Genetics in primary care: a USA faculty development initiative

The Genetics in Primary Care (GPC) project is a USA national faculty development initiative with the goal of enhancing the training of medical students and primary care residents by developing primary care faculty expertise in genetics. Educational strategies were developed for the project by an executive committee with input from an advisory committee, comprising individuals with primary care, medical education and genetics expertise. These committees identified the key issues in genetics education for primary care as (1) considering inherited disease in the differential diagnosis of common disorders; (2) using appropriate counseling strategies for genetic testing and diagnosis, and (3) understanding the implications of a genetic diagnosis for family members. The group emphasized the importance of a primary care perspective, which suggests that the clinical utility of genetic information is greatest when it has the potential to improve health outcomes. The group also noted that clinical practice already incorporates the use of family history information, providing a basis for discussing the application of genetic concepts in primary care. Genetics and primary care experts agreed that educational efforts will be most successful if they are integrated into existing primary care teaching programs, and use a case-based teaching format that incorporates both clinical and social dimensions of genetic disorders. Three core clinical skills were identified: (1) interpreting family history; (2) recognizing the variable clinical utility of genetic information, and (3) acquiring cultural competency. Three areas of potential controversy were identified as well: (1) the role of nondirective counseling versus shared decision-making in discussions of genetic testing; (2) the intrinsic value of genetic information when it does not influence health outcomes, and (3) indications for a genetics referral. The project provides an opportunity for ongoing discussion about these important issues.     

The distributions of chain lengths in a crosslinked polyisoprene network

A fundament of classical rubber elasticity theory is the Gaussian chain approximation formula, P(n,r) for the probability distribution of end-to-end distances of a polymer chain composed of n beads. It is considered to provide a realistic distribution of end-to-end distances, r, provided that the length of the polymer chain is much greater than its average end-to-end distance. By considering the number of beads (n) to be the independent variable, we can use P(n,r) to construct the probability distributions of network chain lengths, for fixed r. Since the network crosslinks reduce the probability for the occurrence of longer chains, the formula must be modified by a correction factor that takes this effect into account. We find that, both the shape of the n-probability distribution, its height, and the position of the peak vary significantly with r. We provide a numerical procedure for constructing networks that respect these distributions. The algorithm was implemented in a three-dimensional, random polymer-and-node network model to construct polyisoprene networks at two common crosslink densities. Although the procedure does not constrain the density, we find that the networks constructed have densities very close to the measured bulk density.     

Reactions of OH with butene isomers: measurements of the overall rates and a theoretical study

Reactions of hydroxyl (OH) radicals with 1-butene (k(1)), trans-2-butene (k(2)), and cis-2-butene (k(3)) were studied behind reflected shock waves over the temperature range 880-1341 K and at pressures near 2.2 atm. OH radicals were produced by shock-heating tert-butyl hydroperoxide, (CH(3))(3)-CO-OH, and monitored by narrow-line width ring dye laser absorption of the well-characterized R(1)(5) line of the OH A-X (0, 0) band near 306.7 nm. OH time histories were modeled using a comprehensive C(5) oxidation mechanism, and rate constants for the reaction of OH with butene isomers were extracted by matching modeled and measured OH concentration time histories. We present the first high-temperature measurement of OH + cis-2-butene and extend the temperature range of the only previous high-temperature study for both 1-butene and trans-2-butene. With the potential energy surface calculated using CCSD(T)/6-311++G(d,p)//QCISD/6-31G(d), the rate constants and branching fractions for the H-abstraction channels of the reaction of OH with 1-butene were calculated in the temperature range 300-1500 K. Corrections for variational and tunneling effects as well as hindered-rotation treatments were included. The calculations are in good agreement with current and previous experimental data and with a recent theoretical study.     

In search of a new class of stable nitroxide: synthesis and reactivity of a peri-substituted N,N-bissulfonylhydroxylamine

Acyclic bissulfonylnitroxides have never been isolated, and degrade through fragmentation. In an approach to stabilising a bissulfonylnitroxide radical, the cyclic, peri-substituted N,N-bissulfonylhydroxylamine, 2-hydroxynaphtho[1,8-de][1,3,2]dithiazine 1,1,3,3-tetraoxide (1), has been prepared by formal nitrogen insertion into the sulfur-sulfur bond of a sulfinylsulfone, naphtho[1,8-cd][1,2]dithiole 1,1,2-trioxide. The heterocyclic ring of 1 is shown to adopt a sofa conformation by X-ray crystallography, with a pseudo-axial hydroxyl group. N,N-Bissulfonylhydroxylamine 1 displays high thermal, photochemical and hydrolytic stability compared to acyclic systems. EPR analysis reveals formation of the corresponding bissulfonylnitroxide 2 upon oxidation of 1 with the Ce(IV) salts CAN and CTAN. Although 2 does not undergo fragmentation, it cannot be isolated, since hydrogen atom abstraction to reform 1 occurs in situ. The stability and reactivity of 1 and 2 are compared with the known cyclic benzo-fused N,N-bissulfonylhydroxylamine, N-hydroxy-O-benzenedisulfonimide (6), for which the X-ray data, and EPR of the corresponding nitroxide 10, are also reported for the first time.     

Reactions of coordinated hydroxymethylphosphines with NH-functional amines: the phosphorus lone pair is crucial for the phosphorus Mannich reaction

Non-coordinated hydroxymethylphosphines react readily with primary and secondary amines by the phosphorus Mannich reaction. To determine if this reactivity can be used to synthesize phosphine macrocycles, trans-Fe(DHMPE)(2)Cl(2) (DHMPE = 1,2-bis(dihydroxymethylphosphino)ethane) was prepared and reacted with various amines. However, no phosphorus Mannich reactivity was observed. In order to understand why no reactions occurred, the Mannich reactivity of the borane-coordinated hydroxymethylphosphines DHMPE·2BH(3) and Ph(2)PCH(2)OH·BH(3) was investigated. These borane-coordinated phosphines also did not undergo the phosphorus Mannich reaction. These results suggest that the lone pair of electrons on the phosphorus atom is essential for the phosphorus Mannich reaction to occur, and therefore it is not possible to use this reaction in a templated synthesis of phosphine macrocycles. It is speculated that the mechanism of the phosphorus Mannich reaction may involve a methylenephosphonium intermediate, analogous to an iminium in the standard Mannich reaction. X-ray crystal structures of trans-Fe(DHMPE)(2)Cl(2) and DHMPE·2BH(3) are also presented. Both crystal structures display an extended hydrogen-bonding network in the solid state.     

A new paradigm for the molecular basis of rubber elasticity

The molecular basis for rubber elasticity is arguably the oldest and one of the most important questions in the field of polymer physics. The theoretical investigation of rubber elasticity began in earnest almost a century ago with the development of analytic thermodynamic models, based on simple, highly-symmetric configurations of so-called Gaussian chains, i.e. polymer chains that obey Markov statistics. Numerous theories have been proposed over the past 90 years based on the ansatz that the elastic force for individual network chains arises from the entropy change associated with the distribution of end-to-end distances of a free polymer chain. There are serious conceptual objections to this assumption and others, such as the assumption that all network nodes undergo a simple volume-preserving linear motion and that all of the network chains have the same length. Recently, a new paradigm for elasticity in rubber networks has been proposed that is based on mechanisms that originate at the molecular level. Using conventional statistical mechanics analyses, Quantum Chemistry, and Molecular Dynamics simulations, the fundamental entropic and enthalpic chain extension forces for polyisoprene (natural rubber) have been determined, along with estimates for the basic force constants. Concurrently, the complex morphology of natural rubber networks (the joint probability density distributions that relate the chain end-to-end distance to its contour length) has also been captured in a numerical model (EPnet). When molecular chain forces are merged with the network structure in this model, it is possible to study the mechanical response to tensile and compressive strains of a representative volume element of a polymer network. As strain is imposed on a network, pathways of connected taut chains, that completely span the network along strain axis, emerge. Although these chains represent only a few percent of the total, they account for nearly all of the elastic stress at high strain. Here we provide a brief review of previous elasticity theories and their deficiencies, and present a new paradigm with an emphasis on experimental comparisons.     

Wavelength modulation diode laser absorption spectroscopy for high-pressure gas sensing

A general model for 1f-normalized wavelength modulation absorption spectroscopy with nf detection (i.e., WMS-nf) is presented that considers the performance of injection-current-tuned diode lasers and the reflective interference produced by other optical components on the line-of-sight (LOS) transmission intensity. This model explores the optimization of sensitive detection of optical absorption by species with structured spectra at elevated pressures. Predictions have been validated by comparison with measurements of the 1f-normalized WMS-nf (for n = 2–6) lineshape of the R(11) transition in the 1st overtone band of CO near 2.3 μm at four different pressures ranging from 5 to 20 atm, all at room temperature. The CO mole fractions measured by 1f-normalized WMS-2f, 3f, and 4f techniques agree with calibrated mixtures within 2.0 %. At conditions where absorption features are significantly broadened and large modulation depths are required, uncertainties in the WMS background signals due to reflective interference in the optical path can produce significant error in gas mole fraction measurements by 1f-normalized WMS-2f. However, such potential errors can be greatly reduced by using the higher harmonics, i.e., 1f-normalized WMS-nf with n > 2. In addition, less interference from pressure-broadened neighboring transitions has been observed for WMS with higher harmonics than for WMS-2f.     

Optimality and duality with generalized convexity

Hanson and Mond have given sets of necessary and sufficient conditions for optimality and duality in constrained optimization by introducing classes of generalized convex functions, called type I and type II functions. Recently, Bector defined univex functions, a new class of functions that unifies several concepts of generalized convexity. In this paper, optimality and duality results for several mathematical programs are obtained combining the concepts of type I and univex functions. Examples of functions satisfying these conditions are given.     

Zero temperature phase transitions in spin-ladders: Phase diagram and dynamical studies of Cu2(C5H12N2)2Cl4>

In a magnetic field, spin-ladders undergo two zero-temperature phase transitions at the critical fields H_c1 and H_c2. An experimental review of static and dynamical properties of spin-ladders close to these critical points is presented. The scaling functions, universal to all quantum critical points in one-dimension, are extracted from (a) the thermodynamic quantities (magnetization) and (b) the dynamical functions (NMR relaxation). A simple mapping of strongly coupled spin ladders in a magnetic field on the exactly solvable XXZ model enables to make detailed fits and gives an overall understanding of a broad class of quantum magnets in their gapless phase (between H_c1 and H_c2). In this phase, the low temperature divergence of the NMR relaxation demonstrates its Luttinger liquid nature as well as the novel quantum critical regime at higher temperature. The general behavior close these quantum critical points can be tied to known models of quantum magnetism. Received: 13 March 1998 / Received in final form and Accepted: 21 July 1998     

Measurement of aerosol size distribution functions by wavelength-multiplexed laser extinction

Previous work on the measurement of aerosol size distribution functions (SDFs) by laser extinction mainly relied on light sources from a relatively narrow wavelength range. This paper investigates the potential advantages of extending the extinction method to a general wavelength-multiplexed laser extinction (WMLE) concept by incorporating an arbitrary number of laser sources from a wider wavelength range. This extension improves the sensitivity of SDF measurements over wider aerosol diameter ranges and enables a stable algorithm to invert the extinction data to obtain SDFs. These advantages are illustrated by an example WMLE scheme employing wavelengths in the spectral range from 0.25 to 10μm to measure SDFs of water aerosols. Application of this approach to other aerosol systems is also considered. The WMLE scheme was found to provide stable determination of a variety of SDFs with Sauter mean diameters ranging from sub-micron to about 10μm. The sensitivity of such determinations was evaluated to reveal the optimum applicable range of the wavelengths employed. The analyses performed here provide theoretical background and motivation for practical applications of the WMLE concept.