The relevance of rapid assessment to health research and interventions

This paper introduces the special issue on rapid assessment methods for tropical disease research. It highlights disease control problems that the combined skills of social and biomedical scientists must address, as well as problems hampering multidisciplinary research. Traditional social science and epidemiological methods are often too time-consuming to address the immediate and urgent needs of disease control programmes. Rapid assessment methods to provide information on health status, health impact, health services and health behaviour are therefore essential. A distinction is made between the efficacy of disease control tools and community effectiveness (the efficacy of the tools as applied at the community level), and the potential for rapid assessment to improve community effectiveness is emphasized. The development and validation of rapid assessment methods is discussed, and the techniques described more fully in subsequent papers are introduce

Off-diagonal hyperfine interaction between the 6p1/2 and 6p3/2 levels in 133Cs

The off-diagonal hyperfine interaction between the 6p1/2 and 6p3/2 states in 133Cs is evaluated in third-order MBPT giving 37.3 Hz and 48.3 Hz, respectively, for second-order energies of the 6p3/2 F=3 and F=4 levels. This result is a factor of 10 smaller than one obtained from an uncorrelated first-order Dirac-Hartree-Fock calculation and used in the analysis of a recent high-precision (< 2 kHz) measurement of the 6p3/2 hyperfine structure [Gerginov et al. Phys. Rev. Lett. 91, 72301 (2003)]. The factor of 10 difference has negligible effect on the conclusions of the recent experiment but will become important for experiments carried out at a precision of better than 1 kHz

Biochemical and Microbiological Investigations of Inhibitors for β-Lactamases from Human Pathogenic Bacteria

The majority of antibiotics prescribed for treatment of bacterial infections are β-lactam antibiotics. Resistance to these has evolved in a few different ways, notably by regulating permeability and by the expression of β-lactamases which hydrolyze the antibiotic before it reaches its target. Three of the classes of β-lactamases (classes A, C and D) are serine-β-lactamases (SBLs) and the fourth class (Class B) consists of metallo-β-lactamases (MBLs) that rely on one or two zinc ions for their catalytic activity. Bacteria producing β-lactamases that are capable of hydrolyzing the β-lactam bond in all of the classes of β-lactam antibiotics including penicillins, monobactams, cephalosporins and carbapenems are of great clinical concern. As a consequence of the increasing prevalence of resistance, there is much interest in the discovery of inhibitors for such clinically important β-lactamases as well as in the discovery of β-lactam antibiotics that are less susceptible to inactivation by β-lactamases. Described in this thesis are the kinetic properties of new chromogenic cephalosporin-type substrates that are susceptible to hydrolysis by clinically important SBLs and MBLs but that exhibit a much more pronounced colour change upon hydrolysis than does the commercially available and widely used chromogenic cephalosporin called nitrocefin. Some of these substrates also offer more favourable kinetic properties for assaying MBLs in vivo. Also in this thesis, biochemical as well as microbiological investigations of several classes of SBL and MBL inhibitors are describes as well as one class of cephalosporins that exhibit inhibition of MBLs and surprising antibacterial potency against certain clinically significant MBL-producing Gram negative bacteria. More specifically, 6-phosphonomethylpyridine-2-carboxylates (PMPCs) and a number of derivatives thereof, synthesized previously in this research group have been shown in this thesis research to be potent inhibitors (low to submicromolar Ki) of the major Class B1 MBLs, IMP-1, VIM-2, NDM-1 and SPM-1 as well as the Class B3 MBL L1, all of which are dizinc enzymes, and somewhat less potent inhibitors of the monozinc Class B2 MBL, SFH-1, which is of lesser clinical significance. These compounds that are expected to exhibit metal-binding characteristics were found to exhibit a time-dependent inhibition mechanism which fits a kinetic mechanism that is consistent with slow binding to the active site and even slower release of the inhibitor without expulsion of the metal ions form the MBL active site. Microbiological investigations were also carried out involving combinations of PMPCs with the carbapenem antibiotic meropenem and demonstrated an ability of the PMPCs to lower the MICs of meropenem against of MBL-producing clinical strains of Eschericia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, Acinetobacter baumannii and Stenotrophomonas maltophilia thus encouraging further research on even more potent PMPCs for potential clinical use in combination with carbapenems. Another class of MBL inhibitors that was studied consist of cephalosporin derivatives that incorporate an aromatic thioester linked to C3ʹ of the cephalosporin core. It was found that inhibition of the Class B3 MBL L1 was likely the consequence largely of the binding of an arylthioacid conjugate base to the active site zinc ions after its expulsion from the hydrolysis product of the cephalosporin. This led to a study of the MBL-inhibitory properties of a series of synthetic arylthioacids, a class of compounds that have not been well studied as metallo enzyme inhibitors. These compounds were found to be poor inhibitors of Class B1 MBLs (IMP-1, VIM-2, NDM-2 and SPM-1) but good inhibitors of the B3 MBL L1. These observations are consistent with inhibition of Class B1 MBLs arising not from the arylthicarboxylate released but from binding the cephalosporin-derived metal-binding species formed upon expulsion of the arylthiocarboylate from the active site. A further enzyme kinetic study revealed that synthetic samples of pyridine-2,6-bis(carbothioic) acid and 6-thiocarboxy-picolinic acid, previously known as Fe3+-binding siderophores produced by some species of Pseudomonas, were good inhibitors of Class B1 and B3 MBLs and also exhibited an ability to lower the MIC of meropenem against MBL-producing clinically important Gram negative bacteria. One cephalosporin called UW-123 with at C3ʹ-arylacylthio group and a siderophore mimic attached to the amide group at C7 was studied in some detail microbiologically and found to exhibit good standalone antibiotic activity against certain MBL-producing Gram-negative bacteria especially those producing the widespread MBL VIM-2. UW-123 was also shown to be bacteriostatic and to bind preferentially to induce filamentation of E. coli cells. It was found to bind most strongly to PBP 3 and 1a but also significantly to PBP1b and 4 in P. aeruginosa. In E. coli, UW-123 bound most tightly to PBP3 but also significantly to PBP1a/b and PBP2. Finally, the ability of a cyclobutanone mimic of penem antibiotics JJ05-1058, previously prepared in this laboratory, to inhibit both SBLs and MBLs was demonstrated and the ability of this compound to bind to the low molecular weight penicillin binding proteins was observed suggesting that such compound may have some promise as broad spectrum MBL/SBL inhibitors and possible also as antibiotics that inhibit penicillin binding proteins

Precision Measurements of Atomic Lifetimes and Hyperfine Energies in Alkali Like Systems

Financial support of this research project has lead to advances in the study of atomic structure through precision measurements of atomic lifetimes, energy splittings, and transitions energies. The interpretation of data from many areas of physics and chemistry requires an accurate understanding of atomic structure. For example, scientists in the fields of astrophysics, geophysics, and plasma fusion depend on transition strengths to determine the relative abundances of elements. Assessing the operation of discharges and atomic resonance line filters also depends on accurate knowledge of transition strengths. Often relative transition strengths are measured precisely, but accurate atomic lifetimes are needed to obtain absolute values. Precision measurements of atomic lifetimes and energy splittings also provide fundamentally important atomic structure information. Lifetimes of allowed transitions depend most strongly on the electronic wave function far from the nucleus. Alternatively, hyperfine splittings give important information about the electronic wave function in the vicinity of the nucleus as well as the structure of the nucleus. Our main focus throughout this project has been the structure of atomic cesium because of its connection to the study of atomic parity nonconservation (PNC). The interpretation of atomic PNC experiments in terms of weak interaction coupling constants requires accurate knowledge of the electronic wave function near the nucleus as well as far from the nucleus. It is possible to address some of these needs theoretically with sophisticated many-electron atomic structure calculations. However, this program has been able to address these needs experimentally with a precision that surpasses current theoretical accuracy. Our measurements also play the important role of providing a means for testing the accuracy of many-electron calculations and guiding further theoretical development, Atomic systems such as cesium, with a single electron outside of a closed shell, provide the simplest open shell systems for detailed comparisons between experiment and theory. This program initially focused on measurements of excited state atomic lifetimes in alkali atomic systems. Our first measurements of atomic lifetimes in cesium surpassed the precision and accuracy of previous measurements and sparked renewed interest in the need for greater precision in lifetime measurements throughout the atomic physics community. After enhancing the capabilities of the laser systems built for these initial measurements, we began a study hyperfine energy splittings in cesium using a thermal atomic beam. The results surpassed previous measurements by more than an order of magnitude and lead to the first observation of the nuclear magnetic octupole moment in cesium demonstrating the inadequacy of the nuclear shell model for predicting high order nuclear moments. The laser system and atomic beam apparatus developed for these endeavors turned out to be perfectly suited for exploring the possibility of making absolute optical frequency measurements of atomic transitions. We initiated collaboration with researchers at NIST so that the desired optical frequencies could be reference with respect to the primary microwave frequency standard (Cs atomic fountain NIST-FI) via a femtosecond laser frequency comb. Our first absolute optical frequency measurement, of the cesium D2 line, surpassed the accuracy of a previous measurement by more than an order of magnitude. An absolute optical frequency measurement of the cesium D1 line, now near completion, also surpasses previous results and places us in a position to be able to report a new value for the fine structure constant which is the fundamental dimensionless constant that underlies all electromagnetic interactions

Femtosecond frequency comb measurement of absolute frequencies and hyperfine coupling constants in cesium vapor

We report measurements of absolute transition frequencies and hyperfine coupling constants for the 8S_{1/2}, 9S_{1/2}, 7D_{3/2}, and 7D_{5/2} states in ^{133}Cs vapor. The stepwise excitation through either the 6P_{1/2} or 6P_{3/2} intermediate state is performed directly with broadband laser light from a stabilized femtosecond laser optical-frequency comb. The laser beam is split, counter-propagated and focused into a room-temperature Cs vapor cell. The repetition rate of the frequency comb is scanned and we detect the fluorescence on the 7P_{1/2,3/2} -> 6S_{1/2} branches of the decay of the excited states. The excitations to the different states are isolated by the introduction of narrow-bandwidth interference filters in the laser beam paths. Using a nonlinear least-squares method we find measurements of transition frequencies and hyperfine coupling constants that are in agreement with other recent measurements for the 8S state and provide improvement by two orders of magnitude over previously published results for the 9S and 7D states.Comment: 14 pages, 14 figure

Measurement of the hyperfine coupling constants and absolute energies of the 8p 2P1/28p \ ^2P_{1/2} and 8p 2P3/28p \ ^2P_{3/2} levels in atomic cesium

We report measurements of the hyperfine coupling constant for the $8p \ ^2P_{1/2}$level of atomic cesium,$^{133}$Cs, with a relative uncertainty of$\sim$0.019\%. Our result is$A = 42.933 \: (8)$MHz, in good agreement with recent theoretical results. We also examine the hyperfine structure of the$8p \ ^2P_{3/2}$state, and derive new values for the state energies of the$8p \ ^2P_{1/2}$and$8p \ ^2P_{3/2}$ states of cesium.Comment: 8 pages, 7 figures, 5 table

Measurement of the static Stark Shift of the 7s 2S1/27s \ ^2S_{1/2} level in atomic cesium

We report a new precision measurement of the dc Stark shift of the 6s\hspace{1mm} ^2S_{1/2} \rightarrow 7s\hspace{1mm}^2S_{1/2} transition in atomic cesium-133. Our result is 0.72246 (29) $\textrm{Hz}(\textrm{V}/\textrm{cm})^{-2}$. This result differs from a previous measurement of the Stark shift by $\sim$0.5\%. We use this value to recalculate the magnitude of the reduced dipole matrix elements $\langle7s ||r||7p_{j}\rangle$, as well as the vector transition polarizability for the $6s \rightarrow 7s$ transition, $\tilde{\beta} = 27.043 \: (36) \ a_0^3$. This determination helps resolve a critical discrepancy between two techniques for determining the vector polarizability.Comment: 5 pages, 3 figures, 3 table

Determination of copper in tap water using solid-phase spectrophotometry

A new application of ion exchange films is presented. The films are used in a simple analytical method of directly determining low concentrations of Cu(2+) in aqueous solutions, in particular, drinking water. The basis for this new test method is the color and absorption intensity of the ion when adsorbed onto the film. The film takes on the characteristic color of the adsorbed cation, which is concentrated on the film by many orders of magnitude. The linear relationship between absorbance (corrected for variations in film thickness) and solution concentration makes the determinations possible. These determinations agree well with flame atomic absorption determinations