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The effects of high doses of frusemide on plasma and muscle electrolyte composition were investigated in 20 patients with chronic renal failure (CRF), in 5 of them complicated by superimposed cardiac

Summary Investigations into the analgesic effect of thiambutene and its value as a pre-anaesthetic agent were carried out in the horse and the sheep. Special emphasis was placed on the post-anaesthetic recovery period. Thiambutene produced analgesia in both species. Toxic effects such as muscle tremor and hyperkinesia occurred with high doses. Prior administration of acepromazine increased the tolerated doses of thiambutene, and satisfactory neuroleptanalgesic states were produced. Combined use of thiambutene and acepromazine in pre-anaesthetic medication reduced the dose of thiopentone required for anaesthesia in both species and significantly improved post-anaesthetic recovery. Administration of nalorphine in both species reduced the duration of the recovery period. In the horse, even after prolonged thiopentone anaesthesia, nalorphine produced a shorter, quieter recovery. It was concluded that pre-anaesthetic medication with thiambutene and acepromazine facilitated thiopentone anaesthesia and greatly reduced the problems of post-anaesthetic recovery in horses.

The behavioral effects on rats of various doses of tetraethyl lead, administered intragastrically, were measured on the following: bar press responding for food, two-choice discrimination under negative reinforcement, and emotional responses in the open field. Bar press response rates were drastically curtailed following administration of high doses of lead. Both trials to criterion and mean latency to criterion were detrimentally affected by administration of single doses of lead prior to acquisition of the discrimination. Lead had similar effects on these same measures in reversal of the original discrimination and in retention of the reversal. The performance deficits were not attributable to the tetraethyl radical; control injections of tetraethyl silane were without effect on all behavioral measures in the discrimination task. In addition, the results did not appear to be a function of emotional factors as lead did not influence trials to avoidance criterion or open field behavior. It was concluded that lead given intragastrically can impair learning and memory in the rat.

The genetic response of the mouse spermatogonial stem cell to high doses of X-rays given in two fractions is dependent upon the fractionation interval. When 800 R was administered in two fractions, 500 plus 300 R, separated by intervals varying from 24 h to 12 days, the recovered translocation yield was consistent with addivity. However, with intervals of 3 to 12 days, the response was less than additive and was closer to that of the single 800 R dose. When 1000 R was administered in two fractions of 500 R separated by intervals of 4 days and 7 days, the recovered yield of specific locus mutations approximated the additive levels. There was no enhancement of the response, as obtained with 24-h fractionation. In neither experiment was there an indication of any kind of correlation with stem cell killing, as indicated by length of sterile period. It is proposed that the results could be interpreted on the assumption of a spermatogonial stem cell having a long cell cycle (several days) such that in the first two days following one radiation exposure the surviving cells are particularly sensitive to the induction of both gene mutations and translocations by a second treatment. It is further suggested that the relative response of gene mutation and translocation to fractionated treatments is essentially the same but approximately half of those cells carrying translocations are eliminated by selection.

A venom gland extract of Microbracon hebetor (Say) was injected into representatives of different insect orders. A high susceptibility to this paralysing venom is restricted to the order of the Lepidoptera . A few species of Hemiptera, Diptera and Hymenoptera could be paralysed but only if high doses of the venom were injected.

The behavioural effects of a range of high doses of D-amphetamine and DL-fenfluramine were investigated in rats. Subjects were observed individually for 1 min in every 5 for a period of an hour. During each observation period the presence of any of 6 behavioural patterns was recorded in an “all or none”; fashion Behaviour patterns recorded included: Rearing, Forward Locomotion, Immobility, Backward Locomotion, Circling and Head Swaying. The last 3 behaviours are considered “Abnormal”; in that they were never observed in saline treated controls. The results indicate that, at the doses used in this study, both compounds induce abnormal behaviours, the latency of onset of which is directly proportional to dose. For both compounds an inverse correlation was found between normal and abnormal behaviours. However, the type of abnormal behaviour observed differed considerably between drugs in that fenfluramine elicited Backward Walking and Circling with no Head Swaying, over the dose range 10–30 mg per kg; whilst the predominant abnormal behaviour elicited by D-amphetamine, over the range 5–20 mg per kg, was Head Swaying. At the highest doses of amphetamine used some Backward Walking was elicited, behaviour which was totally absent at the lower doses. The implications of these results for the concept of “stereotypy”; are discussed, and attention is drawn to an important distinction between abnormal and stereotyped behaviour.

Low levels of total plasma protein and albumin have been detected in growing pigs infected with 200 000 and 350 000 larvae of Hyostrongylus rubidus . Further studies using 131 I labelled albumin and 131 I polyvinyl pyrrolidone have shown that this depression in total plasma protein and albumin results from plasma protein leakage into the gastro-intestinal tract at a time when the worms were migrating, or, had just finished migrating from the gastric glands on to the mucosal surface.

Previous data have indicated that in decorticated curarized rabbit preparations, administration of 5-HTP or Dopa significantly modifies the pattern of rhythmic efferent nerve discharges, which mimic the locomotor-like movements of the hind limbs developing in the non curarized preparation. The present data tend to favour the hypothesis that the active substances are, respectively, 5-HT and DA or NA. Animals were given Ro4-4602, an inhibitor of Dopa and 5-HTP decarboxylase (DC) at low and high doses. Low doses had a potentiating action on the 5-HTP and Dopa effects, while high doses delayed their action. Assuming that at low dosage the inhibitor was acting on the peripheral DC and at high doses on both the peripheral and central DC, it may be concluded that the precursors act centrally through transformation into 5-HT and DA or NA respectively.

Four cases are described of the use of prolonged and/or high doses of adrenaline in the treatment of the low cardiac output syndrome following cardiac surgery. Adrenaline was chosen because it produced a more favourable effect on central cardiovascular haemodynamics and myocardial metabolism when compared with isoprenaline, while its detrimental effects on renal function were less marked than those found when using noradrenaline. The renal insufficiency encountered was reversed in those cases without previous renal disease. Tachyphylaxis was demonstrated and weaning was achieved by gradual withdrawal of the vasopressor with concomitant blood volume expansion. Two cases with predominant right ventricular failure developed gross ascites and peripheral oedema, making control of fluid balance difficult. These problems are discussed with a summary of the relevant pharmacology of isoprenaline, noradrenaline, adrenaline and glucagon. The conclusions reached regarding the use and management of adrenaline infusion are given.

The urinary excretion of catecholamines and of the acidic metabolite 4-hydroxy-3-methoxymandelic acid were measured before, during and after 24-to 72-hour infusions of glucagon (5 to 7.5 mg/h) in 14 patients with congestive cardiac failure. Total adrenalin excretion was unchanged but total noradrenalin and 4-hydroxy-3-methoxymandelic acid increased during and 24 h after the infusion ( P P P P The results indicate that unphysiologically high doses of glucagon promote catecholamine synthesis and storage in the adrenal medulla of patients with congestive cardiac failure.

Eggs, larvae, and pupae of Culex tarsalis Coquillett were treated with ecdysones, juvenile hormone analogs, and 6-oxooctanoic acid. Effects of these agents on mortality, induction of supernumerary stages, and adult emergence were determined. Topical treatment of eggs with CRD9499 (a juvenile hormone analog), β-ecdysone, and 22-isoecdysone caused a reduction in adult emergence. Treatment of fourth-instar larvae with these chemicals not only induced mortality but also caused the formation of supernumerary intermediate stages. Larvae of C. tarsalis were very susceptible to CRD9499, but pupae were resistant. The ecdysones caused some mortality but only at very high doses and would thus be of little use as larvicides. 6-Oxooctanoic acid caused high rates of mortality at 0.001 M concentrations.

The radiation therapist is often confronted with a therapeutic dilemma. He must decide whether to compromise with curative doses of radiation therapy, or run the alternate risk of producing severely incapacitating, if not lethal, damage to normal tissues necessarily included in the beam.Many methods are used by radiation therapists to minimize normal tissue damage.Relatively simple surgical techniques described in this paper were used to protect the lung, the testicle, and the rectum.

Using the coprecipitation technique and rabbit antisera specific for mouse IgG1, IgG2a, IgG2b, IgA and IgM, the responses of BALB/c mice to a wide range of doses of human serum albumin have been studied. Antibody activity was detected in all five classes. At lower doses, below 1 mg, the distribution of antibody activity among the immunoglobulin classes was fairly constant, but at higher doses a decrease in antibody activity occurred in certain subclasses only, particularly IgG1. The actual effect obtained depended on whether the antigen was given with or without Bordetella pertussis. To study the subclass suppression further, mice were also subjected to neonatal treatment with soluble antigen. The suppression here was again mainly in the thymus-dependent IgG1 subclass.

SummaryThe effect of subcutaneous injection of synthetic LRF was evaluated in normal and castrated rats under tribromoethanol (TBE) anesthesia. The procedure of anesthetization with TBE followed by injection and bleeding produced no change in plasma LH in intact males, but a decline followed by a rebound to initial levels in castrates. FSH levels showed a delayed rise in the intact animals and a decline followed by return to initial values in the castrates. In both intact and castrate animals, prolactin levels declined acutely and remained low throughout the experiment. Subcutaneous administration of LRF produced a dose-related acute release of LH in intact and castrate males. The response was prolonged compared to that observed in previous studies following intravenous administration of the peptide. Minimal and delayed FSH release occurred following high doses of 100 or 500 ng of the peptide in intact animals, but dose-related increases of considerable magnitude took place in the castrates. In general, r...

Summary The effect of high doses of the synthetic adrenocorticotrophic hormone (ACTH) on rat brain was investigated. The treatment was started at the age of 2 weeks and lasted for another 2 weeks. ACTH caused a significant reduction in the body and brain weight, but no differences were observed in the water content of the brains. The yields of myelin tended to be slightly higher in the ACTH treated groups but the differences were not significant. A stimulating effect was observed in the protein, cholesterol and NANA contents of the glial fractions and myelin after the first week but after the second week the effect became negative. The only exception was the cholesterol content of the neuronal fraction which was lower in the controls at the end of the experiment. No increases were observed in the amounts of the specific proteins of myelin, and the maturation of the myelin proteins seemed to proceed normally. The results further justify the use of ACTH in demyelinating diseases until more specific forms of treatment become available.

In Sweden there has been a long-lasting epidemic of amphetamine abuse. It became evident at the end of the fifties and seems to have culminated around 1969. At that time the approximate number of intravenous abusers of high doses of amphetamine was estimated to be 10,000, the majority of whom lived in, or close to, the capital of Sweden (Inghe, 1969). In this area mainlining amphetamine abusers represented about 0.5% of the total population, corresponding to a similar percentage of heroin addicts in New York City at the same time. Since 1969 we have witnessed a rise in opiate abuse, which has gradually changed the drug scene into a more Americanlike picture. The present report deals with pharmacokinetic and clinical studies of effects of high amphetamine doses in intravenous abusers. All studies were carried out in a specialized four-bed metabolic unit, where appropriate cases were received during the period of investigation.

A clear dose-response relationship was observed between given doses of cadmium (Cd) and levels of sulfhydryl (SH) groups in the special protein fractions extracted from livers and kidneys of the exposed mice. Correlation efficients were 0.906 and 0.892 between doses and SH levels in livers and kidneys respectively.Several heavy metals other than Cd were examined in regard to dose-response relationship in the same manner as Cd. Administration of Fe, Zn and Cr, even though in high doses, did not clearly increase the SH contents both in livers and kidneys. On the other hand, an obvious increase of SH levels was observed in the proteins from livers obtained from Cu-exposed mice.These data indicate that the SH contents in the tissue give the most valid in-formation as to the evaluation of the degree of Cd-exposure. In these connections, differnt responses of the living systems to various heavy metals and a possible roll of the SH-rich proteins which increase in the tissues exposed to heavy metals were discussed.

After a theoretical survey of the general problems of filtration, the standardization of measurements by which the kinetics of platelet aggregation can be evaluated in vitro by means of a screen filtration pressure test, is described. The variations of filtration pressure and PRP optic density are observed during 8 minutes, and whatever the dose of ADP employed, (from 0,1 to 10 γ/ml), it is demonstrated that the curve of filtration pressure is biphasic in function of time, with a maximal pressure between 1 and 2 minutes, whereas an irreversible photometric aggregation is noted for high doses. Such phenomenon is not easily interpretable, and one must consider: 1) the problems of cohesion and mechanical properties of aggregates; 2) the variation of the size of aggregates; 3) the eventual release of a platelet factor after two minutes.

The suppressive effect of thymus cells on the agglutinating antibody response in chickens is shown to be antigen-specific. Experiments reveal that this effect can be seen several weeks after thymus cell transfer, if the respective antigen (A) is given 3 times weekly after transfer. Repeatedly applied high doses of the antigen (A) result in a stronger effect than low antigen doses, and mercaptoethanol-resistant antibody (IgG) is usually more affected than the total titer (of which IgM is the major contributor). Finally, several weeks after thymus cell transfer, when the response to antigen A is still lower than that of the normal controls, the antibody response to an unrelated antigen B is normal. By these three criteria, as well as by the degree of suppression, the suppressive effect of thymus cells strikingly resembles the phenomenon of antigen-specific suppression that is seen after antigenic stimulus in the prenatal or early postnatal period. The suppressive effect is already given by thymus cells from 10-day old donors. As in previous studies, the suppressive activity was significantly diminished in thymus cells from neonatally bursectomized donors. The data indicate that a specifically acting suppressor cell compartment exists which is different from B cells and cooperative or graft-vs-host-active T cells. The results are discussed in light of current concepts of “self-tolerance”.

This study deals with the absorption of sterols and cholesterol esters in a prawn, Penaeus japonics. The apparent percentage absorption of these substances was estimated by an indirect method using chromium oxide as an indicator. The sterols and cholesteryl esters examined gave percentage absorptions of 60.8-98.8% and 67.0-87.3%, respectively. The cholesterol level in the diet affected somewhat the percentage absorption of cholesterol in this prawn. The prawns fed on the 0.05-1.0%, levels of cholesterol showed similar percentage absorptions whereas the high doses (2.0% and 5.0%) of diet cholesterol caused a decrease in the percentage absorption of cholesterol.

1. The metabolism of flavanone in the rat was studied after oral or intraperitoneal administration of the compound. Flavone and flav-3-ene together with five other unidentified minor metabolites were excreted in the urine. 2. The formation of flavanone metabolites was not suppressed by the administration of high doses of the antibacterial compounds aureomycin and phthaloylsulphathiazole. 3. No aromatic acids that could be attributed to ring cleavage of flavanone were detected. 4. Administration of 100 or 200mg of flavanone daily per rat caused some deaths during the 7–14-day period. 5. The application of combined gas–liquid chromatography/mass spectrometry and proton nuclear-magnetic-resonance spectroscopy to the separation and identification of the flavanone metabolites is described. 6. Measurement of the two major flavanone metabolites was carried out by gas–liquid chromatography.

Intraventricular and intraperitoneal administration of d-amphetamine impaired asymptotic shuttle box avoidance performance in rats. Low ip doses (0.5, 1.0, 1.5, and 2.0 mg/kg) had no effect whereas higher ip doses (2.5, 3.0, 3.5, 4.0 mg/kg) impaired performance in a dose-related fashion. An inverted U-shaped function was obtained with the ivent doses; low dose (25 ug) and high doses (200 and 400 ug) impaired performance whereas intermediate doses (50 and 100 ug) had little effect. The cannulation procedure itself produced only minimal acquisition effects. The data tend to support the contention that amphetamine acts on the brain to cause the deterioration of well learned avoidance responding.

Die spezifische gegen eine akute Leukamie gerichtete Wirksamkeit einer hochdosierten Prednisolon-Behandlung ist 24–48 Std nach Therapiebeginn an einem Aktivitatsabfall der bei der DNS-Synthese beteiligten Enzyme Thymidin-Kinase und DNS-Polymerase sowie der Einbauraten von DNS-Vorstufen — Thymidin und Desoxyuridin — nachweisbar. Entsprechende Stoffwechseluntersuchungen an leukamischen Blasten bei akuten Leukamien im Erwachsenen- und Kindesalter zeigen, das sich die antileukamische Wirksamkeit der Corticosteroide auf die akuten Lymphoblasten- und undifferenzierten Leukamien beschrankt. Diese Ergebnisse werden durch klinische Verlaufsbeobachtungen und Angaben in der Literatur bestatigt. Es ergibt sich daraus, das nur bei der akuten Lymphoblasten- und undifferenzierten Leukamie eine Indikation zur Behandlung mit Corticosteroiden in therapeutisch wirksamen Dosen besteht.

A clinical experience in the treatment of arterial hypertension based only on the administration of high doses of furosemide and sodium is reported. Ten cases of severe hypertension showed a decrease

DNA synthesis in peripheral blood leucocytes following renal transplantation. DNA synthesis in peripheral blood leucocytes following renal transplantation was measured during the postoperative period in 22 renal allografted patients. Significant increases in synthesis were considered in relation to rejection episodes and immunosuppressive therapy. Results in 17 patients with good renal function showed a correlation between acute rejection episodes and the presence of a preceding or coincident period of increased DNA synthesis. Absence of rejection was associated with an absence of any increase in synthesis. Corticosteroid-induced granulocytosis characterized by immature DNA-synthesizing myeloid cells did not appear to be reflected in the levels of DNA synthesis unless prednisone in excess of 100 mg/day was administered. In oliguric patients treated with high doses of prednisone (> 200 mg/day), high levels of DNA synthesis occurred following drug administration. It is concluded that in order for measurement of DNA synthesis to be of use in the detection of rejection, particularly in oliguric patients, it is necessary to assess DNA synthesis in lymphocyte suspensions free of any myeloid cells. Synthese de DNA dans les leucocytes du sang peripherique apres transplantation renale. La synthese de DNA dans les leucocytes du sang peripherique a ete mesuree au cours de la periode post-operatoire chez 22 malades ayant recu une allogreffe. Des augmentations significatives de la synthese ont ete considerees dans leurs rapports avec les episodes de rejet et le traitment immunodepresseur. Les resultats obtenus chez 17 malades ayant une bonne fonction renale ont montre une correlation entre les episodes de rejet aigu et l'existence d'une periode d'augmentation de synthese de DNA prealable ou coincidante. L'absence de rejet a ete associee a l'absence d'augmentation de la synthese. La granulocytose induite par les corticosteroides, caracterisee par des cellules myeloides immatures synthetisant le DNA, n'a pas paru etre refletee par les valeurs de la synthese de DNA sauf quand la prednisone etait administree a des doses superieures a 100 mg/jour. Chez les malades oliguriques traites par des doses de prednisone superieures a 200 mg/jour des valeurs elevees de synthese de DNA ont ete observees au decours de l'administration. Il est conclu que pour qu'elle soit utile a la detection du rejet, surtout chez les malades oliguriques, il est necessarie de mesurer la synthese du DNA dans des suspensions de lymphocytes exemptes de toute cellule myeloide.

We report the effects of three ecdysone analogues in the presence and absence of fat body on the wing imaginal disks of Cadra cautella, Paramyelois transitella, and Plodia interpunctella cultured in vitro in a modified Grace's medium. Alpha-ecdysone, unlike beta-ecdysone, did not stimulate cuticle deposition in Plodia disks at low doses and was only slightly effective at high doses. Also, the response of wing disks of Cadra and Paramyelois to beta-ecdysone and alpha ecdysone with and without fat body was similar to that of Plodia. Combinations of alpha-ecdysone and beta-ecdysone were more effective than beta-ecdysone alone in Plodia disks, but a synthetic analogue, 22-iso-ecdysone, had no effect on cuticle deposition when it was used alone or with beta-ecdysone in the presence or absence of fat body. Thus, the results with alpha-ecdysone and beta-ecdysone were not non-specific steroidal effects.

SummaryThe clinical presentation, the incidence, and the results of radioiodine tests in 80 patients with hyperfunctioning thyroid nodule confirmed by scanning are presented. 52 patients had toxic adenoma and 28 were euthyroid.The value of different radioiodine tests of thyroid function in confirming the diagnosis is discussed.The topographical changes in both hyperfunctioning nodule and suppressed tissue of the thyroid gland following exogenous TSH and radioiodine therapy showed refunctioning of suppressed thyroid tissue.Relatively high doses of radioiodine were required to treat toxic adenoma of the thyroid gland.

Plasma corticosterone concentrations were determined in serial plasma samples from individual rats as a measure of pituitary-adrenal activity. Pentobarbital produced a fall in corticosterone concentration in the absence of noxious stimuli but did not block the rise in plasma corticoids following mild stress. Morphine, in large doses, stimulated the pituitary-adrenal mechanism while smaller doses, in combination with pentobarbital, had a blocking effect on the pituitary response to surgery and hemorrhage. Some degree of tolerance developed to the ability of morphine to prevent the rise in plasma corticosterone when given in combination with pentobarbital. Chronic administration of diphenylhydantoin diminished the pituitary-adrenal response to stress under the conditions of this study but it did not block the ACTH releasing effect of high doses of morphine.

Fast neutron irradiated barley and Vicia seeds were treated with 5-fluorodeoxyuridine (FUDR) at a concentration below that at which cytological disturbances are produced by FUDR alone. In Vicia , FUDR produced an increase of chromosome breaks (chiefly isolocus breaks) at all doses (40–300 rad). Sister unions and chromosome exchanges were decreased at high doses, and probably increased at low doses. The frequencies of minute deletions were increased at all doses. Corresponding effects were found in barley. The mutation rates studied in this material were not affected by FUDR. Especially with respect to the increased frequencies of breaks the action of FUDR is similar to that previously described for Myleran. The effect is discussed in view of a possible modification of the rejoining of radiation induced breaks.

Methotrexate (MTX) was given by weekly rapid intravenous injections to 27 patients with inoperable oropharyngeal carcinoma. 9 cases were untreated while 18 had received radiotherapy or chemotherapy before administration of MTX. In 20 cases the dose was 40 mg/m2/week (patients over 50 years) and in 7 cases 60 mg/m2/week (table 1). In responsive patients, maintenance treatment was given at the dose of 15 mg/m2 every 4 days either orally or intramuscularly. 23 cases were adequately evaluable, i.e. they received treatment for a minimum of 3 weeks. Response to treatment was evaluated according to Karnofsky's scale. Considering only category 1 regressions, 11/16 (75%) patients adequately treated with 40 mg/m2 showed objective improvement and respectively 4/7 (57%) given 60 mg/m*. 8 out of 15 cases (41%) with category 1 response showed a regression greater than 50%. The mean duration of response for category 1 patients was 3.5 months, while the longest regression lasted 9 months (table 2). 18 patients had one or more side effects: 9 had oral lesions or gastroenteritis, 12 bone marrow depression, 3 hepatic and 1 renal toxicity. One patient died from hepatic and renal toxicity; in the remaining cases the side effects were quickly reversible (table 3). The percent regression rate for category 1 response and its average duration obtained with intravenous MTX seems comparable to intraarterial infusion (table 4). Systemic toxicity seems also comparable (table 5). Furthermore, intravenous administration obviates the typical local complications occurring with intra-arterial treatment and therapy can be given also at outpatients. For this reason, intravenous administration of MTX is preferred to intra-arterial infusion in the control of primary inoperable oropharyngeal carcinomas, provided no severe depression of liver, kidney and bone marrow is present.

SUMMARYImmunosuppressive therapy with high doses of methotrexate beginning 1 day after allogeneic bone marrow transplantation was evaluated for its effectiveness in preventing or delaying the lethal graftversus-host disease in dogs. A short-term regimen of methotrexate for 6 days after transplantati

The position of mouse eggs in the reproductive tract was determined following the administration of various doses of reserpine by the intraperitoneal route on Day 1 of pregnancy. High doses caused arrest of egg transport, while lower doses caused delay. The possibility that reduced hormone secretion is responsible was investigated by administration of ovarian, hypophysial and thyroid hormones. The failure of these various treatments to reverse the reserpine-induced arrest of egg transport suggests that alterations in hormone secretion are not the primary cause of the arrest.

The higher functional activity induced by amphetamine is associated with an increase in the labelling of α, β and γ-phosphates of ATP in mouse brain, suggesting an adaptation of oxidative phosphorylation to a higher functional activity. After administration of high doses of amphetamine slight quantitative changes in RNA content are found, whereas a clear activation is observed in the metabolism of all cerebral RNA fractions.

An equation has been formulated to describe the theoretically expected kinetics for two-hit chromosome exchanges whether detected genetically as translocations or cytologically as dicentrics and rings. Data from diverse biological systems have been found to fit the expected values computed from this equation without having to rely upon such explanations as the occurrence of a large amount of inviability appearing at high doses or a large linear component.

The effects of cis or trans isomsrs of clomiphene citrate or estradiol-17β on uterine weight, uterine glycogen and liver glycogen were studied in rats undergoing delayed implantation. Comparative estrogenicity of the cis or trans isomers with estradiol-17β was assessed with reference to changes in uterine glycogen and liver glycogen in response (a) to different doses of the isomer s i.e. 150, 300 or 1SOO gmg/kg and (b) to a small dose (150 gmg/kg) of the compound at different time intervals (6, 18 and 48 hours). High doses of cis clomiphene increased uterine weights more than trans clomiphene. Neither of the two isomers, in small doses, caused any change in uterine weights at any of the time intervals studied. Trans clomiphene caused an increase in glycogen concentration in the uterus and liver 18 hours after the administration of the drug whereas a similar increase was not seen with the highest dose (1800 gmg/kg) of the cis isomer administered. It is concluded that the trans isomer of clomiuhene citrate is more estrogenic than the cis isomer using glycogen as an estrogen sensitive parameter, whereas cis clomiphene is more uterotropic than the trans isomer at higher doses.

Experiment has been carried out using UV-sensitive mutant of uvs 1 of Saccharomyces cerevisiae, presumably lacking ability of dark repair, to investigate genetic nature of UV-induced premutational damages leading to three-different types of mutation under the dark and illuminated conditions. Yields of these types of mutation in uvs 1 are markedly higher than those in wild type at equal doses. At the dark condition, logarithmically plotted dose-response curves of true-back mutations from arg 4-17, his 5-2 and lys 1-1 induced in uvs 1 consist of two straight lines. Slopes of the curves at high doses are more steeper than those at low doses and almost the same as those in wild type in all the dose range. The curves for induced frequency of super-suppressor mutation and that of back mutation from his 1-1, i.e., addition-deletion type mutation consists of one component, and their slopes are nearly equal for both uvs 1 and wild-type strains. Furthermore, ratios of true back mutation yields between uvs 1 and wild-type strains at equal doses are greater than those of super-suppressor mutations or reversion of addition-deletion type. To account for these results it is postulated that premutational damage leading to true-back mutation is preferentially repairable compared with damages responsible for the other types of mutation. Molecular natures of the premutational damages leading to the three types of mutation are discussed.

Experiments were performed to study the effects of the ethylene releasing compound Ethrel on sex expression in cucumbers and squash, and of Alar (B-995) plus Ethrel in muskmelons. As a result of foliage sprays with one or both of the above compounds normally monoecious plants produced female flowers only, for the first 2–3 weeks of flowering. The optimum treatments for cucumbers were two foliage sprays with Ethrel 250 ppm or 500 ppm applied at the second and the fourth true leaf stages. The optimum treatments for squash were Ethrel 250 ppm and 500 ppm applied at the first and the third true leaf stages. High doses (1000 ppm) or repeated applications of Ethrel retarded growth of muskmelons and cucumbers. Applications of B-995 (5000 ppm) plus Ethrel (500 ppm) at the second true leaf stage inhibited male flowering for 2–3 weeks of the flowering period. F1-hybrid seeds of muskmelons were experimentally produced in large isolation cages in the field, using two monoecious lines as female parents. The merits and some of the problems associated with the production of F1-hybrid seeds by the above methods are discussed.

Feeding Oxytetracycline in high doses to rats for 26 months results in a distinctly elevated body weight. This increase depends on enhanced endogenous synthesis of triglycerides. Furthermore the organs are enlarged by tissue formation.

The suppressive effect of adrenocortical steroids on thyroid function is well documented in laboratory animals1 2 3 4 and in human beings.5 6 7 8 9 The relation of adrenocortical steroids and the thyroid gland has been comprehensively reviewed by Ingbar and Freinkel.9 The evidence presented suggests that short-term ACTH and cortisone administration suppress the hypophyseal secretion of thyroid-stimulating hormone (TSH). There are few experimental data utilizing long-term administration of these substances. The histologic data of Halmi and Barker10 present evidence of activation of rat thyroid glands as well as probable increased pituitary production of TSH. The following case reports of hyperthyroidism in patients on long-term, high-steroid . . .

Total body exposure to ionizing radiations results in widespread cellular damage which is manifest by the promptly ensuing “toxemia” known as radiation illness. The cellular damage has in the past been considered largely due to (a) protein denaturation and (b) the formation of “toxic products.” These concepts resulted in various forms of symptomatic and replacement therapy for radiation illness. Recent reports have stimulated new investigative and therapeutic endeavor in this field by calling attention to the effects produced by the ionization products of irradiated water on the sulfhydryl enzyme systems. These ionization products of irradiated water (OH, O2H and H2O2, etc.) (1, 2) are active oxidizing agents and have been shown to inhibit the sulfhydryl-containing enzymes (3–6), the degree of inhibition being directly related to the dosage of radiation. High doses of radiation produce irreversible enzymatic inhibition presumably by protein denaturation, whereas the inhibition from low doses may be revers...

The behaviour of the in vitro-activities of an alkaline and an acid deoxyribonuclease (DNase I and II, resp.), and of an inhibitor of DNase I of the kidney of mice, as well as of the DNA- and protein-content of kidneys and thymus, was studied in about 500 mice 4 hours to 21 days after exposure to folic acid in doses of 60 — 180 mg/kg body-weight. The most important results can be summarized af follows: 1. Activity of DNase I decreased and activities of DNase II and of a DNase I-inhibitor increased under the influence of high doses of folic acid. Significant effects were observed 16 — 24 hours after folic acid-injections. Extreme values (80% decrease [DNase I], 180% increase [DNase II, DNase I-inhibitor]) were reached after 2 and 4 days and were dose-dependent. Control values reappeared within 1 — 3 weeks. 2. Protein- and DNA-content of the thymus behaved very similarly to DNase I-activity of the kidney. 3. The increase of the DNase II-activity of the kidney under the influence of folic acid resulted from enzyme induction. As to the behaviour of DNase I loss of enzyme out of damaged cells and the induction of a DNase I-inhibitor in the kidney must be taken into account. 4. In many systems DNase I may control DNA-synthesis. Preliminary studies on the behaviour of folic acid-induced reaction of the kidney, when inhibited by X-irradiation, Actinomycin D, Actidione, or poly (vinylsulfate), suggest that DNase I-inhibitor plays a certain role in combining protein- and DNA-synthesis by inhibiting DNase I.

SummaryVery high doses of A. C. T. H. and Cortisone can enhance the apparition of thrombosis. The authors observed, an increase in blood platelets and a decreased clotting-time in rheumatic patients treated with small doses of A. C. T. H. Changes in prothrombin level have been inconstant.

The response of intact Fundulus heteroclitus to intraperitoneal injections of ACTH at two hours post-injection depends on the dose: leucopenia at low doses, leucocytosis at high doses. The two hour response to cortisol, at 5 μg/g, depends on the condition of the fish: leucocytosis in sexually mature or hypophysectomized fish, leucopenia in sexually regressed intact fish. At a physiological dose (0.025 μg/g) cortisol elicits a time sequence response in hypophysectomized recipients that is, initially, the reverse of that observed after coldshock: three minute leucocytosis, 15 minute leucopenia, and return to normal at 45 minutes. Leucocytosis emerges at two hours. Pretreatment with Metopirone for five to six days in the aquarium water is not well tolerated. Such treatment effectively blocks all phases of the cold-shock response. Pretreatment for two days was tolerated and, in such fish, injection of epinephrine (1 μg/g) elicits both three minute and 30–60 minute leucopenia, but the leucocytic phases are blocked. A tentative interpretation of the cold-shock sequence is proposed on the assumption that catecholamines (presumably epinephrine) are leucopenic and that cortisol is leucocytic.

The effects of single sc injections of various doses of estradiol benzoate (Eb) and testosterone propionate (Tp) on plasma levels of LH, FSH and prolactin have been reinvestigated in castrate rats of both sexes. Our results indicate that Eb or Tp inhibited release of LH in castrate rats of both sexes. Males were more sensitive to the inhibitor effect of the low dose of Tp than females. The steroids also lowered plasma FSH levels in spayed females; however, in castrated males Eb stimulated FSH release and a decrease in FSH followed the injection of only the highest dose (2 mg) of Tp. Eb and Tp had a synergistic effect in inhibiting FSH release in the male. Both steroids stimulated release of prolactin in castrate males and females (no sex difference in release of prolactin in response to Eb was observed; however, males appeared more sensitive to Tp treatment). Single injections of progesterone (P) in spayed females produced variable results. High doses inhibited LH release and elevated prolactin levels. Ef...

The effect of DOC on sodium chloride (saline) intake was studied in intact and adrenalectomized rats under "two-bottle" self-selection conditions. It was found that in adrenalectomized rats low doses of DOC produced a decrease in saline intake (restoration of sodium-retaining ability), whereas high doses produced an increase in saline intake (stimulation of sodium appetite). At high doses, however, intact rats consumed more saline and manifested a greater preference for it than did similarly treated adrenalectomized rats. Treatment with corticosterone increased both absolute saline intake and saline preference of DOC-treated adrenalectomized rats.

Dogs that develop a biomicroscopically visible corneal granularity associated with the prolonged oral administration of chlorpromazine at high doses (30 mg/kg/day) have a distinct granule within the cytoplasm of corneal stromal cells. The dense oval to spherical granules occur singly or in aggregates and have a characteristic internal structure. They are identical with the biomicroscopically and histologically visible chlorpromazine-associated corneal stromal granules and are dissimilar to any other known granule occurring in the canine eye.

Summary1. Intravenous injection of 0.3 γ/min. 5-hydroxytryptamine creatinine sulfate (5-HT) caused transitory elevation of local venous pressure; higher doses induced more marked elevation of local venous pressure and, when administered in short period of time, of arterial pressure. Elevation of systemic venous pressure was not obtained even with extremely high doses of 5-HT. 2. Intraarterial administration of 5-HT induced sustained elevation of pressure in the homolateral veins (30 minutes or longer). 3. Elevation of arterial pressure and generalized flushing followed injection into a patient with septal venous-arterial shunt of a dose of 5-HT unable to cause such effect in normal subjects. 4. It is postulated that injected 5-HT is quickly removed from the circulation, perhaps by platelets or by other cellular elements retained in capillary beds and released slowly at a later time.

Ovulation was induced in mature female rats by appropriately timed injections of pregnant mare serum gonadotrophin (PMSG) and human chorionic gonadotrophin (HCG). Various combinations of the gonadotrophins were used. Maximal ovulatory response was consistently obtained with 50 I.U. PMSG and any combination of HCG between 50 I.U. and 5000 I.U. On the basis of the results obtained it is recommended that 50 I.U. PMSG and 50 I.U. HCG be injected to obtain a maximal ovulatory response in mature rats. High doses of PMSG (but not HCG) suppress ovulation markedly.