Interaction of endothelin-1 and nitric oxide in endothelial barrier failure in the cat hindlimb.

OBJECTIVE: To determine the interactions of endothelin-1 (ET-1) and nitric oxide (NO) in the regulation of endothelial barrier function in skeletal muscle. METHODS: The protein sieving coefficient (1 - sigma f) was measured as an index of microvascular permeability in the isolated, perfused cat hindlimb preparation. The measurement was made to determine 1) the effects of ET-1 and NO on basal permeability by blocking the ETA receptor with BQ123 and NO production with the NO-synthase inhibitors L-NAME or L-NMMA; 2) if elevated NO (SNAP) affects permeability; and 3) the interaction of ET-1 and NO by ascertaining if NO-synthase inhibition or elevated NO can block the ET-1-induced permeability increases. Additionally, vascular resistance was determined under these conditions to see if increased microvascular pressures or increased shear stress might play a role in the permeability changes. RESULTS: Blocking either the ETA receptor or basal NO production did not affect basal permeability. Likewise, raising NO levels did not affect this permeability. Blocking the ETA receptor blocked the ability of ET-1 to cause a profound barrier failure. Increased NO also could block this ET-1-induced effect. Blocking the ETA receptor or elevating NO blocked the 2.5-fold increase in vascular resistance induced by ET-1. CONCLUSIONS: Since the ETA receptor does not reside on skeletal muscle endothelium, it is not likely that ET-1 acts directly on the endothelium to produce its effects. It could act through 1) increases in shear stress secondary to an ET-1-induced vasoconstriction; 2) ET-1-induced increases in microvascular pressure sufficient to cause an inflammatory reaction; or 3) stimulation of other cell types, such as leukocytes, to release inflammatory mediators that could damage the endothelium.

Effects of hyperbaric oxygen on ventricular performance, pulmonary blood volume, and systemic and pulmonary vascular resistance.

The cardiovascular effects of hyperbaric (3 atm abs) air, 100% oxygen, and hyperbaric oxygen (HBO2) at 3 atm abs were investigated in 13 pentobarbital-anesthetized dogs. We measured heart rate, arterial pressure, pulmonary artery pressure, right atrial pressure, left and right ventricular pressure, and cardiac output. From these we determined end diastolic pressure, +/-maximal dp/dt, maximal (dp/p), end systolic elastance, cardiac work, and systemic (SVR) and pulmonary vascular resistance (PVR). Pulmonary blood volume was obtained from the mean transit time of ascorbic acid. The significant results with HBO2 were a decrease in heart rate, cardiac output, and cardiac work. All left ventricular performance indices decreased, without a change in preload or afterload. In contrast, only right ventricular -dp/dt decreased. SVR increased but PVR did not change; 100% O2 produced similar but less pronounced responses. Hyperbaric air had only mild effects. Pulmonary blood volume and lung wet/dry ratio did not change. Our data suggest that HBO2 may act by a differential effect on the autonomic innervation of the right and left ventricles. The resultant ventricular imbalance may be of clinical importance in the mechanism of pulmonary edema in patients in congestive heart failure undergoing hyperbaric therapy.

Identification of childhood psychiatric disorder by informant: comparisons of clinic and community samples.

OBJECTIVE: To compare the identification of psychiatric disorder as informed by parents versus teachers in children aged 6-11 years and parents versus adolescents in youth aged 12-16 years in clinic versus community samples. METHOD: Study data come from parallel surveys in Hamilton, Ontario, of children aged 6-16 years. The surveys included consecutive referrals (N = 1150) between 1989 and 1991 to the region's 2 agencies providing outpatient child mental health services. Also, a simple random sample (N = 1689) was used, drawn in 1989 from students attending public schools. Conduct disorder, hyperactivity, emotional disorder, and somatization disorder were assessed by informants using the original Ontario Child Health Study scales. RESULTS: The percentage of children identified with a disorder was markedly higher in the clinic sample, irrespective of the type of disorder, the age and sex of the child, and who provided the assessment. Also, there was a statistically significant differential shift between parents and teachers in the percentage of children identified with disorder. The ratio of children aged 6-11 years identified with conduct disorder or hyperactivity by parents versus teachers was higher in the clinic sample than in the community sample. Among youth aged 12-16 years, a similar pattern emerged for parents as informants versus the adolescents themselves, but it was statistically nonsignificant. CONCLUSIONS: The data suggest that the relative contribution of informants to the identification of childhood psychiatric disorder varies by sample type: clinic and community. If risk factors for child disorder are influenced by contextually specific factors wedded to informants, then studies conducted in clinic versus community samples may lead to discrepant information about the determinants of psychopathology. The extent of this problem needs to be assessed by comparing the results of parallel studies conducted in clinic versus community samples.

Endothelin-1 induces endothelial barrier failure in the cat hindlimb.

Our purpose was to see whether endothelin- (ET) 1 could produce a change in the endothelial membrane barrier to protein in skeletal muscle. Previous studies in other tissues have suggested that ET-1 affects this barrier, but the measurement methods used could not exclude vascular protein extravasation due to microvascular pressure changes or the effects of changes in perfused capillary surface area. We measured the protein sieving coefficient, a specific measure of the permeability of the membrane to protein, in the isolated, perfused cat hindlimb preparation. The integral-mass balance method determined this coefficient from the changes in hematocrit and plasma protein concentration induced by a period of transvascular fluid filtration. The data clearly indicate that ET-1 produces a dose (1-20 nM) dependent increase in permeability indicative of barrier dysfunction. Hence, elevated ET levels may contribute to the perivascular edema, hemoconcentration, and impaired tissue perfusion found in systemic inflammatory response syndromes and related diseases.

Prediction of permeability-surface area product data by continuous-distribution pore models.

OBJECTIVE: To investigate the ability of continuous-distribution pore models to accurately predict permeability-surface area product (PS) experimental data in skeletal muscle. METHODS: Models having a water-only (WO) pathway and continuous distributions of microvascular transport-pathway sizes were fit to solute reflection-coefficient (sigma) experimental data (approximately 0.5-16 nm Stokes radii) obtained from skeletal muscle to determine optimal parameter values. Without further modification, these models were used to predict experimental PS values obtained from the literature for small solutes ranging in size from NaCl to inulin and for three proteins, alpha-lactalbumin, ovalbumin, and albumin (approximately 0.23-3.7 nm radii). The protein PSs were determined from fluorescent tracer-diffusion curves and a nonlinear model of tracer diffusion in the cat hindlimb preparation. The model's PS predictions were compared to those of a discrete-pore model previously developed and a fiber-matrix (FM) model. RESULTS: A log-normal (LN) continuous pore-size distribution plus WO-pathway model (three free parameters) fit the sigma data to within the 95% confidence intervals of each of eight solutes spanning a 32-fold size range and was nearly as close to the data as was the two discrete-pore plus WO-pathway model (four free parameters). Both models closely described the PS data for nine solutes spanning a 14-fold size range. The fit of a fiber-matrix plus WO-pathway model (three free parameters) to the sigma data was much poorer than for the other models. CONCLUSIONS: The LN and two-discrete-pore models accurately describe sigma and PS experimental data in cat and human skeletal muscle. Therefore, experimental data resulting from complex microvascular transport processes are well characterized by simple pore models.

Distribution of coronary arterial capacitance in a canine model.

The capacitative properties of the major left coronary arteries, left main (LM), left anterior descending (LAD), and left circumflex (LCX), were studied in 19 open-chest isolated dog hearts. Capacitance was determined by using ramp perfusion and a left ventricular-to-coronary shunt diastolic decay method; both methods gave similar results, indicating a minimal systolic capacitative component. Increased pericardial pressure (PCP), 25 mmHg, was used to experimentally alter transmural wall pressure. The response to increased PCP was different in the LAD vs. LCX; increasing PCP decreased capacitance in the LCX but increased capacitance in the LAD. This may have been due to the different intramural vs. epicardial volume distribution of these vessels and a decrease in intramural tension during increased PCP. Increased PCP decreased LCX capacitance by approximately 13%, but no changes in conductance or zero flow pressure intercept occurred in any of the three vessels, i. e., evidence against the waterfall theory of vascular collapse at these levels of PCP. Coronary arterial capacitance was also linearly related to perfusion pressure.

A single mothers' group for mothers of children attending an outpatient psychiatric clinic: preliminary results.

OBJECTIVES: To provide a preliminary report of data from 2 support groups for single mothers, all of whom were mothers of children attending a child outpatient psychiatric clinic. The groups' 2 purposes were: 1. to assess the feasibility of adding structured evaluation to a common clinical intervention; 2. to improve single mothers' parenting skills through raised levels of self-esteem, increased capacity for family functioning and reduced levels of depression. METHOD: Three structured evaluation instruments were used to measure the domains of self-esteem, family functioning and depression. These instruments were given to both groups of women on 3 occasions: 1. before the group; 2. after the group; 3. at a follow-up session 4 months after group termination. Open-ended questions were also asked at group termination. RESULTS: The questionnaire response rate was 100%; overall response rate for the 3 open-ended questions was 89%. Comparisons of pre-group and post-group scores showed that there was a significant increase in self-esteem (p < 0.01) and significant improvements in family functioning (p < 0.05) and depression (p < 0.01). CONCLUSION: It is possible to introduce a structured evaluation component into a common clinical intervention, and this support group seemed to assist single mothers' parenting skills. Methodologic concerns and future directions are discussed.

Effect of entrainment time on pulmonary deposition of cigarette smoke in dogs.

Chronic inhalation of tobacco smoke can produce a nonuniform pattern of lung disease, with apical (nondependent) areas affected more often and more severely than other lung regions. This localized tissue damage might be the result of uneven deposition of inhaled smoke aerosol. There is some evidence to suggest that the way in which an aerosol is inhaled can influence its deposition in the lung. This study sought to determine the effects of entrainment timing on the deposition of tobacco smoke in the lung. Anesthetized mechanically ventilated dogs (n = 14) inhaled 35-ml boluses of 14C-labeled mainstream cigarette smoke once per minute in either a supine or erect posture. Boluses were entrained at the start of inspiration (group 1) or at midinspiration (group 2). Lungs were removed, sectioned, and assayed for 14C. Group 1 lungs experienced deposition in regions distant from the tracheal axis, with peripheral lung units averaging twice the deposition of 14C as central units. Group 2 lungs had a more uniform 14C distribution pattern. Early smoke entrainment favored peripheral deposition. One explanation for this finding is that peripheral lung units may have shorter time constants, thus filling sooner and more completely than those located centrally.

A programmable inspiratory flow generator for aerosol bolus delivery.

A microcomputer-controlled system that generates a discrete digital approximation of a desired inspiratory flow profile is described. Discrete flows between 0 and 387.5 ml/s can be achieved in increments of 12.5 ml/s with five solenoid valves. This pneumatic digital-to-analog converter is coupled to a mixing apparatus so that boluses of aerosol can be delivered at precise moments during an inspired breath. Between bolus deliveries, the system provides maintenance ventilation and allows flow pattern, tidal volume, inspiratory-to-expiratory time ratio, and respiratory rate to be programmed as desired.

Fractal perspectives in pulmonary physiology.

Like other organs that exchange substantial quantities of material with blood, the lung accommodates a large two-dimensional surface in a component three-dimensional volume. The lung's structure shows a resemblance to certain one- and two-dimensional mathematical functions that possess plane- and space-filling properties. When viewed from a conventional geometric perspective, many of the familiar forms and functions of pulmonary tissue appear to possess unusual qualities that defy explanation. Mathematically, they behave as though they had a fractional geometric dimension. This property is shared by a class of functions known as fractals. Fractals are described, and practical techniques are presented to measure the properties of the edges and surfaces of the lung. The consequences of fractal structure are also considered for the bronchial tree, pulmonary vasculature, and microcirculation. Insights arising from viewing the lung in this new perspective are summarized.

Prevention of suicide.

We reviewed the epidemiologic features of suicide in Canada and evaluated suicide prevention programs. Three groups were found to be at increased risk for suicide: men aged 70 years or more, women aged 65 to 69 and men aged 20 to 24. The other groups, in decreasing order of risk, were the mentally ill, people who have attempted suicide, those with a life-threatening illness, native people, people with a family history of suicide and prisoners. Studies that evaluated suicide prevention programs showed that none significantly reduced the incidence of suicide; however, the studies were found to be methodologically inadequate or used noncomparable systems of data collection. On the basis of our findings we recommend that primary care physicians routinely evaluate suicide risk among patients in high-risk groups and that intervention include counselling, follow-up and, if necessary, referral to a psychiatrist. Close follow-up is recommended for newly discharged psychiatric patients and those who recently attempted suicide.

Fractal character of pulmonary microvascular permeability.

The pulmonary microvasculature offers a heterogeneous barrier to the motion of large solutes as they pass between blood and lymph. While this barrier has been approximated by a few discrete pathways or by statistical ensembles of many pathways, these descriptions only partly capture the structural and functional properties of the pulmonary microcirculation. The concept that this barrier may be a fractal object is explored. Endothelial cleft geometry displays scaling in junctional path length and self-similarity in its spatial organization. It is shown that a fractal cleft produces heterogeneous spaces capable of transporting water and macromolecules. Cleft location, size, and depth are characterized, in part, by a fractal dimension of approximately 0.8. The consequences for transport through a fractal barrier are then determined. Predicted sieving of macromolecules by a fractal barrier is found to be consistent with lung microvascular transport data. Nonlinear transport phenomena are one consequence of a barrier having a fractional dimension.

Distribution of transvascular pathway sizes through the pulmonary microvascular barrier.

Mathematical models of solute and water exchange in the lung have been helpful in understanding factors governing the volume flow rate and composition of pulmonary lymph. As experimental data and models become more encompassing, parameter identification becomes more difficult. Pore sizes in these models should approach and eventually become equivalent to actual physiological pathway sizes as more complex and accurate models are tried. However, pore sizes and numbers vary from model to model as new pathway sizes are added. This apparent inconsistency of pore sizes can be explained if it is assumed that the pulmonary blood-lymph barrier is widely heteroporous, for example, being composed of a continuous distribution of pathway sizes. The sieving characteristics of the pulmonary barrier are reproduced by a log normal distribution of pathway sizes (log mean = -0.20, log s.d. = 1.05). A log normal distribution of pathways in the microvascular barrier is shown to follow from a rather general assumption about the nature of the pulmonary endothelial junction.

A method to label cigarette smoke with 99mTc.

A method is described to label with 99mTc the particulate matter in the smoke from commercially obtained cigarettes. A solution of technetium heptasulfide is applied to the paper wrapper of the tobacco rod and then dried. Smoke from a cigarette treated in this way contains measurable amounts of 99mTc in the particulate phase. In contrast, no measurable radioactivity is found in the non-particulate (gaseous) phase of smoke. This method yields a gamma-emitting cigarette smoke which will permit future observation of particulate intake, deposition and clearance in experimental animals and man.

Cigarette smoking pharmacokinetics and its relationship to smoking behaviour.

The yield of a cigarette is determined by the tobacco blend, the length of the cigarette, the cigarette paper, the filter and air dilution. Cigarette yield has been defined by tradition and by law to be the yield of nicotine, tar and carbon monoxide obtained from a 35 ml puff volume of 2-second duration taken every minute during the burning time of the cigarette. Normally smokers draw a puff into their mouth and then inhale. Mouth delivery is largely determined by personal smoking behaviour. The puff volume, number of puffs taken per cigarette, and number of cigarettes smoked per day determine both the volume and the mass of daily mouth delivery. There are marked differences in smoking behaviour, and the delivery is substantially altered from the yield values obtained with the standardised test procedure. Body uptake of smoke ingredients is determined by smoke chemical parameters, smoker inhalation behaviour, lung morphology, and physiological parameters. The physiological parameters include tidal volume, vital capacity, rate of breathing, and rate of clearance for the lung. Given these behavioural and physiological differences in individual delivery and uptake it is not surprising that differences in measured parameters occur within smokers of cigarettes with a particular yield. Biological differences among individuals, such as metabolic and size differences, cause additional variations in these values. Therefore, the estimates of nicotine and tar delivery can vary widely in studies of individual uptake when the estimates are based upon sample population data. The variables in both smoking behaviour and in chemical and physiological factors which alter uptake make it essential to have a crossover design for any study. The large standard error for the plasma concentration of cotinine (a major metabolite of nicotine) within a sample population, and the log linear nature of the plasma cotinine concentration curve, requires a very large sample size for any study of cigarette delivery or uptake. When comparisons of brands are made, average values are misleading in that the skew to the high values obscures frequency differences among the lower values within the samples. It is important to remember that smoker compliance with study design is very essential.(ABSTRACT TRUNCATED AT 400 WORDS)

Histamine decreases selectivity of sheep lung blood-lymph barrier.

Histamine increases lymph flow and protein flux from the sheep lung. This increase in water and protein movement has been attributed to an increase in lung microvascular permeability-surface area product caused by histamine. Whether it was permeability that was changed or whether it was surface area cannot be discerned from past work. Histamine might increase either of these determinants of transport in the sheep lung. Previous measurements of several plasma protein fractions in plasma and lymph showed no change in the sieving behavior of the microcirculation with intravenous histamine, suggesting that only surface area was changed. In the present study, even larger test molecules were used to probe the limits of transport through the lung's blood-lymph barrier. Fluorescein isothiocyanate-labeled dextrans (FITC-dextran) that can normally permeate lung lymph do so more readily after intravenous histamine infusion (3 micrograms X kg-1 X min-1). Formerly impermeable FITC-dextran fractions also appear after histamine administration. No definitive size limit to the transport of dextran was found in histamine-stimulated sheep lungs. Intra-arterial histamine does not increase lung lymph, protein, or FITC-dextran flow. These results suggest that histamine changes the permeability or sieving characteristics of the lung microvascular barrier making it less size selective to large molecules. Surface area for transport may also increase.