A proposal for optical diagnostics through the enhancement of diffraction patterns using thin-film interference filters

Coarse clumping of solid materials within diseased biological cells can have a marked influence on the light scattering pattern. Perturbations in refractive index lead to distinct variations in the cytometric signature, especially apparent over wide scattering angles. The large dynamic range of scattering intensities restricts collection of data to narrow angular intervals believed to have the highest potential for medical diagnosis. We propose the use of an interference filter to reduce the dynamic range. Selective attenuation of scattering intensity levels is expected to allow simultaneous data collection over a wide angular interval. The calculated angular transmittance of a commercial shortwave-pass filter of cut-off wavelength 580 nm indicates significant attenuation of scattering peaks below ∼10°, and reasonable peak equalization at higher angles. For the three-dimensional calculation of laser light scattered by cells we use a spectral method code that models cells as spatially varying dielectrics, stationary in time. However, we perform preliminary experimental testing with the interference filter on polystyrene microspheres instead of biological cells. A microfluidic toolkit is used for the manipulation of the microspheres. The paper intends to illustrate the principle of a light scattering detection system incorporating an interference filter for selective attenuation of scattering peaks.     

Mammalian models of extended healthy lifespan

Over the last two centuries, there has been a significant increase in average lifespan expectancy in the developed world. One unambiguous clinical implication of getting older is the risk of experiencing age-related diseases including various cancers, dementia, type-2 diabetes, cataracts and osteoporosis. Historically, the ageing process and its consequences were thought to be intractable. However, over the last two decades or so, a wealth of empirical data has been generated which demonstrates that longevity in model organisms can be extended through the manipulation of individual genes. In particular, many pathological conditions associated with the ageing process in model organisms, and importantly conserved from nematodes to humans, are attenuated in long-lived genetic mutants. For example, several long-lived genetic mouse models show attenuation in age-related cognitive decline, adiposity, cancer and glucose intolerance. Therefore, these long-lived mice enjoy a longer period without suffering the various sequelae of ageing. The greatest challenge in the biology of ageing is to now identify the mechanisms underlying increased healthy lifespan in these model organisms. Given that the elderly are making up an increasingly greater proportion of society, this focused approach in model organisms should help identify tractable interventions that can ultimately be translated to humans.     

Scattering of ultrasound in cancellous bone: predictions from a theoretical model

An understanding of the interaction between acoustic waves and cancellous bone is needed in order to realize the full clinical potential of ultrasonic bone measurements. Scattering is likely to be of central importance but has received little attention to date. In this study, we adopted a theoretical model from the literature in which scattering was assumed to be proportional to the mean fluctuation in sound speed, and bone was considered to be a random continuum containing identical scatterers. The model required knowledge only of sound speeds in bone and marrow, porosity, and scatter size. Predicted attenuation, broadband ultrasonic attenuation (BUA) and backscatter coefficient were obtained for a range of porosities and scatterer sizes, and were found to be comparable to published values for cancellous bone. Trends in predicted BUA with porosity agreed with previous experimental observations. All three predicted acoustic parameters showed a non-linear dependence on scatterer size which was independent of porosity. These data confirm the value of the scattering approach and provide the first quantitative predictions of the independent influence of structure and porosity on bone acoustic properties.     

Streptozocin model of diabetes mellitus in the mollusc Anodonta cygnea: functional state of the adenylyl cyclase mechanisms of action of peptides of the insulin superfamily and their effect on carbohydrate metabolism enzymes

In terms of development of evolutionary biomedicine using invertebrate animals as models for study of molecular grounds of various human diseases, for the first time the streptozocin (ST) model of insulin-dependent diabetes in the mollusc Anodonta cygnea has been developed. This model is based on the following authors' data: (1) redetection of insulin-related peptides (IRP) in mollusk tissues: (2) discovery of the adenylyl cyclase signal mechanism (ACSM) of action of insulin and other peptides of the insulin superfamily in tissues of mammals, human, and mollusc. A. cygnea; (3) concept of molecular defects in hormonal signal systems as causes of endocrine diseases. Studies on the ST model have revealed in mollusc smooth muscle on the background of hyperglycemia at the 2nd, 4th, and 8th day after the ST administration a decrease of the ACSM response to activating action of insulin, IGF-1, and relaxin. These functional disturbances were the most pronounced at the 2nd day of development and rather less marked at the 4th and 8th day. Analysis of data on effect of hormonal and non-hormonal (NaF, GIDP, and forskolin) ACSM activators has shown that the causes of impair of signal-transducing function of this mechanism are (1) a hyperglycemia-induced increase of the basal AC activity and as a consequence--a decrease of the enzyme catalytic potentials in response to hormone; (2) a decrease of functions of Gs-protein and of its coupling with AC. Besides, administration of ST produced in the mollusc muscles an attenuation of regulation by insulin of carbohydrate metabolism enzyme (glucose-6-phosphate dehydrogenase, glycogensynthase). The pattern of disturbances in the studied parameters in the mollusc is very similar to that revealed by the authors in rat and human muscle tissues in type 1 diabetes.     

Streptozotocin model of diabetes mellitus in the mollusc <Emphasis Type="Italic">Anodonta cygnea</Emphasis>: functional state of the adenylyl cyclase mechanisms of action of insulin superfamily peptides and their effect on carbohydrate metabolism enzymes

In terms of development of evolutionary biomedicine using invertebrate animals as models for study of molecular grounds of various human diseases, for the first time the streptozotocin (ST) model of insulin-dependent diabetes in the mollusc Anodonta cygnea has been developed. This model is based on the following authors’ data: (1) redetection of insulin-related peptides (IRP) in mollusc tissues: (2) discovery of the adenylyl cyclase signal mechanism (ACSM) of action of insulin and other peptides of the insulin superfamily in tissues of mammals, human, and mollusc A. cygnea; (3) concept of molecular defects in hormonal signal systems as causes of endocrine diseases. Studies on the ST model have revealed in mollusc smooth muscle on the background of hyperglycemia at the 2nd, 4th, and 8th day after the ST administration a decrease of the ACSM response to activating action of insulin, IGF-1, and relaxin. These functional disturbances were the most pronounced at the 2nd day of development and rather less marked at the 4th and 8th day. Analysis of data on effect of hormonal and non-hormonal (NaF, GIDP, and forskolin) ACSM activators has shown that the causes of impair of signal-transducing function of this mechanism are (1) a hyperglycemia-induced increase of the basal AC activity and as a consequence—a decrease of the enzyme catalytic potentials in response to hormone; (2) a decrease of functions of G_s-protein and of its coupling with AC. Besides, administration of ST produced in the mollusc muscle an attenuation of regulation by insulin of carbohydrate metabolism enzyme (glucose-6-phosphate dehydrogenase, glycogensynthase). The pattern of disturbances in the studied parameters in the mollusc is very similar to that revealed by the authors in rat and human muscle tissues in type 1 diabetes.     

Image reconstruction of optical attenuation coefficient variation in biological tissues

A procedure for non-invasive imaging of the optical attenuation coefficient variation of in vivo thick organs/tissues is developed. The laser back-scattered surface profiles at various locations of human forearm, by multi-probe reflectometer, are measured. These profiles are matched by iterative procedure, with that as obtained by Monte Carlo simulation and the corresponding values of attenuation coefficient (equal to the sum of absorption and reduced scattering coefficients) are determined. By interpolation of this data a 100 x 100 grid is constructed and after median filtering of this data a color-coded image of the variability of the optical attenuation coefficient of the forearm is obtained. These images in different subjects show variation due to change in overall tissue composition and blood pooling. This non-invasive imaging procedure may help in identifying the diseased affected regions in healthy tissues and in application of photodynamic therapy.     

Evaluation of Exploration and Monitoring Methods for Verification of Natural Attenuation Using the Virtual Aquifer Approach

Though natural attenuation (NA) is increasingly considered as a remediation technology, the methods for proper identification and quantification of NA are still under discussion. Here the "Virtual Aquifer" approach is used to demonstrate problems which may arise during measurement of concentrations in observation wells and for interpolation of locally measured concentrations in contaminated heterogeneous aquifers. The misinterpretation of measured concentrations complicates the identification and quantification of natural attenuation processes. The "Virtual Aquifer" approach accepts the plume simulated with a numerical model for a heterogeneous aquifer as "virtual reality". This virtual plume is investigated in the model with conventional methods like observations wells. The results of the investigation can be compared to the virtual "reality", evaluating the monitoring method. Locally determined concentrations are interpolated using various interpolation methods and different monitoring set-ups. The interpolation results are compared to the simulated plume to evaluate the quality of interpolation. This evaluation is not possible in nature, since concentrations in a heterogeneous aquifer are never known in detail.     

Differential scattering of circularly polarized light as a unique probe of polynucleosome superstructures

A theoretical approach to modeling Circular Intensity Differential Scattering (CIDS) of native chromatin as multiple scattering of dipoles is discussed without the Born approximation. The model can explain the experimental data in the literature. It is shown that CIDS contains more structural information than does total light scattering and to a good approximation is independent of the length of the scattering molecules. Finally, CIDS in conjunction with traditional light scattering measurements should aid in discriminating between various alternative models of higher order chromatin structure now being proposed. Generalization of this theoretical study to other complex biomolecular structures, is also briefly discussed.     

Daily variations in the optical properties of a small lake

1. The major components of the underwater light field (ULF: vertical attenuation, absorption, scattering and suspensoids including plankton fractions) of Las Madres Lake, a small wind‐sheltered, oligohumic lake in Central Spain, were investigated daily over a period of 3 months at the onset of vernal circulation. 2. Gilvin, arising mostly from the decomposition of reeds in the littoral in autumn, was the main component of vertical attenuation, and its variability explained the highest fraction of absorption variability. Tripton appeared to be the main factor responsible for scattering, and might have resulted from dust deposition from the surrounding mining land. The plankton community played a minor role in attenuation, absorption or scattering throughout the investigation period. 3. Vertical and horizontal mixing dynamics may control the ULF to a certain extent, as most optical properties changed within different mixing periods and poor advective exchanges may have resulted in uneven distribution of water colour in this small lake. 4. Time series analysis showed that most autocorrelations were shorter than a week, inherent properties (absorption, scattering) being delayed longer than apparent properties (attenuation, transparency) as a result of their lower dependence on solar irradiance. A 2‐day lag was observed in cross‐correlations between either gilvin and absorption or tripton and scattering. When different mixing periods at early circulation were considered, however, ULF components changed their relationships and delays with suspensoids and dissolved substances over such periods, probably tracking the dynamics of their controlling factors. 5. Our study, and others at daily, weekly, seasonal, interannual and long‐term scales, demonstrates that ULF is a system upon which different processes are operating at different time scales. Contrary to expectations, however, the variability in the ULF does not increase with time scale and depends partly upon the trophic status of lakes.     

Differential scattering of circularly polarized light as a unique probe of polynucleosome superstructures. A simulation by multiple scattering of dipoles

A theoretical approach to modeling Circular Intensity Differential Scattering (CIDS) of native chromatin as multiple scattering of dipoles is discussed without the Born approximation. The model can explain the experimental data in the literature. It is shown that CIDS contains more structural information than does total light scattering and to a good approximation is independent of the length of the scattering molecules. Finally, CIDS in conjunction with traditional light scattering measurements should aid in discriminating between various alternative models of higher order chromatin structure now being proposed. Generalization of this theoretical study to other complex biomolecular structures, is also briefly discussed.     

Comparison of acoustic characteristics predicted by Biot's theory and the modified Biot-Attenborough model in cancellous bone

Biot's theory and the modified Biot-Attenborough (MBA) model are applied to predict the dependences of acoustic characteristics on frequency and on porosity in cancellous bone. The phase velocities and the attenuation coefficients predicted by both theories are compared with the experimental data of bovine cancellous bone specimens published in the literature. Biot's theory successfully predicts the dependences of the phase velocity on frequency and on porosity in cancellous bone, whereas a significant discrepancy is observed between the predicted and the measured attenuation coefficients. The MBA model agrees well with the frequency and the porosity dependences of the phase velocity and the attenuation coefficient experimentally measured in bovine bones. Although the MBA model relies on phenomenological parameters derived from the experimental data, its approach to cancellous bone can be usefully employed in the field of clinical ultrasonic bone assessment.     

Natural Attenuation Rate Clarifications: The True Picture is in the Details

The term “Natural Attenuation” (NA) has been defined as naturally occurring processes in soil and groundwater environments that act without human intervention to reduce the mass, toxicity, mobility, volume, or concentration of contaminants in those media. Monitored natural attenuation (MNA) protocols generally involve the collection of biogeochemical data from groundwater monitoring wells at sites. The data are correlated in time and space with the various chemicals of concern (COC's) to establish predominant biodegradation mechanisms. Modelers using the first-order decay expression typically use the rate coefficient as a calibration parameter and adjust it until the transport model results match field data. With this approach, uncertainties with a number of parameters (e.g., dispersion, sorption, biodegradation, etc.) are lumped together in a single calibration parameter. The problems associated with the lumped parameter approach are illustrated using two commonly used models, BIOSCREEN and Buscheck/Alcantar Analytical Solution, in a variety of practical examples. The natural attenuation decay rate estimated using the lumped parameter approach is distinguished from a biodegradation rate established by isolating processes and examining biodegradation lines of evidence. The half-life determined from empirical data using the lumped parameter approach is often mistakenly interchanged with a biodegradation half-life when it is an all-encompassing half-life based on the interaction of numerous processes. Isolation of the processes, as they are represented in the governing transport equation, and a rationale approach at parameter estimation to avoid the potential pitfalls of the all-inclusive “attenuation rate,” are provided. In closing, it is imperative to implement the following steps to dissern lumped process degradation rates from biodegradation half-lives: (a) be sure the rate/half-life processes are clarified as to what they encompass, (b) establish exactly how the rate/half-life was determined, (c) make certain other processes, such as dispersion, were estimated correctly, and (d) if the half-life is presented as a first-order biodegradation rate, examine the available lines of evidence to substantiate it.     

Monitored Natural Attenuation of Explosives

Explosives are subject to several attenuation processes that potentially reduce concentrations in groundwater over time. Some of these processes are well defined, while others are poorly understood. The objective of the project was to optimize data collection and processing procedures for evaluation and implementation of monitored natural attenuation of explosives. After conducting experiments to optimize data quality, a protocol was established for quarterly monitoring of thirty wells over a 2-year period at a former waste disposal site. Microbial biomarkers and stable isotopes of nitrogen and carbon were explored as additional approaches to tracking attenuation processes. The project included a cone penetrometry sampling event to characterize site lithology and to obtain sample material for biomarker studies. A three-dimensional groundwater model was applied to conceptualize and predict future behavior of the contaminant plume. The groundwater monitoring data demonstrated declining concentrations of explosives over the 2 years. Biomarker data showed the potential for microbial degradation and provided an estimate of the degradation rate. Measuring stable isotopic fractions of nitrogen in TNT was a promising method of monitoring TNT attenuation. Overall, results of the demonstration suggest that monitored natural attenuation is a viable option that should be among the options considered for remediation of explosives-contaminated sites.     

Multivariate approach to calculating the recurrence risk in families with multifactorial diseases

To resolve one of the main theoretical problems of genetic counselling, namely, calculation of the recurrence risk for common diseases, a multivariate approach is suggested, based on the multifactorial model. The model suggests partially different liability for several diseases or various forms of a disease. The specified recurrence risk for each family can be calculated with the account of different morbidity rates for different sexes and the degree of kinship to proband. The input data for computer calculations are: population incidence of diseases, their heritabilities as well as genetical and environmental correlations between the diseases. Our method is illustrated by calculation of the recurrence risk for diabetes mellitus (DM) and bronchial asthma (BA), each of which may be subdivided into several forms. It is proposed that the nature of genetic correlations is different for two diseases. The phenotypic forms of DM are genetically independent, whereas the forms of BA have a common genetic basis.     

Psoas muscle attenuation measurement with computed tomography indicates intramuscular fat accumulation in patients with the HIV-lipodystrophy syndrome.

The human immunodeficiency virus (HIV)-lipodystrophy syndrome is characterized by abnormalities of lipid metabolism, glucose homeostasis, and fat distribution. Overaccumulation of intramuscular lipid may contribute to insulin resistance in this population. We examined 63 men: HIV positive with lipodystrophy (n = 22), HIV positive without lipodystrophy (n = 20), and age- and body mass index-matched HIV-negative controls (n = 21). Single-slice computed tomography was used to determine psoas muscle attenuation and visceral fat area. Plasma free fatty acids (FFA), lipid profile, and markers of glucose homeostasis were measured. Muscle attenuation was significantly decreased in subjects with lipodystrophy [median (interquartile range), 55.0 (51.0-58.3)] compared with subjects without lipodystrophy [57.0 (55.0-59.0); P = 0.05] and HIV-negative controls [59.5 (57.3-64.8); P < 0.01]. Among HIV-infected subjects, muscle attenuation correlated significantly with FFA (r = -0.38; P = 0.02), visceral fat (r = -0.49; P = 0.002), glucose (r = -0.38; P = 0.02) and insulin (r = -0.60; P = 0.0001) response to a 75-g oral glucose tolerance test. In forward stepwise regression analysis with psoas attenuation as the dependent variable, visceral fat (P = 0.02) and FFA (P < 0.05), but neither body mass index, subcutaneous fat, nor antiretroviral use, were strong independent predictors of muscle attenuation (r2 = 0.39 for model). Muscle attenuation (P = 0.02) and visceral fat (P = 0.02), but not BMI, subcutaneous fat, FFA, or antiretroviral use, were strong independent predictors of insulin response (area under the curve) to glucose challenge (r2 = 0.47 for model). These data demonstrate that decreased psoas muscle attenuation due to intramuscular fat accumulation may contribute significantly to hyperinsulinemia and insulin resistance in HIV-lipodystrophy patients. Further studies are needed to assess the mechanisms and consequences of intramuscular lipid accumulation in HIV-infected patients.     

Pore-Scale Modeling of Pore Structure Effects on P-Wave Scattering Attenuation in Dry Rocks

Underground rocks usually have complex pore system with a variety of pore types and a wide range of pore size. The effects of pore structure on elastic wave attenuation cannot be neglected. We investigated the pore structure effects on P-wave scattering attenuation in dry rocks by pore-scale modeling based on the wave theory and the similarity principle. Our modeling results indicate that pore size, pore shape (such as aspect ratio), and pore density are important factors influencing P-wave scattering attenuation in porous rocks, and can explain the variation of scattering attenuation at the same porosity. From the perspective of scattering attenuation, porous rocks can safely suit to the long wavelength assumption when the ratio of wavelength to pore size is larger than 15. Under the long wavelength condition, the scattering attenuation coefficient increases as a power function as the pore density increases, and it increases exponentially with the increase in aspect ratio. For a certain porosity, rocks with smaller aspect ratio and/or larger pore size have stronger scattering attenuation. When the pore aspect ratio is larger than 0.5, the variation of scattering attenuation at the same porosity is dominantly caused by pore size and almost independent of the pore aspect ratio. These results lay a foundation for pore structure inversion from elastic wave responses in porous rocks.     

C-phycocyanin hydration water dynamics in the presence of trehalose: an incoherent elastic neutron scattering study at different energy resolutions

We present a study of C-phycocyanin hydration water dynamics in the presence of trehalose by incoherent elastic neutron scattering. By combining data from two backscattering spectrometers with a 10-fold difference in energy resolution we extract a scattering law S(Q,omega) from the Q-dependence of the elastic intensities without sampling the quasielastic range. The hydration water is described by two dynamically different populations--one diffusing inside a sphere and the other diffusing quasifreely--with a population ratio that depends on temperature. The scattering law derived describes the experimental data from both instruments excellently over a large temperature range (235-320 K). The effective diffusion coefficient extracted is reduced by a factor of 10-15 with respect to bulk water at corresponding temperatures. Our approach demonstrates the benefits and the efficiency of using different energy resolutions in incoherent elastic neutron scattering over a large angular range for the study of biological macromolecules and hydration water.     

Modeling repeated count data subject to informative dropout

In certain diseases, outcome is the number of morbid events over the course of follow-up. In epilepsy, e.g., daily seizure counts are often used to reflect disease severity. Follow-up of patients in clinical trials of such diseases is often subject to censoring due to patients dying or dropping out. If the sicker patients tend to be censored in such trials, estimates of the treatment effect that do not incorporate the censoring process may be misleading. We extend the shared random effects approach of Wu and Carroll (1988, Biometrics 44, 175-188) to the setting of repeated counts of events. Three strategies are developed. The first is a likelihood-based approach for jointly modeling the count and censoring processes. A shared random effect is incorporated to introduce dependence between the two processes. The second is a likelihood-based approach that conditions on the dropout times in adjusting for informative dropout. The third is a generalized estimating equations (GEE) approach, which also conditions on the dropout times but makes fewer assumptions about the distribution of the count process. Estimation procedures for each of the approaches are discussed, and the approaches are applied to data from an epilepsy clinical trial. A simulation study is also conducted to compare the various approaches. Through analyses and simulations, we demonstrate the flexibility of the likelihood-based conditional model for analyzing data from the epilepsy trial.     

Effects of testosterone and exercise on muscle leanness in eugonadal men with AIDS wasting.

Loss of lean body and muscle mass characterizes the acquired immunodeficiency syndrome (AIDS) wasting syndrome (AWS). Testosterone and exercise increase muscle mass in men with AWS, with unclear effects on muscle composition. We examined muscle composition in 54 eugonadal men with AWS who were randomized to 1) testosterone (200 mg im weekly) or placebo and simultaneously to 2) resistance training or no training in a 2 x 2 factorial design. At baseline and after 12 wk, we performed assessments of whole body composition by dual-energy X-ray absorptiometry and single-slice computed tomography for midthigh cross-sectional area and muscle composition. Leaner muscle has greater attenuation. Baseline muscle attenuation correlated inversely with whole body fat mass (r = -0.52, P = 0.0001). This relationship persisted in a model including age, body mass index, testosterone level, viral load, lean body mass, and thigh muscle cross-sectional area (P = 0.02). Testosterone (P = 0.03) and training (P = 0.03) increased muscle attenuation. These data demonstrate that thigh muscle attenuation by computed tomography varies inversely with whole body fat and increases with testosterone and training. Anabolic therapy in these patients increases muscle leanness.