Absence of a 'cholinergic link' in the apomorphine-induced feedback inhibition of dopamine synthesis in rat striatum.

The blocking effect of apomorphine on the rise in striatal dopamine (DA) content, induced by 1-hydroxy-3-amino-pyrrolidone-2 (HA-966) was taken as a measure for the intrastriatal feedback inhibition of DA synthesis. The effects of cholinergic drugs on this feedback system were assessed in order to verify the hypothesis that this mechanism is mediated via an intrastriatal cholinergic link. We presumed that DA receptors were located on a cholinergic neuron, while the cholinergic terminals in turn made direct or indirect axon-axonal contact with the dopaminergic nigro-striatal pathway (N.S.P.). Although cholinergic agents could modify the effect of HA-966 on striatal DA content, it proved to be impossible to counteract the blocking effect of apomorphine with cholinergic drugs as was to be expected. Therefore we concluded that the effect of apomorphine was not brought about in the way which had been postulated.


A comparison of the vasodepressor effects of the cyclic effects of the cyclic endoperoxides PGG, and PGH2 with those of PGD2 and PGE2 in hypertensive and normotensive rats.

The vasodepressor actions of the cyclic endoperoxides PGG2 and PGH2 were compared with those of their products PGD2 and PGE2 using anaesthetised normotensive and genetically hypertensive rats. Given into the aortic arch of normotensives PGE2 was approximately 6 times more potent than PGH2  and 11 times more potent than PGG2 and PGD2. Hypertensive animals were 1.5-10 times more sensitive than normotensives to the depressor effects of PGG2 and PGH2, but their sensitivity to either PGD2 or PGE2 was similar. Thus in hypertensives the endoperoxides may be converted more readily to PGE2 and other products. In both types of rat PGG2 and PGH2 given intravenously were as active or more active than after intra-arterial. Therefore PGG2 and PGH2 may be converted more readily to more active products during passage through the lungs but whereas small doses of PGE2 are almost completely eliminated large doses may saturate uplmonary removal mechanisms.


Effects of prostaglandin E1 on the positive inotropic actions of noradrenaline, nerve stimulation and calcium in the isolated blood-perfused papillary muscle of the dog.

The effects of PGE1 on the dog heart were studied using the blood-perfused sinus node and papillary muscle preparations isolated separately from the same animal. PGE1 administered into the papillary muscle artery as bolus injections in doses of 1-1000 ng caused a dose-dependent increase of the developed tension and dT/dt of the papillary muscle. The effect was not inhibited by the beta-adrenoceptor blocking agent pindolol. PGE1 injected into the sinus node artery in doses of 3-300 ng did not change the rate of contraction of the sinus node preparation. PGE1 in the blood concentrations of 4.4 X 10(-9) to 1.7 X 10(-7) M enhanced the positive inotropic responses to noradrenalin and field stimulation as well as to calcium. The influence of PGE1 on the positive inotropic effect of perivascular nerve stimulation was not consistent: the action of perivascular nerve stimulation was enhanced by PGE1 in the majority of preparations but was reduced in one third of preparations. PGE1 in the same blood concentrations as used in the papillary muscle significantly depressed the positive chronotropic responses to noradrenaline and dopamine. The present results indicate that PGE1 induces multiple actions on the dog heart. Its predominant effect on the ventricular myocardium appears to be enhancement of the adrenergic stimuli probably via the facilitation of calcium movement through the myocardial cell membrane. In addition, PGE1 may decrease the sensitivity of beta-adrenoceptors to adrenergic stimuli in the sinus node.


Effect of neuroleptics and of combinations of d-amphetamine and neuroleptics on 3H-dopamine uptake by homogenates from rat striatum.

Triperidol was found to be a more potent 3H-dopamine uptake inhibitor than chlorpromazine in homogenates from rat striatum. Inhibition kinetics were competitive for triperidol and non-competitive for chlorpromazine. When drugs were given in vivo, d-amphetamine (10 mg/kg) blocked the 3H-dopamine uptake by about 50% whereas the neuroleptics did not modify the process even at highly sedating doses. Combined treatments with d-amphetamine and neuroleptics showed that only triperidol potentiated the blocking effect of d-amphetamine on 3-H-dopamine uptake. However, such a potentiation was not observed when triperidol and d-amphetamine were simultaneously added in vitro. The results tend to suggest that the postulated actions of neuroleptics on presynaptic sites in the striatum may be more important with the butyrophenone, triperidol than with the phenothiazine, chlorpromazine.


The effects of isoxsuprine on non-myelinated nerve fibres.

A study has been made of the effect of isoxsuprine on non-myelinated nerve fibres of the desheathed rabbit vagus. Isoxsuprine did not affect the membrane potential, the membrane resistance, or the sodium pump activity. Isoxsuprine diminished the amplitude and rise time of the compound action potential. This indicates that isoxsuprine decreased the peak sodium current during the action potential. This local anesthetic action of isoxsupring is more pronounced than that of lidocaine.


Effects of verapamil on regional myocardial blood flow and ST segment. Role of the induced bradycardia.

The effects of verapamil on regional myocardial blood flow and on the ST segment were studied in both normal and ischemic regions in dogs with and without cardiac pacing. In the absence of cardiac pacing, verapamil (0.05 mg/kg/min/10 min) induced marked bradycardia, a drop in blood pressure and an increase in epicardial and endocardial flows both in normal and ischemic regions of the heart. However, in ischemic regions, redistribution was favorable since the endo/epi ratio increased from 0.46 to 0.61 (p less than 0.01) whereas this ratio did not vary in normal regions (0.94 vs. 0.92). This increase is accompanied by less marked ST segment elevation during coronary occlusion in dogs treated with verapamil. In dogs with cardiac pacing, administration of verapamil under the same conditions again induced a drop in blood pressure and, in normal regions only, a homogeneous but less marked increase in epicardial and endocardial flows, the endo/epi ratio varying from 0.94 to 0.98. In contrast, in ischemic regions, blood flow was not modified by verapamil, but the endo/epi ratio dropped from 0.46 to 0.31 (p less than 0.01), while the ST segment elevation observed did not differ from that recorded during the control occlusion. These results demonstrate the major role of verapamil-induced bradycardia in the anti-anginal affects of this drug.


Blockade of the specific lethal effects of narcotic analgesics in the mouse.

The capacity of the narcotic antagonists naloxone and nalorphine and the benzodiazepine derivatives diazepam and oxazepam to increase the LD50s of the narcotic analgesics morphine and methadone administered at convulsant doses was eveluated in the mouse. Naloxone produced a dose-related increase in the LD50s of both morphine and methadone. Iiazepam and oxazepam were also effective in increasing the LD50s of the narcotics; this effect was additive with that of naloxone. However, the maximal increase in the LD50s of the narcotics produced by pretreatment with naloxone alone was not increased further by the combined pretreatment of naloxone and a benzodiazepine. The anticonvulsant trimethadione did not elevate the LD50s of methadone, nor did it potentiate the effects of naloxone. These results suggest that the benzodiazepines may reduce the lethality of narcotic analgesics administered at high doses by a mechanism other than by an anticonvulsant effect alone. Therefore, the present results support the conclusion that the capacity to increase the convulsant LD50 of the narcotic analgesics is a general property of the narcotic antagonists.


The anticonvulsant activity of ketamine agains siezures induced by pentylenetetrazol and mercaptopropionic acid.

The activity of the dissociative anaesthetics ketamine and gamma-hydroxybutyrate against seizures induced by mercaptopropionate and pentylenetetrazol have been determined. Ketamine (90 mg/kg) prevented the seizures induced by both convulsants, but gamma-hydroxybutyrate had negligible anticonvulsant activity. Mercaptopropionate (150 mg/kg) produced a rapid fall in whole brain glutamate decarboxylase activity which correlated with the onset of convulsions. Ketamine given prior to the mercaptopropionate prevented the convulsions, but had no effect on the reduction of enzyme activity. It was concluded that although ketamine was an anticonvulsant it did not act by preventing the inhibition of glutamate decarboxylase responsible for mercaptopropionate-induced convulsions.


A laminar flow superfusion technique with much increased sensitivity for the detection of smooth muscle-stimulating substances.

The classical superfusion technique was modified by immersing the isolated assay tissues in mineral oil, making it possible to superfuse the preparations through the oil with a drip of Krebs solution at very low flow rates (0.1 - 0.2 ml/min). In this way the sensitivity of the preparation for the detection and quantitation of endogenous biologically active substances was extended to the picogram level.


Histamine receptor-mediated calcium ion movement in a receptor-rich microsomal fraction.

The histamine receptor-rich microsomal fraction from the longitudinal muscle of cat small intestine, which consists of membrane vesicles, was loaded with 45Ca ions and the Ca ion efflux from it was examined. Histamine increased the efflux of 45Ca ions. The effect of histamine was blocked by diphenhydramine. Histamine had no effect on the histamine receptor-free microsomal fraction from dog small intestine muscle. This suggests that the ion movement may be mediated by histamine receptors.


The dependence of the blood level of the oxime HS-6 on the severity of organophosphate poisoning.

Atropinised anaesthetised rats were injected i.v. with 4, 6 or 8 X LD50 of the organophosphorous anticholinesterase soman. Subsequent treatment with one dose of HS-6 (100 mg/kg, i.v.) delayed respiratory failure by 1 h or more; a further postponement was obtained when an additional HS-6 infusion was given. At the same infusion rate, HS-6 blood levels after 4 X LD50 soman remained stationary, but rose after the higher soman doses. The rise was greater the higher the soman dose had been. This rapid rise in oxime blood levels after high doses of organophosphate may seriously complicate therapy.


Determination of clonazepam ("Rivotril" or "Ro 5-4023") in plasma by gas chromatography using an internal standard.

A method has been developed for gas-chromatographic determination of clonazepam ("Rivotril" or "Ro 5-4023") in plasma, using methyl-clonazepam ("Ro 4082") as an internal standard. Following extraction of the benzodiazepines and hydrolysis, the benzophenones are analyzed by gas-chromatography, using a glass column filled with 3% OV 225 on Gas Chrom Q and a 63Ni electron-capture detector. The technique has good selectivity. The limit of sensitivity is less than 1 ng/ml of plasma. Using this method the plasma kinetics of clonazepam may be studied in man and the correlations between plasma levels and therapeutic activity investigated. It is also available for toxicological analysis, as well as pharmacovigilance purpose. The same internal standard and a similar method can also be used for the determination of flunitrazpem ("Rohypnol" or "Ro 5-4200") and its major metabolite (N-desmethyl-flunitrazepam) in plasma.


[Interference of minovine (a Vinca minor alkaloid) on hospital emergency toxicologic tests for derivatives of 5H-dibenzo(b,f)azepine].

The authors report the possible interference due to minovine when seeking tricyclic antidepressant derivatives in biological material or pharmaceutical substances. However, their work has shown that kinetic studies using absorption spectrophotometry of the colouration obtained with phosphoric-ceric reagent and thin layer adsorbant chromatography make it possible to eliminate the doubt and identify the Vinca-Minor alkaloid.


[The relationship between the course of bismuth encephalopathy and the amount of bismuth in blood and urine].

Study of the course of bismuth encephalopathy following the ingestion of a bismuth salt in relation to blood and urinary bismuth levels indicates a close parallel between the improvement in the clinical picture and the decrease in the degree of toxic impregnation of the body. This confirms the direct responsibility of bismuth for the disorder. Regression of myocolonic movements goes with the fall in blood bismuth levels, whilst improvement in the confusional syndrome is aomewhat delayed. There is a significant correlation between bismuth levels in the blood and urine. The excretion of bismuth is slow, and the persistence of blood and urinary bismuth levels higher than normal for several weeks after the acute phases and the interruption of the ingestion of bismuth salts reflects the existence of stable bonds between the metal and cellular constituents. The authors have observed a non-negligeable solubility of bismuth sub-nitrate in certain drinking waters, which brings up the hypothesis of a possible role of the hydrosobulity of bismuth in the pathogenesis of the intoxication.


[Specific assessment of the cerebral and cardiac effects of asphyxic hypoxia. Application to the study of substances with protective activity].

The influence of asphyxia on electrocorticogram (E. Co. G.) and electrocardiogram (E. C. G.) has been studied in curarized rats. The delay between the heightening of the ST component of E. C. G. and the disappearance of E. Co. G. pattern was measured. It provided more useful information on cerebral survival during asphyxia than the only study of E. Co. G. did. This delay was increased (cerebral antihypoxic effect) after intravenous treatment with pyritinol (50 mg/kg), vincamine (5 mg/kg) or propranolol (1 mg/kg), but it was not influenced by pentobarbital (60 mg/kg).


[Continuous inhalation of small amounts of formaldehyde: experimental study in the rat].

The results of experiments on the Rat, about the effects of continuous inhalation of 1.60, 4.55 and 8,07 ppm of formaldehyde, are reported: 150 SPF male rats were observed during one and an half to three months. These experiments concerned the clinical observation of the rats, their body weight and food intake, the relative weights of their lungs, liver, kidneys and spleen, the number and activity of their alveolar macrophages harvested by pulmonary washing. 1degree At 1.60 ppm it was only observed a yellowing of the hair of the intoxicated rats. 2degrees At 4.55 ppm, besides, the body weight of the intoxicated animals became significantly lower than the controls. 3degrees At 8.07 ppm, in addition to those differences, it appeared signs of irritation in the upper respiratory tract and in the eyes of the intoxicated rats, a significant underfeeding and a percentage of liver weight lower than the controls. Besides, the relative number and the phagocytic ability of alveolar macrophages of intoxicated rats was significantly lower than the controls. It was not observed the phenomena of adaptation previously described in the experimental rat intoxication by acrolein.


[Treatment of acute lithium poisoning with forced furosemide diuresis (physicopharmacodynamic bases)].

The basis of the treatment of acute lithium intoxication is clearance of the poison from the blood. Lithium and sodium ions being excreted under the influence of furosemide, the authors feel, in the light of one case, that forced diuresis, non-agressive, using furosemide appears to be the method of choice.


Fibroblast precursors in normal and irradiated mouse hematopoietic organs.

Using the in vitro colony assay, clonogenic fibroblast precursor cells (CFU-F) were detected in the bone marrow, spleen and thymus from adult mice. The survival curve for CFU-F of mouse bone marrow irradiated in vitro has a D0 of 220 r. Regeneration of bone marrow CFU-F after whole-body irradiation with 150 r is characterized by a marked secondary loss and post-irradiation lag and dip, lasting 6 days, followed by return to normal values by about the 25th day. This pattern of post-radiation recovery of CFU-F is similar to that of the CFU-s. In addition, during the first 6 hours following irradiation the number of CFU-F increased approximately twofold.


Techniques for induction of neutropenia and granulocytosis in rats.

After a single administration of vinblastine, rats develop profound neutropenia. The agranulocytosis lasts 3 days, and it is observed on the third, fourth and fifth day after vinblastine administration. The granulocytosis that develops on days 7-14 after vinblastine administration was significantly increased when androgenic steroids were administered. Deca-Durabolin induced greater granulocytosis than testosterone. The peak values were observed 10 and 12 days, respectively, after drug administration. All values of WBC's, granulocytes and hematocrit ratios were obtained in unanesthetized, unrestrained rats from an aortic cannula implanted at least 10 days prior to the experiment.


The influence of steroids on erythropoiesis in mouse fetal liver cell cultures: relevance of cell cycle state.

It has been shown that erythropoietin-mediated stimulation of heme synthesis in mouse fetal liver cells in vitro is correlated with hydroxyurea sensitivity. Assuming that OHU is specifically cytotoxic for cells in DNA synthesis this suggests that erythropoietin sensitivity may be related to this phase of the cell cycle. The direct effects of 19-nortestosterone and 3beta-hydroxy-5beta-pregnan-20-one on heme synthesis correlated with the capacity of these steroids to initiate DNA synthesis. It is suggested that the ability of these steroids to increase the proportion of cells in the Ep-sensitive phase of the cell cycle is probably the mechanism responsible for the erythropoietic effects of these agents. 17beta-hydroxy-5alpha-androstan-3-one appears to have a different mode of action since it has only minimal effects on heme synthesis and did not increase hydroxyurea sensitivity.


Effect of androgens on maturation and metabolism of erythroid tissue.

Specific changes taking place in the erythroid tissue following depletion or replacement of androgens were studied in rats. The reduction of testosterone levels in blood of orchiectomized animals did occur in conjunction with a decline of erythrocyte glucose-6-phosphate (G6P) and lactate levels. No evidence of anemia was observed. The subcutaneous administration of testosterone propionate (16.0 mg/kg) to orchiectomized rats restored, within 12 hours, blood testosterone levels as well as erythrocyte G6P levels and lactate production. The in vitro incorporation of glucose-1-14C into rat erythrocytes incubated with testosterone was comparable to that of control cells. A radioautographic study of rat erythroid marrow pulsed with glucose-1-14C showed a lower labeling when testosterone propionate was administered. The authors conclude that testosterone does directly affect glucose metabolism of erythroid cells, via the pentose shunt pathway. The possible role of the androgen-dependent enhancement of erythroid glycolysis is discussed in relation to the function of testosterone receptocytes present in marrow cells and a 17beta-hydroxysteroid dehydrogenase present in erythrocytes.


Effects of radiation on hematopoietic stroma.

The effects of x-irradiation on the CFU-S and on the hematopoietic stroma (HS-P) were studied and compared. Exposure to 300 rad reduced the CFU-S population to less than 1% of normal; by contrast more than 500 rad was required to detectably damage the HS-P. Although exposture to 500 rad did not detectably affect HS-P function, a second exposure to 500 rad as much as 4 weeks later did appreciably affect the HS-P. In addition, whereas the CFU-S returned to the pre-irradiation level within 6 weeks, the HS-P did not significantly recover. From these data we conclude that, with respect to the initial impact and exposure dose, HS-P is more radioresistant than CFU-S, but recovery from radiation induced damage of HS-P occurs slowly or does not take place.


Time-lapse characterization of erythrocytic colony-forming cells in plasma cultures.

The development of erythrocytic colonies in plasma cultures of C3H/Bi mouse fetal liver cells stimulated with erythropoietin was recorded by time-lapse cinemicrography, in order to investigate the nature of the colony-forming unit (CFU-E) from which they arose. Each colony was found to develop from a single cell, which in most cases underwent two divisions before acquiring hemoglobin, as detected by absorption in the Soret band. Less frequently, there were one or three divisions before hemoglobin appeared at 11.7 to 29.2 h. The diameter of the colony-forming cells in G2 was 16.0+/-1.3 mum (mean+/-SD). Daughter cells in each colony had similar generation times, with a TG of 11.0+/-2.2 h (mean+/-SD) for the first generation of colony cells. Evidence is presented that while some of the colony-forming cells were triggered into division by the erythropoietin added at plating, others had already been stimulated by endogenous erythropoietin in the fetus.


Fulminant Purkinje cell death following axotomy and its use for analysis of the dendritic arborization.

Young and adult cats were operated upon and a number of the vermal cerebellar folia were either transected with a vertical incision or isolated by a horizontal cut. In the proximity of the lesion, Purkinje cell bodies and their dendritic trees became stainable with the Fink-Heimer method. Electron microscopy of the silver stained sections show that the argyrophilic Purkinje neurons undergo an electron dense type of degeneration. Stellate cell dendrites adjacent to the degenerating Purkinje trees are normal, suggesting that the cause of cell death is axotomy close to the perikaryon rather than direct injury. The retrograde Purkinje cell degeneration is fulminant since it is evident 6 hours after the lesion. In Fink-Heimer stained sections the entire dendritic tree is impregnated 1-3 days after the lesion. 4-10 days post-operatively, the flattened dendritic tree becomes fragmented and is partially phagocytized. The silver stained arborizations are approximately 280 mu in width and have an uneven thickness (8-16 mu). In longitudinal and horizontal silver stained sections of lesioned cerebellar folia, uninterrupted fields of degenerating Purkinje cell arborizations can be seen, suggesting that the arborizations overlap. The overlap was demonstrated in electron micrographs of single degenerating arborizations surrounded by normal dendritic trees. The degree of overlap varies with the thickness of the arborization and is in the order of 1-2 mu. This approach indicates that each Purkinje tree occupies an exclusive sheet of molecular layer 8 mu thick and may overlap for as much as 2 mu on each side with neighboring trees. The average thickness of the Purkinje tree is approximately 12 mu.


Eye tracking of self-moved targets in the absence of vision.

Smooth pursuit eye movements have been described as resulting from the tracking of self-moved targets in total darkness. This study investigated the nature of the signal responsible for the release of smooth pursuit in this particular situation. Simultaneous monitoring of eye and hand positions shows that in total darkness smooth pursuit can only be released if the imagined target is either passively or actively moved by the subject's hand. An ischaemic block applied at the level of the biceps allowed us to selectively remove the afferent signal preferentially to the efferent copy in tasks involving eye tracking of an imaginary target actively or passively moved. The results show that an afferent signal was necessary and sufficient to release smooth pursuit, whereas the efferent copy alone could not trigger smooth pursuit. However, the efferent copy could play an important role in the phase relationship (prediction) between eye and finger events and in the activation of the concomitantly active saccadic system. Analysis of the eye movement characteristics, in various non-visually guided, load-affected situations, suggested that the main input to the smooth pursuit system was derived, in a non-graded way, from the position detector activation of the target-moving structure.


Quantitative ultrastructural observations on the inhibited recovery of the hypoglossal nucleus from the axotomy response when regeneration of the hypoglossal nerve is prevented.

Electron micrographs of the left hypoglossal nucleus were quantitatively analyzed in adult rats 52 to 98 days after transection of the left hypoglossal nerve and implantation of the proximal stump into the already innervated ipsilateral sternomastoid muscle, a procedure which prevented the transected nerve from regenerating. Many presynaptic boutons with clear spherical synaptic vesicles and symmetrical synapses were lost from the injured perikarya and dendrites. Some perikarya and dendrites (and, rarely, boutons) became electron dense, and astrocyte or microglial sheaths partly surrounded them. Numbers of dendrite profiles in the neuropil decreased. These statistically significant effects persisted throughout the postoperative period, whereas after axotomy with unimpeded nerve regeneration, these features would have returned to normal by 84 days postoperatively. It was therefore suggested that their recovery depended upon successful regeneration and reconnection of the hypoglossal nerve with the tongue. Subsurface cisterns, and profiles containing unusual inclusions, were numerically normal 52 to 98 days postoperatively, so it was suggested that their early response and recovery after simple axotomy might be entirely dependent on nerve disconnection and not on nerve reconnection.


Age dependence of the effect of squint on cells in kittens' visual cortex.

The period of susceptibility of the visual cortex of kittens to the effect of squint is limited to the first three postnatal months. The reduction of binocularity found in these kittens as reflected by the distribution of neurons according to their ocular dominance is especially emphasized in animals operated on between the ages of 4-7 weeks in comparison to animals operated on between the ages of 8-11 weeks. The proportion of monocularly dominated neurons within the first three postnatal months is significantly (0.05 greater than p greater than 0.025) reduced with age. Similar effect on cortical neurons was found for animals who were under the influence of squint for 6 weeks or 15 months and for animals with wide range of deviation angles.


The synaptic organization of the cerebello-olivary circuit.

Section of the superior cerebellar peduncle just rostral to the deep cerebellar nuclei results in degenerating axon terminals within the contralateral inferior olive. The nuclear origin of this fiber system and its distribution within the subdivisions of the inferior olive were described in a companion study (Martin et al., 1976). Precise localization of these degenerating terminals within the nucleus was accomplished by the examination of 1 mu plastic sections cut from each tissue block prior to thin sectioning. Degenerating axon terminals are present in all the nuclear subdivisions and when seen with the electron microscope they frequently are localized in the previously described synaptic clusters (King, 1976). These terminals demonstrate an electron dense reaction at survival times of 2 and 3 days. By day 4, they are shrunken and irregular in shape, and typically are surrounded by astrocyte processes. Cerebello-olivary axon terminals measure 1-3 mu, contain spherical, clear synaptic vesicles and typically contact spiny appendages within the synaptic clusters (glomeruli). Thus, we have demonstrated that one of the primary axon systems which terminates within the synaptic clusters is from the cerebellar nuclei. We have yet to determine the origins of the remaining terminals within the synaptic clusters which include endings with either smaller spherical, pleomorphic or numerous dense core vesicles.


Unusually large receptive fields in cats with restricted visual experience.

The receptive fields of striate cortex neurons were analyzed in cats which had restricted or no visual experience. Two groups of animals were investigated: 1. cats which were deprived from contour vision over variable periods of time up to 1 year and 2. kittens whose visual experience was restricted to vertically oriented gratings of constant spatial frequency which moved unidirectionally at a fixed distance in front of the restrained animals. In both preparations exceedingly large receptive fields (up to 20 degrees in diameter) were encountered, especially in cells located in supragranular layers. These large receptive fields never extended over more than 2 degrees into the ipsilateral hemifield. Their sensitivity profile was frequently asymmetric and contained discontinuities. Many of these large receptive fields consisted of several excitatory subregions which were separated from each other by as much as 15 degrees. Often but not always the most sensitive area was located where the retinotopic map predicted the receptive field center. The orientation and direction selectivity and also the angular separation of such multiple excitatory bands often matched precisely the orientation, direction and spatial frequency of the experienced moving grating. In other fields with multiple excitatory subregions such a correspondence could not be established; the various subregions could even have different orientation and direction selectivities. From these unconventional receptive fields it is concluded that the function of cat striate cortex is not confined to a point by point analysis of the visual field in retinotopically organized and functionally isolated columns.


Input from trigeminal cutaneous afferents to neurones of the inferior olive in rats.

Extracellular recordings were obtained from inferior olivary neurones of the rat. The responses of fifty neurones evoked by electrical stimulation of a branch of the trigeminal nerve were recorded. Maxillary nerve stimulation was most effective. The response was characterized by an early discharge (single spike and wave, typically with latencies between 16 and 30 msec) and a weak late discharge which followed a period of inhibition of about 100 msec. Half of the neurones responded to one branch of the trigeminal nerve only whereas the other neurons displayed a varying degree of convergence, including sometimes a convergence from limb nerves. Forty-nine olivary neurones were tested for cutaneous receptive fields. Ten out of these had small receptive fields (less than 20% of the contralateral face) and a low threshold to mechanical stimuli. Twenty neurones which had larger receptive fields responded also to low-threshold or to medium-threshold (i.e. non-nociceptive) mechanical stimuli. None of the neurones displayed receptive fields more extensive than half of the contralateral face and some of the larger fields had a small, low-threshold focus. Olivary neurones responding to electrical stimulation of trigeminal nerves or mechanical stimulation of the face were located in the medial segment of the olivary complex (dorsal accessory and principal olive). A few cells only were located in the lateral segment. It is concluded that neurones of the inferior olive receive a substantial input from trigeminal afferents and are capable of transmitting precise somatotopical information to the cerebellum.


Elevated kidney glucosyltransferase activity in genetic prediabetic mice.

Glucosyltransferase activity in the renal cortex of genetic diabetic KK mice was significantly increased at 40 days of age when compared to that of Swiss albino and F1 hybrid mice. This increase in enzyme activity in the absence of glucose intolerance can be regarded as an earlier genetic marker for the diagnosis of diabetic microangiopathy.


Metabolism of 1,3,7-trimethyldihydrouric acid in the rat: new metabolic pathway of caffeine.

[1-CH3-14C] 1,3,7-trimethyldihydrouric acid which, in quantity, is the most important caffeine metabolite, was isolated and purified from the urine of rats fed with [1-CH3-14C] caffeine. The oral administration of this metabolite to rats showed that 1,3,7-trimethyldihydrouric acid was excreted unchanged in urine and was therefore an end product of caffeine metabolism. This result implies a new metabolic pathway of caffeine.


The desulphation of hexosamine sulphates by arylsulphatase B.

The sulphation of Carbobenzoxyglucosamine by chlorosulphonic acid resulted in formation of N-carbobenzoxyglucosamine-4,6-disulphate. UDP-galactosamine 4-sulphate and glucosamine 4,6-disulphate were the competitive inhibitors of arylsulphatase B. Arylsulphatase B can hydrolyze UDP-galactosamine 4-sulphate and glucosamine 4,6-disulphate but not galactosamine 6-sulphate.


[Effect of 6beta-Methoxy-9beta,10alpha-pregna-4,6-diene-3,20-dione (Ro 6-1963) on the steroid reductases in rat liver].

6beta-Methoxy-9beta,10 alpha-pregna-4,6-diene-3,20-dione inhibits the delta4-3-oxosteroid-5alpha-reduction in microsomes and the delta4-3-oxosteroid-5beta-reduction in the soluble fraction of male rat liver. The 3alpha- and 3beta-hydroxysteroid dehydrogenase are not inhibited by these substances.


Reactions of the goldfish (Carassius auratus auratus L.) to quantified mechanical and thermal stimuli.

Goldfish can differentiate between mechanical and thermal stimuli components in combined stimulations. Reactions to heated thermode (deltaT = + 3 degrees C) differ from those to isotherm thermode by up to 30%. Additional pretension (0.5 p) increases the reaction more than double; at simultaneously varied temperature (deltaT = + 3 degrees C and + 5 degrees C), there is a further increase in reaction of 25% and 35%. The significance for the organism of the two stimuli components is discussed.


Thiamine diphosphatase in rat small intestine.

TDPase is located mostly in the proximal portion of the small intestine and its activity, like that of ALPase, decreased markedly in thiamine deficiency. The decreased enzyme activities were restored after thiamine or vitamin D3. Kinetic and other studies of the purified enzyme indicated the identity of the two enzymes.


Kinetics of lymphocyte division in blood cultures studied with the BrdU-Giemsa technique.

Normal human lymphocytes were cultured for 72 h with different doses of BrdU. The analysis of metaphases processed with the BrdU-Giemsa method shows that in leukocyte cultures 3 different lymphocyte populations coexist which are able to perform 1, 2 or 3 rounds of replication in vitro. Moreover, it was concluded that 5 mug/ml is the minimal dose of BrdU inducing good differentiation in the areas of sister chromatid exchanges.


The effect of sulfhydryl reagents upon the activity of 40S ribosomal subunits.

p-Chloromercuribenzoate inhibited the poly (U)-dependent binding of the Phe-tRNA to the 40S ribosomal subunit but displayed no inhibitory effect on the binding of poly (U) to the ribosome. Other sulfhydryl reagents tested, like N-ethylmaleimide and iodoacetamide, did not affect the binding of Phe-tRNA to the small ribosomal subunit.


Juvenile hormone analogue counteracts growth stimulation and inhibition by ecdysones in clonal Drosophila cell line.

Depending on concentration, ecdysones either stimulate or inhibit proliferation of a clonal Drosophila cell line. Both effects are counteracted by ethyl dichlorofarnesoate, a juvenile hormone analogue, which by itself is growth inhibitory. Qualitatively no difference was seen between alpha- and beta-ecdysone.


Chromosome banding patterns and the nucleolar organizer region of the eastern mole (Scalopus aquaticus).

The C and G chromosome banding patterns and the AgAS positive sites (NOR regions) of cultured lung cells of the Eastern mole (Scalopus aquaticus) are presented. A distinctive secondary constriction is found on a pair of autosomes instead of on the X-chromosome as previously believed. The presence of a heterochromatic heteromorphism is noted and a large amount of constitutive heterochromatin is present in the karyotype.


Acid phosphatases in Drosophila auraria.

A study was carried out dealing with the acid phosphatases, in larvae, pupae and adults of Drosophila auraria. The most interesting finding is that the acid phosphatases are observed in 3 different phenotypes appearing as groups of 3 bands of different mobilities in the homozygotes and giving a 5 band phenotype in the heterozygote. A hypothesis is discussed in an attempt to explain the phenotypes observed and their variation during the development of the species.


Direct relationship between urinary prostaglandin E and sodium excretion in essential hypertensive patients.

Urinary prostaglandins (PGEs and PGFs), sodium and potassium were measured in 17 essentially hypertensive patients. Significant positive correlations were found between a) PGEs secreted in 24 h and sodium excreted in 24 h, b) the ratio PGEs/UnaV before and PGEs/UnaV after volume expansion and c) the ration Na/K and urinary PGEs. It was suggested that renal PGEs, potent natriuretic and diuretic substances, play an important homeostatic role in the extracellular fluid regulation, and consequently in long-term control of the arterial blood pressure.


The action of cycloheximide on the action potential and protein synthesis in medullated Xenopus axons.

Cycloheximide depresses maximum rate of change in membrane potential observed during the rising phase of the action potential in single medullated axons of Xenopus. To,e course of depression is independent of cycloheximide concentration over a range that almost completely inhibits leucine incorporation into axonal proteins.


Effects of various degrees of undernutrition of mice on pregnancy and conceptus.

Maternal intake of drastically (1/2 of control) and substantially (1/2 of control) reduced feeding was studied in pregnant mice during gestation and embryonic development. Resorptions, fetal mortality rate and fetal weight were significantly affected by maternal undernutrition during the treatment period. The number of fetuses with intrauterine weight retardation was also significant.


The change of vagal activity evoked by spinal cord thermal stimulation in anesthetized rabbits.

Vagal activity decreased significantly during spinal cord warming and increased significantly during spinal cord cooling in anesthetized, immobilized rabbits. The results provide the first direct proff of changes in parsympathetic activity during spinal thermal stimulation.


Transmural pressure as a determinant of basic intrinsic heart rate.

It was observed that the heart rate was minimum at zero transmural pressure. The mean heart rate at zero transmural pressure was 23+/-5/min. This mean heart rate increased from 23+/-5/min to a peak value of 40+/-6/min (74% acceleration) when the transmural pressure was raised from 0 to +4 mm Hg and to a similar peak value of 36+/-8/min (56% acceleration) when the transmural pressure was lowered from 0 to -4 mm Hg. The peak values attained at +/-4 mm Hg were highly significant (p less than 0.001). It is concluded that the heart rate at zero transmural pressure represents the basic intrinsic pacemaker frequency independent of neural, humoral, thermal and haemodynamically induced mechanical influences.


Rudiments of an ability for time measurement in the cavernicolous fish Anoptichthys jordani hubbs and innes (Pisces Characidae).

Rudiments of an ability for endogenous time-measuring are indicated a) by bimodal activity in the dark phase of LD-cycles of 16:16 or 24:24 h and b) by damped activity oscillations frequently following a transition from LD to constant conditions. These oscillations always have the same period length as the applied LD.


Distribution of H3-dimetacrine in rat cerebral cortex by electron microscopic autoradiography.

The cellular distribution of H3-dimetacrine in rat cerebral cortex was studied by electron microscopic autoradiography. A considerable proportion of autoradiographic grains (40.6%) was located over the synaptic areas, while the other strictires (i.e., dendrites, axons, glial and neuronal cells) contained less autoradiographic activity.


The role of calcium in the negative inotropic effect of lanthanum.

Lanthanum reduces the rate of calcium fast exchanging processes, whereas the slowly exchanging phase is not modified. Experimental data also confirm the importance of calcium fast exchanging fraction in regulating contractile force of cardiac muscle.


Lipoperoxide formation in the retina in ocular siderosis.

Insertion of iron nail into the vitreous cavity provoke the formation of lipoperoxide in the retina. In acord with the increase in lipoperoxide in the retina, ERG began to decrease. In vitro experiment using isolated retina, lipoperoxide was found to be increased in the presence of ferric or ferrous ions, while it was inhibited by adding antioxidants or ethylenediamine tetraacetate. From these results, direct cause of retinal degeneration in siderosis could be ascribed to the formation of lipoperosice by iron-ions liberated from the piece of iron, resulting into the degeneration of the visual cell layers of the retina.


The subcommissural organ of the lizard Lacerta s. sicula Raf. ultrastructure during the winter.

The secretory activity of the SCO cells of Lacerta s. sicula Raf. is strongly reduced during the winter. Such reduction is documented by the decrease of the decrease of the number of secretory granules type A and B described in previous papers in the summer SCO cells. Also the sacks of RER filled with electron-dense material (type C secretion) are very few; in their place there are, in the basal region of the cells, large vacuoles. In the distal region of the cells, at the free cell surface, a pronounced increase in the number of microvilli is noticed.


On the mechanism of water uptake by the developing eggs of Calotes versicolor.

Experiments show that osmotic gradient has a role in the absorption of water by the semi-cleidoic egg of Calotes versicolor. The observations also indicate that in nature the eggs need to be laid in water-saturated soil and can easily withstand flooding but not dryness.


[Germinal population of gonads in some chimerical embryos obtained by connecting pieces of japanese quail and domestic chick blastoderms (author's transl)].

The experimental realization of chemerical embryos (Martin's13 technic) permits a quantitative appreciation of the modalities of the colonization of quail gonads by chick germ cells. Results clearly show that nature and origin of the somatic part of the gonad areas settle the characters of the genital ridges populating, and specially the specific index of asymmetry expressed by the percentage of PGC colonizing the right gonad.


Origin of ovarian follicle cells in birds.

In the embryonic Japanese quail ovary, transplanted on chicken chorioallantoic membrane (CAM), follicle cells are derived from somatic cells of the ovarian surface epithelium. No evidence was found for a contribution of other cell groups of the quail ovary in the formation of follicle cells. This may be demonstrated on PAS stained sections, by following the transfer of carbon particles, initially applied on the surface epithelium.


Association of mastopoiesis with haemopoietic tissues in the neonatal rat.

Mast cells in the newborn rat occur in harmopoietic foci of liver and spleen, but disappear from those foci as extramedullary harmopoiesis ceases during the initial postnatal month. At the same time, mast cells increasingly populate bone marrow and connective tissues of heart, lung, stomach and portal tract of liver.


Blood plasma investigations by resonance Raman spectroscopy: detection of carotenoid pigments.

Using Raman spectroscopy, we demonstrate that low levels of beta-carotene, lycopene, and xanthophyll give rise to resonance enhanced bands in blood plasma. These results explain the significance of previously unidentified spectral maxima which have been related to the state of health of the blood donor.


Limitations of the direct linear plot in evaluation of drug-protein binding parameters.

The applicability of the direct linear plot is compared with that of the Scatchard plot for the estimation of protein binding parameters. Only, if one class of binding sites exists in the system tested, binding parameters may be estimated by use of the direct linear plot. On the other hand the Scatchard plot also provides estimates in systems with more that one class of binding sites.


Funding for reproductive research: the status and the needs.

Just to maintain the admittedly inadequate level of research in reproduction and contraceptive development attained in 1974 would require an investment of $143 million this year--a level that has not been reached. To take advantage of existing knowledge, at least $361 million would be required--increasing to $498 million by 1980. To achieve a high-priority research program--10 percent of health expenditures--would require $500 million this year--rising to $766 million by 1980.


How old is too old? Age and the sociology of fertility.

Are we due for a new baby boom as couples who had postponed childbearing begin to make up for lost time? Analysis of National Fertility Study data suggest that "later means fewer"--quite apart from the declining fecundity that occurs at older ages. Couples who delay having children until relatively late in life are subject to fewer pressures to have children (or more children) even as the reasons not to begin (or increase) their families become more salient.


Family planning needs and services in nonmetropolitan areas.

More than 215 million low- and marginal-income women living in rural areas are still without access to family planning services they want and need. Priority attention to more populous areas where there are no organized programs, or just one agency providing services, is suggested. Increased involvement of hospitals is necessary if the rural-urban gap is to be closed.


The U.S. fertility decline, 1961-1975: the contribution of changes in marital status and marital fertility.

Changes in marital fertility have accounted for 83 percent of the decline in total fertility since 1971; changes in marital status accounted for 19 percent, and changes in nonmarital fertility had only a negligible effect. Declines in the level of marital fertility account for a substantial part of the overall decrease; postponement of childbearing did not occur in any significant degree until the 1970s.


Quantitative studies of the pathway to acute carrageenan inflammation.

A 12-step scheme representing initiation and development of acute carrageenan inflammation in the rat has been devised. Simultaneous quantitative temporal measurement of the number of inflammatory cells mobilized and edema volume produced as carrageenan pleurisy developed helped elucidate several of the early steps, In the pleurisy a 20-min lag phase preceded both the mobilization of neutrophils and edema formation. Temporal histological studies suggested that the lag phase represents the time needed for the neutrophil chemotactic factor to be generated and/or released (steps 2 and 3) in addition to the time required for these cells to move through the walls of the capillaries into the pleural space (steps 4 and 5). The neutrophil chemotactic factor is unknown. The complement system is not involved since cobra venom factor-treated animals produced a normal edematous and cellular response to carrageenan in spite of severely depressed complement levels. The mobilized neutrophils are believed to phagocytize the carrageenan(step6). In this process lysosomal enzymes are released (step 7). Drug inhibition studies suggest that lysosomal enzymes are not the edemagenic agents in carrageenan inflammation. In the scheme these enzymes are responsible for activation of the prostaglandin biosynthetic chain (step 8). Prostaglandin biosynthesis (step 9) leads to the release of an intermediate (step 10), as yet unidentified, which is responsible for increased tissue permeability (step 11) and edema formation (step 12). Histamine, serotonin, bradykinin, arachidonic acid, and prostaglandin's E1 and E2 are not deemagenic in the rat pleural cavity and therefore cannot be responsible for edema formation. Aspirin and indomethacin reduce the edema produced by carrageenan in a dose-related manner without affecting the magnitude or the time course of neutrophil mobilization. These findings led to the concept that edema formation is not the result of inflammatory cell mobilization but is rather a consequence of cellular activity, presumably phagocytosis, after mobilization.


The effect of certain vitamin deficiencies on hepatic drug metabolism.

There is increasing evidence that the liver microsomal drug metabolizing system is affected by various vitamins such as ascorbic acid, riboflavin, and alpha-tocopherol. In regard to ascorbic acid deficiency there is a decrease in the quantity of hepatic microsomal electron transport components such as cytochrome P-450 and NADPH-cytochrome P-450 reductase, as well as decreases in a variety of drug enzyme reactions such as N-demethylation, O-demethylation, and steroid hydroxylation. In addition, young animals given high supplements of vitamin C have increased quantities of electron transport components and overall drug metabolism activities. Kinetic studies indicate no change in the apparent Km of N-demethylase, O-demethylase or hydroxylase for drug substrates in animals depleted or given high amounts of the vitamin. However, there are qualitative changes in both type I and II substrate-cytochrome P-450 binding. Ascorbic acid is not involved in microsomal lipid peroxidation or in any qualitative or quantitative change in phosphatidylcholine. Replenishing vitamin C-deficient animals with ascorbic acid required 3 to 7 days for the electron transport components and drug metabolism activities to return to normal levels. Induction with phenobarbital and 3-methylcholanthrene is not impaired in the deficient animal since drug metabolism activities are induced to the same extent as normal controls; however, the administration of delta-aminolevulinic acid, a precursor of heme synthesis, to deficient animals caused an increase in the quantity of cytochrome P-450. The effects of riboflavin deficiency on electron transport components and drug metabolism activities have been noted only in adult animals after prolonged periods of deficiency. Decreases in drug metabolism activities occur with both type I (aminopyrine and ethylmorphine) and type II (aniline) substrates. As was found with ascorbic acid deficiency, drug enzyme induction occurred to the same extent with phenobarbital in deficient and normal animals. In addition, it required from 10 to 15 days for the drug metabolism activities to return to normal levels when deficient animals were replenished with riboflavin. The effect of vitamin E on drug metabolism is specific in N-demethylase activities decrease while O-demethylase activities are not affected in the deficient state. This vitamin differs from ascorbic acid and riboflavin in that several laboratories have reported no quantitative decrease in cytochrome P-450, although there are some reports that it and delta-aminolevulinic acid dehydratase are lowered quantity of cytochrome in E-deficient animals. The effect of vitamin E, if any, on the P-450 is unresolved; an important question that requires further clarification. As with ascorbic acid there is no difference in the apparent Km of N-demethylase enzymes for varous substrates and the protective effect of vitamin E does not appear to be one of an antioxidant inhibiting microsomal lipid peroxidation.


The effect of quantity and quality of dietary protein on drug metabolism.

Dietary protein deficiency is known to modify the response to the pharmacotoxicological activities of drugs and foreign compounds, due in part to altered rates of metabolism. Prediction of whether in vivo susceptibilities to foreign compounds are increased or decreased in protein deficient animals has been said to be related to the relative toxicites of the metabolic products. We have shown that weanling rats fed semipurified casein diets for 15 days show a 75% depression of hepatic microsomal mixed function oxidase activities. About one-fourth of this decrease is due to a retardation of the normal rate of liver cell proliferation and less microsomal protein; the remaining three-fourths is due to a reduction of the specific enzyme activity. This latter decrease is closely correlated with similar decreases in cytochrome P-450 and cytochrome c reductase activities and cytochrome P-450 contents. Although protein deficiency affects the relative contents of phosphatidylcholine and cytochrome P-450, this does not result in modifications of the Km for metabolism, as is seen with phenobarbital administration in the various dietary groups. The depression of mixed function oxidase enzyme activities caused by feeding the protein deficient diet for 15 days can be restored to normal by feeding the 20% casein diets for an additional 30 days in the case of aniline hydroxylase but only partially in the case of ethylmorphine N-demethylase. The complexities of determining the role of metabolism as a modulator of protein deficiency effects on foreign compound toxicity are discussed.


Angiotensin antagonists and the adrenal cortex and medulla.

Several analogs of angiotensin in which the phenylalanine in position 8 of the peptide chain was replaced by an aliphatic amino acid residue are specific antagonists of angiotensin in aorta, the adrenal medulla, and adrenal zona glomerulosa. In the adrenal cortex and medulla, all actapeptide analogs have more agonist activity than in aortic strips. In studies with N-terminally substituted analogs, it appears that adrenal degradation of the angiotensin molecule by aminopeptidase(s) does not occur or is not retarded by N-terminal mocifications such as sarcosine substitution. The decapeptide analog [Ile8]-angiotensin I and heptapeptide analog [des-Asp1, Ile8]-angiotensin II were excellent antagonists in the adrenal medulla and each peptide was devoid of intrinsic activity. These substituted homologs of angiotensin may offer a novel approach for the development of selective antagonists of angiotensin receptors. In the adrenal cotex, [des-Asp1, Ile8]-heptapeptide possessed greater receptor affinity than any of the angiotensin octapeptides studied. This C-terminally substituted heptapeptide does have significant intrinsic activity in the adrenal cortex which would limit the use of this compound as an antagonist of vascular responses to angiotensin II. In studies with [Ile8]-angiotensin II, [Sar1, Ile8]-angiotensin II, and [des-Asp1, Ile8]-angiotensin II, the pA2 values calculated indicate that the N-terminal residue is not important for receptor binding in the adrenal cortex but may be of significance in binding to adrenal medullary and aortic smooth muscle receptors. At the present time it appears unlikely that any single animal model or assay system can reliably predict the agoinst/antagonist activities of angiotensin analogs for all the various end organs which respond to the angiotensins.


The use of angiotensin II blockade to study adrenal steroid secretion.

In the dog, the renin--angiotensin system appears to be a primary control mechanism for aldosterone secretion since angiotensin II blockade decreased aldosterone production to undetectable levels. Angiotensin II blockade also decreased cortisol secretion strikingly in dogs with thoracic caval constriction, a finding which suggests the presence of an angiotensin II receptor in the two inner zones of adrenal cortex. An important incidental finding after angiotensin II blockade in both sodium-depleted dogs and dogs with thoracic caval constriction was the striking drop in arterial pressure. It is suggested that angiotensin II acts on the peripheral arterioles to provide an important compensatory mechanism and, thereby, maintain arterial pressure in these low cardiac output states. In the rat, both the nonapeptide converting enzyme inhibitor and [Sar1, Ala8]-angiotensin II produced a marked decrease in aldosterone secretion in hypophysectomized, sodium-depleted animals. Both synthetic angiotensin II and its heptapeptide fragment produced striking increases in aldosterone secretion when the obscuring effect of ACTH was excluded in the rat. These findings provide evidence that the renin--angiotensin system is an important control mechanism for aldosterone biosynthesis in the rat.


Clinical pharmacology of angiotensin antagonists.

The early clinical pharmacologic investigations of saralasin were facilitated by the availability of a highly sensitive and specific radioimmunoassay for this peptide. In these studies, plasma concentrations of saralasin were correlated with inhibition of angiotensin receptors in each of three organ systems: vascular smooth muscle, adrenal cortex, and the renin release control mechanism in the kidney. The biochemical half-life of plasma saralasin was 3.2 min and an infusion time-to-plateau was 12--15 min. Saralasin inhibited adrenal cortical, vascular, and intrarenal (renin release) angiotensin receptors. The time required for manifesting these blocking actions was short(3--10 min) except for the 30--60 min required to suppress plasma aldosterone. Saralasin-induced blood pressure lowering was dependent on previously elevated serum renin activity and volume depletion. Expansion of intravascular volume prevented hypotensive responses to saralasin even in high-renin patients. Saralasin-induced renin release occurred independent of hypotension and could be inhibited by propranolol, a beta-adrenergic blocking agent. Thus, saralasin is a selective angiotensin antagonist which lacks organ specificity. It is a highly useful tool in pharmacologic studies of the renin--angiotensin axis in man and shows promise as a diagnostic tool.


Luteinizing hormone and progesterone in women under postcoital contraception with D-norgestrel.

Luteinizing hormone (LH) and progesterone (Pg) levels in blood were measured simultaneously by radioimmunoassay during 53 menstrual cycles in order to investigate the effect of 400 mug of D-norgestrel, administered postcoitally, on pituitary and ovarian function. Of 31 control cycles, 2 appeared to be anovulatory, since the LH peak and subsequent Pg elevation were absent. Twenty-nine cycles showed typical LH surges in the middle of the cycle, followed by a manifold Pg increase. Twelve women received 5 to 13 tables of D-norgestrel. A total absence or at least marked suppression of LH and Pg elevations was observed. In a third group, D-norgestrel was administered on scheduled days. Each woman ingested one to four tablets between the 6th and 18th days of the cycle. Two or more tablets disturbed LH and Pg ovulatory patterns. Of four women who received a tablet on day 10, one failed to show characteristic ovulatory patterns and three exhibited a delay in the time of the LH and Pg increase. These results demonstrate that D-norgestrel in a postcoital regimen alters pituitary and ovarian function, strongly suggesting an antiovulatory effect.


A comparison of endometrial histology with simultaneous plasma progesterone determinations in infertile women.

A retrospective analysis of 238 endometrial biopsies and simultaneous plasma progesterone determinations performed during the course of infertility evaluations is presented. The data suggest a high (93%) correlation between the two procedures for the detection of ovulation. Endometrial abnormalities were detected in 5% of the biopsies. Shortening of the cycle was noted in 36% of the patients, while only 3% demonstrated a longer cycle. Simultaneous measurement of plasma progesterone levels in association with the endometrial biopsy is believed to better document corpus luteum defects. One should be aware of the frequent occurrence of a shortened cycle on the basis of postbiopsy bleeding. Basal body temperature graphs should be utilized prior to biopsy in patients with a history of irregular menstrual cycles.


Hysteroscopic procedures in 257 patients.

Two hundred and fifty-seven hysteroscopic examinations were performed on patients who complained primarily of infertility and abnormal uterine bleeding. Organic intrauterine lesions were identified, and correlations were made with preoperative hysterograms and the tissue obtained for pathologic evaluation. The technique proved of special value for the location and resection of intrauterine devices. Failure to observe the cavity adequately and to complete the examination occurred in 20 (8%) of the patients. The most serious complication, uterine perforation, occurred in five instances but did not require additional treatment.


Pregnancy during the hysterogram cycle.

Because of potential mutagenic effects of radiation on the soon-to-be fertilized ovum, we questioned whether we should advise against conception during the cycle in which a hysterosalpingogram is performed. Our results do not suggest any increase in the incidence of spontaneous abortion or congenital anomalies in these patients. Therefore, we see no need to advise against conception during the cycle in which a hysterosalpingogram is performed.


Reconstructive surgery for congenital atresia of the uterine cervix.

Reconstructive surgery for congenital atresia of the uterine cervix, utilizing the atretic cervix as a conduit for the permanent fistulous communication between the endometrial cavity and vagina, has resulted in the establishment of cyclic menses in four patients followed for up to 27 months postoperatively. A detailed review of maternal obstetric histories failed to reveal a common factor causally related to this extremely unusual and formerly hopeless congenital anomaly of the Müllerian ducts.


Improved motility recovery of human spermatozoa after freeze preservation via a new approach.

A new sperm isolation technique was studied in conjunction with the short-term freeze preservation of human spermatozoa. The isolation procedure yielded subpopulations of spermatozoa with very high percentage motility and progressive motility score, and which were virtually free of seminal debris. For 24 semen samples from 13 donors, the mean prefreeze values of percentage motility and motility score were 53% (2.8), 73% (3.1), and 88% (3.5) for the parent semen, 7.5% BSA (middle) fractions, and 17.5% BSA (bottom) fractions, respectively. These samples were used without a priori constraint on semen quality. Eleven samples were preselected on the basis of good motility in the semen. These yielded prefreeze motility values of 66% (3.2), 70% (3.4), and 87% (3.9) for the semen and two fractions, respectively. Sperm motility in the middle fractions was thus intermediate to that in the semen and in the bottom fractions, although closer to the former in these 11 cases. The sperm freeze preservation procedure involved dilution of the semen samples and separated sperm fractions with a cryoprotective semen extender, and freezing and thawing in a conventional manner. Post-thaw percentage motility, motility score, and percentage survival were substantially higher for the separated fractions than for the parent semen. For the 24 cases, the bottom fractions yielded mean values of 57% motility, 3.0 motility score, and 70% survival, in comparison with the respective values of 20%, 2.3, and 34% for the semen. In the 11 preselected cases, the bottom fractions yielded post-thaw mean values of 60% motility, 3.3 motility score, and 72% survival; the middle fractions yielded respective values of 45%, 3.1, and 64%; and the parent semen yielded respective values of 27%, 2.3, and 41%. It was concluded that the major factor in improving post-thaw motility recovery was the separation process as a whole, rather than the degree of separation.


Effect of prolactin on metabolism of human spermatozoa.

The effect of prolactin on adenyl cyclase, rate of fructose utilization, and glucose oxidation by human spermatozoa was studied. Prolactin stimulated all of these processes at a concentration generally available in seminal plasma. These results suggest that prolactin plays an important role in the energy metabolism of human spermatozoa.


Inhibition of the oxidative metabolism of human spermatozoa by a heat-labile factor in seminal plasma.

The effect of different media on the oxidative and glycolytic metabolism and on the motility of human spermatozoa has been investigated. Sperm resuspended in Ringer's solution produce more carbon dioxide than sperm in the original seminal plasma. In addition, sperm resuspended in heated seminal plasma have a higher carbon dioxide production and higher oxygen uptake than sperm in untreated seminal plasma. The mean lactic acid production was not significantly affected by different media. The motility of sperm in heated seminal plasma was poorer than that in untreated seminal plasma, although the percentage of cells that stained with eosin did not differ in the two media. After being heated, seminal plasma not only continued to take up oxygen but did so at a higher rate. The results of the present study suggest that seminal plasma contains a heat-labile component that inhibits the oxidative metabolism of human sperm but does not significantly alter sperm glycolysis.


Relationship between motility and the transport and binding of divalent cations to the plasma membrane of human spermatozoa.

Measurements of fluorescence changes of the divalent cation probe chlortetracycline, which accumulates in the plasma membrane of human spermatozoa, and measurements of radioactive calcium uptake indicate that the plasma membrane of human spermatozoa is impermeable to calcium. Moreover, permeability to exogenous calcium is not changed when sperm motility is stimulated by agents which increase intracellular levels of adenosine 3':5'-monophosphate (cyclic AMP). Evidence is presented, however, which suggests that energy-dependent divalent cation binding to the plasma membrane is lowered when motility is increased by cyclic AMP phosphodiesterase inhibitors.


Temporal relationships critical to estrogen-induced delay of ovum transport.

Previous studies have shown that a pharmacologic dose of estradiol given at the time of injection of human chorionic gonadotropin (HCG) significantly delays the transport of ova through the rabbit oviduct and that the site of delay is located at the ampullary-isthmic junction. The current experiments investigated the effects of varying the timing of the estrogen injection on ovum transport rates. Fifty-eight rabbits received injections of either Depot-estradiol or crystalline estradiol at various times before or after the injection of HCG. "Tube-locking" resulted when estrogen was administered before or at the time of HCG administration, whereas acceleration occurred when estrogen was given 12 to 24 hours after HCG. The results demonstrate that pharmacologic doses of estrogen exert two effects on ovum transport in the rabbit: (1) delay at the ampullary-isthmic junction and (2) acceleration once that junction has been traversed. The possible application of these results to contraception is discussed.


Effect of direct injection of neutrophils from uterine horns of rats containing intrauterine devices into recipient pregnant uteri.

The purpose of this study was to determine whether or not neutrophils from uterine horns containing an intruterine device (IUD) inhibit implantation of rat blastocysts. On day 4 (6:00 P.M. to 8:00 P.M.) of gestation the uterine horns of the recipient rats were exposed and injected with neutrophils, supernatant luminal fluid, or Hanks' solution. The total volume injected was 30 mul. All of the rats were killed on day 12 of pregnancy, and the number of fetuses and resorption sites was determined. The data show that, in rats injected with neutrophils on day 4 of gestation, implantation was significantly increased as compared with controls injected with Hanks' (vehicle) solution. Whether the supernatant fluid had an effect in suppression of implantation could not be determined, since the effect was not statistically different from that observed in either the vehicle- or neutrophil-injected groups. However, the responses observed with the supernatant-injected groups. However, the responses observed with the supernatant-injected group were intermediate between those of the control horns and those of the neutrophil-injected horns. The finding supports the concept that in IUD-bearing animals in which there is a rapid influx of neutrophils the cells play a major role in suppressing implantation.


The hormonal control of the guinea pig corpus luteum during early pregnancy.

Forty guinea pigs were divided into two groups, pregnant and nonpregnant, and were operated upon on days 10, 12, 14, and 16 of the ovarian cycle or of pregnancy. Blood was obtained from the utero-ovarian vein, and prostaglandin F2alpha (PGF2alpha), prostaglandin E (PGE), progesterone, and estrogen content was assayed by radioimmunoassay. Increased levels of PGF2alpha preceded a drop in progesterone levels in nonpregnant animals, reflecting luteolysis. In pregnant animals, the level of PGF2alpha remained low, and progesterone levels increased. PGE levels were similar in the two groups. These results suggest that the low PGF2alpha levels seen during early pregnancy are related to corpus luteum rescue.


Age-related changes in male rat reproductive organ weights and plasma testosterone concentrations after administration of a monoamine oxidase inhibitor.

Experiments were conducted to determine the effects of pargyline, a monoamine oxidase inhibitor, onmale rat reproductive organ weights, testicular histology, and plasma testosterone levels. Pargyline was administered to various groups of rats by implanting it, either dissolved or in a powder form, in Silastic tubing capsules. Additional rats were injected with pargyline solutions. The effects of pargyline.appeared to be age-related with younger animals, weighing under 400 gm (less than 100 days of age), showing a decrease in testicular and accessory organ weights and plasma testosterone. Older animals did not show a decrease in organ weights. Testicular histology in the pargyline-treated groups showed sloughage of cellular material into the tubular lumina, decreases in the number of cell layers, and a reduction of the number of mature spermatocytes. Other areas in the same testis were normal, however, and resembled control histology. The results suggest that pargyline can have detrimental effects on testicular function and that the effects may be age-related.


The effects of hormones and prostaglandins on the calcium pools in cultured myocardial cells.

Determinations of the calcium pools in myocardial cells in vitro have shown the existence of at least three pools of exchangeable calcium. Epinephrine and glucagon were found to produce significant increases in the size of the two slower exchanging pools. Prostaglandins E1 and F1alpha also increased significantly calcium pool size whereas E2 and F2alpha did not; results which correlate well with the effects of the two former prostaglandins on intracellular cAMP levels. The results imply that these agents cause small, but significant, changes in the transmembrane exchange of calcium and large increases in the intracellular calcium pool. Effects which may involve the direct or indirect action of cAMP.


Steroids and growth of a human cell line stemming from a carcinoma of the uterine cervix.

The effect of different steroids on the growth of a human cell line, was examined in NHIK 3025 cells, derived from a carcinoma of the uterine cervix. When this cell line was grown in Eagle's minimal essential medium (MEM) for 4 days, addition to the medium of estradiol-17 beta in concentrations ranging from 10(-9) to 10(-7) M did not promote significant cell growth. Stimulated growth was observed with testosterone in these concentrations, with maximal effect (29% above control) at 10(-7) M. 5alpha-Dihydrotestosterone over the range 10(-9)--10(-6) M gave no such effect. 4-Androstene-3,17-dione, 5alpha-androstan-3alpha,17beta-diol and 5alpha-androstan-3beta,17beta-diol had no significant effect on cell proliferation at a concentration of 10(-7) M, while 4-androstene-3beta,17beta-diol augmented cell number to values 50-60% higher than those of control cultures. The observed increase in cell number was due to a shortening of the cell cycle and to a higher plating efficiency. Thus, cell line NHIK 3025 has not the responsiveness to estradiol-17beta of normal uterine cells. The data suggest that testosterone and/or 4-androstene-3beta,17beta-diol may be growth factors for this cell line.


Ovarian-independent fluctuations of estradiol receptor levels in mammalian tissues.

Three types of periodic fluctuation in tissue concentrations of estradiol receptor protein have been observed. A seasonal variation is described in the uteri of 12-16-week-old calves and of ovariectomized pigs, and in mammary tumor tissue obtained from postmenopausal women. A circadian rhythm has been demonstrated in uteri of ovariectomized rats. An irregular periodic fluctuation has been found in uteri of ovariectomized and of ovariectomized/hypophysectomized rats, with the period varying from 9 to 15 days. These observations establish that a substantial turnover of receptor occurs in the absence of hormone and that 'normal' baseline values of receptor concentration do not exist.


Gastric inhibitory polypeptide (GIP) in maturity-onset diabetes mellitus.

Serum GIP, insulin, and glucose concentrations were determined during a standard oral glucose tolerance test in 80 individuals, 45 of whom were normal and 35 of whom had adult-onset diabetes mellitus according to USPHS criteria. As a group, the diabetics had fasting hyperglycemia (219 +/- 17 mg./dl.) and, in response to glucose, displayed a peak serum glucose of 373 +/- 23 mg./dl. and sustained hyperglycemia (315 +/- 24 mg./dl.) at 180 minutes. There were no statistically significant differences in absolute serum insulin levels between the two groups. However, insulin secretion was delayed, IRI increments were smaller, and the IRI concentrations were inappropriately low for the simultaneous serum glucose concentrations in the diabetics at every time interval tested. Mean fasting serum GIP was 335 +/- 30 pg./ml. in the diabetics as against 262 +/- 15 pg./ml. in normal individuals (p less than 0.025). After the ingestion of glucose, diabetics had significantly higher (p less than 0.001) mean serum GIP levels between five and 120 minutes. By 180 minutes, serum GIP levels remained above fasting in both groups, but the diabetics had higher than normal serum concentrations (p less than 0.05). Peak serum GIP concentrations, which occurred at 30 minutes in both groups, were 1,376 +/- 106 and 806 +/- 75 pg./ml. in the diabetics and normals, respectively (p less than 0.001). Total integrated serum GIP was also greater in diabetics than normals (140,852 +/- 14,208 vs. 64,602 +/- 8,719 pg.-min./ml.-1, p less than 0.001). The higher serum GIP concentrations observed following glucose ingestion in diabetics could not be attributed to obesity or age. We conclude that both fasting and glucose-stimulated GIP concentrations are higher than normal in obese adult-onset diabetics. The significance of this observation is uncertain. However, since our current understanding suggests the GIP may be an important enteric signal for the release of insulin in man, and because GIP has been shown to stimulate the release of immunoreactive glucagon, GIP may play a role in the pathogenesis of diabetes mellitus.


Epidemiologic findings on the relationship of time of day and time since last meal to glucose tolerance.

Data from 10,559 men and women, age 30-64, participating in the morning and afternoon in a Chicago Health Department multiphasic screening project, were used to determine the effects of time of day and time since last meal on the values for plasma glucose one and two hours following oral challenge with 100 gm. of glucose. Mean plasma glucose values and rates of suspect glucose intolerance (based on several cutpoints) were sizeably higher in the afternoon than in the morning. In addition, plasma glucose values increased with time elapsed since the last meal, up to 10 hours postprandially. Thereafter, both one- and two-hour plasma glucose values tended to exhibit a decline. Analysis of covariance confirmed that fluctuations in glucose tolerance were related to time of day and time since last meal, but the effects of each parameter were exerted independently.


Potentiation of glucose-induced insulin release by glucose in the isolated pancreas of fed and fasted rats.

Glucose, apart from its acute insulin-releasing effect, exerts a time-dependent potentiating action on subsequent stimulations of the pancreas. The influence of a 24-hour starvation on these two actions of glucose was studied with the completely isolated, perfused rat pancreas preparation. Starvation had no effect on the time kinetics of the insulin response, but the magnitudes of the early and late insulin-secretion phases were reduced to similar extents. It was demonstrated by using a wide glucose concentration range that the maximal insulin response is not significantly modified by starvation. In contrast, both the threshold of stimulation by and the Km for glucose were higher in the pancrease from fasted rats. Thus, starvation reduces the sensitivity of the islet for the insulin-releasing action of glucose. When the stimulatory concentrations of glucose were preceded for 40 minutes by the perfusion of 8.3 mM instead of the basal, 4.4 mM glucose, insulin secretion from the pancreas of fed animals was not modified. In contrast, raising the glucose concentration of the equilibrium period to 8.3 mM potentiated markedly the insulin response to subsequent stimulations in the pancreas from fasted rats. This potentiation expressed itself as increase in the maximal response: the Km for glucose was not reduced. Thus a 40-minute pretreatment with 8.3 mM glucose does not correct the diminished sensitivity induced by a 24-hour starvation. It is concluded that in starvation (1) the sensitivity for glucose of the mechanisms that initiate insulin release is diminished; (2) the sensitivity of the pancreas for the potentiation-inducing action of glucose is augumented. (3) In both respects, the insulin response of fasted rats is similar to that of mildly diabetic subjects. These and other findings suggest that the effect of glucose in initiation of insulin release and on generation of a state of potentiation in the islet are mediated by different mechanisms.


Effects of acute insulin withdrawal and administration on plasma glucagon responses to intravenous arginine in insulin-dependent diabetic subjects.

To assess further the role of insulin in the abnormal alpha-cell dysfunction found in human diabetes mellitus, the effects of acute insulin withdrawal and administration on plasma glucagon responses to intravenous arginine were studied in eight insulin-dependent diabetic subjects. Arginine infusions (30 gm. over 30 minutes) were performed during and at one and four hours after discontinuation of a 14-hour insulin infusion (1.5 U. per hour), which had rendered the subjects euglycemic, and on another occasion before and one and four hours into a five-hour infusion of insulin (1.5 U. per hour). During the last hour of the 14-hour infusion, glucagon responses to arginine (area under the curve, nanograms per milliliter per minute) were similar to those found in normal subjects (10.3 +/- 0.8 vs. 9.0 +/- 0.8, respectively). After discontinuation of the insulin infusions, glucagon responses increased progressively (p less than 0.01) to values (16.8 +/- 1.2) that exceeded those of normal subjects by four hours (p less than 0.01). These were similar to results found in the same subjects studied when their diabetes was in less than optimal control (14.9 +/- 1.3). Infusion of insulin under these conditions progressively decreased glucagon responses to arginine to values (9.6 +/- 0.8; p less than 0.01) that, at four hours, were similar to those of normal subjects and to values found at the end of the 14-hour infusion of insulin in the same diabetic individuals. These results demonstrate a rapid effect of insulin on glucagon responses to arginine and suggest that the abnormal responses seen in diabetes mellitus are the immediate result of insulin deficiency. Since abnormal glucagon responses to glucose in diabetes are not as readily corrected by insulin, the mechanisms underlying the abnormal responses to these two stimuli may differ.


Imparied plasma insulin response to arginine in hyperthyroidism. Important role of the rise of blood glucose in the second phase of insulin release induced by argiinine.

Intravenous infusion of 30 gm. of L-arginine over a period of 45 minutes elicited a biphasic insulin response and a moderate blood glucose rise in normal subjects. In patients with hyperthyroidism, both insulin peaks, especially the second one, were low, with virtual absence of the blood glucose response. A single intravenous injection of 4 gm. of arginine provoked similar uniphasic plasma insulin responses in both normal subjects and hyperthyroid patients. Pretreatment with either glucose or xylitol almost completely restored the biphasic insulin response to arginine in patients with hyperthyroidism, whereas pretreatment with aminophylline only partially improved the insulin response. Combined administration of a small amount of glucose (2.25 mg./kg./min.) with arginine also restored the normal second-phase insulin release, with blood glucose rises similar to those in normal subjects given arginine alone. It is concluded that the plasma insulin response to arginine is impaired, especially in its second phase, in patients with hyperthyroidism due to the absence of a blood glucose rise. The second phase of arginine-induced insulin release seems more dependent on glucose than the first phase.


Plasma renin activity and hypertension in diabetes mellitus.

Plasma renin activity (PRA) was determined in 48 patients with diabetes mellitus in sodium balance on a 10-20 mEq. Na diet. Nine were normotensive (group I), 11 11 were hypertensive without diabetic nephropathy (group III). Results were compared with those in 16 normal subjects and 49 nondiabetic patients with essential hypertension in similar Na balance. Mean supine PRA did not differ significantly among groups I and II, normal subjects, and patients with essential hypertension. Group III diabetics had a supine PRA of 2.4 +/- 0.4 ng./ml./hr. (x +/- S.E.M.), significantly lower than the other diabetic groups (P less than 0.005) and normal subjects (P less than 0.05). Upright PRA was 12.8 +/- 2.2 in group I diabetics, similar to that in normal subjects (13.3 +/- 2.3), and 8.1 +/- 1.4 in group II diabetics, similar to that in essential hypertensives (6.8 +/- 0.8). In group III diabetics, upright PRA was 4.0 +/- 0.5, significantly lower than that in any other group. These results suggest that (1) PRA is normal in normotensive diabetics, (2) upright PRA in diabetics with hypertension but no nephropathy is similar to that in essential hypertension, and (3) patients with diabetes, hypertension, and nephropathy have "low renin hypertension," explaining the virtual absence of malignant hypertension in this group. Although the major mechanism for this low PRA may be volume expansion, indicating the need for potent diuretics, other mechanisms include hyalinization of the afferent arteriole, decreased cathecholamine stimulation of renin release, and inadequate conversion of prorenin to renin.


Modulation of fatty acid metabolism by glucagon in man. IV. Effects of a physiologic hormone infusion in normal man.

This study was done to explore the role of physiologic elevations of glucagon concentration in plasma ketone body concentration in normal man. During the period of hormone elevation, plasma free fatty acids were pharmacologically elevated to ensure adequate free fatty acid substrate delivery to the liver to support hepatic ketogenesis. Eighty-minute infusions of glucagon resulted in a plasma hormone concentration of approximately 300 pg./ml. During the infusion, ketone bodies declined from their basal concentration and remained below basal for the duration of the infusion. An acute heparin-induced pharmacologic elevation of plasma free fatty acid concentration resulted in a transient rise in plasma ketone body concentration, but at no time did it attain the concentration observed during the control saline infusion. Plasma glucose concentration was not altered by glucagon infusion, but plasma insulin concentration rose by approximately 2.5 muU./ml. These results suggest that glucagon is not ketogenic in normal man as has been previously reported in insulin-deficient diabetics. The glucagon-induced rise in plasma insulin concentration may participate in the observed reduction in plasma ketone body concentration.


Blood glucose monitoring in symptomatic hypoglycemia.

The relationship between blood glucose levels and the onset of hypoglycemic symptoms was studied by continuous monitoring of blood glucose levels after an oral glucose load in nine adults with normal glucose tolerance, five with chemical diabetes without symptomatic hypoglycemia, and nine with chemical diabetes with symptomatic hypoglycemia. Symptoms were associated not only with a low level of blood glucose but with a rapid fall as well. These two parameters were used to calculate a "hypoglycemic index" (defined as the fall in blood glucose during a 90-minute period prior to reaching the minimum level, divided by the value of this minimum level). The hypoglycemic index was 2.3 +/- 0.6 (mean +/- S.D.) in the group of diabetic patients with symptomatic reactive hypoglycemia and 0.7 +/- 0.3 for the other groups. This index may aid in the diagnosis of patients with symptoms of hypoglycemia and equivocally low values of blood glucose.


Renal wastage of insulin in children with diabetes mellitus.

In normal human beings the percentage of serum insulin excreted in the urine is constant over a wide range of values. The quantity of immunoreactive insulin found in the urine is believed to reflect the level of free insulin in the serum. Immunoreactive insulin was measured in the urine of nondiabetic children and diabetic children receiving exogenous insulin. Children with diabetes mellitus excreted greater amounts of immunoreactive insulin (18.5+/-8 muU./mg. creatinine) than did nondiabetic children (11.9+/-5 muU./mg. creatinine). This difference was statistically significant (p less than 0.0005). Children with "poor glycemic control" excreted a greater portion of their administered insulin dose than did those with "good control." The renal wastage of insulin correlated (r=0.94) with the duration of insulin treatment but not with the quantity administered. Antibody binding of serum insulin may explain in part these observations, but an acquired defect in the renal tubular reabsorption of insulin may also exist. Modifications in the management of diabetes that reduce the renal wastage of insulin may improve the metabolic stability of children with "poor diabetic control."


Environmental effects on motor development: the case of "African infant precocity".

In order to clarify the extent and cause of African infants' precocity in motor development, as reported by Geber and others, 64 babies and their families were intensively studied in a rural Kenyan community. It was found that the motor skills of sitting and walking, which the Kenyan babies acquired early (by American standards), are (a) specifically taught by the caretakers and (b) can be practised in the course of their usual daily routines. They are not advanced in skills which are not taught or practised. Middle-class urban Kenyan children from the same ethnic background were found generally to be intermediate in both environmental encouragement and rate of advancement. Preliminary results from other groups in Kenya suggest that encouragement of motor development is widespread and that for behaviors which are differentially encouraged among groups, the average age of attainment is predictable from environmental measures.


Testing of visual acuity in young children: an evaluation of some commonly used methods.

In a comparative study of screening tests for visual acuity in young children, two groups of children were presented with three different tests. In the younger group (three to five years) three single opto-type tests were compared: Sheridan's five and seven letter matching test, the Fooks test and the E card test. The Sheridan test gave the best results and the E card test was found to be unsuitable for this age-group. The Fooks is an attractive test but was less sensitive in the detection of defects than the Sheridan test. In the older group (five to seven years) a single opto-type test, the Sheridan-Gardiner test, was compared with the E chart and the Snellen chart. The Sheridan-Gardiner test was found to have limitations in the detection of defects, including amblyopia, therefore results obtained by this method should not be considered to be directly comparable with those of the Snellen chart. The E chart gave good results in the detection of defects and there was less lateral confusion than had been expected. It has disadvantages, but there is still a place for its use in the screening of normal school-age children. The Snellen chart was the most effective test in the detection of defects, but not all the children were able to co-operate in its use. It is concluded that where it is possible to use the Snellen chart it should always be the method of choice.


Nocturnal enuresis in childhood.

Of some 12,000 children in the National Child Development Study for whom the information was available, 10-7 per cent were enuretic between the ages of five and seven years, and 4-8 per cent were enuretic at 11 years. More boys than girls were wet at 11 years, although there was no difference at seven years. At both ages the manual social-classes were over-represented among the children with enuresis. These findings add support to the theory that nocturnal enuresis has multiple causes. The relative importance of social, developmental and psychiatric factors varies with the different groups of children early bed-wetting being associated with delayed development and later enuresis being more strongly associated with behaviour difficulties.


The behavior of the full-term but underweight newborn infant.

Ten underweight full-term newborns were compared with 10 full-weight newborns on the Brazelton Neonatal Behavioral Assessment Scale. The Brazelton examination differentiated the two groups clearly on the reflexes of walking, crawling and passive movements of arms and legs, and on rooting and sucking. More importantly, it differentiated the two groups on behaviors which are important for the caretaker of the baby: these are attractiveness, need for stimulation, interactive processes and motor processes. The 10 underweight infants were followed up at a later date during the first year. They showed temperamental organizational difficulties and some indication of psychosomatic reaction to stress. It is possible that the underweight newborn's fragile organization elicits anxiety in the caretaker which makes interaction difficult.


The electroencephalogram of normal adolescent males: visual assessment and relationship with other variables.

The electroencephalograms (EEGS) were recorded of 223 boys aged from 12 to 16 years inclusive from four different kinds of schools in the former borough of Warley, an industrial area on the outskirts of Birmingham, England. A battery of psychological tests were also administered and descriptions of behaviour were obtained from parents and teachers, as well as information on development and previous medical history. The data were analysed in terms of (a) prevalence of certain EEG features, usually considered abnormal, and (b) the relationship between the EEG and other demographic, developmental and psychological factors. Only 2-2 per cent of the EEGS showed definite abnormalities, such as localised sharp waves and/or spike and wave complexes in their resting record and/or during hyperventilation and photic stimulation, while a further 13-9 per cent showed very slight abnormalities or "immaturity". The abnormal and immature EEGS were significantly related to social class, type of school and positive medical history (especially a history of convulsions or faints). Comparisons with previously reported data are discussed.


Relationship between changes in somesthetic evoked responses and electroencephalographic findings in the child with hemiplegia.

The results of somesthetic evoked response (SER) and electroencephalogram (EEG) records in 43 children with hemiplegic cerebral palsy have been compared. In all children there was a positive correlation between the SER changes and the affected side of the body. In 12 children the SER of the "damaged" hemisphere disappeared; in 31 children it was less than the response of the "healthy" hemisphere. On the other hand, a positive correlation between the EEG changes and the affected side was found in only 16 of the patients, and there was a dubious correlation in three cases. It is concluded that SER data are more accurate and reliable than EEG results. Moreover, SER findings allow cerebral damage to be suspected earlier than the EEG results and therefore are of greater prognostic value.


Surgical correction of spastic thumb-in-palm deformity.

A series of 31 operations on 27 patients for correction of the spastic thumb-in-palm deformity is reported. 19 patients were followed four years or longer post-operatively; the remainder have been followed for at least one year. In approximately 70 per cent of the operations, supplementary procedures were performed on the hand or forearm, as the deformity is usually only one facet of a complex spastic disability of the upper extremity. The surgical technique and illustrative cases are presented. Augmentation of a markedly weak extensor-abductor motor function is necessary, otherwise the spastic thumb-in-palm deformity will recur, as in two cases in the present series which required a second operation. The remainder of the patients were classified as improved, indicating that the thumb was no longer clenched in the palm, could be used in gross grasping activities, and the hand had become more useful. In no instance did the spastic hand become the primary functioning hand post-operatively.


Platelet mono-amine oxidase activity in the human fetus.

Measurement of the platelet mono-amine oxidase (MAO) activity in the human fetus of 40 weeks gestation showed it to be equivalent to that found in the adult. The level represents a fully-developed mitochondrial MAO system in platelets and may reflect enzyme maturity in other tissues of the newborn.


Neurological disturbance in a phenylketonic child after discontinuation of dietary treatment.

Signs of moderately severe spastic diplegia appeared in 14-year-old late-treated phenylketonuric boy 13 months after dietary restrictions were lifted. The literature contains reports of untreated phenylketonuric patients developing demyelinating conditions in later childhood. The possible implications of relaxing the diet in early- and late-treated cases of phenylketonuria are discussed.


Cerebro-hepato-renal syndrome with parental consanguinity.

A case of cerebro-hepato-renal syndrome with some unusual features is reported. The neuropathological findings are described in detail. Electronmicroscopy showed astrocytes in the demyelinated areas of the brain to contain granules composed of laminated osmiophilic material. These structures could be abnormal mitochondria. The parental consanguinity in this case would further support an autosomal recessive mode of inheritance.


Effect of calcium infusions of serum calcium and gastric acid secretion.

37 patients were studied with calcium infusions. Of these, 20 had previously undergone truncal vagotomy and pyloroplasty for duodenal ulcer disease, and 17 were unoperated patients with duodenal ulcer disease. Calcium was given intravenously either at a dose of 5 mg/kg/h for 3 h, or 4 mg/kg/h for 4 h. Gastric juice was collected by continuous suction. Results showed the 3-hour infusion raised calcium more than the 4-hour infusion. Top serum calcium achieved, however, did not correlate with calcium-stimulated gastric acid output, either with or without vagotomy. Stimulated gastric acid secretion was markedly less with vagotomy than without. It is suggested that the level of gastric acid stimulated by infusions might discriminate complete, from incomplete, vagotomies better than insulin, and that the 4-hour infusion is safer.


The effect of phenobarbital on patients with Dubin-Johnson syndrome.

11 patients with jaundice of Dubin-Johnson type were treated for 2 weeks with phenobarbital. Serum bilirubin diminished and hepatic clearance of sulfobromophthalein was variably enhanced; other measures of hepatic function were not significantly changed during therapy.


Risk factors in ulcerative colitis.

In 504 Jewish patients with ulcerative colitis the following risk factors were evaluated: sex, age at onset of disease, community group, extent of disease, and duration of disease. The disease was more severe in females. Severe attacks, weight loss, iron deficiency, liver disease and arthritis were significantly more frequent in females than in mles. Mortality was higher in patients who contracted the disease above age 50. The disease appeared to be more severe in patiets of Ashkenazi origin as compared to Orientals. The difference failed to reach statistical signifcance except for mortality. We confirmed the well-known adverse effect of extensive colonic involvement. Severe attacks, a severe course of the disease and extensive colonic involvement are more frequent with increasing duration of the disease.