Characterization of the pulmonary arterial response to endothelin-1 and bosentan in neonatal pigs

BACKGROUND: This study determined the pulmonary vascular responses to intravenous (IV) administration of endothelin-1 (ET-1) before and after an IV bolus of bosentan (Ro 47-0203), an endothelin receptor antagonist, in anesthetized open-chest 48-hour-old and 2-week-old Yorkshire pigs. METHODS: Eighteen 48-hour-old and 25 2-week-old pigs were randomly allocated to receive either (1) 400 ng x kg(-1) x min(-1) of ET-1 or (2) 5 mg/kg or 10 mg/kg of Ro 47-0203 followed by 400 ng x kg(-1) x min(-1) of ET-1 over a 10-minute interval. Pulmonary vascular resistance (PVR, dyne sec/cm(-5)), elastic modulus (E(Yo), dyne/cm2), and characteristic impedance (Zo) were determined (+/- SEM). RESULTS: In 48-hour-old pigs, ET-1 decreased pulmonary artery pressure (PAP, dyne/cm2; 21,317 +/- 1,833 versus 17,757 +/- 1,823; p = 0.003). In 2-week-old pigs, ET-1 elevated PAP (19,009 +/- 1,834 versus 21,935 +/- 2,104; p = 0.003) and PVR (1,624 +/- 254 versus 2,302 +/- 416; p = 0.001), whereas bosentan abolished the ET-1 induced pulmonary and systemic vasoconstriction. Neither agent altered E(Y) or Z(o). CONCLUSIONS: ET-1 caused a pulmonary depressor response in 48-hour-old pigs and a constrictor response in 2-week-old pigs, whereas bosentan inhibited the ET-1 induced pulmonary arteriolar vasoconstriction in 2-week-old pigs. The response to ET-1 changes from dilation in 48-hour-old pigs (neonates) to constriction in 2-week-old pigs (infants) suggests a maturational dependent alteration in ET receptors during the first 2 weeks of life. These data suggest that bosentan may have potential clinical application in the treatment of newborn pulmonary hypertensive episodes as it ablated ET-1 induced pulmonary vasoconstriction, while maintaining systemic pressure.     

Effects of isoflurane, sevoflurane, and halothane on myofilament Ca2+ sensitivity and sarcoplasmic reticulum Ca2+ release in rat ventricular myocytes

BACKGROUND: The aim of this study was to describe and compare the effects of isoflurane, sevoflurane, and halothane at selected concentrations (i.e., concentrations that led to equivalent depression of the electrically evoked Ca2+ transient) on myofilament Ca2+ sensitivity, sarcoplasmic reticulum (SR) Ca2+ content, and the fraction of SR Ca2+ released during electrical stimulation (fractional release) in rat ventricular myocytes. METHODS: Single rat ventricular myocytes loaded with fura-2 were electrically stimulated at 1 Hz, and the Ca2+ transients and contractions were recorded optically. Cells were exposed to each anesthetic for 1 min. Changes in myofilament Ca2+ sensitivity were assessed by comparing the changes in the Ca2+ transient and contraction during exposure to anesthetic and low Ca2+. SR Ca2+ content was assessed by exposure to 20 mm caffeine. RESULTS: Isoflurane and halothane caused a depression of myofilament Ca2+ sensitivity, unlike sevoflurane, which had no effect on myofilament Ca2+ sensitivity. All three anesthetics decreased the electrically stimulated Ca2+ transient. SR Ca2+ content was reduced by both isoflurane and halothane but was unchanged by sevoflurane. Fractional release was reduced by both isoflurane and sevoflurane, but was unchanged by halothane. CONCLUSIONS: Depressed myofilament Ca2+ sensitivity contributes to the negative inotropic effects of isoflurane and halothane but not sevoflurane. The decrease in the Ca2+ transient is either responsible for or contributory to the negative inotropic effects of all three anesthetics and is either primarily the result of a decrease in fractional release (isoflurane and sevoflurane) or primarily the result of a decrease in SR Ca2+ content (halothane).     

Accuracy of self-screening for contraindications to combined oral contraceptive use

OBJECTIVE: To estimate how well a convenience sample of women from the general population could self-screen for contraindications to combined oral contraceptives using a medical checklist. METHODS: Women 18-49 years old (N=1,271) were recruited at two shopping malls and a flea market in El Paso, Texas, and asked first whether they thought birth control pills were medically safe for them. They then used a checklist to determine the presence of level 3 or 4 contraindications to combined oral contraceptives according to the World Health Organization Medical Eligibility Criteria. The women then were interviewed by a blinded nurse practitioner, who also measured blood pressure. RESULTS: The sensitivity of the unaided self-screen to detect true contraindications was 56.2% (95% confidence interval [CI] 51.7-60.6%), and specificity was 57.6% (95% CI 54.0-61.1%). The sensitivity of the checklist to detect true contraindications was 83.2% (95% CI 79.5-86.3%), and specificity was 88.8% (95% CI 86.3-90.9%). Using the checklist, 6.6% (95% CI 5.2-8.0%) of women incorrectly thought they were eligible for use when, in fact, they were contraindicated, largely because of unrecognized hypertension. Seven percent (95% CI 5.4-8.2%) of women incorrectly thought they were contraindicated when they truly were not, primarily because of misclassification of migraine headaches. In regression analysis, younger women, more educated women, and Spanish speakers were significantly more likely to correctly self-screen (P<.05). CONCLUSION: Self-screening for contraindications to oral contraceptives using a medical checklist is relatively accurate. Unaided screening is inaccurate and reflects common misperceptions about the safety of oral contraceptives. Over-the-counter provision of this method likely would be safe, especially for younger women and if independent blood pressure screening were encouraged.     

THE EFFECT OF INJECTIONS OF HEMOLYTIC STREPTOCOCCI ON SUSCEPTIBLE AND INSUSCEPTIBLE ANIMALS

1. Streptococci injected into the circulation of cats are quickly withdrawn and are found most numerously in the lung, less numerously in the liver and spleen, and in small numbers in the bone marrow, lymph nodes, muscle, and kidney. 2. The streptococci taken up by the lung are killed within 5 to 8 hours, although they remain visible in films for a number of days. In the liver they are killed less rapidly, and in the spleen a few may remain viable for a considerable period. 3. This bactericidal action may be demonstrated in pieces of excised lung but not in lung extracts, and is apparently dependent on the action of the living cell. 4. Streptococci injected into a susceptible animal, the rabbit, are also promptly removed from the circulation, but are distributed in different proportions, the liver and spleen absorbing almost as many as the lung, and the muscles also taking up an appreciable number. 5. As in the cat, the organisms taken up by the lung and liver of the living rabbit are promptly killed. Those which lodge in the muscles, however, multiply rapidly. 6. About the time that the streptococci have begun to develop in the muscles (4 to 8 hours after injection) the number in the blood stream begins to increase. 7. The increase in the blood stream is not due to exhaustion of the mechanism of their removal nor have these organisms acquired a resistance sufficient to maintain them in the blood stream of a normal animal. The septicemia, then, is probably the resuit of washing out of organisms from the infected tissues. 8. Attempts to immunize rabbits have been unsuccessful, but in certain treated animals the distribution of the organisms among the various organs approached that found in insusceptible animals; i.e., cats.     

ANTIBODY FORMATION AGAINST TREPONEMA PALLIDUM—AGGLUTINATION

It has been shown by our experiments that the serum of rabbits treated with emulsions of Treponema pallidum contains agglutinating substances. Normal rabbit serum also possesses agglutinating power for this organism, but, as in the case of normal bacterial agglutinins, to an extent very much inferior to that possessed by the sera of immunized animals. Normal human sera will agglutinate similar pallidum emulsions, as will the sera of certain syphilitic patients with positive Wassermann reactions. Whether or not there is a quantitative difference of diagnostic value between the sera of normal human beings and those of syphilitics remains to be seen. The sera of rabbits immunized with strain A agglutinate Noguchi''s strain 9 in dilutions as high as 1 to 500. We regard as the most important result of these experiments the demonstration of definite antibodies in the circulation of animals treated with dead emulsions of Treponema pallidum. Since it is our belief that the agglutinating effect is due to an antibody essentially the same as that which produces bactericidal, precipitating, and opsonic effects, i. e., that there is probably one type of antibody only, we believe that the demonstration of agglutinins establishes the fact that in syphilis as in bacterial diseases the host responds by the formation of antibodies or sensitizers specific for the treponema. Spirocheticidal experiments with these sera, both in vitro and in vivo, are in progress.     

Balanced conscious sedation with intravenous induction and inhalational maintenance for patients requiring endoscopic and/or surgical procedures

BACKGROUND AND OBJECTIVE: The use of inhalation sedation with sub-anaesthetic concentrations of sevoflurane and nitrous oxide mixture is expected to reduce amounts of intravenous sedative drugs needed to produce a balanced sedation with the benefits of having reduced side-effects. METHODS: Eighty-two patients requiring endoscopic and/or surgical procedures under conscious sedation and local anaesthesia were recruited for this pilot study. Conscious sedation was induced with a titrated dose of midazolam and propofol given intravenously until the clinical end-point of conscious sedation was achieved. Subsequently, during the procedure, the patient was asked to breathe sevoflurane 0.1-0.3% and a fixed ratio of 40% nitrous oxide in oxygen given through a face mask. RESULTS: In 78 patients (95.1%), the treatment was completed successfully. Patients were discharged back to the wards within 4-16 min (10.1) without significant side-effects. Treatment was satisfactorily accepted by 38 patients (48.7%) and considered excellent by 40 patients (51.3%). CONCLUSIONS: The use of titrated doses of intravenous sedative drugs for induction of conscious sedation followed by the use of low concentrations (0.1-0.3%) of sevoflurane combined with 40% nitrous oxide for maintenance of conscious sedation in patients requiring endoscopic and/or surgical procedures under local anaesthesia, has the potential advantages of reducing amounts of intravenous sedative drugs, less likelihood of problems from drug side-effects and fast recovery and discharge time. Further investigations to establish the technique are currently in progress.