Commentary: An appraisal of tobramycin usage in pediatrics. Tobramycin is a newly marketed aminoglycoside which closely resembles gentamicin in antimicrobial activity, pharmacology, clinical efficacy, and toxicity. It is somewhat more active in vitro against Pseudomonas aeruginosa than is gentamicin and may have a lower ototoxic potential. Tobramycin should be considered a limited-purpose drug for pediatric patients until greater clinical experience has been gained. At the present time the major indication for its use is for treatment of infections caused by coliforms or pseudomonas resistant to kanamycin and gentamicin. Demonstration of in vitro susceptibility is mandatory because resistance to tobramycin and the other aminoglycosides may be mediated by the same episome (R-factor). The recommended dosage is 2 mg/kg every 12 hours (4 mg/kg/day) intramuscularly or as a two-hour intravenous infusion to neonates, with the possible exception of full-term infants over seven days of age who may require administration every eight hours. Beyond the neonatal period, the dosage should be 1.0 to 1.5 mg/kg every eight hours (3 to 4.5 mg/kg/day). Larger dosages may be required for treatment of meningitis, but presently there is no information on which to base a recommendation. Neither is there experience with intrathecal use in infants. It is desirable to monitor tobramycin serum concentration to be certain that peak values are within the therapeutic range of 3 to 8 mug/ml. Dosage must be reduced in patients with impaired renal function and monitoring of serum concentrations is imperative. All patients should be evaluated for evidence of renal and eighth nerve toxicity.


Emotional adjustment of adolescents and young adults with cystic fibrosis. Twenty-seven adolescents and young adults with cystic fibrosis were studied to evaluate the phychological impact of this chronic illness. At first glance, most patients appeared to function adequately on a daily basis. However, four sources of psychological stress, leading to emotional disturbance, were identified: altered physical appearance causing distorted body images and denial of sexuality, strained interpersonal relationships resulting in isolation and mental strain, conflicts in upbringing, and increased awareness of the future and of death. Guidelines for the physician treating these young adults and their families include: (1) encouragement for greater involvement by the patient's father; (2) assisting the mother to find outside interests and to allow more independence to the patient; (3) stressing communication about cystic fibrosis within the home; (4) emphasizing outside activity for each patient; (5) repeated discussions of the patient's concerns while emphasizing his strengths; (6) anticipation of problems, specific to cystic fibrosis, such as sterility in males; and (7) encouragement of interpatient communication.


Proteinuria and hematuria in schoolchildren: epidemiology and early natural history. Over the past several decades screening for disease in large asymptomatic populations has increased, culminating most recently with a federal mandate for early, periodic screening, diagnosis and treatment of all children from low-income families. The present study of five consecutive examinations in over 12,000 schoolchildren shows the cumulative occurrence of proteinuria and hematuria to be surprisingly high (greater than 6%). Comparison of this large number of children with the few individuals in whom death occurs from chronic renal disease annually (less than 0.03%) suggests that the vast majority of these children with urinary abnormalities have either no renal disease or at most a self-limited condition. Observation of 512 children with proteinuria and 78 with hematuria for one to five years after initial detection and referral to their physician or clinic provides a measure of both contemporary management and early natural history. These observations suggest that there is a need to question the overall effectiveness of urinary screening and that early inclusion of roentgenographic and urologic investigations in management seems unwarranted. Rather, these children should be followed for long periods of time. Additional investigations are indicated when worsening of the abnormal findings or other evidence of renal or systemic disease occurs. If routine urinary screening is performed, it should be as one aspect of a multiphasic program by the primary physician so that it can be coupled with a clearly defined plan for follow-up and management of subjects with abnormal findings.


Studies of the contractility of mammalian myocardium at low rates of stimulation. 1. Measurements have been made of tension development in papillary muscles isolated from the right ventricles of young cats. In some cases membrane potentials have also been recorded, using micro electrodes. 2. Regular contractions at a stimulation rate of 20 min(-1) (the 'standard' rate used in this study) had the following characteristics (30 degrees C): peak tension developed, about 43mN mm(-2); time to peak tension and time to 80% repolarization of the cell membrane, about 400 ms. 3. The corresponding figures for the first contraction after a rest of several minutes (rested state contraction) were: tension developed, about 4mN mm(-2); time to peak tension and time to 80% repolarization of the cell membrane, about 560 ms. Sometimes there was also an early peak in the mechanical response, about 250 ms after stimulation. 4. The time course with which tension development declined when the muscle was allowed to rest was examined under various conditions. It was found to decline more slowly when the muscle was potentiated by raising the bathing Ca2+ concentration and by stimulation at rates above 20 min(-1). 5. Tension development in rested state contractions was found to depend on the Ca2+ and Na+ concentrations in the bathing solution. The full effect of a change in either could be produced by exposing the resting muscle to the altered ionic conditions. 6. These experimental findings have been interpreted in terms of a simple model of the calcium movements involved in excitation-contraction coupling in the myocardial cell.


Activation and inhibition of the lateral hypothalamic neurones elicited by medial forebrain bundle stimulation. 1. Single neurone discharges were recorded from the lateral hypothalamus (LH) at the level of the ventromedial nucleus. Single stimulation of the medial forebrain bundle (MFB) at the level of the mesodiencephalic junction elicited a strong inhibition lasting for 100-300 msec in these neurones. 2. However, by the use of multiple stimulating electrodes, it was possible to find a circumscribed locus in the MFB which gave rise to an initial activation of firing discharges with a latency of 1-15 msec (in different neurones) preceding the period of inhibition. 3. One class of the LH neurones was antidromically activated, and was thought to give off axons into the descending MFB. The other was activated orthodromically through a highly efficient synaptic connexion, and was viewed as 'relay' neurones of the ascending MFB. 4. Although the former could also be activated orthodromically, the efficacy of driving was distinctly lower than that observed in the latter. Presumably they integrate the messages from the visceral centres of the medulla and pons, thus participating in the viscero-motor outflow from the hypothalamus. 5. Intracellularly recorded spike potentials of these neurones deteriorated rapidly leaving only hyperpolarization which corresponded in its time course to the suppression of extracellular spike discharges following MFB stimulation. It was suggested that the inhibition was elicited via recurrent routes localized within the hypothalamus.


A voltage-sensitive persistent calcium conductance in neuronal somata of Helix. 1. An intracellular voltage clamp in conjunction with a patch pipette utilizing feed-back to monitor local current from the soma membrane were used to analyse transient and stationary currents in bursting pacemaker neurones in Helix pomatia and H. levantina. 2. A weak, net inward current flows during small (less than or equal 20 mV) depolarizations. This current exhibits slow activation kinetics, persistence during prolonged depolarization, and slow turning off at end of depolarization. Consequently, the steady-state current-voltage curve exhibits a region of negative resistance from about -55 to -35 mV. 3. The slow inward current and the negative resistance characteristic are rapidly and completely abolished by substitution of Co2+ or La3+ for Ca2+ and are partially blocked by the Ca-blocking drug D-600. Substitution of Tris or glucose for Na+ significantly reduces the inward current only after 15-20 min exposure, recovery being equally slow. 4. The inward current and the negative resistance characteristic of the I-V curve are greatly enhanced by Ba2+ substitution for Ca2+. This is ascribed in part to Ba2+ carrying current through the slow inward current channels and in part to a suppression of the late K+ current by Ba2+. 5. The inward current is also present in many non-bursting neurones but fails to appear as a net inward current due to short circuiting by a leakage current or by the delayed potassium current. In these cells the slow inward current contributes to inward going rectification. Replacement of Ca2+ with Ba2+ enhances the current so as to produce a net inward current during small depolarizations in these neurones. 6. It is concluded that the slow inward current is carried primarily by Ca2+ in the soma membrane of bursting pace-maker neurones and a number of non-bursting cells examined in the parietal ganglion of Helix. 7. The sensitivity to small depolarizations and persistence during prolonged depolarization suggests two roles for the Ca system in the generation of slow pace-maker oscillations. In this model the Ca system contributes to the slow depolarization which constitutes the onset of the pace-maker wave, and also contributes to the increment in [Ca] in which activates the Ca-sensitive K+ conductance responsible for repolarization. The inhibition of spontaneous bursting by Ca-blocking agents supports this model.


Effects of isopropylnoradrenaline on tachyphylaxis of gastrin stimulated gastric acid secretion and mucosal blood flow in the anaesthetized cat. 1. Gastric acid and mucosal blood flow responses to sustained gastrin stimulation were studied in anaesthetized cats. 2. Acid and mucosal blood flow showed identical rates of tachyphylaxis to both large (maximal) and small doses of gastrin. 3. Isopropylnoradrenaline infused either intravenously or close arterially to the stomach produced increases in blood flow unrelated to time following the peak response to large doses of gastrin, whereas increases in acid secretion appeared to be a part removal of the acid tachyphylaxis. 4. During stimulation by small doses of gastrin, isopropylnoradrenaline increased both blood flow and acid secretion above the peak responses to gastrin alone. 5. Increases in gastrin stimulated acid and mucosal blood flow were also produced by expansion of the blood volume by dextran-saline infusions. 6. The physiological significance of these findings is discussed. 7. It is concluded that tachyphylaxis of gastric acid secretion to gastrin may be a function of the primary tachyphylaxis of mucosal blood flow.


Involvement of uptake2 in the termination of activity of neurogenic noradrenaline in the rat isolated atrium. 1. An examination has been made of the relative effect of drugs which affect Uptake1 and Uptake2 on the mechanical responses to adrenergic nervous stimulation (0-5-5 Hz for 5 sec) in rat isolated atrium. 2. Inhibition of Uptake1 with desmethylimipramine (2 muM) prolonged by 50-90% the time taken for recovery of normal heart rate after a five sec train of nervous stimulation. Inhibition of Uptake2 with metanephrine (4 muM) prolonged by 20-40% the time taken for recovery of normal heart rate. 3. Neither desmethylimipramine nor metanephrine had any consistent effect on the time course of the inotropic response to stimulation or on the amplitudes of either inotropic or chronotropic responses. 4. After administration of desmethylimipramine, metanephrine had a somewhat greater effect on chronotropic responses than when given alone. After administration of metanephrine, desmethylimipramine still further prolonged chronotropic responses to low frequency stimulation (0-5, 1 Hz) but had no effect at 5 Hz. These results agree with the known affinities of each uptake process for different concentrations of noradrenaline in the rat heart. 5. It is concluded that both Uptake1 and Uptake2 participate in the termination of physiological activity of neurogenic noradrenaline in rat isolated atrium even at low frequencies of nervous activation. 6. No evidence was obtained to indicate that manipulation of circulating oestrogen levels by oöphorectomy and oestrogen-priming of female rats had any effect of the efficiency of the cardiac Uptake2 process.


Interaction between the effects of spinal heating and cooling and of injections into a lateral cerebral ventricle of noradrenaline, 5-hydroxytryptamine and carbachol on thermoregulation in sheep. 1. A study has been made of the interactions of the thermoregulatory effects of spinal cord heating and cooling and of the injections into the cerebral ventricle of noradrenaline, 5-hydroxytryptamine (5-HT) and carbamylcholine in sheep. 2. The interactions of spinal cord heating and the injections into the cerebral ventricle of noradrenaline, 5-HT and carbamylcholine were very similar to those of hypothalamic heating or of high ambient temperature and the injections into the cerebral ventricle of these substances. These results are interpreted as evidence of the synaptic convergence of the pathways from peripheral, spinal cord and hypothalamic warm-sensors at or before the points of action of these synaptically active substances. 3. The only definite thermoregulatory effect of spinal cooling was the onset of shivering which could be due to a purely spinal effect of cold. No substantial evidence was obtained of an interaction between spinal cooling and an injection of noradrenaline, 5-HT or carbamylcholine into the cerebral ventricle. Thus there was no clear indication of centripetal pathways from spinal cold sensors converging with those from the skin and the hypothalamus for which evidence of convergence was obtained in an earlier study. 4. The results of this study are expressed in terms of the neuronal model of Bligh, Cottle & Maskrey (1971) and Maskrey & Bligh (1971), appropriately modified.


An analysis of the action of cations of the lanthanide series on the mechanical responses of guinea-pig ileal longitudinal muscle. 1. The inhibitory effects of lanthanide cations (Ln3+) on mechanical responses and 45Ca uptake in guinea-pig ileal longitudinal smooth muscle were studied. 2. Ln3+ strongly inhibited the phasic and tonic component of the response to the muscarinic agonist cis-2-methyl-4-dimethylaminomethyl-1,3-dioxolane methiodide (CD) the two components being affected to the same extent. Inhibition was also obtained for the responses evoked by high K+ but here the effect was mainly on the phasic response, the tonic component was merely delayed. 3. Other members of the Ln3+ series, with the exception of cerium, were found to be more effective than lanthanum in their ability to inhibit the CD response. Thulium, Tm3+, the thirteenth member of the series was the most effective cation. 4. Analysis of 170Tm uptake revealed at least two components. The concentration-dependence of one component, saturating at 2-5 x 10(-6) Tm, corresponded closely to that of the inhibitory effect of Tm3+ on contraction. 5. 170Tm uptake as a function of time showed a secondary rise after 30 min of exposure to the lanthanide. 6. Although 2-5 x 10(-6) M-Tm3+ produced 90% inhibition of the CD and the high K+ induced responses significant reduction of 45Ca uptake by the muscle was only detected when much higher Tm3+ concentrations (greater than or equal 10(-3) M-Tm3+) were used. 7. It is concluded that Ln3+ combine with membrane sites specifically involved in Ca2+ translocation during excitation-contraction coupling.


The effects of lanthanum and thulium on the mechanical responses of rat vas deferens. 1. The contractile responses of rat vas deferens to noradrenaline and K+ are composed of phasic and tonic components both of which are dependent upon the concentration of extracellular Ca2+. 2. Lanthanum, La3+, and thulium ions, Tm3+, inhibited the noradrenaline and K+ induced responses, complete inhibition being obtained at approximately 10(-3) M-Ln3+. 3. La3+ and Tm3+ were equally effective in inhibiting noradrenaline and K+ responses. The phasic and tonic components of the noradrenaline response were equally sensitive to lanthanide cations, Ln3+, but the phasic component of the K+ response was more sensitive than the tonic component. 4. 170Tm binding did not show any saturable component over the concentration range in which inhibition of the pharmacological response was obtained. 5. It is suggested that the actions of Ln3+ in the rat vas deferens are mediated through some kind of membrane stabilization rather than via a specific Ca2+ binding site concerned with excitation-contraction coupling, the mechanism previously postulated for the Ln3+ action in guinea-pig ileal longitudinal muscle.


The formation of synapses between chick embryo skeletal muscle and ciliary ganglia grown in vitro. 1. Chick embryo ciliary ganglia (explanted) and skeletal muscle (dissociated) were grown together in vitro for up to 3 weeks. Nerve processes sprouted from the ganglia and contacted neighbouring myotubes and striated muscle fibres. 2. Spontaneous action potentials and subthreshold e.p.p.s. were recorded from muscle fibres with intracellular micropipettes. Similar potentials could be evoked by electrical stimulation of the ganglion. The pharmacological effects of curare and tetrodotoxin were identical to those observed at adult vertebrate neuromuscular junctions. 3. The amplitude, but not the frequency, of the spontaneous potentials was affected by changing the muscle fibre membrane potential. The reversal potential of evoked synaptic potentials occurred at a membrane potential of about 0 mV.


Functional and non-functional contacts between ciliary neurones and muscle grown in vitro. 1. In cultures of chick embryo skeletal muscle and ciliary ganglia, muscle fibres near a ganglion were contacted by many individual nerve processes. Experiments were performed to determine if these muscle fibres were multiply innervated, and if any of the nerve-muscle contacts were non-synaptic. 2. Synaptic potentials evoked by electrical stimulation of a ganglion were graded with stimulus strength. When two ganglia were plated near each other, synaptic potentials could be evoked in some muscle fibres by stimulation of either ganglion. These observations suggest that muscle fibres were multiply innervated. 3. Spontaneous synaptic potentials recorded from single muscle fibres with two widely spaced micropipettes varied in a manner which suggested that the synapses were distributed at different points on the surface of the muscle fibres. 4. Stimulation of some nerve processes failed to evoke synaptic potentials in muscle fibres contacted by those processes. Such nerve-muscle contacts were not strongly adhesive, and the nerves were peeled easily from the surface of the muscle with a micropipette. On the other hand, nerve processes which formed synaptic contacts with muscle fibres seemed to be tightly adherent to the muscle. 5. Electron microscopic observations of nerve-muscle contacts revealed that the vast majority of such contacts lacked morphological specializations characteristic of mature neuromuscular synapses.


Ionic fluxes in rat uterine smooth muscle. 1. The K+, Na+ and Cl-fluxes from the oestrogen-stimulated rat uterine smooth muscle were measured using radioactive tracers. 2. The cellular compartment contained a concentration of K+ of 173-6 mM which exchanged at a rate of 5-9 x 10(-12) mol.cm-2.sec-1. 3. Cl- exchanged at a rate of 6-9 x 10(-12) mol.cm-2.sec-1 from a cellular compartment having a concentration of 39-3 mM. 4. The methods used for the evaluation of Na+ movements over-estimate both influx and efflux values. If an average value of flux of 9-2 x 10(-12) mol.cm-2.sec-1 is considered we obtain PNa+/PK+ ratios of 2-4 (-42 mV) or 1-3 (-57-6 mV), which are too high and do not correspond to electrophysiological evidence. 5. The relative permeabilities PCl-/PK+ in the case of a membrane potential of -42-0 mV could be 0-8, or 1-3 in the case of a membrane potential of -57-6 mV. 6. Both conductances GK+ and GCl- seem to play an important role in determining membrane conductance.


The effects of corticosterone and cortisone on the uptake of polyvinyl pyrrolidone and the transmission of immunoglobulin G by the small intestine in young rats. 1. The distribution of polyvinyl pyrrolidone along the intestinal lumen and in the intestinal wall, following oral administration to normal and corticosterone treated rats, was found to be extremely variable. Valid comparisons between the two groups of animals could not be made using this technique. 2. Three, 4 and 5 days after corticosterone treatment there was no significant change in the uptake of 125I-labelled polyvinyl pyrrolidone from standard doses injected into ligated segments of the distal small intestine; nor did the treatment induce precocious replacement of the absorptive cells in this region. Cortisone induced precocious cell replacement, a process which took up to 4 days to complete, and also led to a marked reduction in the uptake of 125I-labelled polyvinyl pyrrolidone from ligated segments of the distal intestine. 3. Three days after treatment with corticosterone (5 mg I.P. at 12 days) there was a marked reduction of labelled immunoglobulin G transport into the blood. Four and 5 days after treatment there was some recovery of the immunoglobulin G transport function. Three days after treatment with cortisone (5 mg I.P. at 12 days) there was closure of the gut to labelled immunoglobulin G. 4. The relevance of these results to antibody transmission and the termination of immunoglobulin transport is discussed.


Visual identification of two kinds of nerve cells and their synaptic contacts in a living autonomic ganglion of the mudpuppy (Necturus maculosus). 1. Many of the nerve cells comprising the cardiac parasympathetic ganglion of the mudpuppy are spread out in a thin, transparent sheet of tissue, enabling one to see cellular details in living preparations with differential interference contrast optics. The aim of this study was twofold: to establish the morphology of the nerve cells and their synaptic connections by light and electron microscopy, and to determine which aspects of the ganglion's structure could be reliably identified in the living tissue. 2. There are two types of neurones in the ganglion: (a) principal cells that send post-ganglionic axons to cardiac muscle fibres, and (b) interneurones whose processes are confined to the ganglion. 3. Interneurones are distinguished from principal cells by the presence of numerous granular vesicles seen with the electron microscope, and by intense formaldehyde-induced fluorescence. The interneurones are thus similar to catecholamine-containing interneurones in autonomic ganglia of other vertebrates. 4. Principal cells are innervated by processes that terminate mainly on the cell body, forming up to forty-five synaptic boutons and covering, on the average, 5% of the perikaryal surface. The synaptic terminals are derived from three sources: (a) axons from the vagus nerves, (b) interneurones and (c) other principal cells. Vagal terminals contacting principal cells contain agranular vesicles typical of preganglionic cholinergic endings. At regions of contact between processes of interneurones and principal cells, the interneurones have granular vesicles focused at membrane specializations; in addition there are small areas of close plasma membrane apposition, probably gap junctions. Some of the contacts between principal cells are characterized by gap junctions; others are structurally similar to vagal endings but persist after vagal degeneration. 6. Interneurones are innervated by axons that make contact mainly with their processes. The axon terminals on processes of interneurones contain agranular vesicles similar to vagal terminals on principal cells. 7. In live preparations principal cells are distinguished from interneurones by their size and the appearance of their organelles. Synaptic contacts on principal cells could often be identified and, in some cases, large contacts from interneurones or those from other nearby principal cells could be traced back to their cell bodies of origin. The validity of these identifications was confirmed by subsequent electron microscopic examination of the same cells.


Muscle responses during sudden falls in man. 1. E.m.g. activity in soleus during an unexpected fall is found to be more complex than that described by Melvill Jones & Watt (1971b). After a silent period of about 80 msec an initial peak of activity lasts until about 100 msec after release. In falls from sufficient heights a second peak of activity occurs before landing. 2. The initial peak of activity is found in muscles throughout the body and is absent during falls in which the subject releases himself. It is suggested that this initial peak is a startle response to release and on landing during the initial peak any deceleration due to tension in the leg muscles is in part coincidental. 3. The second peak of activity is found in muscles of the lower limbs. Its timing is related to the timing of landing. It is suggested that this is the activity concerned in thhe voluntary control of landing. 4. No initial peak of activity could be recorded in two patients with absent labyrinthine function.


Increase by visual stimuli in turnover of 5-hydroxytryptamine in the superior colliculi of the rabbit. 1. Irregular light falshes were played on to one eye of dark adapted rabbits for periods of 20-80 min. The concentration of 5-hydroxyindol-3-ylacetic acid (5-HIAA) and of 5-hydroxytryptamine (5-HT) were estimated in left and right superior colliculi, thalami and hippocampi. 2. In rabbits exposed to such visual stimuli for 30-60 min, there was an increase in the 5-HIAA content of the colliculus contralateral to the stimulated retina which aberaged 17% (P = 0-02), but no rise was seen if the exposure was shortened to 20 or prolonged to 80 min. At no time was there a difference in 5-HIAA content between right and left thalamus or right and left hippocampus. 3. Stationary or strictly repetitive visual stimuli produced no difference between the 5-HIAA content of left and right superior colliculus. 4. No difference in 5-HT concentration between the two colliculi was found after any form of visual stimulation, nor did any changes occur in the other parts of the brain which were examined. 5. Irregular, prolonged visual stimualtion thus appears to activate tryptaminergic neurones terminating in the colliculi. The possibility is discussed that the 5-HT released at this site might act as a brake to neuronal activity under conditions when habituation to the stimuli is not yet complete.


The contractile properties of slow muscle fibres in sheep extraocular muscle. 1. The diameters of nerve fibres in the sheep trochlear nerve were measured and they fell into two distinct groups. 2. Selective stimulation of the small diameter group of nerve fibres gave rise to a slow contraction of the superior oblique muscle which was attributed to multiply innervated muscle fibres. 3. The slow fibre contraction following a single stimulus to the small diameter nerves had a rise time of 20-50 msec and was 150-980 mg in size. On repetitive stimulation, a maximum slow fibre contraction was developed at 120-140 Hz, and maximum velocity of tension development at 170-200 Hz. 4. The maximum slow fibre tetanic tension was 7-0-12-3 g, which amounted to 5-3% of the whole muscle tetanic tension, while the maximum  contracture following an injection of suxamethonium was 7% of the whole muscle tetanic tension. 5. The slow fibres were very resistant to fatigue and their contraction increased the resistance of the muscle to stretching. 6. Discrepancies from earlier work and the possible significance of the slow fibres are discussed.


The off-duty arrangements of general practitioners in four European countries. Continuity of care has been regarded as an essential feature of good general practice. It may be jeopardised by many diverse factors such as the mobility of the population, a shortage of family doctors, and by some forms of group practice. A shorter working week which many doctors enjoy or anticipate is another threat to continuity as it increases the time off duty and leads to the frequent use of rotas and deputising services.Criticism of the off-duty arrangements of family doctors has been made not only in the United Kingdom, but also elsewhere in Northern Europe. A study of the systems used or planned in four different countries is described and compared with some of the deputising arrangements commonly used in the United Kingdom.Research is required to elucidate whether continuity is fundamental to good medical care and how it can be achieved, bearing in mind the needs of both patient and doctor.


Deputising services in Denmark--some implications for Great Britain. In Denmark charges for home visits were abolished in April 1973. This paper analyses how this change affected the number of consultations undertaken by the deputising service in one Danish town and how the increase in consultations was distributed in time and place in a sample of individual families. It also describes how, in comparison with the deputising services sponsored by the British Medical Association in Great Britain, the more widely-used Danish deputising services operate.


Seeing the same doctor.

Seeing the same doctor. It is not known how many general practices are organised so that patients usually see the same doctor (separate list practice) or how many are arranged so that patients are encouraged to see any partner (combined list practice).A survey was carried out in Wiltshire which obtained an 85 per cent response to a questionnaire. This showed that a majority of general practitioners working in partnership in Wiltshire no longer organise their practices so that they care for a defined list of patients.


The work of an accident and emergency department. In a six month period 2,379 new patients were treated in a designated major accident centre. Of these cases two thirds (67.9 per cent) were thought to be appropriate for management by general practitioners. I suggest that these cases are properly treated in an accident and emergency department and that these departments should be developed as part of the primary health care teams.


Night calls in a group practice.

Night calls in a group practice. All the night calls attended in 1974 by seven doctors in a group practice were analysed. Each call was classified by the doctor attending, into categories of urgency.Half of all the night calls were found to be genuine emergencies, and only seven per cent were judged to be totally unnecessary.


Emergency call service.

Emergency call service. Of 153 home visits I made when employed by an emergency call service only 21 (14 per cent) were in my opinion medically essential. Thirty two (21 per cent) patients had no symptoms when visited. A nocturnal visiting fee payable by the patient is suggested to reduce unnecessary requests.


Synthesis and evaluation of 1,omega-diaryl-l,omega-alkanediamines related to the fibrinolytic bis(tetrahydroisoquinolines) and bis(benzylamines). Since the previously investigated bis(tetrahydroisoquinolines) 1 and bis(benzylamines) 2 may be classified as 1,omega-diaryl-1,omega-alkanediamines, it appeared worthwhile to examine this structural concept as a guideline for predicting significant fibrinolytic activity. The prototype bis compounds 7, 14, 15, and 29-31, which were synthesized for this purpose, incorporate such molecular modifications as replacement of the tetrahydroisoquinoline nuclei of series 1 with tetrahydrobenzazepine (7) and tetrahydropyridoindole (14-15) nuclei. The latter compounds, as well as 29-31 which possess features common to both series 1 and 2, showed good to moderate activity in the standard rat (ip) screen. Significant departures from the 1,omega-diaryl-1,omega-alkanediamine structural concept led to compounds (35 and 40) of weak to moderate activity.


Basic derivatives of 6,7-dihydroindolo(1,7-ab)(1) benzazepine and 6H-indolo(7,1-cd)(1,5) benzoxazepine as potential antidepressant agents. Basic derivatives of 6,7-dihydroindolo[1,7-ab][1]benzazepine and 6H-indolo[7,1-cd][1,5]benzoxazepine incorporating the imipramine basic side chain were synthesized and screened for antidepressant activity in mice. With few exceptions, the compounds unsubstituted at C-2 antagonized reserpine-induced ptosis and hypothermia showing negligible anticholinergic and antihistaminic properties. The compound 1-[2-(N-methyl-N-benzylamino)ethyl]-6,7-dihydroindolo[1,7-ab][1]benzazepine had the highest toxicity-activity ratio.


Preparation and in vitro antifungal activities of some quinolizidine derived hemiaminals and beta-tert-amino sulfides. New alpha-thiohemiaminals, 7alpha-phenylthio-7-epideoxynupharidin-6-ol, the diasteriomeric 7beta-phenylthiodeoxy-nupharidin-6-ol, and 3-methyl-3-methylthio-4-hydroxyquinolizidine, were prepared and reduced to the corresponding beta-tert-amino sulfides. The configuration at C-7 of the beta-tert-amino sulfides was determined by observing the direction of the solvent-induced shift of the C-7 methyl proton resonance. The configuration at C-7 of the new alpha-thiohemiaminals was established by correlations with the beta-tert-amino sulfides and confirmed, in the case of the deoxynupharidine derivatives, by circular dichroism and ascertaining the sterochemistry of deuteride incorporation upon sodium borodeuteride reduction of the alpha-thiohemiaminal. The in vitro antifungal activities of six compounds possessing the quinolizidine skeleton, including all the newly synthesized compounds as well as some previously reported ones, and amphotericin B were tested against several human pathogenic fungi. Besides amphotericin B, only the two deoxynupharidine alpha-thiohemiaminals were active, especially against Histoplasma capsulatum and Blastomyces dermatitidis. The observations indicate activity is derived from the 3-furyl group and the functionality from which alpha-thioimmonium ions can be produced.


Cycloalkanones. 8. Hypocholesterolemic activity of long-chain ketones related to pentadecanone. Aliphatic analogs of 2,8-dibenzylcyclooctanone which includes C15-C18 ketones have been investigated for hypocholesterolemic activity in rats. The position of the carbonyl group in the chain for maximum activity appears to be the 2 position. 2-Hexadecanone reduced serum cholesterol levels significantly without altering serum triglyceride levels. This drug was not estrogenic at effective doses which is in contrast to the cyclooctanones which possess this activity.


Hypocholesterolemic activity of 1,3-bis(substituted phenoxy)-2-propanones. A series of 1,3-bis(substituted phenoxy)-2-propanones was found to be active hypocholesterolemic agents at 10 mg/kg/day. The p-chloro- and p-methyl-substituted phenoxy compounds possess the highest activity. These compounds did not possess the estrogenic and antifertility activities of the related previously reported derivatives of the bis(beta-phenylethyl) ketone series. The 1,3-bis(p-methylphenoxy)-2-propanone (7) also lowered serum triglycerides and glycerol which appeared to be due to increased levels of serum lipase and reduced activity of liver lipase. There was reduced incorporation of free fatty acids into complex lipids by the liver. Cholesterol was excreted faster in the treated animals.


Synthesis and some pharmacological properties of five analogs of oxytocin having L-homocysteine in position 6. Five analogs of oxytocin have been synthesized with a homocysteine residue in position 6 and 2-, 3-, or 4-carbon residues in position 1. The compounds, which contain 20-, 21-, and 22-membered disulfide rings, respectively, were [1-alpha-mercaptoacetic acid,6-homocysteine]oxytocin, [6-homocysteine]oxytocin, [1-beta-mercaptopropionic acid,6-homocysteine]oxytocin, [1,6-homocystine]oxytocin, and [1-gamma-mercaptobutyric acid,6-homocysteine]oxytocin. The appropriate protected polypeptide intermediates were prepared by the solid-phase method of peptide synthesis. The protecting groups were removed by treatment with Na in NH3 and the disulfide bond was formed by oxidation with ICH2CH2I in aqueous MeOH. Purification was effected by partition chromatography followed by gel filtration. The pharmacological activities of all five analogs are reported for the oxytocic, avian vasodepressor, and rat pressor assays. Compared to oxytocin, these analogs exhibited sharply reduced agonist potencies, and several exhibited antagonist acitivty.


Synthesis and biological inactivity of some 4alpha,6-cyclo steroids. Two different synthetic routes have been used to synthesize a series of cyclopropyl conjugated ketones in which 4alpha,6-unsaturation replaces the usual 4,5-unsaturation. The synthetic routes involve intramolecular ketocarbene addition to a 5-6 double bond and intramolecular 1,3-elimination of 6beta-substituted 5beta-3-keto steroids. Both routes give 5beta products. The analogs of progesterone, testoterone acetate, and norethisterone have been prepared and shown to be remarkably biologically inactive when compared with the corresponding standard. Possible reasons for such inactivity are discussed.


Interferon inducing activities of derivatives of 1,3-dimethyl-4-(3-dimethylaminopropylamino)-1H-pyrazolo(3,4-b)quinoline and related compounds. Syntheses and interferon inducing acitivites are reported for 137 relatives of 1,3-dimethyl-4-(3-dimethylamino-propylamino)-1H-pyrazolo[3,4-b]quinoline (1). Three different generalized synthetic schemes for the preparation of pyrazolo[3,4-b]quinolines are presented and limitations contrasted. Other heterocyclic nuclei containing the 3-dimethylaminopropylamino side chain include pyridine, quinoline, acridine, pyrazolo[3,4-b]pyridine, pyrazolo[3,4-B][1,8]naphthyridine, pyrazolo[4',3':5,6]pyrido[2,3-d]pyrimidine, dipyrazolo[3,4-b:4',3'-e]pyridine, pyrrolo-[2,3-b]quinoline, isothiazolo[5,4-b]quinoline, and pyrido[2,3-h]pyrazolo[3,4-b]quinoline. Structural requirements for interferon induction in this series are discussed and two of the more active compounds (172 and 196) are compared directly with tilorone.


Antifertility agents. 12. Structure-activity relationship of 3,4-diphenylchromenes and -chromans. Synthesis and antiimplantation activity of variously substituted 2,2-dialkyl-3,4-diphenylchromenes and 3,4-cis- and trans-chromans derived from them are described. Pregnancy-inhibiting activity in rats was exhibited by a number of these compounds, which was particularly marked in the case of 3,4-trans-3-phenyl-4-p-(beta-pyrrolidinoethoxy)-phenyl-7-methoxychroman (32), the corresponding 2,2-dimethyl analog 34, and 3-phenyl-4-p-(beta-pyrrolidinoethoxy)phenyl-7-methoxychromene (26). The structure-activity relationship of these compounds is discussed.


Relationship of molecular structure to in vivo scintigraphic distribution patterns of carbon-11 labeled compounds. 3. (11C)Hydantoins. The preparation and gamma-scintigraphic evaluation of the in vivo distribution patterns in dogs of a series of structurally related hydantoins labeled with the positron emitting, 20.4 min half-life radionuclide, carbon-11 are described. Carbon-11 labeled HCN was collected in water or aqueous Me2SO containing carrier KCN following cyclotron bombardment of 99% N2-1% H2 gas mixture with 22 MeV protons for 1 hr at 25-35 muA. Five 11C-labeled 5,5-dialkylhydantoins, three [11C]diarylhydantoins, five [11C]-5-alkyl-5-phenylhydantoins, and five [11C]spirohydantoins were prepared by heating generally under pressure, a mixture of 11C-labeled KCN, which was produced by isotopic exchange with carrier KCN, the corresponding aldehyde or ketone, and excess (NH4)2CO3 in aqueous ethanol or Me2SO solvent. The 11C-labeled hydantoins were dissolved in 1-1.5% aqueous NaOH for intravenous administration to dogs. Total synthesis time was 70-106 min and 1-59 mCi of final product was available for conducting serial in vivo imaging for up to 2 hr or more with the gamma-scintillation camera. Carbon-11 activity from all compounds showed initial blood-pool distribution with variable concentration of activity in the brain, lungs, liver, and kidney. All of the 11C-labeled diarylhydantoins, and most having one phenyl substituent, and one having a hexamethylene moiety showed initial accumulation of 11C activity in brain. Carbon-11 labeled 5,5-diphenylhydantoin (dilantin) showed the greastest qualitative accumulation of activity in the brain. Those 11C-labeled hydantoins having a carboxyl substituent showed prominent renal concentration and urinary excretion of activity. Most 11-c-labeled hydantoins showed a progressive homogenous whole body distribution of activity in all cellular tissues of the body. The relatively uniform distribution of activity in cellular tissues and slow excretion from the body support the thesis that the pharmacologic action of the hydantoins is related to physical effects on biomembranes rather than to specific chemical interactions with cell constituents.


Synthesis of tetrazole ribonucleosides and their evaluation as antiviral agents. Synthesis of 1-beta-D-ribofuranosyltetrazole and two 5-substituted derivatives, i.e., the 5-carboxamide and 5-acetamide, is described. The stereochemical structure of the parent tetrazole ribonucleoside has been established by means of nuclear Overhauser effect and x-ray crystallography. By analogy to the parent compound, the two 5-substituted tetrazole nucleosides are also assigned the beta configuration on the basis of the NMR coupling constant of the anomeric proton and the site of N-ribosylation is determined by 13C NMR studies. Results are also presented on antiviral testing of these synthetic tetrazole nucleosides against influenza A2/Asian/J-305 virus infection in mice.


Antiinflammatory activity of some 2,3-dihydrobenzofuran-5-acetic acids and related compounds. A series of 2,3-dihydrobenzofuran-5-acetic acids and related compounds was prepared as potential antiinflammatory agents. As measured by the carrageenan-induced edema method for the preliminary screening test, introduction of a methyl group alpha to the acetic acid function enhanced the antiinflammatory activity, and alpha-(7-chloro-2,2-dimethyl-2,3-dihydrobenzofuran)-alpha-methyl-5-acetic acid (13a) showed the most potent activity in this series.


Potential antitumor agents. Synthesis of bifunctional alpha-methylene-gamma-butyrolactones. A series of alkoxy-substituted di- and monolactones including the (E,E)-3,3'-(dioxaalkanediylidene)bis[dihydro-2(3H)-furanones] (17a-f), monolactones 6, 7, 8, 14, and 15, and dilactone 19 was synthesized by reaction of enolate 4 with appropriate alkyl halides (6, 7, 17a-f, 19), tosyl chloride (8), or acid chlorides (14, 15). Reaction of enolate 9 with tosyl chloride gave both Z and E isomers which allowed unequivocal assignment of stereochemistry to 8, 14, and 15. A series of open-chain bis(alpha-methylene-gamma-butyrolactones) (21a-d) was also prepared by a Reformatsky-type reaction between ethyl alpha-(bromomethyl)acrylate and appropriate dialdehydes. These compounds were tested for antitumor activity as part of a study of the influence of beta-substituents and distance between alkylating sites on the antitumor activity of alpha,beta-unsaturated lactones. The testing was carried out in standard NCI screens and selected compounds were tested against the Walker tumor. The alkoxy-substituted lactones were inactive in L1210 and were not cytotoxic. The open-chain bis(alpha-methylene-gamma-butyrolactones) showed borderline activity in 9KB and were inactive in L1210. Compound 21a gave a 45% inhibition of the Walker tumor at 18.75 mg/kg and was toxic at 37.5 mg/kg.


Potential central nervous system antitumor agents. Aziridinylbenzoquinones. 1. A series of 3,6-substituted 2,5-diaziridinyl-1,4-benzoquinones was prepared as potential CNS antitumor agents. Activity was evaluated in the murine leukemia L1210 system. The diurethane derivative 9 was found to have significant activity in that system as well as in the intraperitoneal P388 and B16 tumor models. Marginal Lewis lung activity was observed. Reproducible activity was seen in the intracerebral L1210 and P388 systems. Multiple cures were observed in the murine ependymoblastoma brain tumor model. The effect of substituent type on aziridinylquinone activity is discussed.


Carboxyarylindoles as nonsteroidal antiinflammatory agents. An extensive series of carboxyarylindoles has been evaluated for antiinflammatory activity in the carrageenin paw edema assay. The requirements for optimal antiinflammatory activity in this series are relatively specific: a central pyrrole nucleus with (a) a 3-carboxy-4-hydroxyphenyl moiety substituted directly on the nitrogen, (b) a 2-phenyl group (R2) with a substituent of low electronegativity, (c) absence of a substituent in the 3 position (R3), and (d) a system fused across the 4,5 positions (X), which is lipophilic, quasiplanar, and does not interact sterically with the N-phenyl group. One derivative, 3-(3-carboxy-4-hydroxyphenyl)-2-phenyl-4,5-dihydro-3H-benz[e]indole (42), has been selected for further study.


Synthesis and some biological activities of the tyrosine-8 analog of substance P. [Tyr8]-substance P, an undecapeptide having the structure Arg-Pro-Lys-Pro-Gln-Gln-Phe-Tyr-Gly-Leu-Met-NH2, has been synthesized by the solid-phase technique on a Beckman automatic peptide synthesizer, appropriately purified and biologically characterized. At twice the dosage, [Tyr8]-substance P showed the same biological activity response as synthetic substance P for stimulation of contraction of the isolated guinea pig ileum and for decrease in the systemic blood pressure of dogs. On the dog's blood pressure, no qualitative differences were observed, but on the isolated gut, the Tyr8 analog gave a more gradual increase in the muscle tone than synthetic substance P. [Tyr8]-substance P released, in vitro, the luteinizing and follicle-stimulating hormones at a very high dosage but did not release growth hormone, prolactin, or thyrotropin.


Synthetic metabolites of neurohypophyseal hormones. (Des-9-glycinamide)oxytocin and (des-9-glycinamide, des-8-leucine)oxytocin. Syntheses and biological properties are reported for two analogs of oxytocin in which the glycinamide and the leucylglycinamide moiety, respectively, have been deleted from the parent hormone. Both [des-9-glycinamide]oxytocin and [des-9-glycinamide,des-8-leucine]oxytocin are weak agonists in the rat uterotonic and antidiuretic assays but possess no detectable rat pressor activity. In addition, [des-9-glycinamide]oxytocin is an inhibitor of the oxytocin-induced vasodepressor response in fowl but is a potent agonist in the hydroosmotic assay of the toad urinary bladder.


Synthesis and pharmacological evaluation of some 3-substituted octahydropyrido(2,1-c)(1,4)oxazines. 3-Phenyloctahydropyrido[2,1-c][1,4]oxazine hydrochloride and the 10R and 10S diastereomers have been synthesized from (+/-)-, (+)-, and (-)-2-piperidinemethanol. Treatment of 2-piperidinemethanol with alpha-bromoacetophenone gave 3-hydroxy-3-phenyloctahydropyrido[2,1-c][1,4]oxazine which was readily converted to the 3-phenyl derivative by catalytic hydrogenolysis. These compounds were shown to possess a depressant action on the CNS which was quantitated in terms of reduction of locomotor activity in mice. Qualitative differences were noted in the central effects of the 3-phenyl compound and its hemiketal derivative. Further, qualitative differences in the effects of the diastereomers of the 3-phenyl compound on locomotor activity of mice were also noted. The results of this study suggest that the octahydropyrido[2,1-c]1,4]oxazine system may provide a useful molecular framework for the construction of agents exhibiting pharmacologically useful actions in the CNS.


Synthesis of N-hydroxythiourea.

Synthesis of N-hydroxythiourea. The synthesis of the title compound (1) was accomplished by the conversion of 2,4-dimethoxybenzylamine (2) into an isothiocyanate (3) using thiocarbonyl diimidazole. Treatment of 3 with hydroxylamine and removal of the DMB group with trifluoroacetic acid gave 1. N-Hydroxythiourea (1) showed no activity in the L1210 mouse tumor.


Inhibition of tumor cell transplantability by iron and copper complexes of 5-substituted 2-formylpyridine thiosemicarbazones. The cytotoxicity of copper and iron complexes of 5-substituted 2-formylpyridine thiosemicarbazones against Ehrlich ascites tumor cells has been measured. Brief in vitro incubation of cells and drugs is followed by implantation into host mice. Subsequent degree of tumor development is a measure of cytotoxicity. A spectrum of activities for the iron complexes is observed, starting with the least active as designated by its 5-substitution: OH less than OCOCH3 approximately N(CH3)2 less than H less than CH3 approximately Cl approximately CF3. The last three complexes can prevent completely tumor growth in the new host. Copper complexes of 5-H and 5-CH3 also prevent successful tumor cell transplantation.


A protocol for program evaluation.

A protocol for program evaluation. In May 1975 the Center for Educational Development, College of Medicine, University of Illinois at the Medical Center, conducted a workshop titled, "Evaluation in the Health Professions." Five tracks were offered at the workshop and one focused on program evaluation. The 12 participants from this track worked on their respective projects for four-and-one-half days from an earlier version of the protocol presented in this article. Much of the workshop was tape recorded, and this article is the result of reviewing the tapes and recording the problems that were encountered with the original version of the protocol for program evaluation.


A conceptual framework for measuring clinical problem-solving. Most attempts to measure clinical competence start by modeling the clinician's problem-solving process. The conflicting data from studies built around this approach suggest the need for rethinking the underlying concepts. Presented is a conceptual framework for clinical competence which is a natural expansion of earlier approaches. The framework is based upon defining the domain in which the clinician functions as the starting point for measuring clinical competence. There are three dimensions to the framework-problem-solving process, clinical discipline, and context of care. The intersection of the dimensions defines the clinical practice domain to be measured. For each domain specific problems can be identified and clinicians asked to demonstrate competence in resolving them.


Teaching toxicology as a basic medical science. In this report the author describes a four-year effort at the Yale University School of Medicine to teach toxicology as an elective basic medical science from the standpoint of organ-specific toxic effects. The primary objective is to prepare physicians to understand, recognize, and manage adverse effects from drugs and other environmental chemicals. It is a multidisciplinary program which integrates easily into the medical school curriculum in a manner that is appealing to the students.


Medical anthropology in the curriculum: a revisit to the subject. A survey of U.S. medical schools and their branch campuses was made to determine the magnitude of the teaching of medical anthropology in American medical schools. Curriculum committee chairpersons were sent postcard questionnaires to establish the number of campuses that include the subject in their curricula. Thirty representatives of the 103 campuses responding replied in the positive. In July 1974 these 30 were sent an 11-item questionnaire; 27 were returned. Although progress has been made in the last 15 years in the development of medical school departments with interests in the various behavioral science fields, including anthropology, based on this study only 5 percent of U.S. medical students had the opportunity to attend lectures in the field of medical anthropology.


A mandatory course in scientific writing for undergraduate medical students. All students at Mayo Medical School take a course in scientific writing during their sophomore and junior years. Early in the sophomore year they receive a self-instructional text designed to help them avoid 15 common writing faults. Comparison of pretest and posttest results for two classes, with a total of 89 students, indicates significant improvement (p less than .001). Later in his sophomore year, each student writes a minithesis; and during his junior year he reports on work done in a clinical or laboratory research project, preparing it as a paper submissible to a scientific journal. Professional editors work as preceptors with the students, critiquing their manuscripts, which are revised until they receive satisfactory ratings.


Chiang Mai and Illinois: a cooperative international project, 1962-1970. Participants in the Chiang Mai-Illinois Project had unique opportunities to work toward the goals of medical education in an attractive but alien environment. Concepts concerning public health and preventive medicine did not have high priority as the new medical school at Chiang Mai began, but a growing department made some progress in the teaching of these concepts with discussions, library and record room projects, and limited village investigations. Studies of hospital and clinic patients and of specific diseases disclosed useful data about northern Thai people. A productive experience in the foreign setting is believed to require sound training, energy, adaptability, and an investment of years.


Pancreatic pseudocysts presenting as thick-walled renal and perinephric cysts. Posterior extension of a pancreatic pseudocyst should be considered in the differential diagnosis of a thick-walled renal or perinephric cyst seen on infusion pyelography with tomography. Opacification of the wall of a pancreatic pseudocyst by this technique has not been reported previously and lack of knowledge of this possibility can lead to mistaken diagnosis and the possibility of an unnecessary exploratory operation, particularly when angiography is inconclusive and a gastrointestinal series is negative or equivocal. The mechanism of opacification of the wall of a pancreatic pseudocyst is discussed. Parasitization of the renal capsular arteries by a pancreatic pseudocyst can further compound the difficulty of diagnosis.


Gallium-67 scintigraphy for the diagnosis and localization of perinephric abscesses. Four patients with suspected perinephric abscess were evaluated by gallium-67 scintigraphy. Gallium-67 scintigraphs proved instrumental in correctly diagnosing and localizing 4 left perinephric abscesses. Roentgenographic examinations were negative in 2 cases. Gallium-67 scintigraphy can be a useful non-invasive technique to evaluate patients with suspected perinephric abscess.


Recovery of renal function after prolonged unilateral ureteral obstruction. Concepts of renal counterbalance and animal experiments have long supported nephrectomy for prolonged complete unilateral ureteral obstruction. The situation in humans has been clarified by only a few reported cases. Herein we report 3 cases with relief of obstruction after at least 28, 28 and 150 days. Evidence is presented to support renal preservation in similar cases.


Experience with non-sterile intermittent self-catheterization. Although a patient subjected to intermittent self-catheterization must carry a catheter and catheterize himself under a non-sterile technique at regular intervals this method is considered the best one available for patients who lead an active social life. When family cooperation is available intermittent catheterization is a cleaner procedure, causes less complications and is easier to manage for a patient confined to bed than the indwelling catheter, cystostomy or other urinary diversion procedures. The technique is also useful for patients with spinal cord injuries, promoting the early return of bladder activity and a life free of the catheter. It is an ideal method for children with meningomyelocele, after the upper tract has been maintained carefully by an indwelling catheter or cystostomy until the child is able to catheterize himself. In these cases a small capacity bladder may be enlarged using the colon and urinary incontinence may be corrected by other operative procedures. We have treated 26 patients with this technique, including 1 with a 17-year followup. The upper urinary tract has not deteriorated in any case and the urine has remained sterile in 39 per cent of the cases.


Hematoporphyrin derivative: a possible aid in the diagnosis and therapy of carcinoma of the bladder. The distribution of hematoporphyrin derivative has been studied in patients undergoing transurethral resections and total cystectomy for carcinoma of the bladder. Although hematoporphyrin derivative fluorescence was not confined to malignant tissues with the dose used there was preferential localization in malignant and pre-malignant epithelium. Also high intensity illumination of an area of hematoporphyrin derivative sensitized carcinoma caused tumor destruction. Therefore, it is suggested that hematoporphyrin derivative could be used as an aid to the diagnosis and treatment of carcinoma of the bladder.


Further experience with the Young-Dees procedure for urinary incontinence in selected cases. Experience with the Young-Dees procedure confirms that this is a useful operation for restoring urinary continence, particularly in selected female patients with non-neurogenic incontinence. Of 21 incontinent patients 15 have achieved good to excellent postoperative urinary control.


Combined cystometry and perineal electromyography in the diagnosis and treatment of neurogenic urinary incontinence. Function of the bladder and periurethral striated muscle was determined simultaneously by combined cystometry and electromyography studies in 120 patients. The coordinated tests were extremely helpful in identifying the different types of periurethral striated muscle activity in neurogenic bladder dysfunction, diagnosing the mechanism of incontinence and determining the appropriate therapy.


Human prostatic epithelial cells in culture: clonal selection and androgen dependence of cell line EB 33. The permanent epithelial strain EB 33 was initiated from primary cultures of a human prostatic adenocarcinoma in June 1973. To establish androgen dependence of growth EB 33 cells were grown in various media. The effect of androgen withdrawal was studied by the application of media containing sera that had undergone steroid extraction procedures with dichloromethane and activated charcoal. The growth rate of the original EB 33 population was not influenced by withdrawal or addition of androgenic hormones. There were 111 clones developed by single cell plating of EB 33 cells and 23 clonal lines responded to extracted media with a depression of growth of at least 50 per cent. These findings were verified in growth curve experiments. Testosterone and 5-alpha-dihydrotestosterone slightly accelerated growth but did not fully compensate the depression of cell counts seen in extracted media. These findings may be consistent with hormone dependence of growth of clonal lines developed from the human prostatic epithelial strain EB 33.


Primary treatment of prostatic carcinoma with estramustine phosphate: preliminary report. Estramustine phosphate has been used as primary treatment in 38 patients with advanced prostatic carcinoma. Of these 38 patients 36 responded objectively to treatment, regression occurring in 10 patients with soft tissue metastases, 3 with pulmonary metastases and 3 with bony metastases. Primary cytotoxic treatment in patients with far advanced prostatic carcinoma is advocated and a randomized clinical study is suggested.


Urologic complications following abdominoperineal resection. In a retrospective study we analyzed the high incidence of 75 urological complications after abdominoperineal resection in 52 patients. A prospective study was done also to anticipate as well as to minimize or eliminate these highly significant complications. Direct injury leading to obstruction and fistula formation was avoided. Obstructive uropathy in 10 of 25 male patients was found as a direct result of preoperative evaluation. Same day prostatectomies in 5 patients made no appreciable difference in the urological management, complication rate or end results. Neurogenic bladder dysfunction of various degrees was found in 50 per cent of all patients but represented a long-term problem in only 10 per cent.


A new surgical procedure for revision of ileal conduit stoma in children. The etiology of hypertrophic keratotic peristomal lesions is discussed and a new simple, cosmetic and functional operative procedure for excision of peristomal keratosis and revision of ileal loop stoma is described. This advancement (full skin and subcutaneous fat) triangular flap is also useful in the surgical management of other stomal problems, such as prolapsed bud, peristomal hernias and peristomal scarring. Postoperative use of the proper size and type of collecting device, and the importance of achieving sterile acid urine are stressed to prevent further stomal complications.


Pyelocancerous backflow: a radiologic finding in renal malignancy. Pyelocancerous backflow is a radiologic finding strongly suggestive of renal malignancy that has had little attention in the urologic literature. Its appearance is an ominous sign and, when present, renal adenocarcinoma invading the collecting system or infiltrating transitional cell carcinoma with parenchymal extension must be suspected. An illustrative case is presented and its significance is discussed.


Changes in endocrine pancreatic function produced by altered dietary protein intake in drinking alcoholics. The effect of dietary protein intake on abnormal endocrine pancreatic function was studied in five male chronic alcoholic patients with a recent history of heavy alcohol and poor dietary intake. Pancreatic function was assessed by means of the pancreozymin-secretin stimulation test. Immediately on admission and throughout the study, the patients were given ethanol, 250 g/day in divided doses. Initial administration of a low protein (25 g) 1800 calorie diet resulted in no improvement in pancreatic function. Institution of a normal protein (100 g) 2600 calorie diet for 10 days led to a return to normal in the output of bicarbonate, amylase, lipase, and chymotrypsin. Readministration of the low protein diet for 10 days resulted in decreased output of amylase and chymotrypsin. The volumes of secretion and outputs of trypsin and protein remained unchanged throughout the study. This study shows that the transient dysfunction of the exocrine pancreas frequently observed in actively drinking chronic alcoholic patients is caused by deficient dietary protein intake.


Indocyanine green dye fluorescence and infrared absorption choroidal angiography performed simultaneously with fluorescein angiography. The sensory retina of the eye is nourished by two essentially separate blood circulations. The more superficial of these, the retinal circulation, is easily evaluated by direct visualization or routine fluorescein angiography. However, the underlying choroidal circulation, which is attributed with maintenance of the outer layers of the retina is not easily visualized due to the pigment epithelial layer and choroidal pigment. Fluorescence and infrared absorption angiographic techniques using indocyanine green (ICG) dye, which can be used to evaluate the choroidal circulation routinely, are described in this paper. A method is also described which can provide these angiograms simultaneously with standard fluorescein fluorescence angiograms of the retina. Finally, a comparison of all three types of angiograms is made. Limitations to the resolution of fundus details in angiograms imposed by optics of the fundus camera, photographic films, and optics and anatomy of the eye are examined.


Immunological reactions involving leukocytes: I. Detection of antibodies to human granulocytes by measurement of the metabolic events associated with phagocytosis. During phagocytosis, glucose oxidation via the hexose monophosphate shunt (HMS) is markedly stimulated in human polymorphonuclear leukocytes. A method is described for the detection of antibodies to human granulocytes which exploits this fact. The source of antibodies was rabbit antihuman leukocyte serum (RAHLS) obtained by repeated immunization of normal rabbits with human granulocyte homogenates. HMS activity was quantitated by measuring the release of 14CO2 from glucose-1-14C. Under precisely defined experimental conditions, RAHLS and its IgG fraction inhibited 14CO2 release. The inhibitory effect of RAHLS on human granulocyte phagocytosis-associated HMS activity could be reduced by prior absorption of RAHLS with human granulocytes. Compared to the cytotoxic and leukoagglutination tests, this method appears more sensitive with respect to detection of xenogeneic antibodies to human granulocytes.


The syndrome of bronchial atresia or stenosis with mucocele and focal hyperinflation of the lung. Three cases of "the syndrome of bronchial atresia or stenosis with mucocele and focal hyperinflation of the lung" are added to 28 proven cases (26 with atresia and 2 with stenosis) previously reported in the English literature. One case is of particular interest since serial roentgenograms during the first week of life showed fetal lung fluid to be trapped distal to the atresia. The radiographic findings in this syndrome are reviewed and the presumed etiology and pathophysiology discussed.


[Differentiation of the proteinuria by microelectrophoresis in continuous polyacrylamide-gradient gels (author's transl)]. It is possible to differentiate the proteinuria of glomerulonephritis by means of microelectrophoresis in polyacrylamide-gradient gels. The advantages of this method (quick, cheap, concentration of the urine not required) led to its introduction into clinical use. Upon separating the urinary proteins according to their molecular weight and form, four patterns of proteinuria may be differentiated: low molecular, intermediate and high molecular. Those forms of glomerulonephritis which show constant morphological and clinical findings (e.g. minimal proliferative glomerulonephritis, mesangioproliferative glomerulonephritis with crescents) can be related to one of the four patterns of proteinuria, whereas the pattern of proteinuria in other forms of glomerulonephritis (e.g. (peri-)membranous glomerulonephritis, mesangioproliferative glomerulonephritis) are dependent on the phase of the disease.


[The mortality from ischaemic heart diseases in hospitalized psychiatric patients (author's transl)]. In 1357 chronic hospitalized psychiatric patients (641 men and 716 women) aged between 40 and 69 years the mortality during 30 months was registered, referring for a prevalent study about riskfactors. The death rates for ischaemic heart diseases in hospitalized patients were 2,5-3,5 times as high as states in the statistic for total population of BRD. The majority of dead patients had two or more of the known riskfactors, more as the half of the dead patients had a manifest diabetes mellitus or a disorder of oral glucose tolerance test.


The different forms of glomerulonephritis morphological and clinical aspects, analyzed in 2500 patients. Comparative morphological and clinical studies of 2,500 patients suffering from glomerulonephritis, enabled us to divide the different forms of diffuse glomerulonephritis into 3 distinct groups and to separate these groups from the focal glomerulonephritides. The different forms of diffuse glomerulonephritis in group I are: 1. endocapillary (acute) glomeruloenphritis (of the post-streptococcal type), 2. mesangioproliferative glomerulonephritis, 3. mesangioproliferative glomerulonephritis with focal crescents, 4. mesangioproliferative glomerulonephritis with focal scarring, 5. minimal proliferating intercapillary glomerulonephritis without nephrotic syndrome. It is emphasised that these forms can transform into one another, that they seldom occur with nephrotic syndrome, and with varying frequency with hypertension. Group II consists of: 1. minimal proliferating intercapillary glomerulonephritis with nephrotic syndrome, 2. focal sclerosing glomerulonephritis, 3. perimembranous glomerulonephritis, 4. membranoproliferative glomerulonephritis, 5. lobular glomerulonephritis. It is stressed that these glomerulonephritis forms usually do not develop out of group I type glomerulonephritis forms, and that in this group a nephrotic syndrome is the most prominent clinical syndrome. In the third group are 1. mesangioproliferative glomerulonephritis with diffuse crescents, 2. necrotising glomerulonephritis. It is shown that this form of glomerulonephritis does not usually develop from either group I of II forms. The fourth group of focal glomerulonephritis is uncommon. This disease is characterized by a necrotising and proliferative inflammatory lesion found segmentally and focally in the glomeruli. Most of the other glomeruli appearing normal. It is emphasised that in the literature the diagnosis focal glomerulonephritis is made far too often. This is because glomeruli in which the inflammatory process in a few lobules is of varying prominence, are included in the focal glomerulonephritis group. The classification of the different forms of glomerulonephritis into 3 groups here described, is thought of as a basic classification. It is compared with Ellis' classification (1942), with which it has much in common.


Haemodialysis in imipramine poisoning? An experimental study. In the last several years an increasing number of severe imipramine intoxications have been observed. Though standard principles for the treatment of acute tricyclic poisoning have been established, nonetheless there still exists doubt on the most effective method of tricyclic removal in cases of massive overdose. Haemodialysis was successfully employed until now but has not found general acceptance as only insignificant amounts of imipramine could be recovered from the dialysate. An experimental clearance study was undertaken using radiolabelled imipramine (14C-I) to obtain insight into the usefullness of haemodialysis in imipramine poisoning. 14C-I clearances which were calculated in a closed circuit dialysis system ranged between 18 ml/min and 48 ml/min depending on the constitution of the dialysate, i.e. aqueous or lipid solution. Surprisingly a rapid and significant uptake of imipramine by the plastic material (polyvinylchloride) of the extracorporeal blood line system was detected. This escape of imipramine from the blood into the tubings explains the poor recovery of tricyclics from the dialysate, which discredited haemodialysis as a therapeutical method in imipramine poisoning. The results of our experiments may offer a new method of rapid tricyclic elimination in severe imipramine intoxications.


["Soiuz-Apollo" experimental flight. Preliminary results of medicobiological studies, carried out during the flight of "Soiuz-19" spaceship]. The paper presents brief information on the Apollo-Soyuz test mission, its program biomedical investigations to be carried out in flight and specific medical aspects. It discusses the main tasks of the joint US-USSR experiments and Soviet experiments. It gives and analyzes preliminary results of medical monitoring and postflight examinations of the crew members.


[Phosphatase activity in bone tissue and blood serum during 90-day hypokinesia]. Activities of alkaline and acid phosphatases in femoral epiphysis and diaphysis and those of alkaline phosphatase in the serum of rats that were exposed to a 3-month hypokinesia were measured. Phasic changes in the phosphatase activities were found in bone tissue. During the beginning of the hypokinetic experiment activities of both enzymes decreased as compared with the controls, the decrease of alkaline phosphatase being more significant. After the stress period activities of both phosphatases increased (especially of acid phosphatase in diaphysis) and by the end of the experiment were higher than the level of the enzyme activity in control rats. The activity of alkaline phosphatase in the serum varied in parallel with the enzyme activity in bones. The results give evidence for significant metabolic changes in the bone tissue during hypokinesia which lead to predominant resorption processes.


[Effect of different schedules of motor activity on the processes of human adaptation to high-altitude conditions]. Responses of external respiration, hemodynamics and blood were studied in 12 test subjects during their step-by-step adaptation to altitudes of 2200 and 3200 m. The test subjects were subdivided into two groups who were exposed to different schemes of motor activity--free motor activity and diminished motor activity during bed rest. The results indicate a direct relationship between positive adaptive reactions of physiological systems of the human body and motor activity.


[Effect of impact stresses on the rat heart and hemodynamics]. An experimental impact on the rat chest in the cardiac area induced bradycardia, arrhythmia, ectopic beats, atrio-ventricular blockade that was followed by a fall of the arterial pressure and a rise in the venous pressure, a decrease of the cardiac output and blood volume. Breakages in cardiac myofibers were seen under the microscope. These changes can be brought about by a direct effect of impact accelerations on the heart. It is concluded that tolerance of the animal heart to impact accelerations is limited by bradycardia, arterial pressure fall and a 25% decrease of the cardiac output. Greater effects may produce breakages in myofibers. An active alertness and unloading of the right atrium increase the heart tolerance to impact accelerations and potassium chloride prevents hazardous cardiac arrhythmias.


[State of labyrinth tonic posture reflexes during administration to rabbits of microelements (copper, manganese and cobalt)]. The influence of varying doses of copper, manganese and cobalt chlorides on the labyrinthine tonic reflexes of rabbits was studied electromyographically. The presence and intensity of the reflexes were measured with respect to changes in the electric activity of muscles-extensors of forelimbs and occiput during the rotation of an animal along the bitemporal axis. Under the influence of cobalt (0.01 and 0.001 mg/kg), copper (0.1 mg/kg) and manganese (0.01 mg/kg) the threshold of adequate stimulation of the labyrinthine apparatus decreased and the time of the reflex response increased. This can be related to increased excitability of stem centers that are responsible for the realization of these reflexes. Larger doses of copper (1.0 mg/kg) and manganese (0.1 mg/kg) resulted in a significant and prolonged inhibition of tonic reflexes from the labyrinth to the limbs of rabbits. These data suggest an important role played by trace elements in the regulation and adjustment of the vestibular system.


[Effect of transversely directed accelerations on gastric motor function]. The motor function of the human stomach and starvation activity of dogs were investigated after their exposure to accelerations of various values and duration. Inhibition of the motor function of the stomach and alteration in the periodicity pattern were found. The alteration included suppression of hungry contractions, development of continuous motor activity and gradual recovery of periodic activity of the stomach. Motor changes were related to the acceleration value. The reaction of the motor apparatus of the stomach to accelerations was shown to be nonspecific. The changes in the motor function of the stomach seem to be secondary and to be associated with the changes in the functional state of regulatory centers of motor activity.


[Adaptation times of flight-technical personnel to work in subtropical climate conditions]. The results of studying the process and time of adaptation of two groups of the flying personnel who arrived from moderate climate to the subtropic climate show that the early stage of acclimatization lasts from two to four weeks, depending on the season. From the physiological point of view the best season is spring-summer. During this period the time of acclimatization is two times shorter than in winter.


Early lymphoreticular viral tropism and antigen persistence. Tamiami virus infection in the cotton rat. Tamiami virus was inoculated into its natural reservoir host, the cotton rat (Sigmodon hispidus), and the course of infection was followed by sequential organ titrations, frozen-section immunofluorescence, and light and electron microscopy. In animals infected at 2 days of age, there was an early lymphoreticular tropism with peak concentrations of virus and viral antigen in lymph nodes, splenic white pulp, thymus, and bone marrow at 16 days postinoculation. Megakaryocyte infection was early and pronounced. Viral antigen concentration peaked in liver and salivary glands at day 30 and in kidney, adrenal cortex, respiratory tract, and bladder epithelium at day 60-long after viral infectivity in these organs had disappeared. Central nervous system infection was only modestly productive of infectious virus, but viral antigen continued to increase in the brain until day 90 and then did not decline throughout the 360-day study. Reticuloendothelial hyperplastic foci were found late in some target organs, but there was never any histologic or ultrastructural evidence of cytonecrosis. Older animals were virtually uninfectable; therefore, this susceptibility of newborns and their slow termination of infection represent the key to virus transmission and perpetuation in nature. These aspects of viral natural history contribute to an understanding of human exposure to the pathogenic arenaviruses which exist in similar rodent niches.


[Characteristics of morphological reactions in dog internal organs and endocrine glands during 6-year gamma irradiation]. Dogs were exposed to six-year gamma-irradiation with doses of 21-1140 rad/year; pathomorphological changes were studied in testicles thyroid gland, adrenals, liver and kidneys. The level of morphological changes in the organs during the six-year exposure was dissimilar and depended on the radiosensitivity of a specific organ, dose rate and acute irradiations that were applied during the experiment. In testicles morphological changes (reduction of layers of the spermatogenous epithelium, decrease of the number of spermatozoids in testicular canals) appeared during the first year of irradiation at a dose rate of 0.34 rad/day. Later, these changes progressed and by the end of the six-year exposure were followed by a distinct sclerosis of the interstitial tissue and hyperplasia of Leydig's cells. In the thyroid gland signs of the hypofunctional state were seen by the end of the second year of irradiation at a dose rate of 0.34 rad/day and persisted afterwards. In adrenals hypertrophy of the bundle and glomerular zones were observed during the second-fourth years of irradiation at a dose rate of 0.34 rad/day. As irradiation proceeded hyperplastic processes developed in the thyroid gland and adrenals (adenomatous nodes in the thyroid gland, adenomatous hyperplasia in the adrenal cortex). Vacuolar and fat dystrophy of hepatocytes and disturbed permeability of glomerular capillaries in the kidneys were detected only at the end of the third year of irradiation. During the fifth and, particularly, the sixth year of the exposure sclerotic changes in the liver vessels, hyalinosis of small arteries and nephrosclerotic foci in the kidneys were found.


[Development of peripheral blood reticulocytosis during exposure to a constant magnetic field]. It has been shown that red blood cells are sensitive to a constant magnetic field. Under this influence reticulocytosis develops whereas the hemoglobin level and red blood cell count remain unaltered. Changes in the reticulocyte content during a continuous many-day exposure to a constant magnetic field give evidence that an animal body can adapt to this effect.


Serum-free and protein-bound sugars and cardiovascular complications in diabetes mellitus. Free and protein-bound serum sugars and serum lipids were analyzed in 65 adult diabetic patients, 10 age-matched controls, and 24 male medical students for correlation of carbohydrate changes with the extent of retinal, renal, and cardiovascular disease. In diabetic sera, both protein-bound sugars and free mannose, fucose, and hexosamine were significantly elevated; free galactose and inositol were elevated in some diabetic patients, and essentially undetectable in sera from controls. Serum triglycerides and pre-beta-lipoproteins were also elevated in diabetics, but alpha-lipoproteins decreased. Although no specific relationships were observed with the extent of retinal and renal disease, bivariate analyses by Pearson coefficients of correlation showed correlations between levels of serum-free mannose and systolic blood pressure, free hexosamine and duration of diabetes, and serum protein-bound fucose and age. Serum triglycerides and pre-beta-lipoprotein levels correlated with insulin therapy. These are preliminary leads of laboratory studies related to carbohydrate macromolecular changes which might aid in a better understanding of the cardiovascular complications associated with diabetes.


[Attempt to upset the circadian rhythm of urine excretion of potassium]. The paper describes an attempt of shaking (i. e. decreasing inertness) the diurnal rhytnm of urine excretion of potassium in two test subjects under the conditions of 72-hour continuous wakefulness. It is concluded that continuous wakefulness exerts no shaking effect on the diurnal periodicity of the function. It is found that the rate of rearrangement of the diurnal rhythm of urine excretion of potassium after inversion of the diurnal cycle was lowest during sleep and immediately after it. It is emphasized that when evaluating the completeness of inversion of the diurnal rhythm of the function it is important to pay attention to the parameters recorded at night and morning hours.


Effects of aminonucleoside, daunomycin, and adriamycin on carbon oxidation by glomeruli. The purpose of these experiments was to determine whether reported changes in substrate metabolism by isolated glomeruli from rats with aminonucleoside nephrosis could be explained by the glomerular changes associated with proteinuria or, alternatively, whether these metabolic changes and proteinuria were synchronous but causally unrelated events. Aminonucleoside of puromycin produced proteinuria within 7 days when injected intraperitoneally or subcutaneously. However, when aminonucleoside of puromycin as well as adenine were given, the onset of proteinuria was delayed until after day 7. A significant reduction in U-14C-glucose oxidation to CO2 was found at day 7 by glomeruli from rats given aminonucleoside of puromycin intraperitoneally but no significant changes were found with aminonucleoside of puromycin given subcutaneously on days 7 and 9 and aminonucleoside of puromycin + adenine given subcutaneously on days 7 and 9. Rats given daunomycin or adriamycin had developed proteinuria by day 14. U-14C-glucose oxidation to CO2 was significantly reduced on day 14 in glomeruli from rats given daunomycin but no significant changes were found on day 21 with daunomycin, or on days 14 and 21 with adriamycin. There was a reduction in pyruvic-acid carbon metabolism but not in glutamine-carbon oxidation 14 days after treatment with daunomycin. These results suggest that the observed changes in glomerular metabolism occur independently of, albeit synchronous with, the development of proteinuria. A causal relationship between these metabolic alterations and proteinuria therefore may be unlikely.


Morphology of delayed-type hypersensitivity reactions in man. II. Ultrastructural alterations affecting the microvasculature and the tissue mast cells. Profound alterations in the dermal microvasculature and the closely related fixed tissue mast cells were observed in allergic contact dermatitis reactions to dinitrochlorobenzene and urushiol in man. The vascular changes were of two types. The superficial capillary venule, a distinct anatomical and functional vessel system in the dermal papillae, developed interendothelial cell gaps, maximal at 3 days after skin test, which very likely were responsible for locally increased vascular permeability and consequent dermal edema. The products of degranulating tissue mast cells and infiltrating basophils may have been partly responsible for these changes. By contrast, vessels of the superficial venular plexus, oriented parallel to the cutaneous surface at the junction of the papillary and reticular dermis, were the site of diapedesis and perivascular cuffing by lymphocytes and other inflammatory cells. The superficial venular plexus vessels exhibited striking endothelial cell and pericyte hypertrophy, occasional necrosis of endothelial cells, endothelial cell mitoses, and an extensive and progressive laying down of new and abnormally disposed basal lamina. These changes, somewhat slower to develop than those affecting the superficial capillary venule, were present in all biopsies taken at 3 days or later and were accompanied by mast cell mitoses and the appearance of immature dermal mast cells. The basal lamina-alterations persisted and evolved for at least several weeks. The mechanisms initiating these vessel and mast cell changes have not been identified, but circumstantial evidence suggests that lymphocytes or their products or both may have been responsible.


Ribosome structure and chylomicron formation in rat intestinal mucosa. Sucrose gradient sedimentation and electron micrographic studies were made on the ribosomes of the cells of intestinal mucosa isolated from control, bile fistula, and puromycin-treated rats.  In comparison to controls, there was a 40 to 60 per cent decrease in polysome content of the cells following administration of puromycin or deprivation of luminal choline by creation of a bile fistula.  Feeding of lysolecithin of choline to the bile fistula rats or addition to the isolated cells in vitro resulted in a complete restoration of the polysome profile along with lipprotein synthesis and chylomicron release.  Addition of lysolecithin to isolated cells treated with puromycin in vitro also brought about a reaggregation of the ribosomes and a reactivation of phospholipid biosynthesis.  Choline had no detectable effect on phospholipid synthesis or ribsosme aggregation when fed to ppuromycin-treated rats or when added to puromycin-treated cells in vitro.  The results suggest that chylomicron formation and the release by the muscosal cells depend upon intact rough endoplasmic reticulum and an active protein adn phospholipid biosynthesis.  The role of lysolecithin in this process is ratonalized on the basis of its ability to supply a precursor of lecithin as well as a surfactant which affects the aggregation, or membrane rebinding of ribosomes, or both.


Radiation nephritis. Chronic changes following moderate doses of radiation. Experimental radiation nephritis in the rat is the result of progressive injury involving glomeruli and tubules. Vascular damage plays litter or no role in the initial stages although arterial necrosis and thrombosis develop in the late stages. The radiation nephritis is essentially a degenerative process and the inflammatory reaction, if any, appears to be secondary to necrosis. Within the range employed in this and in previous experiments (1,500 to 10,000 rads), the nature of changes is the same regardless of the dose; large doses of radiation merely accelerate and aggravate the process. During the "latent'' phase there are progressive ultrastructural alterations which eventually become evident by light microscopy.


Effect of tryptophan on hepatic polyribosomal disaggregation due to hypertonic sodium chloride. The effect of tryptophan on the disaggregation of hepatic polyribosomes and on the inhibition of hepatic protein synthesis in rats due to the administration of hypertonic NaCl solutions was studied. Overnight-fasted rats were given by stomach tube or intraperitoneally hypertonic (6.2 to 10.7 per cent) NaCl alone or with 30 mg. of L-tryptophan and were killed 30 minutes later. The hypertonic NaCl treated rats revealed marked hepatic polyribosomal disaggregation and inhibition of hepatic protein synthesis (in vitro incorporation of 14C-leucine into proteins). Rats that received tryptophan alone or in a complete amino acid mixture in addition to hypertonic NaCl revealed a marked improvement in the patterns of hepatic polyribosomes and an increase in in vitro hepatic protein synthesis over that in hypertonic NaCl treated rats. The incorporation of 14C-orotate in hepatic messenger RNA (peak appearing between the 4 S and 18 S RNA fractions) associated with hepatic polyribosomes was studied. Administration of hypertonic NaCl alone caused a decrease in incorporation into hepatic messenger RNA whereas administration of hypertonic NaCl plus tryptophan caused an increase in incorporation into hepatic messenger RNA. Thus, tryptophan appears to cause an increase in hepatic messenger RNA as well as to prevent to a great extent the hepatic polyribosomal disaggregation and the inhibition of hepatic protein synthesis due to hypertonic NaCl.


Rehabilitation problems of head and neck cancer patients. Head and neck cancer and its treatment result in varying degrees of disability affecting various organ systems. Ideal treatment of such patients requires a unit capable of managing problems in the areas of: Reconstructive surgery, maxillofacial prosthodontia, dentistry, deglutition disorders, and psychological, social, and vocational rehabilitation. Provision of such facilities in an integrated manner will give the patient the optimal chance for rehabilitation from the complex disabilities occurring in head and neck cancer.


Sweat gland carcinoma: a clinico-pathological reappraisal. A case of sweat gland carcinoma arising from the right fifth finger which later metastasized to the regional lymph nodes and the lungs is the subject of this report which attempts to establish further the true characteristics of this definite pathological entity. The diagnosis of sweat gland carcinoma has been loosely applied to a variety of lesions, and it was not until recently that more exact and appropriate criteria were used to establish the diagnosis of sweat gland carcinoma. The case reported in this manuscript possesses most if not all the criteria necessary to make a diagnosis of sweat gland carcinoma. Further review of the literature shows that this is a rare and aggressive neoplasm as this case illustrates. Radical surgery of the primary lesions with radical regional lymph node dissection whenever possible is recommended for the initial treatment, and combination chemotherapy and radiotherapy may be employed in the palliative treatment of the more advanced forms of the disease.


Cytotoxicity reactions during immunotherapy of melanoma with neuraminidase altered autologous tumor cells. Lymphocyte cytotoxicity, serum cytotoxicity, and the ability of the serum to inhibit lymphocyte cytotoxicity (blocking effect) were studied in a melanoma patient treated with six monthly injections of her own (autologous) tumor cells incubated with neuraminidase to increase their antigenicity. The same tumor cells grown in tissue culture were used as target cells for the cytotoxicity test. Large fluctuations of blocking effect in the serum were found, which correlated with the clinical course of tumor removal, recurrence, and regression. After the fifth injection of autologous tumor cells, the blocking effect disappeared from the serum (unblocking). In general, changes in serum cytotoxicity corresponded with changes in the amount of blocking effect produced by the serum. The results suggest that active immunotherapy may play a role in the prevention of metastases and, that when used within the autologous system, the cytotoxicity test is valuable in studying response to this type of therapy.


Insulin metabolism in depancreatized dogs during hemorrhagic shock. This study was done to determine why the plasma insulin remained elevated during shock. Mongrel Female dogs (12-15 kg) were depancreatized and maintained on a constant intraportal infusion of porcine insulin while they were bled to reduce and maintain the mean arterial blood pressure at 50 mm Hg for 165 min. Blood samples were taken for glucose and plasma insulin at 15 min intervals. The data show that there was a progressive rise of plasma insulin during the course of hemorrhagic shock. This occurred despite a constant infusion of insulin, the sole source of insulin available to these depancreatized dogs. Since removal of plasma insulin is largely due to insulin utilization, our findings imply that the rise of plasma insulin in hemorrhagic shock is caused by decreased utilization.


Adoptive transfer of tumor immunity between twins by in vitro immunized nodal macrophages and lymphocytes: reversal of serum enhancement. The lymphocytes and serum of a nonidentical twin male with advanced colon cancer were evaluated in vitro for their ability to inhibit the growth of autologous tumor cells. The patient's serum enhanced autologous tumor cell growth. Three siblings including an HL-A matched grade A female twin underwent similar studies. Benign lymph nodes of the twins and one sibling were evaluated for the ability of nodal macrophages to be sensitized to the patient's tumor antigen. The male twin patient received intralymphatically in vitro sensitized nodal macrophages and lymphocytes from the female twin donor. Thirty days after treatment the patient's lymphocytes and serum inhibited the growth of autologous tumor cells.


A survey of epithelial inclusions in the ovarian cortex of 470 patients. The ovaries of 470 patients obtained for various indications at operation revealed 178 with 193 ovarian cysts and tumors - including 63 serous, 23 endometrial, and 27 mucinous - as well as 103 with tubal (serous), 35 with endometrial, and 2 with cervical (mucinous) epithelial inclusions. A very high frequency of transformation of mucinous epithelial inclusions into cysts and tumors contrasted with about 40% similar transformation of serous and endometrial inclusions into cysts and tumors.


Impaired cytotoxicity of lymphocytes from patients with cancer. We have investigated the ability of peripheral blood lymphocytes from 57 cancer patients and from 54 normal controls to exert cytotoxic activity in vitro on allogeneic target cells by using a residual tritiated proline assay. Phytohemagglutin was added to the cultures for potentiating the reaction. The cytotoxic potential of lymphocytes from cancer patients was significantly lower than that of healthy controls. Increased survival of target cells was found in numerous reactions with patients' lymphocytes, probably reflecting a "feeder" effect. The source of plasma used for testing, i.e., autologous or pooled normal homologous plasma, did not affect the strength of cytotoxicity reactions displayed by lymphocytes from either normal or cancer patients. A lower reactivity was generally seen in patients with metastatic disease than in patients with no evidence of distant spread.


Percutaneous transhepatic cholangial drainage: direct approach under fluoroscopic control. We devised a direct percutaneous transhepatic cholangial drainage under fluoroscopic control. The principle is as follows. After percutaneous transhepatic cholangiography, the three dimensional structure of intrahepatic bile ducts is projected to a two dimensional plane under fluoroscopy; the needle can then be introduced into the selected bile duct with accuracy. The technique can be used as a preoperative management of operations of patients with jaundice and also as a palliative management of advanced cancer without much complication.


Reconstruction of right ventricular outflow tract with a valved conduit in 75 cases of congenital heart disease. Reconstruction of the right ventricular outflow tract with an aortic homograft conduit was performed in 75 patients from 1966 to 1974. The types of congenital heart disease were as follows: pulmonary atresia, 35 cases; severe tetralogy of Fallot, 22 cases; truncus arteriosus, 6 cases; transposition of the great arteries (TGA), 3 cases; single ventricle, 2 cases; and tricuspid atresia, 7 cases. Ninety per cent of the patients had one or more previous shunts, and this was a factor affecting the mortality rate. Other factors included age, pulmonary vascular resistance, surgical anatomy, and technical problems such as bleeding, prolonged bypass, coronary artery injury, and compression of the conduit by the sternum. Our present approach is to avoid shunts, define the anatomy precisely by angiography, and to attempt total correction when severe hypoxia or effort intolerance occurs or before increased pulmonary vascular resistance develops.