Effect of intermittent warm blood cardioplegia on functional recovery after prolonged cardiac arrest

BACKGROUND: There is some evidence that continuous warm blood cardioplegia offers good myocardial protection; however, the effects of interrupting cardioplegia remain controversial. To study this, we compared the effects of continuous and intermittent antegrade warm (37 degrees C) blood cardioplegia on functional recovery after prolonged cardiac arrest (180 minutes). METHODS: Twenty-four juvenile pigs were randomly assigned into four groups. Group 1 received continuous cardioplegia, group 2 underwent several periods of 15 minutes of cardioplegia interrupted by 5 minutes of normothermic ischemia, and group 3 underwent several periods of 10 minutes of cardioplegia interrupted by episodes of 10 minutes. The hearts of group 4 received no cardioplegia. Left ventricular systolic function was assessed from fractional left ventricular shortening and percentage left ventricular wall thickening, and left ventricular diastolic function was determined from the time constant of relaxation and the constant of myocardial stiffness. RESULTS: Systolic and diastolic functions were slightly depressed 1 and 2 hours after cross-clamp removal in all four groups, without significant differences among the groups. CONCLUSIONS: These data suggest that antegrade warm blood cardioplegia can be interrupted for up to 10 minutes without obvious negative effects on left ventricular function in the normal myocardium, provided that the intermittent doses of cardioplegia are sufficient to restore the metabolic demands of the arrested myocardium.     

High blood levels of nitric oxide in rats subjected to prolonged respiratory arrest and their modulation during adrenocorticotropin-induced resuscitation

OBJECTIVES: Recent clinical trials have implied the cytotoxic and antiproliferative effects of combining 5-fluorouracil and interferon-alpha in the treatment of metastatic renal cell cancer. We therefore conducted an open multicenter trial to test the efficacy of such a combination on this cancer. METHODS: Human lymphoblastoid interferon (3 MIU per patient) was administered subcutaneously three times weekly for 12 weeks, while 5-fluorouracil was administered (600 mg/m2/day) as a continuous infusion for the first 5 days, followed by an intravenous bolus infusion of 600 mg/m2 once a week from the 3rd week until the 12th week. RESULTS: Of the 63 patients entered into the trial, 55 were eligible and evaluable for systemic toxicities, and 53 were evaluable for their response. All patients had undergone a prior nephrectomy, and their European Cooperative Oncology Group (ECOG) performance status ranged from 0 to 3 (median 0). Three complete and eight partial responses were induced, with an overall response rate of 20.0%. The median time to progression and the median survival time were 11 and 33 months, respectively. World Health Organization grade 3 toxicities were observed in 8 patients; however, no grade 4 toxicities or toxicity-related deaths were noted. CONCLUSIONS: Combination therapy of interferon-alpha plus 5-fluorouracil at the above-described dosage and schedule produced no better responses than interferon monotherapies. Prolongation of survival could be attributable to the fair performance status of the patients. This regimen has limited value for the treatment of patients with advanced renal cell cancer.     

Primary respiratory arrest due to basilar aneurysm

A healthy woman had two episodes of transient, complete respiratory arrest without preceding neurologic abnormalities. Following the second episode, she lapsed into coma and autopsy disclosed a thrombosed basilar artery aneurysm. Primary respiratory arrest is a rare condition but should prompt extensive and immediate neurologic evaluation.     

Protein kinase A-anchoring inhibitor peptides arrest mammalian sperm motility

Cyclic AMP-dependent protein kinase (PKA) is anchored at specific subcellular sites through the interaction of the regulatory subunit (R) with protein kinase A-anchoring proteins (AKAPs) via an amphipathic helix binding motif. Synthetic peptides containing this amphipathic helix domain competitively disrupt PKA binding to AKAPs and cause a loss of PKA modulation of cellular responses. In this report we use S-Ht31, a cell-permeant anchoring inhibitor peptide, to study the role of PKA anchoring in sperm. Our analysis of three species of mammalian sperm detected three isoforms of PKA (RIIalpha, RIIbeta, and RIbeta) and one 110-kDa AKAP. The addition of S-Ht31 to bovine caudal epididymal sperm inhibits motility in a time- and concentration-dependent manner. A control peptide, S-Ht31-P, identical to S-Ht31 except for a proline for isoleucine substitution to prevent amphipathic helix formation, had no effect on motility. The inhibition of motility by S-Ht31 is reversible but only if calcium is present in the suspension buffer, suggesting a role for PKA anchoring in regulating cellular calcium homeostasis. Surprisingly, inhibition of PKA catalytic activity had little effect on basal motility or motility stimulated by agents previously thought to work via PKA activation. These data suggest that the interaction of the regulatory subunit of PKA with sperm AKAPs, independent of PKA catalytic activity, is a key regulator of sperm motility and that disruption of this interaction using cell-permeable anchoring inhibitor peptides may form the basis of a sperm-targeted contraceptive.     

Influence of preconditioning on rat heart subjected to prolonged cardioplegic arrest

BACKGROUND: Ischemic preconditioning (IP) can reduce lethal injury to the myocardium induced by prolonged ischemia. However, little is known about the effect of preconditioning on the heart subjected to cardioplegic arrest and hypothermic preservation. We evaluated the effect of IP on myocardial metabolism, mechanical performance, and coronary endothelial function after cardioplegic arrest and prolonged hypothermic preservation. METHODS: An isovolumic Langendorff perfused rat heart model was used, and hearts were divided into two groups. The first group (IP, n = 14) was preconditioned by 5 minutes of global normothermic (37 degrees C) ischemia followed by 10 minutes of normothermic reperfusion before 6 hours of cold (4 degrees C) preservation, followed by 60 minutes of reperfusion. The second group (control, n = 15) was subjected to 6 hours of cold preservation followed by 60 minutes of reperfusion without preconditioning. Mechanical function was assessed using left ventricular balloon by constructing pressure-volume curves in two ways: at defined left ventricular volumes or at defined left ventricular end-diastolic pressures. Initially, the volume of the balloon was increased incrementally from 0 to 150 microL in 25-microL steps. Measurements were then repeated with loading balloon to achieve left ventricular end-diastolic pressure of 5, 10, 15, or 20 mm Hg. Myocardial function was assessed before ischemia and at 15 or 60 minutes of reperfusion. Metabolic status of the heart was evaluated by measuring the release of purine catabolites during the initial 15 minutes of reperfusion and concentrations of myocardial nucleotides at the end of reperfusion. Endothelium-mediated vasodilatation was evaluated using 10 mumol/L 5-hydroxytryptamine before and after ischemia. RESULTS: Left ventricular end-diastolic pressure values were significantly lower in the IP group, by 20% to 40%, during the reperfusion phase at each volume of the balloon compared with the control group. The rate-pressure product was more favorable during reperfusion in the IP than in the control group because of a 15% increased heart rate in the IP group. The release of purine catabolites from the heart during the reperfusion phase was reduced (p < 0.01) in the IP group (0.66 +/- 0.04 mumol) relative to the control group (0.92 +/- 0.06 mumol). No difference in the recovery of systolic function, myocardial adenosine triphosphate concentration, or endothelial function was observed between the groups. CONCLUSIONS: Under conditions of cardioplegic arrest and hypothermic preservation, IP can offer additional protection for the heart by preventing an increase in diastolic stiffness. However, metabolic improvement or better preservation of the systolic or endothelial function was not observed in this model.     

Thermal arrest memory effect

The course of the martensitic transformation is affected by strain fields in the untransformed parent phase, One of the consequences of this NiTi shape memory alloys is the “Thermal Arrest Memory Effect” (TAME), where the martensite to parent phase transformation “remembers” the temperature of arrest in the previous thermal cycle. From the results of the calorimetric investigations in this study, it is deduced that the TAME is the result of locked-in transformation strain energy in the self-accomodating martensitic microstructure. Thus it is found that on account of the large difference in the degree of self-accomodation achieved in the martensitic microstructures, TAME is observed to be significant in NiTi and not in CuAnAl shape memory alloys.     

The effects of melanocortin peptides and corticosterone on habituation in the great plains toad, Bufo cognatus

Four patients with long-chain 3-hydroxyacyl-coenzyme A dehydrogenase deficiency are presented. Clinical onset in the form of acute encephalopathy occurred between the ages of 9 months and 3 years. The clinical course included recurrent metabolic crises in 4 patients, cardiac involvement and retinopathy in 3, and myopathy in 2. None had signs of peripheral neuropathy. Three patients died and one is currently well. Hypoketotic hypoglycemia with C6-C14 3-hydroxy-dicarboxylic aciduria during metabolic crises associated with decreased plasma carnitine levels was the main biochemical finding. Enzymologic studies disclosed long-chain 3-hydroxyacyl-coenzyme A dehydrogenase deficiency in all patients. Homozygosity for a G to C mutation at position 1528 in the encoding region of the enzyme was found in 2 patients. Histologic and electron microscopic studies of liver biopsy specimens revealed steatosis in 3 patients and mitochondrial abnormalities in 2. Skeletal muscle biopsies disclosed nonspecific degenerative changes in 2 patients and were normal in the remaining 2. Ultrastructural abnormalities in mitochondria were found in 3 patients. A review of the literature combined with the data from our series (total 22 patients) disclosed acute clinical onset in 77% of cases and subacute in 23%. In the combined series, the average age at onset was 11 months, family history was positive in 32% of patients and overall mortality was 50%. We describe the clinical spectrum of this disease and emphasize that, among patients with suspected beta-oxidation defects the finding of pigmentary retinopathy should lead to the suspicion of long-chain 3-hydroxyacyl-coenzyme A-dehydrogenase deficiency.     

Complete neurological recovery following prolonged cardiac arrest. Description of a clinical case

The therapy of fibular ligament ruptures is still a controversial subject. Reports on healing processes following operative or conservative treatment have been verified hitherto by means of clinical examinations and stress tests. The MRT, as a highly sensitive non-invasive method, allows exact documentation of the ligament structures in the ankle joints. This technique was used in a randomized clinical trial over a 6-month period. The 29 patients (ages 17-51 years) had recent ligament rupture [admission criteria: clinical signs of trauma, talar tilt in anteroposterior stress radiographs (15 kp) > or = 10 degrees, talar shift > or = 10 mm] were examined with regard to ligament healing during functional therapy with AIRCAST pneumatic leg braces. Within the first week an MRT was done for verification of ligament injury. Treatment was conservative and functional: lower leg cast for 2 weeks and subsequent mobilization with protection provided by an AIRCAST brace. Follow-up examination was 3 months after injury, taking the form of clinical examination, a-p-radiographs with stress tests, and MRT. In all patients both clinical and radiological examination confirmed that ligament structures had healed, as was also verified by MRT.     

Acute respiratory response to prolonged, moderate levels of sidestream tobacco smoke

Carefully controlled, clinical research has shown psychiatric rehabilitation to significantly help persons with severe mental illness address their disabilities and obtain a higher quality of life. For psychiatric rehabilitation to yield its greatest effect, discrete principles and skills that are part of the rehabilitation paradigm must be disseminated to staff working in real-world settings. Staff training strategies that help the rehabilitation team develop effective programs are especially important. This paper reviews Interactive Staff Training (IST), an approach to team building and program development that combines educational and organizational strategies. IST comprises four stages--introduction to the system, program development, program implementation, and program maintenance--with each stage defined by behavioral tasks that engage the team and corresponding products that serve as markers of progress. Testing treatment dissemination strategies poses interesting problems for the researcher, some which are reviewed here. Outcome studies completed on IST are summarized in light of these problems. The paper ends with a consideration of some future directions for research in this area.     

Neonatal sepsis after prolonged premature rupture of membranes

The objective of this study was to prospectively evaluate the incidence of neonatal sepsis after prolonged premature rupture of membranes (PROM), to correlate sepsis with gestational age and with the duration of PROM, and to evaluate the necessity for prophylactic antibiotic therapy in neonates born after PROM. Of 12,182 infants, 135 (1.1%) were delivered after PROM with a latency period of > 24 hours. Neonatal sepsis occurred in 11 infants (8.1%), 10 of whom were premature. The only term, septic newborn was a small-for-gestational-age infant. A latency period > 72 hours was not associated with an increased incidence of sepsis. Maternal fever, neonatal signs of infection including leukopenia, leukocytosis, thrombocytopenia, and positive gastric aspirate cultures, were not good predictors of sepsis. Of premature infants with PROM, 15% had sepsis, and thus the administration of prophylactic antibiotic therapy in these cases may be warranted. However, it may be unnecessary to administer prophylactic antibiotics to term, appropriate-for-gestational-age infants born after PROM.     

The effect of N-methylation on helical peptides

In N-methyl amino acids, the hydrogen of the N-H group is replaced with a bulky methyl group. While this change is expected to destabilize helical structures, the amount of destabilization is not known. Here the N-methyl group is placed into several positions of the helical peptides, acetyl-WGG(EAAAR)4A-amide and acetyl-WGG(RAAAA)4R-amide, and the melting of the peptides followed using CD. When analyzed using a simple two-state model, the destabilization associated with the H to CH3 substitution at 0 degree C is between 0.3 to 1.7 kcal/mole and is position dependent. The melting data may also be analyzed using a modified form of the Lifson-Roig statistics that should more correctly model the helix-coil transition in this small peptide. This analysis fails, however, apparently because the destabilization energy is greater than the energy that can be attributed to a single residue in this model.     

Advantages of continuous hyperpolarized arrest with pinacidil over St. Thomas'' Hospital solution during prolonged ischemia

vlf-1 is a baculovirus gene that regulates very late gene expression (J. R. McLachlin and L. K. Miller, J. Virol., 68, 7746-7756, 1994) and also plays a crucial role in the replication of the budded form of Autographa californica nuclear polyhedrosis virus (AcMNPV) (S. Yang and L. K. Miller, "Expression and mutational analysis of the baculovirus very late factor 1 (vlf-1) gene." Virology, 245, 99-109, 1998). To examine the influence of vlf-1 expression on baculovirus infection, we constructed recombinant viruses that expressed only low levels of VLF-1 and recombinants with vlf-1 under the control of different promoters. Viruses with mutant alleles of vlf-1 that produced low levels of VLF-1 replicated the budded form of the virus normally but produced no occlusion bodies. Thus, a higher concentration of VLF-1 was needed to activate very late gene expression than was needed to support budded virus production. By altering the level and/or timing of vlf-1 expression, the timing of polyhedrin gene (polh) expression, which normally occurs very late in infection, could be advanced or delayed. Early overexpression of vlf-1 increased the level of expression from the polh promoter but caused premature cellular disintegration. The data indicate that VLF-1 is the limiting factor in very late gene expression and that the level of VLF-1 controls the onset of occlusion.     

Maternal and neonatal outcomes after prolonged latent phase

Glycol ethers such as 2-ethoxyethanol (EE) are widely used as solvents because they are miscible in aqueous and organic solutions. Toxic effects of EE in rodents include teratogenicity, fetotoxicity, hematotoxicity, and testicular atrophy. The purpose of this study was to determine the effect of dose on the absorption, metabolism, and excretion of 2-ethoxy [U-14C]ethanol by F344/N rats after inhalation exposure. Rats were exposed to either 5 ppm EE for 5 hr 40 min or 46 ppm EE for 6 hr. The uptake and metabolism of EE were linear in the concentration range studied. Significant percentages of the retained doses were exhaled during (22%) and after exposure (16%) as 14CO2. Forty-six percent of the retained dose was excreted in the urine. Approximately 10% of the retained dose was detected in the carcass 66 hr after exposure. The major urinary metabolite was ethoxyacetic acid (EAA), the toxic metabolite of EE. The amount of EAA excreted was linearly related to exposure concentration. Ethylene glycol and N-ethoxyacetyl glycinate were identified as minor metabolites excreted in the urine. The results of this study suggest that the toxicity of inhaled EE should be directly proportional to the exposure concentration up to 46 ppm if the toxicity of EE is due to EAA.