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PubMed1981

The conduct and principles of randomized clinical trials.

Some of the guiding principles as well as the pitfall of long-term randomized clinical trials are presented. Examples have been chosen from trials in the cardiovascular field. A typical long-term clinical trial is divided into five phases: planning, preparation, recruitment, clinical follow-up and termination, and finally analysis. Administrative, legal, and ethical aspects of a trial are discussed, as well as the cost of clinical trials. Organization patterns are described and some prevalent ones are criticized. Further, practical matters such as recruitment techniques, obtaining informed consent from the patients, determining drug dosage and formulation as well as the problem of interaction with nonstudy drugs are referred to. Adherence testing remains a problem, because of our inability to test for placebo adherence.

Clinical Trials as Topic↗
PubMed1985

Status of the toxicity reports of pesticides for their registration in Finland.

Recently, attention has centered on the validity of toxicity reports for the registration of pesticides. In Finland, a study was conducted to evaluate the validity of the toxicity reports of pesticides done in U. S. laboratories. Twenty-seven pesticide formulations of the 230 on the market in Finland were selected for the study. The material contained 61 toxicity reports of 16 pesticide formulations done in U. S. laboratories considered questionable, 64 reports from U. S. laboratories considered reliable, and 142 reports originating from European laboratories, totally 267 reports. These reports were divided into valid according to the Organization for Economic Cooperation and Development (OECD) guidelines, and included those with minor discrepancies but in compliance with the good laboratory practice at the time of the study (group I), and and invalid according to the OECD guidelines (group II). After a closer evaluation of the 125 U. S. reports, 85 reports were considered valid and 40 invalid. As a function of time, the proportion of valid studies of all studies on pesticides for the registration purposes in Finland increased during 1961-1981 from 47 to 93%, being 100% at the present time. The lack of information of pesticide formulations registered earlier creates a problem to be solved in the future in Finland, rather than the lack of the validity of toxicity reports.

Animals↗
PubMed1989

[Methodologic and epistemologic reflections on acupuncture].

Methodological difficulties met in acupuncture cannot be overcome without epistemological analysis by researchers and practitioners. This is because of the 'cognitivo-cultural' gap between Occidental and Chinese traditions. With this aim, the author considers the role of cognitive expectancies in the effect of antalgic acupuncture, and draws epistemological then methodological conclusions. After comparing the advent of the holistic movement with the crisis of rationalism in medicine, an attempt is made to formulate an evaluation of the problems in acupuncture in terms of metaphysical realism. The author challenges the holistic model compared to the orthodox bio-medical model.

Acupuncture Therapy↗
PubMed1979

A factor-analytic examination of the unitary OR concept.

Recent studies have generated a four-system structure proposed as a replacement for Sokolov's unitary OR concept. This conceptualisation developed from a logical consideration of stimulus--response relationships based upon mean response magnitudes over subjects, and paid no attention to individual response types. It is conceivable that no individual subject exhibited responses compatible with such a formulation. This paper addressed that problem by using factor analysis as a means of descriptively summarising the data of each subject, and examining its compatibility with both unitary and four-system structures. Of 72 subjects, none exhibited a factor structure compatible with Sokolov's unitary concept, while 70 exhibited structures compatible with the four-system structure. These results support the validity of the structure proposed to replace the unitary OR.

Arousal↗
PubMed1989

An algorithm for design of beam compensators.

Beam compensators are optimally designed to give a uniform dose to any plane or midsurface that intersects a single beam, or to give a uniform dose to the volume defined by the intersection of two or more beams. The primary and scatter components are taken into account separately, as well as the patient's shape and internal heterogeneities. The design of the beam compensators is formulated as a linear programming problem and solved with a variation of the Simplex Method. Beam weighting factors are also obtained as part of the solution.

Algorithms↗
PubMedDate not supplied

Telomeres, telomerase, and aging: origin of the theory.

In 1971 I published a theory in which I first formulated the DNA end replication problem and explained how it could be solved. The solution to this problem also provided an explanation for the Hayflick Limit, which underpins the discovery of in vitro and in vivo cell senescence. I proposed that the length of telomeric DNA, located at the ends of chromosomes consists of repeated sequences, which play a buffer role and should diminish in dividing normal somatic cells at each cell doubling. I also proposed that the loss of sequences containing important information that could occur after buffer loss could cause the onset of cellular senescence. I also suggested that for germline cells and for the cells of vegetatively propagated organisms and immortal cell populations like most cancer cell lines, an enzyme might be activated that would prevent the diminution of DNA termini at each cell division, thus protecting the information containing part of the genome. In the last few years, most of my suggestions have been authenticated by laboratory evidence. the DNA sequences that shorten in dividing normal cells are telomeres and the enzyme that maintains telomere length constant in immortal cell populations is telomerase.

Aging↗
PubMed2005

Significance analysis of qualitative mammographic features, using linear classifiers, neural networks and support vector machines.

Advances in modern technologies and computers have enabled digital image processing to become a vital tool in conventional clinical practice, including mammography. However, the core problem of the clinical evaluation of mammographic tumors remains a highly demanding cognitive task. In order for these automated diagnostic systems to perform in levels of sensitivity and specificity similar to that of human experts, it is essential that a robust framework on problem-specific design parameters is formulated. This study is focused on identifying a robust set of clinical features that can be used as the base for designing the input of any computer-aided diagnosis system for automatic mammographic tumor evaluation. A thorough list of clinical features was constructed and the diagnostic value of each feature was verified against current clinical practices by an expert physician. These features were directly or indirectly related to the overall morphological properties of the mammographic tumor or the texture of the fine-scale tissue structures as they appear in the digitized image, while others contained external clinical data of outmost importance, like the patient's age. The entire feature set was used as an annotation list for describing the clinical properties of mammographic tumor cases in a quantitative way, such that subsequent objective analyses were possible. For the purposes of this study, a mammographic image database was created, with complete clinical evaluation descriptions and positive histological verification for each case. All tumors contained in the database were characterized according to the identified clinical features' set and the resulting dataset was used as input for discrimination and diagnostic value analysis for each one of these features. Specifically, several standard methodologies of statistical significance analysis were employed to create feature rankings according to their discriminating power. Moreover, three different classification models, namely linear classifiers, neural networks and support vector machines, were employed to investigate the true efficiency of each one of them, as well as the overall complexity of the diagnostic task of mammographic tumor characterization. Both the statistical and the classification results have proven the explicit correlation of all the selected features with the final diagnosis, qualifying them as an adequate input base for any type of similar automated diagnosis system. The underlying complexity of the diagnostic task has justified the high value of sophisticated pattern recognition architectures.

Analysis of Variance↗
PubMed2006

LC and LC-MS study of stress decomposition behaviour of isoniazid and establishment of validated stability-indicating assay method.

Isoniazid was subjected to different ICH prescribed stress conditions of thermal stress, hydrolysis, oxidation and photolysis. The drug was stable to dry heat (50 and 60 degrees C). It showed extensive decomposition under hydrolytic conditions, while it was only moderately sensitive to oxidation stress. The solid drug turned intense yellow on exposure to light under accelerated conditions of temperature (40 degrees C) and humidity (75% RH). In total, three major degradation products were detected by LC. For establishment of stability-indicating assay, the reaction solutions in which different degradation products were formed were mixed, and the separation was optimized by varying the LC conditions. An acceptable separation was achieved using a C-18 column and a mobile phase comprising of water:acetonitrile (96:4, v/v), with flow rate and detection wavelength being 0.5 ml min(-1) and 254 nm, respectively. The degradation products appeared at relative retention times (RR(T)) of 0.71, 1.34 and 4.22. The validation studies established a linear response of the drug at concentrations between 50 and 1000 microg ml(-1). The mean values (+/-R.S.D.) of slope, intercept and correlation coefficient were 35,199 (+/-0.88), 114,310 (+/-4.70) and 0.9998 (+/-0.01), respectively. The mean R.S.D. values for intra- and inter-day precision were 0.24 and 0.90, respectively. The recovery of the drug ranged between 99.42 and 100.58%, when it was spiked to a mixture of solutions in which sufficient degradation was observed. The specificity was established through peak purity testing using a photodiode array detector. The method worked well on application to marketed formulation of isoniazid, and a fixed-dose combination containing isoniazid and ethambutol HCl. It was even extendable to LC-MS studies, which were carried out to identify the three degradation products. The m/z values of the peaks at RR(T) 0.71 and RR(T) 1.34 matched with isonicotinic acid and isonicotinamide, respectively. The product appearing at RR(T) 4.22 was isolated using preparative LC-MS, and turned out to be a yellow compound that was identified as isonicotinic acid N'-(pyridyl-4-carbonyl)-hydrazide based on mass, FTIR and (1)H/(13)C NMR spectral data. The same was indicated to be responsible for discolouration of isoniazid bulk drug substance and formulations, which is a familiar problem. The mechanism of formation of the said compound is outlined.

Biological Assay↗
PubMed2005

Segmentation of fetal ultrasound images.

This paper describes a new method for segmentation of fetal anatomic structures from echographic images. More specifically, we estimate and measure the contours of the femur and of cranial cross-sections of fetal bodies, which can thus be automatically measured. Contour estimation is formulated as a statistical estimation problem, where both the contour and the observation model parameters are unknown. The observation model (or likelihood function) relates, in probabilistic terms, the observed image with the underlying contour. This likelihood function is derived from a region-based statistical image model. The contour and the observation model parameters are estimated according to the maximum likelihood (ML) criterion, via deterministic iterative algorithms. Experiments reported in the paper, using synthetic and real images, testify for the adequacy and good performance of the proposed approach.

Algorithms↗
PubMed2002

Development and implementation of the Clinical Privileges for Dietitian Nutrition Order Writing program at a long-term acute-care hospital.

A patient nutrition care plan is of little value unless it is quickly and efficiently implemented. Recognition of the value of appropriate and timely medical nutrition intervention in improving patients' nutritional status led to the development of the Clinical Privileges for Dietitian Nutrition Order Writing (CPD NOW) program at a long-term, acute-care hospital. CPD NOW is a formalized approach specifying the types of nutrition care orders that may be written by a registered dietitian (RD), allowing nutrition recommendations to be implemented immediately. More than 95% of the facility's primary attending physicians participate in this optional program. Development included an initial evaluation of physician use of RD recommendations, identification of problems in implementing these recommendations, formulation of an efficient nutrition order writing system, and adoption of this system by the medical staff. In the first 5 years of implementation, the benefits achieved by this program were: expedited order implementation, improved patient nutritional response, and increased RD responsibility. A survey demonstrated physician support of this new RD role. CPD NOW may be applicable as a model to develop similar systems in other hospitals.

Critical Care↗
PubMed1989

Mechanics and control of the cytoskeleton in Amoeba proteus.

Many models of the cytoskeletal motility of Amoeba proteus can be formulated in terms of the theory of reactive interpenetrating flow (Dembo and Harlow, 1986). We have devised numerical methodology for testing such models against the phenomenon of steady axisymmetric fountain flow. The simplest workable scheme revealed by such tests (the minimal model) is the main preoccupation of this study. All parameters of the minimal model are determined from available data. Using these parameters the model quantitatively accounts for the self assembly of the cytoskeleton of A. proteus: for the formation and detailed morphology of the endoplasmic channel, the ectoplasmic tube, the uropod, the plasma gel sheet, and the hyaline cap. The model accounts for the kinematics of the cytoskeleton: the detailed velocity field of the forward flow of the endoplasm, the contraction of the ectoplasmic tube, and the inversion of the flow in the fountain zone. The model also gives a satisfactory account of measurements of pressure gradients, measurements of heat dissipation, and measurements of the output of useful work by amoeba. Finally, the model suggests a very promising (but still hypothetical) continuum formulation of the free boundary problem of amoeboid motion. by balancing normal forces on the plasma membrane as closely as possible, the minimal model is able to predict the turgor pressure and surface tension of A. proteus. Several dynamical factors are crucial to the success of the minimal model and are likely to be general features of cytoskeletal mechanics and control in amoeboid cells. These are: a constitutive law for the viscosity of the contractile network that includes an automatic process of gelation as the network density gets large; a very vigorous cycle of network polymerization and depolymerization (in the case of A. proteus, the time constant for this reaction is approximately 12 s); control of network contractility by a diffusible factor (probably calcium ion); and control of the adhesive interaction between the cytoskeleton and the inner surface of the plasma membrane.

Amoeba↗
PubMed1997

Combinatorial approaches to gene recognition.

Recognition of genes via exon assembly approaches leads naturally to the use of dynamic programming. We consider the general graph-theoretical formulation of the exon assembly problem and analyze in detail some specific variants: multicriterial optimization in the case of non-linear gene-scoring functions; context-dependent schemes for scoring exons and related procedures for exon filtering; and highly specific recognition of arbitrary gene segments, oligonucleotide probes and polymerase chain reaction (PCR) primers.

Base Sequence↗
PubMed1997

An audit tool for assessing the learning environment for Project 2000.

In preparation for the introduction of Project 2000 throughout Scotland, a need was identified to monitor the quality of the learning environment for student nurses in the practice setting. No mechanism existed to measure quality and standards, and a group was formed to devise, pilot and implement an educational audit tool which could address these requirements, since limited information was available in the literature. Using this tool, the group subsequently examined the learning opportunities available, concentrating on the physical environment, the learning climate/environment, and the students' perceptions of the learning environment within the practice setting, across hospital and community sectors, including residential accommodation and nurseries, in the wide geographical area covered by the health board. This paper describes the process by which the tool was formulated, tested and implemented, the problems encountered, and the improvements in communications between teaching and clinical staff, leading to improved opportunities for the provision of excellence in patient care.

Education, Nursing, Baccalaureate↗
PubMed1997

Overview of severe mental illness.

The severe mental illnesses are psychiatric disorders characterized by their persistence and extensive disability. Classification of these disorders has seen improved reliability, but problems remain with validity. Etiological formulations emphasize the biological origins of the disorders, but psychological factors, chiefly in the area of stress, are recognized as important in the management of relapse. Psychological features, especially those apparent during psychotic episodes, make the disorders particularly difficult to treat. Patients tend to be noncompliant. In addition, these features dispose people with severe mental illnesses to behaviors that place them at risk for HIV and other catastrophic illnesses. New psychopharmacological treatments may improve compliance and reduce relapse, but none has made psychosocial treatments unnecessary. Progress in developing effective treatments has been slow, but prospects are encouraging.

Acquired Immunodeficiency Syndrome↗
PubMed2003

The binding of HIV-1 protease inhibitors to human serum proteins.

The non-specific binding of a drug to plasma proteins is an important determinant of its biological efficacy since it modulates the availability of the drug to its intended target. In the case of HIV-1 protease inhibitors, binding to human serum albumin (HSA) and alpha(1)-acid glycoprotein (AAG) appears to be an important modulator of drug bioavailability. From a thermodynamic point of view, the issue of drug availability to the desired target can be formulated as a multiple equilibrium problem in which a ligand is able to bind to different proteins or other macromolecules with different binding affinities. Previously, we have measured the binding thermodynamics of HIV-1 protease inhibitors to their target. In this article, the binding energetics of four inhibitors currently in clinical use (saquinavir, indinavir, ritonavir and nelfinavir) and a second-generation inhibitor (KNI-764) to human HSA and AAG has been studied by isothermal titration calorimetry. All inhibitors exhibited a significant affinity for AAG (K(a) approximately 0.5-10 x 10(5) M(-1)) and a relatively low affinity for HSA (K(a) approximately 5-15 x 10(3) M(-1)). It is shown that under conditions that simulate in vivo concentrations of serum proteins, the inhibitor concentrations required to achieve 95% protease inhibition can be up to 10 times higher than those required in the absence of serum proteins. The effect is compounded in patients infected with drug resistant HIV-1 strains that exhibit a lower affinity for protease inhibitors. In these cases the required inhibitor concentrations can be up to 2000 times higher and beyond the solubility limits of the inhibitors.

Biological Availability↗
PubMed2002

Non-viral gene delivery systems.

Non-viral gene delivery systems have the potential to create viable pharmaceuticals from nucleic acids. These DNA delivery systems contain lipids and/or cationic polymers. In order for these systems to be developed into commercial products, several barriers must be overcome. These include obstacles in manufacturing, formulation and stability. In vivo, problems of extracellular non-specific interactions and intracellular trafficking to the nucleus are also encountered. Recent progress has been made in overcoming these issues.

Biological Transport, Active↗
PubMed1998

Adjustment for regression dilution in epidemiological regression analyses.

PURPOSE: The term "regression dilution" describes the dilution/attenuation in a regression coefficient that occurs when a single measured value of a covariate is used instead of the usual or average value over a period of time. This paper reviews the current knowledge concerning a simple method of adjusting for regression dilution in single and multiple covariate situations and illustrates the adjustment procedure. METHODS: Formulation of the regression dilution problem as a measurement error problem allows existing measurement error theory to be applied to developing methods of adjustment for regression dilution. This theory leads to a precise method of adjustment for linear regression and approximate methods for logistic and Cox proportional hazards regression. The method involves obtaining the naive estimates of coefficients by assuming that covariates are not measured with error, and then adjusting these coefficients using reliability estimates for the covariates. Methods for estimating the reliability of covariates from the reliability and main study data and a method for the calculation of standard errors and confidence intervals for adjusted coefficients are described. RESULTS: An illustration involving logistic regression analysis of risk factors for death from cardiovascular disease based on cohort and reliability data from the Busselton Health Study shows that the different methods for estimating the adjustment factors give very similar adjusted estimates of coefficients, that univariate adjustment procedures may lead to inappropriate adjustments in multiple covariate situations, whether or not other covariates have intra-individual variation, and when the reliability study is moderate to large, the precision of the estimates of reliability coefficients has little impact on the standard errors of adjusted regression coefficients. CONCLUSIONS: The simple method of adjusting regression coefficients for "regression dilution" that arises out of measurement error theory is applicable to many epidemiological settings and is easily implemented. The choice of method to estimate the reliability coefficient has little impact on the results. The practice of applying univariate adjustments in multiple covariate situations is not recommended.

Analysis of Variance↗
PubMed1999

Strategic development.

Strategic development is more diverse, multifaceted and eventful than previously realized. Individual children know and use multiple strategies for solving a given kind of problem; they choose adaptively among available alternatives; and they frequently discover new strategies that enhance their problem-solving abilities. A recently formulated computer simulation (SCADS) indicates how associative and metacognitive processes work together to produce adaptive choices among existing strategies and discovery of useful new approaches.

Journal Article↗