Involvement of uptake1 and uptake2 in terminating the cardiovascular activity of noradrenaline in normotensive and genetically hypertensive rats. 1. In pithed, pancuronium-treated rats, inhibition of Uptake1 with desmethylimipramine (2.5 mg/kg i.v.) increased the time course of the pressor response to vasomotor nerve stimulation (1 and 5 Hz for 5 sec) but not the time course of the pressor response to injected noradrenaline (10 and 50 ng i.v.). 2. Subsequent inhibition of Uptake2 with metanephrine (3 mg/kg, i.v.) did not affect the time course of responses to either vasomotor nerve stimulation or injected noradrenaline. 3. It is concluded that Uptake1 but not Uptake2 is important in terminating the activity of noradrenaline released from rat vasomotor nerves and that neither process inactivates intraluminal catecholamine. 4. By contrast, chronotropic responses of rat atria to adrenergic nerve stimulation were prolonged by blockade of both Uptake1 and Uptake2, in agreement with previous evidence for involvement of both processes in terminating sino-atrial adrenergic responses. 5. Animals from the Otago strain of genetically hypertensive animals were identical to normotensives in their vascular handling of catecholamine. However, they lacked an atrial Uptake2 process. 6. This defect may be related to the high resting heart rate and abnormal cardiac catecholamine turnover observed to exist in the Otago hypertensive rats.


Acute compensatory adaptation of renal function following contralateral kidney exclusion in Brattleboro rats with diabetes insipidus. 1. The function of the remaining kidney following ligation of a single renal pedicle in anaesthetized rats with hereditary hypothalamic diabetes insipidus (DI) was studied using clearance methods. Values were compared with those obtained in DI rats which had been sham operated. 2. A small increase in the glomerular filtration rate of the remaining kidney was observed, which was statistically significant after 150 min. Increases in effective renal plasma flow were also observed, but these were not statistically significant. 3. The fractional excretion rates of Na and K increased immediately after contralateral kidney ligation; as a result total Na and K excretion rates remained similar to values in sham operated animals with both kidneys intact. 4. Fractional urine flow (V/GFR) increased by approximately 40% after contralateral ligation. It is argued that, since water reabsorption in the diluting segments of the nephron was unlikely to have been reduced, the increase in V/GFR was an indication that fractional fluid reabsorption in the proximal nephron had been inhibited. 5. Clearance determinations showed that the fractional reabsorption of Na in the proximal nephron was similarly reduced after contralateral ligation. However, Na reabsorption in the distal nephron increased, though not by enough to prevent a doubling of fractional sodium excretion. 6. The osmolalities of interstitial fluids obtained from the medulla and papilla of the contralateral kidney 2 hr after unilateral renal pedicle ligation were slightly, but significantly, higher than corresponding values in sham operated rats. This raises the possibility that salt reabsorption in the ascending limb of Henle might be enhanced immediately after contralateral renal exclusion.


Microvascular pressures and filtration coefficients in the cat mesentery. 1. Filtration coefficient and hydrostatic pressure have been measured in single capillaries and venules in the cat mesentery using a modification of the Landis (1927) single vessel occlusion technique. 2. Venules were found to be filtering fluid, not absorbing it as is often supposed. 3. The mean filtration coefficient in capillaries was 0.018 micrometers . s-1 . mmHg-1 (1.35 X 10(-10)m . s-1 . Pa-1) while that in venules, was 0.027 micrometers . s-1 . mmHg-1 (2.02 X 10(-10)m . s-1 . Pa-1). 4. In both capillaries and venules, filtration coefficient increased with decreasing pressure. 5. The difference between directly measured venular pressure and that calculated from the occlusion data was used to determine the contribution of the interstitium to fluid exchange. In the mesentery superfused with Krebs solution the tissue pressure so determined was found to be zero or subatmospheric initially but became increasingly positive with lengthening exposure of the mesentery.


Simultaneous measurement of pressure in the interstitium and the terminal lymphatics of the cat mesentery. 1. Simultaneous measurements of the pressure in terminal lymphatics and interstitial tissue have been made in the exteriorized cat mesentery superfused with either physiological salt solution (Krebs solution) or a water-immiscible fluorocarbon, FC-80. 2. The pressures within individual terminal lymphatics were measured using glass micropipettes attached to a servo pressure-measuring system. Tissue pressures were recorded using saline-filled cotton-wool wicks. 3. Mean pressure recorded in the terminal lymphatics of the Krebs-superfused mesentery were slightly above atmospheric (+0.2 mmHg, n = 45), while those recorded in the FC-80-superfused mesentery were slightly below atmospheric (-0.2 mmHg, n = 46). 4. Tissue pressures were also slightly subatmospheric in the in situ mesentery, and the recently exposed tissue. Continuous superfusion with Krebs solution caused the tissue pressure to rise to atmospheric pressure or above; with FC-80-superfusion the tissue pressure also rose, but never to above atmospheric pressure. 5. Isolated strips of mesentery immersed in Krebs solutions of different concentrations gained weight, but when immersed in FC-80 no change in weight was detected. 6. It was concluded that the interstitial gel of the mesentery is normally unsaturated and that superfusion with Krebs solution leads to tissue oedema. This tendency is less marked in FC-80-superfused preparations. Possible mechanisms for lymph formation and propulsion are discussed.


Relaxation of ventricular cardiac muscle. 1. The load bearing capacity during relaxation of ventricular cardiac muscle from various animal species was investigated. 2. The effect of load on the time course of relaxation was analysed either by comparing afterloaded contractions against various loads or by imposing abrupt alterations in load (load clamps). 3. In heart muscle from the mammalian species studied relaxation was sensitive to loading conditions, whereas in frog heart muscle relaxation was largely independent of the loading conditions. The mechanical properties of relaxation of cardiac muscle appear, therefore, governed by the interplay of a load-controlled and an activation-controlled decay mechanism, the relative importance of which differs with species. 4. Load-dependence may be the mechanical expression of the ratio of the number of force generating sites at any time during contraction and relaxation to the load to be carried; this mechanism would predominate in mammalian animal species with a well developed calcium sequestering sarcoplasmic reticulum. Activation-dependence would seem to predominate in animal species, such as frog, in which calcium sequestration appears to be the rate limiting step during relaxation.


The force-velocity relation of isolated twitch and slow muscle fibres of Xenopus laevis. 1. A study has been made of the relation between force and speed of shortening, or lengthening, in isolated twitch and slow muscle fibres, dissected from the iliofibularis muscle of Xenopus laevis. Both after-loaded and quick-release contractions were studied. Twitch fibres were stimulated electrically to give tetanic contractions (5-20 degrees C); slow fibres were activated by a rapid change to solutions with high K concentration (30-75 mM; experiments at 21-24 degrees C).2. The velocity of slow fibres was constant during shortening over 10% length change in after-loaded contractions, except at forces exceeding about 0.8 of isometric tension, P(0). In quick-release experiments, shortening velocity was found to depend not only on the relative load, P/P(0), but also on the instant when the release was made. With increasing time after onset of contraction the initial rate of shortening decreased; also, a progressive fall in speed during shortening became more marked.3. The fall in initial shortening speed with time of release from the onset of a contracture was more pronounced at high [K](o) than at low.4. The relation between the relative force, P/P(0), and shortening velocity, V, in after-loaded contractions (75 mM-K) and quick-release contractions (45 mM-K, early releases) in slow fibres could be represented by a hyperbola with the constants a = 0.10P(0), b = 0.11 lengths/sec; extrapolated V(max.) was 1.10 lengths/sec.5. Isometric tension and maximum shortening velocity in slow fibres were very nearly constant between 32 and 75 mM-K. a/P(0), however, was clearly reduced at 32 mM-K, representing a more curved P-V relation.6. Force-velocity data for twitch fibres (quick-release contractions, 20 degrees C) were reasonably well fitted by a hyperbola (a = 0.38P(0), b = 1.97 lengths/sec, V(max.) = 5.20 lengths/sec), but a systematic deviation was observed for forces exceeding 0.6P(0).7. a/P(0) for twitch fibres was found to be independent of temperature in the range 5-20 degrees C. Q(10) for b was 2.24 (10-20 degrees C), and 2.86 (5-10 degrees C).8. V(max.) for twitch fibres was calculated to be 6.34 lengths/sec at 22.5 degrees C, the average temperature in the slow fibre experiments. The maximum shortening velocity in twitch fibres is thus 6 times higher than in slow fibres.9. When loads in the range 1.1-1.4P(0) were quickly applied to an actively contracting slow fibre, lengthening of the fibre occurred in two phases, an initial rapid phase, followed by a phase of extremely slow lengthening. In corresponding experiments on twitch fibres lengthening was rapid at first and then gradually became slower.10. Factors affecting the shape of the force-velocity curve are discussed. Calculations based on A. F. Huxley's (1957) model for muscle contraction indicated that cross-bridge turnover rate is about 15 times lower in slow than in twitch fibres.


Spatial summation in the receptive fields of simple cells in the cat's striate cortex. 1. We have examined the responses of simple cells in the cat's atriate cortex to visual patterns that were designed to reveal the extent to which these cells may be considered to sum light-evoked influences linearly across their receptive fields. We used one-dimensional luminance-modulated bars and grating as stimuli; their orientation was always the same as the preferred orientation of the neurone under study. The stimuli were presented on an oscilloscope screen by a digital computer, which also accumulated neuronal responses and controlled a randomized sequence of stimulus presentations. 2. The majority of simple cells respond to sinusoidal gratings that are moving or whose contrast is modulated in time in a manner consistent with the hypothesis that they have linear spatial summation. Their responses to moving gratings of all spatial frequencies are modulated in synchrony with the passage of the gratings' bars across their receptive fields, and they do not produce unmodulated responses even at the highest spatial frequencies. Many of these cells respond to temporally modulated stationary gratings simply by changing their response amplitude sinusoidally as the spatial phase of the grating the grating is varied. Nonetheless, their behavior appears to indicate linear spatial summation, since we show in an Appendix that the absence of a 'null' phase in a visual neurone need not indicate non-linear spatial summation, and further that a linear neurone lacking a 'null' phase should give responses of the form that we have observed in this type of simple cell. 3. A minority of simple cells appears to have significant non-linearities of spatial summation. These neurones respond to moving gratings of high spatial frequency with a partially or totally unmodulated elevation of firing rate. They have no 'null' phases when tested with stationary gratings, and reveal their non-linearity by giving responses to gratings of some spatial phases that are composed partly or wholly of even harmonics of the stimulus frequency ('on-off' responses). 4. We compared simple receptive fields with their sensitivity to sinusoidal gratings of different spatial frequencies. Qualitatively, the most sensitive subregions of simple cells' receptive fields are roughly the same width as the individual bars of the gratings to which they are most sensitive. Quantitatively, their receptive field profiles measured with thin stationary lines, agree well with predicted profiles derived by Fourier synthesis of their spatial frequency tuning curves.


The central control of shivering and non-shivering thermogenesis in the rat. 1. To test whether the preoptic area controls only non-shivering and the spinal cord only shivering thermogenesis, ten rats were chronically implanted with a preoptic and a spinal cord thermode each. The following were then studied: (a) the effect of propranolol (8 mg/kg.hr) on the metabolic response to cooling the preoptic area, and the spinal cord, (b) the effect of exogenous noradrenaline (0.5 mg/kg) on the metabolic response to cooling the preoptic area, and the spinal cord, and (c) the effect of warming the preoptic area on the metabolic response to cooling the spinal cord, and vice versa. 2. Administration of propranolol inhibited the metabolic response to cooling each of the thermosensitive areas, but the response to cooling the preoptic area was more strongly inhibited than that to cooling the spinal cord. 3. Administration of exogenous noradrenaline did not prevent the metabolic response to cooling either the preoptic area or the spinal cord. 4. Warming the spinal cord completely inhibited the metabolic response to cooling the preoptic area, and warming the preoptic area fully inhibited the metabolic response to cooling the spinal cord. 5. It is concluded that exogenous noradrenaline underestimates the capacity for non-shivering thermogenesis, and that both thermosensitive areas can control both forms of thermogenesis, but that the preoptic area threshold of non-shivering thermogenesis is probably lower than that of shivering, while the spinal cord threshold of shivering is probably lower than that of non-shivering thermogenesis.


Action potentials of embryonic dorsal root ganglion neurones in Xenopus tadpoles. 1. Several classes of action potentials can be distinguished in dorsal root ganglion cells, studied by intracellular recording techniques in Xenopus laevis tadpoles 4.5--51 days old. The ionic basis of the action potential was investigated by changing the ionic environment of the cells and applying various blocking agents. 2. The Ca2+-dependent action potential is a plateau of relatively long duration (mean 8.7 msec). It is unaffected by removal of Na+ but blocked by mM quantities of Co2+. It is present only in small cells. 3. Ca2+/Na+-dependent action potentials. Type I is a spike followed by a plateau or hump of different durations (mean 8.1 msec). The spike is selectively blocked by removal of Na+, leaving the plateau which is in turn blocked by Co2+. It is present in cells of small and intermediate size. Type II is a spike of short duration (mean 2.0 msec) with only an inflection on the falling phase. The spike is blocked by removal of Na+ and no other components can be elicited. The inflection is blocked by Co2+. It is present in cells of all sizes. Type III is similar to type I but is seen only in solutions in which the outward current is blocked. It was observed only very infrequently. 4. Na+-dependent action potentials. Type I a is a short duration spike (mean 1.1 msec). It is abolished by removal of Na+ or addition of tetrodotoxin (TTX), but largely unaffected by Co2+ or La3+. It is present in cells of all sizes. When the outward current channels are blocked and cells exposed to Na+-free solutions, all cells are capable of producing an action potential in which the inward current is carried by divalent cations. Type I b is a spike with a smooth, more slowly falling phase. It has the same pharmacological properties as type I a action potential and is present in cells of small size. 5. Na+-dependent action potentials. Type II is a spike with an inflection on the falling phase (mean duration 3.4 msec). It is prolonged by Co2+ and La3+. Removal of Na+ abolishes the spike but TTX does not block it. It is present in cells of all sizes. The mean resting potential is less than that of cells with Na+-dependent type I action potentials, while the mean input resistance is greater. 6. Tetraethylammonium chloride (TEA) prolongs the different kinds of action potentials. The amount of prolongation varies among cells with a given type of action potential, so that no distinction could be made of the different actionpotential types based on the effect of TEA. 7. The percent of cells with each kind of action potential varies with the developmental age of the animal. The number of cells with Ca2+ and Ca2+/Na+ action potentials decreases with age, while the number of cells with a Na+ type I action potentials increases. The Na+ type II action potential appears only at later stages. 8...


Receptive field organization of complex cells in the cat's striate cortex. 1. All complex cells in the cat's striate cortex exhibit gross non-linearities of spatial summation when tested with sinusoidal grating stimuli. Their responses to moving gratings of all but the lowest spatial frequencies are usually dominated by a component that is not modulated by the passage of the bars of the grating across the receptive field. They give responses to temporally modulated stationary gratings that consist mostly of even harmonics of the stimulus frequency and that vary little in amplitude or wave form as the spatial phase of the grating is varied. 2. We compared complex cells' receptive fields with their sensitivity to sinusoidal gratings of different spatial frequencies. Qualitatively, the receptive fields are usually two to five times wider than the bars of the gratings that stimulate them most effectively. Quantitatively, the receptive field profiles of complex cells are invariably broader than those predicted by Fourier synthesis of their spatial frequency tuning curves, and in particular lack predicted spatially antagonistic regions. 3. We further examined the receptive field organization of these cells, using pairs of stationary lines flashed synchronously on their receptive fields. If both lines are of the same polarity (bright or dark), complex cells respond to the paired stimulus much less well than they do to either of its component bars, unless the bars are separated by less than about one quarter of the width of the receptive field. If the lines are of opposite polarity, one bright and one dark, the opposite situation obtains: closely spaced bars elicit small responses, while paired bars of larger separation are much more effective. In either case, the results are independent in general character of the absolute positions of the stimuli within the receptive field; rather, they depend in a manner characteristic of each cell on the relative positions of the two bars. 4. The two-line interaction profile that plots the change in a complex cell's response to one bar as a function of the position of a second added bar corresponds closely to the receptive field profile predicted from Fourier synthesis of the cell's spatial frequency tuning curve. These profiles may thus reveal the spatial characteristics of subunits within complex cell-receptive fields. We examined the nature of the interaction between these subunits by performing several two-line interaction experiments in which the onset of the second bar was delayed some time after the onset of the first. The results suggest that neighbouring subunits interact in a facilitatory fashion: for an interval after the presentation of one bar, responses to neighbouring bars are enhanced. 5. The subunits of a complex receptive field may, by their spatial properties, determine the spatial selectivities of complex cells, while the nature of the interaction among the subunits may determine these cells' sensitivity and selectivity for moving visual stimuli...


Developing role of sensorimotor cortex and pyramidal tract neurons in contact placing in kittens. Unilateral or bilateral removal of kitten sensorimotor (SM) cortex prior to the fourth postnatal week was followed by recovery of contact placing (CP) to stimulation of any of the four forepaw cutaneous fields. However, immediately after a removal under ethyl chloride, CP was depressed contralaterally, especially to lateral stimulation (lateral CP). When the operated kitten aged to 5--9 weeks, the likelihood of CP secondarily declined contralateral to the SM cortical extirpation, but was restored by administration of d-amphetamine. An initial extirpation after the fifth postnatal week was followed by a severe deficit in CP. 2. Cooling the SM cortex, internal capsule or bulbar pyramid during the 2nd and 3rd week was followed by reversible, contralateral loss of lateral CP, extension of the forelimb and, later, by reduced movements. Lateral CPs were often hypermetric prior to loss. By contrast, cooling SM cortex in the first week was usually ineffective. Thus, during the 2nd week, lateral CP developed a dependence on SM cortex, and in particular on PT neurons. 3. After a delay usually of 1 or more min, cooling the SM cortex reduced the resting discharge of individual neurons in buried motor cortex; the antidromic conduction time in PT neurons was significantly increased and the spike height was reduced.


Influence of the cortico-spinal system on cervical and lumbar motoneurons in the rat. In rats the connections of cortico-spinal fibres to cervical and lumbar motoneurons were examined using epicortical stimulation techniques. In cervical motoneurons, the synaptic response started in nearly 50% of the units with a monosynaptically transmitted EPSP, was of short duration and proved to be very effective. In contrast to that, the synaptic sequence found in lumbar motoneurons consisted in a small oligosynaptic and a prominent polysynaptic part. The differences in cortico-motoneuronal linkage correspond well with the different types of motor performance in fore- and hindlimbs.


Topical versus diffuse organization of the corticospinal tract in the cat. 1. The organization of the corticospinal system has been studies, in the cat, using electrophysiological techniques (stimulation of the lateral corticospinal tract at different spinal levels, recording in the contralateral cortex by means of transcortical bipolar electrodes) and anatomical techniques (HRP injection localized in the grey matter of a chosen spinal level). These two approaches give complementary results. Different cortical zones can be defined according to their spinal projections. 2. Some restricted cortical zones are at the origin of only contralateral corticospinal projections specific to a given spinal enlargement, cervical or lumbar. 3. Other larger cortical zones are at the origin of bilateral spinal projections specific to a given spinal enlargement, at least in the case of the cervical one. 4. Finally, a cortical zone is at the origin of bilateral cortical projections both to the cervical and lumbar enlargements. The question of multiple branching of individual cortisospinal neurons is considered, but cannot be answered using out techniques.


Pattern of projections of individual pyramidal tract neurons to the spinal cord of the monkey. The results suggest : (1) that PT neurons sending axons to motor nuclei innervating distal forelimb muscles branch less than other PT neurons; (2) that a group of PT neurons located close together may influence various species of motoneurons, but that this influence is the strongest on motoneurons of one species; (3) that individual PT neurons terminate only on a small fraction of a given motoneuron group.


The intraspinal branching patterns of fast and slow pyramidal tract neurons in the cat. Antidromic activation of single pyramidal tract neurons (PTNS) was obtained in cats by stimulating either the dorso-lateral funiculus with ball-electrodes, or the spinal gray matter with microelectrodes. The results indicate that the distribution area of single PTNS is much wider than the area of a single motor nucleus, suggesting that single PTNS may influence different motor nuclei.


Red nucleus cell activity in awake cats during a placing reaction. It is known that the discharges of the posterior red nucleus (RN) cells are modulated during locomation (Orlovsky, 1972). The aims of the present investigation were to look for a possible relationship between the unitary activity of RN cells and movements as well as postural reactions of the forelimbs. In the experimental arrangement used, the cat stood on four transducers which recorded to forces on each limb. The animal was restrained by a hammock supporting a part of the total body weight. A horizontally moving plate touched one forepaw and pushed it backwards until a placing mavement was induced. During the first part of the sequence, the mechanically stimulated limb was actively unloaded just prior to the placing movement, while the contralateral forelimb simultaneously presented a loading postural reaction. The results can be summarized and interpreted in the following way: 1. The RN cells exhibit large variations of discharge frequencies during phasic muscular activities linked to movement and to postural adjustments, but no correlations can be established between tonic cell activity and static postural forces exerted by the limb. 2. During the swing phase, the neuronal activity of some RN cells is maximal during flexion, while for others the maximum is during extension. 3. When there is a modification in frequency at the onset of the placing reaction relative to activity during the unloading reaction, the beginning of this change occurs after the onset of the movement as recorded by a potentiometer placed at the elbow joint. 4. The increases of frequency are higher during reciprocal muscle activation (during the movement) than during coactivation of antagonistic muscles (during the postural loading reaction). 5. During the loading reaction (with mostly extensor activation) the frequency of firing of those neurones discharging during the flexion phase. Thus the data may indicate that the RN is included in a feed-back loop which is linked not to muscle activities but rather to phasic spinal reflexes.


Discharge of red nucleus neurons during voluntary muscle contraction: activity patterns and correlations with isometric force. Discharges of red nucleus neurons were analyzed in the cat during voluntary muscle contractions performed under isometric and anisometric conditions. The observations established: (1) that neurons of the red nucleus modulate their firing in advance of the motor output under both conditions; (2) that increased activity of these neurons is specific to the direction of the force exerted ; (3) that this increase is primarily related to the magnitude of the rate of force change generated by the animal.


Reading and detecting color-word stimuli presented at various retinal locations. Four experiments, using a total of 70 male and female undergraduates, examined the speed and accuracy of reading and detection responses to color-word stimuli presented at retinal locations from the center out to 6 degrees in the right and left visual fields. Reading and detection responses were found to interact with retinal location. For stimuli presented at the farther retinal location, detection responses were quicker and more accurate than reading responses, but the reverse occurred with foveally presented stimuli. The Stroop phenomenon was present in the detection data and was found to be diminished with parafoveal presentation of the stimulus materials. These findings support the peripheral search guidance process of Hochberg's model of reading and provide added evidence of processing variations across retinal location.


Measurement of psychopathy as a state.

Measurement of psychopathy as a state. It was hypothesized that psychopathic states could be measured by systematically changing items in psychopathy scales so as to suggest current feelings, thoughts, motives, and actions. The scales chosen for revision were the Psychopathic Deviate, Mania, and Antisocial scales of the Minnesota Multiphasic Personality Inventory (MMPI); Responsibility and Socialization scales of the California Psychological Inventory (CPI); and Psychopathy scale from the Addiction Research Center Inventory (ARCI). Male alcoholics (N = 53) and opiate addicts (N = 28) exemplifying psychopaths were compared with normals (N = 54) on each of the above scales. Alcoholics and opiate addicts were significantly higher on the total of the psychopathic scales and each of the above state scales except for Mania. Reliability was significant on all scales except the Antisocial scale. Also, 58% of 560 items differentiated these groups from normals.


Problems in the Munz and Smouse procedure for operationalizing reactions to test anxiety: proposal of a new procedure. Three problems in the Munz and Smouse procedure make it unacceptable as an operationalization of four reactions to test anxiety alluded to by Alpert and Haber. As a demonstration of two of the problems, the procedure was applied to the scores of 176 male and female college students. A new procedure for operationalizing the four reactions, which avoids the problems in the Munz and Smouse procedure, was described. Practical problems likely to be encountered in using the new procedure were discussed.


A study of object concept development in institutionalized and home-reared infants. Institution- and home-reared infants were tested in five areas: language development, object concept development, play, social responsiveness, and social maturity. The sample consisted of 104 infants ranging in age from six months to two years, thus broadly encompassing object concept stages 3 to 6 described by Piaget. The relationship of each of the five functions to IQ and background was examined. This paper describes the specific nature of the object concept function as reflected by the investigation. It was found statistically that object concept scores, as measured by Piagetian tests, were relatively unaffected by the background variable but were significantly related to IQ. The other measures were sensitive to both IQ and background variables. The fact that the object concept score was relatively independent of the background variable suggested that it represents the most stable developing function and provides the most accurate reflection of the cognitive potential of the infant.


Normative beliefs about tobacco smoking on campus in relation to an exposititon of the viewpoint of the nonsmokers' rights movement. A 147-item questionnaire on the effects of tobacco smoking on campus was administered to 307 University of New Hampshire undergraduates. Questions were asked in relation to an exposition of the viewpoint of the nonsmokers' rights movement. A group of 21 items, dealing with attitudes and normative beliefs related to issues of smokers' and nonsmokers' rights, were selected for analysis in this paper. Descriptive statistics and t tests contrasting the smokers and nonsmokers were presented. A majority of both groups agreed that smoking on campus should be limited to special areas and agreed that the right to breathe smoke-free air is the primary right. Nonsmokers in particular affirmed that nonsmokers who find smoke aversive often hide their true feelings and do not request that smokers abstain. Interpretation of results focused upon the normative structure of our society as the key element involved in perpetuating smoking in shared areas. At the present time it appears that smoking in these areas without permission is defined as normative (i.e., appropriate), whereas objecting is implicitly characterized as a norm violation.


Relation of personal space to the human menstrual cycle. A behavioral measure of personal space was obtained from 84 female undergraduates who had completed a menstrual cycle questionnaire. They ranged in age from 17 to 27 years, with a mean age of 19.2 years. A significant relationship between personal space and the female's menstrual cycle was found. The personal space zone tended to be larger during the menstruous flow than during the approximate middle of the cycle. Results were discussed in the context of sexual responsiveness.


Effect of induced elation and depression on internal-external locus of control. This study tested the notion that depression is associated with external locus of control and elation is related to internal locus of control. Temporary mood states (depression, elation, neutral) were produced by means of Velten's auto-suggestion technique. Fifteen female undergraduates were assigned to each mood condition, and locus of control scores were obtained both before and after the mood induction procedure. Pre-post changes were as predicted: elation caused an increased sense of internality, and depression caused an increased sense of externality. Neutral mood induction did not alter locus of control.


Mitosis in the hemoflagellate Trypanosoma cyclops. The ultrastructure of interphase and mitotic nuclei of the epimastigote form of Trypanosoma cyclops Weinman is described. In the interphase nucleus the nucleolus is located centrally while at the periphery of the nucleus condensed chromatin is in contact with the nuclear envelope. The nucleolus fragments at the onset of mitosis, but granular material of presumptive nucleolar origin is often recognizable in the mitotic nucleus. Peripheral chromatin is in contact with the nuclear envelope throughout mitosis, and it seems reasonable to assume that the nuclear envelope is involved in its segregation to the daughter nuclei. Spindle microtubules extend between the poles of the dividing nucleus and terminate close to the nuclear envelope. The basal body and kinetoplast divide before the onset of mitosis and do not appear to have any morphologic involvement in that process. Spindle pole bodies, kinetochores, and chromosomal microtubules have not been observed.


Scanning electron microscopy of schizogony in Eimeria tenella. Developing 2nd- and 3rd-generation schizonts of Eimeria tenella were found in the ceca of chicks infected orally with sporulated oocysts. Several free 2nd-generation schizonts, which varied in diameter from 11 to 21.6 micrometer, were found on the epithelial surface of the cecum. Some schizonts appeared to have lost merozoites. Other schizonts were intact, one of which was surrounded by an unbroken membrane that followed the contours of the merozoites. Third-generation schizonts, much smaller than 2nd-generation schizonts and with fewer merozoites, were found only on cut or fractured surfaces of the cecal tissue. Third generation merozoites appeared shorter and thicker than those of the 2nd-generation and were attached to the schizont residuum. A form with conical protuberances and another with 4 triangular segments were found; they were believed to be developing stages 3rd-generation schizonts.


Motility events of trichocyst insertion in Paramecium tetraurelia. Following electroshock-induced extrusion of its inserted trichocysts, Paramecium tetraurelia rapidly begins replacement of the population of lost organelles. Light microscopy of the cortical insertion of new trichocysts reveals a series of characteristic motility activities. An uninserted trichocyst in the cyclotic flow of the cell appears to be "captured" and removed to the noncyclotic, subcortical regions. The trichocyst then makes a series of saltatory motions which apparently serve to transport it to the cortex, with proper orientation (tip first) for insertion. Trichocyst saltations end with either cortical insertion of the organelle, or return to cyclosis. If the trichocyst is inserted, it makes a series of unique pivoting movements around the motionless tip. This form of motility, termed "wobble," continues for a short period of time. After cessation of wobble, the insertion of the trichocyst is apparently complete, since no further motility is observed. With the aid of these observations it was possible to identify saltatory motility as the means for transporting trichocysts to the cortex for insertion, and also to observe a motility of unknown significance (wobble) apparently associated with the process of cortical insertion.


The effect of Eimeria neischulzi infection on leukocyte levels in the rat. Rats inoculated with 10,000 sporulated oocysts of Eimeria neischulzi had significantly higher total leukocyte counts on postinoculation days (PI) 1, 5, 6 and 7 when compared to control rats. Relative and absolute neutrophil counts increased concomitantly with a decrease in the relative lymphocyte levels in E. nieschulzi-infected rats on PI day 7. Absolute and relative neutrophil counts in infected rats on PI days 7 and 8 were closely correlated with the host's total oocyst discharge. The E. nieschulzi infection had no significant effect on the relative or absolute levels of monocytes or eosinophils. The described changes in leukocyte levels were not paralleled by a significant change in the erythrocyte count.


Continuous cultivation of Trypanosoma theileri at 37 C in bovine cell culture. Trypanosoma theileri was cultivated at 37 C in bovine bone marrow cell culture through 50 consecutive subcultures. Medium 199, supplemented with Bacto-peptone, vitamin B12, and fetal bovine serum, was utilized both for primary and continuous cultivation. The number of trypanosomes produced in culture averaged 8 x 10(6) (1-26 x 10(6)) trypanosomes/ml. In each subculture the organisms divided as epimastigotes and transformed into trypomastigotes; a round from was observed during the stationary and declining phase of growth. Gradual changes such as increased generation time, size reduction, and decreased trypomastigote production were observed as subculturing progressed. Cultured trypanosomes were infective for the bovine through the 48th serial transfer and could be cultivated at 26 degrees C.


Effect of colchicine on cell membrane and on biopterin transport in Crithidia fasciculata. Incorporation of 14C-labeled biopterin into Crithidia fasciculata was inhibited by 1 mM colchicine or lumicolchicine. These substance do not penetrate the cell membrane, hence they cannot interact with the subpellicular microtubules. In view of this, interference of colchicine with biopterin transport must occur on the outer surface of the cell membrane. Binding of colchicine to Crithidia was not temperature-dependent and did not exhibit saturation kinetics. These facts exclude a binding as in the case of tubulin, or similar proteins which may be present in the membrane. The results suggest an inhibition reflecting steric hindrance of the biopterin carrier system.


Differentiation-dependent decline of DNA synthetic activities in Naegleria gruberi. DNA of Naegleria gruberi strain NEG, grown in axenic culture, forms a band at a density of 1.6912 in CsCl gradient and has a GC content  of 31.8%. Incorporation of [3H]thymidine into DNA is much reduced in differentiating Naegleria immediately after the stimulation to transform, primarily because of the reduction in thymidine uptake by differentiating cells. In addition, there is a marked decrease in the rate of incorporation of [3H]thymidine and [3H]uracil into DNA at from 45 to 60 min after the stimulation for differentiation. This decrease in the rate of precursor incorporation into DNA appears to be due to the differentiation-dependent cessation of nuclear DNA synthesis. The differentiated phenotype (the flagellate) emerges at approximately 70 min after the stimulation, and over 90% of the population differentiates within the next 30 min. Synthesis of mitochondrial DNA is detectable until 190 min after the stimulation. Since the S phase of Naegleria lasts approximately 180 min, some cells in the population must cease synthesizing nuclear DNA in the middle of the S phase.


[Cryptogenetic osteolysis of the mandible (author's transl)]. A case of "cryptogenetic osteolysis of the mandible" is reported. This is a rare affection as only 13 cases of "phantom mandible" are known, but other sites exist (91 cases of phantom bone are known). The diagnosis is suspected after radiography, and confirmed by anatomopathological examination. No treatment for this affection has been described.


[Technical restatement about double contrast enema (author's transl)]. The prevention of the rectum and colon carcinoma consists principally in the radioendoscopic detection of colonic polyps. The double contrast enema is the best method for this detection. The usual practice of double contrast imposes the restatement of a comfortable method for the patient, simple and reliable for the doctor. The authors mean in this study to compare two groups of patients (group I and II) which differ by the double contrast technique used. If the colonic preparation, the injection implements and the investigation preliminaries are the same in both groups, there is no evacuation time of the barium enema which is added to trimebutine and stopped to the left iliac crest are specific with this method. The results allows an accuracy diagnosis of polyps.


[Radiological aspects of diffuse pulmonary lymphangiomyomatosis (author's transl)]. The authors report on 5 cases of diffuse pulmonary lymphangiomyomatosis. This disease occurs in women during the period of genital activity and usually presents with pulmonary signs (9/10) : dyspnoea, pneumothorax, pleural effusion, and hemoptysis. It is also found in association with renal angiomyolipomas and uterine fibromyolipomas. X-ray films of the lungs show : an interstitial syndrome, gas or fluid pleural effusions, and thoracic distention. None of these signs is constant, but the association of an interstitial syndrome with thoracic distention in a young woman appears to be specific for this affection.


[Highly selective arteriography and embolization in the treatment of angiodysplasias with shunt, in the limbs (author's transl)]. The authors discuss the role of highly selective arteriography and embolization in the treatment of angiodysplasias with shunt, in the limbs, after analyzing the results in three cases of embolization for congenital arterio-venous fistula of the limbs. They review the arteriographic data necessary for a better understanding of the physiopathology and compare the different therapeutic methods available. The importance of highly selective arteriography in guiding therapy, where embolization is of primary value, is stressed.


Seasonal variation in the histology of the testis of the red deer, Cervus elaphus. A histological study of the testes of stags shot in autumn (sexual season) and spring (quiescent period) indicated that the 3-fold increase in testicular size observed in the autumn was accompanied by increases in nearly all features studied (volumes of intertubular tissue, Leydig cells, blood vessels and peritubular cells; diameter and length of seminiferous tubules; the number of A1 spermatogonia and products of spermatogonial divisions, meiosis and spermiogenesis). There were, however, fewer A0 spermatogonia in the testes in autumn.


[Radiological aspects of cancer of the breast in men (author's transl)]. The radiological signs of malignant mammary tumours in men, which are similar to those observed in women, are reviewed. Several points have to be remembered, however; the common retro-mammillary location, the frequent nodular character, the skin involvement and the usual mamillary retraction, and, finally, the absence of characteristic microcalcifications. The interest of mammography to rate T in the TNM classification is also mentioned.


[Non-surgical extraction of iatrogenic intravascular foreign bodies : a report on 4 cases and review of the literature (author's transl)]. Four cases of non-surgical extraction of iatrogenic vascular foreign bodies are reported, in two of which a basket sound was used, and two others a metallic collar. The percutaneous route was used without denuding the veins. A review of the literature showed 83 cases of non-surgical extraction of vascular foreign bodies, and the methods and materials used are discussed.


[Lower limb lymphography in moderate lymphodynamic disturbances (author's transl)]. Based on the analysis of 87 pathologic complementary lymphangiographies of the lower limbs performed concomitantly with a lymphographic check-up of the pelvi-abdominal lymph nodes in various diseases, the authors have tried to establish the relationships of the moderate secondary disturbances of the lymph flow with the different pathologic antecedents affecting the lower extremities and their clinical symptoms. Emphasis is layed on the non-specificity of the early and delayed lymphangiographic aspects. The widest semeiology was recorded in phlebites and the less marked in arthroses. The more numerous and severe the antecedents, the more evident were the clinical and lymphographic signs. Penetrating wounds have a long lasting effect on the lymphatic walls. Lymphodynamic disturbances may occur in many pathologic states, phlebites, certain skin diseases, traumas. The therapeutic implications of these observations are discussed.


Hormone production by the intact human corpus luteum in vitro. Human CL removed during the menstrual cycle were cultured for up to 5 days. Production of progesterone, measured by radioimmunoassay of the culture fluid, continued throughout each experiment. Addition of hCG to the culture medium stimulated progesterone production in a biphasic manner.


[Hyperplastic Brunner glands and chronical renal insufficiency (author's transl)]. Enlarged Brunner glands (EBG) are an occasional finding in upper gastro-intestinal barium studies. The clinical manifestations vague upper abdominal symptoms or bleeding are rare. Brunner gland secretion is stimulated by different stimuli but especially by secretin. In our report E.B.G. has been observed in 9/15 chronically hemodialysed patients. This uncommon frequence of E.B.G. can be related to the high blood levels of secretin found in patients with chronic renal failure. E.B.G. could explain some of the gastro-intestinal complications occuring in these patients.


A local signal from the gravid horn to the ovary for the onset of parturition in rats. Rats were unilaterally ovariectomized on Day 17 of pregnancy and the times of onset of parturition were recorded. Unilateral ovariectomy did not delay the onset of parturition in bilaterally pregnant rats. In rats which were unilaterally pregnant (spontaneously or after ligation of one uterine horn), removal of the ovary on the side of the gravid horn led to delayed or partial parturitions. When fetuses and placentas were removed from one uterine horn on Day 13 and the ovary from the opposite side on Day 17, or when the uterine artery and/or vein were ligated on one side and the ovary removed from the other, about half of the parturitions were abnormal. It is suggested that a substance produced by the gravid uterine horn is transmitted to the ovary, primarily by a local circulatory system, and thus initiates the onset of parturition.


[Reflections concerning the radiological assessment of static flat foot in the child (author's transl)]. After a precise review of the numerous parameters studied classically in AP and lateral films of the feet under load, the authors emphasis 5 measurements which are easy to determine and which they feel to objectively cover all the deformities which may be found in the static flat foot. These are: Talo-calcaneal divergence in AP and lateral views, the angle between the calcaneum and the floor, the lateral cavitation index and, finally, the angle of the axis of the talus and of the 2nd metatarsal in AP. A score of 20 is attributed to each. A score of 0 to 20 is attributed to each of these points, with a possible total, therefore, of 100. A study of 119 cases of flat foot in the child treated surgically over a period of 6 years made it possible to draw the distinction between the severe flat foot requiring operation and with a total of less than 45 points, and flat foot requiring medical orthopaedic treatment only (more than 45), the score for the normal foot being of the order of 90 points. This radiological study also makes it possible to distinguish, amongst flat feet in children, straight flat foot with collapse of the medial arch but no valgus of the forefoot and valgus flat foot where there is pronation of the calcaneum and abduction of the forefoot. This distinction is important since it determines the choice of operation. Thus in a case of valgus flat foot Judet's so-called "horseman" operation is indicated whilst in a flat foot without valgus, transposition of the tibialis anterior is preferable. In many cases, the lesion is mixed and both surgical gestures are required.


[Arteriography of renal metastases of bronchial origin : use of angiotensin in one case (author's transl)]. A case of renal metastases from epidermoid bronchial cancer, discovered during an attack of hematuria, is reported. The patient had been operated upon for bronchial cancer two years ago and was in good general condition. Au I.V.U. showed the presence of an ill-defined renal mass. Selective renal arteriography demonstrated that the mass was hypervascularized and that a previous injection of angiotensin produced a malignant type of hypervascularization in the mass.


Effect of antisera against eggs and zonae pellucidae on fertilization and development of mouse eggs in vivo and in culture. A single intraperitoneal injection of female mice with rabbit antisera against denuded mouse eggs and isolated zonae pellucidae inhibited fertilization for at least 25--30 days. Intraperitoneal injection appeared to be more effective and lasted longer than subcutaneous or intramuscular injection but oral administration had no effect. Such a passive immunization of females given after fertilization had no effect on embryonic development or the sex ratio of fetuses. The fertilizing capacity of mouse spermatozoa was suppressed by treatment of the sperm suspension with anti-egg but not with anti-zona serum. Treatment of mouse eggs with these antisera did not affect their development to blastocysts in culture but did inhibit the shedding of the zona pellucida and attachment to the dish.


Studies of pregnancy-associated murine serum proteins. A pregnancy-associated murine protein (PAMP) with alpha1 electrophoretic mobility and an estimated molecular weight of 140,000  was present in serum from pregnant and sexually mature non-pregnant females, but could not be detected in the serum of males. During pregnancy the serum concentration of alpha1-PAMP rose to a maximum in mid-pregnancy followed by a decline to preconception levels before parturition; the protein was also present in fetal and neonatal serum and in amniotic fluid at low concentrations.


Testicular and epididymal sperm reserves of crossbred European boars raised and maintained in the humid tropics. The testicular and epididymal sperm reserves of 32 adult crossbred European boars (mean age 17.4 months, range 15--21 months) raised and maintained in Ibadan, Nigeria were 43.77 x 10(9) and 207.20 x 10(9) cells respectively, and were correlated (P less than 0.01) with age and organ weight. The distribution of spermatozoa in the epididymis was 16, 6 and 78% in the caput, corpus and cauda epididymidis respectively. The testicular and epididymal sperm reserves were correlated (P less than 0.05), suggesting that sperm production and storage are associated. All the values studied were comparable with those reported for boars kept in temperate climates.


The importance of prostaglandin synthesis for the initiation of blastocyst implantation in the hamster. In hamsters, localized areas of increased uptake of Evans Blue dye, representing the first uterine sign of blastocyst implantation, had an increase concentration of PGE and their appearance on Day 4 was prevented by treatment with indomethacin, an inhibitor of PG synthesis. Indomethacin treatment did not terminate pregnancy: the proportion of animals pregnant on Days 5, 7, 10 and 16 was not affected, although fetal mortality was slightly greater in these animals. Indomethacin treatment caused a decrease in the weights of Evans Blue sites on Day 5 and implantation swellings on Day 10, and the duration of gestation was slightly increased, indicating that implantation had been delayed. This delay did not result from changes of circulating progesterone levels or uterine blood supply. The PG synthesis inhibitors, indomethacin and meclofenamic acid reduced uterine PG concentrations and prevented the appearance of Evans Blue sites in ovariectomized pregnant hamsters treated with progesterone. It is suggested that PGs may be mediators in the uterine Evans Blue response which precedes implantation in the hamster.


Age-related differences in the response of the isolated testicular capsule of the rat to norepinephrine, acetylcholine and prostaglandins. The contractile response of the isolated testicular capsule to acetylcholine, norepinephrine and prostaglandins (A-2, E-1 and F-2alpha) was related to the age of the rat. Norepinephrine and PGA-2 caused an increased capsular response between 45 and 60 days of age, the time at which spermiogenesis begins. It is suggested that the activity of the testicular capsule is involved in the transport of non-motile spermatozoa from the testis and into the epididymis.


Role of FSH in regulating granulosa cell division and follicular atresia in rats. The effects of PMSG on the mitotic activity of granulosa cells and atresia of large folicles in 24-day-old rats were examined. The results showed that the labelling index (1) decreased in atretic follicles parallel with a loss of FSH binding, and (2) increased in hypophysectomized rats treated with FSH. It is concluded that FSH stimulates granulosa cell divisions and that atresia may be caused by reduced binding of FSH to the granulosa cells.


Observations on the calving of free-ranging tame red deer (Cervus elaphus). Calving was observed in 27 farmed red deer, most of which were calving for the first time. On average, parturition lasted 107 min and the placenta was released 98 min after calving. The postnatal development of 23 calves was watched. On average, the first sucking occurred 33 min after birth and the calves were able to stand 47 min after birth. There was wide variation in these times. Male first calves had a mean weight of 6.59 kg and females a mean weight of 6.00 kg, weighed dry after the first sucking. Out of 50 hinds put to the stag at 16 months of age, when their mean weight was 66 kg, 48 calved. None of 56 pregnant hinds, of which 50 were in their first pregnancies, died at calving time. Calf losses were 3 born dead and a further 6 which died soon after calving: these losses were 16.1% of pregnancies and 11.3% of calves born alive.


Plasma FSH, LH and testosterone levels in the male rat during degeneration of the germinal epithelium caused by severe heat treatment or ligation of the vasa efferentia. Rats were treated by exposure of the scrotum to a temperature of 43 degrees C for 30 min or bilateral ligation of the vasa efferentia and bled at 0, 3, 7, 14 and 21 days after treatment. In heat-treated rats FSH levels rose linearly from pretreatment levels while those in efferenticectomized animals remained unchanged for 3 days before increasing. In both groups FSH concentrations reached similar maximum values after 7 days and were significantly higher than those of intact controls at 7, 14 and 21 days. LH levels, although not generally different from those in the controls, rose from pretreatment levels in parallel with FSH. No differences were found in testosterone concentrations in any of the groups. Histological examination at 3 weeks after treatment confirmed that the germinal epithelium consisted mainly of spermatogonia and Sertoli cells. The cytoolgical appearance and lipid content of the Leydig cells of the aspermatogenic testes were indistinguishable from those of the controls and the weight and histological appearance of the accessory sex organs and the fructose content of the coagulating glands were also normal. It is concluded that the sterilizing effects of heat treatment and efferentiectomy are independent of changes in Leydig cell function and that the increase in gonadotrophin levels is related to the germ cell degeneration.


Activity and subcellular distribution of mouse uterine alkaline phosphatase during pregnancy and pseudopregnancy. The biochemical assay of alkaline phosphatase in the uterus of mice revealed a 13-fold increase in the activity of the enzyme during the peri-implantation period with a relatively short-lived maximum being reached on Day 7 of pregnancy. A similar increase in the activity of the enzyme occurred between Days 5 and 7 of pseudopregnancy in uterine horns of mice receiving a deciduoma-inducing stimulus on Day 4. The presence of factors in uterine homogenates which could possibly modify the activity of the enzyme could not be detected. Low and unaltered levels of alkaline phosphatase activity were found in the blood serum of mice between Days 1 and 10 of pregnancy, suggesting that no appreciable entry of the uterine enzyme into the circulation occurs in this species. Alkaline phosphatase activity in the uterine homogenates was associated with particulate fractions sedimented during centrifucation at at 500, 10,000 and 105,000 g, and only about 29% of the activity was associated with the cytosol fraction. The subcellular distribution of the enzyme activity was the same in decidualized and non-decidualized horns. The association of the enzyme with the particulate material in uterine cells was considered to involve lipoprotein membranes because treatment of homogenates with 0.2% (v/v) Triton X-100 solubilized the enzyme without affecting its catalytic activity.


Maternal and embryonic gene effects on placental weight in mice. Placental weight was measured on Days 12 and 18 of pregnancy in a population of mice consisting of two inbred strains and their derived generations. Maternal and embryonic genotypes influenced placental weight, the maternal genotypic effects changing with the stage of pregnancy. Effects of specific maternal and embryonic genotypes are discussed in terms of possible influence on the growth of maternally and embryonically derived placental tissues throughout pregnancy. Genotype-dependent differences in placental weight could not be accounted for simply by the presence or absence of H-2 antigenic differences between mothers and embryos. On Day 18 male embryos had heavier placentae than female embryos. The correlation between embryonic weight and placental weight declined in some mating groups from 12 to 18 days, suggesting differential placental weight loss late in pregnancy.


Ovulatory response of hypophysectomized hamsters to deferred injection of LH. Follicles failed to respond to the ovulating hormone stimulus (5 or 25 microgram LH) when this was given 8 h after hypophysectomy. Shorter delays resulted in full or partial (less than 6 ova) ovulation.


The effects of ingested petroleum on oviposition and some aspects of reproduction in experimental colonies of mallard ducks (Anas platyrhynchos). Compared to unmated mallard ducks fed an uncontaminated diet, unmated birds given food contaminated with 3 ml South Louisiana crude oil per 100 g dry weight showed an 84% decline in the daily rate of oviposition, a 33% decrease in egg-shell thickness and at autopsy more than 82% of the ovarian mass consisted of atretic follicles. Similar studies on groups of mated females showed that although the addition of 1 ml South Louisiana crude oil/100 g dry food had no effect on the daily rate of oviposition, none of the eggs had been fertilized while a concentration of 3 ml South Louisiana crude oil/100 g dry food suppressed the daily rate of oviposition significantly. Less than 25% of these eggs had been fertilized and only 40% of the fertilized eggs yielded viable ducklings. In both of these groups of mated birds, normal patterns of oviposition, fertilization and hatchability were restored after removal of petroleum from the diet. The addition of 1 ml Kuwait crude oil/100 g dry food had no effect on the rate of oviposition, the incidence of fertility or the hatchability of the fertilized eggs. The addition of 3 ml oil/100 g dry food completely abolished oviposition, but a normal rate of oviposition was restored when the concentration of the crude oil was reduced from 3 to 1 ml/100 g dry food. However, the incidence of fertilization remained low and none of the fertilized eggs gave rise to viable ducklings. Kuwait crude oil had no effect on shell thickness.


Uterine blood flow and prostaglandin levels in ovariectomized rabbits. Blood flow (measured by radioactive microspheres) through the uteri of ovariectomized rabbits increased significantly by 2 h, was lower at 4 and 8 h, and returned to control values by 24 h after an injection of 25 microgram oestradiol-17beta. Blood flow through the kidneys was not affected. Concentrations of PGF and PGE in uterine vein blood were elevated after oestrogen treatment. PGF values were significantly greater than control. PGE concentrations, while elevated, were not significantly different from control, although the pattern of release was similar to that of PGF. Pretreatment of animals with progesterone or L11204, or concurrent treatment with indomethacin did not modify the blood flow through the uterus. It is concluded that the increased uterine blood flow seen after oestrogen treatment is not related to prostaglandin production.


Glucose-6-phosphate dehydrogenase activity in somatic and germinal cells of the mouse testis. The activity of G6PD was examined by spectrophotometric and electrophoretic assays in cell fractions from the testes of mice at different ages (5-62 days). (1) The G6PD activity of the cells of the seminiferous tubule was as high or higher than that of the interstitial tissue. (2) The high G6PD activity of the testis of the immature mouse was mainly due to a high specific activity of the Sertoli cells which declined with age. (3) The G6PD activity was more easily lost during culture from the germinal cells than from the interstitial or Sertoli cells. (4) All the cell types of the testis contained G6PD and hexose-6-phosphate dehydrogenase. The functional significance of the high G6PD activity in the Sertoli cells of immature mice is not at present understood.


The effect of passive immunization against oestrogens on the onset of parturition in the ewe. Six ewes were treated twice daily with intravenous injections of antiserum to oestrogens and 3 ewes received normal sheep serum from Day 140 of gestation until parturition. All 9 ewes experienced normal parturitions and produced healthy active lambs after similar gestation lengths. Progesterone and prostaglandin F concentrations in maternal jugular venous plasma were similar in the immunized and control ewes, but total unconjugated oestrogen concentrations were significantly higher in the immunized ewes (P less than 0.005). It is concluded that immunization of the ewe against total unconjugated oestrogens did not affect the normal occurrence of parturition.


Embryonic stimulation of ovine and bovine corpora lutea. Preimplantation embryos, recovered from sheep on Days 13-15 of pregnancy, were incubated with luteal tissue from cyclic ewes. Extracts of ovine embryos were incubated with luteal tissue from cyclic Holstein cows. Embryos and embryo extracts significantly increased progesterone production by ovine and bovine luteal tissue in vitro. The embryos themselves did not produce measurable amounts of progesterone. We suggest that the ovine preimplantation embryo produces a substance with luteotrophic properties which contributes to the maintenance of early pregnancy.


Effects of medium composition and progesterone on maturation in vitro of rabbit oocytes from Graafian follicles of different sizes. Rabbit oocytes from large (1-1.5 mm diam.), medium (0.5 mm) and small (0.15-0.25 mm) antral follicles were cultured in five chemically defined media. In all media, oocytes from large antral follicles showed the highest incidence of meiotic activity followed by those from follicles of medium size. Most oocytes from small follicles did not resume meiosis in culture. The addition of glutamine to a standard medium for ovum culture significantly improved maturation of oocytes from medium-sized follicles but did not affect those from large or small follicles. When polyvinylpyrrolidone was substituted for bovine serum albumin, maturation of oocytes from large and medium-sized follicles was reduced. Progesterone at a concentration of 10 micrometer did not affect maturation, but 100 micrometer-progesterone blocked germinal vesicle breakdown in oocytes from medium-sized follicles and reduced both germinal vesicle breakdown and polar body formation in oocytes from large follicles. This effect was reversible.


The effect of cold shock on mouse oocyte maturation in vitro. Maintenance of mouse ovaries in ice-cold medium for 1, 2 or 4 h before removing the oocytes did not alter the incidence of spontaneous maturation or increase the number of oocytes degenerating, fragmenting or forming 2 equal blastomeres in culture.


The effects of glycerol on the metabolism and ultrastructure of boar spermatozoa. Cooling diluted boar semen to 5 degrees C and the addition of glycerol at 20 degrees C and 5 degrees C all depressed the subsequent metabolism of glucose, but had no effect on total oxygen uptake or lactate production. Ultrastructural studies showed that although glycerol had no effect on middle-piece cytology, it increased the incidence of acrosomal vesiculation at 5 degrees C. It is concluded that acrosomal vesiculation does not affect the metabolism of spermatozoa and it is suggested that the reported detrimental effect of glycerol on the fertilizing capacity of spermatozoa is related to its membrane activity.


The protective action of glycols against freezing damage of mouse and rat embryos. Eight-cell mouse and rat embryos were frozen to -79 degrees C or -196 degrees C in the presence of ethylene, diethylene, triethylene, propylene or polyethylene glycol. Ethylene glycol was the most effective cryoprotectant for mouse and rat embryos and considerable protection against damage during freezing and thawing was also afforded by propylene glycol. The degree of protection given by the other glycols was relatively low. Mouse embryos survived freezing after only 0.1 min exposure to ethylene glycol at 0 degrees C but exposure for longer periods was necessary with the other glycols. Mouse embryos that survived freezing and thawing with a glycol as the protective agent were capable of developing to full-term fetuses.


The expression of surface antigens on three trophoblastic tissues in the mouse. The expression of paternal and maternal antigens on three types of mouse trophoblast cultured in vitro has been examined with the mixed haemadsorption test. Primary trophoblastic giant cells outgrown from blastocysts and placental trophoblast from 16-day pregnancies expressed antigens of both sources at all stages in culture. Secondary trophoblastic giant cells outgrown from the tip of 8-day ectoplacental cones did not give a positive reaction until they had outgrown for 3-5 days. Microdensitometry after Feulgen staining showed that the cells which gave a positive mixed haemadsorption response were polyploid. Incubation of blastocysts and ectoplacental cone tissue with progesterone, oestradiol-17beta and hCG did not affect the results.


Milk progesterone levels in relation to conception, repeat breeding and factors influencing acyclicity in dairy cows. Milk samples were collected twice weekly from 535 dairy cows between parturition and the re-establishment of pregnancy to monitor ovarian activity by measurement of milk progesterone levels by radioimmunoassay. The mean progesterone levels after fertile and non-fertile first inseminations were similar from 21 days before until 13 days after insemination, those in non-pregnant animals declined while those in pregnant animals continued to rise until Day 22. Progesterone profiles of 47 repeat breeder cows (i.e. receiving greater than 3 inseminations) demonstrated that a variety of patterns was associated with the poor conception rate. A study of the post-partum interval showed that cows resumed cycles by 24 +/- 0.6 days after calving; the length of this interval varied significantly with the season of calving and non-significantly with the lactation number (i.e. age) of the cow, but was not related to yield. Of the 535 cows studied, 5.2% had not started to cycle within 50 days of calving and a further 5.2% resumed cycles which subsequently ceased. The progesterone profiles of acyclic cows indicated that after treatment with 0.5 mg LH-RH or a progesterone-releasing intravaginal device (PRID) for 14 days 75% of animals apparently ovulated but the calving to conception interval was not significantly altered compared with that of untreated control cows.


The effect of exogenous intrauterine progesterone on the amount and prostaglandin F2alpha content of menstrual blood in dysmenorrheic women. Women with complaints of moderate or severe dysmenorrhea received intrauterine progesterone contraceptive system (16 patients) or placebo systems releasing no hormone (8 patients). Tampons were collected during the period prior to insertion and from 11 and 6 women, respectively, in the two groups at the second and fourth postinsertion periods. Prostaglandins in menstrual blood were extracted, and the amount and concentration of PGF2alpha analyzed for each patient. The menstrual blood loss (MBL) was determined by the method of Hallberg and Nilsson. The total PGF2alpha content was significantly lower in the group using progesterone systems than in the placebo group at collections 2 and 4 and was well below the preinsertion level; in placebo users the content tended to be slightly higher than it had been before insertion. The MBL increased approximately 60% above preinsertion levels in five of the six women using placebo units and decreased approximately 40% in 10 of 11 women with progesterone systems. Of the eight women in the progesterone group who had reported severe dysmenorrhea prior to insertion, seven reported an improvement; three of six in the placebo group reported a lower degree of improvement. These findings suggest that the decreased biosynthesis of PGF2alpha is a concomitant of intrauterine progesterone administration and may be a basis for the ability of the Progestasert system to diminish menstrual pain.


Suction curettage of the endometrium in an ambulatory patient. A review is presented of patients in whom suction curettage of the endometrium was performed as an office procedure. A total of 978 curettages were performed on 943 patients. In 14 patients (1.1%) the procedure was not completed primarily because of marked cervical stenosis. Fifteen cases of adenocarcinoma of the endometrium and 28 cases of adenomatous hyperplasia and atypical adenomatous hyperplasia of the endometrium were diagnosed. The suction curettage was demonstrated to be a simple, safe, efficient and cost-saving alternative to a hospital D&C.


Monitoring care in abortion clinics.

Monitoring care in abortion clinics. Medical directors of clinics must monitor three aspects of service to ensure high-quality care in abortion clinics: (1) physician training and selection, (2) patient selection, and (3) abortion outcome monitoring as a means of providing an ongoing audit of clinic performance standards. Methods and criteria for monitoring and evaluating these parameters are discussed, and the importance of such monitoring is emphasized.


Prenatal diagnosis of the Lesch-Nyhan syndrome. Amniocentesis provides the prenatal diagnosis of chromosomal abnormalities and many biochemical disorders. Many of the biochemical assays are not routinely performed in many institutions. Those institutions utilizing autoradiographic studies routinely can make a diagnosis of biochemical disorders satisfactorily by utilizing a combination of bank cells, amniotic fluid cells and autoradiographic techniques. An example is given of this technique used in a patient with a family history of Lesch-Nyhan syndrome.


The psychiatric abortion consultation.

The psychiatric abortion consultation. The role of the psychiatric consultant has changed with the recent liberal "on demand" abortion legislation. This paper emphasizes factors relevant to the psychiatric consultant in the evaluation of the adolescent patient, the retarded patient and the patient with psychiatric illness. In addition, a survey of the literature is made to identify the patient who is at high risk of developing postabortion psychiatric complications. The authors conclude that postabortion complications are infrequent and that there are no absolute psychiatric contraindications to elective abortion.


Forceps operations in perspective. II. Failed operations. Eighteen recent cases of failed forceps operations are reviewed. Although no maternal or fetal deaths occurred, low Apgar scores were found in more than half of those patients considered at significant risk with the use of the Perinatal Morbidity Index (PMI) and Maternal Morbidity Index (MMI) developed at our institution. Among low-risk patients more favorable results were found. Whenever difficulty in a forceps delivery is encountered because of misjudgement of pelvic capacity or fetal size, further attempts at vaginal delivery should cease and a cesarean section should be performed. This procedure will most likely lead to a favorable outcome for mother and child. A patient already at significant risk should, under ordinary circumstances, not be considered a candidate for a forceps trial. If the trial is successful, the infant has a nearly 50% chance of unfavorable outcome; if it is unsuccessful, the chance of an unfavorable outcome is 64%.


Treatment of benign breast disease with danazol: a follow-up report. One hundred thirty-five women with benign breast disease (BBD) were treated with danazol, an impeded androgen. Their ages ranged from 19 to 60 years (mean age, 30). The dose varied from 100 to 800 mg per day for 90 to 180 days, depending upon the severity of the disorder. Overall relief of pain was observed in 97% and of tenderness in 90.5%. There was complete or marked improvement of nodosities in 73%. Seventy-eight patients were followed every six months for two to four years. The recurrent symptoms were pain in 6%, tenderness in 6% and nodosities in 10%. Incidentally, we found that 29.3% of infertile women with BBD conceived within 24 months after cessation of a course of therapy. The side effects, when present, were trivial.


Rupture of a gravid bicornuate uterus in a primigravida associated with clostridial and bacteroides infection. The case is presented of a primigravid patient with spontaneous rupture of a bicornuate uterus associated with significant anaerobic infection. Thinning of the myometrium at the site of the rupture was noted in the pathologic specimen. The anaerobic infection, primarily contained in the intact amniotic sac, resolved with total abdominal hysterectomy, bilateral salpingo-oophorectomy, pelvic drainage and antibiotic therapy.


Synthesis and biochemical evaluation of inhibitors of estrogen biosynthesis. The synthesis and biochemical evaluation of various C19-steroidal derivatives as inhibitors of estrogen biosynthesis are described. Steroids with substitutions on the A or B ring were synthesized by Michael addition of various thiol reagents to appropriate dienone intermediates. An in vitro assay employing the microsomal fraction isolated from human term placenta was used to evaluate aromatase inhibitory properties. Agents exhibiting high inhibitory activity were further evaluated in inital velocity studies (low product formation) to determine apparent Ki values. Several 7alpha-substituted androst-4-ene-3,17-diones were effective competitive inhibitors and have apparent Ki values equal to or less than the apparent Km of 0.063 microM for the substrate androstenedione.


Cholecystokinin (pancreozymin). 4. Synthesis and properties of a biologically active analogue of the C-terminal heptapeptide with epsilon-hydroxynorleucine sulfate replacing tyrosine sulfate. The influence of tyrosine O-sulfate, the 27th residue in the sequence of cholecystokinin (pancreozymin) (CCK-PZ), on the contraction of gall bladder of guinea pigs and on the release of amylase in isolated pancreatic cells of the same animal was studied with an analogue of the biologically active C-terminal heptapeptide, CCK-PZ-(27--33). In the new analogue, tyrosine O-sulfate was replaced by epsilon-hydroxynorleucine O-sulfate. The synthetic peptide was found a full agonist in these tests, not quite as potent as the unaltered heptapeptide, but much more active than the previously prepared and studied serine O-sulfate containing analogue. Thus, the distance of the sulfate ester group from the peptide backbone has a major influence on the biological activity of CCK-PZ.


A new warfarin metabolite: structure and function. The metabolism of the clinically utilized, anticoagulant warfarin [4-hydroxy-3-(3-oxo-1-phenylbutyl)-2H-1-benzopyran-2-one] by rat liver microsomes has been investigated. The structure of a new warfarin metabolite [4-hydroxy-3-(3-oxo-1-phenyl-1-butenyl)-2H-1-benzopyran-2-one] (dehydrowarfarin) has been determined by mass spectral comparison with the chemically synthesized compound. The formation of dehydrowarfarin is catalyzed by cytochrome P-450 and is unusual in that the final product is effectively dehydrogenated warfarin.


Synthetic sulfur-containing amino acids. Inhibition of transport systems in S37 ascites tumor cells. The preparation of a series of synthetic sulfur-containing amino acids is described. These compounds included heterocyclic analogues of L-cysteine, DL-norcysteine, and DL-homocysteine. The amino acids were assessed for their ability to inhibit the neutral amino acid transport systems of the Sarcoma 37 ascites tumor cell and their inhibitions were compared with those of L-methionine and L-ethionine. Transport studies indicated that the amino acids synthesized were capable of inhibiting the uptake of [3H]-L-histidine in the S37 cell.


Synthesis of potential hypolipidemic agents. Reaction of substituted phenyl 2,3-epoxypropyl ethers with adenine, uracil, and thymine. Three adenine derivatives were found to be active hypolipidemic agents at 10 mg/kg/day. The most active compound was 9-(p-chlorophenoxy-2-hydroxypropyl)adenine (5). Compound 5 significantly lowered serum triglyceride and cholesterol content in male Sprague-Dawley rats and inhibited hepatic phosphatidate phosphohydrolase activity in vitro. The synthesis of these agents involved reacting adenine, uracil, and thymine with a series of substituted phenyl 2,3-epoxypropyl ethers.


New synthetic routes to tilorone dihydrochloride and some of its analogues. New synthetic routes to the orally active, interferon-inducing antiviral agent tilorone dihydrochloride, 2,7-bis-[(diethylamino)ethoxy]fluoren-9-one dihydrochloride (1a), were developed. The routes involved the preparation and solvolysis of tetrazonium fluoroborate salts of 2,7-diaminofluoren-9-one. Nonplanar (1b), 9-sulfone (1c), and fluorene (1d) analogues of tilorone dihydrochloride were also prepared. Compounds 1b and 1c were evaluated for interferon induction.


Synthesis and analgetic activity of some benzomorphan analogues. The benzomorphan analogues, 8-hydroxy-3-methyl-2,3,4,5-tetrahydro-1,4-methano-1H-3-benzazepine (1), 8-hydroxy-2-methyl-2,3,4,5-tetrahydro-1,4-methano-1H-2-benzazepine (2), 9-hydroxy-2-methyl-1,2,3,4,5,6-hexahydro-1,5,-methano-2-benzazocine (3), and 10-hydroxy-2-methyl-2,3,4,5,6,7-hexahydro-1,6-methano-1H-2-benzazonine (4), have been synthesized in order to evaluate their analgetic activity. Only slight analgetic activity was found in any of these compounds. The importance of nitrogen to aromatic ring distance for the analgetic-receptor interaction is discussed.


Structure-activity relationships for the inhibition of acrosin by benzamidine derivatives. A series, consisting of 52 benzamidine derivatives, was evaluated for inhibitory activity against homogeneous boar sperm acrosin. All of the compounds in the series proved to be more potent than benzamidine (Ki = 4.0 x 10(-6) M), with one of the derivatives, alpha-(4-amidino-2,6-diiodophenoxy)-3-nitrotoluene (compound 16), showing outstanding potency with a Ki value of 4.5 X 10(-8) M. Although all of the derivatives were effective acrosin inhibitors, structural specificity was observed within homologous groups of compounds. The information gained from this preliminary study should prove extremely beneficial in the design and synthesis of future acrosin inhibitors.


Phosphorus-nitrogen compounds. 22. Synthesis and antitumor activity of arylsulfonylhydrazone analogues. A series of pyridine-2-carboxaldehyde N-oxide and pyridine-2-carboxaldehyde (thio)phosphoric hydrazones and two cupric chelates was synthesized. The hydrazones, chelates, and combinations of hydrazones and cupric chloride were tested against mice bearing P388 lymphocytic leukemia, Sarcoma 180, or Ehrlich carcinoma ascites cells. The effects of various structural modifications of the hydrazones on antineoplastic activity for this latter system were determined. In general, the pyridine-2-carboxaldehyde thiophosphoric monohydrazones containing P-phenyl or P-phenoxy substituents possessed the highest activity when concurrently administered with cupric ion, whereas the ligands themselves were inactive. Two of the compounds were prepared with P-hydroxyl groups to permit increased hydrophilicity. The ability of the hydrazones to chelate cupric, ferrous, and cobaltous salts was investigated, and discrepancies between determined and calculated log P values for three compounds are discussed.


Three-dimensional mapping of the sweet taste receptor site. The active sites of the receptors for sweet and bitter tastants are shown to be related by a simple symmetry operation. This relationship, in turn, allows the identification of the critical geometrical features of both receptor sites. The model proposed for the sweet site is shown to be consistent with a large number of (conformationally rigid) sweet molecules.


Potential anticancer agents. 16. Methotrexate analogues with a modified peptide side chain. Nine analogues of methotrexate, in which the side chain is modified by replacement of the terminal glutamyl moiety with other amino acids, were synthesized from 2,4-diamino-6-(chloromethyl)pteridine. None of these compounds exhibited significant activity against L1210.


Potential anticancer agents. 17. Analogues of methotrexate with a tripeptide side chain. Nine tripeptide analogues of methotrexate were synthesized from 2,4-diamino-6-(chloromethyl)pteridine. Only N-[N-[4-[2,4-diamino-6-pteridinyl)methyl]amino]benzoyl]glycyl-DL-aspartic acid (1a) showed moderate activity against L1210 murine leukemia (ILS = 69%) and W 256 carcinosarcoma (TGI = 55%).


Synthesis of substituted 1-hydroxy-2-naphthanilides as potential cestodicidal agents. A series of substituted 1-hydroxy-2-naphthanilides 4--14 has been synthesized by treating 1-hydroxy-2-naphthoic acids 2 with substituted anilines 3. The nitronaphthanilides, on reduction and subsequent treatment with thiophosgene, gave the corresponding substituted 2-naphthanilide isothiocyanates 30--33. Substitution of the chlorine of 8 by various cyclic amines gave 3'-nitro-4'-substituted 1-hydroxy-2-naphthanilides 15--21. Various 3-aryl-4-oxo-2,3-dihydro-1,3-naphthoxazine-2-thiones 34-43 and 3 aryl-2,4-dioxo-2,3-dihydro-1,3-naphthoxazines 44--51 have been prepared by reacting the corresonding naphthanilides with thiophosgene and ethyl chloroformate, respectively. All the compounds were tested for their cestodicidal activity against Hymenolepis nana infection in rats; 30 was found to be the most active compound of the series, showing 100% clearance of infection at a single oral dose of 7.5 mg/kg.


Stereoselective effects of cis- and trans-cyclopropylbis (dioxopiperazines) related to ICRF-159  on metastases of hamster lung adenocarcinoma. The synthesis for cis-4,4' (1,2-cyclopropanediyl)bis(2,6-piperazinedione) (cis-3) is discussed. Stereoselective effects on metastases of cis-3 and the previously reported trans-2 isomer were compared to conformationally mobile ICRF-159 using a Syrian hamster lung adenocarcinoma (LG1002). Whereas ICRF-159 and cis-3 significantly inhibited lung metastases the trans-2 isomer significantly increased the number of metastatic nodules in the lung. Thus, these studies have revealed that, at least in one tumor model, antimetastatic activity can be separated from metastatic potentiating activity by controlling drug geometry.


Synthesis and pharmacological evaluation of a clofibrate-related tricyclic spirolactone, 5-chloro-4',5-dihydrospiro[benzofuran-2(3H),3'(2'H)-furan]-2'-one. The chemistry and pharmacology of the title compound, spirolactone 4, are reported. The synthesis represents a new approach to the preparation of spiro compounds. The pharmacological profiles of 4 are compared to that of clofibrate in Triton-induced hyperlipidemic, sucrose-fed, and normal Sprague-Dawley rat models. Clofibrate was effective in all animal models, but the spirolactone 4 exhibited antitriglyceridemic activity only in the Triton model. The inactivity of 4 in sucrose- and chow-fed rats could not be attributed to a resistance to hydrolysis by serum esterases. Comparative studies revealed that inhibition of hepatic HMG-CoA reductase activity may not be an index of hypocholesterolemic action in sucrose-fed rats. Additionally, only clofibrate exhibited significant changes in components of the hepatic microsomal monooxygenase system.


Molar volume relationships and the specific inhibition of a synaptosomal enzyme by psychoactive cannabinoids. The ability of a number of lipophilic compounds to inhibit the mouse-brain synaptosomal enzyme acyl coenzyme A:lysophosphatidylcholine acyltransferase has been measured in vitro. Psychoactive cannabinoids inhibit the enzyme at concentrations much lower than is predicted from their capacity to act as lipid-soluble anesthetics. Nonpsychoactive cannabinoids do not show specific inhibition. Molar volume relationships are used to show that, while all lipid-soluble molecules exert some inhibitory effect in proportion to their ability to dissolve in biological membranes, psychoactive cannabinoids have an inhibitory effect greatly in excess of their anesthetic potency. The isoprenoid convulsant thujone has been suggested to have psychoactivity similar to cannabinoids but does not mimic the cannabinoids in inhibiting the synaptosomal enzyme. Molar volumes and specific interactions are used in structure-activity correlations which yield information on the relative concentrations of biophase in drug-responsive systems and the specificity of membrane-active drugs.


Prodrugs of 9-beta-D-arabinofuranosyladenine. 1. Synthesis and evaluation of some 5'-(O-acyl) derivatives. A number of 5'-(O-acyl) derivatives of 9-beta-D-arabinofuranosyladenine (ara-A, VIRA-A) (2a-k) were prepared by direct acylation of the parent nucleoside 1 in pyridine-N,N-dimethyliformamide. These compounds, designed as prodrugs for 1, offer a range of solubilities and lipophilicities indicating for several examples improved solubility and the potential for improved membrane transport over 1. All are resistant to deactivation by adenosine deaminase. Of special interest is the 5'-(O-valeryl) derivative 2d that shows a marked increase in antiviral activity over 1.


Synthesis and antiinflammatory activity of some 1,2,3- and 1,2,4-triazolepropionic acids. All possible "nonadjacent" phenyltriazolepropionic acids were synthesized and tested for antiinflammatory activity. Two of the isomers displayed activity approximately equal to phenylbutazone: the 4-phenyl-1,2,3,-triazole-2-propionic acid (7) and its reverse counterpart, 2-phenyl-1,2,3-triazole-4-propionic acid (6). The other five isomers were inactive. Since these seven acids are geometrically congruent and possess similar lipophilic characters, antiinflammatory activity must depend on some property that is a function of how the carbon and nitrogen atoms are arranged in the triazole ring.


4-(6-Methoxy-2-naphthyl)butan-2-one and related analogues, a novel structural class of antiinflammatory compounds. A series of compounds related to 4-(6-methoxy-2-naphthyl)butan-2-one has been prepared and tested for antiinflammatory activity by the cotton pellet granuloma method. Compounds possessing a small lipophilic group such as methoxyl, methyl, or chloro in the 6 position in conjunction with a butan-2-one side chain in the 2 position of the naphthalene ring were most active. The indtroduction of a methyl group along the side chain was invariably deleterious. Good activity was generally retained by forming esters of a butan-2-ol side chain.


Studies on 1-substituted 4-(1,2-diphenylethyl)piperazine derivatives and their analgesic activities. 2. Structure-activity relationships of 1-cycloalkyl-4-(1,2-diphenylethyl)piperazines. Forty-six 1-cycloalkyl-4-(1,2-diphenylethyl)piperazines were synthesized. The influence of substituents on phenyl groups of 1-cycloalkyl-4-(1,2-diphenylethyl)piperazines 4a-c on the analgesic activity was investigated in experimental animals. The most active compounds, 5a-c, in this series had a m-hydroxyl group on the 2-phenyl group of 4a-c, while morphine has a phenolic hydroxyl group para to th- aminoethyl moiety. Their activities were 23-56 and 23-38 times those of their original compounds 4a-c and morphine, respectively, tested by the D'Amour-Smith method after subcutaneous administration.


Absolute configuration of (+)-5-(o-hydroxyphenyl)-5-phenylhydantoin, the major metabolite of 5,5-diphenylhydantoin in the dog. 5-(3-Hydroxyphenyl)-5-phenylhydantoin (m-HPPH) has been resolved by crystallization of the brucine salts. The (+) enantiomer has been converted to (-)-5-cyclohexyl-5-phenylhydantoin, a compound previously demonstrated to have the R configuration. The R configuration can accordingly be assigned to (+)-m-HPPH, the principal metabolite of 5,5-diphenylhydantoin (phenytoin) in the dog.


Calculated properties of arene oxides of biological interest. 1. Molecular orbital examination of simple models. The INDO calculational formalism is shown to account for the relative ease of carbonium ion formation and for the variation in isomerization rates of some simple arene oxides. Transition-state energy differences provide a reasonable correlation with observed isomerization rates for benzene oxide, methyl-substituted benzene oxides, naphthalene 1,2-oxide, and phenanthrene 9,10-oxide.


Synthesis and quantitative structure--activity relationships of some antibacterial 3-formylrifamycin SV N-(4-substituted phenyl)piperazinoacethydrazones. A series of 14 3-formylrifamycin SV N-(4-substituted phenyl)piperazinoacethydrazones has been synthesized and evaluated for their antimicrobial activity. The compounds were found active against Bacillus subtilis, Staphylococcus aureus, Mycobacterium phlei, and Mycobacterium tuberculosis but not as active as rifampin. The compounds also exhibited significant activity against Clostridium perfringens and in this bacterial system some were more active than rifampin. The QSAR showed that the activity against B. subtilis depended only on lipophilicity, and the regression equation was linear. A parabolic relationship between the antibacterial activity and lipophilicity of the compounds was found in Staph. aureus. Additionally, the activity was dependent upon the electronic and steric effects of the phenyl substituents. The sensitivity of M. phlei to the compounds was found to correlate well with a linear combination of hydrophobic, electronic, and steric parameters. No statistically significant correlation was possible between the physicochemical parameters studied and the activity of the compounds against C. perfringens and M. tuberculosis.


Potential inhibitors of S-adenosylmethionine-dependent methyltransferases. 7. Role of the ribosyl moiety in enzymatic binding of S-adenosyl-L-homocysteine and S-adenosyl-L-methionine. A series of 2',3'-acyclic analogues of S-adenosyl-L-homocysteine were synthesized and evaluated as inhibitors of S-adenosyl-L-methionine-dependent methyltransferases. The 2',3'-acyclic analogues were prepared by periodate oxidation of the corresponding ribonucleosides, followed by reduction of the intermediate dialdehydes with sodium borohydride. These 2',3'-acyclic ribonucleosides were inactive as inhibitors of histamine N-methyltransferase, catechol O-methyltransferase, phenylethanolamine N-methyltransferase, and hydroxyindole O-methyltransferase. These results suggest that the rigidity of the ribosyl ring of S-adenosyl-L-homocysteine is crucial to its enzymatic bindings.


Pharmacology on rat ileum of certain 2-substituted 3-(dimethylamino)-5,6-dimethoxyindenes related to 5,6-(methylenedioxy)indene calcium antagonists. Whereas the 2-propyl- and 2-butyl-5,6-(methylenedioxy)indene calcium antagonists reversed the spasmogenic action of several agonists including PGF2alpha and acetylcholine at 5 X 10(-5) to 10(-4) M on the rat ileum, the corresponding 5,6-dimethoxy analogues exhibited spasmogenic activity at higher concentration (10(-4)-10(-3) M) and exhibited neither spasmogenic nor spasmolytic activity at lower (10(-6)-10(-5) M) concentration. The results are compared to the methyl and 2-ethyl analogues. At 10(-4) M only the butyl analogue was capable of moderate antagonism of acetylcholine and at 10(-3) M all four analogues were capable of moderately antagonizing the actions of acetylcholine.


Antitumor activity of 1,2-diaminocyclohexane--platinum complexes against sarcoma-180 ascites form. Platinum complexes derived from three isomers of 1,2-diaminocyclohexane have been synthesized and their antitumor activities were evaluated against ascites Sarcoma-180. All the platinum complexes had high antitumor activity. Platinum complexes derived from cis-1,2-diaminocyclohexane were more effective than those derived from trans-l-and trans-d-1,2-diaminocyclohexane. Among the platinum complexes tested, oxalato(cis-1,2-diminocyclohexane)platinum had a remarkably high therapeutic index. Modification of the nonleaving group as well as that of the leaving group is important in order to find better antitumor platinum complexes.


Synthesis and antinociceptive activity of 7-methoxycodeine. (-)-7-Methoxycodeine was synthesized from (-)-1-bromosinomeninone in three steps with an overall yield of 29%. The introduction of the 7-methoxy group into the C ring of codeine did not decrease its oral activity. 7-Methoxycodeine was unstable in acidic media. Its oral activity was however, not likely to be due to conversion to the acid-stable (-)-sinomeninone, since the latter was orally inactive.


2,6-Methano-3-benzazocine-11-ropanols. Lack of antagonism between optical antipodes and observation of potent narcotic antagonism by two n-methyl derivatives. Resolution of a 2,6-methano-3-benzazocine-11-propanol analogue of buprenorphine showed that the biological activity resides in the levo antipode. An attempt to enhance agonist activity by preparation of N-methyl derivatives resulted in two compounds three and five times as potent as nalorphine as antagonists of phenazocine. These compounds are the most potent N-methyl narcotic antagonists reported to date.


Electronic aspects of the antibacterial action of sulfanilamides. Intramolecular interactions in N1-substituted sulfanilamides (SA) can rationalize the trend of their antibacterial powers with the use of a resonance scheme, derived from d orbital symmetry and tested with an extensive spectroscopic investigation on amidic, imidic, and anionic SA. On quantitative grounds, a good relationship is presented between the antibacterial power and the proton chemical shift of the p-amino group. The electronic features for high activity are described.


Antiallergic activity of some 9H-xanthen-9-one-2-carboxylic acids. The synthesis and antiallergic activity of a new series of 9H-xanthen-9-one-2-carboxylic acids are described. Antiallergic activity was evaluated in the rat passive cutaneous anaphylaxis (PCA) screen. Biological results were analyzed using regression analysis techniques, and the antiallergic activity of the compounds in the series was found to be highly correlated with substituent size.


Antineoplastic properties of arylsulfonylhdrazones of 3-formylpyridazine 2-oxide and 4-formylpyrimidine 3-oxide. The antineoplastic activity of several arylsulfonylhydrazones of 4-formylpyrimidine 3-oxide and of 3-formylpyridazine 2-oxide has been investigated. Derivatives of the latter heteroaromatic N-oxide showed excellent antineoplastic potency against the murine neoplasm Sarcoma 180 but were inactive against leukemia L1210. In contrast, derivatives of 4-formylpyrimidine 3-oxide were inactive against both of these transplanted tumors.


Antimycotic imidazoles. 2. Synthesis and antifungal properties of esters of 1-[2-hydroxy(mercapto)-2-phenylethyl]-1H-imidazoles. The synthesis of carboxylic and (thio)carbonate esters of 1-[2-hydroxy(mercapto)-2-phenylethyl]-1-H-imidazoles, some of which are formally related to miconazole and its analogues by replacement of an ether with an ester linkage, is described. In antifungal bioassays a number of compounds display in vitro and, in a few cases, in vivo activities comparable to that of miconazole. In this series lipophilicity within a relatively narrow range is shown to be a necessary, although not sufficient, criterion for in vitro and, in particular, in vivo antifungal activity.


alpha-(2-Pyridine)benzyl aryl ketones as potential hypocholesteremic agents. A series of alpha-(2-pyridine)benzyl aryl ketones were prepared as potential hypocholesteremic agents. The synthesis of these compounds was by conversion of 2-benzylpyridine to its anion with n-butyllithium and condensation of the anion with selected aromatic esters. The ketones were tested for their hypocholesteremic activity in rats, and those compounds showing activity were further tested for estrogenicity. Only those aryl ketones with substituents in the ortho position showed a statistically significant reduction in serum cholesterol. Of these compounds the tert-butyl derivative had the most favorable hypocholesteremic to estrogenic ratio.