Neurosarcoidosis: radiologic features in five patients.

This paper describes the radiological features in five biopsy-confirmed cases of neurosarcoidosis. The imaging appearance of neurosarcoidosis is highly variable, making the diagnosis difficult on the basis of intracranial images alone. However, if there is evidence of spread along the pia mater, and meningeal mass formation with a lower intensity in the central area and higher intensity in the peripheral area on T2-weighted and FLAIR images, neurosarcoidosis can be considered.

Migration of 4-nonylphenol from polyvinyl chloride food packaging films into food simulants and foods.

Migration of 4-nonylphenol (NP) from polyvinyl chloride (PVC) films for food packaging into food simulants and foods has been studied in domestic applications such as wrapping of food and reheating in a microwave oven. The migration of NP from the PVC films was determined by high-performance liquid chromatography with electrochemical coulometric-array detection (LC/ED). Twelve PVC films intended for commercial use and ten for domestic applications (total: 22 samples) were analysed. Some of the PVC films (two home-use and ten retail-use) contained NP at concentrations of between 500 and 3300 microg/g. Migration of NP from the films was influenced by the test conditions (n-heptane at 25 degrees C for 60 min, distilled water at 60 degrees C for 30 min and 4% acetic acid at 60 degrees C for 30 min). The amount of NP migrating from the PVC films into n-heptane (0.33-1.6 microg/cm2) was higher than the amount migrating into distilled water or 4% acetic acid (up to 9.7 ng/cm2) for the 11 films in which NP was detected. Up to 0.23% of the NP migrated into distilled water and 4% acetic acid and up to 62.5% into n-heptane. In addition, we investigated NP migration into cooked rice samples wrapped in PVC film. Using spiked samples the method gave an average recovery of 83.7% (n = 5) with a standard deviation of 2.5%. Migration of NP ranged from not detectable (< 1.0 ng/g) to 410.0 ng/g by reheating samples in a microwave oven for 1 min and from not detectable to 76.5 ng/g by keeping samples at room temperature for 30 min.

Antioxidant and pro-oxidant actions of flavonoids: effects on DNA damage induced by nitric oxide, peroxynitrite and nitroxyl anion.

Antioxidant and pro-oxidant activities of flavonoids have been reported. We have studied the effects of 18 flavonoids and related phenolic compounds on DNA damage induced by nitric oxide (NO), peroxynitrite, and nitroxyl anion (NO-). Similarly to our previous findings with catecholamines and catechol-estrogens, DNA single-strand breakage was induced synergistically when pBR322 plasmid was incubated in the presence of an NO-releasing compound (diethylamine NONOate) and a flavonoid having an ortho-trihydroxyl group in either the B ring (e.g., epigallocatechin gallate) or the A ring (e.g., quercetagetin). Either NO or any of the above flavonoids alone did not induce strand breakage significantly. However, most of the tested flavonoids inhibited the peroxynitrite-mediated formation of 8-nitroguanine in calf-thymus DNA, measured by a new HPLC-electrochemical detection method, as well as the peroxynitrite-induced strand breakage. NO- generated from Angeli's salt caused DNA strand breakage, which was also inhibited by flavonoids but at only high concentrations. On the basis of these findings, we propose that NO- and/or peroxynitrite could be responsible for DNA strand breakage induced by NO and a flavonoid having an ortho-trihydroxyl group. Our results indicate that flavonoids have antioxidant properties, but some act as pro-oxidants in the presence of NO.

Synergistic induction of DNA strand breakage by catechol-estrogen and nitric oxide: implications for hormonal carcinogenesis.

Estrogen is a known risk factor for human breast cancer, although the mechanism by which estrogens induce cancer remains unestablished. We have demonstrated that DNA strand breakage is induced synergistically when pBR322 plasmid DNA is incubated in the presence of both a nitric oxide (NO)-releasing compound (diethylamine NONOate, etc.) and a catechol-estrogen (2- or 4-hydroxyestradiol or -hydroxyestrone). Either the NO-releasing compound or the catechol-estrogen alone induced much fewer strand breaks. Estradiol, estrone, O-methylated catechol-estrogens, and diethylstilbestrol did not exert such DNA damaging effects. Strand breakage induced by NO plus 2- or 4-hydroxyestradiol was inhibited by carboxy-PTIO (an NO-trapping agent) and, to a lesser extent, by superoxide dismutase. Antioxidants (e.g., N-acetylcysteine, ascorbate), but not HO. scavengers, exhibited inhibitory effects. A possible mechanism for this strand breakage would be: (1) NO mediates conversion of catechol-estrogens to quinones, (2) the quinone/hydroquinone redox system produces O2.-, and (3) O2.- reacts with NO to form peroxynitrite, which causes DNA strand breaks. Our results imply that interaction of catechol-estrogens and NO, both known to be formed in human breast and uterus, leads to production of a potent oxidant(s), which could cause damage in cells and DNA, thus playing an important role in hormonal carcinogenesis.

Synergistic induction of DNA strand breakage caused by nitric oxide together with catecholamine: implications for neurodegenerative disease.

Oxidative damage in neuronal cells and DNA has been implicated in the pathogenesis of various neurodegenerative diseases. We have demonstrated that DNA strand breakage is induced synergistically when plasmid DNA is incubated in the presence of both an NO-releasing compound (diethylamine NONOate, spermine NONOate, sodium nitroprusside) and a catecholamine (e.g., L-DOPA, dopamine, etc.). Either an NO-releasing compound or a catecholamine alone induced much fewer strand breaks. Tyrosine and tyramine as well as O-methylated derivatives of DOPA and dopamines did not exert this synergistic effect in the presence of NO. The DNA strand breakage induced by NO plus dopamine was inhibited by carboxy-PTIO (a trapping agent of NO and possibly other radicals), superoxide dismutase, and antioxidants such as N-acetylcysteine and ascorbate but not by HO. scavengers such as dimethyl sulfoxide, ethanol, and D-mannitol. These results suggest that the free HO. is not involved; rather a new oxidant(s) formed by the reaction between NO and catecholamine could be responsible for causing the DNA strand breakage. We propose that one of the responsible compounds is peroxynitrite (ONOO-), which is a strong oxidant and nitrating agent formed by the reaction between NO and O2.-. NO has been shown to oxidize catecholamines to form quinone derivatives, which lead to the generation of O2.- by the quinone/hydroquinone redox system. O2.- then reacts rapidly with NO to form peroxynitrite. However, it is also possible that other compounds such as NOx generated from catecholamines and NO may cause DNA damage. Our results implicate a synergistic interaction of catecholamines formed in dopaminergic neurons and NO formed by microglia or astrocytes or the two compounds produced within the same neuronal cells to produce a potent oxidant(s) which could cause damage in cells and DNA, thus playing an important role in the pathogenesis of various neurodegenerative diseases.

Synergistic induction of DNA strand breakage by cigarette tar and nitric oxide.

Cigarette smoking is a major cause of human cancer at a variety of sites, although its carcinogenic mechanisms remains unestablished. Cigarette smoke can be divided into two phases, gas phase and particulate matter (tar). Both phases contain high concentrations of oxidants and free radicals, especially nitric oxide (NO) and nitrogen oxides in the gas phase and quinone/hydroquinone complex in the tar. We have found that incubation of pBR322 plasmid DNA with aqueous extracts of cigarette tar and a NO-releasing compound (diethylamine NONOate) caused synergistic induction of DNA single-strand breakage, whereas either cigarette tar alone or NO alone induced much less strand breakage. This synergistic effect of cigarette tar and NO on DNA strand breakage was prevented by high concentrations of superoxide dismutase, carboxy-PTIO (an NO-trapping agent) or N-acetylcysteine, whereas hydroxyl radical scavengers such as dimethylsulfoxide, ethanol and D-mannitol did not show inhibitory effects. Possible mechanisms for this synergistic effect mediated by cigarette tar and NO are proposed, including involvement of peroxynitrite, which is a strong oxidant and nitrating agent formed rapidly by the reaction between NO and O2.-. NO is present in the gas phase of smoke and may be formed by a constitutive or inducible NO synthase in the lung, whereas O2.- is generated by auto-oxidation of polyhydroxyaromatic compounds such as catechol and 1,4-hydroquinone present in cigarette tar. Thus, potent reactive species including peroxynitrite formed by the interaction between cigarette tar and NO may play an important role in smoking-related diseases including lung cancer.

Nitric oxide synergistically enhances DNA strand breakage induced by polyhydroxyaromatic compounds, but inhibits that induced by the Fenton reaction.

Reactive oxygen and nitrogen species play an important role in many human diseases including cancer. We have found that incubation of pBR322 plasmid DNA with a nitric oxide (NO)-releasing compound such as diethylamine NONOate and a polyhydroxyaromatic compound such as catechol, 1,4-hydroquinone, or pyrogallol caused synergistic induction of single-strand breakage, whereas either compound alone induced much less breakage. Phenol, resorcinol, or guaiacol (O-methylcatechol) did not exhibit this synergistic effect of DNA damage with NO. The strand breakage induced by NO with pyrogallol was prevented by excess superoxide dismutase, carboxy-PTIO (an NO-trapping agent), or anti-oxidants (urate, ascorbate). Possible mechanisms for the induction of this synergistic effect of NO and polyhydroxyaromatic compounds on the strand breakage are proposed, including involvement of peroxynitrite formed from NO and O2.- derived from autooxidation of polyhydroxyaromatics. This pathway for generation of reactive species from NO and catechol-type compounds (e.g., L-dopa, catechol-estrogen) may be important in many pathological conditions, because both compounds are concurrently formed or present in vivo. On the other hand, NO dose-dependently inhibited the strand breakage mediated by 1,4-hydroquinone plus Cu2+ or Fenton reaction (H2O2, iron or copper). This inhibition could be due to formation of a complex between NO and a metal ion, inhibiting generation of reactive species from H2O2. Our results can account for contrasting activities of NO reported in relation to tissue injury. NO can play both detrimental and beneficial roles in DNA damage, depending on the type and amounts of reactive oxygen species and metal ions concurrently present.

Effects of carbon dioxide/bicarbonate on induction of DNA single-strand breaks and formation of 8-nitroguanine, 8-oxoguanine and base-propenal mediated by peroxynitrite.

Carbon dioxide has been reported to react with peroxynitrite (ONOO-), a strong oxidant and nitrating agent, to form an ONO2CO2- adduct, altering the reactivity characteristic of peroxynitrite. We found that bicarbonate (0-10 mM) caused a dose-dependent increase of up to 6-fold in the formation of 8-nitroguanine in calf-thymus DNA incubated with 0.1 mM peroxynitrite, whereas it produced no apparent effect on 8-oxoguanine formation. In contrast, bicarbonate inhibited peroxynitrite-induced strand breakage in plasmid pBR322 DNA and thymine-propenal formation from thymidine. We conclude that C02/HCO3- reacts with peroxynitrite to form a potent nitrating agent, but also to inactivate hydroxyl-radical-like activity of peroxynitrous acid.

Hormone-sensitive adenylate cyclase system in lymphocytes from asthmatic patients: possible defects at the postreceptor sites.

To clarify the mechanism of beta adrenergic hyporesponsiveness, which is related to bronchial hypersensitivity in asthmatic patients, cAMP responsiveness in peripheral lymphocytes was examined. The cAMP response to isoproterenol significantly decreased in the lymphocytes from asthmatics compared with those from healthy subjects. In contrast, the responses to GTP, Gpp(NH)p (a GTP analogue), sodium fluoride, and forskolin (a direct stimulator of the catalytic unit) were similar between the two groups. These results suggest that impairment of the stimulatory GTP binding protein or the catalytic unit is not the major cause of beta adrenergic hyporesponsiveness in asthma, and that hyporesponsiveness may be due to other mechanisms in the hormone-sensitive adenylate cyclase system.

Inhibitory effect of midaglizole on alpha adrenoceptor agonist-induced contractions of canine tracheal smooth muscle.

To determine why midaglizole is effective in some patients with severe asthma, we investigated the inhibitory effects of midaglizole, prazosin or yohimbine on the BHT 920-, phenylephrine-, or noradrenaline-induced contractions of canine tracheal smooth muscle. After pretreatment with atropine (10(-6) M) and propranolol (10(-6) M) and precontraction with serotonin (3 x 10(-7) M), the tracheal muscle showed contractile responses to the exogenous administration of both alpha 1 and alpha 2 adrenoceptor agonists. Every alpha antagonist inhibited these agonist-induced contractions. Inhibitory activity of midaglizole (10(-4) M) for the alpha agonists was BHT-920 greater than noradrenaline greater than or equal to phenylephrine, while that of prazosin (3 x 10(-6) M) was phenylephrine greater than noradrenaline greater than BHT-920. Moreover, yohimbine completely inhibited the contractions at the lower concentration of 3 x 10(-7) M than that of other two antagonists. Our findings demonstrate that midaglizole dose-dependently inhibits airway contractions induced by alpha adrenoceptor agonists.

A refractory type asthmatic whose symptoms markedly improved by midaglizole.

We present a patient with refractory intrinsic asthma who showed a good response to both a single oral dose and a 4-week period of administration of the selective alpha-2 adrenoceptor antagonist, midaglizole. After the single dose, bronchodilation was immediately observed. With continuous administration, the peak expiratory flow rate (PEFR) was increased and the total daily intake of aerosol was decreased in a dose-dependent fashion. These results suggest that the addition of midaglizole to the usual antiasthmatic agents can be of value in the management of refractory asthma.

The inhibitory effect of a selective alpha 2-adrenergic receptor antagonist on moderate- to severe-type asthma.

Midaglizole (DG-5128), a novel selective alpha 2-adrenergic receptor antagonist, was administered to 17 patients with moderate to severe asthma in a single-dose, double-blind, randomized, crossover study. All patients also continued their regular treatment regimens. FEV1 increased significantly (p less than 0.05), and respiratory resistance decreased significantly (p less than 0.05). Wheezing and dry rales on auscultation improved in patients receiving 200 mg of midaglizole, and their assessment of overall benefit was also significantly better (p less than 0.05). Blood pressure and heart rate were unaffected. However, plasma glucose levels fell slightly. This study demonstrated the bronchodilating effect of midaglizole in moderate to severe bronchial asthma. This selective alpha 2-adrenergic antagonist may prove to be a useful addition to current treatment regimens for asthma.

Pituitary and adrenal functions during late asthmatic responses.

The purpose of the present study was to examine the role of low cortisol levels which were observed during late asthmatic responses (LAR). Selective functions of the adrenals and pituitary glands were studied in three groups of asthmatics who showed LAR, immediate asthmatic responses (IAR), and DAR (dual asthmatic responses). Serial plasma ACTH levels in each group showed no apparent abnormalities when compared with diurnal levels. The cortisol response to ACTH changed within the normal range in all three groups with minor differences. We suggest that low cortisol levels that appear during LAR are not principally due to any dysfunction in the pituitary adrenal system.

Inhibitory effect of DG-5128 on steroid-dependent asthma.

To study the possible role of alpha-2 receptors in intractable asthmatics, we investigated the ameliorative effects of 2-[2-(4,5-dihydro-1H-imidazol-2-yl)-1-phenylthyl]pyridine dihydrochloride sesquihydrate (DG-5128) on 10 steroid-dependent asthmatic patients. The forced expiratory volume in 1 second (FEV1) and the respiratory resistance (Rrs) were measured 1, 2, and 3 hours after oral administration of 200 mg DG-5128 and compared with the premedication measurements. Two hours after DG-5128 administration, the FEV1 rose significantly (p less than 0.01) and the Rrs decreased significantly (p less than 0.05). Asthmatic symptoms (cough, wheezing, dyspnea) also improved in 80% of the patients. This finding raises the possibility that alpha-2 adrenoceptors exist in human airways, that they play an important role in the pathophysiology of asthma, and that the overfunction of these alpha-2 adrenoceptors and/or Gi-protein cause intractable asthma.