Modifications of striatal D2 dopaminergic postsynaptic sensitivity during development of morphine tolerance-dependence in mice. Alterations in the activity of striatal dopaminergic neurons have been implicated in the development of morphine tolerance-dependence in rodents. To further explore this possibility, we examined the activity of these neurons in mice exposed to morphine during 4 days (addiction group) and subsequently treated with naloxone (withdrawal group). The efficiency of opiate treatment was assessed behaviorally. Striatal dopaminergic activity was evaluated by measuring: a) the ratio between the amounts of L-3,4-dihydroxyphenylacetic acid (DOPAC), the main intraneuronal metabolite of dopamine (DA), and the neurotransmitter itself, as an index of presynaptic activity; and b) the number and affinity of D1 and D2 dopaminergic receptors, as well as the amount of their coupled second messenger, cyclic adenosine monophosphate (cAMP), as postsynaptic parameters. Spontaneous motor activity was decreased in chronically morphine-exposed mice. In these animals, the number of striatal D2 receptors also decreased, with no changes in their affinity, whereas the number and affinity of D1 receptors remained unchanged. This hyposensitivity of D2 receptors was paralleled by an increase in the amount of cAMP with a good statistical correlation between both parameters. Treatment with naloxone of morphine-exposed mice resulted in the typical jumping behavior indicative of opiate withdrawal. The differences in D2 receptors between placebo- and morphine-exposed mice disappeared after naloxone-induced opiate withdrawal, although this effect was due more to the inhibitory effect of naloxone on the density of these receptors in placebo-exposed mice rather than to a stimulatory effect in morphine-addicted mice. The morphine-induced increase in cAMP content also disappeared after naloxone treatment.(ABSTRACT TRUNCATED AT 250 WORDS)


Gamma-aminobutyric acid type A receptor blockade at the intermediate area of the ventral surface of the medulla counteracts the cardiorespiratory depression produced by intravenous midazolam. Intravenous administration of midazolam (2 mg/kg) to 8 pentobarbital-anesthetized cats produced a significant decrease in minute ventilation, tidal volume, blood pressure and heart rate. Treatment with the gamma-aminobutyric acid (GABA) type A receptor antagonist bicuculline (10 micrograms/side) at the intermediate area of the ventral surface of the medulla (VSM) oblongata completely reversed the cardiorespiratory depressant effects of intravenous midazolam. In contrast, treatment with bicuculline at the same area failed to counteract the respiratory depressant effects of intravenous morphine (1 mg/kg). We conclude that the cardiorespiratory depressant effects of intravenously administered midazolam are due to enhancement of GABAergic transmission at the intermediate area of the VSM.


Effects of ketamine on voltage-dependent Ca2+ currents in single smooth muscle cells from rabbit portal vein. The effects of ketamine on membrane potentials and long-lasting type (L-type) voltage-dependent Ca2+ currents were investigated in dispersed single smooth muscle cells from rabbit portal veins. The amplitude and duration of the action potentials evoked by intracellular stimulation were inhibited by ketamine and were completely blocked by 10(-3) mol/l ketamine. Ketamine, however, did not alter the resting membrane potential. Whole cell voltage clamp experiments revealed that ketamine at concentrations higher than 10(-4) mol/l reduced the peak L-type voltage-dependent Ca2+ currents. These effects of ketamine were concentration-dependent and reversible at concentrations from 10(-4) to 10(-3) mol/l. Moreover, the activation threshold of L-type Ca2+ current (approximately -30 mV) was slightly shifted to the positive potential side by ketamine. This effect can explain that the action potential was abolished by 10(-3) mol/l ketamine. It is concluded that relaxation of the vascular smooth muscle by ketamine may have to be attributed to the inhibition of L-type voltage-dependent Ca2+ current.


Structure-activity study of some newly synthesized ergoline derivatives on 5-HT2 receptors and alpha-adrenoceptors in rabbit isolated aorta. In a structure-activity study, carried out in rabbit isolated aorta, the effect of different structural modifications in the ergoline nucleus upon the activity at 5-HT2 receptors and alpha-adrenoceptors was determined. 9,10-didehydro-N-methyl-N-(2-propynyl)-6-methylergoline-8 beta-carboxamide (LEK 8842) was chosen as the basic backbone of this study. The parent compound LEK 8842 showed strong alpha-adrenoceptor agonistic activity and partial 5-HT2 receptor agonistic activity, and its potency (pD2 = 6.41) was comparable with that of 5-hydroxytryptamine (5-HT, pD2 = 6.84) and noradrenaline (pD2 = 6.82). Hydrogenation of the double bond in the position 9,10 (LEK 8822) attenuated the potency (pD2 = 5.35) as well as the intrinsic activity on alpha-adrenoceptors and eliminated 5-HT2 receptor agonistic activity. LEK 8822 acted on the alpha-adrenoceptors not only as a partial agonist but also as a competitive antagonist of responses elicited by noradrenaline. When tested against 5-HT, LEK 8822 acted as an antagonist. Bromination in position 2 yielded the derivative LEK 8841 with no agonistic activity at concentrations up to 3 mumol/l, yet the affinity for 5-HT2 receptors and alpha-adrenoceptors was preserved. LEK 8841 was the only one that acted as pure simple competitive antagonist of responses elicited by 5-HT (pA2 = 7.93) and noradrenaline (pA2 = 6.45). Its activity was qualitatively similar to that observed with the 5-HT2/alpha-adrenoceptor antagonist ketanserin which was tested for comparison. Concerning selectivity for 5-HT2 receptors versus alpha-adrenoceptors, LEK 8841 proved to be more selective for 5-HT2 receptors than ketanserin. pA2 values for ketanserin antagonistic activity to 5-HT and to noradrenaline were 8.22 and 7.48, respectively. Finally, quaternization in the N(6) position (LEK 8827) almost completely eliminated affinity for 5-HT2 receptors and for alpha-adrenoceptors. This study has shown that relatively small modifications in the structure of the ergoline system led to pronounced changes in the affinity as well as intrinsic activity at both receptors studied.


In vivo exposure to ultraviolet radiation enhances pathogenic effects of murine leukemia virus, LP-BM5, in murine acquired immunodeficiency syndrome. LP-BM5 murine leukemia virus (MuLV) induces an immunodeficiency syndrome (MAIDS) in C57BL/6 mice which resembles immunological abnormalities observed in early stages of human AIDS. In our study, MAIDS virus-infected mice were exposed to low doses of ultraviolet radiation (UVR) before and after virus inoculation and compared with MAIDS-infected but not UVR-exposed mice. In all tested parameters (blood IgM levels; mitogenic responses to PHA, ConA, LPS and anti-mu; MLR; antigenic response to SRBC; enlargement and histopathologic changes of the spleen) we observed the same trend: changes due to MAIDS infection were more pronounced in the UVR-exposed group than in the unexposed group. Statistically significant differences between these two groups were seen for mitogenic responses at two different time points after virus inoculation. These results demonstrate that in vivo UVR exposure enhances the immunosuppressive effects of a retroviral infection. UVR exposure may affect the progression of AIDS in a similar manner.


Light-dependent generation of superoxide from human erythrocytes. Using the cytochrome c reduction method, we investigated light-dependent erythrocytic superoxide production. After 4 h light and dark exposure of erythrocytes from eight healthy human subjects, an average of 18.6% more superoxide was generated by erythrocytes exposed to light. Pretreatment of erythrocytes with the superoxide dismutase inhibitor N,N-diethyldithiocarbamate increased detection of superoxide while pretreatment with the anion channel blocker 4-acetamido-4'-isothiocyano-2,2'-disulfonic acid stilbene decreased detection. These findings indicate that substantially more spontaneously generated superoxide is produced and escapes from normal erythrocytes at ambient oxygen tensions on exposure to light. This excess generation and escape of superoxide from erythrocytes exposed to light may result in tissue photosensitization, especially in the retina of the eye, where high oxygen tension, blood and chronic light exposure occur simultaneously.


Calcium signaling in cell volume regulation. It is evident from the present analysis that although a role for Ca2+ in controlling hypertonic cell volume regulation and RVI mechanisms has not been shown, Ca2+ plays a central role in activating and controlling hypotonic cell volume regulation and RVD mechanisms in most cells. However, this Ca2+ dependency is highly variable among cell types and tissues. Cells can be grouped into three general categories based on the relative dependency of RVD on Ca2+: 1) cells that are highly dependent on extracellular Ca2+ and the activation of Ca2+ influx, supposedly reflecting activation of Ca2+ channels, such as observed for the renal PST cells and osteosarcoma cells; 2) cells that are not dependent on extracellular Ca2+ and Ca2+ influx but that require at least a certain basal intracellular Ca2+ level or transient release of Ca2+ from internal stores, such as observed for the Ehrlich ascites tumor cells and medullary thick ascending limb cells; and 3) cells that display little if any Ca2+ dependency, such as the lymphocytes. There is initial evidence that this variable dependency of RVD on Ca2+ may reflect, in large part, a variable Ca2+ threshold of RVD processes, although this notion has not been fully investigated. The site and mechanism of Ca2+ dependency of RVD are poorly understood. Initial studies pointed to a possible direct control of K+ and/or Cl- channels by Ca2+ to modulate KCl efflux and, hence, RVD. This view appears to be too simplistic, however, as it is increasingly evident that the ion channels involved in RVD may not be directly Ca2+ dependent and that some other regulatory process controlling the channels, perhaps a phosphorylation step, may be the Ca(2+)-dependent event. Given the added complexity of the time-dependent variability of the action of Ca2+, i.e., the Ca2+ window, coupled with the variability of the RVD mechanisms among cell and tissue types, it is likely that the RVD mechanism is a highly complex process involving events and biochemical pathways throughout the cell rather than events simply localized to the inner face of the plasma membrane. It remains for future studies to determine the exact biochemical events that underly the RVD mechanism and its control, and the Ca2+ dependency of each step, before a full understanding will be attained of the role of Ca2+ in modulating RVD.


Anti-oxidant activity of dibenzocyclooctene lignans isolated from Schisandraceae. The anti-oxidant activity of nine dibenzocyclooctene lignans isolated from Schisandra chinensis, S. rubriflora, and Kadsura longipedunculata, respectively, was studied. Seven of the 9 lignans (1 mM) inhibited iron/cysteine-induced lipid peroxidation (malondialdehyde, MDA, formation) of rat liver microsomes as well as superoxide anion production in the xanthine/xanthine oxidase system. The actions of the 7 lignans were much more potent than vitamin E at the same concentration of 1 mM. Among the lignans, schisanhenol was the most active one. This compound also prevented the decrease of membrane fluidity of liver microsomes induced by iron/cysteine. The results indicated that seven of the lignans such as schisanhenol have anti-oxidant activities.


Activity of polyphenolic crude extracts as scavengers of superoxide radicals and inhibitors of xanthine oxidase. In view of the pharmacological interest in phenolic substances, we have determined the total amount of anthocyanins and polyphenols present in the berries of several cultivars of Ribes, Rubus, and Vaccinium genera. The in vitro antiradical activity of the crude extracts on chemically-generated superoxide radicals as well as the inhibitory activity towards the enzyme xanthine oxidase were studied. All the crude extracts examined showed a remarkably high activity towards chemically-generated superoxide radicals. The activities were greater than those expected on the basis of the quantities of anthocyanins and polyphenols present in the samples. Furthermore, the extracts showed a certain inhibitory activity towards xanthine oxidase. Ribes nigrum extracts exhibit the highest activity, being the richest in both anthocyanins and polyphenols. On the other hand, Ribes rubrum extracts seem to contain more active substances than the other crude extracts.


[Group psychotherapy in inpatient drug treatment--its position in the therapeutic community]. A model of therapeutic community for the stationary treatment of patients with addictive diseases is outlined. Its leading idea says that the main task for patients as well as therapists is to try to integrate the polar concepts of empathy and discipline. Consequences of this framework for group psychotherapy are discussed with regard to the attitude of the therapist and to his behaviour within the session.


Serotonin function in schizophrenia: effects of meta-chlorophenylpiperazine in schizophrenic patients and healthy subjects. This study examined serotonin (5-hydroxytryptamine; 5HT) receptor responsivity in 22 chronic schizophrenic patients and 17 healthy control subjects. The 5HT agonist meta-chlorophenylpiperazine (MCPP) was used as a probe of serotonergic function. MCPP (0.35 mg/kg) or placebo was administered orally after a 3-week drug-free period in a randomized double-blind design. Hormonal (adrenocorticotropic hormone and prolactin), temperature, and behavioral responses and MCPP blood levels were assessed for 210 minutes after administration of the capsules. The schizophrenic patients had blunted temperature responses compared with those of the healthy control subjects: MCPP raised body temperature in the control subjects, but not in the patients. Behavioral responses also differed in the two groups: MCPP increased the total Brief Psychiatric Rating Scale (BPRS) score in the control subjects and tended to decrease it in the patients. In patients, MCPP decreased the BPRS psychosis subscore. Hormonal responses did not differ significantly in the two groups. These findings suggest that further exploration of 5HT function in schizophrenia is warranted.


Noradrenergic responses to clonidine in acute and remitted depressed male patients. To investigate noradrenergic function in depression, plasma 3-methoxy-4-hydroxyphenylglycol (MHPG), plasma norepinephrine (NE), mean arterial pressure (MAP), and heart rate responses to intravenous clonidine (2 micrograms/kg), an alpha 2-adrenergic agonist, were measured in 27 acutely depressed patients, 18 remitted depressed patients, and 27 normal control subjects; a placebo infusion was administered to a subgroup. Clonidine compared with placebo, over a 150-minute time course, decreased plasma NE, MAP, and heart rate, but not plasma MHPG, in the control subjects. Plasma MHPG, plasma NE, MAP, and heart rate at baseline or in response to clonidine and placebo over 150 minutes did not indicate any group differences. The only significant plasma MHPG response to clonidine in the normal control subjects occurred 60 minutes after the infusion. A significantly diminished plasma MHPG response to clonidine at 60 minutes was found in the acutely depressed group compared with the normal control subjects. These results suggest that peripheral inhibitory noradrenergic responses to clonidine are normal in depressed patients, while plasma MHPG responses to clonidine, which have a limited central contribution, appear to be a weak reflection of central noradrenergic function and appear insufficiently robust for a meaningful evaluation of hypothetical group differences in central inhibitory alpha 2-adrenergic activity in this population.


Effects of the ACTH4-9 analog Org2766 on brain plasticity: modulation of excitatory neurotransmission? ACTH-like neuropeptides have been investigated in various paradigms such as cognition, neuronal damage and neuronal excitation. All their effects may be collectively described as modulation of neural plasticity. However, the mechanism of action accounting for these effects remains to be demonstrated. This report is an overview of the data and has incorporated some additional findings of the influence of the ACTH4-9 analog, Org2766, on neuronal excitation, especially in the hippocampus. An interaction with NMDA receptors may account for the various aspects of plasticity. Based on recent findings demonstrating that the ACTH4-9 analog counteracts both the NMDA antagonist, AP5, and NMDA-induced explosive running behavior, the hypothesis is put forward that glutamatergic neurotransmission is involved in behavioral changes induced by the ACTH4-9 analog.


Hippocampal type I and type II corticosteroid receptors are modulated by central noradrenergic systems. The effects of corticosteroids on various brain functions, including the negative feedback control of hypothalamo-pituitary-adrenal (HPA) axis activity, are mediated by two types of receptors (type I, or mineralocorticoid, and type II, or glucocorticoid) in the central nervous system. Although receptor numbers are thought to be regulated by circulating levels of corticosterone, there may be a direct neural control of corticosteroid receptors. In the present experiments, we demonstrate that 6-OHDA lesioning of noradrenergic (NA) ascending pathways in the pedunculus cerebellaris superior (PCS) reduces corticosterone secretion in response to novelty and increases the number of hippocampal type I corticosteroid receptors in rats 24 hr after adrenalectomy. The same lesion in adrenalectomized animals in which corticosterone levels were maintained within normal limits by corticosterone replacement implants also led to an increase in the number of type I corticosterone receptors and a decrease in the apparent affinity (Kd) of type II receptors in the hippocampus. These results suggest that the NA system may regulate HPA axis activity via a direct control of the number of type I receptors and the apparent affinity of type II receptors in the hippocampus. The possibility that there is a neural control of corticosteroid receptors may throw light on mechanisms controlling HPA axis activity and may suggest other approaches to the treatment of dysregulation of the HPA axis observed during stress and in certain psychopathological conditions.


Differential impact of naltrexone on luteinizing hormone release during single versus repetitive exposure to restraint stress. The objective of the present study was to determine the impact of repeated exposure to the same stressor on opiate receptor-mediated inhibition of basal and stress-related alterations of pituitary LH release. Groups of intact adult male rats were exposed to 8 hr of restraint stress for either 1 or 14 consecutive days. Animals in each group were injected intravenously with the specific opioid receptor antagonist naltrexone (NALT, 2 mg/kg bodyweight) or the vehicle saline (SAL) prior to the final scheduled stress episode. Rats pretreated with SAL prior to the single exposure to stress exhibited an increase in plasma LH over the 1st hr of stress, followed by a decline in hormone levels, which reached significance between 3 and 7 hr after initiation of the stress. NALT pretreatment of rats prior to restraint significantly blunted the suppressive effect of stress on circulating LH. Rats repeatedly exposed to stress did not show any significant alteration in plasma LH levels from prestress values at any time during their final stress episode. Pretreatment of chronically stressed rats with NALT before reexposure to stress resulted in plasma hormone levels that were not different from those in animals pretreated with SAL. When the opioid antagonist was administered to animals 24 hr after termination of single or multiple exposures to restraint, NALT-induced increases in basal plasma LH were significantly attenuated in the chronically stressed rats compared to animals subjected to stress only once or not at all.(ABSTRACT TRUNCATED AT 250 WORDS)


The brain as a target for adrenocortical steroids: cognitive implications. It is well established that a reciprocal control exists between the brain and glucocorticoid hormones. The brain regulates adrenocortical function via hypothalamic corticotrophin releasing hormone-41 (CRH-41), glucocorticoids act at specific receptors in the hippocampus, thus promoting negative feedback mechanisms. Because the hippocampus is a major site for memory processes, a role for excessive/long-lasting plasma glucocorticoid levels has been suggested in conditions of mental impairment. Major depression, Cushing's disease, and dementia of the Alzheimer type are disorders which share hyperactivity of the hypothalamo-pituitary-adrenal axis, as well as symptoms of cognitive decline. Although the mechanisms leading to hypercortisolemia appear to be different in each case, the neuropsychological features of these three disorders accord with the hypothesis of glucocorticoid-associated brain damage. It therefore is important to find pharmacological strategies that will avert or reduce these potential consequences on brain function.


Serotonin does not mediate the adrenal catecholamine-releasing effect of acute lithium administration in rats. The activity of central serotonin (5-hydroxytryptamine, 5-HT) systems has been reported to be affected by repeated, and to a lesser extent by acute, lithium chloride (LiCl) treatment. Because (1) acute LiCl administration increases sympathoadrenal function, and in turn plasma glucose levels, and (2) stimulation of either the 5-HT1A, the 5-HT1C or the 5-HT2 receptor subtype has adrenal catecholamine-releasing and hyperglycemic effects, we have investigated the influence of prior blockade of either of these receptor subtypes on plasma catecholamine and glucose responses to acute LiCl administration in conscious, catheterized rats. Acute administration of LiCl (1-8 mEq/kg IV) triggered dose-dependent increases in plasma epinephrine (Epi), norepinephrine (NE), and glucose levels throughout the 60-min analysis. In contrast, administration of NaCl (8 mEq/kg IV) did not alter plasma Epi or NE levels, nor did it affect plasma glucose levels. Prior blockade of 5-HT1A receptor and beta-adrenoceptors by means of (-)-propranolol (5 mg/kg IV), 10 min beforehand) did not affect plasma Epi and NE responses to LiCl (4 mEq/kg), but it did prevent the hyperglycemic effect of LiCl. Plasma Epi, NE and glucose responses to LiCl remained intact in rats pretreated with the 5-HT1C/5-HT2 receptor antagonist LY 53857 (1 mg/kg IV), 10 min beforehand). These results strongly suggest that LiCl-induced adrenal catecholamine release (and hyperglycemia) is not mediated by increased 5-HT release.


The pharmacological potential of neurotrophins: a perspective. Until recently nerve growth factor (NGF) was the only widely characterized neurotrophic factor which had been shown both in vitro and in vivo to be essential for the survival of selected populations of neurons during development and to be important for maintenance of the differentiated phenotype of mature neurons. The recent cloning of new members of the NGF family, namely brain-derived neurotrophic factor neurotrophin-3 (NT-3), NT-4 and NT-5, has greatly expanded our knowledge of the structural properties and neurotrophic activities of these proteins. Elucidation of their developmental and topographical expression and associated receptors in both the central nervous system and peripheral nervous system is proceeding at a brisk pace, leading to proposals for a potential pharmacological use of these proteins. This possibility will ultimately rely upon a more complete understanding of the roles of these trophic factors in human nervous system physiology and pathology.


Thyroid functions in patients treated with interleukin-2 and lymphokine-activated killer cells. Treatment of malignant disease with interleukin-2 and lymphokine-activated killer cells activates autoreactive T lymphocytes, stimulates release of cytokines and induces expression of HLA-class II antigens by tumour cells. We studied eight patients with hepatocellular carcinoma treated with a total of 16 courses of recombinant human interleukin-2 and lymphokine-activated killer cells and observed them for features of autoimmune thyroid disease. During the course of treatment there were significant decreases in total serum T4 and T3 and free thyroxine levels, but no change in TSH levels when all patients were analysed as a group. This was due to a number of factors including suppression of thyroid hormone release, haemodilution during interleukin-2 infusion and actual removal of thyroid hormones from the circulation during leukapheresis. Thyroid hormones returned to normal levels during resting period. One patient subsequently developed compensated hypothyroidism (normal total T4, total T3 and free T4 but elevated TSH) and four patients had features of 'sick euthyroid syndrome' (low total T4, total T3 or free T4 but normal TSH). None of the patients studied developed antibodies to thyroglobulin or microsomes. In contrast, no abnormality of thyroid function was seen in any of the nine subjects who received no active treatment. In conclusion, thyroid dysfunction was associated with immunotherapy of malignant disease with interleukin-2 and lymphokine-activated killer cells. This may arise from direct hormonal effects of the cytokines on thyroid hormone production.


Inverse dose-rate effect of DNA breaks and inactivation of transforming activity induced by tritiated water and 60Co gamma-rays. When an aqueous solution of plasmid DNA at a constant low concentration of 5 micrograms/cm3 was irradiated with 60Co gamma-rays, D37 dose of single-strand breaks was decreased from 18 Gy at a dose-rate of 6.77 Gy/h of acute irradiation to 2.3 Gy at a dose-rate of 0.00212 Gy/h. Or G value was increased from 0.0010 to 0.0081. Similar dose-rate dependency of D37 dose and G value were also found when the plasmid DNA solution was treated with various concentrations of tritiated water at various dose-rates, ranging from 5.13 Gy/h to 0.000118 Gy/h. RBE of tritium beta-rays for single-strand breaks was ranged from 0.3 to 0.5 in a wide range of dose-rates. When the DNA solution was saturated with argon to remove oxygen, the dose-rate dependency of gamma-rays was abolished and that of tritium beta-rays was significantly suppressed. When the DNA solution in air was kept at 4 degrees C for 50 h or 25 days after acute irradiation, the G value of DNA breaks was the same as that kept at -20 degrees C for the same period, but much lower than that of the solution irradiated for the same period at a lower dose-rate to give the same total doses. This shows that the inverse dose-rate effect could not be induced from the different exposure periods but from continuous irradiation of different dose-rates. The inverse dose-rate effect for inactivation of transforming activity of DNA irradiated with tritiated water was also observed in the range from 0.0588 Gy/h to 0.00118 Gy/h.


Early biological effects of whole body irradiation on rat lungs. The influence of whole-body irradiation (WBI) with 4, 8 and 15 Gy ionizing radiation upon some biochemical indices in the bronchoalveolar lavage fluid (BALF) of rat lungs was studied. It was established that lactate dehydrogenase (LDH), alkaline phosphatase, (APH) and acid phosphatase (AcPH) activities show a dose-dependent decrease on the day 1 and day 5 after the irradiation. A similar trend was observed in the total protein content on the day 1. Angiotensin converting enzyme (ACE) activity was increased on the day 1 in the groups irradiated with 8 Gy and 15 Gy in comparison with the controls (190,2% and 187,5%, respectively). It was concluded that WBI decreases LDH, APH and AcPH levels in the lung cells, which secrete them into bronchoalveolar spaces. An irradiation with 8 Gy and 15 Gy WBI provokes an early damage on cytoplasmic membranes of the endothelial cells in lung capillars. It was considered that the bronchoalveolar lavage can find a more wide application for evaluation of the biological effect of ionizing radiation in lungs.


Possibility of using a low-energy proton beam for particle-induced X-ray emission microanalysis. The present analysis concentrates on the utilization of low-energy proton accelerators of several hundred kilovolts for particle-induced X-ray emission microanalysis. Experiments on stainless-steel and carbon matrices for thick target conditions have been carried out at several proton energies. The ionization cross sections for some elements are calculated using the ECPSSR theory. The effective cross section and minimum detection limits are calculated for the two matrices. With the availability of ultra LE-Ge detectors low-Z elemental detection is discussed.


Aspartic acid as a trap for gamma-radiation energy in the amorphous Al5(OH)15(Asp)3.3H2O. Paramagnetic molecular centers produced by gamma irradiation at 77 K and at room temperature in the novel compound Al5(OH)15(Asp)3.3H2O were studied by ESR spectroscopy. The g value of 2.0034 and the lack of such lines in pure aluminum hydroxide suggested that all the paramagnetic centers observed are related to the aspartic acid molecule. However, none of the paramagnetic centers gave an ESR spectrum characteristic for gamma-irradiated pure aspartic acid powder. The influence of the oxygen on the formation of the paramagnetic centers was noticed. The extreme stability of the paramagnetic molecular centers formed in Al5(OH)15(Asp)3.3H2O suggests that aspartic acid complexed in aluminum hydroxide is a good trap for gamma-radiation energy.


Ionization of adenine derivatives: EPR and ENDOR studies of X-irradiated adenine.HCl.1/2H2O and adenosine.HCl. Following X irradiation of adenine.HCl.H2O at 10 K, evidence for five distinct radical products was present in the EPR/ENDOR. (In both adenine.HCl.1/2H2O and adenosine.HCl, the adenine base is present in a cationic form as it is protonated at N1). From ENDOR data, radical R1, stable at temperatures up to 250 K, was identified as the product of net hydrogen loss from N1. This product, evidently formed by electron loss followed by proton loss, is equivalent to the radical cation of the neutral adenine base. Radical R2, unstable at temperatures above 60 K, was identified as the product of net hydrogen addition to N3, and evidently formed by electron addition followed by proton addition. Radicals R3-R5 could not be identified with certainty. Similar treatment of adenosine.HCl provided evidence for six identifiable radical products. Radical R6, stable to ca. 150 K, was identified as the result of net hydrogen loss from the amino group, and evidently was the product of electron loss followed by proton loss. Radical R7 was tentatively identified as the product of net hydrogen addition to C4 of the adenine base. Radical R8 was found to be the product of net hydrogen addition to C2 of the adenine base, and R9 was the product of net hydrogen addition to C8. Radical R10 was identified as the product of net hydrogen abstraction from C1' of the ribose, and R11 was an alkoxy radical formed from the ribose. With the exception of R11, all products were also found following irradiation at 65 K. Only radical R8 and R9 were stable at room temperature. Most notable is the different deprotonation behavior of the primary electron-loss products (radical R1 vs. R6) and the different protonation behavior of the primary electron-gain products (radical R2 vs. no similar product in adenosine.HCl). The major structural difference in the two crystals is the electrostatic environment of the adenine base. Therefore, this study provides further evidence that environmental influences are important in determining proton transfer processes.


Thrombomodulin as a marker of radiation-induced endothelial cell injury. Cultured confluent human umbilical vein endothelial cells were irradiated in vitro with 60Co gamma rays at doses from 0 to 50 Gy. After irradiation thrombomodulin was measured at different times over 6 days in the supernatants of endothelial cell culture medium, on the surface of the cells, and within the cells. At 24 h after irradiation, an increase in the release of thrombomodulin from irradiated endothelial cells and an increase in the number of molecules and the activity of thrombomodulin on the surface of the cells were observed; these reactions were dependent on radiation dose. The capacity of the cells to produce and release thrombomodulin was decreased from 2 to 6 days after exposure to 60Co gamma rays. Our data indicate that radiation can injure endothelial cells, and that thrombomodulin may be used as a marker of radiation-induced injury in endothelial cells. The interrelationship between the dysfunction of irradiated endothelial cells and the pathological mechanisms of acute radiation disease is also discussed.


Changes in gene expression by 193- and 248-nm excimer laser radiation in cultured human fibroblasts. Tissue ablation by ultraviolet excimer lasers results in exposure of viable cells to subablative doses of radiation. To understand the potential biological consequences better, we have studied changes in gene expression in cultured human skin fibroblasts exposed to either 193- or 248-nm laser light. Northern blot analyses revealed that both treatments up-regulate a common set of genes, including interstitial collagenase, tissue inhibitor of metalloprotease, metallothionein, and the proto-oncogene c-fos. Dose-response and kinetic studies of collagenase induction by 193-nm radiation showed a maximal effect with 60 J/m2 and at approximately 24 h. The induction was still persistent 96 h later. In addition to the commonly affected genes, known to be activated also by conventional UV light (254 nm) and tumor-promoting phorbol esters, other genes were found to be selectively induced by the 193-nm radiation. The heat-shock hsp70 mRNA, undetectable in controls and in cultures irradiated at 248 nm, was transiently induced 8 h after exposure to 193-nm radiation. Furthermore, a selective up-regulation of collagen type I expression was observed. The results indicate that the 193- and 248-nm radiations by excimer lasers elicit specific and different cellular responses, in addition to an overlapping pathway of gene activation common also to UV radiation by germicidal lamps. The laser-induced genes could serve as molecular markers in evaluating cell injury in situ.


Excision of sugar-phosphate products at apurinic/apyrimidinic sites by DNA deoxyribophosphodiesterase of Escherichia coli. It has been shown previously that the DNA deoxyribophosphodiesterase (dRpase) activity of Escherichia coli excises 2-deoxyribose 5-phosphate moieties at apurinic/apyrimidinic (AP) sites in DNA following cleavage of the DNA at the AP site by an AP endonuclease such as endonuclease IV of E coli. A second class of enzymes that cleave DNA at AP sites by a beta-elimination mechanism, AP lyases, leave a different sugar-phosphate product remaining at the AP site, which has been identified as the compound trans-4-hydroxy-2-pentenal 5-phosphate. It is shown that dRpase removes this unsaturated sugar-phosphate group following cleavage of a poly(dA-dT) substrate containing AP sites by the action of the AP lyase endonuclease III of E. coli. The Km for the removal of trans-4-hydroxy-2-pentenal 5-phosphate is 0.06 microM; the Km for the removal of 2-deoxyribose 5-phosphate is 0.17 microM. It was verified that the sugar-phosphate product removed by dRpase from the endonuclease III-cleaved substrate was trans-4-hydroxy-2-pentenal 5-phosphate by conversion of the product to the compound cyclopentane-1,2-dione. The dRpase activity is unique in its ability to remove sugar-phosphate products after cleavage by both AP endonucleases and AP lyases.


The suppression of the synthesis of a nuclear protein in cells blocked in G2 phase: identification of NP-170 as topoisomerase II. Previous studies of a nuclear protein of molecular weight 170 kDa (NP-170) have shown it to have two interesting properties. First, NP-170 synthesis began in mid- to late S phase and became maximal in G2 phase. Second, the synthesis of NP-170 was suppressed in cells blocked in G2 phase following irradiation with 6.8 Gy (J. M. Holland et al., Radiat. Res. 122, 197-208, 1990). The molecular weight of NP-170 is the same as that of Topoisomerase II (Topo II), an enzyme involved in the alteration of DNA supercoiling status with a double-strand passing function. This study was undertaken to determine whether NP-170 could be Topo II. The results from the present study show that both the proteins have identical cell cycle synthesis patterns. The synthesis of both these proteins is suppressed following irradiation. NP-170 was found to be recognized by a Topo II antibody in both Western blots and immunoprecipitation. This study characterizes NP-170 as Topo II.


Effect of pH on low-density lipoprotein oxidation by O2-./HO2. free radicals produced by gamma radiolysis. This study aimed to analyze quantitatively the initiation and the consequences of low-density lipoprotein (LDL) peroxidation by O2-./HO2. free radicals produced by gamma radiolysis. The action of increasing radiation doses on aqueous LDL solutions has been monitored simultaneously by several parameters: a decrease in endogenous vitamin E, the formation of thiobarbituric acid-reactive substances (TBARS) and conjugated dienes, the appearance of a differential fluorescence (excitation wavelength = 360 nm), and an increase of the relative electrophoretic mobility. Initial radiation yields (decrease in vitamin E, formation of TBARS) have been determined at pH 7 and pH 5.7 as a function of LDL concentration (from 0.75 to 9 g liter-1). From the comparison of these yields with those of O2-. radicals produced by water radiolysis, we have deduced reaction mechanisms for LDL peroxidation initiated by O2-./HO2. free radicals.


[Magnetic resonance tomography of the bone marrow for the detection of metastases of solid tumors]. The bone marrow is a common site of metastases in patients with solid tumors. Metastatic bone marrow involvement is found much more frequently at autopsy than in routine staging procedures. The purpose of this study was to evaluate the diagnostic efficacy of bone marrow MRI in such patients, and especially in those with small cell lung cancer and female breast carcinoma. MRI is a fast and reliable method for the early detection of bone marrow metastases in patients with carcinoma. In many studies and according to our own experience, it is much more sensitive than radionuclide bone scan, iliac crest biopsy and plain film radiography. However, a clear clinical benefit of its use in the initial staging has so far been proven only for patients with small cell lung cancer. As a consequence, MRI should be applied for the staging of solid tumors only when clinical examination does not yield unambiguous results. Owing to its superiority to biopsy and bone scan, bone marrow MRI should become an integral part of the initial staging procedure in small cell lung cancer and wherever it is sufficiently available it can replace the conventional diagnostic procedures.


ONO-4057, a novel, orally active leukotriene B4 antagonist: effects on LTB4-induced neutrophil functions. ONO-4057(5-[2-(2-Carboxyethyl)-3-[6-(4-methoxyphenyl)-5E- hexenyl]oxyphenoxy]valeric acid), an orally active leukotriene B4(LTB4) antagonist, displaced the binding of [3H] LTB4 to the LTB4 receptor in human neutrophil (Ki = 3.7 +/- 0.9 nM). ONO-4057 inhibited the LTB4-induced rise in cytosolic free calcium (the concentration causing 50% inhibition (IC50) = 0.7 +/- 0.3 microM) and inhibited human neutrophil aggregation, chemotaxis or degranulation induced by LTB4 (IC50 = 3.0 +/- 0.1, 0.9 +/- 0.1 and 1.6 +/- 0.1 microM) without showing any agonist activity at concentration up to 30 microM. ONO-4057 did not inhibit fMLP or C5a-induced neutrophil activation at concentrations up to 30 microM. In the in vivo study, ONO-4057 given orally, prevented LTB4-induced transient neutropenia or intradermal neutrophil migration in guinea pig (the dose causing 50% efficacy (ED50) = 25.6mg/kg or 5.3mg/kg). Furthermore, ONO-4057 given topically, suppressed phorbol-12-myristate-13-acetate (PMA)-induced neutrophil infiltration in guinea pig ear (the effective dose = 1 mg/ear). These results indicate that ONO-4057 is a selective and orally active LTB4 antagonist and may be a potential candidate for the treatment of various inflammatory diseases.


[Studies of the clinical use of cycloplatin--a new derivative of cisplatin]. The preliminary results of Cycloplatin in non small cell lung cancer were presented. Cycloplatin is a new derivative of Cisplatin but less nephrotoxic. Its. referring preparation is Carboplatin 14% remissions were found in the cases of inoperable non small cell lung cancer and 12% remissions in advanced ovarian cancer. 84% of patients suffered from vomiting what was the most common reported side-effect.


[Parotid tumors treated at the II Department of Laryngology, Silesian Medical Academy, Zabrze]. The authors present data on 46 cases of tumors of parotid gland treated in the IInd Department of Laryngology of Sl. AM. in the Zabrze city in years 1979 to 1988. The analysis of histopathological examinations of operated tumors and the principles of the parotid gland neoplasia has been presented.


A quantitative assessment of the addition of MRI to CT-based, 3-D treatment planning of brain tumors. Quantitative 3-D volumetric comparisons were made of composite CT-MRI macroscopic and microscopic tumor and target volumes to their independently defined constituents. Volumetric comparisons were also made between volumes derived from coronal and axial MRI data sets, and between CT and MRI volumes redefined at a repeat session in comparison to their original definitions. The degree of 3-D dose coverage obtained from use of CT data only or MRI data only in terms of coverage of composite CT-MRI volumes was also analyzed. On average, MRI defined larger volumes as well as a greater share of composite CT-MRI volumes. On average, increases in block margin on the order of 0.5 cm would have ensured coverage of volumes derived from use of both imaging modalities had only MRI data been used. However, the degree of inter-observer variation in volume definition is on the order of the magnitude of differences in volume definition seen between the modalities, and the question of which imaging modality best describes tumor volumes remains unanswered until detailed histologic studies are performed. Given that tumor volumes independently apparent on CT and MRI have equal validity, composite CT-MRI input should be considered for planning to ensure precise dose coverage for conformal treatments.


Biodistribution of intravenously injected [131I]Lipiodol in rats. Tissue distribution studies of intravenously injected [131I]Lipiodol in rats were performed, and serial whole-body autoradiograms were obtained simultaneously for seven days. Most of the radiotracer was retained in the lungs. Lung uptake reached a maximum (42.44% ID/g) at 1 day, with an effective half-life of 3.0 days. The other organs showed markedly lower uptakes (less than 0.56% ID/g). The ratio between liver and lung reached a maximum (0.01) at 3 hr and then decreased with time, precluding adequate external imaging of the liver as compared with the lung.


Effect of oxytocin on the pattern of electromyographic activity in the oviduct and uterus of the ewe around oestrus. This study tested the hypothesis that the administration of oxytocin in doses equivalent to endogenous concentrations at and around oestrus could affect uterine and oviductal muscular activity at the time of gamete transport. Four ewes were fitted with recording electrodes in the left ampulla, ampullary-isthmic junction, utero-tubal junction and uterine horn. After surgical recovery, recordings from conscious free-standing animals were made for up to 10 h per day from Day -3 to Day +3 relative to oestrus in each ewe. Daily blood samples were taken for progesterone radioimmunoassay, and a vasectomized ram used to assess oestrus. A range of physiological doses of oxytocin (10-100 mU), or control saline injections were given intravenously. Electromyographic (EMG) activity was measured before and after injections. Spontaneous activity throughout the reproductive tract was low on Day -3 but increased to peak at oestrus (P < 0.05), when the pattern of activity consisted of short (2-10 s) co-ordinated high amplitude bursts (2-5 min-1). After oestrus, as overall activity declined, longer episodes of activity appeared but these occurred with a much slower frequency (1-4 h-1). Responsiveness to oxytocin was greatest on the day of oestrus at all electrode sites. Elevated responsiveness (relative to Day -3, the late luteal phase) was seen from Day -1 to Day +2 at the ampullary-isthmic junction and uterus, but on the day of oestrus only at the ampulla and utero-tubal junction. Duration of increased EMG activity after oxytocin injection ranged from 5 to 20 min. These results show for the first time that the uterine and oviductal musculatures of the ewe in vivo reached a peak in sensitivity to physiological concentrations of oxytocin at oestrus. When combined with information on oxytocin receptor populations and endogenous circulating concentrations, this suggest that endogenous oxytocin could influence oviduct and myometrial activity at this time.


Hormonal control of concentrations of endometrial oxytocin receptors in the ewe. Uterine oxytocin receptors have been shown to play a major role in the regulation of uterine prostaglandin F2 alpha release during the oestrous cycle and early pregnancy in sheep. The concentration of endometrial oxytocin receptors increases sharply from around Day 13 of the oestrous cycle to reach a maximum between Days 15 and 16. The high concentration of endometrial oxytocin receptors at this time coincides with the release of endogenous uterine prostaglandin F2 alpha during luteal regression and the maximum uterine prostaglandin F2 alpha response to an oxytocin stimulus. The concentration of uterine oxytocin receptors appears to be regulated by both progesterone and oestradiol. Studies in ovariectomized ewes have shown that initially progesterone lowers the concentration of endometrial oxytocin receptors, but after prolonged treatment with progesterone the concentration of oxytocin receptors increases; this suggests that the uterine-PGF2 alpha response to oxytocin has become refractory to the inhibitory effects of progesterone. The concentration of endometrial oxytocin receptors is also lowered by short-term oestradiol treatment. However, oestrogen treatment of ewes after long-term treatment with progesterone does not result in an increase in the concentration of oxytocin receptors following the cessation of progesterone treatment. On the basis of these and other data it is proposed that in the normal oestrous cycle the concentration of endometrial oxytocin receptors is initially depressed by both oestradiol and progesterone but that the marked increase in the concentration of oxytocin receptors over Days 13-16 of the cycle is due primarily to the withdrawal of the inhibitory influence of progesterone alone. During early pregnancy the release of uterine prostaglandin F is suppressed.(ABSTRACT TRUNCATED AT 250 WORDS)


Giant metastatic cystosarcoma phyllodes to the lung: CT and MR findings. The authors present a case of giant pulmonary metastasis from cystosarcoma phyllodes of the breast, and correlate the CT and MR findings with the pathological findings. Although CT showed homogenous low density in most parts of the tumor, T 2-weighted MR images presented a more variegated appearance, namely, peculiar slit-like areas of low intensity between areas of high intensity. The MR findings reflected the characteristic gross pathology of cystosarcoma phyllodes, showing narrow cavities filled with bloody fluid surrounding intracystic protruding tumors with abundant necrotic change.


Interaction between oxytocin and prostaglandin F2 alpha during luteal regression and early pregnancy in sheep. The pulsatile release of oxytocin from the corpus luteum in the sheep is responsible for the pulsatile release of prostaglandin F2 alpha (PGF2 alpha) from the uterus at luteolysis. It has been proposed that PGF2 alpha also reinforces this process by stimulating the release of oxytocin from the corpus luteum. It is, however, unlikely that PGF2 alpha is the major stimulus for oxytocin release at this time. Although the stimulus for the pulsatile release of oxytocin from the corpus luteum appears to reach the ovary from the peripheral circulation, the nature of the stimulus is unknown. Pulses of oxytocin originating from the corpus luteum have also been observed during early pregnancy, but the release of PGF2 alpha, in response to this signal, is abrogated in some way by ovine trophoblast protein-1 (oTP-1). This protein has been shown to inhibit endometrial prostaglandin production and to decrease the amount of PGF2 alpha released in response to oxytocin. Reduction of uterine oxytocin receptor concentrations by conceptus secretory proteins or by interferons related to oTP-1 remains equivocal. Inhibition of uterine oxytocin receptors is, however, probably the major mechanism that prevents luteal regression during early pregnancy. In cyclic sheep the specific inhibition of uterine oxytocin receptors by 1-deamino-2-D-Try (oET)-4-Thr-8-Orn-oxytocin (CAP), a synthetic oxytocin receptor antagonist, inhibits luteal regression and suppresses pulsatile, but not basal, secretion of uterine PGF2 alpha. Thus, the effects of CAP directly parallel the endocrinological changes that occur in early pregnancy in the sheep.


Demonstration of [125I]VIP binding sites and effects of VIP on cAMP-formation in rat insulinoma (RINm5F and RIN14B) cells. Vasoactive intestinal polypeptide (VIP)-immunoreactive nerves have been demonstrated in close association with the islets of Langerhans, and VIP has been shown to stimulate insulin and somatostatin secretion. Using [125I]VIP and membranes prepared from rat insulinoma (RIN) cells, i.e., the subclones m5F (m5F; mainly insulin-secreting) and 14B (14B; mainly somatostatin-secreting), it was found that VIP (10(-10)-10(-7) M) competitively inhibited the binding of [125I]VIP. A single class of high affinity binding sites with Kd values of 0.40 +/- 0.06 nM and 0.36 +/- 0.08 nM for m5F and 14B, respectively, with a corresponding number of binding sites (Bmax) of 163 +/- 20 and 254 +/- 51 fmol/mg protein was observed. The rank order of potency in inhibiting [125I]VIP binding was in both cell lines: VIP greater than helodermin greater than pituitary adenylate cyclase activating polypeptide 1-27 (PACAP27) greater than peptide histidine isoleucine (PHI) greater than secretin. VIP caused a dose-dependent increase in cAMP-formation in both m5F and 14B cell membranes with EC50 values of 3.0 and 3.5 nM, respectively, but VIP (1.10(-9)-3.10(-6) M) had no effect on insulin secretion (over 2 h) from the m5F cells. Thus, the data suggest that the VIP-receptors in these neoplastic rat cell lines, despite an apparent coupling to adenylate cyclase activity, seem to be functionally uncoupled to an effect on insulin secretion following an acute exposure to VIP.


A novel bombesin receptor antagonist (2258U89), potently inhibits bombesin evoked release of gastrointestinal hormones from rats and dogs, in vitro and in vivo. Several bombesin-receptor antagonists are available that inhibit secretory and growth effects of bombesin, in vitro. In the present study, we examined the effects of a new class of bombesin receptor antagonists (modified GRP(15-27) peptides, with D-Pro26 and D-Ala24 moieties), on bombesin mediated effects, in vivo and in vitro. Of the 10 different compounds tested, BW-10 or 2258U89 ([de-NH2)Phe19,D-Ala24,D-Pro26 psi(CH2NH)Phe27]-GRP(19-27)) was most potent towards inhibiting bombesin binding to rat pancreatic acinar cancer cells with an ID50 of 0.5 nM. BW-10 (1 and 10 nM) significantly inhibited the gastrin response to 1 nM bombesin, from isolated rat stomach, in vitro, in a dose-dependent fashion. BW-10 (10-100 nmol/kg) was equally effective at significantly inhibiting bombesin evoked gastrin release in anesthetized rats, in vivo. [D-Phe6]Bombesin(6-13)-propylamide (BIM), a member of another class of antagonists, reported previously to be the most potent antagonist, in vitro, on the other hand, enhanced bombesin provoked gastrin release in rats. The antagonistic effects of BIM, in vivo, may thus be more selective. Intravenous infusion of BW-10 (10 nmol/kg/h) partially depressed gastrin and pancreatic polypeptide and completely abolished insulin released in response to bombesin, in conscious dogs. These results suggest that BW-10 functions as one of the most potent bombesin receptor antagonists, in vitro and in vivo, which could potentially be used as a therapeutic compound in treatment of some human diseases.


Purification of cationic cystine-rich peptides from rat bone marrow. Primary structures and biological activity of the rat corticostatin family of peptides. Seven cationic, cystine-rich peptides of 29 to 32 amino acid residues have been purified from extracts of rat bone marrow (R-1, R-1a, R-1b, R-2, R-3, R-4 and R-5). Structural analysis clearly indicated that all seven peptides belong to the corticostatin/defensin family of leukocyte-derived peptides known to participate in oxygen-independent killing of phagocytosed bacteria. For R-1 to R-5, six cysteine residues were found at characteristic and highly conserved positions. R-1a and R-1b were partially characterized and appear to be structural variants of R-1. Aside from the conserved cysteines, there is a remarkable degree of structural diversity evident within the sequences of those members of the corticostatin/defensin family characterized so far. The structures of the peptides that we have purified can be compared directly with the sequences obtained for rat defensins isolated from extracts of peritoneal neutrophils (Lehrer, Ganz and Selsted, Cell, 64 (1991) 229-230). Some discrepancies are apparent which can be explained in terms of proteolytic cleavage of several of these peptides at both amino- and carboxyl-termini. The corticostatins owe their bioactivity to their ability to compete with corticotropin for occupancy of the corticotropin receptor (Zhu, Hu, Mulay, Esch, Shimasaki and Solomon, Proc. Natl. Acad. Sci. USA, 85 (1988) 592-596). The potency of these peptides can be expressed in terms of their capacity to inhibit the steroidogenic response of isolated rat adrenocrotical cells half-maximally stimulated by corticotropin (i.e., at the ED50 concentration for corticotropin in this assay, namely 33 pM). In this assay, the rat peptides R-1, R-2 and R-3 were shown to be inactive. In contrast, the more cationic peptides R-4 and R-5 were found to inhibit steroidogenesis. R-4 was somewhat less active than rabbit corticostatin (IC50 25 nM) showing an IC50 value of 50 nM. R-5 appeared to be significantly less potent than R-4. The lower yield of R-5 precluded an accurate estimate of the corticostatic potency of this peptide. R-4 differs in structure from R-5 in having an arginine to serine substitution at position 7. It can be concluded that an arginine at this position accounts, at least in part, for the corticostatic activity of R-4.(ABSTRACT TRUNCATED AT 400 WORDS)


Neuropeptides of the vasoactive intestinal peptide/helodermin/pituitary adenylate cyclase activating peptide family elevate plasma cAMP in mice: comparison with a range of other regulatory peptides. A number of regulatory peptides were investigated for their ability to elevate plasma cAMP. Pituitary adenylate cyclase activating peptide (PACAP)-27, PACAP-38, helodermin, helospectin I and II, vasoactive intestinal peptide (VIP), glucagon, parathyroid hormone (PTH), calcitonin and calcitonin gene-related peptide were among the peptides that were highly effective in raising plasma cAMP when given intravenously in equimolar doses to conscious mice. PACAP-27 and -38 were more effective than any of the other peptides. PACAP 16-38, secretin, gastrin-17, galanin, somatostatin, cholecystokinin-8s, pancreatic polypeptide, substance P, peptide YY and neuropeptide Y were inactive and also did not interfere with the PACAP-27-evoked rise in plasma cAMP levels. Repeated injections of PACAP-27 every 30 min caused a progressive reduction in the plasma cAMP response (measured 5 min after each injection). Forskolin, an activator of adenylate cyclase, dose-dependently raised the plasma concentration of cAMP and displayed a synergistic effect when given in a low dose concurrently with PTH or PACAP-38. The phosphodiesterase inhibitor rolipram dose-dependently raised the plasma concentration of cAMP. Combined treatment with PACAP-27 and a threshold dose of rolipram resulted in an exaggerated plasma cAMP response. Kidney hilus ligation suppressed the responses to PACAP-38, PTH, helodermin, helospectin, VIP, glucagon and calcitonin. Hepatectomy suppressed the response to glucagon but was without effect on the response to the other peptides. Pancreatectomy and spleenectomy reduced the response to VIP, but was without effect on the response to the other peptides. PACAP-27 stimulated cAMP efflux from the isolated rat tail vein. Hence, it cannot be excluded that blood vessels contribute to the peptide evoked plasma cAMP response in vivo.


Vascular effects of pituitary adenylate cyclase activating peptide: a comparison with vasoactive intestinal peptide. The effects of pituitary adenylate cyclase activating peptide (PACAP) on the blood pressure of the anesthetized rat and on the isolated rat tail artery were investigated and compared to those of vasoactive intestinal peptide (VIP). PACAP-38, PACAP-27 and the C-terminal fragment 16-38 caused a dose-dependent decrease in the systemic blood pressure. PACAP-27 and PACAP-38 were equipotent with VIP. The C-terminal fragment 16-38 was much less potent than VIP. The duration of action was longer for equimolar doses of PACAP-38 and PACAP-27 than for VIP and much longer than for PACAP 16-38. PACAP-27 and the phosphodiesterase inhibitor rolipram given in combination produced additive vasodepressive responses. In vitro PACAP-38, PACAP-27, VIP and PACAP 16-38 relaxed the phenylephrine-precontracted rat tail artery. PACAP-38 and PACAP-27 were equipotent with VIP. PACAP 16-38 was much less potent than the full-length peptides. The responses were resistant to atropine and propranolol. Addition of VIP 1 microM to preparations exposed to 1 microM PACAP-38 or -27 did not produce a further relaxation. VIP-like peptides, PACAP in particular, are known to activate adenylate cyclase and to elevate the plasma cyclic AMP (cAMP) concentration. cAMP was found to be a potent vasodepressor in the anaesthetized rat and a potent vasodilator of precontracted blood vessels. On the basis of these results it cannot be excluded that the vascular effects of PACAP are secondary to the effect of elevated levels of extracellular cAMP.


Circadian influences on feeding-induced changes in ACTH and corticosterone secretion in rats. Food ingestion has a variable influence on pituitary-adrenal hormone secretion depending on the species studied and/or the experimental design. In this study, changes in plasma concentrations of ACTH and corticosterone following 30 min of food ingestion were compared in both 24 h fasted and ad libitum fed rats tested during either the early light cycle or the early dark cycle. In the dark, food ingestion caused significant decreases in both ACTH (to 80% of control) and corticosterone (to 32% of control) in both fasted and ad libitum fed rats. In contrast, in the light, food ingestion by the fasted animal resulted in a doubling of corticosterone concentrations. Such a response was not seen in ad libitum fed animals; however, these animals ate very little during the test. There were no significant changes in ACTH during the light phase. These data indicate that time of day has a significant impact on the responses of the pituitary-adrenal system to food ingestion. This circadian effect may be due to the influence of the endogenous levels of ACTH/corticosterone existing at the time of food ingestion.


Effect of enterostatin given intravenously and intracerebroventricularly on high-fat feeding in rats. The effect of enterostatin, the amino-terminal pentapeptide of pancreatic procolipase, on high-fat food intake has been investigated after intracerebroventricular as well as after intravenous injection. After an overnight fast enterostatin given i.c.v. at doses of 167 pmol and 333 pmol produced a significant and dose-dependent reduction in high-fat food intake, while a higher dose of 667 pmol had no effect. Following intravenous injection of enterostatin the intake of high-fat food was suppressed at doses of 8.3 nmol and 16.7 nmol, while no effect was observed at higher doses. The inhibition of feeding started 3 h after the initiation of feeding and persisted to the end of the test period (6 h). Enterostatin at a dose of 16.7 nmol gave no sign of aversion in an aversion test comparing the effect of enterostatin, lithium chloride and saline on liquid intake. The data suggest that enterostatin may exert its satiety effect on high-fat feeding by being absorbed into the bloodstream.


[Retinitis caused by cytomegalovirus in patients with AIDS. Clinico-therapeutic aspects and relationship with HIV retinal microangiopathy in a series of 38 patients]. We evaluate retrospectively 38 patients with AIDS and Cytomegalovirus (CMV) retinitis. In 72.5% (45 from 62 eyes) it carried an important sight risk; 50% of the end of the follow-up. Evidence of extraocular illness in 28.5% of the patients. Using control groups the AIDS microvasculopathy is neither more frequent in CMV-retinitis nor associated with a special risk group (p greater than 0.05), we review treatment, follow-up and complications. The median survival was 6 months without significan differences (p greater than 0.05) with or without the finding of microvasculopathy, bilaterality or extraocular illness.


[Malignant fibrous histiocytoma of the mediastinum]. Soft tissue sarcomas are neoplasms which envolve from mesodermic tissue, being characterized for their low incidence (1% of all malignant tumors), histologic heterogeneity and diverseness regarding their localization. We present a new case of this infrequent tumor: malignant fibrous histiocytoma of exceptional localization: mediastinum.


[Presence of viruses in drinking water in Croatia]. Drinking water must be virus-free. However, it has been observed and demonstrated that various pathogenic viruses are capable of transmission through water and that such viral diseases may have far-reaching health and socio-economic implications. Over a four-year period 135 drinking water samples were collected in a middle-sized town in Croatia. The percentages of positive findings varied from 0 to 10%, the average being 3.7%. These results are compared with the ones given by similar studies in different parts of the world.


[The Lambert-Eaton syndrome].

[The Lambert-Eaton syndrome]. The Eaton-Lambert syndrome is a clinical and electrophysiological entity, which affects less than 3% of patients with a small cell cancer. In the majority of cases the syndrome is present before the discovery of cancer. The diagnosis is primarily suggested by proximal muscle fatiquibility in the lower limbs. The confirmation of the diagnosis is carried out by an electromyography. The occurrence of non-para neoplastic cases are frequently associated with disorders of immunity (Auto-immune Disease, and various auto-antibodies) in the groups HLA B8 and DR3. The efficacy of immunosuppressants has led to a search for an auto-immune mechanism as the basis for this myasthenic type syndrome. The demonstration in recent years of anti-calcium channel antibodies at the origin of the pre-synaptic junctional block has confirmed this hypothesis. The demonstration of the auto-immune character of this para-neoplastic syndrome has led to better understanding of the host tumour relationship from an immunopathological stand point.


[Results of surgery of non-small cell primary bronchial cancers. Retrospective analysis of 452 resections]. Data from 452 patients who underwent pulmonary resection for a non small cell bronchogenic carcinoma from 1980 to 1985 were analysed retrospectively. The operative mortality rate was 5.5%. Mortality was significantly increased in patients who underwent enlarged resections for T4 tumors (20%; p < or = 0.05), and in patients who were 70 years and older (12.8%; p < or = 0.05). The overall 5-years survival rate was 32.7% at 5 years. Prognosis in patients who were 70 years and older was similar to that in younger patients. No difference in survival was observed in patients with lymph node metastases with regard to the operative procedure (pneumonectomy versus lobectomy). Survival in patients without lymph node metastases who underwent a lobectomy was similar to those who underwent a conservative resection. Prognostic significance of the histologic cell type and the tumor formula (pTNM) was assessed by multivariable analysis. There were statistically significant differences between squamous cell carcinoma and both adenocarcinoma (p < or = 10(-5)) and undifferentiated carcinoma (p < or = 0.01). This study confirmed the validity of the TNM classification (4th ed) for the accurate prognosis evaluation. Lymph node involvement appeared to be the most pejorative factor (p < or = 10(-5)).


Effect of salmon calcitonin on the lethality of quinolinic acid, an excitatory amino acid. The effect of salmon calcitonin (SCT) on the lethality of quinolinic acid (QA), an endogenous excitatory amino acid, was investigated in relation to the excitatory amino acid receptor/ion channel complex. SCT increased the LD50 value of QA in a bell-shaped fashion, but the difference was not significant. The non competitive N-methyl-D-aspartate (NMDA) receptor antagonists MK-801 and phencyclidine (PCP) inhibited QA lethality dose-dependently. SCT potentiated the inhibitory effects of these antagonists. The competitive and glycine site antagonists 3-((+-)-2-carboxypiperazin-4-yl)propyl-1-phosphonic acid (CPP) and 7-chlorokynurenic acid (7ClK), respectively, inhibited QA lethality in a dose-dependent fashion. SCT did not potentiate the effect of either drug. These results suggest that SCT inhibits NMDA receptors by interacting with Ca ion channel.


Phorbol ester attenuates inositol 1,4,5-trisphosphate-induced Ca2+ release in electropermeabilized rat pancreatic acini. To investigate the mechanism of inositol trisphosphate (IP3)-induced Ca2+ release from the internal Ca2+ store, we examined the effects of heparin, phorbol ester and cyclic nucleotides on Ca2+ release induced by carbachol or inositol 1,4,5-trisphosphate (1,4,5-IP3). For monitoring changes of Ca2+ we used the fluorescent indicator, fura-2, in electropermeabilized rat pancreatic acini. An amount of 100 micrograms/ml heparin inhibited the Ca2+ release induced by 1 microM 1,4,5-IP3 in permeabilized acini. Pretreatment with 12-O-tetradecanoyl-phorbol-13-acetate (TPA) for 10 min reduced the release of Ca2+ induced by 10 microM carbachol and 1 microM 1,4,5-IP3 in permeabilized acini. Staurosporine, a protein kinase C inhibitor, blocked the inhibitory effect of TPA. Cytosolic calcium concentration was restored by staurosporine in TPA-treated acini. Although cyclic AMP exaggerated the amylase release induced by carbachol, cyclic AMP and cyclic GMP had no effect on the carbachol-induced release of Ca2+ in permeabilized acini. These findings suggest that protein kinase C may act at the level of the IP3 receptors or the IP3-operated Ca2+ channels of the internal Ca2+ store and indicate that cyclic nucleotides do not affect the IP3-induced release of Ca2+ in rat pancreatic acini.


Malignant fibrous histiocytomas in dogs and cats: an immunohistochemical study. Immunohistochemical staining was performed on seven canine and 10 feline soft tissue tumours histologically diagnosed as malignant fibrous histiocytomas (MFHs) or MFH-like tumours, and eight other histologically specified tumours (non-MFH). This was done to determine if commercially available antibodies that are used routinely in human diagnostic pathology for MFHs would express the same immunohistochemical patterns in canine and feline MFHs and MFH-like tumours. The antibodies were directed against human alpha 1-anti-trypsin (AT), human alpha 1-anti-chymotrypsin (ACT), human lysozyme, bovine S-100 protein and human desmin. AT did not show any immunoreactivity in the tissues investigated. Except for one MFH, all canine MFHs and other soft tissue tumours with a 'histiocytic' character stained for lysozyme and not for S-100. Six out of seven canine MFHs and MFH-like tumours stained positive for desmin as did most non-MFH sarcomas. Most of the canine and feline MFHs and MFH-like tumours were positive for ACT. These findings for ACT staining in canine and feline MFHs and MFH-like tumours are in agreement with the findings in human MFHs. The immunohistochemical results of canine MFHs and MFH-like tumours were different from those in cats. Feline MFHs differed from canine MFHs for both lysozyme and desmin staining.


Platelet activating factor is a mediator of equine neutrophil and eosinophil migration in vitro. Platelet activating factor (PAF) is known to be a chemoattractant for equine neutrophils in vivo and in vitro. In this study the in vitro migratory response of equine eosinophils and neutrophils to PAF has been examined and compared with that to leukotriene (LT)B4. PAF (10(-8) to 10(-5) M), but not lyso-PAF (10(-6) M), caused dose related migration of both equine eosinophils and neutrophils, maximal responses occurring at 10(-6) M. Responses to PAF were inhibited by the receptor antagonist WEB 2086. LTB4 (10(-8) to 10(-6) M) also induced migration of both cell types, although the maximum effect was observed with a 10-fold lower concentration. Moreover, the maximum response of equine eosinophils to LTB4 was significantly greater than to PAF. It is concluded that LTB4 and PAF, if released in vivo at sites of allergic or inflammatory reactions, could mediate the recruitment of leucocytes to the involved tissue.


Efficacy of danofloxacin in the therapy of experimental mycoplasmosis in chicks. Specific pathogen free day-old chicks were inoculated with a virulent strain of Mycoplasma gallisepticum. Birds received either danofloxacin (50 ppm), tylosin (500 ppm) or no medication in the drinking water from 24 hours after infection for three days. The effects of medication on mortality, weight gain, serology, lesions and reisolation of M gallisepticum 21 days following infection were studied. Treatment with danofloxacin and tylosin significantly decreased mortality and increased weight gain compared with infected unmedicated birds. Twenty-one days after infection, M gallisepticum was isolated from 96 per cent of unmedicated birds compared with only 6 per cent of danofloxacin-treated and 40 per cent of tylosin-treated birds, and the percentage showing positive serological tests was reduced from 100 per cent of unmedicated birds to 0 per cent of danofloxacin-treated and 29 per cent of tylosin-treated birds. In both cases, the proportion of positive birds from the danofloxacin-treated group was significantly lower than that from the tylosin-treated group. The occurrence of air sac lesions was also significantly lower in danofloxacin-treated than in tylosin-treated birds.


Endothelin-1 stimulates chloride secretion across canine tracheal epithelium. Although much attention has been paid to the effect of endothelin on the bronchopulmonary system, there are few reports concerning the effect of endothelin on Cl- secretion across airway epithelium. We examined the effects of endothelin-1, -2 and -3 on bioelectric parameters of canine tracheal epithelium, a tissue in which Cl- is actively secreted and Na+ is absorbed. Potential difference (PD) and short-circuit current (SCC) were measured using an Ussing chamber with 0.5 cm2 of exposed area, and conductance (G) was calculated by dividing SCC by PD. Luminal endothelin-1 produced transient increases in PD and SCC, returning to baseline values within 5 min after stimulation in a dose-dependent fashion and reached mean responses of 123 and 126% of baseline PD and SCC, respectively, at 10(-6) M of endothelin-1, whereas submucosal endothelin-1 did not alter PD and SCC. G remained unchanged when stimulated by endothelin-1. Endothelin-2 and -3 did not produce any significant alterations in PD and SCC. Endothelin-1 evoked increases in PD and SCC, which were not altered by pretreatment with luminal amiloride (10(-4) M), or by treatment with submucosal propranolol (10(-5) M). Ionic substitution of Cl- with nontransported anions, iodide and gluconate, inhibited endothelin-1-induced increases in PD and SCC. Pretreatment with 10(-5) M indomethacin partially inhibited Endothelin-1-evoked increases in PD and SCC. These findings indicate that endothelin-1 stimulates Cl- secretion partially through the generation of cyclooxygenase products of arachidonic acid.


Macrophage activation by OM-85 BV.

Macrophage activation by OM-85 BV. Peritoneal or bone-marrow-derived murine macrophages were exposed for 24 h in vitro to dilutions of the bacterial extract OM-85 BV, in the presence or absence of other added compounds [macrophage-activating factor (MAF), recombinant murine interferon-gamma (IFN-gamma)]. Various metabolic responses and functional activities were then measured. Glucose oxidation through the hexose monophosphate shunt pathway was markedly stimulated in OM-85 BV-treated macrophages compared to control macrophages. Similarly, OM-85 BV primed macrophages for superoxide production upon triggering by phorbol myristate acetate. Both effects were further enhanced by simultaneous treatment of the cells with MAF with OM-85 BV. The bacterial extract also induced macrophages to release large amounts of nitrite (a marker of the activated state). As regards functional responses, coincubation with MAF and OM-85 BV activated macrophages to destroy target cells as well as intracellular microorganisms; in the latter case, similar results were obtained when MAF was replaced by IFN-gamma. In all these tests, the possibility that the observed effects were due to contamination of the bacterial extracts by endotoxin could be excluded. The above results indicate that OM-85 BV induces metabolic and functional properties in macrophages that are characteristic of the activated state and are important for host defence.


Video recording of cardiac arrest management: an aid to training and audit. A video camera and microphone are used to record the management of cardiac arrests in the accident and emergency department. The recordings provide a useful tool for training and audit.


Multifocal cerebral blood flow by Xe-CT and global cerebral metabolism after prolonged cardiac arrest in dogs. Reperfusion with open-chest CPR or cardiopulmonary bypass. Using the stable xenon-enhanced computed tomography (Xe-CT) method in dogs, we studied local, regional and global cerebral blood flow (LCBF, rCBF and gCBF) in two sham experiments and nine cardiac arrest experiments. Within the same experiments without arrest, gCBF and rCBF values were reproducible and stable. LCBF values varied over time. In group I (n = 4), ventricular fibrillation cardiac arrest (no blood flow) of 10 min was reversed by open-chest cardiopulmonary resuscitation (CPR). In group II (n = 5), ventricular fibrillation cardiac arrest of 12.5 min was reversed by brief closed-chest cardiopulmonary bypass. This was followed by controlled ventilation, normotension, normoxia, normocarbia and normothermia to 4 h (n = 7) or 20 h (n = 2) postarrest. The postarrest CBF patterns were similar in both groups. Open-chest CPR during ventricular fibrillation generated near-baseline gCBF and lower LCBF ranges. During postarrest spontaneous circulation, transient diffuse hyperemia was without low-flow regions, longer in brain stem and basal ganglia than in neocortex. During delayed hypoperfusion at 1-4 h postarrest (n = 9), mean gCBF was 44-60% baseline, rCBF in primarily gray matter regions was 15-49 ml/100 cm3 per min and LCBF voxels with trickle-flow and low-flow values, in percent of CT cut area, were increased over baseline. Global CMRO2 (n = 3 of group II) recovered to near baseline values between 1 and 4 h postarrest, while gCBF and O2 delivery were about 50% baseline (mismatching of O2 uptake and O2 delivery).


A study of school students' long term retention of expired air resuscitation knowledge and skills. This study addresses the issue of the long term retention of Expired Air Resuscitation (EAR) knowledge and skills. The subjects were one hundred and two secondary school students, half of whom had received training in EAR procedures 5 years prior to this study. Data were collected from these subjects in relation to their knowledge of the EAR procedures and their ability to implement these procedures. In general the students who had undergone the EAR training 5 years ago performed better in the practical tasks than did their untrained counterparts. While there was virtually no difference in the theoretical knowledge section overall, the trained group did perform better on a number of questions.


Knowledge, skills and counselling behaviour of Belgian general practitioners on CPR-related issues. General practitioners (GP) can identify potential cardiac arrest victims. They have the opportunity to inform cardiac patients and their families about the risk of sudden cardiac death and can motivate family members to attend a CPR-course. To study actual counselling practices concerning basic CPR-training a questionnaire was mailed to a representative sample of Belgian GPs (n = 1119). The level of CPR-training of the GPs was fairly good: 67% had received BLS training on a manikin and 63% had already attended a cardiac arrest event. A discrepancy was observed between the positive attitude towards CPR and the counselling of family members to attend a CPR-course (9%). GPs feared to inflict additional stress to the patient (32%) or the family (43%) or did not know where CPR courses were organised (37%). GPs are a primary target group for CPR-training and should learn how to counsel potential bystanders of a cardiac arrest to attend a CPR-course without inflicting additional anxiety on the patient or his family.


The role of central venous oximetry, lactic acid concentration and shock index in the evaluation of clinical shock: a review. Initial therapy of shock in the emergency department emphasizes the normalization of hemodynamic variables e.g. heart rate (HR), mean arterial pressure (MAP), central venous pressure (CVP) rather than optimization of systemic and regional oxygenation. Central venous oximetry (ScvO2), arterial lactic acid concentrations (Lact) and the shock index (SI) were examined during initial hemodynamic stabilization of clinical shock in the emergency room. Although initial therapy normalized MAP, CVP and HR; ScvO2, Lact and SI continued to be abnormal indicating inadequate systemic oxygenation and left ventricular (LV) performance. Measurement of ScvO2, Lact and SI may provide valuable additional information on the adequacy of systemic oxygenation and LV function during initial therapy of shock. This may identify patients who require further monitoring and intervention to optimize systemic oxygen transport and cardiac performance and reduce their morbidity and mortality.


Use of open chest cardiopulmonary resuscitation after failure of standard closed chest CPR: illustrative cases. Compared to standard closed chest CPR, open chest cardiac massage improves vital organ perfusion and survival in animal models of medical cardiac arrest. Yet its use is essentially limited to the treatment of traumatic arrest. Three cases of medical cardiac arrest are presented in which open chest compression was used after failure of external chest compression. These cases illustrate the range of potential outcomes and how this therapy can be optimally applied. Approaches we have used to prevent application of futile intensive therapy in patients unlikely to be neurologically intact survivors are described. Replacement of open chest CPR by closed chest CPR as the standard of care for the in-hospital cardiac arrest was not justified by experimental data. The circumstances of refractory cardiac arrest make it unlikely that well controlled human studies will be able to demonstrate the superiority of open chest CPR in selected patients. The decision to use this therapy will likely remain within the art of medicine.


Resuscitation training for cardiac patients and their relatives--its effect on anxiety. It is feared by many doctors that teaching basic life support (BLS) to high risk cardiac patients or a member of the family increases their anxiety. We trained a group of patients with recurrent ventricular tachycardia in BLS together with a friend or family member. Measurement of anxiety before and three months after training demonstrated a reduction in anxiety in both groups. This suggests that basic life support training can be targeted to high risk groups without fear of increasing anxiety.


Efficacy of out of hospital defibrillation by ambulance technicians using automated external defibrillators. The Heartstart Scotland Project. During the Heartstart Scotland project all 407 ambulances in Scotland were equipped with automated external defibrillators (AEDs). All cases of chest pain or collapse aged over 10 years were monitored and multiple 3-s rhythm strips recorded in a solid state memory module. A shockable rhythm was defined as an organised rhythm of > or = 180 beats/min or a disorganised rhythm of > or = 100 beats/min and amplitude > 0.1 mV. We analysed all the stored rhythm strips in two patient populations to determine the ability of the AED and ambulance crews to detect a shockable rhythm and to initiate appropriate defibrillation. The first population comprised 493 patients, all of whom had received shocks. A total of 4741 rhythm strips were analysed, of which 1461 were true positives, 33 false positives, 3161 true negatives and 86 false negatives. Overall sensitivity of the AED was 94.4% and specificity 99.0%. The second population comprised a random sample of 200 shocked and 200 non-shocked arrests. The combined group contained 4154 rhythm strips of which 562 were true positives, 12 false positives, 3460 true negatives and 120 false negatives. Overall sensitivity of the system (AED+crew) was 82.4% and specificity 99.7%. However, only 66 of the 120 false negatives were attributable to the AED giving a sensitivity of 90.3% for the AED. The sensitivity of the AED is dependent on the prevalence of shockable rhythms, but will be within the range 90.3-94.4% for most emergency medical services. We conclude that early management of potentially lethal arrhythmias by ambulance technicians using AEDs is practical with acceptable sensitivity and specificity.


Viral pneumonia in the immunocompromised adult with neoplastic disease: the role of common community respiratory viruses. Until recently, the viruses most often identified in lower respiratory tract infections among immunocompromised adults with neoplastic disease have been the herpesviruses (cytomegalovirus, herpes simplex virus, varicella-zoster virus, human herpesvirus-6) and adenovirus. These viral pneumonias occur with greater frequency and/or severity among these adults than among immunocompetent adults. During the last decade, mounting evidence has suggested that the RNA viruses that commonly cause lower respiratory tract disease in the general population, namely influenza virus, respiratory syncytial virus, and parainfluenza virus, are also an important cause of serious community-acquired and nosocomial lower respiratory tract disease among immunocompromised adults. Because these infections are associated with considerable morbidity and mortality and are potentially preventable and treatable, it is important that they be recognized and treated promptly. Various therapies have been tried with some reported success, including amantadine (specifically for influenza A), ribavirin, and intravenous immunoglobulin. The optimal therapy or combination of therapies for these infections among immunocompromised adults remains to be defined in controlled trials.


Analysis of aberrations in public health surveillance data: estimating variances on correlated samples. The detection of unusual patterns in health data presents an important challenge to health workers interested in early identification of epidemics or important risk factors. A useful procedure for detection of aberrations is the ratio of a current report to some historic baseline. This work addresses the problem of finding the variance of such a ratio when the surveillance reports are correlated. Results show that, when estimating this variance or the variance of the sample mean from a series of observations with an estimated correlation structure, bootstrap and jackknife estimates may be overly optimistic. The delta method or a classical method may be more useful when such model dependence is inappropriate.


[Small-cell lung cancer: survival analysis over the last 10 years: 1980-1990]. A review of 269 papers published between 1980 and 1990 has been performed in order to evaluate the median survival (MS) of patients with small cell lung cancer (SCLC) in relationship with different therapeutic modalities. We found that therapies with cisplatin and etoposide were associated with a significantly longer MS than those without these drugs. Alternating regimens, short therapies (< or = 6 months) and maintenance treatments have a similar MS. Initial and late intensification does not significantly prolong the MS as compared to conventional treatments. Neither radiation therapy to the chest and/or to the brain does increase the MS. Overall, MS of patients with limited SCLC is significantly longer than that of patients with extensive disease.


[Oligodendroglial inclusions, a marker of multisystemic atrophies]. Nine cases of multiple system atrophy and 1 case of autosomal dominant olivopontocerebellar atrophy (neuropathological diagnosis) were retrospectively examined for the presence of oligodendroglial inclusions. Clinical diagnosis in the first 9 cases had been: olivopontocerebellar atrophy (3 cases), atypical Parkinson's disease (2 cases), Shy-Drager syndrome (2 cases) and multiple system atrophy (1 case); one of the patients could not be included in any of the above mentioned groups. The oligodendroglial inclusions were argyrophilic and located in the cytoplasm around the nucleus. They were revealed by Bodian's method in all cases of multiple system atrophy. They were not found in the case of autosomal dominant olivopontocerebellar atrophy. They were labelled by anti-ubiquitin antibodies, and were negative with anti-tau antibodies. At electron microscopy, they consisted of rectilinear profiles coated with a fuzzy material (diameter: 20-33 nm); this aspect was compatible with microtubules. Oligodendroglial inclusions were prominent in regions selectively vulnerable in multiple system atrophy (tegmentum pontis, putamen, inferior olives, substantia nigra and cerebellar white matter), even in those areas where neuronal loss or fascicular atrophy were minimal or absent. They were also observed in regions considered to be spared in multiple system atrophy, such as the motor cortex and the corpus callosum. Argyrophilic oligodendroglial inclusions are an early and specific marker of multiple system atrophy. It is suggested that autosomal dominant olivopontocerebellar atrophy lacking oligodendroglial inclusions does not belong to multiple system atrophy.


Clinical, histologic and genetic characterization of non-Hodgkin's lymphomas in Mexicans. We describe the anatomical distribution, histological and molecular characteristics of 32 cases of NHL. Staging of the NHL was made according to conventionally accepted schemes. Histologically the NHL were classified in grades following the criteria defined by the Working Formulation. Rearrangements in one or more Ig or TcR receptor genes were detected in Southern blots and allowed us to determine the cell type and stage of differentiation. Serological analysis of 26 serum samples revealed the existence of antibodies against EBV epitopes; eight of these patients carried viral sequences in the tumor genome as determined by slot blot hybridization. Our studies indicate that the use of various methods is of paramount importance in order to improve our understanding of the natural history of NHL.


[Inclusion body myositis and neuromuscular diseases with rimmed vacuoles]. A retrospective study of 40 patients with various neuromuscular disorders and more than 3 muscle fibers with rimmed vacuoles has been performed. Two subgroups of patients were distinguished according to the presence or absence of inflammatory exudates. In the first group (14 patients), inflammatory exudates were observed and numerous fibers showed partial invasion. Abnormal filamentous inclusions (16-18 nm in diameter) were found by electron microscopy in muscle fibers cytoplasm and/or nuclei. The diagnosis of inclusion body myositis (IBM) was made in these cases. They presented with insidious proximal muscle weakness and were not improved by immunosuppressive therapy. Immunohistological studies demonstrated T lymphocytes predominance, only few natural killer and B lymphocytes. The number of T8 lymphocytes was high in endomysial sites while T4 were more numerous in perivascular exudates. Abnormal membranous expression of class I MHC antigens was observed on muscle fibers lying near the inflammatory exudates. In the second group of cases (26 patients), no inflammatory exudate was observed. This group of neuromuscular diseases with rimmed vacuoles was heterogeneous. In 10 cases, abnormal filamentous inclusions (16-18 nm in diameter) were observed in rimmed vacuoles. However, this ultrastructural feature did not help in distinguishing subgroups. Various neuromuscular disorders were observed in this group: oculopharyngeal muscular dystrophy (12 cases with IBM like filaments in 4 cases), chronic spinal atrophy (5 cases with IBM like filaments in 3 cases), post poliomyelitis syndrome (2 cases with IBM-like filaments in one), muscle glycogenosis with IBM like filaments (2 cases), hereditary limb girdle myopathy or distal myopathy (3 cases) and 1 patient clinically presenting with polymyositis and another with cramps and myalgias. No abnormal sarcolemmal expression of class I MHC was found in this group. The pathogenesis of IBM is discussed. Besides T cell mediated cytotoxicity, denervation may be involved. The nature of the abnormal 16-18 nm filamentous inclusions remains unknown. These filaments are not IBM specific.


[Metabolic acidosis in severe acute asthma. Effect of alkaline therapy]. Respiratory acidosis of severe acute asthma is a severity factor. In this paper the treatment of associated metabolic acidosis is discussed. Among 34 consecutive episodes of severe acute asthma with acidosis (pH < 7.35) treated with continuous adrenaline perfusion, theophylline and hydrocortisone hemisuccinate, respiratory acidosis was observed in 12, metabolic acidosis in 2 and mixed respiratory and metabolic acidosis in 20. The association of hypercapnic acidosis with hypochloraemic acidosis reflected a time of installation longer than when respiratory acidosis only was present (p < 0.05). Among the 22 patients who had metabolic acidosis on admission, 14 were treated with 168 +/- 82 mmol of sodium bicarbonate, the remaining 8 patients being untreated and acting as controls. The rapidity with which pH was corrected was the same in the treated and untreated groups (9.1 +/- 5.5 hours vs 6.7 +/- 3.7 hours), whereas dyspnoea (respiratory rate < 18/min) was more rapidly corrected in the treated group that in controls (11.6 +/- 5.7 hours vs 5.9 +/- 5.9 hours; p < 0.05). It is concluded that in more than 50% of the cases respiratory acidosis of severe acute asthma is associated with a metabolic acidosis. Correcting this metabolic acidosis with sodium bicarbonate results in improvement of respiration, perhaps by facilitating the action of bronchodilator catecholamines.


Utilization of hearing aids issued by the public health service. Hearing aid use in Ribe County, Denmark. A prospective survey was carried out to evaluate the efficiency of public audiological rehabilitation. Two hundred and fifty-four of 256 consecutive patients were interviewed six months after hearing aid issue. One hundred and sixty-eight (66%) were full-time users, 225 (88%) wore an aid either all the time or every day. Eight were successful situational users, while 21 (8%) were non-users. Eighty-six of the 233 users (37%) made use of their telecoil. Of a total of 363 aids dispensed, 26 (7%) were out of use. Experienced users differed significantly from first-time users: they had poorer hearing, they used their aids more than first-time users and they were more often treated binaurally.


Sorbitol in isolation of rat pancreatic islets. Effects on islet yield, insulin secretion and accumulation of inositol phosphates. Tissue aggregation and exocrine contamination are problems encountered in gradient separation of pancreatic islets. Here we report that sorbitol used as an osmotic component in Percoll gradients gives a low ionic strength gradient with improved purity of islet fraction, less islet aggregation and reduced time for final manual rinsing following separation in gradients with NaCl as osmotic component. Previous reports have indicated that long-term (weeks) exposure to high sorbitol concentrations leads to low intracellular levels of inositol phosphates and subsequent effects on the intracellular signal transduction in cells. In our model, short-term exposure to high sorbitol concentrations had no effect on the accumulation of the inositol phosphates or insulin secretion caused by glucose. On the other hand, sorbitol increased the basal insulin secretion three-fold, apparently via a non-stimulatory mechanism. Therefore, we conclude that sorbitol is preferable to NaCl as the osmotic component in Percoll gradient separation of rat pancreatic islets, although long-term exposure should be avoided due to potential toxic effects.


The control of anti-coagulation in acute dialyses with sensitive laboratory parameters. In seven patients who had to be dialysed between four and 13 times due to acute renal failure, low molecular weight heparin (LMWH) Fragmin was used for anticoagulation. According to dose-finding studies, 80-90 U kg-1 body weight of LMWH as a single bolus were administered initially, producing dose-related levels of 0.3-1.5 anti-factor Xa U ml-1 in plasma. Apart from the anti-Xa activity in the plasma, the thrombin anti-thrombin III complex (TAT complex) and a fibrin degradation product (D-dimer) were measured as parameters of a coagulation activation. A sufficient anti-coagulation during dialysis was supposed to exist at a normal range (5.0 micrograms l-1 or below) of TAT complex. Pathological TAT concentrations at the end of dialysis indicated the requirement of an increased dose for the next dialysis. These concentrations reflected a need for more heparin if, for example, inflammation, indicated by increasing C-reactive protein levels (CRP), occurred. The increase of TAT complex and D-dimer during dialysis showed a good agreement (p less than 0.001). Due to a single bolus application before dialysis, one measurement of TAT at the end of the dialysis was sufficient. The determination of the TAT complex concentration enabled a heparinization better adapted to the clinical situation of intensive-care patients undergoing acute dialyses, so that the coagulation system was not additionally activated by the extracorporeal circulation.


The lipoxygenase inhibitor nafazatrom inhibits stimulated prolactin secretion in cultured rat lactotrophs (GH4C1 cells). Arachidonic acid metabolites are involved in the regulation of prolactin (PRL) secretion from rat lactotrophs (GH4C1 cells). Phospholipase A2 (PLA2) stimulated PRL secretion, while the PLA2 inhibitor quinacrine reduced both thyrotropin-releasing hormone (TRH) and vasoactive intestinal peptide (VIP) stimulated PRL release. Hormonally stimulated PRL release was further increased in the presence of the cyclo-oxygenase inhibitor indomethacin. Nafazatrom, a lipoxygenase inhibitor, reduced stimulated PRL secretion regardless of the mechanism of stimulation [hormonally (VIP and TRH) or by increasing intracellular Ca2+ concentration by KCl or Bay-K and cAMP by forskolin]. None of the inhibitors used in this study had any effect either on the basal PRL secretion or on the production of cAMP. Lipoxygenase products seem to be involved in the regulation of PRL secretion, probably by affecting a late step in the signal transduction.


Effect of calcium on oxalate uptake and transport by the rat intestine. The effect of calcium concentration (0-10 mmol 1(-1)) on oxalate uptake and transport was investigated in vitro using everted gut segments and sacs. Increase in calcium concentration in the incubation medium led to an increase in the amounts of precipitated oxalate on the intestine; however, the net oxalate flux to the serosal side decreased. The ions, i.e. Ca2+, Ox2-, H2PO4-, HPO4(2-), present in the incubation medium favoured formation of hydroxyapatite and calcium oxalate crystals, as evidenced by Equil II analysis and free energy of the system. The nature of precipitates was confirmed by elemental analysis, X-ray diffraction spectrometry and electron microscopy. Oxalate precipitated on the intestine following incubation with calcium could be released into a calcium- and oxalate-free medium. Animals fed oxalate in the absence and presence of calcium revealed that, during 1 h in the absence of calcium, oxalate moved down the intestinal tract as a distinct peak of greater than 50% (70-90 cm in the intestine), leaving less than 10% in the stomach and first 50 cm of the intestine. In the case of animals fed calcium along with oxalate, 35% of the oxalate was still present in the stomach, and the amounts of oxalate in the intestinal segments gradually increased from 4.5% to 21.7% (0-90 cm) and dropped to 2.1% in the next 20 cm. Since oxalaemia and oxaluria appear to be influenced by intestinal oxalate absorption, the present observations may help to improve understanding of the pathophysiology of disorders exhibiting altered oxalate metabolism.