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PubMed1991

A nonparametric approach to analyzing large human populations.

There are many statistical techniques that require the assumption that the population being studied is normally distributed--regression analysis, multivariate analysis, time series analysis, and so on. Unfortunately, as the development of survey sampling has long acknowledged, large human populations are usually stratified into several different subpopulations. Since the boundaries between the strata are somewhat blurred, they are not independent, so the overall distribution of the population tends to be multimodal rather than normal. In this paper, a technique is developed to find these multimodal techniques using nonparametric density estimation. Its effectiveness is demonstrated by means of an example.

Analysis of Variance↗

PubMed2004

Malignant and benign lymphoid lesions of the lung.

Lymphoid lesions of the lung produce a complex of problems for the practicing pathologist. Although these lesions are eventually referred to hematopathologists, it is still the general surgical pathologist who first encounters them and confronts the problem of formulating an initial diagnosis. Over the last 20 years there has been a revolution in our knowledge of the classification and natural history of the pulmonary lesions, a plethora of information which warrants a thorough review. The purpose of this discussion is to report the clinical features and courses, pathologic features and, when known, etiologies or pathogenesis of the major "primary" pulmonary lymphoid lesions and present a brief approach to differential diagnosis. I will divide the lesions into malignant and benign, discussing each in turn.

Diagnosis, Differential↗

PubMed2004

Analysis of two-component signal transduction by mathematical modeling using the KdpD/KdpE system of Escherichia coli.

A mathematical model for the KdpD/KdpE two-component system is presented and its dynamical behavior is analyzed. KdpD and KdpE regulate expression of the kdpFABC operon encoding the high affinity K+ uptake system KdpFABC of Escherichia coli. The model is validated in a two step procedure: (i) the elements of the signal transduction part are reconstructed in vitro. Experiments with the purified sensor kinase and response regulator in presence or absence of DNA fragments comprising the response regulator binding-site are performed. (ii) The mRNA and molecule number of KdpFABC are determined in vivo at various extracellular K+ concentrations. Based on the identified parameters for the in vitro system it is shown, that different time hierarchies appear which are used for model reduction. Then the model is transformed in such a way that a singular perturbation problem is formulated. The analysis of the in vivo system shows that the model can be separated into two parts (submodels which are called functional units) that are connected only in a unidirectional way. Hereby one submodel represents signal transduction while the second submodel describes the gene expression.

Base Sequence↗

PubMed2005

Mass transport in micellar surfactant solutions: 1. Relaxation of micelle concentration, aggregation number and polydispersity.

The surfactant transfer in micellar solutions includes transport of all types of aggregates and the exchange of monomers between them. Such processes are theoretically described by a system containing tens of kinetic equations, which is practically inapplicable. For this reason, one of the basic problems of micellar kinetics is to simplify the general set of equations without loosing the adequacy and correctness of the theoretical description. Here, we propose a model, which generalizes previous models in the following aspects. First, we do not use the simplifying assumption that the width of the micellar peak is constant under dynamic conditions. Second, we avoid the use of the quasi-equilibrium approximation (local chemical equilibrium between micelles and monomers). Third, we reduce the problem to a self-consistent system of four nonlinear differential equations. Its solution gives the concentration of surfactant monomers, total micelle concentration, mean aggregation number, and halfwidth of the micellar peak as functions of the spatial coordinates and time. Further, we check the predictions of the model for the case of spatially uniform bulk perturbations (such as jumps in temperature, pressure or concentration). The theoretical analysis implies that the relaxations of the three basic parameters (micelle concentration, mean aggregation number, and polydispersity) are characterized by three different characteristic relaxation times. Two of them coincide with the slow and fast micellar relaxation times, which are known in the literature. The third time characterizes the relaxation of the width of the micellar peak (i.e. of the micelle polydispersity). It is intermediate between the slow and fast relaxation times, in the case of not-too-low micellar concentrations. For low micelle concentrations, the third characteristic time is close to the fast relaxation time. Procedure for obtaining the exact numerical solution of the problem is formulated. In addition, asymptotic analytical expressions are derived, which compare very well with the exact numerical solution. In the second part of this study, the obtained set of equations is applied for theoretical modeling of surfactant adsorption from micellar solutions under various dynamic conditions, corresponding to specific experimental methods.

Kinetics↗

PubMed2004

Imaging diagnosis of congenital uterine malformation.

Congenital anomaly of the female reproductive system is associated with higher rate of infertility, spontaneous abortion, intrauterine growth retardation, premature birth and postpartum bleed. Because of the variable clinical pictures of obstruction of menstrual flow in adolescence to hypomenorrhea, vaginal discharge, dyspareunia, and fertility problems in adult life, early and accurate diagnosis is difficult. Complete uterine and vaginal septum can be easily confused with uterus didelphys. Management of these two müllerian duct anomalies is different. With improved treatment methods for complete relief of symptoms and prevention of further sequelae, comprehensive evaluation is important to identify the underlying problem and formulate appropriate therapeutic plan. The embryology, classification, and clinical presentation of uterine malformation, advantages and limitations of diagnostic methods including hysterosalpingogram, ultrasound, magnetic resonance imaging, laparoscopy, and hysteroscopy are discussed. The imaging features of different types of uterine anomalies are illustrated.

Adult↗

PubMed2005

Centrifugation equilibrium for spheres and spherocylinders.

The centrifugation equilibrium problem is formulated and solved using a new procedure in which the specified variables are the temperature, system volume, particle dimensions and concentrations, angular speed, cell length, and cell distance from the rotation axis. As a result, we obtain the concentration profiles for all types of particles present in the system, which are considered to be immersed in a fluid. The particles are modeled as hard nonattractive spherocylinders using an equation of state, but the procedure is not restricted to any geometrical shape, and can be used with any equation of state available. The fluid is treated as a continuous medium, responsible for centrifugal buoyancy. We make calculations for colloidal suspensions of silica, often used for separations in biotechnology. Results are in good agreement with experiments and show excellent agreement in comparison with Monte Carlo simulations. Our calculations also predict focusing and shifting phenomena that have been experimentally observed in separations of fine particles.

Centrifugation↗

PubMedDate not supplied

2D fast rotational matching for image processing of biophysical data.

In 3D single particle reconstruction, which involves the translational and rotational matching of a large number of electron microscopy (EM) images, the algorithmic performance is largely dependent on the efficiency and accuracy of the underlying 2D image alignment kernel. We present a novel fast rotational matching kernel for 2D images (FRM2D) that significantly reduces the cost of this alignment. The alignment problem is formulated using one translational and two rotational degrees of freedom. This allows us to take advantage of fast Fourier transforms (FFTs) in rotational space to accelerate the search of the two angular parameters, while the remaining translational parameter is explored, within a limited range, by exhaustive search. Since there are no boundary effects in FFTs of cyclic angular variables, we avoid the expensive zero padding associated with Fourier transforms in linear space. To verify the robustness of our method, efficiency and accuracy tests were carried out over a range of noise levels in realistic simulations of EM images. Performance tests against two standard alignment methods, resampling to polar coordinates and self-correlation, demonstrate that FRM2D compares very favorably to the traditional methods. FRM2D exhibits a comparable or higher robustness against noise and a significant gain in efficiency that depends on the fineness of the angular sampling and linear search range.

Algorithms↗

PubMed2004

Seven fundamental, unsolved questions in molecular biology. Cooperative storage and bi-directional transfer of biological information by nucleic acids and proteins: an alternative to "central dogma".

The Human Genome Mapping Project provided us a large amount of sequence data. However our understanding of these data did not grow proportionally, because old dogmas still set the limits of our thinking. The gene-centric, reductionistical side of molecular biology is reviewed and seven problems are formulated, each indicating the insufficiency of the "central dogma". The following is concluded and suggested: 1. Genes are located and expressed on both DNA strands; 2. Introns are the source of important biological regulation and diversity; 3. Repeats are the frame of the chromatin structure and participate in the chromatin regulation; 4. The molecular accessibility of the canonical dsDNA structure is poor; 5. The genetic code is co-evolved with the amino acids and there is a stereochemical matching between the codes andamino acids; 6. The flow of information between nucleic acids and proteins is bi-directional and reverse translation might exist; 7. Complex genetic information is always carried and stored by nucleic acids and proteins together.

Animals↗

PubMed2005

Bubble oscillation and inertial cavitation in viscoelastic fluids.

Non-linear acoustic oscillations of gas bubbles immersed in viscoelastic fluids are theoretically studied. The problem is formulated by considering a constitutive equation of differential type with an interpolated time derivative. With the aid of this rheological model, fluid elasticity, shear thinning viscosity and extensional viscosity effects may be taken into account. Bubble radius evolution in time is analyzed and it is found that the amplitude of the bubble oscillations grows drastically as the Deborah number (the ratio between the relaxation time of the fluid and the characteristic time of the flow) increases, so that, even for moderate values of the external pressure amplitude, the behavior may become chaotic. The quantitative influence of the rheological fluid properties on the pressure thresholds for inertial cavitation is investigated. Pressure thresholds values in terms of the Deborah number for systems of interest in ultrasonic biomedical applications, are provided. It is found that these critical pressure amplitudes are clearly reduced as the Deborah number is increased.

Elasticity↗

PubMed1998

Confidence in, and self-rating of, driving ability among older drivers.

Active drivers (n = 125) in a representative cohort of older individuals age 77 years and older in New Haven, Connecticut were interviewed. Confidence in different driving situations, self-rating of driving ability, and driving patterns were assessed during these in-person interviews. A history of crashes, moving violations and being stopped by police was available for approximately the past 6 years. Concurrent driving performance was assessed in a subsample (n = 35). Analyses focused on determining the relationship of confidence and self-rating of driving ability to: (1) each other; (2) driving patterns; (3) adverse driving events; and (4) driving performance. All participants rated themselves as being average or above average drivers compared to others their age, with the majority rating themselves as above average. Individuals who drove more miles and more frequently were more likely to rate themselves better drivers than same-age peers. Individuals who rated themselves as "much better" drivers than their peers tended to have higher confidence levels than those who rated themselves a "little bit better" or the "same" as other drivers. On-road driving performance and history of adverse events were not associated with self-ratings of driving ability. Confidence was associated with driving frequency and mileage, but not age or education. Although men were more likely to drive under risky conditions, for those conditions in which each drove, men and women were equally confident. No relationship was found between confidence and adverse driving events or driving performance. Understanding the relationship of confidence and self-rating of driving ability to driving patterns, adverse events and driving performance may provide additional insights into identifying older drivers at increased risk for problems and formulating intervention strategies to help lower risk.

Accidents, Traffic↗

PubMed1979

Network thermodynamic approach compartmental analysis. Na+ transients in frog skin.

We introduce a general network thermodynamic method for compartmental analysis which uses a compartmental model of sodium flows through frog skin as an illustrative example (Huf and Howell, 1974a). We use network thermodynamics (Mikulecky et al., 1977b) to formulate the problem, and a circuit simulation program (ASTEC 2, SPICE2, or PCAP) for computation. In this way, the compartment concentrations and net fluxes between compartments are readily obtained for a set of experimental conditions involving a square-wave pulse of labeled sodium at the outer surface of the skin. Qualitative features of the influx at the outer surface correlate very well with those observed for the short circuit current under another similar set of conditions by Morel and LeBlanc (1975). In related work, the compartmental model is used as a basis for simulation of the short circuit current and sodium flows simultaneously using a two-port network (Mikulecky et al., 1977a, and Mikulecky et al., A network thermodynamic model for short circuit current transients in frog skin. Manuscript in preparation; Gary-Bobo et al., 1978). The network approach lends itself to computation of classic compartmental problems in a simple manner using circuit simulation programs (Chua and Lin, 1975), and it further extends the compartmental models to more complicated situations involving coupled flows and non-linearities such as concentration dependencies, chemical reaction kinetics, etc.

Animals↗

PubMed1994

Influence of a channel-forming peptide on energy barriers to ion permeation, viewed from a continuum dielectric perspective.

The continuum three-dielectric model for an aqueous ion channel pore-forming peptide-membrane system is extended to account for the finite length of the channel. We focus on the electrostatic influence that a channel-forming peptide may exert on energy barriers to ion permeation. The nonlinear dielectric behavior of channel water caused by dielectric saturation in the presence of an ion is explicitly modeled by assigning channel water a mean dielectric constant much less than that of bulk water. An exact solution of the continuum problem is formulated by approximating the dielectric behavior of bulk water, assigning it a dielectric constant of infinity. The validity of this approximation is verified by comparison with a Poisson-Boltzmann description of the electrolyte. The formal equivalence of high ionic strength and high electrolyte dielectric constant is demonstrated. We estimate limits on the reduction of the electrostatic free energy caused by ionic interaction with the channel-forming peptide. We find that even assigning this region an epsilon of 100, its influence is insufficient to lower permeation free energy barriers to values consistent with observed channel conductances. We provide estimates of the effective dielectric constant of this highly polarizable region, by comparing energy barriers computed using the continuum approach with those found from a semi-microscopic analysis of a simplified model of a gramicidin-like charge distribution. Possible ways of improving both models are discussed.

Ion Channels↗

PubMedDate not supplied

Effect of a participatory intervention with women's groups on birth outcomes in Nepal: cluster-randomised controlled trial.

BACKGROUND: Neonatal deaths in developing countries make the largest contribution to global mortality in children younger than 5 years. 90% of deliveries in the poorest quintile of households happen at home. We postulated that a community-based participatory intervention could significantly reduce neonatal mortality rates. METHODS: We pair-matched 42 geopolitical clusters in Makwanpur district, Nepal, selected 12 pairs randomly, and randomly assigned one of each pair to intervention or control. In each intervention cluster (average population 7000), a female facilitator convened nine women's group meetings every month. The facilitator supported groups through an action-learning cycle in which they identified local perinatal problems and formulated strategies to address them. We monitored birth outcomes in a cohort of 28?931 women, of whom 8% joined the groups. The primary outcome was neonatal mortality rate. Other outcomes included stillbirths and maternal deaths, uptake of antenatal and delivery services, home care practices, infant morbidity, and health-care seeking. Analysis was by intention to treat. The study is registered as an International Standard Randomised Controlled Trial, number ISRCTN31137309. FINDINGS: From 2001 to 2003, the neonatal mortality rate was 26.2 per 1000 (76 deaths per 2899 livebirths) in intervention clusters compared with 36.9 per 1000 (119 deaths per 3226 livebirths) in controls (adjusted odds ratio 0.70 [95% CI 0.53-0.94]). Stillbirth rates were similar in both groups. The maternal mortality ratio was 69 per 100000 (two deaths per 2899 livebirths) in intervention clusters compared with 341 per 100000 (11 deaths per 3226 livebirths) in control clusters (0.22 [0.05-0.90]). Women in intervention clusters were more likely to have antenatal care, institutional delivery, trained birth attendance, and hygienic care than were controls. INTERPRETATION: Birth outcomes in a poor rural population improved greatly through a low cost, potentially sustainable and scalable, participatory intervention with women's groups.

Adolescent↗

PubMedDate not supplied

Physical recovery in anorexia nervosa: is this the sole purpose of a child and adolescent medical-psychiatric unit?

Patients with anorexia nervosa are discharged from inpatient medical psychiatric wards on achievement of their target weight ("physical recovery") or even earlier. However, recent studies have consistently revealed that a very high percentage relapse, usually within a year. We hypothesized that the more rapid pace of physical compared with psychological recovery in anorexia nervosa creates a gap or interim stage when inpatients are particularly vulnerable. This phase has its own identifiable characteristics and prognostic value. To counter this problem, we formulated a treatment model where patients in the "physical recovery" stage participate in a follow-up program within the inpatient unit itself concomitant with individual psychotherapy at the outpatient community service. The program helps to preserve the strong therapeutic alliance established during hospitalization and to maintain the patient's base of security against the loss of the "anorectic solution." The program provides a full range of services--inpatient, day-treatment and follow-up, adapting itself to the changing needs of the patient. It has been in effect in our unit for three years, and the rate of relapse has decreased dramatically. Further controlled studies are needed to confirm these findings.

Adolescent↗

PubMed1984

Assessing possible late treatment effects in stopping a clinical trial early: a case study. Diabetic Retinopathy Study report No. 9.

Suppose a fixed-sample trial in a disease with a long response time shows a statistically significant benefit of the experimental treatment before patients have completed the planned follow-up period. The question may then arise--and did arise in the Diabetic Retinopathy Study (DRS)--whether the observed early benefit of treatment may be offset at some time in the future by the subsequent development of harmful treatment effects. If this question raises serious concerns, then the investigators are faced with a dilemma. If the trial is stopped because of the observed early treatment benefit and the treatment is administered to the untreated control group as well as to patients outside the study, and if the treatment is later found to have deleterious effects, then it may ultimately do more harm than good to patients. Moreover, the fact that the treatment is harmful may never become known. If, on the other hand, the trial is not stopped and the treatment proves to have no deleterious effects, then the control group and patients outside the study would be harmed because the treatment was withheld. We show how, in the DRS, this very problem was formulated and resolved. First a severe, delayed harmful treatment effect was postulated. Projections based on this postulation showed that the early gains were so great that they were unlikely to be offset--ever. Based in part on these projections, the following decisions were made: (a) the study protocol would be changed so as to allow treatment of the untreated control group, and (b) patients would continue to be followed in order to make possible the detection of late, harmful treatment effects, should they develop.

Clinical Trials as Topic↗

PubMedDate not supplied

On a non-Markov neuronal model and its approximations.

Single neuron's activity modeling is considered with reference to some earlier contributions in which a non-Markov Gaussian process is assumed to describe the time course of the neuron's membrane potential. After re-formulating the problem in a rigorous framework and pinpointing the limits of validity of such a model, the available results on the firing probability density are compared with those obtained by us by means of an ad hoc numerical algorithm implemented for the leaky integrator diffusion firing model and with some data constructed by a simulation procedure of non-Markov Gaussian processes with pre-assigned covariances. Throughout this paper, the notion of 'correlation time' plays a fundamental role for the neuronal coding process modeling.

Markov Chains↗

PubMed2003

FINEX: a Probabilistic Expert System for forensic identification.

A series of recent papers have shown how to formulate complex problems of forensic DNA identification inference, such as occur in disputed paternity or criminal identification cases, in terms of Probabilistic Expert Systems (PESs). However, at the present time, general purpose PES software is not particularly well suited to the repetitive tasks of: specifying an appropriate set of marker networks for a specific problem; for editing the many local conditional probability tables; and combining evidence from several genetic markers to evaluate likelihoods. Here, I describe a user-friendly prototype software tool called FINEX developed both to automate such tasks and also to evaluate likelihoods of interest. Ease of use is achieved by a graphical specification language that enables a user to quickly specify a range of forensic DNA problems. I describe the algorithms by which FINEX converts the user input in the graphical specification language and data on observed markers to the Bayesian networks used in PES.

Algorithms↗

PubMed2002

Pharmacologic management of childhood hypertension: current status, future challenges.

The treatment of childhood hypertension has been hampered by several factors, including a lack of extensive scientific data regarding drug efficacy and pharmacokinetics in children, a lack of manufacturer's recommendations for the use of antihypertensive agents in children, and a lack of age-appropriate drug formulations. These problems have forced clinicians either to rely on limited data from older studies of agents empirically no longer considered first-line choices for use in children, or to adapt agents studied in adults for pediatric use. Recent developments, including publication of single-center studies of newer agents and the proliferation of industry-sponsored trials spurred by the Food and Drug Administration Modernization Act, have increased the amount of data available. Investigators involved in such studies must ensure that the unique aspects of using antihypertensive drugs in children are adequately addressed.

Antihypertensive Agents↗