Functional significance of projection from the cerebellar nuclei to the motor cortex in the cat.

The functional organization of projections from the cerebellar subcortical nuclei to the motor cortex through the nucleus ventralis lateralis (VL) of the thalamus was studied using tungsten microelectrodes for stimulation and recordings in acute and chronic cats. The following results were obtained. (1) Microstimulation of a small area of the ventral thalamus produced contraction of a single limb muscle as well as movements of whiskers. (2) The stimulus parameters for producing low threshold contraction of limb muscles were different from those for face muscles. The decrease of the frequency gradualy increased the threshold values for face muscles whereas the decrease abruptly increased the threshold for limb muscles. The optimum duration of the train for the lowest thresholds was longer for face muscles. (3) Stimulation of cerebellar nuclei (interpositus and lateralis) produced contraction of limb muscles. The stimulus parameters for the minimum threshold were similar to those for producing contraction of limb muscles from the ventral thalamus. (4) The peripheral receptive fields of neurons located around the low threshold sites in the thalamus were diffuse, i.e. they were driven insecurely by twisting the joints or pressure to the deep structures, but could not be driven by touch or light pressure on a circumscribed area of the body. (5) Chronic ablation of the motor cortex did not abolish the muscle contractions produced by thalamic stimulation, excluding the possibility that the effects were produced by stimulation of the branches of the pyramidal tract fibers reaching the ventral thalamus. (6) Chronic section of the brachium conjunctivum abolished or changed the characteristics of the contractions produced by thalamic stimulation indicating that the previous effects were produced by stimulation of cerebellar efferent fibers reaching the thalamus. (7) From these results it was concluded that the efferent impulses originating from the cerebellar nuclei can produce contraction of a particular muscle through activation of the red nucleus. These impulses are, at the same time, transmitted to a small group of neurons in the VL and then forwarded to the neurons in the motor cortex. (8) The functional significance of the VL projection system has been discussed in relation to the efferent zones within the motor cortex.


Input-output relations of the red nucleus in the cat.

In unanesthetized cats, microstimulation within the red nucleus produces contraction of single muscles of the contralateral limbs and face. Separate zones may activate different muscles. Forelimb muscles were primarily activated from areas in the dorsomedial quadrants of the red nucleus whereas hindlimb muscles were predominantly activated from the ventorlateral quadrants. With stimulus currents of 10 muA there was considerable overlap in the effective zones activating different muscles. In the majority of cases the minimal threshold was under 10 muA when stimilating with a 50-msec pulse train. Current thresholds for electromypgraphic changes in the muscles varied inversely with pulse frequency and train duration. When long stimulus trains were applied to the red nucleus, the resulting muscle contraction was sustained for the duration of the stimulus. These motor effects did not depend upon the motor cortex or pyramidal tract but were mediated by a tract in contralateral dorsal quadrants of the spinal cord which was likely to be the rubrospinal tract. Units within the red nucleus typically had wide cutaneous receptive fields and responded to deep pressure and joint rotation in one or more limbs. Usually the focus driving the cell most briskly was located in one of the contralateral limbs and corresponded to the limb where muscle contraction was elicited by microstimulation with the same electrode. It is concluded that the red nucleus includes overlapping efferent neuronal colonies controlling individual muscles irrespective of their functional class. This property is shared by the motor cortex and suggests that these two structures may complement each other in the control of movement. The more diffuse activation of rubral than cortical neurons by natural stimuli suggests that rubral activity may not be as tightly linked as that of the motor cortex to specific peripheral input.


Canine glomerulonephritis: prevalence in dogs submitted at random for euthanasia.

The kidneys from 71 stray dogs submitted for euthanasia were examined by fluorescence microscopy (IF) for evidence of immunecomplex glomerulonephritis (GN) and by histology for evidence of renal pathology. Dogs were divided into three groups according to estimated age: less than one year old (A), adult (B) and aged (C). IgG deposits were found in 0/31 dogs in group A, 6/20 in group B and 10/20 in group C. Diffuse proliferative GN was evident in 0/31, 5/19 and 7/15 dogs in group A, B and C respectively. One dog in group B and two in group C had histological signs of membranous nephropathy. No definite correlation between results of IF and clinical findings were noted and in the aged group the correlation between results of IF and histopathology was poor. These results serve to show that GN may be more common in dogs than previously recognized and that pathological changes may be always accompanied by clinical nephritis.


Dairy calf mortality rate: the association of daily meteorological factors and calf mortality.

The number of dairy heifer calves born each day, the number of these calves which died prior to 36 days of age and the actual date of death were recorded and analyzed for possible associations with weather factors. The demographic data on dairy calves were supplied by 16 farms in Tulare County, California for the months of July to December 1973. High temperatures in the summer and low temperatures in the winter were associated with an increased risk of death. Calves born during the periods of extreme temperatures had a higher risk of death than those born on more temperate days, while death, when it occurred was temporally related to days of extreme temperatures. Periods of increased risk of death often were associated with large temperature fluctuations irrespective of the absolute temperature. Nonmeteorological factors specific to invidual farms also appeared to influence daily calf mortality rates.


Histopathology of hereditary muscular dystrophy of the domestic turkey (Meleagris gallopavo).

The histopathology of hereditary muscular dystrophy was studied in homozygous dystrophic turkeys of various ages. Myopathy was severe at ten weeks of age but absent at seven weeks or less. Lesions at ten weeks consisted of variation in fiber size and contour with acute necrosis of individual muscle fibers. Myopathic characteristics were similar at 16 and 24 weeks but with fewer dystrophic fibers and slower fiber destruction. Fat deposition was mild at 24 weeks and there were disseminated foci or endomysial proliferation in dystrophic muscle at 16 and 24 weeks. Pectoral and alar muscles were dystrophic but no lesions were detected in gastrocnemius muscle, myocardium, central and peripheral nervous system tissue or visceral organs. Mean diameters and nuclear numbers of muscle fibers were significantly less in pectoral muscles of dystrophic turkeys than in controls and did not have increase significantly from ten to 24 weeks of age as did controls.


The ocular lesions of naturally occurring lymphocystis in fish.

Six cases of ocular lymphocystis, a virus disease, are described. Lymphocystis is generally known as a benigh, unique, giant cell disease of fishes causing nodules on the skin and fins. It has been studied extensively because of the virus-host cell relationship that results in extreme size and lack of quick cellular destruction or stimulation to neoplasia. Lymphocystis cells were found behind or in one or both eyes and were also found on the cornea or adjacent skin surfaces. A retrobulbar mass produced extreme exophthalmos. Uveal (choroid and iris) masses were present in most cases. Optic nerve involvement was also seen. It is probable that the virus reached the eye by the blood with the resulting masses forming in situ rather than by direct extension from skin lesions.


Studies on dioctyl sodium sulfosuccinate toxicity: clinical, gross and microscopic pathology in the horse and guinea pig.

Concentrations of dioctyl sodium sulfosuccinate (DSS) ranging from three to five times the recommended dosage produced severe diarrhea, rapid dehydration and death in seven horses and 66 guinea pigs when administered experimentally per os. Clinicopathological findings indicated hemoconcentration in both horses and guinea pigs. There was a leucocytosis in the guinea pigs given the highest dosages. In all cases the principal finding at necropsy was extreme fluid distention of the intestinal tract. There was histopathological evidence of epithelial denudation and vascular stasis. The LD50 in the guinea pig was approximately 0.65 g DSS/kg body weight.


Effects of asphyxia and potassium on canine and feline electrocardiograms.

The effects of asphyxia and potassium on the electrocardiogram (ECG), lead II, were recorded from dogs and cats anesthetized with sodium pentobarbital and halothane. Electrocardiographic recordings were made during control periods, during asphyxia (occluded endotracheal tube), during infusion of an isotonic KCl solution and during infusion of an isotonic NaCl solution. Arterial and venous blood gas partial pressures (PaCO2, PvCO2, PaO2 and and PvO2), plasma Na+ and K+ concentrations, heart rate and mean arterial blood pressure were measured during control periods, asphyxia and during the periods of infusion. The vagi were severed to assess the effect of vagal tone on the ECG changes. The characteristic ECG changes during asphyxia and the electrolyte imbalances resulting from infusion of isotonic KCl and NaCl were determined during sodium pentobarbital and halothane anesthesia in both dogs and cats. The combination of halothane and high PCO2 caused cardiac arrhythmias. Spontaneous recovery from ventricular fibrillation, as a result of hyperkalemia, was recorded from cats. Disappearance of the P waves, which is characteristic of hyperkalemia, was infrequent in this study and the U waves associated with hypokalemia were not found. Severing the vagi did not alter the ECG changes characteristic of asphyxia, hyperkalemia and hypokalemia. It was found that asphyxia and infusion of fluids high or low in potassium can produce ECG changes in both dogs and cats that can be correlated with blood gas partial pressure changes or plasma potassium concentrations.


Combined scanning electron and light microscopy of biopsy samples of bovine uterus.

Uterine biopsies from normal cyclic cows were optimally prepared for examination in a scanning electron microscope. After examination in the scanning electron microscope the same tissues were routinely processed for paraffin sectioning and reexamined with the light microscope. Results indicate that the scanning electron microscope is satisfactory for examination of the fine surface structure of the endometrium and the light microscope for subsurface structures of the bovine uterus.


The recovery of Mycoplasmas from the genital tracts of bulls in artificial breeding units in Ontarïo.

One hundred and thirty-two penial-preputial swabbings, 140 raw and 42 processed semen samples were cultured for mycoplasmas. Mycoplasma or acholeplasma were recovered from 87, 32 and one respectively, while ureaplasmas were recovered from 46, 34 and six respectively.


Effects of the diethyl and dimethyl esters of glutamic acid on morphine anti-nociception in the rat.

The effects of pretreatments with various doses of glutamic acid diethyl or dimethyl esters on morphine-induced anti-nociception in the hot-plate and tail-flick tests on rats were examined. While neither substance alone altered control reaction times, they both antagonized the effects of morphine, suggesting the possible involvement of glutamate receptors in narcotic "analgesia". However, several aspects of the data inveigh against the significance of the findings with regard to narcotic mechanisms.


Comparative effects of opiate agonists methadone, levorphanol, and their isomers on the release of cortical ACh in vivo and in vitro.

The effect of analgesically active opiate agonists dl-methadone, levorphanol, and their less active forms d-methadone and dextrorphan, respectively, were tested on, (a) the spontaneous release of cortical acetylcholine (ACh) in vivo; (b) the spontaneous and K+-evoked release of cortical ACh in vitro. The injections of dl-methadone, but not d-methadone, inhibited the output of ACh in vivo. Naloxone completely reversed this effect of methadone. Levorphanol in small doses inhibited, and in larger doses stimulated, the in vivo release of ACh. Both effects were antagonized by naloxone. Its dextroisomer dextrorphan was completely inactive. The in vitro release of ACh from cortical slices was inhibited by all four agents. The effects of analgesically active opiates dl-methadone and levorphanol on the in vitro release were not clearly separable from the effects of their inactive forms d-methadone and dextrorphan.


Interactions of respiration and the bradycardia of submersion in harbor seals.

Six harbor seals with percutaneous tracheostomies were artificially ventilated while immersed. Changes in the oxygen content of the inspired gas and in the minute-volume altered the magnitude of the bradycardia observed after the animal had been submerged for 30 s. The average heart rate in five seals changed from 16.7 (S.D. = 4.4) beats per minute during artificial ventilation with N2, to 58.7 (S.D. = 10.4) beats per minute while breathing air, but this cardiac chronotropic effect of oxygen was blocked by addition of 7% CO2 to the inspired gas. Ventilatory minute-volumes above approximately 3 litres/min caused cardiac acceleration in a manner related to ventilation; below this, changes in heart rate were inconsistent. While being artificially ventilated with air, the average heart rate in five seals changed from 16.5 beats per minute to 73.4 beats per minute as ventilation was increased from 0 to greater than 8 litres/min. These experiments demonstrate that O2, CO2, and ventilatory minute-volume have significant effects upon the heart rate of seals under water and suggest the presence of chemoreceptor-mediated effects on heart rate during submersion.


Endogenous prostaglandin release contributes directly to coronary artery tone.

An in vitro coronary artery preparation of beef heart was found to synthesize and release continuously large amounts of a prostaglandin of the E type. Inhibition of prostaglandin synthesis with aspirin, indomethacin, or eicosa-5,8,11,14-tetraynoic acid induced a sustained contraction of the coronary artery, and pretreatment with indomethacin diminished markedly the output of prostaglandin into the bathing medium. It appears that prostaglandin E1, generated from within the vessel wall itself, may act as an intrinsic regulator of coronary artery tone in the beef heart, and that blockade of this function leads to vasospasm.


Endogenous acetylcholine release and labelled acetylcholine formation from [3H]choline in the myenteric plexus of the guinea-pig ileum.

The spontaneous release of acetylcholine (ACh) from the guinea-pig myenteric plexus - longitudinal muscle preparation superfused at a constant rate in the presence of physostigmine was 10 nmol-g-1-h-1. This release was decreased to one-third by tetradotoxin or by MnCl2 and increased 2.5 times by 0.1 Hz and 20 times by 16 Hz stimulation. The formation of [3H]ACh from [3H]choline increased from 3 to 33 nmol-g(-1)-h(-1) when the concentration of [3H]choline was increased from 1 muM to 50 muM. The rate of [3H]ACh formation was not affected by tetrodotoxin, MnCl2, or physostigmine in the absence of stimulation. It was increased by 50% by 0.1 Hz and by 100% by 16 Hz stimulation during the first 9 min of exposure to [3H]choline but not subsequently. The myenteric plexus - longitudinal muscle preparation contains 200 nmol/g choline. Results suggest that the apparent small [3H]ACh formation from low concentrations of [3H]choline is due to the dilution of [3H]choline by endogenous choline. The major part of [3H]ACh formation appears to be due to the intracellular turnover of ACh while the evoked release of [3H]ACh appears to originate from a small pool.


Roles of the AV junction in determining the ventricular response to atrial fibrillation.

The statistical properties of RR interval sequences during cholinergic atrial fibrillation were studied in anesthetized dogs both in control conditions and after the selective injection of dromotropic agents into the atrioventricular (AV) node artery. It was observed that RR interval histogram configurations depended mainly on the mean heart rate, regardless of whether it was a control or a post-injection sequence. The sequences were found to vary from almost regular at fast rates to highly irregular at slow rates, covering all intermediate possibilities. Since the injections of dromotropic agents into the AV node artery were carried out during sinus rhythm between the episodes of fibrillation, their influences on the AV junction, as reflected both on the length of the PR interval during sinus rhythm and on the RR interval dispersion during fibrillation, could be compared. The dispersion of RR intervals was found to increase as the PR interval duration became longer. In addition, it was observed that the generally random character of the RR interval sequences during fibrillation was not affected by the injection of dromotropic agents into the AV node artery. These results were interpreted as an indication that, for a well-established atrial fibrillation, the degree of ventricular irregularity (dispersion of RR intervals) is related to the conductivity within the AV junction and that the random character of RR interval sequences is related to the atrial fibrillatory activity itself.


Stability and biological activity of catecholamines and 5-hydroxytryptamine immobilized to sepharose and glass beads.

[14C]Noradrenaline, [14C]adrenaline, and 5-[14C]hydroxytryptamine were complexed to several types of Sepharose derivatives through an amide or a diazo linkage. Complexes were also made with arylamine glass beads through a diazo linkage. After the reaction the complexes were extensively washed with distilled water or dilute HCl or both, plus other solvents. Radioactivity appeared in the storage solutions and the amount increased with time. When initial low levels of release were achieved by extensive washing, the addition of a different solvent produced a marked increase in release. The biological activity of these complexes was tested on isolated rabbit aortic strips and rat fundus strips. All complexes caused the tissues to contract. The biological activity, however, closely paralleled the release of the ligands from the complexes and the release of ligand was demonstrated through the use of oil immersion and dialysis sac. These data do not support the recent claims that catecholamines bound to glass beads exert their pharmacological effects as covalently bound complexes on isolated tissue. The lack of stability of these complexes indicates the need for caution in drawing conclusions as to the site or the mechanism of action of immobilized catecholamines and other drugs.


Stress response patterns of plasma corticosterone, prolactin, and growth hormone in the rat, following handling or exposure to novel environment.

Corticosterone, prolactin, and growth hormone responses to 5 s of handling or 3 min of novel environment were compared in rats at crest and trough of the diurnal adrenal rhythm 0, 5, 15, 30, and 60 min after stimulation. All hormones responded to stimulation, corticosterone and prolactin with a dramatic rise, and growth hormone with a precipitous fall. Resting corticosterone levels evidenced the expected diurnal variation, and prolactin but not growth hormone also showed a baseline diurnal variation of small magnitude at the times studied. Growth hormone response characteristics were unaffected by time of day or type of stimulation. Both corticosterone and prolactin response profiles differed at both times of day and following both types of stimulation. Corticosterone and prolactin levels were highly correlated and each was negatively correlated with growth hormone levels. This study confirms that hormone responses to stress are complex and depend not only on the stimulus but the context of stimulation.


Organ distribution of 3-hydroxy-3-methylglutaric acid, a potential anticholesterolemic agent.

The distribution of radioactivity after oral administration of 3-hydroxy-3-[3-14C]methylglutaric acid has been studied by whole-body autoradiography in the mouse. The compound (a potential anticholesterolemic agent) was promptly and almost completely absorbed. Relatively high and persistent levels of radioactivity were seen in organs responsible for cholesterol synthesis, mainly liver and intestinal wall. Rapid and pronounced uptake of radioactivity was seen in the kidney and the time course of the level of radioactivity indicated that the kidney is not only the main excretory route of 3-hydroxy-3-methylglutaric acid but also represents an important site of distribution of the compound. Detectable uptake of radioactivity, mainly in the first phase, occurred also in the lungs, the salivary glands, the lacrimal glands, the skin, and the brown fat. Results obtained by autoradiography have been checked in part by direct measurement of radioactivity in individual organs and data obtained with the two techniques are in agreement.


The effect of glucagon on glomerular filtration rate in dogs during reduction of renal blood flow.

Glucagon in small intravenous (i.v.) doses markedly increases glomerular filtration rate (GFR) in normal anesthetized dogs. In this study, the effects of glucagon 5 mug/min (i.v.) on renal hemodynamics was tested in four canine models of acute pre-renal failure (hemorrhage, barbiturate overdose; renal arterial clamping and renal arterial infusions of noradrenaline) and in a model of unilateral acute tubular necrosis at 4 h and 6-7 days following completion of the ischemic insult. Following hemorrhage and barbiturate excess, with arterial blood pressure maintained at 65-70 mm Hg, whole-kidney GFR and clearance rate of p-aminohippurate decreased by 50-70%. During this reduction of perfusion pressure, the subsequent infusion of glucagon increased GFR by 90-130%. In models where arterial pressure was normal during the period of ischemia (clamping and noradrenaline infusion), not only did glucagon significantly increase renal perfusion, but the ischemic kidney proved to be far more sensitive to the hemodynamic effects of glucagon (delta GFR - 120-160%) than the contralateral control (deltaGFR = 30-40%). In three dogs completely anuric following renal arterial clamping, glucagon was able to improve blood flow and restart urine formation. Glucagon, but not dopamine, was able to simulate the beneficial effects of hypertonic mannitol on renal function in dogs with hemorrhagic hypotension. Glucagon was without effect in established acute tubular necrosis. This study, therefore, indicates that, during renal ischemia, glucagon may be quite effective in preserving urine output and perfusion of the kidneys.


The influence of chronic ethanol consumption on the distribution of thiopental in rats.

Ethanol was administered chronically for 14 days to male Sprague-Dawley rats. Day 15 was ethanol-free. On day 16 the rats received 25 mg of thiopental per kilogram (intravenously). One minute after the injection, the ethanol-treated rats showed lower blood levels of thiopental and higher liver levels of the drug than control rats given sucrose in place of ethanol. Samples of blood drawn 5 and 10 min after injection showed no significant difference in thiopental levels between the ethanol and control groups. The ethanol-treated group slept for a significantly shorter period of time. It is concluded that chronic ethanol consumption for 14 days decreases the pharmacological effects of thiopental and alters its initial distribution in the body.


In vitro production of prostaglandins by isolated aorta strips of normotensive and hypertensive rats.

When suspended in oxygenated Krebs solution at 37 degrees C, strips derived from thoracic aortae of spontaneously hypertensive rats maintain their initial intrinsic tone and release prostaglandin-like material in the suspending medium, while similar preparations from normal Wistar rats relax progressively and produce significantly smaller amounts of prostaglandins. Indomethacin, a potent antagonist of prostaglandin synthesis, has two major effects: it favors the relaxation of both strips of hypertensive rats and of normal rats; and it inhibits the accumulation of prostaglandin-like material in the suspending medium, as evaluated with a specific and sensitive biological assay (rat stomach strip or chick rectum). Carotid and femoral arteries taken from the same animals show similar differences as the aorta strips, with regard to the production of prostaglandin-like material. The generation of prostaglandin is markedly decreased by the absence of O2, while it is unaffected by the absence of the extracellular Ca2+. It is proposed that the absence of relaxation of aorta strips taken from hypertensive, compared to normal rats, is due to increased intramural synthesis and release of prostaglandins.


Evidence for sodium specificity of the receptors in the fourth cerebral ventricle affecting sodium excretion in the cat.

Perfusion of the fourth cerebral ventricle with artificial cerebrospinal fluid, made hypertonic by the addition of 0.89 M sucrose, resulted in no change in the rate of renal sodium excretion. These data lead us to conclude that the putative receptive field in the area of the fourth ventricle which is capable of affecting urinary sodium excretion contains elements that are sodium-specific


Morphine excitation in the cerebral cortex.

Microiontophoretic administrations of morphine to cholino-excitable neurones in the cerebral cortex of decerebrate cats evoked a weak excitation which became more prominent upon repeated administrations of the alkaloid. This effect was not antagonized by naloxone. Iontophoresis of methylatropine prevented the excitation induced with acetylcholine and morphine, leaving that caused by glutamate relatively unaltered. Similar applications of morphine to neurones which were not excited by test applications of acetylcholine did not result in excitation but elicited mainly a depression of glutamate-evoked firing. It is suggested that the muscarinic effect of morphine in the cortex may be related to the excitation and convulsions, but not the analgesia, which occurs upon systemic administrations of the narcotic.


Morphological responses of cerebral tissues to temporary ischemia.

The ultrastructural responses of cerebral tissue following temporary periods (1/2, 1,2,3, or 4 hour) of right, middle cerebral artery, (MCA) occlusion were studied acutely after a 3 day or 7 day interval following the removal of the MCA clip. Cortical and basal ganglia tissues for each ischemic duration were compared at 3 post-occlusive periods (acute, 3 days, 7 days). With the short periods of ischemic insult (1/2, 1, 2, 3, and 4 hour), the temporal and insular cortex contained no greater changes in the 7 day group than in the 3 day group. The basal ganglia were more susceptible to MCA occlusion as indicated by more marked cytological changes and/or necrosis in all intervals of ischemia.


The effect of diazepam on presynaptic inhibition in patients with complete and incomplete spinal cord lesions.

The effect of diazepam on presynaptic inhibition in man has been examined in 5 patients with complete spinal transections and 7 patients with incomplete lesions. The inhibition of the H reflex by vibration applied to the tendo Achilles was used to assess presynaptic inhibition of the Ia monosynaptic pathway. Diazepam increased this inhibition in the patients with incomplete lesions, but had no significant effect on the inhibition in the patients with complete spinal transections. Evidently diazepam can enhance presynaptic inhibition in man. The effect, however, cannot be demonstrated in patients with longstanding complete spinal lesions possibly because of some alteration in the segmental presynaptic inhibitory mechanism in this group.


Analysis of 128 patients with angiogram in acute head trauma.

A computerized analysis of 128 patients admitted with acute head injury and who underwent angiography is shown. Patients were divided into groups according to: age, sex, type of accident, state of consciousness and presence of localizing signs on admission, types of cerebral lesions on angiography, and discharge condition. There is a preponderance of young males in this series of patients, related mainly to MVA. A total of 71% of the patients had abnormal angiograms, but the incidence of normal and abnormal results did not correlate significantly with any of the chosen parameters. The same parameters were also analysed to assess their value as a prognostic index for the patient. The conclusion was drawn that the angiogram per se has no significant value as a prognostic tool, and that state of consciousness on admission is the best single index for prognosis.


Memory and growth in the superior temporal gyri.

The superior temporal gyri were measured in 33 infants and in 33 adults. In the adults, most right superior temporal gyri were larger. This asymmetry was not found in infants, a difference which suggests greater growth of the right superior temporal gyri in the population from which our sample was taken. The asymmetry may be related to the functional asymmetry found by Penfield: some of his patients reported re-experiencing of past sensory experiences with electrical stimulation of the temporal lobe. This response was more frequently evoked from the right hemisphere.


The nature of primary vocal tremor.

Three elderly women with marked progressive voice tremor, without other neurological symptoms, and negative family histories were investigated. All had a 4-5 Hz respiratory tremor in expiration and, to a lesser degree, in inspiration; and all had vocal tremulousness synchronous with their respiratory irregularity. Articulation of phonemes was normal. In two cases the neurological examination was otherwise normal; in the third case there was a minimal 71/2 Hz tremor in the left thumb and index finger. Simultaneous speech and vocal air pressure recordings, as well as cinematographic studies of the vocal apparatus and diaphragm were carried out. It is suggested that these cases represent primarily an action tremor of respiration, that they belong in the spectrum of essential tremor, and hence may be amenable to treatment with propranolol.


Clinical problems of motor system disease.

This prologue to a symposium of research studies on motor mechanisms is a general commentary by a clinical neurologist. The vast extent and intricacy of modern basic neurological scientific knowledge presents a rather bewildering challenge to reasonable clinical application. In some degree this is being handled by complex and diverse neurological subspecialization. It is recalled that many past advances in the knowledge of neurological disease were achieved by a series of alternating and supporting bedside and laboratory observations and studies.


Principles underlying new methods for chronic neural recording.

Chronic recording is possible from nerve fibers which have grown through holes in an insulating medium (regeneration electrodes) or which are enclosed by an insulating sheath (cuff electrodes). Use of three electrodes in a balanced configuration permits good rejection of electromyographic (EMG) signals and other sources of electrical interference (fluorescent lights, 60 Hz signals from the mains, etc.). Equations are derived and tested for predicting the amplitude and form of the signals expected for a given cuff length and diameter. These equations can be used to design electrode units optimally for a given application. Finally, the use of transformers permits the neural signals to be carefully matched to the recording apparatus and further optimizes the neural signal-to-noise and signal-to-EMG ratios. Use of these methods in several physiological and clinical applications, as well as potential abuses, are discussed.


The effects of motor cortical stimulation on the excitability of spinal motoneurons in man.

The pyramidal tract and particularly the direct cortico-motoneuronal components (DCM) have become increasingly important in the higher primates. Minimal single pulse precentral stimulation in man evokes EMG discharges from the contralateral hand muscles with a latency of 18-21 milliseconds. The excitability changes produced by such cortical stimulation on the upper limb H-reflex has been observed to include a short duration early facilitation probably corresponding to the DCM input and a later, longer lasting facilitation mediated by the same and probably other corticofugal projections. Potentiation of the H-reflex in the upper libs by means of postcentral excitation required much higher single pulse stimulus intensities and the changes in excitability produced on the spinal motoneurons could have been explained by physical extension of the stimulus current to the precentral region. Isometric contraction potentiated the H-reflex produced by combinations of precentral cortical and peripheral nerve stimulation but no direct evidence was found to support a possible transcortical basis for the V2 stretch reflex.


Physiological basis of cerebellar dysmetria.

A primary control system for the arm position is formulated. The hypothesis that the cerebellum is a part of the system controller is checked by studying the nerve cells responses in the cerebellum, and motor cortex, to natural activation of muscular receptors. The results show that the cerebellum receives feedback information related to the speed of these receptors. The discussion concentrates on how the interruption of this feedback may result in excessive oscillations to instability. These observations are the base for evaluating how the cerebral lesions produce dismeasurements.


Fracture healing.

The sequence of events occurring after fracture is now relatively well understood. Healing takes place in three phases--inflammatory, reparative and remodelling. In each phase certain cells predominate and specific histologic and biochemical events are characteristic. Factors that influence fracture healing are both local and systemic; the former include particularly the degree of local trauma and bone loss, the type of bone affected, the degree of immobilization and local pathologic conditions; the latter include age, hormones, local stress and electric currents. Natural processes of healing should be allowed to take their usual course and interference should be attempted only when there is demonstrable need or substantial advantages for the patient.


Hyperparathyroidism: evaluation of four decades of parathyroid surgery.

A review of 98 patients with hyperparathyroidism operated on at the University of Iowa during a 45-year period reveals a very great increase in the frequency of the clinical diagnosis. More patients are being operated on each year and more glands are being removed or biopsied. The proportion of patients in whom light microscopic examination of the parathyroid reveals hyperplasia remains less than 25%. Better methods are needed for identification of hyperplasia. Clinically, a few patients in whom the diagnosis of adenoma is made appear later to have more diffuse parathyroid disease. At present, however, when an adenoma is found, the decision to perform subtotal removal of apparently normal parathyroid tissue is made only reluctantly. The conclusion drawn from this review is that patients with hyperparathyroidism must be studied more intensively and followed for many years, whether or not an operation is performed. Although the diagnosis of hyperparathyroidism is now made readily and operative treatment seems to be more effective, much has yet to be learned about hyperparathyroidism.


Effect of sympathetic inhibition on maximal muscle blood flow in the normal and atherosclerotic human leg.

The control of blood flow in skeletal muscle is incompletely understood, and for this reason the effect of sympathetic inhibition on muscle blood flow in the leg was studied. One group of patients selected for study comprised 20 patients without evidence of vascular disease; a second comprised 20 with peripheral occlusive arterial disease, in whom the site of occlusion varied from the aorta to the lower leg arteries. None had undergone previous vascular surgery or sympathectomy. Variables studied included resting muscle blood flow; maximal muscle blood flow; interval from tourniquet release to onset of peak flow; duration of peak blood flow; muscle blood flow after tourniquet release; and skin temperature in the foot. Muscle blood flow was calculated from xenon-133 clearance. The variables were studied before and after ischemic (thigh tourniquet) and before and after sympathetic inhibition (immersion of hands and wrists in water at 45 degrees C). The significant differences between the two groups related to peak flow after ischemic exercise, the interval from tourniquet release to peak flow and duration of peak flow. Sympathetic inhibition was followed by no significant changes in maximal muscle blood flow, though there was a significant decrease in resting muscle blood flow. The results of the present study, in which noninvasive sympathetic blockade was used, confirm the findings of others that muscle blood flow does not change after operative sympathectomy.


TNM classification of malignant tumours of the bladder, prostate, testis and kidney.

TNM classification is a short description of a cancer at a point in its natural history--the onset of definitive treatment--and should be considered in planning treatment, in assessing prognosis, in evaluating end results, in facilitating the exchange of information between treatment centres and thus in contributing to the continuing investigation of human cancer. For four cancers of urologic sites there are new TNM classifications. Although previous classifications of bladder cancer were satisfactory, the new classifications for kidney, prostate and testis are the first internationally accepted classifications for these three organs that are clinically practical. Widespread use of these classifications is recommended.


Solitary epididymal schistosomiasis.

A 54-year-old Canadian presented with a 1-month history of painless swelling in the right testis. The diagnosis was thought to be a sperm granuloma, a leiomyoma, or an adenomatoid tumour of the epididymis; histologic examination, however, revealed evidence of schistosomiasis, probably due to Schistosoma haematobium. Solitary schistosomiasis of the epididymis has been reported previously in only two cases. Epididymal schistosomiasis has never been diagnosed preoperatively because it is so rare, but even if it were suspected preoperatively and confirmed by biopsy, chemotherapy alone would not prevent impairment of epididymal function due to scarring. Surgical excision of the lesion, therefore, is recommended.


Prognostic factors in multiple myeloma.

The effect of certain disease parameters on remission and survial time was evaluated in 482 patients with multiple myeloma treated with intermittent courses of melphalan-prednisone combinations. Increasing degrees of anemia, hypercalcemia, azotemia, and high serum myeloma protein levels were associated with progressive lifespan shortening. The short survival of patients with anemia and hypercalcemia was associated with short remissions in responding patients with these abnormalities. The extent of tumor mass was defined from specific laboratory parameters reported by Durie to be associated with large numbers of plasma cells. More advanced stages of myeloma were associated with higher frequencies and degrees of normal immunoglobulin depression. The response rate was not affected by the tumor mass grade, but increasing tumor mass was associated with a shorter lifespan. Greater degrees of tumor reduction were associated with longer remission and survival times. Patients in whom a marked tumor reduction was rapid had shorter survival and remission times than patients who responded more slowly.


A controlled study in the use of combined drug therapy for metastatic breast cancer.

Three prospectivelyly planned and controlled cooperative clinical studies in the use of combination drug therapy for metastatic breast cancer are reported. Each study contained two drug regimen arms.  A total of 326 evaluable patients were treated with one of the five various drug combinations employed. As the number of drugs used in each regimen was increased from two to five, a concommitant increase in remission rates from 50% to 75% was observed. Remission duration of approximately 8 months and survival from the onset of treatment, however, remained relatively constant at 13 to 16 months in all drug regimens. Patients achieving tumor remission survived an average of three times longer than those with progressive disease under therapy. The results are correlated to patient age and predominant metastatic type. Subjective improvement was definitely related to objective tumor regression or stabilization. Treatment was relatively well tolerated and well applicable to outpatient care. Dosage adjustments were often necessary during the initial phases of therapy. Combined cystostatic drug therapy is highly effective in the prognostically worst forms of metastatic breast cancer, and is the treatment of choice for younger patients with visceral type metastases.


A comparison of nitrogen mustard, vincristine, procarbazine, and prednisone (MOPP) vs. nitrogen mustard in advanced Hodgkin's disease.

A randomized study of patients with advanced Hodgkin's disease was designed to determine whether the improved therapeutic effectiveness of combination chemotherapy was due to the use of a combination of drugs or might be achieved with a single agent if given as intensively and for as long a period. A combination of nitrogen mustard, vincristine, procarbazine, and prednisone (MOPP) was compared with nitrogen mustard (HN2) alone. Treatment with both regimens was given to tolerance on cylic basis and was continued for six cycles of treatment. Sixty-one evaluable patients were treated with MOPP and 47 with HN2. The complete remission rate of 47.5% with MOPP was significantly better than the 12.8% with HN2 (p less than .05). Complete remission lasted a median of 15 months after MOPP and 12 months after HN2. The survival of patients initially treated with MOPP was significantly better than that of those initially treated with HN2.


Effects of cyclophosphamide and adriamycin on the healing of surgical wounds in mice.

Administration of therapeutic dose levels of cyclophosphamide as a single dose or as daily treatments for 5 days during the perisurgical period resulted in a significant decrease in the strength of surgical skin wounds in mice as measured 21 days after surgery. Administration of a single dose of 200 mg/kg either at the time of surgery or up to 4 days prior to or after surgery impaired 21-day wound strength, with the most extensive depression observed when the drug was given 1 or 2 days after surgery. Earlier stages of wound healing (day 3 or day 7) were not as sensitive to cyclophosphamide. Adriamycin in the therapeutic dosage range for mice did not significantly impair wound healing. This drug had an effect only at the LD10 dosage level. Combination treatment with cyclophosphamide plus adriamycin at the time of surgery impaired 21-day wound strength to a greater degree than observed with either agent alone, but did not significantly depress wound strength 3 or 7 days after surgery. These studies indicate that dosage level, the time of drug administration relative to surgery, and the time at which wound strength measurements are made are important parameters in determination of the effects of antineoplastic agents on wound healing.


Humoral and cell-mediated immune response in patients with malignant melanoma. I. In vitro lymphocyte reactivity to PHA and antigens following immunization.

In vitro lymphocyte function was evaluated in 61 patients with different clinical stages of malignant melanoma. Thirty-one of these patients had localized disease, 13 regional metastases, 10 distant lymph node or skin metastases, and 7 visceral metastases. Following immunization, in vitro lymphocyte reactivity to three antigens (diphtheria toxoid, tetanus toxoid and alpha-hemocyanin of Helix pomatia) was studied in the presence of autologous serum, in addition to lymphocyte reactivity to phytohemagglutinin (PHA). The relationship of these tests with the clinical stage and the subsequent course of the disease in a 6 months' observation period was determined. The patients with visceral metastases (7) had a lowered lymphocyte reactivity to PHA compared with controls and the patients with other stages, while they also had a low reactivity to the test antigens (only significantly lowered compared with patients with localized disease). All these patients showed tumor progression or died from metastatic disease. Between the other stages (54 patients) there was no difference in lymphocyte reactivity to the test antigens or PHA. No correlation between lymphocyte reactivity to PHA and the subsequent course of the disease could be demonstrated in these 54 patients. However, lymphocyte reactivity to the test antigens following immunization showed a definite correlation with the subsequent course. Sixty-four percent (9/14) of patients without any lymphocyte reactivity to the three antigens showed tumor recurrence or progression, against 3% (1/40) of patients with positive lymphocyte reactivity to one, two, or three antigens. A suppressive effect of autologous serum on lymphocyte reactivity could be found only in 1 of 20 patients with a low reactivity to PHA or antigens. It is concluded that defects in lymphocyte function are related to subsequent tumor growth in patients with malignant melanoma.


Efficacy of intralesional BCG therapy in guinea pigs with disseminated tumor.

It has been previously demonstrated that transplanted syngeneic tumors established in the skin of inbred (strain-2) guinea pigs regressed and regional lymph node metastases were eliminated after intralesional injection of viable Mycobacterium bovis (BCG). During the course of this reaction there is the development of tumor-specific immunity. This experimental model was further manipulated in order that it would more closely approximate a clinical reality. In the present study an evaluation was made of the effectiveness of the developing tumor-specific immunity in this BCG therapy model, to abrogate artifically induced distant tumor deposits and to assess the requirement for tumor-specific immunity in the local BCG-mediated tumor regression. During BCG-mediated regression of established intradermal tumor, the developing tumor-specific immunity inhibited the growth of artificially induced vascular metastases in animals receiving a 10(4) or 10(5) tumor cell dose. However, there is a direct causal relationship between the distant tumor burden and the escape of skin tumor and regional lymph node metastases from BCG-mediated regression. Thus, multiple tumor deposits as low as 10(4) cells are capable of competing for or preempting tumor-specific immune reactivity, which must be a requirement during some phase of the intralesional BCG-mediated therapy of established tumor and regional lymph node metastases. Thus, a significant therapeutic effect could be achieved in guinea pigs with established skin tumors and limited vascular metastases when the modality of therapy included BCG intralesional injection, followed 6 weeks later by surgery of the treated skin tumor and regional lymph node.


Regression of pulmonary metastatic disease associated with intralesional BCG therapy of intracutaneous melanoma metastases.

A 77-year-old white man with 64 intracutaneous melanoma metastases and a pulmonary metastatic deposit was treated with immunotherapy. Over an 8-month period, 17 intracutaneous lesions were inoculated with BCG. All 17 injected lesions and all 47 uninjected intracutaneous lesions resolved; no new nodules appeared and the pulmonary metastasis regressed (greater than 50%). This is the first documented case of a pulmonary metastatic focus responding to intralesional BCG therapy of intracutaneous metastases.


HL-A in cancer family "N".

Actual HL-A typing has been performed on 115 members of cancer family N, a large kindred (over 1000 members ascertained) showing the findings consistent with the cancer family syndrome. In the cancer-prone line (branches C and D) of the family, 20 of 21 members with cancer had one HL-A haplotype, HL-A2-HL-A12 (relative odds = 6.30), including some decreased family members who had haplotypes assigned. Eleven of 12 family members with cancer in branches C and D, actually typed, had HL-A2-HL-A12 (relative odds = 6.06). The single exception showing cancer and another haplotype in branch D is a child of a family member with haplotype HL-A2-HL-A12.


Concurrent monoclonal IGM and IGA proteins in lymphocytic lymphoma.

A case of lymphocytic lymphoma with monoclonal elevations of both IgA and IgM is described. The cytogenetic and immunoglobulin findings in this case suggest that the cells producing the abnormal elevated proteins were different cells that appeared to be derived from a common percursor cell.


The platelet in leukemic reticuloendotheliosis. Functional and morphological evidence of a qualitative disorder.

Platelets were studied in a group of 10 patients with typical clinical course, morphological findings, and specific histochemical criteria for leukemic reticuloendotheliosis. In 8 of these, marked qualitative abnormalities were found. These included lack of aggregation following epinephrine stimulation (6 patients), and decreased platelet factor 3 availability following ADP stimulation (4 patients). In addition, platelets in 4 of the 10 patients were studied by electron microscopy. All had granular abnormality, and 1 case showed the presence of rough-surfaced endoplasmic reticulum. The functional and ultrastructural abnormalities of platelets reported here may be responsible for the clinically important bleeding episodes which were not attributable to thrombocytopenia in 2 of our patients. The findings also provide a clue to the basic nature of this histogenetically controversial malignancy.


Malignant lymphoma after diphenylhydantoin (dilantin) therapy.

A history of prolonged diphenylhydantoin (Dilantin) therapy was reported by 8 of 516 patients (1.6%) with Hodgkin's disease or non-Hodgkin's lymphoma, as compared with 3 of 516 patients (0.6%) with other cancers, and 2 of 516 (0.4%) tumor-free individuals. The findings, together with other published data, suggest a small excess risk of malignant lymphomas in patients receiving long-term treatment with this drug. The immunosuppressive effects of chronic diphenylhydantoin therapy may be involved in the pathogenesis of these neoplasms.


Papillary meningioma: a malignant variant of meningioma.

A series of 17 meningiomas histologically characterized by a papillary pattern is reported. This pattern was invariably associated with other histologic features of malignancy. The tumors often displayed aggressive clinical behavior marked by a high rate of local recurrence or the development of distant metastases. A relatively large proportion occurred in children. It is suggested that this variant of meningioma is sufficiently characteristic to justify its separation as a distinct clinicopathologic entity.


Malignant peritoneal mesothelioma after cholangiography with thorotrast.

Reported is a 59-year-old patient, who died of a peritoneal mesothelioma 36 years after contamination with thorotrast of the peritoneal cavity during cholangiography at cholecystectomy. Eleven years before death, the right kidney had to be removed for hydronephrosis due to fibrous stenosis of the pyeloureteral junction, because of thorium dioxide deposits.


Leukoplakia revisited. A clinicopathologic study 3256 oral leukoplakias.

During a 13-year period, 3256 specimens clinically diagnosed as leukoplakia (('keratosis," "white patch") were submitted to the oral pathology laboratories of Indiana University School of Dentistry and Emory University School of Dentistry. These comprised 6.2% of the tissue specimens processed by these laboratories. The cases were analyzed as to age of occurrence, site of involvement, and pathologic findings. It was found that: leukoplakia occurs chiefly in the 5th, 6th, and 7th decades; about half of the lesions involved the mandibular mucosa, mandibular sulcus, and buccal mucosa; leukoplakia was slightly more common in men (54.2%). Microscopic study showed that 80.1% of the leukoplakias were varying combinations of hyperorthokeratosis, hyperparakeratosis, and acanthosis without evidence of epithelial dysplasia. Mild to moderate epithelial dysplasia was noted in 12.2% of specimens, and severe epithelial dysplasia or carcinoma in situ was found in 4.5%. Infiltrating squamous cell carcinoma was diagnosed in 3.1% of specimens submitted with a clinical diagnosis of leukoplakia. The risk of epithelial dysplasia, carcinoma in situ, or carcinoma varied between the anatomical locations of leukoplakia. The incidence of epithelial alteration, ranging from dysplasia to carcinoma, was 42.9% for lesions of the floor of the mouth, 24.2% for tongue lesions, and 24.0% for lip leukoplakias. The incidence of similar epithelial alterations in other sites varied from 18.8% for palatal lesions to 11.7% for leukoplakias of the retromolar area. The data suggest that there are regional differences in the incidence and character of leukoplakia in the United States. The Emory material, obtained almost exclusively from patients residing in the Southeastern United States, showed a proportionately higher total incidence, a lower male/female ratio, and a greater frequency of epithelial dysplasia, particularly in females, than the Indiana material, which came almost entirely from residents in the Northcentral United States.


Autogenous leukocyte migration in human malignancies.

The leukocyte migration test (L.M.T.) was utilized for in vitro study of cell-mediated immunity in human malignancies. Tumor cells and autogenous peripheral blood leukocytes from 35 patients with various malignancies, who were not receiving any therapy, were studied. There was inhibition of the migration of the autogenous leukocytes in 18 of 20 patients with resectable tumors who had no evidence of hematogenous metastasis or widespread disease, whether the local lymph nodes were involved or not. However, the migration of autogenous leukocytes from patients with hematogenous metastasis or widespread disease was not inhibited in 14 of 15 patients whether the tumor cells were obtained from the primary or metastatic sites. The utilization of fresh, frozen-thawed (dead) tumor cells, or tumor cell extracts gave almost the same results. This could indicate that localized tumors were recognized as antigenic by the presensitized autogenous leukocytes, resulting in the inhibition of the migration. This state seemed to disappear in the presence of hematogenous metastasis. Normal tissues did not inhibit the migration of the autogenous leukocytes, presumably because these had not been recognized as foreign or antigenic.


Ultrastructural study of amyloid material in the calcifying epithelial odontogenic tumor.

A typical calcifying epithelial odontogenic tumor of the maxilla was examined with the electron microscope. The tumor cell resembles the ameloblast at an early stage of enamel deposition. Formation of extracellular amyloid masses probably proceeds both by active cellular secretion and cell death, each process adding similar granulofibrillar material to these masses, which tend to calcify. The amyloid masses are probably a relatively homogenous protein material and represent a specific tumor cell product. Further characterization of this neoplasm must include chemical and physical studies of this extracellular tumor product, which is an amyloid material because of classic staining characteristics.


Burkitt's lymphoma cell leukemia in a Turish boy.

Burkitt's lymphoma, associated with massive bone marrow and eyelid involvement that terminated with a manifested leukemic picture, was observed in a Turkish boy. Review of the world literature revealed the fact that Burkitt's lymphoma with a frankly leukemic picture is a rare condition, and usually has a very acute course with a poor prognosis.


Urinary cholesterol. VII. The significance of the excretion of nonesterified cholesterol in patients with uterine carcinomas.

The urinary excretion of nonesterified cholesterol (NEC) in 170 women with cervical and endometrial carcinomas has been investigated. Control patients (236) included: 1) women with other types of (benign and/or malignant diseases of the pelvic organs; 2) patients with non-steroid-related neoplasms; 3) patients with benign and/or malignant breast diseases other than carcinoma; and 4) patients with a variety of non-neoplastic diseases. NEC was determined by a gas-liquid chromatographic procedure. The range of NEC excretion for clinically healthy normal women (64) was previously established by this method. NEC hyperexcretion was defined as any NEC value over 1.5 mg/24 hours. The results showed NEC hyperexcretion in 65 of 68 women with active carcinoma of the cervix, including 13 patients with carcinoma in situ, and in 42 of 45 women with active carcinoma of the endometrium. In contrast, a normal excretion of NEC occurred in all the patients (77) of the first and second control groups, in 39 (80%) of the 48 patients of the third control group (high-risk group), and in 101 of the 111 patients of the fourth control group. Sequential studies performed in patients with uterine carcinomas have demonstrated an almost perfect correlation between the NEC excretion and the clinical status of the patient following surgical and/or radiation therapy. Of 57 patients (31 cervix and 26 endometrium) in which the NEC studies were started after treatment was instituted, 53 have normal NEC excretion in the multiple determination performed to date. Presently these patients have no clinical, chemical, or radiologic evidence of cancer. It is concluded that urinary NEC determination can be used as an additional diagnostic biochemical test to detect active carcinoma of the steroid-producing glands and their main target organs, and that in women with uterine carcinomas, the test can be used as an objective laboratory method to monitor the course of the disease and the response of the patient to therapy.


Plasmacytoma of the testis. Report of a case.

An unusual case is described of plasmacytoma of the testicle occurring in the absence of bone lesions, multiple myeloma, or immunoglobulin abnormalities.


Microscopic pulmonary tumor emboli associated with dyspnea.

A syndrome is described in which severe, clinically unexplained dyspnea is found at autopsy to be caused by multiple microscopic tumor emboli. Such a situation was found in 8 of 16 cases of multiple microscopic tumor emboli in the pulmonary arteries without significant lymphatic or parenchymal involvement of the lungs. The origins oftumor emboli included carcinomas of the prostate, breast, stomach, pancreas, and liver. In the 8 cases that presented with unexplained dyspnea, initial physical, roentgenographic, and electrocardiographic examinations were not diagnostic. Clinical or morphological evidence of car pulmonale was pre emboli did not invade the walls of pulmonary vessels but were frequently associated with thrombi. Recognition of this clinicopathologic entity becomes important as progress is made in cancer therapy.


Measurement of urinary CEA-like substance. An aid in management of patients with bladder carcinoma.

Urine and serum samples from patients with bladder carcinomas were studied for the occurrence of and variations in CEA content before, during, and after radiation therapy. The concentration of CEA-like substances in urine increased with a more advanced clinical stage of the tumor, although there were large intercase variations. In serum, slightly increased values were noted only in advanced cases. During radiation therapy, high CEA values were found at around mid-course. This could be related to a breakdown of tumor tissue. Judging from data for urine from radiation-treated prostatic carcinomas without known tumors in the bladder, radiation alone was not responsible for the elevation of CEA. Urinary infections contributed to raised levels of CEA-like substances in some cases. At the end of successful radiation therapy (as verified by cystoscopy, cytology, and clinical examination), 25 patients had CEA values in the urine comparable to normal values (14 +/- 7 ng CEA/ml). The decrease was significant from the initial values to those after radiotherapy (p less than 0.01). Four patients whose tumors persisted had high values (68 +/- 46 ng CEA/ml). In patients who had previously received radiation treatment for bladder carcinomas, CEA values were high in 20 with recurrences (58 +/- 36 ng CEA/ml) while they were lower in 13 who were free of recurrence (14 +/- 6 ng CEA/ml). These findings indicate that urinary CEA determinations may be used in the immediate followup and management of patients treated for bladder carcinoma. It also appears to be of prognostic significance.


Thermographically measured normal skin temperature asymmetry in the human male.

The detection of thermal asymmetry may lead to the diagnosis of significant disease states, especially those of a neoplastic or vascular nature. Estimates of acceptable thermal asymmetry have been made; thermal asymmetry has not previously been quantified in normal subjects. In 10 normal male volunteers, ages 17-38, thermal difference between symmetric areas of the chest, abdomen, and back never exceeded 1 degrees C. Statistical treatment of these data suggests that thermal differences in excess of this in the male are abnormal.


Pleural effusion in cancer patients. A prospective randomized study of pleural drainage with the addition of radioactive phsophorous to the pleural space vs. pleural drainage alone.

Sixty-seven patients with disseminated cancer were randomly allocated to treatment with continuous closed chest drainage removing all fluid for 72 hours (PD) or pleural drainage for 72 hours with the instillation into the pleural space of radioactive colloidal chromic phosphate (PD + 32P). Forty-nine patients had breast carcinoma, and the remaining 18 patients had other cancers. Four of 49 patients with breast cancer and 13 of 18 with other cancer were dead in 8 weeks from the onset of effusion. In the group of patients with breast cancer PD + 32P controlled the effusion in 12 of 22 (54%) and PD alone in 15 of 30 episodes (50%). In the nonbreast group of patients PD + 32P controlled the effusion in five of six evaluable episodes (83%), and PD alone was successful in two of nine (22%). In 33% of breast cancer patients and 25% of the nonbreast-cancer patients, systemic chemotherapy produced objective remissions. Pleural effusion did not recur in any of these patients.


Carcinoid tumors of the appendix in children.

Carcinoid tumors of the appendix in 30 children younger than 15 years showed no recurrence with up to 24 years' followup, regardless of size, depth of invasion, or presence of perineural involvement. All were treated by appendectomy. Twenty-three of the tumors were in girls, confirming the female preponderance reported in other series.


Chemical assay for the antitumor agent inosine dialdehyde (NSC-118994) in biologic fluids.

Inosine dialdehyde, an antitumor agent highly active against several murine tumors, ispresently undergoing clinical trial for potential activity in man. To aid in the clinical evaluation of this drug, a chemical assay has been developed for the determination of concentrations of inosine dialdehyde in biologic fluids. The method involves reaction of inosine dialdehyde with phenylhydrazine in an acetic acid medium, followed by extraction of the product into ether and determining its absorbance at 378 nm. The reaction is specific for free inosine dialdehyde and will quantitate amounts as low as 1.0 mug.


Enhancement of the effectiveness of daunorubicin (NSC-82151) or adriamycin (NSC-123127) against early mouse L1210 leukemia with ICRF-159 (NSC-129943).

The LD50 of intraperitoneally (ip) injected daunorubicin in nonleukemic mice (1.8 mg/kg, q4d times 3) can be increased several fold by the concomitant ip injection of ICRF-159. In addition, the survival of leukemic mice treated with daunorubicin and ICRF-159 on Days 1, 5, and 9 after ip inoculation of L1210 tumor cells was substantially greater than after treatment with either drug alone. This potentiation of survival with combination treatment usually occurred with doses of daunorubicin greater than the LD50 of daunorubicin alone. The LD50 of subcutaneously (sc) injected daunorubicin alone (14.0 mg/kg, q4d times 3) was not increased by concomitant ip treatment with ICRF-159. However, when leukemic mice were treated sc with daunorubicin and ip with ICRF-159 on Days 1, 5, and 9 after ip injection of L1210 leukemia cells, survival was greater than with treatment with either drug alone. The toxicity of ip injected adriamycin was not reduced by ICRF-159, but treatment of leukemic mice with this combination was more effective in prolonging survival than treatment with either drug alone. Combination treatment with daunorubicin plus ICRF-159 showed much less therapeutic enhancement against sc implanted L1210 leukemia than against the ip implanted tumor.


Effects of levamisole (NSC-177023) and tetramisole (NSC-102063) in experimental tumor systems.

Levamisole and tetramisole had no antitumor effect against the following transplantable syngeneic murine tumors: L1210 leukemia, P388 leukemia, B16 melanoma, Madison 109 lung tumor, and Lewis lung carcinoma. In the Lewis lung carcinoma system there was no effect on primary tumor growth, metastasis, or survival. Tetramisole had a variable effect on the growth of rhabdomyosarcomas and the survival of BALB/c mice following intramuscular inoculation of Moloney sarcoma virus. In two experiments treatment with tetramisole either prior to or following inoculation of Moloney sarcoma virus increased the number of mice with tumor regression as opposed to progressive tumor growth, incrneased the number of long-term survivors, and prolonged the lifespan of mice that died of tumor. In two further tests neither levamisole nor tetramisole had an effect in this system. In mice immunosuppressed with cyclophosphamide prior to virus inoculation, there was not effect of treatment with levamisole or tetramisole.


Toxicologic screening of daunorubicin (NSC-82151), adriamycin (NSC-123127), and their derivatives in rats.

The cardiotoxicity of seven anthracycline antibiotics was evaluated in small groups of rats treated with repeated intraperitoneal injections. The electrocardiogram showed a widening of the QRS complex often with the appearance of a distinct S-wave trough and occasionally with an increase or flattening of the T wave. Ventricular extrasystoles, intraventricular block, bradycardia, and heart failure developed either during treatment or after discontinuation of therapy. Based on the cumulative dose required to induce significant electrocardiographic changes, the compounds were ranked in the following order of decreasing cardiotoxicity: adriamycin, daunorubicin, NSC-149584, rubidazone, NSC-143496, daunomycin-semicarbazone, and NSC-118714. For three of these compounds used in humans (adriamycin, daunorubicin, and rubidazone) the rat screening results are in good agreement with the clinically observed cardiotoxicity.


Potential biologic markers in Burkitt's lymphoma.

Specific biochemical molecules used as potential biologic markers, including modified nucleosides, polyamines, and pyrimidine catabolic end-products, were quantitatively measured in the urine of seven patients with Burkitt's lymphoma before, during, and after one or more courses of therapy. The results of this preliminary study demonstrated that patients with this disease frequently excrete significantly increased amounts oof modified nuceleosides (considered to be derived primarily from transfer ribonucleic acid), polyamines, and beta-aminoisobutyric acid during the course of their disease. With successful treatment and rapid destruction of tumor cells, a concomitant rise in these molecules occurs. Elevations were observed prior to chemotherapy and changes in levels associated with treatment or tumor progression appeared to correlate with disease status and to aid in assessing antitumor response. Periodic follow-up analysis of these molecules may be helfful in appraising relapse or recurrence of the malignancy prior to overt evidence of tumor by existing clincial means.


The effect of noradrenaline, adrenergic blocking agents, and tyramine on the intrarenal distribution of blood flow in the baboon.

The intrarenal distribution of blood flow in the baboon was measured using the 133xenon clearance technique, and dose-response curves for the various components of renal blood flow were determined during intra-arterial infusions of noradrenaline; the alpha-adrenergic blocking agent, phenoxybenzamine; the beta-adrenergic blocking agent, propranolol; and tyramine which causes the release of endogenous NA. High doses of noradrenaline reduced flow in the outer cortex; this effect was attenuated by phenoxybenzamine, but not by propranolol. Tyramine had no effect. These r results suggest that there are alpha-adrenergic receptors in the resistance vessels of the kidney but are inconsistent with an important role for NA-mediated autonomic control of renal blood flow.


Preliminary pharmacokinetic model for adriamycin (NSC-123127).

The systematic chemical control of cancer requires a quantitative knowledge of the pharmacologic disposition of antitumor drugs in both healthy and malignant tissues in the body. Pharmacokinetic models can predict the drug concentration in both tumor sites and healthy organs and hence may provide a predictive capability regarding both antitumor action and concomitant toxicity. Adriamycin is an anthracycline antibiotic that has been demonstrated to possess a broad spectrum of antitticularly solid tumors. Its major toxicity is manifested by the depression of normal cell proliferation in the bone marrow and a delayed dose-dependent cardiac toxicity eventually resulting in congestive heart failure. This study is concerned with the development of a predictve analytic model for the pharmacokinetics of adriamycin. The analytic approach embodies a physiologic multicompartmental model as a framework. This model postulates that specific organs or tissue masses may be simulated by a compartment whose elements consist of physiologic properties such as tissue volume and blood flow and pharmacologic behavior such as tissue binding and metabolic activity. A mass balance is set up across each compartment and all compartments are linked by an independent blood compartment. The mass balance includes terms representing inflow and outflow of the drug as well as its metabolism, protein-binding, and other pharmacologic behavior. A model has been developed that has ten compartments which represent the plasma, heart, liver, kidney, lung, lean tissue, adipose tissue, gut, bone marrow, and spleen. Solutions of the system of equations yield the time course of the drug in each organ. Predictions of adriamycin concentration-time curves in the ten tissues after intravenous (iv) administration were generated using this model. With few exceptions, agreement between predicted and actual tissue data in rabbits was excellent. Human plasma levels of adriamycin were predicted and comparison with patient data demonstrated a reasonable first approximation.


Plasma renin activity during and after dynamic and static exercise.

The effect of dynamic and static exercise on plasma renin activity was investigated in three normal males. Near maximal supine exercise for 10 min on a bicycle ergometer caused a small increase in plasma renin activity during exertion with a much larger increase during recovery which reached a peak between 10-20 min. Supine exercise at half this level and static exercise (hand-grip) had no detectable effect on plasma renin activity.


Continuous measurement of left ventricular volume using a single dimensional transducer: a comparison of two techniques in open chested dogs.

A comparison has been made of the continuous measurement of left ventricular volume in open chested dogs by two simple dimensional transducer systems: a mercury-in-rubber strain gauge measuring epicardial arc length at the ventricular equator and a pair of electromagnetically coupled coils placed on opposite sides of the left ventricle to measure its diameter. The single dimensional measurements were converted to volume measurements after death by filling an intraventricular ballon with known volumes of liquid. The strain gauge proved clearly superior to the coupled coils because it was not possible in practice to position the coils precisely facing each other and they did not remain tangential to the epicardial surface throughout the cardiac cycle. A single epicardial strain gauge can provide sufficiently accurate measurements of left ventricular volume to warrant its use in physiological studies of cardiac function. Although considerable attention to detail is required this technique has the advantages of being inexpensive and producing a continuous record which is easily interpreted.


Some fundamental considerations of the applications of pharmacokinetics to cancer chemotherapy.

The purpose of this paper is to document the procedures needed to construct pharmacokinetic models based on physiologic, physicochemical, and pharmacologic principles. Extensive descriptions of the basic ideas are provided, along with the corresponding equations. The notions of scaling between various animal species will be described and examples will be given. The important factors determining the choice and number of compartments are based on the properties of the drug and the desired purposes of the pharmacokinetic model. The important concept of flow-limiting conditions with regard to local uptake will be described. The quantitative description of plasma and tissue binding is discussed, along with the notion of effective protein concentrations for the latter. Using these basic ideas, the fundamental mass balances describing the flow, diffusion, and reactions of the drug are presented. An example of the prediction of the pharmacokinetics of a strongly bound drug is used as an illustration of the methods, and this example also indicates the types of useful simplifications that can be made. The special, but important, case of linear binding is next derived, and an example involving the drug methotrexate will illustrate the principles involved. Finally, cytosine arabinoside will be used to indicate methods that can be used for rapidly metabolized drugs. Since existing examples are primarily utilized, this paper brings together a comprehensive collection of the several sets of physiologic data and modeling techniques that have been used for the past several years. It is hoped that this documentation will provide a useful basis for the those wishing to use this approach to pharmacokinetics.


Mathematic models for cancer chemotherapy: pharmacokinetic and cell kinetic considerations.

This paper presents a theoretic study of pharmacokinetic and cell kinetic models for cancer chemotherapeutic systems. The mathematic analysis is based on a modified procedure deduced from DeVita's scheme of the relationship between the cellular kinetics of normal and tumor tissues and the pharmacokinetics of antitumor agents for designing an optimal dose and schedule for cancer treatment. In this scheme pharmacokinetic models and cell-drug interactions at the tumor site are incorporated into the cell cycle kinetic models to form the cancer chemotherapeutic model systems. Three cell cycle kinetic models are presented under alternative hypotheses concerning the mechanism of the resting cells, while each tumor mass is comprised of cells in proliferating (consisting of the four cycle phases G1, S, G2, and M), resting (Go), and non dividing (D, dead) states. An algorithm and a computer program for simulating the tumor populations during scheduled treatments have been prepared. By a suitable selection of expressions for cell-drug interactions, the program is able to simulate tumor behavior during scheduled treatments with different classes of anticancer agent such as cell cycle phase-specific, cell cycle-specific, or cell cycle-specific, or cell cycle-nonspecific drugs. A preliminary study of the L1210-ara-C therapeutic system is included to demonstrate the computer simulation procedures.


Quantitative evaluation of postectopic beats in the normal and failing human heart using indices derived from catheter-tip manometer readings.

Postextrasystolic potentiation was studied by means of a catheter-tip manometer in patients with and without cardiomyopathy. The results imply that the enhancement of the left ventricular contraction is increased in patients with cardiomyopathy.


Stress-induced and sympathetically-mediated electrocardiographic and circulatory variations in the primary hyperkinetic heart syndrome.

As shown by the inotropic changes, the sympathetic discharge on the heart, is selectit syndrome. In the steady state the electrocardiogram shows flat, diphasic, or "tucked' T waves. Mental stimulation or isoproterenol, and, respectively, pain or beta blockade induce changes of the repolarization phase divergent from steady state. The former causes ST depression and deep T-wave inversion and the latter fully normalizes the repolarization phase. It is concluded that the electrical activity of the heart is directly influenced by the adrenergic drive in this disorder, and that different stressful factors can alter the repolarization phase in opposite ways in relation to the influence of the stimulus on the cardiac sympathetic tone.


Calcium-induced damage of rat heart mitochondria.

The damage which may be caused to heart mitochondria by the rapid uptake of calcium when oxygen is restored after a period of anoxia is monitored by the deterioration in phosphorylation performance. Methods of protecting mitochondria from this damage by preventing calcium uptake and by chelating cytoplasmic calcium are considered.


Myocardial function in general and regional left ventricular ischaemia in dogs at control and high aortic blood pressure.

End-diastolic dilation and reduced systolic shortening are the characteristic dimensional changes during myocardial ischaemia. Elevation of systolic aortic blood pressure by 5.3 kPa (40 mm Hg) normalized shortening and reduced myocardial dilatation when the tissue rendered ischaemic by coronary artery occlusion was less than 20% of the left ventricle. However, when the ischaemic lesion was more extensive, an adverse effect of raising aortic blood pressure was observed.


Effects of dopamine on isolated canine coronary arteries.

Dopamine contracted isolated canine coronary arteries at initial concentrations of 5 times 10(-6) mol/l. In the presence of phentolamine or phenoxybenzamine and after contraction of the arteries with K+ or prostaglandin F2alpha, dopamine caused dose-related relaxation at initial concentrations of 5 times 10(-6) mol/l and 10(-6) mol/l. Propranolol, 10(-6) mol/l, and haloperidol, 10(-5) mol/l, did not antagonize the relaxation.


The feasibility of detecting His-bundle activity from the body surface.

Electrocardiograms were recorded from human patients using a bipolar chest lead together with simultaneous His-bundle electrograms. These were then subjected to the technique of signal averaging in an attempt to extract His-bundle activity from the surface record. This was successful in three out of 10 cases subjected to the truly non-invasive surface technique. Methods are discussed by which the technique could be improved.


Influence of hypertonic mannitol on regional myocardial blood flow and ventricular performance in awake, intact dogs with prolonged coronary artery occlusion.

The influence of hypertonic mannitol on regional myocardial blood flow and ventricular performance in awake, intact, unsedated dogs with myocardial infarction resulting from chronic occlusion of the proximal left anterior descending coronary artery was studied. tmannitol given to increase serum osmolality 20 mOsm increased regional myocardial blood flow to that portion of the left ventricle supplied by the occluded left anterior descending coronary artery by 22 +/- 2.8% (1.06 +/- 0.19 to 1.36 +/- 0.23 ml/min with g-1) without changing the inner:outer wall flow ratio. Mannitol also significantly increased regional myocardial blood flow to other areas of the left ventricle and the ventricular septum. Mean aortic pressure, maximal LV dP/dt, LV dP/dt/P, and cardiac output also increased significantly after mannitol. Thus hypertonic mannitol increases regional myocardial blood flow and ventricular performance in the awake, unsedated dog with prolonged occlusion of the proximal left anterior descending coronary artery. The increase in regional myocardial blood flow after mannitol under these circumstances probably is at least in part secondary to the increase in blood pressure and contractility. The increases in regional myocardial blood flow after mannitol in this study are less impressive than those that have been previously reported in the setting of either no myocardial ischaemia or acute myocardial ischaemia; this is probably due to the vasodilatation that chronic myocardial ischaemia itself produces in the canine heart.


A statistical prognostic study of pump failure in acute myocardial infarction.

Repeated measurements of maemodynamic status were made and were subsequently subjected to analysis to assess prognosis in a group of patients with acute myocardial infarction and pump failure. Two multivariate methods were used: correspondence analysis and discriminant analysis. Both these methods agreed with the highest prognostic reliability of left ventricular function indices. Using various discriminant functions a prospective study was carried out on a test sample and a rate for well-classified subjects ranging from 80% to 90% was obtained. For each discriminant function the different causes of misclassification were analysed; among them a right ventricular dysfunction was allowed to account for discrepancies between expected and observed data on inferior infarction.


A simplified technique for the production of experimental aortic regurgitation.

A simple and effective method for the production of aortic incompetence in dogs is described. The instrument used in the procedure can be made easily and is robust. Controlled rupture of one or more of the three aortic valve cusps can be achieved without thoracotomy. There was no immediate operative mortality in the study and the time required to complete the procedure averaged 30 min. No evidence of healing of the cusp rupture could be found at necropsy even in dogs sacrificed 480 days after operation.


A new method for the direct estimation of blood oxygen content.

Identical blood samples were estimated for oxygen content by a fuel cell analyser (the "Lex-O2-Con'), and by the Van Slyke manometric technique. The new instrument was found to be accurate and repeatable, as well as quicker and easier to operate. Its response to oxygen was found to be unaffected by the presence of common anaesthetic agents.


Recovery of brain noradrenaline after 5,7-dihydroxytryptamine-induced axonal lesions in the rat.

Time-dependent changes in regional CNS noradrenaline (NA) concentration, 3H-NA uptake and fluorescence morphology of CNS NA neurons were analysed in the adult rat up to 6 months after intraventricular injection of 5,7-dihydroxytryptamine (5,7-DHT), and compared with the time-course of changes in brain and spinal cord indolamine neurons. Following a substantial depletion of both amines in all CNS regions (telodiencephalon, brainstem and spinal cord) at 10 days after 150 mug 5,7-DHT, brain NA--but not 5-HT--levels recovered to near-normal values in brainstem and forebrain (35% below the age-matched controls) within 4 months. This was accompanied by a total restoration of the initially decreased capacity of the brain tissue to accumulate 3H-NA in vitro. Within 10 days after 5,7-DHT, there was a disappearance of NA terminals from many telencephalic, diencephalic and lower brain stem nuclei, from the cerebral and cerebellar cortices, and the grey matter of the spinal cord, concomitant with the appearance of numerous distorted, highly fluorescent swellings along the non-terminal axons of the major noradrenergic projection pathways. The recovery of the NA levels was paralleled by a re-appearance of fluorescent fibres, signifying an intense sprouting and regrowth of the drug-lesioned axons, which eventually re-innervated some of the previously denervated telodiencephalic regions. Except for a permanent loss of some surface-near perikarya in group A1 (the main source of the bulbospinal projections) there was no evidence of a retrograde degeneration of noradrenergic cell bodies in the rat CNS. The results are compatible with the idea that 5,7-DHT mainly causes a lesion of NA axons at a distance from the cell bodies, and this is followed by sprouting and regrowth of axons from the lisioned neurites, and formation of new terminal-like fibres in some previously denervated telodiencephalic regions. These findings indicate that chemical axotomy of central NA neurons induced by 5,7-DHT is--in contrast to that induced by 6-hydroxydopamine--followed by extensive axonal regeneration.


Electron microscopic observations on the innervation of the sphincter of Oddi in the dog.

The ultrastructure and acetylcholinesterase activity of the intrinsic innervation of the sphincter of Oddi of eight adult dogs was studied by electron microscopy. A rich distribution of unmyelinated axons embedded individually or as groups within Schwann cell cytoplasm ("innervation fasciculee"), is to be observed. A few myelinated fibres were also observed. Many of the axons are acetylcholinesterase-positive. Three main types of nerve terminals are distinguished according to their vesicle populations. Individual nerve cells or small groups of nerve cells were scattered between the smooth muscle bundles and in the lamina glandularis mucosae. The cytoplasm of some neurons contains many electron dense spherical bodies resembling "myeloid bodies", and many lysosomes. Nerve terminals synapse onto both neuronal perikarya and their dendrites. Within the nerve fascicles, close appositions between the terminals occur frequently probably representing the most peripheral inter-neuronal integrative link in the neural regulation of the function of the sphincter of Oddi. -- The gap between nerve terminals and smooth muscle cells usually measures several thousands of A. Closer appositions are seldom seen, and no synaptic complexes can be observed.


Lymphocyte capping and lymphocyte migration as associated events in the in vivo antigen trapping process. An electron-microscopic autoradiographic study in the spleen of mice.

The fate of 125I labeled antigen-antibody complexes in the first two hours after intravenous injection was followed in the spleen of mice by light and electron microscopic autoradiography. It appeared that AAC were phagocytized by granulocytes and by macrophages in the marginal zone and were present over the surface of lymphocytes in that area. By rinsing the spleen before fixation it could be shown that AAC were indeed bound to the lymphocyte membrane and not merely present in the blood plasma between the cells. The label was present in a spotty fashion or over a so-called uropod. The majority of labeled uropods (13 out of 17) pointed away from the follicle. From this it was inferred that these lymphocytes moved to and most probably into, the follicles. Inside the follicles, at 1 hour post injectionem, most of the label was associated with interfaces between lymphocytes. At 2 hours post injectionem there was a preferential localization over interfaces between lymphocytes and dendritic reticulum cells. It is conceivable that antigen that is introduced into the circulation is ultimately presented to dendritic reticulum cells in a complexed form with antibody, probably with complement, and with the B-cell receptor, since receptor shedding is a normal event following capping.


Identification of neurophysin producing cells. III. Immunohistochemical demonstration of neurophysin I-producing neurons in the bovine infundibular nucleus.

Immuno-enzyme histochemical investigations on the bovine hypothalamus showed that the infundibular nucleus contains neurons that produce either neurophysin I or a neurophysin I-like substance. Fine processes of these neurons run in the direction of the median eminence. The possibility that these processes could be the origin of the "neurophysin I-oxytocin" containing nerve fibres of the external region of the median eminence is discussed.


Correlations between brain catecholamines, neurosecretion, and serum corticoid levels in osmotically stressed mallard ducks (Anas platyrhynchos).

The effects of depleting brain catecholamines with a combined treatment of reserpine and alpha-methyl-p-tyrosine on serum corticosterone levels and release of immunoreactive neurophysin from the median eminence, in osmotically stressed and unstressed mallard ducks, were studied. Corticoid levels in salt loaded birds were more than three times that of unstressed birds. The combined treatment of reserpine and alpha-methyl-p-tyrosine significantly decreased the concentration of brain monoamines in all experimental groups and raised serum corticoid levels in non-stressed birds to the same level found in the osmotically stressed animals. Immunoreactive neurophysin in the zona externa of the median eminence was depleted in all birds subjected to either osmotic stress and/or reserpine treatment but not in unstressed control birds. These preliminary data indicate that catecholamines may exert an inhibitory influence on both ACTH release from the anterior pituitary and neurophysin from the median eminence and that these two events may in some way be interrelated in the duck.


Comparative scanning electron microscope study of boar, bull and ram spermatozoa.

The comparative ultrastructure of ejaculated boar, bull and ram spermatozoa is studied by scanning electron microscopy. After washing, the spermatozoa are fixed in glutaraldehyde or im picric acid-formaldehyde-glutaraldehyde mixture. Samples are prepared either by critical point drying (Freon) on Millipore filters or by air drying on glass cover slips. In all the species studied, three regions may be distinguished in the paddle-shaped head of the sperm: an anterior segment (surrounded by the marginal thickening) and an equatorial segment constituting together the acrosome, and the postacrosomal region. Most of the feature of the postacrosomal lamina described in transmission electron microscopy are visible through the plasma membrane, particularly after air drying. The surface morphology of the neck and of the different segments of the flagellum is also evident. Some species differences are encountered, e.g. rough surface of acrosome and absence of serrations in postacrosomal lamina of boar spermatozoa only. The techniques employed result in good general morphology and fine resolution of surface detail of the sperm samples; they also permit analysis of spermatozoa treated by freezing or submitted to acrosomal extraction.


An electron microscopic radioautographic study of the uptake of tritiated serotonin by nerve fibres in the posterior salivary duct and gland of cephalopods.

In the posterior salivary duct and gland of Octopus vulgaris and of Eledone cirrhosa, the duct secretory nerve trunks and their ramifications in the gland tubules include many fibres that incorporate labelled serotonin. However, there are also unlabelled secretory fibres, which cannot be discriminated from incorporating fibres on morphological grounds. Neuroglandular junctions are not apparently established by incorporating fibres. In the duct, the motor nerve trunks contain a small number of labelled fibres, and nerve bundles supplying the duct muscle contain, in variable proportions, serotonin incorporating fibres. Both labelled and unlabelled nerve fibres reach the duct muscle fibres, but neuromuscular junctions involve only unlabelled presynaptic fibres. The nerve fibres which join the gland muscle are usually unlabelled, and the small quota of incorporating fibres in the motor trunks apparently supply only duct tissues. Both secretory and motor trunks, originating from different ganglia, can be considered to contain heterogeneous fibres, releasing different neurotransmitters at the terminals. Certain of these fibres could be serotoninergic.


The structure of the rectal papilla in a parasitoid hymenopteran Nasonia vitripennis (Walker) (Hymenoptera Pteromalidae).

The ultrastructure of the rectal papillae of the parasitoid hymenopteran, Nasonia vitripennis (Walk), is described. These organs in this insect consist of four distinct cell types arranged as a closed, hollow cone. The majority of the cells are present in the raised cone, and are characterised by large numbers of mitochondria arranged in a membranous labyrinth. A series of cells form a collar around the base of the cone. Junction cells have been identified which are present at the point of insertion of the cone into the rectal epithelium. The base of the cone consists of cells with elaborately folded plasma membranes facing both the central cavity of the cone, and the haemolymph. The structure of this rectal papilla is compared with those found in other insects.


The sensory cilium of retinal rods is analogous to the transitional zone of motile cilia.

The connecting cilium of rat retinal rods was studied by freeze-fracture and thin-sectioning techniques. Transverse strands of intramembranous particles could be observed on fracture face B on the ciliary plasma membrane. The strands were essentially similar to those found at the transitional zone of motile cilia ("ciliary necklace"). The larger number of intramembranous particles obscured the pattern on fracture face A of the membrane. On longitudinal sections of the cilia, beads showing a periodicity similar to the necklace strands were observed. Each bead consisted of two structures apposed to both sides of the plasma membrane. Transverse sections of the cilia revealed radial Y-shaped structures that connected each ciliary doublet with the plasma membrane. Axial tubules, central sheath, radial spokes and dynein arms were missing in the connecting cilium. Comparing the fine structure of the retinal cilia with that of motile cilia it becomes evident that the connecting cilium is analogous in structure with the transitional zone of motile cilia. The present observations suggest that periodic membrane beads along the plasma membrane on thin sections correspond to strands of necklace particles as observed on freeze-fractured membranes. The arrangement of the particles in transverse strands is probably ensured by the radial connecting structures.


Ultrastructure of the grasshopper proximal femoral chordotonal organ.

This paper, the first in a series concerning the neurobiology of sensory cilia, describes the ultrastructure of our chosen model system--the proximal femoral chordotonal organ (FCO) in pro- and mesothoracic grasshopper legs. The FCO is a bundle of 150-200 longitudinally oriented chordotonal sensilla. Each chordotonal sensillum is a mechanoreceptive unit that contains two bipolar neurons whose dendrites bear sensory cilia. The structure of the sensory cilia leads us to suggest that they are motile cilia that respond to the mechanical stimulus with an "active stroke" which excites a transducer membrane at the dendrite tip.


Studies on the juxtaglomerular apparatus. IV. Freeze-fracturing of membrane surfaces.

The juxtaglomerular apparatus of the rat was studied after freeze-fracturing with special respect to intercellular junctions. It was found that juxtaglomerular granulated cells of the vas afferens are interconnected by gap junctions to adjacent cells (granulated cells, possibly also smooth muscle cells). Gap junctions have also been found on the surface of lacis cells and mesangial cells. It is therefore concluded that these cells of the juxtaglomerular apparatus and the glomerulus--granulated cells (possibly also smooth muscle cells) of the vas afferens, lacis cells and mesangium cells--form a functional system reacting in a coordinated manner to physiological stimuli.


Lymphoid cells in chicken intestinal epithelium.

The intraepithelial lymphoid cells of chicken small intestine were studied by light microscopy using 1 mu Epon sections, and by electron microscopy. Three cell types were found: small lymphocytes, large lymphoid cells, and granular cells. These cells correspond to the theliolymphocytes and globule leucocytes of previous authors. The numbers of all cell types increased with age. Correlation was found between the number of small lymphocytes and large lymphoid cells, but not between granular cells and either of the other two. A hypothesis is proposed, assigning these cells with a function in mucosal immunity.


Innervation of the anterior byssal retractor muscle in Mytilus edulis L. II. Ultrastructure of the glio-interstitial cells.

Studies on the intrinsic innervation of the anterior byssal retractor muscle (ABRM) in Mytilus edulis L. were continued at the ultrastructural level. Electron micrographs show nerve processes ensheathed by glio-interstitial cells running between muscle fibers. The glio-interstitial cells may represent all the types of osmiophilic cells previously described by the light microscopic ZIO technique in the anterior byssal retractor muscle.