Evidence for persistent dysfunction of wild-type aldosterone synthase gene in glucocorticoid-treated familial hyperaldosteronism type I

Background In familial hyperaldosteronism type I (FH-I), glucocorticoid treatment suppresses adrenocorticotrophic hormone-regulated hybrid gene expression and corrects hyperaldosteronism. Objective To determine whether the wild-type aldosterone synthase genes, thereby released from chronic suppression, are capable of functioning normally. Methods We compared mid-morning levels of plasma potassium, plasma aldosterone, plasma renin activity (PRA) and aldosterone : PRA ratios, measured with patients in an upright position, and responsiveness of aldosterone levels to infusion of angiotensin II (AII), for 11 patients with FH-I before and during long-term (0.8-14.3 years) treatment with 0.25-0.75 mg/day dexamethasone or 2.5-10 mg/day prednisolone. Results During glucocorticoid treatment, hypertension was corrected in all. Potassium levels, which had been low (< 3.5 mmol/l) in two patients before treatment, were normal in all during treatment (mean 4.0 +/- 0.1 mmol/l, range 3.5-4.6). Aldosterone levels during treatment [13.2 +/- 2.1 ng/100 ml (mean +/- SEM)] were lower than those before treatment (20.1 +/- 2.5 ng/100 ml, P < 0.05). PRA levels, which had been suppressed before treatment (0.5 +/- 0.2 ng/ml per h), were unsuppressed during treatment (5.1 +/- 1.5 ng/ml per h, P < 0.01) and elevated (> 4 ng/ml per h) in six patients. Aldosterone : PRA ratios, which had been elevated (> 30) before treatment (101.1 +/- 25.9), were much lower during treatment (4.1 +/- 1.0, P < 0.005) and below normal (< 5) in eight patients. Surprisingly, aldosterone level, which had not been responsive (< 50% rise) to infusion of AII for all 11 patients before treatment, remained unresponsive for 10 during treatment. Conclusions Apparently regardless of duration of glucocorticoid treatment in FH-I, aldosterone level remains poorly responsive to AII, with a higher than normal PRA and a low aldosterone : PRA ratio. This is consistent with there being a persistent defect in functioning of wild-type aldosterone synthase gene. (C) Rapid Science Publishers ISSN 0263-6352.

Ni-II and Zn-II complexes of the hexadentate macrocyclic ligand cis-6,13-dimethyl-1,4,8,11-tetraazacyclotetra- decane-6,13-diamine

The title pendent-arm macrocyclic hexaamine ligand binds stereospecifically in a hexadentate manner, and we report here its isomorphous Ni-II and Zn-II complexes (both as perchlorate salts), namely (cis-6,13-dimethyl-1,4,8,11-tetraazacyclotetradecane-6,13-diamine-kappa(6)N)nickel(II) diperchlorate, [Ni(C12H30N6)](ClO4)(2), and (cis-6,13-dimethyl-1,4,8,11-tetraazacyclotetradecane-6,13-diamine-kappa(6)N)zinc(II) diperchlorate, [Zn(C-12 H30N6)](ClO4)(2). Distortion of the N-M-N valence angles from their ideal octahedral values becomes more pronounced with increasing metal-ion size and the present results are compared with other structures of this ligand.

The polar ionosphere at Zhongshan Station on May 11, 1999, the day the solar wind almost disappeared

The solar wind almost disappeared on May 11,1999: the solar wind plasma density and' dynamic pressure were less than 1 cm(-3) and 0.1 nPa respectively, while the interplanetary magnetic field was northward. The polar ionospheric data observed by the multi-instruments at Zhongshan Station in Antarctica on such special event day was compared with those of the control day (May 14). It was shown that geomagnetic activity was very quiet on May 11 at Zhongshan. The magnetic pulsation, which usually occurred at about magnetic noon, did not appear. The ionosphere was steady and stratified, and the F-2 layer spread very little. The critical frequency of dayside F-2 layer, f(0)F(2), was larger than that of control day, and the peak of f(0)F(2) appeared 2 hours earlier. The ionospheric drift velocity was less than usual. There were intensive auroral E-s appearing at magnetic noon. All this indicates that the polar ionosphere was extremely quiet and geomagnetic field was much more dipolar on May 11. There were some signatures of auroral substorm before midnight, such as the negative deviation of the geomagnetic H component, accompanied with auroral E-s and weak Pc3 pulsation.

Excitatory synaptic transmission in the lateral and central amygdala

The amygdala plays a major role in the acquisition and expression of fear conditioning. NMDA receptor-dependent synaptic plasticity within the basolateral amygdala has been proposed to underlie the acquisition and possible storage of fear memories. Here the properties of fast glutamatergic transmission in the lateral and central nuclei of the amygdala are presented. In the lateral amygdala, two types of neurons, interneurons and projection neurons, could be distinguished by their different firing properties. Glutamatergic inputs to interneurons activated AMPA receptors with inwardly rectifying current-voltage relations (I-Vs), whereas inputs to projection neurons activated receptors that had linear I-Vs, indicating that receptors on interneurons lack GluR2 subunits. Inputs to projection neurons formed dual component synapses with both AMPA and NMDA components, whereas at inputs to interneurons, the contribution of NMDA receptors was very small. Neurons in the central amygdala received dual component glutamatergic inputs that activated AMPA receptors with linear I-Vs. NMDA receptor-mediated EPSCs had slow decay time constants in the central nucleus. Application of NR2B selective blockers ifenprodil or CP-101,606 blocked NMDA EPSCs by 70% in the central nucleus, but only by 30% in the lateral nucleus. These data show that the distribution of glutamatergic receptors on amygdalar neurons is not uniform. In the lateral amygdala, interneurons and pyramidal neurons express AMPA receptors with different subunit compositions. Synapses in the central nucleus activate NMDA receptors that contain NR1 and NR2B subunits, whereas synapses in the lateral nucleus contain receptors with both NR2A and NR2B subunits.

trans-Cyano(6-methyl-1,4,8,11-tetraazacyclotetradecan-6-amine)cobalt(III) bis(perchlorate) hydrate and trans-hydroxo(6-methyl-1,4,8,11-tetraazacyclotetradecan-6-amine)cobalt(III) bis(perchlorate)

The crystal structures of a pair of closely related macrocyclic cyano- and hydroxopentaaminecobalt(III) complexes, as their perchlorate salts, are reported. Although the two complexes, [Co(CN)(C11H27N5)](ClO4)2.H2O and [Co(OH)(C11H27N5)](ClO4)(2), exhibit similar conformations, significant differences in the Co-N bond lengths arise from the influence of the sixth ligand (cyano as opposed to hydroxo). The ensuing hydrogen-bonding patterns are also distinctly different. Disorder in the perchlorate anions was clearly resolved and this was rationalized on the basis of distinct hydrogen-bonding motifs involving the anion O atoms and the N-H and O-H donors.

Cost effectiveness of adding magnetic resonance imaging to the usual management of suspected scaphoid fractures

Objective: To determine the cost effectiveness of a magnetic resonance imaging scan (MRI) within 5 days of injury compared with the usual management of occult scaphoid fracture. Methods: All patients with suspected scaphoid fractures in five hospitals were invited to participate in a randomised controlled trial of usual treatment with or without an MRI scan. Healthcare costs were compared, and a cost effectiveness analysis of the use of MRI in this scenario was performed. Results: Twenty eight of the 37 patients identified were randomised: 17 in the control group, 11 in the MRI group. The groups were similar at baseline and follow up in terms of number of scaphoid fractures, other injuries, pain, and function. Of the patients without fracture, the MRI group had significantly fewer days immobilised: a median of 3.0 (interquartile range 3.0-3.0) v 10.0 (7-12) in the control group (p = 0.006). The MRI group used fewer healthcare units (median 3.0, interquartile range 2.0-4.25) than the control group (5.0, 3.0-6.5) (p = 0.03 for the difference). However, the median cost of health care in the MRI group ($594.35 AUD, $551.35-667.23) was slightly higher than in the control group ($428.15, $124.40-702.65) (p = 0.19 for the difference). The mean incremental cost effectiveness ratio derived from this simulation was that MRI costs $44.37 per day saved from unnecessary immobilisation (95% confidence interval $4.29 to $101.02). An illustrative willingness to pay was calculated using a combination of the trials measure of the subjects' individual productivity losses and the average daily earnings. Conclusions: Use of MRI in the management of occult scaphoid fracture reduces the number of days of unnecessary immobilisation and use of healthcare units. Healthcare costs increased non-significantly in relation to the use of MRI in this setting. However, when productivity losses are considered, MRI may be considered cost effective, depending on the individual case.

The Gothic scene of international relations: ghosts, monsters, terror and the sublime after September 11

Accepting Furet’s claim that events acquire meaning and significance only in the context of narratives, this article argues that a particular type of international relations narrative has emerged with greater distinction after the traumatic experience of September 11: the gothic narrative. In a sense the political rhetoric of President Bush marks the latest example of America’s fine tradition in the gothic genre that began with Edgar Allan Poe and Nathaniel Hawthorne and extends through Henry James to Stephen King. His discourse of national security, it will be shown, assumes many of the predicates of gothic narratives. The gothic scenes evoked by Bush as much as Poe involve monsters and ghosts in tenebrous atmospheres that generate fear and anxiety, where terror is a pervasive tormentor of the senses. Poe’s narratives, for example, turn on encounters with dark, perverse, seemingly indomitable, forces often entombed in haunted houses. Similarly, Bush’s post-September 11 narratives play upon fears of terrorists and rogue states who are equally dark, perverse and indomitable forces. In both cases, ineffable and potently violent and cruel forces haunt and terrorise the civilised, human world.

N-methylation of diamino-substituted macrocyclic complexes: Intramolecular cyclisation

Two new macropolycyclic hexaamines L(2) and L(4) as their copper(II) complexes have been isolated as products from the condensation of the diamino-substituted macrocyclic complex trans-(6,13-dimethyl-1,4,8,11-tetraazacyclo-tetradecane-6,13-diamine)copper(II) [CuL(1)](2+) with aqueous formaldehyde. Both of the complexes exhibit methylene bridges between the pendant amine and the adjacent co-ordinated macrocyclic N-donors. Their crystal structures have been determined: [CuL(2)(NCS)][SCN], triclinic, space group P (1) over bar, a = 7.133(2), b = 9.813(2), c = 16.745(3) Angstrom, alpha = 101.05(2), beta = 99.36(2), gamma = 99.77(2)degrees, Z = 2; [CuL(4)Cl][ClO4]. H2O, triclinic, space group P (1) over bar, a = 9.3327(8), b = 10.8989(6), c = 12.672(1) Angstrom, alpha = 68.591(6), beta = 78.899(6), gamma = 87.384(6)degrees, Z = 2. The complexes exhibit square-pyramidal geometries, and significantly lower-energy electronic maxima relative to their parent complex [CuL(1)](2+). Electrochemistry of [CuL(2)](2+) revealed a reversible Cu-II-Cu-I redox couple, by contrast to those of macromonocyclic analogues.

Nitrogen- and carbon-based isomerism in the copper(II) complexes of 6,13-dimethyl-1,4,8,11-tetraazacyclotetradecane-6,13-diamine

A number of N- and C-based diastereomeric copper(II) complexes of the pendant-arm macrocyclic hexaamines trans- and cis-6,13-dimethyl-1,4,8,11-tetraazacyclotetradecane-6,13-diamine (L-1 and L-2) have been isolated and characterised. The crystal structures of the complexes RRSS-[CuL1(OH2)(2)][ClO4](2), SSRR-[Cu(H2L1)(OClO3)(2)]-[ClO4](2) . 2H(2)O RSRS-[CuL1(OClO3)]ClO4, RSRS-[CuL2(OClO3)]ClO4 and RRSS-[Cu(H2L2)(OClO3)(2)][ClO4](2) have been determined. Some unusual structural and spectroscopic variations are found across this series of diastereomers. The protonation constants of the pendant primary amines are dependent on the relative dispositions of the adjacent macrocyclic secondary amine H atoms, which is indicative of intramolecular hydrogen-bonding interactions.

Lipid content and fatty acid composition of 11 species of Queensland (Australia) fish

The fatty acid composition of 11 species of fish caught off the northeast coast of Australia was determined. No fatty acid profiles have been previously published for fish from this area nor for nine of these species. Although the percentage of polyunsaturated fatty acid (PU FA) was the same as the calculated average for Australian fish (42.3%), the percentage of n-3 fatty acids was lower (24.4 +/- 5.4% vs. 30.7 +/- 10.1%) and the n-6 fatty acids higher (16.5 +/- 4.5% vs. 11.2 +/- 5.9%), P < 0.001 in each case. The major n-3 PUFA were docosahexaenoic (15.6 +/- 6.3%) and eicosapentaenoic acid (4.3 +/- 1.1%) while the major n-6 PUFA were arachidonic (8.3 +/- 3.2%) and n-6 docosatetraenoic acid (3.1 +/- 1.3%). The second-most abundant class of fatty acid was the saturates (31.6 +/- 3.5%) while the monounsaturates accounted for 17.4 +/- 4.3% of the total fatty acids. The monounsaturate with the highest concentration was octadecenoic acid (11.8 +/- 2.6%). There was a positive correlation between the total lipid content and saturated and monounsaturated fatty acids (r = 0.675 and 0.567, respectively) and a negative correlation between the total lipid content and PUFA(r = 0.774).

Conformational analysis of LYS(11-36), a peptide derived from the beta-sheet region of T4 lysozyme, in TFE and SDS

The solution conformation of a peptide LYS(11-36), which corresponds to the beta-sheet region in T4 lysozyme, has been examined in aqueous solution, TFE, and SDS micelles by CD and H-1 NMR spectroscopy. Secondary structure predictions suggest some beta-sheet and turn character in aqueous solution but predict a helical conformation in a more hydrophobic environment. The predictions were supported by the CD and NMR studies which showed the peptide to be relatively unstructured in aqueous solution, although there was some evidence of a beta-turn conformer which was maintained in 200 mM SDS and, to a lesser extent, in 50% TFE. The peptide was significantly helical in the presence of either 50% TFE or 200 mM SDS. TFE and SDS titrations showed that the peptide could form helical, sheet, or extended structure depending on the TFE or SDS concentration. The studies indicate that peptide environment is the determining factor in secondary structure adopted by LYS(11-36).

Photodegradation of irinotecan (CPT-11) in aqueous solutions: Identification of fluorescent products and influence of solution composition

The photodegradation of irinotecan (CPT-11), the semisynthetic derivative of the antitumor alkaloid 20(S)-camptothecin, has been investigated. The drug was exposed to laboratory light for up to 5 days in 0.9% saline solution (pH 8.5). Five significant photodegradation products were observed and a high-performance liquid chromatography (HPLC) assay was employed to isolate them from CPT-11 using gradient conditions. The structures were elucidated by nuclear magnetic resonance spectroscopy and tandem mass spectrometry and shown to be the result of extensive modifications of the lactone ring of CPT-11. Three of the compounds were found to belong to the mappicine group of alkaloids. In addition, the effect of light on the stability of CPT-11 in aqueous solutions and biological fluids was also assessed, Potassium phosphate buffers (0.05 M, pH 5.0-8.2) and saline, plasma, urine, and bile solutions containing 20 mu M CPT-11 were equilibrated in the dark for 24 h before being exposed to laboratory light for up to 171 h at ambient temperature. Four of the five identified photodegradation products were observed and quantitated by isocratic HPLC, using a different detection mode (fluorescence) than the one used for gradient elution, In general, CPT-11 was found to be unstable under neutral and alkaline conditions for all solutions investigated, with the exception of bile. We conclude that CPT-11 is photolabile and that care should be taken to protect samples, particularly those intended for the isolation and identification of novel metabolites of CPT-11.