Progesterone binding by human endometrial tissue during the proliferative and secretory phases of the menstrual cycle and by hyperplastic and carcinomatous endometrium.

Cytosol receptors for progesterone were assayed in human endometrial tissue during the proliferative and secretory phases of the menstrual cycle and in the hyperplastic and carcinomatous endometrium. The assays were performed utilizing a technique involving prior treatment of the cytosol extract with dextran-coated charcoal to remove endogenous progesterone. The results showed that the progesterone receptor activity was higher during the later proliferative and early secretory phases of the menstrual cycle. Hyperplastic and carcinomatous endometrium also contained specific cytosol receptor for progesterone, and the binding activity of the hyperplastic endometria and endometrial polyps was comparable to that found during the later proliferative phase of the menstrual cycle. No apparent correlation between the progesterone receptor level and the morphologic degree of differentiation in Grades 1 and 2 adenocarcinomas of the endometrium was observed.


Free and protein-bound steroids in amniotic fluid of midpregnancy.

Ninety-seven amniotic fluid (AF) specimens, 67 with male fetuses and 30 with female fetuses, were obtained by amniocentesis at 14 to 18 weeks of gestation for analysis of free and protein-bound estrone (E1), estradiol (E2), androstenedione (A), testosterone (T), and progesterone (P). Ten maternal plasma (MP) samples of comparable gestational age were analyzed for the same free and protein-bound steroids. Significantly lower total E1, E2, A, and T, but not P, levels were found in AF when compared to MP. The percentage of free steroids was higher in AF than in MP, while the percentage of specific protein-bound steroids was lower in the AF than in MP. Free (unbound) steroid levels of E1 and P were higher in AF than in MP, whereas levels of E2 were lower in AF than in MP. The free A and T levels in MP were lower than in AF with male fetuses, yet higher than in AF with female fetuses. Possible biologic activity of steroids in this fluid may depend on the dynamic balance between the free, the specific protein-bound, and the nonspecific protein-bound steroids.


20 alpha-Hydroxysteroid oxidoreductase activity and 20 alpha-dihydroprogesterone concentration in human placenta before and after parturition.

The objective of this investigation was to determine if decreased biosynthesis or increased catabolism of progesterone (P) during labor was responsible for the decreased concentration of hormone observed in the human placenta after labor and vaginal delivery. No significant difference was found in P biosynthesis by placental tissues examined before and after labor as evidenced by a similar activity of 3 beta-hydroxysteroid dehydrogenase: delta 5-isomerase. In contrast, there was a marked increase in P catabolism during labor, as shown by a significant (p less than 0.05) change in placental 20 alpha-hydroxysteroid oxidoreductase activity which increased from 835.5 +/- 103 (mean +/- SEM) pmoles of 20 alpha-dihydroprogesterone (20 alpha-DHP) generated per milligram of protein per hour before labor to 1,160.4 +/- 101 pmoles/mg/hr after labor. A similar significant (p less than 0.02) increase in enzyme activity was noticed in parallel assays of the reverse (20 alpha-DHP leads to P) reaction. As a consequence of increased P catabolism, placentas after labor had a 20 alpha-DHP concentration of 63.7 +/- 9.5 (mean +/- SEM) ng/mg protein, a value which was significantly (p less than 0.05) larger than that found before labor (37.8 +/- 8.3 ng/mg protein). These changes resulted in a modification of the placental tissue P/20 alpha-DHP ratio which decreased from 2/1 before to 1/1 after labor. The results indicate that the catabolism of P to 20 alpha-DHP increases significantly during human parturition. This phenomenon may be of importance in the mechanism of initiation and continuation of labor.


Effects of maternal smoking on circulating catecholamine levels and fetal heart rates.

Eight pregnant chronic cigarette smokers were studied after 34 weeks of gestation to determine the effects of acute cigarette (two nonfilter cigarettes) inhalation on maternal neuroendocrine and cardiovascular changes and on the fetus. Cigarette smoking was found to induce rapid (within 2 1/2 minutes) elevations in maternal plasma norepinephrine and epinephrine levels and this was associated with a rise in maternal pulse and blood pressure. These changes are followed, with a 5 minute lag time, by a significant increase in fetal heart rate. A relatively slow but sustained increase in maternal carboxyhemoglobin (HbCO) concentration occurred. The time course of this increase in HbCO did not seem to be responsible for the acute changes in fetal heart rate. Maternal cortisol levels also showed a slow but sustained elevation. Our present findings, together with data obtained from animal models, suggest that cigarette smoking during pregnancy induces fetal hypoxia through two independent but additive pathways: (1) An acute effect is caused by nicotine activation of adrenergic discharge, resulting in vasoconstriction, a decreased uterine perfusion, and a consequent transient fetal tachycardia, and (2) a delayed but prolonged increase in HbCO may cause a sustained reduction of fetal oxygenation.


Catechol-O-methyltransferase activity in erythrocytes of women taking oral contraceptive steroids.

We have measured catechol-O-methyltransferase (COMT) activity in erythrocytes (red blood cells, RBCs) obtained from 64 women taking oral contraceptives steroids and compared these values with those found in RBCs obtained from 73 women using nonsteroidal contraceptives. The COMT activity in the RBCs of women taking oral contraceptives steroids and of women not taking contraceptive steroids was 9.1 +/- 0.28 (mean and standard error) and 8.8 +/- 0.26 nmoles 2-methoxyestrone X ml-1 RBC X hr-1, respectively. This difference in the COMT activity in RBCs from these two groups of women was not statistically significant. This finding differs from that of others who found that COMT activity in RBCs of women taking oral contraceptive steroids was greater than that of women not taking such drugs.


Placental uptake and transfer of lipid in the postterm rabbit.

Gonadotropin-injected pregnant rabbits were delivered by cesarean section near term (30 days after conception (term, 31 days) and 3 1/2 and 4 days post term. Lipid metabolism of the postterm and near-term fetus was compared. Fetal and placental uptake of radioactivity and rate of lipid entry into the fetus, as well as fetal and maternal plasma free fatty acid (FFA) specific activities (at equilibrium) were determined following a single maternal injection of [1-14C]palmitate (50 muCi) administered at cesarean section. Evidence of placental malfunction in the postterm period includes decreased placental uptake and transport of labeled FFA occurring while maternal and fetal FFA dynamics (half times) remain unchanged and a loss in "organization": The strong positive correlation (p less than 0.001) between placental uptake and transfer to the fetus at 30 days' gestation is lost 5 days later. A comparison of maternal and fetal plasma FFA specific activities indicates a substantial (62%) near-term fetal contribution to its own circulating FFA pool. Total plasma FFA is elevated in the postterm fetus concomitant with a decreasing maternal supply. A postterm fetus must therefore contribute lipid from its own reserves (probably liver) in excess of amounts attributed to a near-term fetus, i.e., greater than 62%.


Organophosphorous neuropathy. I. A teased-fiber study of the spatio-temporal spread of axonal degeneraion.

The spatio-temporal spread of axonal degeneration in organophosphorous neuropathy has been studied by means of the teased-fiber technique. Young adult cats were given a single intraperitoneal injection of di-isopropylfluorophosphate (DFP) and were killed 14, 18, 20, 21, and 28 days later by intracardiac perfusion with aldehydes. The cats developed clinical signs of delayed neurotoxicity 16 to 18 days after DFP injection. A histologic survey of the central and peripheral nervous systems revealed that the topographic distribution of axonal degeneration was characteristic of a dying-back neuropathy. In teased-fiber preparations from the left recurrent laryngeal nerve, we found that the axonal degeneration was initially focal and nonterminal but that the axonal degeneration subsequently spread in a somatofugal direction to involve the entire distal axon. Nerve fibre varicosities and paranodal demyelination preceded the axonal degeneration. It is concluded that neurotoxic organophosphates induce a focal, distal but not terminal axonal degeneration. This "chemical transection" of the axon then precipitates wallerian degeneration of the more distal axon. Thus, the traditional hypothesis that dying-back neuropathies evolve from a retrograde axonal degeneration is not valid for organophosphorous neuropathy.


Organophosphorous neuropathy. II. A fine-structural study of the early stages of axonal degeneration.

The early stages in the evolution of axonal degeneration in organophosphorous neuropathy have been studied by electron microscopy of single nerve fibers. Two young adult cats were given a single, intraperitoneal injection of di-isopropylfluorophosphate (DFP). Eighteen and 20 days later, respectively, after intracardiac perfusion with glutaraldehyde, single nerve fibers were teased from the cats' left recurrent laryngeal nerves. Four nerve fibers in progressive stages of axonal degeneration, were subserially sectioned and studied in the electron microscope. Unique, mid-internodal nerve fiber varicosities preceded an axonal degeneration which was initially focal and nonterminal. The varicosities were associated ultrastructurally with intra-axonal and/or intramyelinic vacuoles. Accumulations of axonal agranular reticulum were found in all four fibers but were associated with less than one half the varicosities. It appeared, both by light and electron microscopy, that the nerve fiber varicosities progressed to the focal, nonterminal axonal degeneration.


Characterization of chronic N,N'-diacetylbenzidine-induced nephropathy.

Rats given N,N'-diacetyl benzidine (N,N'-DAB) by intraperitoneal injections were studied to further characterize the ensuing renal disease. Significant proteinuria and albuminuria occurred at 10 weeks and thereafter and was enhanced by prior unilateral nephrectomy. Glomerular epithelial cell vacuolization and cyst formation were marked in proteinuric rats. Focal glomerular sclerosis and synechia were present, but proliferative crescent formation was not. Glomerular fibrinogen was noted, but no immunoglobulins or C3 was detected by immunofluorescence microscopy. Glomerular epithelial cell cysts and disruption were noted ultrastructurally, but no electron-dense deposits were seen. Tubular basement membrane thickening and wrinkling were noted in N,N'-DAB rats, and maximum urine osmolarlity was decreased. None of the animals developed renal insufficiency. Parenteral N,N'-DAB-induced renal disease is different from crescentic glomerulonephritis noted in rats fed N,N'-DAB and has similarities to an experimental model of aminonucleoside induced focal sclerosis, supporting the theory of primary glomerular epithelial cell injury mediating proteinuria and focal sclerosis.


Nuclear inclusions in alveolar epithelium of patients with fibrotic lung disorders.

Ultrastructural study of pulmonary biopsy specimens from patients with fibrotic lung disease disclosed the presence of nuclear inclusions in 1% or less of cuboidal alveolar epithelial cells in 9 of 19 patients, including 6 of 12 patients with idiopathic pulmonary fibrosis, 2 of 3 patients with collagen-vascular disease, and 1 of 3 patients with sarcoidosis. Nuclear inclusions were not observed by ultrastructural study in 5 control patients. The inclusions consisted of masses or aggregates of tubules which probably were derived from the inner nuclear membranes. These tubules were smooth-walled, showed branchings and bifurcations, were composed of single trilaminar membranes, usually had a clear content, and ranged from 500 to 1000 A in diameter. They resembled nuclear tubules which occur in other cell types under conditions of rapid growth or specific hormonal stimulation. Statistically significant differences between the groups of patients with and without nuclear inclusions in cuboidal alveolar epithelial cells were not found with respect to smoking history, degree of fibrosis in the lung biopsy specimen, or the degree of pulmonary physiologic impairment. However, the average age of the patients having nuclear inclusions was significantly greater than that of patients not having nuclear inclusions. In addition, the frequency of indentations in the nuclei of cuboidal alveolar epithelial cells was greater in patients with nuclear inclusions than in patients without nuclear inclusions. Highly significant correlations were observed between the presence of nuclear inclusions and the presence of a) anchoring fibrils and hemidesmosomes along the basal surfaces of alveolar epithelial cells and b) multilayering of the alveolar epithelium.


Transplantable acinar cell carcinoma of the rat pancreas.

An acinar cell carcinoma of the pancreas, which developed in a F-344 rat after long-term nafenopin administration, was serially transplanted into inbred weanling rats by subcutaneous and intraperitoneal routes. The transplantability rate was 95% or more by both routes. The tumor implants became palpable in 20 to 30 days after subcutaneous transplantation, increasing in size rapidly thereafter during the next 25 to 30 days. In intraperitoneal recipients the abdomen was markedly distended within 1 month. No metastases were observed in this series of transplantations. Amylase and lipase levels in serum and tumor homogenates increased with tumor size. Morphologically, only a few cells contained zymogen granules immediately after the appearance of a palpable tumor; at later intervals, however, these granules were observed in many tumor cells. Seventy-two hours after the surgical removal of tumors, the serum amylase and lipase levels returned to control values. This transplantable pancreatic acinar cell carcinoma can be dissociated into functionally viable single cells by a simplified enzyme digestion and divalent cation chelation procedure. By light microscopic autoradiography, approximately 20% of these isolated cells were found to incorporate (3)H-thymidine in vitro into nuclear DNA. The data presented in this paper should serve as a baseline for future studies on this transplanted tumor.


The heterophagic granules of mast cells: dipeptidyl aminopeptidase II activity and resistance to exocytosis.

Dipeptidyl aminopeptidase II (DAP II) was demonstrated cytochemically in rat peritoneal mast cells. The bright red reaction product in smears of peritoneal wash fluid tended to be localized in one to eight granules in the perinuclear region of the cell. This finding was confirmed at the electron microscopic level, where a small proportion of the granules, most often located near the nucleus, revealed electron opacity indicative of DAP II. Focal areas in the nuclear envelope densified by DAP II reaction product resembled reactive foci observed previously in the nuclear envelope of peritoneal macrophages. In mast cells exposed 1 to 2 hours to phosphate-buffered saline containing horseradish-peroxidase--coated colloidal gold, the spherules of gold were internalized and transported exclusively to the DAP II-reactive granules. Their content of endocytosed gold thus identified DAP II-reactive granules as secondary lysosomes of heterophagic nature. Mast cells induced to release their granules by stimulation with the divalent cation ionophore A23187 retained exclusively those granules possessing DAP II or acid phosphatase reactivity. This selective granule retention after ionophore exposure further differentiated granules with DAP II reactivity from the other non-reactive mast cell granules, presumably indicating a difference between the limiting membrane of granules that are converted to secondary lysosomes and the membrane of those that are not altered and persist as primary lysosomes. Demonstration of the DAP II reactivity in a minority of mast cell granules and of the heterophagic nature of these granules provides evidence that tissue mast cells in vivo function in endocytic activity by transporting material of extrinsic origin to some of their granules which are thereby transformed to heterophagic bodies or constitute previously existing heterophagosomes.


Hypersecretion of mucus glycoproteins in rat airways induced by tobacco smoke.

An animal model of chronic bronchitis has been produced in vivo by exposing rats for 6 weeks to tobacco smoke: the laryngeal and tracheal glands have been studied in vitro by organ culture to analyze glycoprotein precursor incorporation and glycoprotein secretion by individual cells, a feature not previously studied. In the hypertrophied glands produced by tobacco smoke exposure, the cellular rate of glycoprotein secretion was increased. The in vivo administration of phenylmethyloxadiazole (PMO) to rats exposed to tobacco smoke blocked this effect. In vitro analysis of glands from unexposed rats that received PMO showed that it modified cell function directly by reducing the rates both of glycoprotein discharge and or precursor incorporation into intracellular glycoproteins.


Ferritin in rat kidneys with specific lesions due to a single dose of lead.

In the proximal tubular cells of rats or mice given a single, parenteral dose of lead, clusters of ferritin are frequently associated with characteristic cytoplasmic fibrillar bodies. To learn more about this relationship, we have investigated content and synthesis of ferritin protein and incorporation of iron into ferritin in rat kidneys 48 hours after a single parenteral dose of lead (10 microgram/g). By immunoradiometric assays, we found that the kidneys of female rats, whether treated with lead or not, contained significantly more ferritin protein than did kidneys of males of the same age and provenance. Administration of lead diminished (or did not significantly alter) the incorporation of 14C-amino acids into newly synthesized ferritin protein. Contrary to expectation, administration of lead tended to depress incorporation of 59Fe into kidney ferritin in rats maintained on standard rations and distilled water. Electron microscopy confirmed the presence of clusters of ferritin in close association with dense fibrillar bodies in the cytoplasm of proximal tubular cells of rats given lead. Considered together, the findings indicate that clustering of ferritin next to the dense fibrillar cytoplasmic lesions is a selective effect of lead that requires neither augmented synthesis of ferritin protein nor increased incorporation of iron into preexisting ferritin.


alpha-Actinin deficiency in thrombasthenia: possible identity of alpha-actinin and glycoprotein III.

Blood platelets contain a variety of contractile protein species, including the glycoprotein alpha-actinin, which is found at the Z disc in skeletal muscle cells. In the present study, we have considered the possibility that alpha-actinin might be one of several previously described platelet surface glycoproteins. Purified anti-alpha-actinin antibody was found to react strongly with partially purified platelet glycoprotein III, weakly with platelet glycoprotein IIb, and not at all with platelet glycoproteins Ib and IV. Platelets from three siblings with thrombasthenia, a disorder characterized by severe deficiency of platelet glycoproteins IIb and III, were found also to be equally deficient in alpha-actinin. These findings indicate that alpha-actinin and glycoprotein III are identical and suggest that this protein may be an anchor point for actin on the inside of the membrane. Combined with ultrastructural studies of normal and thrombasthenic platelets, the new findings provide a clearer understanding of contraction in single cells and small aggregates.


Phagocytosis of chrysotile fibers by pleural mesothelial cells in culture.

Pleural mesothelial cells (PMC) from the parietal pleura of rats were incubated in culture with UICC A chrysotile fibers. The sequence of events in phagocytosis was studied by electron microscopy: phases of attachment sequestration, and degranulation of lysosomal content into the phagocytic vacuole were observed. This demonstrates that PMC can engage in phagocytosis of chrysotile fibers.


Mechanisms of platelet response to monosodium urate crystals.

The mechanisms of urate-crystal-induced release of platelet constituents has been studied morphologically and biochemically. Urate crystals provoked an early energy-dependent release of the dense-body constituents serotonin, ADP, and ATP from washed platelets. Concurrently, platelet ultrastructure showed evidence of shape change, contractile wave, and aggregation. These are typical morphologic concomitants of platelet secretion. By 30 minutes' incubation, urate-induced platelet lysis occurred, as shown by loss of the cytoplasmic enzyme lactic dehydrogenase (LDH) and ultrastructurally by disruption of platelet membrane integrity. Cytochalasin B inhibited the urate-crystal-induced shape change, aggregation, and disruption of cell membranes. Platelet degranulation was not inhibited and the initial component of serotonin release was not affected. Cytochalasin B also abrogated crystal-induced LDH loss. Thus, the initial crystal-induced serotonin release does not depend on platelet lysis. It is concluded that urate-crystal--induced release of serotonin, ATP, and ADP represents an example of platelet secretion.


Smooth muscle cell proliferation in the occluded rat carotid artery: lack of requirement for luminal platelets.

The relationship of intimal smooth muscle cell proliferation in the permanently occluded rat carotid artery to the presence or absence of luminal platelets was examined. Blood was rinsed from the arterial lumen immediately after occlusion and was replaced by autologous, citrated platelet-rich plasma (PRP, 6 to 20 X 10(5) platelets/microliter) or filtered platelet-poor plasma (PPP, less than 100 platelets/microliter). Occluded arteries were studied after 1 to 28 days by light and electron microscopy. Events occurring within the first 2 days included fibrin clot formation, endothelial degeneration and denudation, transmural migration of polymorphonucelar leukocytes and monocytes, and, in PRP-filled arteries, degranulation and disappearance of platelets. By 7 days a neointima was formed by macrophages and undifferentiated cells. The latter cells had some features of vascular smooth muscle cells and were apparently derived from medial cells which traversed the internal elastic lamina. After 14 days, identifiable smooth muscle cells emerged as the predominant cell type in a rapidly growing intimal plaque. No differences could be discerned between arteries originally filled with PRP or PPP. This experimental model is similar to atherosclerosis in dimensions of avascular area and in coexistence of degenerative, inflammatory, and proliferative processes. Cell proliferation deep within an atherosclerotic plaque could be initiated by factors other than platelets, perhaps by products of inflammatory cells.


The effects of induced prenatal hypothyroidism on lamb mandibular third primary molars.

Intrauterine thyroidectomies were performed on nine lambs on or about the ninety-sixth postconception day. Seven other control and shamoperated lambs, and the cretin lambs were sacrificed immediately after birth. The mandibles were removed and sectioned at the midline. The right side molars were removed by dissection and caliper measured. The distal cusps of the third primary molars were sectioned, dehydrated, and embedded in Bioplastic. A slow speed diamond saw was used to section the plastic blocks and the embedded teeth. Subsequent grinding and polishing produced high quality 75 micrometer sections of the lamb molar cusps. No significant differences in tooth size or enamel thickness existed. Microscopic examinations show that parts of the cretin enamel were poorly calcified, an observation that was correlated to the intrauterine thyroidectomies. The data suggest that hypothyroidism alters ameloblastic activity during the secretory phase of enamel formation.


Effects of serum on membrane transport. III. Serum and inhibition of lysine transport.

Rabbit lung macrophages have been shown to transport lysine by means of a single carrier-mediated system that is depressed after relatively short incubations with 1% normal rabbit serum (NRS). Our present results show that three amino acids, glutamine, phenylalanine and tyrosine, at or near the concentration found in 1% NRS, are involved intracellularly in regulating lysine influx across the plasma membrane. The means by which they do so requires a 20- to 30-min preincubation, the effect is maintained for 45 min in their absence, and both maximal velocity and affinity of lysine for its carrier are altered in an apparently uncompetitive fashion. The kinetic data are unlike those reported for other trans phenomena involved in amino acid transport. We propose that the effect of internal inhibitor on lysine influx probably does not involve the direct interaction of the transamino acid on the lysine carrier.


Cadmium transport in isolated perfused rat liver: zinc-cadmium competition.

The hypothesis that one component of cadmium uptake by rat hepatocytes involves a mediated transport pathway normally operative for zinc transport was tested in the isolated perfused rat liver preparation. Excess zinc in the perfusion medium suppressed cadmium uptake as indicated by the decrease in the normalized clearance (initial clearance divided by liver weight) from 0.340 +/- 0.019 (ml/min)/g in the presence of normal zinc concentrations (Zn:Cd molar ratio, 1.6) to 0.138 +/- 0.017 (ml/min)/g (Zn:Cd molar ratio, 13.0). In excess-zinc control experiments (no cadmium present) little zinc is accumulated by the liver, apparently due to competition between intrahepatic and extracellular binding. Exposure to cadmium increases both zinc secretion into the perfusion medium and biliary excretion of zinc. The effect at the sinusoidal membrane is probably a result of both the blockage of zinc resorption during cadmium uptake and the displacement of intrahepatic zinc. The effect on biliary excretion of zinc is due solely to displacement of intrahepatic zinc. These results are consistent with the proposed hypothesis for cadmium transport.


Micro-light guides: a new method for measuring tissue fluorescence and reflectance.

Three-way light guides containing one or more strands of 25-micron or 80-micron diameter optical fibers in each channel have been constructed and used to measure the NADH fluorescence and UV reflectance from mitochondrial suspensions, the perfused, hemoglobin-free rat liver, and the perfused beating interventricular septum of the rabbit. The optical changes measured with these so-called micro-light guides, which have channels containing one or several strands of optical fibers less than 100 micron, are comparable in magnitude with those measured using much larger conventional light guides. The effect of light scattering on the fluorescence channel has been determined and an empirical equation for correcting the fluorescence channel for light scattering has been obtained for mitochondrial suspensions. A mathematical equation characterizing the optical behavior of a two-way micro-light guide has been derived and has been shown to account satisfactorily for reflectance and fluorescence measurements of a mat surface in air.


Localization of [3H]ouabain-sensitive Na+ pump sites in cultured pig kidney cells.

Pig kidney cells, LLC-PK1, grown by standard tissue-culture techniques form monolayers and maintain morphological features characteristic of epithelia. Cultures exposed to 2 X 10(-6) M [3H]ouabain for 30 min at 37 degrees C bound 7.77 +/- 0.37 pmol/mg protein. This could be reduced by 58% by incubation in the presence of 45 mM K+. Freeze-dry radioautographic localization of [3H]ouabain-binding sites revealed grains distributed only along that fraction of the plasmalemma directly facing the culture-dish surface. Binding and localization of [3H]ouabain were correlated with an inhibition of the Na+ pump in these cells because analysis of cellular electrolytes in control cultures versus those exposed to 10(-3) M ouabain revealed a fall in K+ from 419 +/- 9 to 173 +/- 4 mmol/kg dry wt with a reciprocal increase in Na+. There was no change in cell H2O. Similarly, oxygen consumption was reduced by 32% after exposure to ouabain. These results provide direct evidence that in epithelial cells in culture the membrane facing the culture dish corresponds to the basolateral membrane of epithelial cells in vivo.


Potassium permeability of embryonic avian heart cells in tissue culture.

The relationship between the external potassium concentration ([K]o) and membrane permeability has been reexamined using a tissue-cultured preparation of embryonic chick heart cells in which diffusional limitations are minimal. The unidirectional K efflux and electrochemical gradients were determined as a function of [K]o, and the results showed that potassium permeability was constant within the range of 1-20 mM [K]o. Membrane potentials were obtained in K-free solutions and correlated with 42K efflux and intracellular ion content measurements under the same conditions. In contrast to preparations of the intact embryonic chick heart, 42K efflux does not decrease in K-free media. Simulations of tracer measurements at reduced [K]o from naturally occurring cardiac muscle indicate that the experimentally observed decrease in 42K efflux could result from diffusional limitations. This observation, when coupled with the experimental results, suggests that the effect of low [K]o on membrane permeability in homeothermic preparations of cardac muscle should be reevaluated.


Adrenal epinephrine in hyperuricemia induced by hypothalamic stimulation of the rat.

Peripheral neurological mechanisms involved in hyperuricemia following ventromedial hypothalamic electrical stimulation was studied in the conscious rat. The intensity of 0.2 mA was near the maximum intensity of stimulation current producing a linear increase in plasma uric acid throughout the 15-min period of stimulation, as well as a subsequent rise and fall of plasma allantoin. Bilateral adrenal demedullation abolished the stimulation-induced hyperuricemia and markedly impaired the accompanying rise of allantoin. Prior treatment of the animal with hexamethonium significantly inhibited the uric acid increase, but did not reduce the allantoin elevation so markedly. Moreover, propranolol eliminated both responses of these plasma purine metabolites, whereas phentolamine greatly increased the response. It is concluded therefore that the hypothalamic stimulation-induced rise of plasma uric acid is the result of acceleration of epinephrine release from the adrenal medulla and that, whereas some unknown extra-adrenal mechanism may be partially involved, the primary part of the accompanying allantoin elevation is explained by the combined effects of the increased uric acid and the hepatic uricase.


Effect of perfusate glucose concentration on rat lung glycolysis.

We investigated the relationship between perfusate concentration of glucose and its utilization and lactate production derived from exogenous glucose and from metabolism of endogenous substrates. Isolated rat lungs were ventilated with 5% CO2 in air and perfused for 100 min with Krebs-Ringer bicarbonate buffer containing 3% bovine serum albumin, 10(-2) U/ml insulin, [U-14C]glucose and [5-3H]glucose. Glucose utilization, total lactate production, [14C]lactate production, and 3H2O production were measured. The apparent Km and Vmax for glucose utilization were 3.4 mM and 72.5 mumol/g dry wt per h, respectively. Lactate production from endogenous substrates, calculated as the difference between total and [14C]lactate, was 37.6 +/- 2.2 mumol/g dry wt (n = 36); it was unaffected by perfusate glucose concentration and by omission of insulin, but increased threefold with anoxia. Lactate production from 1.5 mM glucose was significantly less (P less than 0.02) with insulin omitted. Glycogen content was unchanged during perfusion without glucose. These results suggest that: 1) protein catabolism contributes to lung lactate production; 2) glucose utilization by lung is not maximal at resting physiological glucose concentrations; and 3) insulin is required at low glucose concentrations for maximal glycolytic rates.


Effects of glutamine deprivation on glucose and amino acid metabolism in tissue culture.

The effects of glutamine deprivation on cultured skeletal muscle cells were analyzed by incubating 10-day-old myotube preparations in glutamine free Dulbecco's modified Eagle medium containing 10% fetal calf serum for up to 48 h. Under these conditions net glutamine production was not observed, but active ammonia production (average rate = 1.0 nmol/min . mg protein) continued despite glutamine withdrawal. Glutamine deprivation was associated with a progressive depletion of intracellular aspartate and glutamate. Maximal aspartate depletion correlated with a 15-fold increase in the intracellular lactate:pyruvate ratio and a 3-fold decrease in the estimated intracellular glutamate:(alpha-ketoglutarate) (ammonia) ratio. Despite wide shifts in cell metabolite concentrations, the mass action ratios of alanine and aspartate aminotransferase approximated the expected equilibria constants. These results suggest that 1) glutamine deprivation is associated with a marked reduction of aspartate, and the maintenance of aspartate depletion is due in part to the tendency of aspartate aminotransferase to maintain the metabolites of this reaction at a near equilibrium level; 2) the transport of reducing equivalents from the cytosolic to the mitochondrial compartments via the malate-aspartate shuttle may be limited under conditions of aspartate depletion.


Effects of selective insulin or glucagon deficiency on glucose turnover.

To study the importance of glucagon and insulin in diabetes, somatostatin (ST) was infused, alone or with insulin or glucagon, in 11 conscious dogs. Plasma immunoreactive insulin (IRI) and glucagon (IRG) levels fell 65 +/- 4% and 33 +/- 3%, respectively, with somatostatin infusion. Glucose production (Ra) assessed by [3-3H]glucose, [2-3H]glucose, or [1-14C]glucose decreased transiently. This is in contrast to the rise in Ra seen after insulin withdrawal in depancreatized dogs, which have normal levels of IRG. Thus, suppression of IRG with somatostatin prevented an increase in Ra in spite of suppression of IRI. When near basal IRG levels were provided during ST infusion in normal dogs, Ra increased, indicating that glucagon contributes to the acute development of diabetes. When basal IRI levels were provided with ST, suppression of Ra was maintained, suggesting that the transience of the metabolic effects of ST-induced glucagon suppression requires concomitant insulin suppression. A comparison of glucose turnover measured using different tracers showed that ST-related hormonal changes did not alter the rate of futile cycling in the liver. ST induced a rise in plasma free fatty acid (FFA) levels, attributed solely to insulin deficiency, as glucagon suppression did not significantly alter FFA concentrations when normal insulin levels were maintained.


Deoxythymidine kinase activity of human implanted sponge connective tissue in zinc deficiency.

The activity of deoxythymidine kinase was assayed in implanted sponge connective tissue in three groups of subjects: 1) five normal controls (having normal levels of plasma and red cell zinc); 2) four patients with sickle cell anemia who had low zinc in red cells and hair; and 3) two volunteers (under strict dietary controls), after 6 mo of zinc restriction (2.7 mg/day) and repeated after 3 mo of zinc repletion (30 mg/day). Total protein, total collagen, RNA/DNA, and deoxythymidine kinase activity were measured by techniques reported previously. In sickle cell anemia patients, deoxythymidine kinase activity was not detected, and RNA/DNA, total collagen, and total protein contents were decreased compared to normal controls (statistically significant). In human volunteers deoxythymidine kinase activity was not detected during the zinc restriction phase. After supplementation with zinc, deoxythymidine kinase activity became 70% of normal control levels, and RNA/DNA, total collagen, and total protein contents of sponge connective tissue increased. In conclusion, an adverse effect of zinc deficiency on deoxythymidine kinase activity of implanted sponge connective tissue of man has been demonstrated for the first time.


Normophosphatemic phosphate depletion in growing rat.

To study the influence of phosphate depletion (PD) on the serum, urinary, bone, and soft tissue phosphorus, we studied growing rats given a high-phosphorus (HP), normal-phosphorus (NP), or low-phosphorus (LP) diet. We obtained the following results. a) With an LP diet, animals did not grow but developed the characteristic biochemical changes of PD. b) The NP rats had an unexplained accelerated rate of growth, and developed all the biochemical changes of PD, although they were normophosphatemic. c) Bone P and Ca were significantly lower in the LP and NP rats compared to the HP rats, suggesting that minerals were mobilized from bone to support soft tissue P needs. d) Soft tissue P was not different in HP, NP, and LP rats, confirming previous observations that soft tissue P is maintained even in PD. We conclude that 1) the physiologic adaptation to PD may occur in growing rats on an apparently normal phosphorus diet when the metabolic demand is unusually high, e.g. accelerated growth; 2) the evolution of the biochemical parameters of PD in the face of normophosphatemia suggest a sensor mechanism sensitive to change in dietary P concentration.


Kidney metabolite levels and ammonia production in acute acid-base alterations in the rat.

Acute acid-base disturbances cause rapid changes in renal ammonia production in the rat. To investigate the regulation of ammonia production in acute acid-base stresses, we examined the effects of such conditions on tissue levels of metabolites such as alpha-ketoglutarate (KG), which inhibits kidney mitochondrial glutamine uptake and deamidation at physiological concentrations. In rats given low (5 mmol/kg) or high (20 mmol/kg) doses of NH4Cl by stomach tube or placed in a 10% CO2 atmosphere, kidney KG levels fell after 1-h by 44, 69, or 73%, respectively. NaHCO3  administration produced no change in KG levels. Renal glutamate and glutamine levels changed little, if at all, in any group, and renal phosphoenolpyruvate levels were not altered except for a decrease in the NH4HCO3 group. In livers of the same rats, treatments produced different patterns of metabolite changes; KG fell only in the NaHCO3 and NH4HCO3 groups. These results support the concept that KG is a specific regulator of renal ammonia production in acute acid-base stresses.


Frequency content of esophageal peristaltic pressure.

Fourier analysis of esophageal peristaltic pressure waves was performed by computer fast Fourier transform. The highest power spectral density was obtained in the frequency range below 1 Hz. The Fourier analysis showed spectral components up to about 12 Hz in the upper esophageal sphincter (UES). The significance of different frequency components was investigated by low-pass filtering at different cut-off frequencies. A reduction in the amplitude of UES contractions was obtained at a cut-off frequency of 4 Hz, whereas the cut-off frequency of 8 Hz did not show any distortion. For perfused manometry systems, only a low-compliance perfusion pump will have sufficient bandwidth for accurate recording of esophageal peristaltic pressures.


Altered copper absorption in tumor-bearing and estrogen-treated rats.

Intestinal copper absorption was studied in normal, tumor-bearing and estrogen-treated rats, using 64Cu(NO3)2. Rats bearing Dunning mammary tumors (DMBA 5A) of more than 2 g absorbed 70-100% more of an intragastric copper dose than controls, and a much larger percentage was found in the plasma, with less in liver and kidney. The distribution of copper measured chemically mimicked these findings, and the enhanced capacity for absorption was also demonstrated in vitro with everted duodenal segments. Further examination of the intestinal mucosa revealed that binding of radioactive copper to a 10,000-dalton component of the cytosol was inversely proportional to the amount absorbed into the body, tumor-bearing rats retaining much less in, and transferring much more from, the intestine than controls. Daily injection of 17 beta-estradiol over 2 wk had the reverse effect. It is concluded that the absorption of copper is an endogenously regulated process that may be altered by cancer and estrogen treatment and mediated by the extent of its binding to a component (possibly metallothionein) within the mucosal cell.


Relationship between arterial and cisternal CSF oxygen tension in rabbits.

Oxygen tension was measured in samples of blood and cisternal cerebrospinal fluid taken from anesthetized, paralyzed, and mechanically ventilated rabbits at various levels of arterial PO2. Cerebrospinal fluid oxygen tension (CSF PO2) was correlated with arterial PO2 (linear regression equation PCSFO2 = 0.2472 Pao2 + 42.34). During hypoxia CSF PO2 was higher than arterial PO2 in most experiments. These data can be attributed to the Bohr effect, which would increase the PO2 of the blood in choroid plexus capillaries as a result of its acidification. The  acidification was suggested by Maren (Am. J. Physiol. 222: 885-889, 1972) to be a part of the ionic exchanges involved in cerebrospinal fluid formation. Such a mechanism may be of importance for supporting choroid plexus metabolism and function during hypoxia. This mechanism is most clearly seen in the rabbit.


Regulation of cell volume in separated renal tubules incubated in hypotonic medium.

The regulation of cell volume was studied in separated renal tubules (SRT) whose basement membrane had been removed by collagenase. Regulation occurred when SRT were immersed in a hypotonic medium, the increase in cellular water content being half that expected in the absence of regulation. Regulation was immediate, with no initial swelling, and was accompanied by a loss of NaCl, with no change in cellular K. This regulation was eliminated by 10(-3) M ouabain. We conclude that: 1) Cell volume regulation which occurs in a hypotonic medium is due to an immediate loss of NaCl. 2) Loss of NaCl might be due to blocking of the net passive NaCl entry into the cells resulting from the drop in the transmembrane NaCl electrochemical gradient. The high membrane sodium permeability, probably located on the luminal side of the tubular cells, might explain why regulation was instantaneous. 3) Elimination of volume regulation by ouabain suggests there is no need to assume that a ouabain-insensitive pump regulates cell volume.


Coupling of NaHCO3 and NaCl reabsorption in dog kidneys during changes in plasma PCO2.

To study the relationship between proximal tubular reabsorption of bicarbonate, sodium, and chloride, the effects of changes in plasma PCO2 were examined in anesthetized dogs. Distal tubular reabsorption was inhibited by ethacrynic acid; plasma bicarbonate concentration was kept constant at 33.4 +/- 0.3 mM; glomerular filtration rate (GFR) was varied over a wide range to examine glomerulotubular balance (constant fractional reabsorption). Hypercapnia (PCO2, 112.0 +/- 2.5 mmHg) increased bicarbonate reabsorption by about 30%, and hypocapnia (PCO2, 19.8 +/- 0.6 mmHg) decreased reabsorption of bicarbonate by more than 50% and altered reabsorption of sodium, chloride, and bicarbonate in the molar ratios 2.7:1.6:1, respectively. During hypercapnia the range of glomerulotubular balance was extended to a GFR 125% of control. During hypocapnia glomerulotubular balance was present only at GFR below 50% of control; reabsorption of bicarbonate sodium, and chloride was constant at GFR exceeding 50% of control. During metabolic acidosis hypercapnia had no significant effect on reabsorption of bicarbonate, sodium, and chloride. These observations support the hypothesis that bicarbonate reabsorption is the main driving force for osmotic reabsorption of water and NaCl in the proximal tubules.


Renal and nephron hemodynamics in spontaneously hypertensive rats.

Renal and nephron hemodynamics were compared between anesthetized, nondiuretic, spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY). Although the mean arterial pressure was higher in SHR than in WKY, 158 VS. 114 mmHg, glomerular filtration rate (GFR) and renal blood flow (RBF) were similar in both groups. So were intrarenal hydrostatic pressures, single nephron GFR (SNGFR), and single nephron blood flow (SNBF). Accordingly, the increased renal vascular resistance (RVR) in SHR was due to predominant preglomerular vasoconstriction. In a second group of SHR, SHR-AC, the femoral arterial pressure was reduced acutely to 114 mmHg by means of aortic constriction above the renal arteries. The mean values for GFR, RBF, SNGFR, SNBF, and intrarenal hydrostatic pressures resembled those in SHR, whereas RVR was less in SHR-AC. These autoregulatory adjustments of RVR were again largely limited to the preglomerular vasculature. Efferent arteriolar resistance was similar in all three groups. We conclude that the enhanced RVR in 12-wk-old SHR is primarily a consequence of a physiological, autoregulatory response of afferent arteriolar resistance to the elevated arterial pressure. Further, RVR in SHR is not fixed and constant but responds appropriately to reductions in renal perfusion pressure.


Effect of acute ureteral obstruction on terminal collecting duct function in the weanling rat.

Micropuncture techniques were employed to evaluate the effects of unilateral ureteral obstruction (UUO) of 18 h duration on the function of the terminal collecting duct in weanling rats 90-120 min following release of obstruction. In control animals and after release of UUO, water and sodium reabsorption continued along the terminal segment of the collecting duct. Fractional delivery of water (FRH2O) and sodium (FRNa) to this segment was increased after release of UUO. A significantly greater amount of the FRH2O and FRNa was reabsorbed along the terminal collecting duct following release of obstruction than in controls. Potassium was not consistently reabsorbed or secreted in either group. Following release of UUO, the osmolality of collecting duct fluid was lower than in controls, but was not different from the osmolality of fluid obtained from the bend of the loop of Henle. The results suggest that the permeability to water and the reabsorptive capacity of the collecting duct are not altered by acute obstruction.


Ionic requirements of proximal tubular sodium transport. III. Selective luminal anion substitution.

The effect of substitution of luminal anions on sodium and fluid absorption in rat renal proximal convoluted tubules was studied with continuous luminal microperfusion methods. Substitution of bicarbonate in the control Ringer perfusion fluid by 25 mM acetate reduced net sodium reabsorption by 40%; substitution by chloride reduced it by 25%; and substitution by cyclamate reduced it by 70%. Infusion of acetazolamide reduced net sodium and fluid transport in all cases except chloride-Ringer perfusion. Cyanide added to the perfusion fluid inhibited fluid and sodium movement completely when there was no imposed chloride concentration gradient, but only reduced fluid and solute movement by 68% when a nominal 36 mM transepithelial chloride concentration gradient existed. We conclude from these observations that passive forces for sodium reabsorption can account for a moderate amount of sodium transport, that the effects of acetazolamide in low concentrations are dependent on the presence of bicarbonate in the lumen, and that some anions alter net sodium transport either by reducing the availability of permeant anion for co-transport with sodium or by a direct effect on the sodium and/or chloride transport systems.


Potassium secretion along the inner medullary collecting duct.

Potassium transport along the inner medullary collecting duct (IMCD) was evaluated by the microcatheterization technique in Charles River CD (cesarean derived) rats 7-9 days after sham operation (S) or uninephrectomy (UNPX). The fraction of filtered potassium (TF/P)K/In) as a function of IMCD length was analyzed by linear regression. In 13 S rats there was a significant correlation and slope (P less than 0.001) and (TF/P)K/In increased from 14% at the beginning of the IMCD to 25% in the urine. IMCD potassium secretion accounted for about half of the excreted potassium. In the UNPX rats a significant correlation and slope was also obtained (P less than 0.001); (TF/P)K/In at the beginning of IMCD was 24% and increased to 36% in the urine. No difference in slope was noted between the groups. There was a slightly greater absolute potassium secretion after UNPX (0.77 +/- 0.03 S vs. 0.93 +/- 0.04 mueq/min UNPX), but this did not account for most of the difference in potassium excretion noted. We conclude that net potassium secretion occurs along the IMCD in S and UNPX rats. After UNPX, there is significantly greater potassium delivery to the IMCD and a greater kaluresis. The increased kaluresis cannot be accounted for primarily by increased potassium secretion along the IMCD.


Luminal Na+ entry into Necturus proximal tubule cells.

The dependence of intracellular Na+ activity on the electrical driving force across the luminal membrane and the presence of Cl- in the luminal perfusate was studied in Necturus proximal tubule. Intracellular Na+ and K+ activities were measured with microelectrodes filled with liquid ion exchanger. Perfusion of the tubule lumen with a NaCl-free solution caused cell Na+ activity to fall from the control value of 29.7 to 6.6 mM. In the absence of luminal driving force across the luminal membrane in accordance with simple diffusion of Na+ across this membrane. When the tubule lumen contained Na+ and Cl-, an electrically neutral component of Na+ entry into cells from the lumen appeared in addition to the diffusional component of Na+ entry.


Temperature dependence of transepithelial potential in isolated perfused rabbit proximal tubules.

The response of the transepithelial potential to rapid cooling in isolated perfused proximal convoluted (PCT) and proximal straight (PST) tubules has been studied. Tubules were perfused with solutions which simulated glomerular filtrate (A), filtrate minus glucose and alanine (B), and late proximal tubular fluid (C). The values of the potentials at 37 and 10 degrees C as well as the temperature-sensitive component were found to vary with perfusate composition. Temperature sensifound to vary with perfusate composition. Temperature sensitivity in PCT was seen only when glucose and alanine were present in the perfusate. In contrast, a portion of the potential difference in PST was temperature dependent under each of the perfusion conditions. Temperature sensitivity in PST was inhibited by 10(-5) M ouabain in the bath. It is concluded that the lumen-negative, temperature-sensitive component of PCT potential may reflect the coupled luminal entry of Na+ along with glucose and alanine. In PST, the temperature-sensitive component can be associated with Na+ transport but is not dependent on luminal concentrations of glucose, alanine, HCO3- or Cl- over the ranges examined. Potentials in both segments at 10 degrees C are interpreted as resulting from processes that are passive in nature.


Effect of parathyroid hormone on plasma renin activity and sodium excretion.

The interaction between parathyroid hormone (PTH) and the renin-angiotensin system was evaluated in pentobarbital-anesthetized dogs. An intravenous infusion of bovine PTH (1-34) for 1 h was accompanied by a 57% increase (13.7-21.6 ng/ml per h) in plasma renin activity (PRA) which returned toward control levels during the recovery period. Sodium and phosphate excretion also increased. Second the endogenous secretion of PTH was stimulated by infusion of citrate into the blood supply of the thyroparathyroid glands to determine if the stimulatory effect on renin occurred with endogenous secretion of PTH. Phosphate excretion increased, which confirmed PTH secretion. There was a significant rise (57%) in both PRA (6.1-9.8 ng/ml per h) and sodium excretion, the magnitude of the sodium response modulating the increase in PRA. Blood pressure remained constant. In a third set of experiments, thyrocalcitonin was infused intravenously and had no effect on PRA. These data indicate that both exogenous and endogenous PTH can elevate PRA and increase sodium excretion. The sodium effect is probably the result of inhibition of proximal sodium reabsorption by PTH. The mechanism by which PTH elevates PRA is not known.


Renin-angiotensin system in stroke-prone spontaneously hypertensive rats.

The development of malignant hypertension was studied in stroke-prone spontaneously hypertensive rats (SHR) kept on 1% NaCl as drinking water. Along with salt-loading, blood pressure gradually increased and reached a severe hypertensive level (greater than 230 mmHg), which was followed by increases in urinary protein (greater than 100 (mg/250 g body wt)/day) and plasma renin concentration (PRC, from 18.9 +/- 0.1 to 51.2 +/- 19.4 (ng/ml)/h, mean +/- SD). At this stage, renal small arteries and arterioles showed severe sclerosis and fibrinoid necrosis. Stroke was observed within a week after the onset of these renal abnormalities. The dose of exogenous angiotensin II (AII) producing 30 mmHg rise in blood pressure increased with the elevation of PRC, from 22 +/- 12 to 75 +/- 36 ng/kg, which was comparable to that in rats on water. The fall of blood pressure due to an AII inhibitor, [1-sarcosine, 8-alanine]AII (10(microgram/kg)/min for 40 min) became more prominent with the increase in PRC in salt-loaded rats, but was not detected in rats on water. These findings suggest that the activation of renin-angiotensin system participates in malignant hypertension of salt-loaded stroke-prone SHR rats that show stroke signs, proteinuria, hyperreninemia, and renovascular changes.


Carotid sinus reflex function in the alloxan diabetic rabbit.

Baroreflex function was studied in three groups of adult rabbits. Seven animals were given alloxan (100-200 mg/kg) and became diabetic (group D) with mean blood sugar values of 348 +/- 30 mg/dl. Eight animals were given alloxan, but did not develop significant hyperglycemia (135 mg/dl) (group A). Nine controls (group C) were also studied (glucose, 101 mg/dl). All animals were anesthetized with pentobarbital (30 mg/kg). Blood pressure (BP) and heart rate (HR) responses to bilateral carotid occlusion (BCO) were measured before and after depressor nerve sectioning (DNx) and sinus nerve sectioning (SNx). Before sectioning, BCO caused a rise in BP of 30 +/- 4 mmHg in group C. 35 +/- 3 in group A, and 36 +/- 4 in group D. HR increased about 13 beats/min in each group. After DNx, resting BP increased in group C from 97 to 104 mmHg (P less than 0.005), but no change occurred in the other groups. Responses to BCO were significantly but similarly enhanced in all groups after DNx. HR did not increase in group D. Resting BP increased after SNx only in the controls (group C). Differences in BP elevation with BCO before and after SNx ("pure" reflex response) were identical, averaging about 35 mmHg. Thus, no alteration of BP or HR responses to BCO was identified in early alloxan diabetes. However, resting tone in the buffer nerves may have been less.


Influence of albuterol on erythropoietin production and erythroid progenitor cell activation.

The effect of albuterol, a potent beta2-adrenergic agonist, on kidney production of erythropoietin (Ep) was studied. Its effects on erythroid colony (CFU-E) formation in vitro in rabbit bone marrow cultures were also assessed. Albuterol produced a significant increase in plasma Ep levels in conscious rabbits following 7 h intravenous infusion (50 (microgram/kg)/min). This effect was blocked by pretreatment of the rabbits with butoxamine (5 mg/kg ip), a potent beta2-adrenergic blocker. Albuterol in doses of 10(-10) to 10(-8) M in combination with Ep was also found to produce a significant increase in the numbers of CFU-E in the plasma clot culture system of rabbit bone marrow. This effect was blocked completely by DL-propranolol (10(-8) M) and by butoxamine (10(-8) M). The data presented suggest that albuterol, a potent activator of beta2-adrenergic receptors, increases kidney production of Ep in vivo and also produces a direct effect in combination with Ep on the proliferation of the erythroid progenitor cell compartment.


Renal vascular and excretory responses to prostaglandin endoperoxides in the dog.

To determine whether the prostaglandin endoperoxides PGG2 and PGH2 have direct effects in the kidney, PGG2 and PGH2 were administered into the renal artery of anesthetized dogs and their effects were compared to those of PGE2. Like PGE2, PGG2 and PGH2 induced a dose-related renal vasodilation. A 50% increase in the renal blood flow was observed with 0.05 microgram/kg body wt of PGE2 and with four- and sixfold higher doses of PGH2 and PGG2, respectively. Infusion of all three compounds at doses inducing a 50% increase in the renal blood flow resulted in 1) increases in blood flow to all cortical areas, with the greatest increase occurring in the juxtamedullary area, 2) diuresis with no change in the glomerular filtration rate, and 3) natriuresis and kaliuresis. In vitro incubation of PGH2, a maneuver known to result in its conversion to other prostaglandins, had no influence on its renal effects. The data indicate that PGH2 and PGG2 are biologically active when infused into the renal artery of the anesthetized dog and suggest that the endoperoxides exert their effects after bioconversion to other prostaglandins.


Minute-to-minute covariations in cardiovascular activity of conscious dogs.

Cardiovascular activity of chronically instrumented conscious dogs was monitored continuously during daily sessions of rest or of intermittent aversive stimulation. Data analysis of minute-to-minute averages revealed that cardiovascular variables changed in patterns, rather than as isolated independent events. Variations in cardiac output were highly positively correlated with concurrent variations in heart rate in all subjects under both conditions (mean r = +0.93). Variations in heart rate were two to five times as great as stroke volume, which was remarkably constant (coefficient of variation averaged only 4.6%). Variations in mean arterial pressure were consistently correlated with the variations in cardiac output (mean r = + 0.66) and heart rate (mean r = +0.68), but were poorly correlated with the small changes in stroke volume (mean r = -0.17) and total peripheral resistance (mean r = -0.16).


Sympatho-adrenal responses of spontaneously hypertensive rats to immobilization stress.

Blood pressure, heart rate, and circulating levels of norepinephrine, epinephrine, and corticosterone were measured before and during the first or seventh period of immobilization stress (150 min per day) in spontaneously hypertensive (SHR) and Wistar-Kyoto (WKY) normotensive male rats. A catheter was inserted into the tail artery of each rat to permit direct measurement of blood pressure and heart rate and serial sampling of blood in conscious, unhandled animals. During the first immobilization, SHR rats had significantly higher circulating levels of norepinephrine, epinephrine, and corticosterone than did WKY rats. One day after the sixth immobilization, basal levels of norepinephrine and epinephrine were significantly higher and mean blood pressure was significantly lower in repeatedly stressed SHRs compared to unstressed SHRs. In addition, adaptation to the repeated stress in SHRs was attended by reduced adrenomedullary secretion and an increased blood pressure response. These results demonstrate that adaptive changes in the cardiovascular and sympatho-adrenal medullary systems of repeatedly immobilized rats are greater in SHR than in WKY rats.


Circulating catecholamines and control of plasma renin activity in conscious dogs.

Uninephrectomized dogs were prepared with indwelling catheters in the aorta, inferior vena cava (IVC), and renal artery, and after recovery they were studied in the conscious state. Basal aortic epinephrine and norepinephrine concentrations were 57 +/- 11 and 101 +/- 18 pg/ml, respectively. Elevation of epinephrine concentration to over 2,000 pg/ml by IVC infusion resulted in a sustained 3.5-fold increase in plasma renin activity (PRA), with only a transient decrease in arterial blood pressure. The PRA response to epinephrine was completely blocked by l-propranolol; isoproterenol increased PRA more than did epinephrine. Increasing norepinephrine concentration to 1,600 pg/ml by IVC infusion resulted in only a 1.5-fold increase in PRA. Infusion of epinephrine or norepinephrine directly into the renal artery to achieve similar increments of renal arterial concentration did not increase PRA. Insulin injection or hemorrhage resulted in elevations of arterial epinephrine (but not norepinephrine) concentration greater than the concentrations achieved during IVC infusion in these studies. We conclude that circulating epinephrine in the physiologic range plays a role in the control of PRA by activation of an extrarenal beta-receptor.


Exercise hyperemia in potassium-depleted dogs.

The experiments reported here are designed to evaluate the role of potassium (K+) in exercise hyperemia. Desoxycorticosterone acetate was implanted subcutaneously in six dogs, which were then placed on K+-deficient diets. Experiments were performed 3 or 4 wk later. Exercise vasodilation was much reduced in K+-depleted animals. However, when muscle stimulation caused very little vasodilation (i.e., in the most depleted animals) the muscle also produced little tension and extracted very little O2. O2 extraction was not limited by O2 availability. When the change in vascular resistance was plotted against O2 extraction, the data from K+-depleted dogs fell on a line constructed for control dogs. We conclude that the reduced exercise hyperemia of K+-depleted dogs is a result of reduced muscle O2 consumption rather than decreased K+ release. However, there was reduced vasodilation in response to brief tetanus and a loss of the triphasic initiation of exercise vasodilation with twitch work. This suggests that absence of K+ release does directly affect initiation of exercise vasodilation.


External mechanical work from relaxing ventricle.

The possibility has been proposed earlier that the specific pressure-volume (P-V) area bounded by the left ventricular end-systolic and end-diastolic P-V curves and the isovolumic relaxation part of the P-V loop represents mechanical potential energy that has been built during systole and is stored at end systole in the wall of the ventricle. In the present study on canine left ventricles, as much as 70% of the P-V area was actually converted into external mechanical work when ventricular volume was allowed to decrease at an appropriate speed (about 55 ml/s in 70 g left ventricle) during relaxation. Less external work was extracted from the same P-V area when the speed of volume reduction was either higher or lower than that speed. These results indicate that the P-V area is equivalent to a form of potential energy, which is wasted with isovolumic relaxation but most of which is convertible to external mechanical work if the ventricle is allowed to eject against an appropriately decreasing afterload during relaxation.


Total mechanical energy of a ventricle model and cardiac oxygen consumption.

Mechanical energy (ENG) required by a time-varying elastance model of the ventricle was compared with oxygen consumption per beat (VO2) of the canine left ventricle contracting under a variety of loading conditions. ENG needed for this model to increase its elastance during systole is shown to be equal to the sum of the potential energy built in the elastance during systole plus the external mechanical stroke work. This ENG is equivalent to the area (PVA) bounded by the end-systolic and end-diastolic P-V curves and the systolic limb of the P-V loop trajectory in the P-V plane. There was a high correlation (r = 0.89) between VO2s documented in the literature and PVAs assessed by the author from the accompanying P-V data from both isovolumic and ejecting contractions in 11 hearts. A linear regression analysis yielded an empirical equation: VO2 (ml O2/beat) = a . PVA (mmHg . ml/beat) + b, where a = 1.37 X 10(-5) and b = 0.027, which can be used to predict VO2 from PVA. A preliminary experimental study in my laboratory confirmed the validity of this empirical equation.


Accuracy of ventricular lumen volume measurement by intraventricular balloon method.

To assess the accuracy of left ventricular volume measured by the intraventricular balloon method, we measured the space between the endocardium and the gradually inflated balloon in six Formalin-fixed canine left ventricles. The space was as small as 1-1.5 ml for intraballoon pressure of 100-200 mmHg and tended to increase to 2 ml with decreases in pressure to 50 mmHg.


A multichannel telemetry system for recording cardiovascular neural signals.

A multichannel telemetry system was developed for use with chronically instrumented unrestrained cats. This system can simultaneously record efferent and afferent cardiovascular neural signals, bioelectrical noise arising near the electrode recording the neural signals, EEG, ECG, and a standard calibration signal. The miniature (18 cm3), lightweight (24 g), telemeter is a five-channel, time-multiplexed, pulse width modulation (PWM)/FM device employing a high frequency subcarrier (60 kHz) and two sampling frequencies (30 kHz and 6 kHz). The device is powered by two small 120 mA . h silver oxide cells; it has an indoor transmission range of 10 m and can operate for 48 h. One channel transmits a standard signal (a square wave of 100 Hz and 200 mVp-p) used to monitor and regulate the system's performance. When the variation in either the amplitude or frequency of the standard signal is greater than 10% of the control value, the transmitted bioelectrical signals are automatically discarded.


A simple method for volumetric measurements in isolated cardiac muscle.

A new method for the study of extracellular space and cell volume of cardiac muscle is described. Canine cardiac Purkinje strands and cat papillary muscles were placed within a fluid-filled aperture connecting two sides of an experimental chamber. Direct electrical current was passed through the hole, and changes in the voltage drop across it were correlated with Purkinje strand extracellular space and cell volume. The results of experiments on 21 Purkinje strands and 4 papillary muscles yielded an extracellular space of 51 +/- 2.1% (SEM) and 23.3 +/- 2.1%, respectively. When strands were superfused with hyper- (600 mosM) and hyposmotic (150 mosM) solutions, the preparations were found to attain new steady-state volumes that were 75 +/- 3.1% and 121 +/- 9% of control, respectively. This method can be used for volumetric studies in numerous cardiac muscle preparations and should be applicable to the study of volume abnormalities associated with certain disease states.


On model and data requirements for determining the bioavailability of oral therapeutic agents: application to gut absorption of thyroid hormones.

A two-pool model is proposed as a first approximation of the dynamics of thyroid hormone dissolution and absorption in the human gut. It is shown that this model, or any more complex one of the same process, must be imbedded in a larger whole-body model for the purpose of quantifying its parameters. Parameter identification experiments are designed with the aid of identifiability analysis and a complete quantification is obtained, for both triiodothyronine (T3) and thyroxine (T4) absorption, using kinetic data obtained from the literature. The average percent absorption of oral dosages calculated from the model for T3 (95.8%) and for T4 (49.3%) are exceptionally close to reported measured values. Other data not used in model development also serve to validate the results, for use in applications not demanding greater physiological detail, such as for determining the bioavailability of orally administered hormones, or for the "inverse problem," computing optimal dosage regimens for hormone therapy.


Diminished sympathetic silent period in spontaneously hypertensive rats.

To determine if elevated sympathetic activity occurs in spontaneously hypertension, the silent period induced in splanchnic nerves following electrical stimulation of dorsal medullary sympathoexcitatory sites was compared in anesthetized normotensive Wistar Kyoto rats (WKYs) and Okamoto spontaneously hypertensive rats (SHRs). The strength of silent periods was defined as the degree of inhibition of responses to testing stimuli delivered at various latencies following conditioning trains, and it was assumed to be inversely related to the level of sympathetic activity. Weanling SHRs exhibited weaker silent periods than weanling WKYs although, at that age, the arterial pressures of the strains were not significantly different. Silent periods were also weaker in adult SHRs than in adult WKYs. This difference persisted after arterial pressures, which fell under anesthesia, were raised by phenylephrine infusions to the respective "normal" levels in each strain. These results support the hypothesis that elevated sympathetic activity exists during both the development and maintenance of spontaneous hypertension in rats.


Effects of central injection of biogenic amines during arousal from hibernation.

Simultaneous measurements of heat production (HP) and heat loss (HL) and brain and rectal temperatures were made in Richardon's ground squirrels (Spermophilus richardsonii) rewarming from hibernation at an ambient temperature of 6.0 +/- 0.5 degrees C. Calculations from HP and HL measurements from control animals showed that due to differential rewarming, there was a reduction of apparent specific heat of the animal to 0.59 cal/g. degrees C. This resulted in an energy saving of 30%. Three intracerebroventricular injections of 5-hydroxytryptamine (5-HT) of 56 microgram each at brain temperatures of 10, 20, and 30 degrees C caused initial suppression of HP and a greater overall HL, which resulted in a slower rate of arousal as compared to the controls. Injections of norepinephrine (NE) of 12.5 microgram each at similar brain temperatures caused a greater rate of HP, which resulted in a faster rate of arousal as compared to the controls. The respective actions of 5-HT and NE on thermoregulation during rewarming are similar to those in some euthermic hibernators and nonhibernating species. Our data indicated that these substances evoke thermoregulatory responses during arousal in much the same manner as during normothermia.


Intrathoracic electrical impedance measurements from an esophageal probe.

The sensing of intrathoracic electrical impedance from an esophageal probe may allow relatively noninvasive monitoring of cardiac and respiratory functions of particular interest in anesthesia and intensive care. We have obtained a partial solution of the intrathoracic current-field problem for impedance measurements made from a four-terminal linear array of electrodes located in the esophagus. It allows prediction that aortic root motion will exceed aortic distension as a major determinant of the cardiac intrathoracic esophageal impedance signal. This prediction was confirmed for a specific carefully selected and placed electrode array in anesthetized dogs. In general, motions of organs will be more important than volume changes in affecting the esophageal impedance signal. Thus, timing information (preejection period and left ventricular ejection time) is available from electrodes on an esophageal probe, but cardiac output information appears to be inaccessible for fundamental reasons.


Diurnal rhythms of bile acid production in the rat.

Diurnal rhythms of bile acid synthesis were studied in Sprague-Dawley rats maintained in 12 h of illumination and 12 h of darkness each day. Synthesis, measured as output from a chronic bile fistula, underwent a consistent diurnal change with an amplitude of about 20% around mean daily synthesis and a peak in the dark period. The peak in cholate synthesis preceded the peak in chenodeoxycholate synthesis which preceded the peak in alpha-muricholate synthesis which preceded the peak in beta-muricholate synthesis. Fasting, intravenous infusion of dexamethasone (100 microgram/kg . h), adrenalectomy, and ocular enucleation all failed to abolish the diurnal rhythm in synthesis. In one rat studied 30 days after ocular enucleation the diurnal rhythm in synthesis persisted; however, relative to 4 days after enucleation the phase of the rhythm shifted about 90 degrees suggesting that light deprivation caused the rhythm to become free-running with a period slightly different from 24 h.


Development of fever in the newborn lamb.

Newborn lambs do not become febrile in response to intravenous (iv) bacterial endotoxin in moderate doses. Newborn lambs were tested to see if they could become febrile to large doses of endotoxin or to endogenous pyrogen. At 5 h of age lambs do not become febrile to relatively large doses of endotoxin or to endogenous pyrogen, but rather become hypothermic. At 32 h and all subsequent times, fevers could be elicited. Onset time of fevers in lambs was short initially and gradually lengthened over 9 days, at which time it was similar to the onset time of the adult fever. With respect to the febrile response, newborn lambs showed varying degrees of tolerance after 10 days of daily injections of endotoxin, as compared to the ewe which becomes tolerant in 2 or 3 days.


Renal and hindlimb vascular control during acute emotion in the baboon.

Blood pressure, heart rate, oxygen consumption, and blood flow to the renal and hind-limb vasculatures were measured in healthy, unanesthetized baboons (Papio cynocephalus) in a controlled environment. Appropriate behavioral techniques were applied to allow the reproducible elicitation of a conditional emotional response (CER). Section of renal nerves and autonomic pharmacologic interventions were used to determine the mechanisms for the cardiovascular responses accompanying the CER. The resistance changes in the renal and hind-limb vascular beds were generated by rapid, neurally mediated vasoconstriction of the renal vasculature and by a slower acting, circulating vasoactive agent, most probably epinephrine, which causes a delayed second constriction in the renal bed and a net dilation in the hind limbs.


Plasma volume and electrolyte shifts with heavy exercise in sitting and supine positions.

Plasma volume (PV) and electrolyte shifts were measured before and for 60 min after a continuous peak oxygen uptake (VO2 peak) test in four men (26-45 yr) on a bicycle ergometer. Mean (+/-SE) sitting VO2peak (3.16 +/- 0.32 1/min) was the same as supine VO2peak (3.13 +/- 0.33 1/min). In recovery (R + 1.5 min), mean PV had decreased by 477 ml (-16.1%, P less than 0.05) in the sitting and by 548 ml (-17.6%, P less than 0.05) in the supine positions, whereas total osmolality increased progressively with its peak at R + 3.5 min. The percentage losses of protein, total Ca2+, and ionized Cai2+ were about half as great as the percentage loss in PV, indicating a selective retention of these constituents. Calculated osmolality (sigma Na+, K+, Cl-, Cai2+) returned to control levels within 1.5 min after sitting exercise but required about 15 min after supine exercise. These small increases in protein concentration were not likely to significantly aid restitution of plasma volume and the ions were probably in equilibrium across the capillary membrane. So a change in hydrostatic and/or systemic blood pressures most likely provided the force for restitution of plasma volume.


Body water compartments with human aging using fat-free mass as the reference standard.

Forty-five healthy men and women aged 16-39 and 59-89 yr were studied for total body water (TBW) and extracellular water (ECW); intracellular water (ICW) was calculated as the difference (ICW = TBW - ECW). An independent measurement of total body fat by inert gas uptake provided a value (+/- 2%) for fat-free mass (FFB is wt minus body fat). Results agreed with observations by others that TBW and ICW are lower in the aged and lower in women, whether expressed as absolute volumes or per unit of weight, surface area, or height. However, with FFB as the reference standard very different aging trends appeared. TBW/FFB remained constant to our oldest measured subjects (704 +/- 7 ml/kg). ICW/FFB was slightly lower at advanced age, but the 4-5% decrease for each sex was within statistical variability. With age ECW increased slightly and its proportion within the fat-free body (ECW/FFB) was significantly higher. Based upon FFB, the distribution, proportions, and aging trends of body water compartments were similar for men, women, and male rats. Although its potential limitations must be appreciated, the FFB appears widely useful as a reference standard. The stability of ICW volume and of fat-free mass in aging man does not support the hypothesis that cellular mass is lost by healthy mammals with age.


Blood oxygen transport and organ weights of two shrew species (S. etruscus and C. russula).

Blood parameters concerning oxygen transport and relative organ weights of 11 Suncus etruscus and 13 Crocidura russula under light halothane anesthesia were investigated. Mean body weight of S. etruscus was 2.5 g and for C. russula was 9 g, hemoglobin concentration was 17.4 and 15.6 g/100 ml blood, hematocrit was 50 and 44%, red blood cells were 18 and 11 X 10(6)/microliter, respectively. Mean corpuscular volume was calculated to be 26 and 41 micron3, mean diameter 5.5 and 7 micron, and mean thickness 1.2 and 1.1 micron, respectively. Mean corpuscular hemoglobin concentration was in the normal range of mammalian red blood cells. A blood oxygen half-saturation pressure of 35 and 34 Torr at pH 7.4, 37 degrees C and a Bohr factor deltalog P50/deltapH of -0.61 and -0.66 was measured. Experiments with stripped hemoglobin showed that 2,3-diphosphoglycerate is the main oxygen affinity reducing allosteric factor. Relative weights of heart, kidney, and liver are remarkably high in S. etruscus. The maximal oxygen transport of 400 ml . kg-1 . min-1 of S. etruscus is feasible by an enormous heart rate, a large relative stroke volume, a high hemoglobin concentration combined with a low oxygen affinity, and a large Bohr effect.


Bradycardia during stimulation of the septum and somatic afferents in the rabbit.

Experiments were done in paralyzed rabbits anesthetized with either pentobarbital sodium or alpha-chloralose to test the possibility that the septum may alter the cardiovascular responses elicited by stimulation of somatic afferent fibers. Electrical stimulation of the lesser saphenous nerve (LSN), a branch of the sciatic nerve, at certain parameters elicited bradycardia, which could be abolished by bilateral vagotomy or intravenous injection of atropine methylbromide. Distinct and characteristic changes in mean arterial pressure and heart rate were elicited by electrical stimulation of histologically localized sites in five septal areas. Septal sites from which stimulation elicited bradycardia were chosen for the study of interaction between the septum and LSN. The cardiac slowing elicited by combined stimulation of the lateral septum and LSN was significantly greater than the sum of the responses elicited by separate stimulation of the two different structures. In contrast, the bradycardia elicited by combined stimulation of medial septal structures and LSN was significantly smaller than the sum of the individual responses. These experiments demonstrate that the magnitude of heart rate responses elicited by stimulation of somatic afferent fibers may be modified by the septum.


Twenty-four-hour pattern of circulation by radiotelemetry in the unrestrained dog.

Eight dogs with indwelling transducers for continuous radiotelemetry of the hemodynamic function were acclimatized in an unisolated room under 12:12 LD photoperiods, in phase with the solar day cycle, and constant temperature (20 +/- 1 degrees C). Light was turned on at 0600 and off at 1800. Mean aortic blood flow (ABF), mean aortic blood pressure (ABP), heart rate (HR), respiratory rate (RR), and cardiac work (CW) were maximal at about 1800 and minimal at time 0600. Total peripheral resistance (TPR) was highest and stroke volume (SV) lowest at about 1200. The 24-h mean was for HR 77 beats/min, SV 28 ml/beat, RR 11 breaths/min, ABF 177 ml/min per kg body wt, ABP 102 Torr, TPR 3,960 dyn . s . cm-5, and CW 218 Torr . 1/min. The range of amplitude fluctuations for daytime means was about 6% for ABP and SV and 11-17% for all others. It is suggested that the homeostatic balance and timing of circulation is circadian time dependent.


Delirium after cataract surgery: review and two cases.

The authors define the delirium seen after cataract surgery on the basis of Dupuytren's original description and review studies using the criteria they set up on this basis. They then present prospective data on 2 patients with postcataractectomy delirium and 25 patients who did not experience this delirium. The data suggest that delirium after cataract surgery represents anticholinergic toxicity.


The impact of normal volunteers on a psychiatric research unit.

Normal subjects were admitted to a psychiatric unit devoted to the study and treatment of affective illness. Initially the authors were concerned about the difficulties volunteers might have living with psychiatric patients. However, the volunteers adjusted with relative ease, while the patients' depressive symptoms were exacerbated. Their confrontation with the volunteers "normality" triggered an acute awareness of their underlying sense of failure. This response is analogous to depressed patients' reactions before discharge, when they struggle not only with their special vulnerability to separation and loss but with inevitable challenges to their fragile self-esteem during reintegration into the outside world. The presence of normal volunteers highlighted these issues and led to increased therapeutic work and considerable resolution.


Whatever happened to psychiatry? The deprofessionalization of community mental health centers.

The authors describe the dichotomy in the concept of community mental health centers. One view regards the community mental health center as a service provider for underserved populations, and another holds that it is an agent of social change. Deprofessionalization of community mental health centers has resulted from this lack of clear purpose, curtailment of funds, and conflicts over authority, service delivery, and control of the centers. Deprofessionalization has led to a decline in the number of psychiatrists in community mental health centers and a potentially negative impact on the quality of patient care.


Plasma growth hormone: effect of anxiety during flooding in vivo.

The treatment of phobias by rapid in vivo exposure to the feared situation was accompanied by an increase in plasma growth hormone levels on at least one of two occasions in 8 of 11 subjects. The average growth hormone response was greater on the second occasion, even though subjective anxiety was less. Plasma growth hormone was not elevated during the subjects' adaptation to the laboratory. Strong subjective and behavioral anxiety responses failed to elevate plasma growth hormone levels in some subjects. The probability of a growth hormone response was the same whether or not baseline levels were elevated prior to exposure.


Acid-base and electrolyte disturbances in anorexia nervosa.

The literature on anorexia nervosa largely ignores the acid-base and electrolyte disturbances that may accompany this condition. In an attempt to assess the magnitude of these disturbances in anorexia nervosa the authors reviewed the laboratory profiles of 7 patients with the disease who were consecutively admitted to a hospital over a period of 8 years. Several acid-base and electrolyte disturbances were observed; the most frequent was chloride-responsive metabolic alkalosis. The authors suggest that all patients with anorexia nervosa receive diagnostic studies for these disturbances, including ECG and urinary electrolytes when necessary, so that abnormalities can be diagnosed and treated appropriately.


The relationship of early maternal separation to borderline personality in children and adolescents: a pilot study.

The author compared 14 child and adolescent borderline patients, diagnosed by the criteria of Gunderson and Singer (1), with a control population for history of separation from the mother or significant caretaker before age 10. The borderline patients experienced a statistically greater number of separations than the psychotic controls, the nonpsychotic psychiatric controls, and the nonpsychiatrically-referred delinquent controls before age 5 but not between ages 5 and 10. The author concludes that the study provides statistical support for the theoretic role of disruption of the early infant-mother bond in borderline pathology.


The development of an acute short-term inpatient child psychiatric setting: a pediatric-psychiatric model.

The authors describe the establishment of a unit for children that emphasizes the integration of the pediatric model of acute, short-term inpatient care with the psychological and developmental perspective of the psychiatric model. Of the 145 children admitted during the first year, more than 33% manifested aggressive or hyperactive behavior and 25%, depression or suicidal behavior. Eighty-five percent were discharged to their homes or previous residences after an average length of stay of 24 days. The authors suggest that similar units established in children's hospitals or general hospitals could help meet the urgent need for acute inpatient psychiatric care of children in this country.


Adolescents' adjustment to chronic hemodialysis.

The author compares the adjustment of 18 adolescents on chronic hemodialysis to that of 63 adult patients on hemodialysis. The adolescents tended to comply less well with the medical regimen, their vocational rehabilitation was significantly lower, and their social activities were more restricted. The adolescents suffered more from the changes in body functioning and appearances. They were more hostile and overtly aggressive but seemed to have fewer psychiatric complications and, especially, less suicidal ideation. The author suggests that chronic disease is especially difficult for adolescents to handle because it creates stress in areas already problematic for this age group.


Juvenile firesetters: do the agencies help?

In an attempt to find out what was being done for juvenile firesetters in their metropolitan community the authors reviewed the records of the local fire marshal, juvenile court, and psychiatric clinic. They found that the various agencies involved with 69 juveniles over a 3-year period were unable to coordinate their efforts and were largely unsuccessful in controlling the firesetting. Because the families of firesetters seem to have many other social problems, the authors recommend early inpatient assessment and possible referral to foster homes or residential treatment settings for juvenile firesetters.


The Mini-Mental State Test and computerized tomography.

In order to evaluate the clinical usefulness of the Mini-Mental State (MMS) test, the authors had 63 patients complete the test after undergoing computerized tomographic (CT) scans of the brain. Patients with positive CT scans scored significantly lower than those with negative CT scans. Further analysis showed that cerebral atrophy was more closely related to cognitive impairment than focal cerebral lesions only. The authors conclude that the MMS can discriminate organicity in some instances but that further refinement and modification of its subtests are needed for maximum usefulness.


Adjustment of a group of Vietnamese people to the United States.

The authors collected data on 50 Vietnamese families living in Baton Rouge, Louisiana, by individual and group interview questionnaire. They also used interviews of all of the Vietnamese people who came to the local community mental health center and studied the records of the center and other local social agencies for sociodemographic data. They define a number of specific sociological stresses encountered by Vietnamese refugees but conclude that basically these people are adjusting well without losing their cultural identity.


Peer review of group therapy: Washington, D.C., 1972-1977.

The author discusses the evolution of psychiatric peer review in Washington, D.C. In its first six years (1972-1977) the Washington Psychiatric Society Peer Review Committee evaluated 146 cases, 23 (16%) of which focused on group therapy. Eight of these cases (35%) were partially or fully denied. Most of the cases involved outpatients with neuroses or character disorders who were treated in combined group and individual therapy. The author presents specific cases illustrating group therapy issues and peer review decisions. He discusses the benefits and liabilities of peer review and emphasizes its importance as a flexible, clinically sensitive, confidential, and meaningful process.


Life events, coping, stress, and depressive symptomatology.

The author presents data on the relationships between life events, coping resources, and depressive symptomatology. A probability sample (N = 517) was interviewed three years apart. Respondents with high life-event scores had significantly more depressive symptomatology than those with low scores. Those with personal, familial, and interpersonal resources had significantly less depressive symptomatology than those without such resources in both the low- and high-life-event groups. The best predictor of Time 2 depressive symptom scores was Time 1 symptom scores; losses and resources were also statistically significant factors. These findings demonstrate the complex interrelatedness of life events, coping resources, and depressive symptomatology.


Life events at the onset of bipolar affective illness.

The authors assessed the occurrence of stressful life events before the initial or subsequent episodes of affective illness in a group of 79 bipolar I manic-depressive patients who were attending a lithium clinic. About half of the patients recalled a life event in the 3-month interval before their initial episode; postpartum onset was prominent among these events. Few patients recalled life events for subsequent episodes. Finally, history data did not differentiate patients who recalled life events and those who did not. These data may be useful in assessing environmental antecedents of populations at risk for bipolar illness.


Childhood depression: interpersonal interactions and depressive phenomena.

The author discusses the impact of parental disability, particularly parental depression, on children. Depression in children, which takes different forms according to the child's developmental level, may mirror or be a response to similar affect in a parent. Clinicians need to take note of the relationship between child and caretaker and of the various manifestations of childhood depression in order to avoid underdiagnosing this disorder.


The psychopathology of suicide: a clinical model approach.

The author hypothesizes that certain types of persons at high risk for suicide constitute definable clinical models, that the process of arriving at a suicidal outcome involves elements unique to each model, and that these elements can be considered manifestations of psychopathology. This approach is investigated using two models: "Males Under Forty" and "Stable with Forced Change." The results indicate statistically reliable differences between the models in the distributions of estimated risks for persons who subsequently committed suicide compared with those who did not. The implications of the associated highrisk variables as reflections of psychopathologic processes are considered.


Depression simulating organic brain disease.

The authors report four cases of depression manifesting as organic brain syndrome in adult nongeriatric patients. The correct diagnoses in three cases were made by a psychiatrist's or resident's empathic response to the patient, and in the fourth by the patient's history of depression. The authors state that only by maintaining a high degree of suspicion and trusting one's empathic response to the patient will unusual presentation of depression be recognized.


Depression in the wives of nuclear submarine personnel.

The authors compared levels of depression among 24 wives of nuclear submarine personnel under conditions of husband-presence and husband-absence in a crossover research design. The wives had significantly higher depression scores under conditions of husband-absence on both the Zung Depression Scale and the Multiple Affect Adjective Checklist. The results are discussed in terms of the tremendous stresses imposed on the wives as a result of the nuclear submarine deployment schedule and the failure of the Navy and the spouses to recognize and reward the wives for their efforts.


Depression in Viet Nam veterans and civilian controls.

In order to investigate the long-term psychological consequences of Viet Nam combat, the authors located and personally interviewed a group of 571 randomly selected Viet Nam veterans and 284 matched civilian controls 3 years after the veterans returned to the United States. In the veterans they found a weak association between combat and subsequent depressive symptoms, but the association did not persist after controlling for preservice factors. The incidence of depressive symptoms and syndromes was similar when veterans were compared with nonveterans. Results are contrasted with a 12-month follow-up study of the same veterans in which a stronger association between combat and later depression was found.


Depressed mood and subsequent physical illness.

The authors describe the results of a matched case-control analysis in which 82 pairs of subjects were selected from a large-scale community study carried out in two general populations. Cases were those of persons hospitalized during an interval between two interviews for an illness starting during that interval or persons who died during the interval. Controls were persons with no new illnesses or hospitalizations during the interval. No relationship between measures of depressive symptomatology or depressed mood and subsequent physical illness was shown. This result corroborates the findings of prospective studies in more selected populations and suggests that it is unlikely that depressed mood is related to subsequent physical illness.


Depression: new evidence in support of biological differentiation.

The authors studied monoamine metabolism in patients with bipolar (manic-depressive) and unipolar depressive illness and in normal control subjects under strict dietary conditions before and during administration of carbidopa, a peripheral decarboxylase inhibitor. They found that unipolar depressed patients excreted higher amounts of 3-methoxy-4-hydroxyphenylglycol (MHPG) and 5-hydroxyindoleacetic acid (5-HIAA) in the drug-free period and while receiving carbidopa and significantly less tryptamine only after carbidopa administration. Plasma tryptophan levels differed in the three groups. The authors state that their research design reveals changes in serotonin and nonrepinephrine metabolism in unipolar depressed subjects that distinguish this group from normal and bipolar depressed subjects, suggesting a reduced CNS uptake of tryptophan in unipolar depression.


The 24-hour dexamethasone suppression test in a clinical setting: relationship to diagnosis, symptoms, and response to treatment.

Of 54 male psychiatric patients undergoing dexamethasone suppression tests in a clinical setting, 40% of those with a major depressive disorder showed escape from suppression over the 24 hours after dexamethasone administration, while all of the patients with schizophrenia, neurosis, alcoholism,and drug abuse showed normal pituitary-adrenal suppression. Only 10% of the depressed patients showed resistance to suppression 8 hours after dexamethasone administration. There was no difference between depressed patients who did and did not show escape from suppression in type of previous episodes, family history, symptoms, or medication. However, those who showed escape tended to respond better to treatment and to be rated as having a more severe depression. The theoretical and clinical implications of these findings are not yet clear.


Facial muscle electromyography in depressed and nondepressed hospitalized subjects: a partial replication.

Imagining happy events, sad events, and the events of a typical day led to measurable electromyographic (EMG) changes in the corrugator muscle of the face in both depressed and nondepressed subjects. The depressed and nondepressed subjects could not be differentiated on the basis of muscle activity, whether depression was defined by a self-rating scale, an adjective checklist, or research criteria. Previous investigators have observed differences in the facial EMG patterns of depressed and nondepressed subjects who were not hospitalized; the authors suggest that such changes are a consequence of a general psychological stress state rather than of depression specifically.


Diagnosis and lithium treatment of affective disorder in the retarded: five case studies.

The authors report on five institutionalized retarded patients who had symptoms strongly suggestive of manic-depressive illness and who showed significant symptom reduction in a single-blind placebo-controlled three-year trial of lithium. The number of illness episodes was reduced, and symptoms decreased in all major illness dimensions. These findings indicate that major affective disorder can be both diagnosed and treated in individuals with primary mental retardation.