Physiologic characterization of endothelin A and B receptor activity in the ovine fetal pulmonary circulation.

To determine the potential contribution of endothelin (ET) to modulation of high pulmonary vascular resistance in the normal fetus, we studied the effects of BQ 123, a selective ET-A receptor antagonist, and sarafoxotoxin S6c (SFX), a selective ET-B receptor agonist, in 31 chronically prepared late gestation fetal lambs. Brief intrapulmonary infusions of BQ 123 (0.1-1.0 mcg/min for 10 min) caused sustained increases in left pulmonary artery flow (Qp) without changing main pulmonary artery (MPA) and aortic (Ao) pressures. In contrast, BQ 123 did not change vascular resistance in a regional systemic circulation (the fetal hindlimb). To determine whether big-endothelin-1 (big-ET-1)-induced pulmonary vasoconstriction is mediated by ET-A receptor stimulation, we studied the effects of big-ET-1 with or without pretreatment with BQ 123. BQ 123 (0.5 mcg/min for 10 min) blocked the rise in total pulmonary resistance caused by big-ET-1. CGS 27830 (100 mcg/min for 10 min), an ET-A and -B receptor antagonist, did not change basal tone but blocked big-ET-1-induced pulmonary vasoconstriction. Brief and prolonged intrapulmonary infusion of SFX (0.1 mcg/min for 10 min) increased Qp twofold without changing MPA or Ao pressures. Nitro-L-arginine (L-NA), a selective endothelium-derived nitric oxide (EDNO) antagonist, blocked vasodilation caused by BQ 123 and SFX. We conclude that: (a) BQ 123 causes sustained fetal pulmonary vasodilation, but did not change vascular resistance in the fetal hindlimb; (b) Big-ET-1-induced pulmonary vasoconstriction may be mediated through ET-A receptor stimulation; and (c) ET-B receptor stimulation causes pulmonary vasodilation through EDNO release. These findings support the hypothesis that endothelin may play a role in modulation of high basal pulmonary vascular resistance in the normal fetus.     

Ca2+-Mg2+ ATPase of mouse cardiac sarcoplasmic reticulum is affected by membrane n-6 and n-3 polyunsaturated fatty acid content

White mice, 18-20 g, were fed purified diets containing two weight percent safflower oil plus ten weight percent menhaden, corn, or olive oil for 2 wk. Menhaden oil ingestion resulted in significantly higher levels of 22:6(n-3) and 20:5(n-3), particularly 22:6(n-3), and lower levels of 20:4(n-6) and 18:2(n-6) in cardiac sarcoplasmic reticulum (SR) phospholipids than did corn or olive oil ingestion. These changes in fatty acid composition resulted in a significant decrease in the value of the n-6/n-3 fatty acid ratio of cardiac SR phospholipids. The ratio was 2.8 versus 0.2 in choline phospholipids and 1.9 versus 0.2 in ethanolamine phospholipids in SR of mice fed corn or menhaden oil, respectively. This reduction in the n-6/n-3 fatty acid ratio was associated with a lower relative activity of Ca2+-Mg2+ ATPase, and a lower initial rate of calcium transport and maximum calcium uptake in SR vesicles from mice fed menhaden oil rather than olive or corn oils. The specific activity of NADPH cytochrome C reductase (EC 1.6.2.3) of cardiac SR was not affected by dietary lipids. These data indicate that modification of SR by 22:6(n-3) may change the SR bilayer structure resulting in alteration of the calcium transport properties of SR vesicles. In addition, our results suggest that reduction of calcium flux across cardiac SR following fish oil consumption may also reduce the susceptibility of myocytes to rapid changes in calcium concentrations which may occur during ischemia and reperfusion.     

Plasma Histamine After Methacholine, Allergen, and Aspirin Challenges

Plasma histamine levels were measured by radio-enzymatic technique in seven patients following 10 challenges: five methacholine challenge tests, four antigen inhalation challenge tests, and one oral aspirin challenge test. Baseline plasma histamine was the same in all patients except in the aspirin-challenged patient, who had a higher baseline histamine level. There was no statistical change in the level of histamine throughout the test in either the methacholine-challenged or the antigen-challenged patients, whereas there was a marked increase in histamine levels in the aspirin challenged patient. A possible explanation is that methacholine and antigen are inhaled and therefore have primarily local effects on the lung, whereas oral aspirin has a systemic effect with consequently systemic changes in histamine which are detectable as changes in plasma level.     

Sequential comparison of low dose rate and hyperfractionated high dose rate endobronchial radiation for malignant airway occlusion.

A pilot trial (S2) was conducted at the University of Wisconsin to determine the feasibility, efficacy, and toxicity of hyperfractionated high dose rate endobronchial radiation. To avoid multiple bronchoscopies, an optimized hyperfractionated schema was derived from the linear-quadratic model. Utilizing a single bronchoscopy, 31 patients with malignant airway occlusion received 4 Gy x 4 fractions over 2 days at 2 cm from source center using a high dose rate remote afterloader. Response and morbidity were compared to a previous trial (S1) in which 66 patients were treated with conventional low dose rate endobronchial radiation. Response was assessed by change in performance status, symptom resolution, percent of lifetime rendered symptom-free or improved, and radiographic reaeration. These parameters were highly comparable between the two groups. The mean ECOG performance status improved from 2.2 to 1.8 for S1 and 2.1 to 1.6 for S2; symptom improvement or resolution was noted in 78% for S1 and 79% for S2; lifetime rendered symptom-free or improved was 54% for S1 and 57% for S2; and the overall radiographic response rate was 78% for S1 and 85% for S2. The overall incidence of fistulae was 7/101. We conclude that endobronchial radiation is an effective and safe modality for palliation, and hyperfractionated high dose rate endobronchial radiation achieves responses similar to low dose rate endobronchial radiation with a similar complication rate.     

Ductal shunting and effective systemic blood flow following single dose surfactant treatment in the premature baboon with hyaline membrane disease.

We studied the hemodynamic effects of using natural surfactant in premature baboons with hyaline membrane disease (HMD). Study animals (n = 5) received a single dose of surfactant immediately after delivery and control animals (n = 8) did not. Using microspheres at 3, 8, and 23 h we found no significant differences in left ventricular output, effective systemic flow, systemic-to-pulmonary patent ductus arteriosus (PDA) shunting, or in cerebral or renal organ blood flow. However, both groups had large PDA shunts (fraction of LVO to lungs greater than 0.40-0.55 at 3 and 8 h) resulting in low systemic perfusion (less than 80 ml/min/kg). Single dose surfactant did not improve the myocardial dysfunction and low cerebral and renal blood flow which occur during treatment for HMD.     

Defining the role of radiosurgery in the management of brain metastases.

The role of stereotactic radiosurgery in the management of recurrent and newly diagnosed brain metastases was evaluated prospectively. From December 1988 to March 1991, 58 lesions in 40 patients were treated with accelerator-based stereotactic radiosurgery. All patients were followed for a minimum of 6 months or to death. The primary purpose was to determine the impact of radiosurgery on local control and its subsequent effects on quality of life. An overall tumor control rate of 82% with a complete response rate of 43% were achieved. As anticipated, the response rate for smaller tumors was substantially better than that for larger tumors (78% for lesions < 2 cm3; 50% for lesions > or = 10 cm3). Although the overall in-field progression rate was 18.5%, only 1/23 (4%) complete responders subsequently recurred. The in-field failure rate is highly comparable with recently published surgical data. Progression outside the brain was noted in two-thirds of patients. One quarter of the deaths were neurologic. The median survival for this minimally selected patient population was 6.5 months. Stereotactic radiosurgery was also associated with improved quality of life as measured by Karnofsky score, neurologic function, and steroid dependence. Long-term steroid dependence was encountered in only four patients. We conclude that stereotactic radiosurgery can be used effectively in patients with brain metastases. In this series, a high tumor response rate was achieved which was associated with improved quality of life.     

Everyday memory following traumatic brain injury

Residual memory deficits may represent a problem to the everyday functioning of a large number of people, including those who have sustained traumatic brain injury (TBI). The present exploratory study sought to investigate the interrelationships between subjective memory reports, performance on traditional memory tests, and performance on tests of prospective memory. These interrelationships were contrasted between a group of 24 adults who had sustained TBI and a group of 24 matched control subjects. Prospective memory was hypothesized to be indicative of everyday memory functioning. The results provided preliminary evidence that prospective memory tests are sensitive to TBIrelated neurological impairment and, in comparison to traditional tests, may be better indicators of functional memory capacity. This pattern was particularly true for control subjects, possibly because TBI subjects had difficulties in evaluating their memory functioning.