The site and receptors responsible for the inhibition by sympathetic nerves of intestinal smooth muscle and its parasympathetic motor nerves.

1. The effects of three inhibitory stimuli, sympathetic nerve stimulation, noradrenaline (NA) and isoprenaline have been examined on three forms of motor activity in the rabbit colon, the response to pelvic (parasympathetic) nerve stimulation, acetylcholine (ACh) and spontaneous tone.2. The response to pelvic nerve stimulation is most effectively inhibited by sympathetic nerve stimulation, much less effectively by NA and hardly at all by isoprenaline. The sympathetic nerves can inhibit the pelvic response at frequencies of stimulation which do not affect spontaneous tone. The inhibitory effect of sympathetic stimulation, and of NA, on the pelvic response is reduced by phentolamine 5 x 10(-6)M and unaffected by propranolol 5 x 10(-6)M suggesting the effect is mediated via alpha receptors.3. The response to ACh is inhibited by all three stimuli equally. The inhibitory effect of sympathetic nerve stimulation and of isoprenaline is reduced by propranolol 5 x 10(-6)M. The inhibitory effect of NA is also reduced by propranolol but to a lesser extent. Phentolamine 5 x 10(-6)M has a small effect in reducing the inhibitory effect of sympathetic nerve stimulation or of NA. This effect of phentolamine is lost if the participation of motor nerves in the response to ACh is excluded by either tetrodotoxin 10(-7) g/ml. or cold storage for 10-14 days. These results suggest that inhibition of the ACh response takes place mainly at the muscle by activation of beta receptors but that ACh may have a small indirect stimulant action through motor nerves and this is susceptible to inhibition through alpha receptors.4. All three stimuli are equally effective in lowering smooth muscle tone. This inhibitory effect of sympathetic nerve stimulation and of isoprenaline is reduced by propranolol 5 x 10(-6)M and unaffected by phentolamine 5 x 10(-6)M. The inhibitory effect of NA is reduced by propranolol but again is less sensitive to block than the other two inhibitory stimuli. Phentolamine is without effect on the inhibitory action of NA and the combination of phentolamine with propranolol is no more effective than propranolol alone. These results suggest that NA liberated by sympathetic nerves and isoprenaline inhibit myogenic tone in the smooth muscle by an action on beta receptors but the action of NA added to the bath cannot be fully explained in this way.


Movements of radioactive potassium in isolated rat ganglia.

1. Isolated rat superior cervical ganglia were continuously superfused with (42)K (or (86)Rb) solution and the amount of radioactivity taken up was monitored using scintillation counting.2. Entry of (42)K into the ganglia could be resolved into two components, one amounting to 83% of the total (42)K uptake, with a rate constant of 0.015 min(-1), and the other of 17% of the total, with a rate constant of 0.15 min(-1).3. With 6 mM-K in the bathing solution, the equilibrium uptake of (42)K after 4 hr corresponded to an intracellular concentration of 147 mM-K. Changes in the K concentration of the bathing solution (0.5-20 mM) had little effect on this value.4. Carbachol or nicotine caused a rapid net loss of (42)K. (42)K was recaptured on washing out the depolarizing agents, with a rate constant of about 0.3 min(-1). This recapture rate was slowed by ouabain, dinitrophenol, cyanide, mersalyl and by reducing the K concentration in the bathing solution.5. Efflux of (42)K from preloaded ganglia occurred with a rate constant of 0.017 min(-1). This rate was increased about sixfold by 180 muM carbachol in 6 mM-K but not in 150 mM-K suggesting that the increase in efflux was mainly a consequence of the depolarization caused by carbachol.6. (86)Rb fluxes and the effects of carbachol thereon were similar.


Oscillation of the human ankle joint in response to applied sinusoidal torque on the foot.

1. Low-frequency (3-30 Hz) oscillatory rotation of the ankle joint in plantarflexion-dorsiflexion was generated with a torque motor. Torque, rotation about the ankle and electromyograms (e.m.g.s) for the gastrocnemius-soleus and the anterior tibial muscles were recorded.2. Fourier coefficients at each drive frequency were used to calculate the effective compliance (ratio of rotation and torque). The compliance has a sharp resonance when tonic, voluntary muscle activity is present.3. The resonant frequency of compliance is between 3 and 8 Hz. The location of the resonant frequency and the magnitude of the compliance at resonance depend upon both the degree of tonic muscle activity and the amplitude of the driving torque. The resonant frequency increases with increasing tonic activity.4. With tonic muscle activity, the compliance in the frequency range below resonance increases with increasing amplitudes of driving torque.5. The e.m.g., when evoked by the rhythmic stretch, lags the start of stretching by between 50 and 70 msec.6. When tonic muscle activity is present, the resonant frequency of the stretch reflex is between 5 and 6.5 Hz.7. Following the start of driven oscillation at frequencies near resonance, slowly increasing amplitudes of angular rotation (to a limit) are observed.8. Distortion (from the sinusoidal wave shape) of angular rotation is frequently observed with drive frequencies between 8 and 12 Hz during which there sometimes occur spontaneous recurrences of oscillation at the drive frequency. For the angular rotation, a significant portion of the power may be in subharmonic frequency components of the drive frequency when that frequency is between 8 and 12 Hz.9. Self-sustaining oscillation (clonus) near the resonant frequency of the compliance is sometimes observed after the modulation signal to the motor is turned off. This is most often seen when the gastrocnemius-soleus muscles are fatigued. Clonus may be evoked by driven oscillation at any frequency.10. The hypothesis that physiological tremor, which occurs between 8 and 12 Hz, is a consequence of stretch reflex servo properties seems to be at odds with the observations of resonance in the compliance and of self-generated clonus both occurring in the 5-8 Hz region.


Reconstruction of the action potential of ventricular myocardial fibres.

1. A mathematical model of membrane action potentials of mammalian ventricular myocardial fibres is described. The reconstruction model is based as closely as possible on ionic currents which have been measured by the voltage-clamp method.2. Four individual components of ionic current were formulated mathematically in terms of Hodgkin-Huxley type equations. The model incorporates two voltage- and time-dependent inward currents, the excitatory inward sodium current, i(Na), and a secondary or slow inward current, i(s), primarily carried by calcium ions. A time-independent outward potassium current, i(K1), exhibiting inward-going rectification, and a voltage- and time-dependent outward current, i(x1), primarily carried by potassium ions, are further elements of the model.3. The i(Na) is primarily responsible for the rapid upstroke of the action potential, while the other current components determine the configuration of the plateau of the action potential and the re-polarization phase. The relative importance of inactivation of i(s) and of activation of i(x1) for termination of the plateau is evaluated by the model.4. Experimental phenomena like slow recovery of the sodium system from inactivation, frequency dependence of the action potential duration, all-or-nothing re-polarization, membrane oscillations are adequately described by the model.5. Possible inadequacies and shortcomings of the model are discussed.


Membrane properties of Aplysia neurones intracellularly injected with phospholipases A and C.

1. The effects of phospholipases A from bee venom and from porcine pancreas and of phospholipases C from Clostridium welchii and Bacillus cereus on active and passive membrane properties of Aplysia neurones have been studied. Consistent alterations in electrical membrane properties were found following intracellular application of three of these enzymes.2. Bee venom phospholipase A produced a rapid decrease of membrane potential and resistance. Voltage clamping revealed a marked depression of peak transient current with little or no effect in the late outward current.3. Mammalian phospholipase A was found ineffective in changing either the resting or active membrane properties.4. Phospholipase C from Bacillus cereus led to a strong hyperpolarization and a fall in membrane resistance. Voltage clamping revealed a marked increase in the late outward current.5. Neurones injected with Clostridium welchii phospholipase C manifested a several-fold rise in resting membrane resistance as well as a tendency to slight hyperpolarization.6. All enzymes were ineffective when externally applied.7. It is tentatively concluded that the internally applied phospholipases affect specific ionic permeabilities both in the resting and active excitable membrane. Various mechanisms by which the differing actions of enzymes of the same type could be explained are discussed.


Sodium currents in mammalian muscle.

1. A method is described which allows the approximate computation of membrane current from measurements with three electrodes in the mid-region of a muscle fibre.2. Measurements of inward sodium current in frog muscle are compared with the results of previous clamping studies to test the validity of the new method.3. Sodium current in rat muscle (extensor digitorum longus) is in general similar to sodium current in frog muscle. Two differences in detail have been found between sodium current in rat and frog muscle: (a) at the same temperature (in the range 0-20 degrees C) inactivation is slower in the rat than in the frog; (b) in rat the steady-state activation is shifted negatively on the voltage axis by some 10-15 mV.4. Delayed outward current and charge movement (Schneider & Chandler, 1973) are present in rat muscle.5. Rat muscle fibres are more resistant than frog muscle fibres to the action of tetrodotoxin. Inward current is still detectable in rat muscle at 100 nM tetrodotoxin. We found no evidence to suggest the existence in rat muscle of two kinds of sodium channel, one sensitive and one less sensitive to tetrodotoxin.


Inhibition of cuneate neurones: its afferent source and influence on dynamically sensitive "tactile" neurones.

1. Responses were recorded in decereberate, unanaesthetized cats from individual cuneate neurones in order to determine firstly, the afferent sources of inhibition on cuneate neurones and secondly, the influence of afferent-induced inhibition on those response features of dynamically sensitive tactile neurones which determine their capacity to code information about parameters of tactile stimuli.2. For all cuneate neurones which displayed afferent-induced inhibition from areas surrounding or within their excitatory receptive field (71% of the sample) it was consistently found that 300 Hz vibration at low amplitudes (< 25-50 mum) which selectively engages Pacinian corpuscles was an effective source of inhibition. In contrast, steady indentation which activates slowly adapting tactile afferents was quite ineffective, as was low frequency vibration (30 Hz) at amplitudes of < 50-100 mum. The latter stimulus can be used to engage rapidly adapting receptors either within glabrous skin (presumed to be Meissners corpuscles) or in association with hair follicles. It is concluded that afferents from Pacinian corpuscles are the dominant or exclusive source of afferent-induced inhibition of cuneate neurones.3. For dynamically sensitive neurones responsive to low frequency cutaneous vibration (30 Hz) there was a reduction in the slope of stimulus-response relations with afferent-induced inhibition, but no expansion of the range of stimulus amplitudes over which the neurone responded.4. The influence of afferent-induced inhibition on the phase-locking of impulse activity to a cutaneous vibratory wave form was examined by constructing post-stimulus time histograms and cycle histograms. Measures of dispersion of impulse activity around the preferred point of firing in the vibratory waveform indicated that the capacity of individual cuneate neurones to code information about the frequency of the cutaneous vibration was not systematically changed in the presence of afferent-induced inhibition.


Human erythrocyte anion permeabilities measured under conditions of net charge transfer.

1. The permeability of the human erythrocyte to anions has been measured under conditions of net charge transfer: for Cl(-) and HCO(3) (-) ions, at 37 degrees C, this permeability is 5 orders of magnitude too small to account for the rate of the electroneutral anion exchange which is responsible for the chloride, or Hamburger, shift.2. The method is an indirect one in which the ionophore, valinomycin, is used to increase the erythrocyte K(+) permeability: in the absence of permeant cation externally, the rate of the resulting K(+) efflux may be limited by the slowness of the accompanying anion efflux, allowing the true anion permeability to be estimated.3. The average Cl(-) permeability estimated in ACD-stored erythrocytes (seven experiments) and erythrocytes from fresh blood (two experiments) was 2.1 x 10(-8) cm/sec at 37 degrees C and pH 7.4: this may also be expressed as a Cl(-) conductance of about 1.0 x 10(-5) Omega(-1) cm(-2). The apparent activation energy for net efflux of Cl(-) was found to be 3.9 kJ/mole (16.4 kcal/mole).4. In fresh cells, the ratios of Cl(-), HCO(3) (-), Br(-) and I(-) permeabilities (or conductances) were 1:0.8:1.5:5. The three halide ions follow Eisenman's Sequence I, representing a binding site of low field strength.


Calcium currents and conductances in the msucle membrane of the crayfish.

1. Membrane currents in calcium type muscle membrane of the cray-fish Astacus fluviatilis were analysed by a method in which a membrane microarea was isolated by circulating sucrose rings contacting the fibre perpendicular to the fibre surface.2. The early calcium inward currents were separated from the total membrane currents by subtraction of the early and delayed potassium currents from the total membrane current.3. The isolated calcium currents show a time course characteristic for a transient change of calcium conductance. The presence of inactivation was further checked by the time course of the tail currents at the end of voltage clamp pulses of variable duration.4. The reversal potential of the early calcium currents determined from the current-voltage relations was +85 +/- 4.2 mV. The calcium potentials were used to express the calcium currents in the form of chord conductances.5. Calcium conductances (g(Ca)) as functions of time and voltage were found to be described quantitatively on the assumption that g(Ca) is determined by two variables (m and h), according to the equation g(Ca) = m(6)hg(Ca), where g(Ca) is a constant and m and h obey first order differential equations of the Hodgkin-Huxley type.6. The activation parameters of the g(Ca) were determined by fitting the solutions of the above equations to the experimental values of the g(Ca). This method was also used to check the inactivation parameters.7. The inactivation parameters of the g(Ca) were obtained from the inactivation curves, which were determined for several membrane potentials by variation of the duration of the conditioning step.8. The average calcium conductance constants were tabulated and compared with sodium conductance constants in excitable membranes.


Supporting effects of myoepithelial cells in submandibular glands of dogs when acting against increased intraluminal pressure.

1. In dogs under chloralose-urethane anaesthesia secretion from the submandibular gland was recorded with the outflow at gland level and at heights of up to 50 cm above the gland.2. With the outflow level increased, secretion elicited by sympathetic nerve stimulation was far better maintained before than after injection of the alpha-adrenoceptor blocking agent dihydroergotamine.3. When the outflow level was raised while no secretion occurred, fluid flowed into the gland. Part of this amount was returned on lowering the outflow to gland level. This volume was assumed to have been accommodated in the distended luminal system, whereas some fluid was obviously lost into the gland tissues.4. Both these fractions of the fluid flowing into the gland when the outflow level was high could be reduced by injecting the alpha-receptor agonist phenylephrine. Bradykinin, which like phenylephrine is known to contract salivary myoepithelial cells, had the same effect on the two inflow volumes.5. It is concluded that myoepithelial contraction reduced the distensibility of the luminal system and in addition supported the acini, thereby diminishing backflow into the glandular tissues and enabling the gland to discharge saliva against a high pressure.6. Morphologically it was found that in resting glands PAS-positive saliva was displaced from the ductal system when the outflow cannula was raised, but it was preserved in the lumina under similar conditions when the myoepithelial cells were being stimulated by phenylephrine or bradykinin.7. Although sympathetic secretion could be maintained against a head of pressure, so long as it was accompanied by myoepithelial contraction, the increased force caused by the secretion led to disruptive damage of striated ducts which are the first part of the luminal system not supported by myoepithelial cells.8. The morphological findings reinforce the belief that contraction of myoepithelial cells gives active support to the underlying parenchyma.


Maintained function of foreign and appropriate junctions on reinnervated goldfish extraocular muscles.

1. The ability of a multiply innervated muscle to become dually innervated, that is to accept a functional innervation from both its original and a foreign nerve, was investigated using the superior oblique muscle (s.o. muscle) of the goldfish.2. Dual innervation of s.o. muscles was achieved by allowing the original nerve (cranial NIV) to regenerate to its s.o. muscle which had been previously denervated and cross-innervated by a foreign nerve (cranial NIII), or by allowing the original and the foreign nerve to regenerate simultaneously to a denervated muscle.3. Behavioural observations suggested that in some fish reinnervation of the s.o. muscle by its original nerve repressed the function of a previously established foreign innervation. However, physiological tests which involved the stimulation of both foreign and appropriate nerves, and the recording of mechanical and electrical activity of the s.o. muscle, demonstrated that there was no functional displacement of foreign innervation on these muscles, even on individual dually innervated fibres.4. Dual innervation of the s.o. muscle persisted, apparently unchanged, for as long as the observations were continued (up to 7 months). The s.o. muscle contains two populations of fibres, fast and slow, and both types became and remained dually innervated.5. When both NIII and NIV were allowed to regenerate simultaneously to a denervated s.o. muscle there was no obvious selectivity in the final pattern of innervation. On the average both nerves elicited approximately equal tension from s.o. muscles, and evoked excitatory junctional potentials (e.j.p.s) of similar mean quantal contents.6. ;Myotypic respecification' was shown not to be responsible for the discrepancy between the behavioural results which sugested that repression of foreign innervation had occurred, and the physiological results which demonstrated that this was not the case. Anatomical and physiological findings indicated that the discrepancy was attributable to eye rotation produced by regenerated inferior oblique muscle fibres which contracted simultaneously with the cross-innervated s.o. muscle. The net result was an eye movement in which the activity of the s.o. muscle was masked.7. It is concluded that repression of established foreign neuromuscular connexions following reinnervation by the embryologically correct nerve does not occur on goldfish extraocular muscles. The s.o. muscle can become non-selectively innervated by both foreign and appropriate axons, and remains so, at least for several months.


Self-facilitation of ganglion cells in the retina of the turtle.

1. Ganglion cells responses to illumination and to optic nerve stimulation were recorded intracellularly from the retina of the turtle. All ganglion cells were identified by their antidromic responses to optic nerve stimulation.2. When solitary spikes are produced following antidromic, orthodromic or intracellular stimulation, about 20% of the recorded ganglion cells show an additional depolarization along the falling phase of the action potential (post-spike depolarization, PSD).3. The PSD following the antidromic action potential disappears upon collision with a direct spike or when the antidromic spike is prevented from invading the cell soma.4. By pairing two optic nerve stimuli the PSD is depressed with brief interstimulus intervals, but gradually recovers to the control amplitude 600-800 msec after the conditioning shock.5. The PSD is tentatively interpreted as an e.p.s.p. transmitted by ganglion cell collaterals originating at the level of the soma dendritic complex of the recorded cell.6. The interspike interval histogram of ganglion cells showing PSD is characterized by a peak at about 10 msec, as opposed to a peak between 12 and 100 msec observed in cells without PSD. It is suggested that the occurrence of PSD facilitate the onset of additional action potentials at brief interspikes intervals, thus potentiating ganglion cell discharges.


Short-circuit current and total conductance measurements on rabbit ileum.

1. Short-curcuit current (SCC) and total conductance (Gt) measurements were made in in vitro preparations of rabbit terminal ileum. 2. Successive additions of D-glucose increased the SCC and Gt in a stepwise way and both effects were seen to correlate linearly. 3. Measurements of SCC ant Gt were also made after replacing Na in the Krebs solution by K or sucrose. The SCC decreased to nearly zero in both cases but the decrease in Gt was larger when sucrose was used. 4. SCC and Gt were monitored after the addition of ouabain. SCC decreased to nearly zero but Gt remained constant. 5. On successive additions of sucrose after the preparation was mounted in 1/4 Na Krebs without osmolal compensation, SCC decreased and Gt increased, a linear relationship being found between both changes. 6. Successive additions of 2-deoxy-td-glucose caused a stepwise decrease of SCC and an increase in Gt. These effects seemed independent of the presence of glucose. 7. A model in which a resistance in series is added to the basic model by Ussing & Windhager (1964), modified by Rose & tschultz (1971), is proposed to account for these findings.


Laminar differences in receptive field properties of cells in cat primary visual cortex.

1. Cells in area 17 of the cat visual cortex were studied with a view towards correlating receptive field properties with layering. A number of receptive field parameters were measured for all units, and nearly every unit was marked with a microlesion to determine accurately the layer in which it was found.2. Cells were defined as simple or complex by mapping with stationary stimuli, using the criteria of Hubel & Wiesel (1962). Complex cells fell into two groups: those that showed summation for increased slit length (standard complex) and those that did not (special complex).3. The simple cells were located in the deep part of layer 3, in layer 4, and in layer 6. This corresponds to the distribution of afferents from the dorsal layers of the lateral geniculate nucleus. In these cortical layers the simple cells differed primarily with respect to their receptive field size, cells in layer 4 having the smallest, layer 3 intermediate, and layer 6 the largest fields. Layer 4 was the only layer in which simple cells showed end-inhibition (a reduction in response to slits extending beyond the excitatory portion of the receptive field).4. The standard complex cells were found in all layers, but were quite scarce in layer 4. As with the simple cells, field size varied with layer: in layer 2+3 they had small to intermediate field sizes, in layer 5 intermediate, and in layer 6 very large. Layer 6 cells showed summation for slits of increased length up to very large values, and responded best when the slits were centred in the receptive field. The only standard complex cells that showed end-inhibition were those in layer 2+3, and these were similar to the layer 4 simple cells in terms of proportion of end-inhibited units and degree of end-inhibition.5. The special complex cells, originally described by Palmer & Rosenquist (1974), were found in two tiers: the upper one at the layer 3/layer 4 border and the lower one in layer 5. They were different from the standard complex cells in having a high spontaneous activity, high velocity preference, and large fields which were similar in size (at a given eccentricity) from one cell to the next. Many showed reduced response to slits of increasing length, even for slits that did not extend beyond the borders of the responsive region.6. Cells in layer 6 (the origin of the corticogeniculate projection) were antidromically activated from the lateral geniculate nucleus. The antidromically activated units included both simple and complex cells, and they had the long receptive fields characteristic of the overall population of cells in layer 6.7. The results showed that there are different types of simple and complex cells, and that cells in different layers have different properties. Taken together with their differences in site of projection, this demonstrates that the anatomical lamination pattern is reflected in functional differences between cells in different layers.


Appearance of new acetylcholine receptors on the baby chick biventer cervicis and denervated rat diaphragm muscles after blockade with alpha-bungarotoxin.

1. The recovery of contractile responses and appearance of new alpha-bungarotoxin-binding sites were studied in the baby chick biventer cervicis and the rat diaphragm muscles after saturating the existing acetylcholine (ACh) receptors (AChR) with alpha-bungarotoxin in vitro.2. Washout of alpha-bungarotoxin restored gradually the response to exogenous ACh attaining about 30% recovery in 3 hr either in the chick muscle or in the denervated rat diaphragm. No recovery was obtained, however, for the response to nerve stimulation.3. The recovery of ACh-response was abolished by decreasing the bath temperature to 9 degrees C during the washout of the toxin whereas the recovery was not reduced in the presence of cycloheximide.4. The half-life of [(3)H]acetyl alpha-bungarotoxin bound specifically on the existing AChRs, junctional and extrajunctional receptors combined, was 16 hr in the chick muscle. That on the extrajunctional AChR was estimated to be 8 hr.5. New toxin-binding sites were found to be incorporated on the membrane of extrajunctional site rapidly after treatment with alpha-bungarotoxin in the chick and the denervated rat muscles along the muscle fibres but not in the innervated rat diaphragm. Treatment with (+)-tubocurarine, ACh or decamethonium did not cause an appreciable increase of the toxin-binding sites.6. The appearance of new binding sites was progressive during 5 hr at a rate of 24 sites/mum(2).hr in the chick muscle and 42 sites/mum(2).hr in the rat diaphragm denervated for 7 days. The existing extrajunctional AChR were about 50/mum(2) and 192/mum(2), respectively.7. ACh effectively antagonized the binding of alpha-bungarotoxin with the new sites whereas (+)-tubocurarine was less effective than its effect on the existing AChR.8. The new toxin-binding sites appeared to have a reduced capacity to evoke ACh response.9. The incorporation of new binding sites was reduced by lowering of the temperature, treatment with dinitrophenol, high K(+), high Ca(2+) and by the stimulation of either nerve or muscle. Cycloheximide, ACh, decrease of [Na(+)](o) and increase of [Mg(2+)](o) were without effect.10. It is suggested that binding of the extrajunctional AChRs with alpha-bungarotoxin cause a change of membrane architecture and trigger the incorporation of cytoplasmic AChR-precursor or hidden AChR into the membrane.


The effect of internal and external 4-aminopyridine on the potassium currents in intracellularly perfused squid giant axons.

1. The effect of 4-aminopyridine (4-AP) on the K outward and inward currents in perfused giant axons of Loligo forbesi has been studied with the voltage-clamp technique.2. Small internal or external 4-AP concentrations (10-100 muM) considerably delay the rise of the K outward current. Repetitive pulsing with a pulse interval of 0.1-5 sec leads to a faster rise of the K current; in 10 muM 4-AP a small effect is visible even with a pulse interval of 60 sec.3. The phenomenon has been studied quantitatively by using a prepulse of varying height and duration, followed after 5 sec by a constant test pulse. The effect of changing the holding potential has been investigated.4. The effect of repetitive pulsing disappears in higher 4-AP concentrations; 1-10 mM 4-AP markedly reduce the size of the K outward current; the blocking effect is less pronounced for large depolarizing pulses than for small.5. In K-rich sea water 4-AP reduces both the K outward current and the K inward current; the blocking effect on the K outward current is smaller than in K-free sea water.6. The K outward current in fibres treated with 10 muM 4-AP and immersed in K-rich sea water is increased and accelerated by repetitive depolarizing pulses. The effect of repetitive pulsing is not dependent on the size of the K outward current (which can be increased by removing K inactivation).7. The effect of repetitive pulsing and the voltage dependence of the 4-AP block can be explained by the hypothesis that 4-AP molecules are displaced from their blocking sites during the pulse and slowly rebound afterwards. Removal of the 4-AP block by a depolarizing pulse seems to be a direct effect of the potential during the pulse and not related to K current.


Properties of vestibular neurones projecting to neck segments of the cat spinal cord.

1. Vestibular neurones projecting to the upper cervical grey matter (vestibulocollic neurones) were identified by localized microstimulation in the C3 segment of the cat spinal cord.2. The neurones were found in the lateral (Deiters'), medial and descending nuclei bilaterally and projected to the spinal cord in the lateral and medial vestibulospinal tracts (LVST and MVST). Ipsilateral axons of Deiters' neurones were mostly in the LVST, axons of medial and descending neurones in the MVST; a few Deiters' neurones had axons in the MVST; some descending neurones had axons in the LVST. Most axons of contralateral neurones were in the MVST.3. The axons of 62% of ipsilateral vestibulocollic Deiters' neurones not only gave off a collateral to C3, but also extended as far as the cervical enlargement (;branching'); some of these neurones projected as far as the upper thoracic cord, almost none to the lumbar cord. Ipsilateral descending nucleus neurones branch in the same fashion, but there is no branching in the relatively small medial nucleus population.4. A large majority of vestibulocollic neurones receive monosynaptic excitation from the ipsilateral labyrinth and a number are inhibited by stimulation of the contralateral labyrinth (commissural inhibition). It is possible that commissural inhibition acts on a broad population of vestibular neurones involved in the control of eye, head and trunk movement.5. Vestibulocollic neurones do not make up a homogeneous population acting only on the neck. Instead it is likely that subpopulations, for example branching and non-branching neurones, have different functions.


Sensory deprivation during development decreases the responsiveness of cricket giant interneurones.

1. The effect sensory deprivation, early in development, has on the adult response properties of identified neurones was studied in the abdominal nervous system of the cricket Acheta domesticus.2. Neural activity in the cercal-to-giant interneurone system was lowered by blocking the movement of the mechanosensitive hairs, located on each cercus, with a facial cleansing cream.3. When specimens were treated unilaterally one of a pair of homologous neurones exhibited drastically altered response properties. The neurone which received its afferent input from the treated receptors was much less sensitive to tones. Its threshold was increased approximately 20 db with respect to its untreated homologue.4. Bilateral treatment lowered the responsiveness of both of the bilaterally homologous neurones.5. Increased levels of inhibition impinging on the treated neurones accounts for part of the altered responsiveness. The inhibitory pathway is activated by the untreated mechanoreceptors.6. Control experiments demonstrate that the sensory apparatus is not injured or modified by the treatment.7. The results suggest that normal development of some invertebrate neural pathways may be more dependent on experience during ontogeny than has previously been assumed.


The gecko visual pigments: a microspectrophotometric study.

1. A dual system of visual pigments having absorbance maxima in the green and blue respectively has been found in the retinas of geckos both by single cell microspectrophotometry and by the method of extraction. Microspectrophotometry has shown the system to be present in four species of geckos representing four genera. Along with previous work with extracts (Crescitelli, 1972) this indicates a fundamental property in this family of lizards. No other photopigments have been detected.2. For Gekko gekko, the species most intensively studied, the two pigments have absorbance maxima at 521 and 467 nm respectively. Both are based on vitamin A(1) and both are characterized by absorbance spectra that nearly conform to the Dartnall nomogram.3. In situ, the 521-pigment is not temperature-sensitive, and has virtually the same absorbance spectrum at 23 degrees C as at 5 degrees C. On extraction into digitonin solution, however, the absorbance spectrum of the pigment becomes temperature-dependent and, though identical when measured at low temperature (2-5 degrees C) with the constant in situ curve, is displaced to shorter wave-lengths at higher temperatures (10-25 degrees C). Thus the extract spectrum is relevant to the in situ spectrum only at low temperature (and in the presence of chloride ions).4. Unlike the rhodopsins of several vertebrates, the gecko 521-pigment displays no evidence of a meta-III stage in the sequence of products following photic bleaching, even at low temperatures. This is true for the pigment in situ as well as in the extracted condition.


Mechanical work and efficiency in level walking and running.

1. The mechanical power spent to accelerate the limbs relative to the trunk in level walking and running, W(int), has been measured at various ;constant' speeds (3-33 km/hr) with the cinematographic procedure used by Fenn (1930a) at high speeds of running.2. W(int) increases approximately as the square of the speed of walking and running. For a given speed W(int) is greater in walking than in running.3. In walking above 3 km/hr, W(int) is greater than the power spent to accelerate and lift the centre of mass of the body at each step, W(ext) (measured by Cavagna, Thys & Zamboni, 1976b). In running W(int) < W(ext) up to about 20 km/hr, whereas at higher speeds W(int) > W(ext).4. The total work done by the muscles was calculated as W(tot) = W(int) + W(ext). Except that at the highest speeds of walking, the total work done per unit distance W(tot)/km is greater in running than in walking.5. The efficiency of positive work was measured from the ratio W(tot)/Net energy expenditure: this is greater than 0.25 indicating that both in walking and in running the muscles utilize, during shortening, some energy stored during a previous phase of negative work (stretching).6. In walking the efficiency reaches a maximum (0.35-0.40) at intermediate speeds, as may be expected from the properties of the contractile component of muscle. In running the efficiency increases steadily with speed (from 0.45 to 0.70-0.80) suggesting that positive work derives mainly from the passive recoil of muscle elastic elements and to a lesser extent from the active shortening of the contractile machinery. These findings are consistent with the different mechanics of the two exercises.


[Tomodensitometric appearances in "medical" cerebral haemorrhages (author's transl)].

On the basis of experience of more than 5,000 cases (since 1974), the authors describe the tomodensitometric appearences of non-surgical cerebral haemorrhages, together with the correlation between values of radiodensity and histological lesions. They emphasise the chronological changes which take place in the tomodensitometric appearance of the lesions and the possibility of easy repeated studies. Such studies, in combination with observation of the clinical course, have enabled the authors to give the scanner an important place in decisions to proceed to surgery. The authors stress the superiority of the scanner over invasive techniques used to explore such patients, from both an ethical as well as a diagnostic standpoint. They consider that it will be of value in the future in experimental studies aimed at elucidating the physiopathology of these lesions.


[Triple ureter. One case. Diagnostic problem and review of the literature (author's transl)].

In the light of a case of right triple ureter in a 5 month old girl, the authors review the embryology of the ureter and describe the different types of triplication. A general review of the literature including 70 cases gives an indication of the circumstances of discovery and the contribution of radiology. The complications of complete ureteral triplication are the same but greater than those of complete duplication and are related to the ectopic position of the ureteral orifices with regard to the trigone. They are dominated by reflux and stasis in the case of high ectopia and by false incontinence (20% of cases) in low ectopia.


[Ambulatory preparation for double contrast enema. Retrospective study involving 100 nonhospitalised patients (author's transl)].

The authors present a technique of preparation for double contrast barium enema, using the oral route only. It was used in 100 consecutive, suitable non-hospitalised patients with the following results: colonic empyting was perfect in 64% of cases, satisfactory in 25% and inadequate in 11%. Tolerance was deemed to be good. The authors do not suggest that the technique should be used in hospitalised patients, often proving inadequate under such circumstances.


[Appendicular abcess presenting as an abdominal mass in early childhood. Radiological diagnosis (author's transl)].

Two boys (two years and a half old) were admitted in this hospital for an abdominal tumor. In both cases a pelvic abcess was present, secondary to a pelvic appendicitis. Symptoms have been deeply modified by previous antibiotherapy. Radiological examinations including opacification of the urinary tract by a intravenous pyelogram and opacification of the recto-sigmoid by a baryum enema allowed in both cases to localize the mass and to lead to the diagnosis with the clinical data.


A comparison of general practice in Britain and Ireland.

The work patterns of general practitioners in the British NHS and in the General Medical Services Scheme in the Republic of Ireland are compared. Doctors in the Republic have higher consultation and domiciliary visiting rates. These differences are not explainable in terms of the different age/sex structures of the populations under care.


Asian mothers' use of general-practitioner and maternal/child welfare services.

A matched control study was carried out to determine whether Asian immigrants in Nottingham made more or less use of the general-practitioner services than British-born white subjects.The study was limited to antenatal, postnatal, and infant care in one general practice, and information was collected from general-practitioner and health-visitor records and by an interview with the mother. The findings showed no difference between the two groups in the use of the general-practitioner or maternal and child welfare services.


Communications between doctors and social workers in a general practice.

This study describes an investigation into the information and attitudes which were held by a social worker and general practitioners about the same clients, and records the communication between them about these clients.


[Acetyl-cysteine in colonic mucography (author's transl)].

Acetyl-cysteine, its origin, nature, the constitution of its molecule and its main properties are reviewed. This study involved essentially the best means of using the mucolytic properties of this amino acid. Acetyl-cysteine has an excellent detergent effect on the mucosa, with good evacuation, and favourises the adhesion of barium, all the better when the particles of the latter are finer. It is thus possible to obtain good thin layer and double contrast pictures. Prior preparation remains of the utmost importance.


Social workers and their clients: a comparison between primary health care and local authority setting.

A social work attachment scheme to several general practitioners was established. Data from the first 300 referrals to the scheme were compared with data from a previous study of referrals to the ;intake' teams of the social services department of the same London borough. In addition, data about the activities of the social workers in the ;attachment' were collected, and the work was found to be predominantly short-term.The populations referred to social workers in both settings were found to be similar in age and sex. Although general practitioners in the area referred only a few clients to social services departments, the clients in both groups were generally in poor health.The psychiatric morbidity of those referred to the attached social workers was significantly higher, however, than those referred to the intake team (p < 0.01), and their problems were also more likely to need psychological help rather than practical measures. These differences were considered to be due mostly to the different types of referral agencies operating in the two settings and to their perceptions of the social worker's role.THE FINDINGS SUPPORT THE ARGUMENT FOR CLOSER LIAISON BETWEEN MEDICAL AND SOCIAL SERVICES IN THE COMMUNITY: the attachment of social workers to general practices proved to be particularly valuable in the management and treatment of patients with emotional and mental illness.


Total care usage of a defined population.

The North Staffordshire (Stoke) Morbidity Survey was set up to bring together data about the total use of general practice, hospital and local authority services by each individual patient in a representative sample of the population of Stoke, and to examine the associated problems of data linkage and confidentiality. Approximately 47.8 per cent (32.1 per cent if allowance is made for all measurable possible errors) of the patients attending hospital and 43.8 per cent of patients attending local authority services during the year, did not attend their general practitioner.Primary automation of the registered list of patients at risk is essential to the success of any automated linkage study. Where the list consists of Hogben numbers to identify individuals, this also ensures the necessary confidentiality of sensitive data.


Unrecognized amnionitis and prematurity: a preliminary report.

Quantitative amniotic fluid cultures were performed on 12 patients delivered of premature infants (10-premature labor, 2-premature rupture of membranes). Specimens from patients in premature labor were obtained at the time of amniotomy via transcervical needle aspiration or intrauterine catheter. Of the seven patients with colony counts greater than 1,000 per ml, two mothers and four neonates had clinical evidence of infection. Blood cultures from two infants and one mother and cerebrospinal fluid cultures from one newborn infant were positive for the same organism isolated from amniotic fluid. Anearobic bacteria were the predominant isolates in four specimens and included Bacteriodes species in two. In contrast, the five mothers and infants associated with counts of less than 1,000 per ml exhibited no infectious morbidity. Three had no bacterial growth from amniotic fluid, and factors commonly associated with prematurity were recognized in four. These clinical and microbiologic observations suggest that current methods of evaluating patients with premature labor and delivery are incomplete, and the role of unrecognized amnionitis should be reevaluated.


[Tick resistance to pesticides in the R.S.A. - some observations (author's transl)].

Observations on the screening for resistance against acaricides in both larvae and adults of tick species commonly found on cattly in South Africa, have shown that widespread resistance of varying degrees occurs in strains of all these species against compounds of the arsenical, organochlorine and organophosphorous groups. With few exceptions the degree of resistance is of a low order and probably indicative of selection at the low acaricide concentrations generally used by stockowners. The distribution of less susceptible and resistant strains is patchy, and fully susceptible strains are found in the same areas.


[Sheep scab: control and problems in South Africa (author's transl)].

This is a summary compiled on a regional basis from reports of officials of the Division of Veterinary Services in respect of sheep scab outbreaks occurring between 1967 and 1976. Possible sources of infection responsible for outbreaks occurring between 1940 and 1966 are discussed. Action to be taken where the disease is suspected, and control measures in terms of the Animal Diseases and Parasites Act (13/1956) when the disease has been confirmed, are dealt with. Possible causes for the continuing spread of the disease and dipping problems are discussed. Recommendations for the future control and eradication of sheep scab in the Republic of South Africa are put forward.


An inactivated rift valley fever vaccine.

The immunising potency of an inactivated Rift Valley fever (RVF) vaccine prepared from RVF virus infected mouse brain and RVF infected cell culture was studied in cattle and sheep. Different doses and adjuvants were compared. In laboratory trials both cattle and sheep developed neutralising antibodies against virulent RVF virus and in cattle antibodies were still detectable 9 months after immunisation. Although the immunity produced was inadequate to prevent viraemia after challenge, evidence of protection against clinical RVF was obtained. Field trials in sheep showed that vaccination induced a good immunity in pregnant ewes.


The effect of sample size and culture method on the recovery of salmonella spp. from naturally contaminated carcase meal.

The results of parallel examination by two methods of 223 consignment samples of carcase meal were compared. Selective pre-enrichment of 5 g of sample prior to plating on to a solid media disclosed that 2,7% of consignments were contaminated with Salmonella. Non-selective pre-enrichment of 100 g followed by selective enrichment prior to plating food 21,5% of the consignment to contain Salmonella.


Schistosoma mettheei infestation in the ox: the intestinal syndrome.

Twenty-eight Friesland calves were infested at 7 to 11 months of age with 5 000-45 OOO cercariae of Schistosoma mattheei. At 7 to 8 weeks post-infestation the majority developed an acute intestinal syndrome characterised by diarrhoea or dysentery, anorexia and loss of condition, from which they recovered spontansously. The severity and duration of illness was proportional to the level of infestation. Two heavily infested animals on a low plan of nutrition developed a subacute syndrome in which the initial acute disease was succeeded by prolonged unthriftiness, without diarrhoea, from which recovery occurred when the nutritional status was improved. Both acute and subacute forms of the syndrome were encountered in natural outbreaks.


Resistance to toxaphene by the Bont tick, Amblyomma hebraeum (Koch).

A series of in vitro and in vivo trials confirmed resistance by the three-host Bont tick, Amblyomma hebraeum (Koch), to Toxaphene in the Cape, Natal and Transvaal Provinces of the Republic of South Africa, and in Swaziland and Transkei. Resistance was present in 80 of 97 field strains examined. Lindane and DDT resistance was present in the one field strain tested. The results of comparative in vivo hand spraying and plunge dipping trials confirmed those of the larval in vitro tests, thus validating the usefulness of this latter technique for identifying changes of susceptibility in field tick strains to ixodicides. Selection of Toxaphene resistance in A. hebraeum occurred within a period of four years when a 14-day interval of treatment was used continuously. The presence of all three tick instars in all stages of engorgement at the time of each treatment under this regimen is thought to have enhanced this selection.


New inhibitors of steroid 11beta-hydroxylase. Structure--activity relationship studies of metyrapone-like compounds.

A series of metyrapone analogues was synthesized for study as inhibitors of steroid 11beta-hydroxylase. Racemic mixtures of the new compounds were evaluated in vitro. Preliminary results revealed several analogues to be effective inhibitors of deoxycorticosterone hydroxylation. 2-(3-pyridyl)propiophenone (13) and alpha,beta-diphenyl-3-pyridineethanol (16) were the most active new compounds. Each was 65% as potent as metyrapone; 3-Pyridyl alpha-3-pyridylbenzyl ketone (3), 2-phenyl-2-(3-pyridyl)acetophenone (4), alpha-(diphenylmethyl)-3-pyridinemethanol (17), and 1,2-di-3-pyridyl-1-propanol (26) were 52, 32, 25, and 41% as inhibitory as metyrapone, respectively. Diphenylmethyl 3-pyridyl ketone (5), benzyl 3-pyridyl ketone (10), 2-(3-pyridyl)acetophenone (12), 2-phenyl-1-(3-pyridyl)-1-propanone (11), alpha,beta-di-3-pyridylphenethyl alcohol (15), and 1,2-di-3-pyridylethanol (27) had less than 25% the activity of metyrapone. All compounds displaying a metyrapone-like inhibition contained appropriately substituted alcoholic or ketonic functions. A phenyl or methyl group alpha to the carbon bearing the oxygen was necessary for appreciable activity. A 3-phridyl group alpha to the carbonyl carbon could be replaced by a phenyl group. For optimal activity, however, the other 3-pyridyl group of metyrapone could not be exchanged for a phenyl group.


Comparative stereochemistry in the aziridine ring openings of N-methylmitomycin A and 7-methoxy-1,2-(N-methylaziridino)mitosene.

A useful method was found for the conversion of mitomycin C into N-methylmitomycin A. The latter compound gave only two products on acid hydrolysis, the cis- and trans-1-hydroxy-7-methoxy-2-methylaminomitosenes. This selectivity allowed the cis--trans ratio to be quantitatively determined as 4:1. Such a predominance of the cis isomer is unexpected in view of the trans stereochemistry obtained in the opening of simple aziridines. In order to determine if the 9a-methoxy group of mitomycins controlled the direction of aziridine ring opening 7-methoxy-1,2-(N-methylaziridino)mitosene, which lacks this substituent, was prepared and hydrolyzed in acid. It gave the same two products in a 3:1 cis-trans ratio. In the induction of lambda-bacteriophage in Escherichia coli cis-1-hydroxy-7-methoxy-2-methylaminomitosene was more active than the corresponding trans isomer, but both of these compounds were less active than the aziridinomitosene or the mitomycins. Mitomycin A, mitomycin C, and N-methylmitomycin A were active against P388 leukemia in mice.


Synthesis and antiinflammatory activity of some 2-aryl-6-benzoxazoleacetic acid derivatives.

Various approaches to the synthesis of 2-aryl-6-substituted benzoxazoles are described. The products, which included the 6-methyl derivative 4a, ethylamines 10 and 19, ethanols 12 and 14, the acetic and alpha-methylacetic acids 9 and 16a--f, and the acetic ester 11, were screened for antiinflammatory activity on the carrageenan-induced rat paw edema test. Some of the compounds possessed activity superior to that of phenylbutazone and of the same order as that of benoxaprofen.


Synthesis and antileukemic activity of 5-substituted 2,3-dihydro-6,7-bis(hydroxymethyl)-1H-pyrrolizine diesters.

Treatment of N-acylproline derivatives, 2, with acetic anhydride--dimethyl acetylenedicarboxylate (DMAD) gave 5-substituted derivatives of dimethyl 2,3-dihydro-1H-pyrrolizine-6,7-dicarboxylate (5). The reaction proceeds via a 1,3-dipolar addition of DMAD with the mesoionic oxazalone intermediate 3, generated in situ, with concomitant elimination of carbon dioxide. Reduction of 5 gave the diols 6 which upon subsequent acylation gave 1. The bis(N-methylcarbamate) 1d and the diacetate li show a modest level of in vivo antileukemia activity in the L1210 assay. A majority of the diesters, 1, showed significant antileukemic activity in the in vivo P-388 assay. The bis(carbamate) 1d afforded "cures" at dose levels as low as 12.5 mg/kg; 1 q showed potent activity at doses as low as 0.78 mg/kg. Several other compounds showed potent activity against P-388 over a greater than fourfold dose range with no acute toxicity. Half-lives for several diacetate derivatives of 1 were determined for aqueous Me2SO solutions. The preparation of 7 and 8 shows that 1 may react by O-alkyl ester cleavage.


Antiarrhythmics. 2. Synthesis and antiarrhythmic activity of N-(piperidylalkyl)trifluoroethoxybenzamides.

Benzamides characterized by one or more 2,2,2-trifluoroethoxy ring substituents and a heterocyclic amide side chain have been prepared and evaluated for oral antiarrhythmic activity in mice. The most potent compounds are derived from 2,5-bis(2,2,2-trifluoroethoxy)benzamide, and, within this group, both tertiary as well as secondary benzamides are active. Considerable variation in the heterocyclic ring is permissible, but antiarrhythmic activity is strongly influenced by the basicity of the amine nitrogen and the nature of the link between heterocycle and amide nitrogen. One of these compounds, N-(2-piperidylmethyl)-2,5-bis(2,2,2-trifluoroethoxy)benzamide acetate (flecainide acetate, USAN), was studied extensively in animals and selected for clinical trial as an antiarrhythmic.


Synthesis of 5-chloro-3'-nitro-4'-substituted salicylanilides, a new series of anthelmintic and antimicrobial agents.

A number of 5-chloro-3'-nitro-4'-substituted salicylanilides (6--23) have been synthesized by treating 4',5-dichloro-3'-nitrosalicylanilide (5) with various sodium aryl oxides, alkoxides, or amines. These compounds have been tested against Hymenolepis nana infection in rats and have also been evaluated for their in vitro antimicrobial activity against various strains of bacteria and fungi. In the former test 17 was the most active cestodicidal agent showing activity at 30 mg/kg. In the antimicrobial screening, 22 inhibited the growth of all the bacteria and fungi used while 6 was active against the penicillin resistant Staphylococcus aureus at a minimum inhibitory concentration of 0.00609 microgram/mL.


Synthesis of medroxyprogesterone bromoacetate for affinity labeling.

Medroxyprogesterone bromoacetate (17alpha-hydroxy-6alpha-methyl-4-pregnene-3,20-dione 17-bromoacetate) was synthesized by reaction of 17alpha-hydroxy-6alpha-methyl-4-pregnene-3,20-dione with bromoacetic acid--trifluoroacetic anhydride followed by treatment of the intermediate with dilute ethanolic HBr. The product forms conjugates with L-cysteine, L-histidine, and L-methionine and inactivates 20beta-hydroxy steroid dehydrogenase (E.C. 1.1.1.53.) from Streptomyces hydrogenans in a time-dependent and irreversible manner. The title compound possesses a long-acting progestational effect in day 9 pregnant bilaterally ovariectomized rats. The affinity labeling analogue of the oral contraceptive medroxyprogesterone acetate is proposed for use in reproductive biological experiments.


2,3-Disubstituted 1,8-naphthyridines as potential diuretic agents. 2. 5,7-Dimethyl derivatives.

A variety of 2,3-disubstituted 5,7-dimethyl-1,8-naphthyridines was synthesized and tested in saline-loaded rats for their diuretic properties. The 2-amino-3-carbomethoxy and four 2-amino-3-N-alkylcarbamoyl compounds exhibited significant activity as measured by volume output; however, they were generally less potent than the corresponding 5,7-unsubstituted naphthyridines previously reported. Further screening without saline-loading indicated that the amides lacked kaliuretic properties; while, interestingly, the ester lacked an effect on either urine volume or sodium excretion.


Preparation and antitumor activity of 1-aryl-3,3-dimethyltriazene derivatives.

Several 1-aryl-3,3-dimethyltriazene derivatives have been synthesized and tested for their antitumor activity against the TLX5 lymphoma in mice. These compounds are characterized by the presence of a carbonyl group bound to the benzene nucleus in the para position to the triazene funciton. Three p-sulfamoyl derivatives have also been included and proved to be inactive. Among the carbonyl derivatives compounds 1 and 20, which can be used as reference, cause ILS of about 50%, respectively, at four and three dose levels. Compound 16, the o-nitro-phenylhydrazone of the hydrazide 1, is active at all six dose levels studied. The adduct 19, obtained from the same hydrazide and p-nitrobenzaldehyde, is active at four dose levels, and the ILS values at two optimum doses are significantly greater than those caused by compound 1.


Various 5-substituted and 2,5-disubstituted 1,3-dioxanes, a new class of analgesic agents.

A series of 5-substituted and 2,5-disubstituted 1,3-dioxanes was prepared and evaluated for analgesic activity in mice and rats. Some of the compounds possessed significant analgesic effects; their structure-activity relationships and chemistry are discussed. These compounds represent a unique series of analgesic agents.


Isoquinolines. 5. Synthesis and antiarrhythmic activity of benzylisoquinoline derivatives.

The synthesis of a series of benzylisoquinolines 2-9 containing aminoacetamide side chains is described. The method involved reduction of the appropriately substituted nitrobenzylisoquinolines followed by acylation to the chloroacylamide derivatives. Amination with the appropriate amine yielded the desires secondary and tertiary amines. The primary amines were prepared via the phthalimides. Two acetanilides 14 and 15 are also described and compared with the benzylisoquinoline derivatives. All compounds were evaluated for their ability to protect against chloroform-induced ventricular fibrillation in mice. The active compounds 6 and 7 were tested for their effect against ventricular arrhythmias in dogs with myocardial infarction. All compounds with the exception of 5 and 12 exhibited some antiarrhythmic effect. The most potent compound, 1-[2-(2-ethylaminoacetyl)amino-3,4-dimethoxybenzyl]isoquinoline (7), showed greater antiarrhythmic potency, was considerably less toxic than lidocaine, and is a candidate for further evaluation.


Synthesis of octanoyl[8-leucyl]angiotensin II, a lipophilic angiotensin antagonist.

Octanoyl[8-leucyl]angiotensin II (oct-LAT) was synthesized with the aim of obtaining a longer acting angiotensin (AT) inhibitor. The new compound, with a partition coefficient K=7.00 in n-BuOH-HOAc-H2O, was compared with [Leu8]angiotensin II (LAT, K=0.18) as an AT antagonist in two isolated smooth muscle preparations and in the rat blood pressure assay. The two compounds were equally potent in the rat uterus, but LAT was more effective in the guinea pig ileum and the in vivo assay. LAT's effect was longer lasting in the smooth muscles, but the duration of in vivo inhibition was the same for the two compounds. It is concluded that partitioning between external medium and biophase is not a limiting factor for antagonistic potency and permanence of effects of 8-substituted AT derivatives.


Antitumor agents. 25. Synthesis and antitumor activity of uracil and thymine alpha-methylene-gamma-lactones and related derivatives.

Uracil and thymine alpha-methylene-gamma-lactones and related derivatives have been synthesized as novel potential alkylating antitumor agents. The synthesis of these compounds involved the convenient Reformatsky-type reaction between ethyl-alpha-(bromomethyl)acrylate and the proper pyrimidinyl ketones. Preliminary in vivo tumor assay indicated that these compounds were active against the Walker 256 carcinosarcoma in rats and the P-388 lymphocytic leukemia as well as the B-16 melanotic melanoma in mice at 2.5-25 mg/kg.


Isoxazole anthelmintics.

A series of 3-halo-5-phenyl- and 3-phenyl-5-haloisoxazoles has demonstrated anthelmintic activity at doses ranging from 16 to 500 mg/kg orally against the rat roundworm, Nippostrongylus braziliensis. In the 5-phenyl series a halogen at the 3 position of the isoxazole ring was required for activity. However, in the 3-phenyl series activity was maintained after replacement of the 5-halogen with certain alkoxyl, thioalkoxyl, or amino groups. The 3-phenyl and 5-phenyl series apparently are not acting biologically at a common receptor site. Synthetic methods and structure-activity relationships are discussed.


Anticoccidial 1-substituted 4(1H)-pyridinone hydrazones.

4-Chlorobenzaldehyde 1-(4-chlorophenyl)-4(1H)-pyridinylidene hydrazone fluorusulfonate (4) was found to have excellent anticoccidial activity in chickens. The synthesis and biological evaluation of related analogues are presented. Presumably 4 shares a common mechanism of action with robenidine (25) since it was not active on a robenidine tolerant strain of E. tenella. Structural comparisons of the two molecules are presented.


Hydrophobicity of several rhodium(II) carboxylates correlated with their biologic activity.

Rhodium(II) carboxylates differ greatly in antitumor activity and toxicity depending on the properties of the carboxylate group (methoxyacetate, propionate, butyrate, etc.) involved. The solubility characteristics of rhodium(II) carboxylates correlate well with both the antitumor activity and toxicity that these compounds display. The amount of rhodium which is adsorbed by tumor cells in vitro also correlates with the partition coefficient of the rhodium(II) compounds studied. Survival and toxicity studies show rhodium(II) pentanoate to possess the highest therapeutic index against the Ehrlich ascites tumor strain and also show that lengthening the carboxylate R chain beyond the pentanoate reduces the drugs' therapeutic efficacy.


Synthesis and central nervous system evaluation of some 5-alkoxy-3H-1,4-benzodiazepin-2(1H)-ones.

A series of 1-R-5-alkoxy-3H-1,4-benzodiazepin-2(1H)-ones was prepared and evaluated for central nervous system depressant activity. Several of these compounds, in particular, 7-chloro-5-ethoxy-1-methyl-3H-1,4-benzodiazepin-2(1H)-one (2), gave a profile and activity level similar to diazepam when measured in mice.


Hydrolysis of 3-chloro-3-cephems. Intramolecular nucleophilic attack in cefaclor.

The chemical reactivity of 3-chloro-3-cephems was found to be similar to that of the correspondingly substituted 7-aminocephalosporanic acids and 12-13 times greater than that of the correspondingly substituted 7-aminode-acetoxycephalosporanic acids. Cefaclor, 7-(D-2-amino-2-phenylacetamido)-3-chloro-3-cephem-4-carboxylic acid, was found to undergo intramolecular nucleophilic attack at the beta-lactam. Loss of chlorine from 3-chloro-3-cephem may be a general reaction subsequent to beta-lactam opening.


Cephalosporin degradations.

The acidic aqueous degradation of the 7alpha-aminophenylglycinamido-containing cephalosporin cephalexin (1a) has been examined. Two major degradation products have been isolated and characterized: 3-formyl-3,6-dihydro-6-phenyl-2.5(1H,4H)-pyrazinedione (5) and 3-hydroxy-4-methyl-2(5H)-thiophenone (6). By carrying out the reaction in 18O-enriched H2O, the intramolecular nature of the cephalexin degradation has been demonstrated.


3-hydroxyisoxazole-5-hydroxamic acid.

The synthesis of the title compound, 3-hydroxyisoxazole-5-hydroxamic acid (4b), by two procedures is described. The first, involving the treatment of dimethyl acetylenedicarboxylate with hydroxylamine, had previously been reported to give the 3-hydroxyisoxazole-5-carboxylic acid (4a). In the second, treatment of chlorofumaroyl dichloride with hydroxylamine also gave the intermediate chlorofumarodihydroxamic acid (6). Compound 6 was found to have some activity against P388 lymphocytic leukemia.


Cancer and truth.

In this paper the authors discuss the continuing dilemma for doctors who have to tell a patient that he has cancer, particularly the moment when he should confirm a diagnosis that most patients have already sensed. For the writers it is most important that the doctor should be a bridge for the patient to return to his everyday world from the physical and spiritual isolation which his disease has created.


A comparison of medical students from medical and nonmedical families.

A total of 1,195 students from 11 classes at the University of California, San Francisco, School of Medicine was studied. Of these, 162 were from medical and 1,033 from nonmedical families. Those from medical families were insignificantly different from their classmates on premedical scholastic achievement and Medical College Admission Test scores, but they were slightly younger and attended more prestigious undergraduate colleges. Academic and clinical performance in medical school was equivalent for the two groups. However, long-range consequences in regard to choice of specialty were observable. Psysicians from medical families were more likely than their peers to be in ophthalmology and otorhinolarngoloy, dermatology, and surgery and less likely to be in psychiatry, pediatrics, and obstericsgynecology.


Selection of medical specialties: preferences versus choices.

This study was undertaken to examine the extent to which there are differences between preferences and choices of specialty areas among medical students. A total of 350 medical students completed a questionnaire dealing with various aspects of a career in medicine, including specialty preference and choice decisions. The Intolerance of Ambiguity Scale was included as part of the questionnaire. Differences between specialty preference and choice were found for the total group as well as for male and female comparisons. Intolerance of ambiguity was found to be associated with the specialty decision process. Factors contribution to the differences were examined and recommendations for further research were discussed.


Some considerations in the design of family practice residency experiences.

A time-study of residents in a family practice training program is reported. Data concerning time with patients and time with attending physicians tended to be inversely associated with patient volume. The proportions of time spent in these two activities are compared with related activities reported for other participants in postgraduate medical education and for practicing physicians. Study results are used to illustrate and develop some issues involved in thd design of residency experiences for primary care physicians.


Physician participation in health administrator education.

A seminar in quality of care analysis was developed with three objectives in mind: (a) to familiarize health administration students with methods for measuring the quality of health care (b), to sensitize students to complexities of the medical care process, and (c) to provide a setting where students interact directly with physicians in dealing with a common problem. Students developed individual evaluation projects at participating institutions in cooperation with faculty of the program and staff at the institutions. Evaluation of the seminar in terms of state objectives was performed both quantitatively and qualitatively. Indications are that the course was well accepted by students and achieved its major goals.


Evaluation of clinical skills for a specialty board during residency training.

Since 1971 the directors of residency training programs in internal medicine have had the responsibility for evaluating the clinical skills of their trainees for the American Board of Internal Medicine. Satisfactory performance is required by the board as a qualification for admission to its written certifying examination. This report presents the board's experience with the evaluation of clinical skills through June 1975 based on visits with the administrators of 166 residency training programs. Described are the evaluative methods employed by the programs, the delineation and observation of acceptable minimum standards of performance, and the benefits to training in internal medicine accruing from the institution of these evaluation procedures and from the related visits to hospitals by representatives of the board.


An educational program to modify laboratory use by house staff.

An earlier study showed that the prothrombin time determination is overutilized as a routine admission laboratory test. In the present study the investigator evaluated the effectiveness of an educational program in decreasing utilization of the prothrombin time determination by house staff physicians at a teaching hospital. Six months after the educational program, use of the prothrombin time determination as a routine admission test had decreased significantly from 87 percent to 55 percent. Eighteen months after the educational program, the use of this test by the study group had returned to initial levels. These results emphasize the need to measure the long-term outcome of educational programs aimed at modifying the clinical behavior of physicians and to institute follow-up programs to ensure that an educational effort will have a lasting effect.


Development and evaluation of a sex education program for medical students.

This paper describes the development of a sex education program for medical students at the University of Missouri-Columbia School of Medicine. A description is given on the method used to achieve the objectives of giving knowledge of sexual behavior, modifying attitudes which block understanding of sexuality, and developing skills for the evaluation and management of sexual problems. The importance of using discussion groups assisted by skilled group facilitators to reach these objectives is discussed. The Sex Knowledge and Attitude Test, by which pretest and posttest differences in knowledge and attitude were assessed, and the results obtained are discussed.


Gleno-humeral joint in the chimpanzee: comparative anatomical analysis for use in endoprosthetic replacement.

The gleno-humeral joint of the adult chimpanzee is morphologically compared to the human shoulder to assess the feasibility of this animal for use in experimental prosthetic replacement. The anatomical structure appears similar enough to man to warrant investigation of this animal as a vehicle for experimental implant design in the shoulder. Several anatomical structural differences were noted which necessitated modification of the fixturing segments of a "Floating Socket" total gleno-humeral endoprosthesis.


Elimination of the Shigella carrier state in rhesus monkeys (Macaca mulatta) by trimethoprim-sulfamethoxazole.

The Shigella carrier state was eliminated from its nonhuman primate host, Macaca mulatta. Each of 31 animals was treated twice a day for ten consecutive days with 16 mg trimethoprim and 80 mg sulfamethoxazole delivered via stomach tube. Fresh rectal swab and stool enrichment cultures were taken for seven consecutive days as well as the 35th and 78th days after treatment, and all were negative for shigellae. In addition, no clinical signs of shigellosis were observed during or following an extensive period of stress.


The effect of prostaglandins on the electromyogram and motility of the monkey uterus and oviduct in late pregnancy and postpartum.

The electromyogram of the monkey (Macaca fuscata fuscata and Macaca mulatta) uterus in labor presents spike bursts which accompany the rising intrauterine pressure. Asynchronous localized electrical activity develops into synchronous activity during the course of labor. The early postpartum uterus shows an irregular pattern or continuous small bursts of spikes. During labor it responds markedly to prostaglandins (PGs); this declines in postpartum. Direct intrauterine injection of PGF2a is effective in the early postpartum. Intravaginal application of PGE2 (5 mg/kg) in late pregnancy induces regular, frequent bursts of spikes and successful delivery. Electrical activity of the oviduct was not affected by PGs except in early postpartum.


Organometallic and organometalloid compounds as standards for microprobe analysis of epoxy resin embedded tissue.

X-ray microanalysis of phosphorus, transition elements and heavy metals in biological tissue is frequently carried out on thin sections of specimens embedded in epoxy resin. A logical choice for the quantitive microprobe analysis of these specimens is a standard, consisting of a homogenous solution of the elements of interest in the epoxy resin. Four kinds of compounds were found suitable  for this purpose: (1) phenyl compounds containing group Vb elements, (2) cyclopentadienyl-derivatives, (3) a pentanedione derivative (acetylacetonate) and (4) complexes of metals with dialkyldithiocarbamates. In the latter case, the standard also contains sulphur. Standards for P, Sb (1) Mn, Fe (2) Ni (3) Cu, Zn, Cd, Hg, Pb, Bi (4) were prepared in Epon 812 or Spurr epoxy resin. The compounds were mixed with the resin (without accelerator) to which some propylene oxide may be added, and dissolved immediately or after short heating. The maximal concentration of metal was in the order of magnitude of several promilles to 1%. Solubility in the Spurr resin was better than in Epon 812. After addition of the accelerator, polymerization was carried out as usual. The compounds used are commercially availalbe at low cost or can be easily prepared.


How dangerous is sodium cacodylate?

Circumstantial evidence suggests that sodium cacodylate may be a far greater health hazard than has been generally assumed. Until further information is available, electron microscopists should see that extreme care is exercised during the preparation of cacodylate buffers by their staff.


Structure and carbohydrate histochemistry of the esophagus in ten teleostean species.

The histology and carbohydrate histochemistry of ten teleostean esophagi were compared. Structurally, the four layers of atypical vertebrate digestive tract were consistently present. The epithelium was always stratified and in all but one species (Ictalurus nebulosus) contained taste buds. Esophageal mucous cells were not the typical goblet cells seen in other vertebrates but appeared to be of six different types, pairs of which were associated with particular families. In esocids, poorly developed mucous acini and serous monogranular cells were present. In all species, the subepithelial connective tissue was not divided into definitive lamina propriae submucosae due to the absence of muscularis mucosae. Variably present in this connective tissue region were argentophilic fibers and in esocids only, randomly dispersed striated muscle fibers. The arrangement of the muscularis was reverse to that of the general vertebrate plan. In mucous cells, three general types of epithelial mucosubstances were identified and in broad terms were recognized as sulfomucins, sialomucins and neutral mucosubstances. Morphological differences were accompained by differences in carbohydrate localization, each esophageal epithelium containing at least two different mucosubstances. However, the mucosubstances identified in each mucous cell had a profile of characteristics different in some respects from any other. Thus teleostean esophagi appear to perform an integrated diversity of functions as reflected by their complex morphology and carbohydrate histochemistry.


Morphology of the macula neglecta in sharks of the genus Carcharhinus.

Ears from several species of carcharhinid sharks were studied by gross dissection, light microscopy, transmission electron microscopy, and scanning electron microscopy. Structures along a possible sound transmission path to the ear are described, but main consideration is given to the structure of the macula neglecta. The macula neglecta is composed of two patches of sensory epithelium which line part of the posterior canal duct. In an adult shark the larger of these contains 224,000 sensory hair cells oriented so as to detect forces directed posteroventrolaterally in the duct. The smaller patch contains 43,000 hair cells oriented so as to detect oppositely directed forces. These receptor cells project through numerous small terminals to a total for both patches of 4,700 myelinated nerve fibers. Cytostructural variations throughout the hair cell population are also reported. Estimated acoustic properties of the tissues in this complex and the processing potential of the neural elements are interpreted as suggestive of auditory function. A mechanism based on the geometry of the receptor arrays is proposed to explain behaviorally observed instantaneous sound localization from the farfield. Evolution of the macula neglecta is reviewed, and evidence for homology of the macula neglecta and amphibian papilla is presented.


Splenic erythroid response to friend polycythemia virus: time course in vitro after infection in vivo.

When spleen cells removed from plethoric BALB/c mice shortly after infection with Friend polycythemia virus were cultured, they subsequently increased their rate of hemoglobin synthesis in vitro without the addition of the hormone erythropoietin. The increased 59Fe incorporation into hemoglobin in vitro was part of a well-defined single wave unlike the progressive increase in hemoglobin synthesis that occurs in vivo. The peak occurred within the same total time (85-105 hr after infection), irrespective of either the virus dose or time after infection when the cells were removed from the animal and cultured. However, the magnitude of the peak increased with an increase in either of these two variables. Medium change experiments indicated that the time during which the peak occurred was not artificially determined by depletion of some medium component or the accumulation of an inhibitor. This system may be useful in separating the early events of Friend virus infection from the late effects on erythroid differentiation.


The uptake and secretion of 3-methylcholanthrene by the prostate glands of the rat and dog.

In anesthetized rats in which prostatic fluid was collected over a 2-hour interval from 24 to 26 hours after a single ip dose of 5 mg [6-14C]3-methylcholanthrene ([14C]MCA)/kg, radioactivity was found in the fluid at levels only slightly less than those in plasma; at 26 hours after treatment, levels of radioactivity within the prostate were higher than those in prostatic fluid or plasma. When unanesthetized dogs with surgically prepared prostatic fistulas were given a single ip dose of 0.5 mg [14C]MCA/kg and when serial prostatic fluid and plasma samples were collected over the ensuing 50 hours (2 dogs) or 212 hours (1 dog), radioactivity appeared in the prostatic fluid at levels initially greater than those in plasma and then fell progressively with time to less than those of plasma. At 50 hours after treatment, radioactivity was recovered from the prostate glands of 2 dogs with fistula and 2 dogs without fistula at levels of about one-fourth those of plasma. Thus it was found that [14C]MCA and/or its metabolites entered the prostate glands and prostatic fluids of the rat and dog.


Acute effects of N-methyl-N'-nitro-N-nitrosoguanidine on canine gastric mucosa.

The electrophysiological effects of the chemical gastric carcinogen N-methyl-N'-nitro-N-nitrosoquanidine (MNNG) were determined in an in vivo chambered canine stomach and in an in vitro canine gastric mucosal preparation. In the in vivo stomach, the topical application of 2.5 mg MNNG/ml decreased the transmural electrical potential difference, and the systemic blood pressure was essentially unchanged. In the in vitro preparation, exposure of the mucosal side of the isolated canine gastric mucosa to 0.25 and 2.5 mg MNNG/ml for 1 hour sequentially or exposure of the serosal side to 2.5 mg MNNG/ml for 2 hours inhibited net Na+ and Cl- fluxes. With longer duration, the undirectional fluxes of Na+ and Cl- increased, indicating an increase in permeability. These findings suggested that inhibition of active transport in the gastric mucosa may have an important function in the gastric carcinogenicity of MNNG.


Corynebacterium parvum-induced radiosensitivity and cycling changes of hematopoietic spleen colony-forming units.

Ten days after total-body irradiation with 550 rads of b0Co, spleen colonies were observed in adult C57BL mice. A change in radiosensitivity induced by Corynebacterium parvum, as measured by increased numbers of colony-forming units that survived the 550 rads, began shortly after C. parvum stimulation and extended for at least 7 days before irradiation. C. parvum given 4-24 hours before, followed by high specific activity [3H]thymidine (HSATT) 1 hour before total-body irradiation greatly reduced survival of the stem cells that formed spleen colonies (CFUs) and CFUs radiosensitivity to control levels. The HSATT sensitivity by "suicide" assay in vivo and the time-response change in radiosensitivity corresponded with the decrease in radiosensitivity, which showed that CFUs were stimulated by C. parvum administration and entered the S-phase shortly after stimulation. The data indicated a resting population close to the S-phase. After stimulation, this population entered S-phase. Syngeneic mouse lymphoma cells injected iv 24 hours earlier did not elicit any effect as a stimulus to CFUs radiosensitivity change.


Lower limb paralysis induced in mice by a temperature-sensitive mutant of Moloney leukemia virus.

A temperature-sensitive mutant of Moloney murine leukemia virus defective in an early function and injected into newborn mice produced lower limb paralysis. Susceptible mice were inbred strains CFW/D, CBA/H, C3H/Bi/Ka, and outbred NIH Swiss stock. Inbred W/Fu rats and C57BL/Ka mice did not develop the paralysis, though the latter were infected with virus; the sera from these mice produced paralysis in susceptible CFW mice.


Inhibition or enhancement of rat mammary tumors dependent on dose BCG.

The effect of BCG on the growth of transplantable rat mammary tumors in W/Fu rats was studied. Admixture of mycobacteria to tumor cells in vitro prior to their injection in vivo either had no effect on or resulted in inhibition of or enhancement of the growth of the tumor transplants. Inhibition occurred at high and enhancement at low mycobacteria:tumor cell ratios. However, following suppression of local tumor growth with high doses of BCG, the growth of a second tumor graft was enhanced. Pretreatment of rats with BCG alone also enhanced the growth of a subsequent tumor graft. These results suggest an inverse relationship between the optimal dose of BCG for suppression of local tumor and that required to induced systemic immunity.


Rapid assays for evaluating the drug sensitivity of tumor cells.

Assays that assess the ability of cells to incorporate labeled precursors into acid-precipitable material in the presence of adriamycin, daunorubicin, puromycin, vinblastine, melphalan, or methotrexate were investigated as an approach to the detection of resistant cells in human tumor samples. Each assay was evaluated with suitable drug-resistant Chinese hamster ovary cell lines and normal human fibroblasts to determine whether the assays reflected the drug sensitivity of these lines. Moreover, the ability to detect the presence of drug-resistance cells in a mixed population was evaluated. Validated assays were then used to measure the drug sensitivity of cell samples from pleural and peritoneal effusions of patients, mainly with carcinoma of the breast or ovary. Though the responsiveness of the majority of the samples in these assays was similar to that of a human fetal lung fibroblast line, 37 of 142 samples displayed responses consistent with the presence of a significant proportion of drug-resistant cells. Of these 37 nonresponsive samples, 12 displayed nonresponsiveness to three drugs.


Reduced forms of aminopterin and methotrexate in L1210 lymphoma.

We examined several characteristics of reduced forms of folate antagonists. Dihydro and tetrahydro derivatives of aminopterin and methotrexate (MTX) were chemically prepared. When titrated with dihydrofolate reductase, reduced derivatives were equipotent with the parent compounds and titrated stoichiometrically with the enzyme at pH 6 and nonstoichiometrically at higher pH conditions (pH 7.4 and above). When incubated with L1210 cells in vitro, rates of uptake of tritiated reduced compounds were significantly less in L1210 and L1210/MTX cells compared with the respective oxidized parent compounds and significantly less in L1210/MTX than in L1210 cells. Although dihydroaminopterin and tetrahydromethotrexate increased the survival rate of mice bearing L1210 tumors, these compounds had no such effect on the life-spans of animals with L1210/MTX tumors.


Pepstatin, an ascites retardant of L1210 tumor-bearing mice.

The effect of pepstatin on the kinetics of ascitic fluid accumulation in L1210 tumor-bearing mice (DBA/2) was observed. Following inoculation of 1.5x10(6) tumor cells, untreated mice reached a peak of fluid accumulation on day 6 and remained at this level until death on day 9. A "lag" phase of 4 days occurred before fluid accumulation was seen. Pepstatin administered SC in a single dose of 80 mg/kg during the lag phase, significantly retarded fluid accumulation as compared to untreated animals. Pepstatin administered following fluid accumulation was much less effective. We concluded that pepstatin prevents fluid accumulation rather than acts as a diuretic agent. The term "ascites retardant" is suggested for the pharmacologic actions of pepstatin, since it prevents fluid accumulation without diminishing the cell count.


Effect of different doses of BCG on an allogeneic cell-mediated antitumor response in mice.

The effect of BCG on the development of cell-mediated cytotoxicity (CMC) in the spleens of allogeneic tumor-bearing (C57BL/6 X A)F1 mice was studied. BCG-treated tumor-bearing animals elicited a stronger CMC response than did the untreated tumor-bearing animals. Furthermore, the degree of activation was dependent on different doses of BCG, so that if the BCG was administered at doses above or below the optimum dose, a less marked stimulation of the CMC resulted. The combination of BCG given before the tumor implant plus an intratumor inoculation resulted in a significantly higher CMC than did either treatment alone.


Glycosyltransferase levels in tumors metastatic to liver and in uninvolved liver tissue.

Elevated levels of three plasma glycosyltransferases were associated with neoplasia in cancer patients, notably those with tumor metastatic to liver. We examined levels of sialyltransferase, galactosyltransferase, and fucosyltransferase in metastatic tumor and apparently uninvolved host liver tissue in attempts to delineate possible sources of elevated plasma enzyme levels. Highest levels of fucosyltransferase activity were found associated with tumor tissue; in contrast, sialyltransferase and galactosyltransferase activity was often highest at the tumor-liver interface.


Cell proliferation in human cutaneous squamous cell carcinoma.

Squamous cell carcinoma (SCC) of the skin, a fairly slow-growing locally invasive tumor that occasionally matastasizes, was studied in 12 patients in vivo with the use of intralesional tritiated thymidine as a marker for cell proliferation kinetics. Analysis of the cell cycle of the germinative population revealed that the duration of S-phase was 12.5 hours; G1-phase, 28.8 hours; mitotic period (M-phase), 2 hours; G-pahse, 6.9 hours; and the total germinative cell cycle, 50.2 hours. The application of cell kinetics to programming chemotherapy for skin cancer with phase-specific cytotoxins was discussed.


Hormonal status of breast cancer. III. Further analysis of ovarian-adrenal dysfunction.

Detailed studies of urinary steroids in patients with breast cancer and normal controls have shown that abnormal aging processes and depressed corpus luteum function were associated with the presence of this form of cancer. The ratio of androsterone to tetrahydrocortisol, an index of the aging process, was significantly lower in a breast cancer group than in a normal group at both premenopausal and postmenopausal stages. In premenopausal women, the ratio decreased in the order of rural controls, urban controls, and patients with breast cancer. It was indicated that the ratio may serve as a measure of risk for breast cancer. Aside from the general depression of menstruation-dependent steroids, breast cancer was associated with disproportionately low excretions of prenanediol and pregnanetriol within the menstruation-dependent steroid family. The notion that this finding reflects the delay or complete failure of ovulation was supported by a reduced parturition rate of our patients with breast cancer as compared with that of our normal controls. The physiologic significance of steroidal disturbances was considered in relation to the genesis of breast cancer.


Relationship between steroid excretion patterns and breast cancer incidence in Israeli women of various origins.

A nationwide study of the steroid excretion patterns in postmenopausal Israeli migrant women demonstrated differences between high- and low-risk groups for breast cancer in the following variables: age at first parturition, number of pregnancies, number of live births, height, and weight. The direction of the differnces was in line with those observed for breast cancer patients. The groups also differed in the exretion of estriol, 17-ketosteroids, and allotetrahydrocortisol. Multiple regression analysis revealed that the exretion of estriol was significantly lower in population groups in whom breast cancer incidence was high. Possibly this trend--which has also been observed in adolescent and premenopausal women--reflected environmental influences on peripheral estrogen metabolism.


Surgical aspects of intestinal ascariasis.

At the University College Hospital, Ibadan, Nigeria, a common differential diagnosis of acute abdomen is intestinal ascariasis. This condition mimics many causes of acute abdomen so that accurate pre-operative diagnosis depends mainly on a high index of suspicion.The purpose of this paper is to call attention to this condition which is prevalent in tropical countries, where preventive and social medicine have not reached their peak, and to review the pathological processes resulting from this disease.


Care of the patient with a critical illness.

A method of care applicable to all forms of critical illness is presented. A patient is considered to be critically ill when he is threatened with hypoxia. According to this concept, procedures to understand and solve problems of critical care are coordinated and unified. The relevant physiology and monitoring of the components of the oxygenating system are described. The treatment of patients with impaired function of these components is described.


The gold button technique for intraoral interstitial implants with iridium-192 seeds.

The higher the radiation dose, the better is tumor control. High tumor doses are feasible only by interstitial irradiation. To achieve uniform dose distribution throughout the area or volume of implant, one has to use established distribution rules. In straight tube technique we have to use heavy endloading to compensate for uncrossed ends. In implants for intraoral lesions, heavy endloading gives a high dose to the opposing normal mucosa. The new gold button technique considerably reduces the dose to the normal mucosa, thus minimizing the morbidity.


Cancer of the prostate in blacks.

The exact etiology of adenocarcinoma of the prostate gland remains an enigma. However, there appears to be a clear-cut mandate to search for, and to eradicate if possible, all infections of the genital tract including prostatitis. Diets with adequate zinc or zinc supplements should be considered. Sexual practices could be more closely scrutinized. Finally, an urgent appeal is made for intense investigation of this malady.Two cases of prostatic carcinoma are presented and pertinent literature is reviewed.


Albright's syndrome in a Nigerian: a case report.

A Nigerian male with typical features of Albright's syndrome will be described. Although the lesions were predominantly unilateral, his main complaint was that of severe facial deformity. He had a radical excision of the facial lesion which was followed by a rapid recurrence. The differential diagnosis of Albright's syndrome will be discussed.


Success rate of detoxification from methadone maintenance in an ambulatory care unit.

The success rate of detoxification of patients on methadone maintenance in four outpatient clinics is studied. In comparison with patients in an in-house program, or a hospital environment, the study group did relatively poorly. It is felt that a confined and carefully structured therapeutic environment is much more likely to produce patients who are amenable to successful detoxification from hallucinogenic drugs, than is a walk-in clinic.


Pulmonary edema: an anatomic, pathophysiologic, and roentgenologic analysis.

Pulmonary edema is a complex subject. Knowledge of the anatomy of the distal air space is essential to the understanding of the pathophysiology of pulmonary edema.Histological evaluation of experimental pulmonary edema in dogs by Staub et al using the quick freeze method indicates that the edema begins in the interstitium. An x-ray examination at this time would be interpreted as negative or normal. Similarly, with only partial filling of the alveolus, a negative reading may be given.A method for classification of pulmonary edema by mechanisms is reviewed.Cases of pulmonary edema caused by different etiologies are presented for an overview of the problem.


The drug insert and the physician's concern.

The package insert has achieved an increasingly important role, not only as a device to communicate prescribing information to physicians, but also as a key element in the standards used to determine the liability of physicians for adverse drug reactions. Regulations recently proposed by the FDA illustrate the significance of the package insert from the governmental perspective. This paper deals with the impact of these regulations on the medical profession.


A closed-flow water caloric system.

This paper describes a new method and apparatus to induce nystagmus. Flow of fluid into the ear to induce nystagmus is eliminated by utilization of a closed-flow system. A probe adapted for insertion to a standardized depth into the ear, provides a flow-through path for nystagmus-inducing liquid while expanding in response to the pressurized liquid to conform to the contours of the external auditory canal and tympanic membrane. Thermal conductivity through the membrane-like probe material permits heat exchange between the flowing liquid, and the external auditory canal and/or tympanic membrane to induce nystagmus.At this time, the authors can state only that the quality of nystagmus produced is similar to that produced by current conventional methods. In the small number of patients tested, discomfort appeared to be almost negligible. The system appears to be a promising improvement dependent on the establishment of accurate parameters for diagnosis.


Adverse effects of intravenous cannabis tea.

Adverse effects occurred in four youths after intravenous injection of an aqueous cannabis-seed tea, which was prepared by boiling the seeds. The effects were immediate and included nausea, vomiting, abdominal pain, watery diarrhea, chills, fever, hypovolemic shock, hypotension, and non-oligemic transitory renal failure. Other manifestations included persistent hypoglycemia, tachycardia, gastrointestinal bleeding, conjunctival hemorrhage, injury, jaundice, splenomegaly, leucocytosis, myalgia, arthralgia, motor weakness, and prostration. Ischemia was noted on electrocardiogram (EKG). All manifestations appeared to reverse within weeks, but these effects had been potentially fatal.


Non-Hodgkin's lymphoma in Ibadan, Nigeria.

One hundred patients with non-Hodgkin's lymphoma were admitted to the University College Hospital in Ibadan, Nigeria between 1960 and 1975. Their cases have been analyzed with respect to clinical findings, histological classification, and response to therapy. There was a preponderance of males over females (2:1) and the majority of the patients (87 percent) had reticulum cell sarcoma. Therapy consisted mainly of single-agent chemotherapy but a few patients had either surgical excision combined with chemotherapy or multiple-agent chemotherapy. The results of treatment were poor because of the very high default rate, late presentation, inadequate supply of drugs, and lack of radiotherapeutic facilities.


Osteomyelitis of the calcaneus secondary to heel pad puncture: a case report.

Heel pad puncture, a well-established procedure for obtaining hematologic samples from infants, may be complicated by acute osteomyelitis of the calcaneus. One such case is presented which involved a 3½-month-old female. Physicians are cautioned that calcaneal osteomyelitis should be suspected if soft tissue swelling and erythema are present around the heel area.


The strip graft as a means of hairline replacement.

The strip-graft hairline replacement is a surgical procedure requiring meticulous tissue handling and attention to detail. Even then, the unpredictability of successful "takes" causes the cosmetic surgeon some concern. When combined with the original Orentreich autograft technique it can be valuable in the surgical treatment of male pattern baldness.