Evaluation of serum ionic calcium measurement in a general hospital population. Direct measurement of ionic calcium was evaluated in light of conflicting reports concerning the correlation of ionic calcium with total calcium and ionic calcium as predicted from total calcium and serum protein. Ionic calcium in the sera of normo- hypo-, and hypercalcemic adult hospitalized patients was measured anaerobically using an Orion model 98-20 calcium flow-thorugh electrode. Good correlation (r = .77) was found with the calculated ionic calcium value derived from total protein and total calcium, using the McLean-Hastings nomogram. Good correlation was also present between the measured ionic and total calcium (r = .80). In view of these correlations, the introduction of serum ionic calcium measurements into the general hospital laboratory repertoire is of questionable value.


Stability of several brands of ampicillin and penicillin V potassium oral liquids following reconstitution. The stability-time profiles of the active ingredient of five generically equivalent brands of penicillin V potassium for oral solution, and of five generically equivalent brands of ampicillin for oral suspension, were studied. Three controlled conditions were employed-refrigerated, room and elevated temperature-and all the samples were assayed chemically for drug remaining at specific time intervals after reconstitution. The results showed that considerable variations in the initial concentrations of active component existed among the various ampicillin and penicillin products. In one penicillin product the official content requirement was not met. The data also showed that although the labels on each of the commerical penicillin products tested indicate that the reconstituted products may be stored in a refrigerator for 14 days without significant loss of potency, only one penicillin product still met 90% of label claim (minimal potency requirement of the United States Pharmacopeia for dry powder). All ampicillin products tested were stable when stored at the conditions recommended by the manufacturers, but the trihydrate forms exhibited greater stability than the anhydrous forms, probably because of the more rapid dissolution rate of anhydrous ampicillin.


Comparison of microelectrode, DMO, and methylamine methods for measuring intracellular pH. The intracellular pH (pHi) of giant barnacle muscle fibers was measured with glass microelectrodes and also calculated from the distribution of 5,5-dimethyl-2,4-oxazolidinedione (DMO) and methylamine (MA). Simultaneously applying any two of these methods to muscle fibers of the same barnacle, we found the pH measured with an intracellular electrode (pH-Elec) to be about 0.06 higher than the DMO-derived pH (pH-DMO), and pH-DMO to be about 0.10 higher than the MA-derived pH (p-ma). in studies on the pHi of squid giant axons, we found that pH-Elec (7.35) and pH-DMO (7.36) were not significantly different. In the barnacle experiments, DMO required about 30 min to reach a steady-state distribution, while MA required more than 5 h. The deviations of pH-DMO and pH-MA from pH-Elec for the barnacle can be explained by a) an error in the assumed intracellular pKa' of DMO or MA, b) membrane permeability to the ionic form of DMO or MA, or c) intracellular compartmentalization. Included is a detailed study of the apparent dissociation constant of DMO as affected by temperature, and ionic strength and composition.


Cardiovascular and metabolic responses during burn shock in the guinea pig. The hemodynamic and metabolic responses of fatally burned, nonfatally burned, and unburned control guinea pigs were compared. The burns were induced in temporarily anesthetized animals by immersion to either the xyphoid process (70% fatal) or the midabdomen (100%survival) in boiling water for 3 s. Although cardiac output was reduced in all animals postburn, the survivors (MAG) has higher cardiac outputs at lower arterial pressures than the nonsurvivors (XPN). The postburn lactate levels in the XPN were higher than in the MAG, and the postburn values for pH, oxygen consumption, and core temperature were lower in the XPN. In each group, hyperglycemia was evident for 8 h postburn and terminal plasma glucose concentrations were usually elevated or similar to the prevalue. It was concluded that fatal and nonfatal burn shock were distinguished primarily by differences in tissue perfusion.


Autoregulation of cerebral blood flow and its relation to cerebrospinal fluid pH. Internal carotid artery blood flow (IFBF) was determined in each of nine Macaca mulatta by means of a flow transducer implanted around an internal carotid artery. The monkeys were lightly anesthetized, intubated, and paralyzed. Normoxia and normocarbia were maintained stable throughout the experiment. ICBF was monitored while mean arterial blood pressure (MABP) was lowered by withdrawal of blood. MABP was kept within the known limits of autoregulation in order not to compromise CBF. Cerebrospinal fluid (CSF) from the cisterna magna was analyzed for pH PCO2, and PO2 before and after a 30-min hypotensive period in which MABP was lowered from 116 +/- 4 to 70 +/- 2 mmHg (mean +/- SE). Corresponding HCO3- concentrations were calculated. The decrease in MABP did not result in a significant reduction in ICBF but elicited a 37% reduction in calculated cerebrovascular resistance, indicating normal autoregulation. Mena CSF pH was not significantly decreased (P less than 0.05); it changed from 7.320 +/- 0.010 to 7.317 +/- 0.010 after the induced hypotensive period. Thus CSF pH does not appear to have a significant role in cerebral blood flow autoregulation.


Characteristics of phosphate transport in isolated proximal tubule. The characteristics of inorganic phosphate transport in isolated perfused proximal tubules of the rabbit were examined using radioisotopic techniques. When tubules were perfused with an ultrafiltrate of rabbit serum, the mean lumen-to-bath flux of phosphate in the convoluted segment was 6.60 +/- 1.41 (SE) pmol/mm-min with a simultaneous back-to-lumen flux of 0.45 +/- 0.08. In the straight portion of the proximal tubule, the lumen-to-bath flux was significantly lower (P less than 0.01) at 2.22 +/- 0.48 pmol/min-min with a bath-to-lumen flux of 0.31 +/- 0.05. The lumen-to-bath flux was not affected by increases in the intraluminal phosphate concentration from 2.00 +/- 0.19 to 3.12 +/- 0.34 mM or by the isohydric replacement of bicarbonate in the ambient fluids with chloride. However, phosphate absorption was completely inhibited by ouabain 10(-5) M in the bath. These data indicate that phosphate absorption in these segments occurs by a mechanism other than independent diffusion and is saturated at phosphate concentrations characteristic of normal glomerular filtrate. There is no evidence for significant phosphate transport from bath to lumen.


Atypical facial pain as a defense against psychosis. The author describes three women who presented psychotic symptoms 24--48 hours before scheduled neurosurgical procedures for atypical facial pain; all had had extensive dental reconstruction and attempted nerve blocks with no relief. Psychiatric hospitalization and administration of major tranquilizers resulted in control of symptoms and relief of pain. Two patients were followed for a year and have had return of psychiatric symptoms or facial pain; both have been maintained on medication and have returned to normal activities. The author suggests that the facial pain may have served as a defense against the emergence of psychosis.


The effect of lorazepam on the vasoconstriction of fear. Volume-pulse digital plethysmography performed under ideal conditions on relatively fit adults has shown that lorazepam 4 mg intravenously abolishes the vasoconstriction of fear and restores the digital vasodilatation of the tranquil mind. The sedative effect of the drug is prolonged and is associated with several hours of anterograde amnesia from the time of its administration. The drug has no effect on the vasoconstrictor reaction to cold, pain, noise or other forms of adrenergic stimuli. Lorazepam seems to modify or prevent the psychomotor reactions which may complicate ketamine anaesthesia.


Anaesthesia for Caesarean section with ketamine. Fifty healthy mothers, with normal placental function, were anaesthetised with ketamine for Caesarean section. Anaesthesia was maintained with nitrous oxide, oxygen, muscle relaxants and controlled ventilation. Surgery was conducted in the lateral tilt position. Arterial blood samples were drawn from the mothers, and from the vessels of a double clamped section of umbilical cord, for blood-gas analysis. Results obtained were compared with those of a previous series anaesthetised with thiopentone, nitrous oxide, oxygen and muscle relaxants. Eight infants were clinically depressed, judged on the basis of their modified Apgar score 2 minutes after delivery. The average time to sustained respiration (TSR) was 58.1 seconds. The mean maternal pH and base excess values in the ketamine group were significantly greather than those reported after thiopentone anaesthesia. Mean Uv and Ua pH levels were also significantly higher after ketamine; in contrast, the average fetal base excess values did not differ from those obtained previously with thiopentone. The mean (Ma-Uv) and (Ma-Ua), pH gradients were 0.019 and 0.025 pH units greater respectively in the ketamine group compared to the thiopentone (P less than 0.005). The average (Uv-Ua) PO2 gradient was 3.4 mmHg less after ketamine anaesthesia (P less than 0.005). A significant inverse correlation was observed relating the I-D interval to the Ma and Ua pH values. Maternal arterial base deficit values appeared to increase with delay in delivering the fetus. Prolongation of the uterine incision to delivery (U-D) interval was associated with a decrease in Ua pH and base excess values. (Ma-Ua) pH and base excess gradients increased with lengthening of the U-D interval. No convincing evidence of awareness during anaesthesia was found during the study. Five patients, appeared to be hallucinated in the immediate post-anaesthetic period. Unpleasant dreams were reported in 5 instances. In this study ketamine appeared to be unassociated with significant biochemical asphyxia, but may have been responsible for some element of drug induced neonatal depression. In view of our own experience and that of other workers, it is suggested that ketamine induction for Caesarean section should be re-evaluated using a lower dose of the drug.


Preoperative magnesium trisilicate in infants. Three groups, each of forty children aged less than five years and prepared for elective surgery, had their gastric contents' volume and pH measured. The control group showed an incidence of 67-5 per cent with high acidity (pH equal to or less than 2-5). In the second and third groups magnesium trisilicate mixture was given within thirty minutes prior to induction of anaesthesia. The second group, sampled after induction of anaesthesia, showed a marked reduction in acidity, while the third group, sampled at the termination of anaesthesia and surgery, demonstrated that in most cases the neutralization of gastric acidity was still effective.


A diagram to facilitate the understanding and therapy of mixed acid base disorders. A diagram based on in-vivo relationships between arterial hydrogen ion activity (H+) and carbon dioxide tension (PCO2) in primary abnormalities of acid base homeostasis is presented. It is designed to facilitate the interpretation of pH data by including the 95% confidence limits described in patients with simple metabolic and respiratory acid base disorders. These bands have been formulated from observation of simple acid base abnormalities and indicate the appropriate respiratory or renal compensatory response to the primary pH defect. A plot which falls outside these limits therefore indicates the presence of a mixed acid base disorder. The diagram presents a physiological approach to clinical disorders of pH regulation demonstrating maintenance of intra-cellular fluid homeostasis during primary extracellular fluid disturbances. Diagnostic and therapeutic advantages are further illustrated and discussed in six case reports.


Molecular mechanisms of nerve block by local anesthetics. Local anesthetics block nerve conduction by preventing the increase in membrane permeability to sodium ions that normally leads to a nerve impulse. Among anesthetics containing tertiary amine groups, the cationic, protonated form appears to be more active than the neutral form. However, the neutral forms, as well as uncharged molecules like benzocaine and the aliphatic alcohols, also depress sodium permeability. Studies of single myelinated nerves and squid axons show no direct interaction between calcium ions and local anesthetics, thus disproving theories based on competition between these two agents. Likewise, hypotheses attributing local anesthesia to changes in electrical potentials at the membrane-water interface are disproven by the demonstrated potencies of electrically uncharged anesthetics. Hypotheses that propose that local anesthetics act by expanding the nerve membrane and causing a change in protein conformation that blocks sodium permeability are vague in conception and difficult to test experimentally. Evidence from voltage-clamp studies of single nerve fibers indicates that anesthetic molecules interact with the sodium channels directly, from the inner side of the nerve membrane. Anesthetics bind within sodium channels which have opened during membrane depolarization, preventing the normal sodium ion flux. Anesthetic molecules can dissociate from open channels, but not from channels that remain closed when the nerve is kept at rest. The "gating" properties that regulate the opening and closing of sodium channels are reversibly modified during anesthesia. Specifically, the inactivation function responds more slowly and requires more negative membrane potential changes to reach the same values as in unanesthetized nerves. A second, slow inactivation is observed following external application of tertiary amine anesthetics. The selective binding of anesthetics to open sodium channels provides a simple explanation for Wedenski inhibition, in which the block increases with the frequency of nerve impulses. When impulses occur at higher frequencies more sodium channels are open over a period of time comparable to the time necessary for the anesthetic binding reaction, thus more channels are blocked. In addition the changes of the inactivation function result in a longer refractory period and, thus, a decrease of impulse height at higher frequencies. Charged anesthetic molecules may bind in the pore of the sodium channel. Their binding can be modulated by the electrical field in the membrane. The channel has a higher affinity for larger anesthetic molecules, but this may result from their greater hydrophobicity as well as from their size. The binding site favors molecules that contain more polar linkages between the amine group and the aromatic residue. Binding of amine anesthetics is weakly stereospecific and, surprisingly, shows no absolute requirement for the terminal alkyl ammonium moiety present in most local anesthetics...


Further studies of the anti-recall effect of lorazepam: A dose--time--effect relationship. The time of onset and duration of the anti-recall action of lorazepam were assessed under clinical conditions by measuring recall and recognition of visual stimuli 24 hours after intravenous administration of lorazepam. The visual stimuli were first presented 5-240 minutes after 2 mg and 5-360 minutes after 4 mg lorazepam. Retrograde amnesia was not produced. Lorazepam, 2 mg, produced a short anti-recall effect (anterograde amnesia) in 50 per cent of the cases, with a latency of 30 minutes and a duration of less than half an hour. Duration and frequency of the anti-recall effect were greater after 4 mg, while the latency was shorter. More than 70 per cent of the individuals tested were amnesic for the visual stimuli 15 minutes to 4 hours after 4 mg lorazepam. Sedation was satisfactory and long-lasting following both doses of lorazepam, but was not related to the anti-recall effect.


Influence of anesthetic agent on survival following hemorrhage. One hundred and twenty-eight Sprague-Dawley rats were each anesthetized with one of four anaesthetics and subjected to a standard hemorrhage protocol to determine the effects of anesthetics on survival following hemorrhage. The anesthetics studied were: halothane, 1.26 vol per cent; fluroxene, 4.5 vol per cent; pentobarbital, 50 mg/kg ip; ketamine, 125 mg/kg, im. Mean arterial pressure was conrolled at 40 torr during 60 minutes of hemorrhage. Cumulative survival rates were determined at the end of hemorrhage and 24 hr, 48 hr, 72 hr, and 7 days after hemorrhage. Twenty-four-hour survival rates were: halothane, 50.0 per cent; fluroxene, 56.3 per cent; pentobarbital, 59.4 per cent; ketamine, 84.4 per cent. Seven-day survival rates were: halothane, 46.9 per cent; fluroxene, 18.7 per cent; pentobarbital, 53.1 per cent; ketamine; 81.3 per cent. Survival rates were significantly higher (P less than 0.05) in animals anesthetized with ketamine compared with survival rates associated with the other anesthetics. Long-term (72-hr and seven-day) survival rates were significantly (P less than 0.05) lower in animals anesthetized with fluroxene. Microscopic examination of livers and small intestines revealed significantly fewer (P less than 0.05) athologic changes in the splanchnic organs of hemorrhaged rats anesthetized with ketamine compared with animals anesthetized with the other drugs.


[Structure of the interalveolar wall].

[Structure of the interalveolar wall]. The wall, which unites as well as separates two contiguous pulmonary alveoli is composed of: - a conjuntival partition, the veritable skeleton of the wall, which is occupied, to the largest extent, by capillary blood vessels. Between the capillaries, conjunctival cells are dispursed: fibrocytes, fibroblasts and histiocytes, of which some can be mobilised, transformed into macrophages, and penetrate into the alveolar lumen; - modified epithelial cells, whose very thin, vast expansions cover the conjunctival partition; - a liquid film, 0.2 mu in thickness, which separates the epithelial cells, or pneumocytes from the alveolar air. Numerous physiological implications result from this organisation.


[Pulmonary edemas of drownings].

[Pulmonary edemas of drownings]. Patients who are victims of near drowning in fresh water or salt water very frequently have acute edema of the lung which occurs either immediately, or after a free interval of variable duration. The mechanism of this edema is explained, in near drowning in salt water, by the hyperosmolarity of the alveolar fluid leading to a seeping of plasma from the capillaries in the alveoli. In the case of near drowning in fresh water, it is on the contrary the inhaled liquid which passes into the circulation, therby leading to immediate hypervolemia, but this overload is only transitory and is not responsible for the pulmonary edema which occurs later is not accompanied by a rise in pulmonary capillary pressure. It is therefore a lesional edema as is certified by the anatomopathological modifications found in the lungs of drowned patients. Therapeutic management must therefore take into consideration this physiopathology of acute edema of the lung in the drowned.


[Pulmonary edemas. Classification and mechanisms]. Water exchanges in the lung under physiological conditions, are still badly known. Starling's classical equation is a too simplified view of the phenomenon. In addition, a certain number of its factors are badly determined. Such is the case with the hydrostatic pressure and the oncotic pressure of the interstitium. In pathological conditions secondary edema is opposed to lesions of the alveolocapillary membrane and hemodynamic edema where the increase in intravascular pressure increases a loss of liquid between the junctions of the endothelial cells. Between these two situations there are edemas, of which the mechanism is still subject to discussion, for example altitude edema, edema in heroin addicts, neurogenic edema.


[High altitude acute pulmonary edema (author's transl)]. HAAPE has been recognised only recently but is of real interest as much from the clinical as well as the dogmatic stand-point owing to the complexity of its physiopathological findings. It is encountered at altitudes higher than 4,000 meters either during a first contact or in natives returning from low altitude zones. There is an individual or even racial susceptibility.


[Pulmonary edemas of infectious origin]. Diffuse pulmonary edema, capable of arising in the absence of hemodynamic disorders is rare in infectious disease. They take on two different clinical appearances: a) acute edema of the lung with the syndrome of asphysia, b) a subacute dyspneic pneumonia with hypoxemia and hypo or normocapnia. These initial disorders can be followed by progressive respiratory failure secondary to the development of diffuse interstitial lesions with fibrosis and intra-alveolar hyaline deposits. The bronchiolo-alveolar lesions which induce a fibrin rich exudate are directly caused by the patogenic agent: myxovirus, essentially influenzae, and more rarely adeno or herpes virus. The role of bacteria and of certain parasites is more debateable.


[Hemodynamic data in lesional pulmonary edemas]. Pulmonary edema due to disorders in alveolo-capillary permeability (or lesional) are differentiated from hemodynamic pulmonary edema by the fact that they arise in spite of normal pulmonary capillary pressure (PCP). A hemodynamic study was carried out in 42 cases of lesional P.E. The PCP was normal whatever the date of the examination and the gravity of the P.E. Pulmonary arterial hypertension was only found in the presence of frank hypoxemia and disappeared with the correction of the latter. If there was no hemodynamic profile due to P.E. itself, its etiology sometimes induced a hyperkinetic or hypovolemic syndrome. Finally it was apparent that PCP was significantly higher- although normal- at the initial stage than after 6 hours of P.E.; that an elevation in PCP of only a few mm Hg by the perfusion of colloids aggravated the P.E., that despite the normal value for the PCP dehydration evidently improved hematosis. Thus this study confirms that numerous cases of P.E. can occur while the PCP remains normal. It also confirms the noxious nature of too abundant perfusions in these cases and the effectiveness of dehydration.


[Blood gas determination and calculation of shunts in nonhemodynamic pulmonary edemas]. Qs/Qt is usually determined by the "oxygen" method. The standard equation for calculation of percentage shunts is therefore: (see article) In the case for an FiO2 of I and when PaO2 is greater than 150 mm Hg, the equation can be expressed in terms of the difference in partial pressures of oxygen between the alveolus and the artery: (see article) The determination of Qs/Qt then necessitates, apart from calculation of PaO2 measurement of the O2 content of mixed venous blood, taken from the pulmonary artery. When an indwelling catheter for the sampling of mixed venous blood is not available, samples of superior vena cava blood can be used instead. The error thereby introduced into the calculation of Qs/Qt is debatable. Strictly, only the sampling of mixed venous blood permits precise determination of Qs/Qt. As long as the variations in Qs/Qt, more than its real value at a give time, are worth supervising, superior vena cava blood gives a rather satisfactory approximation. Various graphs relating Qs/Qt to PaO2 or to the alveolo-arterial difference have been proposed and are discussed. The other methods of determining Qs/Qt are also looked at. The value of determination of the shunt during non-hemodynamic edema, and especially in the patient under artificial ventilation with P.E.E.P., is emphasised.


[Continuous measurement, using 2 isotopes, of extravascular pulmonary water. Application of a new method or the analysis of supply and pulmonary capillary filtration in normal man]. Measurement of pulmonary interstitial fluid may be useful in clinical medicine for early diagnosis or measurement of interstitial and/or alveolar pulmonary edema. A modification of the double dilution method of CHINARD and GORESKY is proposed. Compared to previous methods, this technique, using two isotopes gamma  emitters, is rapid, simple, reproductible and may be repeated. The values obtained in normal subjects at rest 3.5 +/- 0.5 ml/kg, are comparable with those of other authors. They increase considerably in cases of fluid load.


[Pulmonary water and thoracic impedance. Evaluation of a measurement technic]. We measured transthoracic electrical impedance in 17 anesthetized and mechanically ventilated dogs with a four-electrode system. A current (5 KHZ, 50 mu A) is injected and detected at axillary levels. Transthoracic impedance was 67 +/- 14 ohms (S.D.) with insignificant shifts in control animals. Pulmonary edemas were induced by saline and dextrose overloads with large but opposite variations in impedance. Fifty to hundred per cent increases in total lung water content (determined at autopsy) were induced by intravenous injection of alloxan or instillation of endotracheal saline. Significant but small decreases in impedance followed. Validity of experimental pulmonary edemas with or without blood resistivity and pulmonary blood volume changes is discussed.


[Regional distribution of pulmonary perfusion during fluid overload in man]. The effects of a fluid vascular overload (Dextran 40,000, 10 p. 100, 44 +/- ml/kg/45 min) were studied in 9 normal subjects in the upright position. The following were found: an increase in pulmonary blood volume (+30 p. 100), and in extravascular pulmonary water (+ 70 p. 100), a significant fall in pulmonary compliance and an increase in bronchial resistance. Radio-isotopic study of the regional distribution of pulmonary perfusion showed a clear inversion with decrease in perfusion at the bases and increase at the apices. From the theoretical standpoint, this inversion of distribution of perfusion can be due to hypoxic vasoconstriction in the lung bases, to an increase in flow and entry pressures recruiting apical vessels or to a perivascular compressive edema in the lower parts of the lungs. Different modifications complementing the initial experimental protocol tend to prove that it is this latter reason which is essentially at the origin of the inversion in regional distribution of pulmonary perfusion.


[Pulmonary edemas. Anatomic study].

[Pulmonary edemas. Anatomic study]. Whatever the etiology of pulmonary edema, i.e. increase in intrapulmonary water, edema passes through three, moreover intricate phases: 1- intracellular edema clearly visible in the type 1 pneumocyte. This intracellular edema appears at the same time as: 2- interstitial edema; that which appears when: 3- numerous vesicules of pinocytosis and separation of the capillary endothelial cells account for it; 4- intra-alveolar edema itself appears later and corresponds to the major clinical phase of pulmonary edema. There is nothing surprising about this as the cellular functions of pneumocytes are impervious as can be shown for example by studies carried out with tracers. This intracellular alveolar edema seems to have two different aspects depending on whether the experimental conditions create an acute or sub-acute pathology. In the acute form, the edema is poor in lipids and in proteins. In the sub-acute of chronic forms, it is on the contrary very rich in them. 5-In the last phase, a veritable desquamation of the pneumocytes then of the endothelial cells is produced which is very frequently lethal. If survival occurs, two sorts of lesions are found: -colonisation of the alveolar surface with type II pneumocytes; - occurrence of possible intersitial fibrosis. The remarkable fact is that such lesions are visible in a more or less identical manner in all cases of pulmonary edema, whether they be hemodynamic or lesional. The morphology does not confirm this physiopathological distinction which is moreover questionable as all pulmonary edema become lesional sooner or later.


[Contribution of radiology in nonhemodynamic pulmonary edemas]. The radiological appearances of non-hemodynamic, lesional edema are univoco; interstitial-type pictures, alveolar-type pictures, either successively or combined, in terms of the intensity or duration of the alveolo-capillary membrane lesions. Inflation of the interstitial medium is reflected by the appearance of Kerley B lines, haziness of the vascular contours and sometimes an axillary bordering line due to subpleural edema. Capillary congestion with increase in permeability especially to proteins and the tearing of connective tissue explains these pictures. In the following stage, edema is alveolar with hazy diffuse, unorganised and confluent opacities. These opacities can predominate in the bases, or take on a butterfly-wing distribution. At this stage atelectatic lesions can be superadded due to inactivation of surfactant. Finally, in the later periods the appearance of interstitial pulmonary fibrosis with fibrinous deposits and fibroblastic proliferation can be noted. The chest X-ray is the objective reflection of the disorders; in enables the making of a diagnosis, and the drawing up of a complete check of the lesions and supervision of its course.


[Severity factors and diagnosis of nonhemodynamic pulmonary edemas]. This syndrome is characterised by changes in the pulmonary capillary bed allowing filtration of edema fluid rich in proteins. It provokes an alveolo-capillary block and a fall in compliance. Positive diagnosis is envisaged from the clinical circumstances implicating a change in the pulmonary capillaries (blast, shock, microemboli). The fall in pO2 is early and intense. The fall in compliance is later and leads to hypoventilation necessitating ventilatory assistance. Diffuse radiological opacification of both pulmonary fields is characteristics, in its appearance and also in its prolonged course. In the differential diagnosis one should try to eliminate acute pulmonary edema and refractory hypoxia of bronchogenic origin. Prognosis of the condition is fixed by the course (of the pO2, of possible hypoventilation, of the radiological pictures), under treatment. Although persistance of the syndrome for more than one or two weeks is of bad prognosis, cases have been known to progress for more than three weeks and to heal leaving no after-effects. The syndrome can be complicated by cardiac incompetence, organic renal failure, which again aggravate the prognosis.


[Reduction and anti-inflammatory technics in non-hemodynamic pulmonary edemas]. All hypervolemia or any decrease in plasma oncotic pressure leads to deterioration in lesional pulmonary edema. The aim of albumin infusions is to restore the plasma oncotic pressure and to oppose the passage of water into the extravascular space. This therapy is however debatable owing to the abnormal increase in the permeability of the alveolo-capillary membrane to proteins. Diuretics enable one to lower the volemia and to maintain the pulmonary capillary pressure at its minimum level. However, strict hemodynamic supervision is absolutely necessary. Cortico-steroids have been recommended without serious physiopathological justification. However, they have a preventive action on interstitial edema in endotoxic shock.


[Justification, methods and indications for positive-pressure respiration in controlled and spontaneous ventilation in lesional pulmonary edeman]. Proposed since 1938 as a treatment for pulmonary edema, continuous positive pressure ventilation (PPP) still called teleexpiratory positive pressure in France (PPTE) and  "Positive End Expiratory Pressure" (PEEP) or even "Continuous Pressure  Breathing" (CPPB) in Anglo-Saxon countries, has taken a place in the first line of therapy in refractory hypoxia and particulary when the latter originate from lesional pulmonary edema. The aim of PPP is to open up the alveolar territories by calling on their elastic properties, to fight against micro-atelectasis and bronchial collapse, to diminish the closing volume, to increase the FRC, thereby improve VA/Qc, decrease Qs/Qt and increase PaO2. Furthermore, in the particular case of pulmonary edema, PPP acts against the hydrostatic pressure by increasing the external component of the transmural pressure and by evening out pulmonary capillary blood flow.


[Treatment of fulminating lesional edemas using extracorporeal circulation with a membrane oxygenator]. Recourse to extra-corporeal oxygenation is legitimate in certain cases of fulminating pulmonary edema, with refractory hypoxemia, particularly when the early onset of the hemodynamic condition and the severity of the hypoxemia do not permit the carrying out of dehydration. Veno-arterial diversion then permits: --the ensuring of half or two thirds of the oxygen consumption; --the restoration of systemic hemodynamics by arterial reinjection; --the very rapid reduction of pulmonary edema by "decompressing" the pulmonary artery.


[Present statues of lung transplantation (author's transl)]. It is difficult to sum up the justifications for pulmonary transplantation in man as out of 34 cases carried out up to now only the patient DEROM, has survived 10 months. In fact, analysis shows that all of the other cases cannot be taken into consideration, as there were technical problems, or the receivers were nearly in the threws of death and this was the case of the patient SALVATOR. Two important problems remain to be resolved: First of all that of obtaining grafts in good condition. In fact the sole source of donors remains irreversible comas, and it is known that after 24 hours of artificial respiration the lung has undergone irreparable damage. It is therefore necessary to develop a reliable method for preservation. Present experimental results show that lungs preserved for 48 hours and regrafted into other animals are not only functional, in the immediate, but the scintigraphic scanning graphs after a month, are comparable with those in control animals. Studies of coagulation have demonstrated that pulmonary rejection is characterised before infiltration by mononuclear cells, by major coagulation disorders. In the treated animals, rejection crises are preceded a few days earlier by hypercoagulability and a fall in circulating platelets. These findings have enabled one, by the addition of appropriate anti-coagulant treatment, to overcome the rejection crises- without any other therapy than the basic classical treatment- (Immuran + corticosteroids). Under these conditions, the few specialised centres are therefore authorised to again attempt human pulmonary transplantation.


[Vaso-active substances and pulmonary circulation]. This study reveals the main vaso-active substances which pass through the lung, by studying in each case the extra-pulmonary of pulmonary origin, the effects of the lung on these substances: capture, discharge, transformation, and the effects of these substances on the lung. Eight groups of substances are studied: mediators of the sympatho-adrenergic system, substances interfering with adrenergic agents, acetyl-choline, serotonin, angiotensin, histamine, kinins, and prostaglandins. The lung behaves either as a neutral organ, or a filtering organ, or a filtering organ, or a secreting organ for these substances. In this way it strangely resembles the kidney. The pulmonary circulation is not completely comprised of simple reaction. It is capable of internal adjustement and redistribution under the effect of these substances. Pulmonary edema probably will always remain difficult to their mechanism of production, in so far as can be estimated from the multitude of substances. It is still rather a delicate matter to distinguish between edema-generating phenomena and phenomena which are secondary to the edema itself.


[Pulmonary edema due to shock, fat embolism, disseminated intravascular coagulation and post extracorporeal circulation]. The appearance of lesional edema in the region of the alveolar wall constitues the initial phenomenon of involvement of the pulmonary parenchyma during shock lung, fat embolism, DIC and post perfusion lung syndrome. The alveolar septum reacts in a monomorphous manner to these various agressions, although the responsible physiopathological factors are numerous and varied. The lung in E.C.C. represents a vertiable experimental post-agressive lung. It has been studied in man from the clinical, radiological, hemodynamic and anatomopathological standpoints. The modifications found enable one to better understand the etiological factors intervening in the other post-agressive lungs.


[Pulmonary surfactants. Generalities].

[Pulmonary surfactants. Generalities]. The alveolar wall on contact with air can be compared with a biological air-liquide interface. As with all interfaces, there are therefore superficial forces which tend to reduce the surface to a minimum. In the case of a pulmonary alveolus with a spherical surface, these forces are at the origin of an internal pressure excess dependent on the radius of the alveolus and on the superficial tension related to the nature of the interface. Owing to the disparity in the alveolar radii, under these conditions the smaller alveoli would collapse to the benefit of a larger one, the pressure being lower and lower in the latter. In addition, at any time in the respiratory cycles, this surpression must be negligible in order to avoid rupture of the equilibrium of the forces exerted on the alveolar wall. Consequently, it is necessary that this air-alveolar wall interface should have a superficial tension on the one hand variable with the surface, and on the other hand always very low. Owing to the demonstration of large concentrations of phospholipid in this area, it can be thought that a superficial film is substituted at the air-biological liquid interface and owing to this fact effectively has superficial properties necessary for alveolar stability. The "surface-tensio-active" effect of this film lead to the giving of the name of "surfactant" to these constituents as a whole.


[Acute neurogenic pulmonary edema].

[Acute neurogenic pulmonary edema]. Neurogenic edema, in the strict sense of the term, has at the present time practically not benefitted from precise hemodynamic investigations in human clinical practice, and owing to this fact, authors still classify them under the heading "mixed edema or of unknown pathogenesis". In contrast with this lack of information in man, animal experimental works are surprising by their coherence and the experimental facility of producing neurogenic edema (cranial hypertension by a small inflatable balloon and cisternal infection of fibrin). If one excludes the now ancient vagal theories (CAMERON 1949; CAMPBELL, 1949) which were never confirmed, all of the most recent experimental works (SARNOFF, 1952; DUCKER, 1968; LUISADA, 1967; MORITZ, 1974) confirm the adrenergic disorder of central origin during neurogenic A.P.E. which from the hemodynamic standpoint is like an authentic hemodynamic A.P.E. with raised left atrial pressure, pulmonary venous pressure and pulmonary capillary pressure.


[Pulmonary edema in hangings].

[Pulmonary edema in hangings]. The authors present two cases of unsuccessful hanging which hat lead to a very severe neurological picture and especially the very rapid appearance of acute pulmonary edema resulting in a vertiable flooding of the alveoli. The victims, aged respectively 21 and 15 years, were free from any pre-existing cardiopathy. These cases of pulmonary edema, resistant to depletive therapy (bleeding, diuretics) and cardiotonic agents (Cedilanid) should only be jugulated after a one hour session of oxygen at 3 ATA with a baro-assisted respirator. The following are discussed with reference to these two cases: 1- The mode of occurrence of this type of pulmonary edema: - implication of sub-acute anoxic cerebral damage; - high negative alveolar pressures owing to a gasp-type ventilation with a closed glottis. 2- The opportunity for the very early treatment of the oxygen deficit contracted by the brain and myocardium.


[Nonhemodynamic pulmonary edema due to toxins]. Lesional pulmonary edema caused by substances which are directly caustic for the gastrointestinal pathways (strong acids and bases, inhaled vomit) are opposed by their immediate and long-term gravity with those due to cardiotropic medicamentatous toxins or volemic overloading which lead to curable pulmonary edema. Material and human factors, in favour of accidental intoxication are compensated for by the fact that many toxins produce vapours which are strongly irritant for the upper respiratory pathways: this prevents prolonged exposure and therefore wards off edema. Drug intoxication by ingestion can lead to pulmonary edema by relative or absolute volemic overload, by allergic accidents or by immaturity of the enzyme degradation systems. It seems to us that the notions of "neurological" and "metabolic" toxic edema should be abandoned. In lesional edema the treatment is that of the acute respiratory failure. The combination of pethidine, promethazine, and chlorpromazine gives good immediate results. Owing to careful follow-up, hemodynamic pulmonary edema should most frequently be avoided.


[Pulmonary edemas due to acute heroin poisoning]. Their frequency is estimated with difficulty, although on autopsy pulmonary edema is found almost routinely. It is a major complication of overdoses (48 p. 100 of severe intoxications). Their formation can be suspected, when after the first phase of respiratory depressions, with coma, myosis, and a variable latent period, a second attack of respiratory insufficiency occurs with tachypnea, and cyanosis. The chest X-ray shows diffuse alveolar infiltration, sparing the apices. The heart being generally of normal size. Rapid disappearance of this infiltrate (24 to 48 hours) enables the elimination of two diagnoses: pneumonia due to inhalation of gastric fluid, an infectious pneumonia. Their pathogenesis remains very debatable: - in the majority of cases abrupt L.V.F. can be eliminated: -on the other hand it could be an allergic accident of the anaphylactic type, or local liberation of histamine, or a local toxic action on the pulmonary capillaries; - hypoxia, secondary to respiratory depression, could lead to pulmonary edema, by the same mechanism as at altitude; - finally, owing to the central neurological disorders a neurogenic theory can be put forward. Their treatment is essentially a combination of Nalorphine with oxygen therapy (by mask, or if necessary by assisted, controlled ventilation) with prevention of inhalation of gastric fluid (gastric emptying) or curative treatment of possible aspiration by antibiotics, and cortico-steroids. Diuretics can be useful, as well as cardiotonics.


[Oxygen toxicity for pulmonary parenchyma. Ultrastructural study by electron microscopy. Physiopathologic data]. The lungs of rats submitted to 24, 36, 48 and 72 hours of pure normobaric oxygen were examined by means of the scanning microscope. The images obtained give a dynamic aspect of the changes in the lesions with two distinct phases: a phase of reactivity at 48 hours, marked by the development of hyperactivity of the granular pneumocytes, a phase of destruction characterised by considerable changes in the alveolar epithelium and filling in of the alveolar lumen with various debris. From these morphological findings, different physio-pathological factors are discussed: the role of the increase in PaO2, the protection provided by the increase in the gradient (A - a) DO2, cerebral and adrenal medullary involvement especially in hypoxemic subjects.


[Pulmonary edema due to inhalation of gas and vapors]. In 1975, France will have manufactured 3.2 million tons of plastic materials which by pyrolysis, liberate chlorine, methyl chloride, hydrocyanic acid, hydrofluoric acid and other toxic gases. Now these materials are burnt in fires in "modern", buildings or vehicles , associated with fats (acrolein) and other gases and toxic industrial or household fumes which attack the lung. At sufficient dosage these agressive agents have first of all a "suffocating" action when in case of survival, a caustic and corrosive action. Pulmonary edema of the lesional type is met with at two stages in these cases. They are due to a direct action on the bronchial epithelium and an indirect action by disturbance of surfactant metabolism. It is an edema which is interstitial above all, and secondarily endo-alveolar. Study of the clinical, radiological, bronchoscopic and hemodynamic symptomatology. Differential diagnosis is not always easy. The possibility of burns of the respiratory pathways, blast, must be looked at. These elements can moreover be associated with lesions due to toxic inhalation. In case of survival the course is one of fibrosis with a restrictive syndrome.


[Classification of corticoids].

[Classification of corticoids]. A pharmacological classification of corticoids can be carried out, based on the ratio of their glucocorticoid and mineralocorticoid activities. Their large number is due to the fact that they are practically all synthetic, and that minimal modifications in their structure gives rise to new drugs with variable gluco and mineralocorticoid activity.


[Glucocorticoids and metabolism].

[Glucocorticoids and metabolism]. After a brief historical account, the physiological effect of glucocorticoid hormones are analysed. Their main point of impact is neoglucogenesis from proteins. To this is added their direct action on carbohydrates, their intervention in the use of lipids, and in the movement of water and salts. Cortisone penetrates into the cell, is fixed by a cortisone receptor in order to be transferred into the nucleus and to act on the transformation of ADN-ARN. Its relationships with cyclic AMP are discussed. The hormonal correlations of glucocorticoids are numerous. (insulin, catecholamine, glucagon, growth hormone, androgen). Synthetic cordicoids have biological actions which are close to those of glucocorticoids, but vary depending on their structure. These physiological and pharmacological notions imply certain precautions in the use of this type of hormone derivative.


[Study of carbohydrate tolerance without and with corticotherapy]. Using the glucose tolerance test by the intravenous route, from which the coefficients K (CONARD) of carbohydrate assimilation and (BERNIER) of fasting glycogenolysis, are deduced, the authors study the carbohydrate tolerance of neuro-surgical patients in acute and chronic phases, under corticosteroid therapy and without corticosteroid therapy. The role of corticosteroid therapy in the decrease in carbohydrate tolerance reported is discussed ; for comparative purposes, the authors present the study of carbohydrate assimilation in irreversible coma and in patients with advanced neuroplegia.


[Corticoids in respiratory pathology].

[Corticoids in respiratory pathology]. After briefly recalling the action of corticosteroids on the normal and pathological lung, the authors review the different etiologies where they can be used in respiratory pathology.


[Immunological aspects of corticotherapy]. The therapeutic effectiveness of corticoids in transplantation, in autoimmune conditions and in numerous diseases in which the pathogenic role of hypersensitivity reactions is invoked, is perfectly established on the empirical basis of clinical cases. The study of the effects of corticoids on the immunological response is on the contrary very fragmentary; it comes up against numerous difficulties, especially against the differences in susceptibility from one species to another. The lymphoid cells have cytoplasmic and nuclear receptors for corticosteroids. The fixation of corticosteroids on lymphocytes inhibits the synthesis of nucleic acids and raises the intracellular level of cyclic AMP. Corticosteroids decrease the mobility of polymorph leukocytes in the presence of a chemotactic stimulus, at high doses, they disturb phagocytosis by marcophages, oppose the degranulation of mast cells and polymorph leukocytes, and the cytotoxic action of sensitised T lymphocytes. In vivo, corticosteroids have little effect on the production of antibodies (primary of secondary response) do not modify the "immunological memory" by through an anti-inflammatory effect, abolish the peripheral manifestations of late hypersentsitivity reactions. Corticosteroids enable the treatment of acute rejection crises in transplantation, they have a symptomatic effect on type I and IV Gel and Cooms hypersensitivity reaction, their activity is less regular in the other phenomena of hypersensitivity.


[Hemodynamic effects of high-dosage corticoids. Their justification in the treatment of shock]. In 61 patients in whom high doses of corticoids had been administered owing to various indications, the hemodynamic modifications caused by this injection were studied. The corticoids administered were : hydrocortisone hemisucccinate (150 mg/kg), methyl prednisolone sulfate (30 mg/kg), prednisone sodium m sulfobenzoate (50 mg/kg), prednisolone sodium m sulfobenzoate (35 mg/kg) and dexamethasone phosphate (2 mg and 6 mg/kg). The results study the modifications caused by each drug on heart rate, arterial blood pressure, cardiac output, systolic stroke volume and peripheral vascular resistance. The expression of the results is given as a percentage of the variation with statistical study. Methyl-prednisolone sulfobenzoate only leads to slightly marked hemodynamic effects : the four other compounds studied have definite hemodynamic effects, of variable intensity and duration. The most important variations are noted with dexametasone phosphate. From these results, the indications and results of the use of corticoids in states of shock are discussed.


[Corticoids and shock].

[Corticoids and shock]. After recalling the major role of catecholamines in the genesis of irreversible shock, the anti-shock action of glucocorticosteroids, owing to properties which are "alpha-blocking" , is discussed in this work. The works of LILLEHEI on the effectiveness of corticosteroids in different types of shock are summarized and discussed, as well as numerous works which have followed and a synopsis of which, done in 1967 in the "Annales de l'Anesthésiologie Francaise", is presented. Since then, following new experimental facts, whereas numerous contradictions have appeared in the clinical and experimental realms, the possible mechanisms of action of corticosteroids in shock are looked at, by emphasizing the relationships between corticosteroids and SHWARTZMAN's phenomenon, in particular. A hypothesis on a probable central action of glucocorticosteroids is proposed following experimental works carried out by H. LABORIT et Coll. (1975). Finally, the author presents a personal experiment in hemorrhagic shock in the rabbit where the adjunction of corticosteroids had no effect on the different parameters such as the decrease in PaCO2, hyperlactacidemia and the liberation of beta-glycuronidase in the blood, mortality being practically the same in the controls and in the animals submitted to corticosteroid therapy.


[Corticosteroids and septic shock].

[Corticosteroids and septic shock]. According to the data in the literature, the authors attempted to sum-up present attitudes on the value of corticoids in the treatment of septic shock. If their cardiovascular effects after a period of enthusiasm, are presently rather controversial, their cellular and sub-cellular actions, on the lysosomal membranes, capillary permeability and perhaps the intimate mechanisms of cellular oxygenation seem to be more real. However, the contra-indications which persist in the results of clinical works have resulted in the fact that the exact place of cortico-steroids in the therapeutic arsenal of septic shock still remains to be specified.


[Plasma cortisol in neurosurgical resuscitation]. The authors study the values of spontaneous cortisonemia in neuro-surgical patients. They analysed the correlations between this parameter and certain clinical criteria (age, etiology, level of consciousness), the duration and nyctohemeral changes in spontaneous hypercortisonism. Furthermore, they presented the values of iatrogenic cortisonemias as a function of increasing doses of hydrocortisone and discussed the possible mechanisms for the disapperance of injected cortisone.


[Indications for anti-inflammatory corticoids in anesthesia-resuscitiation]. The use of anti-inflammatory corticoids in anesthesia and resuscitation is a long-standing fact, but their indications, owing to the risks to which they expose certain patients and owing to the uncertitude concerning their mechanism of action, are still badly defined. If certain indications (attacks of asthma, laryngeal oedema, certain peri-lesional oedemas) are considered as being categorial, the usefulness of anti-inflammatory corticotherapy is being more and more and more debated in other pathological conditions : infectious or chemical pneumonias, drowning, shocked lung, post-traumatic neuro-surgical conditions, cirrhosis. Very useful in precise indications, anti-inflammatory corticoids should not be prescribed, particularly in fragile patients whom we well know in resuscitation, without having weighed up the advantages and disadvantages related to this remarkable therapeutic instrument.


[Complications and contraindications of corticotherapy]. In a review of the classical complications of corticotherapy the aouthors tried, in the light of the literature, to take into consideration the ideas received as compared with the numerical conclusions of statistical studies on large series. Then they presented the patient treated with corticoids, faced with the surgical intervention. They tried to demonstrate that adrenal insufficiency, if present, is only exceptional and that all of the incidents, observed during and immediately after surgery must not be attributed to it.


[Problems posed by surgical patients submitted to long-term corticotherapy]. Contrary to the long-standing attitude which consisted of descreasing the doses of cortisone, or even of weaning patients before undergoing a surgical intervention, the author emphasizes the necessity for a quantitative and qualitative increase in corticotherapy in order to avoid the risks of acute hypocorti-costeroidism.


[Determination of phenobarbital, mephenytoin and diphenylhydantoin in the surveillance of anticonvulsant treatment]. The authors describe a method of simultaneous estimation of phenobarbitone, mephenytoin and diphenylhydantoin in the blood. After extraction with ether, the methylation of these substances by trimethylanilinium hydroxide permits their rapid separation by gas chromatography. Heptabarbitone is used as internal standard and the chromatograph used is supplied with a thermoionic detector. The technique used is simple and rapid. Its reproducibility and sensitivity are satisfactory, permitting daily application to the supervision of anticonvulsant treatment, especially in Pediatrics.


[Determination of isoniazid in blood plasma]. The authors describe a new method of estimation of isoniazid in biological fluids, based on the formation and extraction of aluminium chelate obtained after combination of the isoniazid with salicylic aldehyde. The study of conditions of defecation and reaction permits one to eliminate interference with the metabolites, especially the acido-labile metabolites and obtain results comparable with those of microbiological methods.


[Electrogastroenterographic study of the digestive motor effects of prolonged psychotropic treatment]. Functional digestive complaints are frequent in psychiatri patients: simple constipation, which cannot be explained solely by the loss of the sensation of rectal fullness; occlusions, occasionally hemorragies; the late complication of dolichomegacolon (Bourgeois, 1973). In 160 subjects, an attempt to understand the physio-pathology were made by recording diurnal digestive motor activity using skin electrodes placed on the abdomen and extremities (electrogastroenterography or E.G.E.G.). A hypoactive E.G.E.G. was observed in 2/3 of 18 psychotic depressive patients, in 3/4 of 36 schizophrenies. The nocive effect of giving sedative phenothiazine and antiparkinsonian drugs (trihexyphenidyl or ethybenzatropine) during long periods is clear. Whereas non sedative phenothiazine and clotiapine gicen in small doses, do not have an undesirable effect. Sulpiride has been used in gastroduodenal dyskinesia. The dyskinesia noted by the E.G.E.G., sometimes found in the large intestin, were found in 55% of 30 patients with caracter disorders; they coincide with the high frequency of electro-encephalogram dysrythmies. Finally, in hysterical patients, one usually observes normal E.G.E.G., tracings which confirms the clinical observation that hysterical and psychosomatic symptoms, may succeed each other, but do not appear at the same time. In the same categories of patients, no longer treated in a classical psychiatric environment but in a group with institutional objectives, the same clinic results were obtained with fewer digestive disturbances. This tends to show the inutility and nocivity of excessive doses of psychotropic drugs given alone or in complexe association.


Effect of acid and salt concentration in fresh-pack pickles on the growth of Clostridium botulinum spores. The addition of various amounts of acetic acid to pureed cucumbers inoculated with Clostridium botulinum spores has shown that outgrowth is inhibited at pH 4.8 but not at pH 5.0. Inoculation experiments with whole cucumbers showed that as little as 0.9% acetic acid in the brine was sufficient to prevent outgrowth from spore inocula as high as 10(6)/cucumber. It was further shown that the rapid rate of acetic acid penetration into fresh-pack pickles prevents the growth of any C. botulinum spores that may be present.


[On the ecology of marine chromatiaceae and chlorobiaceae (author's transl)]. Number and genera (types) of phototrophic red and green sulfur bacteria have been determined in the upper layer of eleven marine sediment samples from the euphotic zone in the Mediterranean Sea. Origin and nature of the sediment samples are given as well as their pH, total nitrogen and sulfide content. The results show that the sediments studied did not provide good growth conditions for Chromatiaceae (Chromatium, Thiocystis, Thiocapsa) and Chlorobiaceae (Prosthecochloris). The total number of these bacteria varied in agreement with the total nitrogen content (organic matter) of the samples; the organic matter content is, therefore, of primary importance for the occurrence of the red and green sulfur bacteria in the samples.


Isolation and characterization of an enzyme with esterase activity from Micropolyspora faeni. The isolation and the characterization of one of the enzymes of Micropolyspora faeni that hydrolyzes the substrate N-benzoyl-DL-phenylalanine-beta-naphthyl ester and that seems to be of medical importance are described. This enzyme (enzyme 1) was isolated with an 86-fold purification by using the following seven steps: ammonium sulfate precipitation, gel filtration through Sephadex G-150, heat treatment, chromatography on diethylaminoethyl-cellulose, rechromatography on diethylaminoethyl-Sephadex, gel filtration through Sephadex G-200, and affinity chromatography. Enzyme 1 has a molecular weight of approximately 500,000 and maximum activity at pH 7.8 to 8.0 and at 20 degrees C. The enzyme is stable between pH 7.5 and 10.5 and at temperatures up to 60 degrees C. Its activity is not inhibited by ethylenediaminetetraacetic acid. It is, however, sensitive to diisopropyl phosphofluoride and phenylmethyl sulfonyl fluoride. These properties and the ability to hydrolyze the esters of phenylalanine, tyrosine, and tryptophan without endopeptidasic activity and no marked proteolytic activity suggest that the enzyme is an esterase.


Therapeutic drug monitoring: measurements of antiepileptic and barbiturate drug levels in blood by gas chromatography with nitrogen - selective detector. The nitrogen-specific detector for gas chromatography consists of a non-volatile rubidium silicate bead, around which nitrogen-containing compounds are pyrolyzed. Speed, sensitivity, specificity, accuracy, small sample size and minumum sample handling are characteristics of the nitrogen detector that render it superior to conventional gas chromatographic detectors. The detector has been utilized to effect a simple and rapid quantitation of allobarbital, amobarbital, butabarbital, heptabarbital, pentabarbital, phenobarbital and secobarbital, plus the anticonvulsants diphenylhydantoin and primidone. Extraction of the drugs from acidified serum into organic solvent containing internal standard is followed by oncolumn methylation with methanolic trimethylphenyl ammonium hydroxide. The drugs, separated on a column of 3 percent OV-101 on Gas-Chrom Q, 100-120 mesh are readily quantitated by simple calculations based on peak-height ratios. Therapeutic drug monitoring is discussed in relation to recent concepts of drug-protein binding, drug-drug interactions, drug biotransformation and problems of multiple drug therapy.


Oxidation of ethane by an Acremonium species. Ethane oxidation was studied in ethane-grown resting cells (mycelia) of an Acremonium sp. and in cell-free preparations of such mycelia. From resting cell experiments evidence was found for a pathway of ethane oxidation via ethanol, acetaldehyde, and acetic acid. In vitro studies indicated that ethane-oxidizing activity in such mycelia occurred predominantly in the microsomal fraction of crude homogenates. Microsomal preparations were inactive in the absence of added coenzyme. Marked stimulation of activity was obtained in such preparations with reduced nicotinamide adenine dinucleotide phosphate and to a much lesser degree with nicotinamide adenine dinucleotide phosphate. Ethane oxidation was inhibited by sodium azide and carbon monoxide.


Enzymatic hydrolysis of organophosphate insecticides, a possible pesticide disposal method. A crude cell extract from a mixed bacterial culture growing on parathion, an organophosphate insecticide, hydrolyzed parathion (21 C) at a rate of 416 nmol/min per mg of protein. This rate of enzymatic hydrolysis, when compared with chemical hydrolysis by 0.1 N sodium hydroxide at 40 C, was 2, 450 times faster. Eight of 12 commonly used organophosphate insecticides were enzymatically hydrolyzed with this enzyme preparation at rates ranging from 12 to 1,360 nmol/min per mg of protein. Seven pesticides were hydrolyzed at rates significantly higher (40 to 1,005 times faster) than chemical hydrolysis. The pH optimum for enzymatic hydrolysis of the eight pesticides ranged from 8.5 to 9.5, with less than 50% of maximal activity expressed at pH 7.0. Maximal enzyme activity occurred at 35 C. The crude extract lost its activity at the rate of only 0.75%/day when stored at 6 C. Eight organic solvents, ranging from methanol to hexane, at low concentrations stimulated enzymatic hydrolysis by 3 to 20%, whereas at higher concentrations (1,000 mg/liter) they inhibited the reaction (9 to 50%). Parathion metabolites p-nitrophenol, hydroquinone, and diethylthiophosphoric acid, at up to 100-mg/liter concentrations, did not significantly influence enzyme activity.


Effects of added germination agents on loss of optical density in electron-irradiated spores. Spores of Bacillus megaterium ATCC 14581, subjected to partial-cell iradiation, were exposed to either lysozyme, H2O2, or glucose in an attempt to reduce or eliminate the nonmonotonic behavior in curves of percentage of germination versus energy, obtained when such spores were resuspended in phosphate buffer alone. Except at the lower doses. H2O2 effectively eliminated this anomalous dip in these curves, whereas lysozyme amplified it greatly. Glucose was generally ineffective. Coinciding with the increases in optical density when lysozyme was present was the formation of an occluding product.


The accumulation and loss of dieldrin and endrin in the eastern oyster. Oysters demonstrated an ability to significantly concentrate dieldrin and endrin. Concentration ratios obtained after 168-hr exposures to endrin were 1670 at 0.1 mug/L and 2780 at 50 mug/L. Dieldrin was concentrated to higher levels. Exposure to 14C-labelled dieldrin at 0.5 mug/L produced whole body concentrations 2880 times the ambient level at 168 hr, while exposure to nine mug/L of dieldrin resulted in a concentration ratio of 2070 following the same period of exposure. Both endrin and dieldrin showed distinct linear regions in semi-logarithmic plots of uptake against time. Initial uptake was rapid and was followed by somewhat slower but still rapid uptake over the next 6 to 48 hr. Uptake within each of the stages followed an exponential form.


Fundoplication for reflux esophagitis: misadventures with the operation of choice. Fundoplication, whether performed by thoracic or abdominal approach, is a sound method for control of reflux esophagitis. A series of 312 operations have been reviewed to assess the frequency of complications and the methods by which these can be prevented or treated effectively. Each source of an untoward outcome is examined in detail, and suggestions as to prevention or recognition are advanced. The current low death and complication rates have been lowered even more by a conscious effort to refine the procedure further; such efforts have been associated with a failure rate of less than 5% in a mean followup of 4 years.


Gastroesophageal reflux in esophageal scleroderma: diagnosis and implications. Fifty-three patients with scleroderma were evaluated by history, barium swallow, and esophageal function tests. The most common esophageal symptoms were heartburn and dysphagia. Abnormal motility was seen radiologically in 43 patients, gastroesophageal reflux in only 9. Esophageal function tests demonstrated: (1) abnormal motility in 51 patients and lack of a distal esophageal high-pressure zone in 18; (2) moderate to severe gastroesophageal reflux in 38; and (3) abnormal acid-clearing ability in 50. Eleven patients, including 8 with peptic stricture, underwent the combined Collis-Belsey operation. Symptomatically, reflux was abolished in all and dysphagia in 10. Roentgenograms showed that regression of strictures was complete in 5 and partial in 3. Postoperative esophageal function tests in 9 patients demonstrated a competent distal esophageal valvular mechanism in 7. Gastroesophageal reflux, not impaired motility, is the major cause of esophageal symptoms in scleroderma. Its effecitve operative control is not contraindicated by systemic disease in these patients.


Giant cell arteritis with visceral angiitis. We describe a case in which giant cell arteritis coexisted with microscopic polyarteritis nodosa and focal-local glomerulonephritis. We also review previous cases of renal abnormalities in giant cell arteritis. We believe that this association of inflammatory renal disease and giant cell arteritis has not been documented in the past.


[Experimental electric and biochemical data on ventricular fibrillation due to ischemia]. The author presents the results of prolonged research into ventricular fibrillation during myocardial ischaemia, both from the electrocardiographic and biochemical standpoints. - He emphasises the successive tonic and atonic features of VF due to ischaemia, and the difference between the fibrillation in an ischaemic area and in a control area. The most original concept is that there is often a difference between the onset of VF in an ischaemic zone and in a control zone. This study has been carried out with both acute and progressive ischaemia. - The biochemical studies were carried out on blood samples taken from the origin of the coronary arteries, the coronary veins, and from the saphenous veins. An important finding was the definite increase in the potassium level of the coronary venous blood in proportion to the degree of ischaemia; the sodium level showed little change, and if anything tended to fall. But the most important and distinctive finding was that at the onset of VF the sodium and potassium concentrations in the coronary venous blood suddenly increase. As the VF continues, there is a progressive increase in lactic acid and a fall in pH, which is maximal at the onset of the VF. These findings are valid under normothermic conditions, and when there is no extracorporeal circulation. - The physiopathological and practical implications of these facts are discussed.


Predicting the outcome of psychotherapy for schizophrenics. Relative contributions of patient, therapist, and treatment characteristics. This study was designed to assess the relative prognostic importance of patient factors, therapist characterists, and treatment mode. The sample was 100 schizophrenic outpatients referred to a community mental health center following psychiatric hospitalization. Patients were randomly assigned to either group (N=50) or individual (N=50) psychotherapy. Criteria were rehospitalization and two clinician ratings--adjustment and social effectiveness--at a two-year follow-up. The best predictor of rehospitalization was the number of previous hospitalizations. The best predictor of adjustment status at two years was pretreatment adjustment level. Also, patients with good prognostic indices made relatively large gains. Predictors of outcome for group-treated patients did not differ from those for individually treated patients. Controlling for initial status, treatment mode was almost as good as predictor of adjustment gains as were other patient factors.


Different behaviour of thymus in hosts bearing skin homografts or ehrlich ascites carcinoma. Thymus behaviour in A2G male mice transplanted with skin homografts or Ehrlich ascites carcinoma was followed for a period of 28 days. In comparison with control mice of the same strain in which only a slowly physiological involution of the thymus was observed, a marked, irreversible involution was seen in the tumour-bearing mice in contrast with the transient, completely recovered involution in animals transplanted with skin homografts. Thymus behaviour appears as the major structural difference between a host developping a strongly efficient or an inefficient immune response.


Extracorporeal membrane oxygenation during bronchopulmonary lavage. Extracorporeal membrane oxygenation (ECMO) in a venoarterial perfusion circuit was used to provide support of gas exchange during bronchopulmonary lavage in a 32-year-old man with pulmonary alveolar proteinosis and severe arterial hypoxemia. Prior to the lavage, Pao2 during mechanical ventilation with 100% oxygen and positive end-expiratory pressure was only 125 mm Hg. Extracorporeal perfusion at a flow rate of 3 liters/min, with oxygen delivery of 244 ml/min, increased the Pao2 to 227 mmHg and lowered the mean pulmonary artery pressure from 28 to 24 mm Hg. During bronchopulmonary lavage and ECMO, the Pao2 ranged between 46 and 96 mm Hg. After the procedure, pulmonary performance decidely improved. By reducing the chances of fatal hypoxemia, ECMO allowed treatment to be instituted for this potentially reversible disorder and proved helpful as a form of support during the management of pulmonary alveolar proteinosis when severe hypoxemia may have other wise precluded bronchopulmonary lavage.


[On the toxicology of carbromal. I. Estimation of carbromal and its hypnotically active metabolites in rats and humans (author's transl)]. To analyze the toxic effects of carbromal it was necessary to have information on the concentrations of carbromal and of its metabolites in the organism. This information can be obtained by a simple method based on gaschromatography that allows rapid, specific, sensitive and quantitative estimation of carbromal and of its hypnotically active metabolites bromoethylbutyramide and ethylbutyrylurea. Employing different detectors (flame ionisation or electron capture detector) the limit of detection for carbromal and of its two metabolites was 2-3 nmoles/g of tissue. The method was used to study in rats the absorption and elimination of carbromal including biotransformation of carbromal to bromoethylbutyramide and ethylbutyrylurea. Both metabolites, significant amounts of which were found in serum and brain, distribute evenly between serum and brain as does carbromal. Both metabolites were detectable in the organism for a longer time than carbromal. Carbromal was given orally to 4 healthy volunteers at a dose of 1 g (4.2 nmoles). Highest serum concentrations (30 nmoles/ml) were found 30 min after ingestion. Serum concentrations declined rapidly. Twenty-four hours later 3-4% of the values were present in the serum. Beside carbromal considerable amounts (up to 20 nmoles/ml) of bromoethylbutyramide were detected but only small amounts (2-3 nmoles/ml) of ethylbutyrylurea. Peak concentrations of these metabolites were recorded 4-5 h after ingestion of carbromal. As was the case in rats both metabolites were present in the organism for a longer time than carbromal.


Late-onset acid maltase deficiency. Detection of patients and heterozygotes by urinary enzyme assay. Daily urinary excretion of acid maltase (12.78 +/- 2.10 units/24 hr/mg of creatinine, in 11 normal adults) was significantly decreased in ten patients with late-onset acid maltase deficiency (1.33 +/- 0.16 units/24 hr; P less than .001) and 11 heterozygotes (3.27 +/- 0.62 units/24 hr; P less than .001). Maximal inhibition of urinary acid maltase activity by antibodies against human placental enzyme was 53% in controls, 30% in heterozygotes, and virtually absent in patients. Investigation of pH curves and enzyme inhibition by antibodies confirmed the presence in the kidney of an immunologically distinct "extra" maltase enzyme active at acid pH. Whether acid maltase in normal urine originates in the kidney or cells of the lower urinary tract, the enzyme defect seems to be expressed in these cells in late-onset acid maltase deficiency.


Aspects of the use of lithium for the non-psychiatrist. Lithium carbonate is commonly used in psychiatry, particularly in the management of the manic-depressive syndrome. It is also being increasingly tried in a variety of physical disorders. This essentially practical article summarizes important non-psychiatric aspects of the use of the drug, including its less common actions. Contra-indications to the use of lithium are discussed, and the management of lithium intoxication is outlined.


Homosexuality treated adventitiously in a stuttering therapy program: a case report presenting a heterophobic orientation. The heterophobic orientation toward treatment of homosexuality is discussed. A case report is presented where homosexuality apparently "spontaneously remitted" and heterosexuality was instated while the patient underwent treatment for stuttering. The change in sexual orientation is interpreted as possibly adventitiously induced through generalization effects from treatment of the relevant phobic aspects of the stuttering problem to the associated social aspects of the sexual problem.


[Alterations of cat papillary muscle mechanics induced by changes of preload under variation of physical and chemical parameters (author's transl)]. A rapid change in length of cat papillary muscle induces two reciprocal diastolic and systolic processes: stretching causes a viscoelastic relaxation of the muscle. The opposite behavior is observed after abrupt releases when - subsequent to an increase in resting tension - diastolic force attains its new equilibrium. The stretch-induced process of relaxation is accompanied by a transient decrease in mechanogram amplitudes; a release is accordingly followed by a temporary increase in isometric muscle performance. The mechanograms of the steady state prove to be the function of the degree of stretch or release, whereas muscle contractions in the early phase of stress relaxation depend on the contractile state before the change in length. All interventions which augment developed tension (increased calcium, decreased potassium, increased or decreased sodium concentrations, strontium, postextrasystolic potentiation, sympathicomimetic agents, frequency potentiation) diminish the transient phenomena due to stretch, whereas low frequency or a lesser intensity of electromechanical coupling (Hexobarbital, Iproveratril, Desoxycorticosteron, Ryanodine) increases them. A decrease of bath temperature enhances the transient increase in force due to a release or an initial reduction of isometric tension after a sudden stretch, although the absolute forces increase. No substantial changes could be observed in reserpinized cats with beta-blocking agents or under hypoxia. It is supposed that alterations in the time course of the action potential could be related to post-stretch and post-release systolic phenomena. A final interpretation of mechanical and electrical events after stretch and release is not possible with the methods used in these experiments.


Facultative anaerobiosis in molluscs.

Facultative anaerobiosis in molluscs. The glycolytic fermentation of molluscs is rather complex. Multiple end products accumulate (lactate, alanine, octopine, succinate, propionate, acetate and CO2), which are partly formed in the cytoplasm and partly in the mitochondrion. Various schemes have been presented to account for these end products as well as for the maintenance of the redox balance. With respect to the role of alanine there are two opinions: (1) alanine accumulation is continuous and is essential for the generation of the mitochondrial NADH required in the reduction of fumarate and (2) succinate and alanine (initial end products) accumulate in different compartments and their accumulation occurs independently. Both statements are evaluated in the light of the latest experimental observations including the regulatory properties at the phosphoenolpyruvate branchpoint and the effect of pH and 'energy charge'. For nervous tissue the function of oxygen can be replaced by the lipochrome pigment, which enables carbohydrates to be totally oxidized to CO2 and water. The simultaneous mobilization of carbohydrates and amino acids is not supported by the experimental data. Various advantages of the glycolytic fermentation in molluscs as compared with classical glycolysis in skeletal muscle are discussed.


Adaptations of enzymes for regulation of catalytic function. 1. Enzymes must not only be extremely effective catalysts, but must also be the operating components of very sensitive and sophisticated regulatory systems. Appropriate evolutionary adjustment of the properties of different enzymes causes the sites that bind typical metabolic intermediates to be only partially saturated in vivo, thus allowing flexibility for control by variation in ligand concentration. In contrast, sites that bind such coupling agents as the pyridine and adenine nucleotides seem to be virtually saturated. Thus the ratios, rather than the absolute concentrations, of these compounds are important in metabolic regulation. This type of response is esstial to the function of these compounds simultaneously as thermodynamic energy transducers and modifiers in the kinetics regulatory system. 2. Reaction orders of two to four are frequently encountered. They appear to be essenital to biochemical homoeostasis, which is the maintenance of nearly constant substrate concentrations at the expense of wide variation in flux rates. 3. The strategies of enzyme adaptation are general, but the actual adaptations of enzymes are highly specific, reflecting the place of the enzyme in a metabolic sequence, the place of the sequence in the metabolism of the cell and, in complex organisms, the function of the cell, and of the organ or tissue of which it is a part, in the organism. Patterns of adaptation must be almost infinitely varied. A few are presently known in outline, but probably none as yet in detail. Several examples are discussed.


Early changes in the arterial wall of chickens fed a cholesterol diet. A total of 160 1-2 day old chickens were fed a 2% cholesterol diet for a period of 8 to 42 days and compared with an equal number of controls. Aortas were analyzed for various indexes of reactivity of connective tissue, cholesterol content and scanning electron microscopy (SEM) characteristics of the endothelial lining. Cholesterol feeding for a period up to 6 weeks resulted in doubling the level of serum cholesterol. It was, however, without effect on the activity of prolyl hydroxylase, lysyl oxidase, collagenase and collagen content in the aortic wall. As early as 3 weeks of feeding significant changes occurred in total and esterified cholesterol content. At the same time endothelial cells were characteristically contracted with several long cytoplasmic elongations and protrusions. A significant decrease of activity of the above enzymes was found in aortic tissue with increased age of the chicken. Collagen content in aortas increased with age of chickens. It is concluded that cholesterol as an atherogenic agent induces marked changes in endothelial cells and lipids of chicken aorta at earlier periods, prior to the activation of connective tissue.


Isoprenaline antagonism of cardioselective beta-adrenergic receptor blocking agents on human and rat adipocytes. 1. The beta-adrenergic blocking potencies of practolol, ICI 66082, tolamolol, acebutolol, H 93/26, H 87/07, pindolol and Ro 3-4787 were compared with that of propranolol, on human and rat adipocytes. 2. A good correlation was found between the potencies on adipocytes of the two species but not between our results and literature data on antagonism of isopernaline tachycardia in the anaesthetized cat. 3. The results indicate that differences between adrenergic beta-receptors in heart and adipose tissue may be detected using cardioselective beta-adrenergic receptor blocking agents.


Pharmacological evaluation of cimetidine, a new histamine H2-receptor antagonist, in healthy man. Cimetidine, a new H2-receptor antagonist, was safely administered to eighteen healthy man by the intravenous, intraduodenal or oral route. 2 When gastric secretion was maximally stimulated by either histamine or pentagastrin, the simultaneous administration of cimetidine produced marked inhibition of both acid and pepsin secretion. 3 Cimetidine was well absorbed by mouth and had a blood half-life of 2 hours. 4 Cimetidine was rapidly excreted via the kidneys and about 70% of the excreted material was unchanged drug. 5 Clinical evaluation of cimetidine in patients with peptic ulceration is recommended.


Inhibition of gastric emptying and drug absorption by narcotic analgesics. The effect of intramuscular pethidine or diamorphine on gastric emptying and the absorption of orally administered paracetamol was assessed in eight normal subjects. 2 Both drugs produced a significant and striking delay in gastric emptying and absorption of paracetamol. 3 It seems inevitable that pethidine and diamorphine will retard the absorption of other orally administered drugs.


The effects of atenolol (tenormin) and methyldopa on simple tests of central nervous function. Two identical studies, one comparing the effect of single doses of a new beta-adrenoceptor blocker, atenolol (Tenormin) (50 mg and 100 mg) and placebo, and the other comparing the effect of single doses of methyldopa (250 mg and 500 mg) and placebo, in healthy volunteers, were carried out. 2 In both studies the effect of the drugs upon reaction time, critical flicker frequency, subjective drowsiness, pulse rate and blood pressure was measured. 3 Atenolol produced no effect upon reaction time, critical flicker frequency or subjective feelings, while methyldopa produced a statistically significant prolongation of reaction time and a statistically significant increase in the subjective sensation of drowsiness. 4 Atenolol produced statistically significant reductions in systolic and diastolic blood pressure and in pulse rate while methyldopa was without effect. 5 It is concluded that atenolol is unlikely to produce the side effects of sedation or drowsiness.


Effect of N-desmethyldiazepam (nordiazepam) and a precursor, potassium clorazepate, on sleep in man. 1 The effect of N-desmethyldiazepam (nordiazepam, 5 and 10 mg) and potassium clorazepate (15 mg, a precursor of nordiazepam) on sleep was studied in six healthy adult males. Electroencephalography (EEG) was used for sleep measures, and analogue scales were used for subjective assessments of well-being and sleep quality. 2 Effects on total sleep time were limited to the night of ingestion. There were increases with nordiazepam (5 and 10 mg) (P = 0.05) and 0.001 respectively), and with clorazepate (15 mg) (P = 0.01). Sleep onset latencies were shortened, particularly with nordiazepam, and awakening to stage 0 activity was reduced, by both drugs. The latency to stage 3 was reduced by nordiazepam (5 and 10 mg) (P = 0.05). 3 There were no effects of nordiazepam (5 mg) on the duration (min) of sleep stages. Nordiazepam (10 mg) and clorazepate (15 mg) reduced the duration of stage 0 and stage 1, and there were increases in stage 2. Reduced stage 1 and increased stage 2 sleep were observed during the recovery night. No effects were observed with stage 3, but there was evidence that stage 4 activity was depressed on the recovery night only. No effects were observed on REM sleep, except that the appearnace of the first REM period was delayed with clorazepate (15 mg) P = 0.01). The effect of nordiazepam (10 mg) and clorazepate (15 mg) were comparable, and each modified sleep for about 28-30 h after ingestion. 4 With nordiazepam (10 mg) and clorazepate (15 mg) the subjects, as a group, reported improved sleep, but subjective assessments of well-being were not altered. Correlations were calculated for sleep measures and subjective assessments.


Assessment of drugs in schizophrenia. Basic trial design. Clinical trials with major tranquilizers must take into account the clinical features of patients with schizophrenia and pharmacokinetic and pharmacodynamic properties of the drug. The objectives of the trial must be carefully defined so that appropriate selection criteria for patients, rating instruments and dosage schedules can be selected. It is useful to monitor physiological and biochemical actions of major tranquilizers as well as the clinical effects.


Assessment of drugs in schizophrenia. Asessment of drug-induced extrapyramidal reactions and of drugs given for their control. I have tried to bring out some of the important methodological problems found in examining the effectiveness of drugs used in the control of druginduced parkinsonism by referring mainly to studies in which I have taken part. I hope I have shown that the whole topic is far less well understood than is often assumed. The main points may be summarized as follows: there is doubt as to whether many of the drugs used in controlling drug-induced parkinsonism are really effective; the results of many studies are conflicting; many studies contain serious flaws in design; methods for assessing extrapyramidal signs are not well developed; we are ignorant of the way in which drug-induced extrapyramidal signs change spontaneously. There is a clear need for further research in this area to improve techniques of assessment, to provide basic information on drug-induced syndromes, and to rigorously examine the efficacy of the drugs used in controlling them.


Residual effects and skills related to driving after a single oral administration of diazepam, medazepam or lorazepam. Psychomotor skills and visual functions related to driving were measured double-blind cross-over in ten healthy volunteers before, and 1,3,5 and 7 h after a single oral administration of diazepam (10mg), medazepam (15 mg) or lorazepam (2.5 mg). The late effects of lorazepam were tested in seven other subjects 12 and 24 h after the administration. Lorazepam impaired almost all the measured skills more (P less than 0.05 to 0.001) than diazepam, medizepam or the placebo. The lorazepam impairment of reactive skills and flicker fusion discrimination remained statistically significant (P less than 0.05) for as long as 12 h. Medazepam impaired only reactive skills and flicker fusion, the latter remaining impaired (P less than 0.05) for as long a 5 h after the administration. The magnitude  and duration of the effects of diazepam were intermediate between those of lorazepam and medazepam. Diazepam impaired perceptual speed and reactive and co-ordinative skills as well as flicker fusion discrimination and visual parameters related to driving. Slight impairments in performance were measurable for up to 5 h after administration but at 7 h the results resembled those measured after the placebo. The lack of alterations in adaptation to darkness, sensitivity to brightness or visual discrimination ability in bright counterlight at a time when flicker fusion discrimination was severely depressed suggests that an impaired ability to discriminate flickering light is of no or little clinical significance to driving ability. It is concluded that patients receiving a 2.5 mg dose of lorazepam should not drive or operate machinery for 24 h after the administration. After diazepam (10 mg) or medazepam (15 mg) patients should refrain from driving or participating inskilled performances for only 5 to 7 hours.


Assessment of alpha- and beta-adrenoceptor blocking actions of labetalol. Isoprenaline dose-response curves plotting increases in heart rate before and after labetalol are suggestive of competitive antagonism at beta-adrenoceptor sites. Phenylephrine dose-response curves using increases in systolic pressure before and after labetalol are suggestive of competitive antagonism at alpha-adrenoceptor sites. The ratio of alpha:beta-adrenoceptor antagonism induced by labetalol is approximately 1:3. Peak pharmacological responses after a single oral dose of labetalol (400 mg) occurred between 90-120 min after administration.


The sensitivity of a malignant cell line to hyperthermia (42 degrees C) at low intracellular pH. The postulate that low intracellular pH acts as a preconditioner for the destructuve effects of hyperthermia (42 degrees C) was examined, using  a heat-sensitive line of malignant cells derived from rat mammary gland (SDB). Intracellular pH (pHi) was measured indirectly, from the distribution of the weak, non-metabolizable organic acid 5,5-dimethyl-2,4-oxazolidinedione (DMO) between intra- and extra-cellular water. Respiration, aerobic and anaerobic and anaerobic glycolysis of the cells were studied at normal pHi (pH 7-0-7-4) or at low pHi (pH 6-2-6-6) and at 38 degrees C or 42 degrees C over 6 h in Warburg manometers; the ability of the cells to replicate in culture was examined after 3 h or 6 h incubation in the flasks. The relationship between pHi and extracellular pH (pHe) depended upon the buffer system used and the exact pH in question; no assumption regarding pHi based only on pHe measurement could be made. At 38 degrees C and low pHi, the Pasteur effect became negative due to a relatively greater inhibition of anaerobic than aerobic glycolysis. Respiration was unaffected and cell replicative ability unimpaired. At 42 degrees C and normal pHi, respiration was totally inhibited after 4 h and the Pasteur effect was decreased, in this case due to a compensatory increase in aerobic glycolysis without alteration in anaerobic CO2 production. Low pHi in the presence of hyperthermia enabled cell respiration to continue at a reduced level with no further change in glycolysis. There was delayed cell replication after 3 h at 42 degrees C and inability to multiply following 6 h hyperthermia: low pHi did not influence these results. It is concluded that with these cancer cells, pHi values maintained in the region of 1-0 pH unit below normal for 6 h had no deleterious effect on the cells. No sensitizing effect of the low pHi for the destructive effect of hyperthermia on the cells was observed.


A comparison of the pupilloconstrictor effect of pilocarpine solution administered to the conjunctival sac as a single drop or as a continuous infusion in normal subjects. Pilocarpine was administered into the conjunctival sac of normal volunteers by single-drop administration or by continuous infusion of a solution to the inner canthus by means of a fine Silastic tube. Using pupilloconstriction as a measure of response it was shown that infusion with a 0-01 per cent solution of pilocarpine was as effective as a single drop of 0-5 per cent pilocarpine. The response to the single drop was faster at onset. It was demonstrated that at pH 7-2 pilocarpine was more effective than at acid pH. The infusion method is simple to use, comfortable for long periods, has potential for reducing the need for frequent drop administration and for reducing the total amount of drug administered, and could be used for drugs other than pilocarpine.


Ribose recognition by ribonuclease T1: difference spectral binding studies with guanosine and deoxyguanosine. The binding of ribonuclease T1 with guanosine (Guo) and deoxyguanosine (dGuo) was studied in experiments employing ultraviolet difference spectroscopy in the pH range 3-9 at 0.2 M ionic strength and 25 degrees C. Similar experiments were also conducted with psi-carboxymethyl-glutamate-58 ribonuclease T1 at pH 5.0. At most pH values the characteristic difference spectrum and association constant were obtained. The binding constant for dGuo was  approximately 550 M-1 and did not significantly vary in the pH range 3.5-9.0. The binding constant for Guo increased from pH 3.5 to 5.0, was constant between pH 5.0 and 7.0 (approximately 3200 M-1), and decreased at higher pH values. The binding of Guo and dGuo with ribonuclease T1 could also be distinguished in terms of the wavelength for maximal difference absorbance, lambdamax, between pH 5.0 and 7.0. At higher and lower pH values, lambdamax for Guo approached that found fr dGuo. On the other hand, the value of the binding constant (approximately6500 M-1) and the nature of the difference spectra for Guo and dGuo binding with lambdamax-carboxymethyl-glutamate-58-ribonuclease T1 at pH 5.0 were identical. These results suggest that the discrete interaction of the Guo 2'-hydroxyl group with ribonuclease T1 involves the lambda-carboxylate of glutamate-58 and an imidazolium group at the active site.


Bovine brain purine-nucleoside phosphorylase purification, characterization, and catalytic mechanism. Bovine brain purine-nucleoside phosphorylase (purine-nucleoside:orthophosphate ribosyltransferase, EC 2.4.2.1) was purified to homogeneity at a specific activity of 78 mumol min-1 mg of protein-1. A molecular weight of 78 000-80 000 was calculated for the native enzyme by fel filtration on Sephadex. Gel electrophoresis in the presence of sodium dodecyl sulfate indicated subunits of molecular weight of 38 000. Chemical and kinetic studies strongly implicated histidine and cysteine as catalytic groups at the active site of the enzyme. The pKa's determined for ionizable groups at the active site of the free enzyme were 5.8 and 8.2. Enzyme completely inactivated by p-chloromercuribenzoate was partially reactivated enzyme. A strong susceptibility to photooxidation in presence of methylene blue was observed. Photoinactivation was pH dependent, implicating histidine as the susceptible group at the active site. A rapid loss of catalytic activity upon incubation at 55 degrees C suggested heat lability. An activation energy of 9.6 kcal/mol was calculated. The nature of the catalytic mechanism of the enzyme was investigated, and initial velocity studies showed linear converging patterns of double-reciprocal plots of the data, consistent with a sequential catalytic mechanism. The product inhibition pattern was at variance with both the ordered Bi-Bi and random mechanisms. The observed competition between purine and nucleoside, and between inorganic orthophosphate and ribose 1-phosphate for this ordered mechanism, suggest a Theorell-Chance mechanism. Michaelis constants determined for substrates of the enzyme were 4.35 X 10(-5) M for guanosine, 3.00 X 10(-5) M for guanine, and 2.15 X 10(-2) M for inorganic orthophosphate.


Mung bean nuclease I. Physical, chemical, and catalytic properties. A simplified purification procedure for mung bean nuclease has been developed yielding a stable enzyme that is homogeneous in regards to shape and size. The nuclease is a glycoprotein consisting of 29% carbohydrate by weight. It has a molecular weight of 39 000 as determined by polyacrylamide gel electrophoresis in the presence of sodium dodecyl sulfate. The enzyme contains 1 sulfhydryl group and 3 disulfide bonds per molecule. It has a high content (12.6 mol %) of aromatic residues. Approximately 70% of the enzyme molecules contain a peptide bond cleavage at a single region in the protein. The two polypeptides, 25 000 and 15 000 daltons, are covalently linked by a disulfide bond(s). Both the cleaved and intact forms of the enzyme are equally active in the hydrolysis of the phosphate ester linkages in either DNA, RNA, or adenosine 3'-monophophate. The enzymatic activity of mung bean nuclease can be stabilized at pH 5 in the presence of 0.1 mM zinc acetate, 1.0 mM cysteine, and 0.001% Triton X-100. The enzyme can be inactivated and reactivated by the removal and readdition of Zn2+ or sulfhydryl compounds.


Mung bean nuclease I. Terminally directed hydrolysis of native DNA. Under conditions which favor the duplex structure of DNA, mung bean nuclease catalyzes a limited number of double-strand cleavages (probably less than 50) in the interior of native T7 DNA. However, under conditions which are not as favorable to a tight helical structure, the large duplex polymers previously produced are completely degraded from their termini with a continuous accumulation of mono-, di-, and trinucleotides. The terminally directed activity is an intrinsic property of the enzyme molecule because (1) it is inactivated and reactivated in parallel with the single-strand activity and (2) the two activities coelectrophorese on analytical gels. Kinetic measurements indicate that the apparent Km for the terminally directed hydrolysis of native DNA is relatively high. The pH optimum for both the hydrolysis of denatured DNA and the terminally directed hydrolysis of native DNA becomes more acidic with increasing salt concentration. The relative preference for single-stranded structures increases as the pH becomes more basic.