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Introduction: The United Nations established the Sustainable Development Goals (SDGs) in 2015 to enhance global development. In this study, we examine an SDG indicator: the percentage of women aged 15-49 whose family planning needs are met by modern contraception (mDFPS). We evaluate both the factors influencing its coverage and its progress since 2015., Methods: We used nationally representative surveys data (Demographic and Health Surveys (DHS) and Performance Monitoring for Action (PMA)) from Ethiopia, Kenya, and Nigeria. We assessed predictors of mDFPS. We also computed mDFPS coverage across countries and subnational areas, assessing coverage changes from the SDGs onset to the most recent period, using a Bayesian model-based geostatistical approach. We assessed whether the subnational areas exceeded the minimum recommended WHO mDFPS coverage of 75%., Results: Varied individual and community-level determinants emerged, highlighting the countries' uniqueness. Factors such as being part of a female-headed household, and low household wealth, lowered the odds of mDFPS, while rural-residence had low odds only in Ethiopia and Nigeria. The results indicate mDFPS stagnation in most administrative areas across the three countries. Geographic disparities persisted over time, favouring affluent regions. The predicted posterior proportion of mDFPS and exceedance probability (EP) for WHO target for Ethiopia was 39.85% (95% CI: [4.51, 83.01], EP = 0.08) in 2016 and 46.28% (95% CI: [7.15, 85.99], EP = 0.13) in 2019. In Kenya, the adjusted predicted proportion for 2014 was 30.19% (95% CI: [2.59, 80.24], EP = 0.06) and 44.16% (95%CI: [9.35, 80.24], EP = 0.13) in 2022. In Nigeria, the predicted posterior proportion of mDFPS was 17.91% (95% CI: [1.24, 61.29], EP = 0.00) in 2013, and it was 23.08% (95% CI: [1.80, 56.24], EP = 0.00) in 2018. None of the sub-national areas in Ethiopia and Nigeria exceeded the WHO target. While 9 out of 47 counties in Kenya in 2022 exceeded the WHO mDFPS target., Conclusion: The study unveils demographic, geographic, and socioeconomic mDFPS disparities, signalling progress and stagnation across administrative areas. The findings offer policymakers and governments insights into targeting interventions for enhanced mDFPS coverage. Context-specific strategies can address local needs, aiding SDG attainment., (© 2024. The Author(s).)

Background: COVID-19 forced healthcare systems to make unprecedented changes in clinical care processes. The authors hypothesized that the COVID-19 pandemic adversely impacted timely access to care, perioperative processes, and clinical outcomes for pediatric patients undergoing primary appendectomy., Methods: A retrospective, international, multicenter study was conducted using matched cohorts within participating centers of the international PEdiatric Anesthesia COVID-19 Collaborative (PEACOC). Patients younger than 18 yr old were matched using age, American Society of Anesthesiologists Physical Status, and sex. The primary outcome was the difference in hospital length of stay of patients undergoing primary appendectomy during a 2-month period early in the COVID-19 pandemic (April to May 2020) compared with prepandemic (April to May 2019). Secondary outcomes included time to appendectomy and the incidence of complicated appendicitis., Results: A total of 3,351 cases from 28 institutions were available with 1,684 cases in the prepandemic cohort matched to 1,618 in the pandemic cohort. Hospital length of stay was statistically significantly different between the two groups: 29 h (interquartile range: 18 to 79) in the pandemic cohort versus 28 h (interquartile range: 18 to 67) in the prepandemic cohort (adjusted coefficient, 1 [95% CI, 0.39 to 1.61]; P < 0.001), but this difference was small. Eight centers demonstrated a statistically significantly longer hospital length of stay in the pandemic period than in the prepandemic period, while 13 were shorter and 7 did not observe a statistically significant difference. During the pandemic period, there was a greater occurrence of complicated appendicitis, prepandemic 313 (18.6%) versus pandemic 389 (24.1%), an absolute difference of 5.5% (adjusted odds ratio, 1.32 [95% CI, 1.1 to 1.59]; P = 0.003). Preoperative SARS-CoV-2 testing was associated with significantly longer time-to-appendectomy, 720 min (interquartile range: 430 to 1,112) with testing versus 414 min (interquartile range: 231 to 770) without testing, adjusted coefficient, 306 min (95% CI, 241 to 371; P < 0.001), and longer hospital length of stay, 31 h (interquartile range: 20 to 83) with testing versus 24 h (interquartile range: 14 to 68) without testing, adjusted coefficient, 7.0 (95% CI, 2.7 to 11.3; P = 0.002)., Conclusions: For children undergoing appendectomy, the COVID-19 pandemic did not significantly impact hospital length of stay., (Copyright © 2023 American Society of Anesthesiologists. All Rights Reserved.)

Respiratory adverse events in adults with COVID-19 undergoing general anaesthesia can be life-threatening. However, there remains a knowledge gap about respiratory adverse events in children with COVID-19. We created an international observational registry to collect airway management outcomes in children with COVID-19 who were having a general anaesthetic. We hypothesised that children with confirmed or suspected COVID-19 would experience more hypoxaemia and complications than those without. Between 3 April 2020 and 1 November 2020, 78 international centres participated. In phase 1, centres collected outcomes on all children (age ≤ 18 y) having a general anaesthetic for 2 consecutive weeks. In phase 2, centres recorded outcomes for children with test-confirmed or suspected COVID-19 (based on symptoms) having a general anaesthetic. We did not study children whose tracheas were already intubated. The primary outcome was the incidence of hypoxaemia during airway management. Secondary outcomes included: incidence of other complications; and first-pass success rate for tracheal intubation. In total, 7896 children were analysed (7567 COVID-19 negative and 329 confirmed or presumed COVID-19 positive). The incidence of hypoxaemia during airway management was greater in children who were COVID-19 positive (24 out of 329 (7%) vs. 214 out of 7567 (3%); OR 2.70 (95%CI 1.70-4.10)). Children who had symptoms of COVID-19 had a higher incidence of hypoxaemia compared with those who were asymptomatic (9 out of 51 (19%) vs. 14 out of 258 (5%), respectively; OR 3.7 (95%CI 1.5-9.1)). Children with confirmed or presumed COVID-19 have an increased risk of hypoxaemia during airway management in conjunction with general anaesthesia., (© 2022 Association of Anaesthetists.)

Diarrhoeal diseases remain a significant cause of morbidity and mortality, particularly in poor urban communities in the Global South. Studies on food access and safety have however not considered the sources of discrete food categories and their propensity to harbour and transmit diarrhoeal disease pathogens in poor urban settings. We sought to contribute to knowledge on urban food environment and enteric infections by interrogating the sources and categories of common foods and their tendency to transmit diarrhoea in low-income communities in Accra. We modelled the likelihood of diarrhoea transmission through specific food categories sourced from home or out of home after controlling for alternate transmission pathways and barriers. We used structured interviews where households that participated in the study were selected through a multi-stage systematic sampling approach. We utilized data on 506 households from 3 low-income settlements in Accra. These settlements have socio-economic characteristics mimicking typical low-income communities in the Global South. The results showed that the incidence of diarrhoea in a household is explained by type and source of food, source of drinking water, wealth and the presence of children below five years in the household. Rice-based staples which were consumed by 94.5% of respondents in the week preceding the survey had a higher likelihood of transmitting diarrhoeal diseases when consumed out of home than when eaten at home. Sources of hand-served dumpling-type foods categorized as "staple balls" had a nuanced relationship with incidence of diarrhoea. These findings reinforce the need for due diligence in addressing peculiar needs of people in vulnerable conditions of food environment in poor urban settlements in order to reap a co-benefit of reduced incidence of diarrhoea while striving to achieve the global development goal on ending hunger., Competing Interests: The authors have declared that no competing interests exist.

Objectives/hypothesis: The Aerodigestive Program (the Aero Program) at Children's Hospital Colorado is a multidisciplinary program focused on airway, digestive, and lung disorders in complex children, involving collaboration between gastroenterology, pulmonology, anesthesiology, and otolaryngology in clinic and operating room. These programs have proliferated as institutions focus on providing greater care coordination and family satisfaction. However, few cost, charge, and satisfaction data exist to support these resource-intensive programs. The goal of this study was to investigate the value of combined triple endoscopy delivered by the Aero Program through analysis of institutional charges, direct costs, operating room efficiency metrics, and parent satisfaction., Study Design: Program evaluation., Methods: Finance, satisfaction, efficiency, and quality-of-care metrics were evaluated within and outside of the Aero Program through retrospective queries of electronic health records, administrative databases, and parent surveys at our institution., Results: Mean anesthesia time in the Aero Program was 54 minutes (49-60; 95% confidence interval), which was significantly less (P < .0001) than the estimated 89 minutes of having the three procedures done separately. Average charges and average direct costs for triple endoscopy were 38.8% and 41.9% less than the sum of the averages for separate procedures, respectively. Parent satisfaction was high for the Aero Program care., Conclusions: As organizations move toward greater coordination of care for complex patients, multidisciplinary programs must demonstrate their value by delivering cost-effective care. Aerodigestive programs have the potential to provide satisfying care that is less costly to the organization, insurer, and family. These programs represent a step in the evolution toward higher value care and value-based payment methodology., Level of Evidence: 4 Laryngoscope, 130:521-525, 2020., (© 2019 The American Laryngological, Rhinological and Otological Society, Inc.)

Two simple unsymmetrical monometallic Ir(i) complexes with an N-heterocyclic carbene ligand and an analogous bimetallic Ir(i) complex were synthesised. These complexes were found to be extremely active catalysts for a range of C-X (X = N or O) and Si-N bond forming reactions involving alkyne and imine activation for dihydroalkoxylation, hydroamination and hydrosilylation reactions. These catalysts exhibited reaction rates far exceeding those of other Rh(i) and Ir(i) complexes previously reported. In addition, a small change to the ligand design (phenyl vs. mesityl) substantially affected both the reactivity and product selectivity of the catalyst. The Ir(i) complex bearing a mesitylene wingtip provided unprecedented regioselectivity in the dihydroalkoxylation reaction and a new kinetic product from the typical hydrosilylation protocol of 2-benyzlpyrroline to produce an N-silylaminoalkene. Our mechanistic studies indicated that this transformation proceeded via a dehydrogenative coupling mechanism.

Background: Mental health disorders present significant health challenges in populations in sub Saharan Africa especially in deprived urban poor contexts. Some studies have suggested that in collectivistic societies such as most African societies people can draw on social capital to attenuate the effect of community stressors on their mental health. Global studies suggest the effect of social capital on mental disorders such as psychological distress is mixed, and emerging studies on the psychosocial characteristics of collectivistic societies suggest that mistrust and suspicion sometimes deprive people of the benefit of social capital. In this study, we argue that trust which is often measured as a component of social capital has a more direct effect on reducing community stressors in such deprived communities., Methods: Data from the Urban Health and Poverty Survey (EDULINK Wave III) survey were used. The survey was conducted in 2013 in three urban poor communities in Accra: Agbogbloshie, James Town and Ussher Town. Psychological distress was measured with a symptomatic wellbeing scale. Participants' perceptions of their neighbours' willingness to trust, protect and assist others was used to measure community sense of trust. Participants' willingness to ask for and receive help from neighbours was used to measure personal sense of trust. Demographic factors were controlled for. The data were analyzed using descriptive and multivariate regressions., Results: The mean level of psychological distress among the residents was 25.5 (SD 5.5). Personal sense of trust was 8.2 (SD 2.0), and that of community sense of trust was 7.5 (SD 2.8). While community level trust was not significant, personal sense of trust significantly reduced psychological distress (B = -.2016728, t = -2.59, p < 0.010). The other factors associated with psychological distress in this model were perceived economic standing, education and locality of residence., Conclusion: This study presents evidence that more trusting individuals are significantly less likely to be psychologically distressed within deprived urban communities in Accra. Positive intra and inter individual level variables such as personal level trust and perceived relative economic standing significantly attenuated the effect of psychological distress in communities with high level neighbourhood disorder in Accra., Competing Interests: We declare no potential real or perceived conflict of interest.

Rhodium(I) complexes were explored as catalysts for the hydrogen borrowing reactions of amines and alcohols. Bidentate carbene-triazole ligands were readily synthesized via "click" reactions which allowed a diversity of ligand backbones to be accessed. The catalytic transformations are highly efficient, able to reach completion in under 6 h, and promote C-N bond formation across a range of primary alcohol and amine substrates. Moreover, site-selective catalysis can be achieved using substrates with more than one reactive site. A rhodium(I) complex covalently attached to a carbon black surface was also deployed in the hydrogen borrowing coupling reaction of aniline with benzyl alcohol. This represents the first report of a heterogeneous rhodium catalyst used for hydrogen borrowing.

Stereoselectively fluorinated analogues of the amino acid statine have been efficiently synthesized. The key step is an organocatalytic electrophilic fluorination of a chiral β-oxygenated aldehyde, which provided a test of both diastereoselectivity and chemoselectivity. The target statine analogues were found to adopt unique conformations influenced by the fluorine gauche effect, rendering them potentially valuable building blocks for incorporation into bioactive peptides.

Histones are small proteins critical to the efficient packaging of DNA in the nucleus. DNA–protein complexes, known as nucleosomes, are formed when the DNA winds itself around the surface of the histones. The methylation of histone residues by enhancer of zeste homolog 2 (EZH2) maintains gene repression over successive cell generations. Overexpression of EZH2 can silence important tumor suppressor genes leading to increased invasiveness of many types of cancers. This makes the inhibition of EZH2 an important target in the development of cancer therapeutics. We employed a three-stage computational de novo peptide design method to design inhibitory peptides of EZH2. The method consists of a sequence selection stage and two validation stages for fold specificity and approximate binding affinity. The sequence selection stage consists of an integer linear optimization model that was solved to produce a rank-ordered list of amino acid sequences with increased stability in the bound peptide-EZH2 structure. These sequences were validated through the calculation of the fold specificity and approximate binding affinity of the designed peptides. Here we report the discovery of novel EZH2 inhibitory peptides using the de novo peptide design method. The computationally discovered peptides were experimentally validated in vitro using dose titrations and mechanism of action enzymatic assays. The peptide with the highest in vitro response, SQ037, was validated in nucleo using quantitative mass spectrometry-based proteomics. This peptide had an IC50 of 13.5 mM, demonstrated greater potency as an inhibitor when compared to the native and K27A mutant control peptides, and demonstrated competitive inhibition versus the peptide substrate. Additionally, this peptide demonstrated high specificity to the EZH2 target in comparison to other histone methyltransferases. The validated peptides are the first computationally designed peptides that directly inhibit EZH2. These inhibitors should prove useful for further chromatin biology investigations.

Investigation into the mussel-inspired polymerization of dopamine has led to the realization that other compounds possessing potential quinone structures could undergo similar self-polymerizations in mild buffered aqueous conditions. To this end, 5-hydroxyindazole was added to a dopamine polymerization matrix in varying amounts, to study its incorporation into a polydopamine coating of silica particles. Solid-state (13) C NMR spectroscopy confirmed the presence of the indazole in the polymer shell when coated onto silica gel. SEM and DLS analysis also confirmed that the presence of the indazole in the reaction matrix yielded monodisperse polymer-coated particles, which retained their polymer shell upon HF etching, except when high levels of the indazole were used. Characterization data and examination of incorporation mechanism suggests that the 5-hydroxyindazole performs the function of a chain-terminating agent. Cytotoxicity studies of the polymer particles containing 5-hydroxyindazole showed dramatically lower toxicity levels compared to polydopamine alone., (© 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

A series of new cationic Rh(I), Rh(III) and Ir(III) complexes containing hybrid bidentate N-heterocyclic carbene–1,2,3-triazolyl donor of general formulae [Rh(CaT)(COD)]BPh4 (2a–d), [Rh(CaT)(CO)2]BPh4 (3a–d) and [M(CaT)(Cp*)Cl]BPh4 (M = Rh, 4a–d; M = Ir, 5a–c), where CaT = bidentate N-heterocyclic carbene–triazolyl ligands, COD = 1,5-cyclooctadiene and Cp* = 1,2,3,4,5-pentamethylcyclopentadienyl, were synthesised. The imidazolium–1,2,3-triazolyl pre-ligands (1a–c and 1e–i) were readily prepared using the Cu(I) catalysed ‘click reaction’ between phenyl azide or benzyl azides with propargyl functionalised imidazolium salts. The single crystal solid state structures of complexes 2a–d; 3a–b; 4a–d and 5a–b confirm the bidentate coordination of the NHC–1,2,3-triazolyl ligand with the NHC coordinating via the ‘normal’ C2-carbon and the 1,2,3-triazolyl donor coordinating via the N3′ atom to form six membered metallocycles. These complexes are the first examples of Rh and Ir complexes containing the hybrid NHC–1,2,3-triazolyl ligands which exhibit a bidentate coordination mode. A number of these complexes showed limited efficiency as catalysts for the intramolecular hydroamination of 4-pentyn-1-amine to 2-methylpyrroline.

The aim of de novo protein design is to find the amino acid sequences that will fold into a desired 3-dimensional structure with improvements in specific properties, such as binding affinity, agonist or antagonist behavior, or stability, relative to the native sequence. Protein design lies at the center of current advances drug design and discovery. Not only does protein design provide predictions for potentially useful drug targets, but it also enhances our understanding of the protein folding process and protein-protein interactions. Experimental methods such as directed evolution have shown success in protein design. However, such methods are restricted by the limited sequence space that can be searched tractably. In contrast, computational design strategies allow for the screening of a much larger set of sequences covering a wide variety of properties and functionality. We have developed a range of computational de novo protein design methods capable of tackling several important areas of protein design. These include the design of monomeric proteins for increased stability and complexes for increased binding affinity. To disseminate these methods for broader use we present Protein WISDOM (http://www.proteinwisdom.org), a tool that provides automated methods for a variety of protein design problems. Structural templates are submitted to initialize the design process. The first stage of design is an optimization sequence selection stage that aims at improving stability through minimization of potential energy in the sequence space. Selected sequences are then run through a fold specificity stage and a binding affinity stage. A rank-ordered list of the sequences for each step of the process, along with relevant designed structures, provides the user with a comprehensive quantitative assessment of the design. Here we provide the details of each design method, as well as several notable experimental successes attained through the use of the methods.

Objectives: The authors compared the safety, gastrointestinal tolerance, and clinical efficacy of feeding an enteral diet containing a fish oil/medium-chain triglyceride structured lipid (FOSL-HN) versus an isonitrogenous, isocaloric formula (O-HN) in patients undergoing major abdominal surgery for upper gastrointestinal malignancies., Summary Background Data: Previous studies suggest that feeding with n-3 fatty acids from fish oil can alter eicosanoid and cytokine production, yielding an improved immunocompetence and a reduced inflammatory response to injury. The use of n-3 fatty acids as a structured lipid can improve long-chain fatty acid absorption., Methods: This prospective, blinded, randomized trial was conducted in 50 adult patients who were jejunally fed either FOSL-HN or O-HN for 7 days. Serum chemistries, hematology, urinalysis, gastrointestinal complications, liver and renal function, plasma and erythrocyte fatty acid analysis, urinary prostaglandins, and outcome parameters were measured at baseline and on day 7. Comparisons were made in 18 and 17 evaluable patients based a priori on the ability to reach a tube feeding rate of 40 mL/hour., Results: Patients receiving FOSL-HN experienced no untoward side effects, significant incorporation of eicosapentaenoic acid into plasma and erythrocyte phospholipids, and a 50% decline in the total number of gastrointestinal complications and infections compared with patients given O-HN. The data strongly suggest improved liver and renal function during the postoperative period in the FOSL-HN group., Conclusion: Early enteral feeding with FOSL-HN was safe and well tolerated. Results suggest that the use of such a formula during the postoperative period may reduce the number of infections and gastrointestinal complications per patient, as well as improve renal and liver function through modulation of urinary prostaglandin levels. Additional clinical trials to fully quantify clinical benefits and optimize nutritional support with FOSL-HN should be undertaken.

The standard preservation technique in lung transplantation is cold single pulmonary artery flush (PAF) with Eurocollins solution (ECS). We compared ECS with University of Wisconsin (UW) solution, with and without added indomethacin, in single PAF preservation in an in vivo rabbit model of warm ischemia-reperfusion lung injury. Six groups of four New Zealand white rabbits each underwent isolation and hilar stripping of the left lung. In the four experimental groups, the left lung was flushed with (15 ml/kg) of cold ECS or UW solution, with or without added indomethacin, before warm ischemia for 120 minutes and before reperfusion for 60 minutes. The remaining two groups were the nonischemic and the ischemic "no flush" controls. Transcapillary flux of 99mTechnitium-labeled albumin and electron microscopy were used to demonstrate lung injury. Pulmonary vascular resistance (PVR) and thromboxane B2 (TXB2) concentrations were measured. There was a significant rise in PVR after ischemia/reperfusion in the ischemic control group (54.7 +/- 13.9 to 117.8 +/- 20.7 mm Hg/L.min-1, P < 0.05). The net rise in PVR after ischemia-reperfusion was significantly smaller in the two groups in which indomethacin was added (16.8 +/- 17.5 and 4.5 +/- 10.6 mm Hg/L.min-1 for UW and ECS, respectively) compared with the ischemic control (63.1 +/- 24.6 mm Hg/L.min-1, P < 0.05). Post-reperfusion TXB2 levels tended to be lower in the nonischemic control group and in the indomethacin-flush groups. We conclude that the increase in PVR produced by unilateral ischemia-reperfusion lung injury in this model was improved by single PAF perfusion. There was no significant difference between UW solution and ECS in this regard. The addition of indomethacin to the flush solution was associated with lower PVRs as well as morphologic improvement by electron microscopy. These findings may indicate a prominent role for the provision of PG synthesis inhibition during preservation for lung transplantation.

Although eicosanoid production contributes to physiological and pathophysiological consequences of cardiopulmonary bypass (CPB), the mechanisms accounting for the enhanced eicosanoid production have not been defined. Plasma phospholipase A2 (PLA2) activity, 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha), and thromboxane B2 (TXB2) levels were measured at various times during cardiac surgery. Plasma PLA2 activity increased after systemic heparinization, before CPB. This was highly correlated with concurrent increases in plasma 6-keto-PGF1 alpha, TXB2 concentrations did not increase with heparin administration but did increase significantly after initiation of CPB. High plasma PLA2 activity, 6-keto-PGF1 alpha, and TXB2 concentrations were measured throughout the CPB period. Protamine, administered to neutralize the heparin, caused an acute reduction of both plasma PLA2 activity and plasma 6-keto-PGF1 alpha, but no change in plasma TXB2 concentrations. Thus the ratio of TXB2 to 6-keto-PGF1 alpha increased significantly after protamine administration. Enhanced plasma PLA2 activity was also measured in patients with lower doses of heparin used clinically for nonsurgical applications. Human plasma PLA2 was identified as group II PLA2 by its sensitivity to deoxycholate and dithiothreitol, its substrate specificity, and its elution characteristics on heparin affinity chromatography. Heparin addition to PMNs in vitro resulted in dose-dependent increases in cellular PLA2 activity and release of PLA2. The PLA2 released from the PMN had characteristics similar to those of post-heparin plasma PLA2. In conclusion, plasma PLA2 activity and 6-keto-PGF1 alpha concentrations are markedly enhanced with systemic heparinization. Part of the anticoagulant and vasodilating effects of heparin may be due to increased plasma prostacyclin (PGI2) levels. In addition the pulmonary vasoconstriction sometimes associated with protamine infusion during cardiac surgery might be due to decreased plasma PLA2 activity, with an associated increased TXB2/6-keto-PGF1 alpha ratio.

Objective: To study the effect of intravenous lipid emulsions enriched with gamma-linolenic acid on plasma fatty acids and series-2 prostaglandins to determine if the slow conversion of linoleic acid by delta-6-desaturase to gamma-linolenic acid could be bypassed to provide substrate for the formation of dihomo-gamma-linolenic acid, the immediate precursor for series-1 prostaglandins, in control and injured rats. Dihomo-gamma-linolenic acid can also compete with arachidonic acid for oxidative metabolism by cyclooxygenase to modulate series-2 prostaglandin biosynthesis., Design: Prospective, randomized, controlled, double-blind study., Setting: Research laboratory at a university medical center., Subjects: Thirty-three control and thirty-one injured male Sprague-Dawley rats were randomized into one of four parenteral dietary treatment groups., Interventions: Rats were injured by the combined actions of a 30% body surface area full-thickness skin burn and a nonlethal injection of endotoxin (1 mg/kg ip). The rats were parenterally fed 200 kcal/kg/day, 1.5 g nitrogen/kg/day, and 30% of nonprotein calories as lipid (20% soybean lipid emulsion enriched with 2.7%, 4.4%, or 6.1% gamma-linolenic acid derived from borage oil) for 3 days. Control rats were treated similarly but were not injured. A 20% soybean/safflower oil lipid emulsion was used as the control diet (0% gamma-linolenic acid). Plasma was analyzed on day 3 to determine the concentrations of total fatty acids, thromboxane B2, 6-keto-prostaglandin F1 alpha, and bicyclo-prostaglandin E., Measurements and Main Results: Parenteral nutrition with 2.7%, 4.4%, and 6.1% gamma-linolenic acid increased the plasma percentages (mol%) of gamma-linolenic acid and dihomo-gamma-linolenic acid in a dose-dependent fashion in control and injured rats. Supplementation with gamma-linolenic acid did not increase the plasma percentage of arachidonic acid as compared with the 0% gamma-linolenic acid lipid emulsion in control and injured rats. The ratio of dihomo-gamma-linolenic acid to arachidonic acid was significantly increased in response to 4.4% and 6.1% gamma-linolenic acid in both the control and injured groups. The plasma ratio of thromboxane B2 to 6-keto-prostaglandin F1 alpha was substantially reduced with gamma-linolenic acid compared with 0% gamma-linolenic acid in injured rats. Bicyclo-prostaglandin E concentration was significantly higher with 2.7% gamma-linolenic acid in injured rats. Injured rats were protein catabolic, as evidenced by a net negative nitrogen balance and loss of body mass compared with controls, but neither group showed overt signs of intolerance to the diets., Conclusions: Supplementation of parenteral nutrition with gamma-linolenic acid had the following effects: a) increased plasma gamma-linolenic acid, dihomo-gamma-linolenic acid, and bicyclo-prostaglandin E; b) increased the plasma ratio of dihomo-gamma-linolenic acid to arachidonic acid; and c) favorably reduced the ratio of thromboxane B2 to 6-keto-prostaglandin F1 alpha in injured rats. These results reflect the potential capacity of gamma-linolenic acid-enriched lipid emulsions to have the following actions: a) to increase dihomo-gamma-linolenic acid, which is the fatty acid precursor of the antiaggregatory, anti-inflammatory eicosanoid, prostaglandin E1; and b) to modulate arachidonic acid-derived series-2 prostaglandins after injury.

Nondisjunction in trisomy 21 has traditionally been studied by cytogenetic heteromorphisms. Those studies assumed no crossing-over on the short arm of chromosome 21. Recently, increased accuracy of detection of the origin of nondisjunction has been demonstrated by DNA polymorphism analysis. We describe a comparative study of cytogenetic heteromorphisms and seven PCR-based DNA polymorphisms for detecting the origin of the additional chromosome 21 in 68 cases of Down syndrome. The polymorphisms studied were the highly informative microsatellites at loci D21S215, D21S120, D21S192, IFNAR, D21S156, HMG14, and D21S171. The meiotic stage of nondisjunction was assigned on the basis of the pericentromeric markers D21S215, D21S120, and D21S192. Only unequivocal cytogenetic results were compared with the results of the DNA analysis. The parental and meiotic division origin could be determined in 51% of the cases by using the cytogenetic markers and in 88% of the cases by using the DNA markers. Although there were no discrepancies between the two scoring systems regarding parental origin, there were eight discrepancies regarding meiotic stage of nondisjunction. Our results raise the possibility of recombination between the two marker systems, particularly on the short arm.

We investigated the role of pulmonary granulocyte sequestration in the development of early failure of the autoperfused working heart-lung preparation. A significant decline in the total circulating leukocyte count in 21 preparations at 60 minutes of perfusion (5.0 to 1.4 x 10(3)/microL; 28% of baseline; p less than 0.001) was observed. Differential cell counts in 14 of these preparations revealed a predominant decrease in granulocyte count (8.7% of baseline) and a moderate decline in lymphocyte count (46% of baseline). In study I, indium 111-labeled autologous granulocytes were injected intravenously into 10 adult New Zealand White rabbits. In group I (n = 5), an autoperfused working heart-lung preparation was harvested and perfused for 60 minutes. In group II (controls, n = 5), the heart-lung block was harvested following 60 minutes of in situ perfusion. Organ blocks were imaged before and after saline flush. There was a significant decline in granulocyte counts at 60 minutes of perfusion in group I versus no change in group II (I, 2.3 +/- 0.4 to 0.3 +/- 0.1; p less than 0.01; II, 1.7 +/- 0.2 to 2.3 +/- 0.5; not significant; x 10(3)/microL +/- standard error of the mean). Postflush lung activity was significantly increased in group I versus group II (I, 3,751 +/- 566; II, 1,867 +/- 532; p less than 0.05; counts +/- standard error of the mean). In study II, 15 autoperfused preparations were divided into two groups. Group I (n = 10) preparations were controls. Group II (n = 5) animals were depleted of leukocytes by pretreating with nitrogen mustard. Group I (controls) produced a bimodal survival distribution (Ia, 8.2 +/- 1.0; Ib, 26.4 +/- 2.0; hours +/- standard error of the mean). Group II survival was significantly longer than that of group Ia and similar to that of group Ib (II, 25.3 +/- 2.2; p less than 0.01 versus group Ia, not significant versus group Ib; hours +/- standard error of the mean). Hemodynamic profiles for group II closely paralleled those of group Ib. In conclusion, pulmonary sequestration of granulocytes occurs early in the autoperfused working heart-lung preparation (within 60 minutes of autoperfusion), and preoperative leukocyte depletion prolongs survival of the autoperfused working heart-lung preparation by eliminating the subset group Ia (short survivors) seen in untreated preparations.

Arachidonic acid metabolites may play an important role in liver physiology, yet hepatocyte prostaglandin synthesis has not been characterized extensively. We used RIA to study production and clearance of several eicosanoids in confluent primary cultures of rat hepatocytes in serum-free, hormonally-defined medium. Under basal, unstimulated conditions 6-keto-PGF1 alpha (spontaneous breakdown product of prostacyclin) and 13,14-dihydro-15-keto-PGE (DHK-PGE, a metabolite of PGE) accumulated in the culture medium. Hepatocytes cleared 6-keto-PGF1 alpha, thromboxane B2, and DHK-PGE from the medium. Production of eicosanoids by primary cultures appeared resistant to indomethacin and several other cyclooxygenase inhibitors. This apparent resistance to indomethacin was not caused by rapid metabolism of indomethacin, by failure of the drug to enter hepatocytes, or by insensitivity of hepatocyte cyclooxygenase to the drug. Metabolism of PGE to DHK-PGE may be saturated under in vitro conditions. Hepatocytes can synthesize significant amounts of eicosanoids, although they are probably less active in this regard than are non-parenchymal cells.

We studied the role of leukocyte redistribution and eicosanoid changes in the early stages of instituting 16 rabbit autoperfused working heart-lung preparations (AWHLP). Physiological changes occurring during the transition from the intact animal to the AWHLP may determine the survival and viability of the organ blocks for transplantation. White blood cell (WBC) count decreased from 5,160/microL to 1430/microL (P less than .01) at 60 min of autoperfusion. Differential WBC counts performed in ten of these AWHLP revealed a 63% decrease in lymphocyte count and an 88% decrease in the granulocyte count at 60 min. Thus, the predominant leukocyte remaining in the circulation was the lymphocyte. Blood samples were collected from the intact animal and from the AWHLP for assay of the stable metabolites of thromboxane A2 (TxA2) and prostacyclin (PGI2). Transition from the in situ heart-lung block to the in vitro AWHLP stage caused significant changes in these metabolites. The PGI2 metabolite 6-ketoprostaglandin F1a (6KPGF1a) increased from 2680 +/- 487 to 4339 +/- 478 (pg/mL), P less than .05, while the TxA2 metabolite, thromboxane B2 (TxB2) decreased from 618 +/- 105 to 289 +/- 63 (pg/mL). However, assays of 11-dehydro-TxB2 (11-DHT), a longer lived metabolite of TxA2 (n = 7) increased (668.4 +/- 84.6 to 946.4 +/- 43.7, P less than .05). The transition from the in situ heart-lung block of the intact animal to the AWHLP involves significant physiological changes. Redistribution of leukocytes occurs with a predominant decrease in the granulocyte count, while levels of bioactive lipid mediators show a distinct large rise in the PGI2 metabolites and a lesser increase in TxA2 metabolites.(ABSTRACT TRUNCATED AT 250 WORDS)

The autoperfused working heart-lung preparation has been proposed as a method for long-term heart-lung preservation. We investigated the effects of acellular oxygen-carrying perfusates (study 1) and the effect of donor pretreatment with indomethacin (study 2) on the working ex vivo heart-lung block. In study 1 perfusion with stroma-fee hemoglobin resulted in significantly reduced survival (118 +/- 46 minutes) compared with autologous blood (561 +/- 125 minutes, p less than 0.05) or perfluorocarbon (438 +/- 114 minutes, p less than 0.05). Decrease in survival with stroma-free hemoglobin perfusate is associated with a marked decrease in left ventricular performance and a significant increase in pulmonary vascular resistance. Perfusion with autologous blood is associated with a significant increase in pulmonary vascular resistance after 240 minutes of explantation, which is significantly delayed by perfusion with perfluorocarbon. Perfusion for 6 hours with blood pretreated with indomethacin (study 2) resulted in a decrease in the concentration of prostacyclin and thromboxane A2 metabolites but an increase in the prostaglandin/thromboxane A2 metabolite ratio. This is associated with abrogation of the increase in pulmonary vascular resistance (12,787 +/- 1682 dynes/sec/cm-5, T = 0; 13,134 +/- 2654 dynes/sec/cm-5, T = 360 minutes) observed in preparations perfused with autologous blood (13,194 +/- 1942 dynes/sec/cm-5, T = 0; 24,768 +/- 3325 dynes/sec/cm-5, T = 360 minutes, p less than 0.05). We conclude that alteration of the cellular and humoral components of autologous blood may prove advantageous for increasing the utility of the autoperfused working heart-lung preparation as a preservation technique.

We have investigated the response of systemic and myocardial prostacyclin metabolism to cardiopulmonary bypass and 30 minutes of hypothermic (22 degrees C), hyperkalemic (25 mEq K+) surgical cardioplegia. Thirteen adult mongrel dogs of either sex (range 21 to 36 kg) underwent sterile cardiopulmonary bypass without donor blood. Prostacyclin levels were obtained after cannulation, 20 minutes after onset of partial bypass, and 5 seconds after the onset of cardioplegia 1 (CP-1) and cardioplegia 2 (CP-2, 30 minutes later). Samples were drawn from the thoracic aorta, the aortic root below cross-clamping, and the coronary sinus. The stable metabolite of prostacyclin, 6-keto-PGF1 alpha was measured by double-antibody radioimmunoassay (pg/ml; values +/- standard error of the mean). We found that the onset of partial bypass is associated with significant increase in the systemic production of 6-keto-PGF1 alpha (122 +/- 33 versus 518 +/- 187; p less than 0.05), which persists throughout the experiment. A small but significant positive cardiac gradient of 6-keto-PGF1 alpha is found after cannulation (aortic root 122 +/- 33, coronary sinus 202 +/- 57, p less than 0.05). This gradient is more pronounced during partial bypass (aortic root 518 +/- 187, coronary sinus 686 +/- 186 p less than 0.05), when significant cardiac lactate extraction (p less than 0.005) is observed. After cross-clamping, a significantly increased gradient of 6-keto-PGF1 alpha is found during CP-1 (aortic root 74 +/- 10, coronary sinus 264 +/- 46, p less than 0.05 versus cannulation) in the presence of significant cardiac lactate production (p less than 0.005). A further significant increase in 6-keto-PGF1 alpha production is noted during the CP-2 infusion (aortic root 73 +/- 10, coronary sinus 483 +/- 83; p less than 0.01 versus CP-1), which is inversely related to cardiac oxygen uptake and endocardial/epicardial flow ratio. Our data demonstrate significant production of prostacyclin in the systemic and cardiac circulations during cardiopulmonary bypass and surgical cardioplegia. They further indicate that both ischemic and nonischemic stimuli regulate prostacyclin metabolism during cardiopulmonary bypass.

We assessed the effect of a specific thromboxane synthetase inhibitor (an imidazole derivative) on pulmonary hemodynamics and the concentrations of TxB2 (TxA2), 6-keto-PGF1 alpha (PGI2), and PGF2 in pulmonary lymph and transpulmonary blood samples following intravenous administration of E. coli endotoxin (1 microgram/kg) in sheep. In control animals the rise in pulmonary artery pressure correlated with increases in plasma and lymph TxB2 concentrations and large transpulmonary concentration gradients of this metabolite were measured. In imidazole treated animals both pulmonary hypertension as well as increases in plasma and lymph TxB2 concentrations were substantially reduced. In contrast, peak concentrations of 6-keto-PGF1 alpha (PGI2) and PGF2 alpha were severalfold higher than those measured in control animals. This suggests a shunting of endoperoxide metabolism towards prostacyclin and primary prostaglandins and documents the specificity of the thromboxane synthetase inhibitor. Our study provides evidence that endotoxin-induced pulmonary hypertension is mediated by pulmonary synthesis of TxA2.

The present study demonstrates that exposure of cardiac muscle to high levels of glucose during anoxia appears to retard damage to myocardial protein synthesis. The mechanism of this "glucose" effect is glucose-specific and appears related to the intracellular metabolism of glucose by the anoxic myocardium.

Coronary artery inflammation in Kawasaki disease is accompanied by thrombocytosis and platelet activation. It was hypothesized that abnormal metabolism of bioactive eicosanoids could result from or contribute to these events. Circulating plasma thromboxane B2, 6-keto-prostaglandin F1 alpha and prostaglandin E were measured by double antibody radioimmunoassay in patients with Kawasaki disease before and after aspirin alone or aspirin and intravenous gamma globulin therapy. Plasma prostaglandin E concentrations were normal in all patient groups. Pretreatment thromboxane B2 was elevated compared with age-matched controls, fell moderately with high-dose aspirin (60 to 100 mg/kg/day) and marginally increased with low-dose aspirin (3 to 5 mg/kg/day) 6 to 8 weeks after treatment. Plasma 6-keto-prostaglandin F1 alpha was not detected in 12 of 16 patients before therapy and remained low in all but 1 patients by 6 to 8 weeks. Thromboxane B2 correlated weakly with serum salicylate concentration but had no relation to platelet mass. The results in these patients with Kawasaki disease indicate only partial thromboxane suppression and depressed prostacyclin generation regardless of therapy. This balance favors coronary vasoconstriction and platelet aggregation capable of potentiating myocardial ischemia or infarction. The results justify consideration of higher or more frequent aspirin doses for longer duration and thromboxane receptor blockade in this disease.

Nonpulsatile cardiopulmonary bypass, in patients with coronary artery disease, produces a significant increase in thromboxane, a potent platelet aggregant and putative coronary vasoconstrictor. Pulsatile flow may decrease the incidence of perioperative infarction and the hormonal stress response to bypass. This study assessed the effect of pulsatile blood flow on plasma thromboxane and prostacyclin profiles during cardiopulmonary bypass by serial measurement of their stable metabolites, thromboxane B2 (TxB2) and 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha). Two groups of eight patients each were studied before, during, and after cardiopulmonary bypass. Eight patients had routine (nonpulsatile) bypass and eight had pulsatile flow. In the nonpulsatile group, the TxB2 concentration significantly increased during bypass (65 +/- 39 to 1,224 +/- 306 pg/ml, p less than 0.01) and rapidly returned to control. Prostacyclin also rose (53 +/- 20 to 613 +/- 132 pg/ml, p less than 0.01). In the pulsatile group, TxB2 rose during bypass (53 +/- 18 to 693 +/- 130 pg/ml, p less than 0.01), but peak concentration was significantly lower than in the nonpulsatile group (1,224 +/- 306 versus 693 +/- 130 pg/ml, p less than 0.05). Prostacyclin rose sharply during cardiopulmonary bypass in the pulsatile group (53 +/- 22 to 1,033 +/- 136 pg/ml, p less than 0.01) and was higher than in the nonpulsatile group (1,033 +/- 136 versus 325 +/- 33 pg/ml, p less than 0.01). There were no intragroup differences of plasma hemoglobin, hematocrit, or platelet count. These data demonstrate that pulsatile flow significantly alters prostacyclin and thromboxane profiles during cardiopulmonary bypass and favors production of the coronary vasodilator and platelet disaggregant prostacyclin. This may be an important factor in some of the clinical advantages previously reported with this modality.

The reason for coronary artery occlusion following percutaneous transluminal angioplasty (PTCA) remains an enigma. We postulated that alterations in arachidonic acid metabolism might contribute to coronary artery occlusion, particularly if platelets are perturbed and release thromboxane because of mechanical stimuli during PTCA. We serially monitored coronary sinus and peripheral arterial plasma thromboxane (TX) and prostacyclin (by standard radioimmunoassay of the metabolites TXB2 and 6-keto-PFG1 alpha) during PTCA in 10 patients. TX and prostacyclin were unchanged from control in seven uncomplicated procedures. In one patient with vasospasm, no changes were found. In two patients with occlusion, marked increases were measured in coronary sinus plasma TX. Patient No. 1 increased from 390 to 1375 pg/ml. Patient No. 2 increased from 155 to 1425 pg/ml. Both required emergency bypass grafting. No change in 6-keto-PGF1 alpha was found. Uncomplicated PTCA does not alter arachidonic acid metabolism through cyclooxygenase. Vasospasm need not be associated with TX release, but coronary artery occlusion is. TX may play a role in coronary artery occlusion during PTCA because of (1) increased release and (2) unopposed physiologic effects because increases were not found in the physiologic antagonist prostacyclin.

We measured serial plasma concentrations of thromboxane B2 (TXB2), the stable metabolite of the putative pulmonary vasoconstrictor thromboxane A2 (TXA2), and 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha), the stable metabolite of the pulmonary vasodilator prostacyclin (PGI2) by double-antibody radioimmunoassay during partial venovenous bypass in 25 awake sheep. The onset of bypass caused mean pulmonary artery pressure (PAP) to increase from 16 +/- 1 to 28 +/- 2 mmHg at 12 +/- 2 min, due to an increase of pulmonary vascular resistance, followed by a return to control within 45 min. There was no systemic hypoxia. TXB2 increased simultaneously with the onset of pulmonary hypertension (PH) (236 +/- 36 to 700 +/- 120 pg/ml at 0 and 5 min) and peaked at 1,724 +/- 172 pg/ml 10 min after maximum PAP was achieved. Positive pulmonary artery-to-aortic differences of TXB2 were measured. 6-Keto-PGF1 alpha increased from 51 +/- 3 to 842 +/- 367 pg/ml at 35 min. PGF2 alpha was unchanged (130 +/- 45 pg/ml). PH, TXB2, and 6-keto-PGF1 alpha increases were blocked by pretreatment with indomethacin or ibuprofen. PH and TXB2 increases were prevented with an imidazole derivative. PH caused by a continuous infusion of an endoperoxide analog did not induce lung release of TXB2 or PGF2 alpha. We conclude that 1) transient pulmonary vasoconstriction is caused by thromboxane; 2) the lung is the primary site of thromboxane synthesis; and 3) bypass causes selective alterations in arachidonic acid metabolism rather than general activation of the cascade.

Cardiopulmonary bypass in children with congenital heart disease is associated with significant morbidity manifested by increased complement degradation products, heightened pulmonary vascular activity, and coagulopathy. In adults with cardiac disease, the prostaglandins (eicosanoids) have been shown to contribute to the pathophysiologic response to extracorporeal circulation. This study assessed the effect of cardiopulmonary bypass in infants and children on two potent eicosanoids: thromboxane, a vasoconstrictor and platelet aggregating agent, and prostacyclin, a vasodilator and platelet disaggregating agent. The biochemical profiles of thromboxane and prostacyclin were evaluated in temporal relationship to selected parameters of platelet loss and pulmonary vascular hemodynamics during and after cardiopulmonary bypass. Twenty-one children, aged 3 days to 9 years, with congenital heart defects who were undergoing repair with cardiopulmonary bypass were studied. Nine pediatric patients undergoing palliative heart operations with no cardiopulmonary bypass served as the control group. In the group having cardiopulmonary bypass, the thromboxane concentration significantly increased during bypass (195 +/- 10 to 910 +/- 240 pg/ml, +/- standard error of the mean, p less than 0.005), whereas the control group demonstrated no significant change in thromboxane concentration. The highest thromboxane values were seen in the youngest patients (p less than 0.002). There was no significant correlation between thromboxane changes with alterations in pulmonary vascular resistance, platelet loss, duration of cardiopulmonary bypass or aortic cross-clamping. Prostacyclin levels rose significantly in both the bypass group (100 +/- 20 to 570 +/- 80 pg/ml, p less than 0.01) and in the control group (109 +/- 44 to 589 +/- 222 pg/ml, p less than 0.01), which apparently is due to surgical manipulation of vascular endothelium. These data show that eicosanoid production is significantly altered in children during cardiopulmonary bypass. Although thromboxane, a potent vasoconstrictor, is produced in significant amounts during and after cardiopulmonary bypass, our data show that thromboxane does not directly mediate changes in pulmonary artery hypertension and is not quantitatively related to platelet loss during pediatric cardiovascular operations.

Acute pulmonary and systemic vasomotor changes induced by endotoxin in dogs have been related, at least in part, to the production of eicosanoids such as the vasoconstrictor thromboxane and the vasodilator prostacyclin. Steroids in high doses, in vitro, inhibit activation of phospholipase A2 and prevent fatty acid release from cell membranes to enter the arachidonic acid cascade. We, therefore, administered methylprednisolone (40 mg/kg) to dogs to see if eicosanoid production and the ensuing vasomotor changes could be prevented after administration of 150 micrograms/kg of endotoxin. The stable metabolites of thromboxane B2 (TxB2) and 6-ketoprostaglandin F1 alpha (6-keto-PGF1 alpha) were measured by radioimmunoassay. Methylprednisolone by itself did not alter circulating eicosanoids but when given 2.5 h before endotoxin not only failed to inhibit endotoxin-induced eicosanoid production but actually resulted in higher circulating levels of 6-keto-PGF1 alpha (P less than 0.05) compared with animals receiving endotoxin alone. Indomethacin prevented the steroid-enhanced concentrations of 6-keto-PGF1 alpha after endotoxin and prevented the greater fall (P less than 0.05) in systemic blood pressure and systemic vascular resistance with steroid plus endotoxin than occurred with endotoxin alone. Administration of methylprednisolone immediately before endotoxin resulted in enhanced levels (P less than 0.05) of both TxB2 and 6-keto-PGF1 alpha but with a fall in systemic blood pressure and vascular resistance similar to the animals pretreated by 2.5 h. In contrast to the early steroid group in which all of the hypotensive effect was due to eicosanoids, in the latter group steroids had an additional nonspecific effect. Thus, in vivo, high-dose steroids did not prevent endotoxin-induced increases in eicosanoids but actually increased circulating levels of TxB2 and 6-keto-PGF1 alpha with a physiological effect favoring vasodilation.

Systemic and cardiac metabolism of thromboxane was studied in a canine model (n = 13) of standard cardiopulmonary bypass and surgical cardioplegia. Sterile techniques were applied and no donor blood was used. Systemic samples (thoracic aorta) and transcardiac gradients (coronary sinus - aortic root) were obtained (1) 5 minutes after cannulation, (2) 20 minutes after the onset of partial bypass, (3) 5 seconds after the first administration of cardioplegic solution (CP-1), and (4) 5 seconds after the second administration of cardioplegic solution (CP-2). Cardioplegic doses were administered 30 minutes apart and consisted of 500 ml of hypothermic (8 degrees C), hyperkalemic (25 mEq potassium chloride) solution infused into the aortic root at 60 to 70 mm Hg. Thromboxane B2 was determined by a double-antibody radioimmunoassay (picograms per milliliter +/- standard error of the mean). Onset of partial bypass was followed by a significant rise in systemic arterial thromboxane B2 levels: after cannulation, 115 +/- 21 pg/ml; after the onset of partial bypass, 596 +/- 141 pg/ml; p less than 0.01). Significant transcardiac thromboxane B2 gradients were found during the first and second cardioplegic washouts (CP-1: aortic root 73 +/- 12 pg/ml, coronary sinus 306 +/- 86 pg/ml, p less than 0.01; CP-2: aortic root 65 +/- 11 pg/ml, coronary sinus 355 +/- 98 pg/ml, p less than 0.01). Transcardiac gradients of 6-keto-prostaglandin F1 alpha and thromboxane B2 were obtained at CP-1 and CP-2. Gradients of 6-keto-prostaglandin F1 alpha were not different from thromboxane B2 gradients during CP-1 but were significantly higher than thromboxane B2 gradients during CP-2. In a subgroup of five dogs, transcardiac thromboxane B2, lactate, and platelet gradients were measured simultaneously. Cardiac thromboxane B2 generation was found only in the presence of cardiac lactate production. Transcardiac platelet gradients were significantly higher at CP-1 (13,900 +/- 3,000/mm3) than at CP-2 (4,000 +/- 1,230/mm3) (p less than 0.05), whereas thromboxane B2 gradients were similar at CP-1 and CP-2. Our study demonstrates that thromboxane B2 is released into the coronary circulation during surgical cardioplegic arrest with anaerobiosis.

In order to test the influence of coronary artery obstruction on cardiac prostaglandin metabolism during surgically induced cardioplegia (CP), we have measured transcardiac veno-arterial gradients of prostacyclin and thromboxane A2 (TXA A2) during experimental canine cardiopulmonary bypass. Cardiac arrest was induced by infusion of 500 ml of hypothermic (8 degrees C), hyperkalemic (25 meq) crystalloid CP solution into the aortic root with (group I) and without (group II) occlusion of the left anterior descending artery (LAD). After 30 minutes of cardioplegic arrest the LAD occlusion in group I was released and a second set of CP infusion was applied in both groups. Transcardiac gradients were obtained 5 seconds after onset of the first and second CP washouts. Significant prostacyclin and TXA A2 gradients were observed at both times. Prostacyclin gradients did not differ between group I and group II. In contrast, TXA A2 gradients were significantly higher during the second CP washout in group I as compared to the unoccluded group (group I 918 +/- 221, group II 244 +/- 144 pg/ml, p less than 0.05). The results of our study suggest that cardiac TXA A2 metabolism during cardioplegic arrest is increased distal to a coronary artery obstruction. Cardiac TXA A2 production might contribute to the increased ischemic myocardial injury observed in this setting.