Afferent projections to the central nucleus of the inferior colliculus in the rat. The afferent projections to the inferior colliculus of the rat were studied using the method of retrograde transport of horseradish peroxidase (HRP). Following large injections of HRP into the central nucleus, cells within the cochlear nuclei, superior olivary complex and auditory cortex were stained. Within the contralateral dorsal cochlear nucleus, fusiform cells were heavily labeled. Giant cells were also labeled in deeper layers. In the contralateral ventral cochlear nucleus, virtually all major cell types were labeled, with some types being labeled in greater numbers than others. Octopus cells of posteroventral division of ventral cochlear nucleus (PVCN) were never labeled. HRP-positive cells were found in ipsilateral and contralateral lateral superior olivary nucleus (LSO), ipsilateral medial superior olivary nucleus (MSO), ipsilateral and contralateral lateral nucleus of the trapezoid body (LTB), ipsilateral ventral nucleus of the trapezoid body (VTB), and ipsilateral superior paraolivary nucleus (SPN). Pyramidal cells of layer V of auditory cortex were heavily labeled. Small injections of HRP into the central nucleus resulted in labeled cells within restricted regions of the cochlear nuclei, superior olivary complex and auditory cortex. Injections into dorsal regions of the central nucleus resulted in cells labeled in ventral regions of the dorsal and ventral cochlear nuclei, and in lateral regions of LSO. These regions contain neurons which are considered to have low best frequencies. Injections placed in more ventral regions of the central nucleus led to labeling of cells in more dorsal regions of the cochlear nuclei and more medial regions of LSO in agreement with the tonotopical progressions within these structures.


Observations on the afferent and efferent connections of the avian isthmo-optic nucleus. The efferent and afferent connections of the avian isthmo-optic nucleus (ION) were studied using light microscopic techniques. Injections of [3H]proline into the nucleus resulted in labeling of centrifugal endings in the retina at the junction of the inner plexiform layer and inner nuclear layer, but produced no other transported label to any thalamic or mesencephalic nucleus. The origin of the tectal afferents to the ION was demonstrated by means of injections of [3H]proline into the most superficial layers of the optic tectum and by stereotaxic injections of horseradish peroxidase into the ION. The tectal efferent cell bodies were located in lamin h of the optic tectum and at the junction of laminae h and i.


Entry of [3H]norepinephrine, [125I]albumin and Evans blue from blood into brain following unilateral osmotic opening of the blood-brain barrier. The blood-brain barrier in adult rats was opened unilaterally by infusing 1.58 M L (+)-arabinose in 0.9% NaCl solution into the internal carotid artery, via a catheter in the external carotid. The common carotid remained patent during the procedure. Osmotic barrier opening allowed entry into the brain of three intravascularly administered tracers--a visual tracer Evans blue (pulsely injected) and radioactive tracers [3H]norepinephrine (continuously infused) and [125I]albumin (pulsely injected). In osmotically perfused brain tissue, uptake of both 3H and 125I from blood was increased 2-5-fold above control, with maximal increases observed in the caudate nucleus, hippocampus and thalamus. In control brain regions, Evans blue and albumin remained intravascular, whereas norepinephrine was taken up, possibly by sympathetic nerve endings in cerebral vessels, as a function of blood plasma concentration and duration of exposure. The barrier closed within 4 h after intracarotid arabinose infusion, and barrier opening was not associated with edema as measured two days after infusion.


Differential excitatory and inhibitory effects of opiates on non-nociceptive and nociceptive neurones in the spinal cord of the cat. Morphine, levorphanol, dextrorphan and naloxone were applied microelectrophoretically to cells identified as either having nociceptive inputs or non-nociceptive inputs in the dorsal horn of the cat. Morphine excited non-nociceptive cells and depressed nociceptive cells. Naloxone reversed morphine excitations on non-nociceptive cells, but only reversed about one-third of morphine depressions on nociceptive cells. Levorphanol depressed nociceptive cells, whilst dextrophan ejected with similar currents caused less depression or had no effect. It is concluded that excitation of non-nociceptive cells may constitute a spinal action relevant to the analgesic action of opiates, acting synergistically with a depressant effect on nociceptive neurones.


Auditory cortex lesions and discrimination of spatial location by the rat. Five normal rats and four rats with bilateral lesions of auditory cortex were tested by the conditioned suppression procedure to determine their abilities to discriminate between spatially separated sound sources. The discrimination involved detection of a change in location of a train of clicks from a speaker on the animals' left to a speaker on the right. The separation between speakers was varied from 180 degrees to 90 degrees, 45 degrees, 22 degrees, 12 degrees, 6 degrees, and psychophysical functions were obtained using a method of descending limits. Both normal and brain-damaged animals were capable of discriminating left from right clicks and psychophysical curves were similar for the two groups. Histological analysis indicated that the lesions in each of the four brain-damaged rats destroyed primary auditory cortex as well as surrounding belt areas. Therefore, for the rat, auditory cortex was not found to be essential for discrimination of the spatial locations of auditory stimuli. The results are discussed in light of impairments in sound localization following lesions of auditory cortex in other mammalian species.


Neuronal plasticity in the limbic system during classical conditioning of the rabbit nictitating membrane response. I. The hippocampus. Hippocampal unit responses were recorded throughout classical conditioning of the rabbit nictitating membrane response to a tone conditioned stimulus (CS) using a corneal air-puff unconditioned stimulus (UCS). Multiple unit analysis revealed that a rapidly developing increase in cell discharges (relative to spontaneous activity) occurs within the first block of paired trials and continues to increment with subsequent training, initially in the UCS period and then in the CS period. The pattern of hippocampal activity within paired trials closely parallels the amplitude-time course of the behavioral response and precedes it temporally. Identical recordsings from animals given unpaired CS-alone and UCS-alone presentations showed no such changes. These control results and additional lines of evidence point to the critical necessity of the learning paradigm for the development of the hippocampal response seen in conditioning animals. A single unit analysis indicates that not all hippocampal neurons exhibit the described conditioned discharge pattern. Hippocampal long-term potentiation is considered as a possible mechanism for mediating this early and rapid neuronal plasticity dependent on specific 'contingent' patterns of stimulation.


Influence of elevated pulmonary vascular resistance on the relationship between central venous pressure and pulmonary artery occluded pressure following cardiopulmonary bypass. This study has demonstrated that CVP measurement is an unreliable index of left ventricular filling pressure in unselected patients undergoing A-C bypass procedures. The influence of altered PVR on the disparity between right and left ventricular filling pressures is not of prime importance. The inconsistent relationship between CVP and PAo is primarily a result of ventricular dysfunction and not altered PVR. This suggests that following A-C bypass surgery patients cannot be grouped with respect to altered PVR as the variable which determines whether CVP will be a reliable guide to changes in left atrial pressure. Routine use of Swan-Ganz catheters would improve the precision of monitoring and fluid administration in all patients following CPB. However, it would also increase the cost and complexity of routine care and add a very low incidence of complications to all patients having cardiac surgery. At present, we monitor high risk patients from the time of surgery and advocate early insertion of Swan-Ganz catheters in low risk patients if they are not responding to appropriate management.


Cardiovascular haemodynamics during enflurane-pancuronium anaesthesia in patients with valvular heart disease. The effects of enflurane-pancuronium anaesthesia on cardiovascular haemodynamics were studied before operation in six patients with valvular heart disease. A ten per cent decline in cardiac index and a 20 per cent decline in stroke volume were the only changes observed. Mean arterial, pulmonary arterial, contral venous, and pulmonary capillary wedge pressures were unaffected, as were systemic vascular resistance and pulmonary vascular resistance. The authors therefore conclude that enflurane-pancuronium anaesthesia causes only minimal cardiovascular depression in patients with valvular heart disease.


How rebreathing anaesthetic systems control PaCO2: studies with a mechanical and a mathematical model. Results from a proposed equation for rebreathing systems, (formula: see text), were compared with results from a mechanical model "lung" ventilated either with a Bain Breathing Circuit, or a circle system (Eger-Ethans type A) without soda lime. When values for carbon dioxide excretion (VCO2), dead spacetidal volume ratio (VD/VT), minute volume ventilation (VE), and fresh gas flow (VF) were varied over a wide range, the model and the equation yielded identical values of PaCO2. When VCO2 = 2.25 ml/kg, VD/VT = 0.5, and VE = 140 ml/kg, then fresh gas flows (VF) with both the equation and the model produced values of PaCO2 which were very close to those found by Bain and Spoerel in anaesthetized, artificially ventilated humans. It is concluded that the equation is an accurate mathematical representation of how rebreathing anaesthetic systems control PaCO2. It is expected that the equation will be useful in the clinical application of rebreathing anaesthetic systems, allowing the selection of minute volumes and fresh gas flows which will yield predictable PaCO2 values.


A comparison between the Bain and Magill anaesthetic systems during spontaneous breathing. The efficiency of the Bain system has been compared with that of the Magill system in ten conscious subjects breathing spontaneously. Air was supplied at fresh flow rates of 150 ml/kg and decreased stepwise at four-minute intervals until a flow of 50 ml/kg was attained. Expired minute volume and end-tidal carbon dioxide concentrations were measured. No rebreathing could be demonstrated with the Magill stystem at flow rates above approximately 70 ml/kg. In contrast, rebreathing was evident at all flow rates with the Bain system. It is concluded that acceptable carbon dioxide levels during spontaneous breathing with the Bain circuit can only be maintained by considerable active hyperventilation when using flow rates of 150 ml/kg and less.


A comparative assessment of alfathesin for use in outpatient anaesthesia. Alfathesin and thiopentone were compared in a double blind study where each drug was given by intravenous infusion supplemented with fentanyl and nitrous oxide, in 54 healthy female patients under-going therapeutic abortion. The two drugs were similar in terms of changes in cardiorespiratory variables, side effects, clinical efficacy, and patient acceptability. Alfathesin produced a significantly more rapid recovery from anaesthesia, without the high incidence of dreams found with thiopentone in this study. Alfathesin would seem to be the preferable drug for use in outpatients undergoing minor surgical operations.


Further experience with etomidate.

Further experience with etomidate. We report our further anaesthetic experience with Etomidate in 100 patients. The cardiovascular and respiratory systems were not significantly affected but intraocular pressure was reduced. The occurrence of pain during injection of Etomidate was unaffected by analgesic premedication but was reduced by using a solution buffered to a higher pH and by choosing a big vein for injection. The myoclonic movements often seen with Etomidate anaesthesia were transient and have so far not created any major problem; they were reduced by a slower speed of injection but unaffected by diazepam premedication or pretreatment with low dose of a non-depolarizing muscle relaxant (pancuronium). Etomidate is a satisfactory alternative to thiopentone in situations where depression of the cardiovascular and respiratory systems are undersirable or where barbiturates are otherwise contraindicated and is a usefull addition to the induction agents in our anaesthetic practice.


Sequence of return of neurological function and criteria for safe ambulation following subarachnoid block (spinal anaesthetic). Twenty-three adult men were studied during and after subarachnoid block anaesthesia for elective surgery. Measurements were obtained of mean arterial pressure and pulse, both supine and after standing for five minutes, core body (tympanic) and peripheral skin (toe) temperatures and blood flow in the leg. Time of measurements included one hour after the injection of tetracaine and after regression of the block. Results obtained indicate that the sequence of return of neurological activity following tetracaine subarachnoid block is sympathetic nervous system activity, pinprick sensation, somatic motor function followed by proprioception in the feet. This progression provides the basis for recommended criteria which indicate when it is safe for patients who have been subarachnoid block anaesthesia to become ambulatory. These criteria include: (1) return of pinprick sensation in the peri-anal area (sacral 4--5); (2) plantar flexion of the foot (while supine) at pre-anaesthetic levels of strength; and (3) return of proprioception in the big toe, always provided that the patient is not hypovolaemic or sedated.


Late complications of prolonged tracheal intubation. Questionnaires were sent to patients who had tracheal intubation for periods longer than three days in a large multidisciplinary Intensive Care Unit. The information sought was of complaints related to talking, breathing, coughing, swallowing and chest infection. Of patients who had been intubated for seven days or less, 63 per cent of the 52 patients responding had no complications while only one of the remainder had a major complication requiring surgical removal of a granuloma. Forty-eight per cent of patients intubated for more than seven days had no complaints and the rest of the patients had minor complaints which did not persist. Most complained of hoarseness. Of patients who had a tracheostomy following prolonged intubation, only 23 per cent were free of complications. From this it is concluded that tracheal tubes can be left in place for seven days and at this time direct laryngoscopy should be done. If no significant laryngeal pathology is seen at this examination, tracheal intubation may be continued.


The effect of glycopyrrolate (Robinul) on the lower oesophageal sphincter. Regurgitation and inhalation of acid gastric content, with resultant chemical pneumonitis, remains a common cause of death during anaesthesia. The effects of intravenous glycopyrrolate 0.3 mg on the lower oesophageal sphincter tone was studied in normal human subjects. Glycopyrrolate decreased lower oesophageal sphincter pressure by 0.88 kPa (p less than 0.005). This finding is of clinical importance in the pre-operative preparation of patients presenting for emergency surgery. A drug which decreases lower oesophageal sphincter tone would presumably increase the hazard of gastro-oesophageal reflux and pulmonary aspiration of acid gastric content.


Asymptomatic diaphragmatic defect--a post-operative problem. A three-hour operation on the maxilla of a woman with an unrecognized large left diaphragmatic defect using narcotic-supplemented nitrous oxide anaesthesia resulted in near-complete compression of her left lung. The condition remained asymptomatic until post-operative shivering increased the patient's metabolic requirements, leading to signs of air hunger. Aspiration of large amounts of gas from the stomach promptly relieved all symptoms in spite of significant residual X-ray findings. It is important to keep in mind that the early post-operative period is usually one of intense metabolic activity rather than of rest. Patients who are unlikely to cope with such demand should be identified pre-operatively and supported prophylactically by ventilatory assistance, ample supply of metabolic substrates and judicious sedation.


Post-operative apnoea caused by breath-holding spells. After recovery from anaesthesia for a urological procedure a two-and-a-half-year-old child with a history of breath-holding spells became apnoeic and cyanotic in the immediate post-operative period. The pathophysiology of breath-holding as the cause of the apnoea is discussed. Management includes ventilation with oxygen and avoidance of inappropriate treatment with drugs to reverse muscle relaxants or narcotic anesthetics.


A flexible stilette for replacing damaged tracheal tubes. A simple method to facilitate exchange of a damaged tracheal tube is described. The technique entails the passage of a flexible stilette 4 mm in diameter through a damaged tracheal tube, which is then removed and replaced with a new sterile one passed over the stilette. The technique can be used in conscious or unconscious patients. A case report is included to illustrate application of the technique.


Acute epiglottitis: current management and review. Forty-seven patients treated for acute epiglottitis by nasotracheal intubation under general anaesthesia following a preset protocol are presented. The results are compared with 61 cases treated by tracheostomy following induction of general anaesthesia and intubation in the same institution. Both groups were followed clinically, and 13 of the children treated by nasotracheal intubation alone had a follow-up endoscopic examination of the larynx. There was no mortality in either group, but the morbidity was significantly higher in the children who had tracheostomy. Details of the management protocol are presented. Only inhalation anaesthetic agents are recommended and it is concluded that children with acute epiglottitis should always have an artificial airway inserted. Nasotracheal intubation seems to be associated with less morbidity than tracheostomy in experienced hands.


Nitroprusside, its metabolites and red cell function. The effects on metabolism and red cell function of blood levels of thiocyanate (SCN-) and cyanide (CN-) were studied in 42 patients undergoing surgery under controlled hypotension (CH) induced by sodium nitroprusside (SNP). The mean dosage of SNP administered was 21.38 mg (SD = 12). The durating of perfusion was 121 minutes (SD = 11). All operations were performed under neuroleptanalgesia without complications. No tachyphylaxis was encountered. Under SNP a slight increase of blood SCN- (from 13.9 mg/l +/- 1.1 to 23 mg/l +/- 2.6) was found. Blood levels of CN- are increased mostly in the red cell, the mean value being 0.300 mg/l +/- 0.10 for whole blood after two hours of perfusion. This value decreased when perfusion was stopped. All blood samples were negative for methaemoglobin and cyanmethaemoglobin. Carbonic anhydrase activity was not modified, CN- toxicity levels for this enzyme being 50 times higher than those found during our study. 2,3-DPG levels did not vary. Blood gases, acid-base balance and Davo2 did not change significantly, although a slight increase in blood lactate was measured. As shown by this study, appreciable amounts of CN- are detected in blood during SNP perfusion while SCN- stays at relatively low levels. Fortunately most of the CN- released from SNP moves into the red cell and does not alter its functions at clinical concentrations. The low plasma concentration of CN- is not sufficient to cause important metabolic disturbances. However, dosages of SNP higher than those administered during this study could increase the blood and tissue CN- to toxic levels. A toxicity study shows that, during a relatively short period of time, SNP dosage should not exceed 1.16 mg/kg or a maximum of 10 microgram/kg/min for a period of two hours.


Reductive N,N-dimethylation of amino acid and peptide derivatives using methanol as the carbonyl source. Formaldehyde is readily formed from methanol in the presence of palladium-on-charcoal and air. The use of this methanolic formaldehyde solution for the reductive methylation of amino groups in amino acid and peptide derivatives by catalytic hydrogenation has been studied and found to be superior to the use of aqueous formaldehyde because no contaminating paraformaldehyde is present. Some data on N-isopropylation are given.


Synthesis of and allergic contact dermatitis to bicyclo-[2,2,1]-heptyl-alpha-methylene-gamma-butyrolactones derived from norbornene and camphene. Three new lactones, 2-oxo-3-methylene-4,7-methanobenzofuran and two alpha-methylene spirolactones, 3',3'-dimethylspiro(2-oxo-3-methylenefuran-5,2'-norbornane), were synthesized and their skin activity was tested on one human volunteer and on guinea pigs. The man, sensitized to Frullania, was found sensitive to the above lactones and also reacted to frullanolide and alantolactone. The guinea pigs, experimentally sensitized to alantolactone, cross-reacted to 2-oxo-3-methylene-4,7-methanobenzofuran and the two alpha-methylene spirolactones, and also to isolantolactone and frullanolide.


Vectorial transport of proteins by membrane-bound ribosomes of nongrowing and growing Jerusalem artichoke tuber cells. Both nongrowing (water-incubated) and growing (hormonally stimulated) Jerusalem artichoke tuber cells contain membrane-bound (mb) ribosomes. Using a rapid flotation procedure, a membrane fraction was prepared from both types of cells. This fraction was enriched in mb ribosomes, contained NADH cytochrome c reductase activity, had RNA:phospholipid and RNA:protein ratios similar to those reported for rough microsomes from animal tissues, and supported synthesis of preinitiated proteins in vitro. Using puromycin and detergent release, vectorial transport of labelled polypeptides was measured in the in vitro system. Of proteins made by mb ribosomes from nongrowing cells, on 12% remained associated with microsome membranes following chain termination. The comparable figure for proteins from mb ribosomes of growing tissue was 42%. The membrane-associated proteins were preferentially protected from protease digestion. Some possible reasons are suggested for the correlation between cell growth and the association of newly synthesized proteins with microsomes. The role of proteins synthesized by mb ribosomes but not vectorially transported, in both growing and nongrowing cells, is unknown.


Lactoperoxidase-catalyzed oxidation of [4-14C]estradiol. The conversion of [4-14C]estradiol to water-soluble products by lactoperoxidase (EC 1.11.1.7) in the presence of added or generated H2O2 was studied using albumin or tyrosine as acceptor. The enzyme was able to catalyze the oxidation and binding of estradiol to albumin even in the absence of 2,4-dichlorophenol at very low concentrations of hydrogen peroxide. Other systems in which H2O2 was replaced by oxygen and Mn2+, light-sensitized riboflavin or glutathione was also shown to be active in the conversion of estradiol to water-soluble products and the effect of inhibitors on these reactions was investigated. Possible mechanisms for the peroxidase-catalyzed formation of these estradio metabolites are discussed.


Factors in adjustment to blindness.

Factors in adjustment to blindness. We wished to explore the relationship between certain blinding eye diseases, residual vision and psychosocial adjustment, including acceptance of blindness. One hundred and fourteen patients were grouped according to level of vision, age, type of disease, general physical health and duration of blindness. Psychological symptoms were measured by the Minnesota Multiphasic Personality Inventory (M.M.P.I.) and social function by an adaptation to blindness of the Gunzberg Progress Chart of Social Function. Social adjustment was best and psychological morbidity least in those with non-diabetic retinal disorders, those who had the best vision and those who accepted their blindness. Non-acceptance of blindness was associated with the most psychological distress and the lowest scores in social adjustment. People with glaucoma and diabetic retinal disorders seemed more poorly adjusted. An attempt should be made to identify those most prone to maladjustment so as to assist them in rehabilitation.


The effect of cigarette smoke on the human tear film. We used a corneal microscope to measure the break up time of the tear film (BUT) in 14 young volunteers; four were men and all were non-smokers. Values under controlled conditions and after ten minutes of exposure to filtered air or to cigarette smoke in a room of 14.6 m3 were determined. Exposure to cigarette smoke was associated with a substantial (35--40%) and statistically significant (P less than 0.001) reduction of BUT. This may reflect an alteration in the relative proportions of the three constituents of the tear film. The chemical responsible, and the way in which it increases the flow of watery constituents and suppresses mucus and lipid secretion demand further research.


Can steroid reduce endothelial damage in stored corneas? Effect on cell viability and ultrastructure. We studied the effect of steroid on the viability and integrity of the endothelium of variously stored corneas of different species of animals and man. Paired corneas of rodents and humans were used,--one cornea (experimental) being treated with steroid and the other (control) not. Rat and guinea pig corneas were kept at 37 degrees C for one hour in phosphate buffered saline with or without hydrocortisone 21-sodium succinate (10-6M). Human corneas were kept at 4 degrees C for 4 days in M-K medium with or without hydrocortisone 21-sodium succinate (10-6M). The viability of the endothelia (rat and guinea pig) was tested with para Nitro Blue Tetrazolium and trypan blue dye exclusion tests. The ultrastructural changes in the control and experimental endothelial (guinea pig and human) were examined by scanning electron microscopy. Viable cells P less than 0.001) were more numerous and ultrastructural alteration less in the endothelia of the steroid treated corneas compared to the controls.


Staphylococcal infection superimposed on guinea pig inclusion conjunctivitis. We have studied the effect of superimposed staphylococcal infection on guinea pigs who had inclusion conjunctivitis. Although the acute phase of the inclusion disease was slightly more intense in the superinfected group, the course and duration were unaltered. We did not find any reactivation of the inclusion disease from the subconjunctival injection of glucocorticoid.


Endophthalmitis caused by Propionibacterium acnes. We treated a man who developed endopthalmitis six weeks after a seemingly minor injury. Cultures were positive for Propionibacterium acnes, an anerobic, Gram-positive rod that is a normal inhabitant of the conjunctiva but is rarely a cause of endophthalmitis. The patient underwent vitrectomy and lensectomy with intravitreal injection of antibiotics followed by systemic cephalothin and prednisone. Clinical and visual improvement was rapid.


[Diplopia in monocular aphakia].

[Diplopia in monocular aphakia]. In monocular aphakia, diplopia results from disparities between the two retinal images in form, size, outline, luminous intensity and colour. If one wishes to give the best binocular vision possible to a monocular aphake, it is important to recognize the different factors which may give rise to diplopia.


Effect of glucagon on canine exocrine pancreatic secretion stimulated by a test meal. The effect of glucagon on exocrine pancreatic secretion stimulated by a test meal was studied in three dogs with a chronic gastric fistula and a modified Thomas duodenal fistula which allows easier collection of pure pancreatic juice after a meal. Glucagon was given by continuous intravenous infusion in doses of 5, 10, 15, or 30 microgram/kg per hour, before and during a test meal. At each dose level glucagon significantly reduced the water and electrolyte secretion of the pancreas. At 15 and 30 microgram/kg per hour glucagon inhibited protein output; this effect was absent at lower doses. These findings demonstrate a dose-dependent inhibition by glucagon of the pancreatic bicarbonate and protein response to a meal. Inhibition of bicarbonate output was more sensitive to glucagon than that of protein output.


The correlation of ethanol-induced depression of glucose and water transport with morphological changes in the hamster jejunum in vivo. Glucose and water transport is depressed in the hamster jejunum in vivo by ethanol (4.8%) which also produced fluid-filled blebs at the tips of the villi. The epithelial cells over the blebs appeared stretched and cuboidal, the lateral intercellular spaces (LIS) were no longer recognizable, and the lacteals were closed. Forty-five minutes after discontinuation of the ethanol, water transport returned to normal while glucose transport remained depressed. At this time the villus structure had returned to normal. The blebs had disappeared, the LIS were again recognizable, and their appearance and number were similar to those in the control animals. Thus, the depression of water transport correlated with the obvious structural changes caused by ethanol; however, the depression of glucose absorption is associated with some effect of ethanol not evident by routine light microscopy.


The electrophysiological effects of disopyramide phosphate on canine ventricular muscle and Purkinje fibers in normal and low potassium. We studied the effect of lowering the extracellular potassium concentration ([K+]o) on the electrophysiological actions of disopyramide phosphate, a new antiarrhythmic drug. At low [K+]o, therapeutic concentrations of disopyramide phosphate caused significantly less depression of action potential amplitude and maximum upstroke velocity of both Purkinje fiber and ventricular muscle action potentials. The drug shifted the membrane responsiveness curve along the voltage axis to more negative membrane potentials regardless of [K+]o. However, a greater shift occurred when [K+]o was normal. Disopyramide phosphate prolonged both action potential duration and effective refractory period in all fibers but there was consistently greater prolongation of these parameters at low [K+]o. More importantly, disopyramide phosphate altered repolarization time course of action potentials in such a way that action potentials with dissimilar durations throughout the ventricular conducting system became more equal. The drug was less effective in decreasing this disparity in action potential durations throughout the ventricles in the presence of low [K+]o. These modifications of the electrophysiological actions of disopyramide by low [K+]o suggest that a therapeutic concentration of disopyramide might have less of an antiarrhythmic effect in the presence of hypokalemia.


Primary afferent depolarization of C fibres in the spinal cord of the cat. The excitability of primary afferent terminals of cutaneous C fibres was tested in the spinal cord of decerebrated cats. C fibre terminal excitability was decreased in the spinal state, and increased by conditioning volleys that activated only A fibres of another cutaneous nerve and by stimulating hair mechanically. It is suggested that C fibre input and therefore nociceptive information to the central nervous system is susceptible to presynaptic control by segmental and suprasegmental mechanisms.


The influence of a visual cue on muscle stretch reflexes. Evidence has recently been presented indicating that muscle stretch reflexes have a large supraspinal component. The finding introduces the possibility that stretch reflex parameters may be modifiable by stimuli involving other modalities besides stretch. In this investigation, the effects of a visual cue on the reflex portions of the EMG activity following a sudden muscle stretch were examined. The results, obtained from the flexor carpi radialis muscles of six normal awake subjects, failed to show any significant change in the EMG parameters as a result of visual cues occurring at the instant of onset of muscle stretch. This was interpreted as indicating that visual inputs do not reach the areas of brain involved in the supraspinal reflex in sufficient time to modify the reflex.


Characteristics of a somatostatin-binding protein. The concentrations of a somatostatin-binding protein, found in the cytosol of a number of rat tissues, are similar in both sexes, and hypophysectomy has little or no effect on the level of binding protein in tissue extracts. On the other hand, streptozotocin-induced diabetes mellitus causes a modest decrease. The somatostatin-binding proteins obtained from extracts of several rat tissues are not only similar in molecular weight but also exhibit a similar isoelectric point and electrophoretic mobility. Agents that block thiol groups or prevent the formation of disulfide bridges markedly decrease the binding of somatostatin to the cytoplasmic protein. Studies using thiol reagents and gel filtration suggest that free thiol groups in somatostatin-binding protein are important for the binding of somatostatin.


Effect of L-cycloserine on brain GABA metabolism. The administration of L-cycloserine to mice resulted in a dramatic decrease in the activities of 4-aminobutyrate:2-oxoglutarate aminotransferase (GABA-T) and L-alanine:2-oxoglutarate aminotransferase (ALA-T) in both brain and liver. L-Aspartate:2-oxoglutarate aminotransferase was inhibited only slightly, and brain glutamic acid decarboxylase not at all. Liver ALA-T activity returned to near normal levels within 24 h of L-cycloserine administration whereas liver GABA-T and brain ALA-T activities had returned only halfway to normal levels in the same time period. The recovery in the activity of brain GABA-T was even slower. A consequence of the inhibition of brain GABA-T activity was an elevation in the GABA content of the tissue which was maximal 3 h after L-cycloserine administration and which was still noticeable 8 h after the drug treatment. L-Cycloserine was also a potent in vitro inhibitor of brain GABA-T activity. The inhibition was competitive with respect to GABA, the Ki value being 3.1 X 10(-5) M. The prior administration of L-cycloserine to mice significantly delayed the onset of isonicotinic acid hydrazide induced convulsions.


Fiberoptic ear densitometer for measurement of cardiac output. This study presents theory, operation, and evaluation of a new earpiece method for measurement of cardiac output using the multichannel fiberoptic system recently described. The system includes an earpiece of simple design and small size suitable for applications in all subjects regardless of their age or size. The method requires no withdrawal and analysis of blood samples for calibration. Compared with earlier techniques the present method, based on measurements in three distinct absorption bands in the infrared, provides an increase in accuracy of the estimations. This accuracy was tested in children undergoing routine cardiac catheterization. Comparisons were made in 39 instances (25 subjects) between simultaneously carried out determinations by the earpiece and cuvette densitometer methods. The agreement was good (r = 0.97, p less than 0.001), with a standard deviation of the differences of 0.479 litre/min, or 10.2% of the mean values derived from the cuvette curves. The regression equation describing the values derived from ear curves in terms of values from the cuvette curves differed only slightly from unity (Y = 0.167 + 0.985X). The usefulness of the fiberoptic earpiece technique both in clinical investigations and cardiovascular diagnosis was demonstrated.


Absorption and distribution of sodium [2-14C]barbital in tissues of normal and dystrophic mice. The absorption and distribution of [2-14C]barbital after oral administration was studied in various tissues, including skeletal muscle, of normal and dystrophic mice. There appeared to be a more rapid gastric emptying in the mutant homozygote as reflected in lower levels of the drug recuperated from the gastrointestinal tract. This resulted in initially higher plasma and tissue concentrations of barbital in the dystrophic mice. Two hours after oral administration, this kinetic profile was reversed so that less barbital remained in the tissues of the dystrophic mouse. The tissue:plasma concentration ratios were consistently, but not significantly, higher in all tissues of the dystrophic animals. Analysis of the half-life of the drug in both groups suggests that there is an increase in the distribution volume of barbital in the dystrophic mice. The phenomenon of more rapid absorption of the barbiturate seems to be more consistent as the symptoms of the disease progress. The altered absorption and disposition of barbital in various tissues of the dystrophic mouse support the concept that a generalized multisystemic disorder may be crucial to the pathogenesis of murine muscular dystrophy, in contradistinction to a purely myogenic origin.


A free-running endogenous rhythm of the resting heart rate in man. A sine-wave oscillating rhythm of the heart rate is reported in 24 out of 31 resting healthy subjects. Identification of these free-running cycles was by spectral analysis of minute-by-minute recordings of electrocardiograms, and in a few cases by inspection of cardiotachometer records. The periodicity of this rhythm was circa 10 min and was intermediate in frequency between the rapid fluctuations with frequencies of 15, 30, and 60 s and those of a frequency recurrent every 90 min already described in the literature. Our cycles were independent of age and sex.


Comparison of microspheres and 86Rb+ as tracers of the distribution of cardiac output in rats indicates invalidity of 86Rb+-based measurements. The technique of using gamma-labeled plastic microspheres (15 +/- 5 micrometer) to measure cardiac output (CO) and its fractional distribution (FD) to individual tissues and organs was judged by various criteria to give valid data when applied to barbital-sedated warm-acclimated or cold-acclimated (CA) white rats, which were either resting or responding calorigenically to infused noradrenaline (NA). The FD of CO to each of 16 tissues or organs of CA rats at rest or responding to NA was then estimated both with 86Rb+ and with microspheres, the two tracers being injected simultaneously. For only seven of the tissues examined in resting rats and only one in NA-infused rats was the FD of CO estimated with 86Rb+ not significantly different from that estimated with microspheres. 86Rb+ to microsphere ratios of the FD of CO to individual tissues ranged from 3.5 and 3.0 for liver and skeletal muscle, respectively, down to 0.09 and 0.07 for brown adipose tissue (BAT) and brain. Since microsphere-based estimates of blood flow to the interscapular BAT of CA rats responding to NA were corroborated by direct measurements of venous efflux from the tissue, it is unequivocal that the 86Rb+-based estimate of the fraction of CO directed to interscapular BAT was highly erroneous. When considered along with data from the literature, the present findings support a conclusion that the uptake of 86Rb+ by a tissue frequently does not provide a valid measure of the FD of CO to the tissue. Some of the factors that are likely responsible for this situation are discussed, and it is suggested that only by a fortuitous combination of circumstances does the uptake of 86Rb+ by a tissue sometimes match the FD of CO to the tissue.


Effect of bile salts on the biliary excretion of glycodihydrofusidate in the rat. The biliary elimination of glycodihydrofusidate (GDHF), a structural analogue of bile salts, was studied in bile fistula rats. GDHF was excreted in bile with a maximal excretory rate (Tm = 0.80 mumol min-1 kg-1) which is much lower than bile salts Tm. The effects of dehydrocholate and taurocholate on GDHF biliary secretion suggest a stimulatory effect of bile salts on canalicular excretion of the drug. (a) When a bolus intravenous injection of 3 mumol of GDHF was followed after 2 min by a continuous dehydrocholate perfusion (10 mumol min-1 kg-1), biliary excretion of GDHF was increased in comparison with control rats. (b) Upon attaining the biliary Tm by continuous perfusion of GDHF at a rate of 1.35 mumol min-1 kg-1, infusion with either taurocholate or dehydrocholate increased its Tm to a similar degree. These results are similar to those previously obtained with the effects of bile salt infusions on the Tm of bromosulfophthalein. They suggest therefore that hepatic transport of GDHF and bile salts occurs by routes which are distinct for canalicular transport in spite of the striking structural similarities between GDHF and bile salts.


Effects of lidocaine in rabbit atria.

Effects of lidocaine in rabbit atria. Standard microelectrode recordings were obtained from rabbit right and left atria. Lidocaine (1 X 10(-5) M) had no effect on these, but 5 X 10(-5) M lidocaine significantly slowed rate and Vmax. This concentration had no effect on the duration of the action potential, a result clearly different from the effect of this drug in Purkinje tissue. Lidocaine had much less effect on the 'steady-state' relation of membrane potential to Vmax of phase 0 of the action potential than on the 'membrane responsiveness curve' obtained by the extra stimulus technique. We have demonstrated time-related recovery from sodium inactivation in rabbit left atria and have shown that lidocaine slows recovery in this tissue as it does in Purkinje fibres.


Effects of prolactin, progesterone, and 17beta-hydroxy-5alpha-androstan-3-one on squalene production by the preputial gland of the immature female rat. To examine further the previously demonstrated synergism between prolactin and progesterone on preputial glands of hypophysectomized, ovariectomized, immature rats, their effects on squalene production were determined and compared with the ability of 17beta-hydroxy-5alpha-androstan-3-one (DHT) and prolactin to increase the amount of squalene in the preputial glands. Glands from progesterone-treated rats incubated in vitro with [14C]mevalonic acid incorporated radioactivity into squalene (identified by chromatographic mobility) more rapidly than glands from controls or prolactin-treated rats. Using the same in vitro system, glands from prolactin-treated rats incorporated more [14C]acetate into squalene than those from progesterone-treated animals. In addition, results showed that prolactin and DHT increased nonradioactive squalene (identified by mass spectral analysis) content in the gland while progesterone had no effect. It is proposed that prolactin increases preputial gland squalene content by enhancing synthesis of mevalonic acid, while progesterone increases incorporation of mevalonic acid into squalene.


Redistribution in left ventricular regional flow following acute right ventricular pressure overload. The left ventricular dysfunction following acute pulmowary hypertension remains unexplained. We wondered if acute pulmonary hypertension could alter the transmural flow distribution within the left ventricular myocardium, independent of coronary flow and perfusion pressure. We used a canine preparation in which the left coronary system was perfused at constant flow and induced a two- to three-fold increase in pulmonary artery pressure by banding the pulmonary artery. Regional myocardial blood flow of the left coronary system was measured using radioactive microspheres, injected into the left coronary system before and after 10-30 min of banding of the pulmonary artery. The left ventricular subendocardial:epicardial ratio fell by 12 and 31% (p less than 0.05) of control value, 10 and 30 min, respectively, after banding of the pulmonary artery, the total flow to the left coronary system being kept constant. Left atrial mean pressure increased from 2.9 +/- 2.4 to 3.6 +/- 1.9 and 6.0 +/- 2.1 (p less than 0.05) following banding. The mechanism of the redistribution of coronary flow may relate to inappropriate vasodilation of the right septal myocardium with consequent relative left ventricular subendocardial hypoperfusion which might aggravate left ventricular ischemia in the presence of hypotension and hypoxia.


Calcium influx and spontaneous phasic contractions of portal veins after treatment with reserpine, 6-hydroxydopamine, and cocaine. Reserpine treatment increased the amplitude of the spontaneous phasic contraction (SPC) of portal veins obtained from rabbit and guinea pig but did not alter that of rat. The amplitude of the SPC of portal veins from these animals was increased after 6-hydroxydopamine (6-OHDA) but was not changed after cocaine treatment. Reserpine- and 6-OHDA-induced changes in portal vein SPC amplitude were accompanied by an increase in 45Ca influx. These results indicate that the elevation in SPC amplitude is accompanied by an increase in calcium influx.


The metabolic pattern of spontaneously released [3H]norepinephrine in the presence of uptake inhibitors. The effect of uptake inhibitors on the spontaneous release of [3H]norepinephrine was studied using rat isolated vas deferens. Cocaine, desmethylimipramine, phenoxybenzamine, and guanethidine caused an increase in the spontaneous outflow of tritium, but did not alter the metabolic pattern of released [3H]norepinephrine. Bretylium caused an increase of both total tritium outflow and norepinephrine content. It is suggested that these drugs caused release of norepinephrine from storage sites and that norepinephrine was metabolized within the nerve terminals before reaching the biophase.


Enkephalin and substance P effects related to trigeminal pain. Iontophoretic applications of enkephalin (20-150 nA) reduced the spontaneous firing frequency of nociceptive neurons in the trigeminal nucleus caudalis of decerebrated cats. The response evoked by noxious stimulation (tooth pulp) was gradually inhibited during the 1st minute of application of the opioid and generally remained depressed for 5 min after the current was turned off. These effects of enkephalin were blocked by intravenously or iontophoretically administered naloxone. Nonnociceptive neurons or nociceptive neurons responding to nonnoxious inputs were less frequently inhibited by enkephalin. When tested on nonnociceptive cells, similar applications of substance P usually had little effect. Nociceptive neurons, however, were strongly excited by substance P. This action was not constant and was interrupted by periods of inactivation. Both types of peptide action were similar in temporal aspects. The results suggest a functional interrelationship between enkephalin and substance P in a trigeminal system mediating nociception.


Opiate-like naloxone-reversible actions of somatostatin given intracerebrally. The latency to tail-flick response in the rat was significantly prolonged by cerebroventricular infusion of 1.0 microgram of somatostatin (SRIF) and more so with 10.0 microgram. The D-tryptophan analog was less effective than native SRIF. Pretreatment with naloxone eliminated analgesia but not seizures induced by SRIF. Recording of the EEG activity enabled determination of the specific state of the sleep-waking cycle in which the repeated tail-flick responses were tested: latency was generally longer in both control and test animals when tail immersion was performed during the state of sleep or drowsiness rather than during the awake state. Although animals receiving SRIF were less likely to fall asleep between subsequent test trails, the average latency was actually longer than after control saline infusion when the animals slept more. SRIF, unlike other releasing factors and peptides tested, showed significant activity in an opiate radioreceptor assay. The blockade of SRIF action by naloxone pretreatment, along with binding of SRIF to opiate receptors in vitro, suggest opiate receptors to be involved in the mediation of analgesia observed in present study.


Effect of acute blood volume expansion on cardiac output, plasma dopamine beta-hydroxylase, and renal function in rats with chronic constriction of the ascending aorta. To examine the effect of raised left atrial pressure (AP) on the relationship of cardiac output to renal function, we constricted the ascending aorta in rats (AC) and 1-6 months later tested their response to acute volume expansion (VE) with blood (2% body weight, iv). Sham-operated (SH) rats were controls. In AC rats heart weight increased 38%, but cardiac output was 47% lower. Statistically significant differences in the initial clearance periods were (AC vs. SH): venous pressure (VP) 8 +/- 2 vs. 3+/- 1 cm H2O; inulin clearance (CIN) 0.61 +/- 0.06 vs. 0.84 +/- 0.04 ml/min; sodium excretion (UNAV) 1.2 +/- 0.2 vs. 2.1 +/- 0.3 muequiv./min. Filtration fraction, fractional UNaV, mean arterial pressure (MAP), and plasma dopamine beta-hydroxylase (DBH) were the same in both groups. After VE, cardiac output increased proportionately more in AC (69% vs. 27%); however, the absolute increases were not different. UNaV increased proportionately more in AC rats, but the absolute increase was less (5.1 vs. 7.5 muequiv./min). Multiple variable regression analysis showed that UNaV correlated with CIN, MAP, and VP, with no difference between AC and SH animals. Cardiovascular-renal relationships were indistinguishable from previous descriptions of dogs and rats with chronic vena caval constriction. Modulation of renal function by left AP was not apparent. In both groups after the peak response to VE, UNaV decreased in association with decreased cardiac output and increased sympathetic nervous activity as indicated by raised DBH levels. After VE, VP remained high in AC but not in SH animals.


Effects of anesthetics on diphenylhydantoin metabolism in the rat: possible inhibition by diethyl ether. The effects of diethyl ether and urethane on the elimination of diphenylhydantoin (DPH) in the rat were compared. The apparent half-life of DPH following a dose of 10 mg/kg, iv, under continuous ether anesthesia was 284 +/- 47 min, while the half-life under urethane anesthesia was 25.5 +/- 6.3 min. The latter was in agreement with the literature value for DPH half-life without anesthesia. The effects of both anesthetic agents on bile flow and indocyanine green clearance were not different. Following intravenous administration of DPH (1 mg/kg), DPH metabolites excreted in bile at 2 h were 75.3 +/- 4.8% of the dose with urethane anesthesia and 25.0 +/- 5.0% of the dose with continuous ether anesthesia. The data suggest that ether may inhibit the DPH metabolism in vivo, most likely at the hydroxylation step, while urethane does not.


Alteration of the erythrocyte ultrastructure and blood viscosity by morphine. The effects of acute morphine administration on intact erythrocytes and on their flow properties were studied by measuring the mean cell volume, cell geometry, and whole blood and plasma viscosities. Morphine caused a small (2-7%) increase in mean cell volume. Changes in cell geometry were found to be time dependent and most pronounced in concave portions of the red cells. Whole body viscosity was found to decrease upon morphine treatment; this may be due in part to a concurrent decrease in plasma viscosity.


Sodium intake following destruction of the anterior hypothalamus in the rat. Sodium intake and sodium output were measured in rats before and after lesioning of the anterior hypothalamus. Both parameters were lower than control rats following the lesioning procedure. When an amount of sodium was given orally to these lesioned rats to make up the deficit in sodium intake, no difference was found in sodium intake or output between the rats with lesions and normal rats. Rats with anterior hypothalamic lesions were able to increase their sodium intake following a period of sodium deprivation or adrenalectomy. When presented with concentrations of sodium chloride ranging between 0.9 and 2.5% rats with lesions decreased their intake of sodium in a manner similar to control rats except that the level of intake in the lesioned rats was lower for all concentrations. Control rats and those with lesions were not different in their intakes of KC1 solutions. These findings suggest that the anterior hypothalamus is important in setting the absolute intakes of sodium but does not interfere with the control mechanisms regulating the sodium intake.


Effects of clofibrate on plasma tryptophan, growth hormone, and prolactin and on brain tryptophan and serotonin in prepubertal rats. The effects of clofibrate administration (200 mg/kg, po) on somatic growth, plasma levels of lipids, tryptophan, growth hormone (GH), and prolactin (PRL), as well as on brain concentrations of tryptophan and 5-hydroxytryptamine (5-HT) were studied in prepubertal male rats. The drug did not significantly alter ponderal growth, but an appreciable reduction of tail length was observed in rats treated for 30 days. Triglyceride concentrations in plasma showed a 43% diminution after 30 days of treatment, whereas free fatty acid (FFA) levels were not modified. Clofibrate administration for 7, 15, or 30 days caused a fall in total tryptophan and a significant increase of the free fraction in plasma with no change in brain tryptophan levels. Brain 5-HT was generally unaffected but a marked elevation of this parameter was noted in rats treated for 15 days. Plasma GH and PRL concentrations remained unaltered. It may be concluded from these findings that the slight reduction of somatic growth, the diminution of triglycerides, and the increase of free tryptophan in plasma, induced by chronic clofibrate treatment, are not associated with variations in brain tryptophan and 5-HT levels or with modifications of plasma GH and PRL titers.


45Ca displacement related to pharmacologically induced prolonged action potentials in Nitella flexilis. Nitella cells were loaded with 45Ca2+ to an activity of 2 X 10(5) cpm. Insertion of two glass-capillary electrodes into each of six cells released varying amounts of Ca2+ in the order of 1 mumol per cell, but hyperpolarizing and depolarizing pulses up to 500 ms in duration caused no measurable loss (less than 57 pmol) of Ca2+ even when the latter elicited action potentials. Addition of 10 mumol of Ba2+ or tetraethylammonium (TEA) caused losses up to 1200 pmol of Ca2+ from the cells and prolonged the action potentials by a factor of three or more. Subsequent addition of Ba2+ or TEA to treated cells caused no further losses of Ca. Because prolonged action potentials can apparently only be elicited after the chelation or displacement of Ca2+, we propose that, as in many animal cells, the K+ channels responsible for the normal brief repolarizing phase of the action potential are controlled by Ca2+ in these electrically excitable plant cells.


Hypothalamic catecholaminergic effects on prolactin release in vitro. Hypothalamic catecholaminergic influences on prolactin release were investigated in vitro. Both dopamine and norepinephrine caused long lasting inhibition of prolactin release from either an isolated hemipituitary or a hemipituitary coincubated with a hypothalamus. Epinephrine also inhibited prolactin release. L-Dihydroxyphenylalanine (L-dopa) inhibited prolactin release from pituitaries in the presence of a hypothalamus but not in isolated pituitaries. DL-Threodihydroxyphenylserine (threodops), serotonin, 5-hydroxy-L-tryptophan (5-HTP), tyramine, octopamine, synephrine, thyrotropin-releasing hormone (TRH), luteinizing hormone releasing hormone (LH-RH), and somatostatin all failed to alter prolactin release. Results confirm that dopamine and norepinephrine directly inhibit prolactin release from pituitary and suggest that the hypothalamic mechanism inhibiting prolactin involves dopamine but not norepinephrine.


Epileptiform seizures in domestic fowl. VII. Plasma phenytoin concentrations and anticonvulsant activity. Acute dose-response studies with phenytoin were conducted to determine the relationship between plasma levels and anticonvulsant effect in epileptic chickens. Phenytoin produced statistically significant reductions in both the incidence and severity of seizures in photosensitive epileptic chickens when the plasma concentrations exceeded 8.15 +/- 0.89 microgram/ml. A high correlation exists between plasma phenytoin concentrations and both the reduction in incidence or severity of seizures. However, the appearance of plasma concentration dependent neurological toxicities resulted in a failure to achieve complete protection against intermittent photic stimulation induced seizures.


Hemostatic changes induced by exercise during oral contraceptive use. Exercise-induced changes in hemostatic measurements were studied in 25 women. Twelve of the subjects were not using oral contraceptives and the remainder were using Demulen (ethynodiol diacetate (1 mg) and ethinyl estradiol (0.05 mg)). Exercise on a treadmill induced similar changes in both groups, but during the use of Demulen the levels of fibrinogen and plasminogen were higher, antithrombin level was lower, and the recalcified clotting and dilute whole blood lysis times were shorter in group 2 than in the corresponding samples obtained from the nonpill users.


Stimulating actions of various prostaglandins and noradrenaline in strips of rabbit renal artery. The myotropic effects of prostaglandins E1, E2, F2alpha, A1, and noradrenaline were evaluated in spirally cut strips of rabbit renal arteries suspended in a physiological salt solution maintained at 37 degrees C. The four prostaglandins as well as noradrenaline elicited contractions of the isolated rabbit renal artery. At concentrations higher than 1.0 X 10(-7) g ml-1 the contracting effect of prostaglandin E1 diminished. The vasoconstrictor actions of prostaglandins E2 and F2alpha were potentiated by cocaine and inhibited by phentolamine. On the other hand, phentolamine did not inhibit the vasoconstrictor effect of prostaglandins E2 and F2alpha on strips of rabbit renal arteries removed from rabbits pretreated with reserpine. These results were taken as an indication that part of the contractile effects of prostaglandins E2 and F2alpha on the isolated rabbit renal artery may be due to the release of noradrenaline from adrenergic nerve terminals.


Effect of the external concentrations of potassium and sodium on the release of (--)-[3H]noradrenaline from the adrenergic nerves of the rat vas deferens. The effect of the external concentrations of sodium and potassium on the nerve-induced release of (--)-[3H]noradrenaline from the adrenergic nerves of the rat vas deferens has been investigated. Increasing the external potassium concentration above 5 mM decreased the amount of noradrenaline released, while reducing the external potassium concentration below 5 mM had no significant effect on the induced release of noradrenaline. Decreasing the external sodium concentration below 75 mM progressively decreased the release of noradrenaline. It is concluded that the amplitude of the action potential is optimum for release at the normal resting membrane potential, and only decreasing the amplitude of the action potential alters the amount of transmitter released per nerve impulse.


Disopyramide phosphate: is it just another quinidine. We compared the effects of a therapeutic concentration of disopyramide with those of quinidine and lidocaine on the action potential characteristics and on the steady-state relationship between membrane potential and the maximum rate of rise of the action potential in the same normal Purkinje fiber in which constant impalement was maintained for more than 7 h. All the drugs depressed the steady-state upstroke velocity in the following order of magnitude: quinidine greater than disopyramide greater than lidocaine. Both lidocaine and disopyramide shifted the normalized steady-state curve to more negative membrane potentials indicating a greater depression of upstroke velocity at lower membrane potentials. Quinidine did not shift this curve. Lidocaine abbreviated all phases of repolarization while both disopyramide and quinidine shortened the plateau phase and lengthened the terminal phase of the action potential. The results suggest that the actions of disopyramide on upstroke velocity resemble those of lidocaine, while its effects on action potential duration resemble those of quinidine. The actions of this drug are therefore more complex than previously assumed.


Effects of 6-hydroxydopamine on brain and blood catecholamines, ammonia, and amino acids in rats. The effect of 6-hydroxydopamine (6-OHDA) upon brain and blood catecholamines, ammonia, and amino acids has been studied in rats subjected to increasing doses of the drug. Time dependent effects after injection have also been studied. Systemically injected 6-OHDA significantly, acutely reduced brain adrenaline (A), noradrenaline (NA), total catecholamines (TC), gamma-aminobutyric acid (GABA), and glutamic acid (Glu); concomitantly brain ammonia (NH3) increased. In blood, NA and TC were reduced and A and NH3 increased. The changes in brain monoamines are surprising since it has been reported that 6-OHDA does not cross the blood-brain barrier. We have proposed that these changes result from a general stress response or a reflex peripheral sympathetic response to falling blood pressure which in some manner communicates to the central nervous system. As the dose of 6-OHDA increased, brain NH3 increased and Glu decreased. A similar effect was seen from a single dose as the time after injection for sampling brain and blood constituents increased. Blood ammonia increases without change in Glu, glutamine, or asparagine. The source of NH3 may be from deamination of adenine nucleotide or catechols released from nerve terminals under the abnormal stimulus of 6-OHDA.


Effect of 6-hydroxydopamine on brain and blood catecholamine, ammonia, and amino acid metabolism in rats subjected to high pressure oxygen induced convulsions. Effects of 6-hydroxydopamine (6-OHDA) on rat brain and blood adrenaline (A), noradrenaline (NA), ammonia (NH3), gamma-aminobutyric acid (GABA), and amino acid metabolism prior to and after high pressure oxygen (OHP) induced convulsions have been studied. 6-OHDA reduces GABA and glutamate (Glu) rior to OHP exposure in rat brain so that the concentration is even equal to that seen in nondrugged animals after convulsion. Concomitantly, 6-OHDA reduces the latency of OHP-induced convulsion significantly, and increases brain NH3, glutamine, and asparagine significantly. Although 6-OHDA, in increasing dosage, elevates blood A concentration, convulsion produces a significant further increase in A. Blood NA was not significantly changed in drugged, convulsed animals and was much less than blood NA concentrations in nondrugged convulsed animals. Increasing doses of 6-OHDA also increase NH3 in the blood significantly and convulsion increases its concentration further. Latency of convulsion seems to be related to certain monoamine levels since in some drugged animals where A and total catecholamines are still reduced 96 h after the first of two doses of 6-OHDA, NA concentrations are recovered to relatively normal and the convulsion latency time is also increased although it remains significantly abbreviated from undrugged animals' convulsion time. Low brain GABA levels seem to be a prime effector of convulsive activity.


Glycogen metabolism in the genus Neisseria: synthesis from sucrose by amylosucrase. Eight strains (seven species) of Neisseria were found to possess intracellular amylosucrases capable of synthesizing glycogen directly from sucrose. All eight systems were stimulated by primer glycogen, possessed similar kinetic parameters, and were competitively inhibited to similar degrees by fructose. The enzymes bound tightly to their polysaccharide products but these complexes could be readily dissociated by polyacrylamide gel electrophoresis. Some of the enzyme-product complexes appeared to be virutally free of contaminating proteins.


Increased extracellular production of a cholinesterase-solubilising factor by Cytophaga NCMB 1314 during magnesium starvation. A Cytophaga sp. with the property of liberating a cholinesterase which is found in body muscle of plaice was studied. The liberation was caused by a factor of which more than 90% was found outside the bacterial cell and might possibly be associated within the slime material surrounding the bacteria. Magnesium limitation during growth of Cytophaga sp. in batch cultures resulted in an about 10-fold increase in extracellular factor activity. The increase could be immediately stopped by addition of magnesium ions or chloramphenicol to the medium. The effect of the latter might indicate that the increase in factor activity is dependent on protein synthesis under magnesium-limiting conditions.


Characteristics of Streptomyces coelicolor A3(2) aerial spore rodlet mosaic. Cytochemical analysis of Streptomyces coelicolor (A3(2) indicated that the aerial growth rodlet mosaic is a polysaccharide. Statistical analysis of frequency distributions of individual rodlet lengths from control and ether-reoriented spore mosaics indicated that the rodlet fibrillar image is the result of individual particulates, rather than evaginations in a continuous sheet of material. A model of the mature sport envelope was developed from freeze-etch-replicated, thin-sectioned, and critical point dried S. coelicolor A3(2) mature spores. The rodlet mosaic was situated between the outer spore wall and an external granuloma matrix. Mixture spore envelope layers from the inner surface to the external surface are plasma membrane, inner spore wall, outer spore wall, rodlet mosaic, an undefined granular matrix, and the sheath. The granular matrix had an uneven thickness and much  of the matrix was frequently absent from the interspore spaces of mature spore chains. Streptomyces coelicolor A3(2) mosaic rodlets were isolated by acetic acid refluxing, then ethanol precipitation. Complete acid hydrolysis of rodlets released on sugar which cochromatographed with D-glucosamine-HCl and released acetic acid at 139% of the expected level. Cell associated rodlet mosaics and isolated mosaic rodlets were hydrolyzed with chitinase. Infrared spectra of isolated rodlets were similar to crab chitin spectra.


Microbiological titration of proteins and of single amino acid content in biological materials without purification and hydrolysis. A method is described for the microbiological determination of the protein content of biological materials. This method can also be adopted to titrate the concentration of a single amino acid in the protein and has the following advantages: (1) titration can be done without purification and hydrolysis of proteins; (2) the titration graph is a straight line between 25 and 800 microgram/ml; (3) protein values agree with those obtained using the Kjeldhal method; and (4) each mutant requiring one amino acid may be used to titrate the concentration of a single amino acid of the protein. The leucine content of various kinds of flour was measured with this system.


New Minto virus: a new rhabdovirus from ticks in Alaska. Three strains of a virus were isolated from Haemaphysalis leporis-palustris (Packard) ticks removed from snowshoe hares (Lepus americanus Erxleben) in east central Alaska. We suggest that the virus be named New Minto for the location in which the ticks were collected. Prototype New Minto virus is sensitive to the action of sodium deoxycholate and kills suckling mice by the intracerebral but not intraperitoneal route; weaned mice do not die after intracerebral, intraperitoneal, or subcutaneous inoculation. The virus produces plaque in serially propagated Vero but not in primary Pekin duck embryo cells. By complement-fixation and neutralization tests New Minto is related to Sawgrass Virus, a hitherto ungrouped virus from Florida. The establishment of a Sawgrass group is suggested. In addition, Sawgrass virus was found by electron microscopy to belong to the Family Rhabdoviridae.


Double-antibody radioimmunoassay for staphylococcal enterotoxins A and B. A sensitive double-antibody radioimmunoassay for staphylococcal enterotoxins A and B is described. The separation of the primary antigen-antibody complex of enterotoxin A and B was achieved with an anti-rabbit gamma globulin from goats. Radioiodinated aggregate fractions of staphylococcal enterotoxins exhibited reduced immunological activity and showed little competition with non-radioactive exterotoxin. The radioimmunoassay was successfully applied for the quantitation of enterotoxins in food.


Isolation and characterization of Hfr strains of Erwinia amylovora. Hfr strains (Hfr 159 and its derivatives, Hfr 160 and Hfr 161) were constructed from Erwinia amylovora ICPB EA178 by introducing an Escherichia coli F'his+ plasmid and then selecting for integration of F'his+ after treatment with acridine orange. The Hfr strains were relatively stable upon repeated transfers on nonselective media. Interrupted mating experiments and analyses of inheritance of unselected markers showed that his+ is transferred by Hfr 159 as the proximal marker at a relatively high frequency (about 5 x 10(-4) recombinants per input donor cell), followed by ilv+, orn+, arg+, pro+, rbs+, met+, trp+, leu+, ser+, and thr+ (not necessarily in that precise order). The donor strains, previously constructed in E. amylovora by integration of F'lac+ from E. coli transfer cys+ as the proximal marker followed by ser+. Further analysis of one of those earlier donor strains, Hfr99, showed that ser+ is followed by arg+, orn+, met+, pro+, leu+, ilv+, rbs+, his+, trp+, and thr+ (not necessarily in that precise order). Thus, the Hfr strains constructed by integration of F'his+ are different, in terms of origin and direction of transfer, from those derived from integration of F'lac+. The applicability of these Hfr strains to mapping the genes on the E. amylovora chromosome is indicated.


[The GC content of a group of H2S- enterobacterial related to the genus Citrobacter]. The deoxyribonculeic acid (DNA) of 106 strains of Enterobacteria was analysed for the guanine + cytosine (GC) content. These strains, whose origin and principal characters are described in the text, belong to the genera Citrobacter (C. freundii H2S-) and Levinea (L. malonatica and L. amalonatica). Four other groups or classes named C.D.E. and F. could not be classified on the base of the usual phenotypic criteria. DNA from the strains of Levinea has a GC% of 50.3 to 53.3, while DNA from the strains of C. freundii H2S- has a GC% of 48.6 to 51.7. The representative values from the new classes are C, 50.9%; D, 54%; E, 52.7%; F, 49.5%. For the latter a genomic heterogeneity was shown, expressing itself as two subpopulations whose average GC% are 51.7 and 48.6 respectively. Statistical analysis of the averages give a significant individuality to these new classes.


Diagnosis of penicillin allergy by skin testing: the Manitoba experience. The reliability of skin testing in the diagnosis of penicillin allergy was studied in 86 adults and 167 children with a history of possible hypersensitivity reactions to penicillin. Skin testing was done with the major antigenic determinant of benzylpenicillin and minor determinants of benzylpenicillin, ampicillin, cloxacillin, methicillin and cephalothin. The overall frequency of positive skin reactions was 11.5%. Among the patients with positive skin reactions about half had a history of immediate or accelerated reactions to penicillins, but 2 of 11 adults and 50% of the children in this group had a history of maculopapular rash of delayed onset. There was a low frequency of positive skin reactions when there was a long interval between the times of clinical reaction and skin testing. Of 169 patients reacting negatively to skin testing who received a specific drug challenge only 2 manifested mild urticaria; this indicates the reliability of the skin tests in predicting penicillin allergy. The major and minor determinants of benzylpenicillin were the most useful reagents. One fifth of the patients with penicillin hypersensitivity would have been missed if the major determinant of benzylpenicillin alone had been used for skin testing. The additional use of the minor determinants of other penicillin derivatives, however, did not increase substantially the clinical reliability of the skin testing procedure.


Effect of hydrochlorothiazide on urine saturation with brushite, in vitro collagen calcification by urine, and urinary inhibitors of collagen calcification. To clarify further the beneficial effect of thiazide diuretics on recurrent calcium nephrolithiasis, the effect of short-term hydrochlorothiazide therapy on urine saturation with brushite (CaHPO(4).2H(2)O), in vitro collagen calcification by urine, and urinary inhibitors of calcification was studied.In 22 patients with idiopathic calcium oxalate/phosphate stones the urine calcium excretion decreased, the urine magnesium excretion increased and the urine magnesium/calcium ratio increased significantly (P < 0.001) during hydrochlorothiazide therapy. Supersaturation of the urine with brushite, which was present in 19 of the 22 patients, was reduced significantly (P < 0.001) in all during thiazide therapy, and to the undersaturated range in 16. The ability of urine to calcify collagen in vitro also decreased significantly (P < 0.001) during thiazide therapy, a change that correlated significantly (r = 0.4513, P < 0.05) with the decrease in brushite saturation. The concentration of urinary inhibitors of calcification, as determined with an in vitro collagen calcification system, was decreased significantly (P < 0.01) by thiazide therapy.It was concluded that, in addition to decreasing urine calcium excretion and increasing urine magnesium excretion, thiazide diuretics decrease the urinary brushite saturation and thus may prevent spontaneous nucleation or crystal growth, or both, of calcium phosphate. The ability of thiazides to decrease collagen calcification in vitro suggests that they may also prevent crystal growth on a nidus of organic matrix. Thiazides do not appear to act by increasing the excretion of urinary inhibitors of calcification.


Carbon monoxide poisoning from Sterno.

Carbon monoxide poisoning from Sterno. A high school student became ill and later unconscious while working over a heating table set over three cans of burning Sterno. Measurements of 1000 to 3000 parts per million of carbon monoxide were obtained around and above the apparatus. Although the room was well ventilated there was incomplete combustion of the canned heating fuel because the apparatus was surrounded by aluminum foil, which resulted in poor oxygenation of the flame area. This case demonstrates the hazards of carbon monoxide poisoning from incompletely burned Sterno.


The nonspecific nature of fibrin thrombi in ischemic bowel disease. Twenty cases of ischemic bowel disease were analysed to determine the frequency and significance of fibrin thrombi in this condition. Fibrin thrombi were present in all 10 patients with occlusive ischemic bowel disease and in 7 of the 10 patients with nonocclusive ischemic bowel disease. In addition, fibrin thrombi were noted in a wide variety of specific and nonspecific inflammatory bowel diseases and in acute appendicitis. We conclude that fibrin thrombi are a nonspecific feature of tissue necrosis and that their mere presence in the bowel should not be regarded as an expression of disseminated intravascular coagulation.


Swelling of olecranon bursa in uremic patients receiving hemodialysis. Three patients with chronic renal failure who received therapy with hemodialysis through arteriovenous fistulas in the forearm had fluctuating swelling over the elbow on the same side as the fistula used for the dialysis. The clinical findings in each case were compatible with olecranon bursitis with effusion. The aspirate obtained from the swellings contained lymphocytes, polymorphonuclear leukocytes and histiocytes, a finding similar to that in cases of uremic pericardial and pleural effusion. Biopsy of the bursa in one case showed hyalinized collagenous tissue with infiltration by histiocytes and lymphocytes, reflecting underlying chronic inflammation. Uremia was believed to be the causative factor. Bursitis with effusion is considered to be one of the clinical aspects of uremic polyserositis.


Indian people and community psychiatry in Saskatchewan. A discrepancy is identified between the increase in inpatient admissions and of outpatient contacts of Treaty Indians in Saskatchewan from 1967 to 1976. This is the reverse of the trend in the non-Treaty Indian population, and represents a contradictory effect to the intention of the Community Psychiatry Program of the province's government. No major diagnostic differences were at statistically significant levels, which might have accounted for the higher inpatient admission rates and the relatively lower outpatient contact rates of Treaty Indians. This is an interesting example of the use of governmental statistics and a promising one for the identification and solution of problems in health care delivery.


The diagnosis of personality disorders: a pilot study. A pilot study was carried out to see what levels of agreement on the diagnosis of the different types of personality disorder, described by Schneider, could be obtained by observers with different amounts of clinical experience. Audio-recordings of eight patients were examined by 10 raters, who represented three levels of experience. Two patients had the same diagnosis made by 80 percent of the raters and these cases seemed best described as "typical". In all the cases agreement was increased when a second choice diagnosis was permitted. Significantly greater agreement was recorded by clinical clerks than by psychiatrists or psychiatric residents, though this was probably due to their making use of fewer of the types. It seemed probable that some types were less likely than others to be used for a first choice diagnosis. It is recommended that the most typical patients be employed in research in the field of the personality disorders if high diagnostic reliability is required.


Insanity defense in Canada.

Insanity defense in Canada. The author has reviewed in this paper the difficulties in developing a more generally accepted test of criminal responsibility. Such difficulties are more clearly seen when studying the applicability of the criminal responsibility test in Canadian law, Section 16, which the author describes as a disguised M'Naghten rule. Finally it is agrued that, because of the strictures encountered in the application of M'Naghten, some alternative routes have been developed at the courtroom level, notably Section 215 of the Criminal Code which deals with provocation. Section 215 gives legal footing to emotional conditions, producing an impairment in an accused's ability to form intent.


The use of electroconvulsive therapy.

The use of electroconvulsive therapy. Electroconvulsive therapy is a treatment procedure in psychiatry which has frequently come under considerable critical scrutiny. This paper describes its use mainly in a postgraduate institute of psychiatry and, for comparative purposes, two other types of psychiatric facilities in Toronto. The treatment is given conservatively, varying to hospital, and is prescribed for 11 percent of patients at a postgraduate institute. However, it is used largely for those with depressive disorders as recommended in standard textbooks. Diagnosis and age are the key variables affecting ECT prescription. It is suggested that ECT practice is effective by and large and now efforts should concentrate on making it efficient.


Diazepam addiction: a case report.

Diazepam addiction: a case report. A case of addiction to Diazepam is reported. Severe withdrawal symptoms such as tremulousness, irritability, increased psychomotor activity, generalized muscle cramps, photophobia, retro-orbital pains and insomnia are described. Visual hallucinations, illusions, and paranoid features are also present in this case. Detoxification and management were accomplished by gradual withdrawal and the addition of another tranquilizer, anticonvulsant and muscle relaxant. The author reviews other such reports of abuse and addiction in the literature which call for wide recognition of the addictive properties of Diazepam and for restrictions on its indiscriminate prescription by physicians.


I. Formulation.

I. Formulation. The authors describe a systematic approach to the process of formulation. Four interlocking phases are considered. The longitudinal data collection evaluate the patient's developmental journey. The cross-sectional evaluation includes careful consideration of phenomenological and dynamic factors. The integrative evaluation of these factors permits the construction of both a dynamic and a phenomenological diagnosis. Finally, in hypothesizing a tentative prognosis, we attemt to predict the capacity and quality of a person's potential change and readjustment.


II. A method of reporting formulation.

II. A method of reporting formulation. The authors present a method of reporting and evaluating a formulation. The reporting of a formulation includes a summary introduction, biological considerations, psychosocial considerations and hypothesis construction. Three sample formulations are scrutinized and specific critical evaluations offered. The subsequent reformulations are presented.


Family therapy and schizophrenia.

Family therapy and schizophrenia. The early concepts of family influences in the development of schizophrenic illness have been reviewed. The empirical research which these concepts generated has failed in large measure to confirm many of these hypotheses, but has demonstrated reliable and valid differences between families of schizophrenics and those of patient and non-patient controls. However, these empirical findings have had little impact to date on family therapy as it is practised, and the failure to confirm theoretical concepts from psychoanalysis, systems, and communication theories has not led to a re-examination of family therapy and its theoretical basis. The author suggests that the empirical research on family influences in schizophrenia and particularly those factors which precipitate and perpetuate schizophrenic symptomatology can be applied to evaluation of schizophrenics and their families, specific family therapy with families of schizophrenics, and particularly suggest that evaluative research on the effectiveness of family therapy in schizophrenia will be necessary for family therapy to become more than a highly fascinating and experimental technique in the total management of schizophrenic patients.


Stresses associated with career success for women. In recent years, more women have pursued careers in business and the traditionally male professions. Those that have succeeded live with a high degree of environmental stress. Since some of them are now consulting psychiatrists it is important that the psychiatrist be able to differentiate difficulties which have a cultural basis from those stemming from individual psychodynamics. Cultural stresses have been reviewed under three headings: inaccurate stereotypes; inadequate cultural supports; and role overload. It has been suggested that contact with her peer group is extremely important for this type of woman patient. The peer group provides both support and a frame of reference within which individual problems may be understood.


Carcinoma of the pyriform sinus. An analysis of treatment results and patterns of failure. A retrospective review of 169 patients with carcinoma of the pyriform sinus was accomplished for a ten-year-period from 1964 to 1974. Of the 169, 80 (47%) were treated with low dose preoperative radiation and partial laryngopharyngectomy (PLP), 57 (34%) were treated with radiation and total laryngectomy-partial pharyngectomy (TLP), and 32 (19%) were treated with palliative radiation, surgery or chemotherapy. Act,arial five-year-survival was 31% for all cases, 59% for the PLP group, 21% for the TLP group and 4% for the palliation group. Eighty to 90% of the relapses occurred within two years. The primary and/or nodal failure rates were 23, 37 and 78%, respectively for the PLP, TLP and palliation groups while the distant metastasis rates were 15, 37 and 34% for the three groups. Sites of failure differed for the three groups with a relatively high rate of contralateral neck metastases (23%) in the TLP group and an overwhelming number of primary and ipsilateral failures (78%) in the palliation group. Retreatment of failures resulted in few salvages (15%) and a significant number of fatal complications (26%). The cause of death was tumor related in most cases.


The management of clinical stage I endometrial carcinoma. A retrospective analyses of 307 cases with clinical Stage I endometrial carcinoma was done in an attempt to determine the role of radiation therapy in the optimal treatment of this disease. A review of the modern literature with over 9000 cases served as a useful tool to corroborate inferences and conclusions. The present series has 155 patients (51%) treated with preoperative megavoltage external pelvic radiation with a variation in doses of less than 6%. Five-year survival estimates (79%-83%) in clinical Stage I endometrial carcinoma are similar among the several main treatment combination that are employed; they become a useless parameter for any comparison. The pelvic failure rate constitutes a more useful guideline in assessing the most adequate therapy. The pathologic grade of the tumor is the main prognosticator in endometrial carcinoma. Intimately related to the tumor grade is the depth of myometrial invasion of the carcinoma. The size of the uterus and/or its cavity carry less prognostic significance than traditionally thought. For grade I lesions, there is little error in diagnosis, few pelvic failures and excellent survival (96%); they could be approached with initial surgery and postoperative radiation reserved for selected patients. For grade 2 tumors, the error in diagnosis and the failure rate increases with an overall survival of 87%. For grade 3 tumors, the error in diagnosis and failure rates are quite high with a 5 year survival of only 70%. Preoperative radiation, especially external beam therapy, is suggested for grades 2 and 3 Stage I tumors. The use of this treatment modality yields only 3% pelvic failure and an overall 5 year survival of almost 90%.


Effect of radiation on cell-mediated cytotoxicity and lymphocyte subpopulations in patients with ovarian carcinoma. Lymphocyte subpopulations and cell-mediated cytotoxicity (CMI) were studied during radiation therapy in 16 patients with ovarian carcinoma. The total lymphocyte count became depressed in all patients. The depression was more marked among T cells, while the proportion of B cells remained unaffected. In patients with Stage I and II ovarian cancer, CMI was depressed significantly by radiotherapy after 7 days of treatment, remained low at 14 days but recovered despite continuation of radiation. This depression of CMI occurred at a delivered dose of 1,000 rads with subsequent recovery. Patients with Stage III ovarian cancer given pelvic and abdominal radiation were found to have no consistent depression of CMI, a finding similar to that in Stage III ovarian carcinoma patients given chemotherapy.


An analysis of factors in the successful management of cancer of tonsillar region. A total of 117 consecutive primary cancers of the tonsillar region was irradiated at the University of Illinois Hospitals from 1955 to 1973. Results with 94 patients treated with radiotherapy alone and 23 with a combination of surgery and radiotherapy were analyzed. The modalities of radiation used were electron beam, 22 meV photons and Cobalt-60. Lymph node metastases were noted in 70% of the patients at the initial examination. In patients treated with radiation alone the determinant 5-year survivals were 42% without and 20% with nodal involvement. In the absence of node disease, survivals were 100% in T1, 60% in T2, 37.5% in T3 and 25% in T4 lesions. The significance of age, sex, histological differentiation, extent of the tumor, modality of treatment and the incidence of second primary were analyzed. Time dose relationships and factors influencing the prognosis are discussed and the literature is reviewed.


Intensive postoperative chemoimmunotherapy for patients with stage II and stage III breast cancer. For the past 34 months, a combination of 5-fluorouracil, adriamycin, cyclophosphamide, and BCG (FAC-BCG) was evaluated as adjuvant treatment in stage II and III breast cancer patients with positive axillary nodes. In the group of 131 patients receiving FAC-BCG, the estimated proportion remaining disease-free at 2 years from surgery was 91% compared to an estimated 69% in a group of 151 historical control patients (p less than .01). This advantage was statistically significant in all subgroups except for patients with primary tumor less than 3 cm and for patients with less than 4 positive nodes. Estimated 2-year survival rates were 9,6% for FAC-BCG patients and 86% for control (p = .02). Treatment was well tolerated. Adjuvant FAC-BCG seems effective in prolonging disease-free interval and early survival in patients with stage II and III breast cancer. Its long term efficacy will require longer follow-ups.


Prolonged complete remission following high dose chemotherapy of Burkitt's lymphoma in relapse. Fourteen patients with American Burkitt's lymphoma resistant to conventional chemotherapy were treated with high-dose combination chemotherapy and intensive supportive care. Four patients died shortly after chemotherapy, 3 of an acute carditis. All ten remaining patients demonstrated tumor regression and 3 remain in prolonged complete unmaintained remission 29+, 19+, and 9+ months after treatment. These findings demonstrate that high-dose chemotherapy will benefit some patients with Burkitt's lymphoma unresponsive to conventional chemotherapy, but the medullary and extramedullary toxicity of this treatment strategy remains a formidable obstacle.


Changes in cell-mediated immunity in patients undergoing radiotherapy. The cell-mediated immune status of 147 patients who received radiotherapy was evaluated using in vitro tests (PHA, E-rosette and spontaneous blastogenesis) both before and 6 weeks after the end of radiation. All patients had verified malignancies, involving the bronchus in 29 cases, breast in 28, female genital system in 26, head and neck in 20 and bladder in 15. Patients suffering from bronchogenic carcinomas or malignancies of the head and neck showed a relative high degree of immune suppression. Our findings indicate a trend towards some improvement in PHA reactivity, as well as in as the percentage of E-rosette-forming cells after treatment, which is more noticeable in patients with pelvic or breast tumors. A relationship seems to exist between the tumor load and the immune status, which reverts to a normal pattern when the former is extinguished. Moreover, patients with poor clinical response display a profoundly depressed level of immune status without any improvement after treatment.


Pancreatic carcinoma treated with high-dose, small-volume irradiation. Eighteen patients with unresectable ductal adenocarcinoma of the pancreas received definitive, high-dose, small-volume radiation therapy. All patients had at least one laparotomy, at which time a biopsy was obtained, radio-opaque clips were placed to define the extent of the gross tumor, and usually some form of bypass procedure was performed. External-beam irradiation was delivered from a 45-MV betatron to an area encompassing the clipped tumor volume plus a 1 to 2 cm margin. A three-field technique, employing opposed lateral 45-MV photon beams and an anterior "mixed beam" (50% 45-MV photons and 50% 15- to 35-MeV electrons), was used to treat 13 of the patients. The choice of electron energy used for these patients was based on the depth of the posterior margin of the target volume. Five patients were treated by either four-field "box" or three-field, 45-MV photon techniques. Minimum tumor dose was 6300-6700 rads delivered in 180-rad fractions in 7-9 weeks. With the three-field technique, all fields were treated daily; with the four-field technique, two fields were treated daily. The projected survival rate 12 months post idagnosis is 59%, with the median length of survival, 11.8 months. Seven patients are alive 11.5 to 57 months after diagnosis, all clinically free of disease. Treatment has been generally well tolerated, and there have been no severe late radiation complications. This therapeutic modality appears capable of producing improved palliation, if not offering definitive radiotherapeutic management of localized unresectable carcinoma of the pancreas.


Mammographic parenchymal patterns as a risk indicator for prevalent and incident cancer. Different mammographic parenchymal patterns have been found to be associated with significantly different rates for the development of breast cancer in a screening program of self-referred women. These differences are qualitatively similar but of lesser magnitude than those in previous reports by Wolfe which were based on symptomatic women who had had a previous negative mammogram. In addition, this report indicates a small difference in the rate of breast cancer at first mammographic examination, using the same parenchymal classifications. These findings, coupled with other risk factors, may permit the concentration of mammographic screening on a smaller segment of the population at risk, thus improving the benefit to risk ratio.


Patterns of human thyroid parenchymal reaction following low-dose childhood irradiation. Microscopic changes in the thyroids of 68 patients who had received low-dose childhood irradiation to the head and neck and who presented with palpable thyroid abnormalities culminating in surgery are compared to 34 control thyroids obtained from age- and sex-matched autopsy cases. Eighty-eight percent of irradiated thyroids showed moderate to severe focal hyperplasia, 51% contained single or multiple adenomas or adenomatous hyperplastic nodules, 68% exhibited chronic lymphocytic thyroiditis, 51% revealed colloid nodules, 42% presented with oxyphile change, 25% had mild fibrosis and 59% contained well-differentiated papillary, follicular or mixed thyroid carcinoma averaging 1.6 cm in diameter. Three small carcinomas were of the sclerosing type. The non irradiated thyroids showed 32% colloid nodule formation, 17% focal hyperplasia, 6% adenomatous hyperplasia and no identifiable carcinomas. Several nonspecific histologic abnormalities are now recognized as following low-dose radiation to the thyroid, the most important being focal hyperplasia, which may represent a pre-malignant change in thyroid parenchyma.


Production of several substances by medullary carcinoma of the thyroid. Two patients with the typical morphology of medullary carcinoma of the thyroid are reported. Biochemical analysis of the tumor tissue demonstrated the presence of calcitonin, ACTH and MSH, although symptoms referable to these hormones were hardly manifested. Serum CEA levels were elevated and CEA immunofluorescences in the tumor cells were positive. Moreover, in one patient, serotonin concentration was raised in the tumor tissue, and gastrin level was also elevated in the peripheral blood. These results suggest that the tumors may produce several substances.


Fibrinogen kinetics in patients with neoplastic disease. Fibrinogen half-life was determined in 30 patients with active or inactive malignancies by monitoring survival of administered 125I-labeled autologous fibrinogen. Six patients had no evidence of active disease and served as controls having fibrinogen levels and half-lives within the normal range reported in the literature. Twenty-six studies were conducted on 24 patients with various active malignancies. Significantly shorter fibrinogen half-lives were found in patients with active malignancies. The fractional catabolic rates calculated from both the plasma data and the urinary isotope excretion were significantly increased in patients in this group. Although there is some evidence that exposure to intensive chemotherapy may further shorten fibrinogen survival, there is no significant difference between treated and untreated or responding and nonresponding groups. The major determinant of fibrinogen survival appears to be the presence of active malignant disease, in addition to the specific type of malignancy involved.


Cancer of the nasopharynx in children.

Cancer of the nasopharynx in children. The authors present 15 children with cancer of the nasopharynx. Of seven patients with primary epidermoid carcinomas, only two are alive and well. Only one of four patients with a primary soft tissue sarcoma is alive and well. Two of four patients with lymphoma of the nasopharynx are alive and well. All deaths were due to uncontrolled distant metastases. Only one patient (rhabdomyosarcoma) died with uncontrolled local disease. Radiotherapy to the primary and neck is recommended for all children with primary malignancy of the nasopharynx. Adjuvant chemotherapy may also be of value for all patients regardless of histopathology.


Panhypopituitarism resulting from Hodgkin's disease of the nasopharynx. Nasopharyngeal involvement by Hodgkin's Disease is rare and may result in deafness, headaches, nasal obstructions and other symptoms. Compression of the pituitary gland with resultant panhypopituitarism has not been reported in nasopharyngeal Hodgkin's Disease. This paper documents a patient in whom Hodgkin's Disease of the nasopharynx eroded the bony sella turcica and compressed the pituitary gland causing anterior pituitary insufficiency. The patient presented with a skull x-ray and history compatible with a pituitary neoplasm. The diagnosis was established only by surgical exploration.