Nitrate administration increases blood flow in dysfunctional but viable myocardium, leading to improved assessment of myocardial viability: A PET study.

SPECT with 99mTc-labeled agents is better able to detect viability after nitrate administration. Nitrates induce vasodilation and may increase blood flow to severely hypoperfused but viable myocardium, thereby enhancing tracer delivery and improving the detection of viability. Quantitative data on the changes in blood flow are lacking in SPECT but can be provided by PET. The aim of the present study was to use PET to evaluate whether nitrate administration increases blood flow to chronically dysfunctional but viable myocardium. METHODS: 13N-Ammonia PET was used to quantitatively assess blood flow, and 18F-FDG PET was used as the gold standard to detect viable myocardium. Twenty-five patients with chronic ischemic left ventricular dysfunction underwent 13N-ammonia PET at rest and after nitrate administration. RESULTS: A significant increase in nitrate-enhanced blood flow was observed in viable segments (from 0.55 +/- 0.15 to 0.68 +/- 0.24 mL/min/g, P < 0.05). No statistically significant change in blood flow was observed in nonviable segments (0.60 +/- 0.20 vs. 0.55 +/- 0.18 mL/min/g). A ratio of at least 1.1 for nitrate-enhanced flow to resting flow allowed optimal detection of viable myocardium, yielding a sensitivity of 82% with a specificity of 100%. CONCLUSION: 13N-Ammonia PET showed a significant increase in nitrate-enhanced blood flow in viable myocardium, whereas blood flow remained unchanged after nitrate administration in nonviable myocardium. Nitrate use during myocardial perfusion imaging will lead to improved assessment of myocardial viability.     

Elective aortocoronary bypass grafting in the elderly

Operative mortality, postoperative morbidity and follow up data were analyzed retrospectively from 122 consecutive patients, over 65 years old undergoing elective aortocoronary bypass grafting for symptomatic relief of angina pectoris at the Plains Health Centre, Regina, Saskatchewan, from January 1980 to December 1985. There were two in-hospital deaths (operative mortality 1.6%). Definite perioperative myocardial infarction occurred in 12 patients (9.8%). The 120 survivors were followed for a mean of 32 months. There were three deaths during follow-up, giving a five-year probability of survival of 93%. Twenty-three clinical events (including deaths) occurred during follow-up, giving a five-year probability of event free survival of 72%. Ninety percent of patients say they are pleased with their operation. Seventy-eight percent are currently angina free. These data illustrate the effectiveness of aortocoronary bypass grafting in low risk elderly patients with symptomatic coronary artery disease.     

PLASMA FOLLISTATIN CONCENTRATIONS INCREASE FOLLOWING LIPOPOLYSACCHARIDE ADMINISTRATION IN SHEEP

1. The effect of inflammation induced by lipopolysaccharide (LPS) injection on plasma follistatin (FS) concentrations was investigated. 2. Plasma FS and tumour necrosis factor-α concentrations increase following LPS administration in ewes. 3. The rise in FS is similar, but more sustained, to that previously observed after surgery. 4. These results indicate a possible functional link between FS, inflammation and the acute-phase response.     

Country-specific cost-effectiveness of early intervention with budesonide in mild asthma.

Early intervention with budesonide is an effective strategy for mild persistent asthma, which has been shown to provide additional clinical benefits at a low incremental cost using USA cost data. The present authors analysed whether this strategy would be cost-effective using cost data for other countries. Based on the 3-yr prospective, randomised, double-blind inhaled Steroid Treatment As Regular Therapy (START) in early asthma study (comparing budesonide and placebo combined with usual asthma therapy), the cost-effectiveness was estimated separately for eight different countries, from both healthcare payer and societal perspectives, of adding budesonide to usual asthma therapy. Local unit costs were applied to data for the total trial population. Incremental cost-effectiveness ratios (ICER) were estimated as cost per symptom-free day (SFD) gained. Budesonide increased SFDs by an average of 14.1 days annually. From a healthcare payer perspective, budesonide would reduce the total cost of asthma care in Australia. In Sweden, Canada, France, Spain, UK, China and the USA, the ICER ranged from US$2.4-11.3 per SFD. From a societal perspective, budesonide would be cost-saving in Australia, Canada and Sweden. In conclusion, for countries where costs with budesonide are higher, the policy implication has to be determined by that health system's willingness to pay for an additional symptom-free day. However, where budesonide therapy increases symptom-free days and reduces total costs, the policy conclusion clearly favours early intervention.     

Specificity of different organic nitrates to elicit NO formation in rabbit vascular tissues and organs in vivo.

1. In the present study we assessed the formation of nitric oxide (NO) from classical and thiol-containing organic nitrates in vascular tissues and organs of anaesthetized rabbits, and established a relationship between the relaxant response elicited by nitroglycerin (NTG) and NO formation in the rabbit isolated aorta. Furthermore, the effect of isolated cytochrome P450 on NO formation from organic nitrates was investigated. 2. Rabbits received diethyldithiocarbamate (DETC; 200 mg kg-1 initial bolus i.p. and 200 mg kg-1 during 20 min, i.v.) and either saline, or one of the following organic nitrates: nitroglycerin (NTG, 0.5 mg kg-1), isosorbide dinitrate (ISDN), N-(3-nitratopivaloyl)-L-cysteine ethylester (SPM 3672), S-carboxyethyl-N-(3-nitratopivaloyl)-L-cysteine ethylester (SPM 5185), at 10 mg kg-1 each. After 20 min the animals were killed, blood vessels and organs were removed, and subsequently analyzed for spin-trapped NO by cryogenic electron spin resonance (e.s.r.) spectroscopy. 3. In the saline-treated control group, NO remained below the detection limit in all vessels and organs. In contrast, all of the nitrates tested elicited measurable NO formation, which was higher in organs (liver, kidney, heart, lung, spleen) (up to 4.8 nmol g-1 20 min-1) than in blood vessels (vena cava, mesenteric bed, femoral artery, aorta) (up to 0.7 nmol g-1 20 min-1). Classical organic nitrates (NTG, ISDN) formed NO preferentially in the mesenteric bed and the vena cava, while the SPM compounds elicited comparable NO formation in veins and arteries. 4. Using a similar spin trapping technique, NO formation was assessed in vitro in phenylephrine-precontracted rabbit aortic rings. The maximal relaxation elicited by a first exposure (10 min) to NTG (0.3 to 10 microM) was positively correlated (r = 0.8) with the net increase (NTG minus basal) of NO spin-trapped during a second exposure to the same concentration of NTG in the presence of DETC. 5. Cytochrome P450 purified from rabbit liver enhanced NO formation in a NADPH-dependent fashion from NTG, but not from the other nitrates, as assessed by activation of purified soluble guanylyl cyclase. 6. We conclude that the vessel selective action of different organic nitrates in vivo reflects differences in vascular NO formation. Thus, efficient preload reduction by classical organic nitrates can be accounted for by higher NO formation in venous capacitance as compared to arterial conductance and resistance vessels. In contrast, NO is released from cysteine-containing nitrates (SPMs) to a similar extent in arteries and veins, presumably independently of an organic nitrate-specific biotransformation. Limited tissue bioavailability of NTG and ISDN might account for low NO formation in the aorta, while true differences in biotransformation seem to account for differences in NO formation in the other vascular tissues.     

Cell surface oligosaccharide modulation during differentiation: VI. The effect of biomodulation on the senescent and neoplastic cell phenotype.

These investigations test the hypothesis developed previously, that there are biomolecules which control and integrate cellular differentiation. Our specific interest in cellular differentiation lies in the area of what we refer to as basal or primitive cellular differentiation mechanisms. These mechanisms are common to all cells, and are required for simple recognition and growth regulation. We have investigated two models, the IMR-90 human fetal lung fibroblast model as a representative of normal growth control, and the CG model, canine glioma cells, a transplantable growth transformed cell line. These two models represent normal, and aberrant cellular differentiation control. In previous studies we have shown that the arrangement of the cell surface oligosaccharide structure on these cell types are predictive of phenotypic transition. We have developed, and partially characterized a series of BIOMODULATORS (BM) which delay the onset of display of neoplastic cells. Three classes of BIOMODULATOR have been explored; (1) a large molecular weight natural product (25-35 kDa), PokeWeed Mitogen (PWM); (2) a small molecular weight natural product (500 Da) Cellular Activator and Differentiator (CAD) and a number of natural and synthetic analogs; and (3) an indolizidine alkaloid natural product, Swainsonine (Sw) which has a known cellular target (oligosaccharide biosynthesis). Preliminary data is presented which structurally links some of these BIOMODULATORS in terms of their effective stereochemistry. These BIOMODULATORS, when used before PDL 38, prevent the cell surface oligosaccharide display changes typical of morphological senescence and delay their onset to PDL 100 or more. These BIOMODULATORS also appear to have regulatory effects on the neoplastic cell models. This re-regulation results in increases in generation time and an increase in the ability of these cells to be recognized by cytotoxic lymphocytes. Proton NMR linewidth measurements of the fraction of 'bound' water associated with the cellular surface of treated and untreated cell populations showed induced physical changes in the cell surface related to the use of the BIOMODULATOR and correlated to the oligosaccharide display changes. These data were interpreted as indicating an increase in the organizational level of these cells. The data for normal and neoplastic cell populations are compared and contrasted in an effort to form the basis for an analytical approach to the control and integration of differentiation mechanisms.