Effect of ethanol on levels of isoniazid, sulfanilamide and sulfapyridin in mouse blood. The effect of ethanol of blood levels of free and conjugated sulfonamides (sulfanilamide and sulfapyridin) and isoniazid was investigated in mice. Ethanol (1.5 and 4 mg/g i.v.) enhanced the amount of conjugated isoniazid without affecting the total amount of isoniazid in blood, and tended to raise the total amount of the sulfonamides.


Pharmacological studies of a new analgesic, dl-erythro-1-phenyl-2-(o-chlorophenyl)-2-[4-(p-methoxybenzyl)-1-piperazinyl] ethanol dihydrochloride, in experimental animals. dl-Erythro-1-phenyl-2-(o-chlorophenyl)-2-[4-(p-methoxybenzyl)-1-piperazinyl] ethanol dihydrochloride showed orally a definite analgesic activity, without producing the significant morphine-like physical dependence liability, and its analgesic potency was about a half that of codeine and far superior to aminopyrine in experimental animals.


Gill lesions in Cichlid fishes after intoxication with the insecticide Fenthion. The toxic effects of Fenthion on the gills of Cichlid fishes were investigated. In Herotilapia multispinosa hyperplasia and separation of the respiratory epithelium, lamellar telangiectasis and thrombosis occurred. The lamellar epithelium of surviving fish regenerated in all cases. In Tilapia leucosticta no telangiectasis was found, but all the secondary lamellae were fused due to the severe hyperplasia of the gill epithelium.


The effects of physostigmine on the oxygen uptake in rat brain tissue. Physostigmine in a dose of 0.1 mg/kg i.v. expressly stimulated the oxygen uptake in the rat cerebral cortex. This effect was blocked by propranolol and seems be mediated by catecholamines. Since atropine also antagonized the stimulant effect of physostigmine, it appears that the action of physostigmine is primarily cholinergic and that the adrenergic effect is a secondary phenomenon. The higher dose of physostigmine (0.4 mg/kg i.v.) caused a depression of rat brain oxygen uptake.


Effect of dichloromethane on the sciatic motor conduction velocity of rats. There is a correlation between dichloromethane dosis (X) of 1--6 mmole/kg administered i.p. to rats and the sciatic motor conduction velocity (Y): Y = 57.1--1.091 X. The correlation coefficient 'r' is 0.437 (p less than 0.01). Presumably, the decrease of nerve conduction velocity is caused by the endogenous carbon monoxide production due to dichloromethane biotransformation.


Cell death and phagocytosis in the neuroepithelium of the developing retina. A TEM and SEM study. Phagocytosis by neuroepithelial cells independent of the presence of pseudopodes is observed as the main mechanism of elimination of physiologically degenerating cells during the early development of the retina in the chick embryo.


Cholinesterase in the atherosclerotic intima and in fibroblast cultures. Cholinesterase activity was present in the atheromatous plaque of the rabbit's atherosclerotic aorta. Cholinesterase activity was significantly increased in rat fibroblast cultures grown in the presence of hypercholesterolemic serum. Cholesterol ester synthesis in these cultures was inhibited by neostigmine, a cholinesterase inhibitor.


Induction of lymphomas by urethane in combination with diethylstilboestrol in CFLP mice. The combination of urethane and the non-steroidal oestrogen diethylstilboestrol induced lymphomas in CFLP mice.


Quantitative histological study of spinal afferent innervation on the ventral surface of the cat stomach by horseradish peroxidase (HRP) method. Retrograde axonal transport of horseradish peroxidase (HRP) was applied to the ventral surface of the cat stomach. We investigated the number, size and distribution of HRP-positive cells in spinal ganglia. The unexpected finding was the wide distribution of these cells from T3 down to L3. This would result in a diffuse pattern of referred pain.


Demonstration of cross reaction between anti-macrophage antibodies and mononuclear mesodermal cells. An anti-macrophage antiserum to rat peritoneal macrophages was prepared in rabbits. The antibodies produced showed cross reaction with perivascular adventitial macrophages, with macrophages in thymus and spleen, and with brain microglial cells.


Carcinogenicity examination of betel nuts and piper betel leaves. A dry powder of betel nuts, piper betel leaves and lime was administered to rats. Epidermal thickening was frequently observed in the upper digestive tracts of rats in groups fed the betel nut diet mixed with lime and the betel leaves diet, and a forestomach papilloma was seen in 1 rat given betel leaves diet. These epidermal changes were scarcely seen in rats given either betel nut or normal diet alone.


Effects of 9.4 GHz microwave exposure on meiosis in mice. Exposure to 9.4 GHz pulsed microwaves at low power densities for 1 h/day during 2 weeks induces in adult male Balb/c mice disturbances in meiosis, consisting in an increase of translocations and the appearance of cells with several chromosome pair remaining univalents at MI.


Quantitative ultrastructural features of maturing mononuclear phagocytes in rat peritoneal fluids. Ultrastructural features of the in vivo transformation of macrophage congeners in resident and adjuvant-induced peritoneal populations are evaluated by sterological methods. Maturation involves an increase in cell size by the differential hypertrophy of subcellular compartments, notably remaining cytoplasm, nucleus and lysosome-like granules. Larger cells have more and larger granules, more mitochondria and a greater plasmalemmal surface. In contrast, adjuvant activation tends to produce fewer granules and a nett loss of surface membrane.


Frequency and distribution of tubulo-filamentous nuclear inclusions in the celiac ganglion of the cat as revealed by serial sections. On sections at random of a cat celiac ganglion we counted 68 sections of nuclear inclusions (NI) for 320 sections of neuronal nuclei, i.e. an "apparent' frequency of 0.20. As revealed by serial sections the "actual' frequency is higher since the 5 nuclei entirely explored exhibit 19 NI. Such a study shows that each nucleus may contain at least 3 and up to 5 different tubulo-filamentous NI.


Prefrontal cortex of the cat: evidence for an additional area. Direct projections from the mediodorsal nucleus of the thalamus to ventral parts of the insular region of the cat's cortex were demonstrated by using the horseradish peroxidase technique.


Changes in the plasma membrane surface of lymphocytes stimulated in vivo with DNCB. Stereological principles have been used to evaluate ultrastructural changes which accompany the transformation of lymphocytes stimulated in vivo with dinitrochlorobenzene (DNCB). Whereas unstimulated lymphocytes and blast cells have slightly more than the minimal containing plasmalemmal surface for their volume, stimulated (blast-derived) lymphocytes have an excess surface area in the order of 30%. This observation is discussed in the context of altered cell function and the biosynthesis of additional membrane components.


Innervation of the ovarian interstitial cell of the chick embryo. Electron microscopic examination of the developing ovary of 15-20-day chick embryos revealed that the interstital cells well innervated. Nerve fibres and nerve endings were observed in close contact with steroid-producing cells.


Effect of colicin E3 on leukemia cells P388 in vitro. Proliferation of murine leukemia cells P388 is stimulated by less than 1.0 mg/ml colicin E3, while being inhibited by higher concentrations. By 1.6 mg/ml colicin E3, uptake of thymidine into cold TCA-precipitable fraction is decreased by 59% during 24 h, uptake of uridine by 29%.


Reduction of serum X-prolyl dipeptidyl-aminopeptidase activity in tumour-bearing mice and reversal of reduced enzyme activity by lentinan, an anti-tumour polysaccharide. Serum X-prolyl dipeptidyl-aminopeptidase activity which had been shown to be depressed in cancer patients was clearly reduced in mice with Ehrlich carcinoma and Sarcoma 180, and slightly reduced in mice with methylcholanthrene-induced sarcomas. The reduced enzyme activity was completely reversed during tumour regression of sarcoma 180 by administration of lentinan, which causes regression of sarcoma 180.


Local adjuvants: the influence of sodium dodecylbenzene sulphonate on immunization with aerosolized antigen. Guinea-pig respiratory and serum antibody responses were enhanced following exposure to aerosols of bovine IgG2 dissolved in solutions of sodium dodecylbenzene sulphate (SDBS). Enhanced response was seen in both primary and secondary immunization. Cell-mediated immune response (indirect macrophage migration influencing test) was not altered by SDBS. Results are discussed with a view to the possible utility of SDBS as adjuvant for prophylactic immunization.


Circadian variation in urinary melatonin in clinically healthy women in Japan and the United States of America. Urinary melatonin excretion is lower in East-Asian (Japanese) than in North-American (whites of mixed ethnic origin) women. Moreover, a statistically significant circadian rhythm is demonstrated by population-mean cosinor in the data pool from both groups of women. Furthermore, statistical significance characterizes interactions of effects from geographic differences (between ethnic groups) with temporal factors. Such spatio-temporal interactions await further scrutiny with a view inter alia of carcinogenesis as it is influenced by a spectrum of intermodulating rhythms.


A study of the enzyme activity in the seminal vesicles of castrated and hormone-replaced castrated mice. Castration provokes a time-related decrease in weight, protein, beta-glucuronidase and glucose-6-phosphate dehydrogenase activity of seminal vesicles. A dose-dependent stimulation of these parameters is obtained with 5alpha-DHT. Cryproterone acetate counteracts the stimulatory effects due to androgen. Acid and alkaline phosphatases remain largely unaffected by these treatments.


A new simple assay for total blood lipids by refractometry. A fast simple method for assay of total blood lipids has been devised by precipitating blood proteins with methanol and extracting lipids into diethyl ether. The change in refractive index of the methanol-ether due to dissolved lipids is measured in a refractometer.


The morphology of cytoplasts and karyoplasts produced by cytochalasin D. The denucleation of L cells and human lymphocytes in suspension was carried out by incubation with cytochalasin D25 and 50 microgram/ml and with ultracentrifugation over a discontinuous Ficoll gradient. Ultrastructural examination of the separate layers confirmed the presence of the anucleate cytoplasm (cytoplasts) with intact membrane and the separated nuclei (karyoplasts).


Sectioning of polyacrylamide slab gels with a modified small animal stereotaxic instrument. A simple and inexpensive modification of the Kopf model 900 small animal stereotaxic instrument allows it to be used temporarily as a precision polyacrylamide slab gel slicer.


Leonurine, an improved synthesis.

Leonurine, an improved synthesis. Leonurine (1) is the uterotonic principle of Leonurus artemisia. We have developed a simple, high-yield synthetic procedure of 1 that is adaptable to large scale preparation. The synthesis involves the condensation of syringic acid and 4-guanidino-1-butanol hydrochloride in the presence of DDC using 1:1 HMPT-ether as solvent. The synthetic leonurine showed uterotonic activity in vivo and in vitro.


Altered or increased transfer-RNA methylation in the course of Interferon action on cells in culture? The induction of the antiviral state by Interferon might reflect the decrease of the rate of biosynthesis, the degradation or the alteration of one or several tRNAs. This could result in rate-limiting concentrations for codons common in viral RNA but rare in host mRNA. Altered methylation of tRNA could be the basis of such a phenomenon. However, we could not find an altered extent of methylation of total tRNA or an altered pattern of methylation, if mixed tRNAs were chromatographed on MAK- or BD-cellulose columns, despite a large range of conditions of pretreatment of chick embryo fibroblast cultures with interferon.


Polyamines as activators of AMP nucleosidase from Azotobacter vinelandii. Polyamines at physiological concentrations activate AMP nucleosidase from Azotobacter vinelandii. Biological significance of the activation is discussed in relation to the control of adenylate energy charge and the purine nucleotide synthesis in prokaryotes.


Circadian activity of rat kidney enzymes. Alkaline phosphatase, LAP, beta-glucuronidase and cathepsin D activities and protein content of the kidney homogenate did not show any circadian rhythm in animals sacrificed at different hours of the day. The fluctuations of maltase appear modest and not dependent on a ligh/dark cycle.


Diethylmesoxalate hydrate, a new irreversible inhibitor of cholinesterases. Bovine erythrocyte acetylcholinesterase and human plasma cholinesterase are irreversibly inhibited by diethylmesoxalate hydrate, the inhibition potency being comparable to that of certian insecticidal organophosphates and carbamates. Insect cholinesterases, however, appear to be much less affected by diethylmesoxalate hydrate. The compound was also found to inhibit the hydrolysis of paraoxon by rabbit plasma A-esterase, but in a reversible mode.


Effect of solubilization of Salmonella minnesota Re glycolipid on its interferon-induced activity. Electrodialysis of Salmonella minnesota Re glycolipid, or exposure to 0.2 M EDTA, pH 7.0, yields products capable of eliciting interferon production at concentrations 10-fold lower than that of the original glycolipid.


Persistence of body weight cycles in dormice maintained with a limited food supply. Dormice kept under food restriction for several months continued to exhibit body weight cycles with characteristic periods of about 2 months, despite an impaired ability to attain the high body weight levels observed in ad libitum conditions. These results imply that the cycle is controlled by a mechanism whose properties are more consistent with asn endogenous oscillator than with a sequence of stages, in which the relevant stages are defined by upper and lower body weight limits.


Ketoconazole -- a new broad spectrum orally active antimycotic. Oral treatment with ketoconazole prevented and cured artificial crop candidosis of the turkey, vaginal candidosis of the rat and skin candidosis of the guinea-pig. It was also highly effective against artificial systemic candidosis of the guinea-pig and chicken as well as against dermatophytoses of the guinea-pig.


Adhesion of human red blood cells to polystyrene. Influence of sodium chloride concentration and of neuraminidase treatment. The adhesion on polystyrene of glutaraldehyde-fixed human red blood cells was found to increase with NaCl concentration. Half of the maximum of irreversible adhesion was obtained in 2.2 mM NaCl for neuraminidase-treated cells and in 5.5 mM NaCl for the untreated cells.


Circadian change of sweating rate measured locally by the resistance hygrometry method in man. There existed circadian change in the sweating rate locally measured from the anterior of the left thigh: the sweating rate showed a remarkable decline during the period 2.00--5.00 h, while at other times throughout the day it generally remained high. This reduction seemed to be independent of sleep or sleeplessness.


Distribution of microspheres of 15 +/- 5 micrometer diameter in dog kidneys. The size distribution of plastic non-radioactive microspheres (MS) of 15 +/- 5 micrometer diameter in the dog kidney was investigated. No diameter-dependent redistribution of the MS was found.


Catecholamine levels in newborn human plasma in normal and abnormal conditions and in maternal plasma at delivery. High levels of catecholamines have been found in plasma from the umbilical cord of newborn infants, suggesting a release of catecholamine from the fetus during parturition. Plasma catecholamine levels are also elevated in mothers at delivery.


Direct evidence favouring the notion that erythropoietin alters iron transport across the isolated intestinal tract of the rat. A simple and reproducible method, using the isolated not everted intestine of the rat, for the study of iron transport is presented. Erythropoietin (ESF) enhanced significantly the passage of 59Fe across the intestine augmenting its movement at mucosal and serosal layers of the intestinal well.


The ischemic and postischemic effect on the uptake of neutral amino acids in isolated cerebral capillaries. The uptake of some neurtral amino acids was investigated in cerebral microvessels isolated from brains of gerbils subjected to bilateral cerebral ischemia with and without various periods of recovery. A transiently increased capillary uptake of 3H-isoleucine, 14C-cycloleucine and 3H-phenylalanine was found in both conditions.


Nerve-growth promoting action of isaxonine in rat. After sciatic nerve lesion by freezing, the length of the most rapidly regenerating fibres was significantly increased by i.p. injection of isaxonine (N-isopropyl-amino-2-pyrimidine orthophosphate) in the rat. A dose-effect relationship was demonstrated. Both sensory and motor function returned earlier in treated animals.


Cholecystokinin-like peptides in avian brain and gut. Extracts of turkey brain and jejunum contain a factor closely resembling the COOH-terminal octapeptide of porcine cholecystokinin (CCK). Turkey antral extracts contain factors distinguishable in immunochemical and gel filtration properties from the mammalian forms of gastrin and CCK.


Comparative studies on the covalent binding of the carcinogen benzo(a)pyrene to DNA in various model systems. The covalent binding of tritiated benzo(a)pyrene (BP) to DNA has been determined in rat liver in vivo, in rat liver perfused in situ, after incubation of BP with liver single cells, with liver homogenate, with liver microsomes and DNA, with fibroblasts from a rat granuloma pouch, and with 2 cell lines. Liver single cells were found to be a valuable compromise between the most sensitive system (microsomal incubation of BP and DNA) and the biologically most relevant system (in vivo).


Anticholinesterase-like activity by oriental hornet (Vespa orientalis) venom and venom sac extract. Oriental hornet venom or venom sac extract produces pharmacological and toxicological effects typical of anticholinesterase agents. The effects produced in animals can be counteracted by atropine and heparin.


Ethanol reduces Ca2+ concentrations in arterial and venous smooth muscle. The present results, using isolated rat aortic strips and portal vein segments, demonstrate that ethanol (170--430 mM) significantly inhibits calcium uptake in these 2 different types of vascular smooth muscle.


Effect of beta-phenylethylamine on intraocular pressure. Upon injection of beta-phenylethylamine (PEA) into the subconjunctival space of rabbit, intraocular pressure increased. This effect went parallel with the amount of PEA transferred into the anterior chamber, which indicates that intraocular pressure was elevated by direct action of PEA.


Toxic effect of cadmium nitrate on the liver of Channa punctatus. Exposure of a fresh water fish, Channa punctatus, in a medium containing as low as 0.01 ppm of cadmium nitrate, resulted in the necrosis of hepatic cells. A temporary recovery of these cells was however observed when the animals were exposed to lower concentrations.


Baroreceptor and sympathetic responses to acebutolol, a beta 1-adrenoceptor-blocking agent, in rabbits. Baroreceptor activity was increased after i.v. infusion of acebutolol in rabbits with an intact circulation, and in rabbits with a total cardiopulmonary by-pass. In rabbits with an intact circulation, renal nerve activity was reduced.


[Liver enlargement induced by oxythioquinox: effect of the fat content of the diet (author's transl)]. The relationship between the level of lipid calories in the diet and the effects of oxythioquinox, administered at 200 mg/kg fresh food, for 35 days, was studied on the liver enlargment of rat. The results show that the level lipid calories itself have no effect since, in the treated animals, the liver enlargement is due part to an increase of the water content and part to an increase of the size of the cells.


Offset rate of action of muscarinic antagonists depends on their structural flexibility. Time course measurements of the action of muscarinic antagonists were performed in the spontaneously beating carp atrium. Several high affinity drugs, which embody the quinuclidine structure were examined. The structural flexibility of these molecules was reflected in the dissociation of the drugs from the muscarinic receptor. The dissociation of rigid drugs was very much prolonged as compared to flexible drugs of the same affinity.


Antihypertensive and other cardiovascular effects of 2-(3-pyridyl)- and 2-(4-pyridyl)-4-trifluoromethylimidazoles. 2 new 4-trifluoromethylimidazole derivatives were found which lowered mean arterial pressure in renal and spontaneously hypertensive (SH) rats by the oral route. In SH rats, compounds A and B were 0.1 and 0.3 times, respectively, as potent as hydralazine. No tolerance development was observed in SH rats with either compound over a 1-week period. In anesthetized dogs, both compounds lowered arterial pressure and peripheral vascular resistance but increased cardiac output. By intraarterial administration, both compounds increased femoral arterial blood flow. These findings represent discovery of a new class of vasodilator durgs.


Effects of chronic lithium administration on concanavalin A binding to plasma membranes from the corpus striatum of rat brain. The effects of chronic in vivo lithium administration on mannose-containing components of plasma membranes from rat corpus striatum were examined by a 3H-concanavalin A binding displacement method. No difference on Con A binding was observed between sodium or lithium-treated rats during a 1-month period.


Isolation of a neurosecretory substance which stimulates RNA synthesis in regenerating planarians. An approach to the isolation of neurosecretory material from planarians is described. This material stimulated RNA synthesis, in a dose-dependent response, in regenerating Dugesia tigrina. The data support the concept that neurosecretion plays a key role in the process of regeneration in planarians.


Mitochondrial respiration depressed by camphor: a possible aid in radiotherapy. Camphor has been found to decrease the rate of oxygen consumption by rat kidney mitochondria. The rate of oxygen consumption is nearly halved by the addition of 8 X 10(-3) M camphor. It is suggested that camphor may be of use in oxygenating tumours prior to radiotherapy.


Murine primitive neuroectodermal tumor: nucleolar isolation and RNA polymerase inhibition. A nucleolar isolation procedure was developed for the murine primitive neuroectodermal tumor originally induced with methylcholanthrene. This procedure utilizes sonication for breakage of the nuclei at a magnesium concentration which disperses the extranucleolar chromatin. The nucleoli retain RNA synthetic activity which is inhibited to about 90% by actinomycin D and the chemotherapeutic drug adriamycin.


Promotion of epithelial keratinization by N-methyl-N'-nitro-N-nitrosoguanidine in rat forestomach in organ culture. The effect of N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) on epithelial differentiation of fetal rat forestomach was investigated in organ culture. When forestomach tissues removed from 16.5-day fetuses were treated with 5 microgram and 3 microgram of MNNG per ml for 1 h, epithelial keratinization was observed after 4 and 5 days, respectively, whereas it occurred after 6 days in control cultures. A clear dose-response relationship was found in the promotion of epithelial keratinization by MNNG.


Differences in utilization of tritiated thymidine and tritiated deoxycytidine by rat lymph node cells. Large lymphoid cells and plasma cells in antigenically stimulated rat lymph nodes retain less label after injection of 3H-CdR than after injection of 3H-TdR. There is no difference amongst small lymphocytes. The data are consistent with a defect in the utilization of 3H-CdR in the late stages of B cell maturation in the rat.


Immunological and morphological consequences of vasectomy in the rabbit. Cell-mediated immunity to spermatozoa was detected in vitro 6--18 months after vasectomy in the rabbit. The autoimmunity was accompanied by aspermatogenic orchitis in the testes and epididymides.


Properties of vascular permeability factor in human sera for guinea-pig skin. Properties of vascular permeability factor in native human sera (PF/Nat) showed close similarities with those of necrotizing factor. Time course studies revealed that skin necrosis could be initiated by enhanced vascular permeability.


Catecholamines in adult iron deficiency patients. Patients with iron deficiency whether uncomplicated or associated with other types of anemias, had plasma catecholamine levels which were significantly increased above normal controls. Patients with a variety of other anemias had no significant increase in catecholamine levels. Plasma catecholamine levels in uncomplicated iron deficient patients approached normal values as early as 3 h following oral FeSO4.


Inhibitory effect of cytokinins on PHA-induced human lymphocyte stimulation. The inhibitory effect of various purine derivatives on PHA-induced human lymphocyte blast formation was studied. Two nucleoside cytokinins, N6-benzyladenosine and N6-isopentenyladenosine, inhibited blast formation at concentrations as low as 10(-6) M. However, the other cytokinins, which lacked the ribosyl residue at N9 position, had to be at the higher molar concentration of 10(-4) before they could induce the same inhibitory effect.


Cell proliferation in the rat pituitary gland: a mechanism of control in prolactin cells. We investigated the relationship between prolactin content and DNA replication in the anterior pituitary gland. Thymidine incorporation in pregnant rats is significantly lower than in virgin controls. This is accompanied by a decreased activity of DNA polymerase. Sulpiride administration to pregnant rats enhances thymidine incorporation to levels similar to virgin controls. The results indicate a negative feedback between prolactin content and DNA synthesis in the rat anterior pituitary gland.


Acute effects of unilateral or bilateral superior cervical ganglionectomy on rat pineal N-acetyltransferase activity and melatonin content. Acute bilateral superior cervical ganglionectomy (SCGX) completely prevents the nocturnal rises in pineal N-acetyltransferase (NAT) activity and melatonin content in male rats kept in light-dark cycles of 14:10. Unilateral SCGX causes the NAT and melatonin levels to be intermediate between those in sham-operated control rats and those in rats from which both ganglia had been removed.


The involvement of serotonin in induced ovulation in the immature rat. In pregnant mare's serum gonadotropin (PMS) treated immature rats the cortex, cerebellum, caudate nucleus and hypothalamus were isolated and analyzed for their serotonin (5-HT) content at 6-h intervals for 72 h. Results showed a general trend of significant variation occurring in days 1 and 3 after PMS injection with no major variations observed on the second day. The results obtained suggest a possible involvement of 5-HT in the control of ovulation.


In vitro stimulation of chicken pituitary growth hormone and prolactin secretion by chicken hypothalamic extract. The effect of an acid extract of chicken hypothalami on the in vitro secretion of prolactin and growth hormone (GH) by dispersed chicken pituitary cells has been investigated. Both prolactin and GH release were stimulated in a dose related manner in the presence of the hypothalamic extract (HE). Somatostatin had no effect on the basal or HE stimulated release of prolactin although it did inhibit the HE induced release of GH.


Trans-4-hydroxy-3-methoxycinnamic acid (ferulic acid) inhibits the effect of androgens on the rat prostate. Trans-4-hydroxy-3-methoxycinnamic acid (ferulic acid, FA) antagonized the effect of exogenous androgens on the ventral prostate (VP) in castrated rats as well as the effect of endogenous androgens in intact rats. FA, however, had no effect on the seminal vesicles (SV) and levator ani muscle (LAM), nor oestrogenic effect in female rats and mice. FA did not antagonize the receptor binding of testosterone nor inhibit the conversion of testosterone into 5 alpha-dihydrotestosterone (DHT).


Are there cyclic variations in estradiol secretion in the non-pregnant rabbit? Plasma estradiol-17 beta (E2) concentration was measured in 5 adult non-pregnant rabbits each in 3 different seasons (January, April and September). Blood samples were taken from each rabbit every other day. There was a considerable variation in plasma E2 levels from one sampling day to another, irrespective of the season. The pattern of variation in E2 levels in individual rabbits tended to be cyclic and this cycle was roughly of the order of 8 days. There was no correlation between changes in E2 levels and those in the vaginal appearance.


Serum prolactin levels and maintenance of progeny by prenatally-stressed female offspring. Prenatal stress significantly reduced the number of progeny born to 47% of the female offspring and significantly increased the incidence of low birthweight young. None of these litters survived by the tenth postpartum day when serum prolactin levels were significantly reduced. Upon autopsy, these females had twice as many uterine implantation sites than the number of fetuses they bore, suggesting that a) the reduced postpartum serum prolactin most likely was the cause rather than the effect of the neonatal mortality and b) major hormonal deficiencies (possibly gonadotropic-related) were present even before giving birth.


Effect of testosterone on the hypothalamic-pituitary-gonadal axis of pinealectomized and pineal-intact male rats. Previous studies indicate that steroid hormones alter pineal biochemistry, and it has been suggested that at least part of the negative feedback effect of steroid hormones on pituitary gonadotropin release may be mediated by the pineal gland. In this study, pinealectomy did not alter the inhibitory effect of testosterone on neuroendocine-gonadal activity in the male rat, suggesting that the pineal gland does not mediate the response of the rat hypothalamic-pituitary axis to testosterone.


A source of error in the fluorometric determination of protein in human placental microsomes. When protein is assayed in human placental microsomes by the fluorescamine procedure, 25--30% of the observed fluorescence results from labeling of phospholipids.


Porcine skeletal muscle for physiological studies. The common digital extensor (lateral head) is one of the few porcine muscles of convenient dimensions for in vitro studies of intact cells. Its removal and use in physiological studies are described.


Consideration on the effects of pollution at community and population level. The effects of pollution at population level are considered in relation to demographic characteristics and overall to the birthrate. The direct and indirect effects of pollution on community structure is discussed. The influence of pollution may vary according to the food-chain structure; (as a consequence, the hazard 'ceteris paribus' will be greater in freshwater communities than in marine ones). Relations between 'diversity' and 'stability' are discussed. In addition, the advantages and difficulties in using 'diversity' and 'biotic' indices for monitoring polluted water are taken into account.


[Effect of lithium oxybutyrate on the polypeptide and noradrenaline content in the rat hypothalamus]. It was established that single administration to rats of 200 mg/kg of lithium hydroxybutyrate releases noradrenalin from the terminals of hypothalamus adrenergic fibers and increases output of polypeptides in the neurons of supraoptic and paraventricular nuclei of the hypothalamus. After repeated administration of the drug (200 mg/kg) once a day over 6 days) the nuclei showed depressed output of polypeptides.


[Effect of GABA, sodium glutamate and glycine on evoked potentials in the dental zones of the cerebral cortex]. Intraventricular administration of gamma-aminobutyric acid (GABA) and glycine decreased, whereas sodium glutamate increased the amplitude of primary responses of dental zones of the somatosensory cortex, which arose during electric stimulation of the pulp of the rabbit upper incisors. No changes in the latent periods were recorded.


[Brain catecholamine participation in etimizol activation of the hypophyseal-adrenal cortex system]. In the experiments on rats the influence of aethimizol on the blood plasma 11-corticosteroids level and the brain catecholamines content was studied. It is established that an hour after the aethimizol injection (10 mg/kg) the blood corticosteroids concentration increases and the hypothalamic norepinephrine and dophamine levels decrease. The pituitary-adrenal system stimulating effect of aethimizol is blocked to a great extent by the intraventricular injection of 6-hydroxydophamine (250 microgram, twice), but is not prevented by the intraperitoneal reserpine treatment (1.5 mg/kg, twice). Aethimizol potentiates the behavioral effects of L-dioxyphenylalanine in mice. It is suggested that the stimulating action of aethimizol on the pituitary-adrenal system may be attributed to its activation of the catecholamines release and their uptake by the hypothalamus.


[Pharmacological activity and toxicity of neurotropic agents in experimental hypodynamia]. Comparison of ED50, the indices of pharmacological range, LD50, risk coefficients, the size of the area of toxic activity, maximal tolerated and absolute lethal doses showed in acute experiments on intact and "hypodynamic" mice that under conditions of a short-term tension-producing hypodynamia in the animals, the pharmacological activity of the test neurotropic agents exhibiting a central action changes, whereas their toxicity remains unchanged.


[Change in the antinociceptive effect occurring in stimulation of the rat midbrain under the influence of morphine]. In chronic experiments on rats it was established that electric stimulation of certain areas of the midbrain depresses pain reactions of different genesis. Morphine in subanalgetic doses (2--2.5 mg/kg) reveals and potentiates the antinociceptive effect of central stimulation shown first of all by depression of the complex highly integrated components of an emotionally behavioral conductive reaction to pain.


[Nonachlazine in solution as an arresting agent in stenocardiac attacks]. Nonachlazine infused in the form of a solution penetrates rapidly the blood and organs. In experiments on cats it was shown that infusion of the drug into the stomach enriches the speed of blood flow and oxyhemoglobin amount in the coronary sinus blood after 2--3 minutes. Heart oxygen consumption increases slightly. Nonachlazine solution is little toxic. As a result of pharmacological research it is recommended for removing angina pectoris attacks in patients irresponsive to nitroglycerin.


[Action of nonachlazine on thrombocyte aggregation induced by adrenaline]. Nonachlazine at concentrations 10(-6)--10(-4)M inhibited platelet aggregation in rabbits induced by adrenalin in vitro. The same concentrations of the drug produced an appreciable increase in aggregation reversibility. Intravenous injection of nonachlazine into the rabbit 50 minutes prior to adrenalin protected the platelets against the aggregation activity of adrenalin but did not affect deaggregation.


[Effect of alpha-tocopherol acetate and sodium selenite on the change in ATP content and the RNA synthesis rate in the ischemic myocardium]. The effect of preliminary administration of alpha-tocopherol acetate (1 mg/kg) and sodium selenite (1 mg/kg) on RNA synthesis rate and changes in the macroergic content in ischemic myocardium was studied. It was shown to be conducive to ATP level maintenance after 30- and 60-minute heart ischemia. A statistically significant accumulation of RNA by the myocardium following I-hour ischemia as well as this polynucleotide synthesis activation were recorded. Preservation of the energetic resources by the cell along with RNA metabolism returning to normal contributes to inhibiting the emergence of irreversible cell damage and increases regenerative potentialities of the myocardium.


[Effect of an intravenously administered phosphatidylserine emulsion on blood coagulation and blood system indices]. Experiments on white rats and rabbits showed that intravenous injection of phosphatidylethanol amine- and sphyngomyelin-stabilized phosphatidylserin emulsion produced hypocoagulemia. The effect was observed immediately after injection of the drug, reached a maximum after one hour and returned to normal following 24 hours. The changes became more intensive as the dose was increased and could be reproduced during repeated administrations over a period of ten days. The arterial blood pressure, velocity of the blood flow and volume of the circulating blood remained unchanged. There were no appreciable changes in the peripheral blood parameters or in bone marrow hemopoiesis on repeated administrations over a period of thirty days.


[Study of pharmacological activity of potassium glutamate in an experiment on young and old animals]. It was established that potassium glutaminate is a little toxic compound (LD50 amounts to 4500 mg/kg on administration to white mice by mouth) and shows a marked pharmacological activity. Administration of potassium glutaminate to white rats in a dose 500 mg/kg raises intracellular potassium level in the tissues, makes the acid-balance equilibrium return to normal after unilateral nephrectomy and acid load, activates bile-forming and choleretic liver function, exerts a moderate diuretic effect. The compound potentiates the activity of succinate dehydrogenase and cytochromoxidase in the tissues of old rats.


[Hypervitaminosis A and the state of the chromosome apparatus of the rat bone marrow cells]. In experiments on rats overdoses of vitamin A produced an increased frequency of cells with chromosomal aberrations and elevated number of polyploid cells. Still more pronounced disturbances were recorded in the structure and ploidity of chromosomes if hypervitaminosis A was accompanied by deficient protein nutrition.


[Effect of butadione on the morphohistochemical changes in the joints in adjuvant polyarthritis]. Prophylactic and therapeutic administration of pyrasol derivatives butadion and stampyrine (antipyrilamide of stearic acid), to rats with adjuvant polyarthritis normalize the structure of the synovial membrane, capsule and of the periarticular tissue of the talocrural articulations, stabilize the proteinic-mucopolysaccharide complexes, lower the permeability of the lysosome membranes and vascular walls and inhibit the phagocystic activity of the histiocytes. Both drugs do not lessen the proliferation of the fibroblasts, but normalize the processes of the collagenogenesis them. The prophylactic and therapeutic effects of stampyrine are superior to those of butadion.


[Effect of phosphemide on the glycogen content in the organs of white rats]. Tests on albino rats brought evidence that the antineoplastic drug phosphemide, administered to the animals in doses of 10 mg/kg daily for 7 days reduces the glycogen content in the liver on the 5th day of investigation. In the heart, skeletal muscles, kidneys and spleen no changes in the glycogen were noted. Phosphemide produced morphological changes in the spleen and kidneys.


[Pharmacodynamics of anti-inflammatory preparations in body exposure to a physical therapeutic factor]. The analgetic and antipyretic action of acetylsalicylic acid is potentiated, whereas that of butadion and amidopyrine is decreased in the conditions of prior action of peloid skin applications (body temperature 42 degrees C). The effect of phenobarbital rises and that of butadion remains unchanged, whereas the inhibitory effect of ethazol revealed in the course of investigations of levelled under conditions of the action of the physical factor on the microsomal system. This leads to the changes in biotransformation and pharmacodynamics of the drugs.


[Hypoglycemic activity of aromatic sulfohydrazides and their derivatives]. Tests on rabbits revealed the aromatic sulfohydrazides and their derivatives to display hypoglycemic action. A number of compounds superior to butamide by their sugar-lowering action and of low toxicity were discovered. The relationship between the chemical structure of the study substances and their hypoglycemic action is discussed.


[Effect of insulin on glucose transport in the kidneys]. Chronic experiments on dogs demonstrated an increase in maximum glucose absorption under the effect of insulin (1 ED/kg). The drug was proved to exert a direct action in acute experiments where it was injected (0.1 RD/min) into the renal artery. After administration of cystein the kidneys did not respond to insulin.


[Sulfadimezine and sulfamomomethoxine distribution in the body of white rats in single and repeated administration in combination with UV irradiation]. Experiments on white rats showed that single administration of sulfadimesin or sulfamonomethoxin combined with UV irradiation delays absorption, increases acetylation rate and diminishes excretion of the drugs with urine. During prolonged investigations it was established that repeated combined administration of sulfadimesin and UV irradiation produces a drop in the drug level in the blood and organs, increases acetylation rate and total acetylation activity in the body. Repeated combined administration of sulfamonomethoxin and UV irradiation produces a wave-like changes in the dynamics of the drug accumulation in the body and organs. Acetylation rate and total acetylation activity of the body rise as was shown in the course of prolonged investigations.


[Comparison of the effect of acute hypoxia on the rat liver lysosomal apparatus against a background of adaptation to hypoxia and the administration of gutimine]. Acute hypobaric hypoxia in rats (260 mm Hg., 90 min) was accompanied by a greater liver lysosomes osmotic susceptibility and by an increase in the relative content of the lysosomal enzymes (acid RNAase and acid phosphatase) in the nuclear fraction. This indicates an enrichment of the liver cell lysosomes with secondary lysosomes. No significant signs of labilization of the liver lysosomes were found. The adaptation of rats to hypoxia, as well as administration of the antihypoxant guthimin or of 1,4-bis-(3'-morpholinopropin-1'-yl-1') benzene hinder these changes to occur in the liver lysosomes during the organism reaction to hypoxia. But the effect of stabilization of the lysosomal membranes in a minor component in the antihypoxia action of the treatment.


[Effect of ethanol and acetaldehyde on the positive reinforcement structures in rats]. An activating action of low doses of ethanol and depressant action of acetaldehyde on the hypothalamic and septal structures of positive reinforcement was established in rat experiments using the method of self-stimulation. The relationship between ethanol activating action on these structures and its increased consumption in the conditions of free choice between ethanol and water was demonstrated.


[Toxic and pharmacological characteristics of armin and nibufin homologs]. The experimental studies of alkylesters of phosphonic and phosphinic acids, close homologues of armine and nibufin, showed this series of compounds to have a strongly marked anticholinesterase action. All the substances produce an inhibitory effect on the central nervous system, raise the tone of the smooth muscles on an isolated strip of rabbit small intestine and induce a miotic pupil in the animals. Introduction of butyl radicals into molecules of phosphonic acid derivatives results in diminution of toxicity and a slight decrease in anticholinesterase activity. By their properties butyl paranitrophenyl esters of ethyl- and butylphosphonic acids are closely related to armine and nibufin.


Modulatory actions of norepinephrine in the central nervous system. Early studies have shown that norepinephrine (NE) released synaptically or iontophoretically onto neurons in the central nervous system acts to depress firing by a mechanism associated with a hyperpolarization but no change or an increase in membrane resistance. This in contrast to classical transmitters, which cause hyperpolarization by a conductance increase. Recent studies designed to clarify the functional implications of these biophysical actions have revealed new phenomenons in which the major overall effect of NE on cerebellar Purkinje cells is to enhance conventional synaptic input and induce an increase in signal-to-noise ratio of evoked versus spontaneous activity. NE released iontophoretically or via stimulation of the locus coeruleus also has been found to enhance the inhibitory effects of gamma-aminobutyric acid, an endogenous cerebellar transmitter. The effects appear even at low doses of NE having no direct depressant action on spontaneous activity. Specificity tests have shown no enhancement of glycine-induced inhibition by NE and an inability of dopamine to mimic NE. The hypothesis is presented that a significant action of NE in the central nervous system is to induce a bias that alters postsynaptic responsiveness to conventional transmitter systems, which themselves may be more directly concerned with detailed information transfer.


Dietary influences on resistance to Salmonella infection in chicks. Studies on the influence of nutritional factors on the resistance of chicks to Salmonella gallinarum have been reviewed. Increased dietary protein decreased the resistance of chicks to this infection although resistance to Escherichia coli infections was not appreciably affected. The administration of high levels of iron, particularly when accompanied by a chelating agent such as EDTA, resulted in increased resistance to this infection. The additional iron resulted in the prevention of the transient hypoferremia and anemia during the course of the disease. Fewer viable S. gallinarum were present in the blood, liver, and spleen in the presence of increased dietary or injected iron. Cadmium added to the diet at a nontoxic level also enhanced resistance to this infection.


The function of glucocorticoids in thermogenesis. Studies both in vivo and in vitro implicate glucocorticoids in various aspects of thermogenesis and prevention of heat loss. Many or most of these effects are probably permissive. Adrenalectomized, cold-exposed rats require glucocorticoids for catecholamine-mediated mobilization of free fatty acids, for shivering responses, and for vasoconstriction and piloerection. Glucocorticoid pretreatment of hypothermic hamsters results in a physiological state more similar bioenergetically to hibernation than to hypothermia. For example, such hamsters can arouse to normothermia from a body temperature of 8 C in a 7--8 C cold room. Lipolytic, gluconeogenic, glycogenolic, and pressor actions resulting from several hormone interactions that require glucocorticoids for optimum responses may account for the enhanced thermogenic ability shown by glucocorticoid-pretreated hamsters. Glucocorticoid treatment also results in enhanced blood and liver carbohydrate levels during hypothermia, a condition similar to that occurring in naturally hibernating animals as opposed to the depleted carbohydrate reserves generally seen in hypothermic animals.


Reappraisal of the predictive value of the beta-human chorionic gonadotropin assay in an infertile population. In order to assess the clinical usefulness of human chorionic gonadotropin (hCG) in monitoring early abortion, we studied prospectively 108 pregnant patients. Of these subjects, 70 carried their pregnancies to term and delivered uneventfully, while 38 patients went on to develop first-trimester bleeding. Blood samples were obtained every 1 to 2 weeks during the first trimester, and, when bleeding developed, at least twice 2 or 3 days apart. beta-hCG was measured by a specific double-antibody radioimmunoassay. In the group with normal pregnancies, first-trimester serum beta-hCG gradually rose to reach a peak concentration of 16,875 +/- 4825 (SD) mIU/ml at 10 to 12 weeks of gestation. In the group with abnormal pregnancies, prior to the onset of bleeding, the mean serum beta-hCG level was 4- to 5-fold below that of normal subjects at equivalent gestational age, although with significant overlap in the 95% confidence limit (2 SD). Furthermore, when bleeding occurred, the individual rate of predicting abortion was at best 75% with an unacceptable rate of false-negative and false-positive predictions.


Anti-zona pellucida activity in human sera. One hundred and twenty-five human sera from male and female fertile and infertile subjects were tested by fluorescent techniques against porcine and human zonae for autoantibodies to zona pellucida. A high incidence of positive sera was found in all groups examined, suggestive that all sera from females demonstrating such activity may not represent cases of autoimmunity to a specific zona component.


The endocrine effects of vasectomy: a prospective five-year study. A prospective study of plasma luteinizing hormone (LH) and testosterone in 54 men for 5 years following vasectomy revealed no significant continuing alteration in either testosterone or LH. Plasma LH levels 1 year after operation were higher than preoperative levels but did not increase further. Stimulation studies (4 years postvasectomy) using human chorionic gonadotropin confirmed acceptable Leydig cell functional reserve.


Successful management of infertility due to polyzoospermia. Polyzoospermia is a rare cause of male infertility. In our clinical practice, patients with exceedingly high sperm counts (ranging from 650 million/ml to 1.75 billion/ml) have invariably been found to have associated poor sperm motility and poor sperm migration in postcoital tests, although the sperm appear morphologically normal. Cases of two infertile couples are presented in which each husband had sperm counts greater than 1 billion/ml. Two methods are reported for the successful management of their infertility problems: (1) precoital dilutional douching and (2) in vitro seminal fluid dilution with 5% dextrose-Ringer's lactate solution and artificial insemination homologous. Each method resulted in improved sperm motility, postcoital tests, and pregnancy.


Clinical findings and testicular histology in three hyperprolactinemic infertile men. Three azoospermic infertile men with marked hyperprolactinemia are described. All three men had clinical evidence of distal genital tract obstruction, and one man had evidence of severe spermatogenic arrest. The histology of testicular biopsies taken from each of these men is described and the role of hyperprolactinemia in male infertility is discussed.


Peroxidative breakdown of phospholipids in human spermatozoa, spermicidal properties of fatty acid peroxides, and protective action of seminal plasma. Aerobic incubation of human spermatozoa in the presence of catalytic amounts of ascorbate and ferrous ion results in rapid peroxidative breakdown of sperm phospholipids and fatty acids; most strongly affected are phosphatidyl ethanolamine, ethanolamine plasmalogen, and docosahexanoic acid. Both peroxidation of the endogenous sperm phospholipid and the concurrent loss of motility can be fully prevented, but not reversed, by an "antiperoxidant" factor present in human seminal plasma. Exogenously applied lipid peroxides are powerfully spermicidal. Washed human spermatozoa, at a concentration normally present in semen, treated with as little as 30 nmoles of lipid peroxide/ml become irreversibly immotile within a few minutes. The antiperoxidant factor present in human seminal plasma effectively counteracts the toxic effect of exogenous peroxidized fatty acids upon human spermatozoa, but is unable to restore motility lost by lipid peroxide action.


The concentrations of free L-carnitine and L-O-acetylcarnitine in spermatozoa and seminal plasma of normal, fresh, and frozen human semen. Free-L-carnitine and L-O-acetylcarnitine concentrations have been determined in spermatozoa and seminal plasma of normal, fresh, and frozen human semen. Results show that in fresh semen most of the free L-carnitine (0.213 +/- 0.02 mM) and L-O-acetylcarnitine (0.063 +/- 0.007 mM) is found in the seminal plasma. In contrast to other worker's results, the concentrations of free L-carnitine and L-O-acetylcarnitine in spermatozoa were found to be high and were 0.384 +/- 0.066 mumole/10(9) spermatozoa (22 mM) and 0.376 +/- 0.057 mumole/10(9) spermatozoa (21.6 mM), respectively. It is also demonstrated that the distribution of soluble metabolites such as L-carnitine between spermatozoa and seminal plasma is altered by the freezing of semen. After freezing and storage of semen at -20 degrees C for 7 days, the intracellular concentrations of free L-carnitine and L-O-acetylcarnitine decreased to below the limits of assay.


A new long-acting injectable microcapsule system for the administration of progesterone. A long-acting injectable microcapsule system for the controlled-release systemic administration of progesterone (P4) is described. The system consists of microcapsules made of the biodegradable polymer, d,l-polylactic acid, which contain crystalline P4. Following injection, P4 is released from the microcapsules by diffusion and biodegradation of the polymer matrix. The rate of P4 release from the prototype microcapsule system in vivo is 1.3 microgram of P4/day/mg of microcapsules, and the duration of release is 30 days. Vaginal estrous cycles in rats and cyclic ovarian function in baboons were inhibited for 1 month following a single injection of P4 microcapsules. The effects of continuous progesterone therapy on reproductive function in both rats and baboons are dose-dependent. The utility of the system as a once-a-month injectable contraceptive is established in the baboon model.


Competitive progesterone antagonists: receptor binding and biologic activity of testosterone and 19-nortestosterone derivatives. Testosterone and 19-nortestosterone derivatives were evaluated in a developmental scheme designed to identify competitive progesterone antagonists having abortifacient activity. Compounds that displayed significant binding to the rabbit uterine progesterone receptor were followed in biologic tests for progestational, antiprogestational, and abortifacient activities. Of the seven compounds tested for both progestational and antiprogestational activity, only one, 5 alpha-dihydronorethindrone, behaved exclusively as an antagonist. Five other 19-nortestosterones (19-nortestosterone, 17 beta-hydroxyestra-4, 9(10)-dien-3-one, norethindrone, norethindrone acetate, and R 2323) proved to be mixed agonists/antagonists. 5 alpha-Dihydronorethindrone, norethindrone, and 19-nortestosterone terminated pregnancy during the postnidatory period in rats; in addition, the latter two compounds inhibited progesterone-supported pregnancy in spayed rats and curtailed pregnancy during the postnidatory period in hamsters. These results demonstrate that several 19-nortestosterone derivatives bind to the uterine progesterone receptor and behave either as antagonists or mixed agonists/antagonists.


Development of a reversible vas deferens occlusive device. VI. Long-term evaluation of flexible prosthetic devices. Fifty-three dogs received implants of several types of flexible devices containing valving mechanisms. These devices were constructed entirely of silicone rubber with the exception of the valve stem, which was made of stainless steel. Generally, the devices were (1) implanted in the open mode and left this way for 27 to 44 months, (2) implanted in the closed mode and kept this way for 11 to 12 months before the valves were reopened, (3) implanted in either the closed or open mode and cycled to the opposite mode every 3 months (four or five cycles), or (4) implanted in either the closed or open mode and cycled to the opposite mode every 6 months (two or three cycles). Different implant methods were also evaluated. Semen analyses were regularly performed on all of the dogs, and a number of the animals were bred during the experiments. It can be concluded that (1) the devices can be opened and closed successfully over long periods, respectively allowing and preventing sperm transport; (2) the breeding ability of the animals is not impaired while the devices are in the open mode, independent of the type of device; (3) the devices do not result in an enhanced incidence of congenital abnormalities in the offspring; and (4) the success rate of device performance does not depend on the method of implanatation used. Thus, the results clearly indicate that the basic mechanism of a soft, reversible valve is a feasible approach to conception control.


Better postcoital test for oligospermic patients using split ejaculate artificial insemination. In 25 oligospermic patients who had negative postcoital tests, artificial inseminations were performed with the whole semen and split ejaculates. After 30 minutes, a sample of cervical mucus was obtained and examined microscopically for the presence of motile spermatozoa. There was a significant improvement of 64% using the split ejaculate, as compared with 44% using whole semen. We found a significantly higher sperm count and progressive motility in the split ejaculate (18 patients, 72%).


Impotence, smoking, and beta-blocking drugs. Four patients complaining of erectile dysfunction and using tobacco or propranolol were examined with penile blood pressure measurements and Doppler recordings, calculating the penile acceleration ratio (PAR). After a change in regimen, erectile capacity was restored, PAR returned to normal, and blood pressure measurements revealed increased systolic penile blood pressure in three patients. The changes, especially in PAR, indicate a marked penile vascular reaction during smoking and beta-blocking treatment in these men.


Pituitary tumors associated with hyperprolactinemia and polycystic ovarian disease. Galactorrhea and hyperprolactinemia, or both, have been described in some patients with polycystic ovarian disease. Three patients who had had previous bilateral wedge resection of the ovaries and who manifested persistent amenorrhea were found to have elevated levels of serum prolactin (180 to 540 ng/ml) 5 to 10 years later. All three patients initially demonstrated moderate hirsutism and failed to experience withdrawal bleeding after administration of progesterone or clomiphene citrate. Polytomographic evidence suggestive of an intrasellar tumor was present when elevated serum prolactin levels were noted. (Routine sellar roentgenograms prior to wedge resection had been reported as normal.) Two of the three patients underwent transsphenoidal surgery with removal of an 8-mm diameter chromophobe adenoma in each instance. Although serum prolactin levels decreased to 32 and 102 ng/ml, respectively, amenorrhea has persisted with gradual cessation of galactorrhea over a 1- to 2-year follow-up period. Our experience with the reported three cases supports the conclusion that in some cases an association may exist between polycystic ovarian disease and prolactin-producing adenomas.


Gestational outcome of clomiphene-related conceptions. The experience of the gynecologic endocrinology and infertility clinic at The Johns Hopkins Hospital has been subjected to a nonconcurrent prospective analysis in an attempt to evaluate the gestational fate of clomiphene-related conceptions (study series, n = 86). This latter series was contrasted with a series of pregnancies following bilateral ovarian wedge resection (BOWR) (n = 51) in a comparative analysis of gestational outcome event rates. Post-therapy follow-up was available for varying time spans of up to 15 years. A 12.8% twinning rate constituted the single most important complication of clomiphene therapy, resulting in measurable increments in perinatal morbidity and mortality rates. The observation of a 26.5% spontaneous abortion rate would seem to suggest that clomiphene-related conceptions are at little or more risk for spontaneous abortion than would have been expected from the infertile population under discussion. A 3.1% incidence of post-clomiphene birth defects was not increased as compared with commonly quoted rates for the population at large. The corresponding incidence rates of twinning, spontaneous abortion, and birth defects for the BOWR series were 0%, 21.6%, and 0%, respectively.


Gel chromatographic properities of human prolactin released from decidua tissue in vitro. Human decidua tissue releases immunoactive prolactin into the medium upon incubation in vitro. The prolactin secreted is indistinguishable from pituitary prolactin in its binding and displacement characteristics, using two different antisera. By gel chromatographic criteria more than 90% of the prolactin is monomeric.


Measurement of the ovarian follicle by ultrasound in ovulation induction. Ultrasonic monitoring of ovarian follicles and estimation of serum estradiol were carried out in 12 patients with clomiphene therapy, in 5 patients with gonadotropin therapy, and in 7 normal controls. The average diameter of preovulatory follicles in normal controls was 12,8 mm; in ovulation induction groups it was 2 to 4 mm greater. The level of serum estradiol was also higher in ovulation induction groups than in normal controls. The combined use of these two methods is recommended: ultrasonic monitoring to minimize the risk of multiple pregnancies and estrogen level monitoring to minimize the risk of hyperstimulation. Ultrasound is also safe and practical in following the size of hyperstimulated ovaries.


Ureaplasma urealyticum and human infertility: the effect of antibiotic therapy on semen quality. Semen characteristics were evaluated in 64 men visiting our infertility clinic before and after the eradication of genital infection with Ureaplasma urealyticum. Semen quality was also analyzed in 9 men who were unsuccessfully treated for genital Ureaplasma infection, 11 men who had negative cultures and received no treatment, and 11 men who had negative cultures but received empirical antibiotic therapy. A significant improvement in spermatozoal motility (both the speed of forward progession and the percentage of motile cells) was found in the group that was successfully treated for Ureaplasma infection. Improvements were not demonstrated in any of the other patient groups. A correlation was found between improved motility and a decrease in certain abnormal features of seminal cytology that appear to be associated with Ureaplasma genital infection.


Chorionic gonadotropins in the treatment of the subfertile male. Sixty-four men with idiopathic subfertility were given human chorionic gonadotropin, 50,000 units in 10 divided doses. Sixty-nine per cent of the men demonstrated significant improvement in semen quality in response to the medication, and thirty-six per cent achieved a pregnancy. Eight patients have achieved a second pregnancy without additional therapy.


The influence of fallopian tube length on fertility in the rabbit. The correlation between the length of the oviduct and degree of fertility was studied in 16 New Zealand White rabbits subjected to microsurgical resection of differing lengths of fallopian tube involving the isthmus in each case. A highly significant (P less than 0.005) linear correlation was found, suggesting that more than 47% of an oviduct must remain distally before fertility can be anticipated. Absence of the isthmic segment of the fallopian tube was found to be associated with supracervical fetal implantations in the uterus. The importance of the assessment of tubal length as a prelude to reconstructive surgery, especially for reversal of sterilization, is emphasized.


The effect on fertility of vaccinating female sheep with biochemically defined fractions of ram spermatozoa. Sixty sheep were vaccinated with six biochemically defined fractions of ram spermatozoa obtained by differential extraction procedures with 0.1% Triton X-100 and 2 M MgCl2, followed by ion-exchange chromatography. No one group showed a significant reduction in fertility as compared with the controls, but there was some evidence that MgCl2 extracts were not more potent infertility-inducing agents. Some of the mechanisms by which the immune response could influence fertility are also discussed.


The origin of human seminal leucine aminopeptidase (LAP). Examination of the distribution of leucine aminopeptidase (LAP) activity in the male reproductive system showed the existence of the largest amounts of this enzyme in the prostate. Precipitin electrophoresis revealed that seminal LAP is immunologically identical with the prostatic enzyme and distinct from the enzymes in the other male reproductive organs. It was concluded that the origin of seminal LAP is the prostate, by which the enzyme is secreted into the seminal plasma.


[Lethal midline granuloma. A case report]. In their study of a case of lethal midline-granuloma, the authors describe the relations between this affection, Wegener's granulomatosis and lymphoma. The case under review illustrates the difficulty in accurately defining the nosologic picture of the disease. Anatomo-pathological examinations present two possibilities: one being malignant granuloma of the Stewart type, the other that of lymphoma. From its subsequent evolution, we may eventually learn whether this is purely a local illness or represents the onset of a systemic disease.


[Orthostatic hypotension in complicated diabetes mellitus: study of the renin-angiotensin-aldosterone system (author's transl)]. Plasma renin activity (P.R.A.) and plasma aldosterone (P.A.) were studied basally and after various stimuli in eight diabetic subjects with orthostatic hypotension and autonomic neuropathy. Five of them had chronic renal failure and proteinuria. On a diet containing 100 mEq Na/24 H, mean P.R.A. was 0,80 +/- 0,32 ng/ml/h in the supine position and 0,95 +/- 0,43 ng/ml/h in the upright position (N.S.); mean P.A. was 111 +/- 77 pg/ml in the supine position and 234 pg/ml in the upright position (p less than 0,01). On a diet containing 10 mEq Na/24 H, mean P.R.A. was 1,54 +/- 0,76 ng/ml/h in the supine position and 2,44 +/- 1,53 ng/ml/h in the upright position (N.S.). There was little stimulation of P. R. A. by low sodium intakes. After furosemide (n = 6), epinephrine + norepinephrine (n = 4) or diazoxide (n = 2), there was no stimulation of P.R.A. and P.A. Thus in diabetic patients with orthostatic hypotension and autonomic neuropathy basal values of P.R.A. and P.A. are in the normal range but there is dysregulation of renin-angiotensin-aldosterone system.


The gastro-entero-pancreatic hormone secretion after a mixed meal in normal subjects before and after a 72 hour period of starvation. The responses of plasma gastro-entero-pancreatic (GEP) hormones and free fatty acids (FFA) to a standard mixed meal before and after starvation have been measured. Raised insulin, glucose and FFA levels were found following refeeding after starvation and levels of secretin and C-terminal glucagon-like-immunoreactivity (C-GLI), raised by starvation, were rapidly suppressed on refeeding. The responses of gastrin and N-terminal glucagon-like-immunoreactivity (N-GLI) to a standard mixed meal were not altered by starvation. Although this study does not directly support that secretin and glucagon are responsible for the hyperglycaemia or hyperinsulinaemia of starvation diabetes, a role for both hormones in the raised FFA levels is proposed, as well as a role for glucagon in the initial hyperglycaemic response to a meal after starvation.


Circadian and ultradian rhythms in the feeding behaviour and nutrient intakes of oil refinery operators with shift-work every 3--4 days. Seven healthy adult men, five shift-workers and two non-shift-workers (from 21 to 36 years; mean = 26.4) volunteered to record what and when they ate, both at work and at home, every day, during eight consecutive weeks (Oct. - Dec. 1974). 1) All the subjects maintained the timing of main-meal (lunch and supper) during all shifts. 2) The major intake of protein and lipid was concentrated on the two main meals during all shifts. 3) Only the pattern of carbohydrate intake was modified by the shift-work: e.g. night-shift is associated with nibbling behaviour. 4) However, shift-work and in particular the occurence of nibbling behaviour did not result in change either in the mean 24 h caloric intake, or in the percentage of protein calories. 5) The comparison between the constancy of the timing of major meals and the shift of the timing of circadian rhythm acrophases of the 5 shift-workers leads to conclude that meal timing had a poor synchronizing effect, if any.


[Effect of the streptozotocin diabetes upon the in vivo conversion of [I-14C] gamma-linolenic and dihomo-gamma-linolenic acids into arachidonic acid in rats (author's transl)]. Streptozotocin diabetic rats were administered the same tracer dose of either [1 14C] gamma-linolenic or [1 14C] dihomo-gamma-linolenic acid by stomach tube seven days after streptozotocin injection. They were killed 48 hours later and the radioactivity in individual fatty acids of the liver determined by radio-gas chromatography. Results were compared to those obtained in non diabetic rats similarly prepared. With either radioactive precursor, 14C radioactivity recovered in hepatic dihomo-gamma-linolenic acid was not significantly affected by the diabetic state. On the other hand, 14C radioactivity incorporated into arachidonic acid was considerably decreased in diabetic rats, compared with normal rats, when the weights of hepatic arachidonic acid were the same in the two groups of animals. These results suggest that streptozotocin diabetes causes a partial inhibition of the 5-desaturation of dihomo-gamma-linolenic acid in rat liver in vivo.


Effects of pregnancy and progesterone and/or oestradiol on the insulin secretion and pancreatic insulin content in the perfused rat pancreas. Progesterone and oestradiol treatment of ovariectomized rats was administered leading to plasma steroid concentrations comparable to those of the pregnant rat. In these experimental conditions oestradiol enhanced insulin secretion but progesterone had little effect on B cell response to glucose (0.8 g/l and 1.4 g/l) of the perfused pancreas. At low glucose concentration (0.8 g/l) neither of the two steroids, added to the perfusion medium, had any effect on insulin release of the pancreas of the castrated animals; oestradiol exerted a facilitating action on glucose stimulation (1.4 g/l); progesterone had no effect. During pregnancy biphasic insulin secretion was enhanced, but pancreatic hormonal content was only increased at term. Neither oestradiol nor progesterone treatment changed pancreatic insulin content. It is concluded that oestradiol acts on insulin release at pancreatic level directly, whereas progesterone influences insulin release by causing insulin resistance.


Effects of biguanides on the intermediate metabolism of glucose in normal and portal-strictured rats. Phenformin and metformin treatments may be complicated by lactic adidosis. This metabolic complication seems favoured by preexistent hepatic disease. We have therefore compared the metabolic effects of phenformin and metformin on non fasting normal and portal-strictured rats. The latter group is characterized by impaired hepatic passage of these drugs without hepatocellular lesions. Given orally to normal rats over 5 days, phenformin (20 mg/kg/24 h) and metformin (150 mg/kg/24 h) decreased blood glucose levels and increased blood urea and the substrates of gluconeogenesis (alanine, glutamine, lactic and pyruvic acids), effects more apparent with phenformin than metformin. In non-treated portal strictured rats, blood glucose levels were lower and the intermediate metabolites were higher than in noraml rats, suggesting a modification of gluconeogenesis. Treatment of the portal strictured group by phenformin or metformin induced no changes in the studied parameters. This absence of effect of the biguanides in portal strictured rats supports the postulate that, in normal rats, biguanides act principally on hepatic metabolism by reducing gluconeogenesis and that, in the absence of other hepatic damage, the presence of a peri-hepatic shunt, which, by itself, modifies gluconeogenesis, does not further predispose to lactic acidosis during short term administration of biguanides.


[Hemoglobin A1c and diabetes control (author's transl)]. Hemoglobin A1c (HbA1c) is a minor component of human hemoglobin resulting from a non enzymatic linkage of glucose with the NH2-terminal amino acid of the beta chain of hemoglobin. Under normal conditions, HbA1c represent about 5% of total hemoglobin. The HbA1c blood concentration increases in direct proportion of the duration and degree of hyperglycemia. Available procedures for measuring HbA1c include column chromatography, high pressure liquid chromatography, a colorimetric procedure based on the formation of 5-hydroxymethylfurfural and isoelectrofocusing. In a group of 138 patients, we have confirmed that HbA1c provides a useful means of evaluating the degree of diabetic control: the highest values have been recorded in cases of poor control, the lowest in cases of excellent control. In the latter case, the HbA1c values recorded were not statistically different from those obtained in a control group of 92 non-diabetic subjects. The interest of evaluating this parameter in diabetes is briefly analyzed.


Spontaneous tumors in nude mice: effect of the viable yellow gene. The incidence and type of spontaneous tumors in athymic nude (nu/nu) mice (partially inbred in CBA/H background) which were also carrying the viable yellow gene (Avy, derived from C57BL/6JAvy mice), were comparable to those observed in the phenotypically normal nu/+ and +/+ control crosses carrying the Avy gene. The Avy gene increases the incidence of spontaneous and induced tumors in most mouse strains. These results would argue against the thymus dependency of the putative immunological surveillance mechanisms.


Establishment of human colon carcinoma lines in nude mice. After subcutaneous inoculation into nude mice of 24 human colon adenocarcinomas, growth, defined as histopathologically confirmed tumor growth which has been passed, was observed in 13 cases (54%). Tumors from metastatic sites showed higher take rates (58%) than tumors from primary sites or recurrent tumors (50%). Nine continuous tumor lines were established (69% of growing tumors) with metastatic tumors establishing more readily (100% of growing tumors) than primary tumors (40%). The average period in primary transplant was shorter for metastasis (8.3 weeks), than for primary tumors (18.5 weeks); total material 10.6 weeks. Average periods between passages were shorter than primary transplant times; these periods were shorter for metastases (6.6 weeks) than for primary tumors (9.4 weeks); total material 7.4 weeks. Of four growing tumors not established as continuous lines, three were primary and one a recurrent tumor, and the loss of tumor growth occurred in very early passages, not later than passage 3. All nude mouse-grown colon tumors were moderately well differentiated.


Increased nuclear size in BHK21 cells after treatment with non-toxic levels of calf thymus histones. The effect of treatment with either whole calf thymus histones, or individually isolated histones, or polyarginine, or polylysine, on the nuclear size of BHK21 cells has been investigated. Incubation of the cells with mixed histones (12.5--44 microgram/ml) for 1 h considerably increased nuclear size. Increasing the histone concentration and/or the incubation time resulted in a decrease in the effect and could result in no change in nuclear size. Treatment of the cells with polyarginine or polylysine did not affect nuclear size. Experiments with individually isolated histones showed that the nuclear size effect was almost exclusively due to the histone H4. It is argued that the changes observed most likely resulted from interaction of H4 with the nucleus, and could reflect the properties of this particular histone molecule.


Type C RNA virus proteins: lack of binding specificity to host cell chromosomal DNA in vitro. Through the use of two different DNA-protein reconstitution methods, we examined the potential role of type C RNA tumor virus proteins as putative regulatory agents in the control of virus expression. Rauscher murine leukemia virus, purified from chronically infected rat cell cultures, was iodinated in vitro with [125I], and dissociated in a nondetergent high-ionic-strength urea-containing buffer. The chemically separated [125I]-labeled viral polypetides were reconstituted with purified DNA by affinity column chromatography and by gradient dialysis renaturation. In both instances, no detectable amount of radioactivity specifically bound to double-stranded DNA of any origin. This observation was in contrast to the binding behavior of identically prepared and radiolabeled, nonhistone chromosomal proteins purified from rat cell nuclei. This finding may rule out, in eukaryotic cells, a well-described prokarytoic regulatory mechanism for the control of integrated viral gene expression.


Differential DNA damage induced by chemical mutagens in cells growing in a modified Selye's granuloma pouch. Rapid growth of granulation tissue was induced in rats by injection of croton oil into a subcutaneous air pocket. Growth characteristics of the granulation tissue were evaluated by histopathologic techniques and measurement of 3H-thymidine incorporation into DNA. The DNA of cells growing in the granuloma was labeled with 3H-thymidine. Subsequently, 4 classes of test chemicals (monofunctional and polyfunctional alkylating agents, DNA intercalating agents and chemicals not known to interact with DNA) were injected intraperitoneally. The presence of single-strand breaks was assayed in DNA of granuloma tissue using the alkaline elution technique. DNA breaks were primarily induced by monofunctional alkylating agents and were characteristic for each compound. DNA from animals treated with polyfunctional alkylating agents and DNA-intercalating agents showed a variable degree of resistance to methylmethane sulfonate-induced DNA breakage.


Chick-comb fibroblasts. A new strain of cultured cells sensitive to androgens. An androgen-responsive cell strain of chick-comb fibroblasts has been established in culture. Cells were obtained from combs of 1--2 day old white Leghorn cockerels and cultured in Dulbecco's modified Eagle medium supplemented with 10% fetal calf serum and 6 g/l glucose. The cells required serum but not androgens for growth. In the presence of androgens, growth rate and incorporation of labeled precursors into protein and RNA were markedly increased in exponentially growing cells, but not in confluent cultures. Androgens exerted these stimulatory effects in a dose-dependent fashion. It is concluded that chick-comb fibroblasts, which respond to androgens in vivo, retain this responsiveness when cultured. They furnish a well-defined system of potential value for studies of the molecular mechanisms of androgen action.


Steroid receptors and steroid response in cultured L1210 murine leukemia cells. Murine L1210 leukemia cells were cultured in the presence of various steroid hormones to determine their growth response. Cells maintained in medium containing glucocorticoids such as dexamethasone exhibit a 10--20% inhibition of growth, whereas progesterone of 17 beta estradiol produce a 40--50% inhibition of growth. The response is due to growth inhibition and not to any cytolytic effect of the steroids. L1210 cytoplasmic and nuclear extracts contain high affinity binding sites for [3H]dexamethasone, [3H]progesterone and [3H]17 beta-estradiol. Competition with various steroids indicate that estrogens bind to one class of cytoplasmic binding sites, while glucocorticoids and progestins bind to a second class of receptor sites. These receptors appear not be be completely responsible for growth inhibition since there is no correlation between the magnitude of growth inhibition and the intracellular concentration of receptor sites, and since the concentration of steroid required to cause significant growth inhibition exceeds those concentrations required to saturate the cytoplasmic receptors.


Competitive binding studies with glucocorticoid receptors from rat-thymus cells: differential temperature-dependence of steroid binding. Competitive steroid-binding studies were performed with intact rat thymus cells and with cytosol preparations at different temperatures using [1,2-3H]dexamethasone as the labelled ligand. Steroids lacking a 17 alpha-hydroxyl group, such as corticosterone, were better able to compete with [1,2-3H]dexamethasone for binding to glucocorticoid receptors at 0 degrees C than compounds containing a 17 alpha-hydroxyl substituent, such as cortisol. At 37 degrees C the reverse was true. This temperature-dependent change in relative affinities appeared to be unrelated to steroid metabolism or receptor activation, and to depend only on the thermodynamic parameters of the steroid--receptor interaction. Relative biological activities for different steroids agree more closely with the relative affinities determined at 37 degrees C than with those determined at lower temperatures.


Evidence for Leydig cell dysfunction in rats with seminiferous tubule damage. To study the effects of seminiferous tubule damage on Leydig cell function and morphology, rats were treated by fetal irradiation (to induce Sertoli cell-only syndrome, SCO), 3 months administration of hydroxyurea (HU), or chronic feeding of a vitamin A-deficient diet (VAD). Leydig cell function was assessed by the measurement of serum LH and testosterone and the response of serum testosterone to hCG stimulation, while morphology was studied by electron microscopy after perfusion fixation. Serum LH was significantly elevated in each experimental group, while basal serum testosterone was significantly lower only in SCO rats. In all treatment groups, the serum testosterone response to hCG was significantly decreased when measureed as the area under the response curve. Despite a decreased response to hCG, the Leydig cells were larger than normal and showed striking increases in quantities of smooth endoplasmic reticulum, mitochondria and Golgi complex. Leydig cell dysfunction has been demonstrated in animals with varying degrees of seminiferous tubule damage, but paradoxically the cytological features of the Leydig cells were indicative of hypertrophy.


Biosynthesis of MSH and related peptides in the pars intermedia of the mouse: a pulse-chase analysis. Protein biosynthesis in neurointermediate lobes of mouse pituitaries was investigated using pulse and pulse-chase techniques with [3H]lysine. Electrophoretic analysis of lobe homogenates on acid-urea gels resolved 11 labeled products. One was a large protein which was rapidly synthesized during pulse-incubations and disappeared during chase incubations. Three of the products increased during chase incubations, suggesting a precursor-product mode of biosynthesis for these chasde peptides. One of these three products co-migrated with synthetic alpha-MSH and also corresponds to the major peak of mouse neurointermediate lobe MSH bioactivity and immunoactivity on electrophoretograms. Another case of these peptides has electrophoretic properties similar to those of ACTH.


The endometrial nuclear estradiol receptor of the pregnant cow has a molecular weight of 53,000 in 6 M guanidine-HCl. Cell nuclei isolated from the endometrium of the 3 months pregnant cow were dialysed against 6 M guanidine-HCl + 0.1 M 2-mercaptoethanol. The resulting material (after eliminating the bulk of DNA by centrifugation) was filtered on a Sepharose 6/b column equilibrated in the above denaturing solvent. The molecular weight of the denatured "nuclear" estradiol receptor, estimated by a method described previously (T. Erdos and J. Fries (1974) Biochem. Biophys. Res. Commun. 58, 932-939), was about 53,000. This value is similar to that of the cytoplasmic receptor (55,000) but dissimilar to that of the cytoplasmic receptor transformed by the action of the Receptor Transforming Factor (35,000) estimated under the same experimental conditions, suggesting that the latter form of the receptor is not the biological precursor of the "nuclear" receptor. However, according to indirect estimates, probably not more than 10% of the "nuclear" receptor has been renatured in these experiments. Therefore the alternative that the results obtained are not representative for the "nuclear" receptor, cannot be excluded.


Glucocorticoid receptor in human embryo fibroblasts. I. Kinetic and physicochemical properties. The kinetics of dexamethasone binding to L 809 E cell line cytosol have been investigated by means of the protamine sulfate precipitation assay. The KDeq for dexamethasone was 1.1--3.3 nM. Binding was specific for glucocorticoids. The mean association rate constant (k+1) was 8.5 x 10(5) M-1 x min-1 and the dissociation rate constant was 4.6 x 10(-5) min-1 at 0 degrees C. The concentration of binding sites was 0.3 pmol/mg of cytosol protein. Binding kinetics were compatible with a model of positive cooperativity. The receptor sedimented at 7.5--9 S in glycerol gradients. By a combination of calibrated ultracentrifugation and polyacrylamide gel electrophoresis, a Stokes radius of 8.5 nm, a molecular weight of 268 000 daltons and a frictional ratio of 1.8 were determined in low ionic strength conditions. When the cells were incubated with 10 nM [3H]dexamethasone for 1 h, a more than 90% depletion of cytosol receptor and an equivalent accumulation of nuclear dexamethasone--receptor complexes was observed.


Nature of RNAs synthesised in rat liver in response to hydrocortisone. Experiments on hybridization of [32P]HnRNA from hydrocortisone-treated rat liver with rat-liver DNA, in competition with unlabelled liver HnRNA from hormone-deficient and treated rats, revealed marked differences in their nucleotide sequence homologies. It was found that the hormone-induced new species of HnRNAs were transcribed both on middle-repetitive and non-repetitive sequences of DNA. However similar differences in the sequence homologies were not detectable in respect of mRNA derived from livers of hydrocortisone-administered and adrenalectomised rats. The results imply that the new species of HnRNA synthesized following hormone treatment may be confined to the nucleus.


Estrogen-induced prolactin and DNA synthesis in immature female rat pituitaries. Estradiol is likely involved in stimulating developmental changes in the ability of the rat pituitary to secrete prolactin. To investigate the possibility that these changes involve proliferation of prolactin cells, estradiol effects on pituitary growth and prolactin synthesis were examined. Estradiol treatment of immature female rats stimulates increases in pituitary weight, [3H] thymidine incorporation, DNA content and prolactin synthesis. Treatment of rats with the DNA synthesis inhibitor, hydroxyurea, partially blocked the ability of estradiol to stimulate prolactin synthesis suggesting that at least part of the effect of estrogen is due to cell proliferation. These results suggest that estrogen-induced proliferation of prolactin cells is involved in the developmental processes of the pituitary.


Tissue and serum somatostatin-like immunoreactivity in fed, 15-h-fasted, and 72-h-fasted rats. Somatostatin-like immunoreactivity (SLI) was measured in extracts of gastric antrum, colon, pancreas, and central nervous system, as well as in unextracted portal and inferior vena caval serum from fed, 15-h-fasted, and 72-h-fasted rats. No differences were found in SLI in the central nervous system of the three groups. However, striking variations were found in the gastrointestinal tract and pancreas; the antrum, colon, and pancreas of 15-h-fasted rats contained the least SLI, the content being significantly elevated in these three areas after feeding and after a 72-h fast. Portal serum levels were highest after feeding but lowest in 72-h-fasted rats, in spite of high intestinal and pancreatic SLI content in both. These tissue and serum differences suggest a physiologic role for SLI in nutrient homeostasis not only at tissue level, but also putatively as a hormone in the portal system.


Long-term continuous intravenous insulin therapy with a portable insulin dosage-regulating apparatus. A portable insulin dosage-regulating apparatus (PIDRA) was used with five volunteer diabetic subjects for periods ranging from 1 wk to more than 3 months to explore the possibilities of achieving near normoglycemic control over long time periods with such an apparatus. PIDRA consists of a matchbox size pump with insulin reservoir and a pocket size electronic control box. It can infuse a preprogrammed basal rate of insulin plus externally manipulated supplementary doses in rectangular profiles. The quality of blood glucose control was monitored with the Miles Biostator and through self-testing by the patient in the outpatient phases. Under inpatient conditions, the relatively simple PIDRA insulin administration profile was almost as effective in achieving normoglycemia as the Biostator, and good control could be maintained over long periods of time. The apparatus allows considerably greater ease in variation of insulin dosage with less risk of hypoglycemic epidoses as compared with conventional subcutaneous injections. Several technical problems remain to be solved, but it is concluded that PIDRA represents a viable alternative as a means of achieving tight control, at least as a step toward the goal of an implanted glucose-contingent insulin infusion system.


Glucose-insulin response to oral glucose in a healthy obese population. The characteristics of the glucose and insulin responses during the glucose tolerance test (GTT) in obese people as a group have not been established. We analyzed glucose and insulin levels during GTT in 160 healthy obese patients who averaged 42% over ideal body weight. Statistical upper limit of normal for 2-h glucose was 260 mg/dl in women and 206 mg/dl in men. Although there was a significant correlation between insulin and glucose levels in both sexes and between insulin and degree of obesity in women, r values were relatively low (r less than 0.4 for all). High insulin levels and delayed peak insulin were present in the majority of patients with normal GTT and absent in many of the most obese patients. Results indicate that upper limits of normal glucose for GTT in the obese are much higher than currently accepted criteria.


Maintenance of basal plasma glucose and insulin concentrations in maturity-onset diabetes. Normal and mildly diabetic subjects each have their own "set" of basal plasma glucose and insulin concentrations. Diabetic patients have raised basal plasma glucose, with low-normal basal plasma C-peptide concentrations. Restoring normal glucose levels in mild diabetes by an insulin infusion further reduces the C-peptide concentration, but both the plasma glucose and the C-peptide return to their "set" level when the insulin is withdrawn. These results accord with the action of beta cells and liver in a negative feedback loop that maintains basal plasma glucose and insulin concentrations.


Is juvenile diabetes determined by a single gene closely linked to HLA? The transmission behavior of insulin-dependent juvenile diabetes mellitus (JDM) has been studied with respect to its frequency in the relatives of JDM probands and its possible linkage to the HLA complex. Mathematical analysis shows that under a single locus hypothesis a very restricted range of incidence rates is possible in the full siblings of probands once the concordance rate in monozygotic (MZ) twins is specified. Specifically, for a given population prevalence of the disease, high concordance rates in MZ twins require high incidence rates in siblings, and low rates require low incidence rates, if a single locus model is th be valid. Moreover, if these rates do conform to a single locus model, then they give additional information about possible linkage between the purported JDM susceptibility gene and the HLA complex. By using observations on the identity by descent scores at the HLA locus of sibling pairs, both of whom are affected with JDM, it is shown that tight linkage of a disease susceptibility locus is possible only when the MZ twin and sibling incidence rates are low, whereas high rates support loose linkage. If the single locus model is rejected, then an alternative hypothesis, involving epistasis between a JDM susceptibility locus and genes in (or close to) the HLA complex can be suggested as a mechanism whereby JDM would appear to be linked to HLA within families while maintaining an association with HLA at the population level.


Blood glucose regulates the effects of insulin and counterregulatory hormones on glucose production in vivo. Continuous, low dose, insulin infusion in conscious dogs produced moderate hypoglycemia but only a transient fall in glucose production that rose towards preinfusion levels 20 to 30 min before any detectable increase in plasma counterregulatory hormones. Addition of epinephrine or glucagon to the insulin infusion prevented the fall in glucose production throughout the experiment but only partially diminished the hypoglycemic response. When hypoglycemia was prevented by a variable glucose infusion, neither epinephrine nor glucagon was able to counteract the suppressive effect of insulin on glucose output. These findings suggest that a fall in blood glucose per se may reverse insulin-induced inhibition of glucose production independent of a rise in counterregulatory hormones and that the insulin antagonist effect of counter-regulatory hormones is modulated, at least in part, by blood glucose concentration.


Effect of continuous low-dose insulin treatment on subsequent incidence of diabetes in genetically prediabetic Chinese hamsters. In an attempt to prevent the onset of diabetes, young, genetically prediabetic (but not yet hyperglycemic) Chinese hamsters were treated continuously with insulin via minipump for 4 wk beginning 1 wk before the predicted age of onset of glucosuria (age 7 wk). Continuous insulin infusion which increased the plasma insulin levels by 70%, did not cause hypoglycemia, nor did it reduce the incidence or severity of diabetic symptoms over the ensuing year of observation. In fact, early treatment with exogenous insulin tended to cause increased hyperglycemia and glucosuria. No plasma anti-insulin antibodies were detected 3 and 9 months after stopping insulin treatment.


Variation in thickness of the capillary basement membrane in single muscles of diabetic subjects. Thickness of skeletal muscle's capillary basement membrane was measured in gastrocnemius and quadriceps femoris muscles of diabetic subjects. At least two different sites of each muscle studied were biopsied. Comparison of these biopsy samples revealed a marked and significant variation in thickness of the capillary basement membrane at different sites within the same muscle. In one subject so studied, this variation was found regardless of the method of fixation or the method of measurement of capillary basement membrane thickness used. Variation was present in diabetics suffering from long-term complications of the disease as well as in diabetics free of such complications. A reevaluation of the biologic significance of basement membrane thickness measurements, as presently applied, is indicated in the light of the variability of base-line values.


HLA-D--related (DRw) antigens in juvenile diabetes mellitus. We studied the distribution of HLA-D--related (DRw) antigens in 40 patients with juvenile diabetes mellitus (JDM) and 79 matched controls. We found that DRw2 was significantly decreased in the JDM group, suggesting a protective effect of the antigen and that the decrease observed in B7 was secondary. HLA-DRw3 and HLA-DRw4 were increased in the diabetic group, and, as with B8/B15, these two antigen predisposed to the disease additively. The susceptibility for JDM was found to be more strongly related to HLA-DRw3 that to B8. On the other hand, B15 rather than DRw4 showed the stronger association with JDM. Moreover, we found that this second diabetogenic gene is associated primarily with B15 and only secondarily with Cw3, which is in linkage disequilibrium with B15. This study further emphasizes the immunogenetic heterogeneity of JDM.


Somatostatin release from isolated perfused rat pancreas. Possible role of endogenous somatostatin on insulin release. In order to elucidate the role of endogenous somatostatin in the control of insulin and glucagon secretion, glucagon- or insulin-induced somatostatin release from the isolated perfused rat pancreas was studied. Immunoreactive somatostatin was persistently released for 60 min in response to perfusion by 5.5 mM glucose at concentrations ranging between 10 and 15 pg/ml. The addition of glucagon (10(-8), 10(-7), and 10(-6) M) caused a dose-related increase of somatostatin release. In contrast, insulin release, especially its first phase, was suppressed when concentrations of glucagon were increased. The addition of insulin (10(-7) M and 10(-6) M) had no significant effect on somatostatin and glucagon release. These results raise the possibility that endogenous somatostatin and glucagon together regulate insulin secretion, suggesting a close interrelationship between insulin, glucagon, and somatostatin secretion within the islet.