Mannose-binding lectin alleles in sub-Saharan Africans and relation with susceptibility to infections.

Mannose-binding lectin (MBL) plays an important role in the early stages of primary infections and during the decay of maternal antibodies in infants. Various studies have looked at the relation between serum MBL concentrations, MBL gene alterations and susceptibility to infections. We investigated the distribution of variant MBL alleles in 626 unrelated adults from sub-Saharan African countries and looked for a potential relation between these alleles and the incidence, prevalence and death rate of tuberculosis for sub-Saharan Africa. We also evaluated the relation between MBL genotypes and susceptibility to HIV-1 infection in 188 Gabonese adults. We found that (i) the prevalence of the common variant MBL alleles is correlated with the incidence of tuberculosis in sub-Saharan Africa (r=0.565), (ii) the mutant MBL G57E allele, in either the homozygous or compound heterozygous state, is associated with susceptibility to HIV-1 infection in the Gabonese population (P=0.019).Our data plus those in the literature suggest that individuals who are homozygous for the mutant MBL alleles display increased susceptibility to infections. Interestingly, we found that individuals who are heterozygous for MBL mutations are much less susceptible to infections than those who are homozygous for the wild-type MBL allele.

CYP2D6 polymorphism in a Gabonese population: contribution of the CYP2D6*2 and CYP2D6*17 alleles to the high prevalence of the intermediate metabolic phenotype.

AIMS: To determine the molecular basis of the intermediate extensive metaboliser (EM) CYP2D6 phenotype in healthy Gabonese subjects. METHODS: The CYP2D6 phenotype of 154 healthy Gabonese subjects was assessed by giving the subject a single dose of 30 mg dextromethorphan, and collecting their urine for the next 8 h. The CYP2D6 genotype was determined for 50 individuals of the EM phenotypic group by Southern blotting and various PCR-based procedures aimed at identifying different CYP2D6 alleles. RESULTS: We found that in the studied Gabonese population, as compared with a French population, there is significantly higher frequency of intermediate EM phenotype having lower frequency of CYP2D6 PM alleles. To clarify this discrepancy phenotype-genotype relationship was studied. We found that the CYP2D6*17 and CYP2D6*2 alleles, prevalent in this black population, are characterised by their low capacity for dextromethorphan demethylation. Our data also show that the CYP2D6*1 allele is associated with the highest in vivo activity followed by the CYP2D6*2 allele and then the CYP2D6*17 allele. CONCLUSIONS: The higher frequencies of the CYP2D6*2 and CYP2D6*17 alleles than the CYP2D6*1 allele account for the high frequency of the intermediate EM phenotype in this black population. The polymorphism of the CYP2D6 enzyme activity in African populations could have important implications for use of drugs that are substrates for CYP2D6 and have a narrow therapeutic window.

Asymptotic behavior of the boundary value problem of four-wave mixing in photorefractive media.

Solutions to the four-wave mixing problem asymptotically approach a spatial steady state over large interaction distances. In this limit, intensities of the two-point boundary value problem may be found from solutions to quadratic equations. The different limiting behavior exhibited for positive and negative gain has important implications for applications in which linearity of system response is important. In the regime studied, positive gain leads quickly to maximally depleted pumps with increasing input signal. For negative gain, such depletion does not occur until higher signal levels are reached.

Genotyping of the polymorphic N-acetyltransferase (NAT2*) gene locus in two native African populations.

The hepatic N-acetyltransferase enzyme encoded by the NAT2* gene locus is responsible for the human polymorphic acetylation of numerous arylamine or hydrazine-containing drugs and xenobiotics including AIDS-related therapeutic agents such as isoniazid and sulphonamides. The genetic basis underlying the human acetylation polymorphism has been extensively studied in several populations but native African populations were poorly documented. In the present study, 117 unrelated black Africans, namely Dogons from Mali and Gabonese, were investigated for NAT2* allelic variability and genotype distribution. Thirteen NAT2* alleles were unambiguously identified by combined use of allele-specific reamplifications and restriction endonuclease digestions. Our results confirm the African origin of G191->A substitution in the NAT2* coding region which was previously associated with slow acetylation in African-Americans. The finding of high allelic diversity in the studied populations is consistent with the hypothesis of a single African origin for NAT2*-associated polymorphism. Finally, no excess of the slow acetylator phenotype is predicted in these populations, implying no need for fitting NAT2* polymorphism-sensitive therapies to black Africans, compared to Caucasians.

Sheared-beam imaging: an evaluation of its optical compensation of thick atmospheric turbulence.

Sheared-beam imaging (SBI) should compensate the effects of an idealized layer of turbulence located either in a transmitter/detector plane or in an object plane. This motivated the study of optical compensation of SBI in the presence of uniformly distributed turbulence over long horizontal paths in the cases of ideally smooth and ideally rough extended objects. The phase error along a one-dimensional wave front resulting from SBI observation is computed numerically in the long-path regime and is compared with that of an equivalent conventional system for the case of a large smooth object. It is found that for the conditions considered the phase errors of the SBI system are greater than those of a conventional system. In the case of an ideally rough object the extra information furnished by the SBI observations does not lead to data that can be inverted to compute an image by the conventional shearing-interferometric algorithm. The phase errors in imaging a point reflector, however, are perfectly compensated.

Compensation of spacer-thickness variations in a holographic Fabry-Perot filter.

The fabrication of a solid, holographically recorded Fabry-Perot interferometer that uses plate glass for the spacer has recently been reported. The component produced sharp, circular Fabry-Perot fringes in spite of its use of a plate-glass spacer. We develop a general theoretical characterization of such a component that accounts for its low sensitivity to spacer-thickness variations. We use the Kogelnik theory of volume holograms to calculate the phase change on reflection from the mirrors. This phase change results from the position of the fringes formed throughout the two holographic media during the recording process. An expression for the wavelength location of the transmission peak versus spacer-thickness variation is derived that agrees with the current experimental information available.

Image speckle contrast reduction resulting from integrative synthetic aperture imaging.

Reduction of image speckle noise with the use of an integrative synthetic aperture imaging technique is studied. It is found that the Fourier inversion of the mutual intensity estimate [Appl. Opt. 30, 206-213 (1991)] yields an image intensity that corresponds exactly to the illumination of the object with partially coherent light from source optics imaging a delta-function incoherent source. An expression for the signal-to-noise ratio at an image point is derived for a large rough object with delta-function correlated amplitude reflection. A synthetic aperture system receiver of sufficiently small diameter yields image speckle with a signal-to-noise ratio (SNR) equal to 1. When the receiver and the transmitter diameters are equal, the SNR is 2 for linearly polarized speckle. The SNR continues to increase with receiver size and is linear in the diameter for large receiver-to-transmitter diameter ratios.

Estimator and signal-to-noise ratio for an integrative synthetic aperture imaging technique.

An imaging system is described which uses the following concepts: laser illumination of objects, nonredundant apertures, and phase closure. A sparse transmitter array is envisioned, each aperture of which emits at a different laser frequency such that any pair of beams gives rise to a unique beat signal. The light reflected by an object thus irradiated is sensed by a spatially integrating detector array. An estimator is given for the Fourier components of the object at spatial frequencies corresponding to the unique temporal beats sensed by the receiver array. The standard deviation of the estimator is computed taking both shot noise and laser speckle into account. It is found that the signal-to-noise ratio for both kinds of noise increases with the square root of the area of the detector array. This allows the signal-to-noise ratio of the system to be increased independent of the resolution.

Method for calibrating heterodyne receiver arrays.

Modification of the transmitter section of a heterodyne laser radar to include two additional output beams at appropriate offset frequencies makes calibration of the local oscillator phases of a multichannel receiver possible.

Constraints on passive spatial coherence filtering of imaging systems due to properties of the impulse response.

Properties of the amplitude and intensity impulse responses of passive optical imaging systems have consequences for the spatial coherence filtering properties of such systems. It is shown that imaging systems that have both space-invariant impulse responses and truncating pupil functions have no capability to block spatially coherent sources while imaging those that are incoherent. However, examples of systems with space-variant impulse responses with approximately such capabilities appear to be realizable for a certain range of parameters. However, even space-variant systems cannot block unresolved coherent sources while retaining the capability of imaging those that are spacially incoherent for the same range of source-plane coordinates.

Thermodynamic study of the influence of NADPH on the binding of methotrexate and its metabolites to a mammalian dihydrofolate reductase.

Interaction of methotrexate and some of its metabolites with a mammalian dihydrofolate reductase was studied using two complementary methods, potentiometry and microcalorimetry. The major plasma metabolite of this anticancer agent, 7-hydroxymethotrexate, was found to have a different binding behavior from that of polyglutamyl derivatives and of methotrexate itself. Indeed, 7-hydroxymethotrexate binds without a pK shift to dihydrofolate reductase, whereas polyglutamyl derivatives bind to the enzyme with a proton uptake, as the parent drug does. NADPH increases the association constant of the 7-hydroxy metabolite by a factor of 10-20, while for methotrexate and for polyglutamates this increase is about 100-fold. It was demonstrated that the enhancement of the binding by NADPH had an enthalpic origin. Finally, the binding behavior of dihydrofolate reductase seemed to be independent of its enzymatic activity.

A flow microcalorimetric method for enzyme activity measurements: application to dihydrofolate reductase.

A flow microcalorimetric method was developed for the analysis of enzymatic activities in crude tissue homogenates. It can be applied whenever a heat exchange is involved in an enzymatic reaction. The consequent sensitivity obviously depends on the enthalpy variation observed. Dihydrofolate reductase was chosen as an example; this enzyme is the molecular target of methotrexate, a widely used anticancer agent. This calorimetric method, whose sensitivity limit is 1.48 X 10(-4) units of dihydrofolate reductase per milliliter of reactant medium, allows enzyme activity measurements in tissues with low dihydrofolate reductase levels. A few examples of measurements in animal tissues are given. These measurements are of some interest; indeed, increased activity and increased levels of this enzyme are two of the mechanisms which may explain resistance to methotrexate.

pH-Stat titration method for dihydrofolate reductase activity measurements: application to determination of substrate Michaelis constant and antifolate inhibition constant.

A pH-Stat titration method was developed for measuring dihydrofolate reductase (DHFR) activity; this method permits detection of very low DHFR activities corresponding to 100 pmol of substrate reduced per minute. This value is about ten times lower than those observed using the classical spectrophotometric method. This sensitivity makes it possible to measure the DHFR in crude tissue extracts. With beef liver DHFR, Michaelis constants for the cofactor NADPH and the natural substrate determined by this method were 1.9 +/- 0.3 X 10(-5) and 8.5 +/- 0.5 X 10(-7) M, respectively. The inhibition constant of methotrexate, a competitive inhibitor of dihydrofolate, was 3.4 +/- 1.3 X 10(-11) M.

Three beam interferometer for the observation of kinetic cooling in air.

A three beam interferometer, which has recently been used to measure the time constant associated with kinetic cooling, is described in detail. Design features necessitated by operation of the device over a 5-m path are discussed, as well as system response to vibrational noise and drift, and means used for their monitoring and control. The effective working length resolution of the system, dL/L, was 1 part in 2.6 x 10(9) with a He-Ne laser source operating at 0.63 microm.