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The specificity of anatomo-clinical observations were investigated on 776 out of 982 consecutive persons hospitalized at the University Psychiatric Clinic of Geneva. Discriminant function analysis shows that most of the anatomical classes (no dementia, senile dementia, Alzheimerized senile dementia and Alzheimer's presenile dementia, vascular dementia, combined dementia nnd undefined form of encephalopathy) are at least partially separable (less than 50% overlap). On the basis of anatomical criteria, Alzheimer's presenile dementia is not separable from Alzheimerized senile dementia, and senile dementia is not separable from combined dementia. Differentiation between the anatomical classes is improved by a preliminary analysis based on clinical diagnosis. Senile plaques account for 43.4% of the total variation between the anatomical classes. The coefficient of agreement between anatomical and clinical diagnosis is 0.27, which is highly significant. The diagnosis of senile dementia has a poor specificity, while the diagnosis of senile Alzheimerized dementia has a better one. The diagnosis of combined dementia has to be reserved for cases with a similar intensity of vascular and degenerative changes. Alzheimer's presenile dementia has a distinct dominant hereditary pattern and must be considered a separate entity. The high specificity of the diagnosis of Alzheimer's presenile dementia makes it possible to conduct epidemiologic and genetic surveys based on clinical data.

Cats were trained to discriminate between two different repetition rates of flicker and of click. Both approach-approach and avoidance-avoidance discriminations were used. After substantial overtraining, transfer of frequency discrimination was initiated to stimulation of the reticular formation using bursts of electrical pulses at the same two repetition rates. Significant levels of discriminated performance were obtained in all cats very quickly, indicating good cross-modal transfer between the peripheral discriminanda and the central stimuli. The literature on stimulus generalization and cross-modal transfer is reviewed and the findings of this experiment are discussed in that context. Certain conditions are defined which, if satisfied, justify the interpretation that stimulus generalization or rapid cross-modal transfer indicate that facilitation of subsequent tasks in a training sequence can be attributed to mediation by a specific neuronal mechanism established by training on a previous task. The present experiment was designed in view of such criteria. The evidence of good cross-modal transfer is interpreted to mean that brain mechanisms storing memories about discriminations between visual or auditory stimuli with different repetition rates can be effectively activated by gross electrical stimuli at the same repetition rates. Conflict trials were then carried out in which flicker or click at either frequency was contradicted by concurrent RF stimuli at the other frequency. As the current level of RF stimuli was parametrically increased, it was found that the central stimuli achieved almost complete control over the behavioral outcome in most cases. Concurrent transfer of training, using a counterbalanced training sequence, was then carried out to stimulation of the visual cortex, lateral geniculate, medial geniculate, and the intralaminar nuclei of the thalamus. In each case, rapid transfer was displayed by at least one animal. Once performance to brain stimulation at a given repition rate was established, little change was observed when the fine structure of the stimulus was altered by changing parameters of the stimulus burst. These findings are interpreted as providing support for a statistical theory of memory, since they constitute evidence that previously learned discriminative behavior can readily be elicited by compelling large ensembles of neurons in various brain regions to discharge with particular temporal patterns. It is difficult to reconcile these results with theories which postulate that learning establishes new synaptic pathways in which discharge must occur for memories to be retrieved.

1. Receptive-field properties of single neurons in cat's cortical area 18 were studied before and after partial bilateral lesions of area 17. 2. The majority of cells recorded from animals with intact visual cortex exhibited orientation selectivity, directional selectivity, and could be independently activated through either eye. All cells responded well to moving targets and nearly all of them exhibited broadly tuned preferences with respect to speed of the target. Over 45% of cells responded optimally or exclusively at very fast (above 50 degrees/s) speeds. 3. The majority of neurons recorded from animals with intact visual cortex responded weakly but clearly to appropriately oriented localized stationary stimuli flashed on and off. About one-third of the cells responded with mixed on-off discharges from all over their receptive field. In the receptive fields of 10% of cells, separate on- and off-discharge regions could be revealed. In the receptive fields of the remaining cells, only on- or only off-discharge regions could be revealed. 4. The majority of neurons recorded after ablation of area 17 were orientation selective; 50% of the cells were also direction selective. All neurons responded well to moving targets; about 65% of them responded optimally or exclusively at very fast target speeds. 5. Destruction of the dorsolateral part of contralaterial area 17 and most of contralateral area 18 caused significant reduction in proportion of cells in area 18 which could be activated through either eye. 6. The majority of neurons recorded after ablation responded to appropriately oriented localized stationary stimuli flashed on and off. Cells with mixed on-off discharge regions all over the receptive field with separate on- and off-discharge regions and with only on- or only off-discharge regions were found. 7. It is concluded that the processing of afferent visual information in area 18 is, to a great extent, independent of the information carried to this area by associational fibers from cells of area 17.

1. Discharge pattern has been characterized by autocorrelation analysis of stationary portions of extracellularly recorded discharge trains of cat pontine brain stem neurons during spontaneously occurring desynchronized sleep episodes. 2. Neurons localized to the area implicated in control of the desynchronized phase of sleep, the gigantocellular tegmental field (FTG), show the most phasic or clustered discharge pattern, as evinced by initial peaks in the autocorrelations. At the peak, the FTG population average discharge probability is 3 times that expected had the discharges been evenly distributed over time. The initial peak extends beyond a lag of 3 s, indicating runs of clustered discharge extending beyond this duration. Neurons in other reticular tegmental fields, the tegmental reticular nucleus and pontine gray, show a more sustained or tonic discharge pattern. 3. Discharge patterns of a given cell are consistent from one desynchronized sleep episode to the next; units with phasic discharge patterns remain phasic, and tonic patterns remain tonic. 4. There is a three-way correlation among FTG units recorded at sites with many giant cells, units with high discharge rate increases on transition to desynchronized sleep, and units with a markedly phasic discharge pattern. This implicates the giant cells as the source of both the distinctive discharge rate and pattern changes of neurons during desynchronized sleep. 5. Stereotyped, regular discharge patterns are not characteristic of FTG or other units, suggesting they are not pacemakers and that endogenous activation of pacemaker cells is unlikely to be a mechanism for generation of the marked discharge rate increases on transition to desynchronized sleep that are found in FTG units. The irregular, clustered discharge pattern of FTG is more compatible with generation of discharge rate increases through interaction with other cells. The markedly phasic discharge of FTG units is also consistent with a driving role in generation of the phasic electrophysiologic events of desynchronized sleep.

In the abdominal ganglion of Aplysia californica, seven motoneurons have been described which modulate the myogenic heart beat and vasomotor tone (28). These neurons mediate their motor effects by chemical transmission. In this paper we have attempted to specify the transmitters of six of these motoneurons. We have 1) studied the effects of several common transmitters on the innervated structures and compared these effects with the effects of firing the motoneurons, 2) examined whether blocking agents influence similarly the effect of a putative transmitter applied to the innervated structure and the effect of firing a motoneuron, and 3) tested the capability of the motoneurons to synthesize the putative transmitters from precursors. The positive inotropic and chronotropic effects of firing the excitor motoneuron RB(HE) were mimicked by perfusion of the heart with serotonin at a low concentration. Cinanserin blocked both the effects of motoneuron excitation and serotonin perfusion. RB(HE) was also shown to synthesize [3H]serotonin from L-[3H]tryptophan injected directly into the cell body. The effects of firing the two LD(HI) heart-inhibitory motoneurons were mimicked by perfusion of the heart with acetylcholine. Benzoquinonium blocked the effects of the inhibitory motoneuron and acetylcholine perfusion. Perfusion with arecoline also inhibited the heart beat. Acetylcholine applied to the arteries mimicked the vasoconstriction caused by the LB(VC) motoneurons. Aortic constriction in response to activity in LB(VC) cells or to acetylcholine was blocked by hexamethonium and curare. The heart inhibitor and vasoconstrictor motoneurons synthesized [3H] acetylcholine from [3H] choline injected into their cell bodies. Thus, as in vertebrates, acetylcholine mediates inhibition to the heart. Unlike vertebrates, however, serotonin mediates excitation to the heart and acetylcholine mediates peripheral vasoconstriction.

1. "Association" neurons in the posterior middle suprasylvian gyrus of cat were found to be predominantly polysensory, with 82% of the units in the chloralose-anesthetized preparation responding to auditory, visual, and somatic stimuli. There was no evidence of response differentiation associated with cortical depth distribution. Most units responded with a short-latency response (median 35-60 ms) to all stimulus modalities, with the response to visual stimulation occurring at the shortest latency. Among polysensory cells, almost half responded with equal probability to auditory, visual, and somatic stimulation. The visual stimulus was the most potent for those cells responding with a higher probability to a single modality. Varying degrees of response complexity were noted in some cells in terms of changes in responsivity over time, discharge to stimulus offset, and inhibition of spontaneous activity. The unitary discharge was seen to occur on the negative peak and slope of the locally recorded evoked potential. When only the larger amplitude spikes were analyzed, most of the unitary activity occurred on the negative peak of the evoked potential. Almost half of trimodally responsive cells displayed similar phase relationships between unitary activity and evoked potentials for all three modalities. The absolute refractory period for most cells was from 200 to 300 ms, with relative refractory periods extending up to 30 s...

The latency revealed by poststimulus time histograms of the responses of single units in the cochlear nucleus to tone bursts was compared with the latency of the change in discharge frequency in response to small increments in the amplitude of the stimulus. The latter was derived on the basis of statistical signal analysis of the discharge pattern in response to tones amplitude modulated with pseudorandom noise. The "step response" of the system was computed by time integration of the cross covariance between modulation and spike density. The following observations can be made: 1. The latency of the responses to tone bursts always decreased with increasing sound intensity, whereas the latency of the step response was almost constant for intensities from immediately above threshold to the highest intensity used (60-70 dB above threshold). 2. In most units the latency revealed by the PST histogram of the responses to tone bursts approached the value of latency of the step response asymptotically. 3. In some units with longer latency, the latency of the response to tone bursts was many times greater than the latency of the step response, even at high sound intensities. 4. A histogram of latency values of the step response of the units studied showed narrow peaks at 2.8 and 4.7 ms. 5. On the basis of the present results it is concluded that the latency values of the step response represent the true sum of synaptic and axon dendritical propagation delay, whereas the latency of the responses to tone bursts also includes the temporal summation at the synaptic level.

1. Extra- and intracellular potentials were recorded from neurons and glia during spreading depression (SD) in cerebral cortex of cats. The glial membrane depolarized during SD and the time course of depolarization was concurrent with the surface DC change of SD. The glial depolarization evoked by 20-Hz repetitive cortical stimulation disappeared during the negative DC shift of SD. Simultaneous recording of the extra- and intracellular potentials from a single glial cell with a coaxial microelectrode showed that the extracellular DC potential change was of opposite polarity to the glial intracellular potential, which suggests that the slow glial depolarization concurrent with SD is not the field potential. In contrast to glial cells, the neuronal burst discharges as well as the neuronal membrane depolarization associated with SD did not show a close relationship to SD: the neuronal membrane depolarization and discharge were frequently delayed by 10-3- s from the onset of the SD slow wave. Sometimes SD was observed without accompanying neuronal depolarization. The degree of neuronal depolarization was not always correlated with the amplitude of the negative wave of SD. 2. The effect of tetrodotoxin (TTX) on the negative DC potential of SD was examined. Simultaneous recording of glial membrane potential and the neuronal unit activity as well as extracellular DC potential and surface DC potential during SD was performed and the TTX-treated cortex was compared with the normal state. TTX did not change the DC level of the cerebral cortex. SD could be evoked by KCl when neuronal discharge was completely abolished by TTX application...

Cats were trained to localize sound in space. The animals' localization accuracy was determined before and after one of the following operations: 1) transection of the trapezoid body, 2) unilateral and 3) bilateral transection of the lateral lemniscus, 4) unilateral and 5) bilateral transection of the brachium of the inferior colliculus. The results after bilateral transections of the lateral lemniscus and the one deep bilateral transection of the brachium of the inferior colliculus indicate that some portion of the ascending auditory system must be intact above the medulla for an animal to be able to localize sound. A small loss in accuracy of localization was found after unilateral transection of the lateral lemniscus or brachium of the inferior colliculus. This loss, when compared with the much larger loss that monaural animals show, is an indication that binaural analysis, important for sound localization, occurs at the level of the medulla. Some transections of the trapezoid body resulted in a deficit in localization ability that appeared to be complete and permanent. The position of the lesions in the trapezoid body indicated that important encoding of the binaural cues to localization most likely occurs at the superior olivary complex, probably at the medial superior olive. But the trapezoid body or other commissures of the brain stem auditory system are probably also involved in transmission of information necessary for localization to higher centers.

The neuronal mechanism which gives rise to the synchronization of motor-unit discharges has been inferred from an analysis of the interspike intervals of individual motor-unit discharges recorded from the soleus muscle. The motor units were divided into two groups on the basis of characteristic changes in their spike trains. The first group maintained a stationary discharge pattern throughout the process of synchronization with a firing rate of approximately 10 spikes/s. Small unidentified units simultaneously recorded gradually grouped around the individual spikes of the first group motor unit and with this process, high-frequency force oscillation appeared phase-locked with each of grouped discharges. The mean period of force oscillation was almost identical to the mean discharge interval. Therefore, the first group motor unit was considered as a pacemaker of this force-oscillation. The second group motor unit underwent from its initially stationary process to a transitional process characterized by spike dropouts from an otherwise regular spike train. When both groups of motor units were recorded by the same electrode, it was found that the firing rate of the second group motor unit discharges gradually approached that of the first group, and the spikes of the first and the second group motor units occurred near or at the same time. The number of double intervals decreased in a highly predictable fashion with an increase in a firing rate. It was furthermore observed that the spikes of a given motor unit whose discharges interval-to-period ratio is smaller at the beginning of transitional process was entrained to the first group motor-unit discharges with a faster time course than the unit whose discharge interval-to-period ratio is larger. The synchronizing process was described from the relations between shorter discharge interval-to-period ratios and the longer-to-shorter interval ratios obtained at several stages from the beginning of transitional process to the final synchronization. Their relations were best drawn by the second-order regression lines. The faster time course of synchronization was reflected in the larger value of coefficient a in the equation. The results of this and previous study (23) further provided evidence to justify that interaction of motor-unit discharges is responsible for the synchronization. Although the neuronal limiting device of the firing-rate control to approximately 10 spikes/s still remains unsolved, the possibility was considered that a disinhibitory neuronal network first acts to synchronize independently firing motoneurons and leads to the oscillation of the stretch reflex loop. This closed-loop system was considered as a site for the stored motor program and the use of disinhibitory neuronal network was discussed in relation to the Harmon's model of neuromimes.

Spontaneous and reflex spike trains in the efferent neurons to the claw opener and closer muscles of the crayfish were cross correlated. The opener inhibitor and the slow closer excitor were found to be closely synchronized under all conditions. Details of the correlation suggested an electrical synapse coordinating these neurons, possibly bidirectional, but possibly from CE to OI only. The OE-OI cross correlogram showed signs of direct central inhibition of OE to OI. Polysynaptic inhibition of OI by OE may also occur. CI and OI show signs of mutual inhibition. An unidentified closer bundle efferent was strongly and positively correlated with OE. The results are consistent with the respective muscular effects of the pairs of neurons involved; they disagree, however, with some previous findings (19).

1. Repetitive activity and membrane conductance parameters of crab walking leg axons have been studied in the double sucrose gap. 2. The responses to constant current stimulus could be classified into three catagories; highly repetitive with wide firing frequency range, type I; highly repetitive with narrow frequency range, type II; and nonrepetitive or repetitive to only a limited degree, type III. The minimum firing frequency for type I axons was much greater than for other recording techniques. 3. Voltage-clamp currents in type III axons were qualitatively similar to those of squid or lobster axon. 4. The outward membrane currents of type I and II axons showed a transient phase in addition to the usual delayed current. The magnitude of this transient was a function of both the holding and test voltages. 5. The direction of the transient current reversed in potassium-rich saline. 6. The type I repetitive response in the walking leg axons appears to be generated by the same types of conductance changes that have been demonstrated in molluscan central neurons.

1. Microelectrode recordings from single motor units of the first dorsal interosseus and the extensor indicis muscles of normal human subjects were studied during voluntary, isometric contractions. The conduction velocity of the nerve fiber innervating the muscle unit was used as an estimator of the size of the motoneuron. 2. During slowly increasing contractions, the units were recruited at force levels which were closely correlated to conduction velocity. The units associated with low conduction velocity were recruited first, those with high conduction velocity, last. 3. If small, stepwise force increments were used instead of slowly, continuously increasing contractions, the units were first activated during the steps and became inactive during the subsequent plateaus. If higher steady-force levels were reached, the activity was maintained also during the plateaus. This steady force, where a unit remained continuously active independent of the rate of rise of tension, represents its tonic threshold. 4. The tonic threshold is positively correlated with conduction velocity, as is the threshold force of recruitment. As a consequence, high-threshold units have a large force range below tonic threshold where they can only be transiently activated, whereas low-threshold units have a large physiological force range above tonic threshold where they operate tonically. The phasic or tonic appearance of discharge pattern reflects quantitative differences in tonic threshold between units of different size. All units examined could be activated phasically (below) and tonically (above tonic threshold). No evidence was found indicating the existence of two qualitatively different classes of units corresponding to a tonic and phasic type, although both muscles investigated consist of about equal numbers of type I and type II muscle fibers. 5. The change in firing rate per unit force was inversely related to conduction velocity: the slower conducting units showed larger changes in firing rate per unit force than faster conducting units. This corresponds to the larger excitability of the smaller units indicated by their earlier recruitment. 6. The data of this study are consistent with the hypothesis that the functional characteristics of human motoneurons are determined by the graded excitability of motoneurons according to size.

An account is given of the responses of 432 red nucleus (RN) neurons with axons projecting down the spinal cord. Almost half were in an initial series of 18 experiments on anesthetized cats, and the remainder were in a second series of 12 experiments on decerebrate unanesthetized cats. The differences between the two series were of little significance. All recording was from single neurons using extracellular glass microelectrodes that were inserted throught the right superior colliculus and directed to the right red nucleus at a standard orientation. Identification of RN neurons was both by location, checked by subsequent histology, and by antidromic invasion from the spinal cord. The spinal stimulating electrodes were placed in proximity to the left rubrospinal tract at C2 and L2 segmental levels. Axonal conduction velocities were calculated from the latency differential between the L2 and C2 antidromic responses and were usually in the range 60-130 m/s, 97% of all neurons located in the red nucleus had axons projecting to the C2 level, and 37% projected to the L2 level. The responses of 229 RN neurons were observed with stimulation applied to the contralateral (left) interpositus nucleus. In 10 (5%) there were antidromic responses to both interpositus and C2 stimulation, a finding in good agreement with the anatomical description of rare axon collaterals from rubrospinal fibers to the interpositus nucleus. In 209 (91%), there was a clear monosynaptic excitation. The impulse generation was at a latency usually of 1.0-1.8 ms, which a modal value of 1.4 ms. The afferent inputs to RN neurons were provided by stimulation either of predominantly cutaneous nerves in all four limbs or of cutaneous mechanoreceptors of the contralateral forelimb and hindlimb...

The somatotopic inputs into red nucleus (RN) neurons have been studied with special reference to their level of projection in the spinal cord. As inputs we employed either volleys in predominantly cutaneous nerves of forelimb and hindlimb or cutaneous mechanoreceptor discharges evoked by taps to footpads of forelimb and hindlimb. There has been physiological confirmation of the anatomical findings that RD neurons projecting to the lumbar cord are located in the ventrolateral zone of the pars magnocellularis, whereas in the dorsomedial zone are RN neurons with cervical but not lumbar projection. Somatotopically there was found to be a differentiation of input to RN neurons according as they projected to the lumbar or only to the cervical cord. This finding was presented in the form both of tables and of somatotopic maps. As expected, this discrimination was more restrictive for the more selective inputs from pad taps than for nerve inputs. Nevertheless, forelimb inputs often had a considerable excitatory and inhibitory action on lumbar-projecting RN neurons, and vice versa for cervical-projecting neurons. There were two notable somatotopic findings that suggest specificities of connectivities. First, despite the large convergence of IP neurons onto RN neurons (about 50-fold), the degree of somatotopic discrimination was about the same for interpositus and RN neurons with two testing procedures: between inputs from forelimb and hindlimb; and between inputs from pads on one foot. Second, although there was in the interpositus nucleus a considerable topographical admixture of neurons with dominant forelimb or hindlimb inputs, the axonal projections of these neurons were apparently unscrambled on the way to the target RN neurons, so as to deliver the somatotopic specificities observed for two classes of RN neurons; those projecting down the spinal cord beyond L2 level, and those projecting to C2 but not L2. Finally, there is a general discussion of motor control with reference to the pathway; pars intermedia of anterior lobe of cerebellum leads to interpositus nucleus leads to red nucleus leads to rubrospinal tract leads to spinal motoneurons.

Reflex excitability of the motoneurons innervating the masseter muscle of monkeys was tested before a phasic voluntary activation of the jaw-closing muscles (a RT bite response). Single test shocks were delivered to the Mes V which supplies a monosynaptic excitatory input to the jaw-muscle motoneurons. Changes in reflex excitability were assessed by measuring the amplitude of the synchronous muscle potential evoked by the test shock. Amplitudes of the muscle potentials evoked by shocks which occurred just before the beginning of the voluntary EMG response, as judged by the onset of EMG activity of the masseter muscle contralateral to the test shock were many times larger than potentials evoked immediately following the visual RT stimulus. Curves relating the average amplitude of the evoked response to its time before the beginning of the voluntary response suggest that the reflex excitability of the motoneuron pool begins to increase 25-45 ms before the first detectable EMG activity occurs. These results suggest that inputs arrive at the motoneurons of agonist muscles used in rapid RT tasks substantially before changes in the EMG of the muscle are noted. These results, in part, would account for the time interval noted between the beginning of neural activity in suprasegmental structures which presumably excites spinal motoneurons, and the first EMG activity of muscles which are innervated by these motoneurons.

The left middle cerebral artery was occluded in 12 tranquilized but unanesthetized cats with use of a device implanted transorbitally 5 to 7 days earlier. Bilateral epidural pressures, mean aortic blood pressure, and pulse rate were measured at intervals for up to 48 hours after occlusion. The relationships of these measurements to each other and to the extent and severity of cerebral infarcts is described.

The author used isolated rabbit common carotid and femoral arteries perfused at a constant pressure of 90 mm Hg to examine the variation of flow (F) with transmural pressure (TMP). When the TMP was reduced below 50 to 60 mm Hg in arteries with normal smooth muscle tone, arterial resistance increased significantly causing a reduction in flow. It is suggested that the diffuse arterial narrowing that occurs in patients with severe intracranial hypertension may be the result of a similar reduction in TMP. In the presence of active vasoconstriction, any increase in extraluminal (intracranial) pressure (ICP) resulted in a substantial increase in arterial resistance and subsequent reduction of flow. This F-TMP relationship depended only on the initial degree of constriction and was independent of the vasoconstrictor used to achieve this constriction and of the artery in which this constriction was produced. A review of the literature suggests that human cerebral arteries normally exhibit only mild constrictions in response to subarachnoid blood during the chronic phase of spasm. In the present study, a mild constriction in the absence of increased ICP or a moderate increase in ICP (45 mm Hg) in the absence of constriction produced minor reductions in arterial diameter and an average flow reduction of only 5% to 10%. However, when ICP was increased to 45 mm Hg in the presence of a mild constriction, severe arterial narrowing resulted and flow was reduced by 50%. Therefore, it is suggested that chronic arterial spasm is the result of a mild constriction which is amplified by the simultaneous occurrence of increased ICP. Phenoxybenzamine was found to be effective in reversing and preventing these contractions. The improvement in flow produced by phenoxybenzamine decreased as the TMP was reduced below 60 mm Hg. The effects of both diffuse and local spasm on cerebral blood flow are discussed.

The author reviews a form of management for patients deteriorating preoperatively or postoperatively from apparent ischemia attributed to progressive vasospasm after a subarachnoid hemorrhage. The clinical picture and relative frequency of this complication are considered in relationship to the status (grade) of the patient, location of the aneurysm, and ultimate neurological recovery. Experience suggests that the drug regimen reported is useful when instituted early after the onset of symptoms and is safe with proper monitoring techniques. The data do not justify early operative intervention after a subarachnoid hemorrhage, operation when there is angiographic evidence of severe spasm, or expectation of a dramatic effect in patients with a profound deficit or a fixed deficit several hours old.

Results of proximal anterior cerebral artery occlusion are described in 68 patients with anterior communicating artery aneurysms. The procedure is found useful in the treatment of these aneurysms because of its technical simplicity and the low rates of mortality and morbidity achieved.

A review of four cases of chromophobe adenomas in adolescents suggests that extracapsular extension with invasion of parasellar structures is more common in this age group than in adults. A syndrome of adolescent obesity, oculomotor palsies, and plain x-ray changes of the sella characterizes this group.

The authors report their experience using the operating microscope in 52 anterior cervical discectomies without fusion. They found long-term results highly satisfactory, even in difficult cases with multiple-level disease, and complications from bone grafting were obviated. They highly recommend this approach for radicular, nonradicular, or myelopathic symptoms.

The authors found that cavities in the spinal cord of dogs appearing after the intracisternal administration of kaolin are not due to ischemic softening, but rather to distention and subsequent rupture of the central canal. Ischemic lesions could be produced and were found to have a quite different histopathology; this supports the hydrodynamic hypothesis of cavitary myelopathy following adhesive arachnoiditis, probably as a compensatory mechanism to the associated hydrocephalus. The similarities to human syringomyelia are discussed.

Twenty-eight patients with cerebral tumors were evaluated after craniotomy with combined radionuclide techniques in order to assess presence or absence of tumor recurrence. The combination of a positive pertechnetate or Tc-phosphate scan with a positive gallium scan strongly indicates the presence of recurrent or residual tumor. Infection may also cause uptake but was easily distinguished by the distribution. Negative gallium scans with positive technetium scans were indicative of non-recurrence in this series.

The authors report three patients with abdominal pseudocysts and one with cerebrospinal fluid ascites as late complications of ventriculoperitoneal shunts. The presenting signs and symptoms were those of intraabdominal abnormality, with no neurological symptoms suggestive of shunt malfunction.

A case history of an intramedullary arteriovenous aneurysm of the thoracolumbar junction is presented, and an unusual 14-year follow-up after the original sub-arachnoid bleeding episode is detailed. Embolization of anterior and mixed angiomas involving the artery of Adamkiewicz may be feasible when the artery is large and shunting is present.

The authors describe a case of tuberculous cerebral abscess of the frontal lobe that developed 1 year after an episode of acute miliary tuberculosis. The development of such a lesion indicates a persistence of infection and an immunological breakdown which may partly have been due to protein malnutrition.

The authors describe the occurrence of proatlantal artery as an incidental angiographic observation in a young Indian soldier. This primitive anastomotic channel is seen extending from near the origin of the external carotid artery to the suboccipital region, traversing the foramen magnum and coursing beyond like a vertebral artery. The developmental and roentgenological aspects of carotid-basilar and carotid-vertebral anastomosis are discussed, along with a review of four similar cases reported previously.

Seven men, six suffering from widespread bone metastases of prostatic origin and one with urinary bladder carcinoma, demonstrated minimal or no discernible radioactivity in the kidneys and urinary bladder at the time of bone scanning using 99mTc-stannous polyphosphate. The mechanism behind this scan finding is thought to be rapid and enhanced uptake of the radiopharmaceutical by pathologic bone. The significance of the faint or absent kidney sign in bone scanning, particularly in cases where abnormally homogeneous and symmetric radioactivity exists, is discussed.

A patient with Stage IV-A nodular sclerosing Hodgkin's disease is described who, at initial presentation, demonstrated an apparent large filling defect in the spleen by 99mTc-sulfur colloid scan. Following a 6-month course of MOPP therapy, the patient was clinically free of disease although the spleen scan remained unchanged. After laparotomy, the spleen was found to be entirely normal histologically.

Unusual results were obtained from a cerebral blood flow study and a brain scan performed on a patient with an uncommon, nonvascular scalp tumor eventually identified as a proliferating trichilemmal cyst with acanthosis. The tumor accumulated the radionuclide during the early phase of the cerebral flow study, and the increased radioactivity was persistent, being prominently observable in a scan made 3 min and 2 hr after the radionuclide injection. This unusual, positive finding in a cerebral blood flow study of a nonvascular tumor was thought to be a consequence of the higher counting efficiency resulting from the lack of shielding by the skull and from the larger volume of the tumor tissue.

A detailed study has been made of the method for labeling streptokinase with 99mTc in order to get a radioactive indicator for rapid scintigraphic visualization of thrombi and emboli. The best method found for preparing 99mTc-streptokinase was by reducing 99mTc-pertechnetate with 2 mumole SnCl2 at pH 0.7 and then adding 50,000-75,000 IU of streptokinase at a final pH of about 2. After 1 hr of equilibration the labeling efficiency was 75-80% as determined by the method of gel chromatography column scanning. The dynamic behavior and distribution of 99mTc-streptokinase in different organs was studied in rabbits where a high uptake was found in liver. In a clinical investigation using 99mTc-streptokinase prepared according to this work, however, the liver uptake in man was only 10-20%.

Artificial spherules or vesicles of 900 A in diameter formed from phosphatidylcholine and gangliosides and enclosing 99mTcO4 - (standard preparation) survive intact in the circulation of the mouse. Polyamino acids and protein have been incorporated into and onto the vesicles; such vesicles remain intact as determined by diffusion dialysis studies and by electron paramagnetic resonance studies of vesicles enclosing spin label. In studying the distribution of polyamino acid-vesicles and protein vesicles in vivo, it was found that the latter distribute differently from standard vesicles or free protein alone whereas aromatic polyamino acid-vesicles concentrate in the liver and spleen to a greater extent than standard vesicles. We conclude that the permeability and stability characteristics of vesicles may be preserved when they are modified by the addition of protein or polyamino acids and that such modification of vesicles may be associated with an alteration of their fate in vivo. The potential exists to use vesicles as carriers of radiopharmaceuticals and other drugs and to direct the vesicles preferentially to tissue targets in vivo.

The in vivo distribution of vesicles containing radiopharmaceuticals in their cavities has been studied using three routes of administration: intravenous, subcutaneous, and intraperitoneal. The in vivo distribution in mice was determined by dissection of the animals and calculation of radioactivity in the organs. In rats the in vivo distribution was assessed by scintigraphy using a scintillation camera-digital computer unit. After intravenous injection of vesicles, radioactivity is concentrated to some extent in the liver and spleen but the pattern of distribution is different from that of the corresponding free radiopharmaceutical or radiocolloid made of the corresponding radionuclide. The permeability of the vesicular membrane to contained radiopharmaceutical has been shown to vary according to the chemical composition of the vesicles. Vesicles can be used to introduce materials in vivo and the potential exists for their specific targeting by coupling other molecules to their surfaces.

This paper describes a new approach for computing specific absorbed fractions that can be used for estimating doses that result from the internal administration of radiopharmaceuticals. This approach uses the concept of the tissue-to-air ratio (TAR) which can either be calculated or experimentally determined for the radionuclides of interest. Good agreement exists between the specific absorbed fraction values obtained using measured and computed values of TAR. This implies that the measured values of TAR can be used to obtain specific absorbed fractions for all radionuclides.

The bromide dilutional volume determined by intravenous administration of 82Br has been compared with the corresponding volume determined by oral administration of stable bromide in 11 patients with various medical disorders. Stable bromide was assayed by fluorescent excitation analysis using a 109Cd source and a lithium-drifted silicon detector. The average deviation between the fluorescent and the radiobromide dilutional volumes was 4.2% with a standard deviation of +/- 8.5%. This substantiates both the accuracy of the fluorescent excitation method as applied to this tracer and the validity of utilizing oral tracer administration in comparison with intravenous administration. The derived estimates of extracellular fluid volume averaged 28.7% of body weight in the entire group of 11 patients and 25.8% in the 4 normal subjects included in the group. Evaluation of the extracellular fluid space utilizing fluorescent excitation of stable bromide permits high statistical accuracy of sample measurement with great simplicity compared with current chemical methods and with avoidance of the patient radiation exposure associated with 82Br.

Glycopyrrolate, a synthetic anticholinergic agent, was administered parenterally to two groups of patients referred for 99mTc-pertechnetate brain imaging to assess its ability to suppress pertechnetate uptake by the choroid plexus, oral mucosa, and salivary (parotid) glands. Pertechnetate activity was almost completely eliminated from the choroid plexus and mouth and appeared to be moderately reduced in the parotid gland. The drug can be given orally and may prove valuable in pertechnetate brain imaging.

Left anterior, lateral, and posterior views on 50 consecutive RES-lung scams were examined. Normal patients had continuity of activity between the left lung and the spleen on all three views. Patients with subphrenic abscess or large left pleural effusions showed no continuity between lung and spleen activity on any view, while other abnormalities, most commonly cardiomegaly, accounted for lack of lung-spleen continuity on the anterior view only. It is suggested that in all combined RES-lung studies, the left side be examined as well as the right for abnormalities adjacent to the left diaphragm.

The 16-year-old clinically normal daughter of a patient with the von Hippel-Lindau syndrome demonstrated a vascular posterior fossa lesion on scintiangiography that failed detection in delayed images. Contrast arteriography corroborated the presence of a hemangioblastoma. Noninvasive demonstration of the genetic penetrance of this disorder offers its victims an opportunity for low morbidity early surgical cure of the associated brain lesions.

A case of a diploic extracranial meningioma whose true vascularity was more significantly defined by radionuclide angiography than by selective contrast angiography is presented. The radionuclide angiogram clearly demonstrated large venous channels draining the tumor.

Oleic acid labeled with 14C, (14C-OA) or 131I (131I-OA) and 131I-labeled linoleic acid (131I-LOA) were administered intravenously to rats and tissue distribution studies completed at various time intervals from 5 to 60 min. Tissue distribution of 131-I-labeled oleic acid or linoleic acid was also studied in dogs at 5- and 30-min time intervals after intravenous administration of the tracer dose. There were distinct differences in the patterns of tissue distribution between 14C-OA, 131I-OA, and 131I-LOA. Radioactivity concentration in the myocardium was the highest at all time intervals in the rats given 131I-OA only. In dogs, the myocardial uptake of 131I-OA was significantly higher than the radioactivity in the blood or other tissues at 30 min after injection. The disappearance rates of 131I-OA and 131I-LOA were almost identical but myocardial concentration of 131I-LOA at 30 min after the dose in the dog was half that of 131I-OA whereas 131I-LOA liver concentration was higher than that of 131I-OA. Since the concentrations of our formulated 131I-OA in the blood and in the myocardium are both highest at the earlier intervals, it should be difficult to detect myocardial ischemia or infarction with 131I-OA scanning.

The dose of radiation to the human body and some of its organs after intravenous administration of 75Se-sodium selenite for diagnostic purposes has been calculated on the basis of followup of 26 patients for as long as 517 days with measurements of: 1. The retention of 75Se in the whole body. 2. The retention of 75Se in the blood, liver, kidneys, ovaries, testicles, and hair. 3. The excretion of 75Se in urine and feces. Whole-body counting and profile scanning were done on the patients and samples of blood from different organs, urine, and feces were measured for radioactivity. The dose of radiation received was calculated for an average patient of 70 kg. These doses were found to be slightly higher than previously reported on a smaller number of patients and with a shorter follow-up. They were slightly lower than those from 75Se-methionine to the whole body but higher to the liver and kidneys. The margin of error in this investigation was estimated to be about 20% for the whole-body dose and probably higher for different organs, mostly due to the poorly known rate of retention of selenite in different organs.

Oxygen consumption and colonic temperature of germfree rats are lower than those of conventional and conventionalized rats. Cecectomy of weanling germfree rats prevents the development of the very large ceca characteristic of ordinary germfree rats but did not increase oxygen consumption or change colonic temperature.

Marked fatty liver was found to develop in both KK and KK-Ay (yellow KK) mice when they were allowed free access to a 15% ethanol solution as drinking fluid. The present studies were undertaken to elucidate the characterization of the fatty liver and associated changes. Chemical analysis showed that accumulated lipids were mainly triglycerides, whose fatty acid composition was changed with increases in palmitoleic and oleic acids, indicating augmentation in endogenous lipogenesis. An accumulation of small fat droplets was histologically observed in centrolobular hepatocytes extending to perilobular zones. Among the tested mice of seven strains, only KK and KK-Ay mice developed the ethanol-induced fatty liver, and the latter mice were more susceptible. Growth, food and alcohol intakes, plasma levels of glucose, triglycerides, and immunoreactive insulin were also surveyed during the development of the alcoholic fatty liver. In contrast to high energy diet, ethanol induced neither development of obesity nor exaggeration of diabetic states. A possible correlation between the pathogenesis of the fatty liver and the genetic factor inherited in KK mice is discussed.

Interrelationships between oral contraceptives and dietary lipids on iron and copper levels in plasma and tissues were investigated in rats. Diets containing either 20% (by weight) safflower oil or hydrogenated coconut oil with and without cholesterol (0.5%) were fed to weanling, female, Wistar-strain rats for a period of 19 weeks. Three types of oral contraceptive agents differing in estrogen/progesterone ratios were administered during weeks 16 through 19 of the experiment. Control rats received the dietary treatment without oral contraceptives. Hemoglobin concentration, hematocrit, red blood cell counts, mean cell hemoglobin and hemoglobin concentration, and mean cell volume values were similar among the various dietary and drug-treatment groups. Elevated levels of copper were found in livers of drug-treated animals fed diets containing cholesterol and safflower oil, whereas levels of copper or iron in spleen and kidney were not influenced by oral contraceptives. Dietary safflower or coconut oil had no influence on levels of iron or copper in plasma. However, iron levels were higher in liver, spleen, and kidneys of rats fed coconut oil compared with those fed safflower oil. Cholesterol-fed rats had reduced levels of iron in plasma and tissues and increased levels of copper in plasma and liver. Iron deficiency in cholesterol-fed rats was indicated by low levels of iron in plasma, liver, spleen, and kidney. In experiment 2, animals were fed the 20% safflower oil diet, with and without sodium glycocholate or cholesterol, to determine whether the apparent malabsorption of iron resulted from sodium glycocholate or cholesterol. Sodium glycocholate resulted in a marked increase in the absorption of iron, whereas cholesterol depressed absorption.

The effect of increasing dietary linoleate upon in vivo platelet aggregation and disaggregation in 20 males and 46 female adult humans was studied. In creasing exogenous linoleate for 2 weeks from 2.89 +/- 0.11 to 5.00 +/- 0.26% of energy was associated with the doubling of the aggregation time and halving of the disaggregation time. Decreasing dietary linoleate in the following 2-week feeding period was associated with a reversal of the effect.

Studies were conducted to examine in detail the effects of vitamin A deficiency on fetal growth and development in the rat. The gradations of deficiency were examined in two studies. The first included total vitamin A depletion followed by retinoic acid supplements, and the second included three different levels of restricted intake of retinyl acetate (42, 16, or 8 mug of retinol equivalents/day/kg of body weight) in vitamin A-depleted rats. In the first study, extensive fetal resorption and death were observed in retinoic acid-fed females after day 14 of gestation. These findings confirmed the morphological studies of Thompson and associates (Proc. Roy. Soc. London, Ser. B 159, 510-535, 1964) who found the earliest Detectable histological lesions to be in the placentas at days 15-16 of pregnancy. Analyses were carried out of the total weight, the DNA, RNA, and protein contents of fetuses and placentas of different gestational ages in retinyl ester-fed and retinoic acid-fed females. Biochemical changes indicative of a reduced rate of cell division were observed in both fetus and placenta by day 14 in the retinoic acid-fed rats. The few live fetuses in this group maintained a growth rate of only 60-70% of that of the fetuses of retinyl ester-fed dams after day 14. By contrast, the growth rate of the placentas (of live fetuses) after day 14 of gestation was not as consistently affected by retinol deficiency. Restriction of retinyl acetate intake (in the second study) significantly reduced both the total litter size and the number of live pups per litter. Most of the females in the retinyl acetate-restricted groups delivered pups that had normal body weight and appeared normal on visual inspection. Significant differences from normal controls were seen only in the neonates from dams given 8 mug of retinol equivalents (per kg of body weight per day), which had smaller livers and kidneys than the control neonates. In contrast, the weights of the brains of the neonates in all three retinyl acetate-restricted groups showed no differences from control values. Vitamin A assays on maternal and neonatal sera and livers indicated that the transport of vitamin A across the placenta was well regulated, and suggested that this transport is maintained with high priority in the presence of maternal deficiency. The effects of vitamin A deficiency on fetal growth and development might reflect primary effects on the placenta, with secondary effects on the fetus, or primary direct effects on the fetus itself. The mechanisms of the observed effects remain to be explained.

The carcass composition of young chickens differing in efficiency of feed utilization was obtained to study changes in the carcass composition associated with differences in efficiency of feed utilization. As the efficiency of conversion of food to tissue was changed, there were associated changes in carcass moisture and lipid, regardless of differences between different populations in variability for growth rate. Carcass moisture was increased and carcass lipid was decreased in chickens with relatively better conversion of food into carcass. Carcass protein was significantly increased in chickens with better efficiency of feed utilization in one population, but not in another. Changes in carcass composition associated with efficiency of feed utilization were similar regardless of whether differences in efficiency were due to gain or to a combination of gain and consumption. Significant sex differences in carcass moisture, lipid, and protein were observed in the faster-growing broiler population but not in the lines selected from a slower-growing randombred population. There was a significant decrease in 16:1 and an increase in 18:0 fatty acids of chickens with a lower feed conversion ratio.

Hepatic protein synthesis was measured in vivo and in vitro (liver slice) in 6- and 19-day-old rats. Fed and 15-hour starved rats were compared in each individual experiment. The study demonstrated that in the 6-day-old rat, hepatic protein synthesis is very sensitive to restrictions in dietary influx. In contrast, no significant differences in protein synthesis were detected when 19-day-old rats were fasted for 15 hours. In the fed state, the protein synthetic activity of the tissue unit was the same irrespective of age. Thus, it appears that it is not the maximal capacity for protein synthesis that changes with age, but rather the extent to which the system can adapt to the changing nutritional environment.

Wistar and Long-Evans rats excreted significantly more cystathionine during days 27 to 31 of a vitamin B-6 deficiency than did Spague-Dawley rats. Wistar rats were therefore chosen for experiments designed to test the effects of dietary DL- and L-methionine supplementation upon cystathionine excretion of vitamin B-6-deficient and control rats. Methionine supplementation did not significantly affect mean daily food consumption or weight gain of the control animals. L-Methionine-supplemented, deficient rats gained significantly more during the first 15 days of the experiment and less during the last 11 days than did the other deficient groups. No cystathionine was detected in the urine of methionine-supplemented or unsupplemented control rats between days 8 and 26 of the experiment; but measurable quantities of cystathionine were present in the urine of all deficient groups by days 8 to 12. Deficient animals fed DL-methionine excreted up to 2.33 mg more cystahionine per 4-day period than did the unsupplemented deficient rats, whereas rats fed L-methionine excreted up to 7.44 mg more per 4-day period than did the unsupplemented ones. This difference in cystathionine response was highly significant and indicates that the L supplement stressed the vitamin B-6-deficient rats more than did the DL supplement. An explanation for this may be that the D isomer in the DL supplement was not as efficiently absorbed and/or metabolized as the L form.

One hour after rats fasted for 13 hours consume a single meal of skim milk, whole milk, or light cream, serum nonesterified fatty acid (NEFA) concentrations changed in direct proportion to the fat content of the diet: serum NEFA levels decreased in rats ingesting skim milk (0.09% fat) to 34% of fasting control values; in animals consuming whole milk (3.59% fat), levels dropped to 50% of fasting levels; these levels did not change significantly, however, in rats consuming light cream (18.26% fat). The percentages of total serum tryptophan not associated with albumin in rats ingesting skim milk, whole milk, or light cream were 22.2, 26.0, and 42.5%, respectively. These variations in serum free tryptophan were not accompanied by significant differences in brain tryptophan among the three treatment groups. These results thus confirm that, with a natural food source, (a) postprandial serum NEFA levels reflect the total fat content of the diet; (b) serum free tryptophan concentration shift proportionately with serum NEFA; and (c) serum free tryptophan concentrations do not reliably predict brain tryptophan levels.

Studies were conducted to evaluate the involvement of food intake in the lysine-arginine antagonism. Diets were formulated to compensate for the metabolic consequences of excess dietary lysine; induction of renal arginase activity, depression of heptic glycine transamidinase, and urinary losses of arginine. This was accomplished by inclusion of creatine in the basal diet, use of a moderate excess of lysine that did not increase urinary arginine excretion, and addition of the arginase depressors, alpha-aminoisobutyric acid (AIB) and L-threonine, to diets containing excess lysine. When chicks were fed diets containing excess lysine ad libitum, growth and efficiency of arginine retention were reduced. Supplementation of the diets with AIB and threonine markedly reduced the growth depression and restored efficiency of arginine utilization. When chicks were force-fed the diet containing excess lysine, growth was depressed, and body composition was altered. Inclusion of AIB and threonine in the diet containing excess lysine resulted in growth and body composition equivalent to levels of force-fed controls. In a second experiment the basal diet and basal supplemented with AIB and threonine were pair-fed to lysine-supplemented diets containing AIB and threonine. Body weight gains and body composition of all groups were similar. In other experiments, food intake increased within 24 hours (P less than 0.05) and probably within 12 hours (P less than 0.10) after removal of excess lysine from the diet. It is concluded that a portion of the lysine-arginine antagonism is due to a primary effect of lysine on regulation of food intake.

Normal and adrenalectomized rats were either ad libitum fed or meal-fed a 66.5% glucose diet for 1 to 3 weeks. Ad libitum-fed rats exhibited synchronized daily rhythms in the levels of immunoreactive insulin, glucose, hepatic glucose-6-phosphate dehydrogenase, and malic enzyme activities. These rhythms were shifted late-morning 2-hour feeding period. The rhythms of adrenalectomized ad libitum-fed rats were different from those for nonadrenalectomized rats. These results indicate that differences between ad libitum- and meal-fed animals may be attributable to the timing of food intake with respect to the timing of observation rather than to meal-feeding alone. It is further concluded that the adrenals play a role in the maintenance of these rhythms.

Insulin-carbohydrate relationships were investigated in four groups of young rats fed low protein diets differing in carbohydrate and fat contents: (1) a diet in which the nonprotein energy was provided by fatty acids (FA); (2) a similar diet in which the fatty acids were substituted by neutral fat (NF); (3) FA diet supplemented with glycerol (FA-Glyc); and (4) a carbohydrate-rich diet (HC). Control rats were fed a stock diet. Rats fed the FA diet lost weight, were hypoglycemic and hypoinsulinemic in the fed state and normoglycemic and normoinsulinemic in the fasted state, and had an impaired glucose tolerance and hyperinsulinemia after a glucose load. Liver and muscle glycogen were low in fed rats. Fasting increased glycogen in liver and decreased glycogen in muscle. NF animals gained weight, were hypoglycemic in both fed and fasted states, and their plasma glucose level after an oral glucose load was almost normal. Plasma insulin/glucose ratio, both in fed and fasted states and after a glucose load indicated hyperinsulinism, which was accompanied by obesity. Muscle and liver glycogen were low in fed animals and did not change after a fast. Supplementation of the FA diet with glycerol (FA-Glyc) abolished weight loss and fasting hyperglycemia and normalized plasma glucose and insulin response to a glucose load. Rats fed the HC diet had an improved glucose tolerance and an increased sensitivity to insulin. Liver glycogen was high in the fed state and normal in the fasted state, whereas muscle glycogen was normal in both nutritional states.

Effects of riboflavin repletion of rats at various stages of development were evaluated by biochemical and behavioral parameters. One group of dams received diets containing a suboptimal level of riboflavin, approximately 15 mug, and another group, control, received approximately 40 mug of the vitamin daily 2 weeks before mating. Rats fed the control diet received approximately 120 mug riboflavin daily during pregnancy and lactation; suboptimals received approximately 15 mug daily. Some rats fed the control diet were pair-fed to rats fed the suboptimal ration. A group of dams fed the suboptimal diet was switched to control after parturition. At weaning, male offspring were fed the same riboflavin levels their respective dams received before mating except one group, whose dams were fed the suboptimal diet, received the control diet. Male progeny of dams pair-fed the control diet to suboptimal rats were either pair-fed to offspring of suboptimal dams or to offspring riboflavin-repleted at weaning. Rats that always received the suboptimal diet had significantly higher general activity scores at 60 days of age than the scores of other animals. Brains from rats always fed the suboptimal diet and those receiving riboflavin repletion at weaning had lower, sometimes significantly, DNA, RNA, and protein contents than those from other animals. Riboflavin restriction during gestation and lactation, but not gestation alone, appeared to produce permanent alterations in general activity scores and brain nucleic acid and protein contents of male rat progeny.

Magnesium (Mg) and calcium (Ca) balances as well as determinations of atomic absorption analysis of atomic absorption analysis of total absolute contents of Mg and Ca fat-free dry carcasses were done on gnotobiotic male Sprague-Dawley rats, kept at 28 degrees or 6 degrees, for 69, 240, or 517 days, and fed either a commercial stock diet or a semipurified diet containing a normal or a subnormal amount of Mg. The often-reported observation of negative balances when Mg intake is subnormal has been confirmed. Total Mg and Ca accumulation in the carcass estimated from balance values was totally inconsistent with the actual content of the carcass as determined by direct analysis. The large discrepancy between the actual analysis of the carcass and the estimated content of Mg and Ca in the carcass derived from balance data demonstrates clearly that balance of trace minerals cannot reflect chronic retentions or losses of these minerals. Possible explanation of this discrepancy are dissussed.

Several assays with young chicks fed crystalline amino acid diets were conducted to investigate the effects of supplemental glycine, serine, threonine, arginine, or adenine on the growth depression resulting from consumption of excess methionine. Glycine was partially effective in alleviating the growth depression caused by excess methionine. The addition of threonine together with glycine improved performance still further. Efficiency of food utilization for weight gain was greater in birds fed the methionine-imbalanced diet supplemented with glycine and threonine than in those fed the control diet. Supplemental glycine, threonine, or adenine, but not arginine, was effective in ameliorating the hypoglycemia resulting from consumption of excess methionine. The rate of oxidation of a tracer dose of threonine was increased markedly by feeding 1.25% excess methionine. This was reflected in a 20% depression in threonine utilization for weight gain as measured by slope ratio. The data suggest that both threonine and glycine are antagonized by consumption of excess methionine.

The effects of partial pancreatectomy or adrenalectomy and insulin or corticosterone replacement on the responses of rats to meal-feeding were studied. Partial pancreatectomy lowered glucose-6-phosphate dehydrogenase (G6PD) and malic enzyme (ME) activities and resulted in higher blood glucose levels. Partial pancreatectomy did not affect the ability of the animals to adapt to meal-feeding. Insulin supplementation of the pancreatectomized rats restored G6PD and ME activities to those observed in the intact animals and normalized the blood glucose levels in the ad libitum-fed rats. Adrenalectomy decresed the survival of rats subjected to meal-feeding. Eighty percent of the rats died when meal-fed a high glucose diet. Survival was improved when either a 66.5% starch diet or a 40.5% fat diet was substituted for the 66.5% glucose diet. Adrenalectomized meal-fed animals fed 66.5% glucose had higher G6PD and ME activities and higher liver lipid levels than both the adrenalectomized ad libitum-fed and the sham-operated meal-fed rats. Glucocorticoid supplementation lowered G6PD activity in the adrenalectomized meal-fed rats but had no effect on ME activity or liver lipid. Meal-fed adrenalectomized rats had lower liver and serum cholesterol levels than meal-fed intact rats and ad libitum-fed adrenalectomized rats. These cholesterol levels were increased with glucocorticoid supplementation. It was concluded that adaptation to meal-feeding involves an adrenal response to the periodic absence of dietary energy intake, and that the degree of involvement of this response is determined by the composition of the diet.

The effects of treatment with pyridoxine or 4-desoxypyridoxine, a vitamin B-6 antimetabolite, and of vitamin B-6 deprivation on the blood pressure response to renin and angiotensin II and on plasma angiotensin concentration and renin activity were studied in Long-Evans hooded rats in order to compare the effects on these factors of vitamin B-6 excess or vitamin B-6 deficiency. Both pyridoxine and 4-desoxypyridoxine caused a progressively increasing inhibition of the response to renin, which was totally suppressed after 24 days of treatment. They had no significant effect, however, on the basal blood pressure, the response to angiotensin II, plasma angiotensin levels, or plasma renin activity. The vitamin B-6-free diet caused an increase in basal blood pressure of 23 +/- 5 mmHg, over a period of 5 weeks, along with a simultaneous decrease in the response to renin and, though to a lesser degree, angiotensin II. The basal blood pressure remained steady at this level and then decreased again, after the 10th week of deprivation, while the response to renin remained low. Plasma angiotensin levels increased from 0.40 +/- 0.06 ng/ml in control animals to 0.97 +/- 0.06 ng/ml in the deficient rats, and plasma renin activity increased from 5.19 +/- 0.35 to 11.31 +/- 1.56 ng of angiotensin I/ml/hour.

Purified diets containing sodium sulfate and DL-methionine as sole dietary sources of sulfur were fed to fistulated sheep. The effect of dietary sodium molybdate (50 ppm Mo) on the capacity of the rumen microorganisms to produce sulfide from either sulfate or methionine was assayed in the two sulfur diets. Dietary molybdenum significantly inhibited the production of sulfide from sulfate but enhanced significantly the production of sulfide from methionine. The inhibitory effect of molybdenum on sulfide production in vitro and the number of sulfide-producing bacteria present in the rumen of these sheep are discussed in considering the mechanism of the molybdate effect on sulfide production.

Taurine metabolism in man was defined by an isotope dilution technique during normal taurine intake (five subjects) or increased taurine intake (two subjects). A tracer dose of [35S]taurine was administered intravenously, and the amount and chemical form of radioactivity were determined in blood, urine, bile, and feces. Analysis of plasma specific activity decay curves indicated that taurine metabolism can be described by two exchangeable pools: a small (2 mmoles), rapidly exchanging pool (t1/2 approximately equal to 0.1 hour); and a large (98 mmoles), very slowly exchanging pool (t1/2 approximately equal to 70 hours). A small amount of [35S]isethionic acid was detected in urine, possibly the result of deamination of taurine by tissues; but otherwise no evidence of tissue biotransformation was obtained. Taurine was excreted predominantly (95%) in urine, about 70% as taurine and 25% as sulfate. The sulfate was considered to be formed in the intestine by bacterial degradation of taurine and then absorbed. Supplemental taurine (given orally) was well absorbed, caused a transient increase in plasma taurine levels, was excreted in urine without equilibration with the slowly exchangeable pool, and caused only a modest increase in total body taurine. Thus, taurine resembles other amino acids in having large tissue pools but differs strikingly in being metabolically inert with an extremely slow turnover rate.

Experiments were conducted to determine whether the rate of entry of arginine into liver varies with changes in dietary protein or in the protein-catabolic state of the animal. It was first established by liver perfusion with [14C]ureidocitrulline that release of arginine by liver is sufficiently small that it can be ignored and that disappearance of arginine from a perfusion medium can be used to measure entry rate. Disappearance rates of arginine were then determined for rats that had been starved of fed either a stock control diet, a 15% casein diet, a 90% casein diet, or which had been injected with cortisol. There was no difference in arginine uptake between the control and 15% casein groups. The high protein group showed a threefold increase in rate of entry of arginine into liver as compared with the control group. Cortisol treatment and 48 hours of starvation also caused a threefold increase in arginine uptake. Cortisol treatment combined with high protein adaptation resulted in a sevenfold increase over controls. It was concluded that rate of entry of arginine into rat liver varies with nutritional and endocrine states.

The effect of dietary vitamin E on activities of pyruvate kinase and lactate dehydrogenase was studied in tissues of rats. The activity of pyruvate kinase in plasma of 1-month-old male rats fed a vitamin E-deficient diet for 4 months increased 8.5-fold over that of 45 ppm vitamin E-supplemented animals. Relative to the supplemented group, the enzyme activity increased 23% (P less than 0.001) in red blood cells, was unchanged in liver and lung, and decreased 20% (P less than 0.001) in muscle of vitamin E-deficient rats. The activity of lactate dehydrogenase was not significantly altered by dietary vitamin E in all tissues measured. Similar results were obtained when 2-month-old rats were fed the respective diets for 3 months. The results suggest that vitamine E deficiency in rats may cause muscular damage and release of pyruvate kinase into blood circulation.

Six cases of exposure to Dimethy Phosphorochloridothionate (DMPCT) are reported. All patients suffered cornel injuries. Characteristically the corneal lesions (punctate keratitis) became apparent after an interval of at least eight hours. With proper treatment all patients recovered completely with no impairment of visual acuity.

Colonic biopsies from six patients with normal colons and seven patients with melanosis coli were studied ultrastructurally and histochemically for lysosomal enzymes. Anthraquinone purgatives were found to increase the number of macrophages in the connective tissue of the colonic mucosa. In addition, they cause an increase in the intensity of lysosomal activity and an increase in the number of lysosomes in macrophages, Schwann cells and neurones of the submucosal plexus of the colonic mucosa.

A histochemical and ultrastructural investigation of apocrine cells in the human breast has been carried out. These cells showed strong oxidative enzymatic activity, large numbers of mitochondria and numerous infoldings of the basal plasma membrane. In these features, such cells resemble the normal apocrine gland cells. These observations support the view that this lesion is a metaplastic change in normal breast epithelium.

The morphology of articular cartilage fibrillation is usually studied in sections cut vertical to the surface. The present study instead concerns the appearances seen when the surface is viewed en face. The study has been made on indian ink preparations of unfixed, hydrated tissue mounted in physiological saline and examined by stereomicroscopy at times 10 while in situ on the bone, and by transmitted light microscopy of tangential surface slices at magnifications up to times 150. The results are consistent with an hypothesis that fibrillation represents mechanically induced focal wear of the tissue. Various sorts of "minimal fibrillation" and other types of surface markings are illustrated. The en face pattern of the cartilage lesions is to some extent influenced by anatomical site, and it is suggested that it is modified by the local biomechanical environment and local character of the cartilage. Some, but not all, of the various patterns show orientation in the sense either of being predominantly unidirectional or of having two major alignments one at right-angles to the other. The differing relationships of this orientation, when present, to the direction of joint movement and to the alignment of the superficial collagen and its tensile strength, are described and discussed.

Portions of lung from 25 human foetuses between 12 and 26 wk of gestational age were examined for ultrastructural changes during maturation of the epithelial cells. In 10 cases type I pneumocytes and in five cases type II cells were differentiated. The changes associated with the formation of lamellar inclusion bodies in type II cells are described. It is concluded that this is a synthetic process in which protein and lipid assembly are important. Changes in glycogen and participation of dense bodies are striking.

The glycoproteins in the normal pig bronchial gland are identified by the combined Alcian Blue (AB)-periodic acid Schiff (PAS) technique, with the use of sialidase digestion and AB staining either at pH 2-6 or at pH 1-0. In enzootic pneumonia (produced experimentally by infection with Mycoplasma hyorhinis) the bronchial gland hypertrophies, mucous and serous cells both increase, in number and size; hence the total glycoprotein content of the gland increases. The distribution of glycoproteins in the hypertrophied gland differs from that in the normal. Quantitative analysis of the mucous cells shows that in the hypertrophied gland the acid glycoprotein is increased relative to the neutral. There is also a relative change in the amounts of sialidase-sensitive sialomucin and sulphomucin; both are significantly increased at the expense of the sialidase-resistant sialomucin. Qualitative analysis of the serous cells shows that in the normal gland most of the glycoprotein is neutral and that the small amount of acid glycoprotein is sialidase-resistant sialomucin. In the hypertrophied gland there is relatively more acid glycoprotein which is either sialidase-resistant sialomucin or sulphomucin; in addition, in pigs with enzootic pneumonia there is an increase in the height of the bronchial epithelium and a depletion in both goblet cell number and glycoprotein content, which latter has more neutral glycoprotein and less acid glycoprotein.

Multiple doses of oxytetracycline were administered at regular but different intervals to groups of patients undergoin orthopaedic surgery. It was found that doses of the drug were incorporated at bone growth sites most frequently if the intervals between those doses were 3 or 6 days. This suggests a biorhythm in human bone growth with a periodicity of 3 days: this biorhythm may be altered by hormones or drugs.

Rats were killed at various time-intervals up to 48 hr after a single large dose of paracetamol (3 g per kg) and their livers examined by light and electron microscopy. In general, this revealed glycogen depletion, loss of ribosomes, and cytoplasmic matrix swelling commencing 3-6 hr after administration which in centrilobular hepatocytes progressed to frank coagulative necrosis at 12-24 hr. Midzonal cells showed more prominent aqueous swelling with besiculation of the endoplasmic reticulum, and in some cells, gross hydropic vacuolation.

During expulsion by guniea-pigs of both first and second infections with the intestinal nematode parasite Trichostrongylus colubriformis, increased numbers of basophils and eosinophils were present in the bone marrow and blood. In addition, increased numbers of basophils, mast cells and eosinophils, many possessing reduced numbers of cytoplasmic granules, accumulated at the sites of infection. Blood eosinophil counts, however, did not show significant changes during the early part of a first infection.

Thirteen premature infants were given bovine serum albumin, a cow milk protein, by addition to their formula. Serum antibodies to BSA developed in three infants 36-38 weeks' gestation, confirming that exposure to the antigen in the gastrointestinal tract will immunize infants born after 36 or more weeks' gestation. Serum antibodies to BSA, however, were detected in only one of two infants of 35 weeks' and in none of eight infants of 30-34 weeks' gestation. The results show that the capacity to make specific antibodies to BSA develops around 35-36 weeks' gestation, despite the prior appearance of organized lymphoid tissue and independent of antigen exposure.

Among 195 nephrotic children, ten developed resistance to prednisone therapy after responding to this drug on one or more occasions (late nonresponders). All were found to have "minimal lesions" on renal biopsy. Nine of these patients went into remission: one responded to further prednisone therapy, one went into remission while receiving azathioprine, and the remaining seven children responded to cyclophosphamide. Five of these seven patients subsequently relapsed; three of them have continued to respond to prednisone. The other two eventually became steroid resistant a second time, but in both instances a second course of cyclophosphamide again induced a remission. These nine patients have been followed for periods ranging from 6 months to 9.5 years (median = 53 months); all are doing well and have normal renal function. The tenth patient died from sepsis four months after the onset of steroid resistance.

Of 72 patients with fibrosis, 49 harbored Enterobacteriaceae in the respiratory tract, including Escherichia coli, Klebsiella, and Enterobacter. Colonization by two to four genera was documented in 29 subjects. Staphylococcus aureus was recovered from 44 of these 49 patients. The distribution of serogroups of E. coli was similar to that seen in patients with urinary tract infection. Antibody response against the O antigens of the patients' own Enterobacteriaceae was documented in 29 of these 49 children and encountered more often in patients with severe disease. Colonization by Enterobacteriaceae in the absence of Pseudomonas aeruginosa was seen more frequently in children with the mild form of the illness.

L-Dopa in a dose ranging from 125-500 mg and arginine monochloride in a dose of 0.5 gm/kg were given simultaneously to 56 children with short stature (height less than third percentile). Sixteen of these children were subsequently diagnosed as having growth hormone deficiency. The diagnosis of hyposomatotropism was based on clinical findings and on responses to the combination test and to arginine and L-dopa administered as separate tests. All of the remaining 40 children had a normal GH response of greater than 6 ng/ml to the combination test. However, in this group, nine children were identified who responded to the combination test but who failed to respond to arginine and L-dopa in individual tests. The data suggest that a positive response to arginine and L-dopa in combination in children, who do not respond to the usual provocative tests when administered individually, may fail to identify children with partial GH deficiency who would benefit from treatment. The integrated stimulated GH response in the 31 children in whom a normal GH response to all three tests occurred suggests that the effects of L-dopa and arginine are additive.

Three children had an arteriovenous fistula between an aberrant vessel from the descending aorta and a normal pulmonary vein in the posterior basal segment of a lung. The affected lung was otherwise normally developed. Only a few similar cases could be found in the literature.

Cystinosis was diagnosed in a small quantity of cultured amniotic cells from a 22-week-old fetus by a modified pulse-labeling technique in which intracellular 35SL-cystine retention was measured. As a result of the above finding, the pregnancy was terminated by administration of prostaglandin. The diagnosis was confirmed when the nonprotein-free cystine content of the kidney, liver, placenta, spleen, thymus, and gut, as well as that of a large amount of cultured amniotic cells, was found to be 100-fold higher than normal levels.

The relative effectiveness of phototherapy and exchange transfusion for nonhemolytic neonatal hyperbilirubinemia was compared in two closely matched groups of infants. Although the exchange transfusion achieved an immediate reduction of bilirubin level, the "rebound" was rapid and tended to offset this reduction. The more gradual and steady effect of phototherapy resulted in a significantly lower serum bilirubin level at 1, 2, and 3 days after commencement of therapy; the rebound after phototherapy was small. Phototherapy was demonstrated to be more effective than exchange transfusion in achieving prolonged reduction of bilirubin levels for nonhemolytic hyperbilirubinemia. With more efficient lamps delivering more energy in the desired spectrum, it would seem feasible to treat hyperbilirubinemia of whatever etiology with this safer and more convenient form of therapy, though sometimes only as in adjunct therapy.

Blood concentrations of phenobarbital, following an intramuscular administration of a single large dose of approximately 10 mg/kg, were studied in 39 infants. A rapid rise was obtained with a mean concentration of 9.30 mug/ml at 30 minutes, 12.76 mug/ml at 90 minutes, and a mean peak concentration of 13.28 mug/ml, which was reached in most cases within 2 hours of injection or less. Cerebrospinal fluid values in 13 patients averaged half the blood phenobarbital concentrations.

Sixty-seven 7-year-old children, who had asymptomatic lead exposure between 1 and 3 years of age, were compared in their performance on a series of psychologic tests to 70 children of the same age and socioeconomic background who presumably did not have significant exposure to lead. Exposed children had deficits in global IQ and associative abilities, in visual and fine motor coordination, and in behavior. School failure due to learning and behavior problems was more frequent in the lead exposed than in the control group.

Four studies were done to explore the construct validity of a previously established sex difference in TAT fantasy patterns. The results, both with various clinical groups and with normal children, support the notion that Deprivation/Enhancement fantasy patterns are meaningfully related to sexual identity and sex role development. The correlates of extreme D/E patterns are more clear for women than for men and involve elements of the "hysterical" character and cognitive style.

Self-perception theory predicts that intrinsic and extrinsic motivation do not combine additively but rather interact. To test this predicted interaction, intrinsic and extrinsic motivation were both manipulated as independent variables. The results revealed a significant interaction for task satisfaction and a trend for the interaction on a behavioral measure. These results are discussed in terms of a general approach to the self-perception of motivation.

This study investigated factors affecting compliance, to orders from a formal authority. The design created a two-level status hierarchy in which subjects occupied identical low-status positions and responded to demands from a simulated high-status leader. Four components of authority-normativity,coervice power, collective justification, and success-failure-were manipulated as independent variables. Another component, the endorsement accorded the leader, was included in the design as a measured variable. Results indicated that compliance increased significantly when coervice power was high (rather than low), when justification was collective (rather than partisan), and when demands were normative (rather than counternormative). Contary ti the theoretical expectation, endorsement did not affect compliance by low-status members. The findings show that the normative aspect of legitimacy serves as a compliance-gaining base even when stripped of enforcing sanctions and under-lying goals and that the distinction between normativity and endorsement is valid for research on social power.

A paradign was tested for measuting the tendency of children to send accurate nonverbal signals to others via spontaneous facial expressions and gestures. This paradign was derived from studies on adults that suggest that women are more accurate nonverbal "sendres" than men in certain situations. Eighteeen male and 11 female preschoolers (aged 4 to 6 years) watched a series of emotionally loaded color slides while they were observed via a hidden television camera by their mothers. Results indicated that significant overall communciation occurred, with large individual differences in "sending ability" between children. There was no evidence of a large sex difference in sending ability in choldren, although on one measure girls were more accurate senders than boys when viewed by undergraduates. Sending ability was positively related to teacher's ratings of activity level, aggressiveness, impulsiveness, bossiness, sociability, etc., and negatively related ti shyness, cooperation, emotional inhibition and control, etc.

Nnety male subjects were either attacked or treated in a more neutral manner by a male confederate. On a subsequent maze-learning task, one third of the subjects shocked the confederate, one third observed as the experimenter shocked the confederate, and one third waited for a period of time during which the confederate was not shocked. Finally, all subjects shocked the confederate as part of a code-learning task. Subjects who had been attacked and had shocked the confederate during the maze task delivered shocks of greater intensity on the code task did subjects in the other two conditions, and the former subjects also experienced a greater reduction in diastolic blood pressure than did the latter. The results contradict the hypothesis of aggression catharsis and are discussed in terms of feelings of restraint against aggressing that a subject experiences after committing an aggressive act.

The effects of an intellectualization-denial passage designed to modify cognitive appraisal of stressor stimuli (gory scences) were evaluated in terms of sensory-decision theory analysis. The passage was found to reduce "felt stress" ') for certain pairs of the stimuli addressed by the passage content but to less effective in reducing stress (Lx) was reduced rather than increased wi;h presentation of the passage for the included simuli only. Differences in d' between subjects classified within treatment groups as repressors versus sensitizers were obtained for certain stimulus pairs generally in the direction of lower sensitivity for repressors. Results are discussed in terms of the effects of altered cognitive appraisal on the "prevention of stress" and on "defensive"denial.

Right handers moved their eyes leftward when solving spatial problems and rightward for verbal problems when the questioner sat behind them. When facing the questioner, the same subjects moved their eyes predominantly in only one direction, either right or left, regardless of problem type. The results indicate that the cerebral hemispheres, though specialized for problem type, are also preferentially activated within the same individuals.

This study set out to investigate whether the risky shaft found in group consensus decisions as compared to group members' personal decisions extends to situations that combine risk and aggression. In a between-subjects design, subjects were exposed, either alone or as members of unisex triads, to an experimental task in which the risk entailed severe noxious consequences. The findings show that for both sexes, groups take significantly greater risks than individuals even when risk taking is mediated by aggressive means. The results are seen and discussed as limiting the explanatory scope of the risk-as-a-value hypothesis and as more consistent with the diffusion of responsibility hypothesis.

Sixty-four undergraduate males participated in an experiment designed to examine the effects of level of prior anger arousal, exposure to an aggressive model, and ambient temperature on physical aggression. On the basis of Bandura's social learning theory of aggression, it was predicted that uncomfortably hot environmental conditions would be most effective in facilitating later aggression when subjects had both witnessed the actions of the model and been exposed to strong provocation from the victim, but least effective in this regard when they had neither witnessed the actions of the model nor been exposed to prior instigation. In contrast to these predictions, results indicated that high ambient temperatures facilitated aggression by nonangered subjects but actually inhibited such behavior by those who had previously been provoked.

Three experiments considered whether there are differences between overweight and normal weight subjects in time perception which represent the obese subjects' lack of internal responsiveness as well as heightened external reactivity in a noneating setting. In the first study, no time-relevant cues were provided, and overweight subjects were inaccurate in their temporal judgments and showed significantly higher group variability than did normals. In the second study, the effects of differential temporal information generated by interesting and boring cues was considered. The presentation of these time-relevant external cues reduced the judgment variability of the overweight subjects and influenced their perceived passage of time significantly more than normals. The third study examined the influence, on eating behavior, of differences in perceived passage of time as a consequence of manipulating cues for interest or boredom. When bored, overweight subjects perceived time to pass more slowly than did normals and thus ate sooner. Similarly, they delayed eating, judging time to have passed more quickly than it actually had, when they were attending to interesting cues. The implications of a generalized lack of internal sensitivity for a theory about the development and consequences of obesity are discussed.

The present study investigated the role of self-concept as a moderator of the similarity-attraction relationship described by Byrne. Subjects conducted face-to-face interviews with confederates who played roles as job applicants. Similarity-dissimilarity was manipulated by the confederate roles as well as by the information given the subjects in accordance with the procedures described by Byrne. The hypothesis was tested and confirmed that persons with favorable self-concepts would be more attracted to others with similar attitudes than to others with dissimilar attitudes. Persons with negative self-concepts did not show a preference for similar others. It was suggested that earlier studies in this area suffered from methodological flaws and did not constitute an adequate test of the hypothesis. Suggestions for future work in the area were given.

Rats and mice that were not genetically or otherwise predisposed toward audiogenic seizures were rendered susceptible to auditory stimuli by chronic treatment with large doses of rubidium chloride (RbCl). Animals given drinking water, 0.03 N with respect to RbCl, for four weeks responded with convulsive seizures when exposed to signals of 2 to 22 kHz and 74 dbA. The rate of development of audiosusceptibility was dose-related. Less rubidium was needed if the diet was deficient in potassium. No differences were found between tissue rubidium in treated rats which became audiosensitive and their counterparts which remained resistant to auditory stimuli.

The localization of the central cough mechanism was studied by electrically stimulating the lower brainstem in cats lightly anesthetized with pentobarbital sodium or in unanesthetized midcollicular decerebrate preparations. Cough responses were recorded with the aid of a microphone. The cough responsive region was concentrated in an area dorsomedial to the trigeminal tract and nucleus. The sites of action of antitussive agents (dextromethorphan, codeine, clonazepam, diazepam and caramiphen) were studied on the centrally induced cough responses. Each of these drugs was administered intravenously to determine the dorsal levels for cough suppression. In other series, the threshold dose via the intravertebral route was determined first. Because the agent necessary to prevent cough via this route was so small in amount, recovery usually occurred in 20 to 90 minutes. Then the same agent was given intravenously in an attempt to obtain an effective dose which was close to the minimum dose for blocking the cough. The mean effective doses of these agents to abolish the cough via the vertebral artery were only about 1/20 of those required via intravenous injection. The findings suggest that these agents act centrally to suppress the cough responses. Clonazepam was found to be the most potent antitussive among these agents, the mean effective dose being about 1/35 of that of codeine. The antitussive potency of benzodiazepines is not well correlated with their muscle relaxant activity. For instance, clonazepam and diazepam have the same potency in depressing polysynaptic spinal reflexes, whereas the former is 6 times more potent than diazepam as an antitussive. This finding indicates that clonazepam has a high specificity as an antitussive.

Taurine, a ubiquitous sulfonic amino acid, has been described as a regulator of membrane activity in both normal and pathologic states of nerve and muscle. The common feature of its effects on brain activity and its interaction with muscle, can be summarized in terms of a stabilizing function on excitable membranes. In this paper, we report data on the ionic mechanisms by which taurine modulates membrane behavior of the lobster giant axon. Our data show that taurine increases membrane permeabilities to potassium and chloride but not to sodium. This increase is transient, showing membrane desensitization during taurine application. A reversal potential for the taurine response was observed at about -85 mV, causing the membrane potential to stabilize near the resting level. In addition, taurine causes a reduction of the action potential duration, resulting primarily from an acceleration of the depolarization phase. These ionic actions of taurine may explain its overall inhibitory effects in the central nervous system and in the retina and may account for its antiarrhythmic properties.

Monoamine oxidase (MAO) increases in an age-weight relationship in the hearts of male rats. Accumulation of MAO is not related to the activities of such mitochondrial enzymes as succinic dehydrogenase or cytochrome oxidase which do not change with age. Our previous experiments, utilizing serotonin as a substrate, have determined that cardiac MAO in the young rat does not change after chemical sympathetectomy with 6-hydroxydopamine. In this study, rats of different ages were treated with 6-hydroxy-dopamine to investigate the neuronal vs. non-neuronal distribution of MAO in the heart. After sympathetectomy, various parts of the hearts and fractions of the hearts isolated by differential centrifugation were tested for changes in MAO activity with two different substrates (kynuramine and 14C-tryptamine). It was not possible to detect any changes in MAO activity in any parts or subcellular fractions of the heart as a result of denervation. Studies with clorgyline, the MAO inhibitor, in control and sympathetecomized animals revealed that rat cardiac MAO is mostly of the type A enzyme, which was originally thought to be neuronal. A histochemical technique for the electron microscopic demonstration of MAO with osmiophilic thiocarbamyl nitro blue tetrazolium was used in the rat heart in order to determine the ultrastructural location of the enzyme. Histochemical localization of MAO with the electron microscope using tryptamine as the substrate indicates that a substantial portion of rat cardiac MAO is located near the outer membranes of mitochondria within myocardial cells. This histochemical technique provides no evidence to support differential centrifugation data which suggests the presence of a sarcoplasmic reticular (microsomal) MAO in rat heart.

The biogenic monoamines, phenylethylamine and 5-hydroxytryptamine are rapidly and extensively deaminated when perfused in Krebs' solution through rabbit lung. Deamination of phenylethylamine is inhibited approximately 70% by 10(-5) M pargyline and 30% by 10(-3) M semicarbazide. Deamination of this monoamine is unaffected by 10(-6) M harmaline whereas deamination of 5-hydroxytryptamine is inhibited about 75%. These data indicate that the intact perfused rabbit lung contains three forms of amine oxidase two of which are analogous to the A and B forms of the mitochondrial enzyme, monoamine oxidase described previously only in broken cell preparations of lung and other tissues. The third form of amine oxidase is similar to the enzyme found in plasma and several large arteries. Since uptake and metabolism of these amines, as well as loss of their deaminated metabolites, occurs very rapidly, it is suggested that all these forms of monoamine oxidase are associated with vascular endothelium.

We have investigated the dynamics for the removal of 5-hydroxytryptamine (5-HT) from the circulation using the isolated perfused rabbit lung. 5-HT was removed from the circulation at a constant rate and metabolized completely to 5-hydroxyindoleacetic acid which effluxed from the lung into the circulation. Two methods were developed to determine the constant rate of removal of 5-HT: (1) the constant rate is equal to the difference between the 5-HT concentration flowing into the lung and the 5-HT concentration in the effluent times the flow rate and (2) extrapolation of the rate of appearance of radioactivity in the effluent to zero time. With these methods, we have confirmed the 5-HT is removed by the lung by a carrier-mediated Na+-dependent transport system. Studies of transport systems in perfused organs required an adequate supply of the chemical to the lung. Supply rates less than removal rate will result in erroneous measurements of the constant removal rate. The relationships between the rate of removal, perfusate concentration and perfusion rate were analyzed.

Prostaglandins (PG) E2 and F2alpha, characterized by thin-layer chromatography and bioassay, were released from guinea-pig trachea contracted with acetylcholine or histamine. Inhibition of contraction with atropine or mepyramine, or by the removal of calcium, abolished the prostaglandin release. PGE2 and PGF2alpha were also released after gentle mechanical irritation of the mucosal surface, but not the adventitial surface, of the trachea. This release of prostaglandins occurred in the absence of calcium and was prevented by treatment of the trachea with indomethacin. Incubation (20 minutes) of tracheal spirals with indomethacin (0.6 mug/ml) 1) reduced the basal tension of the spiral; 2) reduced responses to low doses of histamine, serotonin, acetylcholine, barium or potassium; and 3) increased responses to high doses of these agonists. These effects lasted despite washout but were reversed by the addition of arachidonic acid. Subthresholdquantities of PGF2alpha after indomethacin treatment restored responses to minimally effective doses of the agonists. Aspirin (50 mug/ml), 5,8,11,14-eicosatetrayonic acid (2 mug/ml) and sodium salicylate (100 mug/ml) had effects similar to indomethacin (0.6 mug/ml). Alterations produced with 5,8,11,14-eicosatetrayonic acid and sodium salicylate were reversed with washing. Restoration of resting tension after indomethacin did not qualitatively change the results. Indomethacin at higher doses (greater than 30 mug/ml) inhibited responses to all histamine doses but this effect was reversible with washing. The results suggest that basal tension of the guinea-pig trachea may be due to an intramural production of PGF2alpha and that during the development of active tension, prostaglandins E2 and F2alpha are released which modulate the intensity of the contraction.

The binding in vitro of an opiate agonist, 3H-dihydromorphine, was studied using a particulate fraction obtained from rat brain homogenates and compared with that of an opiate antagonist, 3H-naloxone. The binding of 3H-dihydromorphine may be separated into two components: one a saturable component and the other nonsaturable. The saturable binding may be calculated from the differences in binding observed in the absence and presence of high concentrations of levorphanol. The use of dextrorphan results in an artifactual separation of this component, although relative stereospecificity was observed for levorphanol and dextrorphan. There were marked regional differences in the distribution of saturable 3H-dihydromorphine binding in the brain. These were primarily due to the difference in the concentration of the saturable binding sites within various brain regions. It appeared that the saturable binding sites from various brain regions had similar affinities for dihydromorphine except for the binding site from cerebral cortex which had a higher affinity. In contrast, saturable binding sites for naloxone in various brain regions had different affinities for naloxone. It appears that naloxone has at least two types of saturable binding sites, one of which is not available to dihydromorphine. This is based on observations 1) that the total concentration of saturable binding sites for naloxone was greater than that for dihydromorphine in each brain region studied irrespective of the assay medium used and 2) that unlabeled dihydromorphine inhibited the 3H-naloxone binding in striatum but failed to alter it significantly in cerebellum, whereas unlabeled naloxone reduced 3H-naloxone binding significantly in both brain regions. The difference in concentrations of saturable binding sites for naloxone and dihydromorphine was relatively small in striatum but larger in cerebellum, indicating that the saturable binding sites in cerebellum are predominantly naloxone-specific, whereas those in striatum are capable of binding both naloxone and dihydromorphine. In cerebrospinal fluid or in simulated intracellular fluid, the apparent affinity for dihydromorphine was lower and that for naloxone was higher than in Tris-HCl buffer. It is concluded that naloxone binds to dihydromorphine binding site and to another site, which has a different affinity for naloxone and is not available to dihydromorphine. Studies in which opiate receptor binding was assayed in Tris-HCl buffer may need to be re-evaluated. Further, in studies where opiate binding in vitro is assessed following pharmacologic intervention, such binding should be estimated in a relevant physiological medium rather than in Tris-HCl buffer.