The cholinergic nervous system and immediate hypersensitivity. 1. Eccrine sweat responses in allergic patients. The cholinergically innervated human eccrine sweat gland is a readily available organ permitting the assessment in allergic patients of cholinergic reactivity with few or no adrenergic influences. The sweat responses of four matched groups (male allergic, female allergic, male control, and female control) to intradermal Mecholyl from 0.1 mug to 100 mug was compared; the 45 male and 45 female allergic patients demonstrated statistically significant increases in sweat responses to essentially all concentrations of Mecholyl examined. No difference in the sweat responses of patients with allergic rhinitis alone was compared with patients with both allergic rhinitis and allergic asthma was noted. Five patients with intrinsic asthma most closely resembled the allergic groups in their responses and 8 patients with vasomotor rhinitis sweated at or below the control groups. The increased sensitivity of allergic patients to cholinergic stimulation as measured by eccrine sweat responses suggest that this hyperresponsiveness may be one of the underlying defects in allergic disease.


Risk factors for developing asthma and allergic rhinitis. A 7-year follow-up study of college students. Nine hundred three former college freshmen were followed 7 yr after entering college by means of a detailed allergy questionnaire. Original data collected from the students as freshmen, including a history of atopy and allergy skin test results, were evaluated in relation to the frequency of developing new allergies. During the 7-yr follow-up period, new cases of hay fever occurred in 12.6%, nonseasonal allergic rhinitis in 4.8%, and new asthma in 2.5%. The risks of developing asthma and allergic rhinitis are both significantly associated with a prior positive allergy skin test. The risk of developing asthma, not hay fever, is significantly associated with a prior history of atopy. The association of positive allergy skin tests with the development of new cases of allergy remains significant throughout the 7-yr follow-up period. However, individuals who had all negative skin tests developed significantly fewer new cases of clinical allergy during the first 3 yr of follow-up; in the next 4 yr of the 7-yr follow-up, increased numbers of individuals with negative scratch tests developed new cases of allergy. Thus, negative skin tests proved of less prognostic value during the last 4-yr period of this 7-yr study, although significant differences still are apparent between the positive and negative reactor groups.


Comprehensive evaluation of fatty acids in foods. VIII. Finfish. Recent (since 1960) data on the lipid content and fatty acid composition of fish were surveyed as part of the continuing USDA program to provide information on the nutrient composition of foods. Tabulated values of total lipid and fatty acids in finfish are presented. The most prominent fatty acids occurring in finfish are palmitic (C16:0), C18:1 (in some species C20:1 and C22:1), and the highly polyunsaturated C20:5 and C22:6. The general nutritional value of finfish is discussed. Two measures of polyunsaturation are presented for some commercially important domestic finfish: the total amount of polyunsaturated fatty acids (PFA) and the relative degree of polyunsaturation (PI).


Nutritional beliefs and practices in primigravid Mexican-American women. One hundred and thirty-one young Mexican-American women were interviewed and assessed nutritionally at their first obstetrical visit in a city-county hospital. About half had an intake of less than the recommended allowance for one or more nutrients or were frankly anemic, as judged by hemoglobin levels. The majority demonstrated little accurate information concerning foods as sources of nutrients. Considerable confusion was shown in their answers to questions concerning newborn birth weight, diet, and maternal weight gain. The fundamentals of prenatal education regarding nutrition for these patients must begin with foods and their relative values, emphasize the dependence of the fetus on maternal diet, and clarify the relationship of weight gain to obstetrical health. Ideally, such an educational effort should begin in early childhood.


Melanoblast-tissue interactions and the development of pigment pattern in Xenopus larvae. The melanophores of larval Xenopus laevis are disparately distributed on the hypomere in that the upper region (UHT) is densely pigmented, the median region (MHT) is moderately pigmented, and the lower region (LHT) is unpigmented. The roles of the melanoblasts and their tissue environment in determining the melanophore pattern was investigated by heterotopic transplantation of hypomeric tissues, culture of neural crest explants in vesicles derived from hypomeric tissues and radioactive marking of neural crest cells. Somite-situated grafts of UHT, MHT and LHT were found to possess melanophore densities similar to those exhibited by such hypomeric tissues when in their normal situation. The number and distribution of trunk melanophores in 'crestless' second host larvae bearing grafts of UHT, MHT and LHT transferred from the somites of primary host embryos indicated that (a) many melanoblasts entered all transplants during neural crest migration in the primary host: subsequently, a small number of melanoblasts were lost from transplants of UHT, a greater number from transplants of MHT and almost all from transplants of LHT; (b) almost all melanoblasts migrated out from transplants of MHT and LHT and entered the tissues of the 'crestless' host, whereas a considerable number of melanoblasts remained in the transplant when it was formed from UHT. Grafts of UHT placed mid-ventrally in the hypomere failed to exhibit melanophores. Vesicles of (a) UHT + MHT and (b) LHT containing neural crest tissue possessed similar numbers of melanophores. Vesicles of LHT differed from those of UHT + MHT in that melanophores were densely aggregated in the implanted neural tissues. Following radioactive marking of neural crest cells labelled nuclei were found on the dorsal ridges of the somites, the surfaces of the neural tube and notochord and in the mesoderm of the upper hypomere and the fin, but were absent from the lateral surfaces of the somites. These results showed that the melanophore pattern in larval Xenopus depended upon melanoblast-tissue interactions, which influenced the migration, rather than the differentiation, proliferation or destruction, of melanoblasts and suggested that tissue selection by migrating melanoblasts enabled these cells to distribute themselves in embryonic tissues in accordance with a hierarchy of melanoblast-tissue affinities. Melanoblast-tissue affinities appeared to be related to the adhesiveness of mesodermal cells: melanoblast extensibility appeared to facilitate exploration of the surrounding tissues. The formation of pigment pattern in larval Xenopus appeared to depend upon the interaction between the melanoblast population pressure and melanoblast-tissue affinities. The present results and those of other workers on amphibian pigmentation were used to construct a model capable of accounting for species-specific differences in larval amphibian pigment patterns, in terms of interactions between species-specific differences in melanoblast-tissue affinities and melanoblast population pressure.


Foetal and placental ornithine decarboxylase activity in the rat--effect of maternal undernutrition. The activity of the enzyme ornithine decarboxylase and the accumulation of nucleic acids were examined in the rat foetus and placenta during normal development and during maternal undernutrition. Maternal undernutrition resulted in a reduced rate of increase in weight of both the foetus and placenta towards the end of gestation. In the placenta the failure to increase in weight was accompanied by a failure of DNA to increase. In the foetus the amount of DNA failed to increase over a short period and then made a compensatory response to return to a normal amount by the end of gestation. Undernutrition failed to affect RNA in either the foetus or placenta. These results differ from those obtained during maternal protein deficiency. The activity of foetal and placental ornithine decarboxylase was normal during much of gestation in the undernourished group. However, at the same time as the compensatory increase in foetal DNA, there was a marked increase in enzyme activity in both tissues. It is suggested that a single compensatory stimulus is responsible for the changes in both ornithine decarboxylase and DNA.


The mechanism of chick blastoderm expansion. At the time of laying, the domestic fowl blastoderm measures 4 mm across. After 4 days' incubation, the extra-embryonic yolk-sac tissues have expanded to encompass the whole yolk mass. This expansion involves the migration over the inner surface of the vitelline membrane of a specialized band of 'edge cells' at the blastoderm periphery. As they move, they pull out the blastoderm behind them, setting up a considerable tension. Expansion also involves cell proliferation and changes in cell shape. This paper attempts to show how locomotion, tension, proliferation and changes in cell shape all contribute to the orderly process of expansion. As a simplification, only the extra-embryonic epiblast is considered here. The findings are: 1. Expansion does not occur at a constant rate, but starts slowly, rises to a peak (over 500 mum/h) at around 3 days, and then slows as coverage of the yolk mass nears completion. 2. During the first day of incubation, edge-cell migration produces a tension in the blastoderm. This rises to peak at 20-24 h, then declines. This tension may be due to an imbalance between expansion by migration and expansion by proliferation. 3. Migration of edge cells can be affected by tension in the blastoderm, i.e. very high tension may hold them back. However, the tension level normally found in the blastoderm seems not to do so. The low rate of expansion in the first day is therefore not due to the high level of tension. It may instead be due to changes in edge-cell organization. 4. Proliferation occurs throughout the extra-embryonic epiblast during the expansion period. It is not restricted to the blastoderm periphery. After the yolk has been covered, the epiblast continues to grow, with proliferation restricted largely to band just distal to the advancing edge of the area vasculosa. 5. Cell shape and arrangement change considerably during expansion. The epiblast of the unincubated embryo is a monolayer of tall cells. During expansion, these become considerably flattened so that each contributes a larger amount to yolk-sac surface area.


The use of 'normal' and 'transformed' gynandromorphs in mapping the primordial germ cells and the gonadal mesoderm in Drosophila. The primordial germ cells and the gonadal mesoderm were mapped in the Drosophila embryo by analyzing the patterns of mosaicism in 'normal' and 'transformed' gynandromorphs. Relative to the adult cuticular markers the germ cells map as the posterior most structure, which coincides with their known location in the blastoderm embryo. These data support the hypothesis that the gynandromorph map reflects the real position of the primordia in the embryo. Since after the blastoderm stage the primordial germ cells migrate anteriorly these data also indicate that the map in fact corresponds to the blastoderm stage and not to a later stage of development. The genital disc maps at a single median primordium anterior and ventral to the germ cells, the gonadal mesoderm is located anterior to the genital disc and also forms a single median primordium on the ventral side of the embryo. The primordia for the genital disc and the gonadal mesoderm are unusually large in size, which presumably reflects some indeterminacy of the cell lineage leading to an 'expansion' of the map.


Stage-sensitivity and dose-response curve of u.v. effect on germ cell formation in embryos of Xenopus laevis. Ultraviolet light (u.v.) irradiation of the vegetal hemisphere of Xenopus laevis eggs resulted in the elimination of primordial germ cells in tadpoles. Quantitative studies were performed on this phenomenon. The stage sensitivity to u.v. inactivation of germ cell formation was obtained for the early developmental stages ranging from immediately after fertilization to small-cell blastula. It was found that u.v. irradiation at the stage immediately after fertilization was more injurious than irradiation at the beginning of the first cleavage. After deciding optimal conditions for this u.v. irradiation experiment, a dose-response curve of the phenomenon was obtained. It showed a good agreement with the theoretical expectation, which the authors had previously presented.


[Quantitative aspects of the colonization of the gonads by germ cells in the quail embryo (Coturnix coturnix japonical)]. A quantitative analysis made on quail embryos coming from 13 isolated parent-couples reveals some significative variations of a genetic origin, between some of the offspring studied: the differences observed concern both the quantitative importance of the colonization of gonads by germ cells and the asymmetrical distribution of PGGs (primordial germ cells) between the two genital ridges. The chronological study of the colonization in the quail shows, as in both the duck and the chick, two periods of rapid and regular increase of the number of gonadic PGC, at stages from 13 to 18 and from 24 to 30 of Hamburger & Hamilton. The distribution of germ cells between the two genital ridges is, at the beginning of the colonization, not very asymmetrical. Between stages 18 and 24 the asymmetry increases and remains stable so that the mean value of D% (percentage of the number of PGC contained in the right gonad) from that moment on is equal to 29-34%. This value is specific for the quail embryo.


[Morphogenesis of the chick embryo foot as studied by Janus green B-induced malformations]. Janus green was injected into the amniotic sac of 6-5-day-old chick embryos at a single dose of 8-5 or 15 mug; the dye causes respectively 55 and 82% malformations of the feet. Toe are affected by partial or total soft tissue syndactyly, hypophalangy and infrequently by hyperphalangy. Lateral toes are more severely and more frequently affected by syndactyly and hypophalangy than medium ones. Hyperphalangy is found exclusively in toes I and II and causes the formation of one excess phalanx at most. Syndactylous toes are joined by an overdeveloped digital membrane. Hypophalangic toes have a truncated (non-pointed) distal tip. Two phalanges are lacking at most. These malformations are due to two distinct phases of the Janus green action. The first one, which is early and fast, inhibits interdigital programmed cell death, causing in term the non-regression of the interdigital membranes and thus syndactyly. The second one, which is late and slow, blocks the apical growth; this leads to hypophalangy.


Calcium transport in intact human erthrocytes. Intact human erythrocytes can be readily loaded with calcium by incubation in hypersomotic media at alkaline pH. Erythrocyte calcium content increases from 15-20 to 120-150 nmol/g hemoglobin after incubation for 2 h at 20 degree C in a 400 mosmol/kg, pH 7.8 solution containing 100 mM sodium chloride, 90 mM tetramethylammonium chloride, 1 mM potassium chloride, and 10 mM calcium chloride. Calcium uptake is a time-dependent process that is associated with an augmented efflux of potassium. The ATP content in these cells remains at more than 60% of normal and is not affected by calcium. Calcium uptake is influenced by the cationic composition of the external media. The response to potassium is diphasic. With increasing potassium concentrations, the net accumulation of calcium initially increases, becoming maximal at 1 mM potassium, then diminishes, falling below basal levels at concentrations above 3 mM potassium. Ouabain inhibits the stimulatory effect of low concentrations of potassium. The inhibitory effects of higher concentrations of potassium are ouabain insensitive and independent of the external calcium concentration. Sodium also inhibits calcium uptake but this inhibition can be modified by altering the external concentration of calcium. The effux of calcium from loaded erythrocytes is not significantly altered by changes in osmolality, medium ion composition, or ouabain. It is concluded that hypertonicity increases the net uptake of calcium by increasing the influx of calcium and that some part of the sodium potassium transport system is involved in this influx process.


Spectral relations of cone pigments in goldfish. Dark-adapted retinal cones of goldfish were measured microspectrophotometrically. The three types of spectra so obtained were subjected to a new method of data analysis. In order of types blue (B), green (G), and red (R), the best estimates for  lambdamax were 453, 533, and 620 nm; for main band half width, 6,700, 4,700, and 3,900 cm-1. The extinction spectra of 11-cis 3,4-dehydroretinal and those of the three goldfish pigments were progressively fitted with Gaussian curves starting at the low-energy end of their spectra. The sum of the oscillator strengths of the first three Gaussian components throughout the four spectra were found to have nearly equal magnitudes. Functional relationships that connect the Gaussian parameters were obtained by curve-fitting, enabling partial absorption spectra to be generated for any lambdamax. The generated curves predicted the half width and peak extinction of porphyropsin-type absorption spectra more accurately than previously existing nomograms or hypothesis. The epsilonmax values thus obtained were 28,500, 32,000, and 35,700 liter/mole cm for the B-, G-, and R-type goldfish pigments; these were found to be consistent with the experimental determinations of +/- 10% estimated accuracy.


Binding of tetrodotoxin to squid nerve fibers. Two kinds of receptors? The effect of tetrodotoxin on the sodium currents of the squid (Doryteuthis plei and Sepioteuthis sepiodea) giant axons was studied under potential control conditions. The axons were immersed in artificial seawater at 21 degrees C and pH 7.5. When the effect of the toxin is studied in concentrations ranging from 0.1 to 50 nM the Eadie-Haldane plot is not a straight line and indicates that there are two populations of sodium channels open during activity. 19.0 +/- 4.7% of the channels are accociated to receptors with an apparent dissociation constant of 0.11 +/- 0.05 nM and 84.0 +/- 4.1% of the channels are related to receptors having an affinity constant of 4.90 +/- 0.49 nM (nine nerves).


Intermittent meningitic reaction with severe basophilia and eosinophilia in CNS leukaemia. Light- and electron-microscope studies were performed on CSF cells from a patient with CNS leukaemia presenting with an intermittent meningitic reaction. Numerous fully matured basophilic and eosinophilic granulocytes with excess glycogen content accompained undifferentiated leukaemic blast cells in the CSF. Such a CSF cell reaction has not been previously reported. It is suggested that this isolated CSF reaction represents a special type of immediate hypersensitivity reaction triggered by an abnormal leukaemic giant cell clone, and mitigated by the accompanying eosinophilic granulocytes.


[Golgi-Cox study of the distribution of dendritic spines in the cerebral cortex of the kitten. Part 1. The first 15 days of the postnatal period]. In order to study quantitatively the development of dendritic spines of pyramidal neurones, the suprasylvian cortex of kittens (1 to 15 days of age) was fixed and embedded by the Golgi-Cox (Sholl) method. The spines seen at different cortical levels were counted to establish their distribution along apical and basal dendrites. Disposition of spine contacts varied during the first month of post-natal cortical development. three periods were established in relation to the morphological growth of neurones. The first period(days 6 to 9), showed better defined layers and differentiation of spines in areas of maximal density. The third period (days 10 to 15) was defined by a remarkable enlargment of cellular processes, neural stratification and spinal distribution comparable to that of adult animals, although with a smaller number of spines. It is concluded that the organization of dendritic spines is closely related to neuronal development, coinciding with the initiation of cortical afferent systems.


A method for estimating the refractory period of motor fibers in the human peripheral nerve. A simple method has been devised to measure the refractory period of motor fibers in man. With paired shocks of just maximal intensity, the second response of the pair was first elicited at an interstimulus interval of 1.00+/-0.20 msec (mean +/- SD in 24 ulnar nerves). With longer intervals there was progressive return of excitability until it recovered completely at 2.88+/-0.72 msec. When paired shocks of 50% supramaximal intensity were used, return of the second response was faster, beginning at 0.77+/-0.18 msec and achieving full recovery at 2.03+/-0.57 msec. The inpulse was conducted at a slower speed than normal, if transmitted at all, during the relative refractory period.


Postcritical-period reversal of effects of monocular deprivation on striate cortex cells in the cat. 1. The possibility that effects of monocular deprivation on cat striate cortex could be reversed after the developmental critical period by removal of the normal eye was investigated. In addition, the time course of any postcriticalperiod reversal was studied. Single-unit recording was conducted in the striate cortex of kittens anesthetized with nitrous oxide.2. Six control kittens were raised with monocular lid suture until they were 4-8 mo old (group MD). In agreement with previous investigators, from 0-10% of the striate cortex cells could be driven by visual stimulation of the deprived eye in these kittens.3. Eleven kittens were raised with monocular lid suture until they were 4-5 mo old, at which time the normal eye was enucleated. In five of these (group MD-DE-immediate), recording was conducted in striate cortex on the day of the enucleation. In these animals, 29-39% of the striate cortex cells could be driven by the deprived eye. In four kittens (group MD-DE-3 mo), the deprived eye remained closed for an additional 3 mo before recording was conducted. In these animals, 17-45% of the striate cortex cells could be driven by the deprived eye. In two kittens (group MD-DE greater than 12 mo), the deprived eye remained closed for 14-15 mo after the normal eye was enucleated. In these kittens, 26-40% of the striate cortex cells could be driven by the deprived eye. Thus, removal of the normal eye after the critical period in monocularly drprived kittens results in a rapid increase in the percent of striate cortex cells that can be driven by visual stimulation of the deprived eye, and there is no further increase in responsiveness over a period of more than a year.4. The receptive-field properties of the cells which responded to the deprived eye following enucleation of the normal eye were usually abnormal; 61% of them had nonspecific receptive fields, 39% of the responsive cells were direction selective, and only 12% were both direction and orientation selective.5. The increase in responsive cells was observed in the striate cortex of both hemispheres. However, the increase was greater in the hemisphere contralateral to the deprived eye. The responsive cells tended to occur in clusters of two to four adjacent cells separated by regions containing nonresponsive cells. These clusters were not related to the horizontal cortical layers; however, they may be related to the ocular dominance columns in striate cortex.6. Several mechanisms were considered for the present findings, including neuronal sprouting, denervation supersensitivity, and release from inhibition. It was suggested that the increased responsiveness to the deprived eye was probably not the result of rapid sprouting in the 4- to 5-mo-old kittens. If this is so, then the results indicate that functional connections from the deprived layers of the DLG to the striate cortex remain following rearing with monocular deprivation...


Receptive-field characteristics of neurons in cat striate cortex: Changes with visual field eccentricity. 1. Receptive-field properties of 214 neurons from cat striate cortex were studied with particular emphasis on:  a) classification, b) field size, c) orientation selectivity, d) direction selectivity, e) speed selectivity, and f) ocular dominance. We studied receptive fields located throughtout the visual field, including the monocular segment, to determine how receptivefield properties changed with eccentricity in the visual field.2. We classified 98 cells as "simple," 80 as "complex," 21 as "hypercomplex," and 15 in other categories. The proportion of complex cells relative to simple cells increased monotonically with receptive-field eccenticity.3. Direction selectivity and preferred orientation did not measurably change with eccentricity. Through most of the binocular segment, this was also true for ocular dominance; however, at the edge of the binocular segment, there were more fields dominated by the contralateral eye.4. Cells had larger receptive fields, less orientation selectivity, and higher preferred speeds with increasing eccentricity. However, these changes were considerably more pronounced for complex than for simple cells.5. These data suggest that simple and complex cells analyze different aspects of a visual stimulus, and we provide a hypothesis which suggests that simple cells analyze input typically from one (or a few) geniculate neurons, while complex cells receive input from a larger region of geniculate neurons. On average, this region is invariant with eccentricity and, due to a changing magnification factor, complex fields increase in size with eccentricity much more than do simple cells. For complex cells, computations of this geniculate region transformed to cortical space provide a cortical extent equal to the spread of pyramidal cell basal dendrites.


Changes in responses of medial pontomedullary reticular neurons during repetitive cutaneous, vestibular, cortical, and tectal stimulation. 1. In cats anesthetized with chloralose, responses of medial pontomedullary reticular neurons to stimulation of the body surface, vestibular nerves, superior colliculi, pericruciate cortices, cerebral peduncles, and spinal cord were studied at different stimulus rates. Raising the rate from 1/10 s to between 1/4 s and 2/s caused a significant decrement or increment in the response of most neurons tested. Response decrement typically began near the beginning of the higher frequency stimulus sequence and increased throughout the sequence. Response increment usually began somewhat later, rose to a peak, and then declined. Recovery from response decrement or increment usually occurred within 30-60 s at a 1/10 s stimulus rate.2. Measurements of response latency and of changes occurring in the initial and longer latency portions of responses indicated that all components of a response typically decreased or increased in parallel. Background spontaneous activity did not change during response decrements, but sometimes increased during response increment.3. Where changes could be detected, response decrement usually developed more rapidly when a sequence of repetitive stimulation was repeated.4. Response decrement was most pronounced at the highest stimulation rates and lowest stimulus intensities. Response increment was usually maximal at a stimulus rate of 1/s: at lower rates less increment occurred; at higher rates responses began to exhibit decrement.5. Response changes varied with the type of stimulus applied. Response decrements predominated when the body surface, vestibular nerves, or ipsilateral superior colliculus were stimulated. Approximately equal amounts of response increment and decrement were produced by repetitive stimulation of the cerebral peduncles and contralateral superior colliculus. Stimulation of the surface of the pericruciate cortex or of the spinal cord usually produced a long-lasting response increment.6. Generalization of response decrement and increment was observed in cases where trains of stimuli at a rate of 2/s applied to one point produced changes in the response to stimulation of another point which was tested once per 10 s and where single-shock stimulation of the first point was without effect on the test response. Generalization of response decrement occurred most often when two nearby points were stimulated. Generalization of response increment appeared to spread widely between distant cutaneous points and stimuli of different kinds.7. The response decrement and increment observed in medial pontomedullary reticular neurons displayed most of the parametric features of behavioral habituation and sensitization (8, 33) and therefore appear to represent neural analogs of these latter phenomena. The properties of response decrement suggest that it may occur to a large extent within afferent pathways leading to medial reticular neurons...


Dynamic response and transfer characteristics of joint neurons in somatosensory thalamus of the cat. 1. The dynamic response of neurons sensitive to knee joint rotation in the cat somatosensory thalamus was studied during sinusoidal variation of joint angle. The input sine waves were applied with a precise voltage-controlled, electromechanical actuator. The average rate of discharge of a single cell was considered as the output parameter. Describing functions of the sensory system were extracted by correlation and spectral analysis techniques. The effects of anesthetic, bias angle, and excursion angle were investigated. Discrete and swept sinusoidal waveforms between 0.1 and 7.0 Hz were used as inputs.2. The majority of joint cells in the thalamus were rapidly adapting and had frequency-response curves that were characterized as highpass filters. Although the major features of the response curves for individual cells were very similar, they could not all be fit with a single transfer function. The describing function of all the rapidly adapting cells averaged together was well fit by a transfer function that could be termed velocity sensitive in the bandwidth between 0.1 and 6.5 Hz. Most of these phasic cells showed a phase-locking tendency, particularly at high frequencies.3. The dynamics of the response for the rapidly adapting cells was relatively independent of anesthetic, bias angle, and excursion angle. Threshold and saturation effects were exhibited by some cells for very small (less than 1 degree) and large (greater than 10 degrees) input amplitudes, respectively. In addition a few (17%) showed a bidirectional response, i.e., responded at both flexion and extension of the limb. The anesthetic had a strong effect in depressing the spontaneous discharge of the cells and seemed to change the character of the tonic response by introducing a bursting component.4. The transfer characteristic of the thalamic cells was found to be a single-pole low-pass filter plus a time delay. The optimized value for the filter was found to have a corner frequency of 6.0 Hz with a time delay of 6 ms.5. Of the knee joint sensitive cells, 17% were slowly adapting or tonic, and more tonic cells were found in the unanesthetized animals. Only one tonic cell was studied in detail, and its dynamic characteristics were similar to that of the slowly adapting  joint receptors at low frequencies. In this respect the rapidly adapting and slowly adapting joint cells in the thalamus have strikingly different frequency-response curves, the former curves have a much steeper slope in the magnitude.6. The functional implications of these results and of other recent findings in relation to the probable role of joint receptors in mediating proprioception are discussed.


Receptive-field properties and neuronal connectivity in striate and parastriate cortex of contour-deprived cats. An attempt was made to relate the alterations of cortical receptive fields as they result from binocular visual deprivation to changes in afferent, intrinsic, and efferent connections of the striate and parastriate cortex. The experiments were performed in cats aged at least 1 jr with their eyelids sutured closed from birth. The results of the receptive-field analysis in A17 confirmed the reduction of light-responsive cells, the occasional incongruity of receptive-field properties in the two eyes, and to some extent also the loss of orientation and direction selectivity as reported previously. Other properties common to numerous deprived receptive fields were the lack of sharp inhibitory sidebands and the sometimes exceedingly large size of the receptive fields. Qualitatively as well as quantitatively, similar alterations were observed in area 18. A rather high percentage of cells in both areas had, however, preserved at least some orientation preference, and a few receptive fields had tuning properties comparable to those in normal cats. The ability of area 18 cells in normal cats to respond to much higher stimulus velocities than area 17 cells was not influenced by deprivation. The results obtained with electrical stimulation suggest two main deprivation effects: 1) A marked decrease in the safety factor of retinothalamic and thalamocortical transmission. 2) A clear decrease in efficiency of intracortical inhibition. But the electrical stimulation data also show that none of the basic principles of afferent, intrinsic, and efferent connectivity is lost or changed by deprivation. The conduction velocities in the subcortical afferents and the differentiation of the afferents to areas 17 and 18 into slow- and fast-conducting projection systems remain unaltered. Intrinsic excitatory connections remain functional; this is also true for the disynaptic inhibitory pathways activated preferentially by the fast-conducting thalamocortical projection. The laminar distribution of cells with monosynaptic versus polsynaptic excitatory connections is similar to that in normal cats. Neurons with corticofugal axons remain functionally connected and show the same connectivity pattern as those in normal cats. The nonspecific activation system from the mesencephalic reticular formation also remains functioning both at the thalamic and the cortical level. We conclude from these and several other observations that most, if not all, afferent, intrinsic, and efferent connections of areas 17 and 18 are specified from birth and depend only little on visual experience. This predetermined structural plan, however, allows for some freedom in the domain of orientation tuning, binocular correspondence, and retinotopy which is specified only when visual experience is possible.


Analysis of afferent responses from isolated semicircular canal of the guitarfish using rotational acceleration white-noise inputs. I. Correlation of response dynamics with receptor innervation. The small-signal linear characteristics of afferent responses from the isolated semicircular canal were described by the use of white-noise rotational acceleration inputs. The results, based on cross-correlation analysis, showed a striking and systematic variation in linear system impulse response characteristics from afferents which innervated different regions of the receptor. Afferents from centrally located nerve bundles innervating the crest region of the crista exhibited an initial maximum response amplitude followed by a rapid decay. In contrast, afferents from extreme rostral and caudal nerve bundles innervating the crista slopes exhibited an initial rise up to a low-amplitude maximum followed by a slower decay. These results imply that the afferents innervating a single canal do not merely carry redundant information concerning current head acceleration, but could be considered an ensemble of specific classes of filters that are tuned individually to specific classes of head movements. On the basis of these considerations, a new hypothesis of matched filter detection was proposed as relevant to information processing and dynamic control in central vestibular pathways.


Analysis of afferent responses from isolated semicircular canal of the guitarfish using rotational acceleration white-noise inputs. II. Estimation of linear system parameters and gain and phase spectra. Quantitative estimates were computed for exponential coefficients and rate constants contributing to afferent unit impulse responses obtained from bundles innervating specific regions of the semicircular canal. The grouping of these estimates into specific response classes provided quantitative correlations with specific anatomical regions of innervation of the crista. Linear system gain and phase spectra were computed also, by applying Fourier transformations to unit impulse responses, for purposes of comparison with previous studies employing frequency domain analyses. Responses fitted by third-order linear system equations were specific to afferents innervating the crest and transition regions of the crista; whereas those fitted by overdamped, second-order equations were specific to afferents innervating the slopes and transition crista regions. It was concluded that strictly mechanical models of the transduction process are inadequate to account for the diverse and spatially distributed classes of observed responses and, moreover, structural features such as different hair cell types or efferent innervation effects could be excluded as inoperative in this preparation. The alternative hypothesis was suggested that certain of the observed subcomponents could be direct  reflections of the initial mechanical stimulus, but that other subcomponents were reflections of more complex filtering mechanisms operating at the cellular or synaptic levels.


Neurosurgical materials and devices. Report on regulatory agencies and advisory groups. The current status of voluntary consensus standards writing procedures in neurosurgery and the current progress of government efforts to regulate materials and devices are described. A survey of the national and international standards writing bodies is presented, along with an introduction to related organizations and agencies and nomenclature. The intent of this review is to provide the neurosurgeon with a reference source regarding past and present neurosurgical activities in the materials and devices field. When President Ford signed the 1976 Medical Device Amendments on May 28, 1976, the Food and Drug Administration assumed direct legal authority to control medical devices and potentially assumed the power to regulate those professionals using them.


Microsurgical anatomy of the anterior cerebral-anterior communicating-recurrent artery complex. The microvascular relationships important to surgery of aneurysms in the anterior communicating region were defined in 50 cadaver brains. The recurrent artery of Heubner was frequently exposed before the A-1 segment in defining the neck on anterior cerebral aneurysms because it commonly courses anterior to A-1. It arose from the A-2 segment of the anterior cerebral artery (ACA) in 78% and most commonly terminated in the area of the anterior perforated substance, and lateral to it in the Sylvian fissure. The anterior communicating artery (ACoA) frequently gave rise to perforating arteries which terminated in the superior surface of the optic chiasm and above the chiasm in the anterior hypothalamus. This finding contrasts with previous reports that no perforating branches arise from the communicating artery. The proximal half of the A=1 segment was a richer source of perforating arteries than the distal half. The A-1 branches most commonly terminated in the anterior perforated substance, the optic chiasm, and the region of the optic tract. The ACoA increased in size as the difference in the diameter between the right and left A-1 segments increased. Frequent variants such as double or triple ACoA's, triple A-2 segments, and duplication of the A-1 segments were encountered. The clinical consequences of occlusion of the recurrent artery and of the perforators from the ACoA and medial and lateral segment of A-1 are reviewed.


Ependymomas and ependymoblastomas in children. The authors analyze histologically verified cases of ependymoma and ependymoblastoma (malignant ependymoma) occurring in children in Connecticut from 1935 to 1973. Of the 488 central nervous system tumors diagnosed in that period, 44 (9%) of the 467 intracranial neoplasms and five (24%) of the 21 intraspinal tumors were of ependymal origin. An increase in the incidence of ependymomas was noted since the mid-1950's. The mean ages at diagnosis of ependymomas and ependymoblastomas were 5.6 and 5.0 years respectively. The male to female ratio was 0.6:1 for ependymomas and 1.7:1 for ependymoblastomas. Epencymomas were found above and below the tentorium with similar frequency; however, viturally all of the epencymoblastomas occurred supratentorially. Presenting symptoms and physical findings were reviewed. A significant difference (p less than 0.05) was noted in the seizure rates of supratentorial ependymomas (9%) and ependymoblastomas (38%). A significantly increased survival (p less than 0.05) was associated with supratentorial ependymal neoplasms relative to infratentorial from 42 months following diagnosis onward. Contrary tp the reports of no clinical difference between ependymomas and ependymoblastomas, children with supratentorial ependymomas were noted to have a significantly longer survival (p less than 0.05) than those with similarly situated ependymoblastomas, with the difference noted from 18 months following diagnosis onward. The children treated by operation and irradiation had a significantly greater survival (p less than 0.05) than those treated by other methods; furthermore, with this treatment, longer survivals were noted in the ependymoma patients as compared to those with epencymoblastomas. This difference became significant (p less than 0.05) at 27 months after diagnosis. Operative mortality decreased from 40% to 17% in the last decade of the study as compared to the previous decade. Steroid therapy may have contributed to this decreased operative mortality, but it had no statistically significant effect on length of survival. The clinical course of intracranial ependymal neoplasms in adults and children was compared and appeared to be essentially the same.


Cerebral circulation after head injury. Part 2: The effects of traumatic brain edema. The authors have assessed the effects of subacute traumatic brain edema (BE) on cerebral circulation and metabolism, and on clinical outcome. Fifty-five severely injured, comatose, young patients who survived for more than 24 hours were studied on 78 occasions within 30 days of injury. After hematomas had been surgically evacuated, BE was diagnosed by radiological evidence of brain swelling, demonstrated by cerebral angiograms and ventriculograms. At identical levels of carbon dioxide pressure, intracranial pressure was significantly elevated in the Edema Group to twice the value in the No Edema Group (27.1 vs 14.1 torr). There were, however, no significant differences in cerebral perfusion pressure cerebral blood flow, resistance to blood flow, cerebral metabolic oxygen rate, ventricular cerebrospinal fluid acid-base, lactate, K+ or Na+ concentrations, or in clinical outcome. It is concluded that this type of subacute traumatic BE, which is significantly associated with surgical lesions, is not of major hemodynamic or clinical significance in intensively treated patients, and does not cause cerebral ischemia. Patient outcome is determined more by the severity of the initial diffuse cortical and subcortical injury than by the presence or absence of subacute BE.


Decadron in the treatment of cerebral abscess. An experimental study. Forty rabbits were inoculated with Streptococcus pyogenes or Staphylococcus aureus to produce cerebral abscesses. One-third of the rabbits received no treatment and served as controls. One-third received dexamethasone (Decadron) plus an appropriate antibiotic. One-third received only the appropriate antibiotic in the same dosage. The animals were sacrificed 10 days after inoculation and the brains examined. In the control group, an abscess at the stage of granulation tissue encapsulation containing the inoculated organisms was found. The surrounding brain showed a marked inflammatory response. In the Decadron plus antibiotic group, necrotic lesions were found containing the inoculated organisms and surrounded by relatively normal brain. In the group treated with antibiotic alone, healed glial scars were found in relatively normal brain. Our findings are discussed with reference to the medical literature regarding the influence of glucocorticoids on the inflammatory response and the efficacy of antibiotics when this response is suppressed.


Control of shunt infection. Report of 150 consecutive cases. The author analyzes 150 consecutive ventriculovenous, ventriculoperitoneal, and lumboperitoneal shunt procedures with particular attention to shunt colonization by Staphylococcus epidermidis. There was one primary infection with Staphylococcus epidermidis early in the series, and in two other cases, the organism was felt to be a secondary invader. In those procedures involving either primary placement or revision of a ventriculovenous shunt, there was not a single infection. The operative protocol that has virtually eliminated Staphylococcus epidermidis is outlined.


Mesencephalic spur (beaking deformity of the tectum) in Arnold-Chiari malformation. The beaking deformity of the tectum, referred to in this paper as the mesencephalic spur, is regularly present in the Type II variety of the Arnold-Chiari malformation in varying degrees of severity. When the mesencephalic spur is related to associated myelomeningocele, it was found that the more extensive the myelomeningocele, and the older the affected children, the more prominent was the mesencephalic spur.


Giant intracranial aneurysm associated with Marfan's syndrome. Case report. The authors describe a giant intracranial internal carotid aneurysm in a patient with Marfan's syndrome. Treatment consisted of internal carotid ligation with subsequent thrombosis of the lesion. The patient's course was complicated by carotid arterial dissection and possible laminar thrombosis within the aneurysm increasing the size of the lesion. Three clinical syndromes, Marfan's, Ehlers-Danlos, and pseudoxanthoma esasticum, are discussed. The literature is reviewed with reference to the hazards of treatment of vascular pathology in patients with these connective tissue disorders.


A comparison of the abilities of chlorpromazine and molindone to interact adversely with guanethidine. Chlorpromazine and molindone were tested for their abilities to impair conditioned avoidance behavior of rats. Chlorpromazine was effective within the dose range of 0.3 to 7.0 mg/kg (ID50approximately 2.0 mg/kg); molindone was effective within the range of 0.3 to 5.0 mg/kg (ID50 approximately 0.6 mg/kg). Behaviorally relevant doses of chlorpromazine and molindone were then tested for their effects on blood pressure and on adrenergic mechanisms. When given intravenously to anesthetized, hypertensive animals, both drugs (1.0 mg/kg) produced significant but transient vasodepression. When given intraperitoneally to anesthetized or to conscious hypertensive rats, the drugs did not produce significant effects on blood pressure. Both drugs (1.0 mg/kg) blocked responses to an alpha agonist (methoxamine), but chlorpromazine was significantly more potent than molindone. In addition, chlorpromazine produced a dose-dependent (1.0-10.0 mg/kg) inhibition of 3H-l-norepinephrine uptake into heart, but molindone at the same doses produced no inhibition of uptake. In related experiments, it was found that guanethidine (50 mg/kg) was an effective agent for lowering blood pressure of hypertensive rats. When chlorpromazine (3-10 mg/kg) was administered concomitantly with guanethidine, the blood pressure lowering properties of guanethidine were diminished or abolished. When molindone (1-10 mg/kg) was administered concomitantly with guanethidine, there was no loss of blood pressure control. It is concluded that molindone is an important drug, because it is an antipsychotic agent that does not interact adversely with guanethidine.


Stimulatory effect of vegetables on intestinal drug metabolism in the rat. The intestinal metabolism of hexobarbital, phenacetin, 7-ethoxycoumarin and benzo [a] pyrene in vitro was increased in rats fed either dried Brussels sprouts or dried cabbage in a nutritionally complete semisynthetic diet as compared to rats fed only the semisynthetic diet. Pretreatment of rats with several indoles present in Brussels sprouts and cabbage also stimulated intestinal drug metabolism, but the effect was smaller than when dried Brussels sprouts or dried cabbage was fed. The results obtained suggest a need for studies in man to determine whether vegetables and other dietary constituents can stimulate the intestinal metabolism of drugs and thereby alter their biological effects.


Effect of route of administration on competitive drug biotransformation interaction: salicylamide-ascorbic acid interaction in rats. The effect of route of administration on competitive drug biotransformation interactions was explored with respect to the interaction between salicylamide and ascorbic acid. Previous studies in man have shown that this interaction involves competition for available sulfate and consequent inhibition of drug sulfate formation. Adult rats received salicylamide (100 mg/kg i.v. or 500 mg/kg orally) alone or with ascorbic acid (500 mg/kg i.v. or orally). Plasma concentrations and urinary excretion rates of salicylamide, salicylamide glucuronide and salicylamide sulfate were determined as a function of time. With i.v. salicylamide, i.v. ascorbic acid caused a modest decrease of salicylamide sulfate formation and thereby of salicylamide body clearance. Orally administered vitamin had a somewhat more pronounced effect. The vitamin had no effect on the apparent volume of distribution of salicylamide and on the renal clearances of its conjugates. With orally administered salicylamide, oral ascorbic acid caused a very pronounced decrease of salicylamide sulfate formation and salicylamide body clearance, whereas intravenous vitamin had little or no effect. These observations are consistent with the assumption that the magnitude of competitive drug biotransformation interactions, being a function of concentration, is most pronounced when the interactants are co-administered orally, due to their high concentrations in the intestinal wall and liver during the first pass.


Ascorbic acid and hepatic drug metabolism. Previous in vivo studies indicate that hepatic microsomal drug metabolism decreases in ascorbic acid deficiency and is augmented when high supplements of the vitamin are given to guinea pigs. Kinetic studies with O-demethylase indicate no significant change in the apparent Km of p-nitroanisole in normal, ascorbic acid-deficient animals, or in animals given high supplements of ascorbic acid. The decrease in drug metabolism activity caused by ascorbic acid deficiency is not due to increased lipid peroxidation, nor was phosphatidyl choline significantly altered quantitatively or qualitatively in microsomes from ascorbic acid-deficient animals. Microsomal cytochrome P-450 prepared from ascorbic acid-deficient livers is less stable to sonication, dialysis and treatment with metal chelators. The decrease in cytochrome P-450 and O-demethylase activity associated with dialysis could be prevented by the addition of ascorbic acid. The molar ratio of microsomal ascorbic acid to cytochrome P-450 (plus P-420) is in the order of 2:1. This ratio is maintained during ascorbic acid deficiency in liver and adrenal tissue, during dialysis, on storage and with a partial purification of the cytochrome, which suggests a close association between ascorbic acid and the cytochrome. In addition, ascorbic acid protects cytochrome P-450 and aniline hydroxy lase activity from inhibition by ferrous iron chelators such as alpha, alpha'-dipyridyl. The chelator binds to cytochrome P-450 and prevents formation of the reduced cytochrome P-450-CO spectrum; it in turn gives a reduced spectrum with the cytochrome at 450 nm. These studies suggest that there is an interaction between ascorbic acid and cytochrome P-450 involving the reduced form of the heme iron.


Effects of desipramine treatment on the biliary, fecal and urinary excretion of methadone in the rat. The effects of desipramine (DMI) given i.p. 1 hour before administration of 14C-methadone (5 mg/kg s.c.) on the excretion of methadone in bile, feces and urine were studied. Rats with cannulated bile ducts excreted 52% of administered 14C into bile within 4 hours, 60% of the excretion as 2-ethylidine-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP) and 30% as water-soluble metabolite (WSM). The percentages of 14C excreted within 48 hours into the feces and urine of rats without biliary fistula were 60.6 and 17.4%, respectively. The excretion of 14C in feces consisted mostly of EDDP. Urinary excretion consisted of unchanged methadone, EDDP and WSM in the first 12 hours and consisted mostly of WSM thereafter. DMI treatment increased biliary flow but decreased the biliary excretion of 14C, mainly by a decrease in WSM. The fecal output was greatly decreased by DMI, thus decreasing fecal excretion of 14C in the first 12 hours. DMI treatment markedly decreased urinary volume but did not change the urine pH. The decreased urinary excretion of WSM in DMI-treated rats during the first 12-hour urine sample accounted for most of the decreased elimination of 14C. It is suggested that DMI-induced inhibition of methadone metabolism in the liver is a major factor responsible for the observed decreases in the biliary and urinary excretion of WSM...


A comparative study of the analgesic and respiratory effects of N-allylnorcodeine (nalodeine), nalorphine, codeine and morphine. In this comparative study, the abdominal constriction test was used to determine analgesia in mice, and the body plethysmograph was used to study respiratory effects of nalodeine, nalorphine, naloxone, codeine, morphine and various agonist-antagonist combinations in rats. The analgesia dose-response curves for the surrogate pairs, nalodeine-nalorphine and codeine-morphine, were parallel but had significantly different slopes. Naloxone was a more potent antagonist of morphine and codeine than of nalorphine and nalodeine. In antagonizing morphine and codeine analgesia, naloxone was the most potent antagonist, nalorphine had a biphasic effect with decreasing activity at higher doses and nalodeine was not an antagonist. Moderate doses of nalorphrine depressed minute volume largely by their effect on tidal volume, but high doses stimulated respiratory rate and therefore had less effect on minute volume. Nalodeine depressed minute volume by depressing tidal volume, since all doses initially stimulated and then variably affected respiratory rate. Metabolic rate was not increased by either drug short of convulsant doses. Nalodeine depresses the ventilatory response to CO2 and weakly antagonizes the respiratory depressant actions of morphine.


Acute reductions in serum testosterone levels by narcotics in the male rat: stereospecificity, blockade by naloxone and tolerance. The effects of a single injection of morphine (20 mg/kg) on serum testosterone levels were examined in the male rat. Within 2 hours after the morphine injection, testosterone levels were significantly lower than control levels. The decline in testosterone levels reached a maximum 4 hours after the administration of morphine, at which time testosterone levels were reduced by more than 85% with respect to controls. The ability of a large number of narcotics to depress serum testosterone levels, 4 hours after their administration, was also examined. All narcotics depressed testosterone levels significantly and their potency relative to morphine was comparable to that observed in several other preparations, such as the guinea-pig ileum and mouse vas deferens. The testosterone-depleting effects of the narcotics appear to represent specific narcotic effects since the (-)-isomers of the narcotics were considerably more potent than the (+)-isomers, naloxone competitively inhibited the effects of morphine on testosterone levels and tolerance developed to the testosterone-depleting effects of these drugs. Acute treatment with morphine also lowered serum luteinizing hormone levels, and this reduction preceded the fall in testosterone levels by 1 to 2 hours.


Influence of inhibitors of prostaglandin synthesis on venoconstrictor responses to bradykinin. The interrelationship between prostaglandins (PGs) and bradykinin (BK) was studied in isolated canine saphenous veins. The hypothesis that PGs mediate the venoconstrictor effect of bradykinin was evaluated by determining the influence of low concentrations of indomethacin (Indo) (1 muM) or eicosa-5,8,11,14-tetraynoic acid (ETA) (3 muM), two inhibitors of PG synthesis, on cumulative concentration-response curves for BK or norepinephrine (NE). In the tissue bath, responses to BK improved with time while responses to NE did not vary. When strips were least responsive to BK, Indo and ETA enhanced these responses. When strips were most responsive to BK, neither inhibitor enhanced the responses. Neither Indo nor ETA altered responses to NE. Phentolamine (10(-8) M) did not alter responses to BK. These data suggest that endogenous PGs act to attenuate, rather than mediate, the venoconstrictor response to BK. Progressive enhancement of responses to BK of untreated saphenous vein strips is associated with a decreased ability of inhibitors of PG synthesis to enhance those responses also. Thus, there may be a time-related decrease in the ability of this preparation to synthesize PGs. From the present results, it cannot be determined whether saphenous veins in vivo are highly responsive or relatively unresponsive to the peptide. However, these data do suggest that PGs are a determinant of venous responsiveness to BK.


Effect of alpha and beta adrenergic blockade on oxygen transport in rat skeletal muscle and brain. The effects of phenoxybenzamine HCl and propranolol HCl, 2 mg/kg, on tissue oxygen tension (PO2), perfusion and small vessel blood content of the cerebral cortex and biceps brachii muscle of anesthetized rats were determined. Perfusion and PO2 were measured polarographically and small vessel blood content was measured with 59Fe-siderophilin-labeled blood. Under control conditions PO2, perfusion and small vessel blood content averaged 15.1 mm Hg., 15.6 ml/min/100 g and 0.91 ml/100 g in brain and 15.6 mm Hg, 13.1 ml/min/100 g and 1.63 ml/100 g in muscle. After phenoxybenzamine adminstration, there was a significant increase in muscle perfusion (17.4%) and decrease in cortical PO2 (9.2%). No other factors changed significantly. Propranolol caused no significant changes in any of the above factors. Arteriolar resistance in skeletal muscle decreased after phenoxybenzamine. Small vessel blood content measurements (an estimate of open capillary density) indicate no effects on precapillary sphincters with either agent. Since some changes in metabolism were indicated with these agents, regional oxygen consumption was calculated from this data.


The isolated supported canine heart: a model for the evaluation of drug effects on regional myocardial blood flow. The effect of independently varying heart rate, left ventricular systolic pressure, coronary blood flow or coronary artery perfusion pressure on the transmural distribution of myocardial blood flow was determined in the isolated supported dog heart preparation by use of radioactive microspheres. The distribution of radioactivity was expressed as the epicardial/endocardial blood flow ratio (epi/endo). At a constant coronary blood flow, increases in heart rate (111-250 beats/min) or decreases in coronary artery perfusion pressure (100-46 mm Hg) resulted in an elevation of epi/endo (0.64 to 1.12 and 0.71 to 1.41, respectively). Increasing coronary artery perfusion pressure (40-130 mm Hg) and coronary blood flow from low values resulted in a decreased epi/endo (1.28 to 0.76). The absolute level of coronary blood flow had no direct effect on epi/endo but acted through changes in coronary artery perfusion pressure. The major physiological determinants of intramyocardial blood flow distribution in the isolated dog heart are coronary artery perfusion pressure and heart rate, whereas left ventricular systolic pressure and coronary blood flow are of minor importance. An equation was developed relating the mean epi/endo of the left ventricle to hemodynamic factors studied, and a highly significant correlation was found between predicted and experimental ratios. These results indicate the potential usefulness of this model for predicting epicardial-endocardial blood flow ratios based upon drug-induced changes in hemodynamic parameters.


Effect of propranolol on regional myocardial blood flow and oxygen consumption. The present investigation was designed to determine the effect of propranolol on regional myocardial blood flow and oxygen consumption (MVO2) in the isolated supported dog heart preparation perfused at a constant coronary blood flow. The transmural distribution of blood flow, determined by the radioactive microsphere technique, was expressed as the epicardial/endocardial blood flow ratio (epi/endo). Propranolol (0.5 mg/kg i.v.) produced a significant decrease in heart rate and myocardial contractile force and an increase in coronary artery perfusion pressure due to an increase in coronary vascular resistance. These hemodynamic changes were accompanied by significant decreases in epi/endo (increased endocardial perfusion) and MVO2. Reduction of perfusion pressure to control by a decrease in total coronary blood flow produced no further change in epi/endo or MVO2. However, increasing heart rate to control increased epi/endo to predrug levels. Contractile force and MVO2 remained reduced below control. Norepinephrine infusion (1 mug/min intracoronary) produced a significant increase in heart rate and contractile force and decrease in perfusion pressure. These changes were accompanied by an increase in epi/endo and MVO2. Propranolol (0.5 mg/kg i.v.) abolished the response to norepinephrine. Propranolol may produce beneficial effects in angina pectoris by a decrease in epi/endo (via a reduction in heart rate) and MVO2 and by beta adrenergic blockade of the deleterious effects of catecholamines.


Effects of calcium antagonist, 6-(N, N-diethylamino) hexyl-3, 4, 5-trimethoxybenzoate, on digitalis-induced arrhythmias and cardiac contractions. 6-(N, N-Diethylamino) hexyl-3, 4, 5-trimethylbenzoate (TMB-6) and lidocaine were equipotent (1 mg/kg) in the conversion of ectopic rhythms to normal rhythms in digoxin-toxic dogs. However, TMB-6 had fewer side effects on heart rates and dp/dt than lidocaine. TMB-6 inhibited the contractile force of electrically stimulated dog and guinea-pig atria and ventricles at concentrations ranging from 2.5 X 10(-5) to 1.7 X 10(-4) M. Elevation of extracellular Ca++ concentrations from 2.7 to 5.4 mM produced a significant increase in the ID50 of TMB-6 in atria (from 2.5 X 10(-5) to 5.0 X 10(-5) M in dogs and from 7.2 X 10(-5) to 1.0 X 10(-4) M in guinea pigs). TMB-6 (7.3 X 10(-5) to 2.4 X 10(-4) M) depressed the amplitude of Ca++-dependent action potentials in depolarized dog cardiac Purkinje fibers. These results are discussed with regard to the antagonism of TMB-6 on Ca++ availability in the myocardium which leads to the conversion of cardiac arrhythmias.


Organ specificity of angiotensin II and Des-aspartyl angiotensin II in the conscious rat. Des-Asp angiotensin II (des-Asp AII) is a naturally occurring heptapeptide metabolite of angiotensin II (AII) which is formed by the enzymatic action of aminopeptidase A. Angiotensin II and des-Asp AII were infused into unanesthetized rats while direct mean arterial pressure, serum aldosterone and serum corticosterone were measured. Both AII and des-Asp AII caused a dose-related increase in serum aldosterone with a significant increase occurring with a dose as low as 1 ng/min. This effect was blocked by pretreatment with 1-Sar-8-Ala-angiotensin II, a competitive inhibitor of AII; however, the inhibitor was more effective in blocking the effects of AII (101%) than of des-Asp AII (82%). Both angiotensins induced a dose-related increase in serum corticosterone and mean arterial pressure. Des-Asp AII was however only 1/10 as potent as AII in elevating mean arterial pressure. 1-Sar-8-Ala-AII was also  effective in inhibiting the pressor effects of AII and des-Asp AII. These data illustrate a high degree of organ specificity or selectivity for des-Asp AII and a low specificity for AII. Aminopeptidase A and leucine aminopeptidase were identified in the adrenal cortex and medulla in large amounts. Des-Asp AII may thus be formed from AII locally in the adrenal gland prior to exerting its action at that site.


The effect of indomethacin on renal function in pentobarbital-anesthetized dogs. The effects of indomethacin, an inhibitor of prostaglandin synthesis, on renal blood flow, glomerular filtration rate, urine flow and excretion of sodium and potassium were studied in the anesthetized dog. Indomethacin, 2.5 mg/kg i.v., decreased renal blood flow but increased aortic pressure and calculated renal vascular resistance. Glomerular filtration rate was not influenced by the synthetase inhibitor. Sodium excretion was decreased and para-aminohippurate extraction was increased after administration of indomethacin. Transient decreases in urine flow and potassium excretion were observed; however, both parameters returned to control value 75 minutes after administration of indomethacin. The early decrease in urine flow rate correlated closely with the decrease in sodium excretion. These data suggest that in the anesthetized dog, endogenous prostaglandins may serve to maintain renal blood flow but not glomerular filtration rate. Under the conditions of the present experiments, sodium excretion and to a lesser extent potassium excretion have been suggested as being dependent on prostaglandin synthesis.


Effects of anti-inflammatory agents and some other drugs on prostaglandin biotransport. The inhibitory effects of drugs on prostaglandin biotransport were studied by measuring the concentrative accumulation of 3H by rabbit choroid plexuses, segments of anterior uvea and kidney cortex slices after incubation in tissue culture medium containing 3H-prostaglandin F2 alpha. After 10 minutes of incubation in the absence of an inhibitor, the choroid plexus showed a tissue/medium 3H accumulation ratio of 14 +/- 0.7; after 30 minutes of incubation, the anterior uvea and the kidney cortex slices showed accumulation ratios of 6.4 +/- 0.5 and 5.6 +/- 0.1, respectively. The I50 values for inhibition of 3H accumulation by indomethacin were 10, 8 and 12 muM for the three tissues, respectively. Some related drugs-oxyphenbutazone, D-naproxen, l-naproxen, ibuprofen, phenylbutazone and pirprofen-were also found to be effective inhibitors of 3H accumulation (I50 for anterior uvea, 6-28 muM) whereas aspirin, dexamethasone phosphate and penicillin had an inhibitory effect only at much higher concentrations (I50 0.1-2.0 mM). Papaverine, fursemide and probenecid were approximately as effective as the anti-inflammatory organic acids (I50 0.01-0.1 mM), whereas bromcresol green was at least 10-fold more effective. Diphenhydramine and the nonacidic prostaglandin synthesis inhibitors, phenelzine and paracetamol, showed little (I50 greater than 1 mM) or no inhibitory effect. The inhibition of this transport system by some drugs, most notably nonsteroidal anti-inflammatory organic acids, and consequent alterations in the distribution and disposition of prostaglandins must be taken into account in the development of new anti-inflammatory agents and in the interpretation of the mechansim of action and side effects of such drugs.


Effects of prostaglandins A2, E2 and F2 alpha on erythropoietin production. The erythropoietic effects of the renal prostaglandins were investigated in exhypoxic polycythemic mice and in isolated perfused dog kidneys. Prostaglandins A2 and E2 in a dose range of 100 to 800 mug/kg b.wt. were found to produce a dose-related increase in radioactive iron incorporation in red cells. Prostaglandin F2 alpha was devoid of an erythropoietic effect in polycythemic mice. In that PGE2 is the principal renal prostaglandin, PGE2 (0.5 mug/min) or saline was infused into isolated perfused dog kidneys that had been programmed by prior exposure to hypoxia (0.42 atm) for 4 hours. PGE2-infused kidneys during 5 hours of perfusion with blood from nonhypoxic donor dogs produced significant increases in perfusate titers of erythropoietin when compared with that of saline infusion controls at the same time intervals. These data suggest an involvement of the renal prostaglandin PGE2 in erythropoietin production by the kidney.


A computer program for parallel line bioassays. PARLIN is a program for the statistical analysis of biological assays that are either completely randomized, or in randomized blocks, in which the regression on log dose is linear with a constant variance per response. An earlier program (McArthur et al., J. Pharmacol. Exp. Ther. 153: 573-580, 1966) has been completely rewritten, improved and extended in its facilities. PARLIN, written in FORTRAN IV, will handle up to 99 test preparations, up to 100 doses in all, and up to 50 responses per dose. It is designed with special attention to simplicity for routine use, versatility of facilities and output immediately available for all forms of reporting results. A wide choice of transformations of response is available. The output reproduces the data for verification and tabulates potency estimates with limits at probabilities .95, .99; optional output includes an analysis of variance, information on validity, values of residuals and a rough plot of the dose-response relation.


Endogenous prostaglandins as local regulators of blood flow in man: effect of indomethacin on reactive and functional hyperaemia. 1. The contribution of endogenously formed prostaglandins of the E series (PGE) to the development of reactive and functional hyperaemia was studied in the human forearm. 2. Forearm blood flow was recorded using venous occlusion plethysmography. The concentration of prostaglandin E-like substances (PLS) in the venous effluent from the muscle was analysed using bio-assay. For inhibition of PG biosynthesis, indomethacin (1-25 mg/kg body weight) was administered. 3. Following 5 min of arterial occlusion, a marked hyperaemia developed during the next 150 sec. Indomethacin, while not affecting the resting arterial blood flow, significantly decreased the peak level as well as the duration of the hyperaemia. The total reactive hyperaemia was 25 ml./100 ml. tissue before, and 13 ml./100 ml. tissue after administration of indomethacin. 4. During sustained isometric forearm contraction, and following isometric and dynamic forearm muscle activity, a moderate hyperaemia was observed. This was significantly diminished when indomethacin had been administered, although not to the same extent as the reactive hyperaemia. The total hyperaemia in the absence and presence of indomethacin was 113 and 77 ml./100 ml. tissue, respectively, in connexion with isometric contraction and 206 and 120 ml./100 ml. tissue, respectively, following dynamic work. 5. The venous concentration of PLS was very low at rest. A significantly increased concentration was observed after ischaemia. This increased release of PLS was entirely suppressed by indomethacin. With the present assay method, muscular activity elicited no detectable change in the venous concentration of PLS. 6. It is concluded that reactive hyperaemia depends to a considerable extent on an intact PGE synthesis. It is furthermore suggested that endogenous PGE may contribute to the functional hyperaemia that appears during and after muscle activity.


The regulation of cellular volume in renal cortical slices incubated in hyposmotic medium. 1. Changes in water and ion contents of renal cortical slices from rat, rabbit and guinea-pig incubated in medium of a half normal osmolarity were followed over 60 min incubation at 25 degrees C.2. Metabolizing slices gained water and lost sodium and chloride but not potassium. These changes reflected in part changes in cellular composition, and were complete within 5 min. A new steady-state was then maintained for a further 55 min.3. Slices initially incubated for 60 min with ouabain, also lost sodium and chloride when transferred to the hyposmotic medium but did not, in the first minutes, lose any further potassium. Ouabain, in concentrations sufficient to produce maximal inhibition of the Na-K ATPase, did not cause additional cellular swelling in the hyposmotic medium.4. The results offer no support for the claim that cellular volume in metabolizing renal cortical cells exposed to hyposmotic media is regulated by loss of cellular potassium. They suggest that under such conditions the regulation of volume involves the same ouabain-insensitive mechanism as is seen in cells incubated in isosmotic medium.


Kittens reared in a unidirectional environment: evidence for a critical period. 1. Kittens were reared in the dark from birth except for a period each day when they were put inside a stationary transparent cylinder, around which a drum with vertical black and white stripes on the inside, rotated in one direction. After the end of the period of exposure, we recorded a sample of single cells from their visual cortices, and analysed each cell for direction and orientation sensitivity and other properties. 2. Two kittens were placed inside the drum, rotating rightward, for 2 hr each seekday from 3 1/2 to 7 weeks of age. A greater proportion of the directionally sensitive cells in their cortices showed a preference for rightward movement. 3. Six other kittens were placed inside the drug for 1 hr each weekday from 2 to 12 weeks of age with the drum rotating leftward up to a particular changeover age, then rightward until 12 weeks. The changeover point occurred at 21, 26, 28, 33, 35 and 51 days for different kittens. A changeover earlier than 4 weeks of age led to a preponderance of cells preferring rightward movement. A changeover later than 5 weeks of age led to a preponderance of cells preferring leftward movement. Comparison of these results with others on monocular deprivation suggests that the peak of the critical period for directional deprivation may occur earlier than the peak of the critical period for monocular deprivation. 4. None of the samples of cells showed a preponderance of cells specific for vertical orientations. It is unclear whether this negative effect resulted from the presence of some horizontal contours during exposure, or some more fundamental cause.


Spontaneous activity in denervated mouse diaphragm muscle. Intracellular electrodes were used to study the discrete depolarizations which trigger fibrillation potentials in chronically denervated mouse diaphragm muscles. Provided that the muscles were perfused on both sides spontaneous activity was maintained in vitro. 2. Discrete spontaneous depolarizations, present only in the centre of the muscle, were recorded from the third day of denervation reaching a maximum in prevalence 9-12 days after sectioning the nerve. These potentials had random occurrence and nearly constant amplitude and frequency within a fibre, dependence of amplitude and frequency on membrane potential, and low temperature dependence. 3. The spontaneous activity was enhanced and could be initiated in previously quiescent fibres by lowering the external Ca concentration. The activity was reduced by increasing external Ca and was abolished at 15mM-[Ca] 0. Tetrodotoxin (10-(7)M) blocked spontaneous activity. 4. The spontaneous activity was enhanced by the catecholamines isoprenaline and adrenaline (0.5-10 mug/ml.). This effect of isoprenaline was accompanied by an increase in the rate of rise and the amount of overshoot of the action potential. 5. Ouabain (10-(6)-10-(4)M) of K+-free solutions reversibly blocked spontaneous activity. Ouabain (10-(4)M) reduced the rate of rise and the amount of overshoot of the action potential. 6. Detubulation of muscle fibres with glycerol of the presence of hypertonic solutions abolished spontaneous activity which could not be restarted by reducing Ca or by the addition of isoprenaline. 7. The results support the suggestion that the spontaneous discrete depolarizations which give rise to fibrillation potentials in denervated muscle result from regenerative sodium conductance increases within the transverse tubular system of the muscle fibres. Catecholamines and ouabain could affect this activity either directly, through an action on membrane excitability, or indirectly via the Na+-K+ pump.


The distribution of blood flow between individual muscles and non-muscular tissues in the hind limb of the young ox (Bos taurus): values at thermoneurality and during exposuer to cold. 1. The radioactive microspheres method was used to measure the distribution of blood flow in the hind leg in conscious young steers exposed to thermoneutral and moderately cold environments. Simultaneous measurement of total leg blood flow allowed calculation of blood flow (ml. 100 g tissue-1 min-1) to individual muscles and the major non-muscular tissues in the leg. 2. In the thermoneutral environment, leg blood flow was distributed approximately according to tissue weight, so that about 65% went to muscle and the remainder to bone, skin, connective tissue and fat; 1-7-11-5% of the injected dose of microspheres was found in the lungs, indicating the presence of functioning arteriovenous anastomoses in the leg. 3. During cold exposure leg blood flow increased two-and-a-half fold and 91% of this increase was due to increased blood flow in muscle. This was accompanied by substantial decreases in both total and capillary blood flow in leg skin in three of the four animals. 4. Values for resting tissue blood flow to the six largest individual leg muscles were compared, as well as that for tissue blood flow to the remaining leg muscle. Blood flow in the three large upper thigh muscles (biceps femoris, semimembranosus and semitendinosus) was about half that in muscles in the rest of the leg. 5. Cold exposure caused a threefold increase in total leg muscle blood flow, but the only individual muscles to respond substantially in all four animals were the vastus lateralis and the rectus femoris. Comparison of results from individual animals suggested a relation between total leg blood flow and the number of muscles (apart from vastus lateralis and rectus femoris) involved in shivering. Leg adipose tissue blood flow also increased significantly in the cold.


Measurement of potassium and chloride ion concentrations in the cupulae of the lateral lines of Xenopus laevis. 1. Potential measurements were made with double barrel ion selective electrodes from the cupulae of lateral line organs in the aquatic toad Xenopus laevis. 2. A positive endocupular potential (ECP) of 15-50 mV was recorded within the cupula, immediately above the hair cells. 3. Increases in the Cl- and K+ potentials were recorded when the ion selective electrodes touched the cupula. Cupular Cl- and K+ varied between 35 and 70 mM and 24 and 100 mM respectively. This variation existed between, rather than within, different animals. 4. Subcutaneous injections of 0-4 ml. 2 mM ouabain greatly reduced the ECP and cupular K+, whereas 0-4 ml. of Xenopus Ringer had no effect. 5. Changing the bath Cl- a hundredfold had no effect on the ECP. It was concluded that the ECP was produced by an electrogenic K+ pump which maintained high K+ levels within the cupula.


Inhibition by efferent nerve fibres: action on hair cells and afferent synaptic transmission in the lateral line canal organ of the burbot Lota lota. 1. Intracellular recordings were made from morphologically identified hair cells in the lateral line canal organs of the burbot Lota lota. 2. I.p.s.p.s were recorded from hair cells when the efferent fibres were excited by electrical stimulation of the lateral line nerve. The i.p.s.p.s were abolished when the fish was injected with immobilizing concentration of Flaxedil which is known to block the efferent synapses. 3. The i.p.s.p.s are accompanied by a decrease in the resistance of the hair cell membrane and an increase in the intracellular receptor potential. 4. Spontaneous and mechanically evoked e.p.s.p.s which were recorded intracellularly from the post-synaptic afferent nerve terminals were reduced in amplitude for the duration of the i.p.s.p.


Evaluation of the quality of hospital care for major trauma. A retrospective analysis of trauma care in five hospitals was undertaken. Eight hundred twenty-three charts met criteria for major trauma. A panel of surgeons reviewing 237 selected charts found the quality of care unacceptable in 16%. Unacceptability rates between hospitals ranged from 7 to 58%. Injury severity score rather than length of stay appears to be a better method for selecting patients at greater risk for poor care.


A time-management study of 25 patients with penetrating wounds of the chest and abdomen. The present study prospectively reviewed the time management aspects of 25 patients with penetrating wounds of the chest or abdomen. Each diagnostic procedure or treatment carried out on each patient was recorded to the nearest minute after his arrival in the emergency department. This generated median elapsed times for procedures which could be compared (4+ minutes for starting an IV, 9 minutes for insertion of CVP, 31 minutes for insertion of a chest tube). Two of the 25 patients died; 20 were admitted of whom 8 required immediate surgery. Some preocedures carried out in the accident room were done indiscriminately and for questionable reasons. The tendency was to do as much as possible to "cover" the patient. Some redundancy in the acutely ill patient is desirable but the overtreatment in some cases may have reflected inexperience of some of the physicians. Delay in using radiography and defects in professional coverage appeared to be the most serious errors. Independent monitoring of the functioning of the accident room appears to be an affective means of self-evaluation.


Rupture of the diaphragm caused by blunt trauma. Our experience with 27 patients who sustained traumatic laceration of the diaphragm caused by blunt forces is described. Automobile accident were the most frequent cause of rupture and young adult males the most vulnerable. The left hemidiaphragm is most frequently injured, but with sufficient force significant tears in the right hemidiaphragm will occur. Most of these patients sustained injury to multiple organ systems. The preoperative diagnosis of traumatic diaphragmatic hernia is based on a high index of suspicion, close and continued observation of the patient, and correct interpretation of roentgenograms of the chest. The mortality rate is high, owing to the magnitude of the injuries.


The inadequacy of peritoneal lavage in diagnosing acute diaphragmatic rupture. Thirty-eight patients with acute diaphragmatic rupture secondary to blunt trauma have been reviewed. Peritoneal lavage is diagnostically inexact in patients with diaphragmatic rupture. One-fourth of the patients had falsely negative peritoneal lavages during their initial evaluation. All four patients without associated intra-abdominal injuries had falsely negative peritoneal lavages, as did four of 30 patients (13%) with significantly associated intra-abdominal injuries. We conclude from these data that: 1) peritoneal lavage is falsely negative in patients with isolated diaphragmatic rupture; 2) positive peritoneal lavage in patients with diaphragmatic rupture results from associated intra-abdominal injuries; and 3) peritoneal lavage may be falsely negative despite significant intra-abdominal injuries; because of herniation of injured organ(s) into the thoracic cavity, thus bleeding is excluded from the peritoneal cavity.


Pulmonary function in patients with multiple trauma and associated severe head injury. 1) Sodium and water balance and pulmonary function studies were obtained in five patients with multiple injuries, including pulmonary contusion, plus severe intracranial trauma. All patients received dexamethasone, 4-6 every 6 hours during the 72-hour study period after injury. 2) Results were compared with those from 14 previously reported patients without head injury; none had received corticosteroids. 3) Study patients with head injury achieved negative water balance and almost-zero sodium balance within 72 hours of injury be excreting a high-volume, low-sodium urine. Despite elevated alveolar-arterial oxygen gradients and low-normal pulmonary compliance initially, there was progressive improvement and no patient developed post-traumatic pulmonary insufficiency. 4) The data suggest that the "negative" effects of major intracranial trauma on the kidney, heart, and lung are cancelled by dexamethasone, or that corticosteroids protect pulmonary function in the patient with multiple injuries and prevent post-traumatic pulmonary insufficiency, perhaps through their effect on the kidney leading to rapid restoration of sodium and water balance.


Violent injuries to the upper ureter.

Violent injuries to the upper ureter. Frequently traumatic injury to the renal pelvis or upper ureter is overshadowed by multiple associated injuries. The diagnosis may be particularly difficult, due to the lack of hematuria and absence of pathognomonic findings. All too frequently the delayed manifestations of urinary wound drainage, retroperitoneal mass, or urinary ascites and sepsis first draw attention to the ureteral injury. A review of the problem and our experience with 16 such injuries is presented. As with other infrequent injuries the single and most important diagnostic factor is the prepared mind of the examiner. We feel all patients who have penetrating abdominal trauma, have fractured lumbar processes, or are involved in accidents where deceleration or extension occur should have infusion pyelography even in the absence of hematuria.


Gunshot wounds to the ureter.

Gunshot wounds to the ureter. Since our last review 17 more patients have been treated for ureteral gunshot injuries. In six cases the upper ureter, in two the middle, and in nine cases the lower ureter was involved. Associated visceral injuries were numerous with the small intestine the most commonly injured. In over 50% of the injuries to the lower ureter, the iliac vein was injured. In three patients the ureter was the only major structure involved. There was no hospital mortality. Optimal surgical repair done by generous resection, primary end-to-end anastomosis and stenting and drainage via a proximal ureteral T-tube gave excellent results and no longterm complications in a population subject to careful short and longterm followup. While an uncommon injury, the principles of effective repair are clear and must be applied in the face of serious associated disorders to continue these satisfactory results.


Phenoxybenzamine-a mediator of blood oxygen affinity. Studies of the effect of phenoxybenzamine on oxygen transport have been concentrated on flow and resistance changes. Previous studies have ignored the possible effects of phenoxybenzamine on the ability of red blood cells to offload oxygen itself. After an initial inhibitory effect phenoxybenzamine greatly enhances the ability of the red cell to offload oxygen under conditions seen at the tissue level. The disparity between P50std and organic phosphate changes found in this and other studies warrants extreme caution to be used in interpreting results where P50 itself is not measured.


Sinus node recovery time and abnormal postpacing phase in the aged patients with sick sinus syndrome. The sinus node function was evaluated by rapid atrial pacing in 35 aged patients (mean age 78.2 years) including 10 aged controls, 12 cases with various degrees of AV block, 6 with bradycardia-tachycardia syndrome (BTS), and 7 with sinus bradyarrhythmia (SB). AV block was further divided into A-H block (7 cases) and H-V block (5 cases) by His bundle electrogram which was simultaneously recorded with 3 leads of surface electrocardiogram. Sinus node recovery time (SRT) was measured and its maximum value (SRTmax) was selected from SRTs obtained after pacing with various rates and durations in each patient. SRTmax was also expressed as percentage of the control P-P interval (%SRTmax). For patients in whom the study was repeated 3 to 8 months later, %SRTmax was reproducible in 9 of 14 instances. Prolongation of SRT was not always observed as the rate and/or duration of pacing was increased. SRTmax and %SRTmax were 1,363 +/- 188 msec and 147 +/- 19% (mean +/- SD), respectively, for aged controls, 1,597 +/- 442 msec and 156 +/- 31% for patients with AV block, 2,087 +/- 1,315 msec and 203 +/- 132% for those with BTS, and 3,069 +/- 1,287 msec and 247 +/- 115% for those with SB. SRTmax exceeding the range for aged controls was noted in 4 of 7 cases (57%) with A-H block, 2 of 6 (33%) with BTS, and 5 of 7 (71%) with SB; normal SRT was not infrequently observed in patients with sick sinus syndrome, especially in those with BTS. Analysis of 10 consecutive atrial cycles following cessation of pacing revealed that in 8 cases the first P-P interval (SRT) was followed by longer ones in some occasions (secondary suppression). It was observed almost exclusively in patients with sick sinus syndrome. The possibility of this phenomenon to reflect another feature of sinus node abnormality was discussed.


The phase of supernormal excitation in relation to the strength of subthreshold stimuli. The presence of supernormal excitation was confirmed repeatedly in all 10 cases following cardiac surgery. By the stimulation of minimum subthreshold impulses capable of originating ventricular responses, the supernormal excitation was limited only at the descending limb of T wave. The duration lasted only 0.02 sec at the minimum subthreshold stimuli. But the higher subthreshold stimuli produced the longer duration of supernormal excitation phase. The duration of the excitation phase prolonged towards the following R wave, hardly extending towards the preceding R wave, with the increase of subthreshold stimuli.


Pathological studies of the animals replaced totally with the artificial heart. Part II Concerning liver, gastrointestinal tract, kidney, and general discussion. Twenty-eight goats with an artificial heart (AH) were studied pathologically. Being continued from the previous report, the liver, gastrointestinal tract, and kidneys were taken up in this paper and finally, general discussion was done to get our ideas in shape concerning the pathophysiological status of the goat. Central necrosis of the liver was always observed in the goats which survived for over 140 hours. This finding seemed to be caused mainly by circulatory insufficiency of the portal vein at the latter half of the survival time. Microscopic findings of degeneration, necrosis, and edema were commonly observed at the walls of gastrointestinal tracts, when goats showed poor apetite, mucous feces and constipation. But these problems have been improved by application of a new control method to regulate the output of AH system within a goat's physiological range since October 1974. The lesions seen in the kidneys are classified into 5 groups. The most important findings of them are lower nephron nephrosis and cortical necrosis, both of which indicate the occurrence of long standing vasoconstriction of proximal renal arteries. By means of microangiographic method and others, thrombi were detected frequently in the kidneys. The vascular walls, where thrombi were attached to, were often damaged. Therefore, these thrombi were thought to be formed in the local vessels in situ through renal circulatory insufficiency. The renal pathological lesions have been also improved and severe renal failure from which the previous goats could not escape, has been lessened since the application of a new AH control method. As a whole, the main pathophysiological status of the animals replaced by the AH are thought conclusively to be peripheral circulatory insufficiency. This would be caused by abnormal hemodynamics, so that, the essential clinical etiology is thought to be AH function itself.


Non-infected false aneurysm of the ascending aorta eight years after aortic valve surgery. In this report, the development of false aneurysm of the ascending aorta 8 years following the repair of congenital aortic stenosis is described. A 14-year-old male patient was found to have congenital aortic stenosis in 1966 after medical check-up and subsequently operated upon. In the postoperative period, he was complicated by remittent fever of 1 month's duration, which was finally controlled by antibiotics. Arterial blood cultures taken on a few occasions were negative. Eight years and 5 months after surgery, he was noticed to have a mediastinal mass around the base of the heart and the presence of false aneurysm was confirmed by aortography. Aneurysmectomy was carried out almost 9 years after the previous operation, and it was found that aneurysm was arising from the suture line of the aortotomy with communication to the aorta at the bottom of the aneurysm. Postoperatively, patient's recovery was uneventful and was discharged on the 23rd postoperative day. Etiology, timing of operation and techniques utilizing hypothermia and/or circulatory arrest are discussed.


Microorganism capable of decomposing N-acetylglucosaminyl ribitol teichoic acid of Staphylococcus aureus. Enzyme(s) capable of decomposing N-acetylglucosaminyl ribitol teichoic acid prepared from the cell wall of Staphylococcus aureus FDA 209 P was obtained from the culture supernatant of a gram-negative, rod-shaped, spore-forming soil bacterium. Properties of the bacterium were very similar to those of Bacillus circulans.


Application of the macrophage migration inhibition test to screen patients with early cancer and obtain prognostic determinations of cancer treatment. A modified direct method of the macrophage migration inhibition test (MMIT) was attempted on a large number of patients with malignant or benign tumors. Results of the MMIT in almost all patients with benign tumors were negative except for those with hydatidiform moles, dermoid cysts and viral benign tumors such as verruca plana which were positive. The number of cases determined as false positives were exceptionally few. Conversely, about the half of the patients with malignant tumors were positive. The majority of negative cancer patients were confirmed pathologically to be advanced cases and, therefore, were postulated to have been immunologically unresponsive. The remaining false negative patients were diagnosed to be very early cases with their malignant foci too small to be effective antigenic stimuli. The MMIT was also performed postoperatively on some of the patients using autologous antigens, which had been preserved by freezing, for examination of changes in the per cent migration index. The results led the authors to conclude that postoperative repetitions of the test permitted them to tell that cancer cells had been completely eradicated or that a relapse might occur in the near future. Examinations of cross reactivity between tumor antigens revealed that such reactivity exists between cancer antigens and antigens originating in hydatidiform moles and that there is also a very strong cross reactivity between allogeneic cancer antigens regardless of differences in the organs of origin. This fact suggests that the present test is effective for the screening of preoperative patients with early cancer.


Relationship between the molecular size of poly I-poly C and its biological activity. Seven polyinosinic-polycytidylic acid (poly I-poly C) preparations, ranging from 4.2 S to 21.2 S, prepared from various sizes of polyinosinate and polycytidylate, were examined for toxicity and interferon-inducing activity in mice. The increase in size of poly I-poly C was accompanied by increases both in the maximal amount of interferon produced and in the length of persistence of a high level of interferon in plasma. Toxicity of poly I-poly C was proportional to the molecular size within the range of 8 S to 16 S. The amount of interferon induced by 1/5 LD50 of poly I-poly C depended on the size of the inducer, being increasingly lower with progressively smaller sizes. Next, activities of poly I-poly C in culture cells were examined. The resistance-inducing activity of poly I-poly C in primary chick embryo cells (CEC) increased with the size of the inducer (4.2 S to 11.6 S), whereas the activity in L cells was not so markedly dependent upon its molecular size as in CEC. In the presence of calf serum during induction of resistance the activity was lowered. The activities of preparations with small molecular sizes were affected by calf serum more markedly than those of large molecular sizes. The interferon-inducing activity in RK13 was not appreciably influenced by the size of poly I-poly C, especially in the presence of DEAE-dextran, while the activity in L cells was markedly dependent upon the size of the inducer. These results suggest that the influence of the molecular size of poly I-poly C upon the resistance-inducing and interferon-inducing activities varies among different kinds of cells, and alters in the presence of serum or DEAE-dextran.


Ultrastructure and chemical analysis of the cell wall of Pythium debaryanum. The ultrastructure and component polysaccharides of the cell wall of Pythium debaryanum IFO-5919 were investigated. From results obtained by means of acid, alkali, Schweitzer reagent and beta-1, 3-glucanase treatments and electron microscopy, it was concluded that 1) the acid-extracted fraction was a 1,3-linked branched glucan, 2) the alkali-extranded fraction was a mixture of 1,3-, 1,6-, and 1,3,6-linked highly branched two glucans, 3) the Schweitzer reagent-extracted fraction was a beta-1, 4-linked glucan, 4) the cell wall was constructed from two types of cullulosic microfibrils, as a frame and as a finer network, and amorphous beta-1, 3-glucan including beta-1, 6-linkage, 5) cellulosic microfibrils were covered by matrix material consisting of a mixture of amorphous beta-1, 3-linked and beta-1, 6-linked branching glucans.