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Pyridine aldoxime methochloride (2-PAM) increased the force of contraction of stimulated rabbit left atria in vitro. The threshold concentration was 2.3 times 10- minus 3 M whereas 9.2 times 10- minus 2 M produced the absolute maximum increase in tension of 83%. Pretreatment of rabbits with reserpine (2.5 mg/kg/day for 3 days) had no significant influence on the positive inotropic action of 2-PAM. In addition, propranolol (10- minus 8 and 10- minus 6 M) had no effect. Time to peak tension and the time to complete relaxation during each contraction cycle was significantly prolonged. 2-PAM increased the isometric tension developed by isolated aortic strips. The maximum tension developed by the control aortas to 2-PAM was 1.54 plus or minus 0.17 g and after 10- minus 6 M phentolamine, it remained 1.46 plus or minus 0.19 g. The rate of tension decline of stimulated atria was increased in the presence of 2-PAM from 49.7 plus or minus 2.40 to 28.50 plus or minus 1.32 seconds when the atria were placed in a low calcium (Ca)-containing Ringer's solution (0.24 mM CaCl2). When the bathing medium was changed from a low Ca (0.24 mM CaCl2) Ringer's back to normal Ca (2.4 mM CaCl2) Ringers solution, 2-PAM had no influence on the rate of recovery of the initial tension response of the atria. The 34-Ca uptake and efflux studies demonstrated that 2-PAM had no influence on the inward movement of Ca through the membrane but increased the rate of efflux during the phase II process. 2-PAM depressed the rate of uptake of 45-Ca by the isolated rabbit sarcoplasmic reticulum. The T1/2 for the control uptake was 1.80 plus or minus 0.07 minutes and in the presence of 2-PAM (2 times 10- minus 2, 5 times 10- minus 2, 1 times 10- minus 1 M) the T1/2 was increased to 4.50 plus or minus 0.22, 7.20 plus or minus 0.36 and 11.6 plus or minus 0.44 minutes, respectively. It is concluded from these studies that 2-PAM has a positive inotropic effect on isolated rabbit atria which is probably not related to the autonomic nervous system. The evidence obtained strongly suggests that the mechanism of the positive inotropic action is related to the effect of 2-PAM on the homeostasis of intracellular Ca storage sites.

The biosynthesis of acetylcholine and the fate of intravenously administered choline [methyl- 3-H] were studied in guinea pigs anesthetized with pentobarbital. Choline and acetylcholine were isolated by paper electrophoresis and estimated by use of a specific enzymatic (choline kinase) - radioisotopic assay. The concentration of acetylcholine ranged from 25.5 to 1.1 nmol/g in the following tissues (in order of decreasing concentration): duodenum, corpus striatum, stomach, cerebral cortex, spinal cord, abdominal fat, submaxillary gland, kidney, adrenal gland, spleen, liver, lung, heart and diaphragm. Choline [methyl- 3-H] was converted in the tissues to acetylcholine within 3 minutes after intravenous administration of the precursor. Virtually all the radioactivity in plasma at that time was present as free choline, suggesting that free choline from plasma is the immediate precursor for acetylcholine synthesized in the tissues cited. The concentration of free choline in tissues ranged from 344 nmol/g in adrenals to 40 nmol/g in heart, while that in plasma was 15 nmol/g. The initial half-life of choline in plasma, estimated from the rate of disappearance of choline after intravenous administration of either a tracer dose of choline [methyl- 3-H] (0.031 mumol/kg) or a high dose of choline chloride (200 mumol/kg), was less than 1 minute. This rapid removal of choline from plasma resulted from uptake (or binding) by tissues, with kidney and liver removing about 50% of the administered dose of choline [methyl- 3-H] within 3 minutes after its administration. Uptake of choline occurred in all tissues cited above, but there was a 20-fold difference in the uptake by the most active tissues (kidney and adrenals), as compared to that of the least active (central nervous system). Within 60 minutes after administration of choline [methyl- 3-H], most of the radioactive choline taken up by tissues had been converted to organic-soluble metabolites and to water-soluble metabolites that behaved like either phosphorylcholine or betaine during paper electrophoresis and chromatography. Betaine was the principal metabolite of choline in plasma. Radioactivity was excreted slowly into urine, which contained primarily free choline, betaine and a large amount of an unidentified metabolite. These findings indicate that the principal mechanism for the rapid removal of choline from plasma is uptake into tissues followed by metabolism.

Urinary excretion and tubular handling of 3-H-prostaglandin E2 (3-H-PGE2) were examined in anesthetized rats made diuretic with 2.5% saline infusion using the tracer microinjection technique. Radioactive inulin and PGE2 were simultaneously injected into surface convolutions of proximal and distal tubules with volumetric micropipettes and their urinary excretion were measured. The rate of microinjection was adjusted to approximate tubular flow. Net 3-H-PGE2 recoveries from the microinjected kidney were similar following injections into early (61.2 plus or minus 6.8%) and late (62.9 plus or minus 7.9%) proximal tubules, but significantly higher after injection into distal tubules (91.3 plus or minus 7.0%) indicating absorption of 3-H-PGE2 in the loop of Henle but not in the proximal and distal nephron. Excretion was primarily direct, that is, parallel with inulin excretion when PGE2 was deposited in distal convoluted tubules. After injection of 3-H-PGE2 into early and late proximal tubules, half of net recovery was direct and half showed temporal dissociation from inulin (indirect recovery), revealing retardation of PGE2 excretion in the loop. Segmental tubular efflux occurred primarily in the loop of Henle (48.5%). It was low in the distal nephron (13.5%) and negligible in the proximal convoluted tubule (6.1%). These studies indicate that the loop of Henle is the principal site of transtubular PGE2 movement. They do not suggest a primary tubular route of transfer of medullary prostaglandins to cortical vascular or peritubular sites of action except for possible inhibition of distal reabsorption from the luminal side.

The effect of carbon tetracholoride (CCl4) inhalation (1100 ppm, 30 minutes) on rat hepatic polyribosomal profile, amino acid incorporation and endoplasmic reticulum were studied in phenobarbital or 3-methylcholanthrene (3-MC) pretreated rats. The inhalation of CCl4 alone caused a partial disruption of the hepatic polyribosomal profile. Rats pretreated with phenobarbital or 3-MC showed complete disruption of the hepatic polyribosomal profile. The hepatic polyribosomal profile returned to normal within 24 hours after exposure to CCl4 in saline and 3-MC-pretreated rats as compared to 48 hours in phenobarbital-pretreated rats. The incorporation of 14-C(U)-L-leucine into 9000 x g liver supernatant fraction protein was decreased in phenobarbital-pretreated rats when measured immediately following or 24 hours after inhalation of CCl4. The incorporation was also decreased in 3-MC-pretreated rats when measured immediately after exposure but not at 6 or 24 hours. The centrolobular hepatocytes of phenobarbital-pretreated rats exposed to CCl4 showed dilation and vesiculation of cisternae of the rough endoplasmic reticulum and striking changes in the nuclear double membrane. Partial recovery occurred within 24 hours and complete recovery within 48 hours after exposure. There were no observable changes in these parameters 0, 6, or 24 hours after exposure to CCl4 in 3-MC-pretreated rats. A new hypothesis is put forward which states that the activation of CCl4 to trichloromethyl free radicals takes place at two sites on the reduced nicotinamide adenine dinucleotide phosphate-cytochrome P-450 electron-transport chain of liver microsomes.

1. The membrane resistance of isolated salivary glands was found to decrease in response to 5-HT. The change in resistance was calcium-dependent. 2. The resistance change of the apical membrane was found to be much greater than the change in resistance of the basal membrane. 3. Potential responses under current-clamped conditions showed that one part of the biphasic response to 5-HT (attributed to an increase in chloride permeability) could be reversed and the other part (attributed to an increase in a potassium pump) could not. 4. These observations have been incorporated into a model which, on evaluation, predicts all of the observed potential changes during the action of 5-HT. It suggests that the potential responses reflect changes in the internal chloride concentration produced by the calcium-dependent increases in chloride permeability.

1. S-potential responses to transient and maintained light stimuli have been recorded from units in the mixed rod-cone retina of a teleost fish species Eugerres plumieri. 2. Four spectral classes of S-potential were observed, three cone- and one rod-type. The cone-type responses were subdivided into two L-type (referred to as L1 and L2), and a C-type response. Two classes of transient depolarization response were also recorded from those retinal levels associated with the S-potential responses and these are attributed, tentatively, to rod and cone bipolar activity. 3. L2-type S-potentials do not yield constant hyperpolarization during maintained light stimulation, the time course of the response potential, V, being given approximately by (see article) where Vt is the response potential at time t sec following the onset of stimulation, Vo being the initial response potential. In contrast, both hyperpolarizing and depolarizing components of the C-type response were maintained under conditions of steady illumination. 4. Under maintained light stimulation at saturation illumination level, the rod S-potentials escape from hyperpolarization in a manner similar to that previously observed for the skate (Dowling & Ripps, 1971). 5. L2-type responses to transient test stimuli of illumination level I, superimposed on a steady background field of illumination level I', are in some respects consistent with Alpern, Rushton & Torii's (1970) empirical formula (see article) with K, I one-half and ID constants. However, for the present data, the value of I one-half is dependent on I'. 6. The significance of Ricco's law for S-potential responses is discussed in relation to these findings.

1. A giant dopamine-containing cell, situated in the left pedal ganglion of the water snail Planorbis corneus, was identified in isolated living preparations of the central nervous system. Spectrophotofluorimetric analysis confirms that the cell contains dopamine, whereas noradrenaline appears to be absent. The cell is unique in being a repeatedly identifiable dopamine-containing neurone. 2. Stimulation of the giant dopamine-containing cell resulted in excitatory, inhibitory or biphasic (depolarizing-hyperpolarizing) synaptic potentials in a number of follower neurones. The duration of the e.p.s.p.s and i.p.s.p.s was 0-3-5 sec; they ranged from barely detectable responses to ones 7 mV in amplitude in different cells. The depolarizing phase of a biphasic synaptic potential (b.p.s.p.) was usually less than 1 mV in amplitude (max. 3mV) and lasted 40-400 msec. The latency of i.p.s.p.s was long (70-120 msec) compared with that of e.p.s.p.s and b.p.s.p.s (20 msec). Abolition of the depolarizing phase of b.p.s.ps. by tubocurarine left a long-latency (70-120 msec) i.p.s.p. All responses showed summation and marked facilitation. 3. Evidence is presented that the post-synaptic potentials are produced by direct connections from the giant cell and result from a release of dopamine. Of eight putative transmitter substances tested on these different groups of neurones, only dopamine produced a potential change which in each case was of the same polarity as the post-synaptic potential when this was monophasic. However, generally applied dopamine produced only a hyperpolarization in follower cells showing b.p.s.p.s. This result is probably partly due to rapid desensitization of the receptors mediating the depolarization and also to a masking of the depolarization by the more effective hyperpolarizing response. 4. Erogometrine and 6-hydroxydopamine specifically antagonized the i.p.s.p.s and dopamine receptors mediating inhibition. Neither the e.p.s.p.s nor the excitatory dopamine response were blocked by high concentrations of hexamethonium. Hexamethonium was also ineffective in blocking the depolarizing phase of a b.p.s.p., which was, however, selectively eliminated by tubocurarine. 5. It is suggested that dopamine is the transmitter released from the giant cell and that it can mediate excitatory, inhibitory or biphasic responses in different follower neurones.

1. Polyneuronal innervation is known to occur in several types of vertebrate muscle, including mammalian muscle spindle (Gray, 1957). Previous work had led to the suggestion that the multiply innervated cat extraocular muscles were similarly polyneuronally innervated. 2. The presence of polyneuronal innervation in fibres that show propagated conduction was explored in the two muscles innervated by the abducens nerve: the lateral rectus (which contains multiply innervated fibres) and the retractor bulbus (which does not). 3. Under conditions of twitch and tetanic stimulation, the sum of individual tensions from the two nerve branches was compared with the tension elicited from the whole nerve. An analysis of variance indicated that the lateral rectus and the retractor bulbus did not differ significantly in terms of tension excess. The twitch condition yielded a small but statistically significant (P smaller than 0-01) amount of tension excess, whereas the tetanic condition did not. 4. Twitches elicited by stimulation of one branch of the abducens nerve showed slight potentiation when preceded by a tetanic stimulation to the other nerve branch. This effect could be ready differentiated from the post-tetanic potentiation elicited by applying both twitch and tetanic stimuli to the whole nerve. 5. Muscle fatigue produced by intensive stimulation of one nerve branch did not decrease the amplitude of the tetanic contraction elicited by stimulation of the other branch. In fact, instead of crossed fatigue, a small but significant (P smaller than 0-05) potentiation was observed. 6. Analysis of the results of the three tests led to the conclusion that polyneuronal innervation could not be demonstrated in cat extraocular muslce fibers that showed propagated conduction. Thus, the end-to-end muscle fibre junctions (Floyd, 1970) apparently do not transmit conducted impulses.

1. Extracts were prepared of chicken duodenum and their actions on pancreatic secretion in urethane anasthetized turkeys and in conscious cats were compared with those of pure natural porcine secretin. 2. The chicken extracts and porcine secretin stimulated dose-dependent increases in the rate of flow, but not the rate of protein secretion, from the pancreas in cats and turkeys. 3. Porcine cholecystokinin stimulated both the rate of flow and the rate of protein secretion from the pancrease in turkeys. 4. The doses of chicken extract required to evoke half maximal rates of flow of pancreatic juice were similar in the turkey (0-55 mg/kg) and in the cat (0-72 mg/kg). The highest concentration of bicarbonate recorded in the turkey responses was 30 m-equiv/l. compared with 112 m-equiv/l. in the cat. 5. The dose of porcine secretin required for half maximal rate of flow in the bird (5-9 mug/kg) was 180 times higher than in the mammal (0-33 mug/kg). In the cat the duration of responses to porcine secretin was significantly greater than to the chicken extract. 6. It is concluded that in birds there is a factor with biological properties similar but not identical to those of porcine secretin, and that this factor may regulate pancreatic secretion by a mechanism resembling the secretin mechanism in mammals.

1. The electrical properties of horizontal cells in the mudpuppy in light and dark were measured with a pair of micropipettes separated by about 1 mum with low coupling resistance so that no bridge circuitry was required. 2. All horizontal cells studied showed significant anomalous rectification: the current-voltage characteristic for about 60 per cent of the cells studied had a slope resistance of about 20-30 M omega at the dark potential level; the slope resistance increased by about 15% for each 10 mV depolarization and decreased by about 15% for each 10 mV hyperpolarization. The remaining 40% of the horizontal cells showed a higher input resistance at corresponding potential levels but had similar rectifying properties. 3. The increase in resistance with depolrization developed with a time course of about 1/2 sec when steady steps of outward current were passed across the membrane, but the time course for resistance decrease with hyperpolarization was much shorter for steady inward current steps. In about half the horizontal cells there was a transient decrease in resistance lasting about 100 msec immediately following the outward current steps superimposed upon the slower sustained resistance increase. 4. The normal 20-30 mV hyperpolarizing light response was associated with little or no change in input resistance. However, if the membrane potential was held at the dark potential level with extrinsic current, thereby eliminating the potential-dependent resistance change, a light-elicited resistance increase of about 10 M omega was measured. 5. The time-dependent change in membrane resistance elicited by polarizing steps of current obscured the reversal potential for the response. However, when the reversal potential was measured at short times following polarization of the membrane, before the time-dependent resistance change developed, it was estimated at between +15 and +50 m V. 6. The results suggest that the horizontal cell response is mediated by a light-elicited resistance increase at the synaptic membrane which is obscured by a potential- and time-dependent resistance decrease at another part of the membrane.

1. Physiological properties of developing nerve-muscle junctions were studied in regenerating limbs of adult salamanders. 2. During the period of synapse formation the muscle fibres had diameters of 4-10 mum, resting potentials of minus 90 to minus 100 mV and input resistances of 10-50 Momega. Some, but not all, pairs of adjacent muscle fibres were electrically coupled. 3. At the stage when muscle fibres could first be identified, some of them were not innervated, at least as determined by electrophysiological criteria. 4. During muscle innervation the neuromuscular synapses were encountered in several intermediate phases of maturity. (i) At the least mature junctions small spontaneous synaptic potentials occurred, but stimulation of the motor nerve trunk did not evoke synchronous transmitter release. (ii) At other junctions maximal nerve stimulation evoked only a single end-plate potential of low quantum content. (iii) More mature fibres received synaptic input from as many as four motor neurons, which could be distinguished by their discrete stimulus thresholds. 5. During this period of synapse development the fibres lacked an action potential but often showed a prolonged response to depolarization. 6. Fibres in normal adult muscles had from one to three synaptic inputs, were not electrically coupled, and responded to depolarization with an action potential.

1. The acetylcholine (ACh)-releasing system in the cerebral cortex of pentobarbital anaesthetized cats was investigated by examining the effect of graded afferent volleys in forelimb nerves on ACh release from the sensorimotor cortices contralateral and ipsilateral to the site of stimulation. 2. Cortical ACh release was determined by bio-assay of neostigmine-containing perfusates which had been in contact with the cortical surfaces for 5-10 min periods. 3. Afferent volleys, generated by stimuli that were effective in activating as many fibres of a fibre group as possible without stimulating fibres in the group with the next highest threshold for activation, were monitored from dorsal roots C7 or C8 before entering the spinal cord. 4. Stimulation of the deep (DR) and superficial (SR) radial nerves and the radial (R) nerve proximal to the junction of the DR and SR were effective in enhancing ACh release only when either group III or groups III and IV fibres were included in the afferent volley. 5. The rates of ACh release from the primary receiving area of the sensorimotor cortex contralateral to the site of stimulation did not differ from those from the same area of the ipsilateral sensorimotor cortex. 6. The pertinence of this data to the various hypotheses concerning the nature of the ACh-releasing pathways to the cerebral cortex is discussed.

1. In anaesthetized dogs, stimulation of atrial receptors after destruction of the pituitary gland results in a diuresis. This response was not abolished by the administration of bretylium tosylate and was also observed in a surgically denervated kidney. 2. The diuresis is qualitatively similar to that observed in anaesthetized dogs with intact pituitary glands. 3. It is concluded that the diuresis which results from stimulation of the left atrial receptors is mediated by a blood-borne agent which is not the antidiuretic hormone.

1. Variations in the output of glucocorticoids and catecholamines from the right adrenal gland, in response to insulin hypoglycaemia, have been investigated in calves 2-5 weeks after birth. These have been correlated with changes in the concentration of glucocorticoids and glucagon in arterial plasma. 2. Moderate hypoglycaemia for a limited period (0-1 u. insulin/kg), elicited a prompt increase in steroid output from the adrenal gland followed by a significant rise in plasma glucagon concentration. By comparison, changes in both catecholamine output and peripheral plasma glucocorticoid concentrations were found to be trivial in this group of animals. 3. Administration of a larger dose of insulin (0-5 u./kg) produced a more substantial fall in plasma glucose concentration followed by spontaneous recovery within 2-3 hr. This stimulus elicited the release of greater amounts of both cortisol and corticosterone, followed by a significant increase both in the output of adrenaline and in plasma glucagon concentration. Increase in steroid output was accompanied by an increase in adrenal blood flow and was associated with elevated concentrations of both steroids in arterial plasma. 4. The adrenal cortical response and associated changes in plasma steroid concentration were found to be transient even in response to persistent and intense hypoglycaemia (4 u. insulin/kg). The increase in plasma glucagon concentration in this group of animals was not significantly greater than that produced by smaller doses of insulin. However, substantial amounts of adrenaline (78 plus or minus 14 ng. kg-minus 1 min-minus 1; maximum; n equals 9) together with a little noradrenaline (10 plus or minus 3 ng.kg-minus 1 min-minus 1; maximum; n equals 9) were released from the right adrenal gland under these conditions. 5. Changes in adrenal blood flow could be related to adrenal glucocorticoid output in calves given 0-1 or 0-5 u. insulin/kg. In animals given the largest dose of insulin adrenal blood flow was found to increase coincidentally with rising steroid output but this hyperaemia then persisted after steroid output had subsided to values within the normal range. 6. Calves given the largest dose of insulin (4-0 u./kg) invariably collapsed and convulsed after 2-3 hr, but these symptoms could not be related to any particular endocrine response. No clinical signs of hypoglycaemia were observed in the other animals. 7. The results are discussed in relation to previous studies of adrenal function in this and other species.

1. Secretion of catecholamines (CA) and dopamine beta-hydroxylase (DBH) activity from the perfused cat adrenal gland was studied following splanchnic nerve stimulation or infusion of acetylcholine (ACh). 2. Splanchnic nerve stimulation (30 Hz) or perfusion with a low concentration of ACh (10-minus5 M) caused a marked release of CA in the venous effluent, but release of DBH activity was minimal while a higher concentration of ACh (10-minus 4 M) enhanced the release of CA and DBH. 3. The ratio of DBH/CA released in the perfusate by splanchnic nerve stimulation or ACh infusion was only a small fraction of the ratio in the soluble lysate of purified chromaffin vesicles. 4. Following reserpine treatment, adrenal CA levels fell to 25% of the control value in 24 hr, remained depressed on days 2, 3, 4 and 5 at 5% of the control and recovered to 60% of the control value on the 6th day. DBH activity was unchanged from the control value at 24 hr after treatment, then rose as high as 5 times the control on the 5th day and was still twice the control value on the 6th day. 5. CA secretion in response to ACh (10-minus 4 M) perfusion was reduced to 30% of the control value on the first day after reserpine treatment, while DBH secretion was unchanged. On the 2nd day, CA secretion was depressed further to 5% of the control and remained at this low level up to 5 days after treatment while DBH secretion was twice the control value at 48 hr and then on days 3, 4 and 5 rose up to 5 times the control value. On the 6th day, secretion of CA recovered to 30% of the control while DBH secretion was now twice the control. 6. Isopycnic sucrose density (discontinuous) gradient centrifugation of vesicles from adrenal glands of control cats, and of cats given reserpine 1 or 2 days perviously, indicated that new vesicles or vesicles depleted of CA by reserpine had a lower equilibrium density than the original population of vesicles. 7. These results suggest that the release of CA is quantal in nature, but the release of DBH is not necessarily coupled with it. Release of DBH by ACh from reserpinized glands suggests that the vesicles which were once involved in secretion may be re-used for synthesis and storage of CA.

1. Short segments of isolated longitudinal myometrium from the pregnant rate uterus have been studied in a double sucrose-gap voltage-clamp arrangement. The clamped segment averaged 65 mum times 240 mum times 100 mum, has an average total capacitance of 0-14 muF, and may contain 50-200 individual myometrial cells. 2. A significant resistance exists in series with the membrane, and limits theprecision of the quantitative information. However, it is argued that some qualitative and some comparative information is useful. 3. In Krebs-bicarbonate solution, depolarizing steps produced initial transient inward currents followed by delayed outward currents. 4. When [Na+]o was reduced by 50%, the equilibrium potential Ea shifted by an average of -17-6 mV, the maximum inward current was reduced to 0-5, the time to peak of the early current was delayed by 1-1 msec, and the maximum chord conductances for the early(Ga) and late (GK) currents remained unchanged as compared with those in normal [Na+]o. 5. When [Ca2+] was reduced to 25% of normal, Ea shifted by an average of -20-3 mV, the maximum inward current was reduced to 0-5, the time to peak was delayed 3-1 msec, and Ga was significantly reduced, while GK was unaffected. 6. The early current, and its tail when repolarization was imposed, reversed direction from inward to outward when [Na+]o was reduced from 143 mM to zero, with [Ca2+]o remaining constant at 1-9 mM. 7. From the observations in 4, 5 and 6, it was concluded that Na+ is the main charge carrier for the early current, and that Ca2+ is important in regulating Ga. 8. The late current is outwards when [K+]o equals 5-9 mM, but inwards in some voltage range when [K+]o was elevated to 120 or 148 mM. K+ is the main charge carrier for the late current. 9. The equilibrium potential for the late current, EK, is about 15 mV more negative than the natural resting potential. 10. Prolonged holding of the preparations at voltages that differ significantly from the natural resting potential tends to shift EK in a way consistent with passive changes in [K+]i by the holding current. 11. The steady-state inactivation of the early current, h, is unusual. Inward current is macimum around the resting potential, and declines with both hyperpolarizing and depolarizing changes. Half-inactivation occurred with about 9 mV depolarization and 15 mV hyperpolarization. 12. The instantaneous current-voltage relations of both early and late currents are linear. The chord conductances Ga and GKare similar in form to those in other tissues.

1. The kinetics of absorption of glucose, galactose and alpha-methyl glucoside have been measured in rat jejunum in vivo using a chemical method and a new electrical technique. 2. Sugar absorption estimated by chemical methods exhibited two components. One component was phlorrhizin-sensitive, saturable and generated electrical potential differences (electrogenic active component) while the other was phlorrhizin-insensitive, non-saturable and did not generate electrical potentials (diffusive component). 3. The diffusive component of the actively transported sugars was indentical to the absorption behaviour of sorbose, a hexose that is not actively transferred. 4. A method for correcting the data obtained from chemical absorption studies for the diffusive component was developed. The corrected, operational kinetic constants for 'apparent Km' obtained by this method were not significantly different to values obtained electrically. The identity between the values obtained by both methods supports the concept that they represent a measure of the same rate-limiting step in the absorption process. 5. The application and significance of the techniques is discussed in relation to the clinical assessment of intestinal sugar absorption.

1. In unanaesthetized cats a comparison is made of the hyperglycaemic effects of adrenaline and morphine, when injected or infused through chronically implanted cannulae, into different regions of the cerebral ventricles or of the subarachnoid space, in order to determine their sites of action. 2. On injection into the cerebral ventricles both adrenaline and morphine have to reach the subarachnoid space beneath the ventral surface of the brain stem before they can exert their hyperglycaemic effect. The adrenaline has to reach the region rostral to the pons, i.e. the fossa interpeduncularis, and the morphine the region caudal to the trapezoid bodies. These conclusions are based on the following findings. 3. When adrenaline (55 mug) and morphine (0-75mg) were infused into one or other of these two regions, adrenaline produced strong hyperglycaemia on infusion into the fossa interpeduncularis, but had scarcely any hyperglycaemic effect on infusion into the region caudal to the trapezoid bodies. The reverse result was obtained with morphine. 4. It is concluded that the adrenaline hyperglycaemia is mainly a peripheral effect. It occurs after the adrenaline has been absorbed into the blood stream from the fossa interpeduncularis but an additional central component, an action on brain stem structures reached from the fossa interpeduncularis, cannot be excluded. The morphine hyperglycaemia is a central effect due to an action on superficial structures of the ventral surface of the medulla oblongata, caudal to the trapezoid bodies.

1. 45-Ca efflux and resting tension were measured in isolated guinea-pig auricles under conditions known to change the intracellular free Ca ion concentration. 2. In the presence of [Na]o, caffeine (2mM) increases 45-Ca efflux, but does not produce a contracture, while in the absence of [Na]o and [Ca]o caffeine causes a contracture without increasing 45-Ca efflux. Adrenaline (10-minus5-10-minus 4M) with or without theophylline (0-5-1-0mM) has no effect on either 45-Ca efflux or resting tension. 3. In the presence of caffeine the rate of net efflux of Ca depends on [Na]o-2. Caffeine contractures of muscles in Na-free solution relax upon the addition of [Na]o. Relaxation is correlated with the increase in net efflux of Ca. 4. Cyanide (2mM) produces a variable increase in 45-Ca efflux without a concomitant contracture in Na-containing solutions, but in Na, Ca-free solutions a large contracture occurs without significant increase in 45-Ca efflux. 5. A large increase in 45-Ca efflux and a contracture were observed with the 'Ca-ionophore' X 537 A. 6. Changes in membrane potential (K-depolarization) in hypertonic solutions have no significant effect on Na-dependent 45-Ca efflux, which is an agreement with an electroneutral 2:1 Na-Ca exchange. 7. Cyanide and X 537 A both cause a considerable release of Ca ions from isolated guinea-pig heart mitochondria, while caffeine has no effect. 8. The results suggest a powerful role of the Na-Ca exchange system in reducing the intracellular Ca concentration after Ca release from intracellular stores.

1. An investigation was carried out on single cells in 7 day old rat primary somatosensory cortex, which responded to cutaneous stimulation using mechanical pulses. 3 percent of cells encountered showed stable spontaneous activity, whereas 88 percent were silent in the absence of intentional stimulation. The remainder showed unstable spontaneous activity. In contrast, the great majority of adult cells were spontaneously active in the absence of stimulation, under similar conditions of urethane anaesthesia. 2. The distribution within cortical layers of cutaneously driven cells was similar in adult and 7 day old rats, and similar to that found in adult mammalian cortex by other workers. 3. 7 day old cells showed diminished excitability to cutaneous stimulation with stimuli at intervals below 10-15 sec, whereas adult cells could be successfully repetitively driven with stimuli at intervals of 500 msec. The low ability of the immature cells to follow repetitive cutaneous stimulation is not due to an overall depression of these cells excitability per se. Latencies of unitary responses in these immature cells were about sixfold those found in equivalent cells at maturity. 4. Columnar organization at seven days of age was similar in outline to that of the adult, but much less discrete. Receptive fields were considerably larger at 7 days and evidence is given that this may be due to inadequate surround inhibition. Immature vibrissae-driven units were directionally selective. 5. At 7 days of age, long inter-spike intervals were rare in spontaneously active cells with the result that inter-spike interval histogram distributions (i.h.s.) were approximately normal. Corresponding i.h.s. of adult cells invariably showed skew distributions. 6. Tactile stimulation of centre receptive fields produced an increase in short and long intervals from spontaneously active cells at each age. In contrast to adult cells, the immature cells commonly responded cyclically, with alternating phases of increased and decreased firing rate for periods of up to 3 sec following punctate stimulation. 7. Decrease in spontaneous firing rate, following the first phase of excitation, was profound in 7 day old cells, and implied that inhibitory mechanisms operate at an early age in the rat somatosensory system. These mechanisms also appear to contribute to cyclical activity of 7 day old cells when driven by punctate cutaneous stimulation.

1. A constant specific activity of radioactively labelled amino acids was maintained in the circulation by means of a new technique devised for this purpose. This has made it possible to measure accurately the entry rates of amino acids into the brain in vivo. 2. The rates of entry into the brain of seven nutritionally non-essential amino acids were measured. 3. Glycine and proline enter the brain relatively slowly, at rates comparable to those of amino acids which are not normally found in the blood. Thus their entry is due mainly if not entirely to passive diffusion. 4. Serine (which is used by the brain to make glycine) and alanine (which is used to make glutamate and aspartate) enter the brain as rapidly as the essential amino acids and thus, although not essential for the body as a whole, appear to be essential for the brain. 5. It is suggested that those amino acids that the brain is able to synthesize have low rates of entry, even though they are present at high concentrations in the plasma, but that the transport systems for those amino acids that are not synthesized in the brain ensure rapid entry at rates that are related to the rates of cerebral utilization.

1. Motor units in the first dorsal interosseus muscle of normal human subjects were recorded by needle electrodes, together with the surface electromyogram (e.m.g.). The wave form contributed by each motor unit to the surface e.m.g. was determined by signal averaging. 2. The peak-to-peak amplitude of the wave form contributed to the surface e.m.g. by a motor unit increased approximately as the square root of the threshold force at which the unit was recruited. The peak-to-peak duration of the wave form was independent of the threshold force. 3. Large and small motor units are uniformly distributed throughout this muscle, and the muscle fibres making up a motor unit may be widely dispersed. 4. The rectified surface e.m.g. was computed as a function of force, based on the sample of motor units recorded. The largest contribution of motor unit recruitment occurs at low force levels, while the contribution of increased firing rate becomes more important at higher force levels. 5. Possible bases for the common experimental observation that the mean rectified surface e.m.g. varies linearly with the force generated by a muscle are discussed. E.m.g. potentials and contractile responses may both sum non-linearly at moderate to high force levels, but in such a way that the rectified surface e.m.g. is still approximately linearly related to the force produced by the muscle.

1. Binocularly driven neurones with small receptive fields near the area centralis were recorded in the cat's superior colliculus. 2. Binocular interaction was tested by stimulating both eyes simultaneously with a single moving stimulus at various retinal disparities. 3. Collicular cells in general showed strong summation or even facilitation when the images of the stimulus were in exact correspondence on the receptive fields, sometimes with occlusion when they were out of register. The range of retinal disparity over which there was additive interaction could be as little as 1 or 2 deg, almost as narrow as for the most precisely tuned neurones in the visual cortex. Even cells with large receptive fields sometimes showed a narrow range of binocular interaction. 4. Non-directional cells generally exhibited weaker summation and broader disparity selectivity than did direction-selective cells. 5. Some neurones with virtually no response to a stimulus in one of the eyes can exhibit marked binocular interaction. Other apparently monocular cells show little or no binocular interaction. 6. The disparity of the centres of the receptive fields was measured after correcting for small eye movements, which were assessed by two different techniques. For 132 cells the measured distribution of horizontal disparity (range 4.5 deg; S.D. 0.93 deg) was significantly broader than that of vertical disparity (range 2.2 deg; S.D. 0.52 deg). Sources of error in these measurements are considered. 7. The results are discussed in relation to the known connexions between visual cortex and superior colliculus and the possible role of the latter in the regulation of eye movements.

Intracellular responses were recorded from rods in isolated eye-cups of the snapping turtle, Chelydra serpentina. Responses to small and large diameter spots of 500 nm light were studied. 1. The peak amplitudes of responses smaller than approximately 2 mV were directly proportional to irradiance. Small spots (less than 100 mum diameter) produced approximately 30 muV/rhodopsin molecule bleached. Increasing stimulus diameter to 400-500 mum increased this five to seven times to about 200 muV/rhodopsin molecule bleached in the impaled receptor. The difference is attributed to a neural "enhancement" produced by stimulating neighbouring rods. 2. Enlarging the diameter of a spot altered the shape of responses produced by very dim lights. 3. The variance of responses to a small spot was only slightly less than the mean. The variance of responses to a large spot was much less than the mean. 4. Responses evoked by a small spot of dim light obeyed the superposition principle in that the response to a very dim step of light was the integral of the response of a very dim flash. Responses evoked by a large spot did not obey the superposition principle. The response to a step of dim light covering a spot of large diameter was less than predicted from the integral of the response to a flash. The difference is attributed to a neural "disenhancement" produced by stimulating neighbouring rods. 5. The time course of this disenhancement could be observed by presenting two large diameter, dim flashes within a short interval. The time course of disenhancement did not coincide with that of the voltage response but was delayed such that its maximum occurred after the peak amplitude. 6. Dim background lights of different diameter, which delivered the same quantity of light to the impaled cell but very different quantities of light to neighbouring cells, left the response produced by a small diameter test spot unaltered. It is concluded that rod-rod interaction can modify the intracellular responses of rods in two ways; it produces an early enhancement which increases response amplitude nearly tenfold and also a delayed disenhancement which replaces the wave of enhancement that follows a flash.

The intracellular responses of rods in the retina of the turtle, Chelydra serpentina, were studied with brief flashes of monochromatic light. 1. Flashes of red or green light applied over an area 25 mum in diameter produce responses with the same shape. With such restricted stimuli, the spectral sensitivity of a rod agrees well with the absorption spectrum of the porphyropsin pigment contained in its outer segment. 2. With stimulating spots more than 500 mum in diameter, dim flashes of red or green light produce responses having different shapes. When the spectral sensitivity of a rod is tested using dim lights of large diameter, the sensitivity to red light is much greater than predicted by the absorption spectrum of porphyropsin. 3. The shape of the response produced by large diameter spots of dim, red light resembles that of cones. 4. Increasing the diameter of a dim, red spot beyond 500 mum markedly alters the amplitude and shape of responses from horizontal cells but does not significantly affect the response of rods. It is concluded that rods receive an excitation from neighbouring cones. This interaction is unlikely to be mediated by type I luminosity horizontal cells but may be mediated by either direct connexions between cones and rods or by an interneurone with a small receptive field.

1. A method is described for studying renin release from superfused rat glomeruli following their rapid isolation by a magnetic iron-oxide technique. 2. Microscopically selected glomeruli were free of tubular components. Some possessed vascular pole protrusions of up to 20 mum, unrelated to renin content. 3. Renin content of 102 batches, each of 400 glomeruli, was 1.34 plus or minus 0.08 times 10-4 Goldblatt hog units per 100 glomeruli (plus or minus S.E. of mean). Different osmolarities (305, 355 and 400 m-osmole/1.), sodium concentrations (110 and 135 mM) and buffer compositions of the preparation solution did not alter this value. Renin content per glomerulus in intact kidney was 100-fold higher. 4. At 30 degrees C the contained juxtaglomerular cells released renin at consistent but decreasing rates over 4-6 hr. Initial release rate in 110 mM sodium, 305 m-osmole/1. solutions were 0.86 plus or minus 0.068 times 10-6 units per 100 glomeruli per 30 min (plus or minus S.E. of mean, n = 42) or 0.546 plus or minus 0.046 percent of content per 30 min. In 135 mM sodium, 305 m-osmole/1. solutions, release was 2.4-fold higher (P less than 0.001) and remained elevated for at least 3 hr. When related to renin content per glomerulus resting release rate in vitro was higher by at most one order of magnitude than calculated in vivo values. 5. Release was augmented by gentle physical agitation of the glomeruli. 6. Release rate was inversely ralated to temperature. On reducing temperature from 30 degrees C, release increased 2.6-fold at 20 degrees C and 6.7-fold at 10 degrees C (P less than 0.001, n = 11). The response was reversible. 7. 3 mM sodium cyanide plus 3 mM sodium iodoacetate caused a variable release of renin associated with depletion of content within 4 hr. The response was progressive and reached a peak after 60 min. 8. Sensitivity of renin release to temperature and metabolic blockade indicates that energy is required for retention of renin by the cell. This, together with the release observed with increased sodium concentration at constant osmolarity, suggests a dependence of renin release upon the mechanism controlling the volume of the juxtaglomerular cell or its organelles.

1. Possible influence of different visual environments on the reorganization of retinotectal projection was studied with neurophysiological mapping methods following excision of the caudal half of the optic tectum in adult goldfish. 2. Post-operative light-deprivation showed no significant effects: in the absence of visual input, the visual projection from the whole retina because compressed on to the remaining rostral half-tectum in correct retinotopic order within 4 months, regardless of whether the contralateral optic nerve was left intact, or severed and then allowed to regenerate. 3. When the operated goldfish were continually exposed to visual stimuli without any dark period (post-operative dark-deprivation), two different results were observed: if the optic nerve was sectioned, in addition to excision of the caudal tectum, an orderly field compression was observed within 70 days in the re-established retinotectal projection; on the other hand, if the optic nerve was left intact, the dark-deprived fish retained the original connexions between the remaining rostral half-tectum and the temporal hemiretina without showing any sign of field compression for up to 253 days. 4. When the dark-deprived fish was then transferred into darkness, the suppressive effect disappeared: a compression of the retinotectal projection was induced within 2 or 3 weeks after the transfer. 5. Histological preparations of the fish brains showed consistent morphologic changes in the laminar structure of the remaining half-tectum. The stratum opticum and the stratum fibrosum et griseum superficiale merged together to form a new layer which contained an intricate network of thick fibre bundles.

1. The renal kallikrein-kinin system has previously been linked with renal control of sodium and water excretion. The present investigations were carried out to examine more closely these relationships. 2. In physiological studies with rabbits, urinary kallikrein was measured by a modification of the [3-H]TAME method. 3. With rabbits on free sodium and water intake, urinary kallikrein was positively correlated with both sodium and water excretion. Kallikrein excretion was also negatively correlated with urinary osmolality. 4. In rabbits on chronic high and low sodium diets, urinary kallikrein was positively correlated with urinary volume but not with sodium excretion. 5. In rabbits held to a constant fluid intake but with sodium intake changed, urinary kallikrein was not correlated with sodium excretion. 6. These results indicate that the positive correlation of kallikrein excretion with sodium excretion under conditions of free sodium and water intake may be only secondary to the positive relationship of kallikrein excretion with urinary volume. 7. The results of the present investigations do not support the hypothesis that the renal kallikrein-kinin system is necessarily involved in renal control of sodium excretion under normal conditions but it is where a change in sodium intake leads to a change in fluid intake and consequently of urinary volume. 8. In the above experiments, urinary kallikrein was always positively correlated with urinary volume and negatively correlated with urinary osmolality. This may indicate a functional relationship between renal kallikrein and water excretion.

A study of morbidity on a new housing estate reveals a higher prevalence rate of both physical and mental illness. Much of this is due to physical factors associated with the estate which could have been avoided in the light of previous experience had more attention been given to detail. The proposals embodied in the management arrangements for the reorganised National Health Service should provide the machinery to prevent these faults recurring.

Electrocardiography has a useful place in general-practice cardiology:(1) by bringing to light unexpected findings thereby altering the diagnostic spectrum and, in some cases at least, management.(2) by acting as a monitor in the continuing management of patients suffering from some forms of cardiovascular disease, and, in particular, from essential hypertension.In 1970 the purchase of a ;Cambridge Transrite' 4-2 battery two-speed electrocardiograph made it possible to test the value of this working tool in a practice population of about 5,300 patients. Before this, members of the medical staff of the Department who needed electrocardiograms for any of their patients made the appointments with the Cardiology Department, The Royal Infirmary, Edinburgh, or, later, with the nearby Family Doctor Centre of the Scottish Home and Health Department.

Two Birmingham general practitioners held a series of informal seminars with groups of their patients and an account of the object, method and scope of these sessions is given in the belief that they are of significance for a better understanding of health and the community's responsibility for it.

Quantitative structure-activity relationship studies have been performed on two types of sulfonamides with hypoglycemic activity. In the case of the 2-benzenesulfonamidopyrimidines, substituted in the 5 position of the pyrimidine ring a correlation between hydrophobic forces, expressed as Rm values, and the binding to serum albumin as well as to the heights of the equipotent dose has been found. In the series of 2-benzenesulfonamidopyrimidines additionally substituted in the 4 position of the benzene ring, however, a correlation between electronic parameters, expressed as the chemical shift of the anilide NH-(type IIA) and benzylamide NH-(type IIb) protons and the biological response was observed. This correlation indicated a charge-controlled second fixation of these molecules to the receptor. This is supported by the observation of stereospecificity of the blood-glucose lowering effect and also by the importance of a constant distance between the nitrogen in the side chain and the nitrogen atom in the sulfonamido group. The correlation between the logarithm of the biological response and the electric effects of the substituents is linear as long as one homologous series is considered. If the anilide and benzylamide derivatives are combined, a linear correlation can only be obtained if a dummy parameter is included which may account for differences in conformation within these two series of compounds.

For a homologous series of N-alkylnorketobemidones a statistically significant correlation was found between the relative abilities to bind mouse brain homogenate in vitro and their in vivo mouse hot-plate analgesic potencies. The correlation between in vitro binding in the presence of 100 mM sodium and analgesic potency was not as good AS THAT as that found in the absence of sodium. A statistically significant correlatin was found between thir analgesic potencies and their abilities to antogonize electrically induced contractions of the guinea pig ileum.

The preparation of alpha, alpha-dimethyl analogs of the hypocholesteremic and hypolipemic agent 3-methyl-4-phenyl-3-butenoic acid (beta-benzalbutyric acid, BBA) is described. These compounds were prepared as part of a continuing program directed toward a study of the structure-activity interrelationships of styryl- and phenoxyacetic acid antilipemic agents and the preparation of metabolically resistant analogs of BBA. Preliminary results on the in vitro ability of the compounds to inhibit cholesterol biosynthesis indicate that alpha, alpha-dimethyl substitution reduces activity although the potency of the p-chloro analog 6b was comparable to that of BBA.

Eighty-four 4-quinolinehydrazones were synthesized and tested for antiviral activity. Thirty nine derivatives were active against influenza A2 and/or Coxsackie B1 in mice at a dose of 25 mg/kg sc. Structure-activity relationships of 44 derivatives (21 inactive) were analyzed qualitatively using a modified Free-Wilson approach.

Trimethylsilyl heparin, when administered intraduodenally or intragastrically to rats, did not increase intestinal absorption and, consequently, the clotting times were not influenced. However, suspension of sodium heparin in Carbowax 200 prolonged the whole blood clotting time at a dose of 50 mg/kg when given intraduodenally or intragastrically to rats.

A series of new narcotic antagonists has been synthesized by modifying the C-6 carbonyl group in naloxone (Ia) and naltrexone (Ib). New functional units were introduced by reaction with various phosphorus and sulfur ylides and alkyllithium reagents. The activity of the new compounds were measured by the hot-plate and tail-clip tests after oral administration to mice. The majority of the new narcotic antagonists exhibited oral potencies considerably superior to the parent compounds, with 6-methylene derivatives IIa and IIb showing the most impressive increases.

The primary amine metabolites of alpha-(plus or minus)- alpha-(minus)-acetylmethadol were synthesized. A neutral permanganate oxidation of noracetylmethadol gave a nitroalkane. This unusual oxidation product was readily converted to the primary amine metabolite of acetylmethadol.

15-Ketoprogesterone is as active as spironolactone in blocking the mineralocorticoid effect of deoxycorticosterone acetate. This activity is reduced when a methylene group is attached to the 6beta, 7beta position. The title compound was prepared from 15alpha-acetoxy-6-dehydroprogesterone. Methylenation of the delta6 double bond with dimethyloxosulfonium methylide proceeds steroselectively from the beta side of the molecule.

A series of omegadibenzylaminoalkylamines and related compounds have been prepared and tested as inhibitors of fibrin cross-linking. This structural type was chosen in an attempt to develop noncompetitive inhibitors of fibrinoligase. By the combination of the dibenzylamino moiety at one end and the primary amino group at the other end of a polymethylene chain, the same compound could function both as a pseudo donor substrate and as a noncompetitive alkylating inhibitor. Some of the compounds, notably 74-79, are among the most active fibrinoligase inhibitors described. However, the data indicate that the compounds probably function only as pseudo donor inhibitors.

[1-Beta-mercapto-beta,beta-pentamethylenepropionic acid]oxytocin was prepared from beta-Mpa(beta-(CH2)5)(Bzl)-Tyr(Bzl)-Ile-Gln-Asn-Cys(Bzl)-Pro-Leu-Gly-NH2 by removal of the Bzl-protecting groups with Na-NH3 followed by cyclization of the resulting disulfhydryl compound with K3Fe(CN)6.The analog was purified by desalting on Sephadex G-15 in 50% HOAc and gel filtration on Sephadex G-25 and LH-20. The protected intermediate above was synthesized from Z-Cys(Bzl)-Pro-Leu-Gly-NH2 by the stepwose p-nitrophenyl ester method using Nalpha-Boc protection at the penta-, hexa-, and octapeptide stages. The analog was found to be a potent inhibitor of the oxytocic and avian vasodepressor effects of oxytocin (pA2 values of 7.43 and 8.30, respectively) but was only a weak inhibitor of the rat pressor effect of 8-lysine-vasopressin. The rat antipressor potency of [1-deaminopenicillamine]oxytocin was also determined in this study: pA2 = 6.27. Of the alkyl-substituted 1-position analogs of oxytocin studied so far, [1-beta-mercapto-beta,beta-pentamethylenepropionic acid]oxytocin is the most potent antioxytocic agent.

A series of amino acids, amidino acids, and amidino esters was synthesized and the compounds were evaluated for their inhibitory activity against bovine trypsin, bovine thrombin, and porcine pancreatic kallikrein and as anticoagulants. Among these compounds, ethyl 4-amidino-2-iodophenoxyacetate was found to be the most effective inhibitor of the enzymes in question, with a potency (Ki = 3.16 x 10-6 M vs. trypsin; Ki = 4.8 x 10-5 M vs. thrombin) similar to that of p-amidinophenylpyruvic acid (Ki = 6.0 x 10-6 M vs. trypsin; Ki = 2.0 x 10-5 M vs. thrombin). Ethyl 4-amidino-2-iodophenoxyacetate was also found to be the most effective in blocking the clotting activity of plasma, as indicated by significant prolongation of the partial thromboplastin time. This paper reports the synthetic methods, the enzyme inhibitory activity, and the structure-activity relationships observed.

Structural analogs of S-ADENOSYL-L-HONOCYSTEINE (L-SAG), WITH MODIFICATION IN THE RIBCOSE PORTION OF THE MOLECULE, HAVE BEEN SYNTHESIZED AND THEIR ABILITIES TO INHIBIT CATECHOL O-METHYLTRANSFERECE(COMT), phenylethanolamine N-methltransferase (PNMT) histamine N-methyltransferase (HMT),and hydroxyindole o-methytransferase (HIOMT) have been investigated. From these studies it was concluded that, in general, the 2'-hydroxyl and 3'-hydroxyl groups of the ribcose moiety of SAH play crucial roles in the binding of this molecule to most methyltransferases. However several interesting exceptions to this strict structural specificity have been observed. While S-3'-DEOXY-ADENOSYL-L-HOMOCYSTEINE PRODUCED NO INHIBITION OF HMT and HIOMT, it produced strong inhibition of the transmethylation catalyzed by PNMT and COMT. Likewise, S-2'-DEOXYADENOSYL-L-HOMOCYSTEINE AND S-5'-(9-(arabinofuranosyl)adenyl)-l-homocysteine had little or no effect of COMT, HMT, and HIOMT but were potent inhibtors of PNMT. The significance of these data relative to the nature of the SAH binding sites and the potential inhibitors of PNMT. The significance of these data relative to the nature of the SAH binding sites and the potential for in vivo differential inhibition of methyltransferases will be discussed.

Norepinephrine N-methyltransferase (NMT) from rabbit adrenal glands was inhibited by benzylamine and phenethylamine analogs in which the nitrogen was replaced by an amidino or guanidino group. Mono and dichloro derivatives of benzamidines, phenylacetamidines, benzylguanidines, and phenethylguanidines were studied. The two most potent NMT inhibitors among the compounds examined were 2,3-dichlorobenzamidine and 3,4-dichlorophenylacetamidine, with pI50 values of 5.55 and 5.36, respectively. These inhibitors were reversible and were competitive with norepinephrine as the variable substrate. They inhibited NMT from human, rat, and bovine adrenal glands but were slightly less effective against those enzymes than against the rabbit adrenal enzyme. In exercised rats, 2, 3-dichlorobenzamidine had no significant effect on adrenal catecholamine levels. 3,4-Dichlorophenylacetamidine slightly reduced epinephrine levels in the adrenal glands of exercised rats, but the effect may have been due to release rather than inhibition of synthesis, since heart norepinephrine levels were also reduced significantly by that agent (which is from a chemical series known to release catecholamines). Thus, whereas these compounds are reasonably potent inhibitors of NMT in vitro, they apparently are not effective in blocking enzyme activity in vivo.

Starting with mitomycin C (1), a number of solvolytic reactions were investigated and were found to result in opening of the aziridine ring with loss or migration of the 9a-methoxy group. A careful examination of the resulting 1,2-disubstituted 7-aminomitosenes indicated that there was a strong tendency for the azridine ring on opening to furnish mainly one stereoisomer, always with the oxygen stom at C-1 and the nitrogen atom at C-2. Thus the hydrolysis of 1withdition to small amounts of the trans-aminohydrin (10). Mitomycin A (2) BEHAVED ANALOGOUSLY. Both 1 and 2 generated a cis-1-acetoxy-2-acetamide when they were allowed to react with acetic anhydride. Acetolysis of mitomycin C was found to give the cis-1-hydroxy-2-acetamide (5), the trans-1-acetoxy-2-amine (14), and a cis-trans mixture of 1-acetoxy-2-acetamides (4 and 11, respectively). Routes to cis-1-methoxy-2-acetamide (9) were possible through the methanolysis of 1 or through the methylation of 5. For comparison, the trans-1-methoxy-2-acetamide (16) was obtained through a dnown resin-catalyzed methoxy migration from C-9A TO C-1 IN MITOMYCIN C. The use of 1-H nmr spectroscopy to asign configurations to 1,2-disubstituted mitosenes is discussed.

The preparation, characterization, and estrogenic activity of the two new steroids 3-(cylopentyloxy)-2',3'-dihydroestra-1,3,5(10)-trieno(16alpha,17alpha-b)furan-17beta-ol and 2',3'-dihydroestra-1,3,5(10)-trieno(16alpha,17alphs-b)furan-3,17beta-diol are described. The compounds were found to be 0.1 and 0.002 respectively, as potnet as estrone in a test design to measure the uterine weight gain of treated immature mice relative to controls.

Doubts have been raised concerning the success of minority students in obtaining the more desirable teaching hospital internships in the United States. Earlier reports by others indicated that minority graduates may be anywhere from 41 percent to 70 percent successful in obtaining their first, second, or third choice of internship through the National Intern and Resident Matching Program. Ninety percent of those in the sample reported here were successful. At least one minority applicant was a successful intern candidate in 79 out of the 103 institutions where internships had been most sought after by this group. Possible reasons for these different findings are not adequately explained because of a lack of comparable data on minority and nonminority pools; further sample studies are required to establish the actual facts.

Reluctance to train women for medical careers has been justified by the failure of women to use their education. Using data from studies of physician practice patterns and of educational costs, this article presents a preliminary estimate of the "loss" of investment involved in educating women for medicine. Women physicians are estimated to practice an average of two-fifths fewer hours over their lifetimes than do men, with a consequent loss of educational investment of about $55,000. Suggestions are made for reducing this loss. The finding of some loss of investment should not be used as an argument for discriminatory treatment of women seeking a medical education, as the rights of women as individuals must be recognized.

In 1970 approximately 81 percent of the nation's physicians were in specialty practice, and by 1990 this figure is projected to rise to 94 percent. A phenomenon of this magnitude clearly warrants intensive study. In this inquiry preference ratings for 40 specialties were obtained from 140 male and 20 female physicians and from 71 male and 18 female third-year medical students. Although significant differences were noted, there was a common hierarchy of preference observable in all four groups. For example, family and internal medicine were rated high by all four groups, whereas neurological and colon-rectal surgery were rated low; Males, and particularly male physicians, gave significantly higher ratings to surgical specialties, whereas females expressed stronger preferences for obstetrics and gynecology. Students gave lower ratings than physicians to surgical and eye, ear, nose, and throat specialties.

During the academic year 1969-70 a detailed inventory was conducted of biostatistics teaching in American and Canadian medical schools. Approximately two-thirds of schools required a separate, distinct biostatistics course. This report describes these courses, their content, and the characteristics of the individuals who taught the courses and their perception of the medical student's reaction to biostatistics. A more recent survey covering the academic year 1973-74 revealed that the situation had not changed; slightly more than two-thirds of respondents indicated that exposure to biostatistics was required in their schools' curricula.

Following an extensive review of the literature on the teaching of interviewing to medical students and psychiatry residents, the authors conclude that too much teaching emphasis has been given to the content of the interview and not enough to the process of the interview. A new method to teach interviewing skills to residents in psychiatry is described. The method focuses entirely on the interpersonal aspects of the interview. Within a seminar format, each resident attempts to reduce the "emotional distance" between himself and a patient. Much consideration is given to the individual emotional style of the resident. Through practice with this method and with peer and staff feedback, each resident who was studied improved in this ability, gained much affectual information from the patient, and learned many of the subtle aspects of process that are necessary for good interviewing and good psychotherapy.

A questionnaire study of Yugoslav general practitioners was undertaken to document reasons for the unpopularity of rural practice and to characterize better the GPs who do choose rural practice. Responses indicated that rural GPs were significantly more overworked, had less opportunity for continuing education, had poorer medical facilities, and had less adequate schools for their children than urban GPs. On the other hand, rural work was felt to be more interesting and to provide closer contact with patients. GPs who were happy in rural practice were more likely to have urban backgrounds, to have planned to be rural physicians before entering medical school, and to have undergone GP specialization training than were other GPs in the sample. Relative importances attributed to the various practice location determinants are noted. Possible applications of the study in alleviating rural doctor shortages are discussed.

In summary, there are several changes influencing the NIRMP. The changes noted are: (a) the number of graduates from foreign medical colleges has been increasing rapidly since 1970 and now represents 21 percent of the applicants; (b) the proportion of U.S. medical school graduates in the program has decreased to a low of 84 percent; (c) there is a better balance of numbers between the positions available and matched in 1975.

The urinary excretion of 14 neutral steroids was measured by gas-liquid chromatography in women with early and advanced breast cancer, in women with early uterine cancer, and in healthy women from urban and rural districts. The premenopausal patients with early breast cancer excreted subnormal amounts of five steroids (11-hydroxyandrosterone, 11-hydroxyetiocholanolone, pregnanediol, pregnanetriol, and tetrahydrocorticosterone) and increased amounts of tetrahydrocortisol as compared with the normal subjects of corresponding ages. From our findings, a new parameter was proposed by which a premenopausal breast-cancer patient was separated from the control. Postmenopausal breast-cancer patients excreted greater amounts of five steroids (one steroid from 17-ketosteroids and four from 17-hydroxycorticoids) than the corresponding controls. The discrepancy between premenopausal and postmenopausal breast cancer was tentatively related to ovarian-adrenal dysfunction in the course of aging. Oophorectomy induced a long-lasting tumor regression only in patients with a high value for the ratio of 11-deoxy-17-ketosteroid to 17-hydroxycorticosteroid in urine taken before surgery; the ratio in the responsive patients decreased remarkably after surgery. A constitutional change in 17-ketosteroids, as observed in a postmenopausal breast-cancer patient and a premenopausal healthy woman of urban origin, favored the geographic importance in the genesis of breast malignancy. The steroid abnormalities in uterine cancer were distinguishable from those of breast cancer in both premenopausal and postmenopausal women.

The HL-A antigens were determined retrospectively in a group of 14 surgically cured bronchogenic carcinoma patients and prospectively in another group of 100 untreated patients. In the retrospective group, the frequencies of antigens W-19 and HL-A5 were significantly increased when compared with the noncancer control and the prospective lung cancer populations. In the latter group, 60% of the patients with W-19 and 58% with HL-A5 survived without evidence of tumor for at least 1 year after treatment compared with 15% of patients with neither of these antigens, P less than 0.01 and 0.005, respectively. These comparisons were for adenocarcinoma and squamous carcinoma. The patient groups for oat cell and undifferentiated carcinoma were too small for valid statistical comparisons. This preliminary study suggests that the presence of HL-A antigens W-19 and HL-A5 confers resistance to dissemination of bronchogenic carcinoma.

The effect of exposure to UV irradiation or to the N-acetoxy-ester derivatives of four carcinogenic aromatic amides, 4-acetylaminobiphenyl (AABP), 2-acetylaminofluorene (AAF), 2-acetylaminophenanthrene, and 4-acetylaminostilbene, on cell survival was compared in strains of cultured human fibroblasts possessing normal rates of excision repair of DNA and in three strains of xeroderma pigmentosum (XP) cells, each differing in its rate of excision repair. The survival of each strain after exposure to UV reflected its capacity to repair DNA. Thus the slope of the survival curve for the XP strain with the poorest capacity for excision repair (XP12BE complementation group A) was 5.8-fold steeper than the exponential portion of the curve for the normally repairing strains; that of XP2BE (complementation group C) was 1.95-fold; and that of XP4BE (a variant capable of a normal rate of dimer excision) was only 1.3-fold steeper. The slope of the survival curves after exposure to each N-acetoxy ester derivative for these same XP strains averaged 6.4, 2.0, and 1.4 times steeper, respectively, than that of the normal strains tested. The excision repair capacity of these lines after exposure to N-acetoxy-AAF (50 muM/ml) was tested with alkaline cesium chloride density gradient centrifugation to detect incorporation of tritiated thymidine into nonreplicated DNA. The normal strains and XP4BE exhibited DNA excision repair by this method, whereas XP patients 2 and 12 did not. The cytotoxic effect of the four parent aromatic amide carcinogens, their N-hydroxy derivatives, as well as the N-acetoxy ester of each of the four N-hydroxy compounds and the N-sulfate ester of N-hydroxy-AAF and N-hydroxy-AABP in the XP2BE strain, was compared with their effect on the normal fibroblasts. The parent amides proved to be noncytotoxic at all doses tested. In contrast, the N-hydroxy derivatives of each aromatic amide were highly cytotoxic, as were the ester compounds. For each active derivative, the slope of the survival curve for XP2BE was 2-2.k times steeper than that of the normally repairing strain.

Lymphocytes from cancer patients and normal individuals demonstrated blastogenesis with allogeneic potassium chloride (3 M KCl) extracts of breast carcinoma cells. Normal individuals reacted with a greater frequency and stronger blastogenic responses to tumor extracts than did breast carcinoma patients; allogeneic extracts may have elicited recognition of normal alloantigens rather than tumor-associated antigens. Normal individuals also responded to 3 M KCl extracts of allogeneic pooled normal leukocytes, normal breast tissue, and other cancers, but did not react to extracts of autologous leukocytes.

Antineuraminidase-treated lymphocyte antibody levels in normal individuals were compared to levels in patients with newly diagnosed malignancies, patients with immunodeficiency syndromes (some of whom subsequently developed cancer), and normal and affected members of multiple malignancy families. No correlation between antibody level and the presence of malignancy was found. In normal individuals, antibody levels were high in childhood and declined with advancing age in accord with behavior of other natural antibodies.

The distribution patterns of epithelial blood group AB antigens (BG) in colon polyps of varying degrees of differentiation were studied by the mixed cell agglutination reaction. BG appeared in colon polyps if a certain degree of dedifferentiation was present. Two different distribution patterns were recognized: 1) association of BG with the secretory part of goblet cells with slight-to-moderate atypia and 2) association of BG with the whole cells in cases of pronounced dedifferentiation and loss of secretory activity. The second type resembled the distribution pattern of BG found previously in colon carcinomas. With respect to BG, the mucosa of colon polyps behaved similarly to embryonal colon mucosa. The detection of BG represents a useful method to assess objectively the degree of dedifferentiation in most colon polyps.

Melanomas developed in both sexes of a strain of Tuxedo variety of the swordtail (Xiphophorus helleri) at a relative frequency of 10-15%. They did not metastasize. However, the tumor margin had infiltratitive growth and subsequently ulcerated. This feature, together with the histologic and cytologic features and apparent heteroploidy of the tumors, as revealed by their DNA content, indicated that the tumors were indeed neoplastic. Electron microscopic findings on the melanosomes in these melanomas at various stages of development were comparable with those on the Harding-Passey mouse melanoma, which contains granular premelanosomes.

Plasmacytomas were found in 58% of 373 BALB/cAnN (C) mice given three 0.5-ml doses of mineral oil (Bayol F or light mineral oil) or 2,6,10,14-tetramethylpentadecane (pristane) ip. The incidence of plasmacytomas in C57BL/6N (B6), C57BL/Ka (BK), (C times B6)F1 and (C times BK)F1 was 6.4, 0, 11.5, and 16.5%, respectively. The plasmacytomas occurred in old B6 mice, in contrast to their early appearance in strain C mice. The incidence of plasmacytomas in mineral oil-treated or pristane-treated C times B recombinant-inbred (Rl) strain mice was 28.3% in C times BD, 17.5% IN C times BE, 36.5% IN C times BG, 0% in C times BH, 2.9% in C times Bl, 48% in C times BJ, and 4.3% in C times BK. C times BD, C times BG, and C times BJ strains were considered susceptible to plascytoma induction by mineral oil or pristane; C times BE had a low susceptibility, and C times BH, C times Bl, and C times BK were resistant. The results suggested that there were only a few gene difference between C and B6 or BK that determined susceptibility or resistance to plasmacytoma induction, and that B6 and BK have at least one dominant resistance gene. The distribution pattern of susceptibility and resistance in the C times B Rl strains suggested the presence of a resistance gene on chromosome 9, linkage group II.

The age-related incidence of spontaneously occurring neoplasms and degenerative diseases in the F344 inbred rat strain was established from the histologic examination of tissues from 160 male and 192 female rats kept throughout their natural life-span. The most common neoplasms were leukemias (25%), mammary tumors (females, 40.6%; males, 23.1%), pituitary adenomas (females, 35.9%; males, 23.8%), and testicular interstitial cell tumors (males, 85%). Various less common neoplasms were observed: thyroid interstitial cell tumors, adrenocortical adenomas, carcinomas of the genitourinary tract, representative central nervous system tumors, pheochromocytomas, and tumors of mesodermal origin including mesotheliomas, myoblastomas, fibromas, and fibrosarcomas. Multiple tumor types were found in 176 of the rats; metastatic tumors were uncommon. Degenerative diseases including myocardial degeneration and nephrosis were often observed. The incidence rate of these neoplasms and degenerative diseases generally increased with advancing age of the animals.

A strain-specific transplantable melanoma (S-91) growing progressively in DBA/1 mice and metastasizing selectively to the lungs was maintained for 16 days in organ culture before being grafted to syngeneic (DBA/1) and allogeneic (BALB/c and C57BL/6) recipients. The cultured S-91 grew progressively in the syngeneic mice and to a moderate degree in the allogeneic strains; it showed an increased tendency to metastasize in both the DBA/1 and C57BL/6 recipients. Heterophilic cytoagglutination assays of cultured S-91 were less apt to aggregate in the presence of concanavalin A than were their noncultured counterparts, which suggested alteration of the plasma membrane. Organ culture explantation appeared to alter phenotypically the cell-surface membrane and thus increase the cell's ability to metastasize while possibly reducing the immunogenicity of the cultured tumor cells.

The RNase activity observed in the sera of leukemic guinea pigs was compared to that observed in white blood cell (WBC) lysates of the same animals. The WBC-associated RNase activity directed against polyuridylic acid decreased with the progression of neoplastic disease, though serum RNase activity remained unchanged. With certain forms of cancer, therefore, variations in cell RNase may be more sensitive markers than changes in serum RNase for the evaluation of the progression or regression of disease.

Vitamin A palmitate was incorporated into a laboratory chow (150,000 IU/kg diet) and fed ad libitum to C3H/HeJ female mice inoculated with 1 times 10-6 C3HBA tumor cells, beginning the day of inoculation. Control female mice of the same strain similarly inoculated were fed the laboratory chow alone. Vitamin A did not affect rate for the first 19 days, after which growth rates were independent of treatment. Vitamin A-treated mice survived for significantly longer times than did control mice.

RNA transcription was investigated during the development of F1 phage, which is specific for the strict anaerobe Clostridium sporogenes. RNA species transcribed during F1 phage infection were characterized with respect to time of appearance and molecular weight by polyacrylamide gel electrophoresis. Ten mRNA species were characterized, of which five were produced early in infection and five were synthesized late in infection. All the above 10 species were transcribed from one strand of F1DNA, the heavy strand. Two additional mRNA species were transcribed from the light strand of F1 phage DNA later in infection. Throughout the F1 phage infective cycle, rRNA was continuously synthesized by cells of C. sporogenes.

Replicating chromosomes, called intermediate DNA, have been extracted from the adenovirus replication complex. Compared to mature molecules, intermediate DNA had a greater buoyant density in CsCl gradients and ethidium bromide-cesium chloride gradients. Digestion of intermediate DNA with S1 endonuclease, but not with RNase, abolished the difference in densities. These properties suggest that replicating molecules contain extensive regions of parental single strands. Although intermediate DNA sedimented faster than marker viral DNA in neutral sucrose gradients, single strands longer than unit length could not be detected after alkaline denaturation. Integral size classes of nascent chains in intermediate DNA suggest a relationship between units of replication and the nucleoprotein structure of the virus chromosome. Adenovirus DNA was replicated at a rate of 0.7 x 10-6 daltons/min. Although newly synthesized molecules had the same sedimentation coefficient and buoyant density as mature chromosomes, they still contained single-strand interruptions. Complete joining of daughter strands required an additional 15 to 20 min.

Purified vaccinia virus rapidly inhibited HeLa cell protein synthesis in the presence of actinomycin D. Under these conditions host polyribosomes were extensively degraded but the mRNA was stable as indicated by a greater than 90% recovery of prelabeled polyadenylylated RNA. Although actinomycin D prevented the synthesis of host mRNA and poly(A) in uninfected cells, incorporation of adenosine into poly(A) was inhibited by less than 50% in infected cells. Further analysis indicated that there was little or no normal size viral mRNA but that a unique class of small poly(A)-rich RNA was made in the presence of actinomycin D. From measurements of the RNase resistance and base composition of the RNA, approximately 40% of the nucleotide sequence was estimated to be poly(A). The poly(A)-rich RNA was found associated with small polyribosomes and monoribosomes that were inactive in protein synthesis. It was suggested that the poly(A) segment of the RNA is formed by the poly(A) polymerase previously found in vaccinia virus cores and that the inactive RNA, by competing with host mRNA, may contribute to the virus-mediated inhibition of host protein synthesis observed in the presence of actinomycin D.

Studies have been carried out to elucidate the in vivo function of gene 2 in T7 DNA synthesis. In gene 2-infected cells the rate of incorporation of (3-H)thymidine into acid-insoluble material is about 60% that of cells infected with T7 wild type. Gene 2 mutants do not however produce viable phage after infection of the nonpermissive host. In T7 wild type-infected cells, a major portion of the newly alkaline sucrose gradients. The concatemers serve as precursors for the formation of mature T7 DNA as demonstrated in pulse-chase experiments. In similar studies carried out with gene 2-infected cells, concatemers are not detected when the intracellular DNA is analyzed at several different times during the infection process. The DNA made during a gene 2 infection is present as duplex structures with a sedimentation rate close to mature T7 DNA.

Role of parathyroid hormone in the phosphaturia of extracellular fluid volume expansion. Acute expansion of the extracellular fluid volume increases the urinary excretion of phosphate. The present study examined the importance of increased plasma parathyroid hormone concentration in the phosphaturia accompanying acute extracellular fluid volume expansion (ECVE). Infusion of a calcium-free Ringer's solution into dogs was associated with increased urinary phosphateexcretion and serum immunoreactive parathyroid hormone concentration (iPTH), the latter being significantly correlated with a decrease in plasma ionized calcium concentration. Prevention of the fall in plasma ionized calcium concentration by infusion of a calcium containing Ringer's solution prevented the increase in serum iPTH but the magnitude of the phosphaturia was not affected.

Reaction constants of renin in juxtaglomerular apparatus and plasma renin activity after renal ischemia and hemorrhage. During and after total renal ischemia and acute hemorrhage, renin activity in plasma (PRA) and microdissected juxtaglomerular apparatus (JGA) of rabbits were investigated. In controls, the apparent Michaelis-Mentoen constant (MMC) of semipurified standard renin of rabbits was 1025 plus or minus 223 SD ng/ml. Plasma renin of normal rabbits showed similar values: 1062 plus or minus 138 SD ng/ml. Intrarenal JGA renin, however, showed a great scatter of MMC (920 to 4760 ng/ml) and a significantly higher mean value of 2572 plus or minus 1156 SD ng/ml (pis less than 0.001). After complete renal ischemia by clamping both renal arteries for a 90-min period, the following results wereobtained: 1) Sixty min after the beginning of ischemia, PRA decreased from 20.9 plus or minus 9.8 SD to 7.6 plus or minus 5.2 SD ng/ml-hr (P is less than 0.05) and increased to 103, 68 and 42 ng/ml-hr 10, 30 and 90 min after removal of the clamps, respectively (P is less than 0.05).

Mice from our Nya:NYLAR colony were parabiosed using the skin-to-skin or coelomic method, and more than 150 such pairs survived for periods greater than 1 mo. The oldest pair at this writing survived for 27 mo after parabiosis, which is equivalent to the normal life span of the Nya:NYLAR mouse. No evidence of parabiotic intoxication in any pair, even those kept for several mo, was noted.

Rabbits were orally infected with Taenia pisiformis eggs and then serially killed. The development and regression of focal granulomatous lesions in the liver were observed, and these lesions were considered to be identical with the lesions in the naturally occurring disease. Focal granulomatous lesions containing onchospheres were also observed in the lungs, mesentery, and mesenteric lymph node. Thrombosis was present in some pulmonary arteries, and infarction of the lung was observed in 1 rabbit.

The use of time-lapse and normal speed photography as a tool in evaluating the effect of cage size on physical activity in the beagle dog was examined. Normal speed motion pictures also served to demonstrate the degree of physical activity possible within specific sized cages, and the effect of changes in external activity on the dogs' activity within the cage. Viewing of these films showed that specific activity measurements can be made, providing a feasible scientific method for evaluating cage activity in a wide range of cage sizes. Physiological data collected over the course of this experiment from dogs housed in 2 different sized cages failed to show a cause-and-effect relationship.

The validity of the ultrasonic Doppler technic for indirectly measuring arterial blood pressure over a wide range was tested in anesthetized dogs. Correlation coefficents of 0.99 and 0.97 for systolic and diastolic pressure were verified on the basis of 316 comparisons of direct and indirect measurements. Utility of the method for detecting hypotensive, normotensive, and hypertensive arterial blood pressures was demonstrated. Potential applications of the method by life scientists and veterinarians includes routine monitoring of anesthesia, characterization of disease, and documentation of pharmacologic states.

Studies of red blood cells, white blood cells, platelet function, and clotting factors were performed on banked baboon blood. It was found to be a suitable model for the study of micro-aggregate formation and other coagulation abnormalities encountered in storage of human blood.

Bilateral draining fistulas which communicated with the cheek pouches were noted in the threat region of an adult femal Macaca mulatta receiving isoniazid for tuberculosis prophylaxis. Necrospy findings included enlargedregional lymph nodes and ulceration of cheek pouch mucous membranes. Acid-fast bacilli were demonstrated in tissue section. Cultures of the regional lymph nodes and cheek pouch mucous membrane yielded Runyon Group III mycobacteria. Intrapalpebral tuberculin tests with homologous mycobacterial antigen (Battery strain PPD) and Kochs Old Tuberculin were performed in an unsuccessful attempt to identify additional infected monkeys. This case is considered significant because of the unusual manifestation of mycobacterial disease and its occurrence in an animal receiving isoniazid at levels considered sufficient for the prevention of tuberculosis.

The blood of 6 male and 6 female European hamsters (Cricetus cricetus L) was examined in summer, in winter before hibernation, and 1 da after awaking from hibernation. Blood was drawn from a sublingual vein under ether anesthesia in nonhibernating animals. No influence of hibernation upon the number of erythrocytes and the differentials was found, whereas the number of thrombocytes and leukocytes were reduced to a minimum. From the unchanged numbers of thrombocytes and leukocytes in nonhibernating animals during winter, the influence on the blood of a seasonal cycle independent of hiberation was excluded.

A new method was described for repetitive blood sampling of guinea pigs via percutaneous puncture of the femoral vessels. Either manual immobilization of the animal or a specially designed restraining board was used. This method did not endanger the animal and required neither anesthesia, surgical skill, nor special equipment.

A tooth-grasping forceps with a gas-driven oscillating headpiece was designed for dental extractions in the dog, Compared with the conventional method, the extraction time was shortened considerably, and preliminary results indicate it may cause less trauma to alveolar bone and periodontal ligament.

Thirteen cases of a spontaneous neuropathy were observed among 150 free-ranging Japanese snow monkeys (Macaca fuscata). Necropsy of 4 individuals revealed lesions in the peripheral and central nervous systems. Pathologic changes were associated with ingestion of coyotillo berries (Karwinskia humboldtiana).

Complete absence of kidneys was observed in 3 neonatal guinea pigs which died 2-3 da after birth. Congestion of intestines and other organs was also observed. Renal agencies in the guinea pigs appeared to be of rare occurrence. Agenesis of right kidney was observed in 2 of over 500 opossums examined. Both opossums were males, and the corresponding ureters were smaller in diameter than the contralateral ureters. The left kidney was enlarged as a result of compensatory hypertrophy. The lumina of right ureters were found to be obliterated on microscopic examination.

Normothermic anoxic arrest of 15 and 30 minutes, repeated for up to a total of 90 minutes of anoxia was employed in 24 pigs. The purpose was to determine the effect of varying the duration of anoxia on coronary blood flow, coronary vascular resistance, and the distribution of coronary flow to the free wall of the ventricle. Five minutes of reperfusion at pressures of 50 and 100 mm. Hg with the ventricle fibrillating, was employed between each anoxic interval. Results were compared to control studies performed during ventricular fibrillation without anoxic arrest in 12 pigs. Prolonging the anoxic interval to 30 minutes served to create a maldistribution of coronary flow away from the left ventricular endocardium and to reduce the reactive hypermic response to anoxia. Increasing the perfusion pressure to 100mm. Hg accentuated these changes. Both light and electron microscopy of sections demonstrated edema and early myocardial necrosis in the subendocardial layer of the left ventricle subjected to repeated 30 minute intervals of anoxia at a high perfusion pressure. We postulate that repeated anoxic insults with inadequate repayment of oxygen debt results in subendocardial edema, a decrease in perfusion, increasing necrosis, and further edema. A myocardial infarction must result if this vicious cycle cannot be interrupted.

A study was designed to evaluate the hemodynamic effects of massive doses of methylprednisolone (30 mg. per kilogram) during cardiopulmonary bypass at normothermia and hypothermia. In 427 patients studied, significantly less vasoconstriction (p less than 0.01) and improved perfusion flows (p less than 0.0005) were obtained at comparable pressure levels in the steroid-treated group (272 patients) compared with the control group (155 patients). Because of these measured parameters, methylprednisolone should be considered a valuable adjunct to improving tissue perfusion during cardiopulmonary bypass.

A study was undertaken to determine whether changes occurred in the coronary arteries of dogs after obstruction of the cardiac lymphatics. Other investigators have described changes in the walls of coronary arteries after cardiac lymphatic obstruction that caused compromise of the lumen. Adult mongrel dogs were subjected to an operation which occluded the cardiac lymphatics. Several days later, a second operation was done to remove specimens of the terminal branches of the coronary arteries. The specimens were studied by light and electron microscopy. There was no gross or microscopic evidence of altered morphology of the coronary arterial walls.

The Lande'-Edwards oxygenator has been used for clinical perfusions on 283 patients. Among these patients we have encountered the full range of congenital and acquired defects and a variance in age from 1 day to adulthood. Data are presented concerning the means and methods of perfusion, the defects involved, and the results of treatment. A comparison has been made between two groups of 20 adults each, one group perfused with a bubble oxygenator (Bently) and the other with the Lande'-Edwards membrane lung. This study showed that platelet function is better preserved by the membrane lung, that hemolysis is less severe, and that postoperative bleeding is reduced. Indirect evidence has been accumulated to suggest that pulmonary, cerebral, and renal function is also better preserved when the membrane lung is employed.

Clinical experience with permanent transvenous pacing during a 6 year period at Hannover Medical School is presented. A total of 1,376 pacemaker operations were performed in 799 patients, with a mortality rate of 1.1 per cent. The most common complications were premature battery failure, dislocation of endocardial electrodes, infections of the generator and/or electrodes, and skin ulcerations. In our cumulative follow-up period of 1,225 years, a complication necessitating a reoperation is to be expected after an average function-time of 31 months. Including normal battery exhaustion in this calculation will make reoperation necessary every 21.9 months.

In this report we shall describe a new route for perfusion during long-term support with the membrane oxygenator. The ascending aorta is cannulated so that blood from the oxygenator mixes with blood in the ascending aorta. Thus oxygenated blood is supplied to both the cerebral and coronary systems.

Fibrinolysis in cyanotic and acyanotic children has been studied before and after open intracardiac operations. Preoperatively, shorter lysis times were found in the cyanotic group. Lysis times in individual patients varied at different times before operation. Precise documentation of the timing of fibrinolysis determinations is necessary. The lysis times appear to be affected by variables such as fasting, stress, and anesthesia in addition to perfusion. Postoperatively there was no excessive fibrinolysis in either the cyanotic or acyanotic group, the groups showing no differences. No significant alterations in plasma fibrinogen were present before or after perfusion with the pediatric Bentley Temptrol system.

In this study, we evaluated the accuracy of radioisotope scans in detecting metastatic lesions in patients with bronchogenic carcinoma. To be included in the study, the patient had to have undergone liver, brain, and/or bone scanning within 10 weeks of autopsy. Other means of evaluating these organs for metastatic involvement were used as well. The liver was checked by palpation and by determination of enzyme levels. A history, physical examination, and neurologic examination were used to establish the possibility of brain metastases. For studying bones, a history, physical examination, and conventional x-ray films were employed. Results of the scans and other tests were compared with findings at autopsy, and accuracy rates for each method of study were determined.

In this report, we shall describe a case of interventricular septal defect with severe cardiac and respiratory insufficiency unresponsive to clinical treatment. The critical condition of the patient prompted us to introduce an obstructive balloon into the pulmonary artery with the objective of reducing pulmonary flow and improving respiratory insufficiency. The mean pressure was reduced from 45 to 19 mm. Hg, and the infant's cardiopulmonary status improved dramatically. After 36 hours, during which the clinical picture stabilized, a banding operation was performed with success.

An 11-year-old boy with acute lymphoblastic leukemia in remission developed a bilateral pneumonia which rapidly progressed to acute respiratory failure. During 9 days of intensive therapy the patient's respiratory status progressively deteriorated. When it became impossible to maintain the arterial oxygen tension (PAO2) above 40 mm.Hg by conventional means, extracorporeal blood-gas exchange with a membrane lung was begun. After 5 days of bypass the patient's respiratory function began to improve, and he was weaned from the membrane lung on the tenth day. Seven days later he was discharged from the hospital and is currently in excellemt health 23 months after bypass. This perfusion, the longest successful effort to provide respiratory assist with a membrane lung, attests to the efficacy of this therapeutic modality.

Bullet migration toward and within the pulmonary circulation occurred in a case of gunshot wound to the right upper abdominal quadrant. Difficulties in locating the missile were encountered during surgical attempts to remove it. Finally, a Swan-Ganz catheter was used for pulmonary angiography. The balloon of the catheter was inflated to prevent further migration of the missile until it could be surgically removed.

We have systematically reviewed the literature concerning iatrogenic chylothorax and shall report our personal observations on the subject. Despite an increasing number of thoracic operations, injuries to the thoracic duct are infrequent. Cardiovascular and esophageal procedures are the most frequent causes of chylothorax. Malformations of the thoracic duct and other organs of the mediastinum have often been involved in lymphatic injury. Consequently, we believe that a complicating chylothorax may result from varied causes rather than solely from a surgical error.

Extracts of Acacia longifolia yielded two major histamine aldaloiks which were separated by tlc. Nmr, ms, uv, ir and other physical measurements led to structural assignments of the compounds as N-(2-imidazol-4-yl-ethyl)-trans-cinnamamide and N-(2-imidazol-4-yl-ethyl)-deca-trans-2, cis-4-dienamide. Confirmation of these structures was by comparison of literature data in the case of the cinnamamide and by synthesis of the new decadienamide. Dowex-50 ion exchange resin (H+ form) was found to be highly efficient in the isolation of these compounds from crude plant extracts.

From the weakly antibacterial non-quaternary alkaloidal fractions from Ptelea trifoliata L. (Rutaceae), ten tertiary quinol-2-one and quinol-4-one alkaloids were isolated and identified. In addition, beta-sitosterol, beta-sitosteryl-beta-D-glucoside and bergapten were isolated. None of these compounds possessed perceptible antimicrobial activity. The weak antimicrobial activity of the neutral and alkaloidal fractions was traced to small amounts of pteleatinium chloride which had not been completely separated by bulk processes. Alkaloids previously known to be present in P. trifoliata which were found in this study ptelefoline methyl ether, pteleine and skimmianine. Alkaloids previously known but new to this plant were lunidoine and isomaculasidine. Alkaloids newly found in nature were neohydroxylunine, hydroxylunidonine, 6-methoxylunidoine, 6-methoxylunineand 6-methoxy-hydroxylunidine. The structure of the latter three bases is proposed tentatively.

The carboline alkaloids, harman and norharman, detected in the culture filtrate of Phaseolus vulgaris suspension culture are the two major products of the biotransformation of tryptophan by this culture. The peak concentration of harman and norharman in the medium was reached between the second and fourth day of fermentation, depending on the size of the inoculum. A supplement of 0.1 mg of tryptophan per ml of 67V medium (with a low basal concentration of 15 to 20 mug of tryptophan per ml medium) increased the peak concentration of harman by an average of 2.1 times and of norharman by an average of 4.7 times in medium.

The Mediterranean fruit fly, Ceratitis capitata (Wiedemann), the melon fly, Dacus cucurbitae Coquillett, and the oriental fruit fly, D. dorsalis Hendel, three Hawaiian tephritids of economic importance, were exposed to traps each containing one of 232 ethyl ether extracts of air-dried botanicals. The principal concern was to establish which extracts were attractive judged on the basis of an index determined by the number of times more flies were attracted to the trap baited with water and extract than were attracted to traps baited with water only. Female Mediterranean fruit flies were attracted to 61 extracts and melon fly females to 31 extracts. Female oriental fruit flies were not much attracted. Many extracts were attractive to males of the three species. The extract of Coffea robusta Linden (Family Rubiaceae) was the only material attractive to both sexes of all three species.

Callus cultures were extablished from the seedlings of Cassia tora on a chemically defined medium supplemented with 2, 4-D and kinetin. A phytochemical investigation of callus tissues demonstrated the presence of chrysophanol, emodin, physcion, and an unidentified pigment, all of which are contained in the seeds of the original plant. The maximum content of antraquinones on a fresh weight basis was 0.334 percent, which is higher than the content of total anthraquinones in the dry seeds. Furthermore, it was shown that the production of these compounds is influenced by the concentrations of auxin and cytokinin supplied to the culture medium.

The desaturation of stearic, linoleic, and alpha-linolenic acids by human liver microsomes were studied. The microsomes were isolated from liver biopsies obtained during operation. It was shown that human liver microsomes are able to desaturate 1-14-C-alpha-linoleic acid to octadeca-6,9,12,15,-telraenoic acid: 1-15-C-linoleic acid to gammalinolenic acid; and 1-14-C-stearic acid to oleic acid in the same system described in the rat. However, the desaturation activity obtained was low compared to other mammals. This effect was attributed to fasting, pre-medication, or the anaesthesia.