On differences in the equation-of-state for a selection of seven representative mammalian tissue analogue materials.

Tissue analogues employed for ballistic purposes are often monolithic in nature, e.g. ballistic gelatin and soap, etc. However, such constructs are not representative of real-world biological systems. Further, ethical considerations limit the ability to test with real-world tissues. This means that availability and understanding of accurate tissue simulants is of key importance. Here, the shock response of a wide range of ballistic simulants (ranging from dermal (protective/bulk) through to skeletal simulant materials) determined via plate-impact experiments are discussed, with a particular focus on the classification of the behaviour of differing simulants into groups that exhibit a similar response under high strain-rate loading. Resultant Hugoniot equation-of-state data (Us-up; P-v) provides appropriate feedstock materials data for future hydrocode simulations of ballistic impact events.

WEDGE: an anticoagulant thrombin mutant produced by autoactivation.

BACKGROUND: The production of therapeutically relevant proteases typically involves activation of a zymogen precursor by external enzymes, which may raise regulatory issues about availability and purity. Recent studies of thrombin precursors have shown how to engineer constructs that spontaneously convert to the mature protease by autoactivation, without the need for external enzymes. OBJECTIVES: Autoactivation is an innovative strategy that promises to simplify the production of proteases of therapeutic relevance, but has not been tested in practical applications. The aim of this study was to provide a direct test of this strategy. METHODS: An autoactivating version of the thrombin mutant W215A/E217A (WE), which is currently in preclinical development as an anticoagulant, was engineered. RESULTS AND CONCLUSIONS: The autoactivating version of WE can be produced in large quantities, like WE made in BHK cells or Escherichia coli, and retains all significant functional properties in vitro and in vivo. The results serve as proof of principle that autoactivation is an innovative and effective strategy for the production of trypsin-like proteases of therapeutic relevance.

On the effects of lateral gauge misalignment in shocked targets.

Plate-impact experiments have been used to interrogate the influence of gauge alignment on the shock response of wire-element lateral manganin stress gauges in PMMA and aluminium targets. Embedded gauges were progressively rotated relative to the target impact face. Peak stress and lateral gauge rise-times were found be proportional (negatively and positively, respectively) to the resolved angle of the embedded gauge element. However, lateral stress gradients behind the shock were found to be relatively insensitive to gauge alignment. In addition, investigation of the effects of release arrival showed no connection to either peak stress or behaviour behind the shock.

Partial cloning of putative G-proteins modulating mechanotransduction in the ciliate stentor.

Signal transduction systems known to utilize G-proteins in higher eukaryotes undoubtedly evolved prior to the development of metazoa. Pharmacological evidence indicates that the ciliates Paramecium, Stentor, and Tetrahymena all utilize signaling systems similar to those found in mammals. However, there has been relatively little direct evidence for the existence of G-proteins in ciliates. Since highly conserved heterotrimeric G-proteins form the basis of receptor-coupled signal transduction systems in a wide variety of metazoa, it is of interest to know if these important signaling molecules were early to evolve and are present and functionally important in a wide variety of unicellular organisms. We have previously shown that mechanotransduction in Stentor is modulated by opiates in a manner that may involve pertussis toxin-sensitive G-proteins. Here we utilize drugs known to interact with G-proteins to further test for the involvement of these important signaling molecules in Stentor mechanotransduction. We present behavioral and electrophysiological data demonstrating that putative G-proteins in Stentor decrease mechanical sensitivity by modulating the mechanotransduction process. In addition, we report the partial cloning of 4 G-protein alpha-subunits from Stentor. We confirm that these clones are of Stentor origin and are transcribed. Furthermore, we employ antisense oligodeoxynucleotide-mediated knockout to demonstrate that these ciliate G-proteins exert a modulatory influence on Stentor behavior, and that a G1/G0-like clone mediates the inhibitory action of beta-endorphin on mechanotransduction.

The effects of maternal indomethacin therapy on human fetal branch pulmonary arterial vascular impedance.

OBJECTIVE: To examine whether maternal indomethacin therapy affects human fetal pulmonary arterial vascular impedance without constriction of the ductus arteriosus and to determine the changes in the pulmonary arterial vascular impedance in the presence of ductal constriction. STUDY DESIGN: In this cross-sectional study, 52 normal fetuses without maternal medication (control group), 33 fetuses without ductal constriction (Study group I) and 11 fetuses with ductal constriction (Study group II) during maternal indomethacin therapy between 24 and 34 weeks of gestation were examined by Doppler echo-cardiography. Blood velocity waveforms across the proximal right or left pulmonary artery were obtained and the pulsatility index (PI) of the proximal pulmonary arteries was calculated. RESULTS: In the control group, the proximal pulmonary artery PI was higher (p < 0.0001) at 24-25 weeks (n = 7) (3.73 +/- 0.33; mean +/- SD) than at 33-34 week of gestation (n = 11) (2.98 +/- 0.27). The PI was constantly greater (p < 0.005) in Study group I than in the control group. However, in this group the mean average weekly decrease in the PI of the proximal pulmonary arteries was similar to that in the control group. After 26 weeks of gestation, the PI values in Study group II were significantly higher than in the control group (27 weeks: 4.12 vs. 3.34 (p < 0.005); 30 weeks: 4.48 vs. 3.14 (p < 0.0001); 34 weeks: 4.96 vs. 3.00 (p < 0.0001), respectively). CONCLUSIONS: Human fetal pulmonary arterial vascular impedance is increased by maternal indomethacin therapy even without ductal constriction. In the presence of ductal constriction, the magnitude of the increase in the vascular impedance is related to the gestational age.

Regional hemodynamic effects of dopamine in the sick preterm neonate.

OBJECTIVE: To study the effects of dopamine on renal, mesenteric, and cerebral blood flow in sick preterm neonates. STUDY DESIGN: The pulsatility index was used to assess the dopamine-induced changes in renal, mesenteric, and cerebral blood flow by means of color Doppler ultrasonography in 23 nonhypotensive preterm neonates (birth weight: 981 +/- 314 g; postnatal age: <2 days). Dopamine was given at a dose of 6.1 +/- 3.0 microgram/kg per minute to combat oliguria, impaired peripheral perfusion, or both. Blood flow velocity measurements were made before and during dopamine administration, with each patient serving as his or her own control subject. RESULTS: Dopamine significantly increased blood pressure and urine output. Dopamine decreased the pulsatility index in the renal artery (2.98 +/- 1.18 vs 1.68 +/- 0.45; P <.05) while the pulsatility index in the superior mesenteric and medial cerebral artery was not affected. Thus renal blood flow increased while mesenteric and cerebral blood flow remained unchanged during dopamine treatment. The increase in renal blood flow was independent of the blood pressure changes. CONCLUSIONS: These findings suggest a functionally mature renal, but not mesenteric, vasodilatory dopaminergic response in the preterm neonate. The observations also indicate the lack of an effect of low- to medium-dose dopamine on cerebral hemodynamics in the nonhypotensive preterm neonate.

Reactivity of the human fetal pulmonary circulation to maternal hyperoxygenation increases during the second half of pregnancy: a randomized study.

BACKGROUND: The aims of the present study were to determine whether maternal hyperoxygenation affects human fetal pulmonary circulation and whether there is a gestational age-related response in the fetal pulmonary circulation to maternal hyperoxygenation during the second half of gestation. METHODS AND RESULTS: Twenty women between 20 and 26 weeks of gestation and 20 women between 31 and 36 weeks of gestation with normal singleton pregnancies were randomized to receive either 60% humidified oxygen or medical compressed air (room air) by a face mask. Fetal aortic and pulmonary valve; ductus arteriosus (DA); and right (RPA), left (LPA), and distal (DPA) pulmonary artery blood velocity waveforms were obtained by Doppler ultrasound before, during, and after maternal administration of either 60% oxygen or room air. Left and right ventricular cardiac outputs, DA volume blood flow, and RPA and LPA volume blood flows (Qp) were calculated. Foramen ovale volume blood flow (left ventricular cardiac output-Qp) was estimated. Pulsatility index (PI) values of DA, RPA, LPA, and DPA were calculated. Maternal hyperoxygenation did not change any of the measured fetal parameters between 20 and 26 weeks, whereas between 31 and 36 weeks, the PI values of RPA, LPA, and DPA decreased (P<.0001) and the PI of DA increased (P<.0001). In addition, Qp increased (P<.001), and DA volume blood flow (P<.01) and foramen ovale volume blood flow (P<.03) decreased. Left and right ventricular cardiac outputs were unchanged. All changes returned to baseline after maternal hyperoxygenation was discontinued. CONCLUSIONS: Reactivity of the human fetal pulmonary circulation to maternal hyperoxygenation increases with advancing gestation; this suggests that fetal pulmonary circulation is under acquired vasoconstriction at least after 31 to 36 weeks of gestation.

Human fetal right ventricular ejection force under abnormal loading conditions during the second half of pregnancy.

Our objective was to determine whether abnormal loading conditions can modify human fetal right ventricular ejection force during the second half of pregnancy. By Doppler echocardiography, we studied 73 normal fetuses between 19 and 41 weeks of gestation, 27 fetuses with hypoplastic left heart syndrome (chronic volume overload) between 18 and 38 weeks of gestation, 14 fetuses with mild to moderate constriction of the ductus arteriosus (pulsatility index (PI) between 1.0 and 1.9) and seven fetuses with severe constriction (PI < 1.0) or occlusion of the ductus arteriosus (relatively acute pressure overload) between 28 and 34 weeks of gestation. In the normal and ductal constriction/occlusion groups, blood velocity waveforms were recorded at the level of the aortic and pulmonary valves, and in the group with hypoplastic left heart syndrome at the level of the pulmonary valve. The ventricular ejection forces were calculated. In the normal group, right (RVEF; r = 0.91, p < 0.0001) and left (LVEF; r = 0.86, p < 0.0001) ventricular ejection forces increased and were equal during the second half of gestation. In the group with hypoplastic left heart syndrome the RVEF increased (r = 0.76, p < 0.0001) with advancing gestation. The RVEF (p < 0.0005) and its average weekly increase (p < 0.0001) were greater in the hypoplastic left heart syndrome group than in the normal group. In the group with mild to moderate ductal constriction, both ventricular ejection forces were similar to those of the normal group. The RVEF (p < 0.003) and its average weekly increase (p < 0.03) were lower in the group with severe ductal constriction or occlusion than in the normal group. The LVEF did not differ from that of the normal group We conclude that chronic volume overload increases and relatively acute pressure overload decreases human fetal RVEF. The right ventricular performance is modified by abnormal loading conditions.

Role of the pulmonary circulation in the distribution of human fetal cardiac output during the second half of pregnancy.

BACKGROUND: By using Doppler echocardiography, we determined the normal distribution of human fetal combined cardiac output (CCO) from the left and right ventricles. We also established weight-indexed pulmonary and systemic vascular resistances (Rpi and Rsi, respectively) and changes during the second half of pregnancy. METHODS AND RESULTS: Blood flows at the aortic and pulmonary valve annuli (LVCO and RVCO, respectively), right and left pulmonary arteries (QP), and ductus arteriosus (QDA) were calculated in 63 normal fetuses. Foramen ovale blood flow (QFO = LVCO-QP) was estimated. From 20 to 30 weeks of gestation, the proportion of QP of the CCO increased (from 13% to 25%, P < .001), while the proportion of QFO decreased (from 34% to 18%, P < .001). After 30 weeks, the proportions of QP and QFO were unchanged. At 38 weeks, the proportion of RVCO (60%) was higher (P < .05) than that of LVCO (40%). The proportion of QDA did not change significantly. The correlation between RVCO calculated from blood flow through the pulmonary valve and from QDA and QP was good (r = .97, P < .0001). RPi (P < .001) decreased from 20 to 30 weeks of gestation. From 30 to 38 weeks, RPi increased (P < .0001). Rsi increased (P < .001) from 20 to 38 weeks. The ratio of RPi to RSi decreased (P < .01) from 20 to 30 weeks and later remained unchanged. CONCLUSIONS: The human fetal pulmonary circulation has an important role in the distribution of cardiac output.

Fetal branch pulmonary arterial vascular impedance during the second half of pregnancy.

OBJECTIVE: Our purpose was to establish normal physiologic parameters in the fetal proximal and distal branch pulmonary arterial vascular impedance during the second half of pregnancy and to analyze relationships between proximal and distal pulmonary arterial blood velocity waveforms. STUDY DESIGN: In this cross-sectional study 100 uncomplicated singleton pregnancies were studied by pulsed color Doppler techniques between 18 and 41 weeks of gestation (median 30 weeks). Both right and left proximal (immediately after the bifurcation of the main pulmonary artery) and distal (beyond the first bifurcation of the branch pulmonary artery) pulmonary artery blood velocity waveforms were recorded and pulsatility index values were calculated. Peak systolic velocities and time-to-peak-velocity intervals were measured. Time-to-peak-velocity intervals were also analyzed at the level of aortic and pulmonary valves and at the ductus arteriosus. Right and left pulmonary artery diameters and right lung length were measured. RESULTS: In both right and left proximal and distal pulmonary arteries pulsatility index values decreased (p < 0.0001) and the peak systolic velocities (p < 0.003) and time-to-peak-velocity intervals (p < 0.0001) increased during the second half of pregnancy. In the proximal pulmonary arteries the pulsatility index values decreased linearly until 34 to 35 weeks of gestation and in the distal pulmonary arteries until 31 weeks of gestation. Thereafter they remained unchanged. In pulmonary arteries time-to-peak-velocity intervals were shorter (p < 0.01) than at the pulmonary valve level. There were no significant differences between the right or left pulmonary arteries in the pulsatility index values, peak systolic velocities, time-to-peak-velocity intervals, or pulmonary artery diameters. In the proximal pulmonary arteries the pulsatility index values (p < 0.02) and peak systolic velocities (p < 0.0001) were higher and time-to-peak-velocity intervals (p < 0.0001) were longer than in the distal pulmonary arteries. There was a 2.5-fold increase in pulmonary artery diameters and right lung length. CONCLUSIONS: Fetal branch pulmonary arterial vascular impedance decreases significantly during the second half of pregnancy. The linear decrease in vascular impedance during the second trimester and in the beginning of the third trimester may be related to the growth of the lung and the increase in the number of resistance vessels. During the latter part of the third trimester pulmonary vascular impedance does not decrease further.

Genetic studies reveal that myristoylCoA:protein N-myristoyltransferase is an essential enzyme in Candida albicans.

MyristoylCoA:protein N-myristoyltransferase (Nmt) catalyses the co-translational, covalent attachment of myristate (C14:0) to the amino-terminal glycine residue of a number of eukaryotic proteins involved in cellular growth and signal transduction. The NMT1 gene is essential for vegetative growth of Saccharomyces cerevisiae. Studies were carried out to determine if Nmt is also essential for vegetative growth of the pathogenic fungus Candida albicans. A strain of C. albicans was constructed in which one copy of NMT was partially deleted and disrupted. A Gly-447-->Asp mutation was introduced into the second NMT allele. This mutation produced marked reductions in catalytic efficiency at 24 and 37 degrees C, as judged by in vitro kinetic studies of the wild-type and mutant enzymes which had been expressed in, and purified from, Escherichia coli. The growth characteristics of isogenic NMT/NMT, NMT/delta nmt, and nmt delta/nmtG447D C. albicans strains were assessed under a variety of conditions. Only the nmt delta/nmtG447D strain required myristate for growth. This was true at both 24 and 37 degrees C. Palmitate could not substitute for myristate. Incubation of nmt delta/nmtG447D cells at 37 degrees C in the absence of myristate resulted in cell death as observed by the inability to form colonies on media supplemented with 500 microM myristate. Studies in an immunosuppressed-mouse model of C. albicans infection revealed that the NMT/delta nmt strain produced 100% lethality within 7 d after intravenous administration while the isogenic nmt delta/nmtG447G strain produced no deaths even after 21 d. These observations establish that Nmt is essential for vegetative growth of C. albicans and suggest that inhibitors of this acyltransferase may be therapeutically useful fungicidal agents.

Doppler in non-immune hydrops fetalis.

Fetal ultrasound studies were performed on 24 fetuses with non-immune hydrops to evaluate echocardiographic and cardiovascular Doppler parameters that may be useful in assessing hemodynamics and in predicting outcome. Of all cardiovascular parameters analyzed, only the presence of abnormal pulsations in the umbilical vein (p < 0.001) was found to be significantly different between the 11 survivors and 13 non-survivors. In a smaller subset of 12 fetuses, in whom inferior vena caval waveforms were recorded, survivors (n = 6) had a significantly lower percentage of retrograde flow in the inferior vena cava (p < 0.001) and higher inferior vena caval E/V velocity ratio (p < 0.001) than non-survivors (n = 6). Sixteen of the 24 cases examined had abnormal umbilical venous pulsations; 12 of the 16 (75%) died including all fetuses with hydrops due to twin-to-twin transfusion or congenital heart disease. When fetuses with pulsatile flow in the umbilical vein were compared with fetuses with normal umbilical venous flow, the following significant differences were found: lower right and left ventricular output velocities, larger inferior vena caval diameter, decreased shortening fractions of the right and left ventricles, and lower peak velocities at the aortic and pulmonary valves and in the ductus arteriosus.

Diastolic function of the fetal heart during second and third trimester: a prospective longitudinal Doppler-echocardiographic study.

To generate normal charts of fetal cardiac inflow velocities and to assess physiologic changes of ventricular diastolic function, velocity waveforms of tricuspid and mitral valves were studied longitudinally in 49 fetuses in 4 week intervals from 14 weeks gestation to term. Doppler tracings were analyzed for: peak early (E) and peak late (A) inflow velocities, time velocity integral (TVI) of total inflow and A-wave velocity waveforms and heart rate corrected isovolemic relaxation time. E- and A-velocity as well as total- and A-wave-TVI of both valves increased significantly with gestational age (P < 0.001). Heart rate and A/E ratio decreased significantly with gestational age (P < 0.001). The ratio of A-wave TVI to total TVI of both valves and heart rate corrected isovolemic relaxation time (IVR) was constant suggesting unchanged diastolic function. This study provides normal charts for fetal cardiac inflow velocities. After 14 weeks of gestation all inflow velocities and their respective TVI's increased linearly in the growing fetal heart. There was evidence that diastolic function did not change. Area ratios and IVR should be used to determine changes in ventricular diastolic function, rather than velocity ratios.

Is tube-escape learning by protozoa associative learning?

The ciliate protozoa, Stentor and Paramecium, have been reported to escape from the bottom end of narrow capillary tubes into a larger volume of medium with increasing rapidity over the course of trials. This change in behavior has been considered an apparent example of associative learning. This decrease in escape time is not due to a change in the protozoa's environment, their swimming speed, frequency of ciliary reversals, or the proportion of time spent forward or backward swimming. Instead, most of the decrease results from a decrease in the proportion of time spent in upward swimming. However, a similar decrease in upward swimming occurs when the task is altered to require escape from the upper end of the capillary tubes. Because the protozoa exhibit the same change in behavior regardless of the reinforcing stimulus, tube-escape learning is not associative learning.

Pharmacokinetic and galactopoietic response to recombinant variants of bovine growth hormone.

Two studies were designed to examine the pharmacokinetic and galactopoietic potency of three molecular variants of recombinant-derived bovine GH (rbGH): [Met1, Leu127]-bGH, [Ala1, Val127]-bGH and [Ala1, Val127, His133]-bGH. Histidine substitution for arginine at residue 133 of rbGH was shown to impart thrombin resistance. In a Latin square design, nine lactating Holstein cows received a 25 mg rbGH bolus infusion via the jugular vein followed by frequent blood sampling over the next 12 h. The serum GH concentration data were found to fit a two-compartment open model. Neither primary nor secondary kinetic parameter estimates differed significantly (P > 0.05) among the three rbGH variants. Thus, the disposition of GH concentration at time t was described by the equation C(t) = (1295.5 micrograms/l) (e-(0.11/min)(t)) + (317.3 micrograms/l)(e-(0.03/min)(t)). Overall averages were: area under the curve = 27.1 mg.min per l, clearance = 0.15 litres/min per 100 kg and volume of distribution of the central compartment = 2.59 litres/100 kg. The t 1/2 for the two compartments averaged 8.2 and 29.1 min. In the second study, 36 lactating Holstein cows received i.m. injections of one of four oil-based formulation treatments: control vehicle or 500 mg of one of the three rbGH variants every 14 days for 42 days. Average and maximum serum GH concentrations and area under the curve estimates were increased by approximately 3-6 micrograms/l, 5-15 micrograms/l and 40-90 micrograms.day per 1 respectively. Ala1, Val127 rbGH treatments elicited greater blood GH concentrations than [Met1, Leu127]-bGH when administered in an oil-based formulation. Blood GH responses did not directly translate into milk response differences, possibly due to differences in biopotency or receptor availability. Thrombin resistance resulting from substitution of histidine at position 127 of rbGH did not affect blood GH pharmacokinetic parameters or milk response over other rbGH variants.

A comparative analysis of the kinetic mechanism and peptide substrate specificity of human and Saccharomyces cerevisiae myristoyl-CoA:protein N-myristoyltransferase.

Human myristoyl-CoA:protein N-myristoyltransferase (hNmt) catalyzes the transfer of myristate from CoA to the amino-terminal Gly residue of a number of cellular proteins involved in signal transduction pathways, to structural and nonstructural proteins encoded by retroviruses, hepadnaviruses, picornaviruses, and reoviruses, as well as to several transforming tyrosine kinases. hNmt has been purified 230-fold from an erythroleukemia cell line. The monomeric enzyme has no associated methionyl aminopeptidase activity. To determine the enzyme's kinetic mechanism, we examined the effect of covariation of subsaturating concentrations of myristoyl-CoA and peptide substrate on initial velocity. Double-reciprocal plots excluded a double displacement (ping-pong) mechanism. Product inhibition studies indicated that CoA was a noncompetitive inhibitor against myristoyl-CoA and a mixed-type inhibitor against peptide substrates. Together these results are consistent with a sequential ordered mechanism where, in a typical catalytic cycle, myristoyl-CoA binds to apoenzyme before peptide followed by release of the CoA and then myristoylpeptide products. This kinetic mechanism is identical to that described for Saccharomyces cerevisiae N-myristoyl-transferase (Nmt1p) and emphasizes the impact that regulation of myristoyl-CoA pool size and accessibility may have in modulating protein N-myristoylation in these two species. Comparative studies of the peptide substrate specificities of hNmt and Nmt1p using a panel of 12 octapeptides revealed distinct differences in their tolerance for amino acid substitutions at positions 3, 4, 7, and 8 of parental peptides derived from the amino-terminal sequences of known N-myristoyl-proteins. This finding contrasts with our recent observation that the acyl-CoA substrate specificities of hNmt and Nmt1p are highly conserved and suggests that these differences in peptide recognition provide an opportunity to develop species-specific enzyme inhibitors.

Comparison of the acyl chain specificities of human myristoyl-CoA synthetase and human myristoyl-CoA:protein N-myristoyltransferase.

Human myristoyl-CoA synthetase and myristoyl-CoA:protein N-myristoyltransferase (hNmt) have been partially purified from an erythroleukemia cell line. Their substrate specificities were examined using two in vitro assays of enzyme activity together with a panel of C7-C17 saturated fatty acids plus 72 myristic acid analogs containing oxygen, sulfur, ketocarbonyl, ester, amide, cis and trans double bonds, triple bonds, and para-substituted phenyl groups. There is an inverse relationship between the polarity and the activity of C14 fatty acid substrates of myristoyl-CoA synthetase. Surveys of tetradecenoic and tetradecynoic acids suggest that myristate is bound to the synthetase in a bent conformation with a principal bend occurring in the vicinity of C5-C6. The synthetase can tolerate a somewhat wider range of physical chemical properties in acyl chains than can the monomeric hNmt. However, like myristoyl-CoA synthetase, there is an inverse relationship between acyl chain polarity and the activities of hNmt's acyl-CoA substrates. Moreover, the acyl chain of myristoyl-CoA appears to be bound to hNmt in a bent conformation with bends located in the vicinity of C5 and C8. The acyl chain specificities of both enzymes make them well suited to utilize efficiently any cellular pools of 5Z-tetradecenoic and 5Z,8Z-tetradecadienoic acids and their CoA derivatives. This feature may account for the recent observation that in some mammalian cell lineages, certain N-myristoyl-proteins are heterogeneously acylated with these C14 fatty acids. Finally, the acyl-CoA binding sites of human and Saccharomyces cerevisiae Nmts appear to have been highly conserved. Given their overlapping yet distinct peptide substrate specificities, development of species-specific inhibitors of Nmts should probably focus on structural features recognized in the enzymes' peptide substrates rather than in the acyl chain of their acyl-CoA substrates.

Left ventricular assistance without thoracotomy: mediastinal and transseptal approaches to the left heart.

Two methods to cannulate the left atrium for initiating mechanical left ventricular circulatory assistance using a centrifugal pump were investigated in 25 sheep. A modified Dennis transatrial septal approach produced flow rates of 88.6 +/- 14 mL.kg-1.min-1 through 21F catheters inserted during fluoroscopy through the jugular vein. In 8 animals the septal perforation was plugged after decannulation with a modified Rashkind umbrella plug. Fibroendothelial tissue covered the plug by 4 week. In 7 other animals, the septal defect was not plugged. The septal defect reached pinpoint size by 2 weeks and was completely closed by 4 weeks. In 10 sheep, the left atrium was cannulated from the neck through the mediastinum. Left ventricular assistance flow averaged 71.6 +/- 14 mL.kg-1.min-1. Mean blood loss during 1 hour of left ventricular assistance was 47 mL. In 8 animals, the atrial perforation was plugged with a mean blood loss of 253 +/- 194 mL. In 2 animals, the perforation was intentionally not plugged; mean blood loss was 700 mL. All animals survived. The modified Dennis transatrial method is recommended as a safe, expeditious, cost-effective method to implement left ventricular assistance without thoracotomy. The mediastinal approach, which is technically possible in humans, is more difficult but feasible. Left ventricular assistance has been proven to be the most effective way to rest the failing, ejecting left ventricle. Implementation without thoracotomy potentially expands applications of left ventricular assistance for temporary support of patients with severe manifestations of ischemic heart disease.

Diagnosis, transport, and outcome in fetuses with left ventricular outflow tract obstruction.

Between March 1986 and April 1990, 22 consecutive fetuses (at gestational ages of 21 to 38 weeks) with a suspected diagnosis of critical (ductus-dependent) left ventricular outflow tract obstruction on fetal echocardiogram were referred to our center for delivery and surgical treatment. Diagnoses were hypoplastic left heart syndrome (n = 16), valvular aortic stenosis (n = 2), common atrioventricular canal with subaortic stenosis (n = 3), and single ventricle with subaortic stenosis (n = 1). Postnatal echocardiography revealed that fetal echocardiography was correct in predicting left ventricular outflow tract obstruction to be critical in all but one patient, for a positive predictive value of 96%. Of the 21 patients with true, critical left ventricular outflow tract obstruction, 17 patients underwent cardiac surgery as neonates (birth to 6 days of age, median 2 days); 13 (or 77%) survived and were discharged from the hospital. In addition, one patient underwent successful balloon aortic valvotomy for critical valvular aortic stenosis but later died of sepsis. Lethal chromosomal and congenital abnormalities should be sought and are contraindications for this approach. In utero transport of fetuses with suspected critical left ventricular outflow tract obstruction to a neonatal cardiac surgical center can result in improved neonatal condition and may improve overall survival.