The use of drug concentration measurements in studies of the therapeutic response to propranolol. The dose of propranolol which produces the optimal therapeutic effect in patients with angina pectoris has been found to vary widely among patients. Because the plasma concentration of propranolol also differs markedly due to interpatient variability in absorption it seemed possible that this might be the reason for the wide range of effective doses in angina and that plasma propranolol might provide a useful guide to therapeutic response. To examine this possibility we selected ten patients with coronary artery disease complicated by angina and studied them at varying propranolol doses to a maximum of 320 mg/day. Exercise capacity was tested on a treadmill and plasma propranolol concentration was measured by gas liquid chromatography. In seven normal subjects beta-blockade was quantified precisely as inhibition of exercise tachycardia and was related to plasma propranolol levels at various doses. Maximal beta-blockade occurred at 100 ng/ml of plasma propranolol, but the dose response curve of blockade was relatively flat and the ED50 of plasma propranolol was 8+/-1 ng/ml. In the patients maximal therapeutic benefit from propranolol occurred at 30+/-7 ng/ml and at a dose of 144 mg/day. This resulted in an increase in exercise capacity from an estimated 12-7+/-0-8 ml/kg/min of oxygen consumption during control to 17-2+/-1-1 ml/kg/min on the drug. Thus, there was a wide variation of both dose and concentration among these patients at the maximum therapeutic response. However, when plasma propranolol was related to pharmacologic activity, the maximum therapeutic response was observed between 64 and 98% of total blockade. These studies indicated the extent of beta-blockade necessary to produce an effective therapeutic response in angina, but demonstrate that plasma drug levels provide no practical guide to therapy in patients with angina pectoris. A further study was conducted measuring plasma propranolol in twenty hypertensive patients to investigate the fall in blood pressure in relations to the change in plasma renin activity and the inhibition of cardiac adrenergic receptors. The inhibition of plasma renin closely resemble the response seen in heart rate inhibition in that the maximum response is seen at 100 ng/ml and the ED50 was 11 ng/ml. In contrast propranolol is shown only to begin to have a significant effect on blood pressure at a plasma level of 30 ng/ml and the effect becomes progressively greater as the plasma level increases. This suggests that the hypotensive effect of propranolol may be dissociated from the beta-blocking effects of cardiac and renin releasing receptors.


Haemodynamic effects of beta-blockade in patients with angina pectoris. The pressure-volume relationship of the intact human ventricle during ischaemia and following the administration of a drug commonly used to treat ischaemic heart disease has been studied. Precise quantitation of the effects of the non-selective beta-adrenergic blocking drug propranolol (0-15 mg/kg body weight) on left ventricular function, segmental wall motion and diastolic pressure-volume relationship in man has been performed. High fidelity left ventricular pressure measurements and simultaneous single-plane angiograms were recorded and volumes calculated by a light-pen computer system. Patients were transvenously atrially paced for constancy of heart rate during drug infusion or paced to angina. In patients with coronary heart disease paced to angina, logarithmic pressure-volume relationship showed change in slope (P greater than 0-05) of the regression line and upward shift in intercept b (+0-25; P greater than 0-001). The diastolic effects of propranolol may include substantial increases in ventricular volumes in those patients with impaired cardiac function. With respect to the intact human ventricle, propranolol may increase diastolic volume for a given level of ventricular pressure. Thus, in a static sense, the ventricle in these patients could be viewed as being more compliant following propranolol administration. However, the fact that the length-tension relationship as measured by the slope of the logarithmic pressure versus volume plot is unaltered by propranolol, suggests that the muscle comprising the ventricle itself exhibits no alteration in its passive elastic properties.


Patient acceptability of propranolol and the occurence of side effects. The incidence of adverse effects is reported in a group of more than 400 patients treated with propranolol between 1964 and 1974. Severe side effects necessitating withdrawal of the drug were found in less than 10%; dose-limiting side effects were found in less than 15%. Tolerable side effects are studied in detail. Pharmacologically based side effects are recorded and ways of minimizing their frequency are discussed. The acceptability of propranolol in general terms and its advantages are assessed.


Safeguards in the treatment of schizophrenia with propranolol. Early results for an uncontrolled study of 555 patients with florid schizophrenia suggest that propranolol can be used safely in high dosage, and in a proportion of cases it appears to control schizophrenic symptoms. This method of treatment is now being submitted to controlled trial. Evdence from this uncontrolled study suggests that there was a therapeutic dose range in which symptoms steadily improved as a low dose was ineffective and a high dose, particularly if reached too rapidly, caused toxic effects. Rapid increases (400-800 mg) in the daily total intake when given in divided doses (4 to 10/day) produced gross toxic effects that included ataxia with unprotected falls, drop attacks, visual hallucinations, and confusional states. Severe toxic effects were uncommon when the dose was raised by regular, gradual increments (e.g. by 40-80 mg/day), when propranolol was given twice daily, when the dose was held steady as the patient started to improve, and when the daily total dose was reduced if the fall in pulse rate or blood pressure was excessive, or if there was evidence of toxicity. The observation of gradual, progressive improvement was the most valuable positive guide to the dose of propranolol. All schizophrenic symptoms remitted, at least temporarily, in 26 of 55 patients (in 15 of 17 patients who had been ill for less than one year and in 11 of 38 patients who had been ill for longer than a year). Patients who then stopped propranolol usually relapsed within hours or days.


Port health problems.

Port health problems. As quarantine control of international travellers dies away, health screening of immigrants becomes more important. Port health controls attempt to identify the sick immigrant, thereby limiting disease spread among susceptibles and sparking early treatment. Port health controls also ease the impact of immigrants arriving at destinations by alerting relevant authorities so that they can begin health education procedures early, if they wish. Two problems arise: some destination authorities make little attempt to trace their immigrants and even those that do cannot find more than 70 per cent so notified. For receiving communities the most important disease the immigrant may carry or later develop is tuberculosis. In the indigenous population the incidence of this disease is decaying exponentially but, in communities of recent immigrants, may be stable or even rising. This means that in about ten years the great majority of new tuberculosis cases will be in recent immigrants, unless better preventive techniques are used. The overall trend is likely to be a fall in the number of cases, but the disproportion may provoke problems. What can be done? Assuming incoming immigrants are typical of their country of origin, many must enter Britain mantoux-negative, a fact supported by various destination authorities here which have performed testing. So, the logical solution is to ensure that all receive BCG vaccination, preferably before they migrate or otherwise as they enter Britain, and to ensure their babies born later in Britain also receive the protection of BCG vaccination. Consumption of medical services by the travelling public increases with the number of travellers and, as more people penetrate romantic but unhealthy areas formerly inaccessible, importation of communicable disease also increases. Many of these diseases could be prevented by good advice but, unfortunately, unfamiliarity blunts the edge of prophylaxis and diagnosis. Airport experience indicates that the general practitioner could help his patient more, particularly the overlander, by discussing sanitary precautions and suggesting anti-malarial drugs and immunization against typhoid and infectious hepatitis, when appropriate. Vaccination against smallpox, cholera or yellow fever may be obligatory and a valid certificate required; inoculation against diphtheria, poliomyelitis or tetanus may be sensible, and against rabies if the traveller may come into contact with animals abroad. Although complex queries about health hazards abroad should be addressed to such research centres as the Ross Institute, I suggest much practical advice can be obtained by phoning Heathrow health control 01-759 4361.


Interchondral subluxation or "clicking rib syndrome". A case history of the interchondral subluxation syndrome is presented, the anatomy as related to the symptoms discussed and the literature of this so-called "clicking-rib syndrome" reviewed. Unfortunately, this syndrome is not widely recognized but it is hoped that this article will bring it to the attention of those most likely to encounter it-the primary-care physician-and so save numerous unnecessary investigations and consultations. Once one is aware of its existence, the condition is easily diagnosed by careful history and examination alone.


Effects of induction on the mother-baby relationship. Even though a minority of mothers and babies benefit from the sequence of events which starts with induction, continues with active obstetric intervention, and culminates with the baby in the intensive care unit, it is questionable whether this justifies submitting the majority of women to what many of these mothers described as the misery of enforced separation from their infants, and whether we should permit modern technological innovations in the culture of childbirth to risk interfering with the basic human patterns of attachment between parents and their young.


Tuberculoid leprosy.

Tuberculoid leprosy. The clinical features and management of a case of major tuberculoid leprosy presenting in the United Kindom are described. The possibility of encountering tropical disease in one's practice should be remembered.


Forensic problems in practice VIII.-Sexual offences. In general, the examination of alleged sexual offences is a combination of perception and experience in history taking and observation, of clinical skill in examination and of meticulous retention of material for forensic science examination. It is not a task to be undertaken lightly, especially as the doctor's actions and opinions may well become the subject of intensive cross-examination at any later court proceedings. The frequency with which unfounded allegations of rape or indecent assault are made by girls makes it all the more important to help separate the genuine from the spurious cases and medical evidence frequently plays a vital role in this direction.


[Health hazards to the anaesthesist].

[Health hazards to the anaesthesist]. During the past years there has been increasing concern regarding potential hazards to the anaesthetist presented by, e.g., anaesthetic agents, exposure to X-rays, virus hepatitis. Chronic exposure to inhalational anaesthetics, in particular, has been held responsible for a variety of complants and disorders. Investigations at the Technical University, Munich, have shown no appreciable difference in the sick rate between the staff of the Department of Anaesthetics and the Department of Medicine. Whereas exposure to X-radiation cannot be regarded as a health hazard provided the prescribed safety measures are adhered to, virus hepatitis still constitutes a major risk. There is also some evidence of an increased incidence of miscarriages amoung the female anaesthetic personnel. The causes are unknown. Halothane hepatitis is very rare and does not present a major risk.


[Danger of fire and explosion in anaesthetic and surgical departments]. Corresponding to the fact that flammable anaesthetics are still very seldron in use the possibility of fires an explosions has diminished; the frequency of accidents caused by flammable colonic gases and by desinficients is about unchanged whilst a new kind can and dose occur: Fires and (occassional) explosions with "nonflammable" anaesthetic technics. A survey about 16 cases (including oxygen-fires) should be of interest for surgeons and intensive-care-people as well as for anaesthetists.


Hygienic problems in anaesthesia and intensive care therapy. Cross infection has become a serious risk to hospitalized patients. Potential sources of infection by anaesthetic apparatus and equipment and the danger arising from disregard of proper asepsis are discussed. Prophylactic and hygienic measures to minimize these hazards are reviewed. Since patients receiving intensive therapy are particularly are risk very high hygienic standards are a "must" in these units. The need for thoroughly and regularly checking all equipment for contamination is emphasized.


[Mild form of malignant hyperthermia? OR, ABNORMAL REACTION To succinyldicholine?]. In addition to two published cases of malignant hyperthermia (M.H.) 13 more cases have been observed in this institution since 1971, which are probably early reactions of the M.H. type. All 13 patients were children, 3-12 years of age, who developed a rigor of the jaw muscles after succinyldicholine and/or halothane within minutes after the induction of anesthesia. Further symptoms that could be observed regularly were a tachycardia of several hours duration and a marked elevation of the serum CPK-activity with a peak after 24 hours. Since the anesthesia was terminted immediately and the operations postponed as soon as a M.H. reaction was suspected, the rise in body temperature was minimal or absent and exceeded in no case 39 degrees C. Several children were operated upon later in neuroleptanalgesia (NLA) supplemented by nitrous oxide without any muscle relaxants. None of these children developed the aforementioned symptoms rigor, techycardia and CPK-elevation. One child had Alloferin in addition to NLA-nitrous oxide-anesthesia. This child had postoperatively a tachycardia lasting several hours and 24 hours later a serum CPK activity of 1500 U/1. Since this CPK activity is higher than in comparable cases (see fig. 1) it is concluded, that the nitrous oxide-NLA sequence appears to be safe for patients susceptible to M.H. Alloferin however must probably be regarded as a trigger agent for M.H.


[Report on 2 cases of malignant hyperthermia with different clinical courses]. Two cases of malignant hyperthermia with different clinical courses are reported. The patients showed the classical signs of malignant hyperthermia consisting of tachycardia, tachypnoea, ocasional peripheral cyanosis, high body temperature as well as characteristic rise in serum enzymes. In one of the patients the symptoms were recognized early during the operation. The immediate commencement of therapy with ice-cooled. Ringer-Lactate-Solution, Procainmedication, Corticoids as well as physical body cooling favourably influenced the clinical course and the patient survived. In both cases the patients underwent succinylcholine and halothane anaesthesia, but the symptoms of the second patient appeared after the reduction of anaesthesia. In spite of vigorous therapy the hyperpyrexia resulted in heart arrest and death. Morphologically, both patients showed signs of preexistent myopathy with volumetric alterations of the muscle fibres, centralisation of the nuclei and acute muscle fibre necrosis. On the basis of the observed variable course, the various symptom complexes reported in the literature to data are  reviewed. A detailed discussion of the "carrier problem" and the available treatment possibilities is also made. Realising that malignant hyperthermia is an inheritable disease, prophylactic measures such as, f.i. the issue of medical certificates to the patient and his relatives are suggested.


[Halothane-intoxication by failure of the halothane-vaporizer]. Regular  measurement of the Halothane-concentration delivered by the output of the vaporizer is necessary to avoid a clinically dangerous situation due to Halothane-overdosage.


[Anti-G-suit-a facility of Neuroanaesthesia at operations in the sitting position]. The Anti-G-Suit- an over-all-air-pressure-garment over legs and bowel up to the xiphoid is proposed as a successful method to encounter acute postural decrease of blood pressure in neurosurgical patients. Increase of peripheral resistance and displacement of the circulating blood volume above the diaphragm enhance blood pressure which has fallen by the depressive effect on the vasomotor centre and the negative inotrope effect of narcotics.


[Treatment of alkyl phosphate poisoning with purified serum cholinesterase (author's transl)]. A 26-years-old man injected himself intramuscularly with 3.75 gram of demeton methyl in an attempt to commit suicide. After 36 hours severe symptoms of poisoning developed with loss of consciousness and respiratory arrest. As symptomatic treatment failed to improve his condition has given injections of purified serum cholinesterase. This was followed by a rise in the cholin esterase levels and the increased activity was accompanied by a rapid and definite improvement in the clinical findings. The results clearly indicate the usefulness of this method of treatment. Transfusions of fresh blood to counteract the cholin esterase deficiency are inadvisable because of the risks of complications. Substitution therapy with serum cholinesterase must be accompanied by administration of large doses of atropine.


[Artificial respiration for the postoperative care after major surgery (author's transl)]. An analysis was made of the postoperative course of 158 cases of major surgery performed during 1971-1973. The operations comprised thoraco-abdominal resection of the oesophageal and cardia, abdominal duodenopancreatectomy, partial gastrectomy and enterectomy and partial hepatectomy. 63 per cent of the patients were given artificial respiration either prophylactically immediately after the operation (47 per cent) or at a later stage (53 per cent) on account of respiratory complications (arterial hypoxia below 55 mm Hg pO2). Postoperative mortality for the group of patients who did not have artificial respiration was 46 per cent, as compared with 32 per cent for the artifically ventilated patients - a difference of 14 per cent. The causes for this discrepancy, and especially the role of non-respiratory complications are discussed and the indications for prophylactic postoperative artificial respiration are reviewed.


[The influence of enflurane on the haemodynamics in the pulmonary vasculary system (author's transl)]. The influence of enflurane on the haemodynamics of the main and pulmonary vasculary system was studied in young healthy patients. The results showed no influence in heart frequency and mean arterial pressure, a slight fall in certain output and a significant increase in mean pulmonary arterial pressure. There is no certain explanation for the pathophysiological mechanism in pulmonary vasculary system caused by enflurane. According to our opinion these results are to discuss as a cause of a decrease of left ventricular work and a regulative vasoconstriction in the pulmonary vasculary system.


[Catheterization of the vena cava superior via the internal jugular vein (author's transl)]. A method is described of introducing a catheter into the vena cava superior via the internal jugular vein. Possible complications and the experience gained with the method in 260 cases are discussed.


[Verifying right position of central venous catheters by intracardial ecg derivation (author's transl)]. It is reported on the electrocardiographical method for the location of the position of central-venous catheter. The advantages of this method compared to the usual radiological method: immediate correction is possible no additional apparat is needed.


[Dopamin-therapy for acute postoperative renal failure (author's transl)]. In 10 out 14 patients with acute postoperative renal failure the administration of a dopamin-drip (175-350 mcg/min) resulted in an increase in urinary output more than 30 ml/h. But there was no decrease of the high lethality by postoperative renal failure.


[Abdominal and cremaster reflexes after trauma-induced brain death (author's transl)]. The case is reported of a 42-years-old man who was admitted to hospital with a head trauma following a fall and died 12 hours later. Although irreversible loss of cerebral function had been established neurologically, electoencephalographically, angiographically (carotid and vertebral angiography) and scintigraphically abdominal and cremaster reflexes could still be elicited. The neurophysiological conditions for the reappearance of these reflexes are discussed.


[Prolonged extracorporeal membrane oxygenation in the treatment of burns-induced shock lung (authors transl)]. A case of third-degree burns involving 35 per cent of the body surface is reported with occurred in a 28-year-old man. On the 6th day progressive pulmonary insufficiency developed which 3 days later necessitated extracorporeal membrane oxygenation. Oxygen diffusion capacity gradually improved and the patients resumed spontaneous respiration with oxygen enriched air. He died 5 days after membrane oxygenation was discontinued due to massive haemorrhages from an infection at the site of the femoral by-pass. The technique adopted for the perfusion, which lasted 83 hours, is described.


The effects of ozone on the respiratory epithelium and alveolar macrophages of mice. I. Interferon production. The effects of 0.8 ppm ozone on the capacity of the tracheal epithelium and alveolar macrophages of mice to produce interferon in vitro was studied. Exposure of mice to ozone for a period of 11 days or more affected the capacity of the tracheal epithelial cells in vitro to produce interferon. The inability of the tracheal epithelium in vitro to produce interferon was not due to the inhibition in the release of intracellular interferon but to an inhibition in the production of interferon. There was a complete recovery of the ability of tracheal epithelium to respond to interferon inducers after the mice were returned to ambient air 24 days post ozone exposure. However, ozone did not seem to have any affect on the capacity of the alveolar macrophages to produce interferon in vitro.


Endotoxin-stimulated spleen cells: dissociation between DNA synthesis and IgM production at the cellular level. LPS stimulation of mouse spleen cells in the presence of Hu resulted in almost total suppression of [3H]thymidine incorporation without affecting the percentage of cells induced to produce IgM. Utilizing a method which permitted the simultaneous measurement of IgM production and [3H]thymidine incorporation in individual cells, it was demonstrated directly that LPS stimulation of IgM production can occur in the absence of DNA synthesis.


Kinetics of immunoglobulin transport into canine bronchial secretions. Radiolabeled 125I Preparations of canine IgG, IgM, and F(ab')2 fragments of IgG were injected intramuscularly into normal dogs to quantitate the transfer of immunoglobulins from the intravascular space into the lower respiratory tract and to observe the clearance of these proteins from lung secretions. Respiratory fluids were sampled by serial broncho-alveolar lavages during a 3-4 week interval. Only a small portion (0.15%) of the passively administered IgG was recovered in respiratory specimens indicating that minimal transfer of humoral IgG occurs under normal conditions. Alteration of the IgG molecule by removal of the Fc portion almost eliminates its penetration into lung secretions. Furthermore, IgM, which is not a prominent component of normal lung secretions, is not detected in these secretions following passive intramuscular injection.


Studies on the blood clotting and fibrinolytic system in the plasma from a sei (baleen) whale. Blood clotting and fibrinolytic systems were studied in the plasma of a sei whale (Balaenoptera borealis). The sei whale belongs to the suborder baleen whales of the order Cetacea. Whale plasma had a greatly prolonged kaolin-activated partial thromboplastin time and was deficient in Hageman factor (factor XII), Fletcher factor (a plasma prekallikrein), and PTA (factor XI). All other clotting factor activities were present in amounts comparable to that of normal human plasma. Whale plasminogen was activated by human urokinase, but not by streptokinase. Whale plasma contained inhibitory activities against thrombin, activated Stuart factor, activated PTA, activated Fletcher factor, and plasmin.


Isolation and partial characterization of a major basic protein from rat eosinophil granules. The rat eosinophil granule possesses a major basic protein (MBP) similar to that previously isolated from human and guinea pig eosinophils. This conclusion is based on demonstration that the major protein of the rat eosinophil granule is a low molecular weight, highly basic material with an amino acid composition similar to that of the human and guinea pig MBP.


A radioimmunoassay for serum calcitonin in the rat. A radioimmunoassay for serum calcitonin in the rat is described. Materials for assay of human calcitonin are employed. The sensitivity of the assay is 3 pg and corresponds to a lower limit of detection of 60 pg/ml for peripheral serum. The normal range is up to 650 pg/ml in rats weighing between 125 and 200 g. Serum calcitonin is not detectable in thyroparathyroidectomized animals. It increases and varies directly with the serum calcium after intraperitoneal administration of the ion. Values for serum calcitonin in male and female rats are comparable under basal conditions and after calcium. The radioimmunoassay should allow the further characterization of calcitonin secretion in response to physiologic and pathophysiologic stimuli in this species.


Glutathione peroxidase activity and glutathione concentration in genetically dystrophic mice. The present studies were conducted to determine whether inherited muscular dystrophy in the 129/ReJ-dy mouse was associated with differences in specific activity, substrate availability, or apparent Km of glutathione peroxidase. The results indicate that glutathione peroxidase is elevated in skeletal muscle of mice with genetic muscular dystrophy when the activity is expressed on a protein basis. This elevation precedes the development of severe paralysis since muscles from the fore legs showed increased enzyme activity as early as the more severely affected hind legs. There was no difference in glutathione peroxidase activity in tissues other than skeletal muscle. GSH concentration was elevated in muscle and normal in other tissues of dystrophic mice, showing that adequate substrate was available to the enzyme. The apparent Km for cumene hydroperoxide was also similar for muscle of normal and dystrophic mice. This report provides further evidence that mice with dystrophia muscularis have a functional glutathione peroxidase system in all tissues including skeletal muscle, and that a defect in this in vivo protective system is apparently not a contributing factor in the pathology of the disease.


Seroepidemiologic investigations of human hepatitis caused by A, B, and a possible third virus. Seroepidemiologic studies were made of normal subjects in populations in the United States and Costa Rica and in family outbreaks of hepatitis in Costa Rica. Hepatitis A affected a majority of children of very young age in Costa Rica, while such experience in persons of high socioeconomic status in the United States did not occur before middle life. Persons of low socioeconomic status (paid plasma donors) and residents and attendants of institutions for the mentally retarded showed a far greater incidence of hepatitis A antibody than did their counterparts in the open community. Hepatitis A and B epidemics occurred in families in Costa Rica with rapid spread to other susceptible members of the group. The disease was clinically apparent in roughly half the cases, whether the responsible agent be hepatitis A or B. Five cases of nonhepatitis A or B (hypothetical hepatitis C) were found and all but one of them were subclinical.


Effects of glucose or insulin on myocardial performance in endotoxin shock. Past studies reported by this laboratory have documented myocardial dysfunction and progressively developing hypoglycemia in canine endotoxin shock. The purpose of the present study was to determine the effects of glucose concentrations and insulin infusions on myocardial performance following endotoxin administration. Experiments were carried out on isolated, working canine left ventricular heart preparations exchanging blood with intact dogs. Myocardial function was evaluated following endotoxin and correlated with concentrations of glucose and effects of insulin infusion. Cardiac dysfunction occurred within 2-4 hr postendotoxin and the degree of malfunction was not related to arterial blood glucose concentrations. Maintaining blood glucose at control, preshock, levels by infusion of 50% glucose did not prevent myocardial dysfunction as evidenced by elevations of left ventricular end diastolic pressure, and depressed power. Infusions of insulin reversed cardiac failure and maintained normal performance in spite of wide ranges in glucose concentration (5-120 mg%). Findings suggest that myocardial dysfunction is not precipitated or enhanced by the hypoglycemia of endotoxin shock. The beneficial actions of infused insulin on cardiac performance appear to be elicited on the basis of mechanisms other than myocardial glucose transport.


Plasma glucagon after total resection of the pancreas in man. Serial measurements of plasma "true glucagon" (PG) and of glucagon-like immunoreactive materials (GLI) were carried out during and after total resection of the pancreas in a 62-year-old man with calcified pancreatitis. The postoperative course of this patient was uneventful and diabetes was well controlled. PG disappeared from the blood within 30 min after resection of the pancreas. In spite of the evidence that no pancreatic tissue was present in the abdomen, PG was detected again in the blood from 18 hr after total pancreatectomy until the ninth postoperative day. However, plasma PG did not rise following infusion of arginine during the fourteenth postoperative week. After an initial decrease, plasma GLI rose abruptly on the second postoperative day and remained elevated thereafter. The fluctuations of plasma PG and GLI were not parallel.


Effect of skin or muscle incisions or the loss of blood on serum leucogenenol level. It has been found that damage to a tissue of a rabbit or a rat, such as results from a skin incision or an incision through the skin and muscles into the abdominal cavity, is followed 24 hr later by a significant increase in the concentration of leucogenenol in the animal's serum. Likewise, loss of approximately one-quarter to one-half of the blood in the circulation of rabbits or rats causes an increase 24 hr later in the animals' serum leucogenenol concentration.


Role of the renin-angiotensin system in dogs with perinephritis hypertension. Cellophane perinephritis hypertension was produced in four dogs, while five additional dogs served as normotensive controls. A competitive antagonist of angiotensin II, 1-sarcosine-8-alanine angiotensin II, was infused iv into these conscious dogs at a rate of 6 mug/min/kg of body weight for 45 min. Arterial pressure averaged 170 +/- 11 (SEM) mm Hg in the dogs with perinephritic hypertension, and was not altered significantly during infusion of the angiotensin antagonist. In the normal dogs the arterial pressure averaged 100 +/- 10 mm Hg and likewise, did not change during administration of the angiotensin analog. Plasma renin activity values were essentially the same in these two groups of dogs and did not change during infusion of the angiotensin antagonist. These studies provide strong evidence that the renin-angiotensin system is not involved in maintaining the elevated arterial pressure in dogs with chronic hypertension produced by cellophane perinephritis.


Direct stimulation of renin release by calcium. Calcium directly stimulates renin release from rat kidney slices previously treated with calcium-free medium. The stimulant effect of calcium (0.5 or 6.0 mM) is not seen without the period of calcium depletion. The stimulant effect of calcium is still present in sodium-free medium but is reduced when the incubation is performed at 20 degrees instead of 37 degrees. The results suggest that the underlying mechanism of renin release may be comparable to that of catecholamine release, involving calcium-dependent and energy-dependent steps.


Effect of leukocytic endogenous mediator (LEM) on zinc absorption in the rat. Leukocytic endogenous mediator (LEM) was shown to produce a significant increase in the intestinal absorption of zinc within 7 hr after its administration to normal rats. Consistent with earlier studies, LEM also produced a significant decrease in the plasma zinc concentration and an increased hepatic uptake of this metal which further demonstrates that LEM may be a key intermediate in altering zinc homeostasis during inflammation.


Immunogenic properties of a nonproducer malignant tumor induced by murine sarcoma virus. A cloned cell line H-11 (HP) derived from an MSV-induced neoplasm (a hemangiosarcoma) was found to possess virus-specific tumor rejection antigen(s). The specific nature of the immune response was established through the use of a polyoma virus-induced neoplasm no. 89 both in cross immunization and cross challenge experiments. Virus antigens or surface antigens associated with virus production are not responsible for tumor rejection since virus production could not be detected, nor were any viral fingerprints of MSV found by the several assays used.


Kinetics of the rapid action of interferon. The present study was undertaken to examine some factors which lead to early-appearing resistance in human cells treated with interferon. It was previously shown that two conditions required for rapid development of resistance were continuous maintenance of cultures at 37 degrees and use of more than 10 units/ml of interferon. The decay kinetics of the established resistance appear to be approximately the same whether the resistance was induced under conditions favoring rapid or slow development. With the use of actinomycin D it was shown that the mRNA for the antiviral protein is produced between 30 and 45 min after the first contact with interferon. Ruled out were the possibilities that a priming action of interferon and a newly synthesized intermediary protein were necessary for rapid development of resistance.


Spontaneous development of gluconeogenesis in fetal rat livers during incubation in organ culture. Freshly isolated fetal liver explants in organ culture did not convert L-[14C]alanine or L-[14C]lactate to carbohydrate, but L-[14C]serine and D-[14C]glycerol were both transformed. When explants were subjected to 42 hr of preliminary incubation without supplements, followed by transfer to fresh medium with added precursor, all four substrates underwent gluconeogenic transformation. It was concluded that the ability of fetal rat liver in organ culture to convert alanine and lactate to carbohydrate evolves slowly, but the conversion of glycerol, and to a lesser extent serine, to glucose and glycogen is initiated immediately.


Environmental effects on glutathione-insulin transhydrogenase in rat liver. The dietary and hormonal regulation of the level of glutathione-insulin tranhydrogenase in rat liver was investigated in these studies. In order to make valid comparisons, the assay of glutathione-insulin transhydrogenase was performed at near zero-order kinetics wherein enzyme rate was proportional to enzyme amount. Changing the protein content of the diet or administration of glucagon or cortisone did not significantly affect the specific activity of glutathione-insulin transhydrogenase in microsomes from rat liver. However, the Vmax and Km of this enzyme in the livers of adrenalectomized rats were increased three-and fourfold over these values in microsomes from normal liver. Administration of cortisone resulted in a return to the normal kinetic constants of microsomal GIT within 4 hr.


Developmental studies on glucosamine metabolism. Changes in hepatic hexosamine metabolism and serum seromucoid concentrations during postnatal development were investigated in the rat. A relatively low activity of hepatic L-glutamine: D-fructose-6-phosphate aminotransferase (AT) was observed within 24 hr of birth. This rapidly increased to a maximum at about 2 weeks of age, followed by a decline to adult levels after another 2 weeks. The developmental pattern of hepatic UDP-N-acetylglucosamine 2'-epimerase (EP) closely resembled that of AT. It was relatively low in the newborn, increased to a maximum at about 2 weeks and then declined to adult values after another 2 weeks. The serum seromucoid concentration was low in the new born rats and then increased gradually with development to adult levels at about 50 days. The hepatic concentrations of UDP-GlcNAC and CMP-NANA both were relatively high at 24 hr after birth compared to values observed at 50 days. The developmental pattern observed for both over this time period was quite similar and was almost the reciprocal to that for the seromucoid fraction. After 50 days the concentration of UDP-GlcNAc remained constant at adult levels as did that of the seromucoid fraction, but the concentration of CMP-NANA showed a marked increase. It is suggested that the hepatic concentrations of these amino-sugar nucleotides during development primarily reflect the demand for the hepatic synthesis and secretion of plasma glycoproteins as reflected in the seromucoid fraction.


The sulfhydryl group of monellin: its chemical reactivity and importance to the sweet taste. The presence of a single cysteine in the sweet-tasting protein monellin was confirmed by titrations with p-hydroxymercuribenzoate (PHMB) and 5,5'-dithiobis(2-nitrobenzoic acid) (DTNB). The sulfhydryl group in native monellin reacts very slowly with each of these reagents, indicating that the sulfhydryl is relatively inaccessible. In the presence of either 6 M guanidine-HCl, 8 M urea, or 1% sodium dodecyl sulfate, the rate of reaction of the sulfhydryl group with titrant is dramatically increased. Under a variety of conditions, the presence of 1 mole of sulfhydryl per mole of protein (of molecular weight 10,700) was found. Reaction of the sulfhydryl by titration with PHMB or DTNB leads to loss of sweetness. The free sulfhydryl is also lost by carboxymethylation of monellin in the presence of guanidine-HCl, yielding a protein that is not sweet. Exposure to air in the presence of denaturant leads to a decrease in the sweetness of monellin. Sweetness of the PHMB-reacted monellin can be recovered upon treatment of the protein with mercaptoethanol, and the partial loss of sweetness that occurs with air exposure is lessened in the presence of mercaptoethanol. It is postulated that alteration of the single sulfhydryl group of monellin leads to a change in the tertiary structure of the protein and hence its sweet taste.


Effect of tryptophan and its metabolites on gastric emptying of liquid meals in dogs. The effects of tryptophan and its metabolites were studied to determine whether the known inhibiting effect of tryptophan on emptying was due to local or systemic effects or due to tryptophan metabolites. In five dogs with chronic gastric fistulas, instillation of 300 ml of DL-kynurenine (5mM), 5-hydroxytryptophan (mM), or 5-hydroxytryptamine (20 mM) into the gut did not slow gastric emptying. Furthermore, iv infusion of L-tryptophan (5, 20, 50 mM), DL-kynurenine (2, 5, 10 mM), 5-hydroxytryptamine (2mM, 10 mM), and 3-indolepyruvic acid (2, 5, 10 mM) also did not slow gastric emptying. These studies indicate that tryptophan slows gastric emptying by exciting a receptor in the gut and not by a direct effect on the stomach or brain or via its major metabolites.


Contribution of luminal concentration of nutrients and osmolality to postprandial intestinal hyperemia in dogs. Intestinal blood flow is increased during digestion. This study assesses if the concentration of nutrients and/or osmolality of chyme in the intestinal lumen are factors determining the hyperemia. Six digested food mixtures containing different concentrations of nutrients and/or having different osmolalities were placed into the jejunal lumen, and their effects on local venous outflow compared. The 100% (999 mOsm/kg), 33% (291 mOsm/kg), and 20% (183 mOsm/kg) food mixtures all increased flow, but the 10% food mixture (94 mOsm/kg) did not. The hyperemic effect of 33 and 20% food was similar, but 100% food produced a greater increase in flow than did 33 or 20% food. Luminal placement of a 30% solution of a nonabsorbable substance polyethylene glycol (1000 mOsm/kg) did not alter flow. Also, the vascular effects of 20 or 10% food mixtures were not altered when these mixtures were made isotonic by the addition of NaCl. These studies indicate that lumen osmolality, within a range of 180 to 1000 mOsm/kg, is not a significant factor contributing to the local hyperemia occurring when nutrients are in the gut lumen. However, the concentration of nutrients in the lumen is a factor determining the local hyperemia.


The contribution of the distal gastrointestinal tract to glucagon-like immunoreactivity secretion in the rat. Radioimmunoassay of acid ethanol extracts of the rat intestinal tract showed the presence of glucagon-like immunoreactivity (GLI) from the duodenum to the colon with maximal concentrations in the ileum and colon. Twenty percent glucose instilled in the duodenum at a dose of 2g/kg body weight stimulated a twofold increase in peripheral plasma GLI concentration. When the instilled glucose load was restricted to only the duodenum and jejunum, or to only the ileum and colon, the increase in peripheral plasma GLI was approximately half that seen when the entire gut was exposed to the glucose. It is concluded that the distal gut as well as the proximal gut releases GLI in the rat.


A study of taste and smell of heavy water (99.8%) in rats. Restricted to heavy water (99.8%), rats drank it freely for the first day, then they drank progressively less and died within 14 days. When given a choice between distilled water and heavy water (99.8%) rats avoided heavy water partly by virtue of some deleterious effects of heavy water and partly by virtue of a faint smell of heavy water with which the untoward effects could be associated. Rats did not taste heavy water. Whether a higher viscosity of heavy water plays any part could not be determined. Apparently the low intensity of any untoward effects of heavy water and the faintness of its smell could explain the erratic variability of the reactions of rats to heavy water that put it in a different category from other substances tested so far.


Palmitate incorporation in the lungs of dogs with granulomatous disease. Moderate hypoxia did not influence the pulmonary incorporation of an intravenous dose of [1-14C]palmitate either in dogs with experimentally produced granulomatous disease or in normal controls. The lung weight in the diseased animals, was, on the average, double that of the controls. There was a proportionate increase in uptake of the radioactive label at 1 hr after infusion in the diseased lungs, hence the specific activity of labeled palmitate (counts per minute per gram of phospholipid) was no different in the two groups. Moreover, half the radioactivity of the phospholipids was recovered in palmitate separated from the phosphatidyl choline fraction in both diseased and normal lungs. Anatomic studies demonstrated increased numbers of Type II pneumocytes lining all alveolar air spaces in the diseased lung. Autoradiographic studies indicated the presence of labeled palmitate in the Type II cells, but not in the inflammatory cells of the granulomata. We conclude that the increased palmitate uptake in this disease is accounted for by the metabolic activity of the Type II pneumocytes.


Energy-selective reconstructions in X-ray computerized tomography. All X-ray computerized tomography systems that are available or proposed base their reconstructions on measurements that integrate over energy. X-ray tubes produce a broad spectrum of photon energies and a great deal of information can be derived by measuring changes in the transmitted spectrum. We show that for any material, complete energy spectral information may be summarized by a few constants which are independent of energy. A technique is presented which uses simple, low-resolution, energy spectrum measurements and conventional computerized tomography techniques to calculate these constants at every point within a cross-section of an object. For comparable accuracy, patient dose is shown to be approximately the same as that produced by conventional systems. Possible uses of energy spectral information for diagnosis are presented.


A technique for measuring the variation of photon spectrum from X-ray generators over the mains voltage cycle. The variation in current and accelerating voltage across an X-ray tube, that occurs over the mains voltage waveform cycle, produces changes in photon flux and spectrum shape. A knowledge of these changes is required to provide an understanding of the parameters affecting X-ray output. Variation in the photon flux will cause distortion of a measured 'mean' spectrum if the dead time of the spectrometry system employed varies over the waveform cycle. A system has been developed that enables the spectrometer to be synchronized to the mains voltage cycle so that variations in photon flux and the instantaneous spectra at selected parts of this cycle can be measured. The variation in photon flux is dependent upon the type of power supplies (both high and low tension). the tube current and the degree of filtration employed. Examples are given of the ripple of photon output due to the voltage and current ripple for a nominally constant potential generator and a half-wave rectified type. The way in which they interact to produce the measured variation is shown.


Saturation corrections for plane-parallel ionization chambers. Experiments described in the literature lead to different formulae for saturation corrections in ionization chambers. To elucidate the differences, saturation curves of an extrapolation chamber irradiated with beta particles from 90Sr+90Y sources have been studied experimentally. The results could be described by one formula which was a combination of known formulae for charge collection losses due to volume recombination, initial recombination and diffusion.


Bone density measured by photon scattering. I. A system for clinical use. A system for the routine measurement of the density of the os calcis is described. Measurements are made of the number of photons scattered by the bone from a 153Sm photon beam. The first results from human subjects are presented.


Bone density measured by photon scattering. II. Inherent sources of error. The origins of inherent sources of error in results of measurements of bone density by a photon scattering technique are described and their effects are predicted theoretically. The predictions are confirmed experimentally. The prime source of error is multiple scattering. A procedure has been developed to correct the observed densities for effects of multiple scattering.


A new technique for radiotherapy planning using quadratic programming. Previous attempts at optimization of radiotherapy planning are described and criticized, and consideration of these attempts has resulted in the development of a new technique using quadratic programming. Uniformity of tumour dose is selected as the most important feature of any plan, and this is achieved by minimizing the variance of the dose to preselected points within the tumour. The dose to vulnerable regions can be constrained not to exceed a given percentage of the mean tumour dose. Optimization of field weight and field type is possible. The operation of the system is described and some typical results are given.


Digital computer processing of brain scans using principal components. Most of the scan processing methods used to date are unable to distinguish between normal and abnormal features. This paper describes a method of constructing a particular orthogonal transform from a set of normal images, the method of principal components, which may be used selectively to filter out normal features, leaving behind abnormal features. The method has been applied to brain scans and has been implemented on a small digital computer system with magnetic disc.


Dosimetry in single lung cells by means of microautoradiographic activity measurements. After inhalation of compounds containing promethium-147 in the lungs of mice most of the activity is deposited in the form of local concentrations (hotspots). By means of a special quantitative microautoradiographic method using stripping film ORWO K 105, measurements of the activity of single hotspots of about 10(-14) Ci are possible. A microphotometer with a variable measuring diaphragm is used for the determination of the density profile of the autoradiographic image in order to get hotspot depth within the biological specimen. To determine hotspot activity it is necessary to calibrate the film with a Pm-147 plane source. The systematic and random errors of the method are discussed in detail, giving a total error of +/- 21% (SD) for one hotspot activity measurement. A few examples of biological results obtained by the method are given. Simple models are used to calculate doses absorbed in macrophage and alveolar cell nuclei from the measured activities.


The response of cells in culture to fractionated radiation: a theoretical approach. A mathematical model has been constructed to simulate the response of cells in vitro to fractionated doses of radiation. The model is capable of describing most of the radiobiological functions that are commonly studied. Input data are measurable cell properties. The details of the model and methods of acquiring the input data are outlined and a comparison with experimental observations on two radiobiological functions, survival curves and recovery curves are discussed in some detail.


Program for cardiac patients: stress testing and training. Dynamic exercise stress testing had become a widely accepted technique in the diagnosis of cardiac patients. The results of standardized exercise testing may be used to evaluate a patient's functional capacity and to derive an exercise prescription to assist him in improving his state of cardiovascular fitness. Because the physical therapist has special training and skill in exercise-related techniques, a stress testing laboratory and an exercise-based cardiac rehabilitation program may be appropriately established in a hospital's physical therapy department. Results are presented of a diagnostic exercise testing and an exercise-based cardiac rehabilitation program organized and supervised by physical therapists in a 300-bed private hospital.


A method of developing and evaluating a clinical performance program for physical therapy interns. A method used by interns and supervisors in developing and evaluating a clinical performance program during a 6-week internship in the Division of Physical Therapy at the University of Michigan Medical Center is presented. This method required a statement of educational resources available, establishment of criteria for judging acceptable performance, statement by the intern of his educational objectives, negotiation of a written contract, and maintenance of a log. The 32 participants thought that this was a rational and acceptable program and stated that they would, if given a choice, elect to follow the same procedure again.


[The motormetric Rostock-Oseretzky scale]. A new motometric scale with 24 tasks was designed taking into account Oseretzky tasks. It was standardized with 325 normal school children ranging in age from 5 to 11 years. The normal presentation in form of C scales and MQ scales, resp., allows a qualitative evaluation of the motor development irrespective of the age of the child. Furthermore, the procedure allows an improvement in the successful diagnosis of cerebral lesions in early infancy; this was verified by an examination of 92 children with proved brain lesions or high risk births. Details are given on the reliability, validity with reference to criteria, and diagnostic value of the scale. The procedure is economic as far as the necessary time is concerned and therefore it can also be applied in the treatment of out-patients.


[The attitude toward learning and favorite subjects in students with reading and spelling disability]. The hypothesis of a general dislike of school and learning aversion in children with reading and spelling disability could not be confirmed. As far as the attitude to the subjects and to the teachers, particularly to the teachers of German, is concerned no deviation from the norm generally existed. The inclination towards lingual subjects is lower than in pupils attending polytechnic high schools. The contrast between frequent behavioural disorders in school on the one hand, and the general positive attitude towards school is interpreted as a appetency-aversion conflict. The dominance of appetency is caused by the favourable social and pedagogic conditions in socialist society and is regarded as a prerequisite of successful therapy.


[Secondary symptoms of reading and spelling disability]. The hypothesis that the secondary symptoms of legasthenia can be derived in a linear and causal way from the primary symptoms is investigated. This study is based on data from the patients' history, diagnosis, therapy, and catamnesis. It is shown, that behavioural and adaptability disturbances are for the major part of prelegasthenic character but may become more pronounced by the manifestation of the primary symptoms. The parallel course of primary and so-called secondary symptoms with different times of manifestation is discussed as a conceptional model. Furthermore, the much less fully authenticated conceptional model based on findings in a childrens' neuropsychiatric clinic, which claims the existence of genuine secondary symptoms in a causal relationship to the primary symptoms, is not put into dispute.


[Excretion of 3,4-dimethoxy phenylethylamine in the urine of schizophrenics]. According to the hypothesis of Osmond, Harley-Mason and Smythies on abnormal methylation products in the catecholamine metabolism in schizophrenics, the excretion of 3,4-dimethoxyphenylethylamine (3,4-DMPEA) in the urine was examined in 80 patients with endogenous psychoses and in 20 normal persons. In 38% of the patients 3,4-DMPEA was found, whereas no 3,4-DMPEA was found in normal persons. When the biochemical findings obtained are correlated to the corresponding diagnoses the highest incidence of positive findings was observed in paranoid-hallucinatory schizophrenics with 71% in males and 75% in females. The signification of controls during the course of the experiments is emphasized.


[Correlation between reflex behavior and EEG in a brain-stem tumor]. In a female patient with a tumour of the brain stem the e.e.g. showed signs of increasing general functional disorders and additional transient high voltage monographic waves with bilateral frontal and central accentuation, which we regarded as brain stem disturbances. At the same time the authors observed a characteristic inhibition of the amplitude of brain reflexes as well as high phases of a polyphasic stimulation--response potential with stimulation of the tibial nerve. Beside these inhibition phenomena, signs of disinhibition were verified (nociceptive, trigemino-trigeminal reflex, polyphasic disinhibited brain reflex?). The photostimulation was without influence on the sensitivity of motoneurons.


An analysis of career enquiries made to a school of radiography over a five-year period. A follow-up enquiry form is described and results provided from a survey over a five-year period. The information gained has enabled a further and we hope more searching questionnaire to be designed. At the time of producing the pro-forma in 1969, career and salary prospects in radiography were not as good as at present. The Halsbury Report in May 1974 was a great advantage to the paramedical professions as a whole. It will be interesting to see how recruitment and job availability proceed over the ensuing five years.


The value of lead shields in reducing radiation dosage to the eye during neuroradiological procedures. Home-made protective eyeshields are described, for use during certain types of skull radiography. Measurements made during the examination of patients and with a phantom skull indicate that a ten-fold reduction in radiation dose may be achieved through their use during certain diagnostic procedures.


A method of measuring the angle of tomographic movement. A technique is described for measuring the angle of two tomographic movements. It requires only simple equipment, most of which is normally available in X-ray departments. The calculation involved is quite simple and the result obtained is accurate even at small angles.


Double-contrast arthrography in meniscal lesions and patellar chondropathy. The technique of double-contrast arthrography is discussed in this paper. The serial exposures included a special exposure of the retropatellar region in order to detect patellar chondropathy. Various types of meniscal rupture and degeneration are discussed with special reference to combinations of these lesions and to lesions of both menisci in the same knee joint. The aetiology and radiological features of patellar chondropathy are discussed in detail. Patellar chondropathy was diagnosed in 19% of patients without meniscal lesions, 23% of patients with medial and 35% of those with lateral meniscal lesions, as well as in 73% of post-meniscectomy cases. Comparison of arthrographic with arthroscopic results revealed a positive correlation in 74% of cases.


Echoscopic and echographic differential diagnosis of pancreatic lesions. Combined echoscopic and echographic examination enables accurate display of the pancreatic region. Furthermore, this method yields reliable results in demonstrating pathological changes of the pancreas caused by acute pancreatitis, acute necrotising pancreatitis, pancreatic pseudocyst and neoplasm of the pancreas. The characteristic ultrasonographic findings in these diseases are presented and the differential diagnosis is briefly discussed.


Serial liver and spleen scanning in patients with malignant lymphomas. Spleen and liver represent target organs for involvement in patients with Hodgkin's disease and with non-Hodgkin's lymphomas. Although histological examination remains the most reliable method in diagnosing the presence of disease in these organs, particularly during the early phases, exploratory laparotomy and liver biopsy cannot be repeated, for practical purposes, on a regular basis. As the incidence of splenic and hepatic involvement continues to rise in the years following the initial diagnosis, we have found that liver and spleen scans performed in a serial manner are helpful in establishing the diagnosis during the follow-up period. By comparing the later studies to the earlier ones, interval changes as related to the size, contour, homogeneity and to the presence or absence of filling defects, become apparent. These changes, should they occur, are related, in our experience to the underlying lymphoma. Conversely, through serial scanning, improvement under treatment of a previously involved organ, is well demonstrated by this noninvasive technique. The limitations imposed by the resolving power of the imaging system must be taken into consideration when interpreting the results.


Frequency of bilateral tumours and primary retroperitoneal localization in tumours of the testicles. Report on 4 patients with bilateral testicular tumours (out of a total number of 181 cases) and the problems arising with a second course of irradiation. The question of histogenesis and therapeutic course in 4 patients with a primary retroperitoneal tumour localization are discussed in the second part.


A short course - low dose preoperative irradiation of endometrial carcinoma. Preliminary report. This is a preliminary and comparative report of a randomized prospective study in which 14 unselected women with a proven histological diagnosis of endometrial adenocarcinoma were subjected to a course of external irradiation treatment with total 1,500 rad mid-pelvic dose delivered on five consecutive days followed by total abdominal hysterectomy and bilateral salpingo-oophorectomy. Surgery was performed within 1 week after the completion of radiation therapy. At the same time, 15 additional patients with identical histological diagnosis were treated with the conventional external irradiation technique of 5,000 rad delivered in 5 weeks followed by surgery 6 weeks later. The stage indicates no significant differences between these two radiotherapeutic modalities in regard to survival rate, recurrences or complications. The short course-low dose approach markedly reduces the cost and overall treatment time.


[Carcinoids of the small intestine. Retrospective study of the radiological diagnosis of 15 patients (author's transl)]. The radiological workup of 15 patients with a carcinoid has been evaluated. As 7 of the 15 patients presented for emergency operation, only the remaining 8 had barium studies (7 barium meals and 1 barium enema). Two of the barium meals were even retrospectively, entirely negative. In two others, initially the diagnosis was missed despite radiological signs, which had been overlooked on follow-up films. Fluoroscopic examination of the small bowel would probably have ensured the detection of the lesion. At the time of diagnosis nine tenth of the tumours were already infiltrating and more than half of them metastasizing. The presence of the carcinoid syndrome implies the production of the causative hormones in the liver or the pulmonary circulation. In order to find the primary intestinal carcinoid in a cureable stage- that is, before it has metastasized-, all patients with diarrhoea and repeated bouts of abdominal pain should have a careful follow-up examination of the small bowel. This examination must include fluoroscopies.


[An analysis of the plain chest films of 109 children with atrial septal defect. The correlation between different radiological criteria and shunt size (author's transl)]. Radiograms of the chest (p.a.--and lateral projection) of 109 children with atrial septal defect taken before cardiac catheterisation have been evaluated under standardized principles; correlation between size of the left-to-right shunt and the radiographic changes has been performed. The examiner evaluated at random radiographs of 213 subjects, of whom 104 had no cardiac disease. Besides the determination of several radiographic criteria the examiner had to decide whether the subject in question had cardiac abnormalities or not. There has been a statistically significant correlation between the size of shunt-volume and the amount of radiographic changes as: 1. pulmonary vascular markings, 2. size of the right ventricle in the lateral projection, 3. cardiac configuration in the p.a.-projection, 4. relative cardiac volume, 5. size and shape of the pulmonary artery segment, 6. size of the aortic arch. The highest diagnostic value is represented by pulmonary vascular markings; this is of great importance. Because pulmonary vascular markings can be in any age group evaluated on technically good radiographs. 78% of the atrial septal defects could be detected by radiographic criteria. In 5% of the children with no cardiac disease a vitium cordis had been diagnosed erroneously.


[Several causes of respiratory insufficiency in children (author's transl)]. Differential diagnosis respiratory insufficiency in children is great problem for pediatricians and a radiologists. The mortality rate for respiratory insufficiency especially in the newborn may be as high as 50 per cent. The etiology of respiratory insufficiency may be of different origin. Considering location one can distinguish between pulmonary and extrapulmonary causes, as congenital oesophageal stresia, diaphragmatic hernia, diaphragmatic relaxation, and tumours of the neck, mediastinum and thoracic wall. Roentgen examinations are important to diagnose of extrapulmonary causes for respiratory insufficiency.


[Radiographic signs of cor pulmonale (author's transl)]. The pulmonary artery pressure of 47 patients was compared with radiological criteria of pulmonary hypertension: in rest and exercise. The diameter of the truncus intermediul is the only measurable criterium. A diameter larger than or equal to 18 mm is an indication for latent or manifest cor pulmonale. If the diameter is less than or equal to 15 mm a pulmonary hypertension is improbably. Additional findings (primary pulmonary disease, diameter of the truncus pulmonalis, loss of lung vessel structure in the periphery, marked reduction in vessel caliber--graded 0-3) leads to the diagnosis of manifest cor pulmonale on the basis of routine x-ray of the chest. The differentiation between manifest and latent cor pulmonale ist possible in most cases. An overestimation of the primary lung disease, particularly by fibrosis, may mistead from the correct diagnosis.


Prostaglandin endoperoxide and thromboxane generating systems and their selective inhibition. Two enzyme systems and their selective inhibition are described. Microsomes from ram seminal vesicles (RSV) incubated with arachidonic acid at 22 degrees C generated a rabbit aorta contracting substance which, after rapid ether extraction, had characteristics similar to purified standard endoperoxides. Incubation of either purified endoperoxide or the product from RSV and arachidonic acid with horse platelet microsomes (HPM) yielded a more potent rabbit aorta contracting substance characterized as thromboxane A2, with a half life of 35.9 +/- 2.2 s at 37 degrees C after ether extraction. Two inhibitors, indomethacin and benzydamine exhibited selectivity for the two enzyme systems. The IC50 for benzydamine against thromboxane synthetase was 100 mug/ml and 250 mug/ml against RSV. Indomethacin showed a greater degree of selectivity with an IC50 of 5 mug/ml for the ram seminal vesicle cyclo-oxygenase compared to 100 mug/ml for thromboxane synthetase.


Paradoxical endogenous synthesis of a coronary dilating substance from arachidonate. Isolated bovine, canine, and human coronary arteries exhibited dose dependent contractions to prostaglandin (PG) E2 and F2alpha (50 ng/ml to 10mug/ml). The ED50 value for both PGE2 and PGF2alpha was 500 ng/ml in the bovine and human coronary arteries. Paradoxically, although PGE2 and gf2alpha are vasoconstrictors, administration of their precursor, arachidonate (100 ng/ml to 10 mug/ml) caused relaxation of the bovine, canine and human coronary arteries. This observation suggests that arachidonate is not being converted by the coronary PG synthetase to PGE2 or PGF2alpha. However, the arachidonate induced coronary relaxation was inhibited by pretreatment with PG synthetase inhibitors, indomethacin, meclofenemate and aspirin. Indomethacin addition to the strips previously relaxed by arachidonate caused contraction. In contrast to other PGs (E2 and F2alpha), PGE1 (10 ng/ml to 10 mug/ml) caused dose dependent relaxation of the bovine coronary arteries (ED50 = 100 ng/ml). Indomethacin induced further relaxation of the blood vessels previously relaxed by PGE1. Since PGE1 cannot arise from arachidonate, the arachidonate coronary dilation and reversal by indomethacin must be independent of PGE1 formation. Linolenate (100 ng/ml to 10 mug/ml) and oleate (100 ng/ml to 10 mug/ml) also caused relaxation of the bovine coronary blood vessels both before and after indomethacin, thereby eliminating a direct non-specific fatty acid effect as the cause of the arachidonate relaxation. These results suggest that in isolated coronaries, arachidonate undergoes a novel conversion, possibly by PG synthetase, to a dilating substance which exerts different contractile effects than exogenously administered PGE2, PGF2alpha and PGE1.


Studies on the effects of prostaglandins E1, E2, A1, and A2 on the dustus arteriosus of swine in vivo using cineangiography. Prostaglandins E1, E2, A1, and A2 have been shown by cineaortography to open and dilate the ductus arteriosus in anesthetised piglets 3 to 6 hours of age. The dosage of PGEs required was 1 to 4 mug/kg/min. and of PGAs 20 to 40 mug/kg/min. The effect of PGEs faded within 20 minutes of stopping infusion but the effect of PGAs was still evident up to 45 minutes after stopping the infusion. Little effect was noted from hypoxia or from the addition of indomethacin to prostaglandin infusion. Side effects were not troublesome with the dosage employed but hypotension and apnea sometimes occurred at the onset of PGE infusions.


Indomethacin inhibits responses to all vasoconstrictors in the rat mesenteric vascular bed: restoration of responses by prostaglandin E2. Indomethacin added to the perfusing buffer inhibited pressor responses to noradrenaline, angiotensin II, arginine vasopressin, histamine, serotonin, calcium ions and potassium ions in the male rat mesenteric vascular bed. For every pressor agent the indomethacin concentration which inhibited response amplitude by 50% was about 7 microg/ml (2.1 X 10(-5) M). With every pressor agent, prostaglandin (PG) E2 could restore normal responsiveness in indomethacin-blocked preparations even while the indomethacin was still present in the buffer. The concentration of PGE2 required was proportional to the concentration of indomethacin. Preparations completely inhibited by indomethacin needed about 5ng/ml PGE2 for complete restoration of normal responses. Aspirin and mefenamic acid could also inhibit responses to all pressor agents tested but with these drugs only a partial restoration could be achieved by PGE2.


Radioimmunoassay of prostaglandins A and B in human blood. A highly sensitive radioimmunoassay for the measurement of plasma prostaglandins A and B, expressed in equivalents of PGA1, is described. This method was used for the measurement of prostaglandins A and B (PGA/B) in 23 healthy volunteers and 25 hypertensive patients. The PGA/B concentration in peripheral venous plasma of 23 healthy normotensive subjects is 115 +/- 15 pg/ml. The repeated measurement of the same plasma samples kept frozen for 60 days at -20 degrees C shows mean 194% increase of PGA/B concentration. The major site of synthesis of PGA/B seems to be the kidney. However in two patients PGA/B concentration in arterial blood was greater than in venous blood suggesting the possibility of cardio-pulmonary synthesis. The major site of inactivation is the hepatic circulation, as PGA/B concentration in hepatal venous blood is by 30% lower than in vena caval blood. The arterial concentration is 3% lower than venous PGA/B demonstrating very low pulmonary inactivation. Therefore the prostaglandins of the A and B series may represent a "circulating hormone". The plasmatic PGA/B is significantly increased in reno-vascular and essential hypertension.


Mechanism of steroid action in inflammation: inhibition of prostaglandin synthesis and release. Acute arthritis was induced by injection of cell-free extract of group A Streptococci into the knee joints of mature male rats. Slices of control and inflamed synovia were incubated for 30 to 240 minutes and the rate of prostaglandin E (PGE) released into the medium was measured by radioimmunoassay. PGE release from inflamed synovia was 5-8 fold higher than that in normal tissue. Incubation of inflamed synovia with corticosterone acetate, dexamethasone or prednisone (100 mug/ml) for one or four hours reduced PGE release by 33% and 55% respectively. Lower concentrations of corticosterone (10 - 30 mug/ml) were ineffective. Aldosterone and progesterone (100 mug/ml) had no effect on PGE release throughout the incubation period. Chloroquine (10 mug/ml) inhibited PGE release from inflamed synovia by 50%. Indomethacin (1 mug/ml) abolished PGE release by 90%. Corticosterone, dexamethasone and prednisone reduced PGE content of inflamed synovia by approximately 45% during a 4-h incubation period. Aldosterone and progesterone were ineffective, while indomethacin reduced PGE content by 70%. The suppressive action of corticosterone on PGE release was prevented by addition to the medium of arachidonic acid (2 mug/ml). By contrast, the inhibitory action of indomethacin was not affected by provision of exogenous substrate. We suggest that glucocorticosteroids reduce PGE release by limiting the availability of the substrate for prostaglandin biosynthesis, and this may well explain some of their anti-inflammatory properties.


Changes in pituitary hormone secretions and corpora lutea following PGF2alpha administration to PMS/hCG-stimulated rats. Pseudopregnancy was induced in 26 day old female rats by giving 30 IU of PMS followed 56 hours later with 5 IU of hCG. Day 1 of pseudopregnancy was considered established 72 hours after PMS administration. Pseudopregnancy lasted 14 to 15 days. Ovarian weights increased for 4 to 8 times due to treatment. Histological examiniation of the corpora lutea (CL) of pseudopregnancy suggested luteolysis began on day 6 and extended to day 8. A "new" crop of CL appeared on day 9 suggesting the duration of pseudopregnancy was supported by more than one generation of CL or by CL maturing at different rates. Twice daily administration of 1 mg PGF2alpha on days 5 to 8 prevented the appearance of the "new" CL on day 9, and increased signs of luteolysis in the initially formed CL. Lower doses (0.01 and 0.1 mg, b.i.d., X 4 days) delayed the appearance of "new" CL until day 10. Blood samples withdrawn between 0930 and 1100 hours were analysed for FSH, LH and prolactin. Animals treated with 0.01 and 0.1 mg of PGF2alpha, b.i.d., X 4 days had increased LH values on day 8, thus the PG appeared luteotrophic. Rats treated with 1 mg of PGF2alpha, b.i.d., X 4 days had decreased LH values on day 7 and the CL showed subsequent luteolysis. FSH levels were relatively constant during pseudopregnancy. However, all doses of PGF2alpha reduced FSH levels on day 7. An associated decrease in uterine weight occurred, possibly due to reduced follicular development. Prolactin levels fell in response to PGF2alpha treatment which undoubtedly contributed to the observed luteolysis. The signs of early cessation of pseudopregnancy were: increased serum FSH on days 9 and 10; increasing uterine weight; and the reappearance of follicular growth. These data suggest that PGF2alpha reduced the duration of pseudopregnancy primarily by inhibiting the secretion of FSH, LH and prolactin.


Extra-amniotic 15 (S)-15 methyl PGF2alpha to induce abortion: a study of three administration schedules. Abortion was induced in 60 patients between 8 and 18 weeks gestation using 15(S)-15 methyl PGF2alpha in one of three extra-amniotic administration schedules: 1.0 mg in viscous medium (Tylose), 1 mg in viscous medium (Hyskon) or 0.5 mg in non-viscous medium repeated at 12 hours. Eighty per cent of patients aborted within 24 hours in each group. The overall mean induction-abortion interval (+/- S.E.) was 17.6 +/- 2.0: there was no significant difference between the three groups. Twenty patients treated with 1.0 mg in viscous medium had the catheter removed immediately following the prostaglandin injection and the success rate was not significantly altered. Gastro-intestinal side effects (vomiting in 50%, diarrhoea in 32.5%) were more frequent in the patients treated with the larger dose though the difference was not statistically significant. No significant haematological or biochemical changes were detected during the 24 hours following the start of treatment in 24 patients investigated. Thirty seven of the 60 patients (61.5%) aborted completely and did not require surgical evacuation, and none lost more than 500 ml of blood, nor required transfusion. It is concluded that abortion can be induced with a single extra-amniotic injection of 1 mg of 15(S)-15 methyl PGF2alpha in viscous medium in a large percentage of patients but that the incidence of side effects is high.


Menstrual induction by the vaginal application of ICI 81008 gel. After approximately 2 weeks menstrual delay (positive Pregnosticon Tests) "menstrual induction" was attempted in 75 gravidas by repeated vaginal application of a gel, containing 200 or 400 mug/ml ICI 81008. After approximately 10 minutes, following the 1st vaginal delivery of 400 mug ICI 81008, the uterus responded to this PGF2alpha analogue with sustained contracture. The highest success rate in induced bleeding (93%) and pregnancy termination (79%), without supportive therapy, was achieved when 400 mug ICI 81008 was administered 2 to 5 times at 4 hour intervals. Those gravidas (21%), who failed in induced menstruation, or stopped bleeding within 24 hour- after treatment, had positive Pregnosticon Tests on day 14 and were curetted. The side effects, mostly vomiting and increased blood pressure, were transient and subjectively and medically acceptable. While the vaginal application of the drug is apparently less effective than the intrauterine (1), it has the advantage of simple delivery and the potential of self-administration.


Evaluation of vaginal delivery systems containing 15[s]15-methyl PGF2alpha methyl ester. Silicone vaginal delivery systems containing 15[S]15-methyl-PGF2alpha methyl ester have been evaluated in vitro, and in vivo in the rhesus monkey. Three types of vaginal devices have been formulated to contain different concentrations of drug. The cumulative amount of 15[s]15-methyl-PGF2alpha methyl ester released in vitro from a planar silicone rubber matrix was dependent upon the initial loading dose of the prostaglandin. Drug-containing vaginal rings were evaluated in early pregnant and mid-trimester pregnant monkeys. Within 10 min after ring administration there was an increase in the amplitude and frequency of contractions. In mid-trimester pregnant animals there was an initial increase in plasma progesterone and then a decrease following treatment, while there was a progressive decrease in plasma progesterone in early pregnant animals. All 6 mid-trimester pregnant monkeys treated with vaginal rings aborted. Pregnancy was terminated in 4 of 5 early pregnant monkeys treated with vaginal rings. Blood levels of 15-methyl-PGF2alpha rose rapidly to attain a peak 1 hr after treatment with vaginal rings. After the peak, plasma levels of 15-methul-PGF2alpha declined to a plateau which was fairly constant between 2 and 8 hr. Vaginal silicone-gelatin laminates containing 15[s]15-methyl-PGF2alpha methyl ester were also effective in causing an increase in uterine muscle activity and terminating pregnancy in mid-trimester in pregnant monkeys. Plasma progesterone also increased shortly after treatment in these animals, and then declined after the peak at 8 hr. The plasma profile of 15-methyl-PGF2alpha when animals were treated with these vaginal laminates was different from that observed following ring treatment. In pregnant animals the concentration of 15-methyl-PGF2alpha rose more slowly following laminate insertion, and the peak values were considerably less than those following ring treatment. Vaginal devices used in monkeys and humans caused plasma concentrations of 15-methyl-PGF2alpha that were generally lower than those observed in monkeys treated with either vaginal rings or laminates. These studies have demonstrated that silicone vaginal delivery systems containing 15[S]15-methyl-PGF2alpha methyl ester result in sustained and fairly constant plasma levels of 15-methyl-PGF2alpha, and terminate both 1st- and 2nd-trimester pregnancies in the monkey. The vaginal device offers the possibility for self-administration of PGs for early pregnancy termination and menstrual cycle regulation.


The use of silastic vaginal device containing (15S)-15 methyl prostaglandin F2 alpha methyl ester for early first trimester pregnancy termination. (15 S) - 15 methyl prostaglandin F2 alpha methyl ester in a silastic vaginal device was administered to 9 gravid women in the first 7 weeks of gestation for elective termination of pregnancy. Continuous intrauterine pressure recording was carried out in one case. Prompt initiation of uterine activity and vaginal bleeding was seen and expulsion of products of conception occurred in under 24 hours in all cases. There were no serious complications and side effects were considered acceptable. Two patients have required subsequent curettage for removal of retained placental tissue. This incidence of failure to complete expulsion, if confirmed in a larger series, is considered to render this technique without modification unacceptable as a routine method for early pregnancy termination.


First experiences with a (15S)-15-methyl prostaglandin F2alpha vaginal device for termination of early first trimester pregnancy with serial sonographic observations. A silastic device containing 10 mg (15S)-15-Methyl Prostaglandin F2alpha was administered vaginally in three parous patients under 50 days gestation who requested therapeutic abortion. Painful contractions appeared within one hour and vaginal bleeding within three hours of application. All patients aborted, although in one tissue had to be removed from the uterus. Plasma progesterone concentrations were measured in two patients: they decreased within four hours, then increased slightly and finally decreased 24 hours after administration of the device. Nausea, vomiting, and diarrhea were observed in all three patients. The estimated blood loss was less than 100 ml and no significant hematocrit changes were observed in all patients. In serial sonographic examinations of one patient, the fragmentation and dislodgment of the gestational sac could be observed within six hours after administration of the device. After these albeit limited experiences, it is concluded that the (15S)-15-Methyl PGF2alpha vaginal device is of great potential value for induction of early first trimester abortion.


Induction of abortion by vaginal administration of 15(s)15-methyl prostaglandin F2alpha methyl ester. A comparison of two delivery systems. 15-methyl PGF2alpha methyl ester in a slow releasing vaginal device was administered to 30 women in the first and second trimester of gestation. Ten women were early pregnant (31-49 days following the last menstrual period) and the remaining 20 patients in the 10th to 20th week of gestation. The first group received either a device containing 10 mg 0.5% 15-methyl PGF2alpha methyl ester or a half of that device and the second group either a 0.5% or 1% device. The results were compared with those found following repeated vaginal administration of triglycerides suppositories, containing 15-methyl PGF2alpha methyl ester, to 50 early pregnant patients and 30 patients in the second trimester of gestation. The mean total dose of the compound given to these two groups was 3.9 and 7.8 mg respectively. All the 60 early pregnant patients aborted following treatment judged from clinical course and decreasing HCG values. Bleeding started as a rule three to six hours following the start of treatment and continued for 10 to 14 days. In two patients the abortion was incomplete. The side effects in the patients who received half the 0.5% device was comparable to those following the repeated vaginal suppositories while in the patients who obtained the whole 0.5% device, the frequency of side effects was increased indicating that an unnecessary high dose was given. In all the three groups of patients in the late first and second trimester of pregnancy, treatment resulted in abortion within 24 hours in 90% of the patients. In the 1% device an accumulation of side effects was found during the first hours following the start of treatment probably due to an initial, more rapid absorption of 15-methyl PGF2alpha methyl ester. With the repeated administration and with the 0.5% device, the side effects occurred mainly in the hours prior to abortion. However, in all three groups of patients the side effects were within acceptable levels. These preliminary results indicate that further development on the device may result in an effective one vaginal administration treatment for termination of both first and second trimester pregnancies.


Measurement of (15S)-15-methyl prostaglandin F2alpha by radioimmunoassay. Antibodies against (15s)-15-methyl prostaglandin F2alpha (15-MF) were produced in rabbits immunized with a 15-MF bovine serum albumin conjugate. Tritium labeled 15-MF was prepared from (15S)-15-methyl prostaglandin E2 by reduction with tritiated sodium borohydride. Antiserum specificity and label specific activity (12 Ci/mM) were sfficient to enable development of a sensitive, accurate and relatively specific radioimmunoassay for this prostaglandin analog. The assay can detect as little as five picograms of 15-MF in 100 mul of unextracted blood plasma. Endogenous concentrations of PGF2alpha should not cause a significant blank using current assay conditions, as cross reactivity with this molecule was less than one percent. There is, however, significant affinity (45%) for the C-1 methyl ester of 15-MF. This makes the assay also applicable for measuring this molecule, although no distinction can be made between it and the free acid when neat plasma is assayed. Plasma samples from human and monkey studies were assayed for 15-MF before and after recipients were treated with pharmacologically active doses of this compound. Blank values (0 Hour) of less than 0.1 nanograms per ml were found for all pre-treatment samples while post-treatment samples contained detectable levels. Results of the human study was compared and found to be in excellent agreement with values that were obtained using a gas-liquid chromatographic - mass spectrographic assay.


Hormone release and abortifacient effectiveness of a newly developed silastic device containing 15-ME-PGF2alpha methyl ester in concentrations of 0.5% and 1.0%. Abortion was successfully induced by intravaginal administration of a newly developed silastic device impregnated with 15(S)-15-methyl-prostaglandin F2alpha methyl ester in a concentration of 0.5% in 26 of 35 women in the 12th to the 24th weeks of gestation and by prostaglandin with concomitant oxytocin infusion in an additional 5 patients. A second comparable group of 35 women, with gestational ages from 9 to 23 weeks, received a silastic device with a concentration of 1.0% of the prostaglandin. Twenty-six women in the second group aborted with prostaglandin alone and an additional 6 patients aborted with combined prostaglandin-oxytocin therapy. Seven patients of the 70 included in this study failed to abort with intravaginal administration of 15-ME-PGF2alpha methyl ester even with concomitant oxytocin therapy; this group included 4 patients receiving the 0.5% device and 3 patients with the 1.0% device. The mean abortion time for the 31 successful abortions with 0.5% device was 15.15 hours and multiparous patients aborted in a mean time of 9.69 hours, significantly faster than the nulliparous patients, mean time 18.49 hours. The mean abortion time for the 32 successful abortions with the 1.0% device was 15.61 hours and there was no significant difference in the mean abortion times between nulliparous and multiparous patients in this group. No significant difference could be demonstrated between the mean abortion times of patients receiving an 0.5% concentrations of prostaglandin and patients receiving a 1.0% concentration of the drug. In both groups more than 40% of the patients had aborted within 12 hours of the insertion of the prostaglandin device and more than 80% had aborted within 24 hours. The intravaginal device appeared to be effective in inducing abortion throughout the gestational ages tested in this series. Peripheral plasma levels of 15-ME-PGF2alpha were analyzed in 15 patients with the 0.5% device and 8 patients with the 1.0% device. In patients with the 0.5% device the mean plasma concentration of prostaglandin peaked 2 hours after insertion, while in patients with the 1.0% device the peak was achieved within 15 minutes of insertion followed by a rapid decline in plasma prostaglandin levels. Diarrhea was the most frequent side effect related to the intravaginal administration of the prostaglandin, and in this series the severity of this gastro-intestinal disturbance appeared to be significantly higher in patients receiving the 1.0% device.


The efficacy of intravaginal 15 methyl prostaglandin F2alpha methyl ester in first and second trimester abortion. Fifteen methyl prostaglandin F2alpha methyl ester prepared within a silastic device for intravaginal administration appears to be advantageous. This study describes the technique carried out and the results observed in 50 patients. The analogue is prepared in 1.0% and 0.5% delivery systems. Twenty-four patients received the 1.0% dosage schedule and all twenty-four patients aborted. Twenty-six patients received 0.5% and twenty-three patients aborted. The coagulation millieu and other parameters were similar to that reported for other prostaglandins.


Clinical observations with a prostaglandin-containing silastic vaginal device for pregnancy termination. A salastic vaginal device containing either 0.5% or 1.0% concentrations of 15(s)-15 methyl prostaglandin F2 alpha methyl ester was used to induce therapeutic abortion in 22 patients at 6-16 weeks gestation. The 1.0% device appeared to be an effacious and safe method with cumulative abortion rates similar to that seen with intra-amniotic and intramuscular prostaglandin administration. The 0.5% device appears less effective. Bothersome side effects of emesis and diarrhea were seen with both devices although no serious complications occurred. Uterine activity and serum levels of 15(s)-15 methyl PGF2alpha appeared to reflect the concentration of prostaglandin in the device. The use of a prostaglandin-containing silastic vaginal device appears to be a safe method of pregnancy termination which is convenient, effective, and applicable to a broad range of gestational ages.


[The exercise factor in the treatment of stutterers (author's transl)]. Speech techniques can always become automatic with exercises provided the only purpose is the initiation and formation of particular habitual speech-motor patterns such as the coordination of respiration and phonation. However, if the speech-technical measures alienate the stutterer's spontaneous speech, exercises designed to automate speech flow seem bound to fail, since the stutterer cannot fully identify himself with a manner of speech which is not the expression of himself. The anxiety inherent in some speech situations should be allayed by the speaker's accustomization to the adverse stimuli they produce. However, in the final analysis, the irrationality of speech situations defies a systematic approach. Thus, it is the relaxation method connected with the process of graded desensitization of the stutterer which is therapeutically effective and not his adaptation to particular speech situations.


Identification of glucuronide metabolites of d- and 1-methadone in bile from the isolated perfused rat liver. Three hydroxylated metabolites of methadone, 2-ethyl-3-(dihydroxyphenyl)-5-methyl-3-phenylpyrroline (di-HO-EMDP), 2-ethyl-3-(hydroxy-methoxy-phenyl)-5-methyl-3-phenylpyrroline (HO-MeO-EMDP) and 2-ethyl-3-(hydroxy-phenyl)-5-methyl-3-phenylpyrroline (HO-EMDP) were excreted as O-glucuronide conjugates in bile from the isolated perfused rat liver following the addition of either d- or 1-methadone to the perfusate. These glucuronide metabolites were identified as intact molecules by combined gas chromatographic-mass spectrometric (GC-MS) analysis of their permethylated derivatives.


Effect of oxygen toxicity and nitric acid-induced lung damage on drug absorption from the rat lung. To investigate the effect of pulmonary oxygen toxicity and nitric acid-induced lung damage on absorption of drugs from the lung, rats were either exposed continuously to approximately 100% oxygen or given an intratracheal injection of 1% nitric acid solution (0.15 ml), and rates of drug absorption from damaged and control lungs were compared after various times. To measure pulmonary absorption rates, 0.1 ml of drug solution (0.1-10 mM) was administered through a tight-fitting tracheal cannula to anesthetized animals, and, after various times, lungs were assayed for unabsorbed drug. Drugs investigated were procaine amide ethobromide, p-aminohippuric acid, procaine amide and mannitol-14C. Rates of drug absorption were increased 1.1-1.2 fold after 48-54 hrs of continuous oxygen exposure and 1.3-1.6 fold at 1-4 days after nitric acid treatment. The results suggest that both types of lung damage increase the porosity of the absorbing membrane, and that nitric acid damage also alters the integrity of lipoid regions of the membrane.


Metabolism of aflatoxin B1 to aflatoxins Q1, M1 and P1 by mouse and rat. We have used a microtechnique to study (a) the metabolism of aflatoxin (AF)B1 by rat and mouse, and (b) the effect of phenobarbital treatment in vivo on the in vitro metabolism of AFB1 by hepatic microsomes from rat and mouse. The results indicate and AFP1, the O-demethylated product of AFB1, is a major metabolite produced by the mouse. Although it is detectable in rat, the amount produced is negligible and was calculated to be at least 10 times less than that produced by the mouse. Using several microincubations, AFP1 was prepared in sufficient quantities to verify its identity by UV spectroscopy and by thin layer chromatography against an authentic standard in six different solvent systems. Phenobarbital pretreatment resulted in an enhancement in the total metabolism of AFB1 as well as in the formation of AFM1, AFQ1 and AFP1.


Bromobenzene hepatotoxicity in lead pretreated rats. We have studied the levels of hepatic GSH in animals intoxicated with bromobenzene. A marked decrease of hepatic GSH was observed in poisoned rats. Such decrease was prevented by previous administration of lead nitrate, an inhibitor of DMES. In the rats treated with lead nitrate alone a rise in hepatic GSH was observed. Such protection was further observed by histological examination. The mechanism of protection exerted by lead nitrate against bromobenzene intoxication is discussed.


Disparate effects of diethylstillbestrol and prednisolone on enzyme efflux from heart and skeletal muscle. We have previously shown that diethylstilbestrol (DES) almost always, and prednisolone (Pr) less frequently, lowered the high serum enzyme activities in Duchenne's muscular dystrophy (DMD). In experimental studies, it was shown that pretreatment of mice with each of these agents lowered enzyme efflux from isolated skeletal muscle incubated in vitro, but efflux was augmented by higher doses of Pr. This suggested that these agents may influence skeletal muscle enzyme efflux in man also, producing the effects noted in DMD. The present studies were undertaken to assess the effect on enzyme efflux from skeletal muscle and heart that these two agents would exert when given in combination. Four groups of mice (14/group) were injected with saline, 250 mug DES, 35 mug Pr, or 250 mug DES plus 35 mug Pr in saline every other day for 22 days. The left gastroecnemius and heart were isolated from animals of each group, and placed in separate tubes containing incubation medium at 25 degrees C. The efflux of creatine phosphokinase (CPK) and lactate dehydrogenase (LDH) which issued from each organ was determined over a 5 hour period. In the doses tested, it was found that: 1) DES selectively reduced enzyme efflux from skeletal muscle, but had no effect on enzyme efflux from heart; 2) a Pr dose which decreased enzyme efflux from the heart, augmented efflux from the gastrocnemius; and 3) DES prevented the enhanced enzyme efflux produced by Pr. These studies indicate that these hormones, in pharmacological doses, influence enzyme efflux from muscle. This suggests, but it is not established, that these hormones also exert a similar physiological role. Finally, this experimental model appears to be useful in assessing the effects of single agents, and agents in combination, on enzyme efflux, and should be of aid in selecting appropriate agents which may be therapeutically useful in Duchenne's muscular dystrophy.


Serum levels of 5-hydroxyindole derivates after administration of L-5-hydroxytryptophan ethyl ester. Serum levels of 5-hydroxytryptophan ethyl ester, 5-hydroxytryptophan, 5-hydroxytryptamine and 5-hydroxyindoleacetic acid (5-HTPE, 5-HTP, 5-HT and 5-HIAA, respectively), were measured after intravenous administration of L-5-HTPE in humans, premedicated with a peripheral decarboxylase inhibitor. Semi-automated methods for the estimation of the 5-hydroxyindole derivatives are described. Only serum levels of 5-HTP and 5-HIAA were found to be increased, indicating that the ethyl ester is rapidly hydrolyzed and that the decarboxylation of 5-HTP is in part inhibited. The levels of 5-HTP increased during the infusion, but dropped rapidly when the intravenous administration was terminated. Serum levels of 5-HIAA remained constant for at least 6 hours, although during the same period the levels of 5-HTP do change markedly. The persistently increased serum levels of 5-HIAA suggests, that this metabolite is formed from the 5-HT stored in peripheral or central tissue. Serum levels of 5-HIAA may therefore be indicative of changes of 5-HT metabolism during drug treatment. Levels of 5-HTP may be used for the estimation of the availability of the ethylester of 5-HTP.