Use of the electrocardiogram as an aid in screening for left ventricular aneurysm. Attempting to cull from a population of patients with coronary artery disease or cardiomyopathy, a subgroup in whom left ventriculography might most reasonably be performed in search of a surgically resectable ventricular aneurysm, the electrocardiograms (ECGs) and ventriculograms of 96 patients were analyzed. This study was conceived to test the value of the ECG as an initial screening technique. Patients with normal ventricular contractile motion in the presence of coronary artery disease rarely showed ST segment elevation exceeding 2 mm in any lead, and even more rarely showed Q waves in corresponding leads. All patients with well defined left ventricular aneurysms had at least 1 mm ST segment elevation, and the majority (73%) had ST elevation of 2 mm or greater; in 80% of these, there were associated Q waves in the same lead. In patients with only local areas of hypocontractility, the frequency of ST segment elevation with concomitant Q waves was significantly less (approximately 50%) than that seen in patients with aneurysms. It is concluded that patients with suspected or proven coronary disease who fail to demonstrate ST segment elevation are unlikely to have ventricular aneurysms and, thus, would receive little diagnostic benefit from left ventriculography. The presence of ST segment elevation, with or without associated Q waves in the same leads, is a helpful screening sign, raising the possibility of a surgically remediable lesion such as a ventricular aneurysm, but similar electrocardiographic patterns are also seen in patients with non-operable localized or generalized disorders of contraction. Having discovered ST elevation, then, left ventriculography becomes a reasonable next step - when otherwise indicated - in delineating the type of contractile disorder as well as the amount of adequately functioning muscle.


Tachycardia upon swallowing. Evidence for a left atrial automatic focus. Evaluation of a patient with tachycardia upon swallowing offers evidence of its origin from the left atrium. The tachycardia appears to arise from an automatic focus discharged after mechanical stimulation by the esophagus. Despite a left atrial origin for this arrhythmia, it does not fulfull previously described electrocardiographc criteria for "left atrial rhythms."


Alternans of the repolarization wave in a case of hypochloremic alkalosis with hypopotassemia. A case of profound hypochloremic alkalosis with hypopotassemia is reported, showing electrocardiographic changes of electrical alternans of the repolarization wave (probably the U wave) without any change in the QRS complex. Transient concomitant P-pulmonale was noted. Hypopotassemia is discussed as a possible mechanism for the development of the electrical alternans.


Permanent atrial paralysis.

Permanent atrial paralysis. A forty-four year old female presented with hemiparesis a slow supraventricular rhythm without "P" wave activity and was subsequently found to have atrial paralysis. On treadmill exercise testing the patient's heart rate increased to 118/min. It is felt that this most likely represents sinus rhythm with sinoventricular conduction and that the slow resting heart rate is secondary to a sick sinus node syndrome.


The junctional premature beat: an instructional exercise in modes of concealment. ?The relative brevity of the main His bundle refractory period compared with that of the A-V node above, and the trifascicular system below, makes it likely that premature beats originating in the His bundle will encounter physiologic delay, or block in both antegrade and retrograde modes. Two clinical cases of junctional premature beats are presented, which demonstrate many facets of concealment (antegrade, retrograde and bidirectional). Hitherto unreported is a ventricular echo which was induced by a junctional premature beat, the antegrade concealment of which was due to functional trifascicular block.


Pacing techniques in the management of supraventricular tachycardias. Part 2. An implanted atrial synchronous pacemaker with a short atrioventricular delay for the prevention of paroxysmal supraventricular tachycardias. An implanted atrial synchronous pacemaker with an atrioventricular delay of 30 msec is described. This pacemaker was implanted into a patient with paroxysmal supraventricular tachycardia due to an intra AV nodal reciprocal mechanism. The pacemaker was able to trigger from atrial potentials following atrial premature beats down to a coupling time of 300 msec. Following each triggering atrial potential, a ventricular stimulus was applied 30 msec later thereby producing a ventricular premature beat in response to each sinus beat or each atrial premature beat. Retrograde conduction from this atrial premature beat blocked the re-entry mechanism within the AV node and prevented the initiation of tachycardia. A detailed discussion on all parameters of function of this pacemaker is presented.


Electrophysiological basis for the spatial dependence of the inhibitory coupling in the Limulus retina. A technique for measuring, with total optical isolation, the inhibition between two individual receptor units in the Limulus lateral eye is described. The extracellular responses of pairs of units were recorded, using light piping microelectrodes. The inhibitory coupling between two units was found to be nonlinear and describable by a simple hyperbolic equation written in terms of saturation rate (S), half saturation (H), and threshold (ft). By plotting reciprocal frequencies, the data could be linearized and compared for different pairs of units. The magnitude of inhibition (in terms of S and H) was found to decrease monotonically as the anatomical distance between receptors increased. An electrical model of the inhibitory system was developed which accounts for many of the properties of the observed inhibitory interactions. Using the equations from the model and the experimental data, it is shown that the "electrical distances" (which are computed in terms of space constants lambda) of the inhibitory synapses from the impulse-generating region of the test unit are directly related to the anatomical distance between receptors. It is also shown that "synaptic strength" is relatively constant with separation. The electrical distances of the inhibitory synapses range from about 0.1lambda to 0.25lambda for adjacent units to greater than 0.5lambda for units seven to nine receptors away. It is concluded that the nonlinear character of the inhibitory coupling is attributable to synaptic effects, and that the decrease of inhibition with distance between receptors is caused primarily by an increase in the electrical distance of the inhibitory synapses from the test unit.


Nonelectrolyte diffusion across lipid bilayer systems. The permeability coefficients of a homologous series of amides from formamide through valeramide have been measured in spherical bilayers prepared by the method described by Jung. They do not depend directly on the water:ether partition coefficient which increases regularly with chain length. Instead there is a minimum at acetamide. This has been ascribed to the effect of steric hindrance on diffusion within the bilayer which increases with solute molar volume. This factor is of the same magnitude, though opposite in sign to the effect of lipid solubility, thus accounting for the minimum. The resistance to passage across the interface has been compared to the resistance to diffusion within the membrane. As the solute chain length increases the interface becomes more important, until for valeramide it comprises about 90% of the total resistance. Interface resistance is also important in urea permeation, causing urea to permeate much more slowly than an amide of comparable size, after allowance is made for the difference in the water:ether partition coefficient. Amide permeation coefficients have been compared with relative liposome permeation data measured by the rate of liposome swelling. The ratios of the two measures of permeation vary between 3 and 16 for the homologous amides. The apparent enthalpy of liposome permeation has been measured and found to be in the neighborhood of 12 kcal mol-1 essentially independent of chain length. Comparison of the bilayer permeability coefficients with those of red cells shows that red cell permeation by the lipophilic solutes resembles that of the bilayers, whereas permeation by the hydrophilic solutes differs significantly.


Sodium flux through the sodium channels of axon membrane fragments isolated from lobster nerves. The efflux of 22Na from vesicles formed by axolemma fragments isolated from lobster nerves was studied in the presence and in the absence of drugs having well-known action on the sodium channels. The vesicles were equilibrated 12-14 h at 4 degrees C with 22Na in lobster solution containing 1 mM ouabain. Afterwards the suspension was divided: one portion was used as control and the others were treated with veratrine (0.025-0.50 mg/ml), tetrodotoxin (1-2,000 nM) in the presence of veratrine, or tetrodotoxin alone. After 3 h at 20-22 degrees C, the suspensions were diluted into nonradioactive solutions and the 22Na efflux followed by a rapid filtration technique. The results revealed that veratrine increases the efflux rate and the additional application of tetrodotoxin abolishes it, e.g., 0.50 mg of veratrine/ml increases the rate, expressed in 10(-2) min(-1), from 0.59 +/- 0.04 (mean +/- SEM; n = 13) to 0.86 +/- 0.05 (n = 13), and the addition of 100 nM tetrodotoxin diminishes it to 0.48 +/- 0.07 (n = 4). This increase and diminution are statistically significant (P less than 0.005), but this is not the case between the control and the veratrine plus tetrodotoxin values (P greater than 0.05). 50% of the diminution is produced by 11.9 +/- 2.4 nM tetrodotoxin. Tetrodotoxin alone produces a slight diminution of the 22Na efflux. Batrachotoxin (0.50 muM) has an action similar to veratrine's. These findings are considered evidence of the presence of functioning sodium channels in the isolated axolemma fragments.


Patulin inhibition of mycovirus replication in Penicillium stoloniferum. Penicillium stoloniferum NRRL5267 contains two electrophoretically distinct viruses (PsV-F and PsV-S). An in vivo system was developed to test whether a number of fungal metabolites had antiviral properties on PsV-F replication in O.erties on PsV-F replication in P. stoloniferum. Preliminary results indicated that the mycotoxin patulin can block mycovirus replication. Portions of 48 h mycelium were incubated in the presence of varying levels of patulin, and after an additional 48 h incubation, PsV-F content was measured in E260 units by polyacrylamide gel electrophoresis. Patulin at 11, 16 and 20 mug/mg dry wt mycelia blocked PsV-F replication 26, 61 and 71%, respectively, compared with untreated controls. At these levels, host biomass RNA and protein synthesis were minimally affected. No-proliferating fungal mycelium is capable of continued support of PsV-F replication, which is sensitive to patulin. Apparently, inhibitory doses of patulin stimulated PsV-S replication during this 48 h incubation. The preferential action of patulin may arise from metabolite binding to functional enzymes required for virus replication.


Free mycolic acids as criteria in the classification of Gordona and the 'rhodochrous' complex. The methyl esters of free mycolic acids from representative strains of Gordona bronchialis, G. rubra, G. terrae and Nocardia kirovani each gave, on mass spectroscopy, homologous series of anhydromycolic esters containing from one to four double bonds with the main components of the parent mycolic acids centered on 56, 58, 62 or 64 carbon atoms (total range from C52 to C66). The mycolic acids from the Gordona strains, with chain lengths centered around C60, form a group intermediate in size between nocardomycolic acids (centered around C50) and mycolie different from those of the 'rhodochrous' complex which have anhydromycolates ranging from C34 to C50. Gordonae are thus more closely related in their mycolic acid composition to Nocardia than to Mycobacterium but can be distinguished from each of these genera.


The effect of rifampicin on the stability of the messenger ribonucleic acid of Bacillus amyloliquefaciens as determined by DNA:RNA hybridization. Rifampicin at a concentration of 10 mug/ml completely inhibited protein synthesis in exponential-phase cultures of Bacillus amyloliquefaciens. At this same concentration the drug was shown to have no effect on the stability of mRNA, determined as the functional and hybridizable material, when compared with hybridizable mRNA in an uninhibited system. In each case, the half-life of the mRNA had a value in the range 5 +/- 1 min, at 30 degrees C.


The molecular mechanism of protoplasmic incompatibility and its relationship to the formation of protoperithecia in Podospora anserina. In Podospora anserina, protoplasmic incompatibility due to interactions between non-allelic genes was suppressed by the effect of mutations in two modifier genes, mod-I and mod-2. It is shown that mod-I and mod-2 are involved in the production of three specific proteins, a phenoloxidase and two previously identified proteases (Bégueret & Bernet 1973 a) which are associated with the phenomenon of protoplasmic disintegration. These enzymes, whose messengers are normallly latent during vegetative growth, appear at this stage of the life cycle only as a consequence of incompatible gene interactions. The mode-I and mod-2 genes and each of the five incompatibility loci involved in non-allelic incompatibility systems also participate in the formation of the protoperithecia. This pleiotropic effect suggests that protoplasmic incompatibility is a deviation in the normal physiological processes of protoperithecial formation.


Diversity of lymphocytic choriomeningitis virus: variation due to replication of the virus in the mouse. Depending on passage history, strain WE infectious LCM virus either damages L cells more or less severely or leaves them morphologically intact. Correspondingly, the plaques which are formed on L cell monolayers are of different appearance, ranging from intensely turbid to clear. Multiplication of LCM virus in certain mouse organs profoundly affects plaque characteristics. The brain, for instance, favours lytic variants while the spleen supports the replication of virus which forms turbid plaques. This statement holds if virus taken from organs of persistently infected mice or virus passaged from mouse to mouse is analysed and is true also if the initial preparation contains virus forming predominantly either clear or turbid plaques on L cell monolayers. Selection is not rapid and not absolute. It may take months of multiplication before a final state is reached, and even then the number of characteristic plaques is usually in great excess of the rest but never reaches 100%. Cloning procedures may alter the proportions, but with our experimental conditions no plaque has ever been isolated which would retain its characteristics upon passage. Differences of plaque type morphology were not reflected in differences of pathogenic properties, and both clear and turbid variants caused persistent infection if used to infect newborn mice and led to disease with signs of neurological involvement and death if inoculated intracerebrally into adult animals.


Comparative studies of some African arboviruses in cell culture and in mice. Twenty African arboviruses, five alphaviruses, nine flaviviruses, three Bunyamwera Group viruses, two Bwamba Group viruses and one ungrouped virus were titrated in parallel in 11 cell systems in suckling mice and adult mice. The relative sensitivities of the in vitro and in vivo systems have been compared. The highest infectivities were obtained in suckling mice. Vero and LLC-MK2 cells produced plaques with the greatest number of viruses and Semliki Forest virus grew most readily. Ntaya virus and Dengue 1 virus were difficult to culture in vitro and Zika virus yielded better in cell culture than in adult or suckling mice. In vitro and in vivo neutralization tests were made on human sera in groups of 50. Each group of sera was tested against one of five viruses, representative of three of the arbovirus groups titrated. Good agreement was obtained between the two test systems with West Nile, O'nyong-nyong and Wesselsbron viruses but there were significant differences in results obtained with Germiston and Pongola viruses.


Effect of murine leukaemia virus age on its 8S RNA components. The effect of virion age on the two A and B 8 S RNA conformational isomers was investigated by electrophoresis on polyacrylamide gels. The relative proportions of A and B 8 S RNA components of the immature virus (rapid harvest, 30 min) are intermediate between those previously found for the mature virus and for the host cell. These results suggest that a change of 8S RNA conformation occurs during virus maturation.


Temperature-sensitive mutants of type 12 adenovirus defective in a late function: protein synthesis and evidence for recombination between mutants in complementation group D. Four temperature sensitive mutants of adenovirus type 12, classified into complementation group D, synthesize most or all of the late virus-specific polypeptides at the restrictive temperature, as shown by sodium dodecyl sulphate-polyacrylamide gel electrophoresis. Infections by these mutants under restrictive conditions apparently result in some over production of the virion hexon polypeptide compared to wild type infection. Genetic recombination between the four mutants has been demonstrated. A partial linear genetic map of the D cistron is presented.


Behavior of alcoholics and spouses in a simulation game situation. The interaction of alcoholics and their spouses in a simulation game was systematically observed and compared to the behavior of nonalcoholic couples. Overall, 28 couples played a mixed-motive bargaining game, the "tax game," which is a modification of Kelly's "game of nines." Alcohol couples as a group did not manifest a distinct game "style." They were less uniform in this respect than "normal" couples and a mixed group of "psychiatrically disturbed" couples. Subgroup trends without the alcoholic sample were suggested and discussed. Extreme behavior, rigidity, and lack of communication were common features in the game behavior of alcoholic couples that did not appear to relate to a particular game style, but did distinguish the game play of alcoholic couples from that of nonalcoholic couples.


The schizophrenia spectrum: a genetic concept. A spectrum concept of schizophrenia is described which hypothesizes that classical schizophrenia results at least in part from a genetic diathesis; that certain other, usually milder, psychopathological states, which do not satisfy the classical criteria for the diagnosis of schizophrenia, represent varying clinical expressions of the same diathesis; and that all of these states can, therefore, be said to constitute a genetically based spectrum of schizophrenic disorders. This concept is, in its broad outlines, not new, but it has had an increasing impact within psychiatry in recent years. Most importantly, it provides a conceptual framework for a variety of schizophrenia studies, particularly those dealing with biological markers, genetic vulnerability, clinical phenomenology, and modes of inheritance. A program of research which has attempted to test the concept, and to identify, describe, and classify the components of the genetic spectrum, is reviewed. Its methodology makes possible an approach to schizophrenia which simultaneously takes into account its two most vexing problems--nosology and etiology.


Determination of grave disability.

Determination of grave disability. There is a historical dilemma concerning the civil rights of psychiatric patients who are believed to need a protected status because of incompetency. California's Lanterman-Petris-Short Act provides a mechanism for putting the patient under the care of a conservator if the patient is unable to provide for his own personal needs of food, clothing, and shelter. If successful, this legislation will likely be the model for the country. Fifty-one patients for whom the clinical staff desired to initiate conservatorship proceedings were given a test consisting of behavioral tasks specifically designed to be appropriate to the legal definition of grave disability. The natural groupings were: chronic organic brain syndrome, chronic schizophrenia, and other. We found that the grave disability of the organic brain syndrome patients was fairly predictable from their mental status examination, while the grave disability of the chronic schizophrenic patients was unpredictable from their mental status examination and required the application of the behavioral test for an appropriate determination of their ability to perform the functions specified in the law: The Lanterman-Petris-Short Act to provide for personal needs of food, clothing, and shelter. When the method or the proceedings were applied to patients of other diagnostic categories, they were found to be inappropriate. At this writing, our method of evaluation is being recognized and requested by public and legal agencies in our area. It has been used as evidence in court. The procedure is clear, relevant, and easily taught to new workers. The results, given in plain English and in essay form, are readily understood by physician, social worker, judge, and jury alike. We began our study with vexation, ambiguous criteria, and a chronic medical and legal problem; we conclude with a practical and relevant answer.


The physician's suicide revisited.

The physician's suicide revisited. The evidence dealing with suicide among physicians was reviewed. Special attention was paid to the statistical treatment of the data, the presence or absence of adequate standardization, and the significance of the sample size. No conclusive evidence was found that suicide rates among physicians, or among any medical specialty, were higher than those in the general population.


Measurement of tricyclic antidepressant levels in an outpatient clinic. Although definitive studies regarding the correlation between tricyclic antidepressant plasma levels and therapeutic effect are lacking, preliminary data suggest that measurement of tricyclic antidepressant plasma levels provides a rational approach to improve clinical management of the depressed patient. Data were collected  to determine if the routine measurement of plasma tricyclic antidepressant levels was practical in a large clinic population, and to determine if such levels could improve patient care. Individual differences in drug metabolism and frequent unreliable ingestion of medication make the measurement of drug plasma levels the only sure means of determining if a patient is receiving a fair therapeutic trial on a particular tricyclic antidepressant. Plasma analysis revealed both the failure to ingest adequate amounts of medication as prescribed and also the abuse of medications. Although generalizations regarding individual variation in drug metabolism or generalizations concerning drug compliance do little to improve patient care, whenever such problems are met on an individual basis, many clinical management problems can be resolved.


Periodic psychosis of puberty. A longitudinal case study. A number of reports indicate that many women experience minor physical and psychological symptoms just prior to or during menses. Rarer episodic psychotic states associated with menses have received scanty attention. In the few available case reports, many hypotheses about their etiology have been advanced, usually unsupported by systemic studies. A 15-year-old girl with periodic psychotic episodes associated with menses was studied over many months. The interval between her periods was around 45 days. Psychotic episodes usually started a few days before or in association with menstural bleeding. Typically characterized by withdrawal, negativism, an apprehensive attitude, and suspiciousness, they remitted fully in 10 to 12 days with or without treatment. To facilitate necessary behavioral observations and complete various investigations, the patient was kept for nearly 60 days without treatment as an inpatient. Repeated vaginal smear cytology examinations during the menstrual cycle indicated a predominant estrogen influence throughout the cycle with an absence of the expected progesterone predominance in its later part. The patient gained 5 pounds between two cycles. Therapy with progesterone was instituted following the observation period. This patient's Rorschach revealed strong conflicts in relation to her sexuality. Concomitant with change in vaginal cytology reflecting a more balanced estrogen/progesterone influence, the patient stopped having psychotic episodes with menses. During a trial period when progesterone therapy was stopped, the psychotic episodes recurred but were prevented with its subsequent reinstitution. A complex interplay of hormonal factors that brings heightened sexual drive and possibly water retention in a predisposed patient can contribute to the causation of psychotic episodes at menstrual onset. Menstrual bleeding can associatively facilitate sexual fantasies and heighten conflict. Under this combined stress, the ego's defensive structure is likely to crumble with resultant psychotic episodes.


Change in a schizophrenic adolescent as a result of a series of rage-reduction treatments. A 15-year-old schizophrenic girl with many autistic features was observed to have minimal gains from verbal (individual and family) psychotherapy. A course of six rage-reduction sessions was carried out. Effects of the treatment was assessed by daily ratings made by attendants in the ward setting and by a recreation therapist. Both short term and long term effects were assessed. Short term improvement was noted in the ward ratings on dimensions assessed: eye contact when requested; eye contact, spontaneous; speech quality; expression of feelings; interaction with peers; frequency of autistic behaviors; and interaction with adults. In recreation therapy (using fewer observations), short term improvements were noted in all except two of the dimensions: eye contact, spontaneous; and interaction with peers. Long term (pretreatment vs. post-treatment) gains were evident in the ward ratings on all areas except expression of feelings. In the recreation therapy setting, only frequency of autistic behavior showed a stable improvement. The therapist working with the patient also noticed more global changes, and suggested that rating such dimensions as depth of self-disclosure and willingness to confront important issues in verbal psychotherapy would also show interesting results. Methodological weaknesses of the study are mentioned, and guidelines for future work on this problem are suggested.


Core formation in the muscles of rats intoxicated with triethyltin sulfate. Young adult Osbourne-Mendel rats intoxicated for up to 23 days with triethyltin sulfate (TET) at a dose of 20 mg/liter of drinking water given ad libitum, developed core-like structures in type 1 extrafusal fibers of the soleus muscles. Frozen sections revealed an absence of oxidative enzyme activity (NADH-tetrazolium reductase) and diminished or absent myosin ATPase (pH 9.4) in the core regions. The main electron microscopic features within the cores were loss of mitochondria and streaming of the Z-disks. The histochemical and electron microscopic similarities and differences between the TET-induced cores, other core models, and those reported in some human neuromuscular disorders are discussed. The present experiments do not clarify whether the cores are produced from a direct effect of TET upon skeletal muscle or upon the neural component of the motor unit.


Reactive microglia with membrane features of mononuclear phagocytes. An inflammatory response was induced by the implantation of cover-slips into the brains of rabbits. The cytomorphology of the glass-adhering cells, their phagocytic properties and their enzymatic activity were characterized and these features were correlated with the presence of membrane markers. Mononuclear cells with foamy cytoplasm, with marked phagocytic potential and strong activity of nonspecific esterases consistently showed IgG- and C-receptor activity. Multinuclear giant cells, which increased in number after prolonged implantation, exhibited comparable features. In contrast, mononuclear cells of fusiform appearance with a low activity of nonspecific esterases and a poor phagocytic potential lacked the IgG-receptor. A close relationship between the mononuclear phagocytic cell and reactive microglia is postulated. The authors conclude that the inflammatory response observed under their test conditions was characterized by the prevalence of phagocytic cells with membrane characteristics of the monocyte-macrophage series.


Histological defects in the cerebellum of adult lurcher (Lc) mice. The adult cerebellum of the heterozygous lurcher mouse (Lc/+) shows severe defects which affect particularly the Purkinje cells and granule cells. The cytoarchitecture of the cerebellar cortex is disturbed, and the granular and molecular layers are poorly defined. The population of Purkinje cells is depleted, except for a few large neurons scattered in the granular layer and white matter. Although a discrete Purkinje cell layer does not exist, pyridine-silver preparations reveal a row of arborizing basket cell axons and climbing fiber terminals which suggests the site previously occupied by Purkinje cell bodies. Granule cells are also affected and are distributed throughout the molecular layer, granular layer, and white matter.


Edema of the cortical gray matter of the human cerebrum. Five cases of brain tumor are reported in which an extracellular edema of the cerebral cortex was recognized in the form of lakes of eosinophilic, PAS positive material, presumably serum proteins, permeating among the neuronal and glial cells and processes. In three, the astrocytes and their processes were stained in replicate paraffin sections by a gold sublimate technique. The astrocytic changes were variable. Most often, the astrocytes changed from protoplasmic to fibrillary, with long deeply stained processes, the cells sometimes becoming large and distorted. Many became enlarged and smudgy, with short stubby processes. Only a few showed the fragmentation and disintegration of processes. Only a few showed the fragmentation and disintegration of processes which are regularly observed in edematous white matter. The neuronal processes remained essentially normal. In comparison with edema of white matter, edema of the cortex is rare, involves only small portions of tissue, and differs in its effects on astrocytes. The edema in both cortex and white matter is extracellular. We have not been able to recognize a specific intracellular form of edema, grossly or with light microscopic techniques.


The pathologic characteristics of leukostasis and leukemic nodules occurring in the central nervous system of guinea pigs with L2C/NB leukemia. Leukostasis and leukemic nodules are found in the central nervous system (CNS) of at least 75% of guinea pigs during the terminal stages of untreated L2C/NB leukemia, a transmissible, acute lymphocytic leukemia. The CNS lesions develop after extensive visceral leukemic infiltration at a time when the white cell count is rising to 10(5)-5 x 10(5) cells/mm3, and the differential examination shows predominantly blasts. Leukostasis precedes formation of the nodule. Both lesions may be found in any part of the central nervous system including the spinal cord, but are most numerous in the diencephalon and rostral brain-stem. Ultrastructural studies demonstrate that parenchymal leukostasis develops chiefly within capillaries, and is associated with endothelial cell degeneration and necrosis. Fibrin deposits are not seen within affected capillaries. The sequence of development, pathologic and hematologic characteristics of leukostasiss and leukemic nodules in human and L2C/NB leukemia are virtually identical. The CNS lesions of untreated L2C/NB leukemia are a precise, convenient model for the study of intracerebral leukostasis and leukemic nodules.


Degenerative lumbar spondylolisthesis with an intact neural arch (pseudospondylolisthesis). Twenty patients treated for degenerative spondylolisthesis with an intact neural arch principally at the L4-5 interspace had neural compression caused by dislocation of the vertebral bodies and intrusions of lamina and enlarged, arthrotic facets into a stenotic spinal canal. The resulting "pincer" effect caused complete or partial block demonstrable on myelography, with nerve root and cauda equina compression. Most of the patients were women aged 45-84 years. Seven had neurogenic claudication. The majority had unrestricted straight-leg raising, and no signs of acute neural entrapment were seen as in patients with a herniated disc. Absent ankle reflexes, and weakness and atrophy of the anterior tibial muscle group were common, while sensation was relatively undisturbed. Treatment consisted of liberal laminar decompression including foraminotomy and medial or total facetectomy. Good-to-excellent results were obtained, and no patient was made worse by the procedure.


Effect of intermittently raised intracranial pressure on breathing pattern, ventilatory response to CO2, and blood gases in anesthetized cats. In anesthetised cats, breathing pattern, blood gases, and ventilatory response to CO2 were recorded before and during intermittent 10-minute episodes of hydrostatically raised intracranial pressure. The first effect on breathing was a stimulation which was followed at higher pressures by irregularity, depression, and periods of apnea; hyperventilation at high intracranial pressure (ICP was rare. Raised ICP did not consistently depress the ventilatory response to CO2 until ventilation during airbreathing was already depressed; therefore, we cannot experimentally justify applying this test clinically to detect incipient ventilatory depression. When hypoxemia developed during raised ICP, it was compatible with the degree of hypoventilation due to central depression of breathing; thus, there was no evidence of a neurally mediated effect on the lungs, causing defective gas exchange.


Effect of dopamine-beta-hydroxylase inhibition on cerebral vasospasm in the cat. Inhibitors of dopamine beta hydroxylase (DBH) administered intraperitoneally were shown to prevent spasm of the basilar artery caused by blood application in cats. A low or nondetectable blood DBH activity level may be related to the absence of spasm. In several instances, however, moderate spasm did occur with a low blood DBH activity level. Possible mechanisms for these findings are discussed.


Spasmogenic qualities of prostaglandin F2alpha in the cat. Available data indicate that the concentration of prostaglandin F2alpha required to produce arterial spasm in an experimental model is approximately a thousand-fold higher than the concentration that occurs under physiological conditions. The spasmogenic platelet factor which has been previously described is shown to be a substance other than prostaglandin F2alpha because of differences in susceptibility of the two substances to enzymatic digestion.


Fibromatosis presenting as a cranial mass lesion; case report. The authors report a case of fibromatosis presenting as a mass lesion following previous craniotomy and radiation therapy. The clinical and pathological characteristics of this rare condition are discussed.


Traumatic fistula between a lacerated middle meningeal artery and a diploic vein; case report. A traumatic fistula occurring between a lacerated middle meningeal artery and a diploic vein was treated conservatively, and was no longer demonstrable at follow-up examination about 1 1/2 years after the injury.


Cardiovascular complications on upper vagal rootlet section for glossopharyngeal neuralgia; case report. Acute hypotension and right bundle-branch block occurred when the authors sectioned the uppermost rootlet of the vagus nerve in a case of glossopharyngeal neuralgia. Hypotension lasted for 20 minutes and arrhythmia for 4 days. A possible mechanism is discussed and cardiovascular disorders are reviewed in similar cases.


New lumboperitoneal shunt for communicating hydrocephalus; technical note. The authors describe a T-tube Silastic shunting device which has been used for lumboperitoneal shunting in 62 patients with communicating hydrocephalus during the past 3 years. In 38 patients it was inserted as a primary shunting procedure; 24 patients had the shunt inserted following problems secondary to arachnoiditis created by a polyethylene-type lumboperitoneal shunt. The shunt described here has not led to arachnoiditis when inserted as a primary shunting procedure. In 61% of patients no operative revisions of their shunt has been required to date, and 81% continue to do well on their T-tube type shunt.


Splenic accumulation of 99mTc-diphosphonate in a patient with sickle cell disease: case report. Splenic accumulation of 99mTc-diphosphonate is shown in the bone scan of a patient with sickle cell disease. This uptake is assumed to result from splenic infarction and subsequent calcification. The conventional liver-spleen scan with 99mTc-sulfur colloid shows no splenic activity, and a radiograph shows calcification in the left upper quadrant of the abdomen in the expected anatomic location of the spleen.


Diagnosis of posterolateral congenital diaphragmatic (Bochdalek) hernia by liver scintigram: case report. A characteristic liver scintigraphic finding was observed in a 2-month-old infant with hepatic herniation through a right-sided posterolateral congenital diaphragmatic defect (Bochdalek). The liver scintigrams showed an oblique band of decreased radioactivity dividing the liver into an inferior anteromedial portion and a superior posterolateral portion. In spite of the markedly abnormal liver scintigram, other diagnostic studies, including pneumoperitoneum abdominal radiography, remained negative. The liver scintigram can provide life-saving information in the diagnosis of congenital diaphragmatic hernia, as in the present case. The distinctive liver-scan findings among the various types of common diaphragmatic hernias are also briefly reviewed.


Adenocarcinoma of the lung with marked uptake of 99mTc-pertechnetate: case report. Following biopsy of a hilar mass, a heart scan performed with 99mTc-pertechnetate showed intense uptake in the mass. The degree of radionuclide concentration suggested that the mass was glandular tissue, most likely an adenoma or adenocarcinoma. Biopsy revealed a mucinsecreting adenocarcinoma. Review of the literature showed examples of active glandular concentration of pertechnetate in the thyroid, gastric mucosa, breast, lacrimal glands, and colon. This case provides an example of reasoning by which the scan interpretation came closer to the actual tissue diagnosis than is usually possible.


Tracer accumulation in a subdural hygroma: case report. A surgically proven case of traumatic subdural hygroma gave a "positive" image during 111In-DTPA cisternography, This was probably secondary to a communication between the subdural and subarchnoid spaces.


Tagging of iron oxide particles with 99mTc for use in the study of deposition and clearance of inhaled particles. This paper describes a method of tagging iron oxide aerosol particles with 99mTc. The tagging is achieved by reducing the heptavalent pertechnetate form to its reduced state using stannous chloride in a nitrogen atmosphere. Tests by ultracentrifugation and paper chromatography shown that the tagging is virtually complete. Separation of the tag from the particles in sputum is shown to be minimal. Monodisperse aerosols of the tagged particles are produced with a spinning-disk atomizer. (Deposition and clearance of the particles in the airways and lungs is easily followed by scintigraphy.) Factors affecting attachment and separation of the tag are discussed.


A simple kit for the preparation of 99mTc-labeled red blood cells. A simple kit for the preparation of 99mTc-labeled red blood cells in a closed sterile system is described. Whole blood (3-6 ml) is automatically drawn from the patient into a 10-ml Vacutainer tube, containing a freeze-dried stannous citrate formulation, with heparin as an anticoagulant. The kit provides consistent 97% yields in 20 min with small blood samples. The radionuclide is added at the end of the labeling sequence to minimize operator exposure. Freeze-dried kits have performed well after more than 12 months. Some technetium solutions produced low labeling yields. Experimental evidence suggests that the poor yields were due to carrier 99Tc. This effect may explain low labeling yields obtained with some other radiopharmaceuticals.


Evaluation of labeling procedures and in vivo stability of 99mTc-red blood cells. Stable labeling of red blood cells (RBCs) with 99mTc, in yields of about 66%, was achieved by using stannous chloride as a reducing agent. In a study of 12 patients, the stability of technetium-labeled RBCs in the circulation varied significantly among individuals, but the average biologic half-life of the labeled cells was 16.8 hr. Although the labeling yield was lower when the labeling was carried out without EDTA with the addition of stannous chloride after the pertechnetate, this sequence appears to be the best for labeling RBCs for use in obtaining images of the blood pool or the cardiovascular system because of the increased viability of the RBCs.


Methods of correcting Anger camera deadtime losses. Three different methods of correcting for Anger camera deadtime loss were investigated. These included analytic methods (mathematical modeling), the marker-source method, and a new method based on counting "pileup" events appearing in a pulse-height analyzer window positioned above the photopeak of interest. The studies were done with 99mTc on a Searle Radiographics camera with a measured deadtime of about 6 musec. Analytic methods were found to be unreliable because of unpredictable changes in deadtime with changes in radiation scattering conditions. Both the marker-source method and the pileup-counting method were found to be accurate to within a few percent for true counting rates of up to about 200 K cps, with the pileup-counting method giving better results. This finding applied to sources at depths ranging up to 10 cm of presdwood. The relative merits of the two methods are discussed.


Thallium-201: scintillation camera imaging considerations. Modulation transfer functions, line spread functions, and energy spectra were obtained for an Anger scintillation camera using three different collimators and commercially produced 201Tl. Images of a thyroid phantom were obtained using these collimators. For each of the three collimators, line spread functions and modulation transfer functions were obtained for both the 75-keV x-ray and 167-keV gamma photon of 201Tl. Although the intrinsic resolution of the scintillation camera is superior when imaging with the 167-keV gamma photon, system performance was superior when the 75-keV x-ray was imaged. Contamination form 202Tl, which emits abundant 439-keV gamma photons, degraded images taken at 167 keV because of septum penetration. At 75 and 167 keV the converging collimator yielded the best system performance. Imaging time was significantly shorter using the 75-keV x-rays.


Inadvertent 131I therapy for hyperthyroidism in the first trimester of pregnancy. Of 963 physicians surveyed to determine therapeutic attitudes toward, and experience with inadvertent radioiodine therapy for hyperthyroidism during the first trimester of pregnancy, 116 physicans (of 517 responding) reported 237 cases. Therapeutic abortion was advised for 55 patients by 22 physicans. From the 182 remaining pregnancies there were two spontaneous abortions, two stillborn, one neonate with biliary atresia, and one with respiratory distress. This complication rate was not greater than might be expected in a similar number of random pregnancies. On the other hand, six infants were hypothyroid (transient for one) and four of these were mentally deficient. Three mothers of hypothyroid infants had received radioiodine therapy in the second trimester. None of the six mothers of hypothyroid infants had had pregnancy tests prior to radioiodine therapy. Survey responses indicate that routine pregnancy testing prior to radioiodine therapy for patients in the child-bearing age is not yet a standard procedure. It should be.


Effectiveness of direct and indirect radionuclide cystography in detecting vesicoureteral reflux. A modification of the direct radionuclide cystography technique to include filling, voiding, and postvoiding phases of the examination permitted a simulated comparison between direct and indirect radionuclide cystography. One hundred thirty-seven examples of reflux were documented with this technique. Of these, 96 instances of reflux (70%) were recorded during two or more phases and thus would have been detected by either technique. Twenty-nine examples (21%) were only detected during filling and thus would have been missed by the indirect radionuclide technique and by some roentgenographic techniques. Only 12 examples (9%) were detected during the voiding phases only. The modified direct method of radionuclide cystography, which continuously monitors the urinary tracts during filling, voiding, and postvoiding, is offered as the best current technique for assessing vesicoureteral reflux.


Relative accretion of 99mTc-polyphosphate by forming and resorbing bone systems in rats: its significance in the pathologic basis of bone scanning. The relative roles of osteogenesis andd osteolysis in the production of positive radionuclide images of skeletal lesions were investigated. The uptake of 99mTc-polyphosphate (Tc-PP) by each process was measured in an animal model that permitted bone formation and resorption to be studied independently. Ten rats received intramuscular implants of bone-forming demineralized matrix (DM) and resorbing devitalized bone (DV). Radiographs and Tc-PP scintiscans were made each week thereafter. At 6-10 weeks, the implants and normal bone samples were removed, counted for 99mTc, and examined histologically. The uptake of Tc-PP BY DM implants was first detected on images made 3 weeks after implanatation, and by DV implants, 1-2 weeks later. Serial radiography showed progressive calcification of DM an resorption of DV implants. Microscopic examinations of undecalcified sections, stained with a modified Goldner preparation, revealed vital-bone formation in the DM implants and osteoclastic resorption in the DV. Activity counts per gram of DM and DV implants were, respectively, 200% and 90% that of normal bone. Since only the bone-forming system (DM) accumulated Tc-PP at greater than normal concentrations, this study indicates that positive bone images of osteolytic lesions solely reflect compensatory osteogenic responses.


Dietary lysine and carnitine: relation to growth and fatty livers in rats. Male weanling rats were fed a 72% rice diet containing no detectable carnitine and limiting in threonine and lysine. Such dietary conditions may simulate protein malnutrition in man. Under these conditions growth impairment, anemia, hypoproteinemia, and fatty liver developed. The study focused principally on the fatty liver syndrome which was corrected to varying extents depending on degrees of supplementation with carnitine, lysine, threonine, and appropriate combinations of these nutrients. Such reduction in fatty liver accumulation was accounted for principally by the lowering of triglycerides, but also in part of total cholesterol levels. All the data, which also included monitoring carnitine uptake by the tissues and measurement of plasma triglycerides, were consistent with the view that fatty liver accumulation occurs in amino acid deficient diets because (a) of an impairment in the synthesis of the lipoprotein complex mandatory for triglyceride secretion from the liver and (b) from a deficiency of carnitine needed for the intramitochondrial transport of fatty acids prerequisite for their oxidation.


Influence of certain dietary fibers on serum and tissue cholesterol levels in rats. Pectin, carragheenan, agar gum arabic, cellulose and wheat bran were each fed to rats at a level of 5 to 7% to examine their effect on serum, liver and tissue cholesterol levels. Diets (casein-sucrose diet containing 10-15% soybean oil, or skim milk-wheat flour diet containing 10-15% soybean oil) supplemented with either 0, 0.2, or 0.5% cholesterol were used to test the possibly dietary interactions. Among the fibers tested, pectin displayed the most hypocholesterolemic effect. In some experiments, pectin lowered the level of cholesterol in the serum, liver, and aorta, but it elevated body cholesterol levels. Carragheenan was inconsistent in lowering serum cholesterol levels and tended to increase liver and carcass cholesterol levels. These results probably suggest that pectin and carragheenan can affect the distribution of cholesterol within the body. Gum arabic and agar did not lower serum cholesterol levels and in one case gum arabic elevated them. Furthermore, in some experiments they elevated liver body cholesterol levels. It appears that feeding of gum arabic and agar probably resulted in an expansion of the whole body cholesterol pool. Feeding of wheat bran or cellulose had no significant effect on either serum or liver cholesterol levels. The study indicates that the effect of dietary fiber is dependent on the composition of the diet. Furthermore, while some fibers such as pectin may exhibit a hypocholesterolemic effect in rats, other fibers such as gum arabic and agar may actually elevate serum or tissue cholesterol levels.


Relative activity of alpha-tocopherol and gamma-tocopherol in preventing oxidative red cell hemolysis. The purpose of this study was to compare the antioxidant activities of alpha-tocopherol and gamma-tocopherol in protecting the red cell membrane against lipid peroxidation. Tocopherols were incorporated into the red cell membrane by incubating cells with solutions of the tocopherols in bovine albumin. The cells were then washed and subjected to the dialuric acid hemolysis test. Analysis of variance of the response curves revealed that gamma-tocopherol had 38% of the activity of alpha-tocopherol. No evidence was found for an interaction between the two tocopherols when present in the red cell membranes simultaneously.


Iron absorption by humans from hemosiderin and ferritin, further studies. Iron absorption from hemosiderin and ferritin biosynthetically labeled with radioactive iron has been studied in 61 subjects. The geometrical mean iron absorption from hemosiderin in both normal and iron deficient subjects was 3.4%. Its mean absorption ranged from 1.9% in normal subjects to 4.7% in subjects with moderate iron deficiency and 7.3% in subjects with marked iron deficiency. The iron absorption from hemosiderin was markedly increased when it was administered with ascorbic acid or liver. The absorption of iron from hemosiderin when hemosiderin and wheat were consumed in a meal, was lower than the absorption from wheat. Iron from liver ferritin and liver hemosiderin were less absorbed in this study than that previously reported for liver hemoglobin. The studies presented here support the possibility that ferritin and hemosiderin form an iron pool different from the non-heme pool formed by vegetal iron, egg iron and ferric and ferrous salts.


Intestinal permeability to large particles in normal and protein-deficient adult rats. Intestinal absorption of ferritin and virus particles was assessed in control and protein-deficient rats using light and electron microscopic procedures. Rats weighing 100 to 130 grams were divided into two groups and fed either a 0.5% of 18% lactalbumin diet. At monthly intervals following diet initiation, three rats from each group were administered ferritin (MW-650,000) or adenovirus Type 5 (MW is greater than 1,000,000) via ligated jejunal loops either 15 or 30 minutes prior to loop excision and processing for electron microscopy. Morphological evaluation of jejunal tissues revealed that both control and protein-deficient rats absorbed ferritin and virus particles via pinocytosis and in both situations the exogenous particles were believed to be present in lysosmal bodies of typical absorptive cells. Neither ferritin molecules nor virus particles were identified elsewhere in the jejunal mucosa of control rats. Rats deprived of sufficient dietary protein for four months or longer, however, demonstrated exogenous tracer materials in intercellular spaces of the epithelium and lamina propria. Since these severely protein-deprived rats also demonstrated deterioration of apical intercellular junctions, the possibility exists that large particles moved directly between cells of the epithelial lining and subsequently into underlying connective tissue and vascular compartments for conveyance (as antigens) to other body regions.


Effect of feeding lysine and threonine fortified bread during gestation and lactation on growth of the offspring in rats. White bread, bread fortified with lysine, or with lysine and threonine was fed to female rats as the sole source of protein (13% of diet) during two closely spaced gestation and lactation periods. Comparisons were made with diets containing 13% or 26% casein protein, and a stock diet. Weight changes and food consumption of the mothers were determined, as were birth weights and weaning weights of the offspring. Lysine fortification increased food consumption and decreased weight loss of the mothers during lactation. When threonine was added with the lysine, food consumption during lactation was further increased and maternal weight loss prevented. Average weaning weights for first litters as a function of diet were: bread 17.0 +/- 1.9 g, bread + lysine 26.8 +/- 1.0 g, bread + lysine + threonine 39.8 +/- 3.1 g, 13% casein 42.8 +/- 3.8 g, 26% casein 62.5 +/- 4.7 g, and stock diet 41.5 +/- 7.9 g. First and second litter weaning weights were closely similar for each. Although average birth weights were not greatly affected by dietary treatment, total offspring weight at birth of mothers fed unfortified bread was reduced 40% in the second, as compared to the first litter. This reduction in total offspring weight did not occur in mothers fed amino acid fortified bread.


Effect of feeding lysine and threonine fortified bread during gestation and lactation on growth of the brain in rats. First and second litter offspring brain development was studied following the feeding of bread, bread plus lysine, or bread plus lysine and threonine to rats during pregnancy and lactation. Results were compared with offspring brain growth following maternal consumption of a stock diet, 13% casein or 26% casein diet. Brain weight, protein and cellularity progressively increased as lysine and lysine plus threonine were added to the maternal bread diets. The bread plus lysine and threonine diet resulted in similar or higher total weight, protein and DNA values for all brain areas in comparison with results from the stock diet or 13% casein diet. The 26% casein diet resulted in greater brain weight, protein and DNA values in comparison to the bread, bread plus lysine, 13% casein, or stock diets. First litter pups whose mothers were fed the 26% casein diet, in comparison to the bread plus lysine and threonine diet, had higher or similar brain weight and DNA levels. For second litter pups, all values were similar for both diets with the exceptions of lower brain stem weight for 26% casein and lower cerebellum DNA for bread plus lysine and threonine.


Some factors affecting the nitrogen sparing action of methionine and threonine in rats fed a protein free diet. It was previously reported that methionine and threonine supplementation of a protein free diet had a greater nitrogen sparing action than methionine supplementation alone. Investigated in this study were (1) effects of depletion of labile body protein on the nitrogen sparing action of methionine and threonine supplementation of a protein free diet, (2) the effects of graded levels of methionine and threonine on urinary nitrogen excretion, (3) the effect of supplementation of other amino acids to the protein free diet plus methionine and threonine on the urinary excretion of nitrogen and (4) sex differences in the nitrogen sparing action of methionine and threonine supplementation of a protein free diet. After 10 days of feeding a protein free diet to deplete the body labile proteins, nitrogen excretion in urine of female rats was significantly reduced within the first 2 days of feeding a protein free diet supplemented with methionine and threonine. After 7 days of feeding a protein free diet supplemented with methionine and threonine, nitrogen excretion was reduced when even as little as 0.0188% of each amino acid was added. The supplementation of all essential amino acids to the protein free diet did not reduce the urinary excretion of nitrogen further than the supplementation of methionine and threonine, but improved the nitrogen balance slightly. The excretion of urinary nitrogen by female rats fed the protein free diet supplemented with small amounts (0.0188%) of methionine and threonine was significantly reduced after 7 to 14 days of feeding. In males, small amounts of methionine and threonine had no significant effect at either 7 or 14 days.


Relation of ketosis to metabolic changes induced by acute medium-chain triglyceride feeding in rats. Medium-chain triglycerides (MCT) induce ketosis in several mammalian species including man. To clarify the regulation of this metabolic alteration, we fed rats either MCT or long-chain triglyceride (corn oil) and then attempted to correlate ketosis with changes in (i) concentrations of selected metabolites in plasma and (ii) the synthetic and oxidative capacities of the liver. By 1 hour after MCT feeding, plasma levels of total ketone bodies had increased 18-fold, with a maximum value reached 1 hour later. By contrast, total plasma ketones in rats fed corn oil were increased only about 2-fold at 2 hours after feeding and did not exceed this value at later intervals. Hepatic concentrations of ketone bodies also increased after MCT or corn oil feeding. Although plasma concentrations of glucose decreased and insulin increased in rats fed MCT, they were not affected by corn oil feeding. MCT-induced ketosis was depressed by glucose administration. Neither MCT nor corn oil feeding impaired utilization of glucose by the liver. Hepatic lipogenesis was suppressed 50% and 90% by MCT and corn oil feeding, respectively. A marked increase of long-chain fatty acids in plasma was observed in rats fed corn oil but not in rats fed MCT. The pronounced increase of ketones in MCT-fed rats was closely related to an elevation of octanoate. In liver slices of MCT-fed rats, ketogenesis from octanoate was 10-fold higher than from palmitate, and octanoate was oxidized 4 times more rapidly than palmitate. The ketosis of MCT-fed rats was depressed by administration of 4-pentenoic acid, a potent inhibitor of fatty acid oxidation. These results support the concept that ketosis induced by MCT stems from rapid oxidation of medium-chain fatty acids. Hyperinsulinemia, hypoglycemia and depressed lipogenesis resulting from MCT feeding appear to potentiate but not initiate ketosis.


Relationship between hepatic mitochondrial oxidative metabolism and morphology during riboflavin deficiency and recovery in mice. Changes in hepatic mitochondrial oxidative metabolism were examined during the development of severe riboflavin deficiency in mice, and during recovery from this deficiency. There was a marked reduction in oxidative rates for all substrates tested, with the decline being most pronounced with palmitoyl-1-carnitine. These effects were not enhanced by addition of galactoflavin to the riboflavin-deficient diet. Treatment of the deficient mice with riboflavin restored hepatic mitochondrial oxidation to normal within 24 hours in those mice fed a simple riboflavin-deficient diet, but required 72 hours in galactoflavin-supplemented mice. These metabolic changes in hepatic mitochondria appear to be temporally independent of the striking morphological changes occurring in these organelles during ariboflavinosis and recovery.


Metabolic changes in golden hamsters fed vitamin B-12-deficient diets. Various metabolic changes were observed in male hamsters fed vitamin B-12-deficient diets with or without supplements of cobalt, methionine, and a previously untested cobalt-free pseudovitamin B-12. The effects observed after 31 weeks of consuming the vitamin B-12-deficient diets included a marked increase in the urinary excretion of both methylmalonic acid and formiminoglutamic acid, slight increases in red blood cell mean corpuscular volume, and higher tissue levels of glutathione and activities of glutathione reductase and glucose-6-phosphate dehydrogenase. Vitamin B-12 in the diet prevented these changes, as did inorganic cobalt. The cobalt-free pseudovitamin B-12 showed no vitamin B-12 activity, neither did it have any potent antagonistic effect. Methionine supplementation reversed some of the metabolic changes. Addition of inorganic cobalt to the diet resulted in a significant increase in tissue stores of vitamin B-12.


Proximity factor in color-difference evaluations. The effect of dividing-strip width (sample proximity) upon sensitivity to suprathreshold and threshold color differences is explored by three methods that involve ratio comparisons, liminal determinations, and repeated color matchings. The results suggest, in general, that sample separation impairs lightness discrimination more than chromaticness discrimination and that it may be necessary to introduce a proximity factor into color-difference formulas when evaluating threshold or small-size color differences.


Muon-induced visual sensations.

Muon-induced visual sensations. The visual phenomena induced by the passage of a pulse of extremely relativistic muons through the vitreous humor have been studied at the Alternating Gradient Synchrotron at Brookhaven National Laboratory. The visual phenomena include flashes that range from small crescents of light in the peripheral field of view to large clouds of light that fill the entire field of view as well as bright flashes with dark centers. Three subjects have been exposed to date. Arguments are given to show that the physical mechanism behind these flashes is Cerenkov radiation. Standard psychophysical techniques are used to determine the threshold for muoninduced visual sensations for one subject. Comparison is made with his pion treshold measured under the same condition.


Anomalous disperison of rhodopsin in rod outer segments of the frog. Linear-retardation spectra of single frog-rod outer segments were measured by use of a microspectrophotometer equipped with polarizing optics. The recorded transmitted-flux variation was reduced to a rhodopsin anomalous-dispersion spectrum by use of the Jones calculus. This anomalous dispersion is compared with theoretical predictions.


Letter: Binocularly induced motion of flicker patterns. A new apparent motion phenomenon is described. It occurs when two flashing screens are observed binocularly, one screen for each eye, and the temporal phase between the flashes is suddenly changed. It appears as a low-contrast pattern of vertical stripes that move either to the left or right, depending on the phase of the lights. Changing the relative intensity of the screens alters the effect in a manner consistent with previous measurements on visual time delays.


Respiratory regulation after elastic loading and CO2 rebreathing in normal term infants. Studies of airway pressure, tidal volume, respiratory duration, and total breath duration before and after elastic loading airway occlusions were carried out on ten full-term, normal infants on two occassions in the first week of life. Using these noninvasive techniques we infer that static compliance and the Hering-Breuer reflex are unchanged during the first week; that infants may increase sensitivity to chemical drive toward the end of the first week; and that there may be a volume related threshold for vagal inhibition of inspiration in some infants.


After the child dies.

After the child dies. The parents of a child who dies feel the emotions of shock, mourning, and confusion as they slowly come to accept the finality of the child's death. In contemporary America they frequently feel isolated and abandoned. The individuals and institutions that were sources of emotional support in the period immediately after the child's death are no longer available after a few weeks or months. This is due to several factors: (1) American society is very mobile and the nuclear family often does not have the emotional support of the stable, extended family. (2) Children die less frequently today than they did in the past. In fact, it is almost a unique event. As a consequence, the parents of the dead child have less opportunity to share their feelings with other adults and the community at large. (3) There appears to be a misconception held by the general population that the mourning process and emotional confusion terminate after an interval of a few weeks or months. These factors were influential in motivating a number of parents who had lost children to organize a group which meets bi-monthly. The group is open-ended and nothing said is out of place. The parents have been very helpful to each other in diminishing feelings of isolation, concerns about "strange" thoughts, and feelings of hopeless depression. Requests for information on how to form such a group have come from a number of communities in various parts of the country.


Reactions and serologic responses in young children and infants after administration of inactivated monovalent influenza A vaccine. Infants, two years of age and under, received zonally purified whole-virus A/Aichi/2/68 (H3N2) influenza vaccine. Febrile responses, including one febrile convulsion, were observed in nine of 13 (69%). There was a fourfold rise in serum-neutralizing antibody in nine of 11 (82%) of those lacking initial antibody titers. Purity of the vaccine was documented by electron microscopy, absence of egg protein, and very low levels of endotoxin (0.048mug/dose). It is concluded that the toxicity of vaccine is related to the virus itself and that, despite the good antibody response, influenza vaccine should be administered only to children two years and under at high-risk of complications from influenza, if at all.


Clinical reactions and serologic response following inactivated monovalent influenza type B vaccine in young children and infants. A monovalent, zonally purified, inactivated influenza B vaccine was administered to 29 children, 3 to 6 years of age, and 16 infants, 12 to 28 months of age, as a single dose of 0.25 ml containing 250 chick cell agglutinating units. The vaccine was both antigenic and well tolerated in the older group of preschool children. In the infants the vaccine was also antigenic but poorly tolerated clinically. Febrile reactions to 102 or greater were seen in 9 of the 16 infants, and two of these infants experienced a seizure following vaccination. The clinical reactions observed with the administration of influenza B vaccine in the dose used in this study would suggest significant limitations on its use in children under 3 years of age.


Growth and fat absorption after resection of ileum in childhood. Twelve children who have survived resection of more than 45 cm of ileum (eight during the neonatal period and four later in childhood) have been reassessed at periods ranging from 3 to 16 years. No child had persistent diarrhea for longer than one year after a resection, and only two children had a restricted fat intake for more than two years. These two children showed no advantage in growth compared with the ten who had normal diet within two years of the resection. The weights of individual children are appropriate for their heights. Their heights tend to be less than those of their siblings, but only two are less than the third percentile compared to height expected in relation to that of parents. The older children still have marked steatorrhea but no diarrhea, and serum levels of vitamins A, D, and E are normal. These observations suggest that two years after extensive resection ileum some children may tolerate a normal diet and grow well despite persisting defects in absorption. Infants with more extensive resections are now surviving and may require special diets and vitamin supplements for longer periods of time.


Effect of diet on urinary excretion of VMA, HVA, metanephrine, and total free catecholamine in normal preschool children. Quantitation of the urinary metabolites of catecholamines, including VMA, HVA, and metanephrines, from six normal preschool children was performed during a normal diet, a restricted diet, and a diet with increased amounts of vanilla, vanillin, and phenolic acids. Ingestion of these substances has been suspected of producing elevated values of urinary catecholamines and their metabolites. Urine was collected on the fourth day of each diet in two consecutive 12-hour aliquots, beginning at 8:00 AM. Statistically significant diurnal variation in excretion of all three metabolites and total free catecholamines (epinephrine, norepinephrine, and dopamine) was demonstrated. Diet did not alter exceretion  of total free catecholamines or any of the three metabolites. This study suggests that a three-day restricted diet is not necessary prior to screening children for neuroblastoma when using quantitative assay methods and that all screening tests should be performed on a 24-hour urine sample.


Asymptomatic chronic hypomagnesemia and hypokalemia in a child: Cell membrane disease. An 8-year-old boy was followed for four years because of chronic hypomagnesemia and hypokalemia. THe clinical manifestations were episodic and characterized by spontaneous carpopedal spasm. There were no other signs of magnesium or potassium deficiency. Metabolic studies revealed that the urinary exceretion of magnesium and potassium was elevated in relation to the serum level, but appropriate for a normal boy of that age. No abnormality was detected in the renin-angiotensin-aldosterone system, and the renal functions were normal. Various therapeutic attempts (oral magnesium and/or potassium supplements, spironolactone) failed to correct the abnormal serum concentrations of magnesium and potassium. This disease may represent a defect in the maintenance of a normal gradient between intra-and extracellular magnesium and potassium.


Fetal breathing: induction in utero and effects of vagotomy and barbiturates. Breathing movements were induced in the mature fetal lamb in utero by (1) both electrical stimulation and manipulation of the sciatic nerve, (2) stimulation of cutaneous receptors, and (3) KCI injection into the peripheral circulation. The breathing patterns that were produced included the "respiratory reflex", sustained regular breathing lasting up to three hours, and short bursts of irregular breathing. The latter resembled the spontaneous irregular breathing of the fetus in situ as reported by others. It is suggested that the intensity of peripheral somatic stimulation is an important determinant of the resultant breathing activity, ie, low intensity produces irregular breathing and high intensity, sustained regular breathing. The breathing responses were not affected by bilateral cervical vagotomy, but were inhibited completely by maternal administration of pentobarbital and of quantities of thiopental and methohexital equal to or less than the doses used clinically.


Transfusion therapy for cerebrovascular abnormalities in sickle cell disease. Cerebral angiograms were performed in patients with sickle cell disease and symptoms of stroke to evaluate transfusion therapy for cerebrovascular accidents. Three patients who were transfused repeatedly for one year to maintain less than 30% hemoglobin S were compared to two patients who were not transfused. All patients had abnormal angiograms initially. After one year the angiographic abnormalities resolved in two and improved in one transfused child. The two children who were not transfused showed progressive vascular disease. For all arteriograms, the patients were prepared by transfusion with normal red cells and careful hydration.


Renal arteriography in the evaluation of unexplained hypertension in children and adolescents. Arteriography demonstrated renal artery stenosis in 24% of 101 selected patients whose hypertension was first diagnosed before the age of 20 years. Arteriographic findings were normal in 58%. The prevalence of RAS was greater in the younger than in the older age groups. An abdominal bruit and urographic abnormalities were frequently observed in association with RAS. Adequate follow-up information was available for 16 patients who underwent vascular repair or nephrectomy for RAS. In 14 of the 16, the hypertension was eliminated (81%) or definitely reduced (6%).


Extramembranous glomerulonephritis in childhood: relationship to systemic lupus erythematosus. Extramembranous glomerulonephritis is an uncommon but distinct pathologic lesion in children. The diagnosis is established by the characteristic light, immunofluorescent, and ultrastructural abnormalities in renal biopsy specimens. This report describes seven of the ten children with this lesion studied in the past 11 years. Emphasis is given to the comparison of four children with idiopathic membranous glomerulonephritis with three others who presented with a nephrotic syndrome but subsequently developed evidence of systemic lupus erythematosus. Two of the latter three children, and three others with SLE and MGN not described in detail, demonstrated deposition of IgA by immunofluorescence along glomerular capillaries. Five of six children with SLE and MGN had microtubular structures in glomerular endothelial cells demonstrable by electron microscopy. These observations suggest that children with MGN require careful and continuing study for evidence of SLE.


Shunt nephritis: the nature of the serum cryoglobulins and their relation to the complement profile. The serum complement profiles of four patients with shunt nephritis indicated classical pathway activation of the complement system. The presence of mixed cryoglobulins was correlated with disease activity and the cryoglobulins were shown to be complement reactive. Antisera to two of the cryoglobulins recognized antigens of the infecting organism, and a specific bacterial antibody was identified in one cryoglobulin, giveing evidence that the cryoglobulins contained immune complexes. Bacterial antibody without detectable antigen was demonstrable in the sera indicating antibody excess. Renal morphology demonstrated mesangial proliferation and interposition with subendothelial and mesangial deposits. Parallels are drawn with active lupus nephritis.


Persistent pleocytosis in bacterial meningitis. Persistent pleocytosis of greater than 60 white blood cells/mm3 was commonly seen in children adequately treated for bacterial meningitis. It occurred in 13 of 21 (62%) children with Hemophilus influenzae meningitis and in 2 of 9 (22%) with pneumococcal meningitis. Pleocytosis alone cannot be used as an indication of prolonging therapy; significance of persistent pleocytosis is not known.


Diencephalic syndrome revisited.

Diencephalic syndrome revisited. This report details the histories of five patients with clinical diencephalic syndrome who collectively demonstrate the variability found in the syndrome with respect to: (1) clinical course, (2) site of the tumor, and (3) ease of obtaining radiologic confirmation of the presence of a tumor. A review of an additional 67 patients indicates that the observations are not unique. The anatomic variability combined with the fact that the course of those who are treated is infinitely better than those left untreated adds urgency to the establishment of precise anatomic diagnosis. These considerations led to a critical review of the histories of the 72 patients. From this it can be stated that anteriorly and posteriorly placed tumors do exhibit subtle but significant differences in their clinical course, and roentgenograms of the optic foramina and analysis of the CSF cell and protein content appear warranted early in the investigation of emaciation from unknown cause. Further, an evaluation is made of the role of various radiologic techniques and of endocrine studies in establishing the diagnosis. Similarly, the relative merits of radiotherapy and/or surgery in the treatment of the disease are defined. Finally, the adequacy of the term diencephalic syndrome is discussed.


The "bronze baby" syndrome: postmortem data. The case history and autopsy findings of an infant with the "bronze baby" syndrome are presented. These findings substantiate that kernicterus occurs in term infants receiving phototherapy for concentrations of serum indirect bilirubin below 20 mg/dl. The findings at autopsy suggest that the photodecomposed pigmented products of bilirubin are unable to pass the blood-brain barrier. The need for establishing the cause of jaundice prior to initiation of phototherapy is stressed.


Protamine sulfate titration for heparin activity in neonates with indwelling umbilical catheters. A rapid, simple, semimicro method for neutralization of heparin effect by titration with protamine sulfate is described. Protamine sulfate can be effectively employed to eliminate the effect of heparin on the APTT. Determination of true abnormalities of coagulation has important prognostic and therapeutic implications for the sick newborn infant.


Cerebrospinal fluid evaluation in neonates: comparison of high-risk infants with and without meningitis. Results of CSF examinations from 117 high-risk neonates were reviewed. The mean CSF cell count was 8.4 cells/mm3 and the range was 0 to 32 cells/mm.3 Approximately 60% of the CSF WBC were polymorphonuclear leukocytes. Average CSF protein concentrations were 90 mg/dl (range, 20-170 mg/dl) in term and 115 mg/dl (range, 65-150 mg/dl) in preterm infants. The average CSF glucose was 81% of the blood glucose value in term and 74% in preterm infants. Comparison of these CSF findings with those from 119 infants with bacterial meningitis revealed that there was considerable overlapping of values, but only one of the 119 infants with meningitis had a completely normal initial CSF examination. The decision to initiate antimicrobial therapy in neonates with suspected meningitis must be based on total evaluation of the patient.


Necrotizing enterocolitis with recurrent hepatic portal venous gas. Two separate episodes of pneumatosis intestinalis and hepatic portal venous gas were observed in a premature infant with necrotizing enterocolitis. Although HPVG has previously been considered an ominous roentgenographic sign, the infant survived without surgical intervention. As in several cases reported by others, clinical and roentgenographic signs of NEC reappeared when enteric feedings were restarted prior to 10 days of medical therapy.


Pancytopenia in an infant associated with sulfamethoxazole-trimethoprim therapy. Pancytopenia in a seven-month-old baby is described and attributed to sulfamethoxazole-trimethoprim therapy. Plasma cells and histiocytes were prominent in the initial bone marrow examination and quite unlike the fatty hypocellular marrow usually seen in aplastic anemia.


Warfarin therapy initiated during pregnancy and phenotypic chondrodysplasia punctata. An infant is described who has clinical manifestations and roentgenographic features consistent with the diagnosis of chondrodysplasia punctata. The mother of this infant received warfarin during pregnancy. Eight cases demonstrating an association between warfarin therapy during pregnancy and chondrodysplasia punctata in the child have been reported; in the present case therapy was initiated following conception (see following case report). Warfarin may be teratogenic, producing a phencopy of the heritable forms of chondrodysplasia punctata. Because of the evident association we suggest (1) warfarin is contraindicated in pregnancy and alternative anticoagulants should be used; (2) products of at-risk pregnancies should be screened for the characteristic radiologic findings; and (3) preconceptual counselling and antenatal diagnosis of the disease may be beneficial.


Sudden infant death syndrome temperament before death. A retrospective study was made of the behavioral patterns of 46 infants whose deaths were attributed to the sudden infant death syndrome. Controls were the victims' siblings. Data concerning the infants' behavioral pattern were collected retrospectively from the parents, utilizing a modification of the Carey temperament questionnaire. The parents' recollection of the victims indicated that they: (1) had less intense reactions to environmental stimuli, (2) were less active physically, (3) were more breathless and exhausted during feeding, and (4) had more abnormal cries. The behavioral characteristics had a positive correlation with various postmortem evidences of antecedent chronic hypoventilation and hypoxemia. It would be a serious error for any parent to be told that their infant was at risk based on the behavioral pattern reported retrospectively by parents of victims of SIDS, because the pattern is also a common one in other infants.


Bacterial flora of appendicitis in children. Aerobic and anaerobic cultures were taken immediately upon operative entry to the peritoneal cavity of 114 consecutive children undergoing appendectomy. Stage of appendicitis and clinical presentation could be closely correlated to specific patterns of peritoneal bacterial flora. It was found that appendiceal gangrene and perforation uniformly produce a polymicrobial peritonitis that is based on the symbiosis of aerobes with anaerobes. Ensuing wound and intra-abdominal septic complications were likewise mixed infections. Based on these findings, refinements in the diagnosis of appendiceal gangrene and perforation as well as rationales in the treatment of appendicitis have been discussed.


Wound healing in children as assessed by the CELLSTIC method. Assessment of the quality and speed of wound healing in man has been rather difficult until the present time. By the use of CEELSTIC, a tissue-sensitive test drain composed of a standardized piece of viscose cellulose sponge inside a thin Silastic tube, cells existing between wound edges can be analyzed by histologic, cytologic, and enzyme histochemical means. The 166 pediatric surgical patients studied showed that wound healing is an age-dependent process reflected by the increased time needed for cellular transformation and maximal activation of hexokinase and isocitrate dehydrogenase with increasing age.


The advantages of a ventriculostomy reservoir with the Holter valve system. The use of a Rickham ventriculostomy reservoir incorporated in the Holter valve system is advocated. In a retrospective study of 173 button tape, the clinical assessment of the valve was proved correct in 51% of occasions and in a prospective review of 100 taps the clinical findings were correct in 53%. The complication rate of tapping the reservoir is negligible.


Atresia of the colon.

Atresia of the colon. Eleven infants with colon atresia have been managed by staged procedure with survival and good health in ten. Complications have been relatively few. At the initial operation the proximal atretic segment is exteriorized as an end colostomy. Such a procedure is simple and safe, results in rapid relief of the obstruction, and permits normal feeding by mouth within a few days. At a second procedure several weeks or months later, intestinal continuity is established by an end-to-end or end-to-side anastomosis. Gastroschisis has been an associated anomaly in four of these cases. This association gives additional support to the concept that intrauterine interference to the blood supply to a segment of intestines is the etiologic factor responsible for such atresias.


Levatorplasty: A secondary operation for fecal incontinence following primary operation for anorectal agenesis. A procedure is described which combines the posterior liberation of the levator with the levator plication. This operation was performed in 15 children, born with anorectal agenesis, all of whom were incontinent of feces after primary operation. Four of the 15 children became fully continent following levatorplasty, seven patients now have only occasional soiling, and four patients continue to soil persistently. In all the cases, a good correlation was found between bowel control after levatorplasty and anal canal pressures. Normal resting anal canal pressure was as significant as the voluntary squeeze pressure in relation to continence.


Identification and specific blockade of two receptors for histamine in the cardiovascular system. Histamine caused a fall in blood pressure in anesthetized dogs and cats which was only partially attenuated by mepyramine (pyrilamine), a histamine type H1-receptor antagonist. Further treatment with burimide or metiamide, type H2-receptor antagonists, caused nearly complete attenuation of the response to histamine. Burimamide alone had no effect on vasodilatation produced by histamine in the dog gracilis muscle whereas mepyramine alone caused a partial attenuation. An H2-receptor agonist, 4-methylhistamine and an H1-receptor agonist, 2-(2-pyridyl)ethylamine, both produced vasodilatation which was blocked by metiamide and mepyramine, respectively. Constriction of the saphenous vein produced by histamine was found to involve interaction with H1-receptors only. In the intact dog, histamine increased heart rate and decreased left ventricular dp/dt through direct effects. Mepyramine prevented the increase in heart rate but did not affect the chronotropic actions of isoproterenol and glyceryl trinitrate. H1-receptor blockade did not alter inotropic effects whereas subsequent H2-receptor blockade prevented the negative inotropic effect of histamine. It is concluded that both peripheral vascular and cardiac responses to histamine are mediated through activation of H1- and H2-histamine receptors.


Effects of opiate agonists and antagonists on central neurons of the cat. Morphine, naloxone, nalorphine, levorphanol, dextrorphan and levallorphan were ejected electrophoretically from micropipettes near cholinoceptive and noncholinoceptive cells of the spinal cord, ventrobasal thalamus and cerebral cortex of decerebrate and barbiturate-anesthetized cats. Morphine excited those cells having nicotinic receptors for acetylcholine. Naloxone and nalorphine reduced the action of morphine and acetylcholine on these cells but not the effects of excitant amino acids. Levorphanol excited spinal neurons also excited by acetylcholine, an effect antagonized by naloxone, but also showed atropine-like activity when ejected for prolonged periods. Dextrorphan depressed the firing of both cholinoceptive and noncholinoceptive spinal neurons. Levallorphan reduced the effects of both acetylcholine and excitant amino acids on spinal neurons. The depressant effects of morphine and levorphanol on noncholinoceptive spinal neurons were not antagonized by naloxone.


Stimulus properties of the narcotic antagonist pentazocine: similarity to morphine and antagonism by naloxone. Pentazocine (10 mg/kg) and saline were used as discriminative stimuli in rats. After pentazocine administration, reinforcement could be obtained contingent on pressing one particular lever (left or right) in a two-lever operant chamber. Responding on the opposite lever was reinforced only after saline injections; a drug-lever combination was always held constant for each animal. Discriminated choice responding between pentazocine and saline was learned to an 80% correct criterion. Test injections of morphine produced dose-related responding on the pentazocine lever. Choice responding after 7.5 mg/kg of morphine was not significantly different from choice responding after 10 mg/kg of pentazocine. The discriminable ED50 values for both pentazocine and morphine were estimated from dose-response curves and when given in combination (pentazocine ED50 + morphine ED50), more drug-related responding occurred than occurred after either drug (ED50) alone. Naloxone produced saline-like responding but antagonized the stimulus properties of both pentazocine and morphine. However, the antagonism of the morphine cue by naloxone was significantly greater than the antagonism of the pentazocine cue. The results indicate that pentazocine and morphine are similar in at least one important respect suggesting that these drugs may share a common site of action.


3H-delta9-tetrahydrocannabinol tissue and subcellular distribution in the central nervous system and tissue distribution in peripheral organs of tolerant and nontolerant dogs. Tolerant and nontolerant dogs received one i.v. administration of 0.5 mg/kg of 3H-delta9-tetrahydrocannabinol 30 minutes before they were sacrificed. Plasma, peripheral and brain tissues, as well as subcellular fractions of brain tissues from both treatment groups, were analyzed for radioactivity. Throughout the time period before sacrifice, the plasma concentrations of radioactivity in the tolerant and nontolerant dogs were not significantly different. The percentage of radioactivity in brain and plasma that was due to either unchanged delta9-tetrahydrocannabinol or a major metabolite was the same in each group. Of the radioactivity in brain, 46% was identified as delta9-tetrahydrocannabinol. Regardless of treatment, there was a specific accumulation of radioactivity in adrenals, liver, kidney, heart and pancreas. The only significant differences in radioactivity between tolerant and nontolerant peripheral tissues were found in liver, kidney cortex, heart and lymph nodes. Although all brain areas from tolerant dogs contained less radioactivity than the comparable brain areas from nontolerant animals, only pituitary and putamen were significantly less. There was a specific accumulation of radioactivity in some brain areas that could be associated with behavioral effects. The concentration in cerebellar and cerebral gray was significantly greater than that in white, and there was a marked reduction in the concentration in gray after tolerance developed. The mean percentage of radioactivity in each subcellular fraction was as follows: 23% crude nuclei, 44% mitochondria, 8% cholinergic nerve endings, 7% noncholinergic nerve endings, 2% free mitochondria and 6% synaptic vesicles. The quantity of radioactivity in homogenates of brains from tolerant dogs was 17% less than brains of nontolerant animals, which was merely a reflection of the respective plasma concentrations. The distribution of radioactivity was similar in both groups, although most of the subcellular fractions from tolerant dogs contained a lesser amount of radioactivity. The most notable difference was observed in the synaptic vesicle fraction. The synaptic vesicle fraction of tolerant dogs contained 40% less radioactivity than did the same fraction from nontolerant dogs, which implied a possible mechanism of action. A comparison of the remaining subcellular fractions did not appear to explain the development of tolerance.


The effect of phencyclidine and ketamine on schedule-controlled behavior in the pigeon. Pigeons were trained under a multiple schedule of food presentation with alternating 30-response fixed-ratio (FR-30) and 10-minute fixed-interval (FI-10) components. Average rates of responding were 2.9 and 0.55 responses/sec, respectively. Both phencyclidine (0.03-3.0 mg/kg i.m.) and ketamine (0.1-30.0 mg/kg i.m.) increased response rates at low doses while decreasing response rates at high doses during the FI-10 component. Only a dose-related decrease in response rates was seen in the FR-30 component with both phencyclidine and ketamine. In individual birds, the maximum rate increases in the FI-10 component ranged from 110% to 163% of the control rate. The rate increases in the FI-10 component depended on the control rate of responding. The effects of phencyclidine and ketamine were qualitatively similar to d-amphetamine (0.1-10 mg/kg i.m.).


Metabolism, distribution and anticonvulsant properties of N,N'- dimethoxymethyl-phenobarbital in the rat. The in vivo metabolism of N,N'-dimethoxymethyl phenobarbital (DMMP) and the anticonvulsant properties of its metabolites were studied in the rat. At 10 and 30 minutes after i.p. administration, DMMP (ethyl-1-14C) represented less than 3% of plasma radioactivity, whereas N-monomethoxymethyl phenobarbital (MMP) was 78 and 75%, respectively, phenobarbital (PB) 12 and 20%, apparent mephobarbital 6 and 2% and less than 5% of the radioactivity remained at the origin. Peak levels of MMP were reached at 30 minutes in liver and 60 minutes in plasma and brain. At 4 hours, MMP had declined to 7% in plasma and was not detected in brain while PB rose to 93% of total 14C in plasma and brain. SKF-525A blocked (90%) the in vivo conversion of DMMP to MMP and completely inhibited the formation of PB, apparent mephobarbital and unidentified polar metabolites. MMP after oral administration was effective against maximum electroshock seizures at a time when brain levels of PB derived from MMP were insufficient to account for the total observed protection. However, MMP appears less potent than PB against pentylenetetrazol seizures.


Pharmacological characterization of lithium reabsorption in the rat. The effects of furosemide, chlorothiazide and acetazolamide upon fractional lithium excretion (FELi) were studied in acutely lithium-loaded rats. Changes in FELi were compared with the fractional excretions of sodium FENa and calcium FECa. Furosemide and acetazolamide, given separately, produced large and substantially equivalent increases in FELi. Responses of FENa and FECa to acetazolamide were much less than to furosemide. Chlorothiazide, alone or in combination with the other agents, produced moderate increases in FENa, modest increases in FECa and essentially no change in FELi. When furosemide was superimposed upon a previously established acetazolamide diuresis, the response in FELi was additive to that from acetazolamide alone. These results suggest that lithium reabsorption occurs at nephron sites primarily affected by acetazolamide and furosemide in the rat and that a significant amount of lithium reabsorption may take place in the loop of Henle. Acetazolamide, in combination with furosemide, appeared to depress renal tissue lithium accumulation.


Induction of hepatic enzymes by methaqualone and effect on warfarin-induced hypoprothrombinemia. The effect of methaqualone on the induction of hepatic enzymes was evaluated in rats and compared with that of phenobarbital by measuring effects on hexobarbital and methaqualone hypnosis, plasma and tissue levels of methaqualone, hepatic aniline hydroxylase and aminopyrine demethylase activity and warfarin-induced hypoprothrombinemia. Maximal reductions in hexobarbital hypnosis occurred 3 days after daily administration of 60 mg of methaqualone per kg per day. At this time, the activities of aniline hydroxylase and aminopyrine demethylase were increased 60 and 139%, respectively, and hepatic microsomal proteins increased 15% above controls in methaqualone-pretreated animals. Methaqualone altered its own metabolism as demonstrated by a 48% reduction in methaqualone hypnosis in pretreated animals. The extent and duration of induction by phenobarbital was considerably greater than methaqualone in all experiments. Methaqualone pretreatment did not affect warfarin-induced hypoprothrombinemia, whereas phenobarbital-pretreated animals showed a 32 to 64% reduction in response to the anticoagulant. These studies indicate that methaqualone is a relatively weak inducer of hepatic drug-metabolizing enzymes and has no effect on the anticoagulant acitivty of warfarin.


Theophylline metabolism by the rat liver microsomal system. The metabolism of 8-14C-theophylline (14C-Theo) was investigated in vivo and in vitro in the rat. In vivo, 14C-Theo at an initial blood concentration of 10muM was metabolized to at least two different metabolites, 1,3-dimethyl uric acid and 1-methyl uric acid. The biological half-life of the 8-14C-Theo (6 +/- 1.5 hours) was determined from the urinary excretion of radioactivity. Ten days of oral pretreatment of rats with theophylline resulted in a faster rate of metabolism of both 14C-Theo and zoxazolamine. In vitro metabolism of 14C-Theo was investigated in order to identify the enzyme(s) responsible for theophylline metabolism. A tissue survey utilizing tissue slices demonstrated that the metabolism is localized only in the liver since slices of heart, lung, intestine, brain, adrenals, kidney or spleen did not metabolize 14C-Theo. 14C-Theo metabolism in the liver was localized in the subcellular fraction of microsomes and not in the mitochondria or cytosol. 14C-Theo metabolism by liver slices or liver microsomes was inhibited by typical liver microsomal inhibitors such as 2-diethylaminoethyl-2,2-diphenylvalerate (SKF 525-A) and 3-methyl-4-methylaminoazobenzene. 14C-Theo metabolism in liver slices was increased by the liver microsomal-inducing agents, phenobarbital and 3-methylcholanthrene. 3-Methylcholanthrene also increased 14C-Theo metabolism by the liver microsomal fraction. One of the metabolites, 1-methylxanthine, generated by the microsomal system, is a substrate for xanthine oxidase, and its conversion to 1-methyl uric acid by xanthine oxidase was blocked by allopurinol. 14C-Theo per se was shown not to be a substrate for liver xanthine oxidase or aldehyde oxidase. These results indicate that Theo per se is metabolized by the liver microsomal system and not by liver xanthine oxidase or aldehyde oxidase.