Haemodynamic consequences of citrate infusion in the anaesthetized dog: comparison between two citrate solutions and the influence of beta blockade. We have compared the effects of a solution of acid--citrate--dextrose (ACD) with those of a solution of citrate--phosphate--dextrose (CPD), infused at equal rates, on blood calcium ion concentration and different indices of haemodynamic performance in 17 dogs. The influence of beta adrenergic blockade on these changes was examined. The effects of ACD and CPD were studied in five dogs and were similar. Peripheral vascular changes were the principal cause of arterial hypotension. In six dogs, propranolol 0.5 mg kg-1 intensified the hypocalcaemia-induced left ventricular dysfunction.


Experience with spinal analgesia in a British obstetric unit. A series of 443 spinal anaesthetics is described. The procedures included operative vaginal delivery, removal of retained placenta and a miscellaneous group common to most obstetric units. Failure to provide effective relief of pain occurred in 5.2% of patients. There was one potentially serious complication, but with this exception hypotension was not a feature. Headache following spinal analgesia was experienced by 16.3% of patients, the frequency being greater among those who received spinal analgesia at or shortly after delivery, but was unrelated to the size of the needle (23-gauge of 25-gauge) used. Extradural blood patch promptly and permanently cured the headache. The duration of sensory and motor loss after operation varied considerably with the local anesthetic agent used. The re-introduction of spinal analgesia into British obstetric anaesthetic practice is advocated.


Diazepam and droperidol as i.v. premedicants. The effects of i.v. diazepam and droperidol both alone and in combination administered as premedication were studied in 240 patients. Relief of anxiety, sedation, lack of recall, acceptance by both patient and physician and side-effects were evaluated. Overall, the combination of droperidol 2.5 mg with diazepam 5 mg produced better ratings of these variables than could be achieved with either droperidol 10 mg or diazepam 10 mg alone. Larger doses of droperidol with diazepam produce an increased frequency of anxiety; larger doses of diazepam with droperidol may cause over-sedation.


Cardiorespiratory changes following induction of anaesthesia with etomidate in patients with cardiac disease. The cardiorespiratory effects of etomidate were measured in two groups of six patients with aortic or mitral valve disease. The induction of anaesthesia with etomidate 0.3 mg kg-1 was followed by a second dose 10 min later. After the first dose, a 19% decrease in systemic arterial pressure was associated with a decrease in systemic vascular resistance and left ventricular heart work. Cardiac index, pulmonary artery pressure and wedge pressure all decreased slightly. Central venous pressure and heart rate did not change. A slight increase in respiratory frequency failed to prevent an increase in PACO2. Changes after the second dose were similar. The two groups of patients did not differ significantly in their response to etomidate. No patient complained of pain during injection, nor did myoclonic movements occur.


Absorption and excretion of rapid and slow release oxprenolol and their effects on heart rate and blood pressure during exercise. 1. Plasma concentrations and heart rate and blood pressure effects of 160 mg oxprenolol as standard rapid release (RR) and slow release (SR) tablets were compared in healthy volunteers. Peak plasma concentrations were lower with SR tablets than with RR tablets and the peak was delayed. 2. Absorption of oxprenolol was described adequately by first order kinetics with both preparations. The apparent half-life of absorption was 0.40 h with RR and 2.4 h for the SR formulation. The apparent elimination half-life of oxprenolol was about 2 h. Relative bioavailabilities of the two formulations were similar. 3. The effectiveness of oxprenolol RR and SR were assessed by their effects on heart rate in severe exercise (EHR) and also by their effects on blood pressure at rest and during exercise. 4. Maximum reductions in these variables coincided with peak oxprenolol concentrations. The effects on EHR and blood pressure parameters had a distinct time course but there was no difference between the time course of inhibition of each variable for the two formulations over 24 h.


Bioavailability and disposition of metoprolol and hydrochlorothiazide combined in one tablet and of separate doses of hydrochlorothiazide. 1. The plasma levels and the urinary excretion of hydrochlorothiazide (HCT) have been studied after administration of single doses of 12.5 and 25 mg of the drug in solution and in combination with 100 mg of the selective beta 1-adrenoreceptor antagonist metoprolol in a rapidly dissolving tablet. 2. Metoprolol did not significantly influence the bioavailability or the time-course of HCT. 3. HCT had no significant effect on the time-course or the plasma levels of metoprolol. The average half-life, 4.4 +/- 0.9 h, is about the same as previously observed for separate doses of this drug. 4. It seems unlikely that repeated doses of the combination product studied will lead to biopharmaceutic or pharmacokinetic interactions of clinical importance.


Pharmacokinetics, pharmacology of atenolol and effect of renal disease. 1. The pharmacokinetics of intravenous and oral atenolol (50 mg) in six healthy volunteers was studied. Plasma, saliva and urine were collected up to 24 h after each dose. 2. There was no significant difference in atenolol half-life when administered by the two routes. Bioavailability of the orally administered atenolol was 50%. 3. Atenolol levels in saliva required about 2 h to reach equilibrium with plasma drug levels. 4. A comparison between the pharmacokinetics and pharmacology of atenolol was made in twelve healthy subjects. 5. Dose-independent pharmacokinetics were observed. Reductions in resting heart rate and arterial blood pressure were proportional to either the logarithm of dose or area under the plasma concentration time curve or cumulative urinary atenolol excretion. 6. Plasma elimination half-life in five subjects with renal failure was prolonged.


Interaction of atenolol and adrenaline with respect to intraocular pressure. 1. The effects of topically administered atenolol 4% and adrenaline 1% on intraocular pressure (IOP) were investigated in fourteen healthy male human volunteers. Both the sole and combined effects of single doses of the formulations were recorded over a 7 h period. 2. Adrenaline and atenolol both produced significant reductions in IOP when compared to the placebo control, although the pattern of response differed. 3. Adrenaline had a rapid onset of action, resulting in a significant pressure reduction by 45 min post drug administration. A small upswing in IOP then occurred between 45 and 90 min, followed by a prolonged secondary reduction phase. 4. Atenolol produced a gradual reduction in IOP which reached a maximum at 180 min post drug administration and subsequently declined between 300 and 420 min. 5. Combined treatment with atenolol and adrenaline resulted in additive effects up to 180 min, and the early pressure upswing recorded with adrenaline was completely abolished. 6. The results are compatible with the hypothesis that beta 1-adrenoceptor stimulation elevates intraocular pressure. The correlation of these results with relevant animal and human pharmacological data is discussed.


Pharmacokinetics of hydrochlorothiazide in patients with congestive heart failure. 1. Hydrochlorothiazide (HCT, 50-75 mg) was administered orally to seven patients with cardiac failure. 2. Plasma levels and urinary concentration of HCT were determined by GLC. 3. The gastrointestinal uptake of the diuretic in three patients was reduced to approximately half that seen in healthy controls. 4. Plasma halflife of HCT was correlated with endogenous creatinine clearance. 5. Pharmacokinetics of HCT are considerably changed in cardiac failure.


Effects of aspirin and dimenhydrinate (Dramamine) on visual processes. 1. The effect of three doses of either aspirin (1280 mg each) or dimenhydrinate (Dramamine) (100 mg each) in an 8 h period on visual processes was investigated double-blind on sixteen volunteer subjects. 2. Tests included night-vision, colour-discrimination, stereoacuity and stereopsis, reaction-time, pupil size, eye-movements, visual evoked cortical potentials, electroencephalographs, a dial-reading task, and a test of texture discrimination. 3. Both drugs affected colour discrimination, and dimenhydrinate degraded night-vision, reaction-time, and stereopsis. 4. The effect of aspirin was minor, but the impairments produced by dimenhydrinate appear to be of practical importance.


N-Methyl-benzylamine, a metabolite of pargyline in man. 1. N-methyl-benzylamine was identified in human urine and plasma after the administration of pargyline in man. This metabolite was identified by thin layer chromatography mobility, gas chromatographic retention time and mass spectrum relative to authentic N-methyl-benzylamine. 2. [14C]-N-methyl-benzylamine, together with a small amount of [14C]-benzylamine, was formed in vitro from [14C]-pargyline when this was incubated with human and rat liver microsomes. 3. The urinary excretion rates of pargyline and its metabolite have also been described.


Plasma levels of 5-fluorouracil after oral and intravenous administration in cancer patients. 1. Plasma levels of 5-fluorouracil (5FU) have been determined in eleven cancer patients after 0.5 g and 1.0 g intravenous doses, and in one patient after paired 1.0 g oral and intravenous doses. 2. The plasma half-life after the 0.5 g intravenous dose was relatively constant, irrespective of the stage and spread of the disease. 3. Plasma kinetics of the drug were dose dependent. Doubling of the intravenous dose produced a 1.5-fold increase in plasma half life, a two-fold increase in initial plasma drug concentration, and a three-fold increase in area under the concentration/time curve. 4. In one patient receiving paired 1.0 g intravenous and oral doses nine weeks apart, an increase in the bioavailability of the drug coincided with a marked clinical regression in palpable intra-abdominal metastases. 5. The significance of measuring plasma drug kinetics and their relationship to drug efficacy and toxicity are discussed.


Influence of various antihypertensive agents on lifespan of renal hypertensive rats. 1 Daily treatment of two-kidney clipped renal hypertensive rats with hydrallazine, hydrochlorothiazide (HCTZ) and a new orally active inhibitor of the angiotensin-converting enzyme, captopril (SQ14,225), was correlated with survival rates for up to 9 months. 2 The groups of rats given captopril alone or captopril plus intermittent or chronic HCTZ had the best survival rate, whereas HCTZ alone or hydrallazine did not benefically affect survival. 3 Survival rates correlated well with control of BP in these animals.


Human pharmacology of narcotic antagonists. 1 Human studies at the Addiction Research Center enable narcotic antagonists to be classified into three subgroups: (1) nalorphine-like agents; (2) pure antagonists; and (3) morphine-like agents. 2 Six narcotic antagonists (pentazocine, nalbuphine, cyclazocine, butorphanol, propiram and buprenorphine) developed in recent years seem to have a lesser abuse potential than codeine or propoxyphene. 3 When adjusted for relative availability of the agents, epidemiological data shows that pentazocine is abused less than codeine or propoxyphene in the US. 4 Recent studies with buprenorphine indicate that this agent would find application both as an analgesic of low abuse potential and as a new type of drug for the treatment of addiction.


Pharmacological and clinical importance of narcotic antagonists and mixed antagonists--use in cardiology. 1 The treatment of pain of cardiac origin requires a knowledge of the haemodynamic action of the analgesic agents used. 2 The haemodynamic effects of morphine, diamorphine, pavaveretum, pethidine and pentazocine are reviewed. 3 Clinical experience with the new antagonist analgesic buprenorphine is reported. 4 These studies indicate that buprenorphine may be the agent of choice for the relief of severe pain in patients with unstable circulation.


Use of narcotic antagonists in anaesthesia. 1 The introduction of morphine antagonists into anaesthesiology has aroused great scientific interest, increased our knowledge of analgesia, and opened new frontiers for therapeutics. 2 The advantages and disadvantages of these compounds are described and assessed. 3 The best choices for treatment of pain are the most potent and long-acting drugs of this group with a wide safety margin. As an antidote to narcotic agonists, naloxone seems to be the most suitable drug in the majority of cases, although in certain conditions drugs having less rapid onset of action and of longer duration may be more desirable. 4 In all cases of treatment after anaesthesia when antagonists to narcotic analgesics are used, drug administration must depend on careful control, which necessitates specific and prolonged patient care by specifically trained and competent staff.


Side-effects of mixed agonist-antagonist analgesics used in sequential anaesthesia. 1 Mixed agonist-antagonist analgesics have analgesic action but also possess a range of side-effects. 2 Narcotic antagonists do not reverse the non-specific effects of opiates. 3 Under certain circumstances the effects of agonists and mixed agonist-antagonists can be additive. 4 Chronic dosage of mixed agonist-antagonists leads to a lower level of dependence than that observed with the standard narcotics. 5 Mixed agonist-antagonists may not antagonize the respiratory effects of narcotics and may result in potentiation of such depression.


Purification of a protein associated with human bronchogenic squamous-cell carcinoma. A heteroantiserum raised in rabbits to extracts of human squamous-cell carcinoma of the lung which exhibited marked tumour specificity was used to monitor the fractionation and isolation of a tumour-associated component of the extract. KC1 extracts of pools of both normal lung and bronchogenic squamous-cell carcinoma were subjected to a series of purification steps involving acid precipitation, salting out, DEAE chromatography and preparative polyacrylamide-gel electrophoresis. At each stage, fractions were tested for their ability to react in the complement-fixation assay with the antiserum. A protein was ultimately isolated  which did not appear to be present at detectable levels in an equivalent fraction of normal lung extract, reacted with the heteroantiserum, and appeared to be present in all extracts of squamous-cell carcinoma.


Effect of carrageenan on the non-specific resistance of mice to injected syngeneic tumour cells, alone or in mixtures. The mechanisms of non-specific resistance to syngeneic methylcholanthrene-induced fibrosarcomas of mice were investigated. Results showed that a small tumour graft of 0.05 X 10(5) cells is greatly enhanced in growth when admixed with large numbers of cell fragments, killed cells or viable non-replicating cells. The enhancement of small tumour grafts in cell mixtures was found to be non-specific. Carrageenan, a known anti-macrophage agent, significantly increased tumour growth in normal mice. However, it did not enhance the increased tumour growth of 0.05 X 10(5) cells mixed with 10(6) viable, non-replicating mitomycin C-treated tumour cells. The latter observation indicates that carrageenan and admixed cells interfere with the same tumour-inhibitory mechanism and therefore cannot produce additive effects. The results give support to the concept of a non-specific macrophage "surveillance" system which appears crucial in controlling tumour growth, since it determines the establishment of small numbers of tumour cells while they can still be easily destroyed.


Total urinary and free serum hydroxyproline in metastatic bone disease. The present study examines the possibility of correlation between free serum and urinary total hydroxyproline and whether this correlation can be applied to clinical conditions. The correlation between the two indices was 0.80 (P less than 0.001) in 18 patients, mostly suffering from malignant disease. On comparing the same measurements in 37 patients, all with known metastatic bone disease, we found 29/37 normal results for free serum hydroxyproline, whereas only 2/37 values of urinary total hydroxyproline were normal. The authors therefore conclude that urinary total hydroxyproline, measured as the ratio hydroxyproline/creatinine in a fresh specimen of early-morning urine, is the best index of collagen breakdown in metastatic bone disease and preferable to measurement of free serum hydroxyproline.


Descriptive epidemiology of testicular and prostatic cancer in Los Angeles. Data from the Los Angeles County Cancer Surveillance Program (CSP) from 1972 to 1975 were used to study the descriptive epidemiology of testicular cancer and prostatic cancer. The very high black/white ratio and late age peak of cancer of the prostate contrasted sharply with the very low ratio and early age peak of testicular cancer. However, both sites had higher rates among upper occupational and social class groupings. Avalable descriptive and analytical research suggests that the etiology of prostatic cancer is most probably related to hormonal influences rather than to a horizontally transmitted agent, while the etiology of testicular cancer is most probably related to endogenous or exogenous hormonal influences in utero or in infancy, or to in utero exposure to other exogenous agents.


Oesophageal cancer studies in the Caspian Littoral of Iran: results of a case-control study. The results are presented of a case-control study conducted in the north of Iran. The main aim was to study factors identified in a previous study as potentially causally related to cancer of the oesophagus. Other tumours (lung, stomach, breast, large bowel, larynx and pharynx) were included to distinguish findings specific for oesophageal cancer from general characteristics of cancer patients, due for example to ascertainment bias, and to verify that expected associations, such as between lung cancer and cigarette smoking, would emerge under the prevailing field conditions. Two controls were chosen per case, matched for village of residence, age, sex and language group, Reinterviewing was performed to a limited extent to assess the accuracy of replies to questionnaires. The following were found not to be associated with oesophageal cancer: consumption of sheep's milk and yoghurt, sesame oil, chewing of nass, making of carpets, use of pregnancy diets, salting and sun-drying of meat and use of wild spinach. The use of opium, bread and tea could not be assessed in the retrospective framework. Strongly associated with risk of oesophageal cancer were low socio-economic status and low intake of fresh fruit and vegetables. The two factors each had an independent effect, and were more marked for oesophageal cancer than for the other tumours.


Pharmacokinetic considerations in testing hypoxic cell radiosensitizers in mouse tumours. Bilateral kidney ligation of mice immediately before injection of misonidazole (MIS) prolongs the plasma half-life of this radiosensitizer from about 2 h (in normal mice) to 10-11 h, similar to that in man. Kidney ligation does not, however, change the relative proportions of MIS and its O-demethylated metabolite, Ro-05-9963, for the first 12 h after MIS injection. Kidney ligation was used with the two radiosensitizers, MIS and Ro-05-9963, to investigate the influence of plasma half-life both on peak plasma levels and on the tumour/plasma ratio of sensitizer concentration in the EMT6 mouse tumour. Although the acute LD50 of Ro-05-9963 in normal mice was twice that of MIS, this apparent advantage was offset by peak tumour levels 50% or less of those achieved by equimolar injected doses of MIS. However, by comparing the plasma and tumour levels in mice in which the drug half-lives were prolonged by bilateral kidney ligation, it was concluded that the lower plasma and tumour levels of Ro-05-9963 were a result of its shorter plasma half-life, rather than of an intrinsic barrier to tumour penetration. Because of this rapid clearance, the radiosensitization produced by Ro-05-9963 was less than that produced by equimolar injected doses of MIS. As this difference did not occur in kidney-ligated mice, and hence would not be expected to occur in man, the comparison of MIS and Ro-05-9963 in mice produces an artificially low radiosensitization for Ro-05-9963 and possibly also for other compounds with short plasma half-lives. Although the short plasma half-life of Ro-05-9963 appeared to be responsible for its low peak plasma concentration, it did not produce a low tumour/plasma ratio. Within the limits of plasma nitroimidazole half-lives investigated (0.5-10 h) the tumour/plasma ratio was insensitive to plasma half-life, being 50-70% for both MIS and Ro-05-9963 in both normal and kidney-ligated mice. It is concluded that the common assumption that tumour/plasma ratios of MIS in the mouse are less than those in man is unjustified.


Ascorbate anion potentiates cytotoxicity of nitro-aromatic compounds under hypoxic and anoxic conditions. The nitro-aromatic radiosensitizing drugs are selectively toxic to hypoxic mammalian cells, and this toxicity can be greatly increased by the addition of ascorbate. The ascorbate itself is not toxic to either hypoxic or aerobic cells (as long as catalase is present to prevent the formation of significant concentrations of hydrogen peroxide) and the mixture of ascorbate plus radiosensitizer is not more toxic to aerobic cells. Sulphydryl reducing agents and dithionite have an effect opposite to ascorbate and decrease the toxicity of nitro-aromatic drugs under hypoxic conditions. Sulphydryl reducing agents are also reported to nullify the radiosensitizing properties of nitro-aromatic drugs, in contrast to ascorbate which has no effect on the radiosensitizing properties. The toxicity of nitro-aromatic drugs decreases rapidly with increasing O2 concentration. This decrease is much less rapid when ascorbate is present. The role of ascorbate in this case may be primarily as an O2 scavenger, although it is also possible that the toxic species produced by radiosensitizer-ascorbate mixtures is less easily removed or detoxified by O2.


Rupture strength of skin wounds in jaundiced rats. The rupture strength of 7-day-old wounds in normal rats, in rats in which there had been a previous skin incision, and in sham bile-duct-ligated and bile-duct-ligated jaundiced groups of rats was studied. It was found that wounds in jaundiced rats were significantly weaker than the wounds in the normal group of rats. Skin wounds in normal animals were significantly stronger than wounds in animals with sham bile-duct ligation. No difference was seen between sham bile-duct-ligated and bile-duct-ligated jaundiced rats.


The effect of antibiotics on the intracellular survival of Staphylococcus aureus in vitro. Human blood phagocytes and opsonized Staphylococcus aureus were incubated together in vitro and then treated with the bacteriolytic enzyme lysostaphin in order to remove extracellular bacteria. After washing, the phagocytic cells were incubated for a further 90 min with or without added antibiotics and the effect of these drugs on the survival of sensitive intracellular Staph. aureus measured. Penicillin and cefazolin had no effect on intracellular staphylococcal survival, but rifampicin, streptomycin and gentamicin reduced intracellular bacterial counts. The intracellular survival of antibiotic-resistant strains of Staph. aureus was not affected by the relevant extracellular antibiotics. Pre-incubation of phagocytic cells with either aminoglycosides or rifampicin had no effect on the intracellular survival of antibiotic-sensitive Staph. aureus.


Uptake of Evans blue-bound albumin in the aorta of oestrogen-treated rats. The permeability of the aortic endothelium was studied in oophorectomized female rats following i.m. administration of ethinyloestradiol daily for 10 days. For this purpose a solution of Evans blue: albumin (1%:5%) in Ringer's solution was perfused under controlled pressure through the left ventricle. Areas of blue staining, seen through the intimal surface, were taken to indicate areas of endothelial permeability to albumin. They were traced within the outline of the intimal surface of the whole vessel. The total stained area, expressed as a percentage of the total area of the intimal surface, was determined separately for the various segments in both the thoracic and abdominal aortas. Statistical analysis of data indicated that the uptake of Evans blue-bound albumin in the aortic wall was significantly increased in oestrogen-treated rats as compared to their control. This phenomenon was observed throughout the aorta except for its middle abdominal segment. Also its magnitude was comparable in all segments. These results strongly suggest that endothelial permeability to albumin was increased following treatment with synthetic oestrogen. This would enhance the influex of growth-promoting factors and thus play a role in the pathogenesis of proliferative lesions in the arterial wall associated with oestrogen administration in humans as well as in experimental animals.


An autoradiographic study of 3H-thymidine incorporation and distribution in the dermis of healing skin incisions in the pig. The dermal response to injury in healing incisional wounds aged from 1 to 24 days was studied by in vitro and in vivo 3H-thymidine (3HT) labelling and the use of colcemid to induce metaphase arrest. In vitro 3HT labelling provided mean numbers (+/- s.e. mean) of labelled dermal cells/section within the incision and in 3 zones in the dermis up to 0.875 mm lateral to the incision. There was a progressive increase in the numbers of DNA-synthesizing cells in the incisions as granulation tissue developed from Day 1 to Day 7, and a sharp decline by Day 9. Immediately adjacent to the incision there was a dramatic increase in the number of labelled cells on Day 2, with reduced numbers laterally. This response, which was largely maintained up to 7 days, paralleled the cellular reaction around blood vessels and skin appendages but also included labelled dermal fibroblasts. The in vivo 3HT study, taken in conjunction with the colcemid and in vitro 3HT studies, supported the idea that during the development of granulation tissue there is a continual recruitment of paraincisional cells, including dermal fibroblasts, either by direct migration or by division and then migration, as well as by continued mitosis of cells already within the incision.


Cyproterone acetate-promoted prevention of renal cortical necrosis following testosterone and vasopressin administration. Bilateral focal renal cortical necrosis was observed after vasopressin administration in rats pretreated for 10 days with testosterone phenyl propionate. When the androgen-receptor blocking-agent cyproterone acetate was administered together with the testosterone, the subsequent vasopressin treatment did not cause renal cortical necrosis. The results suggest the role of the androgen receptors in the kidney in the induction of the phenomenon.


Effect of different factors modifying the activity of some enzyme systems of the endoplasmic reticulum on the sensitivity of cell organelles against the damaging action of chemical agents. II. Studies with chlorpromazine, 2,4-dinitrophenol, phenobarbital and DDT. Further investigations on the effect of different stress factors on the stability of intracellular membranes were carried out. Large granule fractions derived from livers of sleep-deprived and dehydrated rats and subjected to preincubation at 37 degrees and pH 5 were shown to release latent acid phosphatase with a delayed rate indicating an increased lysosomal stability towards acid media conditioning. Lysosomes of such animals, however, were found to be more sensitive to mechanical treatments (homogenization procedure in this case) than that of controls, a conclusion made on the basis of enhanced "free" and nonsedimentable phosphatase activities in liver homogenates. The stress factors which previously were included in the group of modifiers of the activity of the endoplasmic reticulum-located enzymes caused some changes in the action of certain chemicals on membranes. Earlier such changes were elicited for carbon tetrachloride and only on low-temperature-conditioned rats for chlorpromazine. The present results show that stress factors studied result in deviations (different in extent and in direction) from the usual effects of chlorpromazine, 2,4-dinitrophenol, phenobarbital and DDT on liver lysosomes and peroxisomes.


Calcium-related changes in the ultrastructure of mammalian myocardium. Isolated rat hearts, perfused with Ca2+-free medium for 5 min, were perfusion-fixed for ultrastructural studies. Increased pinocytotoic activity and characteristic changes in the staining of the intercalated disc coupled with conspicuous staining of the middle lamina in the tight junctions in these hearts indicated an alteration in the sarcolemmal activity as well as cell--cell relationship. The intracellular effects of Ca2+-free perfusion were indicated by the presence of an active Golgi body as well as the loss of heterogenic staining of the nucleoplasm. The latter appears to be a direct consequence of Ca2+ depletion of the cell, as heterogeneity reappeared upon reintroduction of the calcium in the perfusion medium. The extent of structural damage upon reintroduction of calcium was dependent upon the extracellular calcium concentration. These observations suggest that perfusion with Ca2+-free medium causes some membrane changes in the heart which probably make it more vulnerable to the reintroduction of calcium. Furthermore, the structural damage observed upon reintroduction of calcium appeared to be related to the amount of calcium overload.


Mast cell population density, blood vessel density and histamine content in normal human skin. Mast cell population density was determined in normal skin from two regions of the arm of several healthy men and compared with blood vessel density and histamine concentration in the same sites. Mast cell and blood vessel counts were made in 1--1.5 micrometer thick plastic sections, by light microscopy and tissue-histamine concentrations were determined by automated fluorimetric analysis. Statistically significant correlations were found between mast cell counts, blood vessel counts and histamine content in skin from the upper arm but no similar correlations were obtained in the forearm. Anatomical differences between the two sites may have been the cause of this discrepancy. Wide variations in mast cell counts and blood vessel density were found in different sections from the same biopsy samples which confirms the notion that dermal mast cells are unevenly distributed. Analysis of variance of the mast cell counts showed that the variance between sections from different blocks from the same biopsy samples was greater than the variance between adjacent biopsies. There was also a marked variation in the histamine content between biopsy samples from sites only 2 cm apart in the same subject.


Distribution of mast cells in human dermis: development of a mapping technique. A new method was developed to define the distribution of mast cells in normal human skin. The population density was determined in a number of zones of different depth in the dermis. Two regions of the same limb were studied systematically. Both were shown to have mast cell populations of similar size and distribution, with a maximum density immediately below the dermo-epidermal junction, gradually falling to a minimum density in the deeper layers of the dermis. Small secondary peaks were less clearly defined at the base of the dermis. These findings should provide baseline data for comparisons with mast cell population size and distribution in different areas of normal skin, or in similar areas in clinical disorders or experimental conditions.


The aetiology of juvenile plantar dermatosis. Studies of the sweating mechanism in juvenile plantar dermatosis have demonstrated features of miliaria, including inhibition of sweating and occlusion of the sweat coil in the horny layer of the epidermis. These are considered to be a sequel to changes in the composition of children's shoes and hose. Possible remedies are suggested.


Surgical conversion of herpes simplex from an epidermal to a dermal disease. A new post-surgical form of recurrent herpes simplex is described. It appeared as an erythematous bulla at sites of recurrent herpes from which the prior epidermal lesion had been transversely excised. Histologically, it was characterized by a lesion-free epidermis, a large subepidermal bulla, and a marked inflammatory response in the uppermost dermis, complete with diagnostic multinucleate giant cells. It is postulated that epidermal surgery leaves the area immune to future direct herpetic involvement of the epidermis because it denervates the epidermis. The possibility is raised that such dermal forms of herpes may also occur in the natural course of the disease.


The dermatopathology of Cowden's syndrome. During the past 2 years we have studied eighty-nine biopsy specimens from nineteen patients with Cowden's syndrome. Among fifty-three facial lesions, twenty-nine were trichilemmomas. Twenty-three of the others were consistent with trichilemmoma, showed a non-specific benign verrucous acanthoma, or were not diagnostic; one was a blue naevus. All fourteen oral mucosal biopsy specimens were benign fibromas. Nineteen of twenty-two biopsy specimens from the hands and feet showed the pattern of benign keratosis. Multiple trichilemmomas were found in all patients with Cowden's  syndrome, but at times several biopsy specimens were required before a diagnostic picture was uncovered. All patients with multiple facial trichilemmomas were found to have Cowden's syndrome. The combination of multiple facial trichilemmomas, oral fibromas, and benign acral keratoses enables one to diagnose Cowden's syndrome at a stage before serious internal complications develop.


Multiple apocrine cystadenomas.

Multiple apocrine cystadenomas. A 56-year-old man had approximately forty apocrine cystadenomas of the face and ears. Clinical examination and light microscopic findings were typical for apocrine cystadenomas. Electron microscopic findings showed an absence of annulate lamellae, thus differing from the only previously reported study. Review of the literature indicates that a large number of apocrine cystadenomas, such as on our patient, has not been reported previously.


HLA system in relation to carbohydrate metabolism in lichen planus. HLA antigens were determined in a group of fifty-two patients with lichen planus. In the group as a whole the frequency of A28 was increased but not significantly so. When the patients were subdivided according to the results of an oral glucose tolerance test, however, a highly significant increase in the frequency of A28 was found among the non-diabetic patients.


Percutaneous absorption in experimental epidermal disease. Little is known about the absorption of topical drugs in epidermal disease associated with epidermal proliferation and altered keratinization. An abnormal hairless mouse epidermis was produced by three different methods: ultraviolet light irradiation, topical vitamin A acid and topical acetic acid. An increased epidermal thickness resulted and the in vitro percutaneous absorption of 0.1% (4-14C) hydrocortisone was found to be increased when compared with normal hairless mouse epidermis. This is evidence for defective skin barrier function in experimental epidermal disease.


Pemphigus-like antibodies: a report of two cases. Two patients with high titres of circulating intercellular antibodies are described. One had bullous mycosis fungoides and the other had bullous impetigo. In each case, as the underlying disease responded to treatment, the titre of antibodies fell.


Persistent warts protected from immune attack by a blocking factor. Severe warts of 20 years duration, highly resistant to therapy, were found to contain a soluble factor which blocked the local expression of cellular immunity, without affecting systemic immune responsiveness. This finding enabled us to propose therapy by infection, and this had a limited success.


Membrane abnormalities of pyruvate kinase deficient red cells. Two experimental systems have been applied to the study of PK-deficient red cells in an attempt to reveal possible membrane abnormalities of these erythrocytes: (1) the glycoprotein self-digestion of intact erythrocytes during in vitro incubation at 37 degrees C; (2) the red cell sensitivity to the lytic action of mouse macrophages. PK-deficient erythrocytes display a more precocious than normal membrane glycoprotein self-digestion and are much more susceptible than normal to the cytotoxic activity of mouse macrophages. This latter effect is more pronounced in young than in old PK-deficient red cells. These observations indicate the existence of membrane abnormality in PK-deficient red cells other than those so far suspected.


The heterogeneity of normal Hb A2-beta thalassaemia in Greece. Nine patients have been observed with homozygous beta thalassaemia in each of whom one parent has a normal level of Hb A2. On the basis of clinical, haematological and globin chain synthesis studies these families have been divided into two groups. Group 1 (six families). Heterozygotes for normal Hb A2-beta thalassaemia in this group showed minimal red cell abnormalities, normal osmotic fragility but imbalanced globin chain synthesis (alpha/beta=1.6), and appear to correspond to previous descriptions of 'silent' beta thalassaemia. Double heterozygotes with high Hb A2-beta thalassaemia have a clinical picture of mild beta thalassaemia intermedia characterized by relatively low levels of Hb F (less than 20%) and gamma chain synthesis. Group 2 (three families). beta Thalassaemia heterozygotes with normal HbA2 levels in this group showed more marked red cell abnormalities, decreased osmotic fragility and more imbalanced globin chain synthesis (alpha/beta=2.5) than those in group I. Double heterozygotes with high Hb A2-beta thalassaemia are more severely affected and are transfusion dependent. Haemoglobin F and gamma chain synthesis are high in these cases. The frequency of normal Hb A2-beta thalassaemia in Greece may be as high as 10% of all beta thalassaemia genes and this poses a significant problem for genetic counselling. Various molecular mechanisms are discussed which could account for the heterogeneity within these disorders.


Recommendations for fetal haemoglobin reference preparations and fetal haemogloblin determination by the alkali denaturation method. Lyophilized haemoglobin mixtures containing HbF and HbA were investigated as reference preparations in an interlaboratory collaborative study. Haemiglobincyanide mixtures in Drabkin's solution with 450-550 mg Hb/dl and 0.2-60% HbF were divided into samples of 10 ml, lyophilized in plastic containers and stored without vacuum at -20 degrees C. After dissolution in 10 ml distilled water no change in spectral and electrophoretic properties or turbidity was observed; stable values for the total Hb concentration and HbF content were obtained over a period of over 2 years. These HbF standards can be prepared in reference laboratories and are recommended for quality control in HbF determination by alkali denaturation. For fetal haemoglobin determination the alkali denaturation technique of Berke, Marti and Schlicht is recommended for quantitation of HbF concentrations, at least between 2 and 40%. For values below 2% radioimmunoassay and for concentrations above 40% chromatographic procedures are more accurate. However, these methods will not be applicable in smaller haematological laboratories and in developing countries.


Thrombin receptors of human platelets: thrombin binding and antithrombin properties of glycoprotein I. Washed human platelets were solubilized and the proteins were separated by preparative gel electrophoresis in the presence of sodium dodecyl sulphate. The gel was cut into slices and the effect of the eluted proteins on the clotting of fibrinogen by thrombin was evaluated. The isolate from only one gel slice strongly inhibited the clotting of fibrinogen. The prolongation of the clotting time was dependent on the concentration of the protein and reached a plateau around 5 microgram. Gel electrophoresis of this isolate showed a prominent glycoprotein with an apparent Mr=150 000. Gel filtration studies with [125I]thrombin showed that the protein isolate bound a significant amount of thrombin which could be displaced with unlabelled thrombin. Another preparation from the same gel or purified gamma-globulin did not bind thrombin or prolong the clotting time of fibrinogen. Glycoprotein I was isolated from human platelets by affinity chromatography on lectin-Sepharose columns. The isolated glycoprotein prolonged the clotting of fibrinogen and bound [125I]thrombin which could be displaced by unlabelled thrombin. It is proposed that the high affinity receptor of thrombin on human platelets is glycoprotein I. In addition, the antithrombin activity of intact platelets is due to binding of thrombin to this glycoprotein.


Blood eosinophils and eosinophil cationic protein after acute myocardial infarction or corticosteroid administration. Measurements of eosinophil cationic protein in serum (S-ECP) have been made in patients with acute myocardial infarction. In spite of low numbers of blood eosinophils in the acute phase of the disease S-ECP levels fluctuated widely with often markedly raised levels. Peak levels of S-ECP were significantly correlated (P less than 0.001) to peak numbers of blood eosinophils, although the former usually occurred within the first 2-3 d of illness and the latter usually after the sixth day. Intravenous injection of 0.5 g methylprednisolone in healthy individuals reduced blood eosinophil counts for at least 24 h, but S-ECP levels remained within normal limits. These results suggest that ECP is released from eosinophils in vivo. The raised levels of S-ECP in patients with acute myocardial infarction are probably due to the active participation of eosinophils in the inflammatory process.


Metabolic changes in red blood cells in malignant lymphomas. Serum copper levels (SCL) which are concomitantly related to red blood cell free copper are significantly increased in some malignant lymphomas in the phase of activity. This results in a profound inhibition of red cell key glycolytic enzymes, hexokinase (Hx) being the most sensitive. Fifteen patients (eight with Hodgkin's disease and seven with non-Hodgkin's lymphoma) were studied for serum and red cell copper concentrations and Hx activity. The mean red cell life span was determined using 51Cr labelled red cells. The resulting data shows that in active disease an increase in SCL was associated with a decrease in Hx activity and a shortened red cell survival. In these cases there was no evidence of autoimmune phenomena or of direct bone marrow involvement by the disease. It is suggested that the increase in copper levels results in a shortened red cell life span through a copper-induced inhibition of red cell Hx.


Bone marrow fibre production in myelofibrosis: a quantitative study. A digital image processing technique has been used to quantitate bone marrow fibre in histological material (both biopsy and necropsy) from 17 cases of myelofibrosis. An attempt was made to correlate the results of these measurements with other diagnostically relevant parameters. Bone marrow fibre was found to correlate significantly with absolute neutrophil count, the absolute count of immature granulocytic cells and with the number of immature granulocytic cells expressed as a percentage of the total leucocyte count. There was no significant correlation between marrow fibre content and platelet count for the series as a whole, but for those cases in which measurements were made following splenectomy these parameters were highly correlated. Bone marrow fibre content did not appear to correlate with liver or spleen weight at necropsy, nor with the duration of clinical manifestations of the disease. The significance of these findings is discussed.


Haem synthesis in sideroblastic anaemia. Measurement of delta-aminolaevulinic acid (ALA) synthetase has been performed in bone marrow of 24 normal subjects and 20 patients with sideroblastic anaemia (five congenital, two pyridoxine-responsive, 12 primary acquired and one secondary form due to isoniazid therapy). ALA-synthetase activity without added pyridoxal-phosphate in vitro was decreased in four of the congenital cases, and in all 12 primary acquired cases. In two of these 16 cases with low ALA-synthetase activity and in a case with sideroblastic change secondary to isoniazid therapy, the enzyme activity was corrected to normal by pyridoxal-phosphate in vitro. ALA-synthetase activity was normal in both cases of pyridoxine-responsive anaemia while they were receiving pyridoxine therapy but in one of these cases, studied at repeated intervals after withdrawal of pyridoxine therapy, the bone marrow ALA-synthetase activity fell to very low levels unless pyridoxal-phosphate was added in vitro. In this case the Km of the enzyme for pyridoxal-phosphate was substantially greater than that of a control sample. Haem synthetase activity was reduced in the bone marrow of two of six cases of primary acquired sideroblastic anaemia and in one congenital case tested but was normal in the pyridoxine-responsive patient studied on pyridoxine therapy. Nevertheless, this patient showed reduced incorporation of 14C-labelled delta-aminolaevulinic acid into bone marrow haem. It is concluded that both congenital and primary acquired sideroblastic anaemia are a heterogenous group of disorders, with different defects in haem synthesis, reduced activity of delta-aminolaevulinic acid synthetase being common but not invariable in both types. Pyridoxine-responsive (congenital) sideroblastic anaemia may be due to the presence of an abnormal ALA-synthetase apoenzyme which requires excessive amounts of the coenzyme, pyridoxal-phosphate, to achieve normal activity; other abnormalities of haem synthesis may also be present.


Altered erythrocyte pyrimidine activity in vitamin B12 or folate deficiency. The net activity of orotidylic pyrophosphorylase and decarboxylase, sequential enzymes which catalyse the formation of uridine monophosphate from orotic acid in de novo pyrimidine biosynthesis, has been evaluated in erythrocytes of patients with folate or cobalamin deficiency. In patients with normoblastic haemopoiesis and normal cobalamin and folate status a direct relationship exists between the maturity of the peripheral blood erythrocyte population, as indicated by G6PD activity, and net orotidylic activity. In contrast in cobalamin or folate deficiency this co-ordinate relationship is not observed and net orotidylic activity is relatively reduced. Fractionation of erythrocytes by centrifugation demonstrates that this inordinately low orotidylic activity consistently occurs in the young erythrocyte population and is reversed by specific replacement therapy. In vitamin B12 or folate deficiency an impressive array of evidence now exists to implicate altered folate metabolism for the observed alterations in purine and pyrimidine metabolism (Das & Herbert, 1976). Of these changes the cornerstone defect resulting in megaloblastic maturation is impaired methylation of deoxyuridine monophosphate to thymidine monophosphate (Hoffbrand et al, 1976). In this context the reduced serum uridine plus uracil levels in patients with vitamin B12 deficiency (Parry & Blackmore, 1976) and the haematological response of these patients to orotic acid therapy (Rundles & Brewer, 1958) are not readily explicable. Since the conversion of orotic acid to uridine monophosphate depends on the integrity of the coupled activities of orotidylic pyrophosphorylase and decarboxylase, this study has quantitated this capacity in peripheral blood erythrocytes in patients with vitamin B12 or folate deficiency.


Mechanism of the decreased erythropoiesis in the water deprived rat. Radioiron uptake by erythrocytes, metabolic rate, erythropoietin formation during hypoxia and erythroid responsiveness to exogenous erythropoietin were determined in both starved and water deprived rats. The feed intake showed a marked and progressive reduction during water deprivation. The metabolic rates of rats deprived of either food of water declined progressively showing a 40% reduction 5d after water deprivation or starvation began. At this time, the 24 h red blood cells 59Fe incorporation was 85% lower in both starved and dehydrated rats than in normal rats. Plasma erythropoietin levels in response to hypoxia were approximately 50% decreased in both starved and dehydrated rats. Both polycythaemic starved and polycythaemic water deprived rats injected with human urinary erythropoietin showed a 75% decrease in 59Fe incorporation into erythrocytes when compared to control rats. It is suggested that depression of erythropoiesis during water deprivation in the rat depends on a reduced sensitivity to erythropoietin, possibly associated with decreased production of the hormone. Since water deprived rats drastically reduce feed intake it is suggested that secondary starvation is the principal cause of the decreased erythropoiesis induced in the rat by water deprivation.


Erythrokinetic studies in hairy-cell leukaemia. Erythrokinetics were studied in 29 patients with hairy-cell leukaemia. In all cases there was an increase in plasma volume, closely correlated to the size of the spleen, indicating that the true degree of anaemia can only be appreciated by red cell volume measurement. Moderately increased haemolysis was observed in most cases, which did not correlate with the spleen size. Simultaneous study of autologous and isologous red cell life-span suggested an extra-corpuscular mechanism for the haemolysis in most patients. A quantitative erythropoietic defect, either relative or absolute, was found in half the cases, without any qualitative defect. Only one case showed erythroid metaplasia of the spleen. Thus marrow failure appears to be largely responsible for the anaemia and granulocytopenia in hairy-cell leukaemia. A clear correlation was shown between the short-term prognosis after splenectomy and the degree of hypersplenism. However, long-term survival correlated chiefly with the degree of bone marrow failure, whether splenectomy had been carried out or not. The results indicate that isotope studies in hairy-cell leukaemia are useful both in determining the best form of treatment and predicting survival.


Clinical staging in multiple myeloma.

Clinical staging in multiple myeloma. Analysis of 237 patients with myeloma, retrospectively classified according to the staging system proposed by Durie and Salmon, showed highly significant differences (P less than 0.0001) in the survival of patients with low, intermediate and high tumour cell masses (Stages I, II and III respectively). The median survival for Stage I patients was 64 months, Stage II 32 months, and Stage III 6 months. The median survival of patients presenting with renal impairment was only 2 months, compared to 21 months for those presenting with normal renal function (P less than 0.0001). The use of this clinical staging system, which is based on myeloma protein synthesis rates and the calculation of total body tumour cell mass, should be considered in planning future trials of therapy in this disease.


Splenectomy in patients with agnogenic myeloid metaplasia: an analysis of 321 published cases. The available data on 321 published cases of splenectomy in agnogenic myeloid metaplasia were reviewed. Anaemia and thrombopenia were the most common indications for this operation. Patients reported after 1940 had a median postoperative survival of 13 months. Their postoperative mortality was 7.5% after 2 d and 25.7% after 3 months. The postoperative mortality was significantly higher when the weight of the spleen exceeded 2000 g, or in patients with platelet count less than 70 X 10(9)/l. The most common causes of death were infections (34.4%), cardiac or thromboembolic events (26.4%) and haemorrhage (17.6%). Leukaemic transformation was reported in 11.2% of the cases.


Oxidative damage to neutrophils in glutathione synthetase deficiency. Several episodes of neutropenia were observed in a child with glutathione synthetase deficiency (5-oxoprolinuria). Studies of the patient's glutathione-deficient neutrophils were undertaken to examine the responses of the cells to oxidative stress associated with phagocytosis. The patient's neutrophils contained 10--20% of normal glutathione content. Circulating neutrophils in infection-free periods appeared less mature than normal by morphologic criteria, suggesting increased cell turnover. The cells ingested particles, responded to chemotactic stimuli, and oxidized 1-14C glucose normally. However, following ingestion of particles, the cells accumulated excess hydrogen peroxide compared with normal cells, and showed impaired protein iodination and bacterial killing. Electron micrographs revealed damage to microtubules and membranous structures in the patient's neutrophils during phagocytosis. The level of glutathione in the cells appears inadequate to protect against peroxide generated during normal cell function, and the cells are thus damaged and rendered less effective in bacterial killing. The data provide evidence for a protective role of glutathione in normal neutrophil function.


Kinetics of red cell membrane phosphorylation: altered affinity of HS membrane protein acceptors. Membrane ghosts were prepared from red blood cells of normal and hereditary spherocytosis (HS) subjects. Time dependent phosphorylation studies of the membrane (in the presence of gamma labelled AT32P) showed that the HS membrane appeared to incorporate less phosphate than the normal membrane but the results were not significantly different. Using the initial linear rate of phosphorylation and varying the ATP concentration, it was found that the Michaelis constant (Km) for the normal membrane was 24.8 microns ATP and Vmax was 0.120 nmol phosphate bound/mg membrane protein/min. These values for the HS membrane were found to be 39.0 and 0.118 respectively. In one family the affected mother and son each showed a positive cooperativity effect for similar reciprocal plots. This indicates that phosphorylation of various HS membrane proteins may be an ordered rather than random process and suggests biochemical heterogencity of the HS condition. The constants, Km and Vmax, however, were found to be similar to the rest of HS subjects studied. Crude extracts of the enzyme protein kinase, which catalyses the membrane phosphorylation, showed no significant difference in the Km and Vmax value in HS compared with that from normal red cells. The kinetic difference in phosphorylation is probably due to abnormalities in the membrane protein(s) which accept the phosphate from protein kinase in HS red cells.


Nonrecessively transmitted nonspherocytic hereditary haemolytic anaemia associated with increased red cell glutathione. Hereditary haemolytic anaemia not associated with spherocytosis, ovalocytosis, stomatocytosis or haemoglobinopathy was observed in three members of a kindred. There were no demonstrable abnormalities of enzymes of the Embden-Myerhof pathway, the hexosemonophosphate shunt, or of a variety of non-glycolytic enzymatic activities assayed in patient erythrocytes. In each case, red cell glutathione was increased in concentration three to six standard deviations above our normal mean. Erythrocyte glutathione was normally stable and all sulfhydryl reacting material was shown by specific enzyme assays to represent either reduced (97%) or oxidized (3%) glutathione. No abnormality in active transport of oxidized glutathione was demonstrable in the red cells. This syndrome of unknown actiology was transmitted in autosomally dominant fashion or, alternatively, as a possibly x-chromosome linked disorder. Existing data did not permit the differentiation of these two possibilities.


Vitamin B6 metabolism in idiopathic sideroblastic anaemia and related disorders. Patients with idiopathic anaemias associated with abnormal sideroblasts were defined according to morphologic and ferrokinetic criteria and the haematologic and biochemical effects of vitamin B6 therapy were evaluated. While all patients presented similar clinical pictures, peripheral blood changes and bone marrow abnormalities, two distinct groups were identified by sideroblast morphology and ferrokinetics. Patients with more than 5% true ring sideroblasts in the marrow (IRSA) uniformly had marked ineffective erythropoiesis, while those with abnormal sideroblasts but few true ring forms were hypoproliferative. Measurements of red cell pyridoxine kinase (PnK) and intracellular pyridoxal 5-phosphate availability (PLP) as assessed by the activity of the PLP-dependent enzyme asparate aminotransferase (EGOT), revealed slightly decreased PnK levels in IRSA subjects but normal intracellular PLP activities in both groups. Furthermore, when treated with pyridoxine, all patients showed increases in both red cell PnK and EGOT activities which were similar to those seen in normal subjects. Treatment with PLP also effectively increased erythrocyte vitamin B6 activity. Even so, neither pyridoxine nor intramuscular PLP improved erythropoiesis as determined by serial haematocrits, reticulocyte counts and erythron iron turnover measurements.However, since both therapies increased red cell protoporphyrin levels and the excretion of urinary coproporphyrin in a number of subjects, the possibility that impaired haem synthesis in the sideroblastic anaemias is associated with abnormal vitamin B6 metabolism at the level of the mitochondrion must still be considered.


Ferritin as a cytosol iron transport intermediate in human reticulocytes. The major iron-bearing cytosol components of human reticulocytes identified after incubation with 59 Fe-125I-transferrin have been studied further. Component C previously found to behave consistently as an intermediate in the iron transport pathway to haem is shown to consist entirely of ferritin. After a short pulse of labelled transferrin incubation, chase experiments showed a fall of ferritin label with time and a corresponding increase in haemoglobin-iron incorporation. There was no loss of ferritin to the culture medium. Restriction of iron uptake by reticulocytes using both p-hydroxymercuribenzoate inhibition of uptake and incubation with progressively lower saturations of iron-transferrin gave linearly related incorporation of 59Fe into ferritin and haemoglobin at all levels of iron uptake, thus negating the concept of ferritin as an 'overspill' form of reticulocyte iron. The results suggest that cytosol ferritin is an obligatory intermediate in reticulocyte iron transport.


The influence of red blood cells on the effects of aspirin or sulphinpyrazone on platelet adherence to damaged rabbit aorta. The effects of acetylsalicylic acid (ASA; aspirin) or sulphinpyrazone (SP) on the adherence of washed rabbit platelets to the subendotheilial surface of an everted aorta mounted on a probe or to the subendothelial surface of a rabbit aorta attached to a perfusion apparatus were examined. ASA had no effect on platelet adherence to a damaged aorta perfused with a suspension of washed platelets in a medium containing 10% red blood cells (RBC); SP was slightly inhibitory at high concentration. When damaged rabbit aortae were everted on a probe and rotated in a suspension of washed platelets to which RBC were added to a packed cell volume of 10%, both ASA and SP inhibited platelet adherence to the damaged vessel wall. When the PCV was 40%, ASA was not inhibitory and SP reduced platelet adherence only at very high concentrations. It is therefore unlikely that, at the concentrations achieved in man, SP exerts an effect on platelet adherence. The different effects of ASA and SP on platelet survival do not appear attributable to their effects on platelet adherence.


Detection of carriers of haemophilia B.

Detection of carriers of haemophilia B. Plasma levels of factor IX activity and factor IX antigen were determined in 18 definite carriers of haemophilia B-, 10 definite carriers of haemophilia B+ and 40 control subjects. Factor IX antigen was determined by the electroimmunoassay technique of Laurell using a rabbit antiserum against factor IX. In haemophilia B-, statistical tolerance regions were constructed containing 90% of the factor IX activity and factor IX antigen values for the carriers and the control subjects. Of the 18 carriers, 10 were outside the tolerance region for the control subjects, and of the 40 control subjects, 17 were outside the tolerance region for the carriers. A better separation of the probabilities of being a carrier was obtained for the B- carriers and the control subjects when factor IX antigen was determined in addition to factor IX activity. In haemophilia B+, factor IX antigen was present in excess of factor IX activity in nine of the 10 carriers. The values for factor IX activity and factor IX antigen for these nine carriers fell outside the 90% tolerance region for the control subjects. It is concluded that the quantitative determination of factor IX antigen may be of value in the detection of carriers of both haemophilia B+ and haemophilia B-.


Inhibition by phospholipids of haemolytic action of asbestos. Haemolysis by asbestos fibres results from an increase in membrane permeability and not from rupture of red blood cells (RBC). The effect of chrysotile asbestos on RBC is at least partly, if not completely, attributable to lipid extraction and adsorption on to the fibres. This was suggested by the hyperbolic relationship between the haemolytic activity of chrysotile and the relative concentration of both chrysotile and RBC. Moreover, it was shown that pre-incubation of chrysotile with lipids, either as RBC membranes or with pure lipids in the form of liposomes, prevents haemolysis.


HLA antigen frequencies in flax byssinosis patients. Not all workers exposed to flax dust contract byssinosis. It is not known what determines susceptibility or insusceptibility. This study is an attempt to establish whether the incidence of histocompatibility antigens is involved in susceptibility to the disease. Forty patients suffering from flax byssinosis were tissue-typed for HLA-A and -B antigens. HLA-B27 was significantly more common in the patients (22.5%) than in the controls (5.5%); P = 0.029 after correction for the number of antigens compared. HLA-A11 was present in twelve patients (30%) compared with 14% in the controls; after correction for the number of comparisons, this is not a statistically significant increase. Because HLA-B27, though significantly more common in flax byssinosis, is not necessary for its occurrence (77.5% of our patients did not have it), it is possible that the increase in the frequency of HLA-B27 is attributable to an association with other genes, perhaps those regulating the immune response or coding for antigens at other HLA loci.


Mortality and morbidity in a pulp and a paper mill in the United States: a ten-year follow-up. Two hundred and seventy-one men seen in 1963, who worked in a pulp and a paper mill, were followed up ten years later, in 1973. Death certificates were obtained for those who died. There did not appear to be any increased mortality in the group, nor was there any increased specific cause of death. A morbidity study of 200 men seen at both times did not show any differences in respiratory symptoms or prevalence of chronic non-specific respiratory disease. Analysis of pulmonary function showed little, if any, difference between groups. Analysis of retired, deceased, and still-working categories did suggest that exposures to Cl2 or SO2 might have a slight adverse effect on pulmonary function.


Effects of tricresylphosphate on esterase activity of rat serum and tissues. The effect of tricresylphosphate (TCP) was studied in vitro and in vivo on the rat liver and brain enzymes acetylcholinesterase (ACC), butyrylcholinesterase (CHE), arylesterase (ARE), aliesterase (ALI), and the microsomal nicotinamide-adenine dinucleotide phosphate oxidase (NADPH2-oxidase) system. The results show that, in the male rat, TCP given intraperitoneally induces an increase in liver microsomal ARE AND NADPH2-oxidase and a decrease in ALI and cholinesterase; no activation of ARE and NADPH2-oxidase is observed in female rats.


Cardiovascular disease and environmental exposure. This paper reviews the possible association between cardiovascular disease and occupational and environmental agents. The effects of carbon monoxide, fibrogenic dusts, carbon disulphide, heavy metals, noise, radiation, heat, cold, solvents and fluorocarbons are discussed. New directions for investigation are suggested.


Case note descriptions of the placenta: are they worthwhile? In 429 placentae, measurements were made of weight, diameter, shape, eccentricity of the cord and weight and length of the cord, and the results were compared with Apgar score of the infant at birth and its standardized birth weight. There was no evidence that cord eccentricity, placental shape or "thickness", or the dimensions of the cord had any significant relation to the growth of the fetus or its condition at birth. The value of routine recording of crude measurements and qualitative assessments of the placenta in case notes is questioned.


Induction of labour--a six year review.

Induction of labour--a six year review. A retrospective survey of surgical induction of labour has shown that induced patients had a lower perinatal mortality rate and a lower Caesarean section rate than non-induced women.


Plasma HCG levels in patients with bleeding in the first and second trimesters of pregnancy. The prognostic value of maternal plasma human chorionic gonadotrophin (hCG) determinations, measured by a specific beta-subunit radioimmunoassay, was studied in 188 patients with bleeding between 6 and 20 weeks gestation. The patients were arranged into different subgroups according to ultrasound findings as well as clinical and histopathological evidence. In threatened abortion with successful outcome (50 per cent of all patients studied), the weekly mean hCG values were normal or even slightly elevated. In patients with a blighted ovum, the first hCG level measured was in the normal range in 34 per cent of the patients. In patients who aborted embryo with former life signs hCG values were generally normal before the abortion. The hCG levels were usually low in patients with incomplete abortion and ectopic pregnancy. An initially subnormal level of hCG was associated with a poor outcome of pregnancy in 92 per cent of patients. If the first hCG level was within the normal range the outcome of pregnancy was favourable in 79 per cent of patients.


Serum follicle stimulating hormone levels in human pregnancy. We describe a specific radioimmunoassay for follicle stimulating hormone (FSH) and the finding of immunoreactive FSH in human pregnancy sera. A total of 394 serum samples was taken from 204 normal pregnant women at different stages of gestation. The FSH levels remained constant throughout pregnancy and no rise was associated with the late first trimester elevation of human chorionic gonadotrophin (hCG).


Red cell mass during and after normal pregnancy. Red cell mass, derived from plasma volume and haematocrit, was calculated serially in 45 healthy women during pregnancy and 4 to 6 months after delivery. Compared to the non-pregnant, postpartum value there was a reduction of approximately 100 ml at 12 weeks gestation. An increase in red cell mass occurred thereafter: at 36 weeks gestation values 180 ml greater than the non-pregnant were found. Iron and folic acid supplements almost doubled this increment to 349 ml of red cells.


In vitro study of the possible role of the intrauterine contraceptive device tail in ascending infection of the genital tract. Potentially pathogenic bacteria colonized the mucus coating the tails of both monofilamentous and multifilamentous intrauterine contraceptive devices (IUCD) in 72 (55 per cent) out of 132 in vitro tests. This suggests that the IUCD tail may be responsible for the passage of vaginal bacteria into the uterus.


Artificial insemination in Denmark by frozen donor semen supplied from a central bank. A central semen bank in Denmark supplied deep-frozen semen. Selection of donors, freezing technique, and practical details about transport of specimens are described. In one of the gynaecological departments supplied with frozen semen, 22 out of 30 patients who had artificial insemination became pregnant. The advantages and disadvantages of using frozen semen are discussed.


Isolated arteritis of the cervix uteri.

Isolated arteritis of the cervix uteri. Four patients with arteritis apparently isolated to the cervix uteri are presented and the clinical and pathological significance of this condition is discussed.


Malignant change in benign cystic teratoma of the ovary. In a clinico-pathological study of malignant disease of the ovary in the former North East Metropolitan Region, malignant transformation of benign cystic teratoma has emerged as the commonest malignancy of "germ cell" origin. The clinical and pathological details of 12 patients are reported.


Mixed mesenchymal sarcoma of the broad ligament: case report. A 55-year-old patient who presented with a pelvic mass was found to have a mixed mesenchymal sarcoma of the broad ligament. The histogenesis and diagnostic criteria of this rare tumour are discussed.


Idiopathic retroperitoneal fibrosis involving the vagina: case report. A patient with idiopathic retroperitoneal fibrosis involving the vagina and causing urinary symptoms is described. The condition responded satisfactorily to immunosuppressive drugs and steroid.


Pseudo-obstruction of the bowel in pregnancy: case reports. Two patients with intestinal obstruction in pregnancy are presented and discussed. In neither case was there any obvious cause for the intestianl obstruction. Pseudo-obstruction of the bowel has not previously been described as a complication of pregnancy.


Placental intervillous blood flow measured by inhaled 133Xe clearance in relation to induction of epidural analgesia. A method of determining placental intervillous blood flow (IBF) using an inhaled 133Xe technique is described. The method was used to investigate the effect on IBF of epidural analgesia with an initial dose of 37.5 mg bupivacaine. There was no statistically significant reduction in IBF following the initial dose of bupivacaine in spite of a small but statistically significant reduction in mean blood pressure. There was no significant correlation between the change in mean blood pressure and the percentage change in IBF following epidural block although the single largest percentage reduction in IBF was associated with the largest fall in mean blood pressure.


Fetal breathing patterns in intrauterine growth retardation. Fetal breathing movements were studied with real time ultrasound in 21 normal fetuses and 30 fetuses born small-for-dates (less than the 5th centile). The events of the study period were recorded on punched paper tape which was subjected to computer analysis. In the normal group the percentage time of breathing was 54 +/- 12.7 (mean +/- SD). The breath to breath interval was 1.34 +/- 0.25 seconds and the coefficient of variation of this interval was 49.6 +/- 7.7 per cent. In 17 of the small-for-dates group amount of breathing was reduced with short breathing episodes and long apnoea intervals. In the other 13 patients in the small-for-dates group the coefficient of variation for the breath to breath interval was significantly reduced (39.6 +/- 7.9 per cent, p less than 0.01).


Birth weight: analysis of variance and the linear additive model. The normal distribution of birth weight in a Queensland population has been surveyed. A method of analysis is presented which allows for the influence of a number of factors that affect birth weight.


Birth weight of Hausa infants in Northern Nigeria. The birth weight of 1460 Hausa singleton infants was recorded and analysed. The birth weight of Hausa infants (Mean +/- SD) was 3.03 +/- 0.45 kg, being higher in males (3.08 +/- 0.47 kg) than females (2.97 +/- 0.48 kg). The difference was significant (P less than 0.001). The mean birth weight of first born children was significantly lower than the subsequent born, and increasing birth order was associated with higher birth weight irrespective of maternal age. The birth weight was influenced more by the parity as compared to maternal age. The incidence of low birth weight was 15.8 per cent, being lower in males (13.6 per cent) as compared to females (18.1 per cent). Comparison were made with studies from other parts of the country as well as from other countries.


Biochemical changes of normal pregnancy and puerperium in Lagos, Nigeria. A cross-sectional study is presented of biochemical changes in the third trimester of normal pregnancy and puerperium during the wet season in the tropical climate of Lagos, Nigeria. These changes are less marked in first than in subsequent pregnancies, and although qualitatively similar, in some respects they differ from those observed in the temperate climatic zone. The indications are that quantitative differences may exist which could be relevant to the management of pregnancy in the tropics.


Differences in albumin distribution and dynamics between toxaemic and non-toxaemic pregnant women. By using least squares curve fitting techniques, double exponential curves were fitted to points representing the decay of plasma 131I-albumin after blood volume estimation of 48 pregnant women. Data from the fitted curves provided estimates of the distribution of albumin between plasma and extravascular compartments, exchange between the two and rate of albumin catabolism. The lower total extracellular albumin mass of a group of 23 severely toxaemic patients was shown to arise solely from the difference in plasma albumin mass between this group and the remaining 25 patients. Comparison of these results with those in the literature suggests that pregnant women have a higher proportion of their exchangeable albumin mass in the plasma compartment and a higher rate of albumin catabolism than non-pregnant women.


The possible relation between late pregnancy hypertension and 5-hydroxytryptamine levels in maternal blood. The concentrations of the vasoactive substance, 5-hydroxytryptamine (5-HT), were estimated in whole blood samples from 12 pregnant women with hypertension in the third trimester. These were compared with a control group of 15 normotensive pregnant women of the same gestation. The hypertensive patients were admitted for observation and the whole blood 5-HT estimated again after four days bed rest: in all patients the blood pressure had, by this time, returned to within the normal range. No significant difference was found between the mean blood 5-HT concentrations of the hypertensive and the normotensive groups. A small, but not statistically significant, rise occurred in the hypertensive group after four days bed rest. Thus this study gave no evidence that 5-HT is implicated in hypertension in pregnancy.


Changes in coagulation factors in postmenopausal women on ethinyl oestradiol. Coagulation factors II, VII, X, VII + X complex and anti-thrombin III were measured in 10 postmenopausal women before, during and after a four-month course of 20 microgram daily of ethinyl oestradiol, taken three weeks in four. Factors VII, X and VII + X complex rose significantly during treatment but only factor X levels were significantly elevated at the end of the four-month treatment period. There was no change in factor II or anti-thrombin III levels. These effects on coagulation factors during ethinyl oestradiol therapy are, in general, similar to those found during treatment with conjugated equine oestrogens and oestradiol valerate in a previous study from the same laboratory. It seems likely that equipotent doses of ethinyl oestradiol and 'natural' oestrogens have similar effects on these coagulation factors.


HLA antigens in glaucoma and ocular hypertension. Forty-five white patients (32 with open-angle glaucoma and 13 with ocular hypertension) and 63 black patients (41 with open-angle glaucoma and 22 with ocular hypertension) were tissue typed for a total of 38 HLA antigens and the results compared to normal, unrelated, panels of 248 white donors and 150 black volunteers, respectively. No statistically significant differences with regard to the frequencies of 38 HLA antigens were detected among the various groups.


Immunoglobulin concentrations in human tears in ocular diseases. Immunoglobulin concentrations in human tears were determined in 165 patients with different eye diseases by a standard radial immunodiffusion method. IgA was present in all the samples in measurable quantity. The mean IgA values were significantly higher than the controls in patients with acute bacterial conjunctivitis, keratomalacia, corneal graft reaction, blepharoconjunctivitis, and acute keratoconjunctivitis. The values in the patients with vernal conjunctivitis, phlyctenular conjunctivitis, acute bacterial corneal ulcer, and acute endogenous uveitis were not significantly different from those in the controls. IgG could be detected in the majority of the samples but it was in measurable quantity in 18 samples. IgM could be detected in fewer samples. IgD was not detected in any of them. The study indicates that, whenever the immunoglobulin levels in tears are altered in diseased eyes, it is the IgA level that is predominantly altered and not the IgG level.


Cell mediated immunity in relation to cataract and cataract surgery. Two groups of patients suffering from cataract were investigated by the lymphocyte stimulation test. One group was tested before and the other after cataract surgery. Human (total) lens crystallins and bovine alpha crystallin were used as the antigens. Lymphocytes of healthy persons showed practically no positive stimulation with either antigen. Of the patients tested before operation 38% reacted positively with lens crystallins and 15% with alpha crystallin. This difference in sensitisation suggests a leakage of lenticular antigens other than alpha crystallin out of the lens during cataract progression. Extracapsular lens extraction caused an increase in the number of patients reacting positively with lens crystallins and alpha crystallin as compared to patients not operated upon. Intracapsular lens extraction on the other hand resulted in less sensitisation to lens crystallins as compared to patients not operated upon.


Experimental posterior penetrating eye injury in the rabbit. I. Method of production and natural history. A technique has been developed which produces an experimental posterior penetrating eye injury that reproducibly results in traction retinal detachment in rabbit eyes. The standard injury is an incision through the pars plana with vitreous prolapse and incarceration; the wound is then carefully closed with microsurgical techniques. It appears that blood in the vitreous is an essential factor in the development of vitreous traction and of traction retinal detachment. The model, which has been successfully transferred to Rhesus monkey eyes, is considered useful for further histological, electromicroscopical, electrophysiological, and ultrasound studies of posterior penetrating injuries of the eye. Our immediate goal is to assess in a controlled experiment whether pars plana vitrectomy can interrupt the sequence of events leading to traction retinal detachment after a posterior penetrating injury.


Experimental posterior penetrating eye injury in the rabbit. II. Histology of wound, vitreous, and retina. The histological findings of the wound, the vitreous, and the retina in the rabbit eye with experimental posterior penetrating injury are described. Wound healing had just begun at 3 days after injury and was well established by 9 to 12 days. It involved proliferation of cells from the episclera and from the choroid. The progression to a fibrous ingrowth from the wound occurred only in eyes with blood in the vitreous. The intravitreal fibroblastic proliferation had begen at 6 days after injury and seemed to be derived from the choroid, the nonpigmented ciliary epithelium and, posteriorly, from the optic nervehead. During the development of retinal detachment the configuration of the peripheral and posterior retina, together with the orientation of vitreous strands, suggested the presence of vitreous traction. We postulate that the presence of contractile fibroblasts (myofibroblasts) in the vitreous may provide the mechanism for vitreous traction. The retinal detachments were also characterised by epiretinal and subretinal membranes, but these were not prominent. The end-stage appearance of a soft, shrunken eye with cyclitic membrane formation and retinal detachment resembles the outcome in many human eyes after severe penetrating injuries.


One model of outflow damage.

One model of outflow damage. The intraocular pressure, facilities of outflow, and Po/C ratios of 3 groups of eyes were compared. Group 1 consisted of 20 eyes at risk to the development of acute closed-angle glaucoma that had been treated with prophylactic pilocarpine for at least 8 years. Group 2 consisted of 20 eyes at risk that had received no treatment and had been followed up for at least 4 years. Group 3 comprised 20 eyes in which there was no evidence of glaucoma. There were highly significant differences between the 3 groups. The 60 eyes were then provoked with pilocarpine and phenylephrine; 90% of Group 1, 75% of Group 2, and none of Group 3 developed significant gonioscopic angle closure. These results suggest that asymptomatic partial angle closure was the cause of the observed changes and provide a naturally occurring model of one mechanism that can produce outflow damage without clinical symptoms.


Mechanisms in ocular hypertension.

Mechanisms in ocular hypertension. This paper investigates the hypothesis that intermittent partial angle closure is one of the causes of ocular hypertension. 139 eyes from 76 patients with ocular hypertension were provoked with pilocarpine and phenylephrine. Four distinct responses appeared. Firstly, in 39 eyes (from 24 patients, 32%) gonioscopic closure of part or all of the angle appeared. Secondly, in 30 eyes (from 19 patients, 25%) no angle closure occurred but there was a substantial pigment release into the aqueous. Thirdly, in 9 eyes (from 8 patients, 11%) both angle closure and pigment release occurred. Finally, in 61 eyes (from 36 patients, 59%) neither angle closure nor pigment release appeared. (Since the 2 eyes of a patient did not always behave in the same way, for example, 1 eye might develop angle closure and the other not, 1 patient may appear in 2 groups.) From the first group 1 eye from each patient was randomly chosen for iridectomy. A repeat provocative test at least 1 year later produced a significantly different result. It is considered that the evidence obtained in this study supports the hypothesis that intermittent partial angle closure is one of the causes of ocular hypertension.


Changes in refraction between the ages of 1 and 3 1/2 years. A study has been made of the changes in refraction as a sample of 148 children grew between the ages of 1 and 3 1/2 years. There was no decrease in hypermetropia, but there was a significant decrease in the incidence of astigmatism. Study of the changes in the refraction in the horizontal and vertical meridia of individual eyes gave clear evidence of a trend towards emmetropia if the initial refraction in either meridian was myopic or less than +2.50 D. Above that level the refraction became more or less hypermetropic.


Refraction of 1-year-old children after atropine cycloplegia. The refractions of 1648 children aged 11 to 13 months are reported. Atropine 1% was used for cycloplegia. 11.83% of the children had bilateral hypermetropia of +2.00 or more D. 13.23% of them had +1.50 or more D astigmatism in one or both eyes, and 6.5% had anisometropia. Anisometropia was significantly (P=0.000 001%) associated with bilateral hypermetropia, but even more significantly (P=0.000 000 4%) associated with astigmatism of +1.50 or more D in one or both eyes.


Refraction of 1-year-old children after cycloplegia with 1% cyclopentolate: comparison with findings after atropinisation. Cyclopentolate 1% is significantly less effective than atropine 1% at producing cycloplegia in 1-year-old children. If cycloplegic refraction is to be used for investigation or screening children for visual defects during the sensitive period, the more prolonged and profound cycloplegia following atropine could potentially have a disastrous effect on the development of vision. Cyclopentolate 1% would have to be used, and allowance made for its inadequacy as a cycloplegic.


A simple method of detecting abnormal retinal correspondence. A method is described of determining the state of retinal correspondence by means of an ordinary streak retinoscope used to produce a modified after-image test.


Silicone oil in the treatment of massive preretinal retraction. I. Results in 105 eyes. A study of 105 eyes in which intraocular injection of silicone oil was used to treat retinal detachment with massive preretinal retraction showed that early results were encouraging, and anatomical and visual results correlated well. Operative complications had little influence on the immediate outcome, the reasons for failure being poor case selection or inadequate surgical technique. When a deterioration occurred during the postoperative period it was found to be associated with late complications, particularly cataract; redetachment occurred in only a small number (12%) of cases.


Silicone oil injection in the treatment of massive preretinal retraction. II. Late complications in 93 eyes. Long-term assessment of eyes in which silicone oil injection had been used in the treatment of retinal detachment with massive preretinal retraction was undertaken in 92 consecutive patients. While a high incidence of complications, particularly cataract, was confirmed, this study showed that they were probably caused not by any toxic effect of silicone oil but by obstruction of normal metabolic exchange at the silicone-tissue interface. The incidence of complications causing deterioration of vision or serious symptoms was not found to be high, and navigating vision was well preserved.


Efficacy of acycloguanosine against herpetic ulcers in rabbit cornea. The effect of a new antiherpetic compound of very low toxicity called acycloguanosine (Wellcome 248U) on herpetic ulcers in rabbit cornea was studied by the Corneal Epithelial Lesion Therapeutic Assay (CELTA). The therapeutic effect of 3% acycloguanosine ointment on dendritic ulcers was equal to that of 0.5% 5-iodo-2'-deoxyuridine (IDU) ointment. No toxic symptoms could be detected by slit-lamp on 4 days' treatment with this concentration of acycloguanosine. Because of its selective action on virus only, its extremely low toxicity in animals, and its availability for systemic administration, acycloguanosine seems to be an ideal antiviral compound for use in the treatment not only of herpetic keratitis but also of other herpetic diseases in man.


Experimental Pseudomonas keratitis in guinea-pigs: therapy of moderately severe infections. We have previously shown that antibiotic therapy of experimental Pseudomonas keratitis was more effective in early moderate infections than in late severe infections. The purpose of this study was to determine the relative efficacies of various drugs, routes, and vehicles in the treatment of moderately severe infection. As in the late severe infections, the most consistently effective regimen was an aminoglycoside applied topically in solution. No synergistic or additive effect was observed with a combination of aminoglycoside given topically and a penicillin given intramuscularly. Topical therapy with antibiotic in ointment was less effective than topical therapy with antibiotic in solution.


Survey of ophthalmic conditions in a Labrador community. I. Refractive errors. Of the 745 available members of the population of Nain in Labrador 650 (87%) were screened for refractive errors and ocular disease. Refraction by retinoscopy was done in 553 and axial length measured by an optical method in 514. The results showed that the incidence of low degrees of myopia was higher in Inuit (Eskimos) and those of Mixed Inuit-Caucasian blood in the age groups 10 to 40 than in those over 40. 75% of the myopes came from 20 families in which myopia was present in 2 or more generations. Although there was no significant correlation between the refraction of parents and offspring, there were significant correlations between them for axial length. The axial lenths of the myopic eyes of the Inuit and Mixed populations were significantly longer than emmetropic and hypermetropic eyes. The younger memebers of the population were taller than their parents, and except in female Caucasians axial length showed a significant positive correlation with height. More myopes than emmetropes and hypermetropes achieved grade 8 or more in school. It is suggested that the increased incidence of myopia in the younger age groups might be due to environmental factors interfering with the process of emmetropisation in eyes with a genetic predisposition to myopia by virtue of inheriting a slightlt longer eye. Better nutrition resulting in an increase in stature may also have had some influence.


Influence of a prolonged period of low-dosage x-rays on the optic and ultrastructural appearances of cataract of the human lens. Human lenses extracted for cataract 26 years after long-term exposure to an imperfectly shielded radium source were examined by slit-lamp photography, thin-section light microscopy, and electron microscopy. Anterior epithelial cells were fibroblast-like, and germinal epithelium and vacuolated cortical fibres had accumulated at the equator. A zone of light scatter at the anterior pole corresponded to an area of breakdown of cortical lens fibres, where unusual feathery fibres were orientated perpendicular to the lens surface. Two zones of light scatter separated by a 250-microM clear interval were seen in the posterior cortex. The zone at the posterior pole corresponded to an area of fibre liquefaction and large rounded membrane whorls, while the deeper zone comprised small flattened membrane whorls. The characteristic plaques of swollen abnormal cells described in previous histological studies of x-ray cataract were not present. This and other differences probably reflect the extremely long time course and repeated subliminal doses to which the patient was exposed.


Cataract extraction complicated by capsular glaucoma. Synechiae involving the iris pigment epithelium and the peripheral anterior lens capsule occur in capsular glaucoma. During cataract extraction they may bring about traction on the capsule threatening its rupture. The ultrastructural basis of these adhesions is a bonding of pigment cells to capsular surface by pseudoexfoliative material.


Trial of a laminated material to reduce glare in cataract. A recently-introduced laminated material which accepts light only over a small angle on either side of the normal was compared to standard Polaroid sunglasses. A preliminary trial failed to show any superiority of the new material in reducing glare for patients with moderate cataract.


'Silicone rubber' lenses in aphakia.

'Silicone rubber' lenses in aphakia. Tesicon, one of the commercially available 'silicone rubber' lenses, was used in the correction of aphakic patients. In 74% of cases the lenses were considered successful for a daily wear regimen by the patient. Furthermore, a small number of patients could wear this lens without interruption for 3 to 6 days at a time. Despite this good acceptance by patients, corneal problems (mainly staining) and lens problems (dry surfaces) were frequently encountered.


Endothelial bedewing of the cornea in association with contact lens wear. Endothelial bedewing is described as either a cluster of oedematous droplets or a constellation of leucocytes deposited on the surface of the corneal endothelium. The use of marginal retroilumination in biomicroscopy is described for the detection of endothelial bedewing. Some of the clinical characteristics of endothelial bedewing are outlined, and its occurrence in patients who are chronically endothelial bedewing may be indicative of a limited anterior uveal response associated with contact lens wear.


An improved diagnostic contact lens.

An improved diagnostic contact lens. Modification of a standard Goldmann goniolens by reducing the curvature of the contact surface to 8.5 mm radius of curvature (from the standard curvature of 7.4 mm) enabled gonioscopy to be carried out without the nuisance of air bubbles.


Visual loss and foveal lesions in Usher's syndrome. Forty-eight patients with Usher's syndrome were assess for the degree of visual loss, extent of lens opacities, and presence of foveal lesions. Twenty-one patients (44%) showed either atrophic or cystic-appearing bilateral foveal changes. Despite having foveal lesions and variable degrees of lens opacities most patients maintained central visual acuity of 20/60 or better until their middle 30s.


Excessive permeability in diabetic maculopathy. Four cases of diabetic maculopathy with excessive permeability are described. Fluorescence angiography is distinctive, showing profuse early leakage from the entire capillary bed of the posterior pole. Careful studies have failed to reveal any cause for this excessive permeability response at the macula or any constantly associated medical abnormality. The prognosis for visual acuity is poor, and photocoagulation has only rarely been successful in maintaining or improving vision in these patients.


Macular pigment deposits in rhegmatogenous retinal detachment. This is a study of 20 cases of macular migration after operation for retinal detachment. The frequency of pigment deposits on the macula among the total number of operated detachments was 6.4%. The evolution of pigment migration depened on the form and type of the deposits. In some cases the pigment diminished or disappeared. In 6 of the 20 eyes with pigment migration puckering of the macula occurred 4 months or more after surgery. The improvement in visual acuity 6 months and more after operation was relatively less in the group with pigment deposits than in the group without pigment. In the former group static perimetry showed defects corresponding to the pigment migration.


The fishmouth phenomenon in retinal detachment: old concepts revisited. The 'fishmouth phenomenon' seen in some previously treated retinal detachments is associated with large horeshoe tears and scleral buckling techniques. A method of treating patients with this complication is described in which scleral buckling with implant or explant is not used. The technique utilises intravitreal air tamponade with cryopexy and gives good results. The incidence of patients developing the fishmouth phenomenon as a complication of parimary simple retinal detachment surgery is much lower when an intravitreal air technique is used than the expected incidence following a primary scleral buckling operation.


Anhidrotic ectodermal dysplasia with lacrimal anomalies. Ectodermal dysplasia and its related disorders may present with ocular symptoms due to involvement of the ectodermal components of the eye. This paper reports a case of congenital anhidrotic ectodermal dysplasia presenting to the ophthalmologist with epiphora due to lacrimal atresia. The embryonic origin of the lacrimal system suggests that lacrimal anomalies in association with ectodermal disorders are commoner than reports indicate. Their management consists in accurate evaluation of the anomaly followed by surgery.


Inequality of the direct and consensual light reflexes in normal subjects. Anisocoria in darkness and during reflex responses to unilateral light stimulation was studied in 150 normal subjects with television pupillometry. It was commonly found that the direct light reaction of the stimulation eye exceeded the consensual reaction of the other eye. This light-induced anisocoria, termed 'contraction anisocoria', had a mean value of 0.075 mm or 6.1 % of light reflex amplitude. The measurement showed a high degree of repeatability in 20 subjects who were tested on two occasions a year apart. It occurred in the presence and absence of prior dark adaptation and increased proportionally with reflex amplitude as the intensity of the stimulating light was raised. IT IS CONCLUDED THAT, CONTRARY TO PREVIOUS OPINION, A SMALL DEGREE OF CONTRACTION ANISOCORIA IS NORMAL.


Leucocyte ascorbic acid and the leucocyte count. 1. During the course of a nutritional survey on an Antarctic base, leucocyte ascorbic acid estimations (Denson & Bowers, 1961) were found to be significantly affected (P less than 0.0001) by the leucocyte count measured during analysis. 2. The effect was significantly less (P less than 0.05) when leucocyte levels were at or near saturation than when subsaturated. 3. This suggests that leucocytes share available ascorbic acid, especially in subsaturated subjects, and that assessment of nutritional status from the leucocyte ascorbic acid level should take account of the leucocyte count and the plasma ascorbic acid titre.


A preliminary simulated iron fortification trial in South Indian preschool children. 1. The effect of fortification of food with iron to provide 10 mg elemental Fe/child per d was studied in preschool children maintained on a cereal diet, over a 5-month period. 2. The absorption of 5 mg Fe as ferrous sulphate mixed in one meal was 3.3% of the test dose and when 3.3 mg was given with each of three meals over a 2 d period the corresponding value was 4.8%. 3. The mean absorption of a test dose of ferrous ascorbate studied in twenty-four children midway through the trial was 42%. 4. The only beneficial effect of Fe fortification in this time-period in the experimental group was the prevention of the decrease in packed cell volume which occurred in the control groups.