Corticoid regulation of atrial natriuretic factor secretion and gene expression.

This study investigated the acute effects of glucocorticoids and mineralocorticoids on atrial natriuretic factor (ANF) biosynthesis in vivo. Groups of male Sprague-Dawley rats were injected with 1 mg dexamethasone (Dex), 10 mg deoxycorticosterone acetate (DOCA) or vehicle alone. Different groups were studied after periods of 30 min to 8 h. Plasma and left atrial ANF concentrations and ANF mRNA levels were measured 2-8 h after corticoid injection. From 30 min to 2 h after injection, ANF mRNA was analyzed by quantitative and qualitative assessments. There was a two- to threefold increase in plasma levels of ANF in Dex-treated rats compared with controls at all time periods (P < 0.05). Although ANF plasma levels increased over time following DOCA treatment, they were not significantly different from control values. Dex treatment also increased normalized ANF mRNA levels 77% above control levels during the first 4 h after injection (P < 0.05). Thereafter there was a return of mRNA levels to that seen in controls. There was no qualitative difference in the ANF mRNA at any time as assessed by Northern hybridization. In contrast, DOCA increased ANF mRNA levels only after 8 h (P < 0.05). No significant changes in left atrial ANF content were noted during this study. In a separate study, Dex was administered to isolated left atria in vitro in a superfusion system. Superfusion with 2 x 10(-5) M Dex produced a 40% increase in ANF secretory rate within 20 min (P = 0.036). We conclude that Dex induces a direct rapid increase in ANF mRNA levels and ANF secretion in rats.(ABSTRACT TRUNCATED AT 250 WORDS)


Effect of coronary perfusion of heptanol or potassium on conduction and ventricular arrhythmias.

Abnormalities in cellular coupling, modulated in part by intracellular gap junctions, have an important role in the genesis of reentrant arrhythmias in the setting of chronic myocardial infarction. The effects of heptanol, which has a relatively selective action on gap junctional resistance at low concentrations, and potassium, which primarily affects active membrane properties, were assessed using a localized intracoronary infusion system in 11 normal dogs in vivo. Both agents caused a dose-related slowing of conduction. Programmed stimulation during potassium infusion resulted in ventricular fibrillation in two of six animals treated with a low dose (5.0-5.5 meq/l) and five of six animals treated with a high dose (7.0-7.5 meq/l). During the infusion of 1.0 mM heptanol, uniform ventricular tachycardia was induced in four of eight animals. Infusion of heptanol, but not potassium, increased the susceptibility to presumably reentrant ventricular tachycardia in normal myocardium. This suggests that agents that affect cellular coupling may have markedly different arrhythmogenic consequences than agents that primarily alter active membrane properties.


Prostacyclin rather than endogenous nitric oxide is a tissue protective factor in myocardial ischemia.

Nitric oxide (NO) and prostacyclin (PGI2) were determined in effluents of Langendorff-perfused rabbit hearts subjected to 2 h of global low-flow ischemia and subsequent reperfusion. PGI2 release [6-oxo-prostaglandin (PG) F1 alpha] was significantly enhanced during early reperfusion and remained elevated. NO formation was reduced during ischemia but did increase substantially during reperfusion. Indomethacin (3 microM) significantly suppressed ischemia-related 6-oxo-PGF1 alpha and NO release. This was accompanied by severely diminished myocardial recovery. NG-nitro-L-arginine (L-NNA) (100 microM) suppressed NO generation without major effects on 6-oxo-PGF1 alpha generation and cardiac dysfunction but with a remarkable increase in coronary perfusion pressure. These effects of L-NNA were antagonized by L-arginine, whereas the effects of indomethacin were not. There was a substantial loss of creatine kinase specific activity from reperfused ischemic hearts, which was further aggravated by indomethacin but not by L-NNA. These data demonstrate a cardioprotective and endothelium-protective role of PGI2 in myocardial ischemia, which also involves preservation of NO generation. Endogenous NO appears to be important for local regulation of coronary flow.


Extracorporeal circuits and autoregulation: effect of albumin coating.

Autoregulation of muscle blood flow often is difficult to demonstrate when extracorporeal perfusion is used. This could be caused by contact of blood and foreign material. Accordingly, we tested whether autoregulation is preserved when the system is coated with albumin. Polyurethane tubing between the carotid and distal femoral artery of rats was partially occluded for 1-2 min. With the system uncoated (n = 6 rats) autoregulation was absent. With coated systems (n = 6 rats) the closed-loop gain (Gc) of the apparent autoregulation (0 < Gc < 1) for the pressure range from control (137 +/- 14) to 80 mmHg was 0.40 +/- 0.24 (mean +/- SD). In most cases autoregulation was preceded by a period of "superregulation": after a variable delay flow rose above control. When the distance between occluder and tip of femoral cannula was varied in another group of rats (n = 6), the delay (20-75 s) was linearly related to transit time (10-35 s) of blood. Flow increase thus seemed to be caused by a blood-borne vasodilator originating at the occlusion site and not by a myogenic or metabolic response to decreased pressure and flow. The vasodilator did not originate from the albumin coating. Partial occlusion of an extracorporeal shunt thus can increase flow to the perfused tissue when the system is coated with albumin. The reaction readily disappears when the system is not coated.


Hydraulic conductivity of basement membrane with computed values for fiber radius and void volume ratio.

The basement membrane contributes to resistance to ultrafiltration of the capillary wall, but efforts to conduct studies of this material have been hindered by difficulty in obtaining homogenous sources and by compression from high filtration pressures. We utilized Matrigel in a conductivity chamber and showed that it reproducibly yielded a specific hydraulic conductivity of (2.247 +/- 0.328) x 10(-14) cm2, which is within 21% of that obtained for porcine glomerular basement membrane by Robinson and Walton (Microvasc. Res. 38: 36-48, 1989). No compression or hysteresis was observed over 5-25 cmH2O pressure difference. Depending on whether data were fit to drag or hydraulic radius fibermatrix models, fiber radius was 0.626-0.696 nm, and void volume ratio varied between 0.826 and 0.846, the former agreeing with the major components of Matrigel. Ready availability of Matrigel, its uniform hydraulic conductivity, and its fit to fibermatrix theory make it ideal to study changes in basement membrane during physiological and pathological changes. Moreover, results of such studies are likely applicable to endothelial barriers, whose luminal and intercellular surfaces are lined with fibrillar materials.


Relative responses to luminal and adventitial adenosine in perfused arteries.

Responses to luminal and adventitial adenosine were compared in perfused rabbit central ear arteries. Perfused arteries precontracted with 0.5 microM norepinephrine relaxed dose dependently but asymmetrically to luminal and adventitial adenosine. Arteries were more responsive to luminal adenosine in the 0.1- to 1.0-microM range, but they were more responsive to adventitial adenosine at doses > 10 microM. Alternatively, 2-chloroadenosine, a metabolically stable and poorly transported analogue, was equipotent when applied luminally or adventitially. Endothelial damage reduced sensitivity and response asymmetry to luminal and adventitial adenosine. This was consistent with reduced responses to adenosine in luminally rubbed arterial ring segments. Transport inhibition (10 microM dipyridamole) enhanced arterial reactivity to luminal and adventitial adenosine and reduced response asymmetry but was without effect on responses to 2-chloroadenosine. A comparison of the inhibitory effectiveness of adventitial and luminal 8-phenyltheophylline revealed that adventitial antagonist was approximately threefold more effective in inhibiting responses to adventitial adenosine than luminal antagonist (P < 0.05). This "side-dependent" difference was reduced by prolonged antagonist incubation or endothelial removal. The data indicate that adenosine relaxes ear arteries by activation of smooth muscle [half-maximum effective concentration (ED50) approximately 11 microM] and endothelial (ED50 approximately 2 microM) receptors. Nevertheless, a sensitive endothelial-dependent response does not consistently enhance responses to luminal adenosine in perfused arteries. This appears to be attributable to relative differences in the smooth muscle and endothelium-dependent components of the dilator response and transvascular concentration gradients for luminally and adventitially applied adenosine. A transendothelial diffusion barrier also reduces the ability of luminally applied antagonists to inhibit responses to adventitial adenosine.


Reversal by increased CSF [H+] and [K+] of phorbol ester-induced arteriolar constriction in piglets.

We determined whether several dilator stimuli could counteract phorbol ester-induced constriction of pial arterioles. A closed cranial window was implanted, and the diameter of one pial arteriole was determined by intravital microscopy in newborn pigs. Diameter of one pial arteriole was determined during baseline conditions and topical application of 10(-5) M phorbol 12, 13-dibutyrate (PDB) and during subsequent application of one of the following: arterial hypercapnia (inhalation of 10% CO2), topical application of cerebrospinal fluid with 12 mM K+, or topical application of 10(-5) M isoproterenol in cerebrospinal fluid. PDB constricted the arterioles from 101 +/- 5 to 70 +/- 5 microns (27 +/- 4%; n = 28). During this period of constriction which lasted longer than subsequent interventions (> 90 min), arterial hypercapnia dilated the arterioles by 85 +/- 19% (n = 12), and topical 12 mM K+ dilated the arterioles by 59 +/- 12% and caused vasomotion (n = 7). Despite blockade of direct dilator effects of arterial hypercapnia by indomethacin, arterial hypercapnia still reversed phorbol ester-induced constriction, suggesting that acidosis by itself is sufficient to cause this effect. In contrast, topical isoproterenol did not dilate PDB-constricted arterioles (n = 9); however, topical forskolin (2.4 x 10(-7) M) did reverse constriction, implying that protein kinase C activation may interfere with proper functioning of the beta-adrenoceptor. Therefore, increased extracellular fluid levels of K+ and H+, but not isoproterenol, are able to interfere with cerebrovascular consequences of protein kinase C activation.


Adenosine improves recovery of postischemic myocardial function via an adenosine A1 receptor mechanism.

The effects of adenosine in the nonischemic heart have been shown to be mediated via its binding to extracellular adenosine A1 and A2 receptors located predominantly on myocytes and endothelial cells, respectively. We tested the hypothesis that the beneficial effect of adenosine on postischemic myocardial function is mediated via an adenosine A1 receptor mechanism. Isolated rat hearts perfused at constant pressure (85 cmH2O) were subjected to 30 min of global no-flow ischemia (37 degrees C) and 45 min of reperfusion. Hearts treated with adenosine (100 microM) and the adenosine A1 receptor agonist N6-cyclohexyladenosine (CHA; 0.25 microM) recovered 72 +/- 4 and 70 +/- 4% of preischemic left ventricular developed pressures (LVDP), respectively, after 45 min of reperfusion compared with untreated hearts (54 +/- 3% of preischemic LVDP). Adenosine and CHA hearts exhibited greater myocardial ATP contents than control hearts after 10 min of ischemia, but there were no differences in tissue ATP levels after 30 min of ischemia. In contrast, hearts treated with the adenosine A2 receptor agonist phenylaminoadenosine (0.25 microM) failed to demonstrate improved postischemic function (52 +/- 5%). The addition of the A1-selective antagonist 8-cyclopentyl-1,3-dipropylxanthine blocked the cardioprotective effect of adenosine (57 +/- 4%). These results suggest that adenosine enhances postischemic myocardial function via an A1 receptor mechanism.


Characteristics and origin of myogenic response in isolated mesenteric arterioles.

Responses to changes in intravascular pressure of isolated rat mesenteric arterioles were investigated under no-flow conditions. First-, second-, third-, and fourth-generation arterioles were isolated and cannulated. Vascular diameters were measured with an image-shearing device and recorded. The arterioles (except for the first-generation vessels) developed spontaneous tone, corresponding to the step increases in intravascular pressure (from 20 to 160 mmHg, by 20-mmHg steps). For example, at 80 mmHg pressure the mean diameters of first-, second-, third-, and fourth-generation vessels were 286.9 +/- 5.0, 203.4 +/- 8.2, 92.5 +/- 4.6, and 35.6 +/- 4.8 microns, respectively; by use of a Ca(2+)-free solution containing ethylene glycol-bis(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid (1 mM) and sodium nitroprusside (SNP; 10(-4) M) the passive diameters of these vessels were 295.6 +/- 6.3, 238.4 +/- 11.7, 120.3 +/- 3.7, and 59.4 +/- 3.1 microns, respectively, demonstrating that the degree of pressure-induced constriction increased with the increasing order of generations (3, 14, 24, and 43%, respectively). The vasoactive function of endothelium and vascular smooth muscle was assessed by the responses of arterioles to acetylcholine (ACh; 10(-6) M) and SNP (10(-7) M) before and after removal of the endothelium with air. After removal of the endothelium, dilation to ACh was abolished while dilation to SNP was retained. Removal of the endothelium did not significantly alter the changes in the diameter of arterioles in response to step increases in intravascular pressure.(ABSTRACT TRUNCATED AT 250 WORDS)


Glycogen depletion-induced lactate reductions attenuate reflex responses in exercising humans.

Post leg exercise circulatory arrest (PLE-CA) raises blood pressure (BP) and reduces peak forearm vascular conductance (C). This reflex is evoked by activation of muscle afferents that are often sensitive to lactic acid. We tested the hypothesis that lactic acid reductions induced by muscle glycogen depletion would attenuate the lower-limb metaboreceptor-mediated pressor and forearm vasoconstrictor responses. Eleven subjects had C measured (plethysmography) during post leg exercise circulatory arrest (PLE-CA) (supine bicycle exercise for 9 min, 10 s at 75% VO2max before and after undergoing a glycogen-depletion paradigm (24-h fast followed by 10 min of supine leg exercise at 75% VO2max). In six subjects with lower lactate values, C during PLE-CA was higher after glycogen depletion (0.39 +/- 0.05 vs. 0.21 +/- 0.01 ml.min-1.100 ml-1 x mmHg-1; P < 0.01) and BP was lower (113 +/- 6 vs. 128 +/- 6 mmHg, P < 0.01). In five subjects without attenuated lactate responses, C and BP during PLE-CA were not different. Muscle biopsies (n = 5) demonstrated that the paradigm lowered muscle glycogen concentrations. Thus glycogen depletion-induced reductions in muscle lactate are associated with reduced muscle metaboreceptor-mediated responses.


Sarcolemmal Na(+)-Ca2+ exchange activity and exchanger immunoreactivity in developing rabbit hearts.

It has been postulated that as a consequence of an underdeveloped sarcoplasmic reticulum, sarcolemmal Na(+)-Ca2+ exchange assumes relatively greater importance in modulating Ca2+ fluxes in the developing heart. To explore this concept, cardiac sarcolemmal vesicles were prepared from late fetal (28-day gestation), newborn (24-48 h), immature (14-16 days), and adult New Zealand White rabbits. Na(+)-dependent Ca2+ uptake was measured by diluting Na(+)-loaded (140 mM) vesicles into Na(+)-free buffer and measuring 45Ca2+ uptake (40 microM Ca2+) by timed quenching and rapid filtration. Vesicles from all four age groups demonstrated Ca2+ uptake curves characteristic of Na(+)-Ca2+ exchange with stimulation by valinomycin and inhibition by amiloride. Initial uptake velocity (measured at 2 s and corrected for the fraction of competent vesicles) was significantly higher in fetal (23.2 +/- 5.5 nmol/mg) and newborn (26.2 +/- 5.9 nmol/mg) than in adult sarcolemmal preparations (7.3 +/- 1.2 nmol/mg). Uptake was intermediate in the 2-wk-old group (13.7 +/- 1.7 nmol/mg). The relative amounts of exchanger protein were compared by quantitating immunoreactivity using a polyclonal antibody to the Na(+)-Ca2+ exchanger. Densitometric scanning of protein slot blots demonstrated approximately 2.5 times more exchanger protein in fetal and newborn sarcolemma than in adult preparations. The relative amount of exchanger protein detected immunologically corresponded with the age-related differences observed in exchanger activity. Thus the cardiac sarcolemmal Na(+)-Ca2+ exchanger is abundant and functionally well-developed in the late fetal/early newborn rabbit heart and appears to decline postnatally.(ABSTRACT TRUNCATED AT 250 WORDS)


Development of cardiac innervation, ventricular fibrillation, and sudden infant death syndrome.

The effects of bilateral vagotomy and of right, left, and bilateral stellectomy on sinus node and on ventricular fibrillation threshold (VFT) were assessed in three groups of puppies (1, 3, and 5 wk old) and one group of adult dogs. Heart rate was increased by vagotomy and reduced by right stellectomy in all groups. After vagotomy, VFT did not change in the first week, while it decreased in the third week (-21%, P < 0.0001), in the fifth week (-20%, P < 0.001) and in the adults dogs (-18%, P < 0.005). VFT was not modified by right stellectomy in the first week and in the fifth week (0%, NS), while it decreased in the third week (-28%, P < 0.05) and in the adults (-32%, P < 0.001). Left stellectomy, performed after right stellectomy, increased VFT in the third week (+52%, P < 0.05), in the fifth week (+62%, P < 0.001), and in the adults (+45%, P < 0.01). Thus removal of either vagal or right cardiac sympathetic activity increases susceptibility to ventricular fibrillation already during the first weeks of life. By contrast, removal of left sympathetic nerves increases cardiac electrical stability. These findings are consistent with the hypothesis that a developmental abnormality in cardiac innervation may play a role in the genesis of some cases of sudden infant death syndrome.


Baroreflex regulation of forearm vascular resistance after exercise in hypertensive and normotensive humans.

The mechanisms underlying the antihypertensive period following a bout of exercise are not well understood. We examined the aftereffects of exercise on the linear relationship between forearm vascular resistance (FVR) and estimated central venous pressure (CVP) during leg raising and lower body negative pressure to determine whether an alteration of the baroreflex control of FVR was associated with the decreased blood pressure. Blood pressure, forearm blood flow (FBF), and estimated CVP were obtained in 13 hypertensive and 9 normotensive subjects evaluated in a randomized crossover fashion after 30 min of cycle ergometer exercise and after a nonexercise control period. In hypertensive subjects, the reduced blood pressure was accompanied by an increased baseline FBF after exercise. This resulted in a downward shift of the FVR-CVP relationship, while the slope was unchanged. In normotensive subjects, blood pressure and baroreflex control of FVR were unaffected by prior exercise. Four of the hypertensive subjects performed an additional study in which forearm skin was vasodilated with local heating to FVR levels similar to those observed after exercise. Results suggested that the aftereffects of exercise could not be attributed to changes in cutaneous blood flow. We speculate that modulation of the baroreflex control of FVR after exercise contributes to its antihypertensive effect.


K+ATP-channel activation causes marked vasodilation in the hypertensive neonatal pig lung.

We studied the potential role of ATP-sensitive potassium (K+ATP) channel activation in mediating pulmonary vasodilation in newborn piglets. Piglet lungs (n = 14, ages 1-4 days) were artificially perfused with recirculating Ringer solution containing bovine serum albumin and statistically inflated using 95% O2-5% CO2. We measured pulmonary arterial pressure (Ppa) and distribution of pulmonary vascular resistance (using double-occlusion method). Under resting conditions (Ppa 13.7 +/- 1.6 cmH2O, mean +/- SE), the K+ATP channel agonist BRL 38227 (lemakalim, 10(-7) and 10(-6) M) caused small dose-dependent pulmonary vasodilation. This response was diminished by the K+ATP-channel blocker glibenclamide (10(-5) M). Pretreatment of lungs with indomethacin (10(-5) M) and N omega-nitro-L-arginine (10(-5) M) to inhibit cyclooxygenase- and nitric oxide (NO)-related vasodilation, respectively, resulted in a marked increase in the baseline Ppa to 85.6 +/- 11.2 cmH2O. Injection of BRL 38227 (10(-7) M and 10(-6) M) in these lungs decreased Ppa to 72.5 +/- 8.5 (P < 0.01) and 19.3 +/- 0.9 cmH2O (P < 0.01), respectively; the corresponding times for half-recovery of Ppa (t1/2R) were 5.7 +/- 4.3 and > 20 min. Glibenclamide (10(-5) M) abolished the response to 10(-7) M BRL 38227 and significantly diminished (P < 0.05) the decreases in Ppa and t1/2R in response to 10(-6) M BRL 38227 but not to acetylcholine (10(-10) M). We conclude that activation of K+ATP channels has a minimal role in maintaining basal pulmonary vasomotor tone but is able to induce marked vasodilation when NO and cyclooxygenase-dependent vasodilatory mechanisms are inhibited.


Aortic perfusion pressure as early determinant of beta-isomyosin expression in perfused hearts.

Pressure overload in vivo induces an increase in cardiac protooncogene and stress protein expression that may initiate the long-term genetic changes observed in hypertrophy. To known whether mechanical stimulus is linked to specific gene transcription, expression of immediate early genes and synthesis of total proteins and myosin heavy chains (MHCs) were studied in beating and KCl-arrested isolated rat hearts perfused for 2 h under various coronary pressures. The main result of this study is that in the beating heart an augmentation of aortic pressure from 60 to 120 mmHg results in a pronounced enhancement of the synthesis of MHC (+59%) and of the expression of the beta-MHC isomyosin mRNA (iso-mRNA; +104%). Also, total protein synthesis and the amounts of poly-(A)+, c-fos, c-myc, and heat-shock protein HSP68 mRNAs were increased. To arrest the heart at 60 mmHg has no effect on total protein synthesis and on the amounts of poly(A)+, alpha-MHC and beta-MHC iso-mRNAs, and mRNAs coding for oncoproteins, but the synthesis of MHC decreased by 24%. By contrast with what we have observed in the beating heart, the augmentation of the coronary pressure in the arrested heart stimulates total protein synthesis and increases the amount of poly(A)+, c-fos, c-myc, and HSP68 mRNAs but has no effect on the expression of both MHC iso-mRNAs. In conclusion, the activation of myosin synthesis by high coronary pressure in this model has mainly a pretranslational origin when the heart is beating.(ABSTRACT TRUNCATED AT 250 WORDS)


Left ventricular dimensions during hemorrhagic shock measured by biplane cinefluorography.

The effects of hemorrhagic shock on left ventricular dimensions and volume were studied in 15 splenectomized dogs. A 42 +/- 1% decrease in total blood volume caused arterial blood pressure to fall 60% (from 120 +/- 5 to 48 +/- 3 mmHg); the first derivative of left ventricular pressure at a developed pressure of 40 mmHg fell 54% (from 1,930 +/- 94 to 905 +/- 93 mmHg/s, P < 0.05). Cardiac output fell 76% due to a 73% decrease in stroke volume; heart rate was unchanged at the end of hemorrhage but increased 50% during 3 h of sustained shock (from 110 +/- 6 to 166 +/- 8 beats/min, P < 0.05). During hemorrhage the septal-lateral and the anterior-posterior end-diastolic dimensions fell to a greater extent (7.8 mm, -21% and 7.0 mm, -18%, respectively) than the apex-base dimension (2.3 mm, -3.3%, P < 0.05). As a result of these dimensional changes, left ventricular end-diastolic volume fell 39% (from 48 +/- 2 to 28 +/- 1 cm3, P < 0.01). End-systolic dimensions fell in the same proportion during hemorrhage, resulting in a 30% decrease in end-systolic volume (from 30 +/- 2 to 21 +/- 1 cm3, P < 0.05). After 120 min of sustained shock, all end-diastolic dimensions remained unchanged, but end-systolic dimensions and volume increased significantly from values measured at end hemorrhage (P < 0.05), causing ejection fraction and stroke volume to fall to a greater extent. This study confirms a pronounced reduction in the minor axes of the left ventricle during hemorrhagic shock with subsequent reduction in ventricular function.


Tonic sympathetic excitation and vasomotor control from pontine reticular neurons.

The pontine reticular formation (PRF) was explored for regions providing tonic control of arterial pressure, heart rate, and activity of sympathetic nerves. In Saffan (alfaxalone-alfadolone)-anesthetized rats, discharge of neurons in the PRF or rostral ventrolateral medulla (RVLM) was inhibited by microinjections of glycine (1 M; 65 +/- 2 nl). PRF blockade caused large, short-lasting (116 +/- 17 s) decreases in arterial pressure and equal decreases in renal (-47 +/- 4%) and splenic (-45 +/- 4%) nerve activity, indicating that PRF neurons contribute to resting control of vasomotor discharge. In contrast, RVLM blockade caused long-lasting (41 +/- 3 min) decreases in arterial pressure and unequal decreases in activity of renal (-50 +/- 4%) and splenic (-31 +/- 6%) nerves. The short duration of the responses to PRF blockade could not be attributed to compensation by baroreceptors or by actions specific to glycine. Excitation of PRF neurons with amino acids caused increases as well as decreases in arterial pressure and sympathetic activity, and therefore activated neurons distinct from those that are tonically active. These results identify a source of cardiovascular control in the reticular formation of the pons that provides tonic excitatory drive to sympathetic nerves and that differs from the well-known source in the RVLM.


Chronic administration of cardiovascular drugs: altered energetics and transmembrane signaling.

The effects of clinically used cardioactive agents in furazolidone-induced cardiomyopathy in the turkey poult have been recently reported, and note-worthy differences in cardioprotective efficacy of adrenergic effectors, calcium channel blockers, and cardiac glycosides have been noted in animal and human studies of heart failure. We therefore investigated the effects of chronic oral administration of cardioactive agents on ventricular tissue from normal turkey poults, and we determined whether these agents altered cardiac function, energetics, or transmembrane signaling pathways in a manner that might contribute to the varying degrees of cardioprotection and therapeutic efficacy reported previously. Creatine content was significantly higher in propranolol- and atenolol-treated animals. There was also higher lactate dehydrogenase and creatine kinase activities, reflecting an overall increase in energy reserve. Treatment with the calcium channel antagonists verapamil and nifedipine produced a significant increase in adenylyl cyclase activity and beta-adrenergic receptor density. Nifedipine treatment resulted in upregulation of both beta-adrenergic receptors and dihydropyridine receptors. This finding was associated with enhanced peak twitch force at all extracellular Ca2+ concentrations. We demonstrate for the first time that clinically used pharmacological agents (nifedipine and propranolol) result in alteration in two transmembrane signaling pathways, with associated alterations in physiological performance. Moreover, agents without cardioprotective effect in furazolidone-induced cardiomyopathy did not induce alterations in transmembrane signaling or energetics in normal hearts.


Absence of right ventricular isovolumic relaxation in open-chest anesthetized dogs.

During the left ventricular (LV) pump cycle, peak negative first derivative of pressure vs. time (dP/dt) occurs very close to the end of LV ejection, and there is a well-defined isovolumic relaxation period. Despite similarities between the right ventricular (RV) and LV pump cycles, recent studies indicate uncertainty as to whether peak negative RV dP/dt occurs simultaneously with RV end ejection and whether there is an isovolumic relaxation period during the RV pump cycle. To study these questions, we recorded relative timing of peak negative RV dP/dt, RV end ejection, and right atrial-RV pressure crossover in the open-chest anesthetized dog. The data demonstrate that peak negative RV dP/dt occurs an average of 60 ms before end ejection and that there is no RV isovolumic relaxation period. These findings have implications for the possible use of peak negative RV dP/dt as a marker of RV end ejection and for how time constants of pressure decay obtained during RV relaxation can be interpreted.


Neural mechanisms regulating neurohypophysial resistance arteries.

We defined the extent of vasoactive intestinal polypeptide (VIP) and noradrenergic influences on isolated 100- to 200-microns-diameter vessels from the resistance arterial circulation of the neurohypophysis. A dual extracranial (inferior hypophysial) and intracranial (superior hypophysial) arterial supply to the neurohypophysis was confirmed. The inferior hypophysial artery demonstrates noradrenergic and VIP-like perivascular nerves, whereas the superior hypophysial artery shows primarily VIP-like innervation. Pharmacological sensitivity of the inferior hypophysial to VIP [mean effective dose (ED50) = 10(-8.2) M] and to norepinephrine (ED50 = 10(-5.7) M) was demonstrated. The superior hypophysial reacted only to VIP (ED50 = 10(-8.6) M). The physiological relevance of these findings was tested with transmural nerve stimulation. Frequency-dependent vasodilation of both inferior and superior hypophysial arteries was demonstrated. This dilation could not be blocked with atropine or propranolol. Frequency-dependent vasoconstriction was identified in extracranial vessels including the inferior hypophysial artery. This constriction is only partially blocked by prazosin, phentolamine, and guanethidine. When neurohypophysial resistance vessels are compared with larger circle of Willis arteries and similar-size pial vessels of other cerebral regions, they appear to have regionally unique neural mechanisms for regulating blood flow. Specifically whether controlled by periarterial nerves or other tissue influences, the inferior hypophysial artery appears to meet anatomic, pharmacological, and physiological definitions of neural control for both dilator and constrictor activities of flow to the neurohypophysis.


An angiographic method for in vivo study of arteries of the circle of Willis in small animals.

An X-ray imaging technique designed to allow sequential diameter measurements of the cerebral vessels in intact, anesthetized small animals under relatively physiological conditions is described. The ferret and the rabbit were chosen as potentially useful animal models for studying the cerebrovascular system because of the advantageous anatomic characteristics of these relatively small species. A commercially available and relatively inexpensive X-ray imaging system with a small focal spot provides good spatial resolution. An external carotid perfusion loop allows for 1) the introduction of low-osmolality contrast medium without changing perfusion pressure or flow and 2) measurement of internal carotid and circle of Willis pressures at the same time that the vessel images are obtained. In the present study, detection of small changes in the diameters of the small vessels is facilitated by an algorithm utilizing the X-ray absorption by the entire vessel cross section. This avoids some of the problems of edge detection for small cylindrical vessels wherein the contrast is less than optimal and diminishes as the vessel perimeter is approached.


Suction effusion fluid from skin and constituent analysis: new candidate for interstitial fluid.

The authors analyzed the constituents of effuse transcutaneous fluid, labeled suction effusion fluid (SEF), and monitored its glucose concentration during glucose loading in rabbits (Japan White, female) under pentobarbital anesthesia. The SEF was sampled by suctioning corneal layer-stripped skin at 400 mmHg absolute pressure. The SEF proved to have nearly the same concentrations as serum for lower-molecular-weight substances such as glucose, creatinine, and urea nitrogens, but not for higher-molecular-weight substances such as serum proteins. The SEF protein concentration was one-fourth that of serum protein. Proteins > 100 kDa molecular mass were barely detectable in the SEF. Monitoring of SEF glucose change every 10 min during intravenous glucose loading was successfully accomplished, and SEF glucose concentration followed blood glucose concentration with a 10-min delay. The SEF was thought to consist of interstitial fluid and/or effuse fluid from small vessels in subcutaneous tissue.


L-arginine decreases infarct size caused by middle cerebral arterial occlusion in SHR.

L-Arginine, but not D-arginine, serves as a precursor for the synthesis of nitric oxide (NO), a potent dilator of cerebral blood vessels. We examined the effects of administering L-arginine (300 mg/kg ip) on the volume of infarction in two models of focal cerebral ischemia in spontaneously hypertensive rats (SHR). L-Arginine was administered before (16 and 3 h) and after (5 min and 2 h) vessel occlusion, and animals were killed 24 h later. L-Arginine treatment decreased infarct size in rats subjected to distal middle cerebral arterial (MCA) plus ipsilateral common carotid arterial (CCA) occlusion by 31% [147 +/- 12 (saline) vs. 101 +/- 9 mm3 (L-arginine), P < 0.05]. D-Arginine, administered according to the same dosage and protocol, was without effect. In the group subjected to proximal MCA occlusion, L-arginine decreased infarction size in the striatum by 28% [47 +/- 5 (saline) vs. 34 +/- 3 mm3 (L-arginine), P < 0.05] and neocortex by 11% [193 +/- 7 (saline) vs. 171 +/- 8 mm3 (L-arginine), P < 0.05]. Changes in blood pressure or other measured physiological parameters did not account for the observed differences. The possible use of L-arginine for the treatment of focal cerebral ischemia merits further investigation.


Characterization of norepinephrine-stimulated protein synthesis in rat brown adipocytes.

Rat brown adipocytes were incubated for 24 h with or without norepinephrine (NE) in Dulbecco's modified Eagle's medium with albumin, calf serum, and antibiotics. Brown fat cells were viable as defined by unchanged cell morphology, ATP content, or basal and NE-stimulated respiration. However, a 24-h exposure to NE led to a decline in NE-stimulated respiration that was not due to loss of thermogenic capacity. Brown fat cells incubated with or without NE had similar protein, succinate dehydrogenase, and uncoupling protein (UCP) content. These results differ from those observed after food deprivation in rats where loss of mitochondrial proteins occurs within 24 h, suggesting that reduced exposure to NE is not the only factor responsible for brown fat atrophy. NE increased [35S]methionine incorporation into cellular proteins, mitochondrial proteins, and UCP. The effect of NE on cell protein synthesis was inhibited by propranolol but not by prazosin. It was also inhibited 95% by cycloheximide but only partially (50%) by actinomycin D in contrast to NE stimulation of UCP labeling, which required RNA transcription. Chloramphenicol-sensitive protein synthesis was stimulated by NE. These results indicate a trophic action of NE in brown adipocytes exerted both at the level of RNA transcription and translation.


Duodenal preabsorptive origin of gustatory alliesthesia in rats.

Facial consummatory responses reflecting ingestive and aversive perceptions were studied and quantified in rats chronically implanted with gastric, duodenal, and oral catheters. A gustatory stimulus of 50 microliters of 1.75 mol/l sucrose was injected into the mouth every 5 min for 65 min. At time 0, 0.5 ml containing 0.3 g glucose was injected into the stomach or into the duodenum. Typical ingestive facial consummatory responses were observed in response to sweet stimuli prior to the load. Aversive consummatory responses were observed in response to sweet stimuli after the glucose duodenal load (negative alliesthesia). The gastric load of glucose was not followed by negative alliesthesia in response to sweet oral stimuli. In the last part of the experiment the rats were vagotomized. When the rats were subjected again to the same gustatory sessions, the duodenal load was followed by weak and delayed negative alliesthesia in response to sweet stimuli. These results in rats parallel results obtained in human subjects and reinforce the hypothesis of the existence of a duodenal preabsorptive signal for alimentary alliesthesia. They also suggest that the vagus nerve plays a part in the perception of satiety.


Kinetic heterogeneity of Na-D-glucose cotransport in teleost gastrointestinal tract.

D-[3H]glucose transport properties of brush-border membrane vesicles (BBMV) of upper intestine and pyloric ceca of the Pacific copper rockfish (Sebastes caurinus) were characterized and compared. Vesicles from both organs exhibited Na-dependent, phloridzin-sensitive, carrier-mediated transport systems. Kinetic constants for D-[3H]glucose influx across vesicle membranes were as follows: upper intestine, apparent affinity of glucose (Kt) = 0.14 +/- 0.02 mM, maximal glucose influx (JM) = 1,649 +/- 57 pmol.mg protein-1.10 s-1; pyloric ceca, Kt = 0.58 +/- 0.12 mM, JM = 2,439 +/- 178 pmol.mg protein-1.10 s-1. A hyperbolic relationship, following Michaelis-Menten kinetics, occurred between D-glucose influx and external Na concentration for pyloric ceca, while a sigmoidal function, following Hill cooperativity kinetics (n = 1.71 +/- 0.31), was disclosed between the variables for the intestine. External phloridzin, D-glucose, methyl alpha-D-glucopyranoside, and D-galactose were the most potent inhibitors of D-[3H]glucose influx in each organ. Other compounds were generally more inhibitory in vesicles from the pyloric cecum than those of the intestine except for D-mannose which was considerably more potent in the intestine. Results suggest that there may be proximal-to-distal hexose- and Na-binding gradients in the teleost gut for optimizing sugar absorption during passage of food through the gastrointestinal tract.


Pulmonary vascular response to anaphylaxis in isolated canine lungs.

We determined changes in vascular resistance and microvascular permeability during anaphylactic reaction in isolated canine lungs perfused at constant pressure with autologous blood. In lungs with anaphylaxis induced by an intra-arterial injection of Ascaris suum antigen (10 mg), pulmonary vascular resistance and capillary pressure assessed as double occlusion pressure increased transiently by 10 times and 6.3 mmHg, respectively. Pre- to postcapillary vascular resistance ratio decreased from 0.89 +/- 0.05 to 0.21 +/- 0.06, suggesting predominant pulmonary venoconstriction. In lungs perfused in the antidromic direction from the pulmonary vein to the artery, anaphylaxis caused marked precapillary vasoconstriction, consistent with pulmonary venoconstriction. Vascular permeability assessed using the capillary filtration coefficient and isogravimetric capillary pressure did not change significantly for 3 h in either group. No changes were found in any variables in the saline-injected control lungs. The final weight of the anaphylactic lungs was significantly greater than that of the control lungs. Thus we conclude that anaphylaxis in isolated canine lung produces an increase in capillary pressure due to pulmonary venoconstriction without significant changes in vascular permeability. Pulmonary edema accompanied by anaphylactic hypotension may result from an increase in pulmonary hydrostatic intravascular pressure but not an increase in pulmonary vascular permeability.


Sex differences in central cholinergic and angiotensinergic control of vasopressin release.

In conscious, unrestrained rats, the intracerebroventricular injection of the cholinergic agonist, carbachol, or angiotensin II resulted in the transient stimulation of vasopressin secretion, elevation of mean arterial blood pressure, and reduction of heart rate. After the injection of carbachol (25 ng) into a lateral cerebral ventricle, the plasma vasopressin concentration in male rats was increased to twice that of female rats in each phase of the estrous cycle; mean arterial blood pressure was elevated more in males than females, whereas heart rate fell to the same extent in both sexes. In contrast, the increase in the plasma vasopressin concentration of males after the injection of angiotensin II (20 ng) was one-half that of females, and the hypertensive and bradycardic responses were similar in both sexes. Phase of the female estrous cycle had no effect on the responses to either agent. These findings indicate that central cholinergic and angiotensinergic mechanisms controlling vasopressin release are influenced differently by gender. The role of the gonadal steroid hormones in these mechanisms remains to be determined.


Heparin suppresses endothelin-1 action and production in spontaneously hypertensive rats.

Previous studies have shown that chronic subcutaneous administration of heparin significantly reduces blood pressure in hypertensive rats. The intracellular mechanisms of how heparin prevents smooth muscle cell proliferation remain unclear. This study was designed to examine whether heparin affects endothelin-1 action and production, to further elucidate the mechanism of the antihypertensive effect of heparin. Four-week treatment with heparin (300 U/day sc) significantly decreased blood pressure in spontaneously hypertensive rats (SHR; 199 +/- 8 vs. 164 +/- 9 mmHg; P < 0.001) and completely blunted pressor response to endothelin-1 in SHR. Heparin treatment did not decrease blood pressure response nor did it attenuate blood pressure responses to endothelin-1 in Wistar-Kyoto rats (WKY). Heparin significantly suppressed endothelin-1-induced increase in intracellular calcium concentration and inositol 1,4,5-trisphosphate level in cultured vascular smooth muscle cells in a dose-dependent manner and endothelin-1 release from cultured endothelial cells. These inhibitions were significantly more pronounced in SHR than in WKY. In conclusion, our findings indicate that the antihypertensive effect of heparin is mediated, at least in part, by the inhibition of endothelin-1 action on vascular smooth muscle cells and endothelin-1 production from endothelial cells.


Morphological and physiological correlates with swimming performance in juvenile largemouth bass.

Winter- and summer-acclimatized largemouth bass (Micropterus salmoides) were collected from hatchery ponds in eastern Colorado during late winter and midsummer, then challenged with two prolonged swimming performances (step test and constant-velocity endurance). Variation in the step test performances was significantly correlated with variation in the endurance performances in the winter-acclimatized but not in the summer-acclimatized fish. Fourteen physiological and morphological traits were measured on each fish, and correlations among these traits and swimming performance were tested. None of the traits measured were correlated with performance variation in both the winter- and summer-acclimatized fish. The only significant correlate with swimming performance in the summer-acclimatized fish was white muscle lactate dehydrogenase activity (n = 19). Six of the seven factors correlating with winter swimming performance (n = 18-19) could be divided into two categories: traits associated with fasting (condition factor and liver enzymatic activity) and those associated with oxygen delivery (heart mass, heart and red muscle cytochrome oxidase activity). The results of this study suggest that morphological and physiological correlates of swimming performance in juvenile largemouth bass are profoundly influenced by seasonal variation.


Cardiovascular responses to nasal water flow in rats are unaffected by chemoreceptor drive.

Peripheral chemoreceptors generally play a limited role in the initial development of diving bradycardia in mammals. However, T.F. Huang and Y.I. Peng (Jpn. J. Physiol. 26: 395-401, 1976) reported that peripheral chemoreceptors are very important for manifestation of the diving response in conscious rats. The objectives of this study were to reinvestigate those findings and determine whether the cardiovascular responses to simulated diving in the rat were potentiated during preexisting hypoxia or hypercapnia. Responses to simulated diving were elicited by nasal water flow with concurrent apnea in paralyzed, artificially ventilated Sprague-Dawley rats anesthetized with Innovar. The experiments show that nasal stimulation in the rat results in rapid bradycardia and hypotension and that these responses are not due to laryngeal stimulation. The data also suggest that chemoreceptors do not play a role in the initiation of the responses to simulated diving in rats and that preexisting chemoreceptor drive does not alter the cardiovascular responses. Additionally, we found that concomitant expiratory apnea is necessary to sustain the profound initial cardiovascular changes induced by nasal water flow.


Membrane and synaptic activity during anoxia in the isolated turtle cerebellum.

Electrical depression in the turtle brain during anoxia has been suggested as a strategy for sparing energy and promoting the extraordinary survival capacity of this tissue. The present study was aimed toward defining the changes in membrane properties during anoxia that may underlie such electrical depression. Studies were conducted in isolated cerebellum from turtle brain. Anoxia caused transmembrane potentials (TMP) to become relatively less polarized in most Purkinje cells. In no cell, however, was TMP depolarized to levels associated with the complete loss of transmembrane ion gradients produced by tissue superfusion with iodoacetate during anoxia. Sodium (and likely calcium) spike thresholds were increased, postsynaptic responses from the major afferent input pathways to Purkinje cells were depressed, and input resistance decreased significantly during anoxia. These changes likely contribute to the sparing of energy needed for ion transport and perhaps other functions that may be directly related to cell survival.


Renal medullary interstitial infusion of diltiazem alters sodium and water excretion in rats.

The role of renal papillary blood flow in regulation of fluid and electrolyte excretion was examined. The effects of an acute infusion of diltiazem (5 micrograms.kg-1 x min-1) into the renal medullary interstitium on papillary blood flow and sodium and water excretion were studied. Changes of renal blood flow were measured using an electromagnetic flow probe. Cortical and papillary blood flows were measured using laser-Doppler flowmetry. Renal and cortical blood flows were unchanged during medullary interstitial infusion of diltiazem, but papillary blood flow increased 26% (P < 0.05) and remained elevated for 1 h after diltiazem infusion was discontinued. Glomerular filtration rate (GFR) of the infused kidney increased by 21% from a control of 1.0 +/- 0.1 ml.min-1 x g-1 during infusion of diltiazem (P < 0.05), but it returned to control after diltiazem infusion was stopped. Urine flow and sodium excretion increased by 70% (P < 0.05), and fractional sodium excretion rose from 1.5 +/- 0.2 to 2.4 +/- 0.3% of the filtered load during the hour after diltiazem infusion. Renal blood flow, cortical and papillary blood flow, GFR, urine flow, and sodium excretion in the 0.9% sodium chloride vehicle-infused kidney were not significantly altered during the experiment. Intravenous infusion of the same dose of diltiazem (5 micrograms.kg-1 x min-1) increased GFR by 22%, but had no effect on urine flow and sodium excretion. These results indicate that renal medullary interstitial infusion of diltiazem selectively increased renal papillary blood flow, which was associated with an increase of sodium and water excretion.


Role of right heart receptors in the control of renin, vasopressin, and cortisol secretion in dogs.

We have reported that increased left heart pressure inhibits increases in plasma renin activity (PRA), arginine vasopressin (AVP), and cortisol during arterial hypotension. The goal of this study was to determine whether increases in right heart pressure also inhibited hormonal responses to hypotension. Seven dogs were chronically instrumented with inflatable cuffs around the ascending aorta (AA), the pulmonary artery (PA), and the thoracic inferior vena cava (IVC), as well as with catheters in both atria, the abdominal aorta, and vena cava. The IVC, the PA, and the AA cuffs were inflated on different days to cause step reductions in mean arterial pressure (MAP) of 5, 10, 20, and 30% below control MAP. Graded constriction of the AA caused large increases in left atrial pressure and plasma atrial natriuretic peptide (ANP), but had no effect on plasma AVP or cortisol and caused only a small increase in PRA at the maximal reduction of MAP. Constriction of the IVC reduced both atrial pressures and plasma ANP, but stimulated increases in PRA, AVP, and cortisol. Constriction of the PA increased right atrial pressure and plasma ANP and caused increases in plasma AVP and cortisol that were similar to responses during IVC constriction, but the PRA response was only half (P < 0.05). These results indicate that increasing pressure on the right side of the heart can attenuate the PRA response to hypotension, and suggest that the inhibition is mediated by the rise in plasma ANP.


Growth hormone-releasing hormone antibodies suppress sleep and prevent enhancement of sleep after sleep deprivation.

Previous reports suggest that the hypothalamic growth hormone-releasing hormone (GHRH) promotes sleep, especially non-rapid-eye-movement sleep (NREMS). To evaluate the role of endogenous GHRH in sleep regulation, the effects of antibodies to rat GHRH (GHRH-ab) were studied on normal sleep, brain temperature (Tbr), and GH secretion in experiment I and on enhanced sleep after sleep deprivation in experiment II. In experiment I, affinity-purified GHRH-ab (50 and 200 micrograms) raised in goats and a control goat immunoglobulin G (IgG) preparation were injected intracerebroventricularly (icv) in rats 1 h before the onset of the light cycle, and sleep-wake activity and Tbr were recorded for the next 12 or 23 h. Both doses of GHRH-ab suppressed NREMS and REMS throughout the light cycle. Sleep durations at night were normal. Electroencephalographic (EEG) slow-wave activity, characterized by EEG slow-wave amplitudes, was reduced after GHRH-ab during both the light and the dark cycles. Plasma GH concentrations measured 6-12 h after injection of GHRH-ab (200 micrograms) were diminished. Both the control IgG and GHRH-ab elicited fever. In experiment II, the sleep-wake activity and Tbr of rats were recorded for 24 h in three experimental conditions: base-line with icv injection of IgG, 3-h sleep deprivation with icv IgG injection, and 3-h sleep deprivation with icv GHRH-ab (200 micrograms). After sleep deprivation (+IgG), a prompt increase in EEG slow-wave activity (power density analysis) and late increases in NREMS and REMS durations were found.(ABSTRACT TRUNCATED AT 250 WORDS)


Exercise-induced cellular alterations in the diaphragm.

Limited data exist concerning the effects of exercise training on cellular oxidative capacity in the diaphragm of senescent animals. In this study we examined the changes in cellular oxidative capacity, muscle cell cross-sectional area (CSA), and capillarity within the costal diaphragm of senescent animals after a 10-wk endurance-training program. Twelve 24-mo-old female Fischer 344 rats were divided into either a sedentary control group (n = 6) or exercise training group (n = 6). The trained animals exercised on a motor-driven treadmill (60 min/day, 5 days/wk) at a work rate equal to approximately 55-65% VO2max. Capillaries were identified histologically and fiber types determined using adenosinetriphosphatase (ATPase) histochemistry. Succinate dehydrogenase (SDH) activity and CSA in individual fibers were measured using a computerized image analysis system. Exercise training did not increase (P > 0.05) the capillary-to-fiber ratio for any fiber type. However, training significantly decreased CSA (P < 0.05) and increased capillary density (capillary number/CSA) (P < 0.05) in type I, type IIa, and type IIb fibers. Furthermore, exercise training resulted in small but significant increase in SDH activity (P < 0.05) in type I and IIa fibers, whereas training did not alter SDH activity (P > 0.05) in type IIb fibers. These data demonstrate that endurance training in senescent animals results in small relative improvements in both oxidative capacity and capillary density in costal diaphragmatic type I and IIa muscle fibers. The increase in both capillary density and fiber SDH activity was largely due to a reduction in fiber CSA.


Effects of aging on entrainment and rate of resynchronization of circadian locomotor activity.

The phase angle of entrainment of the circadian rhythm of the locomotor activity rhythm to a light-dark (LD) cycle was examined in young (2-5 mo old) and middle-aged (13-16 mo old) hamsters. An age-related phase advance in the onset of locomotor activity relative to lights off was seen during stable entrainment to a 14:10-h LD cycle. In addition, the effects of age on the rate of reentrainment of the circadian rhythm of locomotor activity were examined by subjecting young and middle-aged hamsters to either an 8-h advance or delay shift of the LD cycle. Middle-aged hamsters resynchronized more rapidly after a phase advance of the LD cycle than did young hamsters, whereas young hamsters were able to phase delay more rapidly than middle-aged hamsters. The age-related phase advance of activity onset under entrained conditions, and the alteration of responses in middle-aged hamsters reentraining to a phase-shifted LD cycle, may be due to the shortening of the free-running period of the circadian rhythm of locomotor activity with advancing age that has previously been observed in this species.


Irradiance responsivity and unequivocal type-1 phase responsivity of rat circadian activity rhythms.

Behavioral, neuropharmacological, and molecular studies of light-induced phase shifting of rodent circadian rhythms evaluate carefully the phase dependence of light responsivity. However, much less information is available regarding the dependence of such effects on the duration and irradiance of the photic stimulus used. In this study, very brief (5-min) white light pulses of 50 microW/cm2 (175 lux) administered to hooded rats elicited unequivocal type-1 phase responsivity, without significant changes in period, and with phase shift variability comparable to that in studies using longer, higher intensity pulses. Irradiance dependence was demonstrated in the phase-delay, phase-advance, and crossover portions of the phase-response curve, with minimal phase shifting seen during the dead zone even at very high irradiance. These results indicate that maximal phase-shifting magnitude may be achieved with shorter, less intense photic stimuli than are often used in studies of the neural mechanisms involved in light responsivity of rat circadian rhythms.


Influenza virus-induced changes in rabbit sleep and acute phase responses.

Systematic investigations of sleep after viral inoculation have not previously been described. In the present study, rabbits were inoculated intravenously (iv) with control allantoic fluid followed by two sequential inoculations of influenza virus at intervals of 24 h. After each i.v. inoculation, sleep and brain temperature (Tbr), as well as leukocyte distributions and serum levels of antiviral activity and ceruloplasmin, were monitored. The first viral inoculation elicited several acute phase responses, including increased non-rapid-eye-movement sleep (NREMS), Tbr, serum antiviral activity, and serum ceruloplasmin levels, as well as neutrophilia and lymphopenia. In contrast to the effects of the first inoculation, after the second inoculation of virus, all these acute phase parameters were diminished or absent (the hyporesponsive state). Inoculation of naive rabbits with heat-inactivated virus was similarly ineffective; however, inoculation of this group of rabbits with viable virus 24 h later did induce full-scale acute phase responses. The possible role of cytokines in mediating the acute phase response after influenza viral challenge is discussed. Results support the hypothesis that sleep is a facet of the acute phase response involved in host defense mechanisms.


Metabolic adaptation of fetal hindlimb to severe, nonlethal hypoxia.

To test the hypothesis that an important aspect of the fetal response to severe, nonlethal hypoxia is a relatively large reduction in oxidative metabolism and small increase in lactate production by organs whose O2 supply is selectively reduced, net fluxes of O2, glucose, pyruvate, lactate, and CO2 derived from fetal plasma lactate carbon [(CO2)PL] were measured across the hindlimb and umbilical circulations in six sheep fetuses before and at 200-260 min of hypoxia. During hypoxia, blood lactate reached a high but steady level (15.2 +/- 2.2 vs. 1.7 +/- 0.2 mM; P < 0.001). Hypoxia was induced by reducing uterine blood flow. Limb O2 uptake and (CO2)PL decreased (P < 0.01) and lactate output increased (P < 0.05) (-83.1 +/- 13.9, -28.6 +/- 5.0, and +35.7 +/- 13.7 nmol.min-1 x g-1, respectively), while pyruvate and glucose uptakes remained similar to control. The increase in limb glycolysis was approximately 10% of the value that would compensate for the decrease in oxidative energy metabolism. The ratio of limb O2 uptake to fetus O2 uptake decreased significantly (0.247 +/- 0.029 vs. 0.447 +/- 0.036; P < 0.01). In contrast to fetal limb (CO2)PL, fetal (CO2)PL did not decrease. During severe, nonlethal hypoxia, fetal survival depends on uneven and counterbalancing organ O2 uptake and lactate metabolism.


Steady-state arterial pressure-urinary output relationships during ovine pregnancy.

To determine the effects of long-term changes in sodium intake on mean arterial pressure (MAP) regulation during pregnancy, nonpregnant (n = 16) and 110- to 140-day pregnant (n = 13) ewes received total daily sodium intakes of 10, 30, 100, 400, and 1,200 mmol for 7 days. The sheep were housed in metabolism cages and MAP was monitored 24 h/day. Urinary sodium excretion (UNaV) followed changes in sodium intake, with steady-state levels being achieved with similar degrees of rapidity (2-3 days) in nonpregnant and pregnant sheep. At 10 mmol/day sodium intake, MAP was lower (79 +/- 1 vs. 82 +/- 2 mmHg; P < 0.01) and water intake (2,275 +/- 494 vs. 3,286 +/- 725 ml/day; P < 0.001) and 24-h urine volume (1,454 +/- 279 vs. 2,299 +/- 496 ml/day; P < 0.01) were greater in pregnant sheep. All of these variables exhibited direct relationships with increases in sodium intake. Plasma angiotensin II (pANG II) was increased in pregnancy (10.6 +/- 1.6 vs. 24.5 +/- 6.3 pg/ml; P < 0.001) at 10 mmol/day. Elevation of sodium intake suppressed pANG II to minimal levels in nonpregnant sheep, but to only 25% of the control level in pregnant sheep. During pregnancy, the renal function curve representing the steady-state MAP-UNaV relationship was shifted to lower MAP setpoint, but the sodium sensitivity of MAP was unchanged. Also, the inverse relationship of sodium intake and pANG II was blunted, suggesting a reduced role for ANG II in the maintenance of renal function during pregnancy.


Sympathoadrenal-circulatory regulation of arterial pressure during orthostatic stress in young and older men.

Our purpose was to test the hypothesis that human aging alters sympathoadrenal-circulatory control of arterial blood pressure during orthostasis. Plasma catecholamine and hemodynamic adjustments to two different forms of orthostatic stress, lower body suction (-10 to -50 mmHg) and standing, were determined in 14 young (26 +/- 1 yr) and 13 older (64 +/- 1) healthy, normally active men. During quiet supine rest, cardiac output tended to be lower and systemic vascular resistance higher in the older men, but no other differences were observed. On average, arterial blood pressure was well maintained during both forms of orthostasis in the two groups; the older men actually demonstrated better maintenance of pressure (P < 0.05) and a lesser incidence of orthostatic hypotension than the young men during lower body suction. Despite a blunted reflex tachycardia during orthostatic stress (P < 0.05), cardiac output tended to decrease less in the older men because of a smaller decline in stroke volume (P < 0.05, suction only), whereas the reflex increases in systemic vascular resistance were not different in the two groups. The whole forearm vasoconstrictor response tended to be attenuated in the older men during lower body suction, but was identical in the two groups with standing. Forearm skin vascular resistance was unaltered during lower body suction in both groups. Orthostasis-evoked increases in antecubital venous plasma norepinephrine concentrations were similar in the young and older men, whereas little or no increases in plasma epinephrine concentrations were observed in either group.(ABSTRACT TRUNCATED AT 250 WORDS)


Nitric oxide participates in the cerebrovasodilation elicited from cerebellar fastigial nucleus.

The endothelium-derived relaxing factor, probably NO, is a potent vasodilator that mediates the vasodilating action of acetylcholine (ACh). We studied whether NO participates in the cholinergic cerebrovasodilation elicited by stimulation of the cerebellar fastigial nucleus (FN). Rats were anesthetized with halothane and ventilated. FN or pontine reticular formation (PRF) were stimulated through microelectrodes. Hypertension was prevented by spinal cord transection with arterial pressure maintained by intravenous phenylephrine. Cerebral blood flow (CBF) was continuously monitored through a cranial window over the sensory cortex by a laser-Doppler probe. The window was superfused with Ringer solution (pH 7.3-7.4; 37 degrees C). During Ringer superfusion FN stimulation (100 microA; 50 Hz) increased CBF by 90 +/- 7% (n = 27; P < 0.001, analysis of variance and Tukey's test) and PRF stimulation (100 microA; 100 Hz) by 128 +/- 18% (P < 0.001; n = 9). Superfusion with the guanylyl cyclase inhibitor methylene blue (MB) (1 mM) attenuated the CBF increase elicited by FN stimulation by 77 +/- 3% (n = 22; P < 0.001). MB did not affect the CBF increase elicited by PRF stimulation (+98 +/- 18%; n = 9; P > 0.05). Similarly, superfusion with the NO-synthase inhibitor nitro-L-arginine (L-NA) attenuated the CBF increase elicited by FN stimulation (-67 +/- 3%; n = 14; P < 0.001 from Ringer) but not PRF stimulation (P > 0.05; n = 9). The CBF increases elicited by FN stimulation were not affected by the inactive isomer of nitroarginine, D-NA (P > 0.05; n = 7).(ABSTRACT TRUNCATED AT 250 WORDS)


Changes in regulation of human zinc metabolism with age.

To assess changes in zinc metabolism with age, kinetic studies were performed in healthy adults (26 men, 21 women) aged 20-84 yr after a single oral or intravenous bolus of 65Zn. Studies covered two consecutive 9-mo periods while subjects were on a basal dietary intake of approximately 10 mg Zn/day and while taking an additional 100 mg Zn/day orally. Zinc metabolism was analyzed by compartmental analysis using data from plasma, red blood cells, urine, feces, liver, thigh, and whole body [M. E. Wastney, R. L. Aamodt, W. F. Rumble, and R. I. Henkin. Am. J. Physiol. 251 (Regulatory Integrative Comp. Physiol. 20): R398-R408, 1986]. Changes in observed and model calculated values of zinc metabolism were assessed on age by regression. During basal state, zinc release from red blood cells decreased with age. During zinc loading, response (defined as change from basal state) of plasma zinc concentration, urinary zinc excretion, and liver zinc increased with age, while response of fraction of zinc taken up by red blood cells decreased with age. In men, response of amount of zinc absorbed increased with age and in women response of fraction of endogenous zinc excreted decreased with age. Four responses that changed with age (urinary excretion, red blood cell exchange, absorption, and endogenous excretion) occurred at previously defined sites of regulation of zinc metabolism. Results show that regulation of zinc metabolism changes with age.


Systemic injection of TNF-alpha attenuates fever due to IL-1 beta and LPS in rats.

The effect of tumor necrosis factor-alpha (TNF-alpha) on the febrile response to interleukin-1 beta (IL-1 beta) was investigated in rats. While both of these substances are capable of causing fever when injected into rats, an earlier study showed that the injection of antiserum against TNF-alpha enhanced endotoxin [lipopolysaccharide (LPS)] fever, suggesting that physiological levels of circulating TNF may act to limit the magnitude of fever. In the present study, the intraperitoneal injection of 1 microgram/kg of TNF-alpha significantly attenuated the fever due to the intraperitoneal injection of 10 micrograms/kg of IL-1 beta. Higher doses of TNF-alpha (10 and 50 micrograms/kg injected ip) slightly lowered the febrile response to this dose of IL-1 beta, but these changes were not significant. None of these doses of TNF-alpha alone significantly altered body temperature. The injection of 1 microgram/kg of TNF-alpha also significantly lowered the febrile response to the intraperitoneal injection of 10 micrograms/kg of LPS. The febrile responses to the preoptic area (POA) or intraperitoneal injection of IL-1 beta were not changed when a nonpyrogenic dose of TNF-alpha was simultaneously injected into the POA. Further studies are needed, however, before we can conclude that TNF does not act in the central nervous system to control the febrile response. These data support the hypothesis that nonpyrogenic levels of TNF act in the systemic circulation to suppress the development of fever.


Exhaustive physical exercise causes oxidation of glutathione status in blood: prevention by antioxidant administration.

We have studied the effect of exhaustive concentric physical exercise on glutathione redox status and the possible relationship between blood glutathione oxidation and blood lactate and pyruvate levels. Levels of oxidized glutathione (GSSG) in blood increase after exhaustive concentric physical exercise in trained humans. GSSG levels were 72% higher immediately after exercise than at rest. They returned to normal values 1 h after exercise. Blood reduced glutathione (GSH) levels did not change significantly after the exercise. We have found a linear relationship between GSSG-to-GSH and lactate-to-pyruvate ratios in human blood before, during, and after exhaustive exercise. In rats, physical exercise also caused an increase in blood GSSG levels that were 200% higher after physical exercise than at rest. GSH levels did not change significantly. Thus, both in rats and humans, exhaustive physical exercise causes a change in glutathione redox status in blood. We have also found that antioxidant administration, i.e., oral vitamin C, N-acetyl-L-cysteine, or glutathione, is effective in preventing oxidation of the blood glutathione pool after physical exercise in rats.


Precocious cessation of intestinal macromolecular transport by synthetic trypsin inhibitor in suckling rats.

The effects of repeated oral administration of the synthetic trypsin inhibitor camostat on intestinal macromolecular transport and disaccharidase development were investigated in suckling rats. By daily treatment with camostat, bovine immunoglobulin (Ig) G transport in the intestine declined more rapidly in treated than in control rats. The absorption curve shifted to the left in treated rats 3 days before the controls. Morphological inspection of treated pups showed a decline in the number of epithelial cells that absorb bovine IgG and in their vesicle size from basal to upper regions of the villi. Maltase activity precociously increased with camostat treatment. Chronic subcutaneous injection of camostat did not cause any changes in IgG transport and maltase activity. The depression of IgG transport by oral treatment with camostat was not affected by the cholecystokinin (CCK) receptor antagonist L 364718 and was not inhibited by adrenalectomy. The absorptive responses of IgG and maltase activity were not affected by CCK-8 treatment. These data indicate that oral administration of camostat induces precocious maturation of the small intestine and that the effect is not mediated via endogenous CCK released by camostat.


The listening healer in the history of psychological healing.

The purpose of this paper is the assessment of the healer's listening as an aspect of the history of caring and curing, with particular attention to its place in psychological healing. An extensive range of philosophical, religious, and medical sources from antiquity to the present were studied. Over the centuries, listening has been a crucial aspect of the various endeavors undertaken by healers in the interest of acquiring information from, achieving understanding of, and bringing about healing effects for sufferers. Yet it has been vision rather than hearing that has been emphasized in knowing and understanding, and looking rather than listening that has been emphasized in healing endeavors. Only around the turn of the twentieth century did there emerge the focused study of care in listening, of listening beyond the words themselves, and of the significance of the interested listener as a soothing, empathic force. The place of listening in depth and with empathy is a crucial element in healing. While the emphasis on looking remains significant in the gathering and appraisal of data, at times it threatens to overwhelm the need for an attentive and concerned listener. There appears to be a natural tension between the two modes that has, in modern times, been translated into a tension between the two modes that has, in modern times, been translated into a tension between a scientific mode of gaining information and a humanistic mode of knowing sufferers. A healer neglects either one at his or her peril--and at the peril of his or her patients.


Problems and considerations in the valid assessment of personality disorders.

This article reviews evidence for the reliability and diagnostic concordance of structured-interview and self-report questionnaire methods for the diagnosis of personality disorders. The findings of nine studies that compared two or more axis II diagnostic instruments administered to the same groups of subjects are summarized. Across the eight studies with sufficient data, a summary of the overall diagnostic agreement between any two instruments yielded a low reliability (median kappa = 0.25) for making individual personality disorder diagnoses. Diagnostic concordance was lower between self-report questionnaire and interview methods than between interview methods. Comparing dimensional scores of different methods did not appreciably improve the level of agreement. The author concludes that current methods for making personality disorder diagnoses have high reliability but yield diagnoses that are not significantly comparable across methods beyond chance, which is not scientifically acceptable. Sources for the disagreement include variance due to different raters, interview occasions, data sources (self-report versus observer report), information bases obtained, and instrument sensitivity to state effects (e.g., mood). Serious problems in assessment validity may also arise from the yes/no format, which, despite probes for confirmatory examples, may fail to distinguish adequately between sporadic occurrences and longstanding patterns. Efforts should be made to improve and demonstrate the validity of axis II diagnostic methods. One route to increasing validity is to improve the clinical interview, because personality patterns are best revealed by the recurring patterns one finds when taking a systematic history.


Measuring the determinants of work values for psychiatrists' services in the resource-based relative value scale study.

As part of the Harvard resource-based relative value scale study, the authors investigated how well the codes in the Physician's Current Procedural Terminology, 4th edition, or CPT-4, match psychiatric services to the work involved in evaluating and managing patients and how patient care characteristics affect different levels of psychiatric work. A random sample of over 200 psychiatrists and subspecialists was asked to use 68 typical clinical examples or vignettes to evaluate services described by CPT codes. Data were analyzed by multivariate statistical methods. The survey showed that the existing coding system does not adequately describe the work that psychiatrists do. Within a single code (e.g., 90844, individual medical psychotherapy), there was wide (more than twofold) variation in the estimates, from multiple measurements based on different vignettes, of the amount of work represented. Estimates of work values varied significantly according to treatment setting and patient characteristics: psychiatric services in the hospital showed an average work value 25% greater than that for office services; treating new patients involved 18% more effort than treating established patients; and treating patients described as at risk of harming self or others increased the psychiatrists' work effort by 36%. Revisions in coding evaluation and management services in the new Medicare fee schedule for psychiatric services should be further refined and then implemented. These revisions would bring the coding system into line with psychiatric practice, making it a better way of accounting for the relative work involved in treating patients of varying difficulty.


Assessment of lineality in bipolar I linkage studies.

To assess lineality in families of bipolar I probands, the authors used direct interviews of family members to reclassify families initially categorized as unilineal by family history. The families of 1,800 treated bipolar I probands were screened by the family history method with multiple informants. If the proband had one or more affected sibs and one apparently unaffected parent, the parents (and then other available first- and second-degree relatives) were directly interviewed by psychiatrists. Of the 1,800 families screened, 56 were apparently suitable unilineal families with multiple affected members; 46 families were interviewed directly. After interviews with the parents, 12 families (26.1%) were found to be bilineal. Direct interviews of all available relatives in the 34 remaining families revealed that only 22 (47.8% of the 46 interviewed families) were unilineal or probably unilineal and 12 were probably bilineal. The probably bilineal families had a significantly higher proportion of siblings with unipolar disorder. In addition, the affected sibs from the probably bilineal families tended to have earlier onsets but had significantly fewer symptoms in the most severe depressive episode. Fewer than 50% of bipolar I families appearing unilineal according to family history were found to be unilineal by direct interviews. The phenotypic differences between the affected sibs from the probably bilineal families and those from the unilineal and probably unilineal families suggest differences in genetic mechanisms. These findings highlight the need to systematically assess lineality in all families considered for bipolar I linkage studies and support the preferential inclusion of unilineal families in linkage studies.


Schizoaffective disorder and affective disorders with mood-incongruent psychotic features: keep separate or combine? Evidence from a family study.

This study investigated whether the distinction between schizoaffective disorder and affective disorders with mood-incongruent psychotic features as described in DSM-III-R is reflected by aggregation of schizophrenia in the families of probands with the former disorder and aggregation of affective disorders mainly among the relatives of probands with the latter type of disorders. The probands were 118 inpatients with definite lifetime diagnoses of DSM-III-R schizoaffective disorder or a major mood disorder with incongruent psychotic features according to structured clinical interviews. Diagnostic information on 475 of the probands' first-degree relatives was gathered through direct interviews (with 80% of the living first-degree relatives) or the family history approach. The rates of affective and psychotic disorders among these relatives were then compared with those among the relatives of a comparison group of 109 interviewed individuals from the general population who were matched on sociodemographic factors to the inpatient probands. With regard to the familial aggregation of schizophrenia, the DSM-III-R distinction emerged as valid. However, the risk of unipolar affective disorders was enhanced in the families of all of the subgroups of patients studied. The unipolar/bipolar distinction in both DSM-III-R diagnostic groups was reflected by distinct patterns of bipolar disorders in the relatives. The results partly support the DSM-III-R dichotomy of schizoaffective disorder and affective disorders with mood-incongruent psychotic features. Although the differences between these two diagnostic groups were significant, the magnitude of the differences remained relatively modest.


Reliability of best-estimate diagnosis in genetic linkage studies of major psychoses: results from the Quebec pedigree studies.

Diagnostic classification and reliability are critical in genetic linkage studies of schizophrenia and bipolar disorder. To establish an optimal diagnostic procedure, the authors drew 13 methodological elements from 38 major linkage studies and workshop reports. They determined reliability for a consensus best-estimate diagnostic method based on these 13 features. Each of 59 subjects from several large multiplex pedigrees, densely affected by either schizophrenia or bipolar disorder, received a best-estimate diagnosis from unblind diagnosticians in the field and also from a panel of four research psychiatrists who were blind to the proband's and relatives' clinical status. The best estimate was based on personal diagnostic interviews, all available medical records, and family history data. The diagnostic concordance between the field team and the blind psychiatric board yielded 78% to 90% agreement for the whole sample (kappa = 0.83-0.88) and 71% to 87% agreement for the subjects given field diagnoses (kappa = 0.76-0.83). The diagnoses made by the unblind field diagnosticians were biased toward a greater severity (or certainty) level in the diagnostic hierarchy (schizophrenic or bipolar) and more consistency with the most prevalent diagnosis affecting the pedigree. Since several previous linkage studies used diagnoses made by diagnosticians who were not blind to the status of the probands and the relatives or did not use a consensus best-estimate diagnosis, further reliability studies of different aspects of the best-estimate method and of its effect on linkage studies are needed. Such research is imperative given the serious impact of diagnostic misclassifications on genetic linkage results.


Combined pharmacotherapy and psychotherapy in the acute and continuation treatment of elderly patients with recurrent major depression: a preliminary report.

The authors examined the rate of response to the combination of nortriptyline and interpersonal psychotherapy for acute and continuation treatment of elderly patients with recurrent major depression. The subjects were 73 elderly patients, 61 of whom completed treatment. Nortriptyline steady-state blood levels were maintained at 80-120 ng/ml, and interpersonal psychotherapy was administered weekly for 9.1 weeks (medium) of acute therapy and was decreased from biweekly to triweekly during 16 weeks of continuation therapy. During acute treatment nonresponding patients also received brief adjunctive pharmacotherapy with lithium or perphenazine. Of the 61 subjects given adequate trials of nortriptyline and interpersonal psychotherapy, 48 (78.7%) achieved full remission (Hamilton depression rating of 10 or lower over 16 weeks of continuation therapy), 10 patients (16.4%) did not respond (Hamilton rating never below 15), and three achieved only partial remission (Hamilton rating of 11-14). Early versus late onset was not associated with a difference in response rate. During the placebo-controlled, double-blind transition to maintenance therapy, 19 (76.0%) of the 25 patients randomly assigned to placebo maintenance conditions showed continued recovery and six relapsed. None of the 24 patients assigned to nortriptyline conditions relapsed. Use of nortriptyline plus interpersonal psychotherapy for 9.1 weeks (median) of acute and 16 weeks of continuation therapy appears to be associated with good response and relatively low attrition but about a 25% chance of relapse during double-blind discontinuation of nortriptyline. These data require confirmation in a controlled clinical trial of acute and continuation therapy.


Religious coping and depression among elderly, hospitalized medically ill men.

The investigators examined the frequency of religious coping among older medical inpatients, the characteristics of those who use it, and the relation between this behavior and depression. The subjects were 850 men aged 65 years and over, without psychiatric diagnoses, who were consecutively admitted to the medical or neurological services of a southern Veterans Administration medical center. Religious coping was assessed with a three-item index. Depressive symptoms were assessed by self-rating (the Geriatric Depression Scale) and observer rating (the Hamilton Rating Scale for Depression). One out of every five patients reported that religious thought and/or activity was the most important strategy used to cope with illness. Variables that were associated with religious coping included black race, older age, being retired, religious affiliation, high level of social support, infrequent alcohol use, a prior history of psychiatric problems, and higher cognitive functioning. Depressive symptoms were inversely related to religious coping, an association which persisted after other sociodemographic and health correlates were controlled. When 202 men were reevaluated during their subsequent hospital admissions an average of 6 months later, religious coping was the only baseline variable that predicted lower depression scores at follow-up. These findings suggest that religious coping is a common behavior that is inversely related to depression in hospitalized elderly men.


Visual hallucinations in patients with macular degeneration.

This study was undertaken to determine the prevalence of visual hallucinations in patients with macular degeneration, describe such hallucinations phenomenologically, and possibly determine factors predisposing to their development. Using a case-control design, the authors screened 100 consecutive patients with age-related macular degeneration for visual hallucinations. Each patient with visual hallucinations was matched to the next three patients without hallucinations. The patients and comparison subjects were compared in terms of scores on the Beck Depression Inventory, Eysenck Personality Questionnaire, Telephone Interview for Cognitive Status, and a structured questionnaire including demographic characteristics, family history, and medical and psychiatric history. Ophthalmologic data were obtained by chart review. Of the 100 patients, 13 experienced visual hallucinations. Four variables were significantly associated with having hallucinations: living alone, lower cognition score, history of stroke, and bilaterally worse visual acuity. Hallucinations were not associated with family or personal history of psychiatric disorder or with personality traits. In 11 (84.6%) of the 13 patients, the hallucinations had begun in association with an acute change in vision. These results indicate that visual hallucinations are prevalent among patients with macular degeneration. They appear unrelated to primary psychiatric disorder. The predisposing factors of bilaterally worse vision and living alone support an association with sensory deprivation, while history of stroke and worse cognition support a decreased cortical inhibition theory.


Elderly Israeli Holocaust survivors during the Persian Gulf War: a study of psychological distress.

The aim of the current study was to systematically assess the psychological effects of the Persian Gulf War on a nonclinical group of elderly Israeli civilians with and without a Holocaust background. Sixty-one elderly Holocaust survivors and 131 elderly civilians without a Holocaust background completed questionnaires in their homes. Measures included sense of safety, symptoms of psychological distress, and levels of state and trait anxiety. Findings indicate that Holocaust survivors perceived higher levels of danger and reported more symptoms of acute distress than comparison subjects. In addition, they displayed higher levels of both state and trait anxiety. Findings do not support the notion that prior experience with extreme stress has an inoculating effect that leads to greater resilience in dealing with other forms of stress. On the contrary, Holocaust experience was found to render the elderly more vulnerable rather than less. These findings of greater vulnerability among Holocaust survivors are of particular significance since they stem from a nonclinical group.


Utilization of neuropsychiatric diagnostic tests for general hospital patients with mental disorders.

The author's goal was to determine the frequency and distribution of neuropsychiatric diagnostic tests provided to general hospital patients with mental disorders. Data from the 1989 National Hospital Discharge Survey were analyzed to determine the number, proportion, and general characteristics of 11,628 discharged patients with primary diagnoses of mental disorders who underwent computerized tomography (CT) scanning of the head, EEG, and magnetic resonance imaging (MRI) of the brain. Of the discharged patients with mental disorders, 5.1% had received CT scans, 2.8% had received EEGs, and 0.7% had received MRI. These rates were below the rates for patients discharged with primary diagnoses of neurological disorders but above the rates for patients discharged with primary diagnoses of other medical disorders. Among the patients discharged with mental disorder diagnoses, the likelihood of receiving a CT scan or an EEG was greater if the primary diagnosis was an organic disorder or if the secondary diagnosis was a medical disorder. Patients over age 65 were also more likely to have received a CT scan. Hospital size and location had a modest influence on the likelihood of receiving a CT scan or EEG, but the ownership of the hospital and the patient's source of payment were not significant influences. Neuropsychiatric diagnostic testing is selectively utilized in the routine treatment of general hospital psychiatric inpatients. Clinical variables rather than institutional or financial variables appear to be the most powerful predictors of which patients are selected to receive these tests.


Effect of instructional cues on schizophrenic patients' performance on the Wisconsin Card Sorting Test.

Schizophrenic patients are particularly deficient on measures of executive functioning, notably the Wisconsin Card Sorting Test. This study was conducted to determine the efficacy of a cuing strategy in facilitating performance on this cognitive measure of the integrity of prefrontal brain structures and functioning. Twenty-four schizophrenic inpatients and 24 demographically matched inpatients with mood disorders were administered the Wisconsin Card Sorting Test either with instructional cues at the beginning of the task or with the standard administration procedure. There was a significant benefit of cues for the patients with affective disorders as well as for the schizophrenic patients. The schizophrenic subjects in the uncued condition maintained poor but stable performance throughout the course of the task. The study suggests that the deficit in executive functioning of schizophrenic patients may lie in the formation of concepts, not in their application.


Physical and sexual abuse histories among children with borderline personality disorder.

The purpose of the study was to determine whether a history of physical or sexual abuse is more common in children with borderline personality disorder than in other children evaluated in the same outpatient psychiatric clinic. The authors contrasted rates of abuse in 44 children diagnosed with borderline personality disorder and in 100 comparison children. The borderline personality disorder group had a significantly greater prevalence of physical and combined physical/sexual abuse. Sexual abuse rates alone did not differ significantly between groups. The finding of greater abuse in the group with borderline personality disorder supports the hypothesis that a history of trauma is associated with the disorder.


Lithium-discontinuation-induced refractoriness: preliminary observations.

The authors used a systematic life-chart methodology to observe four patients with bipolar disorder in whom long periods (6-15 years) of effective lithium prophylaxis were followed by relapses on lithium discontinuation. Once the drug was reinstituted, it was no longer effective. The incidence, predictors, and mechanisms underlying this phenomenon all require further systematic study. The current preliminary observations suggest an additional reason for caution when lithium discontinuation in the well-maintained patient is considered.


Side effects and the "blindability" of clinical drug trials.

A novel, simple approach to retrospective assessment of "blindability" was applied to data on outpatients in a controlled, double-blind clinical comparison of a putative antidepressant, etoperidone, and placebo. A "blind" evaluator proved capable of discriminating between the active drug and placebo on the basis of reported side effects alone, raising questions about the true blindness of the study.


The Wolf-Man case: classical and self-psychological perspectives.

Freud's description of his analysis and treatment of the Wolf-Man will be forever regarded as an extraordinary clinical and theoretical achievement. What has been attempted in this paper is to demonstrate how selected aspects of the Wolf-Man case could be interpreted using a self-psychology paradigm. The intent was not to demean Freud or to undermine the theoretical and clinical contributions of drive/structure theory. Rather, I have attempted to show how Freud's analysis and treatment of the Wolf-Man might have been enhanced by a familiarity with more recent developments in psychoanalysis.


The dissolution of the dyad in psychiatry: implications for the understanding of patient-therapist sexual misconduct.

Psychiatry has undergone multiple changes in this century. Some twenty years ago, Kubie describe a move away from patients, particularly in those practitioners involved in academic psychiatry. His concern was warranted; such a trend appears to have involved much of psychiatry. There has been a markedly decreased emphasis in viewing the operative unit of psychiatric inquiry as a dyad of the physician and patient, in which the parties inescapably influence each other. Newer treatments tend to employ the physician as a more independent entity that applies necessary treatment to the patient. Concomitantly, we have seen a trend toward a diminishing focus on sexuality as a primary motivating force in all areas of human endeavor. Freud proposed that libidinal impulses dominated much of our behavior; later psychoanalytic theorists and founders of other modalities of treatment have focused on other sources of motivation. Within the context of a psychiatry less focused on the physician and patient in a dyadic sense, and less focused on sexuality as a universal source of motivation, we have witnessed a marked increase in interest in the sexual misconduct of psychiatrists. Comprehension of this disturbing issue in the service of prevention rests upon reversing these trends. We must attend to the dyad as a bipersonal field serving as the arena for misconduct. We must also parallel our strident disapproval of misconduct with an objective exploration of the dynamics of both parties and the human commonality of sexual feelings. This special section represents such an exploratory effort.


Obstacles to the dynamic understanding of therapist-patient sexual relations.

Several dynamic resistances appear to interfere with rational and empirically based discourse about therapist-patient sexual misconduct. These resistances include the lure of reductionism and a longing for simplicity; wishes for "political correctness"; gender bias; and confusion about the nature of the trauma in sexual misconduct. We conclude that (1) empirical study may produce unpleasant results; (2) "politically incorrect" models of misconduct merit study with care equal to "politically correct" ones; and (3) those reenactments we call transference-countertransference should be viewed in all their human complexity. Only then will our increased understanding of misconduct offer hope of prevention.


Unanswered questions about the criminalization of therapist-patient sex.

Even though much has been written about the issue of criminalization of therapist-patient sex, many questions about the issue remain unanswered, raising doubts about the wisdom of nationwide adoption of criminalizing legislation. From a philosophical standpoint, we need to understand more fully what thoughts, emotions, and behaviors constitute consent. Furthermore we must determine how much value to give consent in relation to other social values and goals. From a clinical standpoint we still need a better understanding of what constitutes the therapist-patient relationship: what it is and when it is over. We must also examine more carefully the nature of power within a psychotherapeutic relationship. From a legal standpoint we must determine how criminalization affects constitutional privacy rights, as embodied both in state constitutions and the federal Constitution. From an empirical standpoint we need to assess the efficacy of current criminalization statutes and determine their effect on tort compensation for patient victims. We also need to assess the practical application of these statutes by juries. Without more thorough analysis of all the issues raised, the criminalization of patient-therapist sex by state legislatures may in fact cause more harm than good.


Risk management in the practice of behavior therapy: boundaries and behavior.

Behavior therapy represents a treatment modality widely utilized by clinicians but to date insufficiently examined from the risk-management standpoint. Given that the determination of negligence is dependent on the role of the therapist as proximate cause of the adverse outcome and on the availability of an accepted standard of care from which deviations can be specified, a number of general characteristics of behavior therapy may render its practitioners potentially vulnerable to litigation. These may include its directiveness, its replicability, and its methodologic rigor. Similarly, certain specific behavioral techniques may carry some medicolegal risks, including the use of aversion methods, utilization of family members or other lay cotherapists, response cost, and exposure therapies. In addition, therapeutic boundaries in behavioral treatment may be different from those in psychoanalytic therapy, allowing for therapist practices that might otherwise be considered unusual or in themselves negligent, but the therapist may have a heavier burden of justification in such cases. The authors suggest that recognition of the possibility of adverse results, ongoing and competent informed consent, adequate documentation, willingness to consult, and careful monitoring of treatment outcome may help mitigate the medicolegal risks of these procedures.


The prevention of psychotherapist sexual misconduct: avoiding the slippery slope.

Therapist sexual misconduct has its genesis in the therapeutic relationship. The mental health professions have long recognized the delicacy with which the therapist must handle the therapeutic relationship, with its power imbalance, inherent vulnerability of the patient, and transference and countertransference reactions. The prevention of sexual contact starts with the careful attention to boundary violations, which, though themselves perhaps not harmful, may escalate into sexualized behavior. Methods of preventing this behavior include the establishment of clear guidelines for practitioners and the expansion of the educational process for therapists, therapists' employers, patients, and other professionals. Last resorts lie in the legal and quasi-legal proceedings available to victims, such as civil suits for damages, criminal complaints, board of licensing complaints, and actions before professional associations. The best method of preventing sexual contact with patients involves respecting the boundaries of the professional relationship and avoidance of the slippery slope.