The Electrical Characteristics of Fixed Charge Membranes: Solution of the Field Equations

A theoretical analysis is made of the electrical characteristics of a membrane containing two fixed charge regions, of opposite sign, in contact. Profiles of ion concentrations, electrostatic potential, space charge density, as well as the voltage-current characteristics were obtained by numerical integration of the field equations on a computer. Comparison with the predictions of an earlier analysis of this system (Coster, 1965) shows that the latter is valid to a good approximation for membranes > 70 A in thickness. In particular the form of the electrical characteristics, including the punch-through effect, have been verified by the computer analysis. The range of useful validity of the earlier analysis, the use of Boltzmann statistics when currents are present, and variation of membrane capacitance with applied potential, are discussed in the light of the results obtained.     

Early cell repair of the lung and the intestine in mice, after irradiation by fast neutrons and gamma rays

Lung tolerance is assessed from LD50 at 180 days after thoracic irradiation, in mice, with d(50) + Be neutrons and 60Co gamma rays. Early intestinal tolerance is assessed from LD50 at 7 days after abdominal irradiation. Additional dose (Dr) to reach LD50 when a single dose Ds is split into 2 equal fractions Di separated by different time intervals "i", is determined (Dr = 2Di - Ds), Dr is larger after gamma than after neutron irradiation, for lung and intestine. After thoracic irradiation with gamma rays, Dr reaches 3.36, 4.38, 5.12 and 5.37 Gy for "i" = 2, 6, 12 and 24 hours respectively; after neutron irradiation, Dr reaches 0.66, 0.9, 1.29, 1.95 and 1.50 Gy for "i" = 1, 2, 4, 12 and 24 hours. Dr is smaller for intestine; after abdominal irradiation with gamma rays, it reaches 1.99, 2.59, 2.74, 3.11, 3.34, 4.44 and 4.56 Gy for "i" = 1, 2, 3.5, 8, 12, 18 and 24 hours; after neutron irradiation, it reaches 0.13, 0.45, 0.42 and 1.33 Gy for "i" = 1.5, 3.5, 5.5 and 24 hours. After gamma irradiation, early repair is complete after 3.5 hours for intestine and needs 12 hours for lung.     

Endocrine and antitumoral effects of R76713 in rats

Some effects of daily oral administration of a new non-steroidal aromatase inhibitor on the pituitary-gonadal and adrenal functions were investigated in female rats. At doses of 1 mg/kg twice daily or higher, R 76713 lowered plasma estradiol levels to the range measured after ovariectomy Plasma progesterone levels and uterine weights decreased whilst LH levels increased but to a lesser extent than after ovariectomy. The other hormonal data show that long-term administration of R 76 713 does not modify the gluco- and mineralocorticoid hormone levels even at the highest dose studied (20 mg/kg, 4 h after treatment). Furthermore, both ovariectomy and R 76 713 treatment (1 and 5 mg/kg twice a day) induced almost complete regression of 9,12-dimethyl-1,2-benzanthracene-induced mammary carcinoma in rats. The appearance of new tumors during the treatment period was completely inhibited by R 76 713 whilst multiplicity of the remaining tumors was dramatically reduced.     

Purinergic P2X7 receptor antagonists: Chemistry and fundamentals of biological screening

The purinergic P2X₇ receptor is a unique member of the ATP-gated P2X family. This receptor has been implicated in numerous diseases and many structurally diverse ligands have been discovered via high throughput screening. This perspective will attempt to highlight some of the most recent key findings in both the biology and chemistry.     

New non-steroidal aromatase inhibitors: focus on R76713

R76713 is a novel triazole derivative which selectively blocks the cytochrome P450-dependent aromatase. In human placental microsomes, in FSH-stimulated rat and human granulosa cells and in human adipose stromal cells, 50% inhibition of estradiol biosynthesis was obtained at drug concentrations of 2-10 nM. In PMSG-injected female rats, R76713 lowered plasma estradiol levels by 50 and 90% 2 h after single oral doses of 0.005 and 0.05 mg/kg respectively. After 1 mg/kg, estradiol levels were suppressed by 90% for 16 h. In male cynomolgus monkeys, R76713 dose-dependently (0.03-10 micrograms/kg) inhibited peripheral aromatization with an ED50 of 0.13 microgram/kg without altering metabolic clearance rates and conversion ratios. In vitro R76713 had no effect on other P450-dependent steroidogenic enzymes up to 1000 nM at least. In rats, LHRH-, ACTH- and sodium-deprived diet stimulated plasma testosterone, corticosterone and aldosterone levels were not modified 2 h after single oral administrations of R76713 (up to 20 mg/kg). Furthermore, R76713 did not show any in vitro or in vivo estrogenic or antiestrogenic property. R76713 also induced regression of DMBA-induced mammary tumors after daily oral administration of 1 mg/kg b.i.d. In male volunteers (n = 4), a single oral dose of 5 and 10 mg lowered median plasma estradiol levels from 70 pM to the detection limit of the assay (40 pM) 4, 8 and 24 h after intake whereas no changes were detected after placebo administration. In premenopausal women (n = 15), receiving a single oral dose of 20 mg, median plasma estradiol levels decreased from 389 pM (before) to 168, 133 and 147 pM, 4, 8 and 24 h after intake whereas they remained above 420 pM after placebo (n = 7).     

Oxo-bridged isomers of aza-trishomocubane sigma (σ) receptor ligands: Synthesis,in vitro binding,and molecular modeling

Isomeric oxo-bridged analogs of aza-trishomocubane sigma (σ) receptor ligands were synthesized and shown to display a reduced affinity for the σ receptor. In the case of phenethyl derivative 4, there was a concomitant introduction of high-affinity for the α_2C adrenergic receptor, and moderate affinity for the dopamine transporter. Molecular modeling was undertaken to rationalize these results.     

<Emphasis Type="Italic">In vitro</Emphasis> and <Emphasis Type="Italic">ex vivo</Emphasis> effect of hyaluronic acid on erythrocyte flow properties

Background  

Hyaluronic acid (HA) is present in many tissues; its presence in serum may be related to certain inflammatory conditions, tissue damage, sepsis, liver malfunction and some malignancies. In the present work, our goal was to investigate the significance of hyaluronic acid effect on erythrocyte flow properties. Therefore we performed in vitro experiments incubating red blood cells (RBCs) with several HA concentrations. Afterwards, in order to corroborate the pathophysiological significance of the results obtained, we replicated the in vitro experiment with ex vivo RBCs from diagnosed rheumatoid arthritis (RA) patients, a serum HA-increasing pathology.     

The small regulatory RNA molecule MicA is involved in <Emphasis Type="Italic">Salmonella enterica</Emphasis> serovar Typhimurium biofilm formation

Background  

LuxS is the synthase enzyme of the quorum sensing signal AI-2. In Salmonella Typhimurium, it was previously shown that a luxS deletion mutant is impaired in biofilm formation. However, this phenotype could not be complemented by extracellular addition of quorum sensing signal molecules.