Reversal of guanethidine blockade of sympathetic nerve terminals by tetraethylammonium and 4-aminopyridine. 1 The effect of tetraethylammonium (TEA) and 4-aminopyridine (4-AP) on the inhibitory effect of guanethidine on noradrenaline (NA) release was investigated in the perfused spleen of the cat. 2 Guanethidine blocked the release of NA evoked by nerve stimulation. TEA and 4-AP readily reversed this inhibitory effect, and the NA output was nearly doubled after repeated stimulation of the nerves. On subsequent perfusion with Krebs solution without TEA or 4-AP, the inhibitory effect of guanethidine reappeared. 3 The reversal of guanethidine blockade of sympathetic nerves by TEA and 4-AP is discussed.


Phospholipase A2 activity of guinea-pig isolated perfused lungs: stimulation, and inhibition by anti-inflammatory steroids. 1 A simple double-isotope assay for phospholipase A2 activity of perfused organs is described; Guinea-pig lungs perfused through the pulmonary circulation exhibit a low background enzyme activity. This activity is blocked by dexamethasone, betamethasone and hydrocortisone, mepacrine, procaine or chlorpromazine. Aspirin and indomethacin are without effect. 3 Mechanical trauma, antigen challenge or injections of bradykinin, rabbit aorta contracting substance-releasing factor (RCS-RF) or histamine increase "basal" phospholipase activity. The effect of these agents, except that of bradykinin, is blocked by dexamethasone or mepacrine. 4 The blocking effect of steroids is cumulative and dose-dependent. They do not work in cell-free systems. Inhibition by mepacrine is rapid and is effective in cell-free lung homogenates. 5 It is suggested that agents which liberate prostaglandin endoperoxides and thromboxane A2 from perfused lungs do so by activating phospholipase A2.


Vasopressin release produced in anaesthetized cats by antagonists of gamma-aminobutyric acid and glycine. 1 In cats anaesthetized with chloralose, the central excitatory substances, tubocurarine, picrotoxin, bicuculline, leptazol and strychnine, were applied to the exposed ventral surface of the brain stem through paired Perspex rings placed across the medulla and their effects on vasopressin release and arterial blood pressure were examined.2 The excitatory substances released large amounts of vasopressin when applied to an area 6-9 mm caudal to the trapezoid bodies. From this area vasopressin release was previously obtained with nicotine.3 With nicotine, the vasopressin release occurred almost instantaneously and tachyphylaxis developed rapidly. With the excitatory substances the release increased gradually and there was no tachyphylaxis. When these substances were applied for several minutes, the release reached its maximum a considerable time after their removal, except with leptazol when release diminished at once after removal.4 The excitatory substances had little or no effect on arterial blood pressure when applied to the vasopressin releasing area, but produced strong pressor responses when applied to a more rostrally situated area.5 It is concluded that the excitatory substances release vasopressin and raise arterial blood pressure because they are antagonists of gamma-aminobutyric acid and/or glycine and that numerous inhibitory neurones which release these amino-acids synapse at the ventral surface of the medulla. The physiological function of those which synapse at the vasopressin releasing area may be to act as a brake on vasopressin release, and of those which synapse at the more rostrally situated area to act as a brake on arterial blood pressure.


The interpretation of posture through an alternative methodology to role play. The purpose of this experiment was to develop a methodology to investigate the postural expression of different emotions and attitudes using a technique which avoided the artificiality implicit in the use of a role play design. Subjects were asked to categorize tape-recorded extracts as either funny, sad, interesting or boring and to rate them in order of intensity. The posture displayed when listening to the recordings were then analysed according to these ratings, the whole interview being recorded on videotape without the subject's knowledge. Results showed distinctive postures for all four categories, such as dropping the head for sadness and leaning the head on one hand for boredom, thus providing empirical support for the utility of this methodology as a way of obtaining observations of non-verbal cues under controlled conditions without inducing any artificial self-consciousness in the subjects.


Bodily communication and personality.

Bodily communication and personality. Fifteen measures of non-verbal communication were coded from videotaped interactions between a female confederate and 18-21 year old female subjects (n = 46). Three measures of extraversion and neuroticism had previously been taken from the subjects, as was a measure of IQ. Correlation and factor analysis revealed significant relationships between certain of the variables. Extraversion was strongly associated with speaking more; a teacher's rating of neuroticism was associated with touching the self, pausing during conversation, and an absence of expressive gesture; lower IQ was associated with smiling while listening; and self-report personality questionnaire neuroticism was associated with gaze aversion.


Sex differences in 'fear of success' among British students. Using a measure derived from Horner's studies of 'fear of success', the attitudes of three groups of British undergraduates towards success and failure were investigated. The results indicate ambivalence towards success and failure among both sexes, but neither the numerical analysis nor the kinds of responses indicated much of the overt sex-stereotype-based 'fear of success' found in the earlier American studies. Both sexes indicated some disillusionment with the 'success ethic'. Males showed somewhat greater anxiety about failure.


Levels of arousal in the premenstrual phase. The inconsistent findings of studies of physical and psychological changes throughout the menstrual cycle are reviewed in terms of three different forms of arousal-behavioural , autonomic, cortical. The review indicates that the premenstrual phase is characterized by increased levels of behavioural and of autonomic arousal. The nature of premenstrual changes in cortical arousal is unclear. It is suggested that differentiation and measurement of the various aspects of arousal throughout the cycle may lead to better understanding of the processes underlying the reported changes and of the practical implications of such information.


Self-management programmes with mentally retarded workers: implications for developing independent vocational behaviour. Three research studies were conducted to investigate the differential effects of externally administered, self-administered and self-determined reinforcement contingencies on the work production rates of developmentally disabled workers. The results of Expt. I indicated that Client 1, a profoundly retarded male, would work at equivalent rates under externally administered or self-administered reinforcers. Experiment II indicated that a severely retarded male would also work at a high work rate under a self-determined reinforcement contingency. The results of Expt. III replicated these findings in a more controlled design. Different tasks adapted from community workshops were utilized in each study. The implications of these studies for developing independent vocational behaviour in the retarded were discussed.


The effects of reducing frequency of negative thoughts on the mood of depressed patients-tests of a cognitive model of depression. Cognitive theories of depression propose that depressed mood is caused by depressing cognitions (negative thoughts). In two studies of depressed patients, presentation of external information at a high rate was used to reduce the frequency of negative thoughts, and the subsequent effect on depressed mood examined. Single-case designs were employed in both studies. In the first study, significant reduction in negative thoughts and depressed mood was achieved in each of two selected patients. In the second study, the same procedure produced reduction in negative thoughts which was individually significant for seven of 13 unselected depressed patients, and also significant for the 13 patients as a group. However, this led to little improvement in depressed mood. This appeared to be due to the small extent of thought reduction achieved. Reduction in negative thought frequency correlated significantly with score on the Newcastle diagnosis scale, being greater for neurotic compared to endogenous depression. Mean depressed mood and mean negative thought frequency were significantly positively correlated across subjects.


Language and social behaviour in severely educationally subnormal children. There is a strong positive relationship between age and the number of social interactions a child is likely to initiate during a typical classroom free-play period. The type of interaction which shows the largest increase is verbally initiated child-child interactions. Verbally initiated child-teacher interactions also increase with age, though not so markedly as child-child interactions. There appears to be no significant change in non-verbal initiations of interactions with age, either to the teacher or to peers. These results give support to the use of observational techniques for language assessment in that they give further information about the growth of productive language skills as reported in a population survey of language abilities in mentally handicapped school children.


A study of work behaviour in a psychiatric rehabilitation unit. A rating scale developed by Griffiths (1973) was used to assess four separate areas of the work behaviour of patients in a psychiatric rehabilitation unit. Assessments were made at an early and a late stage of rehabilitation. The ability of ratings on this scale to predict resettlement was confirmed in a prospective study. The scale was also used to provide information about four separate areas of work behaviour. Social relationships provided the strongest predictor of resettlement in employment, response to supervision and enthusiasm predicted only in psychotic patients; task competence failed to predict. Changes in work behaviour during rehabilitation, and the relationships between self-reported attitudes and work behaviour were also examined.


Vulnerability and defensive reactions in relation to the human menstrual cycle. The effects of alterations of the organism's internal state, attributable to the menstrual cycle, upon heart-rate responsivity and conditioning are reported. Two groups of 24 female phobic patients (one with natural cycles and the other taking the oral contraceptive) were tested, either premenstrually or intermenstrually, using a conditioning procedure in which a small blue light was the CS and white noise the UCS. Subjects tested premenstrually were significantly differentiated from those tested intermenstrually respecting HR responsivity to the first UCS. Significant differences were also found in conditioned responses following three acquisition trials. The type of reactions observed are similar to those which have been called defensive reactions. Subjects taking the oral contraceptives showed increased susceptibility to acquisition of conditioned responses.


Computed tomography in pancreatic disease. Computed tomography (CT) of the pancreas has been evaluated in 50 patients with established exocrine pancreatic disease and 20 patients without pancreatic disease. Increase in size, irregularity in outline and heterogeneity of composition of the pancreas implied disease but were in no way specific to any particular disease entity. In acute pancreatitis, following complete resolution, the pancreas appeared normal whereas incomplete resolution was associated with non-specific swelling and heterogeneity of density. The extent and location of pseudocysts could be accurately delineated. In chronic pancreatitis, duct calculi, duct dilatation and large intrapancreatic cysts aided the differentiation between focal enlargement due to chronic pancreatitis and expansion due to cancer. Hepatic metastases and abnormalities of the biliary system seen in association with cancer further aided this differentiation.


A simple spectrophotometric method for measuring biliary ioglycamide (Biligram) concentration. An extremely simple spectrophotometric method for measuring biliary ioglycamide (meglumine ioglycamate) concentration is described. It was validated by a radioactive technique.


A simple coding system for a diagnostic X-ray department. A simple coding system that codes the work done and diagnoses is described. It is economical and designed to withstand changes in staff.


Bone mineral measurement using an EMI scanner and standard methods: a comparative study. The established techniques of scanning photon densitometry and radiographic microdenstiometry for the analysis of bone mineral content are compared with results obtained using a modified EMI brain scanner. The EMI method shows significantly greater sensitivity to changes in bone density than either of the other two methods. This latter method also has the added advantage of being able to visualize and measure the density of trabecular bone, which is a very sensitive indicator of bone mineral changes.


Penetrameter cassette calibration to 400 kV and effects of extra-focal radiation when measuring tube filtration. The penetrameter cassette, when used with suitable filters and calibrated against the same average wave form, can detect changes of less than 1 kV in the range 20-50 kV, 1 kV from 50-100 and from 1-4 Kv from 100-400 kV. Problems of calibration are discussed together with the necessity to use a suitable shutter with equipment which has a significant build-up and decay time during which the radiation quality may be varying. Extra-focal radiation does not normally present a significant problem in the measurement of kV, but when the penetrameter is used to measure inherent or total filtration extra-focal radiation can be a problem and may be similar in degree to the effects of varying target angles. When used to determine filtration, the generator used for calibration of the penetrameter and the one being measured should be adjusted to have the same target angle and similar degrees of extra-focal radiation by altering the size of the tube aperture as close to the focal spot as practicable. The results presented confirm the accuracy and convenience of the penetrameter for the measurement of kV and filtration over the extended range of energies.


Clinical radionuclide perfusion lymphangiography. In an initial pilot study technetium-99m-labelled human serum albumin was perfused directly into bipedal lymphatic cannulae prior to a standard lymphangiogram, in order to assess rapidly normal and abnormal lymph flow patterns in the lower extremity, pelvic and para-aortic lymph chains. A continuing study of these patients has lent further support to the hypothesis that the radionuclide perfusion study, when negative, may prove more accurate in some patients than the standard lymphangiogram in predicting the clinical course and/or the results of histopathological lymph node examination. The radionuclide technique also seems to meet, in this preliminary evaluation, the requirements for a pre-lymphangiogram screening study, particularly for use in high-risk patients.


A search for an effect of ultrasound alone and in combination with X rays on chromosomes in vivo. Experiments were aimed to establish whether therapeutic doses of ultrasound are liable to cause demonstrable chromosomal damage in marrow cells of the mouse. On evaluation of the chromosome aberrations no significant increase was found after treatment with three different doses of ultrasound. In contrast, our "positive control group" irradiated with 50 R of X rays showed clearly demonstrable chromosomal damage. In another group of animals treated with ultrasound plus X rays, the ultrasonic pretreatment did not increase the damaging effect of X rays significantly.


Pseudo-occlusion of the internal carotid artery. In a ten-year period, 31 cases of pseudo-occlusion of the internal carotid artery were seen; 42 carotid angiograms were available for analysis. On the first film of the series the contrast came to a tapered end in the cervical portion of the internal carotid artery in 16; extended to the carotid canal in 11; to the siphon in eight and to proximal intracranial vessels in seven. In 17 patients later films showed advance of the contrast. In four it did not get beyond the foramen lacerum; in eight it reached the siphon and in five the proximal intracranial vessels. Eight angiograms of patients with intracranial occlusion were examined and showed identical appearances. Contrast opacified the middle menigeal artery in 29 of the 31 pseudo-occlusion cases. The circulation time was slow in 28. The circulation times through the middle menigeal artery were more or less identical with those in the superficial temporal arteries and unaffected by systolic blood pressure. Twenty-three of the pseudo-occlusion cases were being ventilated and 25 had fixed dilated pupils. The commonest aetiological factors were trauma, haematoma due to ruptured aneurysm and primary tumour. In the occlusion group no case was being ventilated and only one had fixed dilated pupils. Course of action on finding the appearances of pseudo-occlusion is suggested.


Study of 8-year-old children with a history of respiratory syncytial virus bronchiolitis in infancy. Thirty-five children known to have had respiratory syncytial virus bronchiolitis in infancy were examined at the age of 8 and their respiratory function tested. The results were compared with those in 35 controls matched for age, sex, and social class. Although 18 of the children who had had bronchiolitis in infancy had experienced subsequent episodes of wheezing, these were neither severe nor frequent in most cases and had apparently ceased by the age of 8. Nevertheless, the mean exercise bronchial lability of the children who had had bronchiolitis was significantly higher than that of the control children and the mean peak expiratory flow rate at rest significantly lower. Atopy, assessed by family and personal history alone, did not seem to be related to either bronchiolitis or wheezing episodes after bronchiolitis. The parents of the children who had had bronchiolitis smoked significantly more cigarettes during the infant's first year of life than those of the control children. The results suggest that bronchiolitis and childhood asthma are not closely related. Bronchial hyperreactivity might be inherited independently of atopy, but environmental factors seem the most likely link between severe respiratory infection in infancy and chronic or recurrent respiratory illness in adult life.


Osteomalacic dialysis osteodystrophy: a trial of phosphate-enriched dialysis fluid. To assess whether phosphate depletion is an aetiological factor in osteomalacic dialysis osteodystrophy we undertook a prospective trial of phosphate-enriched dialysis fluid, in association with oral 1alpha-hydroxycholecalciferol, for this condition. Thirty patients started the trial; of the 27 who completed more than 6 months' treatment, 14 had iliac crest bone biopsies at the beginning and end of the treatment period. Side effects included pruritus, stiffness, and increase in corneal and vascular calcification. Only one patient showed histological improvement of osteomalacia, and eight deteriorated; in seven the osteitis fibrosa worsened. Myopathy showed some improvement in four patients, but became worse in four. This treatment does not seem to have a place in the routine management of non-hypophosphataemic patients on dialysis.


Area security unit in a psychiatric hospital. Since 1974 a psychiatric hospital security unit, designed to serve the whole catchment area, has cared for mentally ill (mostly psychotic) patients with disturbed behaviour that cannot be managed in open wards. There are a few long-term dangerous patients but most stay only briefly. The admission of women to the unit was not followed by the expected reduction in violence. The unit has facilities for occupational therapy, physical recreation, work, and study, which are particularly important for those who are too dangerous to leave it. The unit's calming influence depends as much on the supportive effect of the high staff ratio as on the use of tranquillisers. This type of unit is not suitable for patients with personality disturbances who "act out" or for mentally abnormal offenders; but it functions well as a crisis centre for the disturbed mentally ill, and there is an increasing demand for its services.


Mastalgia: psychoneurosis or organic disease? To test the traditional surgical view that pain in the breast is largely an expression of psychoneurosis, the Middelesex Hospital Questionnaire was given to 317 women with mastalgia and 170 controls with varicose veins. Their scores were compared with those of 173 women psychiatric outpatients tested by the designers of the questionnaire. The results were broadly similar in the mastalgia and varicose veins groups, and where there were significant differences women with varicose veins had a higher psychoneurotic score in each case. Within the mastalgia group no difference in scores was observed between patients with cyclical mastalgia and those with mastalgia due to periductal mastitis. Both groups of surgical outpatients had significantly lower scores in major traits than the psychiatric group, except for a small group of patients with breast pain who persistently failed to respond to treatment. Patients with mastalgia are therefore no more "neurotic" than those with varicose veins, and differ greatly from patients with recognized psychoneurosis. Most patients have a physiological or pathological basis for their breast pain, and they deserve an appropriate diagnostic and therapeutic approach.


Treatment of severe side effects after vagotomy and gastroenterostomy by closure of gastroenterostomy without pyloroplasty. We describe nine patients who had severe, persistent abdominal pain, vomiting, dumping, or diarrhoea several years after truncal vagotomy and gastroenterostomy had been performed for duodenal ulceration. Each patient was judged to have a bad clinical result (Visick grade 4). There was no evidence of recurrent ulceration in any of the patients, and in each the patency of the pyloric canal was confirmed radiologically or endoscopically. Each patient was treated by simply dismantling the gastroenterostomy without addition for a pyloroplasty. In one patient the surgeon suspected that a vagal trunk might have been left intact, and a revagotomy was performed by the "highly selective" technique. Postoperatively, none of the patients developed gastric retention. Symptomatic improvement occurred in eight patients, and four of them achieved perfect results (Visick grade 1). Side effects are common after vagotomy and gastroenterostomy, and are largely attributable to the presence of the gastroenterostomy stoma. Our results show that the symptoms may be alleviated by closing the gastroenterostomy, without precipitating gastric retention.


Acute mitral valve obstruction during infective endocarditis. Five patients were found during surgery or at necropsy to have the mitral valve orifice obstructed by vegetations. They had had unexplained severe and recurrent episodes of acute febrile pulmonary oedema, and four had few cardiac ausculatory findings. Three patients died suddenly and unexpectedly; the other two were operated on and survived. In view of its ominous prognosis, acute mitral valve obstruction should be considered in patients whose pulmonary symptoms are compatible with endocarditis and are not adequately explained by the findings on examination of the heart. The condition, which should be confirmed by echocardiography, requires emergency surgery.


Regional variations in the incidence of upper urinary tract stones in England and Wales. Data from the Hospital In-patient Enquiry were used to define the regional patterns of hospital discharge rates for upper urinary tract stones and renal colic in England and Wales. By combining the rates for stones and colic, and by distinguishing emergency from planned admissions, the biases produced by repeated admissions of the same patient and by regional variations in diagnosis and coding may be reduced. There are regional variations in incidence of upper urinary tract stones: Wales and the southern regions of England have a generally higher incidence than northern regions. These variations may be related to regional differences in diet or occupation; or they may partly depend on associations between stone incidence and atmospheric temperature, exposure to ultraviolet irradiation, and hardness of drinking water.


Birth ranks of spontaneous abortions in sibships of children affected by anencephaly or spina bifida. Data on the birth ranks of miscarriages within sibships in which a case of anencephaly or spina bifida (ASB) had occurred were analysed by the Haldane-Smith statistical test. This showed that miscarriages in ASB sibships tend to have a negative birth order effect--that is, they occur in earlier rather than later pregnancies within the sibship. The strongest source of bias in this analysis--the fact that mothers tend to forget early spontaneous abortions--worked against this finding, so the negative birth order effect is probably genuine. Because ASB itself shows a negative birth order effect and because spontaneous abortions in normal sibships do not show such an effect, the additional spontaneous abortions in ASB sibships are probably of fetuses affected by ASB.


Adrenocortical suppression in workers manufacturing synthetic glucocorticoids. A man who had worked for 16 years in the manufacture of a potent corticosteroid was found to be suffering from chronic adrenocortical insufficiency attributed to chronic absorption of the glucocorticoid. Eleven other symptom-free workers were therefore screened. Two of these workers, like the first patient, gave grossly abnormal responses to the Synacthen (tetracosactrin) test; one had been employed for only seven months. All 12 men had facial plethora, suggesting absorption of the drug in spite of their having adhered to the safety precautions. All workers manufacturing potent steroids should therfore be screened regularly by measurement of their plasma cortisol concentrations and should be moved regularly to processing other drugs.


Parenteral 1,25-dihydroxycholecalciferol in hepatic osteomalacia. Despite regular long-term parenteral vitamin D2 treatment, four patients with biliary cirrhosis had multiple symptoms of bone disease and bone biopsy specimens showed osteomalacia without osteoporosis. Three patients also had a proximal myopathy. Plasma calcium values (after correction for albumin), phosphorus, magnesium, and serum 25-hydroxy-vitamin D were within normal limits. Treatment with 1,25-dihydroxy-cholecalciferol (1,25-(OH)2D3) relieved symptoms in three of the four patients and improved those in the fourth. Histological examination of bone showed improvement in all four patients, but serum and urinary biochemical changes were not pronounced. We conclude that 1,25-(0H)2D3 treatment has a beneficial effect on bone and muscle in hepatic osteomalacia, either because vitamin D 1-hydroxylation fails in biliary cirrhosis or because hepatic osteomalacia is resistant to vitamin D2 metabolites.


NHS locally organised research scheme: regional research committees and the way they work. Regional research committees vary so widely in size, composition, and their methods of judging proposals that the standards of adjudication may also vary. Once the research has started it tends to be poorly monitored, and comparatively little attempt is made to discover whether the inexperienced researcher's ability has been promoted. Fostering the research spirit entails more than the provision of funds, and some regional health authorities may need to establish more formal ways of supervising and evaluating the research they support.


Scleritis and associated disease.

Scleritis and associated disease. One hundred patients (66 women and 34 men) who presented consecutively to Moorfields Eye Hospital with scleral disease underwent medical examination. Thirteen were found to have seropositive rheumatoid arthritis and another 16 also had rheumatoid factor present (Rheumaton test). Autoantibodies were present in 35% of patients, being most common in the elderly and most frequent in cases of necrotising and diffuse scleritis. Although scleral disease is uncommon, it is associated with connective-tissue disorders. Scleritis may be severe and destructive locally, and one series showed that 27% of patients who develop necrotising scleritis are dead from systemic complications within five years. It is therefore important for it to be correctly diagnosed and effectively treated at an early stage.


Changing pattern of drugs used for self-poisoning. In 1967-76 the annual number of admissions to a poisoning treatment centre rose from 964 to 2134. The proportion of admissions caused by taking barbiturate hypnotics and methaqualone fell considerably while that caused by taking benzodiazepines and tricyclic antidepressants increased. As a result the proportion of patients admitted unconscious fell from 23% to 15%. The declining contributions of barbiturates and methaqualone and increased importance of tricyclic antidepressants were significant in all grades of coma. The change in drugs taken, however, has not yet reduced the percentage of unconscious patients needing endotracheal intubation or assisted ventilation, and hypothermia remains as common. Only hypotension has become less frequent as antidepressants replace barbiturates as the main cause of drug-induced coma. The use of salicylates for self-poisoning is declining slowly, and paracetamol poisoning is now as common.


Familial thrombosis: inherited deficiency of antithrombin III. Several members of a family living on the west coast of Scotland and on one of the islands off the coast had serious thrombotic disease. The plasma antithrombin III (ATIII) concentrations were measured by both functional and immunological assay in all available members of the family. Concentrations were 25% to 66% of normal in 12 people, including all seven with thrombotic disease. The inheritance pattern was characteristic of an autosomal dominant disorder. Thrombotic disease generally affected the leg, mesenteric, and axillary veins, although one man who had died before the study began had had severe arterial atheroma. In women the first thrombotic symptoms usually occurred during pregnancy. None of these patients have developed thrombotic symptoms until they were at least 18, so four younger members of the family who have ATIII deficiency but no thrombotic disease may eventually develop symptoms.


Comparison of serum oestrogen concentrations in post-menopausal women taking oestrone sulphate and oestradiol. Mean serum concentrations of oestradiol-17beta, oestrone, and oestrone sulphate in postmenopausal women were the same when measured up to six hours after treatment with either piperazine oestrone sulphate 1.5 mg or oestradiol valerate 2 mg. Maximum concentrations of oestradiol were less than those of oestrone, but oestrone sulphate reached concentrations about 30 times higher than those of oestrone. The rapid conversion of oestradiol valerate to oestrone and oestrone sulphate does not support the suggestion that in menopausal women oestradiol is less likely to be associated with a risk of endometrial carcinoma than oestrone sulphate, since the two preparations appear to become identical after ingestion.


Serum tolbutamide and chlorpropamide concentrations in patients with diabetes mellitus. A selective and sensitive gas chromatographic technique was used to measure the steady-state serum concentrations of tolbutamide and chlorpropamide in 97 patients with maturity-onset diabetes mellitus who had been taking these drugs (37 tolbutamide, 60 chlorpropamide) for at least a year. No other antidiabetic agents had been given. The serum tolbutamide concentrations varied widely between the patients (from close to zero to 370 mumol/l (100 mug/ml)), yet the variation in dosage was only sixfold (0.5-3.9 g daily). The serum chlorpropamide concentrations varied even more widely (from close to zero to 882 mumol/l (244 mug/ml)), though the dosage variation was fourfold (125-500 mg daily). There was no systematic relation between dosage and serum concentrations of the drugs.Only 2 (5.4%) of the tolbutamide-treated patients and 10 (16.7%) of the chlorpropamide-treated patients had normal fasting blood glucose concentrations (below 5.5 mmol/l (99 mg/100 ml)), and fewer than half had values below 8.0 mmol/l (144 mg/100 ml). In most cases, therefore, the treatment was insufficient.There was no significant difference in mean fasting blood glucose concentrations between the two treatment groups. The mean steady-state concentration of chlorpropamide, however, was significantly higher than that of tolbutamide. Thus, contrary to common belief, the intrinsic activity of chlorpropamide is apparently not greater than that of tolbutamide. The alleged greater potency of chlorpropamide seems to be related wholly to kinetic differences, such as the less extensive metabolic degradation and slower elimination of the drug.We conclude that treatment with sulphonylureas in conventional dosage is far from optimal and that monitoring the concentrations of these drugs in the blood may help to improve their efficacy.


Immediate heart-rate response to standing: simple test for autonomic neuropathy in diabetes. The immediate heart-rate response to standing was measured in 22 normal controls and 25 patients with diabetes, 15 of whom had autonomic neuropathy. The response in the controls and patients without autonomic neuropathy was characteristic and consistent, with tachycardia maximal at around the 15th beat and relative bradycardia maximal at around the 30th beat. The diabetics with autonomic neuropathy, however, showed a flat response. In three controls the response was abolished with intravenous atropine but not with propranolol, showing that it is mediated through the vagus. A simplified test using routine ECGs and measuring the R-R interval at beats 15 and 30 with a ruler is easily performed as an outpatient procedure and may be used as a measure of autonomic function in diabetes.


Fall in admission rate of old people to psychiatric units. The numbers of the elderly, and particularly the very old, have been increasing and continue to increase rapidly; but admission rates of old people to psychiatric hospitals in England and Wales suddenly started to fall in 1970. They were still generally falling in 1974 (the most recent year for which figures are available). There is no evidence that the incidence of dementia has suddenly fallen, or that expansion of extramural or other non-psychiatric services is everywhere coping with the severely demented. It is probably becoming more difficult for demented people to be admitted to psychiatric hospitals that are often still overcrowded, in view of the greater scrutiny of institutional care that has become established since the Ely Report of 1969. If this is so the cost to the demented and those who care for them of the undoubted improvements in conditions in psychiatric hospitals needs to be counted.


Thyroid function in lung cancer.

Thyroid function in lung cancer. Thyroid function was assessed at the time of initial diagnosis in 204 patients with lung cancer and compared with that of age and sex-matched patients with non-malignant lung disease. Abnormalities in thyroid function were found in 67 patients (33%). The most prevalent abnormality was a low T3 concentration; this was not associated with other clinical or biochemical evidence of hypothyroidism, but the short-term prognosis of these patients was worse than that of matched patients with lung cancer having normal T3 concentrations. Primary hypothyroidism occurred in three patients, low T4 concentrations and free thyroxine index (FTI) with normal thyrotrophin (TSH) concentrations in four patients, and moderately raised TSH with normal thyroid hormone concentrations in six patients; nine patients had a raised FTI with or without raised T4 concentration as the sole abnormality.Overall, the pattern of thyroid hormone metabolism in lung cancer was a tendency towards reduced T3 concentrations with significantly increased T4/T3 ratios and modestly increased 3,3',5'-triiodothyronine (rT3) concentrations. The altered T4/T3 ratio was particularly noticeable in patients with anaplastic tumours of small ("oat cell") and large cell types, but was not apparently related to detectable extrathoracic metastases.These data suggest that thyroid hormone metabolism is altered in patients with lung cancer by decreased 5'-monodeiodination of T4. The resulting low T3 concentrations and altered T4/T3 ratio may be partly responsible for the reduced ratio of androsterone to aetiocholanolone observed in lung cancer, which is known to be a poor prognostic sign.


Metacarpal morphometry in adults with osteogenesis imperfecta. Osteogenesis imperfecta is often regarded as a form of osteoporosis. In many cases, particularly those in whom the first fracture occurs outside the neonatal period, bones that have not been fractured may appear radiologically normal. In a group of 24 adults with osteogenesis imperfecta the thickness of the metacarpal cortex was normal but their bones were often slender. Osteoporosis is probably not an inevitable feature of such cases, and some of the radiological abnormalities reported may be the results of previous fractures and their treatment.


Fertility after stopping different methods of contraception. Data on the return of fertility after discontinuing various methods of contraception were collected from among the women taking part in the Oxford-Family Planning Association contraceptive study. Return of fertility was measured as the time taken to give birth to a child. The fertility of both nulligravid and parous women who stopped taking oral contraceptives was initially impaired in comparison with that of women who stopped using other methods of contraception. But the effect of oral contraceptives on fertility had become negligible by 42 months after cessation of contraception in nulligravidae and by 30 months in multiparae. Impairment seemed to be independent of the length of use of oral contraceptives. Data relating to IUD users were sparse, but the figures that were available were reassuring. These results suggest that, although women may have temporary impairment of fertility after discontinuing oral contraception, they are unlikely to become permanently sterile through taking the pill.


Smoking, carbon monoxide, and atherosclerotic diseases. Smoking habits and random measurements of the proportion of haemoglobin bound to carbon monoxide (COHb%) were examined for their association with atherosclerotic diseases in 1068 men aged 55 to 74 years from rural areas of Finland. COHb% and smoking history were similarly associated with claudication and coronary heart disease. Random measurements of COHb% did not show a better overall relation to the prevalence of atherosclerotic diseases than smoking history, though COHb% showed a stronger association with a probable previous myocardial infarction. Further studies are needed to clarify the role of carbon monoxide in atherosclerosis.


Influence of induced abortion on gestational duration in subsequent pregnancies. We studied the effect of previous induced and spontaneous abortion on gestational duration in subsequent pregnancies in 12 obstetric departments in the Netherlands. Only primiparae were studied. Of 504 women who had had a previous induced abortion, 18 (3.6%) delivered before 32 weeks' gestational age. Forty of 1313 women with a history of spontaneous abortion (3.0%) and 259 of 12 678 women with no history of abortion (2.1%) also delivered before 32 weeks. The differences between the three groups were not significant. In the Netherlands there are no significant indications that spontaneous midtrimester abortions or premature deliveries are caused by a previous induced abortion.


Bronchopulmonary infection due to Branhamella catarrhalis: 11 cases assessed by transtracheal puncture. Transtracheal punctures were performed in 193 miners of anthracosilicotic coal who presented with an acute exacerbation of chronic bronchitis. The transtracheal aspirates were bacteriologically positive in 104 patients. Branhamella catarrhalis was isolated in 15 patients; 10 of these responded to chemotherapy, as shown by the resolution of all symptoms and the disappearance of the organism on a repeat transtracheal puncture performed 48 hours after the end of treatment. One ampicillin-treated patient, whose bronchial secretions yielded a beta-lactamase-producing B catarrhalis, showed no improvement. But subsequent treatment with cefuroxime was followed by clinical and bacteriological recovery. B catarrhalis probably acted as an opportunistic respiratory pathogen in these patients, who were probably compromised hosts in view of their clinical history. B catarrhalis normally responds to the penicillins commonly used for respiratory infections, but if treatment fails a transtracheal puncture is essential to identify the strain and determine an appropriate antibiotic.


Value of a testicular biopsy rating for prognosis in oligozoospermia. Testicular biopsies of 142 oligozoospermic men were used to obtain a testicular biopsy score count. These scores were clearly related to the chance of fertility, in contra-distinction to data on hormone concentrations and from analysis of semen. In 36 patients with a score of 9-10 there were 15 pregnancies; in 59 patients with a score of 8-9, 12; and in 47 patients with scores below 8 there was only one successful pregnancy, though this last group also contained an additional three patients whose wives' pregnancies ended in miscarriages. Rating of testicular biopsies is more useful for proper evaluation of oligozoospermic patients than are data on hormone concentrations and from semen analysis. Proper evaluation of new treatments should be based on trials where experimental and control groups are matched on these ratings.


Intracellular recording and staining of cat's lateral geniculate neurons. Intracellular staining with recording micropipettes filled with a Procion yellow solution was attempted on 11 lateral geniculate neurons of chloralose-anesthetized cats for the purpose of correlating electrophysiologically identified cell types with morphologically identified cell types. Five neurons were successfully stained: one was located in lamina A and the others in lamina A1. They were all identified as P-cells on the basis of their responsiveness to electrical stimulation of optic disc, optic chiasm and visual cortex. The conduction velocities and synaptic delays for specific optic nerve fibers concerned with these P-cells were estimated from the relationship between latency and conduction distance. Intracellular staining has revealed that a neuron located in lamina A and three of four neurons located in lamina A1 had multipolar configuration, with their main dendrites oriented parallel to the plane of the laminae; while one neuron located in lamina A1 had a configuration similar to that of a class II-type neuron described by Guillery in his Golgi preparations. In these experiments no neurons located in lamina B, central interlaminar nucleus and medial interlaminar nucleus were stained. No interneurons were obtained, either.


Symposium on peptic ulcer disease: 2. Vagotomy and its variations. All the forms of vagotomy that are used in the treatment of peptic ulcer disease lower the acid secretion by the gastric parietal cells. The preferred operation is the proximal selective vagotomy in which the innervation to the antrum and pylorus is undisturbed. Therefore the necessity for any type of drainage procedure is obviated. The results of a number of clinical trials can be considered highly satisfactory. The undue rate of ulcer recurrence sometimes reported after the operation is possibly attributable to its incorrect performance.


Symposium on peptic ulcer disease: 3. Practical management of recurrent peptic ulcer. Recurrent peptic ulcer usually develops as the result of an ill-advised or poorly executed operation. The commonest surgical error is an incomplete vagotomy. Diagnosis is made best by endoscopy. Mandatory investigation includes determination of serum gastrin and calcium, and measurement of basal and maximal acid output. Management is surgical and depends on the initial ulcer operation. Decision-making is aided by the Hollander insulin test, the secretin infusion test and occasionally by a technetium scan. There is no place for procedures that do not reduce acid output. Emergency treatment of a complication should be followed by full investigation and the appropriate operation. Recurrent gastric ulcer should be treated by gastrectomy and excision of the ulcer.


Symposium on carcinoma of colon and rectum: 2. Sphincter-preserving operations for rectal cancer. At St. Mark's Hospital in London, England there has been a steady improvement over 20 years in the results of treatment of rectal cancer. The resectability rate has reached 95% and the overall operative mortality rate has declined to 2%. The corrected 5-year survival rate is about 70% for all who recover from the operation. It is unlikely that these figures can be bettered, so attention has been directed to the use of radiation therapy and adjuvant cytotoxic therapy, but so far no firm conclusions are possible on the benefits of either modality. In order to spare the patient a colostomy, local excision of the growth or the use of a transsphincteric approach can be considered, but few cases are suitable for either procedure or their more radical alternatives.


Symposium on carcinoma of colon and rectum: 3. Radiation therapy in rectal cancer. In a number of studies preoperative irradiation of cancer of the rectum has procured 5-year survival rates higher than those obtained with conventional surgical techniques, whether or not the tumour has spread to lymph nodes. There appears, as well, to be a lower rate of local recurrence and possibly of the development of distant metastases. Also, some tumours of questionable operability are reduced in size to make resection possible. The effectiveness of postoperative radiation therapy is not yet firmly established. Radiation therapy as the primary method of treatment of rectal carcinoma has been used at the Princess Margaret Hospital in Toronto in 79 patients over a period of 18 years. The overall 5-year survival rate is 28%; this rises to 38% when the tumour is not fixed but falls to half this figure when fixity of the growth is evident. These results offer grounds for investigating radical radiation therapy as an alternative to surgical methods of dealing with low-lying carcinomas of the rectum.


Symposium on pancreatitis: 2. Surgical management of acute pancreatitis. While there is general agreement on the indications for surgery in acute pancreatitis, the preferred operation is controversial and the approach ranges from one that is very conservative to one that is extremely aggressive. The author believes that in all cases the gallbladder should be opened to permit exploration and that cholangiography should be performed. If gallstones are discovered they should be removed and the organ drained; cholecystectomy is advised if the procedure is at all feasible. In a personal series of 50 cases of acute pancreatitis, 10 patients had early operation and 19 surgical procedures were performed.


Symposium on pancreatitis: 3. Diagnostic tools in the management of chronic pancreatitis. The chief diagnostic tools used in planning the management of chronic pancreatitis require close collaboration of the surgeon and radiologist. Barium meal, endoscopic retrograde cholangiopancreatography (ERCP), ultrasonography and angiography are the most useful procedures. The barium meal is the initial screening procedure. Uultrasonography should follow if there is suspicion of a pseudocyst or pancreatic abscess. It is also may be of value in demonstrating localized chronic pancreatitis. The most useful of all the tests is ERCP. This shows the pancreatic duct, the common bile duct, or both ducts, so that the surgeon may avoid operation where there is no defect to correct, or it may guide him in selecting an operation that is designed to correct the anatomical abnormalities of either duct. Angiography is occasionally of use when the foregoing procedures have not provided enough information. In over 80% of patients it is possible for the surgeon to undertake an operation with foreknowledge of the pancreas that will help him select the correct procedure to alleviate the patient's symptoms.


Symposium on pancreatitis: 4. Surgery in chronic pancreatitis. When the pain associated with chronic pancreatitis is due to ductal obstruction, it is logical that surgical management should be designed to relieve that obstruction while preserving as much of the functioning gland as possible. A number of cases are described to illustrate the various procedures available and to indicate the features that govern the selection of the one most appropriate for a particular patient. The operations include partial pancreatectomy, Roux-en-Y pancreaticojejunostomy and longitudinal pancreaticojejunostomy; these can be modified to suit the peculiar circumstances of a given case.


Symposium on intensive care: 1. Monitoring of the critically ill surgical patient. The skill and experience of the medical and nursing staff are the factors that have the greatest impact on the quality of monitoring and treatment of the critically ill surgical patient. Basic determinations at the bedside together with periodic evaluation of the whole patient by the medical staff may, in selected cases, be supplemented usefully by more invasive monitoring techniques. The specific complications and technical pitfalls of these techniques should be known, and caution should always be exercised that the values provided are not misinterpreted. A critical care area serving a major teritary referral hospital should be able to measure pulmonary capillary wedge pressure and cardiac output. Mixed venous oxygen content and arterial lactate concentration, as indices of oxygen delivery, are also useful measures.


Symposium on intensive care: 2. Infection control in the surgical intensive care unit. Control of infection in the surgical intensive care unit demands unfailing attention to three distinct areas: a) The bacteria responsible may be endogenous or exogenous. The effects of the former can be limited by careful surgical techniques and judicious use of antibiotics, of the latter by the practice of asepsis and antisepsis, essentially of scrupulous cleanliness. b) The environment of infection concerns the support of natural barriers to infection (notably the integrity of the skin and the adequate drainage of the pulmonary system), and the sterility and appropriate care and use of the many invasive devices currently available. c) The patient's natural defence mechanisms show considerable variation, and those at increased risk can be detected by skin-testing with a number of antigens as well as by recognized clinical features. It is in these patients with anergy and abnormal natural defences that total parenteral nutrition can be of the greatest value.


Problems in the control of hypertension in the community. A hypertension survey was conducted in Montreal to determine the extent, nature and distribution of the control of hypertension. Of the 12 055 persons screened in shopping centres, workplaces and a random sample of homes in four census tracts the hypertension was not controlled in 69.0% to 80.3% of those with the condition in each setting. Nearly two thirds of those with hypertension were aware of their condition, 13% were aware but had never been treated, 13% were receiving treatment inadequate to control their hypertension, and 11% had discontinued treatment, most reporting that they had done so on the advice of their physician. Among those screened in their home, discontinuance of therapy was most often reported by those with a low income, but lack of awareness of their condition was no more prevalent in this group than in the other income groups. Efforts to control hypertension should be directed to the variety of causes of lack of control, which may occur with various frequencies in different communities, and for which screening alone may be inadequate.


Nutritional status of a select group of free-living elderly people in Vancouver. A study was conducted to determine the nutritional status of the free-living elderly population in Vancouver. The response rate of the sample was low. Dietary information from 104 single men and women and 23 couples was collected by the 24-hour recall method. Biochemical tests in 56 single individuals and 13 couples included measurement of hemoglobin concentration and hematocrit, plasma analysis for concentrations of total protein, iron, carotene, vitamin A, ascorbic acid, vitamin E and cholesterol and for transferrin saturation, and urine analysis for concentrations of creatinine, thiamin, riboflavin and N(1)-methylnicotinamide.Mean energy intakes were considerably below the Dietary Standard for Canada. However, mean intakes of individual nutrients were similar to or in excess of the Dietary Standard for Canada for single men and women and for married men. Married women had low average intakes of calcium, iron, thiamin and riboflavin but adequate intakes of other nutrients. Mean values for biochemical variables were within the accepted range as defined by the Interdepartmental Committee of Nutrition for National Defense in the United States. According to the Nutrition Canada definitions of "high risk" there were no individuals in high-risk categories for any biochemical variable except plasma cholesterol concentration and transferrin saturation. The dietary and biochemical data indicated that the nutritional status in this select group of elderly persons was good except for intake of total energy and, in married women, of calcium, iron, thiamin and riboflavin.


Detection and pathogenesis of visceral calcification in dialysis patients and patients with malignant disease. Scintiscanning to detect the uptake of bone-seeking radioactive isotopes by soft tissue is a promising technique for the in vivo study of visceral calcification. Visceral uptake of such radioisotopes was studied in 40 patients: 22 undergoing long-term dialysis, 9 with malignant disease and hypercalcemia and 9 with primary hyperparathyroidism and hypercalcemia.Fifteen patients, 11 undergoing dialysis and 4 with malignant disease, had radioisotope uptake in the lungs, and 5, 3 undergoing dialysis and 2 with malignant disease, had uptake in the stomach. None of the patients with primary hyperparathyroidism had visceral uptake, nor did the patients with uptake have radiologic evidence of pulmonary or gastric calcification. The dialysis patients with visceral uptake had a mean calcium x phosphate product of 84.3 +/- 23.7 (standard deviation), which was significantly greater (P < 0.001) than that of patients without such uptake (59.2 +/- 14.0). Similarly, in patients with malignant disease and visceral uptake the Ca x P product was 72.2 +/- 6.4 - significantly greater (P < 0.005) than that of patients without such uptake (49.3 +/- 6.7).These findings indicate that scintiscanning for the visceral uptake of a bone-seeking radioisotope is a simple and effective technique for the in vivo study of visceral calcification. An elevation in the Ca x P product seems to be the single most important factor in the production of visceral calcification.


Management of anemia in a general city hospital: value of chart review in establishing deficiencies in care. A retrospective review was done of the charts of 50 persons admitted to hospital for investigation of primary anemia. The duration of hospital stay was considered excessive for 80% of the patients and investigation was considered excessive for 34%. Nevertheless, underdiagnosis or misdiagnosis by the time of discharge was evident in 48% and was the result of inadequate investigation or faulty analysis of the results or both. Even when the type of anemia was established, investigations to determine the cause of specific deficiencies were frequently inadequate. Understandably treatment was inadequate for undiagnosed or misdiagnosed conditions but it was also inadequate for many correctly diagnosed conditions. Parenteral administration of iron was prescribed more often than oral administration, and 30% of patients with iron deficiency anemia failed to receive iron by either route. Most patients with vitamin B12 deficiency anemia received treatment late. Blood transfusion was given to 40% of patients but could be justified in only 16%.


The intrauterine contraceptive device.

The intrauterine contraceptive device. This presentation brings into perspective the most recent information on intrauterine contraceptive devices. A comprehensive review of the literature is presented in a manner meaningful to the clinician. The advantages and disadvantages of this method of contraception, the problems that arise and the recommended methods of management are discussed. An updated review of the literature with regard to bleeding, pain, expulsion of the device, infection, uterine perforation and pregnancy is also presented.


Sensitivity of human and murine hematopoietic precursor cells to 2-[3-(2-chloroethyl)-3-nitrosoureido]-D-glucopyranose and 1,3-bis(2-chloroethyl)-1-nitrosourea. The sensitivity of mouse and human bone marrow hematopoietic precursor cells [colony-forming units committed to granulocyte-macrophage differentiatin (CFU-C)] was determined after in vitro incubation with chlorozotocin (2-[3-(2-chloroethyl)-3-nitrosoureido]-D-glucopyranose), or 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU), with the use of drug concentrations achieved during clinical administration. Chlorozotocin, at a concentration of 1 X 10(-4) M, did not decrease mouse CFU-C below the control of 44 colonies/10(5) nucleated cells; 5 X 10(-4) M produced a 70% reduction in CFU-C, and 1 X 10(-3) M chlorozotocin eliminated all colony formation. In contrast, BCNU at 1 X 10(-4) M resulted in a 55% reduction in CFU-C, and at 5 X 10(-4) M it eliminated all colony formation. For human marrow the threshold concentration for chlorozotocin toxicity was 1 X 10(4) M, which resulted in 25% reduction in CFU-C as compared to the control of 32 colonies/10(5) nucleated cells. In contrast, BCNU at 5 X 10(-5) M decreased human CFU-C to 47% of control, and at 1 X 10(-4) M it eliminated all colony formation. Twenty-four hr after in vitro exposure to 1 X 10(-4) M chlorozotocin, there was no reduction in human bone marrow DNA synthesis in contrast to a 42% reduction with 1 X 10(-4) M BCNU. The plasma concentration of drugs following a therapeutic dose in patients was measured and was found to correspond to the concentration range used in the in vitro studies of marrow toxicity.


Demonstration of nonspecific suppressor cells in the peripheral lymphocytes of cancer patients. The response to phytohemagglutinin of peripheral blood lymphocytes was studied in 169 cancer patients. There was a significant decrease compared with control groups (normal persons and those with benign disease). By selecting cancer leukocyte samples with reactivity to phytohemagglutinin that was increased by carrageenan, a macrophage-toxic agent, and by mixing them with normal lymphocytes, we have demonstrated that the depressed phytohemagglutinin of six cancer patients' lymphoyctes was due to the presence of suppressor cells that possibly were monocytes.


In vitro plasminogen activator activity in human brain tumors. Cell cultures were prepared from nine human brain tumors. Fibrin plate assays showed plasminogen-dependent fibrinolytic activity in lysates and in material released by these neoplastic cells but not in those from normal adult human white matter. Antibodies against human urokinase caused catalytic inhibition of the urokinase and of the plasminogen activator from WI-38 cells, simian virus 40-transformed WI-38 cells, human prostatic cells, and human ovarian carcinoma cells. However, the anti-urokinase immunoglobulin G did not inhibit the plasminogen activator activity of any of the human brain tumor preparations. These studies indicate that the plasminogen activator produced by human brain tumor cells is antigenically different from the plasminogen activator of other human normal and neoplastic cells.


Retrospective study of carcinoma of the esophagus in Kenya. A clinical, radiological, histological, and geographical study of carcinoma of the esophagus in Kenya is reported. It was found that this cancer is diagnosed more often in males than in females, with a ration of 8:1 (Kenya Cancer Registry). The most common age in males and females is 50 to 59 years. The regions of the esophagus most commonly involved are the middle and lower thirds, in almost equal proportions. An unexplained tendency for the tumor to be poorly differentiated towards the lower third is noted. In addition a review on the possible etiological factors is presented.


Tumorigenicity studies with diol-epoxides of benzo(a)pyrene which indicate that (+/-)-trans-7beta,8alpha-dihydroxy-9alpha,10alpha-epoxy-7,8,9,10-tetrahydrobenzo(a)pyrene is an ultimate carcinogen in newborn mice. The tumorigenic activities of benzo(a)pyrene(BP), (+/-)-trans-7beta,8alpha-dihydroxy-9beta,10beta-epoxy-7,8,9,10-tetrahydrobenzo(a)pyrene (diol-epoxide 1), (+/-)-trans-7beta,8alpha-dihydroxy-9alpha,10alpha-epoxy-7,8,9,10-tetrahydrobenzo(a)pyrene (diol-epoxide 2), (+/-)-trans-7,8,-dihydroxy-7,8-dihydrobenzo(a)pyrene (BP 7,8-dihydrodiol), and the tetraols derived from the hydrolysis of diol-epoxide 2 were evaluated in newborn mice. The mice were given injections sequentially of 4, 8, and 16 nmoles of each compound on the first, eighth, and fifteenth days of life, and the animals were killed when they were 28 weeks old. Diol-epoxide 1 was highly toxic in newborn mice, and most of the animals treated with this compound died before weaning. Diol-epoxide 2 and BP 7,8-dihydrodiol were, respectively, about 40- and 15-fold more active than BP in causing pulmonary adenomas. Vehicle-treated control animals had an average of 0.13 lung adenoma/mouse, whereas animals treated with BP, BP 7,8-dihydrodiol, or diol-epoxide 2 had, respectively, 0.24, 1.77 and 4.42 pulmonary adenomas/mouse. Diol-epoxide 1 and the tetraols derived from diol-epoxide 2 did not induce pulmonary adenomas. The inactivity of diol-epoxide 1 under the conditions of our study should be interpreted with caution because of the high toxicity of this compound. The results of our study provide evidence that BP 7,8-dihydrodiol is a proximate carcinogenic metabolite and that diol-epoxide 2 is an ultimate carcinogenic metabolite of BP in the newborn mouse.


Hepatobiliary metabolism and excretion of adriamycin and N-trifluoroacetyladriamycin-14-valerate in the rat. In connection with mechanism of action studies with N-trifluoroacetlyadriamycin-14-valerate (AD 32), a superior Adriamycin (ADR) analog under development in these laboratories, serial bile samples were collected from male Sprague-Dawley rats given a single i.v. dose of either ADR (4 mg/kg) or AD 32 (20 mg/kg) and were analyzed for anthracyclines by thin-layer chromatography-fluorometry and high-performance liquid chromatography. For ADR, 20% of the administered dose was accounted for at 24 hr, whereas 80% of the AD 32 dose were excreted into the bile by this time. ADR underwent little biotransformation; 80% of the 48-hr cumulative fluorescence excretion was attributable to unchanged drug, one-half the remainder was adriamycinol, and the balance was polar conjugates. In contrast, AD 32 underwent extensive metabolism to N-trifluoracetyladriamycin, N-trifluoroacetyladriamycinol, and polar conjugates, mostly glucuronides of N-trifluoroacetyladriamycin and N-trifluoroacetyladriamycinol. Based on direct and indirect evidence, ADR was not a metabolite of AD 32.


Dependence on chain length of antitumor activity of (1 leads to 3)-beta-D-glucan from Alcaligenes faecalis var. myxogenes, IFO 13140, and its acid-degraded products. The well-defined (1 leads to 3)-beta-D-glucan with (DPn) 540, produced by cultivation of Alcaligenes faecalis var. Myxogenes (IFO 13140), a mutant of a soil bacterium, had marked inhibitory activity against the s.c.-implanted Sarcoma 180 at 5 to 50 mg/kg for 10 days. It also exhibited very high activity in doses of 60 and 100 mg/kg i.p. by a single injection at 7 days after the initial s.c. transplantation of Sarcoma 180. The inhibition ratios observed with Ehrlich carcinoma, NTF (Nakahara-Tokuzen-Fukuoka) reticulum cell sarcoma, and CCM adenocarcinoma were somewhat less but were still significant. On the other hand the treatment failed to inhibit the growth of ascites Sarcoma 180 or to induce prolongation of life span. The mechanism of action of this glucan was considered to be host mediated because of a lack of effect in vitro and also because of the effectiveness of pretreatment of animals by injection before transplantation of a tumor. The results from the bioassay study of the low-molecular-weight (1 leads to 3)-beta-D-glucans prepared from the glucan with number-average degrees of polymerization (DPn) 540 by hydrolysis with formic acid or sulfuric acid showed that the glucans with DPn greater than 50 inhibited the growth of Sarcoma 180 implanted s.c. in mice, whereas the result of the schedule-dependent effect was obtained in the pretreatment of animals by the glucan with DPn 50. By i.v. administration, even the glucan with DPn 16 showed a strong antitumor effect comparable to that of the glucan with DPn 540.


Quantitation by gas chromatography-chemical ionization mass spectrometry of cyclophosphamide, phosphoramide mustard, and nornitrogen mustard in the plasma and urine of patients receiving cyclophosphamide therapy. Unambiguous and sensitive methods based on gas chromatography-chemical ionization mass spectrometry have been developed to quantitate cyclophosphamide and two alkylating and cytotoxic metabolites, phosphoramide mustard and nornitrogen mustard. The levels of these materials have been determined in the plasma and urine of five patients receiving cyclophosphamide, 60 or 75 mg/kg i.v. Peak plasma levels of phosphoramide mustard of 50 to 100 nmoles/ml were found at 3 hr after cyclophosphamide administration. Variable levels of nornitrogen mustard were found in the plasma. This product may be arising in part from the decomposition of other metabolites during sample storage and preparation.


DNA synthesis and DNA polymerase activity in Leydig cells of diethylstilbestrol-stimulated mouse testes. Using a modification of the collagenase dispersion method of Dufau et al., we examined changes in DNA synthesis produced by estrogens in the interstitial cells of mice that develop malignant Leydig cell tumors after prolonged estrogen administration. Previous work in cryptorchid mice indicated that during continuous estrogen administration [3H]thymidine incorporation into DNA rises to a maximum in 3 to 4 days and then falls to approximately base levels within 2 to 3 weeks. This was confirmed both in Leydig cell concentrates of estrogen-treated mice after either injection with [3H]thymidine or incubation with [3H]thymidine in vitro. This DNA synthesis was blocked by hydroxyurea. DNA synthesis in cells of estrogen-treated BALB/c mice of the Huseby substrain, which have a high incidence of Leydig cell tumors, was 5 to 11 times that in untreated controls. Cells from estrogen-treated C3H/Bi mice, which have a low incidence of Leydig cell tumors, showed only a 2- to 3-fold increase. In the Huseby substrain the rise of DNA synthesis is a peak and subsequent recession were paralleled by a rise and fall in DNA polymerase alpha activity. DNA polymerase beta did not show this variation. In C3H/Bi mice, neither polymerase showed significant change. The evidence suggests that the early estrogen-stimulated DNA synthesis is probably replicative and is associated with increased DNA polymerase alpha activity.


Enhancement of X-ray transformation by 12-O-tetradecanoyl-phorbol-13-acetate in a cloned line of C3H mouse embryo cells. A phorbol ester promoting agent, 12-O-tetradecanoyl-phorbol-13-acetate, enhances X-ray transformation in vitro in a two-stage fashion similar to that shown previously for ultraviolet radiation and chemical carcinogens. In studies with a mouse embryo-derived cell line (C3H/1OT 1/2 clone 8), there were clear interactive effects between X-radiation and 12-O-tetradecanoylphorbol-13-acetate. These were particularly marked when a minimally transforming X-ray dose (50 or 100 rads) was followed by 12-O-tetradecanoylphorbol-13-acetate treatment beginning either immediately after the radiation exposure or 48 to 96 hr later.


Restoration of growth control in malignantly transformed mouse fibroblasts grown in a chemically defined medium. The expression of growth control and morphological transformation was studied in methylcholanthrene-transformed C3H/10T 1/2 CL8 cells serially propagated in CDM by first exposing cells to albumin (0.1%) before dispersing them with trypsin (50 microgram/ml). In serum-supplemented media, methylcholanthrene-transformed C3H/10T 1/2 CL8 cells exhibit various aspects of the transformed phenotype such as irregular morphology, extensive cell overlap, lack of density-dependent inhibition of division, a saturation density of 1.1 X 10(5) cells/sq cm and tumorigenicity in vivo. Cell phenotype in CDM was dramatically altered. Methylcholanthrene-transformed C3H/10T 1/2 1/2 CL8 cells adapted to CDM exhibited a regular epithelioid morphology with no cell overlap and formed confluent monolayers of nonproliferating cells at a saturation density of 5 X 10(4) cells/sq cm. The mean generation time of logarithmic-phase cells was 25 to 27 hr. Reversion to the transformed phenotype followed addition of albumin (0.1%) or serum (2%) to logarithmic-phase cultures or exposure (30 to 60 sec) to trypsin (10 microgram/ml). Cultures in CDM reexposed to serum remained highly tumorigenic in vivo. The data suggest that absorbed proteins may block transformation-sensitive cell surface sites responsible for growth control and that these sites are inactivated by trypsin.


Isolation, partial characterization, and biological properties of polysaccharides from crude papain. Two polysaccharides have been isolated from crude papain by precipitation of papain with ammonium sulfate, further precipitation of other proteins with trichloroacetic acid, and chromatography of the supernatant on DEAE-cellulose. The first polysaccharide to be eluted, designated PP-I, contained D-glucuronic acid, D-glucose, D-galactose, L-arabinose, and L-rhamnose, in the approximate molar ratios of 4:1:12:10:4. The other (PP-II), eluted at a higher salt-concentration, contained the same sugars (with about one-third less glucose and more uronic acid) in the approximate molar ratios of 13:1:40:26:12. Reduction of the uronic acid groups of PP-II produced a polysaccharide (PP-II-R) containing the same sugars in the approximate molar ratios of 2:11:37:28:12. Hydrolysis of a mixture of the two polysaccharides yielded an aldobiouronic acid, D-glucosyluronic acid-D-galactose. Neither polysaccharide preparation contained protein. These polysaccharides dramatically affected aggregation and alignment of normal human fibroblasts but had no effect on a mouse embryo fibroblast aneuploid cell-line that does not exhibit contact inhibition of growth or movement. In aggregating cells, these polysaccharides caused the cells to behave as contact-inhibited cells, that is, cell division and nuclear area were decreased.


Determination of the sugar sequences and the glycosidic-bond arrangements of immunogenic heteroglycans. The complete sugar sequences and glycosidic-bond arrangements have been determined by a combined analytical scheme for a diheteroglycan of D-glucose and D-galactose and a tetraheteroglycan of 6-deoxy-L-talose, L-rhamnose, D-galactose, and D-glucuronic acid. The analytical scheme included methylation analysis by g.l.c. and mass spectrometry, periodate oxidation followed by borohydride reduction and identification of the residual fragments, enzymic hydrolysis followed by characterization of the modified glycan, and chemical degradation followed by characterization of the resulting fragments. The diheteroglycan and the tetraheteroglycan are immunogenic substances on the cell surface of the organisms, and are the group specific carbohydrates in the cell walls of Streptococcus faecalis, strain N, and Streptococcus bovis, strain C3. The combined analytical scheme should be of general applicability for the structural analysis of heteroglycans for which selective-degradation procedures can be devised.


Opposite end assembly and disassembly of microtubules at steady state in vitro. Measurements of tubulin exchange into and from bovine brain microtubules at steady state in vitro were made with 3H-GTP as a marker for tubulin addition to or loss from microtubules. Tubulin has an exchangeable GTP binding site that becomes nonexchangeable in the microtubule. We found that tubulin addition to and loss from microtubules under steady state conditions occurred at equivalent rates, that loss and gain were linear, and that exchange rates (percentage of total tubulin in microtubules lost or gained per hour) were dependent upon microtubule length. Furthermore, we found that podophyllotoxin blocked steady state assembly, but did not alter the rate of steady state tubulin loss. When the assembling microtubule end was pulsed with 3H-GTP at steady state, the label was almost completely retained during a subsequent chase. We conclude that the microtubule assembly-disassembly "equilibrium" is a steady state summation of two different reactions which occur at opposite ends of the microtubule, and that assembly and disassembly occur predominantly and perhaps exclusively at the opposite ends under steady state conditions in vitro.


Inhibition of mycoplasma cell division by cytochalasin B. Mycoplasma gallisepticum has subcellular organelles which may function as a primitive "mitotic-like" apparatus. To investigate these further, we have studied the effects of cytochalasin B (CB) on M. gallisepticum. We found that CB inhibits cell division; this is the only procaryote thus far reported to be inhibited by CB. CB does not inhibit glucose or macromolecule precursor uptake. It stops cellular DNA synthesis, however, although RNA and protein synthesis continue (at a reduced rate). CB removal results in a resumption of DNA synthesis, followed by cell division. There appears to be some degree of cell synchrony in this first division after CB removal. These results, together with morphological data, indicate that CB blocks at two points in the cell cycle: at the time "mitotic-like" structures are formed and at the time of cell division. It is suggested that the CB blocks may result from a disruption of actin-like protein structures required at these points in the cell cycle.


The primary sequence of a crustacean satellite DNA containing a family of repeats. The repeating sequence of isopycnic twin Satellite II of the hermit crab, Pagurus pollicaris, has been determined. More than 95% of the primary sequence of the light strand is composed of (CAG)nCTGCACT. The only detectable variation on the repeating sequence is the number of CAGs included in each repeat which varies from 3-12. The sequence of Satellite II differs markedly from that of its twin, whose light strand is greater than 95% CCTA (Skinner et al., 1974). The absence from Satellite II of repeats where (CAG)n less than or equal to 2 further defines the constraints on a recent model for the origin of satellites (Smith, 1976).


Diameter of afferent arterioles during autoregulation estimated from microsphere data in the dog kidney. Afferent arteiolar diameters, relative flow distribution, and flow conductance factors are estimated by nonlinear regression analysis of the sieving effect on microspheres in different vascular structures of the dog renal cortex. The data presented are from experiments in which microspheres of 10-30 microgram were injected into the abdominal aorta during normotension and after lowering the blood pressure to the lower limit of autoregulation. Microscopic examination of the spheres trapped in the glomeruli and the renal arteries showed an increasing exclusion of microspheres greater than 15 micrometer from the afferent arterioles during normotension. This effect was most pronounced for the deeper cortical layers and can be explained mainly as geometrical exclusion of spheres from afferent arterioles. During hypotension, progressively larger microspheres entered glomeruli and afferent arterioles, presumably due to vasodilation of the vessels. There was a significant redistribution of microspheres larger than 15 micrometer from the outer to the inner cortex during hypotension without a corresponding redistribution of smaller spheres or the estimated blood flow. Approximately the same degree of dilation of afferent arterioles was observed during autoregulatory hypotension in three cortical layers.


Effects of bilateral and unilateral stellate stimulation on canine ventricular refractory periods at sites overlapping innervation. The efffects of unilateral right, unilateral left, and bilateral stellate stimulation on ventricular refractory periods at sites of overlapping cardiac sympathetic innervation were studied in 11 pentobarbital anesthetized dogs. The stellates were stimulated with 10 Hz pulses 4 msec in duration with intensities strong enough to produce T wave changes in a vertical ECG lead and just below the intensity at which control of drive of the ventricle at a 400-msec cycle length was lost. Refractory periods shortened more with left stellate stimulation, 17.8 +/- 5.9 msec (mean +/- SD) than with right stellate stimulation, 10.3 +/- 5.1 msec, P less than 0.001. During bilateral stimulation, shortening of refractory periods was no greater whether stimulation was applied first to the left and then right stimulation was added, 19.7 +/- 6.9 msec, or the stimulation was applied first to the left and then right stimulation was added, 18.3 +/- 6.5 msec. The shortening of refractory periods with bilateral stellate stimulation was not significantly different from that with left stellate stimulation alone. The results of this study suggest that ventricular recovery properties in areas of overlapping cardiac sympathetic innervation are less influenced by increases in tone of the right sympathetics than by increases in left sympathetic tone. In addition, the findings indicate that a bilateral increase in cardiac sympathetic tone has no greater effect on recovery properties than the effects of the left cardiac sympathetics alone.


Mechanism of suppression of renin secretion by clonidine in the dog. The mechanism by which clonidine suppresses renin secretion was investigated in pentobarbital-anesthetized dogs in which renal perfusion pressure was controlled by means of an aortic clamp. Clonidine (30 microgram/kg, iv) lowered mean arterial pressure (MAP) from 124 +/- 8 to 104 +/- 4 mm Hg (P less than 0.01) and reduced plasma renin activity (PRA) to 32 +/- 4 percent of the control value (P less than 0.01) after 60 minutes. Ganglion blockade with pentolinium (3 mg/kg, im) decreased MAP from 148+/- 7 to 117 +/- 3 mm Hg (P less than 0.01) and reduced PRA to 55 +/- 13 percent of the control value (P less than 0.05) after 45 minutes. Pentolinium converted the hypotension produced by clonidine to hypertension (108 +/- 9 to 146 +/- 10 mm Hg at 60 minutes, P less than 0.05) and abolished the suppression of PRA (105 +/- 14 percent of control at 60 minutes, P less than 0.05). In a further series of experiments, the effects of oxymetazoline, an alpha-adrenergic receptor agonist which is closely related to clonidine but which does not cross the blood brain barrier, were studied. Oxymetazoline (10 microgram/kg, iv) increased MAP from 127 +/- 3 to 154 +/- 2 mm Hg (P less than 0.01) and elevated PRA TO 176 +/- 22 percent of the control value (P less than 0.02) after 30 minutes. A higher dose of oxymetazoline (30 microgram/kg) increased MAP from 129 +/- 10 to 161 +/- 9 mm Hg (P less than 0.05) and increased PRA to 256+/- 37 percent of control (P less than 0.05) after 30 minutes. Taken together, these data support the hypothesis that the inhibition of renin secretion by clonidine results from a centrally mediated decrease in sympathetic neural activity.


Effects of norepinephine, calcium, and rate of discharge on 42K movements in canine cardiac Purkinje fibers. We studied the effect of norepinephrine, calcium concentration, and rate of discharge in the presence of different [Ca2+]0 on radioactive potassium movements in cardiac Purkinje fibers. The following results were obtained: (1) norepinephrine increases potassium uptake in quiescent fibers and in fibers driven at constant rate, but more in the latter; (2) norepinephrine also increases potassium uptake in quiescent fibers depolarized at the plateau; (3) increasing [Ca2+]0 increases potassium uptake in fibers driven at constant rate; (4) increasing [Ca2+]0 may decrease K+ uptake in quiescent fibers; (5) increasing [Ca2+]0 decreases the rate of loss of tissue radioactivity in quiescent fibers and increases it in a driven fiber; (6) increasing the driving rate increases potassium uptake in low and high [Ca2+]0; (7) high [Ca2+]0 increases K+ uptake, especially at low rates; (8) norepinephrine is less effective in increasing K+ uptake in the presence of a high [Ca2+]0. We conclude that: (a) norepinephrine increases potassium uptake by different mechanisms; (b) calcium affects potassium movements when it is allowed to enter the cell, presumably by affecting potassium conductance; (c) the effect of an increased rate of discharge on K+ uptake may involve stimulation of active K+ uptake and may include a calcium-dependent component which is largest at high [Ca2+]0 and a slow rate of drive; (d) simultaneous application of two interventions results in a summation that is smallest when one of the mechanisms is already substantially activated.


Determination of chromium sesquioxide in faeces by a spectrophotometric method. Chromium sesquioxide Cr2O3, present as a non-absorbable marker in faeces, may be determined spectrophotometrically as chromate ion in aqueous solution after ashing and alkaline fusion. Recovery of this substance is excellent. The method described is simpler, more suited to the clinical laboratory and less hazardous than previously reported methods.


Glomerular basement membrane collagen and activities of the intracellular enzymes of collagen biosynthesis in congenital nephrotic syndrome of the Finnish type. The composition of pepsin-solubilized glomerular basement membrane (GBM) collagen was studied in kidneys from patients with congenital nephrotic syndrome of the Finnish type (CNF). The 3-hydroxyproline content in the GBM collagen in CNF was only about one half of that noted in the controls. The alanine content was slightly higher in CNF, but no differences were found in the contents of the other amino acids or carbohydrates. Analysis of the GBM collagen by sodium dodecyl sulphate polyacrylamide gel electrophoresis after reduction indicated a lower proportion of one of the major polypeptide chains in CNF than in the controls, while a higher proportion of one low molecular weight minor component was noted. The activities of the five intracellular enzymes of collagen biosynthesis, including prolyl 3-hydroxylase, were not significancy altered in the CNF kidney cortex samples when compared with the controls.


The derivation of reference ranges adjusted for age, sex and other variables. A method for deriving reference ranges has been developed that has wide applications in clinical medicine. Data that is not homogenous but has subgroups (e.g. age, sex or social class) can be analysed and mean values for the subgroups determined. Facilities are included which enable outliers to be identified and the form of the distribution to be examined.


Lanthionine detected in human urine.

Lanthionine detected in human urine. Lanthionine has been detected incidentally in the urine of a patient with an abdominal pseudo-tumor, possibly caused by a Yersinia infection. The L- and/or D-form together with the meso-form were present. The identity of the amino acid was confirmed by GC-MS of the N-trifluoroacetyl methyl ester derivative. The abnormal amino acid was thought to be not of endogenous origin. The possibility that it was produced by gut bacteria is considered.


Electronic pipetting device for repetitive deliveries. An automatic pipette for dispensing liquids is described. It is simple to operate and deliveries show a precision of 0.2% or better for volumes ranging between 2 and 50 ml, the dispensing rate depending upon pipette used.


The stability of dopamine-beta-hydroxylase activity in blood samples. Dopamine-beta-hydroxylase activity was measured in serum samples that were incubated at 37 degrees C for up to seven days and were compared with preincubation values. No change of activity was observed.


Automated immunoprecipitation of meconium albumin for cystic fibrosis screening in the newborn. Cystic fibrosis is the most frequent substantially lethal inherited disease in the United States. Newborn screening for cystic fibrosis has been suggested because early diagnosis permits genetic counselling of parents and improved treatment and prognosis for cystic fibrosis patients. The fact that cystic fibrosis newborns have abnormally high meconium albumin seems to offer the best screening approach. Because we have had equivocal and false positive results with meconium albumin test strips, we have developed a nephelometric automated immunoprecipitation method for the quantitative and specific analysis of meconium albumin. On a total of 3895 meconiums so far examined, eleven albumin elevations of undetermined origin have been detected. Nine of these were associated with prematurity. There have been, so far, no detected true positives and no known false negatives. The normal range for meconium albumin is in agreement with previously published ranges determined using manual immunochemical methods. This method is rapid and economic. The question of sensitivity, specificity and predictive value of this and other detection methods is discussed.


Improved assay procedures for thyroid peroxidase; application to normal and adenomatous human thyroid tissue. We have developed assays for thyroid peroxidase in crude thyroid tissue preparations, in which a linear relationship between activity and amount of tissue could be demonstrated. Linear assays were developed based on the following peroxidase catalyzed reactions in the presence of H2O2:(1) oxidation of I- to I(-3), (2) oxidation of guaiacol, and (3) iodination of human goiter thyroglobulin. To attain satisfactory linearity we found it necessary to solubilize the enzyme beforehand. This was accomplished by a brief treatment of the particulate fraction with trypsin and deoxycholate, followed by centrifugation at 40 000 X g and dialysis. Not only did this treatment facilitate the development of linear assays, but it also resulted in a substantial increase in enzyme activity compared with that in the untreated particulate fraction. The use of a Polytron homogenizer for the initial disruption of the tissue also proved helpful in developing these assay procedures. The three different assays were used to measure peroxidase activities in human thyroid adenomas and in normal tissue derived from adenomatous glands. T he adenomas generally displayed a higher level of peroxidase activity than normal tissue. The greatest difference was observed with the iodination assay and the smallest difference with the guaiacol assay.


Myotonic dystrophy: studies on the lipid composition and metabolism of erythrocytes and skin fibroblasts. With the aim of establishing the underlying biochemical lesion in myotonic dystrophy, the lipids of plasma and of the membranes of erythrocytes and cultured skin fibroblasts were investigated in patients with this disorder and normal age- and sex-matched controls. No qualitative or quantitative differences could be detected in the lipid constituents of either plasma or erythrocytes from patients and controls. Similar growth characteristics and levels of sodium [1-14C]acetate incorporation were found in skin fibroblasts from both groups when grown in medium supplemented with either normal serum or delipidated serum. It is concluded that despite the previous evidence that drug induced myotonia results from a primary disturbance of membrane lipids, and suggestions that myotonic dystrophy might have a similar basis, our results did not support this hypothesis. They do not however exclude a primary membrane enzyme abnormality as the basic defect for the disorder.


Further observations on the differential precipitation of alkaline phosphatase isoenzymes by ethanol. The proportions of the total activities of different isoenzymes of human alkaline phosphatase precipitated from serum by ethanol (20% v/v) were: liver phosphatase, 37%; placental phosphatase, 23%; bone phosphatase, 8.0%, and small-intestinal phosphatase, 3.7%. Treatment of the isoenzymes with neuraminidase reduced the percentages of non-intestinal phosphatases precipitated by ethanol to below 10%. Precipitation of intestinal alkaline phosphatase was unaffected by this treatment. The degree of solubility in ethanol therefore appears to be largely determined by the content of terminal sialic acid residues in the alkaline phosphatase molecules. In contrast the stabilities of the isoenzymes to heating at 56 degrees C were not significantly altered by neuraminidase digestion.


Comparisons of the concentrations of palmitate and cortisol in amniotic fluid for the prediction of pulmonary maturity. The concentrations of palmitic acid, derived from lecithin, and of cortisol in samples of amniotic fluid collected during the last trimester of human pregnancy, ranged from 28 to 420 mumol/l and from 16 to 104 nmol/l, respectively. There was a weak (r = 0.43) but significant (p less than 0.01) correlation between the concentrations of cortisol and palmitate in the samples. Measurement of the cortisol concentration in amniotic fluid provided an unreliable index of pulmonary immaturity, whether this was assessed with reference to the concentration of palmitate or from subsequent development of the respiratory distress syndrome. Measurement of cortisol in amniotic fluid cannot be recommended for this purpose.


A simplified procedure for the analysis of cholesterol, phospholipids and bile salts in human bile. Cholesterol, total bile salts and phospholipids have been measured on alcoholic extracts from human bile-rich duodenal contents. Folch extraction before phospholipid assay was found to be unnecessary and, unless fresh samples are used, it is liable to give misleadingly low values. Removal of bile pigment before measuring cholesterol was unnecessary because this estimation was done by gas-liquid chromatography. The methods described provide a simple, reproducible analysis of bile lipids.


Radioimmunoassay for saralasin by means of anti-angiotensin II sera. A radioimmunoassay for the angiotensin II-inhibitor saralasin has been developed. The assay is based upon an exploitation of the cross-reactivity of antisera raised against angiotensin II, with radioiodinated saralasin as the tracer peptide. Performance data for the assay and results obtained in clinical infusion studies are presented.


The uri nary excretion of 2-phenylethylamine in phenylketonuria. The urinary concentrations of free and conjugated 2-phenylethylamine were determined in phenylketonuric patients and normal subjects by solvent extraction and gas chromatography. Free 2-phenylethylamine excretion was found to be significantly elevated above normal in phenylketonuric adults and children receiving a normal or a slightly restricted intake of phenylalanine. Urinary 2-phenylethylamine was also significantly increased in phenylketonuric children receiving low phenylalaine dietary therapy. Conjugated 2-phenylethylamine excretion was found not to be increased above normal. In the light of these results, a relationship between blood phenylalanine concentration and 2-phenylethylamine excretion is proposed, and the possible role of this amine in phenylketonuria is discussed.


Nuclear binding of triiodothyronine and thyroxine in lymphocytes from subjects with hyperthyroidism, hypothyroidism and resistance to thyroid hormones. Binding of triiodothyronine (T3) and thyroxine (T4) to nuclei of intact human lymphocytes was studied. The binding characteristics were analysed by Scatchard's method. In lymphocytes from euthyroid healthy subjects there was a single set of saturable nuclear T3 and T4 binding sites with an apparent mean equilibrium association constant of 3.3 X 10(10) l/mol and 1.7 X 10(10) l/mol, respectively. The estimated mean maximal specific binding capacity for T3 was 50 fmol/mg DNA and for T4 was 55 fmol/mg DNA, indicating that these two hormones may have a common receptor. In hyperthyroid and hypothyroid patients nuclear affinity for T3 and T4 was very similar to that for euthyroid reference subjects. In hyperthyroidism, T3 and T4 binding capacity was unaltered, whereas in hypothyroidism it was nearly twice as high as in euthyroidism. Lymphocytes from three members of a family with hereditary peripheral resistance to thyroid hormone action were studied. One set of saturable T3 and T4 nuclear binding sites with affinity constants similar to those in the euthyroid group was found. However, in these subjects the estimated binding capacity for T3 and T4 was rather low, indicating that the biochemical defect in this family might be a mild deficiency of nuclear receptor protein. Incubation with diphenylhydantoin and salicylate added in vitro did not alter the binding of T3 and T4 to lymphocyte nuclei. Nuclear binding was also not affected in patients receiving therapeutic amounts of diphenylhydantoin.


A routine method for determination of glycine and taurine distribution in bile acids. A procedure is described in which the content of glycine and taurine in bile acids is determined. Following an alkaline hydrolysis, the amino acids are separated on a column of Dowex 50-X8 and quantitatively estimated by a ninhydrin colorimetric method. The taurine/taurine + glycine ratios in a series of samples were determined by this method and by an enzymatic bile acid analysis and a good accordance between the two methods was obtained.


Skin porphyrin assay in porphyria.

Skin porphyrin assay in porphyria. The analysis of skin porphyrins in biopsies in patients with porphyria cutanea tarda has been achieved by high pressure liquid chromatography. Porphyrins were determined as their methyl ester copper-chelates and 2-,4-,5-,6-,7- and 8-carboxylic porphyrins distinguished and quantified.


Abnormal electrophoretic pattern of albumin in diabetic sera. Human sera collected from normal subjects and diabetic patients were electrophoresed in an urea-containing gel. The albumin fraction separated into several bands. In normal fasting serum the fast-migrating Bands 1 and 2 were observed and the slower-migrating Bands 4 and 5 did not appear. After glucose administration Band 1 disappeared and Bands 4 and 5 appeared for the first time. In diabetic serum Bands 4 and 5 did not appear before or after glucose administration and this abnormality resembles the pattern in C57BL/KsJ-db/db mice but not C57BL/6J-ob/ob mice.


Serum ferritin and iron stores during pregnancy. The iron status of two groups of pregnant women was investigated. One group did not receive iron (group B), the other erceived 100 mg iron/day (group A). 1. In all individuals concentrations of hemoglobin, serum iron, transferrin and serum ferritin were determined at regular intervals from the third month until delivery and at 3 months after delivery. The same determinations were performed in cord blood. 2. Changes in iron status appeared to be less in individuals with iron supplement than in those without iron supplement. A fall in Hb, serum iron and serum ferritin is observed in all individuals. 3. Three months after delivery the Hb concentration has generally returned to the normal female value, but the serum ferritin concentration is still very low. 4. The fetus does not discriminate as to the iron status of the mother. In both groups (A and B) cord blood values appeard to be not significantly different.


A reappraisal of the Coulter Counter technique for measuring calcium oxalate crystal size. A modification of the technique for measuring crystal size using a Coulter Counter is described. The method differs from that previously published in that counts are taken at equal size increments rather than at constant threshold settings. This ensures that equal emphasis is placed on all particles, regardless of size, thereby preventing the contribution of the larger particles being artificially magnified in relation to the smaller particles as has previously been the case. A mixture of latex particles of three known sizes is used to demonstrate the improvement in resolution and accuracy afforded by the modified technique.


Absorption of nicotine from small cigars. The absorption of nicotine from cigars was measured in 7 male subjects who each smoked a single small cigar containing 14C-nicotine. The proportion of nicotine in the mainstream smoke delivered to the smoker's mouth was greater than that observed for cigarettes, but the proportion of nicotine in the cigar smoke which was retained by the smoker was about the same. The total dose of nicotine retained varied between 1 and 4.5 mg. Arterial plasma concentrations of nicotine were as high as those achieved by cigarette smoking but rose more slowly. Some nicotine from small cigars is absorbed by inhalation of the smoke into the lungs and some by buccal absorption.