Abstract: The relationship between plasma concentration of nortriptyline and therapeutic effect after two weeks' treatment with the drug was investigated in 29 psychiatric inpatients. Endogenous depression was diagnosed in all patients. Amelioration of depressive symptoms was estimated as reduction in score on a rating scale, based on a psychiatric interview. Amelioration was not correlated to the patient's sex or age. There was a curved relationship between plasma level of nortriptyline and therapeutic effect. Amelioration was most pronounced in the intermediate plasma level range (50-139 ng nortriptyline/ml plasma) and was slight both at lower and at higher plasma levels. This type of relationship may be due to the dual action of tricyclic antidepressants which has been found in animal experiments. On larger dosages a phenothiazine-like blockade of the monoaminergic receptor is added to the blockade of monoamine reuptake thought to be related to the antidepressant action of the drugs.THIS STUDY THUS SUGGESTS TWO POSSIBLE REASONS FOR A THERAPEUTIC FAILURE WITH NORTRIPTYLINE: a too low or a too high plasma level. The large individual variation in the pharmacokinetics of the tricyclic antidepressants makes prediction of plasma level from dosage in a given individual virtually impossible without knowledge of rate of elimination and apparent volume of distribution. Hence monitoring plasma levels may be a way to increase the efficacy of treatment with these drugs.

Abstract: Subdural haematoma is one of the commonest features of the battered child syndrome, yet by no means all the patients so affected have external marks of injury on the head This suggests that in some cases repeated acceleration/deceleration rather than direct violence is the cause of the haemorrhage, the infant having been shaken rather than struck by its parent Such an hypothesis might also explain the remarkable frequency of the finding of subdural haemorrhage in battered children as compared with its incidence in head injuries of other origin, and the fact that it is so often bilateral

Abstract: Massive pulmonary embolism was confirmed by pulmonary arteriography in 23 patients. All were seen between 2 and 48 hours after the onset of embolism and none had pre-existing cardiorespiratory disease. Fifteen were treated with streptokinase and eight with heparin. Factors which might influence prognosis and rate of resolution were similar in the patients in each group, and there was no significant difference between the groups in terms of pretreatment haemodynamic or arteriographic findings. Haemodynamic and arteriographic findings after treatment for 72 hours provided an objective measurement of resolution, which was significantly greater in the streptokinase-treated patients. There was no mortality in either group, but treatment had to be changed in two heparin-treated patients because of clinical deterioration. The principal complication of treatment, seen more often in the streptokinase-treated patients, was bleeding from cut-down or operation sites.

Abstract: 227 widows and 66 widowers were interviewed to determine the extent to which they had hallucinatory experiences of their dead spouse. The people interviewed formed 80.7% of all widowed people resident within a defined area, in mid-Wales, and 94.2% of those suitable, through the absence of incapacitating illness, for interview.Almost half the people interviewed had hallucinations or illusions of the dead spouse. The proportion of men and women who had these experiences was similar. The hallucinations often lasted many years but were most common during the first 10 years of widowhood. Social isolation did not affect the incidence of hallucination, nor was it related to the incidence of known depressive illness. There was no variation within cultural groups and there was no variation with place of residence, whether this was within town, country, or village, or within England and Wales.Young people were less likely to be hallucinated than those widowed after the age of 40. The incidence of hallucination increased with length of marriage and was particularly associated with a happy marriage and parenthood. Members of the "professional and managerial" group were particularly likely to be hallucinated, while widows of "non-manual and sales workers" were the ones least likely to be hallucinated. The incidence was greater with hysteroid than obsessoid people. It was unusual for the hallucinations to have been disclosed, even to close friends or relatives.These hallucinations are considered to be normal and helpful accompaniments of widowhood.

Abstract: A survey of 105 epileptic children aged 10-16 years at a residential school who were taking anticonvulsant drugs showed reduced serum calcium levels in 30% and a raised serum alkaline phosphatase in 24%. Urinary D-glucaric acid excretion, a quantitative index of hepatic enzyme induction, was raised in 94% of the children, and statistical analysis showed a significant inverse correlation with the level of serum calcium. These findings give further support for the view that an important factor in the development of the hypocalcaemia and occasional clinical osteomalacia in epileptics on anticonvulsant drugs is an alteration of vitamin-D metabolism in the liver as a result of microsomal enzyme induction. As a consequence there is an increased requirement for vitamin D which may not be met by average intakes in Britain.

Abstract: An in-vivo skin perfusion technique has been used to study the pharmacological activity in inflamed skin of patients with allergic contact eczema. Perfusates from 35 out of 45 patients contained a smooth-muscle-contracting agent with prostaglandin-like properties. Solvent partition followed by thinlayer chromatography revealed this activity to be due to a mixture of prostaglandins E and F. This direct evidence supports the view that prostaglandins mediate inflammation in man.

Abstract: This is a preliminary report of a co-operative study of 1,203 episodes of acute myocardial infarction in men under 70 years in four centres in the south west of England. The mortality at 28 days was 15%. A comparison is made between home care by the family doctor and hospital treatment initially in an intensive care unit: 343 cases were allocated at random. The randomized groups do not differ significantly in composition with respect to age; past history of angina, infarction, or hypertension; or hypotension when first examined. The mortality rates of the random groups are similar for home and hospital treatment. The group sent electively to hospital contained a higher proportion of initially hypotensive patients whose prognosis was bad wherever treated; those who were not hypotensive fared rather worse in hospital.For some patients with acute myocardial infarction seen by their general practitioner home care is ethically justified, and the need for general admission to hospital should be reconsidered.

Abstract: Daily rifampicin in a single dose of 600 mg, combined with other drugs, usually streptomycin and isoniazid, was given to 49 patients for three months. It was planned to continue for another 15 months with twice-weekly rifampicin 1,200 mg plus isoniazid 900 mg, but the high incidence of side effects led to cessation of the intermittent regimen when only two patients had completed 18 months.Though there was no serious problem with daily treatment 11 patients (22%) were unable to continue rifampicin on the intermittent regimen. In 8 (16%) a pyrexial syndrome occurred. In one of these patients there was also temporary renal failure, and in another precipitous thrombocytopenia led to epistaxis and bleeding into the tongue and lips. Symptomless thrombocytopenia developed in two other patients, making three cases (6%) of thrombocytopenia in all.In 16 (33%) of the 49 patients antibodies to rifampicin were detected in the blood. Side effects occurred in 9 (56%) of these, including the three developing thrombocytopenia, but in only 2 (6%) of the 33 patients with no antibodies detected. This association of toxic reactions with antibodies is highly significant (P<0.001).

Abstract: The double antibody radioimmunoassay of serum thyroid-stimulating hormone (TSH) allows measurement of circulating levels of the hormone in most normal subjects. The serum TSH level in normal subjects is 1·6 ± 0·8μU/ml. Patients with non-toxic goitre and acromegaly have normal TSH levels. Values are always raised in hypothyroid patients (with primary thyroid disease) and are significantly lowered in those with hyperthyroidism. Of the many stimuli used in an attempt to raise TSH levels in normal adult subjects only three—synthetic thyrotrophin-releasing hormone, ethinyloestradiol, and carbimazole plus iodides—have been effective. The major clinical application of the TSH immunoassay lies in the diagnosis of minor degrees of hypothyroidism. An impaired response of serum TSH to synthetic thyrotrophin-releasing hormone should also help in the diagnosis of hypopituitarism affecting TSH production.

Abstract: From in-vitro studies of breast and cow9s milk preparations, and of the faeces from breast-fed and bottle-fed infants, a number of factors seemed likely to influence the production and maintenance of a lactobacillary flora and low pH in the faeces of newborn infants. These were mainly attributable to the nature of the feed. It is suggested that responsible factors in breast milk include its high lactose, low protein, low phosphate content, together with its poor buffering capacity. Importance is also attached to the fact that breast milk seems to provide a fluid feed of small bulk and low residue, and that its use is unlikely to include periods of starvation. Cow9s milk, on the other hand, which has a low lactose, high protein, high phosphate content, and a high buffering capacity, is a relatively bulky, high-residue feed. Feeding regimens which employ it are likely to include periods of starvation.

Abstract: The coagulation and fibrinolytic mechanisms were investigated in a group of patients with severe pre-eclampsia and eclampsia and the findings were compared with those of healthy women in late pregnancy. In patients with pre-eclampsia the following significant differences were found: (1) greater depression of plasma fibrinolytic activity (euglobulin lysis time) than in normal pregnancy, (2) a higher level of inhibitor to urokinaseinduced lysis, (3) increased levels of serum fibrin degradation products, and (4) reduced platelet counts.In patients with eclampsia a progressive increase of the level of serum fibrin degradation products was found over the three days following eclamptic seizures. No such increase occurred after grand mal seizures in late pregnancy. The findings in this study support the view that intravascular clotting is taking place in pre-eclampsia and that this disturbance of the balance between coagulation and fibrinolysis may be localized to certain areas of the vascular compartment, particularly the placental and renal circulations. Fibrin deposition in the maternal vessels supplying the placenta would impair the placental blood flow, which may explain the placental insufficiency which occurs in pre-eclampsia. Likewise fibrin deposition in the renal vasculature will result in glomerular damage and proteinuria. Hypertension may be related to the renal ischaemic changes or a compensatory response to the presence of fibrin deposition in the vascular compartment. This evidence of intravascular fibrin deposition raises the question of the possible therapeutic value of antithrombotic agents to inhibit the clotting process. On a theoretical basis such treatment might be expected to improve blood flow to the placenta and thereby fetal growth.

Abstract: Liver function and histological changes in liver biopsies were studied in 37 patients who had been treated for psoriasis with methotrexate. Cirrhosis was found in seven (19%) and hepatic fibrosis of varying severity in 10 (27%). Minor abnormalities in another 17 (46%) consisted of fatty change, round cell infiltration, and extensive vacuolation of liver cell nuclei. In only three (8%) was hepatic histology entirely normal. The severity of liver damage was related to the duration of methotrexate treatment. Minor abnormalities of liver function tests and liver histology were also found in eight control psoriatic patients. Standard liver function tests were of little value in predicting the degree of liver damage. It appears that methotrexate, in the doses normally used to control psoriasis, may cause cirrhosis if treatment is prolonged and that liver biopsy is necessary for evaluation of liver damage in these patients.

Abstract: Ventilatory function after three types of exercise-running, cycling, and swimming-was studied in 10 control subjects and 40 asthmatic patients. All performed eight minutes of submaximal aerobic exercise during each of the programmes, which were conducted in a randomly selected order. Biotelemetric monitoring of heart rates was used to equate the intensity of the exertion undertaken during the three systems of exercise. No control subject showed any significant variation in ventilatory capacity after exercise, and the responses after the three forms of exercise did not differ.In asthmatics exercise-induced asthma was observed after 72.5% of running tests, 65% of cycling tests, and 35% of swimming tests. In addition, those patients who developed exercise-induced asthma after swimming were noted to have significantly smaller falls in FEV(1) levels than were recorded after running and cycling. These results were statistically significant (P <0.01).The unexplained aetiology of increased airways resistance after exercise in asthmatics is discussed. This study indicates that swimming should be recommended in preference to running or cycling as an exercise programme for adults and children with asthma.

Abstract: It has been estimated that there are over 100,000 patients with a permanent colostomy in Great Britain.' In 1957 and 1958 editorials in the B.M.J.2 3 asked \"How do these people fare ?\" and emphasized that the problem of colostomy management is of profound importance for many. Nevertheless, since the major postwar reforms of 1945-50 there has apparently been no comprehensive study of the long-term effects of permanent colostomy in Britain. We have had considerable experience with colostomy patients in a hospital environment but felt that the long-term effects of a colostomy were probably underestimated by many clinicians and by those concerned with the domiciliary health and welfare services. The present study was undertaken to find out the effects of a permanent colostomy in daily life and to define areas of unmet need which could be attributed to the colostomy.

Abstract: A double-blind placebo-controlled multicentre study with ritodrine, a β-mimetic uterine relaxant, has been performed in 91 patients in premature labour. All patients were treated according to a fixed dosage scheme consisting of an intravenous infusion followed by oral tablets for a total of seven days. Ritodrine arrested premature labour in 80%, the placebo in 48% of the patients (P=0·02). This short treatment, however, was usually not sufficient to prolong gestation till term. Apart from a slight to moderate rise in maternal heart rate and a slight rise in systolic blood pressure, ritodrine did not give rise to any maternal or fetal side effects. The problems of patient selection and of evaluation of the results are discussed.

Abstract: From human cancer tissue a basic protein can be extracted by the method which yields encephalitogenic factor when applied to human brain. This tumour basic protein (obtained from several different neoplasms) acts as an antigen in the cytopherometric test for malignant neoplasia and in general gives higher results than does brain basic protein. The reverse is true when degenerative disease of the nervous system is studied. The basic protein extractable from brain and from tumours thus has some degree of specificity probably referable to its amino-acid sequence.

Abstract: Plasma concentrations of testosterone were estimated in normal men, in patients before treatment for prostatic cancer, and in patients who had had various forms of endocrine treatment for prostatic carcinoma. There was no decline in plasma testosterone levels with age. Patients with non-metastatic disease had levels similar to those of normal controls, but in advanced metastatic disease the levels were low. After orchidectomy the plasma testosterone level fell to that found in normal women. In every patient stilboestrol in doses as small as 1 mg three times a day suppressed plasma testosterone at first to negligible amounts, irrespective of the clinical response. Subsequently a small but significant rise in the concentration was always observed over a period of six months9 oestrogen therapy. Pituitary ablation with yttrium-90 lowered the plasma testosterone concentration again to negligible amounts in patients who had been on stilboestrol. In advanced metastatic disease this was often associated with relief of pain. Preliminary studies with aminoglutethimide indicate that it can produce biochemical and clinical effects similar to those of pituitary ablation.

Abstract: The rate of absorption of gas from a pneumothorax was studied in 12 patients breathing air and in 10 patients breathing air and a high concentration of oxygen alternately. The mean rate of absorption while breathing air was the same in both groups of patients. In the second group the rate consistently increased during periods of oxygen therapy and decreased again on breathing air. The mean rate of absorption increased fourfold during periods of oxygen therapy. This increase was most pronounced in patients with a large pneumothorax.

Abstract: All patients presenting at the casualty department of King9s College Hospital during the first six months of 1968 with deliberate self-poisoning or self-injury were followed up. Of 211 patients 204 (97%) were traced after a mean interval of 18 months (range one to two years). Despite official hospital policy, 22% had not been seen by a psychiatrist before discharge; these 44 untreated patients were compared with the remaining 160 who had received either brief (one or two interviews) or more prolonged psychiatric and social help. Subsequent suicidal attempts occurred significantly more often among untreated than among treated patients, prolonged treatment being associated with the best prognosis. The same trend was observed in respect of actual suicide, though the numbers were small and differences did not reach statistical significance. These findings held good when the untreated and treated groups were controlled for other variables which were found to be correlated with outcome. These results indicate that psychiatric intervention is associated with a significant reduction in subsequent suicidal behaviour.

Abstract: A pilot study has shown that there is usually but not invariably a fall in systemic arterial blood pressure within 90 seconds of implanting acrylic cement into the femoral shaft during hip arthroplasty. There is usually no change in arterial blood pressure on implanting acrylic cement into the acetabulum. The observed hypotension may be due to absorption of monomer or additives into the circulation, but the role of other factors needs investigation.

Abstract: A microculture technique has been adapted to assay the cytotoxic properties of the lymphocytes from patients with malignant melanoma when cultured with their autologous tumour cells. In a series of patients with established melanoma specific autologous cytotoxicity was extremely uncommon, being detectable in only 3 out of the 22 cases studied. This cytotoxicity did not correlate with clinical staging of the disease but may well have been related to tumour volume. By autoimmunization of patients with an irradiated suspension of their own tumour cells the appearance of cytotoxic lymphocytes could be provoked in 5 out of the 12 patients studied. This cytotoxicity was detectable at the end of the first week after the autograft and disappeared by the third week. Cytotoxic lymphocytes did not correlate in any obvious way with the appearance of specific antitumour antibodies detected by immunofluorescence. So far there has been no evidence of a serum factor capable of blocking the lymphocyte cytotoxicity in these patients.The presence and possible significance of cytotoxic lymphocytes in patients with malignant disease is discussed.

Abstract: House dust from high mountainous areas of Switzerland contains very few house-dust mites. In contrast to lower-lying regions, only very small quantities of house-dust allergen are found at high altitudes. The cause of this phenomenon seems likely to be the climatic conditions in the high mountains of Europe, where cold air leads to extremely low humidity levels indoors. The soil conditions and a type of construction providing good protection against the penetration of water also contribute to dry conditions in houses. These factors prevent the development of large populations of allergen-producing house-dust mites. The beneficial effect of a stay at high altitudes on patients with atopic asthma is probably due to the low concentrations of house-dust allergen.

Abstract: The diagnosis of primary cancer of the liver was reviewed in 75 patients. A definitive diagnosis was made during life in 63% and in a further 20% this condition was suspected though histological confirmation was obtained only at necropsy. The most common presenting complaints were abdominal pain and weight loss and the most frequent findings hepatomegaly and ascites. Less than one-half of the patients were jaundiced and when present it was usually mild. An arterial bruit was heard over the liver in 25% of the patients. A sudden and unexplained deterioration in a patient known to have cirrhosis or haemochromatosis should raise the possibility of a primary hepatic tumour; this occurred in 24% of our patients.Alpha-fetoprotein was found in the serum of 11 out of 18 cases. The presence of a mass in the liver was frequently confirmed by liver scan, portal venography, or hepatic arteriography, but these showed no features diagnostic of a primary tumour. Liver scan also proved useful in localizing the lesion for biopsy purposes. Definitive diagnosis is dependent on the histological demonstration of the features of the tumour. This can frequently be achieved by percutaneous needle biopsy, which was positive in 38 out of 57 patients. Wedge biopsies were positive in a further nine patients.

Abstract: The plasma propranolol levels associated with the abolition of chronic, stable ventricular ectopic beats have been studied. Racemic propranolol (DL) suppressed the ectopic foci at plasma levels of 40-85 ng/ml in eight patients, but levels of 70-200 ng/ml were unsuccessful in four patients. Dextro-(D) propranolol levels of 180-310 ng/ml were ineffective in four patients who had previously responded at levels of 60-75 ng/ml of racemic propranolol. The significance of the sympathetic nervous system in the genesis of ectopic beats is discussed. It is concluded that propranolol is clinically effective by virtue of its beta-adrenergic blocking activity.

Abstract: tamicin and kanamycin. Blood culture also grew E. coli and Staph. aureus. Treatment with gentamicin and cloxacillin was started and within a few days the swelling of the knee abated and the baby started to move the leg. The tip of the big toe demarcated into dry gangrene, which separated on 9 May. The antibiotics were stopped after four weeks when the leg appeared normal and x-ray examination showed that the infection had settled. The baby was discharged home on 18 May when 11 weeks old and weighing 3,410 g.

Abstract: The integrity of the autonomic nervous system was assessed in 11 Parkinsonian patients with symptoms suggestive of autonomic dysfunction. Three had the additional clinical features of the Shy-Drager variant of idiopathic orthostatic hypotension and were found to have a gross disturbance of vasomotor, sudomotor, pilomotor, and bladder function; assessment indicated that a lesion was present at sympathetic ganglionic level or beyond in two cases, though a more centrally placed lesion may well have been present also, as in the third case. In the remaining eight patients with paralysis agitans no unequivocal functional disturbance was found except in the bladder; nevertheless, the low resting blood pressure and the supersensitivity to intravenously infused L-noradrenaline in the three patients in whom it was tested is taken to imply defective regulation from higher centres, with a consequent reduction in impulse traffic at sympathetic nerve terminals. Such a concept is supported by experimental studies in animals and would account for the low renin and aldosterone secretion rates and reduced noradrenaline formation reported by others in patients with paralysis agitans.

Abstract: Estimation of plasma glucose and immunoreactive insulin concentrations in normal subjects after an overnight fast showed that subjects with high basal plasma glucose levels tended to have high plasma insulin concentrations. A similar correlation between glucose and insulin levels was seen in patients with obesity and various endocrine disorders. The suppression of plasma insulin levels associated with hypoglycaemia was used to derive an “amended insulin-glucose ratio,” which appeared to be a good discriminant for the diagnosis of insulinomas. In normal subjects the ratio was less than 30 μU insulin/mg glucose, in obese subjects less than 50 μU/mg, and most of the patients with insulinomas had values over 200 μU/mg.

Abstract: A large-scale survey of steel workers in South Wales has shown a considerable difference between the body weights of smokers and of non-smokers. The difference increases with age so that men over 40 years who have never smoked are on average 13 lb (5·9 kg) heavier than smokers. Even so, smokers are about 15 lb (6·8 kg) heavier than the weight standard considered desirable by the Metropolitan Life Insurance Company, while non-smokers are nearly 30 lb (13·6 kg) heavier. About 20% of the men are attempting to give up the smoking habit. Ex-smokers who have given up smoking for more than eight years approach the body weight of men of the same age who have never smoked. Many reports have been published on the health consequences of smoking and of obesity. Because smoking and obesity are inversely related studies of the interrelation of these two health hazards and of their relative importance are needed.

Abstract: A 22-year-old woman with primary hypothyroidism developed amenorrhoea and galactorrhoea during oral contraceptive therapy. Investigation showed high levels of circulating prolactin which rose in response to insulin-induced hypoglycaemia and were suppressed by an oral glucose load. After treatment with thyroxine normal periods returned, the galactorrhoea improved, and the prolactin levels fell to undetectable levels. The results of the prolactin and human growth hormone assays confirm that it is possible to distinguish between human growth hormone and human prolactin.