Palmar arteriography in acronecrosis.

Palmar arteriography in acronecrosis. Palmar arteriography in patients with acronecrosis complicating collagen vascular disease demonstrated multiple occlusions and stenoses which were most severe in the proper digital arteries. Involvement was prevalent at points of manual stress, i.e., adjacent to metacarpal-phalangeal and interphalangeal joints. An additional observation was the presence of incomplete superficial and deep palmar arches in all instances, a finding which diametrically contrasts with anatomical studies purporting to demonstrate complete palmar arches in 80% of the normal population.


Development of contrast media idiosyncrasy in the dog. A laboratory dog exhibited an altered response to injections of sodium iothalamate. This idiosyncratic response may have been predicated on an earlier series of iothalamate injections. The overt manifestations of the reactions in this dog were vomiting, hypotension, and hyperreflexia. Significant changes in several electrolyte components and serum complement levels were noted when the dog reacted to the contrast material.


Axillary lymphadenopathy simulating an anterior mediastinal mass on the lateral chest roentgenogram. The radiographic impression of an anterior mediastinal mass on the lateral chest roentgenogram must be confirmed by the postero-anterior film, oblique views, or tomograms to avoid inappropriate diagnostic procedures or erroneous staging of malignant disease. Physical examination will readily demonstrate enlarged axillary lymph nodes mimicking an anterior mediastinal mass.


Pressure dressings and postarteriographic care of the femoral puncture site. Patient dissatisfaction with prolonged bed rest and the discomfort caused by pressure dressings led to the following evaluation. Alternate application of pressure dressings and band-aids to femoral artery puncture sites was performed in 754 arteriographic examinations. The application of pressure dressings for 16-24 hours, especially in hypertensive patients, was found to be justified by a significant reduction in delayed bleeding requiring further medical attention. A minimum application time of 8 hours is supported because all instances of delayed bleeding occurred within 8 hours of the procedure. Arterial thrombosis is not affected by the use of pressure dressings. The rationale for recommendation of bed rest is largely anecdotal and is supported by almost all experienced angiographers responding to our questionnaire.


Analysis of activity in A and C fibres under mechanical and thermal stimulation of the skin receptor field. A conduction velocity spectrum in nerve fibres of 0.15 to 90 m/sec was found by means of electrophysiological methods of analysis and computer-aided processing of experimental data. A greater portion of the non-myelinated fibres in the cutaneous nerve proved to be afferent. Patterns of afferent impulse flows entering the central nervous system are determined under various mechanical and thermal stimulations of cat's cutaneous receptive field. Differences of these flows are considered to be the reasons for various sensation modalities. The mechanism of cutaneous mechanoreceptor excitation under temperature stimuli is discussed. Special attention is paid to the contraction of cutaneous collagen under cooling. Experimental data on the change of cutaneous mechanical properties and the electrophysiological changes corroborating the thermomechanical hypothesis of receptor excitation are given.


Termination of pregnancy in cases of fetal death in utero by intravenous prostaglandin F2alpha. Delivery was induced by an intravenous infusion of prostaglandin F2alpha (PGF2alpha) in gradually increasing doses in 30 consecutive cases of fetal death in utero after the 28th week of gestation. Twenty patients delivered during the first day of prostaglandin administration, 9 on the second day, and 1 patient not until the third day of infusion. It is concluded, that intravenous PGF2alpha appears to be superior to oxytocin in termination of pregnancy under these conditions.


Luteolytic activity of a synthetic prostaglandin and PGF2alpha in heifers. Two experiments involving 44 cycling heifers were conducted to evaluate the luteolytic activity of a synthetic prostaglandin, AY 24366, and PGF2alpha. Activity was assessed by the decline in progesterone level of peripheral blood and occurrence of estrus. Progesterone concentrations of jugular blood plasma were quantified by radioimmunoassay. In the first experiment, 36 heifers were treated during diestrus with AY 24366 (A-10mg intrauterine, B-30mg intramuscular and C-60mg im) or with PGF2alpha (D-5mg iu, E-15mg im and F-30mg im). Mean progesterone 0, 24 and 48 hours after treatment were A-6.33, 5.55 and 5.06; B-6.35, 2.79 and 3.92; C-5.23, 2.69 and 3.91; D-5.19, 1.50 and 1.51; E-4.69, 0.85 and 0.61; F-6.66, 0.80 and 0.48 ng/ml. Standing estrus was observed in 1, 1, 1, 4, 5 and 6 females in groups A, B, C, D, E and F respectively within 72 hours of treatment. PGF2alpha resulted in significantly (P less than 0.01) lower progesterone at 24 and 48 hours than AY 24366. However, in administration of the latter did significantly (P less than 0.05) lower progesterone at 24 hours. In the second trial six heifers were treated with either 120 or 180mg of AY 24366 im on day 12 of the cycle. Mean progesterone declined from 3.84 to 2.12 ng/ml (P less than 0.01) by 6 hours and to 1.59 ng/ml by 12 hours. Thereafter the decline was gradual and reached a level of 0.65 ng/ml at 72 hours. All six heifers showed standing estrus at 78 +/-2 hours and were inseminated. Two in each group conceived. Doses of 15mg PGF2alpha and 120mg AY 24366 were effective in causing luteal regression, however, the latter caused respiratory discomfort for 5 to 10 minutes post treatment.


Menstrual induction with the PGF2alpha-analogue ICI 81008. "Menstrual Induction" (MI) has been studied in 79 volunteers, using the therapeutic principle of "PG-Impact". The PGF2alpha analogue: ICI 81008 was administered under strictly aseptic precautions into the uterine cavity during the 4th week of pregnancy. The treatment catheter (inserted through the cervical canal) delivered a single dose of only 100-200 mug ICI 81008 during the pilot study with this new drug. When it was established that the side effects were acceptable, this moderately effective dose was increased at first to 200-300 mug and eventually to 400 mug. At the 400 mug dose level, 29 (76%) of the 38 study patients had complete and 8 (21%) incomplete abortions, while 1 (3%) failed to bleed. Those 9 women who had incomplete abortions or failed to abort were curetted. In comparison with PGF2alpha (428 cases) and PGE2 (114 cases), ICI 81008 (38 cases at the 400 mug level) provoked lesser side effects, excepting the transient increase in blood pressure. All patients (whose intrauterine pressure was measured) responded to the ICI 81008-impact with rapidly developing high level uterine contracture. Plasma progesterone decreased significantly if treatment was successful and insignificantly in cases of treatment failure. In current studies, the efficacy of the vaginal delivery system of ICI 81008 is examined.


High performance liquid chromotography of prostaglandins: biological applications. Two procedures are described for separation and purification of prostaglandins by high performance liquid chromatography. Both systems show excellent resolution of PGA2, PGE2 and PGF2a. Peak definition on the micro-particle silicic acid system is particularly good with the PGs appearing in 2-3 ml of organs effluent. Studies on reproducibility showed that PGE2 and PGE2a could be recovered with a retention volume of 54.2+/-0.76 ml and 64+/-0.6 ml, respectively (n=7, mean +/-50) with good recovery. The column can be run in about one hour and can be regenerated indefinitely (greater than 200 times). The degree of purification is compatible with analysis by gas chromatography-mass spectrometry. Examples showing the application of this chromatographic method to human seminal fluid, human renal tissue, platelet rich plasma and human urine samples indicate that it makes possible analysis of these samples even at low levels.


Altered levels of PGF in cat spinal cord tissue following traumatic injury. Previous studies by others indicated that PGs were present in brain, spinal cord, and c.s.f. of several mammalian species. In the present study we compared levels of PGE and PGF  by R.I.A. in spinal cord tissue from traumatized cats and cats pretreated with indomethacin prior to trauma to those of baseline and sham operated controls in order to assess for the first time, to our knowledge, whether meaningful changes in levels of PGE and PGF could be detected which might shed new light on the etiology of spinal cord trauma. Levels of PGF (nanograms/gram wet wt) in the cord segment immediately adjacent to the point of trauma were 8.05 +/- 1.50, and 13.13 +/- 1.38 for baseline and sham operated cats respectively. Spinal trauma led to more than a 100% increase in PGF levels to 29.26 +/- 3.58. Although pretreatment with indomethacin 30 min prior to trauma gave the expected blockade of the PGF response to trauma, a measurable level of PGF (2.55 +/- 0.17) was found in the cord after indomethacin. Cord levels of PGF declined after 3 hr in both sham operated and traumatized animals. PGF was maximally stimulated by trauma during the first 3 hr with little effect at 72 hr. Although carefully examined, PGE levels in cat spinal cord appeared to be virtually unaffected by trauma. These findings clearly demonstrate for the first time that traumatic injury to the spinal cord is accompanied by marked increases in PG levels at the site of trauma, and that the observed elevation in PGF in response to trauma can be blocked by indomethacin in vivo. Whether PGF changes are causally related to the etiology of spinal cord trauma, or merely represent a manifestation of PG release as a result of non-specific tissue injury, remains to be seen.


Prostaglandin synthesis does not mediate the pulmonary vasodilatory effect of acetylcholine. We wondered if inhibition of hypoxic pulmonary vasoconstriction by acetylcholine was mediated by prostaglandin synthesis. In 5 calves at a simulated altitude of 4,570 m, acetylcholine (10 mug/kg/min) decreased mean pulmonary arterial pressure and total pulmonary resistance by 24 +/- 2 and 35 +/- 3% before and by 21 +/- 2 and 27 +/- 4% after the administration of meclofenamate (2 mg/kg). Since there was no difference in the effect of acetylcholine before and after meclofenamate, it was concluded that pulmonary vasodilation by activation of muscarinic receptors was not dependent on prostaglandin synthesis.


Aspirin and exercise-induced asthma.

Aspirin and exercise-induced asthma. In four subjects with exercise-induced asthma, aspirin and placebo were administered prior to exercise in a double blind study. Pulmonary function tests did not reveal any difference between the response after aspirin or placebo. We conclude that in these four subjects aspirin did not prevent the bronchoconstrictor response. This might suggest that prostaglandins have no significant role in exercise-induced asthma.


Relative biological activity of certain prostaglandins and their enantiomers. A series of mirror image (ent) forms of prostaglandins F2 and E2 have been compared for potency in a hamster antifertility test. In the PGF2 series, ent-compounds surveyed had less potency than corresponding natural structures. For the PGE2 series, 11alpha-(15S)-ent-PGE2 methyl ester was 10-fold more potent than PGE2. Altering the C-9 hydroxy configuration in the PGF2 series from the natural alpha to beta decreased potency dramatically for compounds tested.


[Thiol groups of chicken liver LDH (author's transl)]. Crystallized chicken liver H4 lactatedehydrogenase with PCBM and DTNB, proved to have sic thiol groups per enzyme molecule. Sulphydryl groups seemed necessary for activity since the enzyme became inactive when the groups were blocked by PCMB, DTNB or by Zn (II), Cu (II) or Hg (II). LDH inhibited by Hg (II) recovered its activity after treatment with beta-mercaptoentanol. LDH reversible inactivation, caused by PCMB, was partially impeded by NAD, NADH hand L-lactate but inactivation caused by DTNB was impeded in any way by coenzymes or substrates. PCMB is a competitive inhibitor with the coenzymes but is non-competitive with the substrates whereas DTNB is a competitive inhibitor with NADH or L-lactate. Kinetic studies of the DTNB inactivation suggest the possible formation of a DTNB-LDH-NADH complex. The formation of LDH-NADH and LDH-NAD pyruvate inactive complexes have been detected by U.V. absorbancy measurements. Such inactive complexes have equally been observed experimenting with the PCMB of Hg (II) previously treated enzyme. The results showed that these essential sulphydryl groups are not involved in th attaching of coenzymes or substrates to the chicken liver LDH molecule, but they seem to suggest the participation of --SH groups during the reversible hydrogen transfer between NADH and pyruvate.


[Pharmacological reactivity in cricetus aureus uterus (author's transl)]. The motility of the isolated Cricetus auratus uterus was studied and compared to that of other species. Oxitocyn, epinephrine, norepinephrine, histamine, 5-hydroxy-tryptamine and acetylcholine were used as spasmogen agents. There was not contractil response with epinephrine or nor-epinephrine. Histamine reduced basal tonus. There was contraction with acetylcholine, oxytocin and 5-hydroxy-tryptamine. Cricetus auratus uterus appeared more sensitive when the contraction was registered by the isometric method. No taquifilaxy was produced by 5-hydroxy-tryptamine, as opposed to such effect in rat uterus. The Cricetus auratus uterus has, therefore, shown similar reactivity to that of rat, but different from rabbit and guinea-pig.


[Kinetics of renin reaction in rat plasma (author's transl)]. Important kinetic aspects of renin reaction were studied in order to evaluate the parameters that regulate the formation rate of angiotensin I. This rate decreased throughout the incubation period of normal rat plasma and it showed a linear increase  when plasma was incubated with renin-substrate. When renin was added to normal rat plasma a plateau in the angiotensin I formation rate occurred after 4-6 hours. When plasma samples containing increasing amounts of renin-substrate were incubated, the velocity of their reaction increased in proportion to the renin-substrate concentration. Under these incubation conditions, the reaction between endogenous renin and renin-substrate in normal rat plasma, proved to be a first kinetic order with respect to the substrate.


Electron microscopic evidence for phagocytic properties of human peripheral mononuclear cells cultured with PHA. The time course of the ultrastructural changes induced in human peripheral mononuclear cells, when cultured with PHA, has been studied. In addition to findings common to many mitotic cells, such as an increase in nuclear and nucleolar size, the presence of free polyribosomes, glycogen and lipid globules in the cytoplasma, and a high number of mitochondria, agglutinating properties due to PHA per se were observed in the first 12 hours. At 72 hours certain cells developed phagocytic-like properties, i.e. they were able to incorporate both material from the extracellular compartment and syngeneic cells. These results are discussed suggesting the possible presence of macrophages in culture or the ability of activated T cells to express it.


[Parasympathetic control of secretion of pancreatic juice in the rabbit (author's transl)]. The secretion of pancreatic juice in response to stimulation of the vagus nerves in the neck, and to injection of parasympathomimetic drugs, was studied in anesthetized rabbits. Vagal stimulation caused a marked increase of protein content in pancreatic juice, and also a small increase in flow of juice, highly variable from one amimal to another, preceded by a short period of inhibition. Atropine supressed vagal effect on protein concentration, but failed to abolish the flow response. Injection of parasympathomimetic drugs closely imitated the results of vagal stimulation, with the difference that secretory action was fully abolished by atropine. The possibility that effects the parasympathetic stimulation on the flow of juice were secondary to vasodilatation, was discussed. The obtained data were compared with those described for other mammalian species, and the conclusion was reached that rabbit behaves like carnivora rather than herbivora.


Validation of a heterologous radioimmunoassay for the determination of rat thyrotrophic hormone. A heterologous RIA system is described for the determination of TSH in rat plasma. The antibody was obtained by us in guinea-pigs and directed against bovine-TSH (B-TSH). It was chosen from several antisera as the one showing the greatest potency in vivo against rat TSH, using the McKenzie bioassay. Two different antigens were tried for radioiodination: B-TSH (B-TSH) and a purified mouse tumour TSH  (M-TSH). The choice of labeled antigen proved to be critical. It was not possible to develop a reliable RIA with B-TSH. Using M-TSH, however, a RIA was developed which is sensitive enough to detect differences between normal and lower than normal plasma TSH levels. The reproducibility, sensitivity and specificity of the RIA are described, as well as several procedures which shorten the time spent on a given assay, and at the same time decrease inter and intra-assay variations. Some of the results obtained with experimental plasmas were compared to the in vivo potency of the samples in the McKenzie bioassay. The results obtained with the present RIA have also been validated physiologically by carrying out the determinations on plasmas obtained from rats submitted to situations known to decrease (hypophysectomy, treatment with thyroid hormones, ether anaesthesia) or increase (injection of TRH, thyroidectomy, treatment with goitrogens) circulating TSH levels. The circulating TSH levels of normal rats found with the present RIA compare well with values obtained with the homologous immunoreactants available from NIAMDD at NIH (U.S.A.).


Ferritin intestinal absorption.

Ferritin intestinal absorption. Ferritin as a source of iron was consiered. A good iron absorption rate appears in normal rats with an in vivo absorption technique. The same absorption appears in iron-deficient animals. The iron stored in intestinal wall is lower in anemic rats than in normal ones, suggesting a higher draw of iron from lumen to blood.


[LDH and structural analogues of pyruvate (author's transl)]. Pyruvate related compounds have been tested for their active or inhibitory properties on LDH. Special structure features were needed for compounds to be bound to the enzyme active site. Pyruvate and the LDH molecule were bound by the interaction of the carboxyl group or its ester derivative, with the enzyme. Ethyl pyruvate seemed to behave as a substrate of the enzyme whereas acetophenone, ethyl acetoacetate and beta-oxoglutarate did not act as substrates or inhibitors of LDH. Phenyl pyruvate, alpha-oxoglutarate and L-mandelate are not substrates but inhibitors of the LDH. It seems that a structure having a carbonyl group in the alpha-position to the carboxyl is required for the binding of a compound to the LDH molecule. Glyoxylate alpha-oxobutyrate and alpha-oxovalerianate appear to be worse LDH substrates than pyruvate itself. This seems to suggest that the shortening or the extension of the pyruvate aliphatic chain induces a decrease of the affinity of the enzyme towards their substrate homologues.


The incorporation of hydrophobic protein receptors and artificial lipid membranes. The mechanism of chemical synaptic transmission implies: 1) the existence of a specific protein receptor at the postsynaptic membrane, and 2) the interaction between the transmitter released and the receptor, thus producing a change in ionic permeability. Previous studies from our laboratory have shown that special hydrophobic proteins extracted from postsynpatic membranes of different tissues showed a high affinity binding for the different pharmacological agents. The present paper describes experiments in which different hydrophobic protein binding acetylcholine, noradrenaline, gamma-aminobutyric acid, and glutamate were incorporated into artificial lipid membranes, similar to those first described by Mueller et al. (19). The effect of the different pharmacological agents was tested under experimental conditions of voltage clamp and the d.c. current changes measured. The results were then compared for the different lipid-protein membranes employed during the steady state and during transient conductance changes. The specificity of the responses indicate that artificial lipid membranes containing these hydrophobic proteins from electroplax, myocardium, spleen capsule and shrimp muscle can be used as a model to study pharmacologic receptors.


Control of ion movement by cardiac sarcolemma. The cation affinity sequence based on 45Ca displacement from neonatal rat heart tissue culture cells was La greater than Cd greater than Zn greater than Mn greater than Mg. This sequence correlated with the rate at which these ions diminished contractile tension in neonatal rat papillary muscles. In adult rat interventricular septa elevated extracellular Mg diminished tension development concomitant with a decrease in 45Ca influx. The results support the hypothesis that these cations interfere with contraction by occupying sarcolemmal sites ordinarily reserved for calcium or by interfering with transmembrane Ca movements, both of which are crucial for tension development. The data of Bockman et al. (2) provides further support for this hypothesis. Elevated extracellular Mg reduced potassium exchange by 30% in adult rat interventricular septa but had no effect on 42K EXCHANGE IN CONTROL RABBIT INterventricular septa. Elevated extracellular Mg did inhibit the net 42K loss induced by digitalis glycoside without affecting tension development or glycoside inhibition of 42K influx in the rabbit heart. High Mg also attenuated the increase in 42K exchange produced by elevated extracellular potassium. These data demonstrate that glycoside inotropy is not dependent on potassium loss from myocardium but are consistent with the hypothesis that increased intracellular sodium mediates glycoside inotropy. A model for the effects of Mg in rat and rabbit heart is presented.


Correlation between changes in endogenous catecholamine release from the heart and various physiological responses in anesthetized dogs. Correlations between the concentration of endogenous catecholamines in coronary sinus blood and various physiological responses to adrenergic stimulation were studied in anesthetized dogs. Plasma catecholamine levels both in coronary sinus and aortic blood were measured by means of a modification of the radiometric-enzymatic assay for tissue catecholamines, and found to be 0.769 +/- 0.110(S.E.) and 0.972 +/-0.127(S.E.) ng/ml, respectively, under basal conditions. Circulating catecholamine levels increased after the intracoronary injection of 6-hydroxydopamine, which has an indirect sympathomimetic action. Both the increment in catecholamine release from the heart and the intensity of physiological response were dose-related. A frequency-dependent increase in coronary sinus blood catecholamine levels occurred during right cardioaccelerator nerve stimulation. Maximum values were observed with a stimulation frequency of 10 Hz, at which maximum physiological responses were obtained. A highly significant correlation was found between endogenous catecholamine levels in coronary sinus blood and the dp/dt of left ventricular pressure (r = 0.750, p less than 0.001), as well as mean coronary blood flow (r =0.706, p less than 0.001). The present preparation may prove to be a reliable means of studying the role of the sympathetic system in regulating cardiac function.


Metabolic alterations following chemical sympathectomy with 6-hydroxydopamine in the rat. Until recently the role of the sympathetic nervous system on intermediary metabolism has been difficult to study because of the lack of efficient methods of producing generalized sympathectomy. Various metabolic parameters were measured 24 hr, 72 hr, and 1 week after chemical sympathectomy produced by a single intravenous injection of 6-hydroxydopamine (100 mg/kg) in rats. All animals were fasted 16 hr previous to all measurements. A marked increase was found in blood glucose levels in 6-OH-DA-treated animals. Serum free fatty acids (FFA) were 2 1/2 times higher 24 hr after sympathectomy than in control animals, but returned to normal values thereafter. The glycogen content of the liver was 10 times greater in treated animals 24 hr after 6-OH-DA, whereas cardiac glycogen was more than doubled 72 hr after sympathectomy. In contrast, glycogen content of skeletal muscle was only slightly but insignificantly increased. Immunoreactive insulin levels were also increased by 70 percent in sympathectomized animals after 24 hr, but returned to normal values thereafter. These results indicate an important alteration of carbohydrate and lipid metabolism after chemical sympathectomy, thus supporting a role of the sympathetic nervous system in their regulation.


Valinomycin inhibition of the inward slow current of cardiac muscle. Valinomycin (10(-6) M), a K+ ionophore and uncoupler of oxidative phosphorylation, produced pronounced shortening of the action potential plateau in young (3 day) and old (15-19 day) embryonic chick hearts and isolated perfused guinea pig hearts. The rate of rise of the action potential was usually not affected. Dimethylsulfoxide (DMSO) (2 percent), The vehicle for valinomycin, did not cause plateau shortening. In chick hearts, diminution of the plateau by valinomycin at 10(-6) M usually occurred by 1 hr; larger doses produced prominent effects within 15 min. Young embryonic hearts were more resistant to valinomycin, and 20x10(-6) M for 1-2 hr was necessary to produce a significant diminution in plateau. Several agents were able to partially relengthen the plateau shortened by valinomycin. In both young and old hearts, the resting potential was not increased by valinomycin, even though young hearts have a low resting potential because of a low K+ conductance (gK). In guinea pig, 10(-6) M valinomycin markedly shortened the plateau within 5-10 min. Contractions were abolished, i.e., the hearts became electromechanically uncoupled. When hearts were perfused with 27 mM K+ to depolarize the cells to about -40 mV to inactivate fast Na+ channels, catecholamines or methylxanthines rapidly induced slowly rising (about 10 V/sec), overshooting, plateau-like responses with accompanying contractions. Valinomycin rapidly (within 2-5 min) abolished these slow responses and contractions. Hearts perfused with 10(-6) M valinomycin or 10(-5) dinitrophenol became nearly entirely depleted of ATP within 2-10 min. These results suggest that valinomycin blocks the slow inward current indirectly through ATP depletion, the slow cation channels requiring metabolic energy. The possibility that resting gK or kinetics of changes in gK during the plateau is also affected by valinomycin cannot be excluded.


The effect of digoxin antibody on the washout of tritiated digoxin and its inotropic effect from perfused rabbit hearts. The reversal of digoxin effects by digoxin antibody (Ab) may be mediated by at least two mechanisms. First, the Ab may simply decrease the concentration of free digoxin in the perfusing medium, or second, the Ab may dislodge digoxin from its receptor. To pursue this problem, rabbit hearts were perfused for 20 min with Krebs-Henseleit solution (K-H) followed by a 30-min perfusion with [3H] digoxin in concentrations of 10(-7), 5x10(-7), and 10(-6) M. The hearts were then washed out with K-H alone or with K-H containing Ab. During washout the effluent was collected at 30-sec intervals and the concentration of [3H] digoxin measured in each sample. Washout was continued until the positive inotropic effect of digoxin had returned to its previous level. The [3H] digoxin washout curves were analyzed on the basis of statistical criteria and yielded three exponential components. During Ab washout the half-times t1/2 of these components were 0-25 +/- 0.07, 1.70 +/- 0.28, and 19.5 +/- 6.9 min, while during K-H washout the values were 0.28 +/- 0.02, 1.49 +/- 0.22, and 11.8 +/- 2.7. The decay of the inotropic effect of digoxin was similar during both washout conditions. The results indicate that the apparent tissue to perfusate concentration gradient for the washout of [3H] digoxin was not increased by Ab...


On the mechanisms underlying digitalis toxicity in cardiac Purkinje fibers. The different mechanisms by which digitalis enhances pacemaker automaticity in canine Purkinje fibers has been studied under different conditions. Transmembrane potentials of quiescent, spontaneously active, or electrically driven fibers were recorded in the presence and absence of strophanthidin (10(-5)-10(-7) M). In quiescent fibers, strophanthidin caused the membrane potential to depolarize and to develop oscillations of progressively larger magnitude which were followed by spontaneous activity. In spontaneously active preparations strophanthidin enhanced the slope of diastolic depolarization and therefore the rate of discharge. In both cases, there was no evidence of oscillations during diastolic depolarization. A steepening of diastolic depolarizations without superimposed oscillations (and eventually also followed by spontaneous activity) was observed in preparations driven electrically at very slow rates. However, in fibers driven at faster rates (30/min or more) in the presence of ouabain, oscillations developed during diastolic depolarization. These oscillations were frequency dependent in two respects: 1) at slower rates the oscillations remained constant during the drive, the actual magnitude being proportional to the driving rate; 2) at rate of 60/min or more, the oscillations increased in size with each successive beat. Fast rhythms were initiated by a progressive acceleration of the pacemaker potential or abruptly by an extrasystole. When spontaneous activity ceased, the membrane increased slowly toward the control value. We conclude that digitalis increases the frequency of discharge of Purkinje fibers 1) by enhancing diastolic depolarization when the rate of discharge is slow; 2) by developing a new current which modifies diastolic depolarization when diastole is sufficiently short; and 3) by means of the potassium plateau current when the rate of spontaneous discharge is fast. Whether one or more of these mechanisms are operational in affecting Purkinje fiber automaticity depends critically on the rate of discharge of the fibers.


Effects of ouabain and norepinephrine on the mechanical performance of the normal and failing heart of the myopathic hamster. The effects of ouabain and norepinephrine on the mechanical efficiency of the normal and failing heart of the myopathic Syrian hamster were studied in a modified Langendorff preparation. Ouabain administration to the normal and failing heart caused a significant increase in heart work and energy utilization per beat with no significant change in the mechanical efficinecy of either heart. Norepinephrine caused a significant increase in heart work, energy utilization, and mechanical efficiency of the normal and failing heart. It was concluded that the isolated perfused hamster heart from normal and myopathic hamsters could provide a new model for the demonstration of the effect of cardiotonic agents on the mechanical performance of the heart.


Glucose and palmitate uptake in the myocardium of isolated hearts from adrenalectomized cats. Hearts from chronically adrenalectomized (ADX) cats deprived of any steroid support for 9-12 days were isolated and perfused in a Langendorff apparatus at a constant pressure of 95 mm Hg. The perfusion medium was Krebs-Henseleit buffer with either 10 mM glucose or 0.4 mM palmitate complexed to 3 percent albumin. Labeled 14C substrate was used and the transient rate of glucose and palmitate uptake was measured. Oxygen consumption and [14C] palmitate incorporation into CO2, and heart lipids were also measured. ADX hearts showed an enhanced glucose uptake rate compared with controls, 65 +/- 11.3 mumoles/gm to 16.2 +/- 6. However, the qO2 was not significantly different from control hearts. Palmitate uptake, O2 consumption, and 14CO2 were significantly lower in ADX hearts perfused with fatty acid as the energy substrate. Fatty acid uptake decreased from 9.7 +/- 1.0 to 3.6 +/- 1.1 and lipid fractions in the heart showed significant decreases in [14C] palmitate incorporated into triglycerides (p less than 0.001) and monoglycerides (p less than 0.01). The ADX heart does not appear to have any impairment to glucose uptake but does show an impairment to fatty acid uptake. Because the heart uses lipid as the primary energy source, the impairment probably is not the primary factor responsible for cardiac failure in adrenal insufficiency because of its capability of using other available substrates for energy.


Radiation-induced enzyme efflux from rat heart: sedentary animals. Serum levels of lactate dehydrogenase, creatine kinase, and glutamate oxaloacetate transaminase show initial elevations within 12 hr of exposure to 2,000 rads of gamma-radiation to the thoracic region of rats. Significant decreases in heart muscle homogenate levels of these enzymes parallel initial elevations in the serum and may suggest that enhanced leakage of enzymes is a consequence of radiation injury to heart muscle. Insignificant alterations in mitochondrial glutamate oxaloacetate transaminase levels after exposure indicate that in vivo injury to the mitochondria from therapeutic levels of gamma-radiation is questionable. The results support the contention that ionizing radiation instigates alterations in the dynamic permeability of membranes, allowing leakage of biologically active material out of the injured cell.


Effects of ischemia and reperfusion on myocardial uptake of tritiated digoxin. The effect of coronary reperfusion on the uptake of cardiac glycosides by ischemic myocardium was studied in 17 open chested dogs undergoing anterior wall infarction produced by snaring confluent branches of the left coronary system. Epicardial electrograms delineated ischemic zones of S-T elevation, border, and nonischemic zones. Animals were reperfused by snare release 1, 2, and 6 hr after occlusion. After 15 min of reperfusion, 1.0 mg of [3H] digoxin was given intravenously, and 2 hr later the hearts were excised and endocardial (endo) and epicardial (epi) samples from each zone were analyzed for [3H] digoxin concentration. In five dogs occluded for 1 hr and reperfused, [3H] digoxin uptake was comparable in endo and epi layers of all three zones. In six dogs reperfused after 2 hr of occlusion, mean (+/-S.E.) [3H] digoxin concentrations (nanograms per gm) were significantly reduced by 54 percent in endo (111 +/-18) and 35 percent in epi (151 +/- 23) layers of the ischemic zone as compared with the mean nonischemic concentration (endo249 +/- 34; epi 239 +/- 34). Border zone endo and epi [3H] digoxin uptake was reduced by 21 and 17 percent, respectively. In six dogs reperfused after 6 hr of occlusion, [3H] digoxin uptake in the ischemic zone was markedly reduced by 85 percent in endo (34 +/- 4) and 60 percent in epi (86 +/- 12) layers as compared with the nonischemic concentration (endo 232 +/- 19; epi 217 +/- 15). Border zone uptake was decreased by 54 percent in endo and 38 percent in epi regions. We conclude that coronary reperfusion between 2 and 6 hr of coronary occlusion is associated with markedly reduced myocardial digoxin uptake, more pronounced in subendocardial regions of ischemic tissue. This alteration in digoxin binding by reperfused ischemic myocardium is consistent with ischemia-induced structural or functional alterations in the putative digitalis receptor, (Na++K+)-ATPase.


Effects of calcium-free perfusion on excitation-contraction coupling in heart and skeletal muscle. Interventricular septa and semimembranosus accessorius muscles (SMA) from the guinea pig and frog gastrocnemius (FG) muscles were vascularly perfused and isolated for mechanical and radioisotope flux measurements. Since calcium deprivation causes progressive electrical inexcitability, 100 muM La was included in all calcium-free solutions (0-Ca, 100-La) to stabilize the membrane. Perfusion of ventricular septa with such solutions resulted in tension (P) and dP/dt declines with half-times (t 1/2) = 11 sec, similar to the most rapid phase of 45Ca efflux. In contrast, the major component of tension decline during 0-Ca, 100-La perfusion of the SMA and FG muscles was much slower (t 1/2 =33 min). The rate of the slow component of 45Ca efflux from the SMA and FG muscles was essentially identical with the rate of the major tension decline. Significant tension (10-16 percent) was still present in these perfused skeletal muscles after 1-2 hr of 0-Ca, 100-La perfusion. Subsequent addition of La (200 muM total La) did not change the slope of P decline significantly for an additional 30-45 min. Addition of up to 2 mM EGTA after 30 min 0-Ca perfusion (calculated extracellular [Ca2+] less than 3x10(-9) M) altered but slightly the rate of P decline. These experiments emphasize the difference in the source of contractile Ca in heart and skeletal muscle and make it unlikely that there is a physiological "trigger" Ca for excitation-contraction (E-C) coupling in these muscles.


Drugs and punished responding VI: body weight as a determinant of drug effects. Pigeons were rewarded with grain for pecking a key under a fixed-interval schedule of food presentation. After responding stabilized, each key-peck produced a 3.5 mA electric shock, about 50 msec in duration. Dose-effect curves for pentobarbital, d-amphetamine and chlordiazepoxide on punished responding were determined in these pigeons when their body weights were adjusted to 70%, 90% or 100% of their free-feeding weights. The lower the body weight, the higher the rate of punished responding before drugs were given. Pentobarbital increased punished responding in all three body weights, but it produced the largest increases in punished responding over the widest dose range when the body weight was maintained at 90% of the free-feeding weight. Chlordiazepoxide also tended to produce rate increases at all three body weights, but d-amphetamine increased the rate only when the birds were maintained at 100% of their free-feeding weights.


Absence of collagen stimulating factors for L929 cells in granulation tissue extracts. We have attempted to find collagen synthesis stimulating activity in polyvinyl sponge granulation tissue extracts and inflammatory fluid. The cells studied in culture were mouse L929 cells grown in monolayers. A prior study by another group reported such factors to be present in healing wound extracts and in extracts of CHHl3 injured liver. We have been unable to find such stimulating activity for L929 cells in granuloma tissue fluid. In addition we have examined the procedures used by the prior group and have found major problems in their methodology which are discussed below.


Anticoagulant activity of a naphthoquinone analog of vitamin K and an inhibitor of coenzyme Q10- enzyme systems. Synthetic 2-hydroxy-3-h-dodecylmercapto-1,4-naphthoquinone is an analog of both vitamin K1 and coenzyme Q10. This naphthoquinone analog is an effective inhibitor of coenzyme Q10-enzymes of mammalian mitochondria, which are components of electron transfer mechanisms of respiration and coupled oxidative phosphorylation. This analog increased the prothrombin time in rats when it was administered orally or parenterally. Vitamin K1 reversed the prothrombin time increase, but that form of coenzyme Q, hexahydrocoenzyme Q4, which has the same phytyl side chain as vitamin K1, did not reverse the increase, constituting the biological differentiation between vitamin K and coenzyem Q. Two benzoquinone analogs of coenzyme Q10, 5-n-octadecylmercapto-2,3-dimethoxy-1,4-benzoquinone and 5-beta-naphthylmercapto-2,3-dimethoxy-1,4-benzoquinone, the latter being a strong inhibitor of coenzyme Q10-enzymes, did not increase the prothrombin time under comparable conditions.


Antigenicity of inactivated swine influenza virus concentrated by centrifugation. Swine influenza virus grown in fertile chicken eggs was inactivated with a 1:4000 dilution of formalin for three days. Centrifugation at 47,000 g for 1-3 hours concentrated the viral particles. Reconstitution to 1/10 the original volume for use as a vaccine resulted in a product having an HA titer of 1:64 to 1:512. Two doses of 4 ml given three weeks apart resulted in a serologic response in three of six gilts of breeding age. Experimental challenge of two vaccinated and two control gilts to swine influenze virus showed that vaccinated gilts did not react by production of a marked HI antibody response when compared to unvaccinated gilts.


Increased lung compliance in mice exposed to sulfur dioxide. Mice exposed 6-9 days to 40 ppm. SO2 lost 21% of body weight, but static lung compliance increased 37% (P less than or equal to 0.01). Slopes of saline volume-pressure curves increased 8% (non-sig) pointing to a decrease in surface tension rather than tissue elasticity. Alveolar stability, lung weight and lung wet/dry ratio decreased 2 to 6%, whereas trapped gas in-increased 17%, but none were statistically significant.


Spectral characteristics of some metallo complexes of six-mercaptopurine. Absorption spectra from 400-250 nm were obtained for 6-mercaptopurine (6-MP) and its Bi, Pt, and Pd complexes. The peaks were all grouped in close proximity (+/-5nm) and the curves were similar. Under the conditions of this study, the purine chemistry of 6-MP does not appear to be appreciably altered as a result of the pure compound complexing with the Bi, Pt, or Pd metals.


Non-teratogenicity of prostaglandin F2alpha in the chick. Chick embryos were exposed to prostaglandin F2alpha (10, 40 or 100 mug) at 48 and 72 hours incubation. Compared to the controls there was no significant increase in the incidence of embryonic death and developmental defects.


Mitotic changes in neuroblastoma transplanted into denervated host tissue. Tumors were transplanted to denervated and innervated hind limbs of A/J mice and grown for 5 days in all groups. The host tissues were denervated by femoral and sciatic nerve section 4 days prior to tumor implantation. Dnervation of host tissues resulted in a significant reduction in tumor mitotic rate as assessed by mitotic counts in the histological sections. Neurotrophic factors may thus be an additional feature of the host-tumor environment.


The metabolism of L-ethionine in rats fed alpha-naphthyl isothiocyanate. L-[ethyl-2-14C] ethionine was administered in a single dose to rats fed a diet containing 0.10% alpha-naththyl isothiocyanate for a period of time between 6 and 99 days. Ethionine metabolites excreted into urine were investigated as a function of induced pathologic changes in the liver. A short-time exposure (6 and 14 days) to alpha-naththyl isothiocyanate increased the excretion of free ethionine and S-adenosylethionine at the expense of total ethionine sulfoxide. With the extended feeding period the excretion of total ethionine sulfoxide became normalized while the excretion of free ethionine and S-adenosylethionine decreased. The acetylated fraction of ethionine sulfoxide decreased rapidly and reached a minimum in 14 days of feeding. This fraction subsequently started to increase, but did not reach the values obtained in normal rats.


Methaqualone metabolism by rat liver microsomes. A rat hepatic microsomal system has been established which metabolizes methaqualone. The microsomes are obtained from livers of rats treated with phenobarbital. The methaqualone is dissolved in polyethylene glycol-200 prior to addition to the incubation mixture. A comparison is made between the metabolites obtained in this in vitro system and metabolites obtained from urines of phenobarbital treated rats injected with methaqualone. The same two and sometimes three metabolites, as determined by thin layer and gas liquid chromatography, were found in both the complete microsomal incubation system and the urines.


Metabolism of 5-(p-toluyl)-5-ethylbarbituric acid and 5-(p-toluyl)-5-phenylhydantoin in the isolated perfused rat liver. The primary route of metabolism of 5-(p-toluyl)-5-ethylbarbituric acid (TEBA) and 5-(p-toluyl)-5-phenylhydantoin (MPPH) in the isolated perfused rat liver is oxidation of the aromatic methyl group either to a primary alcohol which is then conjugated with glucuronic acid and excreted in the bile (MPPH only) or to the carboxylic acid which is excreted free in the bile (both TEBA and MPPH). All metabolites were identified by previously described permethylation and GC-MS techniques.


Effects of chronic administration of polybrominated biphenyls on parameters associated with hepatic drug metabolism. Parameters relating to hepatic microsomal drug metabolism were measured in vitro following 2 weeks exposure of rats to polybrominated biphenyls (PBB) as a dietary supplement at 4.69, 18.75, 75 and 300 ppm. The mixture of PBB was a potent inducer of hepatic microsomal drug metabolism. The pattern of induction seen after PBB exposure was compared with that produced by phenobarbital and 3-methyl-cholanthrene and the pattern of induction observed shared similarities with both of these agents.


Treatment with o,p'-DDD (mitotane) decreased cytochrome P-450, heme, and microsomal protein content in the dog adrenal cortex in vivo. Treatment with o,p'-DDD, at a does which markedly inhibits steroidogenesis (60 mg/kg, intravenously), significantly decreased adrenal mitochondrial and microsomal "P-450" and microsomal protein contnet 34%, 55%, and 35% respectively, within 3 hours. The reduction of cytochrome P-450 content was accompanied by decrease in heme content, which explains the apparent loss of cytochrome P-450. This action provides a possible explanation for the inhibition of steroidogenesis caused by o,p'-DDD, and indicates that o,p'-DDD initiates a very destructive process in the dog adrenal cortex.


New method for detecting and quantitating pharmacokinetic drug-drug interactions applied to ethanol-propranolol. A novel method for detecting and quantitating pharmacokinetic drug-drug interactions is described. The method involves perturbation of an existing steady-state whole blood (or plasma) concentration of one drug by the other drug. The method would allow differentiation of "pharmacokinetic" drug interactions from "pharmacologic" interactions. It is shown that a bolus intravenous injection of propranolol reduced a steady-state arterial blood concentration of ethyl alcohol by 26% in the cat.


Excretion, distribution and metabolic fate of 3H-alpha-chaconine. 3H-alpha-Chaconine was poorly absorbed from the gastrointestinal tract and rapidly excreted in feces when administered orally to male rats. Intraperitoneal administration of low doses (5 to 10 mg/kg) resulted in urinary and fecal excretion of metabolites, and probably involved biliary excretion. High, toxic, intraperitoneal doses (15 to 25 mg/kg) depressed fecal and urinary elimination, and resulted in accumulation of tritium in various tissues. The major metabolite appeared to be the aglycone, solanidine. Alpha-chaconine is very similar to alpha-solanine in its elimination  by and distribution in tissues of rats.


Disposition of nicotine in the rat after intravenous administration. The pharmacokinetics of 14C-labeled nicotine were studied in male Fischer-344 rats following the i.v. administration of a single 0.8 mg/kg dose. Serial blood samples were collected and the nicotine in plasma was separated from its metabolites by TLC. The levels of radioactivity corresponding to nicotine, cotinine, and polar metabolites remaining at the origin of the chromatogram were determined by liquid scintillation counting. Plasma nicotine concentration was characterized by a biexponential decay with a mean biologic half-life (t1/2) of 0.96 hrs, a large apparent volume of distribution (5.67 L/kg) and total body clearance (4.04 L/hr/kg). Maximum plasma concentration of cotinine was reached within 1 1/2 hrs post-nicotine administration, followed by a monoexponential decline with a mean t1/2 of 6.4 hrs. The plasma concentrations of origin activity rose to maximum levels within 30 minutes and declined slowly in a biexponential fashion with a mean t1/2 of 23.2 hrs. It appears, therefore, that while nicotine is rapidly eliminated, its metabolites persist in the plasma a long time after its administration.


The human metabolism of caffeine to theophylline. Theophylline peak plasma concentration of over 170 ng/ml average was observed when 300 mg of caffeine, equivalent to 2-3 cups of coffee, was administered to humans. This peak level was not observed until at least 7 hr post administration. Accumulation of caffeine, with its subsequent metabolism to theophylline, in patients, who consume average quantities of caffeine-containing beverages relative to those patients who avoid such drinks could interfere with bioavailability studies in normal volunteers. However, it may account for only a small portion of the variable clinical effects associated with aminophylline administration.


Identification of a methylated catechol metabolite of glutethimide (Doriden) in human urine. A new metabolite of glutethimide has been isolated and identified as a methylated catechol. Gas chromatographic parameters as well as mass spectral data are presented which clearly reveal this metabolite to be present in enzymatically hydrolyzed urine of patients severely intoxicated by the parent drug.


A comparison of 6,7-dihydroxytetrahydroisoquinoline, salsolinol and tetrahydropapaveroline as inhibitors of monoamine oxidase within the adrenergic nerve plexus of the isolated mouse atrium. Three dopamine-derived tetrahydroisoquinolines (TIQs) were tested for their ability to inhibit monoamine oxidase (MAO) within the adrenergic plexus of atria from reserpinized mice. Inhibition of MAO was shown by improved accumulation of 3H-norepinephrine with a concomitant decrease in 3H-deaminated catechols. Salsolinol was less potent than 6,7-dihydroxy-TIQ as a MAO inhibitor. Tetrahydropapaveroline did not appear to inhibit MAO in this system.


Is the serotonin binding protein (SBP) a soluble storage form for serotonin? The binding of serotonin to a soluble, high affinity binding protein (SBP) present in synaptosomes and assoicated with serotonergic tracts, has now been studied for the effect of drugs and, in particular, drugs interacting with contractile proteins. Vincristine, vinblastine, and cytochalasin B were found to cause 50% inhibition of serotonin binding to SBP at 1.5 X 10(-6)M, 7.5 X 10(-6)M and 50 X 10(-6)M, respectively. Colchicine did not affect the binding at 1 X 10(-3)M. When vinblastine was injected intraventricularly, the binding capacity of SBP isolated from brain 20 and 26 hours after injection was decreased 42% and 60% respectively. It is concluded that SBP is an actin-like contractile protein, distinct from microtubulin, and not associated with membranes. The storage of serotonin through binding to a protein with such properties suggests that this compartment is in some way involved in the translocation or transfer of serotonin from one part of the cell to another.


The effect of various phenothiazines and tricyclic antidepressants on the accumulation and release of (3H)norepinephrine and (3H)5-hydroxytryptamine in slices of rat occipital cortex. The effects of various structurally related tricyclic antidepressants and phenothiazines on the accumulation of (3H)-5-hydroxytryptamine, [(3H)5-HT] and (3H)norepinephrine [(3H)NE] and on the release of previously accumulated (3H)5-HT and (3H)NE were determined in slices of rat occipital cortex. Results may be summarized as follows: 1) Each compound was a better inhibitor of accumulation [both of (3H)5-HT and (3H)NE] than it was a releasing agent. 2) The hydroxylation of tricyclic antidepressants made little difference in the potencies of the compounds as inhibitors of both (3H)NE and (3H)5-HT accumulation. 3) The N-dimethylated phenothiazines and tricyclics (tertiary amines) were better inhibitors of (3H)5-HT accumulation than their corresponding secondary amines. 4) The change from a dimethylene bridge in the tricyclic antidepressants to an S atom in the phenothiazines led to a considerable decrease in the potency of the compounds as inhibitors of (3H)5-HT accumulation, but made less difference in the (3H)NE accumulation system.


The fate of intratracheally installed benzo(a)pyrene in the isolated perfused rat lung of both control and 20-methylcholanthrene pretreated rats. The fate of intratracheally installed 3H-benzo(a)pyrene in the isolated perfused rat lung of both control and 20-methylcholanthrene pretreated rats and in perfusion fluid was studied. The covalent binding of benzo(a)pyrene metabolites in the lung tissue itself was greatly enhanced by 20-methylcholanthrene pretreatment of rats. Similarly, the appearance of unchanged 3H-benzo(a)pyrene in the perfusion fluid of 20-methylcholanthrene-lung was decreased as compared to control lung perfusion. This was accompanied with the increase of water-soluble metabolites of benzo(a)-pyrene in the perfusion fluid of 20-methylcholanthrene-lung. When analyzing the metabolite profile of benzo(a)-pyrene in the lungs, especially the phenols (7-fold) and 9,10-diols (5-fold) were found to be increased.


Effects of sound stimulus on gastric secretion and plasma corticosterone level in rats. The effects of sound stimulus were studied on the gastric secretion in rats with chronically implanted cannulas. Attempts were made to correlate the changes in the secretion with those of the plasma corticosterone level. Exposure of the animals to sound stimulus (1 hr or 2 hr) produced a marked decrease in gastric secretion and a concomitant increase in plasma corticosterone. It appears that in producing these effects sound stimulus acted as a stressor. Furthermore, a paradoxical increase in secretion was noted in the first hour collection prior to the sound stimulus. This initial increase in secretion may be due to an adaptive compensatory mechanism in anticipation of its marked inhibition.


Effects of subtoxic lead levels on pregnant women in the state of Missouri. Cords, placentas, placental membranes, and maternal and fetal blood were collected from 249 women delivered in Columbia, Missouri (Region I). The same samples were obtained from 253 women delivered in Rolla, Missouri (Region II), near lead mining areas. The incidence of term pregnancies with early membrane rupture was 0.41% in Region I and 17% in Region II. The incidence of premature deliveries was 3% and 13.04% respectively. Lead concentration in blood and placental tissues of term pregnancies revealed no significant changes. In term with early membrane rupture, blood concentration of lead was higher, as was the case in placental tissues and cord. Lead concentration was highest in membrane tissues, in mug/100 grams (Regions I and II respectively): placenta, 6.0 +/- 0.01 and 7.0 +/- 0.03; cord, 11.0 +/- 0.34 and 12.0 +/- 0.18; membrane, 38.9 +/- 2.64 and 45.3 +/- 3.12. A high positive correlation (r = 0.2941) between lead concentration in maternal and fetal blood existed. Both were significantly (P less than 0.01) higher in preterm pregnancies and early membrane ruptures than in term pregnancies. These data suggest that subtoxic levels of lead could increase the incidence of early membrane rupture and premature deliveries.


Models for clinical disease. I. Biochemical cardiotoxicity of a coenzyme Q10-inhibitor in rats. The pharmacology and toxicity in animals of synthetic analogs of essential metabolites, which show in vitro antagonism of the metabolite, may point out pathology associated with a deficiency of the metabolite. On this basis, 2-hydroxy-3-n-dodecylmercapto-1,4-naphthoquinone, a potent in vitro inhibitor of a mitochondrial coenzyme Q10-enzyme, was administered to rats. The specific activities and the percent deficiencies of the succinate dehydrogenase-coenzyme Q10 reductase in cardiac mitochondria were significantly increased (0.001 less than P less than 0.01). These enzyme activities were unchanged in leucocytes and in the dorsal aorta. This biochemical cardiotoxicity of an antimetabolite of coenzyme Q10 adds to the advancing knowledge on coenzyme Q10 in cardiac metabolism and disease, and could correlate with the cardiotoxicity of the clinical antitumor drug, adriamycin.


Evidence for a dopamine sensitive receptor in the young rat aorta. Dopamine caused relaxation in young rat but not old rat aortae contracted with prostaglandin F2 alpha. The antagonizing action of propranolol was less effective on the relaxing effect of dopamine than that of isoproterenol or norepinephrine. Chlorpromazine or haloperidol abolished the relaxing effect of dopamine but only reduced the effect of norepinephrine and isoproterenol. The relaxing effect of dopamine is mainly mediated by the activation of dopamine sensitive receptors.


A comparison between the haemagglutination inhibition and complement fixation tests for Newcastle disease. The value of the complement fixation (CF) test as a means of assessing the immune response of fowls to Newcastle disease virus was examined using several strains of virus. A close degree of correlation was found between the CF test and the simpler haemagglutination-inhibition (HI) test. Like the HI test, the CF test only gave an indication of the immune status and was not a direct measurement of immunity.


The inactivity of diamphenethide against liver fluke in certain species of mammals. Diamphenethide is inactive against Fasciola hepatica in the rat, although the free amine is active. Extracts of rat liver failed to deacetylate diamphenethide to give the free amine. Diamphenethide is active against fluke in the sheep, less effective in the cow and mouse and not active in the rabbit, even though liver extracts of all four species are capable of liberating the free amine.


The fasciolicidal activity of 4, 4'-diaminodiphenylsulphide. 4, 4'-diaminodiphenylsulphide is an effective fasciolicide against three-week-old Fasciola hepatica in the sheep at 50 mg/kg per os. The di-N-acetyl derivative is also an effective fasciolicide and is less toxic.


A rotavirus in lambs with diarrhoea.

A rotavirus in lambs with diarrhoea. A reovirus-like agent was identified from an outbreak of enteritis in young lambs. From its morphology and immunological relationship with calf rotavirus, it was concluded that it was a rotavirus which infects lambs.


The efficacy of thiabendazole against the arrested larvae of some Trichostrongylidae and Chabertia ovina in sheep. The activity of thiabendazole at 100 mg/kg was tested against the arrested larvae of Ostertagia spp, Haemonchus contortus, Trichostrongylus axei, Nematodirus spp and Chabertia ovina in natural infections, in 10-month-old lambs. The result, assessed by means of worm counts, showed the treatment to be very effective.


Experimental respiratory disease in dogs due to Bordetella bronchiseptica. Young dogs of two age groups, six weeks and 12 weeks respectively, were infected by aerosol with a strain of Bordetella bronchiseptica which had been isolated from a dog with pneumonia. Clinical respiratory disease characterised by coughing and in some cases purulent nasal discharge was induced in both groups of infected dogs and also in dogs kept in contact. B bronchiseptica was recovered from the nasal cavity, trachea, bronchi and lung parenchyma of infected and contact animals. At necropsy, masses of Gram-negative bacteria were found trapped in the cilia of the respiratory epithelia and there was an exudate containing neutrophils in the mucosae of the respiratory tract at all levels. A close similarity was noted between the lesions produced in the dog and those described in pertussis infection in man. Experimental respiratory disease in the dog due to B bronchiseptica may offer a model system for the study of the human disease.


Comparison of the pharmacokinetics of penicillin G and ampicillin in the horse. The affinity and the binding capacity of horse serum proteins for ampicillin and penicillin G were measured by equilibrium dialysis or ultrafiltration technique. From the figures thus obtained it may be concluded that in the range of therapeutic concentrations the protein-bound fraction accounts for 6 X 8-8 per cent of the total ampicillin concentration and for 52-54 per cent of the total penicillin G concentration in serum. The rate of elimination of ampicillin and penicillin G in horses was assessed by following serum concentrations after a single intravenous injection. The biological half life of ampicillin was found to be 93 min and that of penicillin G 53 min in adult horses with unimpaired circulation and intact kidney and liver function.


Inhibition of the bactericidal activity of bovine polymorphonuclear leucocytes and related systems by casein. Polymorphonuclear leucocytes (PMN) obtained from lactating cows' udders were deficient in their ability to kill Staphylococcus aureus compared with PMN isolated from blood. However, blood PMN suspended in separated milk or in the presence of casein were similarly impaired. Casein was found to inhibit in vitro the bactericidal activities of histone, the lactoperoxidase-H2O2-KI system and PMN lysates. Electron microscopy showed that casein was ingested by PMN with the formation of phagocytic vacuoles. These observations provide the basis of a hypothesis explaining the bactericidal deficiency of milk PMN and the consequent susceptibility of the udder to infection.


A cinefluoroscopic study of the caecal base of the horse. Separate mechanisms exist for transporting ingesta and gas from the caecum to the colon. Both involve the isolation of the cranial part of the base by a constriction cranial to the ileal papilla. This involves elevation of the floor of the base and is associated with dilation of the caecocolic ostium which at other times is closed. Contraction of the ingesta-filled cranial compartment expels some material to the colon but allows most to return to the body. Contractions which discharge gas do not result in the passage of significant amounts of ingesta. The gas expelled is at once hurried through much of the ascending colon. Any considerable reflux to the caecum is prevented by the sigmoid configuration of the caecocolic junction.


The relationship between Trichuris trichiura (Linnaeus 1758) of man and Trichuris suis (Schrank 1788) of the pig. Studies were made on the relationship between Trichuris suis of the pig and T trichiura of man. Comparative morphological and developmental studies revealed differences in sizes of the eggs and infective first stage larvae, in the rate of development to the infective larval stage and in development within young pigs following experimental infection. Successful cross infections of man with T suis ova and of pigs with T trichiura ova were achieved for the first time. T suis eggs recovered from one human experimental infection were used to produce a patent infection in a pig. It is argued that while the successful cross infections suggest a close evolutionary link, the differences in morphology, exogenous and endogenous development provide sufficient criteria for the two parasites to be maintained as separate species.


Tissue damage and concentration at the injection site after intramuscular injection of chemotherapeutics and vehicles in pigs. Intramuscular injection sites were examined for macroscopical and microscopical changes and for residues of drugs six and 30 days after injection of chemotherapeutic preparations or vehicles in swine. The chemotherapeutic preparations contained sulphonamide and/or trimethoprim. All the chemotherapeutic preparations and the vehicles except physiological saline and sterile water caused macroscopical and microscopical changes, mainly appearing as areas of necrotic muscle tissue six days after the injection and as scar tissue 30 days after the injection. Residues of drugs were found at nearly all the injection sites six days after the injection, while 30 days after the injection only residues of sulphonamides were detectable in nearly half of the injection sites.


Some consequences of the ingestion by young and growing pigs of feed contaminated with ergot. Growing pigs were fed freshly milled ergot sclerotia (Claviceps purpurea Fr (Tul)) from North American wheat containing 0-31 per cent of total alkaloids of which 30 per cent was ergotoxine, 30 per cent ergosine, 20 per cent ergotamine and 20 per cent other ergot alkaloids. Pigs were induced to ingest a diet heavily contaminated with ergot (10 per cent w/w). The presence of ergot reduced feed intake and growth of the pigs, but there was no evidence of peripheral necrosis, of internal or external haemorrhage, or of changes in haemotological characteristics. Balance experiments in which the diet was contaminated with 4 per cent (w/w) of ergot showed that 90 per cent of the alkaloids were absorbed by the pigs, but none could be detected in tissues or urine. The ingestion of ergot did not affect the digestibility of the diet, but the urinary excretion of nitrogen was increased and the retention of nitrogen reduced. The presence of ricinoleic acid was shown to be a useful diagnostic feature of ergot contamination of diets, digesta and faeces; it was not found in body tissues.


Observations on the alimentary tract of gnotobiotic lambs. Seventeen gnotobiotic lambs were reared up to 21 weeks of age on cows' milk followed by sterile solid diets similar to diets fed to conventional lambs. Seven were inoculated with limited defined populations of rumen bacteria, seven were left uninoculated and three were dosed with rumen contents from conventional sheep ('conventionalised'). Seven naturally-born lambs were reared for purposes of comparison. As with other species of gnotobiotic animals, both the inoculated and the uninoculated gnotobiotic lambs had small, poorly developed lymph nodes, soft colon contents and thin intestinal walls. Unlike other species the caeca of gnotobiotic lambs were of normal size. The overall size of the reticulo-rumen including contents relative to body weight was similar in gnotobiotic and conventional lambs. However, macroscopically, the musculature of the rumen seemed to be poorly developed and histological studies showed hypoplasia of the muscle tissue of both the rumen and reticulum. Rumination was noted only infrequently in gnotobiotic lambs. The epithelium of the rumen and reticulum of the uninoculated gnotobiotic lambs was similar to that of neonatal lambs, but there was normal development of papillae in gnotobiotic lambs inoculated with limited defined populations of rumen bacteria and in conventionalised lambs. Degenerative changes were observed histologically in some of the organs of gnotobiotic lambs which were consistent with nutritional deficiencies.


Isolation of a protective, non-toxic capsular antigen from Pasteurella multocida, types B and E. Separation of the capsular antigen and endotoxin from saline extracts of Pasteurella multocida type B was achieved by fractional precipitation from aqueous solution by addition of polar organic solvents. Biological tests for the presence of endotoxin showed that it was absent from capsular antigen preparations so obtained. Properties of the capsular antigen suggested that it was a high molecular weight acidic polysaccharide. The solvent fractionation method was found to be equally applicable to separation of capsular antigen and endotoxin of P multocida type E. The type B capsular antigen in the presence of aluminium hydroxide gel adjuvant, was poorly immunogenic in rabbits. In cattle, however, a dose-dependent serological response was obtained as demonstrated by the mouse passive protection test.


Osmotic and oxidative haemolysis of erythrocytes in calves with white muscle disease. The stability of erythrocytes to both osmotic and oxidative haemolysis was studied in naturally occuring cases of white muscle disease of calves two to 14 weeks old. During clinical and subclinical disease the incidence of haemolysis when erythrocytes were exposed to 0-588 per cent NaCl was 74-3 +/-18-8 per cent and 76-6+/-18-6 per cent respectively, whereas in clinically healthy animals receiving 30 mg vitamin E per kg feedstuff the incidence of haemolysis was only 55-9+/-12-7 per cent. Erythrocytes of the calves receiving vitamin E supplements were completely resistent to peroxidative haemolysis whereas in the clinical and preclinical cases approximately 12-5 per cent of cells were lysed.


Production of large quantities of interferon with calf testicular cells and leucocytes. Interferon (IF) was induced in calf testicle monolayer cultures and leucocycte suspension cultures with Semliki forest virus and Newcastle disease virus to evaluate the potency of those cells for producing IF in large quantities for clinical experiments. Interferon activity was measured by an RNA-inhibition test using Semliki forest virus as challenge. To produce 10(6) units of IF, leucocytes from 67-5 litres of blood or 7-2 X 10(9) testicle cells were needed.


[Condylar osteonecrosis of the knee in adults and aged. Study of 36 cases]. The authors analyse the clinical symptoms, the etiology, and the evolution of condylar osteonecrosis of the knee with reference to 36 personal cases, including 28 unilateral forms and 8 bilateral forms. They confirm the predominance of the condition in women and the fact that it usually commences after the age of 50 years. They followed the evolution of the condition in 27 patients, in 20 of them for from 3 to 12 years. Evolution was good or excellent in 12 patients. The authors showed that the existence of a healthy lateral segment on the affected condyle is one element that indicates a good prognosis; they found that intra-articular injections of corticoids did not affect the evolution unfavourably, but that the coexistence of several other associated pathological conditions (vasxular, metabolic...) indicated a poor prognosis. If the precipitating cause of the condylar osteonecrosis of the knee is not known, with the exception of some cases commencing after trauma, the authors put forward the hypothesis of chronic condylar circulatory insufficiency or stasis as the cause leading to the condition, the latter occurring in cases when an already delicate vascular equilibrium is upset.


[Osteonecrosis of the femoral condyles in adults. Apropos of 30 personal cases]. On the basis of a series of 30 personal cases, the authors describe the circumstances in which osteonecrosis of the femoral condyles occurs, the clinical and radiological characteristics, the evolution of the disease, and some of the associated therapeutic problems. They emphasize particularly the difference between the primary forms, which are the prerogative of women over 50 years of age and are of a limited character, and the secondary forms that are essentially linked to prolonged corticotherapy. The secondary forms are found in persons of both sexes between the ages of 20 and 40 years and consist of diffuse lesions (frequent extensive epiphyseal reorganization, bilaterality, and associations with other sites). As the evolution of the disorder under simple medical treatment is usually fairly favourable, the authors consider that indications for surgery should be restricted to the infrequent forms (10 to 15% of cases) that progress rapidly towards arthrosis.


[Indications and possibilities of total prosthesis of the hip]. If all the non-traumatic coxopathies are considered, it can be said that there is practically no limit to the possibilities of operations for total prostheses fo the hip. In particular, all the technical problems posed by certain forms of coxopathy can be solved. Only grave deterioration in the general condition of the patient and non-tubercular infections constitute contra-indications. This is, of course, not new and is valid for all orthopaedic surgery. Only the future will show if this concept is true.


[Foot involvement in Paget's disease of bone]. Paget's disease of the bones of the feet is not unusual. Twenty patients out of every hundred present the signs of Paget's disease in the foot bones. The calcaneus is the bone most often affected (18 cases) but the cuboid, the metatarsals, and the astragalus (often as well as the calcaneus) may also be affected. Paget's disease of the foot remains latent clinically: 2 patients complained of talalgia; a third had a deformation of the rear part of the foot which made it difficult to wear a shoe. Pagetic deformations of the lower limb affect the foot but without pain. They are often compensated for by putting more weight on the fore-foot in cases of shortening of the lower limb or on the external arch in cases of bowed deformation of the lower limb.


[Contribution of scanning electron microscopy to the study of normal and pathological human synovial membrane]. Scanning electron microscopy permits three-dimensional morphological study of the outer layer of the synovial membrane. This article concerns the study of 15 surgical samples of normal and pathological human synovial membranes: 3 normal synovial membranes, 6 inflammatory synovial membranes, 5 arthrosic synovial membranes, 1 tuberculous tenosynovitis. The samples were washed, fixed in a mixture of glutaraldehyde and iso-osmotic paraformaldehyde, dehydrated in increasing concentrations of alcohol and at the critical point, and then subjected to double metallization (aluminium and gold). Certain portions were treated with hyaluronidase. Hypertrophy of the villi, considerable in inflammatory synovial membranes, minimal in arthrosic synovial membranes, and absent in the normal synovial membrane, was confirmed. The outer layer is composed of cells of different sizes with spaces betwen, in which images indicating intercellular bridges can just be seen. The surface of the cells is irregular and covered with numerous microvilli. The arthrosic synovial membrane is poorly with large cells; in contrast in an inflammatory synovial membrane they are numerous, globular, and project from the surface.


[Coxarthrosis due to contusion].

[Coxarthrosis due to contusion]. Can a contusion cause coxarthrosis in the absence of both fracture and dislocation? Yes. To demonstrate this the authors report 6 cases that fulfil the following conditions: (1) Simple but violent contusion affecting the greater trochanter or the knee (dashboard accident) or a forced movement, such as in doing the splits; (2) immediate or slightly delayed pain, generally of short duration (a few weeks); (3) absence of coxarthrogenic malformations and absence of pre-existing signs of a pathological hip condition; (4) progressive coxarthrosis on the side of the contusion; (5) chronological relation between the development of the coxarthrosis images and the date of the contusion; (6) subjects less than 35 years of age, in order to eliminate cases with latent primary pre-coxarthrosis. The average age of the six patients at the start of the coxarthrosis was 24.7 years (range: 13 to 33 years); there were four men and two women. In five of the six cases a violent contusion in the trochanter region was involved as a result of a fall on a hard surface or a traffic accident. In one case a forced movement on landing from a jump was involved. Evolution in three periods is usual: the hip is painful either immediately or after a few weeks (particularly on rising after a period in bed for multiple injuries). This post-traumatic pain lasts from ten days to one month, rarely longer. It is followed by a period free of pain that may last from five months to ten years (average: five years). Subsequently there is pain every day and the onset of the limp associated with coxarthrosis. Radiographically the reduction of the joint space and/or the osteophytosis appears after three months to two years (average: one year). However, there may not be any pain associated with these lesions for a long time. The authors propose that the first five conditions enumerated above represent the essential medico-legal conditions of coxarthrosis by contusion. The restriction as regards age (No 6) was introduced only to show clearly the existence of post-contusive coxarthrosis. However, even if one or more of the medico-legal conditions are not fulfilled the imputability may still be valid. Some such cases are discussed.


[Anatomopathology of Paget's disease. Combined approach by conventional methods and ultrastructural study]. Paget's disease is manifested by bone remodelling where the rate of the resorption-osteogenesis pattern is abnormally enhanced. This leads to the formation of a pathologically structured bone. The bone remodelling does not concern the entire skeletal structure and is unequally active. It is limited by the neighbouring healthy bone in which it can spread out. It can be followed by the development of a sarcoma. When the acetabulum or the femoral head are affected this can occasionally, lead to a coxopathy with cartilage deterioration. An anatomo-pathological study of Paget's disease is necessary for understanding the basis and the limits of biopsy diagnosis as well as its various manifestations (clinical, radiological, biological, scintigraphical, thermographical). This study also serves as a basic for pathogenic discussion.


The effect of amitriptyline on forearm blood flow. The local effect of intra-arterial infusion of amitriptyline (AT) on forearm blood flow was studied in seven healthy subjects. AT was infused at rates of 0.05, 0.10, 0.15, and 0.20 mg-min--1 for periods of 5 min. Forearm blood flow showed a dose-dependent increase when the dose exeeded 0.10 mg-min--1. On the highest dose level the blood flow increased on an average by 73%. No systemic effects, as reflected by changes in heart rate, blood pressure, and blood flow in the contralateral forearm, were observed during the infusion. The present data indicate a dilatating effect of AT on resistance vessels possibly mediated by an alpha-adrenergic blockade.


Unimpeded plasma renin increase after intravenous furosemide during saline replacement. The effect on plasma renin activity of intravenous furosemide combined with saline replacement of the volume depletion was studied in twelve patients with insignificant heart disease. In ten of the patients the investigation was repeated without saline replacement. It was found that saline infusion, reducing or eliminating hemoconcentration, had no significant influence on the marked plasma renin increase. In eight of the patients the combined furosemide-saline study was performed during right-hear catheterization. Decrease in atrial pressures, known to occur within 15 min after furosemide intravenously, was virtually absent with the saline replacement. It is concluded that plasma volume reduction after intravenous furosemide is responsible for decreased filling pressures of the ventricles but not for plasma renin increase.


Selection of routine method for determination of glomerular filtration rate in adult patients. The precision and reporducibility of three different clearance methods as used in clinical routine assessment of glomerular filtration rate (GFR) were investigated in 51 patients: total [51Cr]EDTA plasma clearance (E); 24-hr endogenous creatinine clearance (C); and creatinine clearance estimated from the plasma creatinine concentration, weight, and sex- and age-dependent mean creatinine excretion rate (c). The precision and reporducibility (coefficient of variation) for single determinations were, in patients with E greater than 30 ml/min, 5.5 and 4.1% (E); 26.9% (C); and 23.2 and 11.0% (c). The corresponding figures for E less than 30 ml/min were 11.6 and 11.5% (E); 21.9% (C); and 21.4 and 6.5% (c). The precision of C could not be ameliorated by excluding single deviating determinations, but only by excluding patients for whom the precision of 15.5% for mean of three determinations of C (total material) could be reduced to 10% by excluding 25% of the patients. The present data indicate that E in most cases is the method of choice for assessment of GFR in clinical routine work. For changes in renal function, especially at low functional levels, c may be of value.


Cardiac effects of amitriptyline in rats. The effect of intravenous amitriptyline (0.5-2 mg/kg) on heart rate, blood pressure, ECG, and electrolytes in plasma and heart muscle was studied in rats. In addition, the effect on monophasic action potentials was studied in rats with open chest. Amitriptyline caused a significant decrease in blood pressure and heart rate and a significant prolongation of QRS and PQ duration. At the time of maximal QRS prolongation (mean +94%) the duration of monophasic action potentials was virtually unchanged. Beta-adrenergic blockade by means of pretreatment with 0.1 mg propranolol did not influence the amitriptyline-induced prolongation of QRS duration. Amitriptyline administration causing obvious QRS prolongation induced no detectable changes in plasma and heart muscle electrolytes. The results contradict adrenergic dominance or marked imbalance between intra- and extra-cellular electrolytes as a cause of the ECG changes. The present data indicate that the amitriptyline effect is compatible with a direct quinidine-like action on the heart, resulting mainly in a slowing of impulse propagation in the intracardiac conduction system.


Classification of liver diseases by clinical chemical laboratory results and cluster analysis. Patients with liver diseases were classified by cluster analysis using only clinical chemical laboratory results. A strong tendency towards correspondence between this classification, based on functional criteria, and the previous diagnoses, based mainly on liver biopsy findings, was found.


Production and evaluation of high-quality thyroxine antisera for use in radioimmunoassay. High-quality thyroxine (T4) antisera were raised in rabbits. Conjugates of protein and T4 or T4 methyl ester were given intracutaneously in Freund's complete adjuvant at one or two sites on the back at 1/2- to 3-month intervals. Eleven of 16 immunized rabbits produced antiserum with titers higher than 2 commercial antisera and 4 antisera from other laboratories. All 16 antisera had equilibrium constants (K) higher than the 6 reference sera. The highest titer observed was 130,000 with 88 fmol labeled T4 per ml incubate. A drastic increase in K from about 4 X 10(8) to 5.8 X 10(10) 1/mol was observed as the immunization proceeded. Cross-reactivity with triiodothyronine (T3) varied but was generally low. Suppression of the T4 synthesis was attempted by giving 30 nmol (20 mug) T3 per os once a day. Antiserum from rabbits given T3 suppression contained less iodine than antiserum from nonsuppressed control rabbits. The possible reasons for the successful production of the high-quality antisera are discussed.


Correlations between the deoxyuridine-suppressed value and some conventional haematological parameters in patients with folate or vitamin B12 deficiency. The correlations between the deoxyuridine-suppressed value and some conventional haematological parameters (Hb concentration, red cell count, MCV, total white cell count, red cell folate level and serum vitamin B12 level) have been investigated in 40 patients with megaloblastic haemopoiesis due to folate or vitamin B12. deficiency. The only statistically significant correlations found were (a) an inverse correlation between the deoxyuridine-suppressed value and the Hb level or red cell count in both the folate- and vitamin B12-deficient groups and (b) a direct correlation between the deoxyuridine-suppressed value and MCV in the vitamin B12-deficient group. The results indicated that the deoxyuridine-suppressed value was a better index of the magnitude of the disturbance in red cell production induced by folate or vitamin B12 deficiency than either the red cell folate or serum vitamin B12 levels.


Relapsing haemolytic anaemia of pregnancy with negative antiglobulin reaction. Four patients are described in whom seven episodes of haemolytic anaemia associated with pregnancy were observed during a follow-up period of 2 to 16 years. Normal haemoglobin levels were found both before and after pregnancy. Despite consistently negative antiglobulin tests, an autoimmune haemolytic mechanism is suggested by the rapid destruction of transfused blood, favourable response to corticosteroids and the development of transient haemolytic anaemia in three of the infants. In view of its unique clinical and laboratory features and relatively mild course, recognition of this condition as a distinct clinical entitity seems to be justified.


Streptokinase resistance test in patients with streptococcal infection and/or high antistreptolysin titers. The streptokinase resistance test (SRT) has been studied in a group of patients with recent streptococcal infection and/or titres of antistreptolysin higher than 625 units. These patients generally had a higher SRT.


Haemostatic and lipid abnormalities in hypothyroidism. 10 patients with hypothyroidism were examined before and 3 months after initiation of thyroxin treatment. All patients had high levels of plasma total cholesterol and total phospholipids, and 5 had an additional hypertriglyceridaemia. 1 patient had a prolonged primary bleeding time and all had a prolonged activated partial thromboplastin time and recalcification time in plasma. Platelet factor 3 activity in platelet rich plasma was reduced and total phospholipid and protein concentration in platelets were low. No significant correlation could be estiblished between the observed lipid, protein and haemostatic parameters, and it is suggested that they represent independent phenomena. All abnormalities were corrected by thyroxin replacement.


An individual with Hb-Lepore-Baltimore- delta beta-thalassaemia in a Yugoslavian family. The clinical, haematological and biochemical findings in a person with delta beta-thalassaemia and Hb-Lepore are described. The patient was a 24-year-old student who suffered from anaemia of intermediate severity with late onset of the clinical manifestations, had minor bone and facial deformities, but had no necessity for regular transfusions. Haemoglobins A and A2 were absent in this individual, and the Hb-Lepore has been identified as Lepore-Baltimore. Heterogeneity of gamma chain of the Hb-F follows the expected pattern. The study provides further evidence that neither beta nor delta chains are synthesized in cis to delta beta-thalassaemia or Hb-Lepore.


Oxymetholone treatment in aregenerative anaemia. II. Remission and survival--a prospective study. This is a prospective multi-center study in which patients with aregenerative anaemia were treated with a standardized high dosage regime of an anabolic steroid (oxymetholone, Anasteron). 53 patients were included and divided into two groups according to bone marrow cellularity. Furthermore the hypocellular group was subdivided in order to make comparison with earlier studies possible. In the hypocellular group, the frequency of remission was 56% and the 2-year-survival from the onset of symptoms was 75%. This is longer than in some earlier studies, perhaps because of possible differences in etiology and/or because of the effect of systematic high dosage, long term androgen therapy. Patient selection was minimized and was not considered to be of major importance. Patients with hypercellular marrows, on the other hand, responded poorly to androgens. In this group 63% died of acute leukaemia, which confirms earlier suggestions that this form of aregenerative anaemia, frequently is of a preleukaemic nature.


Rheumatoid factor and serum IgG, IgM and IgA levels in rheumatoid arthritis with vasculitis. The authors report a significant increase in the rheumatoid factor titre in rheumatoid arthritis patients with vasculitis. A significant rise in IgG and IgA levels was found in uncomplicated RA, when compared with a normal population. The IgM levels were not found to be elevated in this group of RA patients. In the RA patients with vasculitis, on the contrary, the three Ig classes are increased when compared with the normal population, and the IgM level is increased when compared with the uncomplicated RA group. Significant relation was found between log IgM and log R.F. titre in the RA group with vasculitis. It is shown that the mild reduction of serum (by dithiothreitol 0.004 M) causes a complete negativity of the R. F. in all cases. It is concluded that the haemagglutination and the latex precipitation in vitro are induced by IgM-R. F. and not by IgG and IgA-R. F. molecules. Only free sites of IgM-R.F. play a functional role in the determination of the R. F. -titre. The authors postulated that increase in IgM in RA patients with vasculitis is partially due to the presence of free IgM-R. F. molecules in serum. Finally it is concluded that hidden IgM-R. F. molecules in patients with lower R. F. titre are not quantified by immunodiffusion methods.


Arthritis and hypogammaglobulinaemia. A. Family survey. 1. Hypogammaglobulinaemic patients admitted to the Medical Research Council's immunoglobulin therapy trials up to 1963 were examined for evidence of arthritis and were compared with population samples from Leigh, Wensleydale and Watford which were used as controls. 2. Four out of 60 males had inflammatory polyarthritis compared with an expected 0.4. In addition, 3 had synovitis limited to the knees and 4 had had polyarthritis in the past, the expected figures being 0.12 and 2.4 respectively. None of the patients had definite rheumatoid arthritis as defined by the American Rheumatism Association Criteria, though one satisfied the New York Criteria for Still's disease. All were seronegative and none of the patients with polyarthritis had radiological evidence of arthritis. None of the 18 female patients had arthritis. The prevalence of arthritis of synovitis in males was 29% in 1964, but in the following 3 years varied between 8 and 11%, suggesting a strong environmental influence. 3. All of the 7 males with inflammatory polyarthritis had levels of IgG, IgA, IgM and IgD, which were less than 30% of the standard normals and steatorrhoea was present in three. Steatorrhoea was also noted in 2 of 5 patients wih arthritis who died before the start of the survey, compared with 7% of all the males. 4. Clinical inflammatory polyarthritis was no more common in the first-degree relatives of patients with hypogammaglobulinaemia than in the population as a whole and they had no excess of erosive arthritis visible in X-rays of the hands or feet nor was sacro-iliitis excessively frequent. 5. Positive tests for rheumatoid factor were found in only 2 of the patients with hypogammaglobulinaemia and the first-degree relatives had no more positive sheep cell agglutination or latex fixation tests than expected in random population samples. 6. It is concluded that the seronegative polyarthritis which occurs in patients with hypogammaglobulinaemia is unrelated genetically to rheumatoid arthritis or Still's disease.


Enzymes in intestinal mucosa from patients with rheumatoid diseases. Jejunal mucosa from arthritic and control subjects was obtained by intraluminal biopsy or at operation and analysed for eight different enzymes. Histidinemethyl-esterase showed 6 to 10 times higher values in patients uith rheumatoid arthritis on comparison with control individuals in respective series. A disturbance in the histidine metabolism in these patients, possible depending on their intestinal flora, is discussed.


A study of the incidence of articular chondrocalcinosis in Paget's disease of bone. Amongst 66 pagetic patients, whose average age (median) was 76 years, 9 cases of ACC were found. This represents an incidence of 13.6% of the whole group. Of 72 control subjects, whose average age (median) was 73 years, 7 were found to have ACC. This represents an overall incidence of 9.7% of the control group, but the difference is not statistically significant. From this study we conclude that ACC does not occur more frequently in Paget's disease than in a group of control subjects with the same age distribution.


Chloroquine treatment and bone changes in rheumatoid arthritis. The effect of chloroquine on bone and articular cartilage was studied in 28 rheumatoid arthritis patients. After the administration of chloroquine for a minimum of 6 months, a metatarsal bone specimen was taken at operation. The control material consisted of 24 operated patients treated in the same way, except that they had not received chloroquine. Histological investigation, in which pairs of slides were compared in a blind test, revealed that the changes in the articular cartilage in those given chloroquine were less marked. Moreover, a diminished tendency to pannus formation and a more vigorous bone regeneration were observed in this group. Chloroquine seems thus to have a prophylactic effect on the articular cartilage changes in case of rheumatoid arthritis.


Retention and extra-articular spread of intra-articularly injected 90Y silicate. A study was performed on the retention and distribution of intra-articularly injected colloidal 90Y silicate in 7 patients with rheumatoid arthritis (8 knees). In 5 knees retention was complete within the limits of measuring accuracy, and in the remaining 3, 82-84% was retained. No radioactivity was detected in the liver and heart areas or in the blood samples. The cumulative urine activity was less than 1.8%. In the inguinal lymph nodes, activity was detectable %0.5-2%) in only 3 cases. We conclude that 90Y silicate is a safe radioactive agent for the treatment of knee effusions, provided the limb is strictly immobilized after the injection.


Osmium deposits detected by x-ray after synoviorthesis of the knee. A study of 113 knees of 72 patients treated with intra-articular injection of osmic acid for chronic exudative synovitis caused by various rheumatic diseases is reported. Certain cases presented abnormal radiological opacities, statistically more frequent after the injection of 200 mg than after 100 mg of osmic acid (33.9% and 15.7%). These images appear early after the injection and can remain for years. They should not be confused with intra-articular calcium deposits, or with synovial ossifications or various periosteal osteogenic processes. Their appearance does not seem to be related to the rheumatic disease treated or the therapeutic result obtained. They reflect the fixation of osmium in the synovial fatty tissue, which causes a fibrous reaction at this level. Their longterm action in the cicatrization of the synovia, or their part in a relapse of an inflammatory episode should be clarified.


[Clinical pharmacokinetics].

[Clinical pharmacokinetics]. The action of a drug depends on the quantity which reaches the site of its pharmacological action and how long it remains there. The necessary vital processes of the body dilute the active principle into different compartments of distribution, transform it into metabolites, and excrete it. Since a time duration of drug presence at the site of action is vital for the cure of disease, a comprehensive and quantitative expression of these time courses of drug distribution as a function of dose and route of administration is necessary for the establishment of proper dosage regimens for the treatment of disease and the avoidance of toxicities. The purpose of pharmacokinetics is to study these phenomena and to construct models suitable to explain them and to predict the behavior of drugs in conditions not yet studied. In this review some basic principles of pharmacokinetics (i.e. the compartment, the volume of distribution, the elimination half-life, etc.) are explained. Their clinical implications are shown in the case of multiple dose administration and in the study of the relations existing between blood levels of digoxin and the pharmacological action of this drug.


[The postoperative myocardial infarct in the surgical therapy of pelvic and leg arterial occlusions]. A total of 4063 surgical interventions for arterial occlusions of the lower limbs have been reviewed in a retrospective study. As compared to patients without specific diagnosis of preexisting coronary heart disease, the incidence of postoperative myocardial infarction is 10 times greater in the presence of clinical and electrocardiographic evidence of previous infarction; for patients suffering from typical angina pectoris the risk is 5 times higher and for patients with suspected preoperative infarction the incidence of postoperative infarction is 3 times that in surgical patients without such a history. The mortality rate from myocardial infarction occurring postoperatively in patients with no previous history of coronary heart disease is 26% as compared to 100% for patients who had sustained preoperative infarction. The rate of recurrence is significantly greater when the time interval between previous myocardial infarction and operation is less than three months. Comparison between elective and emergency cases shows that in the group undergoing emergency surgery the incidence of post-operative infarction is twice that under elective surgery, whereas mortality from myocardial infarction is 3 times higher following acute interventions. The problem of critical establishment of surgical indication, the need for accurate prior investigations and the requirement of adequate preoperative treatment are discussed.


[Hypernephroid carcinoma and carcinoma of the urinary tract following phenacetin abuse]. From the 24 683 autopsies performed at the Institute of Pathology of Zurich University from 1963 to 1973, all cases with hypernephroid carcinoma or carcinoma of the urinary tract were listed. For each type of carcinoma the extent of phenacetin abuse, the sex and the mean age of the patients were established. The positive relationship between phenacetin abuse and carcinoma of the renal pelvis and the urinary bladder confirms the results of other investigators. In addition, a relationship between phenacetin abuse and hypernephroid carcinoma is discussed.