Mechanisms of substitution reactions on cyclometallated platinum(IV) complexes: "Quasi-labile" systems

The substitution reactions of SMe2 by phosphines (PMePh2, PEtPh2, PPh3, P(4-MeC6H4)(3), P(3-MeC6H4)(3), PCy3) on Pt-IV complexes having a cyclometalated imine ligand, two methyl groups in a cis-geometrical arrangement, a halogen, and a dimethyl sulfide as ligands, [Pt(CN)(CH3)(2)(X)(SMe2)], have been studied as a function of temperature, solvent, and electronic and steric characteristics of the phosphines and the X and CN ligands. In all cases, a limiting dissociative mechanism has been found, where the dissociation of the SMe2 ligand corresponds to the rate-determining step. The pentacoordinated species formed behaves as a true pentacoordinated Pt-IV compound in a steady-state concentration, given the solvent independence of the rate constant. The X-ray crystal structures of two of the dimethyl sulfide complexes and a derivative of the pentacoordinate intermediate have been determined. Differences in the individual rate constants for the entrance of the phosphine ligand can only be estimated as reactivity ratios. In all cases an effect of the phosphine size is detected, indicating that an associative step takes place from the pentacoordinated intermediate. The nature of the (CN) imine and X ligands produces differences in the dimethyl sulfide dissociation reactions rates, which can be quantified by the corresponding DeltaS double dagger values (72, 64, 48, 31, and 78 J K-1 mol(-1) for CN/X being C6H4CHNCH2C6H5/Br, C6H4CHNCH2-(2,4,6-(CH3)(3))C6H2/Br, C6H4CHNCH2C6H5/Cl, C6Cl4CHNCH2C6H5/Cl, and C6W4CH2NCHC6H5/ Pr, respectively). As a whole, the donor character of the coordinated C-aromatic and X atoms have the greatest influence on the dissociativeness of the rate-determining step.

Charge ordering and antiferromagnetic exchange in layered molecular crystals of the theta type

We consider the electronic properties of layered molecular crystals of the type theta -D(2)A where A is an anion and D is a donor molecule such as bis-(ethylenedithia-tetrathiafulvalene) (BEDT-TTF), which is arranged in the theta -type pattern within the layers. We argue that the simplest strongly correlated electron model that can describe the rich phase diagram of these materials is the extended Hubbard model on the square lattice at one-quarter filling. In the limit where the Coulomb repulsion on a single site is large, the nearest-neighbor Coulomb repulsion V plays a crucial role. When V is much larger than the intermolecular hopping integral t the ground state is an insulator with charge ordering. In this phase antiferromagnetism arises due to a novel fourth-order superexchange process around a plaquette on the square lattice. We argue that the charge ordered phase is destroyed below a critical nonzero value V, of the order of t. Slave-boson theory is used to explicitly demonstrate this for the SU(N) generalization of the model, in the large-N limit. We also discuss the relevance of the model to the all-organic family beta-(BEDT-TTF)(2)SF5YSO3 where Y=CH2CF2, CH2, CHF.

Generalized epilepsy with febrile seizures plus: Mutation of the sodium channel subunit SCN1B

Generalized epilepsy with febrile seizures plus (GEFS(+)) is an important childhood genetic epilepsy syndrome with heterogeneous phenotypes, including febrile seizures (FS) and generalized epilepsies of variable severity. Forty unrelated GEFS(+) and FS patients were screened for mutations in the sodium channel beta-subunits SCN1B and SCN2B, and the second GEFS(+) family with an SCN1B mutation is described here. The family had 19 affected individuals: 16 with typical GEFS(+) phenotypes and three with other epilepsy phenotypes. Site-specific mutation within SCN1B remains a rare cause of GEFS(+), and the authors found no evidence to implicate SCN2B in this syndrome.

Analysis of steady-state heat transfer through mid-crustal vertical cracks with upward throughflow in hydrothermal systems

We conduct a theoretical analysis of steady-state heat transfer problems through mid-crustal vertical cracks with upward throughflow in hydrothermal systems. In particular, we derive analytical solutions for both the far field and near field of the system. In order to investigate the contribution of the forced advection to the total temperature of the system, two concepts, namely the critical Peclet number and the critical permeability of the system, have been presented and discussed in this paper. The analytical solution for the far field of the system indicates that if the pore-fluid pressure gradient in the crust is lithostatic, the critical permeability of the system can be used to determine whether or not the contribution of the forced advection to the total temperature of the system is negligible. Otherwise, the critical Peclet number should be used. For a crust of moderate thickness, the critical permeability is of the order of magnitude of 10(-20) m(2), under which heat conduction is the overwhelming mechanism to transfer heat energy, even though the pore-fluid pressure gradient in the crust is lithostatic. Furthermore, the lower bound analytical solution for the near field of the system demonstrates that the permeable vertical cracks in the middle crust can efficiently transfer heat energy from the lower crust to the upper crust of the Earth. Copyright (C) 2002 John Wiley Sons, Ltd.

The preparation and readiness for voluntary movement: a high-field event-related fMRI study of the Bereitschafts-BOLD response

Activity within motor areas of the cortex begins to increase 1 to 2 s prior to voluntary self-initiated movement (termed the Bereitschaftspotential or readiness potential). There has been much speculation and debate over the precise source of this early premovement activity as it is important for understanding the roles of higher order motor areas in the preparation and readiness for voluntary movement. In this study, we use high-field (3-T) event-related fMRI with high temporal sampling (partial brain volumes every 250 ms) to specifically examine hemodynamic response time courses during the preparation, readiness, and execution of purely self-initiated voluntary movement. Five right-handed healthy volunteers performed a rapid sequential finger-to-thumb movement performed at self-determined times (12-15 trials). Functional images for each trial were temporally aligned and the averaged time series for each subject was iteratively correlated with a canonical hemodynamic response function progressively shifted in time. This analysis method identified areas of activation without constraining hemodynamic response timing. All subjects showed activation within frontal mesial areas, including supplementary motor area (SMA) and cingulate motor areas, as well as activation in left primary sensorimotor areas. The time courses of hemodynamic responses showed a great deal of variability in shape and timing between subjects; however, four subjects clearly showed earlier relative hemodynamic responses within SMA/cingulate motor areas compared with left primary motor areas. These results provide further evidence that the SMA and cingulate motor areas are major contributors to early stage premovement activity and play an important role in the preparation and readiness for voluntary movement. (C) 2003 Elsevier Inc. All rights reserved.

Critical sets in direct products of back circulant Latin squares

To date very Few families of critical sets for latin squares are known. The only previously known method for constructing critical sets involves taking a critical set which is known to satisfy certain strong initial conditions and using a doubling construction. This construction can be applied to the known critical sets in back circulant latin squares of even order. However, the doubling construction cannot be applied to critical sets in back circulant latin squares of odd order. In this paper a family of critical sets is identified for latin squares which are the product of the latin square of order 2 with a back circulant latin square of odd order. The proof that each element of the critical set is an essential part of the reconstruction process relies on the proof of the existence of a large number of latin interchanges.

Role of galectin-1 in the olfactory nervous system

The olfactory nervous system is responsible for the detection of odors. Primary sensory olfactory neurons are located in a neuroepithelial sheet lining the nasal cavity. The axons from these neurons converge on to discrete loci or glomeruli in the olfactory bulb. Each glomerulus consists of the termination of thousands of primary axons on the dendrites of second-order olfactory neurons. What are the molecular mechanisms which guide growing olfactory axons to select sites in the olfactory bulb? We have shown that subpopulations of these axons differentially express cell surface carbohydrates and that these different subpopulations target and terminate in particular regions of the olfactory bulb. Interestingly, the olfactory neurons and glial components in the olfactory pathway between the nose and brain express galectin-1. By using in vitro assays of neurite outgrowth we found that both galectin-1 and it's ligands were capable of specifically stimulating neurite elongation. Examination of the olfactory system in galectin-1 null mutants revealed that a subpopulation of axons failed to navigate to their target site in the olfactory bulb. This is the first phenotypic effect observed in galectin-1 null mutants and indicates that galectin-1 has a role in the growth and/or guidance of a subpopulation of axons in the olfactory system during development.

Structure of galactosylononitol

A cyclitol galactoside was isolated from the seeds of Vigna angularis and shown to be identical with galactosylononitol. However, detailed 2D NMR data and methylation analysis resulted in the revision of the structure of galactosylononitol to O-alpha-D-galactopyranosyl-(1-->3)-4-O-methyl-D-myo-inositol (1). Thus, compound 1 represents the only naturally occuring methylated derivative of galactinol.

Measurement of radiation dose received by the hands and thyroid of staff performing gridless fluoroscopic procedures in children

The aim of this study was to confirm that the radiation doses received by attendants who manually restrain infants during fluoroscopic procedures are low. Doses to the hands and neck of three radiologists and three nurses performing or assisting at all the fluoroscopic procedures in a children's hospital were measured for 1 month using thermoluminescent dosemeters. All fluoroscopy on children at this hospital is performed without an antiscatter grid. Total doses for the neck ranged from 20 to 50 mu Sv per week and for hands from 40 to 210 mu Sv per week. These doses were shared by the three radiologists and the three nurses. Individual doses received per staff member are very small when compared with the doses received by interventional radiology staff. Doses received by staff in this study were of the order of 5% of the limit advised by the National Health and Medical Research Council of Australia (NHMRC) for radiation workers. Nurses received larger doses than radiologists and steps will be taken to reduce this dose further.

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.

The structure of middle management remuneration packages: An application to Australian mine managers

This paper investigates the composition of remuneration packages for middle managers and relates the structure of remuneration contracts to firm-specific attributes. A statutorily defined position in a single industry is studied as an example of middle management. This allows us to control for differences in task complexity across managers and industry-induced factors that could determine differences in remuneration contracts. Higher-risk firms are expected to pay their mine managers a greater proportion of variable salaries and market and/or accounting-based compensation than low-risk firms. Results indicate that high-risk firms pay a higher proportion of variable salaries and more compensation based on market and/or accounting performance.

Asymptomatic primary Epstein-Barr virus infection occurs in the absence of blood T-cell repertoire perturbations despite high levels of systemic viral load

Primary infection with the human herpesvirus, Epstein-Barr virus (EBV), may result in subclinical seroconversion or may appear as infectious mononucleosis (IM), a lymphoproliferative disease of variable severity. Why primary infection manifests differently between patients is unknown, and, given the difficulties in identifying donors undergoing silent seroconversion, little information has been reported. However, a longstanding assumption has been held that IM represents an exaggerated form of the virologic and immunologic events of asymptomatic infection. T-cell receptor (TCR) repertoires of a unique cohort of subclinically infected patients undergoing silent infection were studied, and the results highlight a fundamental difference between the 2 forms of infection. In contrast to the massive T-cell expansions mobilized during the acute symptomatic phase of IM, asymptomatic donors largely maintain homeostatic T-cell control and peripheral blood repertoire diversity. This disparity cannot simply be linked to severity or spread of the infection because high levels of EBV DNA were found in the blood from both types of acute infection. The results suggest that large expansions of T cells within the blood during IM may not always be associated with the control of primary EBV infection and that they may represent an overreaction that exacerbates disease. (C) 2001 by The American Society of Hematology.

Elucidation of reaction scheme describing malondialdehyde-acetaldehyde-protein adduct formation

Malondialdehyde and acetaldehyde react together with proteins and form hybrid protein conjugates designated as MAA adducts, which have been detected in livers of ethanol-fed animals. Our previous studies have shown that MAA adducts are comprised of two distinct products. One adduct is composed of two molecules of malondialdehyde and one molecule of acetaldehyde and was identified as the 4-methpl-1,4-dihydropyridine-3,5-dicarbaldehyde derivative of an amino group (MHHDC adduct). The other adduct is a 1:1 adduct of malondialdehyde and acetaldehyde and was identified as the 2-formyl-3-(alkylamino)butanal derivative of an amino group (FAAB adduct). In this study, information on the mechanism of MAA adduct formation was obtained, focusing on whether the FAAB adduct serves as a precursor for the MDHDC adduct. Upon the basis of chemical analysis and NMR spectroscopy, two initial reaction steps appear to be a prerequisite for MDHDC formation. One step involves the reaction of one molecule of malondialdehyde and one of acetaldehyde with an amino group of a protein to form the FAAB product, while the other step involves the generation of a malondialdehyde-enamine. It appears that generation of the MDHDC adduct requires the FAAB moiety to be transferred to the nitrogen of the MDA-enamine. For efficient reaction of FAAB with the enamine to take place, additional experiments indicated that these two intermediates likely must be in positions on the protein of close proximity to each other. Further studies showed that the incubation of liver proteins from ethanol-fed rats with MDA resulted in a marked generation of MDHDC adducts, indicating the presence of a pool of FAAB adducts in the liver of ethanol-fed animals. Overall, these findings show that MDHDC-protein adduct formation occurs via the reaction of the FAAB moiety with a malondialdehyde-enamine, and further suggest that a similar mechanism may be operative in vivo in the liver during prolonged ethanol consumption.

The pharmacokinetics of once-daily dosing of ceftriaxone in critically ill patients

The aim of this study was to determine the pharmacokinetic profile of the normal recommended dose of ceftriaxone in critically ill patients and to establish whether the current daily dosing recommendation maintains plasma concentrations adequate for antibacterial efficacy. Ceftriaxone at a recommended dose of 2 g iv was administered od to 12 critically ill patients with severe sepsis and normal serum creatinine concentrations. Blood samples were taken at predetermined intervals over the first 24 h and on day 3 for measurement of ceftriaxone concentrations. There was wide variability in drug disposition, explained by the presence of variable renal function and identified by the measurement of creatinine clearance. In nine patients with normal renal function, there was a high level of creatinine clearance(mean +/- S.D., 41 +/- 12 mL/min) and volume of distribution (20 +/- 3.3 L), which resulted in an elimination half-life of 6.4 +/- 1.1 h. In comparison with normal subjects, ceftriaxone clearance was increased 100%, volume of distribution increased 90% and the elimination half-life was similar. Three patients had substantially suboptimal plasma ceftriaxone concentrations. We confirm previous findings that ceftriaxone clearance in critically ill patients correlates with renal clearance by glomerular filtration. The elimination half-life is prolonged (21.4 +/- 9.8 h) in critically ill patients with renal failure when compared with previously published data in non-critically ill patients with renal failure. We conclude that in critically ill patients with normal renal function, inadequate plasma concentrations may result following od bolus dosing of ceftriaxone. Drug accumulation may occur in critically ill patients with renal failure.

EphB2 and two of its ligands have dynamic protein expression patterns in the developing olfactory system

Primary olfactory neurons are located in the olfactory neuroepithelium lining the nasal cavity. Their axons converge and form glomeruli with the dendrites of second-order neurons in the olfactory bulb. The molecular basis of primary olfactory axon guidance, targeting and subsequent arborisation is largely unknown. In this study we examined the spatio-temporal expression of the Eph receptor EphB2 and its ligands, ephrin-B1 and ephrin-B2, during development of the rat primary olfactory system. Unlike in other regions of the nervous system where receptor and ligand expression patterns are usually non-overlapping, EphB2, ephrin-B1 and ephrin-B2 were all expressed by primary and second-order olfactory neurons. In the embryonic animal we found that these three proteins had distinct and different expression patterns. EphB2 was first expressed at E18.5 by the perikarya of primary olfactory neurons. In contrast, ephrin-B1 was expressed from E13.5 and was localised to the axons of these cells up to E18.5 but was then restricted to the perikarya. Ephrin-B2, however, was expressed by olfactory ensheathing cells. EphB2, ephrin-B1 and ephrin-B2 were also expressed in the prenatal olfactory bulb and were restricted to the perikarya of mitral cells. In the post-natal olfactory bulb there was a shift in the localisation of both EphB2 and ephrin-B1 to the dendritic arborisations of mitral cells. The dynamic and tightly regulated spatio-temporal expression patterns of EphB2, ephrin-B1 and ephrin-B2 by specific olfactory cell populations suggest that these molecules have the potential to regulate important developmental events in the olfactory system. (C) 2001 Elsevier Science B.V. All rights reserved.