Proliferation of diffusion chamber colony-forming units (CFUD) in cultures of normal human bone marrow in diffusion chambers in mice. Normal human bone marrow contains cells capable of forming colonies of hemopoietic cells in fibrin clots in diffusion chambers implanted intraperitoneally (i.p.) into irradiated mice. The present paper describes the proliferation of such colony-forming units (CFUD) in cultures in vivo. Cells harvested from diffusion chambers after 1-14 days of culture in 450-R irradiated mice contained CFUD, which formed neutrophilic, eosinophilic, or megakaryocytic colonies when tested by secondary culture in fibrin clot chambers. When bone marrow was precultured in irradiated mice at a concentration of 10(6) cells per chamber, an initial fall in the number of neutrophilic CFUD was observed. This decrease was followed by an increase to a maximum at day 2, and then a secondary decrease. The number of neutrophilic CFUD recovered after 2 days of preculture in irradiated mice varied between 60% and 250% of the number present before preculture. Preculture in nonirradiated mice resulted in a significantly lower recovery of neutrophilic CFUD. In vitro treatment of bone marrow cells with hydroxyurea (OHU) after 2 days of preculture in irradiated mice resulted in a 68% +/- 5% reduction in the number of neutrophilic CFUD. In contrast, OHU had no similar effect on precultures from nonirradiated mice. Both the recovery and sensitivity to OHU of eosinophilic CFUD were independent of host irradiation. Similarly, no effect of host irradiation on the recovery or the 3H-thymidine (3HTdR) labeling index of morphologically recognizable granulocytic cells was observed at day 2. The data suggest an effect of humoral host factor(s) on the proliferation of early precursor cells, which are or become committed to differentiate into the neutrophilic pathway in diffusion chambers.


Congenital neutropenia: an intrinsic cell defect demonstrated by electron microscopy of soft agar colonies. Congenital neutropenia (CN), a disease characterized by recurrent infections leading to death in infancy, shows a maturation arrest of the myeloid series at the promyelocyte-myelocyte level. The potential value of marrow transplantation in this disease would be determined by the nature of the underlying defect. However, studies to date have failed to define whether the defect is intrinsic in the cells or attributable to "environmental" factors. Therefore, marrow of four patients with CN was cultured on soft agar, and the colonies were analyzed by a newly developed ultrastructural method. In parallel, patients' cells were used in feeder layers for normal marrow. Although the patients' colonies appeared grossly normal in size and number, electron microscopy showed only rare neutrophil colonies. These colonies contained markedly aberrant cells exhibiting asynchronous nucleocytoplasmic maturation, convoluted nuclei, excessive cytoplasm, and dearth of granules. Monocyte and eosinophil colonies differentiated normally. Patients' cells and sera supported growth of normal colonies. The studies have demonstrated unequivocally that the neutrophil cell line of patients with CN is intrinsically defective and suggest that attempts at marrow grafting are warranted.


Free erythrocyte porphyrin: hemoglobin ratios, serum ferritin, and transferrin saturation levels during treatment of infants with iron-deficiency anemia. Free erythrocyte porphyrin:hemoglobin (FEP:Hb) ratios were determined on 20 infants with iron-deficiency anemia. FEB:Hb ratios were compared with simultaneously drawn serum ferritin and serum transferrin saturation levels. FEP:Hb ratios dropped steadily during treatment of the anemic infants, but remained elevated compared to age-matched nonanemic infants, until the anemia was corrected. FEP:Hb ratios detected iron deficiency when acute inflammatory disease was present. Serum ferritin levels and transferrin saturation failed to detect iron deficiency after iron therapy was started or when acute inflammatory disease was present. Measurement of FEP:Hb ratios is a reliable and practical way to make a prompt diagnosis of iron-deficiency anemia in infants.


Intraerythrocytic adaptation (2,3 DPG,P50) in thalassemia minor. P50 and 2,3 DPG content of erythrocytes were determined in 25 patients with heterozygous beta thalassemia minor to assess the adaptive mechanisms to anemia. 2,3 DPG levels were appropriately elevated for the degree of anemia. However, P50 values were not proportionately increased. No correlations were noted between hemoglobin level, 2,3 DPG, or P50 and the presence of symptomatic complaints of fatigue or weakness in these heterozygous patients.


Glucose-6-phosphate dehydrogenase deficiency and red cell glutathione peroxidase. The activity of glutathione peroxidase (GSH Px), glucose-6-phosphate dehydrogenase (G-6-PD), hexokinase, and glutamic oxaloacetic transaminase (EGOT) was measured in 78 blood samples. GSH Px activity was not found to correlate with hexokinase or EGOT activity, indicating that it was not a strongly age-dependent enzyme. Although modest elevations of GSH Px activity were observed in the red cells of patients with a variety of hematologic disorders, the most consistent and striking increases in activity were observed in G-6-PD-deficient subjects.


Effects of ascorbic acid on glucose-6-phosphate dehydrogenase-deficient erythrocytes: studies in an animal model. There is little information available concerning the possible effects of ascorbic acid on glucose-6-phosphate dehydrogenase (G-6-PD) -deficient erythrocytes. We therefore studied the survival of G-6-PD-deficient cells, incubated with ascorbic acid, in rats with partial reticuloendothelial and complement blockade. Animals were pretreated with ethyl palmitate and cobra venom factor. They were then transfused with 51Cr-labeled erythrocytes which had been incubated in the presence or absence of ascorbic acid. G-6-PD-deficient cells, incubated with ascorbic acid, had impaired survival when compared to that of controls. G-6-PD-deficient cells, in the absence of ascorbic acid, had survival times equal to those of normal control erythrocytes. At the concentrations used, ascorbic acid did not appear to alter the survival of normal cells. Ascorbic acid causes premature loss of G-6-PD-deficient human erythrocytes in this rat model. On the basis of previous clinical and experimental observations, as well as this study, caution should be used when administering ascorbic acid in large doses to individuals who might be G-6-PD deficient.


Techniques for demonstration of the specificity of circulating anticoagulants against antihemophilic factor (factor VIII), with studies of two cases possibly related to diphenylhydantoin therapy. Circulating anticoagulants against antihemophilic factor (AHF, factor VIII) sometimes seem to inactivate other clotting factors as well. Measurements of the concentration of clotting factors in highly diluted plasma, or after neutralization of the anticoagulant with purified AHF, have demonstrated the specific nature of the anticoagulant in a patient under treatment with diphenylhydantoin. A second case in a patient treated with this agent, and with penicillin, an agent previously associated with the evolution of circulating anticoagulants, is also described.


Migration of transfused granulocytes in leukopenic dogs. Although granulocyte transfusion therapy has been shown to be effective in infected granulocytopenic animals and humans, the relative effectiveness of granulocytes (PMN) harvested by continuous flow centrifugation (CFC) or by continuous flow filtration leukapheresis (FL) remains uncertain. Studies in vitro of morphology and granulocyte functions have suggested cells collected by FL may be damaged. To compare the function in vivo of granulocytes collected by different methods, dogs were made granulocytopenic with cyclophosphamide (CYT) and then transfused with granulocytes collected by CFC or FL. The local neutrophil mobilization (LNM) through a standard skin abrasion into a chamber containing a strong chemoattractant, autologous serum, was measured. Greater LNM was found after transfusions of CFC PMN than after transfusions of the same number of FL PMN (p less than 0.0003). This difference persisted even when the dose of FL PMNs was four times greater than that of CFC mn and when the FL donor was pretreated with steroids (p less than 0.001). These results suggest that during filtration leukapheresis, granulocytes are functionally altered and that their function in vivo may be compromised.


On the measurement of vascular and respiratory smooth muscle responses in vitro. The action of drugs on circular smooth muscle from rabbit renal artery, renal vein, mesenteric vein, inferior vena cava, guinea pig bronchus, and mouse trachea was studied using an inexpensive modification of the method of Bevan, Nielsen and Owman, and Bevan and Osher. Two 30-gauge disposable stainless steel hypodermic needles supported the tissue rings in a standard 10-ml isolated muscle bath. All the blood vessels contracted to norepinephrine, histamine, and KCl. The veins, unlike the renal artery, did not respond maximally to KCl and did not contract at all to serotonin. The guinea pig bronchi contracted to carbachol, histamine, and KCl and relaxed to isoproterenol. The mouse trachea contracted maximally to carbachol, did not contract to histamine, and contracted to 50% of maximum in response to KCl. Thus, standard isolated tissue baths can be inexpensively adapted for the study of relatively small blood vessels and airways (about 1 mm in diameter).


Development of neuroeffector mechanisms in the carotid artery of the fetal lamb. A survey has been made of mechanisms associated with vascular adrenergic neuroeffector transmission in the lamb fetuses between 53 days and term gestation. The common carotid artery was isolated for studies of enzymic activities, uptake of norepinephrine (NE) and reactivity to vasoactive agents. The extra-neuronal NE uptake, monoamine oxidase and catechol-O-methyltransferase activities were present in the carotid artery of the youngest fetuses. The contractile responses to NE and serotonin and neuronal NE uptake preceded the response to adrenergic nerve stimulation during fetal growth. These results suggest that the mechanisms for adrenergic transmitter inactivation, transmitter action on vascular smooth muscle cells, and neuronal transmitter delivery develop in that sequence.


Uptake and metabolism of noradrenaline by the mesenteric arteries of the dog. Uptake and metabolism of tritiated noradrenaline by the mesenteric arteries of the dog and concomitant behaviour changes in endogenous noradrenaline are described. Posterior mesenteric artery strips were incubated for 30 min in Krebs solution containing (-)-7-3H-noradrenaline (1,084 muM); suitable pretreatments and/or preincubations were performed to study the influence of some drugs on these parameters. The atrial strips showed a high capacity to retain, accumulate and metabolize exogenous noradrenaline. At the concentration of noradrenaline studied, neuronal uptake and deamination represented the main inactivation mechanism, however, when neuronal uptake was blocked, extraneuronal deamination and o-methylation played a more important role, o-Methylation represented a vicarious enzymatic route when monoamine oxidase activity was inhibited. Iproniazid pretreatment increased markedly the endogenous noradrenaline content of the mesenteric arteries. During incubation with tritiated noradrenaline both an outflow of endogenous noradrenaline and an inflow of tritiated noradrenaline were observed.


Alterations in calcium transport and binding by the plasma membrane of mesenteric arteries from spontaneously hypertensive rats. The effect of Sr++, Ba++ and Mn++ on calcium uptake by a plasma membrane-enriched fraction from mesenteric arteries of spontaneously hypertensive rats (SHR) was studied to determine what alterations in divalent cation interactions are associated with hypertension. 45Ca++ uptake in the presence of ATP by this fraction from SHR was significantly greater than that of normotensive rats (NWR). This 45Ca++ uptake by these fractions from both types of rat could be reduced by Ba++, Sr++ and nonradioactive Ca++, but not by Mn++; the ability of these cations to compete with 45Ca++ was in the following order Ca++ greater than Sr++ greater than Ba++. In contrast, 45Ca++ uptake in the absence of ATP by this subcellular fraction from SHR was significantly less than that of NWR, and this passive 45Ca++ binding could be displaced by Mn++ in addition to the other cations. Both qualitative and quantitative differences were found between SHR and NWR in this study of the effects of cations on calcium uptake by arterial plasma membrane. These results suggest that the plasma membrane of SHR arteries has calcium-binding and transport properties that are different from those of NWR. However, there is not a complete correlation between the reported effects of the cations on contraction of other arteries in hypertension and on calcium uptake by membranes of SHR and NWR.


Adrenergic potentiation by angiotensin II in isolated canine cutaneous arteries: effect of bathing media and calcium. Contractions were elicited by field stimulation and norepinephrine in canine cutaneous arteries in Krebs-bicarbonate and Krebs-Tris media and the effect of angiotensin II, 1 x 10(-7) M, on these responses was determined. The absolute magnitude of the field stimulation responses was much greater in the bicarbonate buffer. Angiotensin caused potentiation in both media of the responses to field stimulation and norepinephrine. In Triss buffer with 5 mM calcium the responses to field stimulation and norepinephrine were greater than in 2.5 mM calcium, however; the degree of potentiation caused by angiotensin was similar at both calcium concentrations. The angiotensin potentiating effect in vitro appears to involve a postsynaptic action of the polypeptide which is not affected by alteration of calcium concentration or the medium.


Uptake of 3H-norepinephrine in rabbit mesenteric blood vessels. The uptake of traited norepinephrine in isolated rabbit mesoduodenal blood vessels was measured. Neuronal uptake was estimated utilizing the inhibitory effect of cocaine, and expressed on the basis of wet and dry tissue weights as well as circumferential area of the vascular wall. This area was presumed to approximate the area of the adrenergic nerve terminal plexus. The wet weight of smaller tissues was apt to be underestimated due to excessive drying during weighing; dry weight was more consistent over a wide range of tissue size. Either on the basis of weight or circumferential are, neuronal uptake in arteries increased as the diameter diminished, but uptake was practically constant in all segments of the veins. Arterial uptake per unit circumferential area was greater than in the accompanying veins, but this was not necessarily the case when uptake was expressed per unit weight. Neuronal norepinephrine may be a useful index of adrenergic nerve density. On this basis it is suggested that the adrenergic neural vasoconstriction increases with decrease in diameter of both arteries and veins in rabbit mesoduodenum.


Elastin fragmentation in the pulmonary artery of the newborn rabbit. Pulmonary arteries of rabbits aged 1 day to 2 months were distended at 44 mm Hg pressure and sectioned for study with the light microscope. Photographs were enlarged, and the frequency distributions of elastin lengths obtained at different ages. Maximum fragmentation occurred in the inner third of the artery, and was most marked at 3 weeks of age. No significant growth, or change in number of elastin lamellae occurred at this age. The fibres tended to be circumferential except in rabbits 4 weeks of age, where they were slightly helical.


Fibrinogen Marburg a new genetic variant of fibrinogen. A new case of congenital dysfibrinogenemia has been discovered in a 20 year old woman, who suffered from a severe postpartal hemorrhage after the delivery of her first child, followed by episodes of thrombosis. Coagulation studies reveal a prolongation of thrombin time, reptilase time was immeasurable. Thromboplastin time and partial thromboplastin time were slightly prolonged. Low fibrinogen levels were obtained by techniques, which depend on the coagulation velocity following addition of thrombin, while immunological procedures gave slightly diminished values of fibrinogen. Patients's fibrinogen had a moderate inhibitory effect on the fibrin formation in normal plasma. However, inhibitors of the fibrinogen-fibrin conversion could not be detected. Coagulation factors were normal, fibriolysis as well. The cause of the coagulation disorder was found to be a defect of the fibrinogen molecule, leading to an abnormal fibrin polmerization of patient's fibrin monomers. The release of the fibrinopeptides in the paperelectrophoresis was normal. The defect of the fibrinogen molecule did not protect from thrombotic complications. The same defect could be found in the lower scale in patient's father, 4 of her 7 brothers and sisters, and her son.


Clinical and cytogenetic observations during a six-year period in an adult with Fanconi's anaemia. A male adult patient suffering from Fanconi's anemia is described who was diagnosed 5 years before the onset of clinical symptoms by cytogenetic findings of chromosomeinstability in a lymphocyte culture. Repeated clinical, haematological and biochemical investigations of the untreated patient have been made during the observation period of six years. In the same period of time cytogenetic studies have been carried out which show no correlation in results compared with the clinical or physical findings. Four well defined lymphocyte clones have been discovered. The patient is still under observation of the clinic and the cytogenetic department.


[Conditioning of thrombocyte count changes and other components of human capillary blood]. An unconditioned rise in the number of platelets in the capillary blood of man, induced by dynamic exercise in the form of pedalling an ergobicycle (18 mkp/sec, 30 min), was conditioned to blinking light signal of low intensity in 5 healthy men. After 4, 7 and 11 reinforcements (1 per day) in all cases a conditioned rise could be observed, which remained extant---although slightly weaker--for 18 days without any reinforcement after the last trial. The authors assume that this fact is pointing out a direct participation of the platelets on nervous processes.


[Fibrinogen "Hannover", a further abnormal fibrinogen]. Another abnormal fibrinogen--"fibrinogen Hannover"--is reported. As known from most dysfibrinogenemias the clottability is poor, while immunologic test, heat precipitating test and the staphylococcal clumping test give normal fibrinogen concentrations. The clotting time when using thrombin or thrombin like enzymes is prolonged, it can be corrected with high thrombin concentration or thrombin combined with calcium inons, but not with thrombin like enzymes combined with calcium ions. The mild bleeding diathesis was first noted when the patient underwent an operation.


Mercury levels in freshwater fish of the state of South Carolina. Samples of fish from freshwater sources of rivers, lakes and ponds all over the state of South Carolina were collected during the Summer of 1974 and 1975. The fish collected were Bass, Bluegill, Redbreast, Catfish, Shad, Carp, Crappie, Mudfish and Pike. Samples were analyzed using the flameless atomic absorption procedure outlined by Hatch and Ott, and Uthe et al as modified for use with Perkin-Elmer, Coleman MAS-50 mercury analyzer. Triplicate samples of fish tissue were analyzed by wet digestion method. The mean mercury levels in ppb were determined for baseline mercury levels. A significant finding of this report is that those species for which fish of widely differing weights were analyzed, larger fish had higher mercury levels. Mercury levels exceeding the U.S. Food and Drug Administration guideline of 500 ppb for fish tissues have been found in the Mudfish from Edisto River and Pike fish from Lake Murray. Higher levels of mercury occurred in the highly vascularized blood tissues of liver and kidney than in muscle. Carnivorous and bottom-feeding fishes are the most reliable indicators of mercury pollution.


What is Gorlin's syndrome? The diagnosis and management of the basal cell naevus syndrome, based on a study of thirty-seven patients. A series of 37 patients with Gorlin's syndrome is described; 23 had the typical naevi, 19 had jaw cysts and only 10 had both. A wide range of associated deformities was noted. The need for early identification of patients at risk is stressed; follow-up is essential for 2 reasons: The naevi although indistinguishable histologically from basal cell carcinomas only rarely require radical removal. The jaw cysts are locally invasive and should be radically removed when small. In 8 patients examined there was a low level of alpha-globulins in the plasma. Spontaneous involution of the naevi may occur in un-irradiated skin.


Incorporation of stored cell-free dermal collagen allografts into skin wounds: a short term study. Allogeneic dermal collagen has been evaluated as an alternative to skin autografts for the permanent replacement of lost or damaged skin in the rat. All non-collagenous structures were removed from full-thickness back skin by treatment with a solution of crystalline trypsin. Such dermal collagen preparations were grafted into skin wounds, examined up to 8 1/2 weeks after operation, and compared with excised wounds and skin isografts and allografts of the same initial size. The dermal collagen grafts, particularly when dressed with a sheet of dermal collagen, become recellularised, revascularised and re-epidermalised. Unlike the skin allografts, there was no evidence of cellular rejection. Whereas contracture of the excised wounds was delayed, but not suppressed, by applying a conventional dressing, collagen grafts maintained from 60 to 100 per cent of their original size. In contrast, equivalent skin isografts shrank to 50-60 per cent and showed persistent epidermal hyperplasia.


Buried penis.

Buried penis. Six cases of buried penis in childhood are recorded. An attempt has been made to clarify the nomenclature of a number of penile deformities over which there has been some confusion. The treatment of buried penis, which should be completed before school age, depends upon freeing the penile shaft from abnormal attachments and correcting the skin defect. The importance of the tethering fibromuscular bands between the penile shaft and abdominal wall has not previously been stressed.


Accumulation of radioactive cardiac glycosides by various brain regions in relation to the dysrhythmogenic effect. Ouabain was administered at a loading dose of 3 mug/kg followed by an infusion at a rate of 1 mug/kg-1 min-1 in order to produce severe dysrhythmia in dogs within 60 minutes. Similarly, digitoxin at a loading dose of 9 mug/kg followed by an infusion at a rate of 3 mug kg-1 min-1 was administered to compare its effect with that of ouabain. 2 During the 60 min experimental period, the plasma concentrations gradually rose with the continuous infusion of these drugs. However, in comparison to the 60 min plasma value of 119+/-20 pmol/ml for ouabain and 177+/-68 pmol/ml for digitoxin, the cerebrospinal fluid (CSF) concentrations for these drugs at this time were less than 5 pmol/ml. 3 Upon termination of the experiment at 60 min it was found that kidney, liver, heart, adrenal, and the non-neural tissue in the brain such as pituitary and choroid plexus concentrated ouabain and digitoxin to give high tissue to plasma ratios. However, various neural areas of the brain (cerebellum, mesencephalon, hypothalamus, pons, and medulla) showed no preferential localization or uptake of these two glycosides. 4 Concentration of ouabain and digitoxin by the choroid plexus does not seem to affect the ionic composition of the CSF. 5 It was concluded that sampling the large areas of neural tissue above could provide no evidence for local accumulation of digitalis glycosides that might account for a central nervous system origin of digitalis-induced cardiac arrhythmias.


Effect of p-bromophenacyl bromide, an inhibitor of phospholipase A2, on arachidonic acid release and prostaglandin synthesis by the guinea-pig uterus in vitro. The synthesis of prostaglandins F2alpha and E2 by guinea-pig uterine homogenates was inhibited by p-bromophenacyl bromide (PBPAB), an inhibitor of phospholipase A2. 2 Metabolism of prostaglandin F2alpha by uterine homogenates was undetectable; this was not affected by PBPAB. 3 There was no significant difference between the amounts of arachidonic acid released from uterine homogenates on days 7 and 1k of the oestrous cycle. Small amounts of dihomo-gamma-linolenic acid were detected in the homogenates. 4 The release of arachidonic acid from uterine homogenates was greatly inhibited by PBPAB. 5 Addition of exogenous arachidonic acid to uterine homogenates did not overcome the inhibition of uterine prostaglandin F2alpha synthesis produced by PBPAB. 6 It is concluded that PBPAB inhibits both the release of arachidonic acid from the guinea-pig uterus and its subsequent conversion into prostaglandins.


Potentiation of the response to vasopressin (pitressin) by treatment with a combination of chlorpropamide and chlorothiazide in Brattleboro rats with hereditary hypothalamic diabetes insipidus. 1 The effect of a combination of chloropropamide and chlorothiazide in Brattleboro rats with hereditary hypothalamic diabetes insipidus (DI) treated with low doses of vasopressin (Pitressin tannate in oil) was investigated with particular reference to the time course of response from the initiation of treatment. 2 Analysis of the relationship between water intake and body weight indicated no real correlation and body weight accounted for only 4.4% of the variation in water intake. It was therefore decided to use whole body responses as the index in preference to the response per unit body weight. 3 The daily administration of 5 mg chlorpropamide combined with chlorothiazide in the drinking water (4 mg/1) to Pitressin-treated DI rats potentiated the response to small doses of vasopressin (25 and 50 mu Pitressin/24 hours). Water intake was reduced by the drug combination by an average of 12.35 ml/24 h, but only on the second day of treatment was the decrease of any real magnitude (30 ml/24 h but otherwise 9 ml/24 h or less). Analysis of urine volume measurements gave similar results to those obtained for water intake and the potency ratio measured in terms of free water clearance was 1.26 (agreeing closely with the ratio for water intake which was 1.24). 4 A reduction in the solute excretion was observed only in those DI rats treated with the higher dose of Pitressin (50 mu/24 h) combined with the two drugs. 5 Possible reasons for the discrepancy between the effect of the combination of chlorpropamide and chlorathiazide on water metabolism in the DI rat and the DI patient are discussed.


A comparison of the effects of sodium thiocyanate and dantrolene sodium on a mammalian isolated skeletal muscle. 1 A combination of electrical and pharmacological stimulation has been used to compare the effects of sodium thiocyanate and dantrolene sodium on the excitation-contraction coupling (ECC) mechanism of the mouse soleus muscle. 2 Thiocyanate prolonged the 'active state' after electrical stimulation and increased the response to 8 mM caffeine and 80 mM KCl. Dantrolene had an opposite effect to thiocyanate on all the indices studied. 3 It is concluded that the mechanism of action of dantrolene is by inhibition of the release of the calcium ions involved in the ECC mechanism, probably at the level of the transverse tubules.


Interaction of cocaine with chlordiazepoxide assessed by motor activity in mice. 1 Effects of a range of doses of cocaine and chlordiazepoxide given separately and as mixtures were determined on the spontaneous locomotor activity of mice. 2 Cocaine increased locomotor activity (walking) during 3 or 5 min trials in a dose-related manner. 3 Chlordiazepoxide had little effect on the total amount of locomotor activity except for depression at very high doses. A lower dose of chlordiazepoxide increased activity at the beginning of the trials only. 4 Mixtures containing certain doses of cocaine and chlordiazepoxide increased locomotor activity ot a much greater extent than cocaine alone. This high level of activity was manifested throughout 5 min trials. 5 This action of cocaine is similar to that of amphetamine.


The effects of glucagon, secretin, pancreozymin and pentagastrin on the hepatic arterial vascular bed of the dog. 1 The sympathetically-innervated arterial vascular bed of the dog's liver was perfused from a femoral artery. Arterial blood flow and perfusion pressure were monitored continuously and the hepatic arterial vascular resistance (HAVR) calculated from these measurements. 2 Commercial preparations of secretin, pancroezymin, glucagon and pentagastrin were administered by intra-arterial (i.a.) injection and infusion. 3 Secretin and pancreozymin by injection caused dose-dependent hepatic arterial vasodilatation, and on a molar basis were both more potent than glucagon or pentagastrin. 4 Intra-arterial infusions of secretin and pancreozymin caused hepatic arterial vasodilatation at calculated blood concentrations close to those measured under physiological conditions by other investigators. The vasodilatation was of the same duration as that of the hormone infusions. 5 Pentagastrin by i.a. injection caused dose-dependent hepatic arterial vasodilatation; by i.a. infusion, vasodilatation occurred but there was marked 'escape' from the effects during the continued infusion. 6 As reported previously, glucagon by injection caused dose-dependent hepatic arterial vasodilatation of long duration; by infusion, glucagon caused vasodilatation that persisted after the cessation of the infusion. 7 Glucagon infused i.a. inhibited the vasoconstricter effects of i.a. noradrenaline, over the same range of infusions that caused hepatic arterial vasodilatation. 8 Secretin or pancreozymin did not antagonize the effects of noradrenaline on the hepatic arterial vascular bed at any doses used. 9 Pentagastrin did not antagonize the vasoconstrictor effect of noradrenaline whether hepatic arterial vasodilatation resulted from the pentagastrin infusion, or not. 10 These results are discussed with respect to the possible control of the hepatic arterial vascular bed by gastrointestinal hormones.


Effect of anti-thyroid agents, methimazole and propylthiouracil, on brain noradrenaline content. 1 Methimazole (1-methyl-2-mercaptoimidazole, MMI) and propylthiouracil (6-propyl-2-thiouracil, PTU) which are used in the therapy of hyperthyroidism were found to reduce brain noradrenaline (NA) content. Endogenous NA levels in rat brain were reduced from 1 to 6 h after intraperitoneal injection of MMI by doses in excess of 25 mg/kg and by PTU at a dose of 50 mg/kg. However, endogenous NA in the rat heart was only slightly reduced after 50 mg/kg of MMI, and was not affected by PTU (50 mg/kg). 2 Both MMI and PTU effectively inhibited the in vivo conversion of [3H]-dopamine into [3H]-noradrenaline ([3H]-NA) in the brain of rats after a single intraperitoneal injection of doses above 10 mg/kg (MMI) and 25 mg/kg (PTU). This inhibition by MMI and PTU was dose-dependent over the range of 10 mg/kg to 50 mg/kg, was highest after 2-3 h and continued for at least 6 h after their injection; The conversion rates returned to normal after 24 hours. 3 The results suggest that the reduction of brain NA by these drugs is, at least in part, due to the inhibition of brain dopamine beta-hydroxylase.


Thyroid hormone-dependent interconversion of myocardial alpha- and beta-adrenoceptors in the rat. 1 The effects of thyroid state on the properties of adrenoceptors mediating inotropic and chronotropic responses of the rat heart were assessed on the basis of the relative potencies of alpha- and beta-adrenoceptor agonists, the effects of alpha- and beta-adrenoceptor antagonists and the tissue uptake of [3H]-phenoxybenzamine ([3H]-PB). 2 In isolated, electrically driven left atria the ratio of the inotropic potencies of isoprenaline and phenylephrine and the inhibitory potency of propranolol (40nM-4 muM) were significantly reduced after thyroidectomy and were moderately increased after thyroxine treatment of control rats. 3 Block of inotropic responses to noradrenaline and to phenylephrine by PB (7.3 nM-7.3 muM) and the tissue uptake of [3H]-PB were significantly greater in preparations from thyroidectomized than in those from control or from thyroxine treated rats. alpha-Adrenoceptor inhibition by phentolamine (0.26-2.6 muM) also increased after thyroidectomy, and phentolamine effectively protected alpha-adrenoceptors from block by and binding of [3H]-PB. 4 The beta1-receptor antagonist H 93/26 (0.1 muM) significantly potentiated alpha-adrenoceptor blockade by PB in hypothyroid but not in control preparations. 5 In spontaneously beating right atria the chronotropic potency of agonists and the effects of antagonists were altered in the same way as were inotropic responses and the slope of the agonist concentration-response curves were significantly reduced after thyroidectomy. Effects of agonists and antagonists were not significantly influenced by thyroxine treatment. 6 Changes in the effects and tissue uptake of sympathomimetic drugs observed after thyroidectomy were reversed to or beyond control levels by thyroid hormone treatment of thyroidectomized animals. 7 The results presented are interpreted as indicating a thyroid hormone-dependent interconversion of myocardial alpha- and beta-adrenoceptors. It is suggested that this interconversion is similar to that observed earlier in frog hearts at different temperatures, and that both effects may reflect an allosteric transition between two forms of a single basic structure.


Production of prostaglandins by the pseudopregnant rat uterus, in vitro, and the effect of tamoxifen with the identification of 6-keto-prostaglandin F1alpha as a major product. 1 Prostaglandin production by rat uterus homogenates has been studied, in vitro, on days 2 to 13 of pseudopregnancy. 2 The highest production of prostaglandins occurred on day 5. 3 The amounts of prostaglandins F and D formed were higher than the amounts of prostaglandin E on every day studied. 4 The ratios of prostglandins F and D to prostaglandin E produced steadily decreased up to day 6. It then increased with the highest values occurring between days 10 and 13, 5 Progesterone levels in peripheral plasma increased rapidly from days 2 to 5, remained high up to day 9, then steadily decreased between days 10 and 13. 6 The anti-oestrogenic drug, tamoxifen administered on day 2, significantly inhibited the increase of prostaglandin production which occurred on day 5. Prostaglandin E production was inhibited more than the production of prostaglandins F and D. 7 Analysis of the uterine extracts by gas chromatography and mass spectrometry showed prostaglandin F2alpha, F1alpha (in trace amounts), E2 and D2 to be present. 8 The major product detected was 6-keto-prostaglandin F1alpha. Its identification forms an addendum to the paper. 9 Also present as a major product was 6(9)-oxy-11,15-dihydroxyprosta-7,13-dienoic acid.


Anaphylactic contraction of pulmonary blood vessels of chicken. 1 Isolated pulmonary arterial and vein strips from sensitized or non-sensitized chickens exhibited dose-dependent contractions to adrenaline greater than, noradrenaline greater than, 5-hydroxytryptamine greater than, histamine greater than, dopamine. Individual variability in the responsiveness of the vessels to agonists was marked. In general veins were 2 to 25 times more sensitive to agonists than arterial strips. 2 Isoprenaline (a relatively specific beta-adrenoceptor agonist) induced relaxation of the submaximally contracted pulmonary vein and arteries at low doses and contractions at high concentrations. 3 Contractile responses to acetylcholine or carbachol were not regularly recorded; only 50% of the vessels reacted to cholinoceptor agonists over a wide threshold dose range. 4 Chicken pulmonary vessels were found relatively insensitive to bradykinin. 5 Effects of prostaglandins were variable. Prostaglandin F2alpha induced dose-related contractions of the vein and arterial strips; prostglandins E1 and E2 at low doses partially contracted pulmonary artery irrespective of the spasmogen used and further increase in doses induced either no effect or contractions. Prostaglandin E1 induced marked and rapid contractions of the vein. Prostaglandin E2 induced relaxations of the prostaglandin F2alpha-contracted vein only, but produced no effect or slight contractions of the veins partially contracted to other spasmogens. 6 Pulmonary arterial and vein strips obtained from chickens sensitized to horse plasma exhibited Schultz-Dale contractions of variable magnitude and duration to specific antigenic challenge only. In many vessels, antigen-induced contractions were associated with marked increase in spontaneous activity. 7 The importance of the Schultz-Dale reaction in avian pulmonary vessels is discussed in relation to the right heart dilatation associated with anaphylaxis in the chicken.


The effects of reserpine and 6-hydroxydopamine on the concentrations of some arylakylamines in rat brain. 1 The concentrations of p- and m-tyramine were measured in the caudate nucleus of the rat brain following subcutaneous injection of reserpine or intraventricular injection of 6-hydroxydopamine, beta-Phenylethylamine was analysed in the hypothalamus after reserpine. 2 Endogenous levels of p-tyramine and m-tyramine in the caudate nucleus, and beta-phenylethylamine in the hypothalamus were 8.02, 2.25 and 2.52 ng/g respectively. 3 Tyramine concentrations were reduced to less than 20% of control values one day after a reserpine injection of 1 or 10 mg/kg. A single dose of reserpine (0.4 mg/kg) significantly decreased the content of both tyramines in the caudate nucleus. The effects became apparent as early as 45 min after drug case of m-tyramine. 4 The hypothalamic content of beta-phenylethylamine was unaffected by reserpine. 5 Ten days after an intraventricular injection of 6-hydroxydopamine (250 mug), p- and m-tyramine concentrations in the caudate nucleus were significantly below control levels. 6 The results suggest that p- and m-tyramine may be stored by an intraneuronal reserpine-sensitive storage mechanism. Alternatively, the tyramines may replace some of the catecholamines from their storage granules and then be released as false transmitters by the nervous impulse. The observed changes in tyramine levels might also the fact that these amines may be metabolically related to another amine which is stored in reserpine-sensitive granules.


Can barium support the release of acetylcholine by nerve impulses? Conventional electrophysiological techniques were used to study the effects of Ba on the release of acetylcholine (ACh) from frog motor nerve terminals. Equimolar substitution of Ba for Ca eliminated end-plate potentials (e.p.ps) without a corresponding decline in the amplitude of the nerve terminal action potential. Miniature end-plate potentials (m.e.p.ps) were readily detectable in Ba solutions despite a depolarized muscle membrane. Studies on the e.p.p. in curarized preparations bathed with different concentrations of Ca and Ba suggest that Ba may compete with Ca in the process by which depolarization of the nerve terminal leads to the release of ACh. Repetitive nerve stimulation at 1 Hz in Ba solutions caused 5-20 fold increases in m.e.p.p. frequencies (7 experiments). Stimulation of Ba-bathed preparations at 10 Hz elevated m.e.p.p. frequencies to very high levels that could not be measured accurately (''100/s). It is suggested that the asynchronous discharge of m.e.p.ps produced by repetitive nerve stimulation is the electrophysiological correlate of the evoked ACh outflow in Ba solutions detected previously by bioassay of ther perfusion fluid.


Stereospecificity of 2,4-diaminobutyric acid with respect to inhibition of 4-aminobutyric acid uptake and binding. S(+)-2,4-Diaminobutyric acid is at least 20 times more potent than the R(-) stereoisomer as an inhibitor of the sodium-dependent uptake of 4-aminobutyric acid (GABA) in rat brain slices. Both isomers, however, are equipotent as inhibitors of sodium-independent binding of GABA to membranes from rat brain. The latter finding may be relevant to the reported neurotoxicity in rats of both isomers of 2,4-diaminobutyric acid after intracisternal injection.


Dopamine and the depressant action of morphine on stimulated guinea-pig ileum. 1 Morphine reduces the amplitude of the contractions induced by electrical stimulation, in the myenteric plexus-longitudinal muscle preparation of guinea-pig ileum. Dopamine and apomorphine have the same effect but at much higher concentrations. 2 Dopamine, at concentrations lower than those which would normally be inhibitory, partially reverses the depressant effect of morphine. 3 Pre-treatment of guinea-pigs with 6-hydroxydopamine results in a slight supersensitivity of innervated longitudinal muscle preparations to dopamine and has no effect on morphine activity. 4 Naloxone antagonizes the depressant effect of morphine but not that of dopamine or apomorphine. 5 The response of theileum preparation to morphine is not affected by phentolamine or propranolol; the effect of dopamine, however, is abolished by alpha-adrenoceptor blockade.


The effect of non-steroidal anti-inflammatory drugs on adenosine triphosphate content and histamine release from rat peritoneal cell suspensions rich in mast cells. 1 Non-steroidal anti-inflammatory drugs (NSAID) suppressed compound 48/80-induced histamine release from rat peritoneal cells in vitro in a dose-dependent manner. 2 NSAID suppressed the adenosine triphosphate (ATP) content of rat peritoneal cells in vitro and this correlated strongly with the suppression of compound 48/80-induced histamine release. 3 The correlation demonstrated suggests that the mechanism of action of NSAID in the rat peritoneal cells is via depletion of cellular ATP.


Effects of adrenoceptor blockade on plasma catecholamine levels during adrenaline infusion. 1. The present experiments investigate the effects of phenoxybenzamine and propranolol, singly and in combination, on plasma catecholamine levels in sheep receiving a three-hour adrenaline infusion. 2. Five groups of five anaesthetized sheep were studied for a period of 3 h each. One group acted as a control and received only a saline (0.9% w/v NaCl solution) infusion. A second group received a constant infusion of adrenaline (2 mug kg body weight-1 min-1). A third group received a similar adrenaline infusion, having been premedicated with phenoxybenzamine (1 mg/kg body weight). A fourth group recieved a similar adrenaline infusion following premedication with (+/-)-propranolol hydrochloride (7 mug/kg body weight). The fifth group received the adrenaline infusion following premedication with both the alpha- and beta-blocker in the above doses. 3. Plasma catecholamines were measured on blood samples taken at seven intervals before during and following the infusion. 4. Control animals receiving only a saline infusion remained physiologically and biochemically stable throughout the experimental period. 5. Adrenaline infusion in animals not receiving adrenoceptor blocking drugs caused a rise in plasma adrenaline levels from a low basal value of 1 mug/litre to a maximum level of 19.8 mug/litre. Animals premedicated with phenoxybenzamine exhibited a similar response. 6. Animals premedicated with propranolol before the infusion of adrenaline did not demonstrate as marked a rise of plasma adrenaline levels as the two previous groups. The maximum mean plasma adrenaline level recorded in this group was 6.88 mug/litre. 7. Animals premedicated with phenoxybenzamine and propranolol before the infusion of adrenaline showed only a small rise in plasma adrenaline levels compared with animals receiving adrenaline infusion alone. The maximum mean plasma adrenaline level in the group was only 3.43 mug/litre. 8. The studies demonstrate that by an unknown mechanism beta-adrenoceptor blockade with (+/-)-propranolol, either alone or in combination with phenoxybenzamine, lowers the plasma adrenaline response evoked by adrenaline infusion.


Atropine resistance and muscarinic receptors in the rat urinary bladder. The action of an anticholinesterase and an antimuscarinic drug upon nerve-induced contractions of the rat urinary bladder were examined during transmural stimulation at 20 Hz. Responses were graded in magnitude by limiting the duration of the stimulus trains. 2 Responses of low magnitude produced by short stimulus trains were unchanged by atropine; however, maximal responses resulting from long stimulus trains were diminished in magnitude and shortened in duration. 3 Responses of small magnitude elicited by short stimulus trains involve muscarinic receptors in close proximity to the neuroeffector junction and are resistant to atropine. 4 Maximal responses elicited by long stimulus trains involve 'junctional' muscarinic receptors as well as receptors located at the periphery of the junction; the 'extrajunctional' receptors are blocked by atropine. 5 Responses of low magnitude produced by short stimulus trains were unaffected by echothiophate; however, the duration of maximal responses resulting from the long stimulus trains was extended. 6 The inhibition of cholinesterase did not increase the occupation of muscarinic receptors by the transmitter; however, after large quantities of transmitter were released by the long stimulus trains the association between the receptors and acetylcholine was prolonged.


Selective reserpine-induced supersensitivity of the positive inotropic and chronotropic responses to isoprenaline and salbutamol in guinea-pig isolated atria. 1 Dose-response curves for the positive inotropic and chronotropic responses to isoprenaline were obtained in atria from untreated guinea-pigs and those receiving various reserpine pretreatments. 2 Tension responses were unaffected, whereas rate responses were depressed by the lowest dose of reserpine (0.05 mg/kg i.p. at 24 hours). 3 With larger 24 h doses and a 3 day pretreatment, the rate and tension dose-response curves were progressively displaced to the left, indicating supersensitivity which was greater for tension at each pretreatment. 4 No supersensitivity to histamine or Ca2+ could be detected, leading to the conclusion that it was selective for the beta-adrenoceptor agonists possibly at the receptor level. 5 As an indication of the adrenergic neurone depleting effectiveness of each reserpine dosage, preparations were exposed to test doses of beta-phenylethylamine. 6 Salbutamol was a partial agonist in untreated atria, the maximum rate (63.3%) and tension (10.0%) responses being less than those for isoprenaline. In atria from reserpine pretreated animals the supersensitivity was revealed as an increase of this maximum compared with isoprenaline. 7 The significance of this observation in relation to the possible mechanism of the supersensitivity is discussed.


The pharmacological properties of the cholinergic false transmitter, N-2-acetoxyethyl-N-methylpyrrolidinium, and its precursor, N-2-hydroxyethyl-N-methylpyrrolidinium. 1 The pharmacological properties of N-2-hydroxyethyl-N-methyl pyrrolidinium (pyrrolcholine) and its acetate ester, recently shown to be a false transmitter at the cholinergic electromotor synapses in Torpedo marmorata, also those of the corresponding morpholinium compounds (morpholinecholine, acetylmorpholinecholine) have been studied on the guinea-pig ileum, frog heart, rectus abdominis muscle, rat blood pressure, rat gastrocnemius muscle and dorsal muscle of the leech. 2 Acetylpyrrolcholine and acetylmorpholinecholine are full cholinoceptor agonists with dose-response curves parallel to that of acetylcholine. They are, however, less potent. Acetylpyrrolcholine is relatively more potent as a muscarinic drug (molar potency about 30% of that of acetylcholine in the ileum but only 4% on the leech) whereas acetylmorpholinecholine is more strongly nicotinic. The unacetylated compounds are very weak agonists with potencies comparable to that of choline. 3 Pyrrolcholine in high concentration showed a distinct neuromuscular blocking effect in the rat gastrocnemius muscle preparation. It is likely that this is a direct effect and not due to uptake by the presynaptic nerve terminals followed by conversion to a false transmitter since it was not reduced by hemicholinium-3, which is known to block uptake of choline and choline analogues by the presynaptic high affinity choline uptake system.


Theophylline and phenylephrine effects on cardiac relaxation. In the driven isolated left atrium of the rabbit theophylline shortened relaxation time in a similar manner to isoprenaline and histamine. 2 Phenylephrine lengthened relaxation time in a similar manner to calcium. 3 Theophylline caused phenylephrine to shorten relaxation time, which was inhibited by a beta-adrenoceptor blocking drug, but theophylline did not potentiate the effect of phenylephrine on peak tension. 4 Theophylline separated drug effects on cardiac relaxation and contraction: in the presence of theophylline at a low calcium concentration, phenylephrine shortened relaxation time by beta-adrenoceptor stimulation and increased peak tension by alpha-adrenoceptor stimulation. At a high calcium concentration, theophylline potentiated the effect of isoprenaline, histamine and phenylephrine on relaxation time but inhibited the effect on peak tension.


Nicotine stimulates prostaglandin formation in the rabbit heart. Rabbit isolated hearts were perfused according to Langendorff with Tyrode solution. Prostaglandin-like substances (PLS) in the effluent were purified and assayed on the rat stomach strip Noradrenaline (NA) in the effluent was assayed fluorimetrically. 2 Infusion of nicotine (1 muM-50 muM) caused a dose-dependent, brief increase, from 1.2+/-0.4 to maximally 8.3+/-2.1 ng/min, in the outflow of PLS from the heart. The increase was abolished by pretreatment of the heart with indomethacin. 3 Activation of nicotinic receptors in the heart with acetylcholine (ACh, 200 muM) in the presence of atropine (1 muM) also elicited an increase in the release of PLS. This release was smaller than that caused by nicotine. 4 Nicotine (50 muM) and ACh (200 muM) in the presence of atropine (1 muM) each caused a pronounced but brief release of NA into the effluent. There was no evident correlation between the ability of the drugs to cause release of PLS on the one hand, and NA on the other. 5 It is concluded that nicotine acts as a direct stimulus for the synthesis of prostaglandins in the rabbit heart.


Sleep induced by drugs injected into the inferior horn of the lateral cerebral ventricle in dogs. 1 In unanaesthetized dogs, cholinomimetic drugs and their antagonists were injected into the inferior horn of the left lateral cerebral ventricle. Injection volumes of 5 mul were used to limit spread of the drugs beyond the inferior horn. The effects on EEG and behaviour were recorded and compared with the effects of the same doses given into the body of the right lateral ventricle a little behind the foramen on Monro. 2 injections of cholinomimetic drugs into the inferior horn (acetylcholine 1-2 mug, physostigmine 1.0 mug, pilocarpine 100 mug and nicotine 10 mug) induced sleep during the following hour. The same doses injected into the body of the lateral ventricle did not produce sleep. 3 Cholinolytic drugs (atropine 10-20 mug, hyoscine 0.4-1.6 mug (+/-)-tubocuraine 10-20 ng and hexamethonium 40 mug) injected into the inferior horn also produced sleep, but the same doses injected into the body of the lateral ventricle were without effect. The EEG recorded after tubocurarine showed high voltage slow waves during sleep and desynchronized activation during rapid eye movement sleep. 4 Noradrenaline (10 mug) injected into the inferior horn produced sleep whereas the same dose given into the body of lateral ventricle did not produce sleep. The results with 5-hydroxytryptamine were equivocal. 5 It is suggested that the site for induction of sleep lies in structures lining the inferior horn of the lateral cerebral ventricle and that the cholinomimetic drugs probably act by a depolarizing block and the acetlycholine antagonists by a competitive block.


Vascular reactivity of perfused vascular bed in spontaneously hypertensive and normotensive rats. 1 Hypertensive and normotensive rats of the same age group were isolated from an inbred colony of spontaneously hypertensive rats. 2 The perfused hindquarter and mesenteric artery preparations obtained from hypertensive and normotensive rats exhibited an increased reactivity to noradrenaline (NA) and angiotensin II. 3 Dose-response curves to NA obtained from hypertensive and normotensive rats exhibited a steeper slope and higher maximum than those from control rats. 4 These findings suggest that increased vascular reactivity of blood vessels is independent of the development or maintenance of elevated blood pressure.


The role of bacterial contamination in the isolation of apparent anti-inflammatory factors from rabbit anti-lymphocytic serum. 1 Rabbit anti-guinea-pig lymphocytic serum was fractionated by gel filtration to obtain partially purified materials possessing anti-inflammatory activity. The pharmacological properties of these materials were then studied. 2 Two fractions were found which reproducibly contained significant activity. One of these activities caused inflammation at the site of injection and was associated with high molecular weight protein (2008000). The other activity was found in low molecular weight fraction but was shown to be due to small amounts of endotoxin from Gram negative bacteria. These organisms contaminated the fractions in spite of the recommended precautions for gel filtration having been taken. 3 The endotoxin-containing fraction completely abolished leucocyte infiltration into the rat foot which had been injected with kaolin. It had no apparent effect on circulating haemolytic complement. It caused maximal elevation of serum 11-hydroxycorticosteroid concentrations and was found to cause the release of pharmacologically active amines. Many of the previously reported naturally occurring anti-inflammatory substances have similar pharmacological properties to those of the endotoxin-containing fraction. 4 It was concluded that doubt will exist about the presence of anti-inflammatory factors in mammalian body fluids unless stringent precautions are taken to exclude measurable bacterial contamination. 5 These experiments also cast doubt on the validity of accepted procedures for excluding microbial growth from columns used in the fractionation of serum.


Vasoconstrictor response to arachidonic acid in the isolated hind limb of the dog. 1 Arachidonic acid(AA) (25-200 mug/kg) produced a dose-related increase in perfusion pressure in dog isolated hind limbs perfused with either blood or a platelet-free perfusate. 2 Prostaglandin E2 produced vasodilation while prostaglandin F2 alpha produced no vascular change at these administered doses. 3 Phentolamine did not alter the arachidonic acid response, eliminating possible alpha-adrenoceptor mediation. 4 Aspirin and idomethacin blocked the vasoconstrictor response to AA. 5 This study indicates that a vasoactive intermediate in prostaglandin synthesis can be elaborated in the absence of platelets.


Effects of thyroidectomy and L-thyroxine on adrenaline and noradrenaline concentrations in the adrenal glands and plasma of rats during the pro-oestrous phase of the oestrous cycle and pregnancy. 1 The influence of thyroidectomy upon the adrenaline and noraddrenaline content of adrenal glands and plasma in mature female rats in pro-oestrus and in pregnant rats was studied. 2 Adrenal adrenaline and noradrenaline declined significantly after thyroidectomy in pro-oestrous and pregnant females but the effects were more marked in pregnant females. 3 Plasma adrenaline increased by 160% after thyroidectomy in pro-oestrous females but similar treatment resulted in 85% decrease in plasma adrenaline of pregnant rats. The loss of thyroid increased plasma noradrenaline significaantly in both groups of females. 4 The administration of L-thyroxine of thyroidectomized females increased adrenal noradrenaline stores of both the groups. The effects of L-thyroxine in pro-oestrous females resulted in decreased adrenaline stores of the adrenals but the pregnant group showed an increase. Plasma noradrenaline increased after treatment of pro-oestrous and pregnant-thyroidectomized females with L-thyroxine. 5 The thyroidectomized females in pro-oestrous phase receiving L-thyroxine showed a return to the control values for plasma adrenaline but in pregnant females whose plasma adrenaline had declined after thyroidectomy no such change occurred. 6 Considering the variations in total catecholamines in plasma and adrenals, it was observed that the loss of thyroid hormones results in an increase in total catecholamine storyage and output in the blood. The results provide evidence that the thyroid-catecholamine interrelation is significantly affected by pregnancy.


The effects of intraportal injections of noradrenaline, adrenaline, vasopressin and angiotensin on the hepatic portal vascular bed of the dog: marked tachyphylaxis to angiotensin. 1 The hepatic portal vein of the anesthetized dog was cannulated and perfused with blood derived from the cannulated superior mesenteric vein. 2 The portal vein was perfused at constant flow, the hepatic portal venous pressure being monitored continuously together with the inferior vena caval pressure. From these measurements, the hepatic portal venous vascular resistance was calculated. 3 Noradrenaline and adrenaline were injected intraportally in graded doses which caused dose-dependent increases in the hepatic portal vascular resistance. At all doses, adrenaline was significantly (P less than 0.05) more potent than noradrenaline. 4 Intraportal injections of vasopressin caused reductions in calculated hepatic portal venous vascular resistance in most experiments; three effects were dose-dependent. 5 No tachyphylaxis to the effects of noradrenaline, adrenaline or vasopressin was observed. 6 Intraportal injections of angiotensin caused dose-dependent increases in calculated hepatic portal vascular resistance up to 5 mug; therafter larger doses caused smaller increases in portal resistance. 7. Repeated intraportal injections of angiotensin revealed the existence of tachyphylaxis in the hapatic portal vascular bed. 8 Intraportal infusions of anagiotensin caused rises in calculated hepatic portal vascular resistance from which there was almost complete 'escape' despite the continued infusions. Infusions of noradrenaline which caused similar rises in calculated portal vascular resistance did not exhibit equivalent degrees of 'escape'. 9 The development of tachyphylaxisx explains the fact that doses of 10 and 20 mug of angiotensin injected after 5 mug doses produced smaller effects. If a much longer time interval was allowed between injections (30 min), the dose-response curve to angiotensin had a sigmoid shape. 10 These findings are discussed with respect to their possible importance in the functional status of the hepatic portal vascular bed in this species.


The effect of conformationally restricted amino acid. Analogues on the frog spinal cord in vitro. 1 The isolated spinal cord of the frog (Rana pipiens) was used to examine the structural requirement for the activity of neutral amino acids. The potencies of the aliphatic amino acids, gamma-aminobutyric acid (GABA), beta-alanine and glycine were compared with the potencies of conformationally restricted cyclopentane and cyclohexane amino acid analogues. Both motoneurone hyperpolarizing and primary afferent depolarizing activity were examined in this study. 2 On motoneurones beta-alanine was the most potent aliphatic amino acid and glycine the least potent. Of the substituted aminocyclopentane carboxylic acids, that compound with a separation of amino and carboxylic acid groups closest to that of the extended GABA molecule (4.74 A) had a potency similar to GABA. As the separation decreased the hyperpolarizing activity fell off rapidly. The substituted aminocyclohexane carboxylic acids were generally inactive even at a concentration of 10 mM. 3 Strychnine blocked the motoneurone hyperpolarizing responses to all compounds with a distance between the amino and carboxylic acid groups of 3.66 A or less, but did not block the response of compounds with a distance of 4.08 A or greater.  Picrotoxin and bicuculline antagonized all the responses to varying degrees and therefore were of little value in characterizing the responses. 4 On the primary afferents GABA was the most potent aliphatic amino acid and glycine the least potent. The substituted aminocyclohexane carboxylic acids were generally inactive on primary afferents. The response of the substituted aminocyclopentane carboxylic acid whose separation of amino and carboxylic acid groups was closest to that of the extended GABA molecule was most similar to the GABA response. However, (+/-)-cis-3-aminocyclopentane-carboxylic acid (separation=4.08 A),which mimicked the action of GABA on motoneurones, closely mimicked the depolarizing action of beta-alanine on primary afferents. 5 The findings suggest that the hyperpolarizing GABA receptor on motoneurones will accept a molecule whose amino and carboxylic acid groups are separated by a distance of 4.08 A or greater while the glycine receptor will accept a compound with a distance of 3.66 A or less. The depolarizing GABA receptors on primary afferents appear to be more selective since they are not activated by (+/-)-cis-3-aminocyclopentane carboxylic acid (separation = 4.08 A), while the motoneurone receptors are.


The effect of (-)-isoprenaline and (+/-)-salbutamol on pepsinogen and acid secretion in the dog. 1 The beta-adrenoceptor agonists, (-)-isoprenaline and (+/-)-salbutamol, reduced pepsinogen secretion induced by pentagastrin in conscious dogs with Heidenhaim pouches. 2 (-)-Isoprenaline and (+/-)-salbutamol also reduced gastric acid secretion while producing a moderate tachycardia.


The haemodynamic and metabolic effects of MG 8926, a prospective antidysrhythmic and antianginal agent. 1 The antidysrhythmic, haemodynamic and metabolic effects of a new prospective antianginal and antidysrhythmic agent, N-(3-3-dipenylpropyl)-alpha-methyl-beta-cyclohexylethylamine hydrochloride (MG 8926), have been compared with the chemically related substance, prenylamine, in anaesthetized greyhounds and guinea-pigs. 2 When given intravenously 20 min beforehand, both MG 8926 and prenylamine (5 mg/kg) significantly suppressed the early dysrhythmias induced by coronary artery ligation in anaesthetized greyhounds. At a dose of 1 mg/kg, MG 8926 also protected anaesthetized guinea-pigs from dysrhythmias induced by ouabain infusions. 3 In dogs pretreated with MG 8926, metabolic changes indicative of myocardial ischaemia (increased PCO2 and potassium efflux, decreased oxygen content and pH) were less marked than those occurring in control animals. 4 Evidence was obtained that MG 8926, when given either before or after coronary occlusion, was capable of decreasing the severity of myocardial ischaemia as assessed by ST-segment changes in epicardial electrocardiograms.


Modification of cardiovascular responses to histamine by dithiothreitol. 1 Histamine produced dose-dependent contractile responses on both isolated perfused ear arteries and aortic strips of the rabbit. These responses were blocked by mepyramine and potentiated by both metiamide and dithiothreitol. 2 In the presence of maximum potentiation by metiamide, dithiothreitol still potentiated the contractile response to histamine of both preparations. 3 In the presence of mepyramine, histamine produced dose-dependent reductions in the contractile response to noradrenaline. This vasodilator action of histamine was abolished by metiamide but was unaffected by dithiothreitol. 4 The vasodilator action of histamine on the human isolated perfused temporal artery and the positive inotropic effect of histamine on the isolated spontaneously beating atria of the rabbit were blocked by metiamide but unaffected by dithiothreitol. 5 It is concluded that the rabbit aorta, like the ear artery, contains both H1 and H2 histamine receptors and that dithiothreitol potentiates cardiovascular responses mediated by H1-receptors but not by H2-receptors.


The effects of bradykinin and prostaglandin E1 on rat cutaneous afferent nerve activity. 1 The activity produced by intra-arterial bradykinin and prostaglandin E1 was investigated in multifibre strands dissected from the saphenous nerves of anaesthetized rats. 2 Bradykinin (0.5-10mug) alone produced little activity in nerve strands but produced considerable activity following a 10 min infusion, but not a single injection, of prostaglandin E1 (5-100 ng). 3 Prostaglandin E, alone produced a few large height spikes but following several injections of bradykinin smaller height spikes were also produced by prostaglandin E1. 4 It was concluded that the presence of a low concentration of prostaglandin E, is required for bradykinin to manifest its actions and that bradykinin and prostaglandin E1 are mutually potentiating in their effects on afferent nerve terminals.


Nature of histamine receptors concerned in capillary permeability. 1 Histamine and 2-methyl-histamine (H1-receptor agonist) caused dose-dependent increases in capillary permeability in albino mice, but 4-methyl-histamine (H2-receptor agonist) caused no significant increase. 2 Mepyramine (H1-receptor antagonist) blocked the histamine-induced increase in capillary permeability whereas burimamide (H2-receptor antagonist) produced no significant blockade of the histamine-response. 3 Combined mepyramine and burimamide pretreatment did not give any significantly greater protection than mepyramine alone. 4 The results indicate involvement of the H1-receptors in histamine-induced increase in capillary permeability.


The distribution and metabolism of arachidonic acid in rabbit platelets during aggregation and its modification by drugs. 1 Gas chromatographic and radio-isotope labelling techniques have been used to establish the origin of the arachindonic acid used by the platelet cyclo-oxygenase for the synthesis of pro-aggregatory prostaglandin endoperoxide derivatives. 2 Measurements of total platelet arachidonate content indicated that more than 95% is esterified in the phosphatide fraction of the cells. 3 During aggregation by collagen or thrombin as much as 80% of the total platelet arachidonate may be liberated and transformed by the platelet enzymes into hydroxyacids and other more polar compounds. 4 The phosphatidylethanolamine, phosphatidylcholine and phosphatidylinositol fractions are major sources of the arachidonate thus used. 5 Indomethacin, which prevents platelet aggregation by inhibiting the cyclo-oxygenase, did not affect this release of arachidonate from the phosphatides but did prevent the transformation of arachidonate to endoperoxide derivatives. 6 Mepacrine, a drug which possesses weak anti-phospholipase activity in platelets, also prevents aggregation by collagen or thrombin, but seems to do so by preventing substrate release from the phosphatide fraction. 7 It is suggested that phospholipase A2 plays a key role in the initial events during platelet aggregation induced by collagen.


The role of mental concepts in explaining neurotic behaviour. This paper attempts to define the areas of applicability of behavioural and mentalistic explanations of neurotic behaviour. It is argued that intentional behaviour requires mental concepts for its explanation on the grounds that the statement of reasons which form the basis of intentions cannot be submitted to a stimulus-response analysis. This argument applies to situations in which the therapist uncovers the reasons for purposeful action of which the agent may initially be unaware. It is further argued that behaviour of this kind is rule-conforming and not law-abiding and therefore is not susceptible to explanations of the kind that are available in other areas of science. It is nevertheless argued that causal explanations can be given in terms of reasons for action.


'Dissolution of the mental hospital': fifteen years on. The pattern of decline of a mental hospital population over fifteen years is described. Continuing problems are commented on, particularly the presence of 'old' long-stay patients and the accumulation of 'new chronic patients'. The number of beds required for each of these categories is estimated. The dissolution of the mental hospital service by degradation is deplored, and a suggestion is made that some of the good points of the old service might be salvaged before it is too late.


Another style of psychogeriatric service. This paper describes a psychogeriatric service in Gloucestershire. Agreement on policies was reached with general practitioners, Social Services, other psychiatrists and hospital nursing staff. The day hospital is regarded as the preferred area of treatment for a wide variety of patients, including the severely demented. In this service less than five per cent of admissions appear to become long-stay. With emphasis on day hospital and community support the number of beds for this type of patient recommended by DHSS may be excessive.


The discharge of mentally handicapped patients to residential care. The present policy of reducing the number of patients in hospitals for the mentally handicapped involves the discharge of many patients to residential care outside hospital. This paper considers 89 patients discharged from a hospital in the five years 1971-1975. 64 (70%) went to facilities controlled by the Social Services Department, ten to other residential homes, eleven to lodgings and four to other institutions. Thirty five (40%) were subnormal (WAIS Full Scale IQ 55-69); the remainder, an unexpectedly high proportion, severely subnormal (WAIS Full Scale IQ under 55). The majority of the patients discharged were the normal-looking mentally handicapped, few of whom had a specific cause for their condition. The suitability of patients for discharge in relation to the services available was more relevant than their ages or their years in hospital.


Neurological investigation of dementia.

Neurological investigation of dementia. Fifty-two patients thought to be suffering from dementia when first seen as neurological out-patients were fully investigated. Four of them were found to have tumours, whilst in five the dementia was due to a treatable cause. Neither a long history nor an age above sixty-five precludes a dementia being due to a treatable cause.


On the significance of the erythrocyte lithium to plasma lithium ratio. Correlations between the ratio of erythrocyte to plasma lithium (Le/Lp) and clinical status have been reported by some authors and disputed by others. Examination of the literature on Le/Lp and erythrocyte physiology suggests that Le/Lp is determined by peripheral pharmacokinetic parameters and has no direct relationship to central pathophysiology. Because of this, and because of inconsistencies between studies reporting correlations of the ratio with clinical status, such correlations probably cannot illuminate either the pathophysiology of affective illness or the mode of action of lithium.


Plasma levels of antidiuretic hormone in patients receiving prolonged lithium therapy. Among 18 patients receiving prophylactic, long-term lithium treatment for manic-depressive psychosis, a high incidence of increased thirst and frequency of micturition (60-70 per cent) was noted on direct questioning. Symptoms arose at varying times after the start of lithium therapy; in no patient did symptoms antedate the use of the drug. Plasma levels of antidiuretic hormone were found, on average, to be higher than in normal control subjects for a given level of plasma osmolality, although the scatter of results was wide. It is suggested that elevation of antidiuretic hormone occurs as a compensatory mechansims for the polyuria which is a common feature of long-term lithium treatment. The more florid form of nephrogenic diabetes insipidus occasionally seen in lithium takers seems likely to be due to a different mechanism from the more common mild polyuria.


Usefulness of saliva lithium estimation. Estimation of lithium in 24 samples of serum and saliva show that there is a very high correlation between the lithium levels in serum and saliva (r= + 0-88). The ratio found in our patients is very similar to that reported from North America. Estimation of lithium in saliva at different periods of time show there is a good degree of stability for saliva lithium levels. Thus saliva can be used as a substitute for serum for lithium monitoring. The practical advantages of this are discussed.


Family suicide.

Family suicide. Five suicides in one family, mainly by burning, are reported. The ritualistic manner, closeness of events in time and absence of serious exogenous factors suggest the term 'family suicide'.


Mortality in patients with schizophrenia, mania, depression and surgical conditions. A comparison with general population mortality. Mortality data are presented from a four-decade follow-up study of 200 schizophrenic, 100 manic, 225 depressive patients, and 160 surgical controls (80 appendicectomy; 80 herniorrhaphy). Data for this analysis were available on 648 (95 per cent) members of the study population. Using sex-age standardized mortality ratios (SMR), the mortality experience of the study population was compared with that of the state of Iowa, the geographical area served by the admitting medical facility for the study group. Results are presented for a four-decade period beginning 1935-44, and ending 1965-74. All three psychiatric groups had a significant increase in mortality risk. This was most pronounced in the first decade following admission, although schizophrenic patients, especially females, continued to show a significant excess of deaths throughout the entire four decades of the follow-up period. During no decade of the follow-up period did the mortality of the surgical controls differ significantly from that of the Iowa population.


What have cognitive deficits to do with schizophrenic symptoms? This paper considers possible relationships between cognitive deficits and symptomatology in schizophrenia. It is argued that a combination of defective filtering and slowness in response selection results in a state of information overload in acute schizophrenia. The methods by which normal subjects adapt to experimenter-induced overload may therefore be relevant to aspects of schizophrenic behaviour. The considerable intra- and inter-subject variability in symptomatology of schizophrenic patients may represent differeing adaptations to similar cognitive disturbance, such secondary abnormalities being prominent in chronic patients. Sections of the literature on acute-chronic differences are consistent with such a formulation, although one cannot infer intra-individual change from cross-sectional studies; there is a clear need for longitudinal investigations in this area. The preferred method of adaptation will be dependent on the severity of overload, the environment, and personality factors independent of the psychosis. The implications for the modification of schizophrenics' behavioural abnormalities by operant procedures are discussed.


Aspects of intensity of affective constructs in depressed patients. Two groups, 10 subjects in each, one consisting of depressed patients and the others normal controls, ranked photographs of faces for two sets of six constructs. One set consisted of the critical constructs of the Bannister and Fransella grid test, while the other set of constructs were all related to affect. The depressed patients showed a higher intensity score for affective constructs than did the normal subjects. There was no difference for critical constructs. The affective intensity score decreased on two further retestings for the depressed group; for the normal group they remained reasonably constant. These results may shed light on the reorganization in construing aspects of affect which occurs with depression and its remission.


Obsessional personality disorder and remembering. Patients suffering from obsessional personality disorder (anankasts) have been described as possessing 'superior memories', because of the detailed precision of their accounts. At the same time, such classical phenomena as doubt, checking and rumination imply faulty recall. This paradox is discussed, and some predictions drawn from a hypothesis regarding the cognitive charactteristics of obsessional disorder. Findings are presented which indicate that, by comparison with matched psychiatric controls, anankasts do not excel in the long-term recall of factual information or meaningful anecdotal material. But they show the following mnemonic features: (a) Superiority of immediate memory span, reflecting high levels of attention. (b) Superior recall of ambiguous anecdotal material, reflecting a tendency to the pointless 'rehearsal' of such material. (c) Weak redintegration in personal reminiscence. It is suggested that anankasts' doubts about their remembering refer not so much to the correctness of what is being recalled as to the quality of the recalling itself.


Obsessional cognition: performance on two numerical tasks. It is argued that obsessional indecision reflects a formal cognitive characteristic, and should therefore be detectable in slower performance of insignificant, neutral tasks. The obsessional will not be handicapped in structured tasks requiring concentration and a deductive approach, but he will be slower in less structured tasks requiring a predominantly inductive approach. Results from two neutral (numerical) tasks support the predictions.


Group exposure for agoraphobics: a replication study. A replication study was conducted of the treatment of agoraphobics by exposure in cohesive groups, as described by Hand, Lamantagne and Marks (1974). The continuing improvement during follow-up, with consequent large overall improvement, reported in the original study was not replicated. However, the present study confirmed the usefulness of this procedure as a highly cost-efficient treatment. The assumed equivalence of the Gelder and Marks (1966) phobic rating scale and its modification by Watson and Marks (1971) was examined. Large discrepancies between the scales were obtained for initial assessments and change scores. It is suggested that there is a need for workers in this field to agree on methods of measurement.


Renal phleborgraphy in hydronephrosis.

Renal phleborgraphy in hydronephrosis. A phlebographic study of the renal venous tree was made in 24 cases of hydronephrosis. There was an alteration in the renal phlebographic pattern, the most characteristic appearance being the visualisation of extensive free anastomoses among the branches of the renal vein. Elongation of the branches of the renal vein, which is not as typical nor as constant, is presumably caused by enlargement of the pelvis and the distended calyces. In more advanced stages there is a visualisation of a fine network located peripherally to the previously described anastomoses. When there is a secondary disruption of the renal parenchyma there is no visualisation of the branches of the renal vein.


123-Iodine: a new isotope for functional renal scanning. The results are presented of functional renal scanning in 11 urological patients using 123-iodine labelled Hippuran--a new radiopharmaceutical. The 123-iodine isotope possesses distinct advantages over existing isotopes, permitting high resolution imaging whilst delivering a low integrated radiation dose. It is hoped that the expense of this cyclotron-produced isotope will not mitigate against full evaluation of its promising potential.


Primary malignant lymphoma of the testis associated with sclerosis and nodularity. A case of primary malignant lymphoma of the testis associated with an unusual degree of sclerosis and nodularity is reported. The patient, a 21-year-old male, is alive and well 5 years after orchidectomy followed by radiation therapy to the lumbar and para-aortic lymph nodes in spite of very extensive involvement of the testis, epdidymis and presence of tumour deposits within the spermatic cord and in para-aortic lymph nodes. It is suggested that sclerosis and nodularity may be favourable prognostic features in patients with primary malignant lymphoma of the testis.


Recurrent stress urinary incontinence in the female. 1,500 females presenting with recurrent urinary incontinence were investigated in depth. 27% required further surgery, 127 of whom were treated with a 2-team Marlex sling. Careful assessment is the key to treatment including cystoscopy and good radiological documentation. One must be aware of the capabilities and limitations of the various procedures employed for stress incontinence and select the correct procedure for the given problem. When dealing with recurrent stress incontinence the surgical procedure must take down all periurethral scar, anteriorly and posteriorly and adequately elevate the urethrovesical junction so it is not the dependent point at the base of the funnel. The Marlex sling procedure fulfills the above criteria, has been singularly effective, and remarkably free of complications.


Massive bladder stone.

Massive bladder stone. 3 cases of massive bladder calculus are described and are of interest not only because they are rare, but also because of the remarkably few symptoms they produced.


Cystitis cystica: characteristics of the disease in children. Cystitis cystica was found at cystoscopy in 157 children between the ages of 9 1/2 months and 14 years. Girls were affected much more often than boys, the proportion being 153 to 4. Urinary infection, most commonly caused by E. coli, was almost invariable. Urinary tract anomalies, in particular vesico-ureteric reflux, were frequently present. Histologically, the cysts were composed of submucous aggregations of lymphoid tissue. Cystitis cystica affecting the ureteric orifices may contribute to the occurence of reflux and involvement of the bladder neck may produce some degree of vesical outlet obstruction.


The clinical diagnostic value of the carcinoembryonic antigen (CEA) in haematuria. Plasma and urinary CEA levels in patients presenting with haematuria have been studied to assess whether they facilitate the differentiation between benign and malignant urothelial conditions. Plasma CEA is of no diagnostic value although, if raised, it may suggest an invasive tumour. Urinary CEA levels are only of value in the absence of urinary infection; even then, only 37% of the cases with overt urothelial tumours had raised titres. A knowledge of the urinary CEA level, therefore, would seem to contribute little to the diagnosis of patients presenting with haematuria and all patients must still be investigated by the conventional techniques of urinary bacteriology, cytology, intravenous pyelography and cystourethroscopy.


Treatment of advanced carcinoma of the prostate with estramustine phosphate. 40 patients with inoperable, histologically proved carcinoma of the prostate were treated with estramustine phosphate. 35 patients had progressive, symptomatic, metastatic disease unresponsive to conventional oestrogens and/or castration Estramustine phosphate was given intravenously initially at a dose of 150 mg/day increasing to 300 mg/day. After 3 weeks or more oral therapy was substituted in 23 patients at a dose of 560 mg/day. Of 23 evaluable patients given the drug by both routes, 17 died after a mean treatment period of 12.5 months and 6 are alive and well after a mean treatment period of 27.7 months. The cause of death in 2 patients was probably, and in a third certainly, due to myocardial infarction. The other 31 deaths were due to carcinoma of the prostate. 18 patients showed transient toxic side-effects. No haematological abnormalities were found during treatment. An attempt at active treatment with estramustine phosphate in patients with prostatic cancer is justified when the disease is resistant to treatment with conventional oestrogens.


Does ureteric reflux protect against calculus formation? The infrequent association of reflux and kidney stone suggest the possibility that reflux may in some measure protect against stone formation. A simple animal experiment is proposed which should indicate whether this assumption is valid.


Incidence of anencephaly and other major malformations when oestriol excretion is very low. A study of 533 women with very low urinary oestriol excretion during the third trimester of pregnancy showed an incidence of major fetal malformations among their infants of 7-1% and a perinatal mortality rate of 14-6%. Thirteen of the malformations were cases of anencephaly, and 26 of the 78 perinatal deaths were due to or associated with major fetal malformations. The incidence of these complications was higher when maternal oestriol excretion was lower. Routine screening by urinary oestriol assay, with fetal radiography when values below 20-8 mumol/24 hours (6 mg/24 h) are detected is the most reliable method of detecting anencephaly before birth.


Immediate effects of tobramycin on human cochlea and correlation with serum tobramycin levels. Electrocochleography was performed on three patients to monitor the intravenous administration of tobramycin. When peak serum tobramycin levels exceeded 8-10 mug/ml an immediate dramatic reduction in cochlear output was observed, which recovered fully as serum levels fell. The patients had no auditory or vestibular symptoms either during or after treatment.


Falls in the elderly related to postural imbalance. Two hundred and forty-three elderly people aged 60 to 96 years were questioned about their falls, and their sway was measured. For comparison sway was also measured in 63 younger subjects. Sway increased with age and was higher in women at all ages. There was no difference in sway between those with no history of falls and those who fell only because of tripping. In both sexes sway was significantly increases in people who fell because of loss of balance and in women whose falls were due to giddiness, drop attacks, turning the head, and rising from bed or a chair. This suggests that there is a physiological decline in postural control with advancing age and also a decline due to disease of the central nervous system.


Evaluation of 125I-fibrinogen test for venous thrombosis in patients with hip fractures: comparison between isotope scanning and necropsy findings. The results of 125I-fibrinogen leg scanning during life were compared with the findings at a detailed post-mortem dissection of the leg veins in 31 patients with hip fractures who died during the period of isotope scanning or within seven days of the last scan. Thigh scanning on the side of the hip fracture proved valueless, and criteria for the confident isotopic diagnosis of venous thrombosis in the uninjured thigh could not be determined. In the lower leg a difference in uptake of 20% or more that persisted for 24 hours between adjacent positions on one leg or between corresponding positions on the two legs was consistently associated with the presence of venous thrombosis at necropsy.


Who is at risk of a coronary?

Who is at risk of a coronary? The Joint Working Party of the Royal College of Physicians and the British Cardiac Society have recently given advice to medical practitioners about preventing coronary heart disease. We have formulated an easy method by which the medical practitioner may apply a rule to identify individuals who are at moderate to high risk of developing the disease. The simple arithmetic requires finding the product of four numbers and can be done with a pocket calculator costing less than pound 10. The four numbers correspond to known values of the four risk variables--age, systolic blood pressure, serum cholesterol levels, and smoking--for a given individual. Tables of relative risk components for men aged 40 to 59 years for coronary heart disease defined by hard criteria (fatal or definite myocardial infarction) have been drawn up. The overall effect of the four risk variables is multiplicative so that some men aged 40 are at far greater risk than some of 55 year olds.


Perinatal deaths: analysis by clinical cause to assess value of induction of labour. Over the 10 years 1966-75 the rate of induction of labour in the Glasgow Royal Maternity Hospital has increased from 16-3% of all births. During the same period perinatal mortality fell from 33 to 22 per 1000, mainly because of significantly fewer deaths due to antepartum haemorrhage; trauma; maternal diseases; and unknown causes in mature babies. The reduction in the number of deaths of unknown causes in mature fetuses was achieved by preventing deaths occurring after 40 weeks and was recorded in all age and parity groups. The results suggested that increased use of induction of labour has contributed to the improved perinatal mortality rate.


Accidental hypothermia and impaired temperature homoeostasis in the elderly. A longitudinal study of the age-related decline in thermoregulatory capacity was made in 47 elderly people to try to identify those at risk from spontaneous hypothermia. During the winters of 1971-2 and 1975-6 environmental and body temperature profiles were obtained in the home, and thermoregulatory function was investigated by cooling and warming tests. Environmental temperature and socioeconomic conditions had not changed but the body core-shell temperature gradients were smaller in 1976, indicating progressive thermoregulatory impairment. People at risk of developing hypothermia also seem to have low resting peripheral blood flows, a nonconstrictor pattern of vasomotor response to cold, and a higher incidence of orthostatic hypotension.


Can drug compliance in the elderly be improved? Three instruction schemes for self-medication in older patients were designed and compared to see whether they improved drug compliance. Forty-six patients in two rehabilitation units were divided into three different groups. Each group was instructed verbally on the nature and amount of their medication. One group was also given a tear-off calendar and a second group a tablet identification card as a memory aid. Patients were then responsible for taking their own medicine for 14 days. Those with calendars made fewer errors than those with cards, and those with either a card or a calendar made significantly fewer errors than those given only standard instructions.


Clinical trials of the treatment of breast cancer in Britain and Ireland. Report by co-ordinating committee. Thirteen trials of systemic chemotherapy in early breast cancer were identified and protocols obtained. The differences in the latter prevented a true comparison of the results. In setting up any trial it is important to define the primary objectives and to include a statistician from the start. Only truly random allocation of patients is acceptable, while treatment programmes must be fully monitored. Other important aspects include review of the results by an independent member of the trial committee and keeping full, but simple, case records. Though any trial must be designed by a committee and not a single investigator, the individual clinician remains responsible for the patients under his care. To launch a controlled randomised trial without full preparation and guaranteed resources is in the best interests of neither patients nor doctors.


Sexual knowledge and attitudes of general practitioners in Wessex. A survey of the sexual attitudes and knowledge of general practitioners in Wessex found that GP trainees and those in practice for less than 10 years were less conservative and better informed than doctors in practice for 20 years or more, The results suggest that the attitudes of the doctors are determined by their early environmental influences rather than their clinical experience.


Angiotensin II in essential hypertension. Plasma concentrations of angiotensin II (PAC) were measured in a group of 146 hypertensive patients (diastolic pressure greater than 105 mm Hg) who had no apparent underlying cause for their condition and 113 randomly selected normotensive controls (diastolic pressure less than 90 mm Hg). There was no evidence of bimodality in the frequency distribution curves for plasma angiotensin II concentrations among the hypertensive patients. It was concluded that hypertension associated with low angiotensin II concentration and by implication "low-renin" hypertension is not a condition separate from essential hypertension.


Role of dietary energy supplementation in growth of children with chronic renal insufficiency. The effect of dietary energy supplements in children with varying degrees of chronic renal insufficiency was investigated. Despite an increased energy intake of 8-4% there was no increase growth velocity, although some patients reported improved wellbeing and activity. The proportion of dietary energy supplied by protein fell significantly during supplementation. The evidence suggests that the reduced energy intake of children with chronic renal insufficiency is a related but not causal factor in their growth retardation.


Why hypertensive patients vary in their response to oral debrisoquine. The relation between dose, systemic availability, and response to oral debrisoquine was studied in 13 hypertensive patients receiving no other treatment. In 11 who received the same daily dose (40 mg) the fall in mean standing systolic blood pressure varied between 0-3 and 44-4 mm Hg. There was a ninefold difference in the daily urinary excretion and pre-dose plasma concentration of unchanged drug but an inverse correlation between daily urinary excretion of debrisoquine and its 4-hydroxy metabolite (r= -0-86), suggesting that a low recovery of debrisoquine occurs because of extensive metabolism. There was a significant correlation between the fall in standing systolic blood pressure and the mean daily urinary excretion (r= +0-82) and pre-dose plasma concentration (r= +0-82) of unchanged debrisoquine. In contrast, there was a significant inverse correlation between the urinary recovery of the metabolite and the fall in blood pressure (r= -0-82). The availability of debrisoquine is the major determinant of response to this drug. In the absence of side effects a poor response may be an indication to increase the daily dose rather than add another hypotensive agent.


Recurrent breast cancer treated with the antioestrogen tamoxifen: correlation between hormonal changes and clinical course. Forty-five post-menopausal women with recurrent breast cancer were treated with the antioestrogen, tamoxifen, 20 mg twice daily. Clinical assessment after 12 weeks indicated that 18 (40%) showed some remission. Gonadotrophins were suppressed within two weeks to relatively constant concentrations within the post-menopausal range, responses to luteinising hormone-releasing hormone (LH-RH) did not change, and androgen concentrations remained within the normal range in all patients. Oestradiol concentrations rose steadily only in women in whom treatment failed. Serum prolactin concentrations were raised in 18 out of the 44 (41%) patients in whom they were measured; 13 of these did not respond to treatment. Treatment did not change the average prolactin concentration when this was within the normal range, but it significantly reduced prolactin concentrations in hyperprolactinaemic patients--within two weeks (P less than 0-01) in those who responded well and by six weeks (P less than 0-05) in those who showed no remission. Among patients with normal prolactin values the release of prolactin after thyrotrophin-releasing hormone was significantly greater in those with no remission than in those who responded to tamoxifen. Responses in those with hyperprolactinaemia were reduced to about half the control values, and again this change occurred faster in those who were successfully treated. Patients therefore seem to have a better chance of responding to anti-oestrogen treatment if prolactin secretion is low.


Incidence of post-abortion psychosis: a prospective study. Twenty-one cunsultant psychiatrists participated in a prospective study of post-abortion psychosis among a population of 1 333 000 people. During the 15-month study only a single case was reported, concerning a woman who had a history of two previous attacks of puerperal psychosis. The incidence of post-abortion psychosis was 0-3 per 1000 legal abortions. The incidence of puerperal psychosis, which was also studied as an index of validity, was 1-7 per 1000 deliveries. This conforms with currently accepted figures and indicates that the study population was representative. I suggest that physiological changes, which are probably more profound after childbirth than after abortion, may be responsible for the higher incidence of puerperal psychosis.


Blood and vein-wall fibrinolytic activity in health and vascular disease. The resting blood fibrinolytic activity of 120 normal subjects and 294 patients with various forms of vascular disease was assessed by measuring the dilute blood clot lysis time and fibrin plate lysis area before and after 10 minutes of venous congestion. The tissue fibrinolytic activity of several of these subjects was assessed in vein biopsy specimens. The results suggested that there was a correlation between blood and tissue fibrinolytic activity and that certain venous diseases, particularly recurrent superficial thrombophlebitis and venous liposclerosis, were associated with a deficiency of blood and tissue fibrinolytic activity.


Renal insufficiency associated with excessive lead exposure. Water lead concentrations were measured in 970 households throughout Scotland. Blood lead concentrations were measured in 283 people living in houses with water lead levels of over 0-48 mumol/l (100 mug/l). A highly significant correlation was found between lead concentrations in water and blood. Raised blood lead concentrations were associated with renal insufficiency, reflected in raised serum urea concentrations, and with hyperuricaemia, although there was no evidence of clinical disease in any of the affected people. This is further evidence that excessive lead in domestic water supplies has a harmful effect on the community's health.