirm these findings.

Second harmonic electron cyclotron resonance heating has been used for the production of hot electrons in an axisymmetric end mirror of the GAMMA 10 tandem mirror. Heating power is injected in the linearly polarized extraordinary mode into a limited area of the mirror field for the purpose of localized heating and temperature control. A ray tracing code and a Fokker-Planck code are used for a preparatory consideration of the heating configuration as well as for an interpretation of the experimental results. The path of the injected power flow is analysed with a simple model and the localized heating is confirmed. The electron temperature is controlled and the plasma in which the hot electrons form a substantial fraction of the total density (up to 0.8) is maintained macroscopically stable. The hot electron production rate is found to depend on the magnetic field strength, the target plasma density, the gas feed rate and the heating power. Several key factors that are important for successful results to be achieved are found. Experimental observations indicate that, essentially, the concept of quasi-linear diffusion of electrons in velocity space holds. It is also found that warm electrons play an important role in microwave absorption as well as in efficient hot electron production.

1. We investigated the effects of 1-(3-tert-butyl-2-hydroxy-5-methoxyphenyl)-3-(3-pyridylmethyl)urea hydrochloride (T-0162), a novel low-molecular weight free radical scavenger, on the generation of superoxide anions and hydroxyl radicals in vitro and in vivo and on myocardial infarct (MI) size in an in vivo model of MI in rabbits. 2. It was found that T-0162 scavenged both superoxide anions and hydroxyl radicals in a concentration-dependent manner in vitro. 3. In an in vivo rabbit model with 30 min coronary occlusion and 30min reperfusion, T-0162 scavenged hydroxyl radicals generated in the myocardium during reperfusion. 4. Anaesthetized open-chest Japanese white male rabbits were subjected to 30 min coronary occlusion and 48 h reperfusion. The control group (n = 10) was infused with 10% lecithin solution for 220 min from 10 min before occlusion to 180 min after reperfusion. The pretreatment group (n = 10) was infused with T-0162 dissolved in 10% lecithin solution for 220 min from 10 min before occlusion to 180 min after reperfusion at a rate of 400 microg/kg per min. The post-treatment group (n = 10) was injected with an i.v. bolus of 10 mg/kg T-0162 and was then infused with 400 microg/kg per min T-0162 for 190 min from 10 min before reperfusion to 180 min after reperfusion. After 48 h reperfusion, infarct size was measured histologically and expressed as a percentage of area at risk (AAR). 5. There was no significant difference in haemodynamic parameters among the three groups throughout the experimental period. The per cent infarct size of the AAR in the T-0162 groups (24.8+/-4.3 and 30.5+/-3.9% for pre- and posttreatment groups, respectively) was significantly reduced compared with control (44.7+/-4.1%; P0.05). There was no significant difference in the AAR among the three groups. 6. In conclusion, T-0162 reduces MI size through the inhibition of reperfusion injury.

1. We examined whether N-hydroxyethyl-1-deoxynojirimycin (miglitol), a new human anti-diabetic drug with effects to inhibit alpha-1, 6-glucosidase glycogen debranching enzyme and reduce the glycogenolytic rate as well as to inhibit alpha-1,4-glucosidase, could reduce infarct size in the rabbit heart. Rabbits were subjected to 30-min coronary occlusion followed by 48-h reperfusion. 2. The infarct size as a percentage of area at risk was not reduced by pre-ischaemic treatment with 1 mg kg(-1) miglitol (42.7+/-4.0%, n=10) compared with the saline control group (41.7+/-2.3%, n=10). However, it was significantly and dose-dependently reduced by pre-ischaemic treatment with 5 or 10 mg kg(-1) of miglitol (25.7+/-4. 5%, n=10, and 14.6+/-2.4%, n=10, respectively) without altering the blood pressure, heart rate or blood glucose level. However, there was no evidence of an infarct-size reducing effect after pre-reperfusion treatment with 10 mg kg(-1) of miglitol (35.0+/-3.0%, n=10). 3. Another 40 rabbits given 1, 5 and 10 mg kg(-1) of miglitol or saline before ischaemia (n=10 in each) were sacrificed at 30 min of ischaemia for biochemical analysis. Miglitol preserved significantly the glycogen content, and attenuated significantly the lactate accumulation in a dose dependent manner in the ischaemic region at 30 min of ischaemia. 4. Pre-ischaemic treatment, but not pre-reperfusion treatment, with miglitol markedly reduced the myocardial infarct size, independently of blood pressure and heart rate. A dose-dependent effect of miglitol on infarct size, glycogenolysis and lactate formation suggests that the mechanism may be related to the inhibition of glycogenolysis. Thus, miglitol may be beneficial for coronary heart disease as well as diabetes mellitus.

We report a biopsy-proven case of membranous lipodystrophy with cranial CT and MRI findings.

We examined the effects of lung volume change and volume history on lung resistance (RL) and its components before and during induced constriction. Eleven subjects, including three current and four former asthmatics, were studied. RL, airway resistance (Raw), and, by subtraction, tissue viscance (Vtis) were measured at different lung volumes before and after a deep inhalation and were repeated after methacholine (MCh) aerosols up to maximal levels of constriction. Vtis, which average 9% of RL at base line, was unchanged by MCh and was not changed after deep inhalation but increased directly with lung volume. MCh aerosols induced constriction by increasing Raw, which was reversed by deep inhalation in inverse proportion to responsiveness. such that the more responsive subjects reversed less after a deep breath. Responsiveness correlated directly with the degree of maximal constriction, as more responsive subjects constricted to a greater degree. These results indicate that in humans Vtis comprises a small fraction of overall RL, which is clearly volume-dependent but unchanged by MCh-induced constriction and unrelated to the degree of responsiveness of the subject.

The hypolipidemic drug RMI 14,514 (5-tetradecyloxy-2-furoic acid) has an oral LD50 of over 5000 mg/kg in rats. In a chronic toxicity study (6 months drug diet) doses of 30, 100, or 300 mg/kg/day produced no obvious signs of toxicity or abnormal clinical pathology parameters, other than prominent growth retardation at 300 mg/kg, which was somewhat alleviated when the dose was reduced to 200 mg/kg after 6 weeks. Hepatic change in the form of mild lipid accumulation was noted histopathologically after 6 months of treatment at 100 or 300 mg/kg/day, but was not present at 3 months or after 4 weeks off drug. The administration of RMI 14,514 in the diet to pregnant rats at 30, 100, or 150 mg/kg/day on Days 7 thru 21 of pregnancy (day 1 = day sperm detected) did not induce any teratogenic effects. When rats were exposed to the drug from implantation thru sexual maturity (126 days of age) at the same dosage, it produced no adverse developmental or behavioral effects, except for slight reduction in weight gain from birth to sexual maturity at 150 mg/kg/day. The drug caused reductions in plasma cholesterol and total fatty acids, but no distinct changes in various tissue lipids, except in the erythrocyte where fatty acids and phospholipids were reduced. These differences did not affect membrane integrity of the erythrocyte as far as osmotic or mechanical fragility tests could determine. The drug, which bears a structural resemblance to long-chain fatty acids, was incorporated into tissue lipids in detectable amounts, but tended to disappear from tissues at a rate similar to that of expected lipid turnover after treatment was stopped.

—Acetylcholine, 5-hydroxytryptamine, and norepinephrine concentrations were measured in the telencephalon, diencephalon plus mesencephalon (midbrain), and pons-medulla oblongata of rats exhibiting behavioral excitation while working on a Sidman avoidance schedule and injected with 50 mg/kg iproniazid 16 hr before being given 2 mg/kg tetrabenazine. Acetylcholine concentrations in all three brain areas decreased and returned to normal levels at different times. The time course of increased response rates correlated best with the acetylcholine levels in the telencephalon. Both the 5-hydroxytryptamine and norepinephrine concentrations remained similar to the iproniazid control values during the period of behavioural excitation. However, the norepinephrine concentration in the midbrain showed a continuous decreasing trend toward naive control levels. These data suggest that changes in a cholinergic system in the telencephalon and a noradrenergic system in the midbrain operate in the maintenance of behavioural excitation.

Since the introduction of cardiopulmonary resuscitation (CPR) 25 years ago, there have been many advances in cardiopulmonary technology and in our understanding of the factors leading to a successful outcome. Despite these advances, our study of outcomes in 88 patients having CPR at Johns Hopkins Hospital in 1981 revealed a 14% survival rate to discharge compared with 24% from the same hospital from 1959 to 1961. We found that 74% of the 46 patients who initially survived CPR died before discharge. In addition, two of 12 survivors at discharge were dead one week later and one was in a persistent vegetative state three years after CPR. Our findings suggest that this technology, once meant to be applied when cardiac arrest was sudden and unexpected, is now being applied to patients regardless of underlying condition or prognosis. A follow-up survey of 63 Maryland hospitals revealed that many lacked formal plans for CPR management or education. We recommend that a comprehensive approach to CPR be adopted by all hospitals, involving education regarding appropriate patient selection, assurance of skilled application and backup care for survivors, and a mechanism for routinely monitoring outcome.

MDL 19205, 4-ethyl-1,3-dihydro-5-(4-pyridinyl-carbonyl)-2H-imidazol-2-one, is a new drug with cardiotonic properties. Its effects on several biochemical systems considered to be important in myocardial contraction were investigated. Cyclic nucleotide phosphodiesterases (PDEs) from dog hearts were separated into three isoenzymes, F I, F II, and F III, and effect of the drug on these enzymes was tested. MDL 19205 inhibited F III PDE specifically and produced little or no inhibition of F I and F II PDEs. The IC50 for inhibition of F III PDE was 8.6 microM when 0.5 microM cyclic AMP (cAMP) was used, whereas no more than 10% inhibition of F I and 18% of F II PDEs occurred at drug concentrations up to 200 microM when 1 microM cAMP was used. Concentrations of MDL 19205 up to 100 microM had no effect on Ca2+-adenosine triphosphatase (ATPase) or Ca2+ uptake by dog cardiac sarcoplasmic reticulum. At 100 microM, the drug produced a weak (18%) inhibition of Na+,K+-ATPase. It is suggested that inhibition of F III PDE may be the primary mechanism by which MDL 19205 produces its cardiotonic effect. Inhibition of Na+,K+-ATPase may also be involved at very high concentrations of this drug.