Bernhard M. W. Schmidt

Rapid, nongenomic steroid actions: A new age?

In the traditional theory of steroid action, steroids bind to intracellular receptors and modulate nuclear transcription after translocation of steroid-receptor complexes into the nucleus. Due to similarities of molecular structure, specific receptors for steroids, vitamin D(3) derivatives, and thyroid hormone are considered to represent a superfamily of steroid receptors. While genomic steroid effects characterized by their delayed onset of action and their sensitivity to blockers of transcription and protein synthesis have been known for several decades, rapid actions of steroids have been more widely recognized and characterized in detail only recently. Rapid effects of steroids, thyroid hormones, and the steroid hormone metabolite of vitamin D(3), 1alpha, 25-dihydroxyvitamin D(3), on cellular signaling and function may be transmitted by specific membrane receptors. Binding sites in membranes have been characterized, exposing binding features compatible with an involvement in rapid steroid signaling. Characteristics of putative membrane receptors are completely distinct from intracellular steroid receptors, a fact which is further supported by the inability of classic steroid receptor antagonists to block nongenomic steroid actions. A putative progesterone membrane receptor has been cloned and functionally expressed with regard to progesterone binding. Development of drugs that specifically affect nongenomic action alone or even both modes of action may find applications in various, areas such as in the cardiovascular and central nervous systems and treatment of preterm labor, infertility, and electrolyte abnormalities.

Aldosterone, Not Estradiol, Is the Physiological Agonist for Rapid Increases in cAMP in Vascular Smooth Muscle Cells

BACKGROUND Steroid-induced gene regulation in the endocrine tissues and vascular wall is achieved through the interaction of specific receptor proteins and promoters of target genes. In addition to these delayed steroid actions, rapid effects of steroids have been reported in various tissues that were clearly incompatible with the classic theory of genomic steroid action. METHODS AND RESULTS Because high doses of 17beta-estradiol have been shown to modulate intracellular cAMP levels in vascular smooth muscle cells, steroid-induced stimulation of adenylate cyclase stimulation and phosphorylation of cAMP response element binding protein was investigated in porcine coronary artery vascular smooth muscle cells. Aldosterone induces a approximately 1.5- to 2.5-fold increase in intracellular cAMP levels (EC50 approximately 0.01 to 0.1 nmol/L) within 1 minute, whereas 17beta-estradiol and hydrocortisone act only at supraphysiological concentrations (10 micromol/L). Aldosterone-induced changes in intracellular cAMP are calcium dependent; they are not blocked by inhibitors of mineralocorticoid receptors, transcription, or protein synthesis. In addition, aldosterone induces a time-dependent phosphorylation of cAMP response element binding protein with potential transcriptional importance. CONCLUSIONS A nongenomic modulation of vascular smooth muscle cells by aldosterone is consistent with the data that aldosterone, not estrogen, is the physiological stimulus for cAMP.

The New Topical Steroid Ciclesonide Is Effective in the Treatment of Allergic Rhinitis

A randomized, placebo‐controlled, double‐blind crossover study was performed to investigate the efficacy of ciclesonide nasal spray in allergic rhinitis at the dose level of 200 μg per nostril. Twenty‐four subjects (13 males, 11 females; median age: 28 years) with a history of allergic rhinitis but free of symptoms at screening entered the study. Ciclesonide and placebo were given for 7 days each with a washout period of at least 14 days in between. In both treatment periods, controlled intranasal allergen provocation with pollen extracts was performed on the 2 days before start of treatment (days −2 and −1) and on all treatment days (days 1 to 7) about 2 hours after administration of the study medication. At 5 and 30 minutes after each allergen provocation, rhinal airflow was measured by anterior rhinomanometry, and the subjective symptoms of obstruction, itching, and rhinorrhea were assessed by means of a standardized visual analog scale. Rhinal airflow improved significantly from day 5, while the subjective symptom of obstruction improved from day 2. Itching and rhinorrhea also improved significantly. The local and systemic tolerability of ciclesonide nasal spray was excellent. The results of this study clearly indicate that the new topical steroid ciclesonide is effective in the treatment of allergic rhinitis without producing local or systemic side effects.

Experimental determination of ionization cluster size distributions in counting gases

The distribution of the number of electrons contained in the ionization clusters formed along the track of minimum ionizing particles has been determined experimentally. Results are presented for argon, helium, methane, ethane, propane, isobutane and carbon dioxide, i.e., for gases which are commonly used as counting gases in drift chambers. The probabilities w(n) for the formation of a cluster containing n electrons were found to be monotonically decreasing for increasing n. Typical values for w(1) are 0.66 (Ar), 0.77 (He), and 0.79 (CH4). The results are compared with model predictions.

MICROSTRIP GAS CHAMBERS : RECENT DEVELOPMENTS, RADIATION DAMAGE AND LONG-TERM BEHAVIOR

Abstract In the past years the technology of Microstrip Gas Chambers (MSGC) has made considerable progress offering a variety of possible new applications in various fields of research. MSGC are used to detect neutrons, X-rays, synchrotron radiation and VUV light as well as the full range of ionizing particles in nuclear and high energy physics. A variety of systematic studies led to a considerable increase in understanding of the functional principle and limiting parameters of the MSGC technology and enabled improved performances. In view of the large (HERA-B) and very large (CMS) detector systems planning to use MSGC in intense hadronic particle fluxes, the question of radiation hardness and long-term stability is of special importance. The problem of micro discharges, induced by heavy ionizing particles and destroying the electrode structure, turned out to be a major limitation to the applicability of MSGC in hadronic beams and demanded for new and revised solutions. The present status and future perspectives of the various technologies are discussed.

Drift properties of electrons in methane and methane noble gas mixtures

Abstract Drift velocities and longitudinal diffusion coefficients are measured with high precision for pure methane, for mixtures of methane with He, Ne, Ar, Kr and Xe as well as for some other molecular gases. From these data, the inelastic cross sections of methane could be determined for the first time. The momentum transfer cross sections of CH 4 and the noble gases were obtained as well, partially with significant deviations from previous measurements. Reliable predictions of the transport parameters in binary and ternary CH 4 noble gas mixtures are now possible.

Performance of the multianode cylindrical silicon drift detector in the CERES NA45 experiment: first results☆

Abstract A silicon drift detector of circular geometry giving unambiguously the radial and azimuthal coordinates of particles interaction point for events with high multiplicity is part of the experimental set up of the NA45 experiment at CERN SPS. The paper reviews the characteristics of the detector and of its assembly among the other detectors of the experiment. The first experimental results showing the performance of the detector in term of resolution and its effectiveness in reconstructing the position of the event are reported.

Delayed genomic and acute nongenomic action of glucocorticosteroids in seasonal allergic rhinitis

Background  Glucocorticosteroids are effective in the treatment of allergic rhinitis, a disease characterized by a variety of symptoms, e.g. rhinorrhea and itching. The time course of symptomatic relief for allergic rhinitis by steroids has not been examined in detail to date, although the onset of steroid action is one of the main discriminations between genomic and nongenomic actions of steroids. We therefore investigated the time course of subjective and objective measures of nasal affection after steroid administration in patients with allergic rhinitis following specific allergen challenge.

Electron motion in counting gases — New answers and new questions

Abstract An experimental method is described which allows the simultaneous measurement of drift velocity, longitudinal and transverse diffusion coefficients of electrons in counting gas mixtures. Results in CF 4 and argon/CF 4 are presented. In CH 4 and Ar/CH 4 mixtures the problems in the calculation of the transverse diffusion in molecular gases are discussed. An empirical formula which can be used for practical purposes has been derived. A comparison with recently published theoretical results suggests that a multiterm Boltzmann code could be the adequate formalism to calculate the motion of electrons in counting gas mixtures.

Studies of aging and HV break down problems during development and operation of MSGC and GEM detectors for the inner tracking system of HERA-B

Abstract The results of 5 years of development of the inner tracking system of the HERA-B experiment and first experience from the data taking period of the year 2000 are reported. The system contains 184 chambers, covering a sensitive area of about (20×20) cm 2 each. The detector is based on microstrip gas counters (MSGCs) with diamond-like coated (DLC) glass wafers and gas electron multipliers (GEMs). The main problems in the development phase were gas discharges in intense hadron beams and aging in a high radiation dose environment. The observation of gas discharges which damage the electrode structure of the MSGC led to the addition of the GEM as a first amplification step. Spurious sparking at the GEM cannot be avoided completely. It does not affect the GEM itself but can produce secondary damage of the MSGC if the electric field between the GEM and the MSGC is above a threshold depending on the operation conditions. We observed that aging does not only depend on the dose but also on the spot size of the irradiated area. Ar–DME mixtures had to be abandoned whereas a mixture of 70% Ar and 30% CO 2 showed no serious aging effects up to about 40 mC /cm deposited charge on the anodes. X-ray measurements indicate that the DLC of the MSGC is deteriorated by the gas amplification process. As a consequence, long-term gain variations are expected. The Inner Tracker has successfully participated in the data taking at HERA-B during summer 2000.