Desensitization of mutant acetylcholine receptors in transgenic mice reduces the amplitude of neuromuscular synaptic currents

While the slow onset of desensitization of nicotinic acetylcholine receptors (AChRs), relative to the rate of acetylcholine removal, excludes this kinetic state from shaping synaptic responses in normal neuromuscular transmission, its role in neuromuscular disorders has not been examined. The slow-channel congenital myasthenic syndrome (SCCMS) is a disorder caused by point mutations in the AChR subunit-encoding genes leading to kinetically abnormal (slow) channels, reduced miniature endplate current amplitudes (MEPCs), and degeneration of the postsynaptic membrane. Because of this complicated picture of kinetic and structural change in the neuromuscular junction, it is difficult to assess the importance of the multiple factors that may be responsible for the reduced endplate current amplitudes, and ultimately the clinical syndrome. In order to address this we have used a transgenic mouse model for the SCCMS that has slow AChR ion channels and reduced endplate responsiveness in the absence of any of the degenerative changes. We found that the reduction in MEPC amplitudes in these mice could not be explained by either reduced AChR number or by reduced AChR channel conductance. Rather, we found that the mutant AChRs in situ manifested an activity-dependent reduction in sensitivity that caused diminished MEPC and endplate current amplitude with nerve stimulation. This observation demonstrates that the basis for the reduction in MEPC amplitudes in the SCCMS may be multifactorial. Moreover, these findings demonstrate that, under conditions that alter their rate of desensitization, the kinetic properties of nicotinic AChRs can control the strength of synaptic responses.     

Cardiac risk in surgery. A review and guidelines for risk evaluation and reduction of cardiac risk in general surgery

We report herein the phenotypic and functional analysis of human bone marrow and thymus derived early T cells. Commitment to T cell lineage is acquired during CD7 antigen expression by CD34+ precursors in human bone marrow and before thymus colonization. Early thymocytes show similar phenotypic characteristics as bone marrow T cells. They rapidly acquire CD4 before the dual expression of CD4 and CD8. Their expansion and differentiation is regulated by two major factors: thymic stroma and cytokines produced by these stroma cells or by thymocytes themselves. Among cytokines, IL1 and sCD23 produced by thymic epithelial cells support in vitro early T cell development.     

Methods to compare dissolution profiles and a rationale for wide dissolution specifications for metoprolol tartrate tablets

The objectives of this work were to apply several profile comparison approaches to dissolution data of four different but bioequivalent metoprolol tartrate tablet formulations to (1) identify the advantages and disadvantages of each approach, (2) quantify the metric for comparing dissolution profiles of each method, (3) determine metric limits that are consistent with the observed bioequivalence, and (4) rationalize the observed metric limits with respect to the role of dissolution in overall metoprolol absorption. Dissolution was performed by the USP monograph method on four formulations of metoprolol tartrate tablets (Lopressor plus fast, medium, and slow dissolving test formulations). Three general approaches to compare dissolution profiles were examined; they were ANOVA-based, model-independent, and model-dependent approaches. It is concluded that model-independent approaches and several model-dependent approaches yielded numerical results that can serve as objective and quantitative metrics for comparing entire dissolution profiles of the four metoprolol tartrate formulations. However, these methods presented complications. Some metrics were dependent on the length of the dissolution profile and the sampling scheme. Results from the pairwise procedures also depended on the pairing assignment of individual profiles. In spite of complications, these methods suggested wide dissolution specification limits. Wide dissolution specifications were rationalized through an analysis of in vitro-in vivo relationships, which indicated metoprolol dissolution from these formulations was not the rate-limiting step; hence, a range of dissolution profiles can be expected to yield equivalent plasma profiles.     

Microsatellite loci for stringless bees

What ethical concerns regarding the application of new antidementia compounds are pertinent to the best interests of patients with Alzheimer's disease and their caregivers? Based on collected preliminary anecdotal accounts, these concerns are important and should be considered carefully by clinicians, researchers, and families.     

In situ bypass and diabetes

From 1986 through to 1990 a total of 483 in situ bypass procedures were performed in 444 patients. Preoperative risk-factors were equally distributed among diabetic (DM) and non-diabetic (NDM) patients, except for smoking habits (DM:48%, NDM:64%, p = 0.002) and cardiac disease (DM:45%, NDM:29%, p = 0.005). Critical limb-ischaemia was more often present in diabetic than non-diabetic patients (DM:57%, NDM:36%, p = 0.0002). Diabetic patients had a significantly lower distal anastomosis than non-diabetic patients (p = 0.00001). There were no differences among diabetic and non-diabetic patients regarding three years primary and secondary patency (58% and 64% respectively), and regarding major amputations. However, the rate of minor amputations was higher in insulin-dependent compared with non-insulin-dependent diabetics, who in turn had a higher rate than non-diabetics (p < 0.00001). A markedly decreased survival rate was found in diabetics (p < 0.00005). We found the in situ bypass technique very useful in the treatment of critical ischaemia of the lower limb in diabetic patients. The overall results in diabetic patients, whether insulin-dependent or not, were equal to those in non-diabetic patients.     

Expression of a human homeobox-containing gene is regulated by 1,25(OH)2D3 in bone cells

The seasonal variation in the nutrient composition of Enhydra fluctuans and Marsilea quadrifolia, two edible semi-aquatic plants, was studied in order to promote their consumption as green leafy vegetables. Both plants had a high crude protein content throughout all harvesting seasons. Enhydra fluctuans had a low ash content and was a good source of beta-carotene (3.7 to 4.2 mg/100 g on a fresh weight basis). Marsilea quadrifolia exhibited wide fluctuations between seasons and was not very promising in nutrient composition when compared to other commonly used green leafy vegetables.     

Factors limiting the domestic density of Triatoma infestans in north-west Argentina: a longitudinal study

Reported are the environmental and demographic risk factors associated with the domestic infestation and density of Triatoma infestans in three heavily infested rural villages in Santiago del Estero Province, Argentina. In a one-factor unadjusted analysis, the number of T. infestans captured per person-hour was associated significantly and negatively with the use of domestic insecticides by householders, type of thatch used in the roofs and the age of the house; and positively with the following: degree of cracking of the indoor walls and presence of hens nesting indoors. In one model, using multiple linear regression and a backward stepwise elimination procedure, most of the variation in the overall abundance of T. infestans was explained by insecticide use and the presence of hens nesting indoors; in another model using the same procedure it was explained by insecticide use, bug density in 1988 and previous spraying with deltamethrin in 1985. Variations in bug density per capture stratum (household goods, beds, walls and roof) were explained by the bug density in other strata and by one or two of the following risk factors: hens nesting indoors, type of roof, presence of cracks in the walls and number of people living in the house. Bug density might be locally controlled by the availability of refuges in the roofs and walls, by the presence of hens nesting indoors and by the use of domestic insecticides. Certain local materials, such as a grass known as simbol, could be successfully used in rural housing improvement programmes aimed at reducing the availability of refuges for insects in the roof.     

A new boundary-layer wind tunnel at the Danish Maritime Institute

The paper describes a new boundary-layer wind tunnel at the Danish Maritime Institute in Lyngby. The wind tunnel is of the open-circuit type and is integrated into a building raised for the purpose. The design was constrained by the need to provide a simulation of the atmospheric boundary layer (without thermal stratification) and alternatively a uniform flow without excessive turbulence.The wind tunnel has a working section of principal dimensions: length 20.8 m, width 2.6 m and height 1.8 m (adjustable from 1.8 to 2.3 m). The maximum wind speed in the working section when empty is about 26 m s^?1.Data acquisition, analysis and instrumentation in relation to the new wind tunnel are discussed and, finally, an example of a simulated natural wind is presented.     

Viscous and Aeroelastic Effects on Wind Turbine Blades. The VISCEL project. Part I: 3D Navier–Stokes Rotor simulations

Aerodynamic modelling of HAWT rotors by means of “engineering methods” has reached a saddle point, where no further development can be expected without a breakthrough in understanding the physics of unsteady, rotating three‐dimensional flows. However, such a breakthrough becomes ever more necessary, as the size of the wind turbines increases. With the experimental work in that direction being mostly limited to observing the phenomena and interpreting the associated mechanisms, and its increased cost, alternatives are being sought. The use of CFD techniques and state‐of‐the‐art Navier–Stokes solvers is considered a very serious contender, a belief shared by the members of the present consortium, which has worked on the VISCEL JOR3‐CT98‐0208 Joule III project. This project's goal was to determine the aerodynamic characteristics as well as the aeroelastic behaviour of wind turbine blades across their broad range of operational conditions, from attached to highly separated flow regimes. The work programme included specific tasks for the validation and assessment of existing 3D solvers, for the parametric study of 3D flow around realistic blades and for the investigation of aeroelastic stability, at the blade section level. Copyright © 2003 John Wiley & Sons, Ltd.