The effect of etoperidone, a new potential antidepressant drug, on the central serotonin system. The effect of etoperidone--a non-tricyclic potential antidepressant drug--on the central serotonergic system was studied. It was demonstrated that this compound inhibited the head twitch reaction induced by 5-HTP in mice and rats (ED50 values amounted to 2.89 and 2.29 mg/kg i.p. respectively). In the flexor reflex preparation in spinal rats etoperidone used in doses lower than 1 mg/kg i.v. produced no effect, while doses of 1 mg/kg i.v. and higher had a stimulating action which occurred 10--15 min after injection. This stimulating action was abolished by 5-HT antagonists (cyproheptadine, danitracen) and by the drug metabolism inhibitor SKF-525A, but not by the 5-HT uptake inhibitor clomipramine. Etoperidone given in a dose of 0.5 mg/kg i.v. had no effect on the stimulating action of serotoninmimetics (LSD, quipazine, fenfluramine) on the flexor reflex, but it abolished the effect of LSD in rats pretreated with SKF-525A. The above findings indicate that etoperidone has a biphasic action on the serotonergic transmission, revealing characteristics of the 5-HT antagonist and agonist. The agonistic action is probably connected with the formation of a metabolite.


Usefulness of gamma-aminobutyric acid (GABA) therapy in pathologies of neurosurgical competence. The Authors, after giving some theoretical and pharmacodynamic opinions on GABA, report their clinical experience for 18 consecutive years with the use of gamma-aminobutyric acid in cases of central comas, psycho-organic post-operative syndromes, Parkinson's Disease. The drug, in the various above listed pathologies, shows respectively a wakening effect, with actual rising of the level of consciousness, a re-equilibrating action towards psycho-organic involutions, especially acute ones, and a considerable antiakinetic activity. After analyzing the original results obtained, considered especially in the light of the most modern researches on the importance of GABA-ergic mediation on the basal ganglia, some interesting neurofunctional hypotheses are put forward, which are connected with the problem of nervous conduction in human pathology. According to said hypotheses the aminoacid works clinically, owing to its role of inhibiting mediator (rather than of oxidable substrata), and is involved in extrapyramidal nigro-striatal lesions.


Autopsy findings in cases with a clinically uncertain cancer diagnosis. Analysis of the post mortem and clinical evaluation of the underlying cause of death in 471 cancer patients showed that doubt in the clinical situation occurred in approximately one case in four. Doubt was of three kinds, that as to the site of origin of the cancer, that related to lack of morphological confirmation and that as to the aetiology of the disease process. In most cases in the first two groups the decision not to resolve the doubt until post mortem was made clinically. The majority of the others were admitted too late for the doubt to be resolved before death.


Critical evaluation of the hemispheric perfusion brain scanning using Tc99m labeled human albumin microspheres in cerebral ischemic disorders. Preliminary report. Twentytwo patients, 11 with Completed Stroke and 11 with Transitory Ischemic Attacks, were submitted to the Perfusional Brain Scanning (PBS). In all cases the PBS demonstred a pathologic pattern. The test explored the conditions of the arteriolar tree and acquainted us with the degree of the ischemic damage and the functional value of the interhemispheric arterial collateral circle. Further informations on the morphology, site and extension of the lesion were obtained. The pathophysiologic aspects of the procedure are discussed and its safety assessed.


A case of gastric teratoma.

A case of gastric teratoma. This paper reports a case of gastric teratoma in a 3-mth-old boy, with macroscopic and microscopic observations. Forty-five instances of gastric teratoma, including the present case, have been reported.


Recognition memory alterations after severe head injury. Preliminary results in a series of 50 patients. The Authors report a study on recognition memory in a series of 50 severe head injuries. The effect of cerebral trauma is expressed by reduction in recognition memory and in learning. A significant difference is found between frontal lesions and temporal lesions. Left temporal lobe damage causes a more severe deficit than right temporal lobe damage. Extradural and subdural haematomas cause no such severe deficit. Neurological syndrome of level of lesion significantly correlates with the performance. PTA duration shows no relation.


Surgical trial in the vertebral flow alteration due to Kimmerle anomaly. The Author reports 2 cases presenting vertebro-basilar insufficiency. In the first one, surgery was interrupted due to the hyperflexed positioning of the head which caused cardiorespiratory disorders and increased vertebro-basilar insufficiency. In the second case the patient, placed in a different position, survived the operation. The postoperative angiographic control confirmed the disobstruction of the vertebral flow at the level of the malformation. Electromyography detected the presence of innervation of tongue muscles.


Intravital and electron microscopic study of bradykinin-induced vascular permeability changes using FITC-dextran as a tracer. Fluorescein-labelled dextran (FITC-dextran) of molecular weight 145,000 was used to study vascular permeability to macromolecules by intravital and electron microscopy. Anaesthetised hamsters prepared for intravital observation of the cheek pouch microvasculature were given an intravenous injection of FITC-dextran. Leakage of macromolecules was induced by topical application of bradykinin to the cheek pouch microvasculature and observed in fluorescent light. Leakages occurred only from postcapillary venules of a diameter well below 50 micrometer. The cheek pouch preparation was rapidly fixed by immersion and samples of tissue with intravitally identified leakages of FITC-dextran were studied by electron microscopy. FITC-dextran appeared as black precipitates in the vascular lumen and also outside the lumen in bradykinin-treated animals. In most animal; gaps were found between endothelial cells and these gaps contained dextran precipitates. The results support much other evidence that bradykinin induces macromolecular leakage by opening gaps between endothelial cells in postcapillary venules.


Squamous carcinoma of the colorectum and its genesis. A case of pure aquamous carcinoma of the rectum is presented, and the literature reviewed. Squamous carcinomas of the colorectum are rare tumours which have clinicopathological features in common with adenocarcinomas. Evidence is presented to support the proposal that most tumours of the large intestine that consist partly or completely of squamous elements arise from areas of squamous differentiation in pre-existing adenomas. The pathogenesis of squamous carcinoma and adenosquamous carcinoma appears to be similar to that of adenocarcinoma.


Right-sided juxtaposition of the atrial appendages in an anencephalic. A case of the uncommon right-sided juxtaposition of the atrial appendages is presented--to our knowledge the 17th instance reported so far. The interest of this case resides in the fact that there were no associated major cardiac anomalies, and that it occurred in an anencephalic female. It is the second reported case of this association. Both cases had in common the presence of ventricular D-looping, normal relationships of the great arteries and only minor cardiac defects. The absence of major cardiac anomalies, in contrast to the more common left-sided juxtaposition, and the association with anencephaly which has not yet been reported in the left-sided variant of juxtaposition, are features which have to be emphasised.


Externality as a function of obesity in children: pervasive style or eating-specific attribute? The developmental sources of the link between stylistic externality and food-related externality found in the obese by Schacter and others were explored by testing whether the externality phenomena that have been found to differentiate obese and normal adults are also discriminators of obese and normal children. The results suggest that obese children as young as 7-12 years of age show an external responsiveness to salient food cues but not yet a generally external perceptual style. The implications of these findings for the development of obese externality are examined.


Does aggression cause a preference for viewing media violence? Virtually all of the research concerned with media violence has attempted to determine whether the viewing of violence is associated with or causes aggression. Little experimental research has been directed at understanding why persons view media violence. The present research experimentally tested the hypotheses that physical aggression and fantasy aggression would lead to a preference for viewing violence. In Experiment 1, undergraduate men and women were induced to express aggressive, nonaggressive, or no fantasies and were then given an opportunity to select film clips for viewing. The films chosen by men contained more violence than those chosen by women. In addition, aggressive fantasies in males, compared to nonaggressive fantasies, increased the preference for viewing violence. Experiment 2, using only males, replicated the results of the first study and also found that men who were given an opportunity to aggress physically, compared to those who had no such opportunity, were more likely to choose to view films containing violent content. These results provide an additional perspective on the relationship between the observation of violence and the expression of aggression by suggesting that the causal effects are bidirectional: Just as the viewing of violence may increase aggression, so, too, aggressive behavior may increase the preference for viewing violence.


Pharmacokinetics of ampicillin and its prodrugs bacampicillin and pivampicillin in man. Five healthy fasting male subjects were each given single doses of intravenous ampicillin (471 mg), oral ampicillin tablets (495 mg), oral bacampicillin hydrochloride tablets (562 mg ampicillin equivalent), and oral pivampicillin hydrochloride capsules (491) mg ampicillin equivalent) in a crossover experiment. The resulting concentrations of ampicillin were determined in plasma and urine. The pharmacokinetic analysis was made according to a two-compartment open model. The total distribution volume of unbound ampicillin during the disposition phase was 0.247 +/- 0.045 (SD) liter/kg, which is only slightly more than the extracellular fluid, suggesting that tissue binding and intracellular distribution of ampicillin are limited. The bioavailability of the esters bacampicillin (86 +/- 11%) and pivampicillin (92 +/- 18%) was significantly greater than that of ampicillin (62 +/- 17%); however, the difference between the esters was not statistically significant. The adsorption for all drugs given orally proceeded at a constant rate, suggesting zero-order release rates from the products. The adsorption rate was highest for bacampicillin (0.89 +/- 0.39 of dose absorbed per minute), followed by pivampicillin (0.64 +/- 0.19) and ampicillin (0.58 +/- 0.16). Bacampicillin also had the shortest lag time for the start of absorption (7.0 +/- 0.9 min) under the present conditions. Thus, in comparison with ampicillin, the esters have a higher bioavailability, which, in fact, is close to the theoretically highest possible value by clearance concepts. The higher bioavailability in connection with higher absorption rates may be clinically important in ampicillin treatment by the oral route.


Pharmacokinetics of phenylethylacetylurea (pheneturide), an old antiepileptic drug. The pharmacokinetics of pheneturide (a decarboxylation product of phenobarbital), used to prevent psychomotor seizures for many years, was studied in normal human volunteers. To measure the drug in plasma and urine, a highly sensitive and reproducible thin-layer chromatography-reflectance spectrophotometric assay was developed. The results show that pheneturide follows first-order kinetics in the dose range studied. Its half-life after single doses is 54 hr (range 31--90), and its total body clearance (100% nonrenal) is 2.6 liters/hr (range 1.73--3.59). After repetitive administration, half-life is 40 hr (but clearance remains unchanged because of a lower volume of distribution). Because of the long half-life, repetitive administration results in a continuous steady-state level and makes this drug (kinetically) ideal for long-term use.


Pharmacokinetics of clonidine in the rat and cat. To investigate the pharmacokinetic behavior of clonidine, rats were given clonidine intravenously at 125, 250, and 500 micrograms/kg and blood clonidine concentrations were followed for 6 hr. The disposition of clonidine in two brain regions was studied in rats after an i.v. dose of 500 micrograms/kg. The liver clearance in rats was investigated by liver perfusion techniques. The results obtained indicate that the disposition characteristics of clonidine can be described by a two-compartment open model in both rats and cats. The penetration of clonidine into tissues is rapid, and brain levels in rats were about 1.7 times higher than blood levels. Brain tissues were found to be an indistinguisible part of the central (blood) compartment. Dose-dependent pharmacokinetic behavior was found for clonidine in rats at the doses used. This was demonstrated by a decrease of both the rate constant of distribution to the peripheral compartment and the overall elimination rate constant from the body, with increase in dose. As a consequence, the volume of distribution and the clearance both decreased with increasing dose. Possible explanations for the dose-dependent behavior of clonidine are discussed.


Multiple receptor responses: a new concept to describe the relationship between pharmacological effects and pharmacokinetics of a drug: studies on clonidine in the rat and cat. The time course of an observed pharmacological effect is affected not only by the kinetics of the drug levels at the site of action but also by parameters such as the slope and maximum effect of the functional relationship between drug level and response. Using clonidine as a test drug, it was found that the kinetics of its effects on blood pressure and pain responses cannot be described by the time course of clonidine levels in the blood, brain, or the hypothetical tissue compartment of the two-compartment characteristics of this drug. However, the results can be explained assuming that the observed pharmacological effects of a drug are composed of the sum of responses from at least two receptor sites with different slopes and maximal effects. The effect of intravenously administered clonidine on blood pressure in the rat was found to be related to the blood concentrations at least at two receptor sites with opposite effects, one leading to a hypertensive and the other to a hypotensive response. Predictions indicate that a maximum decrease of arterial blood pressure is obtained when the steady-state blood concentration of clonidine is about 1 ng/ml and that no effect is seen at 10 ng/ml. Higher levels will produce an increase of the pressure. The kinetics of the analgesic effect of clonidine in the rat could best be related to the brain levels if the observed effect was considered to be derived from the sum of activity at two receptor sites each producing analgesia. The kinetics of the effects of clonidine on the nictitating membrane of the cat was found to be determined by the kinetics of the drug in the peripheral compartment of the two-compartment open model. Consideration of multiple receptor responses is suggested for future studies on the relationship between the kinetics of drug levels and pharmacological responses.


Number of exponential terms describing the solution of an N-compartmental mammillary model: vanishing exponentials. The solution for a linear mammillary model is always described by a summation of m + 1 negative exponential terms with constant coefficients. m + 1 less than or equal to N, where N is the number of compartments in the model. m is equal to the number of distinct values for the peripheral Ej values. Use is made of matrix notation and the theorems of Browne concerning the eigenvalues of a matrix. The consequences of vanishing exponentials are derived, and in particular the apparent volume of distribution frequently calculated from experimental data is shown not to be unique.


Potential pitfalls in the conventional pharmacokinetic studies: effects of the initial mixing of drug in blood and the pulmonary first-pass elimination. The classical concept of assuming that an i.v. dose instantaneously distributes into the central or plasma compartment is reviewed, as is the potential for pulmonary first-pass effect. Based on available literature, the concept is shown to lead to serious errors in estimating pharmacokinetic parameters, particularly for drugs with high clearance.


Nonlinear least-squares regression programs for microcomputers. Nonlinear least-squares regression can be performed on a microcomputer with BASIC language capability and 8K or more bytes of random access memory. At least five nonlinear regression programs written in BASIC exist, two of which have been implemented on microcomputers. These programs and some of their characteriscics are described. Advantages and disadvantages of performing nonlinear regression on microcomputers are contrasted with use of nonlinear regression programs requiring large computers.


Steady-state plasma concentrations as a function of the absorption rate and dosing interval for drugs exhibiting concentration-dependent clearance: consequences for phenytoin therapy. Model-dependent relationships describing the effects of absorption rate and dosing interval on steady-state phenytoin plasma concentrations are presented and discussed. Utilizing a range of operative Michaelis-Menten parameters that characterize phenytoin elimination via a single capacity-limited pathway, a situation assuming instantaneous absorption (case I) is compared with the situation in which continuous constant-rate absorption occurs (case II). The results of these comparisons demonstrate that average steady-state concentrations do not differ significantly between the two cases. Ratios (case I/case II) of areas under the curve during a steady-state dosing interval substantially deviating from unity are associated with high plasma clearances and clinically low phenytoin concentrations. When the same daily dose is maintained, but the dosing interval is altered (0.25, 0.33, 0.50, 1.0 day), little difference in the average steady-state levels is observed even when absorption is instantaneous. Differences between steady-state maximum and minimum concentrations increase with prolonged dosing intervals as well as faster absorbed phenytoin formulations, but for most patients these fluctuations are therapeutically insignificant. A dimensionless parameter, Q, which is a function of the individual patient's parameters and the dosing regimen, is introduced, and its relationship with steady-state phenytoin concentrations is discussed. Formulation-related differences in phenytoin dissolution rates that may result in significantly altered absorption rates should not affect average steady-state levels unless the extent of absorption is altered. More frequent dosing is not necessary to avoid increases in the average steady-state levels when rapidly absorbed phenytoin products are administered, but may be desirable if the required daily dose is high or the individual patient exhibits a narrow therapeutic range for this drug.


Time-dependent kinetics. V: Time course of drug levels during enzyme induction (one-compartment model). Equations were derived to describe the time course of drug levels during auto- and heteroinduction under a variety of input conditions. These equations were based on a pharmacokinetic theory of induction which assumes that metabolic clearance increases exponentially to a maximum value and that the rate of this increase is governed by the degradation rate constant of the induced enzyme (k'). Closed form solutions could be obtained only for intravenous single-dose (case I) and multiple-dose (case IV) administration. For each of the other cases, constant-rate intravenous infusion (case III), oral single-dose administration (case II), and multiple-dose administration (case V), an exact solution (not closed form) and an approximation (closed form) were derived. Two sets of equations were derived for each of the five cases to take into consideration the possibility of a latency term (lambda). Plots of drug amount X (or concentration C) vs. time (t) were constructed. In case I, a log X vs. t plot was convex, the slope increasing with time. In case II, X increased, reached a peak, and decayed as in case I. In case III (lambda greater than 5 ln 2V/Q) C reached a preinduction steady state before decreasing to a lower (induced) steady state. The behavior of C vs. t for cases IV and V was similar to that for case III. Determination of parameters was attempted in case III. Nonlinear least-square fitting of generated data with 3-9% error yielded reasonable estimates of k'.


A priori lithium dosage regimen using population characteristics of pharmacokinetic parameters. The important problem of initiation of long-term lithium treatment is tackled by means of the selection of an a priori dosage regimen based on the presumed efficacy of lithium and absence of toxicity. The pharmacokinetics of Li+ ion is represented by a four-compartment open model including the supposed first-order processes for the release of the active compound from the dosage form and its absorption. Experimental protocols for measurements of serum concentrations and of urinary amounts after single and multiple dosing to healthy volunteers were derived with several oral dosage forms. Estimation of the pharmacokinetic parameters for each subject made it possible to validate the model for the various dosage forms. The interindividual variability of these parameters is taken into account by estimating the characteristics of the statistical distribution for the whole population. A dosage regimen is considered optimum when serum concentration profiles at steady state range from the threshold of efficacy (0.8 mmol/liter) to the threshold of toxicity (2.0 mmol/liter). When the number of daily intakes is fixed, the search for the optimum dose for the whole population is effected by minimizing the expected value of the random variable which characterizes the risks of excursion out of the therapeutic range. By this means universal dosages are shown to be unsatisfactory. However, certain dosage regimens individualized with respect to the renal clearance value of lithium and based on two or three daily intakes can give excellent results even when conventional dosage forms are used.


Drug elimination interactions: analysis using a mathematical model. A mathematical model was developed to analyze the elimination kinetics of drug interactions in the rat. The model is based on physiological blood flow rates and organ weights and includes Michaelis-Menten equations for enzymatic processes which are involved in the elimination of the drug; competitive inhibition interactions are computed for shared pathways. Using data from the single drugs, the model can simulate the results of experiments of the acute warfarin-BSP interactions in rats.


Interaction of phenylbutazone with racemic phenprocoumon and its enantiomers in rats. The interaction of phenylbutazone with the enantiomers and racemic [3H]phenprocoumon was studied in male inbred Wistar-Lewis rats following a single i.v. dose of the three forms of phenprocoumon and chronic oral treatment with phenylbutazone (average plasma concentration of about 60 microgram/ml). Phenylbutazone augmented the anticoagulant effect of R(+), S(-), and R, S(+/-) phenprocoumon to a similar extent. The free fraction of drug in the plasma of the enantiomers and racemic phenprocoumon increased in the presence of phenylbutazone. However, the rate of elimination of total drug from plasma and liver and the distribution between liver and plasma of all three forms of phenprocoumon remained nearly unaffected by phenylbutazone. Thus there is no evidence for a stereoselective drug interaction between phenprocoumon and phenylbutazone. For racemic [oH]phenprocoumon it was possible to follow the kinetics of free drug in plasma and liver along with the time course of anticoagulant activity. In these studies, free drug concentrations in plasma and liver increased during treatment with phenylbutazone, but the elimination rate constant of free racemic phenprocoumon in plasma and liver remained essentially unchanged. Phenylbutazone markedly decreased the volume of distribution referenced to free drug and the clearance of free phenprocoumon (i.e., intrinsic metabolic clearance). Whereas the total (bound and unbound) drug concentration--effect relationship in plasma and liver was shifted to the left in rats treated with phenylbutazone, such shift was not seen in the free drug concentration--response relationship. In conclusion, the increase in the free concentration of phenprocoumon in plasma and liver and the concomitant decrease in the clearance of free drug are the mechanisms responsible for the marked and sustained enhancement of the anticoagulant effect which follows treatment with phenbutazone.


Regional and systemic serum concentrations of 5-fluorouracil after portal and intravenous infusion: an experimental study in dogs. The serum and urinary concentrations of 5-FU after continuous portal and jugular infusion have been followed by means of a highly sensitive microbiological assay method. Our data indicate that more than 90% of 5-FU was eliminated in the liver after continuous portal infusion of 0.625 mg x kg-1 x hr-1, corresponding to a dose of 15 mg x kg-1 x 24 hr-1. Negligible amounts of intact 5-FU were excreted into the bile, and the urinary excretion was only a few percent of the amount infused. The arterial concentration was on average tenfold higher during the continuous jugular infusion than after the continuous portal infusion, indicating that the route of administration has a pronounced effect on the disposition of 5-FU. Twenty-three percent of the jugular dose reached the liver; 77% was degraded by extrahepatic metabolism. Of these, degradation in the prehepatic splanchnic area accounted for 15%.


Nonlinear regression on multiple-dose data. The examples are given to show how Metzler's nonlinear regression program can be used to estimate parameters in a model with multiple dosing. The model of one example is a set of equations involving sums of exponentials, whereas the other model is a set of differential equations reflecting first order absorption and Michaelis-Menten excretion. In both cases no data were given in one of the dosing intervals.


Suspending agent effects on steroid suspension dissolution profiles. Dissolution profiles and particle-size analyses were determined for two lots of prednisolone acetate. The effects of common suspending agents on dissolution and particle-size distributions of these suspensions also were investigated. Lot-to-lot variation in the prednisolone acetate dissolution rate was observed and was apparently related to the percentage of fine particles within the distribution. Carboxymethylcellulose sodium inhibition of prednisolone acetate dissolution occurred with only one lot of raw material and seemed to be related to aggregation of the fine particles. Hydroxypropyl methylcellulose inhibited both prednisolone acetate lots and was observed with or without small particle aggregation. The dissolution variations observed have important implications in suspension formulation.


Corticosteroid determination in skin preparations by a reaction rate method. A reaction rate method for the determination of beta-methasone, betamethasone valerate, triamcinolone acetonide, and fluocinolone acetonide is described. The method is based on a modification of the widely accepted blue tetrazolium reaction. Analysis times of 30--70 sec are required. Relative standard deviations of 0.3--1.9% are obtained, and the analytical working curves are linear. Analysis of pharmaceutical skin preparations by the new method gave results that correlated well with the time-consuming standard equilibrium method. Analysis of betamethasone and betamethasone valerate mixtures by measuring absorbance values at two different times was performed also.


Effect of heparin injection on plasma protein binding of bilirubin and salicylate in rats. Intravenous heparin injection significantly increased the free bilirubin and salicylate fractions in the plasma of rats. This effect occurred within 2 min after injection of 500 U of heparin/kg and lasted for 15--45 min (bilirubin) or for greater than 45 min (salicylate). In vitro addition of heparin to plasma had no quantitatively significant effect on the protein binding of bilirubin and salicylate. The in vivo effect of heparin on protein binding was reversible by treating the plasma with activated charcoal, a procedure known to remove fatty acids from albumin. Since protein binding affects the pharmacokinetic characteristics and the pharmacological activity of drugs, the heparin--drug interaction may have significant clinical implications. Use of heparinized plasma for exchange transfusion in the treatment of neonatal jaundice may be hazardous.


Correlation of urinary excretion with in vitro dissolution using several dissolution methods for hydrochlorothiazide formulations. Four different hydrochlorothiazide formulations were prepared, and cumulative urinary hydrochlorothiazide excretion was determined in a crossover study using six volunteers. A comparison of in vivo results showed that one formulation (Forumulation D) was significantly different from the others at 2, 3, 4, 5, 8, and 14 hr. A dissolution study was conducted on each formulation using the flask, USP basket, and magnetic basket methods at agitation speeds of 50, 100, and 150 rpm. Formulation D was significantly different from other formulations when determined using the USP basket method at 150 rpm and a sampling time of 10 min; the USP basket method at 100 rpm and a sampling time of 100 min; the flask method at 100 rpm and sampling times of 30, 40, 60, and 120 min; and the flask method at 150 rpm and sampling times of 30 and 40 min. Significant in vitro and in vivo correlations were found using a regression analysis and F test. With a correlation coefficient and 95% confidence intervals, it was established that the USP basket method at 150 rpm was the best predictor of urinary hydrochlorothiazide excretion among the dissolution methods tested.


Flocculation of sulfamerazine suspensions by a cationic polymer. Flocculation by a cationic polymer of sulfamerazine suspensions containing a wetting agent was evaluated. Suspensions with sufficient surfactant concentrations to ensure complete wetting were deflocculated. When the anionic surfactant, dioctyl sodium sulfosuccinate, was used as a wetting agent, the suspensions were flocculated over a limited polymer concentration range. Flocculation was attributed to simultaneous interaction of a polymer molecule with more than one particle. At higher polymer concentrations, the particles were covered completely with polymer, leading to repulsion between the particles and deflocculation of the suspensions. The polymer concentration required for flocculation provided evidence for interaction between the anionic surfactant and the cationic polymer. Suspensions containing a nonionic surfactant also were flocculated using various polymer concentrations. When a surfactant mixture was employed in the suspensions, the peak sedimentation volume of flocculated systems and the concentration of polymer at the peak depended on the surfactant mixture composition.


Solid-state acetylation of codeine phosphate by aspirin. A nonsolvolytic (solid-state) acetylation of codeine phosphate in the presence of aspirin to yield acetylcodeine phosphate is reported. GLC assays for the simultaneous determination of aspirin and salicylic acid and codeine and acetylcodeine are described. The apparent heat of activation for codeine phosphate is estimated, and the possible reaction mechanisms are discussed.


Simple epoxide analogs of trichothecans. To define clearly the epoxide grouping role in trichothecan biological activity, a series of hindered epoxides was prepared. They possessed alpha, alpha'-substitution reminiscent of the epoxide environment of the natural products. None of these analogs demonstrated biological activities similar to the natural toxins.


Structure of polyvinylpyrrolidone-iodine (povidone-iodine). Hydrogen triiodide adducts were prepared from N,N-dimethylacetamide, N-alkylpyrrolidone derivatives, and polyvinylpyrrolidone, and their structures were investigated by IR spectra and X-ray structure analyses and compared with the structure of povidone-iodine USP. The results suggest that the iodine in povidone-iodine USP is complexed by the polymer such that a proton is fixed via a short hydrogen bond between two carbonyl groups of two pyrrolidone rings and that a triiodide anion is bound ionically to this cation.


Effects of phenylbutazone, tolbutamide, and clofibric acid on binding of racemic warfarin and its enantiomers to human serum albumin. The effect of phenylbutazone, tolbutamide, and clofibric acid on the binding of racemic warfarin and its enantiomers to human serum albumin was studied by equilibrium dialysis. Warfarin had one primary and two secondary binding sites on the albumin molecule. No difference in binding was detected at the primary binding site; the extent of R(+)-isomer binding at the secondary binding sites was 2.5 times greater than the corresponding S(-)-isomer binding. Phenylbutazone and warfarin appear to compete for the same primary binding site on the albumin molecule. Tolbutamide interferes with the binding of warfarin enantiomers at their secondary sites. Clofibric acid has a less pronounced effect on warfarin binding than does phenylbutazone or tolbutamide.


Catecholamine analogs as potential antitumor agents. The structural requirements for murine P-388 leukemia activity in the dopamine series were investigated. Eight of the 31 analogs evaluated possessed reproducible antitumor activity. The ortho-aromatic hydroxyl groups were required for activity, but the aminoethyl side chain was not crucial since this group could be replaced by methyl or aminomethyl groups with the retention of activity. The lack of activity of O-alkylated and monosubstituted analogs suggests that o-quinone formation may be important for activity, a possibility supported by the observed P-388 activity of 5-hydroxydopamine compared with the inactivity of the 6-hydroxy isomer.


Adsorption of antineoplastic drugs to polyalkylcyanoacrylate nanoparticles and their release in calf serum. Conditions are described for attaching anticancer drugs to polyalkylcyanoacrylate nanoparticles, a new drug delivery system for cells that exhibit endocytic uptake. They are ultrafine, metabolizable, and able to associate with various drugs in a nonspecific manner. Data are given for the in vitro degradation and for drug release from this new drug carrier system.


High-performance liquid chromatographic studies of reaction of hydralazine with biogenic aldehydes and ketones. To understand hydrazone formation in hydralazine metabolism, the reaction of hydralazine with various biogenic aldehydes and ketones (acetone, pyruvic acid, acetoacetic acid, formaldehyde, and acetaldehyde) in pH 7.4 buffer was studied for potential alterations in hydralazine pharmacokinetics secondary to alcoholism and diabetes. The corresponding hydrazones were isolated, and their structures were characterized. High-performance liquid chromatography was used to monitor the reactions. An aqueous solvent reversed-phase liquid chromatographic system was used to separate hydralazine and its derivatives. Reaction of hydralazine with formaldehyde or acetaldehyde produced the corresponding hydrazones. Formation of an s-triazolo ring system yielded the known s-triazolo[3,4-alpha]phthalazine and 3-methyl-s-triazolo[3,4-alpha]phthalazine metabolites, which also were isolated and characterized and suggested nonenzymatic metabolism.


Liquid chromatographic determination of minocycline in human serum. A rapid, specific, and sensitive liquid chromatographic assay for minocycline in human serum is described. The drug and an internal standard (oxytetracycline) were extracted into ethyl acetate from 0.5 ml of buffered serum (pH 6.5). Chromatographic separation was achieved on a 10-micrometer Lichrospher 100 CH 8 column with acetonitrile--citric acid (0.1 M) as the eluent. The column effluent was monitored at 352 nm. The assay was linear up to 3 micrograms/ml with a mean coefficient of variation of 3.3% (n = 6). An extraction recovery of 89.4 +/- 3.2% (mean +/- SD, n = 17) was obtained over the 0.5--2.6 micrograms/ml range. The detection limit averaged 50 ng/ml. A serum concentration-time profile in humans after oral intake is presented.


Sustained drug delivery systems II: Factors affecting release rates from poly(epsilon-caprolactone) and related biodegradable polyesters. The release rates of several steroids from films and capsules of homopolymers and copolymer of epsilon-caprolactone, DL-lactic acid, and glycolic acid were measured in vitro and in vivo for up to 200 days. Relatively constant release rates from capsules (reservoir devices) were observed only under certain conditions. Factors that influence the drug release kinetics were evaluated. Release from poly(epsilon-caprolactone) and poly(epsilon-caprolactone-co-DL-lactic acid) was diffusion controlled. Release from poly(DL-lactic acid-co-glycolic acid) was associated with polymer degradation. Release from poly(DL-lactic acid) was very slow when diffusion controlled.


Antineoplastic agents LXIV: 1,4-Bis(2'-chloroethyl)-1,4-diazabicyclo[2.2.1]heptane dihydrogen dimaleate. The 1,4-bis(2'-chloroethyl)-1,4-diazabicyclo[2.2.1]heptane dication (II) exhibits remarkable antineoplastic activity. Detailed evaluation of several dianion derivatives showed a curative response level against the murine P-388 lymphocytic leukemia, colon 26, CD8F1 mammary, and the Walker 256 carcinosarcoma (rat) tumor systems. In addition, significant cancer chemotherapeutic activity was found against the murine L-1210 lymphoid leukemia, colon 38, and B16 melanocarcinoma tumor systems. The bicyclo dication (II) first was isolated, evaluated, and stored as the diperchlorate derivative (IIa). Because of the promising anticancer activity of IIa, procedures were developed for obtaining other anion derivatives for comparative biological purposes. Several naturally occurring substances were evaluated, and the dihydrogen dimaleate derivative (IIi) obtained by an ion-exchange technique was the most suitable.


Tablet position and basket type effects in spin-filter dissolution device. The effects of stirring and basket placement on tablet dissolution using the previously developed Shah spin-filter device were investigated. Visualization of flow and dissolution patterns was possible by testing nondisintegrating colored tablets. Dissolution experiments were conducted on nondisintegrating double-layered tablets containing salicylic acid as the dissolving layer and ethylcellulose as an inert nondissolving layer. Visual observations revealed that color was drawn more rapidly from the tablet face resting on the bottom of the basket. Dissolution data from multilayered tablets revealed that when the salicylic acid face was resting on the bottom of the basket, the dissolution was appreciably more rapid than when it was facing up in the basket. This phenomenon was found for several stirring speeds.


Rapid compartment- and model-independent estimation of times required to attain various fractions of steady-state plasma level during multiple dosing of drugs obeying superposition principle and having various absorption or infusion kinetics. A new general equation based only on plasma data was derived for rapid estimation of the average plasma level and the mean fraction of the steady-state plasma level attained during any multiple-dosing interval. It can be applied to any complex absorption or infusion kinetics (i.e., is not limited to zero-order or first-order kinetics) for drugs obeying linear disposition kinetic or superposition principles. The time, t, required to reach a certain mean fraction of the steady-state plasma level is equal to the time at which the plasma area from time zero to time t is equal to the same fraction of the plasma area from time zero to infinity (AUC0 leads to infinity) following a single dose. No other pharmacokinetic parameters are necessary.


Determination of ethylene oxide, ethylene chlorohydrin, and ethylene glycol residues in ophthalmic solutions at proposed concentration limits. A GLC method was developed for the determination of ethylene oxide and its two reaction products, ethylene chlorohydrin and ethylene glycol, in ophthalmic solutions at the levels recently proposed by the Food and Drug Administration. The method requires no extractions, sample preparations, or elaborate trapping and concentrating techniques. All three components can be chromatographed on the same spiral glass column packed with a porous polymer absorbent.


Simple and rapid high-pressure liquid chromatographic determination of papaverine in plasma. A rapid and sensitive high-pressure liquid chromatographic (HPLC) assay is described for the quantification of papaverine in plasma. A paired-ion, reversed-phase system was employed with detection at 254 nm. This procedure yielded reproducible results with a sensitivity of 2 ng/ml. Total extraction and quantification time was less than 1 hr. The suitability of this procedure for plasma sample analysis from a bioavailability study was demonstrated.


Competitive inhibition between folic acid and methotrexate for transport carrier in the rat small intestine. Folic acid absorption from the lumen of the rat small intestine in situ obeyed Michaelis--Menten kinetics. The values of Vmax and Km for absorption were 4.63 x 10(-7) M/min and 1.21 x 10(-6) M, respectively. Folic acid and methotrexate were mutual competitive inhibitors of absorption. Their Ki values were 1.28 x 10(-6) and 1.9 x 10(-5) M, respectively.


Metabolic effects of a new hypolipidemic agent, ciprofibrate. Ciprofibrate, a new orally effective hypolipidemic agent like clofibrate, suppressed tyloxapol-induced hypercholesterolemia in rats. Ciprofibrate at 10 mg/kg was effective. Clofibrate required a dosage of 180 mg/kg to suppress the tyloxapol effect. Norepinephrine-induced free fatty acid release was inhibited by clofibrate in rats in accordance with earlier findings. Ciprofibrate and lifibrate differed from clofibrate in that, at hypocholesterolemically effective doses, neither inhibited the hormone sensitive lipase in vivo.


GLC determination of S-2-(3-tert-butylamino-2-hydroxypropoxy)-3-cyanopyridine in human plasma. S-2-(3-tert-Butylamino-2-hydroxypropoxy)-3-cyanopyridine was recovered (approximately 90%) from human plasma and detected by conversion to a diheptafluorobutyryl derivative for electron-capture GLC. A homolog served as an internal standard. The method measures plasma drug concentrations at the 5-ng/ml level and is suitable for plasma analysis from humans who receive a therapeutic oral dose.


Microencapsulation and dissolution parameters of undecenovanillylamide: a potential coyote deterrent. The microencapsulation and dissolution of undecenovanillylamide (I), a potential coyote-aversive agent for use on sheep, were studied. While I has been shown to protect sheep, its short duration of action makes it economically unfeasible. Compound I microcapsules were prepared, and optimum conditions for encapsulation via complex coacervation were determined. Microcapsules that were hardened for 0.5, 1, and 2 hr, as well as I powder, were characterized according to their dissolution. Longer hardening times resulted in slower release, with all encapsulated I forms being released slower than the powder. The dissolution t50 for unencapsulated powder was less than 3 min; for microcapsules hardened for 30 min, the dissolution t50 was 7.3 min; for those hardened 60 min, the t50 was 17.7 min; and for those hardened 120 min, the t50 was 28 min. The encapsulated I would have a longer field life and, therefore, might be a viable economic and ecologic answer to coyote protection for sheep.


Convenient synthesis of N-alkoxymethylbarbituric acids and N-alkoxymethylhydantoins. A simple one-step method for the N-alkoxymethylation of barbituric acids and hydantoins is presented. The compounds are N-methoxymethylated or N-ethoxymethylated using phosphorus pentoxide and dimethoxymethane or diethoxymethane, respectively, in a chlorinated solvent. 1-Methoxymethyl-3-ethyl-5-phenylhydantoin showed significant anticonvulsant activity in the subcutaneous pentylenetetrazol test, while 1,3-bis(methoxymethyl)-5-ethyl-5-(p-tolyl) barbituric acid was inactive.


Electron-capture GLC determination of pseudoephedrine in serum. A GLC assay was developed for pseudoephedrine in serum using 3-methylamino-1-phenyl-1-propanol as an internal standard. After extraction from serum with benzene under alkaline conditions, pseudoephedrine was derivatized with pentafluorobenzyl bromide and quantitated by electron-capture GLC. The method has a detection limit of approximately 0.02 microgram/ml of serum using 1-ml samples.


Comparative pharmacokinetics of coumarin anticoagulants XLIII: Concentration-dependent hepatic uptake of warfarin in rats. The purpose of this study was to determine if hepatic warfarin uptake, which has a major quantitative effect on warfarin distribution in rats, is concentration dependent. Adult male rats received either 0.1 or 1.0 mg of racemic warfarin/kg iv and were killed 6 hr later. With increasing dose, the concentrations of free and total (free plus protein-bound) serum warfarin increased much more than proportionally, and the total warfarin concentration in the liver increased much less than proportionally. The liver to serum total warfarin concentration ratios 6 hr after injection of the 0.1- and 1.0-mg/kg doses were 11.3 +/- 1.7 and 0.814 +/- 0.222, respectively (mean +/- SD, n = 6, p less than 0.001). The ratio of the total drug concentration in the liver to the free drug concentration in serum (mean +/- SD) was 866 +/- 105 in animals that received the 0.1-mg/kg dose and 111 +/- 42 in animals that received the 1.0-mg/kg dose (p less than 0.001). It is concluded that hepatic warfarin uptake decreases with increasing drug concentration and that this may cause the apparent volume of distribution of warfarin to decrease with increasing dose in rats.


A voltage-clamp study of the light response in solitary rods of the tiger salamander. 1. Single, isolated, rod photoreceptors were obtained by enzymatic dissociation of the tiger salamander (Ambystoma tigrinum) retina. These solitary cells retained the morphological features of rods of the intact retina and could be maintained in culture for several days. Solitary cells were penetrated with one or two micropipettes and their electrophysiology was studied by the voltage-clamp technique. 2. Intracellular recording with two micropipettes demonstrated that the inner segment of a solitary rod was effectively isopotential with the outer segment. 3. The time course of the voltage response to a flash resembled that of responses observed in rods in the intact retina. At low light intensities the response reached a peak in approximately 0.7 sec and then slowly declined. At high light intensities the time to peak response decreased and an initial transient arose as the response, after reaching the peak, quickly decreased to a less polarized plateau. 4. The normal voltage response could be compared with the current observed during a voltage clamp. At low light intensities the time course of the current response resembled the time course of the voltage response. When light intensity was increased the time course of the current response differed from the voltage response in that the time to peak amplitude remained relatively constant and an initial transient did not occur. It was possible to predict the current response produced by any intensity of light by using (i) an empirical equation which reproduced the time course of a dim response and (ii) the Michaelis-Menten equation. 5. The time course of the voltage-clamp current produced by a flash was the same at different values of maintained voltage. 6. The maximum amplitude of the voltage-clamp current produced by a flash or step of light was a non-linear function of membrane potential. It was relatively constant within the physiological range, decreased as the membrane potential was moved toward 0 mV, reversed polarity between 0 and 10 mV, and rapidly increased in magnitude as membrane potential was made more positive. Although this current was voltage dependent, no time dependence was evident (recording resolution greater than or equal to 5 msec). 7. Voltage-clamp experiments demonstrated an inward current which slowly developed after a hyperpolarizing voltage step. The effect of this voltage and time dependent current was to reduce, after a delay, the polarization initiated by light.


Acid secretion from the completely isolated blood perfused canine stomach. 1. The canine gastric arterial supply was isolated and perfused by means of an extracorporeal circuit. The gastric venous blood was returned to the dog's venous system. Histamine acid phosphate (20 microgram min-1) infused intra-arterially gave a mean peak acid output of 2.3 m-mole per 10 min. 2. When a plateau of acid secretion was observed, the gastric venous blood was diverted to the oxygenator, by-passing the dog entirely (vascular isolation). This resulted in an immediate decrease in acid output which fell to or near zero by 90 min after isolation. 3. In three dogs, part of a lung was perfused in series with the stomach before total isolation of the gastric vasculature. With histamine stimulation, acid secretion was observed for about 1 hr with a peak acid output of 0.5 m-mole per 10 min during the period of total isolation. 4. Indomethacin (10 mg kg-1) was given to five dogs approximately 1 hr before vascular isolation. After acid secretion reached a plateau (mean peak acid output 2.3 m-mole per 10 minutes), the gastric circulation was isolated by diverting the gastric venous blood to the oxygenator. Acid secretion was maintained for 50 min, after which it gradually declined to reach 30% of the peak value after 2 hr. 5. Indomethacin (10 mg kg-1) and methysergide bimaleate (1 mg) were given I.V. to five dogs approximately 1 hr before vascular isolation. After acid secretion reached a plateau (peak output 3.0 m-mole per 10 min), the gastric circulation was isolated by diverting the gastric venous blood to the oxygenator. The plateau of secretion was maintained for a further 2 hr with no inhibition. 6. Methysergide bimaleate given alone did not prevent the inhibition of secretion caused by the total vascular isolation of the stomach. 7. These results suggest that in the isolated canine stomach preparation naturally occurring inhibitors of gastric acid secretion, which are normally metabolized at least in part in the lungs, accumulate in the circulation and may account for the observed suppression of acid secretion.


Lateral interactions in human cone dark adaptation. 1. The course of cone dark adaptation after exposure to a strong bleaching light depends on the size of the bleached region. Threshold for brief, tiny test flash centred in the bleached region is elevated more, and recovery is retarded by a small bleach. This effect has its parallel in the sensitization effect observed with steady backgrounds. 2. Previous results, that a similar sensitization effect is not observed in rod dark adaptation, are confirmed. 3. This sensitization effect in cone dark adaptation does not transfer binocularly, and is unaffected by pressure blinding during the bleaching exposure. 4. Threshold following a small bleach may be lowered by adding a steady annular background to the region surrounding the bleached patch. Conversely, bleaching the area surrounding a small, steady background can lower threshold for a test flash centred on the background. 5. These interactions between backgrounds and bleaches may be explained if bleaches produce long-lasting signals from neurones in the bleached area, which then lead into a spatially opponent stage of processing. 6. It is likely that the persisting signals come from the cone receptors, since the Bunsen-Roscoe Law (intensity-time reciprocity) holds for small bleaches as well as large, for durations up to about 3 sec.


After-effects of small adapting fields.

After-effects of small adapting fields. 1. Sensitivity to a small test probe in the centre of a small, steady background is less than when the background is large (sensitization). When an equiluminous steady annulus is added to the region surrounding a small background, rod threshold takes several minutes to stabilize at its new, lower level. The after-effects of the small background follow a time course characteristic of cortical adaptation. 2. The sensitivity loss and time course of recovery after intense bleaching lights in the cone system depend markedly on the size of the retinal region bleached, although no such effect is observed in the rod system. If a steady annular surround is added to the region surrounding the bleached patch, threshold falls rapidly to the value it would have after a large-area bleach of the same intensity. 3. The interaction between bleaches and steady surrounds suggests that bleaches produce long-lasting signals in the cone receptors. 4. The different temporal properties of sensitization on rod backgrounds and sensitization after cone bleaches suggest that different mechanisms underlie the two phenomena. 5. In cone vision, if light is added to the area surrounding a small, steady background, the subsequent readjustment takes minutes to complete, as it does in rod vision. But in addition, for cones, a large proportion of the sensitivity loss caused by the small background can be rapidly restored, as it is with cone bleaches. 6. The above results, together with the known absence of sensitization in rod dark adaptation, are consistent with the hypothesis that sensitization occurs at least partly at the retinal level in the cone system, but not (or only weakly) in the rod system, and that there is an additional, probably cortical elevation, common to rod and cone systems, for small backgrounds, but not for small, brief bleaches.


Hypothalamic sensitivity to leukocytic pyrogen of adult and new-born guinea-pigs. 1. Experiments were conducted to localize the hypothalamic site of action of microinjected leucocytic pyrogen and to compare the pyrogenic sensitivity of this locus in adult and new-born guinea-pigs.2. To identify the site reactive to leucocytic pyrogen, bilateral (0.8-1.0 mm from the mid line) injections of 1 microliter were made into conscious adult guinea-pigs via cannulas stereotaxically palced at 0.5 mm intervals and varying depths from the olfactory tegmentum to the mammillary bodies. Injections into the preoptic area produced sharp monophasic fevers with short latencies, whereas injections into circumjacent sites evoked smaller fevers with longer latencies. 3. To assess the ontogeny of the pyrogenic sensitivity of this locus, the febrile response to 1.00, 0.50, and 0.25 microliter leucocytic pyrogen injected bilaterally was compared to 0 to 5-, 6 to 12-, and 13 to 16-day old and in adult guinea-pigs. The minimum pyrogenic dose in both new-born and adult guinea-pigs was 0.25 microliter, but the 0 to 5-day old animals which responded with a fever to this dose were few in number and large in weight; 'small-for age' neonates became hypothermic. 4. The number of febrile animals increased with age; it also could be increased by increasing the dose of leucocytic pyrogen at any age. 5. These results suggest that febrile responsiveness may depend on the stage of development of, presumably, the pyrogen-receptive mechanism. They further imply that the preoptic sites where leucocytic pyrogen acts and thermoafferents are integrated may not be the same, since thermoregulatory capability is fully competent from birth.


The effects of sudden airway hypercapnia on the initiation of exercise hyperpnoea in man. 1. In three healthy individuals, the first breath of cycle ergometer exercise was characterized by increases of minute ventilation (VE) and pulmonary capillary CO2 output (VCO2), with little change of end-tidal PCO2, suggesting a concomitant increase of pulmonary blood flow (Q) and preservation of V/Q status. Functional residual capacity fell, depleting lung gas stores of O2 and CO2. 2. The following hypothesis purporting to account for the initiation of exercise hyperpnoea was examined (Filley, 1976): (a) assuming pulmonary capillary plasma to remain unexposed to carbonic anhydrase, its slow alkalinization consequent upon CO2 exchange causes a more acid plasma to enter the pulmonary veins if Q increases abruptly, as at exercise onset; (b) the fall of pulmonary venous plasma pH stimulates an intrapulmonary chemoreflux to elicit a proportionate hyperpnoea, so preserving arterial isocapnia; (c) the initial hyperpnoea should therefore be abolished if pulmonary capillary VCO2 is suppressed at exercise onset, as the absence of pulmonary capillary plasma alkalinization should sever the postulated intrapulmonary humoral link between Q and VE. 3. In the present study, while abrupt CO2 inhalation (approximately 6% in air) at exercise onset abolished pulmonary capillary VCO2 during the first breath of exercise, the initial hyperpnoea was unaffected. This observation argues against the hypothesis that exercise hyperpnoea is initiated by an intrapulmonary chemoreflex which detects perfusion-related changes in pulmonary venous plasma pH.


The morphology of group Ib afferent fibre collaterals in the spinal cord of the cat. 1. The enzyme horseradish peroxidase (HRP) was injected into single Ib muscle afferent fibres in anaesthetized cats. Subsequently, histochemistry allowed the morphology of the axons and their collaterals in the lumbosacral spinal cord to be determined. 2. Eleven Ib axons were stained, seven from lateral gastrocneminus-soleus, one from medial gastrocnemius and three from muscles innervated by the posterior tibial nerve. Ten of the axons were traced into the dorsal roots and all but one (from the posterior tibial nerve) bifurcated upon entering the cord. Between 5.1 and 9.9 mm of each axon was stained and the fibres gave off eighty-four collaterals at intervals of 100-2300 micron, at an average spacing of about 900 micron. The spacing between collaterals on the (finer) descending axon branches was generally less than the intervals between collaterals on ascending branches. 3. All Ib collaterals had a characteristic morphology. The collaterals coursed cranially on a direct path through the dorsal horn to lamina IV or V before branching. They arborized widely in the intermediate region, mainly in lamina VI and in the dorsal part of lamina VII. Occasionally, less extensive arborizations were seen more dorsally in lamina IV and V. The rostro-caudal extent of individual collateral arborizations was limited to 200-400 micron and there was no overlap between adjacent collaterals. Each terminal arborization gave rise to 56-384 boutons, mainly of them 'en passant' type. 4. The results are discussed in relation to previous anatomical and electrophysiological studies.


The role of vasopressin in blood pressure regulation immediately following acute haemorrhage in the rat. 1. The possible pressor effect of vasopressin immediately after acute haemorrhage has been studied using anaesthetized Brattleboro rats with diabetes insipidus and rats of the Long Evans parent strain.2. A blood loss of 0.5% of the body weight caused a significant decrease in mean arterial blood pressure, measured 10 min later, in Brattleboro rats, whereas this degree of haemorrhage was non-hypotensive in the control Long Evans rats. Following subsequent blood losses (each of 0.5% of the body weight), mean arterial blood pressure in Brattleboro rats was always significantly lower than in Long Evans rats.3. While no antidiuretic activity was at any time found in the plasma of Brattleboro rats, haemorrhages greater than 1% of the body weight were associated with marked increases in plasma arginine vasopressin (AVP) of Long Evans rats.4. When Brattleboro and Long Evans rats were subjected to a single haemorrhage of 2% of the body weight, the immediate decrease in arterial blood pressure was similar in the two groups. However, 5 and 10 min after the haemorrhage the arterial blood pressure was significantly higher in the Long Evans rats. When vasopressin was infused into Brattleboro rats so that plasma levels of the hormone approached those found in Long Evans rats, the mean arterial blood pressure 0, 5 and 10 min after haemorrhage was similar to that in the Long Evans animals.5. It is concluded that in the anaesthetized rat, vasopressin plays an important role in the regulation of arterial blood pressure during the period immediately following acute haemorrhage.


Responses of visual cortical cells to periodic and non-periodic stimuli. 1. The activity of neurones of the visual cortex (area 17) has been recorded in anaesthetized cats in response to gratings of different profile and to single light and dark bars. 2. At very low spatial frequencies, outside the frequency response range to sinusoidal gratings, the response to square-wave drifting gratings is obtainable from a combination of the response to the single bars of the grating presented in isolation. At higher spatial frequencies this is no longer true. 3. At very low spatial frequencies the responses to square-wave gratings and to missing-fundamental gratings (obtained by subtraction from the square-wave grating of its fundamental gratings (obtained by subtraction from the square-wave grating of its fundamental harmonic) are very similar. 4. At spatial frequencies near the peak of the spatial frequency tuning curve of the cell, the responses to square-wave grating and to sinusoidal gratings are very similar. At these spatial frequencies the response to the missing-fundamental grating is practically zero. 5. At spatial frequencies lower than that of best sensitivity for the cell, the response to square-wave gratings is correlated with the 1st and 3rd harmonic of the stimulus. 6. We conclude that at very low spatial frequencies of the grating the response of cortical cells is correlated with the light or dark edges (or light or dark bars) of the stimulus, because the edges contain high frequencies within the range of sensitivity of the cells. At higher spatial frequencies the results are interpreted best by assuming that cortical cells respond to the harmonics of the visual periodic stimulus. 7. When a background of dynamic visual noise is added to increase the spontaneous discharge of simple cells, their response to visual stimuli becomes linear or quasi-linear. The stimuli could be either single bars or gratings.


The effect of carbon dioxide on the tonic and the rhythmic discharges of expiratory bulbospinal neurones. 1. Extracellular micro-electrodes were used to measure the responses of expiratory bulbospinal neurones to CO2 in anaesthetized, paralyzed cats, ventilated with O2. Simultaneous measurements were made of phrenic nerve and intercostal nerve filament discharges. 2. Hypocapnia produced tonic activity in some of the expiratory neurones and in expiratory filaments but rendered the phrenic and inspiratory filaments silent. 3. A graded excitatory effect of CO2 on tonic activity of both the neurones and the filaments was seen which progressed smoothly and continuously to rhythmic activity as CO2 was increased and to zero as CO2 was decreased. 4. Increases in blood pressure produced effects which were opposite to those produced by CO2, and which had a faster time course. 5. The CO2 response curves of those units showing tonic activity were indistinguishable from the CO2 response curves of those which did not. 6. A mid line lesion in the medulla interrupted inspiratory activity, converting activity of expiratory bulbospinal neurones from periodic to ionic firing patterns. 7. Following such lesions the CO2 threshold for rhythmic excitation of medullary neurones was elevated and the slopes of their CO2 response curves were reduced. 8. These findings fully confirm the hypothesis put forward by Bainton, Kirkwood & Sears (1978b) that bulbospinal respiratory neurones convey both tonic and rhythmic excitation to spinal respiratory motoneurones and that the rhythmic excitation of expiratory muscles derives from a period inhibition of expiratory bulbospinal neurones which are subjected to a tonic CO2 dependent excitation which is continuously variable over the physiological range.


Properties of single central Ia afferent fibres projecting to motoneurones. 1. Electrical potentials in the cat lumbosacral spinal cord evoked by the action of single medial gastrocnemius Ia afferent fibres were recorded using low impedance, bevelled micropipette electrodes and the spike triggered averaging technique. 2. Axonal potentials from the Ia fibres recorded extracellularly appeared as brief triphasic predominantly negative potentials. 3. Terminal potentials recorded in regions of Ia afferent termination appeared as brief diphasic positive-negative waves, often with additional wavelets. 4. Focal synaptic potentials, recorded extracellularly in regions of the medial gastrocnemius Ia afferent termination, appeared as slow (about 10 msec duration) negative potentials following terminal potentials. 5. Excitatory post-synaptic potentials, recorded intracellularly in Ia target cells of the medial gastrocnemius, appeared as slow (about 10 msec duration) positive potentials following terminal potentials. 6. Analysis of the temporal progression of these potentials through the spinal cord allowed calculations of the Ia conduction velocity in the dorsal funiculus stem axon (50-60 m/sec), in major collateral branches (8-19 m/sec) and in terminal branches (0.2-1.0 m/sec). 7. The number of major collateral branches (nine or fewer) and their spacing along the spinal cord (1071 micron mean value) were determined by analysing the extent of the triceps surae motoneurone column. 8. The structural and functional properties of medial gastrocnemius Ia afferent fibres are discussed in relation to recent single fibre anatomical data and the present single fibre electrophysiological data.


Properties of single fibre excitatory post-synaptic potentials in triceps surae motoneurones. 1. E.p.s.p.s and terminal potentials (t.p.s) produced by the action of single medial gastrocnemius Ia afferent fibres were examined with intracellular microelectrodes in cat triceps surae motoneurones. 2. Simple terminal potentials (t.p.s) appeared as positive-negative diphasic waves with a single positive peak. Shape indices of excitatory post-synaptic potentials (e.p.s.p.s) recorded in conjunction with simple t.p.s indicate that these e.p.s.p.s were generated at an electrotonically confined compartment on the motoneurone somadendritic membrane. 3. Compound t.p.s. were similar ones, except that they had two or more positive peaks. Shape indices of e.p.s.p.s recorded in conjunction with compound t.p.s indicate that these e.p.s.p.s were generated at two or more electrotonically separate compartments. 4. E.p.s.p. latency and post-synaptic electrotonic delay were determined for a group of single fibre e.p.s.p.s with simple t.p.s. The shortest recorded latency was 0.26 msec. By subtracting estimated electrotonic delay, the shortest synaptic delay obtained for a medial gastrocnemius Ia single fibre e.p.s.p. was 0.17 msec. 5. The finding of a significant synaptic delay supports the hypothesis that the Ia-motoneurone synapse is a chemically mediated synapse.


Isopotentiality and an optical determination of series resistance in Limulus ventral photoreceptors. 1. Photoreceptor somas in the ventral rudimentary eye of Limulus polyphemus were impaled with three micropipettes. Two micropipettes were connected in a voltage-clamp circuit and the cells were stimulated by brief flashes. The third micropipette did not measure any significant deviations from the 'clamped' voltage during responses to the flashes, in several geometries of electrode placement, even for very bright flashes. Therefore using the described techniques there is no evidence for spatial non-uniformity of intracellular voltage in the soma of these photoreceptors. 2. A voltage-sensitive dye was used to monitor light-induced changes in membrane voltage while intracellular voltage was held clamped by a feed-back circuit. With a known series resistance connected between the bath and ground the dye recorded a light-induced change in membrane voltage. When there was no added series resistance, the light-induced change was smaller and often undetectable. From these data the naturally occurring series resistance was calculated to be less than or equal to 30 k omega. 3. From these measurements, as well as from calculations for a model spherical cell, we conclude that membrane potential can be controlled to within 2 mV using our micropipette 'point clamp' methods, for all but the brightest stimuli.


Saturation of the response to light in Limulus ventral photoreceptor. 1. Limulus ventral photoreceptor cells were voltage-clamped with two intracellular micro-electrodes. The light-induced membrane current was recorded for brief stimuli. From observation of discrete waves (quantum bumps) at low stimulus energies and the early receptor potential at high energies, the stimulus energy was related to the number of rhodopsin molecules photosiomerized. 2. In the dark-adapted cell the log (peak light-induced current) reached almost its maximum value when about 10(3) of the 10(9) rhodopsin molecules in the cell were photoisomerized. 3. The magnitude of the maximum light-induced current was not significantly altered after iontophoresis of EGTA into the cell. This treatment is known to counteract the Ca2+-mediated reduction in sensitivity to light. 4. Current pulses were injected into the unclamped cell during the receptor potential. The form of the voltage deflexion (a step followed by a curve) suggested that the effective electrical equivalent of the cell was a membrane capacitance in parallel with a light-dependent membrane resistance, Rm, and in series with another, light-invariant, resistance, Rs. Rs ranged from 7 to 24 k omega (five cells). 5. During a receptor potential the ratio Rm/Rs was never observed to fall below 1.7 no matter how intense the light flash. Hence, it is concluded that the light-induced current saturated essentially because Rm fell to a minimum value. 6. Charging curves gave a value for the capacitance, and hence the area, of the surface membrane. From this it was estimated that there were 10(5)-10(6) microvilli on each cell. 7. These results show that the light-induced increase in membrane conductance in a dark-adapted cell comes close to its maximum value when the number of photoisomerizations is about 1/1000 the total number of microvilli. We suggest that absorption of a photon by a rhodopsin molecule in a microvillus causes an increase in membrane conductance on parts of the surface membrane beyond that microvillus. 8. In the presence of moderate background illumination the sensitivity to non-saturating superimposed flashes was greatly decreased (e.g. by 10(3) while the saturating light-induced current was only slightly decreased (e.g. by 15%). At higher background intensities the saturating light-induced current was further decreased (e.g., with a background that photoisomerized 10(6.25) molecules per second the saturating light-induced current was reduced by 47%).


Internal effects of divalent cations on potassium permeability in molluscan neurones. 1. Electrophoretic injection of Ca ions into Aplysia pace-maker neurones activates an outward current, carried primarily by K ions, whose magnitude is determined by the intensity and duration of the injection current, the position of the injection electrode within the cell and the holding potential. 2. The efflux of K ions measured with an extracellular K sensitive electrode is a linear function of the Ca activated outward current and disappears at its reversal potential. 3. The outward current decays exponentially with an early and late phase. The early but not the late phase is temperature dependent with a Q10 of about 3-5. 4. Of the divalent cations which activate the outward current, Ca is the most effective followed by Cd, Hg, Sr, Mn and Fe. Injections of Ba, Co, Cu, Mg, Ni and Zn are ineffective. 5. Low temperatures or prolonged injection of Cd or Hg, increase the amplitude of the outward current activated by Ca. 6. Prolonged injection of Ba inhibits the Ca activated outward current and reduces substantially all currents carried by K ions. 7. It is concluded that the effectiveness of a divalent cation in activating the K current is, in part, related to its ionic radius, and that the site of activation can accommodate ionic radii between about 0.76 and 1.13 A.


Pigment transformation and electrical responses in retinula cells of drone, Apis mellifera male. 1. Receptor potentials in honeybee drone retinula cells were recorded with intracellular micro-electrodes in the dorsal part of the superfused retina. The light stimuli were sufficiently weak that the response amplitude was proportional to the intensity. 2. Responses to stimuli of different wave-lengths, although of different amplitude, all had the same time course. 3. The maximal sensitivity in all the cells recorded from was to a wave-length between 450 and 460 nm. 4. Microspectrophotometry showed the presence of a pigment with two stable states, interconvertible by light, absorbing maximally at 445 nm (rhodopsin) and 505 nm (metarhodopsin). 5. There was a good match between the absorption spectrum of rhodopsin and the spectral sensitivity of retinula cells. 6. Transformation of a large fraction of rhodopsin to metarhodopsin by light reduced the sensitivity of the retinula cell but did not alter the shape of the relative spectral sensitivity curve or the time course of the responses. 7. It is concluded that for weak lights the receptor potential is determined only by the number of rhodopsin molecules that absorb photons: neither the presence of metarhodopsin nor its phototransformation to rhodopsin produces a detectable effect.


Epithelial transport pathways of rat colon determined in vivo by impulse response analysis. 1. A method is described for studying transepithelial pathways for the movement of different solutes and water. Using  the blood and the secretory curves of changing tracer activity following an intravenous bolus, the rate of transit of molecules together with their impulse response functions, which reflect the transfer processes can be examined. 2. Movements of Na, Cl, I, urea and water from blood to lumen across rat colonic epithelium were all consistent with simple diffusion through a paracellular route. Most of the secreted K, however, passed through a K selective route associated with a significant K epithelial pool. 3. Adding cyanide to the luminal solution caused a reversible fall of transepithelial potential difference associated with changes in the impulse response functions of water, urea and K indicating reduction of the restriction on diffusion. Cellular K content was unaffected. 4. K entered the bulk of the epithelial cellular K almost exclusively from the blood side. A small epithelial K pool, identified by studies with a miniature GM counter, had kinetic characteristics like those of the K selective pathway observed in the studies of impulse response functions.


Ionic conductances of membranes in ciliated and deciliated Paramecium. 1. Paramecium caudatum was deciliated with ethanol. The ionic conductance of the membrane was investigated with constant current, voltage clamp and mechanical stimuli. 2. The resting potential was not modified by the removal of the cilia. The dependence of the resting potential on the extracellular concentrations of Ca and K was the same in deciliated and control cells. 3. The input resistance in deciliated and ciliated cells increased after the ethanol treatment. 4. The membrane capacitance decreased to 48% after deciliation, suggesting that the ciliary surface area is equal to the somatic surface area. 5. Deciliation completely removed the regenerative response (graded action potential) elicited by depolarizing current pulses or mechanical stimuli. 6. Deciliated cells retained the depolarizing and hyperpolarizing mechanoreceptor responses. 7. Voltage-clamp experiments demonstrated the loss of the early inward current in deciliated cells; it was restored during ciliary regeneration. Steady-state current-voltage relationships were unchanged by deciliation. 8. The time courses of the recovery of the membrane capacitance and of the early inward current were similar, suggesting that the number of voltage-sensitive Ca channels is proportional to the ciliary membrane area. 9. We conclude that the voltage-sensitive Ca channels reside in the ciliary membrane (in confirmation of Dunlap, 1976; Ogura & Takahashi, 1976), while mechanoreceptor channels, rectifier channels and resting conductances are localized in the somatic membrane.


Membrane potential, chloride exchange, and chloride conductance in Ehrlich mouse ascites tumour cells. 1. The steady-state tracer exchange flux of chloride was measured at 10-150 mM external chloride concentration, substituting either lactate or sucrose for chloride. The chloride flux saturates in both cases with a K 1/2 about 50 and 15 mM, respectively. 2. The inhibitory effect of other monovalent anions on the chloride transport was investigated by measuring the 36Cl- efflux into media where either bromide, nitrate, or thiocyanate had been substituted for part of the chloride. The sequence of increasing affinity for the chloride transport system was found to be: Br- less than Cl- less than SCN- = NO3-. 3. The chloride steady-state exchange flux in the presence of nitrate can be described by Michaelis-Menten kinetics with nitrate as a competitive inhibitor of the chloride flux. 4. The apparent activation energy (EA) was determined to be 67 +/- 6.2 kJ/mole, and was constant between 7 and 38 degrees C. 5. The membrane potential (Vm) was measured as a function of the concentration of external K+, substituting K+ for Na+. The transference number of K+ (tK) was estimated from the slope of Vm vs. log10 (K+)e, and tCl and tNa were calculated, neglecting current carried by ions other than Cl-, K+, and Na+. The diffusional net flux of K+ was calculated from the steady-state exchange flux of 42K+, assuming the flux ratio equation to be valid. From this value the K+ conductance and the Na+ and Cl- conductances were calculated. The experiments showed that GCl, GNa, and GK are all about 14 muS/cm2. 6. The net (conductive) chloride permeability derived from the chloride conductance was 4 x 10(-8) cm/sec compared with the apparent permeability of 6 x 10(-7) cm/sec as calculated from the chloride tracer exchange flux. These data suggest that about 95% of the chloride transport is mediated by an electrically silent exchange diffusion. 7. Comparable effects of phloretin (0.25 mM) on the net (conductive) permeability and the apparent permeability to chloride (about 80% inhibition) may indicate that the chloride exchange and conductance pathways are not completely separate and distinct modes of transport, but may involve common elements. The reduced chloride permeability in the presence of phloretin is estimated to be two orders of magnitude larger than the ground permeability of the cell membrane.


[State of the art and prospects on the use of radiofrequency and microwave hyperthermia in cancer treatment (author's transl)]. The use of microwave hyperthermia for cancer treatment is dealt with, first analyzing the present state of the art, second from a prospective viewpoint. Follow current topics are considered: a) biological data from experiments in vitro and of animals; b) fundamental therapeutic modalities: total body hyperthermia, local hyperthermia; c) technological problems: irradiation frequency, applicators, dosimetry (non-interfering probes, microwave radiometers); d) results of preliminary clinical investigations. Prospects refer to following topics: a) technological: improvement or design of systems for producing and controlling hyperthermia; b) fundamental: models, phantoms and postoperative specimens; dielectric and thermal properties on tissues; part of the vascularization; c) clinical: treatment procedures, long-term therapeutic trials (exclusive or combined hyperthermia, cancerous and healthy tissues).


[Treatment of tumors by local hyperthermia in urology and gynecology (author's transl)]. An experimental study by the authors, on the effects of local-regional hyperthermia on bladder B.N.A. induced carcinoma of the dog has been going on since 1966. The authors have observed complete disappearance in the animals of the mucosa and sub-mucosa neoplasia, even after 6 years from the date of treatment. The sterilization of the neoplastic surface was checked by several histological sections observations on two excised bladders. As the results showed no negative secondary effects, the authors have started, since 1973, a clinical study of hyperthermia treatment of the bladder, vagina, female urethra and rectum stump carcinoma. Heat was obtained and introduced into the bladder by leans of an apparatus specifically designed for this purpose; the double-circuit terminal probe supplies a thermocouple controlled constant temperature. We are submitting the cases treated together with a discussion on results obtained and problems faced.


[Experimental study of the relative biological effectiveness (R.B.E.) of a fast neutron beam (author's transl)]. A preliminary experimentation has been done with the synchrocyclotron (28 MeV deuton) in Lyon. The different characteristics of the beam have been determined through various dosimetric measurements. C57Bl mice have been irradiated with single doses and fractionated schedules (5 sessions). 7 day survival has been analysed. Comparison of neutron and cobalt gamma ray shows a R.B.E. of 1.95 for single dose and 2.5 for five fractions. This work is a confirmation of the effect of fractionation on the R.B.E. of the neutrons.


[Endocurietherapy in cancer of the bladder. A new technique by implant of 192iridium with Cyponil tubes (author's transl)]. The Authors propose a new technique of interstitial implant in cancer of the bladder based on the direct implant of 192 Iridium with Cyponil tubes. The tubes are roughly 2 metres in length with a radioactive wire in one third of the tube length. These wires are kept in a lead container during the complete implantation of the tube. After opening the bladder the uncharged part of the tube is passed through the inner walls by means of surgical needles. The number of the tubes depends on the size of the tumour and they are placed parallel to each other. They are then drawn until the radioactive part covers the tumour site. One end of the Cyponil tube is then pulled through the urethra and stitched to the skin, the other end is drawn through the surgical incision and attached to the abdominal skin. A Folley catheter is put on the bladder is such a way as to keep it blown up. It is then sutured. A radiography is carried out so as to determine the dosage. At the end of the therapy the stitches of the Cyponil tubes are cut and are removed by extraction.


[Use of rapid C.T. scanners in renal affections (author's transl)]. The advantages obtained by the use of the new rapid scanners have made computer tomography the method of choice for the investigation of kidney lesions. In fact, the benefits of the second generation of scanners, which were already of excellent quality, have been even furthur increased by the use of the rapid scanners which can be used to study the vascularization of renal lesions, for which traditional nephrotomography has been employed for a long period.


[Inversion of the right hemi-diaphragm associated with abundant pleural effusion (author's transl)]. The radiological appearance and the physiopathological consequences of the phenomenon of the inversion of the diaphragm on the left side associated with abundant pleural effusion, were studied by Felson and his school as early as 1965. Echotomography reveals that the phenomenon occurs on the right side in exactly the same way.


[Discitis in small children (author's transl)]. Discitis was diagnosed in 5 children under 3 years of age, the initial clinical manifestations being difficulty in walking and abdominal pains in one case. Diagnosis was not made before periods varying from 8 days to 3 months, and no etiological basis for the disease was discovered. Pinching of the disc was always present in the first radiographic image, and the vertebral plate was ill-defined in 3 cases. Repeat radiological examinations were carried out in 3 children after 6 months, 2 and 5 years respectively. There was partial restauration of the disc space in 2 cases; the last one presented signs of late collapse after early recuperation. Early perilesional bone sclerosis was noted in 2 cases, while it was posterior and late in one child. There were no sequelae (fusion, vertebra plana, scoliosis). Two investigations are essential if a disc lesion is suspected: -- radiography of the spinal column, even if there are no disturbances in walking or abdominal pains. -- scintigraphy with technitium 99, which is the only means of establishing an early diagnosis.


[Chronic unilateral obstruction to pulmonary venous return. A study on 6 cases and review of the published literature (author's transl)]. The authors describe 6 cases of unilateral obstruction to pulmonary venous return: two cases of Halasz syndrome and postoperative obstruction of the reimplanted collector vein, one patient with Halasz syndrome and spontaneous obstruction of the vein in the form of a scimitar, one case of neoplastic invasion of the atrium-vein junction, one with unilateral absence of the right intra- and extraparenchymatous regions of the pulmonary veins, and lastly, a case of juxta-auricular interruption in the right pulmonary veins. The anatomy and physiopathology of the collateral venous pathways are briefly described, together with the relations between systemic arterial hypervascularization and pulmonary venous obstruction. The authors then review the radiological, clinical, and angiohemodynamic features of the unilateral venous obstruction syndrome, and conclude that precise diagnosis of venous occlusion, its location, and its tolerance are essential for deciding the therapeutic measures required.


[Value of profile aortography for the topographic diagnosis of intraperitoneal masses: a report on 5 cases (author's transl)]. The superior mesenteric artery was found to be displaced posteriorly in 5 patients with intraperitoneal masses. In 3 cases, the mass was a mesenteric tumor, and in the 2 other cases a tumor arising from the retroperitoneal area which had grown into the mesentery. The authors emphasize, therefore, the value of defining the position of the superior mesenteric artery in the sagittal plane for the topographic diagnosis of intraperitoneal masses. This investigation does not, however, eliminate the possibility of a retroperitoneal origin of the tumoral mass.


[The value of arteriography in the diagnosis and treatment of post-traumatic secondary impotence (author's transl)]. Angiographic investigations in 9 patients with partial or total post-traumatic secondary impotence present for several years, confirmed the presence of traumatic vascular lesions involving, in nearly all cases, the artery of the penis or its branches (cavernous and bulbar arteries). Selective angiography of the pudendal arteries was able to guide treatment in 5 of these patients. Epigastrocavernous anastomoses, according to the microsurgical procedure developed by Michal, were performed with excellent results in 3 cases.


[Contribution of panoramic tomography in exploration of maxillary sinuses (author's transl)]. Panoramic tomography (orthopantomography) is useful in exploration of maxillary sinuses, specially of its floor and its connection with teeth alveoles. Interest of this examination in the diagnosis of sinusian cyst of polypus, apical teeth cyst growing in the sinus, fistula from mouth to sinus, repeating sinusitis by dental infectious focus, sinusian stranger corps and finally, in the schedule or surveillance of the extension of sinus maxillary cancer to the posterior wall, particularly to the pterygomaxillary fossae.


[Arthropneumotomography in recurrent dislocations and subluxations of the shoulder. Methods, results, and indications in 45 cases (author's transl)]. The authors describe the results of arthropneumotomography in 45 patients with recurrent dislocations or subluxations of the shoulder. The method used is given in detail and the need for excellent quality glenoid profile sections, as described by Bernageau, is emphasized. The results are analyzed for bone lesions, capsuloligamentary lesions, and intra-articular foreign bodies. The two latter conditions are specifically demonstrated by arthropneumotomography. These results are then described radiological and surgical correlations, and the indications defined. Arthropneumotomography is therefore of value when a decision is to be taken as to the need for operation.


[Arterial thrombosis induced by direct electric current. Clinical applications (author's transl)]. Authors have demonstrated that it is possible to induce arterial thrombosis by applying direct electric current (10 mA -V). By the use of this method several thromboses were formed in the rabbit. This technique is now well established and the first clinical applications on human arteries give rise to considerable hopes, since it is simple, reliable, and much less dangerous than other types of embolisation. Experiments are being done to apply this technique to aneurysms.


[Severe urinary tract and cutaneous lesions after umbilical cord artery puncture and direct injection of hypertonic sodium bicarbonate to the newborn in the delivery room. Report of three cases (author's transl)]. Three cases of necrotizing and calcifying lesions of low urinary tract, buttock and adjacent perineum are reported. These lesions have been induced by direct syringe injection into an umbilical artery of 42% sodium bicarbonate solution at the dose of 5 to 6 ml/kg of body weight. Radiographic examinations are very important to study the urinary tract lesions. These have been surgically controlled in two cases. The follow up ranges from 10 to 21 1/2 months. On the bladder initial necrotizing lesions are followed by calcification and parietal retraction. These bladder lesions induce a more or less important ureterohydronephrosis. To these constant lesions are variably associated urethral calcifications and stenosis, distal ureter calcifications. These lesions seem to be related to the sodium bicarbonate hyperosmolality, to the injection conditions, and to the local hemodynamic features.


[Idiopathic juvenile osteoporosis (author's transl)]. A young girl aged 13 years was hospitalized for metaphyseal fractures of both knees, and was found to have idiopathic juvenile osteoporosis which followed a favourable course over a period of one year. The authors recall the difficulties encountered in diagnosing this rare affection as no specific biological changes have been demonstrated. The criteria used are: the age of the patient, the disease usually becoming evident in the prepuberty period, the contrast between the very severe osteoporosis noted on radiological examination and the perfect general condtion of the patient, the negative biological tests results, and finally, the spontaneous repair of the osteoporosis in one to four years.


[Post-traumatic resorption of a vertebral body in a patient with spondylarthritis (author's transl)]. Rheumatoid pelvispondylitis in the lumbar spine can be the cause of a fracture of a vertebral body following usually minimal trauma. If no treatment is applied, a pseudo-arthrosis with severe bone resorption can occur. The whole vertebral body was affected in this way in the case reported.


Acute superior mesenteric artery occlusion: problems of pre-operative diagnosis. I report five cases of occlusion of the superior mesenteric artery from one general practice; four of these occurred in one year.THE COMMON CLINICAL FEATURES WERE: acute diarrhoea and vomiting in elderly persons (all over 70) with abdominal pain and distension and shock. All had a previous history of auricular fibrillation and cardiac failure and past episodes of clinical arterial occlusive disorders had been experienced by four. Each diagnosis was confirmed at operation and all five patients died. It is important for general practitioners to recognize this syndrome.


Primary medical care in Bhutan.

Primary medical care in Bhutan. I describe a systematic method of planning primary medical services for Bhutan in the light of the needs of the community and coping with current problems which include an infant mortality rate of 153. Objectives were defined which included decentralizing decision taking as much as possible by establishing relatively independent health units consisting of a team of three staff caring for about 10,000 people.I believe that the principle of adapting health services to meet the needs of the local community is equally valid in the United Kingdom.


Counselling in the European Economic Community. Counselling is becoming increasingly important in modern general practice and the relationship between counsellors and general practitioners varies in different places and in different countries. Through a Stanning Overseas Fellowship I had the opportunity of examining this relationship in several countries in Europe in order to compare and contrast arrangements.


An evaluation of direct access radiology in general practice. An analysis of the use of direct access to radiology by 71 general practitioners in Scotland is described and is based on 2,596 x-ray examinations in 2,409 patients during a period of six months. Almost half of the patients had to travel more than five miles for their examinations, but time lost in travelling was a much less important factor than the interval elapsing before the requested examination was completed. Nearly one third waited at least two weeks. Referral for diagnosis was by far the commonest reason and direct access was estimated to save 270 hospital outpatient appointments per month. I believe that general practitioners under-use rather than abuse radiology, which might be extended by a selective system of appointments.


Persistent lone atrial fibrillation--its prognosis after clinical diagnosis. Eighty-three patients whose atrial fibrillation appeared to be permanent and the sole cardiac abnormality at the time of diagnosis were followed for one to 19 years (mean 7.5 years). None suffered systemic embolism. Three died, none of cardiac disease. Sinus rhythm returned in seven. Another six developed features suggestive of other heart disease. In the remaining 67, the initial diagnosis of persistent lone atrial fibrillation remained tenable and they remained well.The medium-term prognosis for patients with this disorder seems good.


Prescribing procrastination.

Prescribing procrastination. In his everyday work the family physician sees many patients whose problems have been diagnosed but for whom postponement of an active treatment plan is indicated. The physician must therefore prescribe procrastination in a carefully planned way. I describe some ideas and practical methods for doing this.


Social workers in primary health care: the general practitioner's viewpoint. The success of general practitioner/social worker collaboration in primary care depends largely on how the doctors perceive the attachment.We examined the replies of a group of general practitioners to a series of questions about such an attachment. Although the collaboration may lead to more work for the doctors, it was much appreciated by them.


Polymorphonuclear leukocyte secretory and metabolic responses to immunoglobulin aggregates. Biologic activities of soluble immunoglobulin G (IgG) aggregates, insoluble IgG aggregates and precipitates resulting from addition of serum containing rheumatoid factor (RF) to soluble or insoluble IgG aggregates were examined in terms of lysosomal enzyme release and/or stimulation of the hexose monophosphate pathway (HMP) in human polymorphonuclear leukocytes (PMN). Granular enzyme release and HMP stimulation were consistently greater for insoluble aggregates and complexes than for soluble aggregates and controls. One role of IgM rheumatoid factor may be its ability to convert relatively inactive soluble IgG aggregates into insoluble IgG-RF complexes capable of stimulating selective release of PMN lysosomal enzymes.


Correlative studies of lymphocyte transformation and plasma protein levels in ankylosing spondylitis. Lymphocyte transformation was studied in 24 patients with ankylosing spondylitis (AS), 21 with rheumatoid arthritis (RA) and 23 control subjects (CS). Enhanced transformation was found in response to phytohemagglutinin (PHA) (p less than 0.01) and human aggregated gamma globulin (p less than 0.025), but not to inulin, for AS patients. Correlation coefficients between the concentrations of each of 8 AS plasma proteins and PHA-induced lymphocyte transformation in autologous plasma showed significance only for C-reactive protein (CRP). However, co-culture experiments with PHA in autologous and allogeneic (AB) plasma, and in CRP-devoid AB serum showed no specific enhancing effect by AS plasma on lymphocyte responses. Although these studied demonstrate that AS is frequently characterized by enhanced in vitro transformation to T lymphocyte dependent mitogens, this response does not appear to be related to the known immunoregulatory properties of CRP.