[Electroplethysmographic determination of the regional relative engorgement of the lungs]. On the strength of the theoretical research of a biophysical model of the lung structure and the following experimental checking of the results obtained a method of calculation of the regional relative blood volume in the lungs by the data of electroplethysmographic examination of the lungs and measurement of specific electrical conductivity of the blood is proposed. Calculation formulae for the determination of the regional relative blood volume in the lungs were derived their working ranges within the limits of application of the proposed calculation method in clinical and physiological examination of the lungs were established.


[Method of simultaneous registration of transpulmonary pressure and the electromyogram of the diaphragm]. Standard esophageal ballon with silver electrodes implanted in it is suggested for simultaneous registration of the hysteresis loop and electromyogram of the diaphragm. The method provides qualitatively new information on the work of the respiratory muscles.


Health information for patients: The hospital library's role. Libraries today, including most hospital-based patients' libraries, are involved only peripherally in providing patient health science information. Hospital libraries should collaborate with health professionals in getting health information to patients--along with the library's more traditional roles of providing recreational reading for patients and serving the informational needs of the physician and medical staff. The library should act as the center for educational materials and programs within the hospital. Many health agencies, health educators, physicians, and librarians have been discussing the need for patient health education, but there are few effectively organized or established education centers. This paper discusses an overview of patient health education and intellectural freedom, proposes a new role for the existing hospital library in patient health education, and suggests guidelines for establishing a patient education center.


Work analysis by random sampling.

Work analysis by random sampling. Random sampling of work activities using an electronic random alarm mechanism provided a simple and effective way to determine how time was divided between various activities. At each random alarm the subject simply recorded the time and the activity. Analysis of the data led to reassignment of staff functions and also resulted in additional support for certain critical activities.


Citation analysis in the literature of tropical medicine. A brief historical account of tropical medicine as a science is given, followed by a short survey of the development of the literature in the field. The citations indexed in Tropical Diseases Bulletin for a forty-eight-month period (1972-1975) were analyzed according to the journal in which they were published and the language in which they appeared. The results of the study conformed to Bradford's law of bibliographic distribution. The reference scattering coefficient was determined to be 0.504, which indicated a high concentration of articles in relatively few journal titles. A rank order list of sixty-one journal titles is given in an appendix. The study showed English to be the most important language in the literature in terms of productivity. The results of the study may be used as an acquisition tool for developing a journal collection in tropical medicine.


Zero-base budgeting and the library.

Zero-base budgeting and the library. This paper describes the application of zero-base budgeting to libraries and the procedures involved in setting up this type of budget. It describes the "decision packages" necessary when this systmem is employed, as well as how to rank the packages and the problems which are related to the process. Zero-base budgeting involves the entire staff of a library, and the incentive engendered makes for a better and more realistic budget. The paper concludes with the problems which one might encounter in zero-base budgeting and the major benefits of the system.


The tachistoscopic recognition of letters under whole and partial report procedures as related to intelligence. Investigations of the short-term memory task performance of retarded individuals have indicated that these individuals demonstrate a deficit in the mechanisms necessary for the acquisition, storage and/or retrieval of information. The present study examined the tachistoscopic letter recognition task performance of retarded and non-retarded individuals under a partial report and a whole report procedure. The results revealed that the retarded subjects did significantly more poorly relative to the non-retarded subjects under both procedures. The data were interpreted as indicating that the retarded subjects were inefficient in their strategy to make the simultaneous imput task manageable. Further, the data provided no support for the suggestion that a visual-to-auditory encoding process exists between iconic and short-term memory.


A study of psychological well-being.

A study of psychological well-being. The concept of psychological well-being is introduced, and scales to measure three of its different facets are described and applied to 1655 British respondents. Results from measures of positive and negative affect are compared with North American findings, and hypotheses are broadly confirmed. Two clusters of specific anxiety items are identified, to do with financial and family anxiety and with health anxiety. The third measure (ratings of present life in general) yields a major cluster of happiness items, but suggests additional dimensions for more detailed investigation. Interrelationships between the several measures and with employment position, motivation to work, job characteristics and age are examined. The study of everyday life as 'normal psychology' is advocated.


Short-term serial tactual recall: effects of grouping on tactually probed recall of Braille letters and nonsense shapes by blind children. The study tested the hypothesis that grouping has adverse effects on the recall of tactual shapes but facilitates the recall of tactual letters on the assumption that this depends on different processes. A further question was the relation of grouping to letter recall span (set-size). Tactually probed recall of tactually presented serial nonsense and letter shapes by blind children was tested under grouped and ungrouped conditions. Results showed a highly significant interaction between list type and grouping, and a (smaller) higher order interaction between set size list type and grouping, in the predicted directions. Grouping had adverse effects on nonsense shape recall. Letter recall was better and was facilitated by grouping, except by subjects with poor letter recall spans who were also slow at letter naming. Mental and chronological age were associated with higher scores, but unlike set size, did not relate differentially to letter grouping. It was argued that the form of coding is a factor in determining the nature of processing and in recall efficiency.


Cross-cultural study of factors influencing orientation errors in the reproduction of Kohs-type figures. The aim of the study was to examine pattern difficulty as a general factor influencing orientation errors, and to explore psychological differentiation and task perception as variables accounting for cross-cultural differences. Samples of 30 boys and 30 girls in Ghana and Scotland were tested with a specially devised apparatus under two treatment conditions. Results confirmed the effect of pattern difficulty, but the extent of psychological differentiation was only indirectly related to orientation errors. Variations in the manner subjects perceived the nature of the task appeared as a major determinant of cross-cultural differences.


Frequency and imagery in word recognition: further evidence for an attribute model. Murdock (1974) located the difference in recognition between common and rare words in the lower frequency of false positives to rare words. Morris & Reid (1974) have similarly located the superiority in recognition of easy to image (high I) words in their lower false positive rate. However, Gregg's (1976) explanation of the word frequency effect in terms of encoding variability and the distinctiveness of word attributes predicts more hits as well as fewer false positives to rare words. Gregg's prediction was confirmed by the experiment reported below. A subsequent survey of dictionary definitions of words differing in frequency and I-value further supported Gregg's model and was incompatible with that of Glanzer & Bowles (1976). A model based upon the likelihood of encoding variability and the distinctiveness of the attributes defining each word meaning accounts for the differences in recognition for items varying in I-value and frequency, and explains Galbraith & Underwood's (1973) finding that abstract words are perceived as more common than concrete words.


Spatial errors made by infants: inadequate spatial cues or evidence of egocentrism? Nine month old infants search correctly for an object which they have seen hidden in one position, but cease to do so after they have been moved to the opposite side of the display, searching instead at a position which is apparently defined egocentrically from their experience before movement. This error can be explained on the one hand in terms of response dependence or egocentrism, or on the other hand as due to a lack of adequate spatial cues to allocentric position. In order to distinguish between these hypotheses, 64 nine month old infants were presented with a hidden object problem in which the two alternative positions had covers of different colours. The results show that infants could search correctly for an object in one location although they saw the problem from different sides. This result combines with those of other conditions to indicate that cover colour provides an adequate spatial cue, allowing the infant to specify position allocentrically, provided the correct cover maintains a stable position.


Cognitive style and lateral eye movements. The lateral eye movement paradigm was employed to test the hypothesis that narrow categorizers, who are believed to be more analytic in information processing, make characteristic use of the left hemisphere, while broad categorizers, being more holistic, depend more on the right hemisphere. Data for narrow categorizers confirmed the hypothesis in that they tended to produce a majority of right shifts. Results from broad categorizers turned out to be less clear, although there was a tendency in the direction of left eye shift. Additionally, narrow categorizers made significantly more total LEMs than did broad categorizers. The results are discussed in terms of cerebral specialization underlying cognitive style.


The effect of catch-trials on speed and accuracy among introverts and extraverts in a simple RT task. Three predictions from the model of extraversion put forward by Brebner & Cooper (1974) were tested in a simple RT task. In line with the model, extraverts were found to make more commissive errors and to be more affected by an increase in the catch-trial rate. The third prediction-that extraverts would tend to produce longer runs of decreasing RTs than of increasing RTs in the condition with 10 per cent catch-trials, was not borne out. This effect was, however, seen in the condition with 40 per cent catch-trials although it was not statistically significant, P = 0.06.


The effect of osmotic diuresis on urinary iodine concentration using contrast media of differing osmolality. The urinary iodine concentrations of a monomer (sodium iothalamate), a dimer (sodium iocarmate) and a non-ionic compound (metrizamide) have been compared in dogs with varying levels of solute excretion. All the animals were undergoing maximal antidiuresis. In dogs with normal solute excretion, metrizamide and iocarmate produced higher urinary iodine concentrations than iothalamate. There was no significant difference between metrizamide and iocarmate. With increasing levels of solute excretion, the differences between the compounds were reduced. These findings suggest that contrast media of reduced osmolality are unlikely to have a special place in advanced renal failure.


Ioglycamide (Biligram) studies in man--relation between plasma concentration and billary excretion. Plasma ioglycamide concentration was linearly related to the rate of intravenous infusion over a dose range of from 1 to 4 mg per kg per min. The relation between plasma and biliary concentration of ioglycamide was studied in 15 anicteric patients with a T-tube in situ. Peak biliary concentrations and excretory rates of ioglycamide were seen when the plasma concentration was greater than 1500 micrograms per ml. The mean biliary transport maximum (Tm) for ioglycamide in man was 31.6 mg/min (range 22.0-40.4). The results suggest that near optimal concentrations of iodine in the bile duct can be obtained during intravenous cholangiography if ioglycamide is infused for one hour at a rate of about 4 mg per kg per min.


The contribution of echography in the diagnosis of proptosis. Echography was used to examine the retro-bulbar space of 150 patients with protosis. An NE Diasonograph was used with an 8 MHz probe using a water bath in the supine position. Lesions were classified ultrasonically as (1) tumour, (2) inflammatory oedema (including pseudo-tumour or other granulomas), (3) traumatic, (4) dysthyroid ophthalmopathy, (5) normal. Thirty-one patients were placed in the tumour group but three of these were subsequently found to have granulomas. In addition, one patient with a normal ultrasonic appearance, was found to have a meningioma en plaque at operation. There were no false positive results in the inflammatory group but again one patient with a normal ultrasonic appearance was eventually diagnosed as having an orbital inflammatory process. The ultrasonic findings in inflammatory disease are non-specific and three were found to be associated with or possibly caused by venous thrombosis or arteritis of the orbit. The changes have to be distinguished from the thyroid ophthalmopathy but this disorder is generally bilateral which is unusual in inflammatory disease. Traumatic oedema and haemorrhage are distinguidhed by the obvious antecedent history. Because of the variability of the amount and position of the retrobulbar fat in the posterior part of the orbit, it is necessary to make a comparative scan of the normal orbit in all patients with suspected retro-bulbar pathology.


Effects of negative pions and neutrons on the growth of Vicia faba bean roots. Vicia faba bean roots have been irratiated with neutrons of various energies and with negative pi-mesons, and the effect on the ten-day growth of the roots has been determened. The neutron irratiations were made in beams of 400 and 600 MeV maximum energy, as well as with neutrons from a plutonium-beryllium source (mean energy 4.4 MeV) and from a 14 MeV neutron generator. The bean roots have also been irradiated at various points along the depth-dose curve of negative pi-mesons, including the gegion where the pions annihilate on coming to rest. The results show a maximum relative biological effectiveness (RBE) of 3.7 for 50% reduction in ten days growth for stopped negative pions and values up to 3.3 for high-energy neutrons, compared to 5.5 for 14 MeV neutrons. The biological effectiveness of high-energy neutrons and stopped pions shows a more pronounced dependence on dose than does the effect with lower-energy neutrons.


Radiological findings in neurosarcoidosis. The radiological investigation of neurosarcoidosis is discussed in relation to a series of 32 patients presenting to a neurological hospital. Cranial computed axial tomography, performed in 13 of these cases, was the most frequently positive procedure (77%). The indications for air studies are now limited but in cases with nerve or chiasmal syndromes and negative CAT they may show small mass lesions, or incomplete filling of basal cisterns due to granulomatous infiltration or fibrosis. Sarcoid masses are avascular and angiography is only useful for exclusion of incidental tumours with pathological circulation. Cord syndromes were present in eight cases, but myelography was only indicated in five of these and was normal in three. The cord may be involved by intra-medullary granulomas or meningeal infiltration causing arachnoiditis, both of which cause myelographic abnormalities though these are not specific for sarcoidosis.


The "mandibular mantle"--a sign of rickets in very low birth weight infants. Mandibular periosteal new bone formation (the "mandibular mantle") is described in very low birth weight infants with other signs of severe metabolic bone disease. In infants with onset of dyspnoea and apnoea, between two and three months of age, this mandibular change suggests that the lung disorder is of skeletal, rather than pulmonary origin and aids in differentiation therefore, from the Mikity-Wilson Syndrome (pulmonary dystmaturity).


Gallstone disease presenting as septicaemic shock. Three patients are described who were admitted to hospital with septicaemic shock due to gallstones, but in none of whom had the presence of gallstones, been diagnosed previously. All 3 had positive blood cultures, Clostridium welchii being isolated in one patient (in another patient this organism was isolated from the bile). Two patients had renal failure requiring dialysis. All 3 patients survived. The management of this serious presentation of gallstones, hitherto poorly described in British literature, is discussed.


Rupture of a hydatid cyst of the liver into the biliary tract. The history of a patient with intrabiliary rupture of a hydatid cyst of the liver is reported. The patient presented with a distended palpable gallbladder, which is a most unusual feature of this condition.


Endoscopic retrograde cholangiography in hepatic hydatid disease. Endoscopic retrograde cholangiography provides safe preoperative documentation of the relationship of hepatic hydatid cysts to the biliary ductal system and accurate distinction from coincident calculus disease.


Cytotoxic perfusion for colorectal liver metastases. A clinical trial  to assess the value of different perfusion techniques in the management of colorectal liver metastases is presented. The perfusion with 5-fluorouracil was commenced at the time of resection of the primary tumour when palpable liver metastases were found. In terms of survival, no benefit was found with hepatic artery ligation and perfusion and with portal vein perfusion alone compared with the control group. However, the combination of the two improved the survival rate and a possible explanation for this is discussed.


Interposition left gastric-caval shunt using internal jugular vein autograft in the treatment of portal hypertension. The selective left gastric-caval shunt is, in theory, one of the better procedures in the surgical treatment of portal hypertension. We have performed a modification of the previously described technique utilizing an internal jugular vein autograft in 4 patients who had had more than one major haemorrhage from oesophageal varices 3-12 months before operation. There were no post-operative deaths. All 4 patients are still alive 3 months to 4 years after shunting, with no episodes of bleeding. On radiological and endoscopic follow-up, the oesophagogastric varices were noted to be markedly smaller in size than before shunting.


The insulin infusion test: a safe procedure? One hundred and thirty insulin infusion tests (dose 0.05 u kg-1h-1) were carried out in 87 patients with peptic ulcer or after a vagotomy. During the test ECG tracings were taken and blood was sampled for blood glucose and serum potassium determination. In 31% of the tests electrocardiographic changes were seen. The cardiovascular effects were supraventricular and ventricular ectopic beats, ST-T changes and U waves. In 2 tests there were potentially dangerous arrhythmias. A significant relationship was seen between ECG abnormalities and the age of the patients. Such a relationship was not present between ECG changes and glucose and potassium values. It is concluded that the insulin infusion test is probably safer than the conventional Hollander test, but constant monitoring is still required.


Operative intubation in the treatment of complicated small bowel obstruction. Intestinal intubation carried out at laparotomy for complicated small bowel obstruction is not yet a generally accepted technique. Experience in 32 patients has shown that it is safe and effective. The procedure was initially described in North America for use in recurrent adhesive small intestinal obstruction but the indications have been extended and it has proved of value in other difficult situations. A technique for intubation is described and the results obtained in various clinical situations are given.


Evaporative water loss in adult surgical patients in the Sudan. Evaporative water loss and urine volume were investigated in 65 healthy adult Sudanese male surgical patients in Khartoum. The mean evaporative water loss per day was found to be 3063 g in the hot dry season and 667 g in the cold dry season. The mean 24-h urine volume was found to be 594 and 1515 ml respectively. There was a significant correlation between evaporative water loss and the air temperature and the effective temperature. These findings support the results reported from other parts of the tropics that the values for evaporative water loss and urine volume quoted for temperate climates are not representative of those encountered in the tropics.


Extra-abdominal desmoid of the face involving the orbit. A case of musculoaponeurotic fibrosis of the face invading the orbit is presented. The need for radical local excision of such lesions to prevent recurrence and the value of adequate prostheses following excenteration of the orbit are emphasized.


The Gritti-Stokes amputation in ischaemia: a review of 134 cases. The results of 134 Gritti-Stokes amputations for ischaemia are presented. The mortality rate was 11% and healing occurred in 88%, reaffirming the good results already reported for this operation. The long term results are reviewed in an attempt to decide whether the most frequently cited criticisms of this procedure are justified. Stump pain and mobility of the patella were not major problems. The difficulties in fitting a suitable prosthesis are discussed and attention is drawn to the advantages of a new prosthesis that has been developed for this amputation.


Familial phaeochromocytoma with von Hippel's disease in one sister and ectopic adrenal cortex in the kidney in another. Two sisters with bilateral adrenal phaeochromocytomas are reported. Von Hippel's disease of the retina was found in the one and ectopic adrenal cortical tissue was found in the kidney of the other. The latter association has not previously been described with familial phaeochromocytoma.


Traumatic diaphragmatic hernia.

Traumatic diaphragmatic hernia. A series of 58 cases of traumatic diaphragmatic hernia following blunt and penetrating injury is reviewed. The problems of radiodiagnosis are outlined and the need for barium contrast studies of the entire gastrointestinal tract to ensure recognition of isolated small bowel herniation is emphasized. Surgical access via laparotomy is recommended in the immediate post-traumatic presentation, whereas thoracotomy is preferable in cases diagnosed after a latent interval. Penetrating injury resulted in smaller diaphragmatic defects, greater morbidity and higher mortality due mainly to infective complications.


The early use of fine-needle percutaneous transhepatic cholangiography in an approach to the diagnosis of jaundice in a surgical unit. Fine-needle percutaneous transhepatic cholangiography (PTC) was performed in a series of 46 patients with jaundice or suspected biliary tract disease. The ductal system was successfully outlined in each of 20 patients with dilated intrahepatic ducts and in 19 of 26 patients with intrahepatic ducts of normal calibre. There were two episodes of septicaemia after PTC, one of them fatal. Valuable accurate diagnostic information was obtained in all cases with biliary tract obstruction. A programmed approach to diagnosis of suspected obstructive jaundice is outlined. Fine-needle PTC is an acceptably safe procedure and need not be followed by immediate laparotomy.


Side-to-side choledochoduodenostomy in the management of choledocholithiasis. Sixty patients with choledocholithiasis (either single or multiple stones of the biliary tree) were treated with lateral choledochoduodenostomy. Of these cases 83.3% were followed up for from 1 to 7 years. Only 1 patient developed cholangitis, which responded well to conservative treatment. The other cases have been asymptomatic following surgery. The diameter of the common bile duct is not an important problem in constructing a functional anastomosis.


Early platelet consumption in pre-eclampsia. One hundred and thirty-one women with chronic hypertension were studied serially during pregnancy to determine the sequence of events in the development of superimposed pre-eclampsia and to discover the time of onset. Twenty-seven women developed a sustained rise in plasma urate concentrations, which began at about 28 weeks' gestation and which is characteristic of pre-eclampsia. The mean platelet count was already significantly reduced and continued to fall until delivery, which was on average at 36 weeks' gestation. A comparable but smaller decrease in platelet count was seen in 55 women who had borderline but consistent increases in plasma urate concentrations. In 49 women whose plasma urate concentrations remained steady the platelet count did not change significantly before delivery. The reduced platelet count in women who develop pre-eclampsia suggests that increased platelet consumption is an early feature of the disorder.


Duodenal ulcer and working-class mobility in an African population in South Africa. The number of Africans in Johannesburg presenting with duodenal ulcers has steadily increased over the past 50 years. The characteristics of 105 patients with duodenal ulcer who presented a Baragwanath Hospital were compared with those of matched and unmatched samples of patients without gastrointestinal conditions in the same hospital. Men with duodenal ulcers were found to be significantly better educated than their controls, most had been born in the town, and more of them were employed at higher, though not the highest, educational levels. These data were used to test Susser's proposition that duodenal ulcers are associated with "early urbanisation." Johannesburg blacks with duodenal ulcer did seem to fit the pattern, but the relation between stress and duodenal ulcer remains unclear.


Coronary heart disease in relation to age, sex, and the menopause. Examination of the Registrar General's mortality data suggested that women do not lose protection from coronary heart disease (CHD) after the menopause. Apparently, at around the age of 50 men begin to lose a factor that had previously put them at increased risk of developing CHD compared with women. Male sex hormones may be risk factors for CHD, and further studies are needed to clarify their role in the aetiology of CHD in men.


One drug for epilepsy.

One drug for epilepsy. We performed prospective trials of phenytoin and carbamazepine, assisted by blood level monitoring, in untreated patients newly referred with grand mal or partial seizures, or both, to a neurological clinic. At the time of follow-up (mean 28.5 months for phenytoin; 12 months for carbamazepine) 76-88% of patients were completely controlled. Twelve per cent of the patients on each drug had further seizures, despite an optimum blood level. When the blood drug concentration was in the optimum range there was a 98% reduction in grand mal attack rate and 92-93% reduction in partial seizure rate. These results suggest that polypharmacy is largely, and possibly totally, unnecessary in newly diagnosed adult epileptics.


Cellular hyperviscosity as a cause of neurological symptoms in leukaemia. Six patients with various forms of leukaemia had neurological signs and symptoms associated with an extremely high white blood cell count and increased whole blood (but not plasma) viscosity. All were treated by leucapheresis with an Aminco Celltrifuge. Rapid and complete reversal of all symptoms occurred in three patients and partial recovery in one. One patient died shortly after leucapheresis and another (from cerebral intravascular coagulation) two days later. It is concluded that a cellular hyperviscosity syndrome may cause neurological dysfunction in patients with extremely high white cell counts, and that leucapheresis, in carefully selected patients, can be an effective method of treatment.


Changing pattern in a general practitioner obstetric unit. Over the past nine years in Watford the proportion of hospital confinements has increased and domiciliary confinements have almost ceased. The proportion of patients originally booked into the general practitioner obstetric unit and subsequently transferred to the consultant unit has increased. Most patients are transferred during pregnancy, and the numbers transferred in labour are decreasing. The proportion of GPs attending their patients for delivery is low: local practitioners appear to be prepared for the consultant unit to supervise delivery with the practitioner co-operating in antenatal and postnatal care and family planning. There seems little doubt that the success of GP units depends on the enthusiasm and interest of individual practitioners.


A biochemical and morphological study of the altered growth pattern of central catecholamine neurons following 6-hydroxydopamine. In this study the effect of administering 6-hydroxydopamine (6-OHDA) intracisternally on brain catecholamine content and fluorescence patterns of cerebellar processes was examined. It was found that intracisternal injection of 6-OHDA resulted in widely diverging effects depending upon the dose of 6-OHDA, age of the animal upon injection and the length of the post injection interval. Small doses of 6-OHDA (3 and 10 microgram) selectively depleted telencephalic and upper brain stem NE while larger doses of 6-OHDA (30 and 100 microgram) infringed on dopaminergic as well as noradrenergic neurons. In addition, the lower doses of 6-OHDA, but not the higher ones, led to an approximately two-fold accumulation of NE in the lower brain stem and cerebellum. Morphological observations suggested that the cerebellar norepinephrine accumulation after 10 microgram 6-OHDA was attributable primarily to an invasion of noradrenergic processes into the cerebellum.


Cardiovascular alteration by nucleus locus coeruleus in spontaneously hypertensive rat. Biphasic electrical stimulation of the nucleus locus coeruleus (LC) produced frequency-related pressor responses associated with increased heart rate in normotensive rats (WKY) at both 50 and 100 microamperemeter. In contrast, spontaneously hypertensive rats (SHR) demonstrated small depressor responses at 50 microamperemeter and 50 Hz, but no consistent pressure or heart rate changes at either 50 or 100 muA stimulation. The LC pressor threshold current (current necessary to increase arterial pressure by greater than or equal 10 mm Hg) was higher in SHR than WKY (136 +/- 5 muA vs. 84 +/- 7 muA; P less than 0.001); and only the SHR LC demonstrated a depressor threshold (current necessary to reduce arterial pressure by greater than or equal to 10 mm Hg) (53 +/- 3 muA). These threshold current levels did not seem to change with acute alterations of arterial pressure produced by either bilateral carotid artery occlusion or caortid sinus stimulation. Therefore, these studies indicate altered levels of responsiveness of the SHR LC to stimulation but that the pressor function of the LC does not seem to be importantly involved in further elevation of abnormally high arterial pressure in the SHR.


Effects of microiontophoretic and intravenous application of gonadotrophic hormones on the discharge of medial-basal hypothalamic neurones in rats. In ovariectomized rats, the responses of medial-basal hypothalamic neurones to gonadotrophic hormones have been recorded. The luteinizing and follicle stimulating hormones (LH and FSH) were applied to neurones both by microiontophoresis and by intravenous injection. Although LH was the more frequently effective, both hormones caused either excitation or inhibition of neurones, and the effects were consistently repeatable on the same neurones. Iontophoretic and intravenous application of the same hormones to the same neurone gave identical responses. Responsive neurones were found throughout the medial-basal hypothalamus and hormones were effective both on neurones which could be antidromically activated from the median eminence and on those which could not be activated. Treatment of rats with oestradiol, either during the experiment or 24 h earlier, did not significantly alter neuronal responses to the gonadotrophins. The results are discussed in terms of possible feedback by gonadotrophic hormones on the brain and it is suggested that such a feedback may not be concerned with control of gonadotrophic hormone secretion.


Spinal myelopathy induced by subarachnoid batrachotoxin: ultrastructure and electrophysiology. A combined structural and electrophysiologic analysis on the effects of subarachnoid injections of batrachotoxin was conducted in rats. Swelling of neuronal perikarya, accompanied by areas of clearing, satellitosis, fatty metamorphosis and central chromatolysis were demonstrated in the spinal anterior horns. Studies on isolated extensor digitorum longus (fast) and soleus (slow) muscles showed membrane depolarization in the extensor 24 h after injection, with progressive augmentation of this phenomenon in animals given multiple injections of the toxin. Differential sensitivity of fast and slow muscles was evident: soleus was only slightly affected. Subarachnoid injections of batrachotoxin, which induced swelling of neuronal perikarya and axonal processes, also caused signs of denervation in the extensor muscle 7 days after injection, while spontaneous transmitter release was still present. Some structural and and most electrophysiologic alterations after batrachotoxin injections were reversible.


Extrinsic control of intrinsic neuronal plasticity: an hypothesis from work on simple systems. All advanced nervous systems use plastic properties of neurons for learning, remembering and achieving other information processing feats. Recent findings on a variety of relatively simple nervous systems or reduced parts of more complex ones suggest the notion that, in addition to having neurons with intrinsically plastic properties, nervous systems also have mechanisms for controlling the development, expression, and maintenance of changes in their inherently malleable neurons. This hypothesis has important implications for understanding both the brain's learning machinery and also aspects of nervous system organization not obviously related to learning.


Slowly-developing depolarization of neurones in the guinea-pig inferior mesenteric ganglion following repetitive stimulation of the preganglionic nerves. Intracellular recordings were made from cells of the isolated guinea-pig inferior mesenteric ganglion. Stimulation of both hypogastric nerves at 30 Hz for 2 sec caused a slowly developing depolarization (SD) and fall in cell input resistance which reached a peak 10-30 sec after the end of stimulation. The amplitude of the SD was increased in a graded manner if the stimulus voltage was increased. The SD was unaffected by tubocurarine, atropine or guanethidine, but was blocked by removing external Ca. These results suggested that the SD was caused by the release of some substance from a large number of nerve terminals.


Identification of vasopressin in the subfornical organ region: effects of dehydration. The subfornical organ (SFO), a neuroendocrine structure implicated in saltwater homeostasis, contains secretory structures histochemically similar to those in the neurohypophysis. Because of these morphological similarities, we compared levels of vasopressin (vp) in the SFO area and the adjacent hippocampal commissure-fornix (HC-F) of normally hydrated and 48 h water-deprived (WD) rats. VP in the SFO region from normally hydrated rats was 44 +/- 5 pg/mg protein, 3.5 +/- 0.4 ng/g wet weight or 3.6 +/- 0.4 pg/SFO. These concentrations increased (P less than 0.05) about twofold after WD. The content of VP, ng/g wet weight, in HC-F was higher (P less than 0.05) than the SFO area and also increased (P less than 0.05) after WD. VP was detected in other fiber tracts, anterior commissure (AC) and fornix (F), but was unchanged by WD. Changes in hormone observed in the SFO and HC-F regions were therefore not part of a generalized increase of VP in the brain, nor can they be ascribed to elevated plasma levels. Thus, VP changes in the SFO region may be functionally significant and related to an SFO endocrine role in hydration. VP in fiber tracts (F, AC) unassociated with the hypothalamo-hypophysial system and unchanged after WD may suggest an unidentified role of this hormone in the central nervous system.


Denervation of the primary olfactory pathway in mice. V. Long-term effect of intranasal ZnSO4 irrigation on behavior, biochemistry and morphology. Intranasal irrigation of mice with 0.17 M ZnSO4 solution results in the immediate and total loss of the ability to find a buried food pellet. This anosmia persists for 6 weeks in at least 80% of the treated mice and for 4 months in half of the animals. This marked behavioral effect is matched by a long-term reduction of the levels of carnosine synthesis and transport in the primary olfactory pathway. These biochemical parameters are virtually undetectable at two weeks after treatment and even at one year after treatment do not exceed 5-10% of average control values. Light microscopic observations of tissues of the primary olfactory pathway at various times after treatment are consistent with these observations and indicate a substantial destruction of the olfactory epithelium with subsequent atrophy of the olfactory bulb. At very long intervals after treatment, some receptor regeneration is apparent with accompanying reinnervation of the olfactory bulb. Estimates from microscopy and biochemistry suggest that much less than 10% of the normal complement of functioning receptor cells is adequate to give apparently normal food-finding behavior.


The development of intersegmental connections in embryonic spinal cord: an anatomic substrate for early embryonic motility. This ultrastructural study of the embryonic chick spinal cord was designed to determine whether intersegmental inputs are formed before the closure of the reflex arc. Lesions were made in the thoracic cord of chick embryos at five days of incubation, when synapses are present in the ventral half of the cord, but before dorsal root afferents have made contacts in the central nervous system. Axons degenerating were observed in the upper brachial and lower lumbar regions of embryos sacrificed two days later. Synapses exhibiting degenerative changes were present up to six segments above and below the lesion. These observations were interpreted to indicate that: (1) intersegmental fibers connect the thoracic cord to brachial and lumbar areas by the fifth day of incubation; (2) early synapses contain both segmental and intersegmental connections; and (3) some intersegmental connections occur prior to the closure of the reflex arc. These morphologic studies, in conjunction with behavioral and electrophysiological data, strongly suggest that the early intersegmental connections are part of the propriospinal system. The development of these intersegmental tracts coincides with the onset of movement and thus provides an anatomical substrate for understanding embryonic motility.


The receptive field structure of visual cells from the optic tectum of the freshwater perch (Perca fluviatilis). Recordings from the intrinsic tectal cells of the perch have allowed a classification of visual units on the basis of receptive field type. Comparisons with retinal and tectal cells in carp, goldfish, pike, trout and in the Anura were made. Most striking are cells with vertical bar-shaped features forming part of the R.F. The relation between the receptive fields of units lying adjacent within the tectum, suggests that parts of the same pattern are derived from cells within the same vertical column.


Trigeminal influences on entopeduncular units. Because considerable work has implicated the basal ganglia in oral-ingestive behavior, an assessment was made of the effects of trigeminal stimuli upon entopeduncular single units. Units wre recorded extracellularly in awake, paralyzed and locally anesthetized cats. The effects of two types of sensory input were tested. Afferents from periodontal mechano-receptors involved in reflex jaw opening were stimulated via electrodes in the inferior dental nerve. Afferents from stretch receptors involved in reflex jaw closure were stimulated via electrodes in the trigeminal mesencephalic nucleus. A significant proportion of cells responded to both types of stimulation. The data were discussed in the context of a basal ganglionic role in oropharyngeal motor processes and a more general role in movement per se.


Cortical projections of the thalamic mediodorsal nucleus in the rabbit. The cortical projection of the thalamic mediodorsal nuclear complex (MD) in the rabbit was mapped retrograde horseradish peroxidase and anterograde tritiated proline techniques. The projection field occupied the entire medial wall rostral to a mid corpus callosal level, wrapped around the frontal pole onto the lateral convexity and tailed off caudally on the dorsal bank of the rhinal sulcus. The projection of the lateral approximately one-half of MD, the half which does not receive olfactory input, was confined to medial cortex supply all but the most rostral region. This projection field of lateral MD was precisely organized in two dimensions with the most lateral part projecting most caudally and the most dorsal part projecting most ventrally. A representation for the third, anterior-posterior (A-P), dimension was not evident since any cortical point within the field was supplied by a cylinder of cells extending the entire A-P extent of lateral MD. The medial half of MD, which does receive olfactory input, projected to the remaining rostral medical cortex, the lateral convexity and rhinal sulcal region. The inverse dorsoventral relationship was partially preserved and on overlapping A-P gradient was present with sulcal projections originating more caudally in medial MD and the rostral medial projection originating more rostrally.


Qualitative and quantitative odour discrimation by mitral cells as compared to anterior olfactory nucleus cells. The responses to odour stimulation of 61 single mitral cells and of 64 single anterior olfactory nucleus (AON) units were simultaneously recorded from rabbits. The test battery consisted of 6 chemical stimuli delivered at two intensity levels corresponding to a hundred-fold difference in concentration. The odour discrimination reaches its best for the mitral cells stimulated weakly; it decreased somewhere when the same cells are stimulated strongly. At AON level the odour discrimination already limited in the case of weak stimuli, almost disappears for strong stimuli. Multidimensional analysis of the odour similarities, respectively in the olfactory bulb and the AON, reveals an unexpectedly high loading of the first axis with an intensity factor. Our results indicate that the discriminatory ability in the mitral cells and in the AON cells are respectively better and poorer than in the chemoreceptors.


A comparison of the proximal negative response and ganglion cell responses to sinusoidal flicker. In the mudpuppy retina, sinusoidal light stimulation of the proximal negative response (PNR) demonstrates two main components whose phases are essentially the same as those of the spike discharges of ON/OFF ganglion cells. Oscillations superimposed upon these components are synchronized with the spike discharges of ON/OFF cells, but not of ON or OFF cells. Intracellular recordings from ON/OFF ganglion cells reveal slow potentials with nearly identical waveforms and phases to those of the PNR. These results, together with previously published comparisons between the flesh-evoked PNR and amacrine cell responses, support the suggestion that the PNR arises from activity in the on/off system (amacrine and/or ganglion cells).


Biochemical evidence for the presence of presynaptic receptors on dopaminergic nerve terminals. Two compartments of striatal synaptosome dopamine were identified by differential labelling with the isotopic presursors, L-tyrosine and Dopa, and from specific radioactivity measurement. Either, endogenous or exogenous L-tyrosine could provide a source for the dopamine pool synthesised and released in response to K+ depolarization, whereas external DOPA did not enter this pool. Acetylcholine (0.1 mM) in the presence of neostigmine (0.1 mg/ml) increased dopamine turnover as shown by increased formation of [14C] dopamine and [14C] DOPAC from [14C] DOPA. Haloperidol (0.65 mM) did not affect the size of dopamine pools but increased the conversion of [14C] DOPA to [14C] dopamine and the formation of [14C] DOPAC. Acetylcholine stimulated the release of dopamine from synaptosomes, which effect could be modified by both muscarinic and nicotinic antagonists. In the presence of the muscarinic antagonist, atropine, acetylcholine stimulated dopamine release, whereas in the presence of the nicotinic antagonists, hexamethonium (0.2 mM) or alpha-bungaro-toxin (0.188 muM), acetylcholine inhibited dopamine release. This showed that presynaptic cholinergic receptors were operational, excitatory nicotinic receptors in the former case and inhibitory muscarinic in the latter. The nicotinic receptor was shown to be saturable and to bind specifically 11.2 fmoles of [3H] alpha-bungarotoxin per mg. protein which could be prevented by hexamethonium or D-tubocurarine.


Neurospecific S-100 protein content in brains of different mouse strains. Total whole brain concentrations of S-100 protein and of its water-soluble fraction were determined in 11 inbred mouse straine: DBA/2J, AKR/J, CBA/Lac, C57BL/6J, C57BL/6J-Ay, C3H/He, C3H/f, DD, A/He, BALB/cLac, CC57BR/Mv, and in cerebral cortex, cerebellum and hippocampus in DBA/2J, AKR/J and CBA/Lac strains. Highly significant differences in the concentrations of the water-soluble S-100 protein were found between some strains. Slight differences were found in total S-100 protein content in whole brains between the strains (0.01 less that P less than 0.05). The DBA/2J mice had the highest brain S-100 protein content, and were characterized by a higher learning rate in shuttle-box as compared to CBA/Lac and AKR/J mice, who had a low content of this neurospecific protein.


Rapid development of keratoacanthoma and accelerated transformation into squamous cell carcinoma of the skin: a mutagenic effect of polychemotherapy in a patient with Hodgkin's disease? A 59-year-old white man developed keratoacanthoma of the nose immediately following one course of MOPP polychemotherapy for clinical state IV B mixed cellularity Hodgkin's disease. Despite the dramatic response of Hodgkin's disease to intensive chemotherapy, the skin lesion was rapidly transformed into squamous cell carcinoma in 10 weeks. The immunosuppressive effect of intensive polychemotherapy may play a significant role in accelerating the malignant transformation. We report here our results concerning this complication which may occur in any patient with Hodgkin's disease undergoing intensive therapy.


Radiation-induced carotid artery disease. Nine patients with atherosclerotic carotid artery disease associated with neck radiation were compared to 40 control patients. The data suggest that significant differences in age, incidence of coronary and peripheral vascular disease, elevated lipids and serum cholesterol, and the angiographic incidence of disseminated atherosclerosis justify the description of radiation-induced carotid disease as a clinical entity. Elevated serum cholesterol and hyperlipidemia may contribute to the development of radiation-induced vascular disease. Successful surgical reconstruction does not appear to be influenced by the prior radiotherapy, although periarterial fibrosis and increased difficulty in separating the plaques from the vascular media was encountered.


Predictive value of bone scans in an adjuvant breast cancer program. Technetium 99m phosphate-complex bone scans were performed in 43 women within two months of mastectomy for stage I (1 patient), stage II (28 patients), and stage III (14 patients) breast cancer. Twelve (28%) initial bone scans were interpreted as either equivocally abnormal (6 scans) or definitely abnormal (6 scans). Radiographs confirmed metastatic disease in 2 patients who were then considered ineligible for adjuvant therapy (adriamycin-cyclophosphamide with or without local radiotherapy). Of the remaining 41 eligible patients, all have received adjuvant therapy and 36 have had at least one additional bone scan at 6-month intervals. Among 20 patients whose serial bone scans were unchanged, there has been no clinical recurrence with a mean followup of 20 months. In contrast, among 16 patients whose serial bone scans have changed (e.g., appearance of new focal lesions, disappearance of old lesions), there have been 6 clinical recurrences (p = 0.01) with a mean followup of 43 months. We conclude that carefully performed technetium pyrophosphate bone scans are helpful in the accurate initial staging of patients being considered for adjuvant breat cancer treatment, and that serial changes in the bone scan identify a group of patients at high risk for early recurrence.


Value of 111Indium chloride bone marrow scanning in the differential diagnosis of blood count depression in lymphoma. In patients with Hodgkin's disease or non-Hodgkin's lymphoma, the etiology of low peripheral blood counts is often difficult to determine. Often it is based on the results of a "random" bone marrow biopsy and/or aspirate, plus evaluation of circulating peripheral blood elements. However, these tests may be misleading. The present study evaluates the usefulness of 111Indium chloride bone marrow scanning in conjunction with marrow biopsies in distinguishing intrinsic from extrinsic causes for low peripheral blood counts. Thirty consecutive patients with Hodgkin's disease or non-Hodgkin's lymphoma, presenting with low peripheral blood counts and without any form of antineoplastic treatment for at least 5 weeks, were analyzed. Scan ratings were felt to be clinically accurate in 27 of the 30 patients analyzed (90%). In 18 patients (60%), the scan provided information which was not provided by any other standard test. 111Indium chloride scanning in conjunction with a marrow biopsy appears to be a useful, accurate means of evaluating bone marrow function in patients with depressed peripheral blood counts.


Chromosomes and causation of human cancer and leukemia. XXX. Banding studies of primary intestinal tumors. The chromosomes of 15 primary intestinal tumors were analyzed with a banding technique. Of the 15 tumors, 12 had some chromosomal abnormalities (8 with numerical changes and 4 with both numerical and structural abnormalities) and in the remaining three no karyotypic abnormalities were found. No common marker chromosomes were seen among the various tumors and no two tumors with chromosomal changes and identical karyotypes, though some chromosomes were involved more often than others. Excessive chromosomes in the primary tumors were usually due to extra chromosomes in the following groups (numbers of tumors involved are shown in parenthesis): No. 8 (7), No. 13 (4), No. 15 (4), No. 17 (6) and No. 21 (6). On the other hand, chromosomes losses, though much less frequent, involved chromosomes No. 5, No. 6, No. 7, No. 10 and No. 16. Most of the tumor cells with chromosomal changes were hyperdiploid and usually contained less than 60 chromosomes. Only one tumor contained hypodiploid cells. The cytogenetic data presented on primary intestinal tumors indicate that they consist primarily of numerical changes, relative infrequency (when compared to metastases) and small number (1-4) of markers.


NMR in cancer. X. A malignancy index to discriminate normal and cancerous tissue. Proton nuclear magnetic resonance relaxation parameters (T1, T2, T1p) were measured on 84 normal and malignant samples of colon, lung and breast tissue at 22.5 MHz. The purpose of this study was to evaluate the ability of NMR measurements to discriminate between normal and malignant tissue. By combining T1 and T2 into a normalized NMR malignancy index, it was possible to discriminate malignant and normal tissue in all 36 colon samples, 22 out of 23 breast samples, and 26 out of 29 lung cases. Furthermore, histologically normal tissue adjacent to malignant colonic tissue was found to have an elevated NMR malignancy index comparable to that of malignant colon.


NMR in cancer. XI. Application of the NMR malignancy index to human gastro-intestinal tumors. One hundred two specimens of human gastro-intestinal tissue taken from eighty-seven individuals were inspected by proton magnetic resonance techniques (at 22.5 Megahertz). The purpose of the study was to evaluate the diagnostic capabilities of the nuclear magnetic resonance (NMR) technique with regard to the diagnosis of malignancy. The combination of two NMR parameters (spin-lattice ((T1) and spin-spin ((T2)) relaxation times) into a malignancy index yielded complete discrimination between the two populations of tissue. The mean and standard deviations obtained were 2.004 +/- 0.342 for normal tissue, and 3.266 +/- 0.642 for malignant specimens. In addition, the NMR technique indicated that histologically normal tissue taken adjacent to the malignancy was pathologically "involved". Analysis of the electrolyte and water content of such tissues confirms this abnormality.


The significance of vascular invasion and lymphocytic infiltration in invasive cervical cancer. Surgical specimens from 100 patients with stage I B cervical cancer undergoing radical hysterectomy and pelvic lymphadenectomy were reviewed with respect to vascular invasion and lymphoplasmacytic infiltration. Lymph nodes from these patients were classified morphologically according to the criteria proposed by Cottier. Vascular invasion was associated with a significant increase in nodal metastases and tumor recurrence particularly to extrapelvic sites. A marked lymphoplasmacytic infiltrate around tumor cells was associated with decreased nodal metastases and tumor recurrence. There was no significant relationship between the degree of lymphoplasmacytic infiltration of the primary tumor and regional lymph node morphology.


Clear cell sarcoma with melanin: report of two cases. Two cases of clear cell sarcoma, one with many melanin pigmented cells and the other scanty, are described. Both are associated with tendons of the lower extremities of young Chinese adults. Their clinical behaviour differed vastly; one patient was dead seven months after local excision and block dissection of regional lymph nodes, while the other had a history of the growth of eight years prior to local excision and is well four years later.


Recurrent and metastasizing gastric leiomyoblastoma (epithelioid leiomyosarcoma) associated with multiple pulmonary chondro-hamartomas: long survival of a patient treated with repeated operations. A 15-year-old girl was operated for gastric leiomyoblastoma (epithelioid leiomysocarcoma) with metastasis to a regional lymph node. She has subsequently been operated on twice: once for local recurrence and metastases 9 years after her initial operation and once for an intraabdominal lymph node metastasis. Now, 13 years after her first operation for gastric leiomyoblastoma she is free from symptoms and signs of disease. Preoperative angiography was helpful in diagnosing the recurrence and planning the second operation. Our observations speak in favor of surgical treatment of recurrent and metastasizing gastric leiomyoblastoma. This patient was also operated for multiple pulmonary chondro-hamartomas, primarily suspected to be metastases. Coincidence of gastric leiomyoblastoma and pulmonary chondro-hamartoma does not seem to be due to chance alone.


Angioimmunoblastic lymphadenopathy: pleural-pulmonary disease. A 48-year-old female with angioimmunoblastic lymphadenopathy is described. Her disease was complicated by pleuritic chest pain, an exudative pleural effusion and pulmonary infiltrates attributable to underlying pleural-pulmonary angioimmunoblastic lymphadenopathy.


Colonic carcinoma: a quantitative assessment of lymphocyte infiltration at the periphery of colonic tumors related to prognosis. Quantitative analysis of the lymphocyte infiltration at the periphery of colorectal carcinomata has revealed a statistically significant difference, p less than 0.001, in the distribution associated with Dukes B compared with Dukes C tumors of moderate differentiation.


The team approach to the management of pediatric cancer. The last 20 years have witnessed remarkable improvements in the prognosis of children with many forms of malignant disease. The reasons for these improvements relate not only to the development of better drugs and more effective radiotherapy, but also to the multidisciplinary approach involving surgeon, chemotherapist, radiotherapist and immunotherapist in providing optimum treatment for the child with a particular cancer. In this paper, the changing role of the pediatric oncologist, surgeon and radiotherapist in improving the management of pediatric cancer is discussed.


Transitional cell tumor of the pituitary gland developing from a Rathke's cleft cyst. A tumor of the pituitary gland is reported which developed from the wall of a Rathke's cleft cyst. This was an incidental autopsy finding in a 79-year-old diabetic woman. The cyst wall was lined by ciliated, mucus producing columnar epithelium with areas of squamous metaplasia, the solid portion of the tumor was composed of cells with light and electron microscopic characteristics of squamous cells, mucus producing cells and anterior lobe cells of the pituitary: they displayed intercellular bridges, intracellular mucus droplets and on electron microscopy varying numbers of intracytoplasmic secretory granules in the 220-450 millimicron range. The cells thus correspond to an early developmental stage of the pituitary anterior lobe, when the still squamous and columnar Rathke's cleft cells begin to develop their endocrine granulation. For this reason it was felt that "transitional cell tumor of the pituitary" would best characterize this hitherto undescribed neoplasm.


Carcinoma of the lower lip: treatment results at Indiana University Hospitals. Sixty-six consecutive cases of carcinoma of the lower lip were seen at the Indiana University Hospitals from 1960 to 1972. Each patient's records were reviewed as to age, sex, race, stage, stage by treatment modality, pathology, treatment methods used and cause of failure. Early lip cancer represents a highly curative lesion whether treated by surgery or radiation therapy. Close followup is mandatory on all patients as the development of neck nodes, if discovered late, carries a grave prognosis. Advanced carcinoma of the lip can be successfully treated with current radiation therapy techniques using fractionated doses providing excellent cosmetic results.


Embryonal rhabdomyosarcoma of the ampulla of vater. The first case to appear in the world literature is described of an embryonal rhabdomyosarcoma in a child  arising from the region of the ampulla of Vater and projecting into the lumen of the duodenum.


Is the risk of morbidity and rare mortality worth the cure? Many more children with cancer are being cured, often as a result of aggressive treatment regimens. These employ several modalities and multiple chemotherapeutic agents. The acute complications resulting from this type of treatment are relatively well known. Those that develop later are becoming better understood; some are formidable. The challenge in pediatric oncology lies in developing better treatment strategies with a view to minimizing normal tissue damage while achieving higher cure rates. The cooperative clinical trial mechanism is well-suited to testing new treatment regimens designed to achieve these goals.


Neuroblastoma in the adult: effective combination chemotherapy. Although neuroblastoma occurs most frequently in children, it also may occur in adults and has been considered of poor prognosis. Six adult patients (greater than 16 years of age) with widespread neuroblastoma diagnosed between 1974 and 1976 are described. Five were treated with a combination of cyclophosphamide, vincristine, adriamycin and dimethyl triazeno imidazole carboxamide (CYVADIC). The sixth received a similar regimen in which actinomycin D was substituted for dimethyl triazeno imidazole carboxamide (CYVADACT). There were two complete responses and three partial responses. The median duration of survival is in excess of 11 months. The results indicate that effective chemotherapy is now available for these patients and the achievement of remission and prolongation of survival are realistic goals in neuroblastoma.


The influence of 5-fluorouracil on cellular and humoral immunity in cancer patients. The effects of 5-fluorouracil (5-FU) on the immune functions of twelve patients with disseminated cancer were studied, using as parameters the peripheral blood lymphocyte count, serum immunoglobulin levels, titers of natural blood group antibodies, percentages of E and EAC rosette forming cells, and lymphocyte proliferative responses to PHA and PPD. No effects on the humoral immune functions or on the percentages of E and EAC rosette forming cells were observed. 5-FU caused a decrease in the proliferative responses of lymphocytes to PHA and PPD. The patients could be divided into two groups: those surviving for six months or more, and those succumbing earlier. The latter ones had already initially poor proliferative responses, particularly to PPD, and the response strongly decreased during the 5-FU treatment. In the patients with a longer survival time, the effects of 5-FU on the PPD and PHA responses were not as striking.


Herpes zoster and varicella infections in children with Hodgkin's disease: an analysis of contributing factors. 181 children with Hodgkin's disease were analyzed with respect to the occurrence of herpes zoster and varicella (HZ-V) infections, possible contributing factors, and prognostic significance. The overall frequency of HZ-V was 34.8%. The occurrence in stage I was significantly lower than in other stages. Previous splenectomy was not found to increase significantly the risk of infection. High-risk patients were those receiving extensive radiotherapy plus combination chemotherapy; 56% developed HZ-V infections in this group. The frequency with extensive field radiotherapy alone was 23.8%. 80% of infections occurred during the first year after completion of treatment. Their occurrence was not a poor prognostic sign in terms of relapse or fatality, even when occurring late. The high frequency of disseminated infection (27%) with its subsequent morbidity should lead toward a better understanding of the immunologic deficiencies in these patients and the possible role of prophylactic measures, in patients undergoing extensive radiotherapy in combination with multiagent chemotherapy.


Effects of hyperthermia on primary and metastatic tumor growth and host immune response in rats. A hot water bath was used to heat locally a metastasizing carcinoma in Wistar/Furth rats. Applying heat such that intratumor temperature is maintained at a mean value of 42.3 degrees for two 90-min sessions results in a decreased growth rate of the primary tumor as well as distant metastases. Heating the primary tumor for only one 90-min session or heating the leg contralateral to the tumor-bearing limb has no effect on the growth rate of either the primary tumor or metastases. Heat therapy has no detrimental effect on the spleen cell-mediated tumor immune response of rats as tested by an in vitro lymphocytotoxicity assay 1 day later. However, heating isolated spleen cells to similar temperatures in vitro reduces their capacity for in vitro tumor cell killing.


Mutagenicity of heterocyclic nitrogen mustards (ICR compounds) in cultured mammalian cells. The mutagenicity of six heterocylic nitrogen mustards (ICR compounds) has been determined in a cultured mammalian cell system by use of resistance to the purine analog 6-thioguanine to select for mutation induction at the hypoxanthine-guanine phosphoribosyltransferase locus in Chinese hamster ovary cells. The six compounds tested are ICR 191, 170, 292, 372, 191-OH, and 170-OH. The first four contain a single 2-chloroethyl group (nitrogen half-mustard) on the side chain and are mutagenic, with the tertiary amine types (170 and 292) 3 to 5 times more mutagenic than the secondary amine types (191 and 372). The remaining two compounds (191-OH and 170-OH) are not mutagenic, indicating that the 2-chloroethyl group is needed for mutation induction.


Alterations in thermal stability of rat liver chromatin and DNA induced in vivo by dimethylnitrosamine and diethylnitrosamine. A study was made of the effects of administration to rats of dimethylnitrosamine and diethylnitrosamine on the transition temperature (Tm) of sheared chromatin and DNA isolated from the liver. The analysis was made by thermal chromatography on hydroxylapatite with the use of DNA prelabeled with [3H]thymidine and following the elution pattern during the operation of a continuous temperature gradient. With a nonnecrogenic dose of dimethylnitrosamine (10 mg/kg), the alterations in chromatin were maximal at 24 hr and disappeared by 3 days. Greatest differences in elution profiles of chromatin after dimethylnitrosamine treatment were observed in the region above 80 degrees. Administration of the carcinogen caused a lowering of the "melting" curve in this region, the displacement from control position being proportional to the dose. The maximum dose (60 mg/kg) displaced the complete chromatin melting curve up to 5 degrees to the lower side. DNA isolated from this chromatin melted 3 degrees less than that from control rats. However, administration of lower doses of dimethylnitrosamine did not affect the melting profile of DNA. The administration of diethylnitrosamine caused a similar type of change. However, the modification was also seen at 50-60 degrees.


Glucocorticoid-binding components in human thymus hyperplasia. Preliminary experiments on thymocyte suspensions derived from human thymus hyperplasia indicated the presence of specific cytoplasmic receptors binding [3H]-dexamethasone with high affinity and specificity. The receptor was rapidly transferred into the nuclei at 28 degrees but not at 2 degrees. With cell-free preparations and ion-exchange cellulose-impregnated paper filters, thymus cytosol bound [3H]dexamethasone with a dissociation constant of 4.3 x 10(-9) M; the concentration of receptor sites was 9.6 x 10(-14) mole/mg cytosol protein. Cytosol contained binding components that sedimented at approximately 7S and 3.6S (low ionic strength) and at 4S (high ionic strength). Competition studies showed high specificity for glucocorticoids since binding of labeled dexamethasone was inhibited in the presence of 10(-6) M beta-methasone, prednisolone acetate, dexamethasone, corticosterone, cortisol, and cortisone. 17beta-Estradiol, testosterone, and dihydrotestosterone at 10(-6) M did not inhibit specific binding of [3H]dexamethasone. Thus, the dexamethasone-binding components of the human thymus hyperplasia had properties similar to those described for steroid hormone receptors present in target tissues.


Effect of hypothermia and hyperthermia on the induction of chromosome aberrations by adriamycin in human leukocytes. When human leukocytes are treated with adriamycin (ADR) for brief durations of 1 to 2 hr at concentrations ranging between 0.04 and 0.25 microgram/ml, a dramatic reduction is observed in the frequency of chromosome aberrations in cells treated at 4 degrees in comparison to those treated at 37 degrees. Conversely, a severalfold increase in the frequency of aberrations is found if temperature at the time of ADR treatment is raised to 43 degrees. At higher temperatures, the most dramatic increase is in the frequency of exchanges. These results point to a parallelism between these studies and those carried out previously for determining cell death with hyperthermia and ADR treatment. This effect on chromosome aberrations appears only if temperatures of 4 of 43 degrees are applied during the period of exposure of cells to ADR. No effect is evident if cells are posttreated at 4 or 43 degrees after ADR is removed from the medium. The question of true synergism versus "facilitation" of influx of ADR into cells is discussed in light of the information obtained by other workers on total quantities of the drug present in the cell.


Nonlinear dose-response relationship for the binding of the carcinogen benzo(a)pyrene to rat liver DNA in vivo. With radioactive compounds of high specific activity, the binding of carcinogens to DNA can be measured with doses that are ineffective in long-term studies. The binding of tritiated benzo(a)pyrene to liver DNA of adult male rats has been determined 50 hr after a single i.p. injection of doses between 40 microgram/kg and 4 mg/kg. The dose-response relationship is linear up to 1 mg/kg, shows a step towards 2 mg/kg, and gives a shallow linear slope above that value. The observed binding ranges from 1.7 to 180 nmoles benzo(a)pyrene per mole DNA phosphate. The nonlinearity could be due to an induction of metabolizing enzymes. The microsomal aryl hydrocarbon hydroxylase activity increases significantly 24 hr after a single dose of 4 mg/kg and 48 hr after doses of 2 and 4 mg/kg, but no induction is found with 1 mg/kg. The binding from an equimolar dose is 35 times lower than the one found on mouse skin DNA and 300 times lower than that of N,N-dimethylnitrosamine in rat liver. A good correlation exists to the respective tumor formation in long-term studies.


A cancer-associated, fast, homoarginine-sensitive electrophoretic form of serum alkaline phosphatase. Serum from patients with a variety of cancers often (p = 70%) contains a characteristic electrophoretic form of alkaline phosphatase detectable by cellulose polyacetate electrophoresis. The lower prevalence of this electrophoretic form in presumably healthy individuals (p = 7%) and noncancer hospitalized patients (p = 30%) suggests that it may be useful as a diagnostic or monitory marker.


Cytological effects of 1-(2-nitro-1-imidazolyl)-3-methoxy-2-propanol (misonidazole) on hypoxic mammalian cells in vitro. Hypoxic Chinese hamster V-79 cells were examined for light-microscope morphology, progression through the cell cycle, chromosomal aberrations, and viability, after incubation with the 2-nitroimidazole, misonidazole [1-(2-nitro-1-imidazolyl)-3 methoxy-2-propanol]. Cytological examination of cells up to 42 hr after incubation with the drug at 37 degrees indicated that increasing contact time and increasing drug concentrations interfered with cell attachment and progressively slowed cell progression through the cell cycle. Forty-two hr after a 5.5-hr treatment with 5 mM misonidazole, the majority of cells contained heteropyknotic nuclei, whereas less than 3% had progressed into mitosis. Of the few cells that reached mitosis by 42 hr, the level of chromosomal aberrations was 6 times that due to hypoxia alone. However, the majority of metaphases (70%) were unaltered; thus about 2% of the treated cell population passed into mitosis unaltered. After a 5.5-hr incubation with 5 mM misonidazole, 98% of the cells also had lost their ability to produce clones. It is suggested that the cytotoxic effect of this drug on hypoxic cells is that the cytotoxic effect of this drug on hypoxic cells is largely mediated via an interphase cell death, with a minor effect due to chromosome aberrations and cell death from genetic inequality of progeny cells. The ability of misonidazole to kill hypoxic, noncycline cells, which may limit the curability of some tumors with conventional X-rays or chemotherapy agents, makes it of considerable potential interest.


A morphometrical analysis of lymph node responses to tumors of different immunogenicity. An immunogenic tumor and a nonimmunogenic tumor were used in C57BL/Ka and CBA/Rij mice, respectively, in a study in which lymph node morphology was quantitatively measured. Lymph nodes were cut in semiseries, and a morphometrical analysis was done on the paracortical and cortical areas as major parts of the active lymph nodes. These parameters could be expressed with confidence in both absolute and relative numbers, since a strong correlation existed between the weight of lymph nodes and the summated surface areas. To determine whether the regional lymph node plays a major role in this response, we performed similar analyses of two nonregional lymph nodes. It was observed that immunogenicity, defined as the ability to evoke an immune response that significantly influences tumor cell take and tumor cell growth, was not relevant in evoking a morphologically evident response. In absolute numbers, the response evoked was strongest in the regional lymph nodes in both systems. However, the percentages of paracortical and cortical areas in the lymph nodes reacting were not essentially different from one node to another during the growth of both tumors. This observation was confirmed by an analysis of variance. These findings suggest that great caution must be exercised when one is interpreting morphological lymph node changes as evidence of an influence of immunological reactions on tumor cell growth.


Skin tumor-initiating activities of the twelve isomeric phenols of benzo(a)pyrene. The skin tumor-initiating activities of the 12 isomeric phenols of benzo(a)pyrene (BP) were determined in mice by use of a two-stage system of tumorigenesis. 11-Hydroxybenzo(a)pyrene was moderately active, whereas 2-hydroxybenzo(a)pyrene and BP were strong tumor initiators when applied topically to CD-1 mice and followed by twice-weekly applications of the promoter 12-O-tetradecanoylphorbol-13-acetate. 1-, 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, and 12-hydroxybenzo(a)pyrene had less than 5% of the tumor-initiating activity of BP when the data were expressed as papillomas per mouse. After 30 weeks of promotion, the number of papillomas per mouse was 8.4, 8.5, and 2.8, respectively, for the animals treated with BP, 2-hydroxybenzo(a)pyrene, and 11-hydroxybenzo(a)pyrene. A 5-week latency period before the appearance of the first tumor was observed after the application of either 2-hydroxybenzo(a)pyrene or BP, whereas a slightly longer latency period of 7 weeks was observed following application of 11-hydroxybenzo(a)pyrene. The time required for 50% of the animals to develop tumors was 13 weeks for animals treated with BP and 15 weeks for animals treated with 2- or 11-hydroxybenzo(a)pyrene.


Immunotherapy of an established rat mammary adenocarcinoma (13762A) with intratumor injection of Corynebacterium parvum. We studied the effects of intratumor injection of Corynebacterium parvum vaccine on the survival of 13762A tumor-bearing rats. Vaccine injection of established (7-day-old) tumors produced dose-related prolongation of survival and cured some animals. Although 30 to 40% of the vaccine-injected primary tumors regressed, recurrences and continued growth of metastases ultimately killed one-fourth of the regressors. Rats given 1500 microgram of C. parvum intratumorally at 7 days, with or without later primary tumor excision at 20 days were cured at a rate of 10 to 40%. Repeated injections improved the results (60%). C. parvum injections delayed until 12 and 17 days were ineffective. Cured rats were immune to rechallenge with 13762A tumor.


Exceptional carcinogenic activity of benz[a]anthracene 3,4-dihydrodiol in the newborn mouse and the bay region theory. Benz[a]anthracene and the five metabolically possible trans-dihydrodiols of benz[a]anthracene were tested for carcinogenicity in newborn Swiss-Webster mice. Four hundred, 800, and 1600 nmoles hydrocarbon i.p. were sequentially injected on Days 1, 8, and 15 of life. The mice were killed at 22 weeks of age. Of the mice treated with trans-3,4-dihydroxy-3, 4-dihydrobenz[a]anthracene, 24% developed malignant lymphoma, whereas 4% of the animals treated with benz[a]anthracene had malignant lymphoma. None of the animals treated with the trans-1,2-dihydroxy-1,2-dihydrobenz[a]anthracene, trans-5,6-dihydroxy-5,6-dihydrobenz[a]anthracene, trans-8,9-dihydroxy-8,9-dihydrobenz[a]anthracene, or trans-10,11-dihydroxy-10,11-dihydrobenz[a]anthracene had malignant lymphoma. trans-3,4-Dihydroxy-3,4-dihydrobenz[a]anthracene caused about 35-fold more pulmonary adenomas than did benz[a]anthracene, whereas the trans-1,2-dihydroxy-1,2-dihydrobenz[a]anthracene, trans-5,6-dihydroxy-5,6-dihydrobenz[a]anthracene, trans-8,9-dihydroxy-8,9-dihydrobenz[a]anthracene, and trans-10, 11-dihydroxy-10,11-dihydrobenz[a]anthracene had little or no activity. The exceptionally high carcinogenicity of trans-3,4-dihydroxy-3,4-dihydrobenz[a]anthracene is consistent with the metabolism of this compound to either or both of the diastereomeric bay region 3,4-dihydroxy-1,2-epoxy-1,2,3,4-tetrahydrobenz[a]anthracenes, and the data support the bay region theory of polycyclic hydrocarbon carcinogenesis.


Role of lipopolysaccharide in the production of plasma cell tumors in mice given mineral oil injections. The lipopolysaccharide (LPS) content of peritoneal fluids of BALB/c mice given mineral oil injections and of normal mice was measured. Peritoneal fluids were passed through DEAE-Bio-Gel columns to remove an inhibitor to the Limulus amebocyte lysate reaction and then were assayed for LPS by a spectrophotometric Limulus amebocyte lysate test. A highly significant difference between control animals and animals given mineral oil injections was found. A clear correlation between LPS concentration and time after first oil injection was shown. P-200 gel chromatography and heat stability of the active material were consistent with the behavior of LPS. The possible role of LPS in the pathogenesis of plasma cell tumor is discussed.


Leukemoid reaction in BALB/c mice bearing primary tumors induced by 3-methylcholanthrene. During the growth of five of ten primary tumors that were induced by 3-methylcholanthrene in BALB/cMk and BALB/cMk X C57BL/6F1 mice, leukemoid reactions, characterized by increase in number of granulocytes in peripheral blood, and splenomegaly were observed. However, no such reactions occurred in five C57BL/6 mice bearing primary tumors induced by 3-methylcholanthrene. The results of leukemoid reactions in mice bearing 3-methylcholanthrene-induced primary tumors are compared with the reactions found in mice bearing transplanted tumors.


Alterations in serum glycosyltransferases and 5'-nucleotidase in breast cancer patients. We have measured sialyltransferase, galactosyltransferase, and fucosyltransferase as sell as 5'-nucleotidase in the serum of breast cancer patients. Serum sialyltransferase values in 65 normal healthy females ranged from 2.6 to 8.5 units, with a mean of 5.4. In 25 women with operable primary breast cancer, serum sialyltransferase levels were found to be between 6.2 and 15.4 units. Marked elevation of this enzyme level (range, 8.8 to 36 units) was observed in 48 patients with metastatic breast cancer. Galactosyltransferase and fucosyltransferase measurements, however, showed considerable overlap between the controls and the cancer patients. On the other hand serum 5'-nucleotidase and sialyltransferase in breast cancer patients showed very similar patterns. Thus, serum 5'-nucleotidase values in 44 normal females ranged from 11.4 to 23.2 units, whereas the levels found in 30 patients with metastasis were between 25 and 71.8 units. The tissue origin of abnormal levels of serum glycosyltransferases and 5'-nucleotidase was discussed in relation to their physiological significance as well as their role as markers for diagnosing early malignant breast neoplasm and for monitoring the extent of metastasis.


DNA repair in normal and preneoplastic mammary tissues. The purpose of this investigation was to obtain a comparative measure of DNA repair synthesis in hormone-dependent normal mammary tissue and hormone-independent D1 hyperplastic alveolar nodule (HAN) outgrowth. Treatment of mammary fragments in culture with 5 mM hydroxyurea inhibits 98% of the semiconservative DNA synthesis. Treatment of mammary fragments with methyl methanesulfonate in the presence of hydroxyurea results in a 4- to 7-fold higher incorporation of [3H]deoxythymidine into the mammary cell DNA than does treatment with hydroxyurea alone. This hydroxyurea-resistant alkylating agent-induced [3H]deoxythymidine incorporation was studied by CsCl density gradient centrifugation and has been found to represent DNA repair replication. Similar levels of repair replication were found in both normal and preneoplastic D1-HAN outgrowth. Autoradiographic analysis of mammary fragments and D1-HAN outgrowth treated with methyl methanesulfonate plus hydroxyurea revealed that 30 to 50% of the epithelial cell nuclei were lightly labeled. No detectable repair synthesis was found in fat or stromal cells. The average number of grains per labeled nuclei was the same for both explants. These results suggest that a reduced DNA repair capacity is not associated with the increased sensitivity of D1-HAN outgrowth to the tumorigenic effect of chemical carcinogens.


Estrogen profiles of premenopausal women with breast cancer. Population surveys have demonstrated an inverse relationship between breast cancer incidence rates and the urine "estriol ratio," the concentration of estriol relative to the sum of the concentrations of estrone and estradiol. In this study, the urine estriol ratio was evaluated in premenopausal breast cancer patients and control women from Boston and San Francisco. Although at least 2 years had passed since last use of oral contraceptives, women with a history or oral contraceptive use for 19 months or longer excreted estrogen in low concentrations compared to nonusers and so were excluded. Among the remaining 73 cases and 55 controls, the cases had lower estriol ratios and higher estrone and estradiol levels than did controls. However, these differences, which averaged about 10%, were not statistically significant. Thus the hypothesis that a low estriol ratio is a cause of breast cancer is given only minimal support. Among women in their 40's, the excretion of estrogens is subject to many influences and is difficult to study. The many determinants of estrogen excretion, including age and oral contraceptive use, should be accommodated in the design of future studies of the estriol ratio.


Kinetics of growth and ectopic production of human chorionic gonadotropin by an ovarian cystadenocarcinoma cell line maintained in vitro. An established ovarian papillary cystadenocarcinoma cell line, designated 163, released immunoreactive human chorionic gonadotropin (HCG) in vitro into the culture medium. The maximal rate of this ectopic activity (10 to 15 ng/day/10(6) cells) occurred at the onset of the logarithmic phase of cell growth and greatly exceeded the intracellular HCG content of cells approaching confluency (0.037 ng/10(6) cells). The HCG production was not detected during the plateau phase of growth. The rate of cellular proliferation and HCG release depended upon the frequency of media change in a manner suggesting that the two processes are interrelated and may be affected by such environmental factors as cell density, nutrient availability, and the accumulation of waste products. The addition of purified HCG to the cultures had no appreciable effect on either the cell growth or the accumulation of HCG. The release of HCG into the medium was greatly stimulated in the presence of sodium butyrate at concentrations from 1 to 10 mM, despite the fact that these concentrations of butyrate resulted in a marked decrease in the cell number/culture in comparison with control media. Equivalent amounts of sodium acetate had no effect on either cell growth or the release of HCG.


Retinoic acid inhibition of the comitogenic action of mezerein and phorbol esters in bovine lymphocytes. 12-O-Tetradecanoylphorbol-13-acetate (TPA) is an effective comitogen in phytohemagglutinin-treated bovine lymphocytes. Concurrent addition of 10(-8) M TPA gives a greater than 6-fold increase in DNA synthesis over cultures treated with the lectin alone. The delayed addition of phorbol ester, relative to the start of the lectin treatment, eliminates this synergistic action. Structure-function studies show that the comitogenic activity of different phorbol diesters runs parallel to their tumor-promoting activity. A nontoxic level (50 micronM) of retinoic acid selectively antagonizes this synergistic effect of phorbol ester. This inhibitory action requires the near-concurrent addition of retinoic acid with TPA. In contrast, the TPA-mediated induction of RNA and protein synthesis is unaffected by retinolic acid. A number of natural and synthetic retinoids were evaluated; none were as inhibitory as was retinoic acid. Lymphocyte cultures appear to provide a useful system for exploring the mechanisms of action of both TPA and retinoic acid.


Covalent binding of the carcinogen trichloroethylene to hepatic microsomal proteins and to exogenous DNA in vitro. Studies were carried out on the in vitro covalent binding of the carcinogen trichloroethylene (TCE) to liver microsomal preparations and to exogenous DNA. The binding of TCE to liver microsomal proteins of male C57BL/6 X C3H/He F1 (hereafter called B6C3F1) hybrid mice, a species and strain susceptible to TCE-induced liver tumorigenesis, was 46% higher than that of [14C]TCE to microsomal proteins from male Osborne-Mendel rats, a species and strain resistant to TCE-induced hepatocellular carcinoma. The in vitro binding of [14C]TCE to liver microsomal proteins was 37% higher for male B6C3F1 mice; female B6C3F1 mice that  have been reported to show a lower incidence of TCE-induced hepatocellular carcinoma than do males. Microsomal proteins from the lung, stomach, and kidney of B6C3F1 hybrid mice also metabolized TCE, as indicated by the covalent binding of [14C]TCE to microsomal proteins from these organs. For rats the binding of TCE to liver microsomal proteins of Sprague-Dawley animals was higher than that of Osborne-Mendel and Fischer 344 rats. Incubation of [14C]TCE with salmon sperm DNA in the presence of microsomal preparations from B6C3F1 hybrid mice resulted in covalent binding of [14C]TCE to DNA. This binding was much higher in the presence of microsomal proteins from male rather than female mice. The binding to DNA and protein was enhanced by in vivo phenobarbital administration. The effects of 1,2-epoxy-3,3,3-trichloropropane on the covalent binding of [14C]TCE to protein and DNA were also examined.


Early steps in mutagenesis by hycanthone. Hycanthone, the most potent mutagen in a series of nine thiaxanthenones, is a potent inducer of nuclear immunoreactivity to antinucleoside antibodies in HeLa cells. This response indicates exposure of single-stranded DNA regions. All classes of mutagens thus far tested share this property with hycanthone. Immunoreactivity to antinucleoside antibodies was also induced by brief exposure to hycanthone, 3 microgram/ml, in human fibroblasts from three normal subjects and in fibroblasts from seven patients with DNA repair deficiencies. Unlike those of many other mutagens, the metabolic effects and immunoreactivity induction of hycanthone were readily reversible. No evidence for covalent attachment of [3H]hycanthone to HeLa macromolecules could be found. Induction of DNA repair synthesis could not be detected by autoradiography after exposure of cells to hycanthone. Exposure of single-stranded DNA regions appears to be an important feature of the mechanism of action of hycanthone as a mutagen. Both hycanthone and lucanthone intercalate with DNA, but hycanthone was much less active than was lucanthone in reducing the rapid sedimentation of cell lysate DNA in alkaline sucrose gradients. Similarities and differences, therefore, have been found in the way the potent and the weak mutagen affect DNA of HeLa cells. This may provide clues to understanding the mechanism of mutagenesis by thiaxanthenones and other mutagens.


Differential repair of 1-(2-chloroethyl)-3-(4-methylcyclohexyl)-1-nitrosourea-induced DNA damage in two human colon tumor cell lines. Two human colon tumor cell lines were examined for their responses to 1-(2-chloroethyl)-3-(4-methylcyclohexyl)-1-nitrosourea treatment when maintained as cultured cell lines and xenograft tumors in nude mice. One tumor line, HT, was resistant to 1-(2-chloroethyl)-3-(4-methylcyclohexyl)-1-nitrosourea treatment both in tissue culture and in vivo. The other tumor line, BE, was sensitive to 1-(2-chloroethyl)-3-(4-methylcyclohexyl)-1-nitrosourea treatment in vitro and in vivo. The DNA of tissue-cultured cells treated with 1-(2-Chloroethyl)-3-(4-methylcyclohexyl)-1-nitrosourea was examined by alkaline elution for DNA damage. 1-(2-Chloroethyl)-3-(4-methylcyclohexyl)-1-nitrosourea was found to produce DNA strand breaks and DNA cross-links in both cell types. The DNA cross-links appear to be completely repaired in the resistant HT line over the 48-hr period following drug removal, but in the sensitive BE line little or no cross-link repair was observed during this interval.


Enhancement by Corynebacterium parvum of the normal and tumor tissue response to hyperthermia. The effect of Corynebacterium parvum treatment on the response of tumor and normal tissue to hyperthermia (43.5 degrees) was studied. Animals were C3Hf/Sed mice from our defined flora mouse colony. The time at hyperthermia that achieved control of one-half of methylcholanthrene-induced fibrosarcomas and the foot reaction were examined after treatment. C. parvum, if given 3 to 32 days before hyperthermia, enhanced the reaction to local hyperthermia of normal tissue. No enhancement was observed if C. parvum was given after hyperthermia. This enhancement was more dramatic for tumor response resulting in a therapeutic gain factor of congruent to 2.3 (3.7/1.6). Comparative studies on combined Corynebacterium and radiation failed to demonstrate the enhancement to normal tissue.


Effect of aging in two-stage carcinogenesis on mouse skin with phorbol myristate acetate as promoting agent. Life table analysis curves have been constructed for some of the data presented in a previous report on the effect of aging and of the interval between primary and secondary treatment in two-stage carcinogenesis on mouse skin. These curves are compared with those in a recent report from another laboratory also concerning aging and skin carcinogenesis. While comparison was difficult due to differences in experimental protocol, our conclusion that age at the onset of secondary treatment is of overriding importance in determining final tumor yields is substantiated.


Pharmacokinetic rationale for peritoneal drug administration in the treatment of ovarian cancer. Evidence from the peritoneal dialysis literature suggests that the peritoneal permeability of a number of hydrophilic anticancer drugs may be considerably less than plasma clearance. Pharmacokinetic calculations indicate that such drugs administered ip in large volumes are expected to maintain a significantly greater concentration in the peritoneal space than in the plasma. This concentration difference offers a potentially exploitable biochemical advantage in the treatment of patients with presumed microscopic residual ovarian cancer confined to the peritoneal cavity.


Antitumor activity of N-trifuloroacetyladriamycin-14-valerate. The antitumor activity and toxicity of N-trifluoroacetyladriamycin-14-valerate (AD 32) dissolved in 10% Tween 80 in distilled water were compared to those of adriamycin dissolved in distilled water in 10% Tween 80 in distilled water, in mice bearing L1210 leukemia, P388 leukemia, Gross leukemia, and solid Sarcoma 180. Treatments were performed ip or iv according to different schedules. The antitumor-activity of AD 32 was not superior to that of adriamycin. The antitumor activity of adriamycin dissolved in aqueous solution of Tween 80 was higher than that of adriamycin dissolved in distilled water after after iv treatment.


Comparative antineoplastic activity of adriamycin and N-trifluoroacetyladriamycin-14-valerate. A comparative investigation of the antineoplastic activity of adriamycin and its derivative, N-trifluoroacetyladriamycin-14-valerate (AD 32), was conducted in murine tumor models employing different treatment schedules and injection routes. In all conditions tested, ie, ascitic and disseminated L1210 leukemia, ascitic LSTRA lymphoma, and advanced Lewis lung carcinoma, AD 32 was significantly more effective in terms of lifespan prolongation and induction of cures than optimal adriamycin treatments. As with adriamycin, AD 32 was ineffective on ic transplanted L1210 leukemia.


Separation and identification of impurities in parenteral methotrexate dosage forms. Eleven lots of parenteral methotrexate (MTX) dosage forms from two manufactures have been analyzed and found to be 93.4% +/- 2.1% (SD) pure by a new procedure employing a DEAE-cellulose column adapted for high performance liquid chromatography instrumentation. In addition to 4-amino-10-methylpteroic acid and N10-methylpteroylglutamic acid, which were previously identified contaminants, and benzyl alcohol, which was added as a preservative, we have also isolated and identified 2,4-diamino-6-methylpteridine, 2,4-diamino-6-bromomethylpteridine, and p-methylaminobenzoic acid. Another impurity has tentatively been identified as 4-amino-10-methylpteroic acid amide. The individual impurities vary from 0.1% to 4.8% of the ultraviolet absorbing material which elutes from the column. Additional impurities were detected by gas chromatography-mass spectrometry. Since "high-dose" therapy may involve the administration of up to 20 g of MTX/day, the effect of the impurities present in these dosage forms on the course of the patient's therapy should be determined.


Metastatic cloacogenic carcinoma of the anus: sequential responses to adriamycin and cis-dichlorodiammineplatinum(II). A case of cloacogenic carcinoma of the anus with pulmonary metastases successfully treated with adriamycin and subsequently with cis-dichlorodiammineplatinum(II) (CDP) is reviewed. Cloacogenic carcinoma of the anus is a very uncommon tumor, and this is the first report of a major response to chemotherapy alone. Adriamycin and/or CDP should be considered in the therapy of this tumor.


Pharmaceutical assessment of amygdalin (Laetrile) products. The National Cancer Institute (NCI) recently acquired a large supply of formulated products of amygdalin manufactured by Cyto Pharma of Mexico, for possible use in a clinical trial in the US. Tablets for oral administration and ampules of the injectable produce were obtained. Both forms were extensively analyzed and evaluated by several analytic and pharmaceutical laboratories under contract with the NCI. Analytic test procedures were developed to determine the chemical integrity and quantitative composition of the formulated products. Routine physical and biologic tests were also performed to evaluate the manufacturing quality of both dosage forms. The results indicate that both the oral and injectable forms of amygdalin were substandard by US criteria for manufactured pharmaceutical products. All samples were determined to be chemically subpotent, mislabeled, and of poor manufacturing quality. More than 20 samples of the ampules were found by visual inspection to contain microbial contamination. Other samples were found to be pyrogenic. Based on the results of the testing performed, both tablet and ampule forms of amygdalin manufactured by Cyto Pharma of Mexico are considered unfit for use in man.


Coronary involvement after a single myocardial infarction. Coronary angiography study. Coronary angiography was performed in 95 patients 3 months to 3 years after a single myocardial infarction. The patients were categorized into 4 groups according to coronary angiography findings: group I with three or four vessels diseased; group II with two vessels diseased; group III with one vessel diseased, and group IV with normal arteries. Vessel disease was considered present if 50% of the lumen was narrowed. The patient population was almost equally distributed among group I (26), group II (26), group II (33) and group III (34). Group IV included only 3 patients in this retrospective study.


Influence of the contractile state of the heart of the preload dependence of the maximal rate of intraventricular pressure rise dP/dt max. In canine heart-lung preparations the relation between dP/Dt max and end-diastolic pressure exhibits the steepest slope shortly after isolation of the heart. When the heart is deteriorating, the slopes of the preload dependence of right and left ventricular dP/dt max are progressively reduced, but increase again after application of calcium. The preload dependence of dP/dt max is influenced by the contractile state of the myocardium. In the right and left ventricle the change in preload dependence of dp/dt max show a linear correlation. In the individual heart the slopes of the preload dependence of dP/dt max and of aortic flow (representing ventricular function curves) change in a very similar manner with varying contractility. In 33 different isolated hearts the slopes of the preload dependence of the two parameters show a good correlation shortly after isolation of the hearts. The preload dependence of dP/dt max can not only be used for assessment of acute variations in in myocardial contractility, but appears also to be at least as reliable as the ventricular function curves for the evaluation of the basic contractile state of different hearts. This study further shows that if dP/dt max is used for evaluation of relative changes in contractility, the quantitative results are influenced by the end-diastolic pressure level chosen.