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PubMed1975

Blood flow measurements in skin flaps.

For the last 50 years, the empirical approach of set length to width ratios for skin flaps has been held valid. Not until Milton's work in 1971 was this concept challenged. This report represents a method where precise, reproducible, and quantitative measurements of skin blood flow can be made using four radioactive nuclide microspheres and measures the blood flow changes in flaps of differing length to width ratios. Conclusions from our data suggest that the cutaneous blood flow in ventrally based, abdominal skin flaps in dogs is independent of base width as measured immediately after outlining and elevation.

Animals↗
PubMed1979

Thought, language, and communication disorders. I. Clinical assessment, definition of terms, and evaluation of their reliability.

Bleulerian psychiatry has considered thought disorder to be a pathognomonic symptom of schizophrenia. Evaluation of the Bleulerian perspective has been severely handicapped by the lack of any standard and widely agreed-on definition of thought disorder. Consequently, the conceptualization of thought disorder has tended to be quite diverse, and evaluation of thought disorder has tended to be quite unreliable. This report presents a set of definitions of linguistic and cognitive behaviors frequently observed in patients. These definitions derive from clinical experience, use an empirical approach, and avoid making inferences about underlying processes of thought. They attempt to define the broad range of language, thought, and communication behaviors observed in patients and are not limited to those considered characteristic of schizophrenia. The reliability of these definitions has been assessed using both tape-recorded and live interviews with patients, and it has been found to be quite good for most of the terms defined.

Adult↗
PubMed1990

A prospective, multicenter study of patients' refusal of antipsychotic medication.

Refusal of treatment with antipsychotic medication was studied prospectively in a sample of 1434 psychiatric patients admitted to four acute inpatient units in state-operated mental health facilities in Massachusetts during a 6-month period. Compared with a control group of patients who accepted prescribed antipsychotic treatment, the 103 patients who refused were older, of a higher social class, and less likely to have been prescribed antiparkinsonian medications. On admission, prior to refusal of medication, patients who refused were found to have significantly higher Brief Psychiatric Rating Scale scores than compliant patients and more negative attitudes regarding their hospitalization and past, present, and future treatment. Treatment refusal had negative effects on the hospital milieu and on the patient; refusers were more likely to require seclusion or restraint and had longer hospitalizations than treatment acceptors. Most refusal episodes ended with voluntary acceptance of treatment. In 23% of cases medications were discontinued. Only 18% of the sample reached formal, judicial review, and in every case that did, involuntary treatment was ordered. The policy implications of these findings are discussed.

Adult↗
PubMed1984

Doctor-patient communication. Clinical implications of social scientific research.

Research in the social sciences has clarified the nature and problems of doctor-patient communication. The development of adequate communication skills is now a goal of training programs in the primary-care specialties. Social structural barriers impede effective communication, however, and information giving remains problematic. Doctors tend to underestimate patients' desire for information and to misperceive the process of information giving. The transmission of information is related to characteristics of patients (sex, education, social class, and prognosis), doctors (social-class background, income, and perception of patients' desire for information), and the clinical situation (number of patients seen). Doctors' nonverbal communication abilities are associated with outcomes of medical care such as satisfaction and compliance. Regarding the sociolinguistic structure of communication, doctors often maintain a style of high control, which involves many doctor-initiated questions, interruptions, and neglect of patients' "life world." Training programs and standards of clinical practice should emphasize that improved doctor-patient communication is both desirable and possible.

Attitude of Health Personnel↗
PubMed1997

Colorectal cancer mass-screening: estimation of faecal occult blood test sensitivity, taking into account cancer mean sojourn time.

Mass screening using the faecal occult blood test (FOBT) can reduce mortality from colorectal cancer. Reliable estimation of FOBT sensitivity is crucial in assessing the potential effectiveness of a mass-screening procedure. Available estimates could be inaccurate because they neglect the temporal aspect of screening. The aim of our study was to estimate the sensitivity of the FOBT in mass screening for colorectal cancer, taking into account the duration of the pre-clinical phase of the disease assessed by the mean sojourn time (MST), and to assess whether MST and FOBT sensitivity differ according to cancer subsite. We analysed data taken from the first round of the mass-screening programme of the department of Calvados (France), involving 164,364 subjects of whom 43.4% participated in FOB screening. MST and sensitivity were estimated using a simple empirical approach, a traditional maximum likelihood method and log-linear modelling using the Bayesian technique of Gibbs sampling. MST was estimated as between 4.5 and 5 years for all subsites combined. According to the Gibbs sampling method, MSTs were 3.5, 6.4 and 2.6 years for proximal colon, distal colon and rectal cancer, respectively. Our estimation methods give a low sensitivity for the FOBT (50%), results for different subsites being closer to each other, slightly higher for proximal cancer. Our results strongly suggest that tumour growth rates are very different according to subsite, slowest for distal cancer and speediest for rectal cancer. Consideration of FOBT sensitivity without MST appears unreliable. Our results by subsite suggest that combining FOBT and sigmoidoscopy could be a good strategy for colorectal cancer screening.

Aged↗
PubMedDate not supplied

Idiopathic granulomatous angiitis of the central nervous system in pregnancy: the first case report.

Idiopathic granulomatous angiitis of the central nervous system (IGANS) is a rare vasculitis primarily affecting the spinal cord and brain not related to any underlying systemic disease. Clinical manifestations range from simple headache to cerebral vascular accidents secondary to vascular occlusion. The management of a pregnancy complicated by multiple risk factors including underlying IGANS is reported. An expectant, empiric approach was adopted and resulted in excellent maternal and neonatal outcomes. The first report of the management of a pregnancy complicated by IGANS is presented. Underlying maternal IGANS may not necessarily represent an indication for pregnancy termination.

Adult↗
PubMedDate not supplied

Efficient selection of high-producing subclones during gene amplification of recombinant Chinese hamster ovary cells by flow cytometry and cell sorting.

The screening procedure for high-producing cell lines is extremely time- and labor-intensive and costly, and is at present guided by an empirical approach based on individual experience. Flow cytometry and cell sorting, with its ability to analyze and separate single cells, an ideal method in the selection of such rare cells. The isolation of recombinant cell lines is especially difficult due to repeated gene amplification, which introduces high mutational variation into the population. We have established and evaluated a modification of a previous method that traps secreted product on the surface of the secreting cell, thus allowing direct analysis of single cell specific production rates. This method was used to select for high-producing subclones of a recombinant Chinese hamster ovary (CHO) cell line producing a human antibody against HIV-1 by repeated rounds of gene amplification and cell sorting. This cell line has been amplified in previous investigations, so that the amount of work and testing required by traditional methods can be compared with the protocol described herein. Forty-five 96-well plates were necessary to obtain a high-producing subclone by limited dilution methods, whereas only five plates were required when cell sorting was used. The specific production rate of the best clone obtained by sorting, however, was five times that of the clone obtained by traditional methods. In contrast to the clones obtained by limited dilution, which consisted of several populations of low- and high-producing cells even at high methotrexate concentrations (6.4 microM), the clones isolated by sorting were already homogeneous at 0.8 microM methotrexate.

Animals↗
PubMed2000

The structure and decay dynamics of exciplexes derived from dibenzoyl-methanatoboron difluoride and alkylbenzenes in cyclohexane

Dibenzomethanatoboron difluoride (DBMBF2) interacted with alkylbenzenes from its singlet excited state to form exciplexes ranging from weak polarity up to contact radical ion pairs (CRIP); this exciplex series shows the characteristics in the Marcus "normal" region. In cyclohexane these exciplexes gave intense fluorescence spectra and high quantum yields (phi(infinity)ex). The dipole moment of these exciplexes calculated from the solvatochromic shift of the fluorescence maximums (vmax) was used to estimate the coefficient ("a" and "c") of the CT and LE terms in the exciplex wavefunction. On the basis of the measured lifetimes and phi(infinity)ex of these exciplexes, the radiative (k(ex)f) and nonradiative (k(ex)NR) rate constants were calculated. The former k(ex)f were also computed from a semi-empirical approach based on the assumption that the exciplex wavefunction could be adequately described by CT and LE states, and that *DBMBF2 primarily contributes to the probability of exciplex emission. Two results agree with each other with small systematic deviations for those less polar exciplexes. The plots of k(ex)r and k(ex)NR (or their logarithmic value) against the LE contribution (c2) and transition energy gaps (hvmax) afford better correlation than those against -deltaG(-et). This indicates the role played by the LE contribution in generating the stabilization energy (U(s)) in these exciplexes through the A-D+)<==> *AD) resonance interaction; U(s), in turn, modifies -deltaG(-et) to afford the decay driving force hvmax. Also, those plots from k(ex)f values (being determined directly from experiments) show better correlation than those from k(ex)NR. In contrast to the CRIP type exciplexes in the Marcus "inverted" region, these k(ex)f and k(ex)NR increase in the common trend with increasing transition energy gaps. The k(ex)NR plots show less steep slopes and attains more quickly a minimum toward the CRIP region; the latter is identified as the turning point from the "normal" to "inverted" region. Both the attenuation and reversal of the k(ex)NR value with increasing polarity are believed to be generated by the emerging contribution of the intersystem crossing process as an additional nonradiative process, which is induced by the increased spin-orbit coupling in highly polar exciplexes.

Journal Article↗
PubMed1991

Efficiency of different criteria for selecting pharmacokinetic multiexponential equations.

Several statistical and empirical approaches have been proposed to select the multiexponential equation that best describes the time course of the plasma concentration of a drug. Recently, a new criterion (Ip) has been proposed according to which the model that best interprets a set of experimental data points is the one with the smallest area between the approximate confidence limits of estimated plasma concentration. We used large Montecarlo simulations to compare the ability of different selection criteria to select the correct model from data generated with an independent, normally distributed random error. The new criterion (Ip), Akaike's information criterion, the Schwartz test, and the F ratio test were studied. In this situation, the correct model was known and the performances of different selecting methods were assessed by examining their sensitivity to the number of exponential terms, the number of data points, and the size of the exponents in the true model. Mono-, bi-, and triexponential equations were studied. Overall mean percentages of right identification were 98.1 per cent for the new index, 82.8 per cent for Akaike's information criterion, 89.5 per cent for the Schwartz test, and 97.7 per cent for the F ratio test. The Akaike and Schwartz tests were not as efficient as the other tests with few (8-10) data points. The Ip and the F test raise the percentages of right identification of the model when the hybrid elimination rate macroconstants differ by at least a factor of four.(ABSTRACT TRUNCATED AT 250 WORDS)

Humans↗
PubMed2004

Estimating the potential refolding yield of recombinant proteins expressed as inclusion bodies.

Recombinant protein production in bacteria is efficient except that insoluble inclusion bodies form when some gene sequences are expressed. Such proteins must undergo renaturation, which is an inefficient process due to protein aggregation on dilution from concentrated denaturant. In this study, the protein-protein interactions of eight distinct inclusion-body proteins are quantified, in different solution conditions, by measurement of protein second virial coefficients (SVCs). Protein solubility is shown to decrease as the SVC is reduced (i.e., as protein interactions become more attractive). Plots of SVC versus denaturant concentration demonstrate two clear groupings of proteins: a more aggregative group and a group having higher SVC and better solubility. A correlation of the measured SVC with protein molecular weight and hydropathicity, that is able to predict which group each of the eight proteins falls into, is presented. The inclusion of additives known to inhibit aggregation during renaturation improves solubility and increases the SVC of both protein groups. Furthermore, an estimate of maximum refolding yield (or solubility) using high-performance liquid chromatography was obtained for each protein tested, under different environmental conditions, enabling a relationship between "yield" and SVC to be demonstrated. Combined, the results enable an approximate estimation of the maximum refolding yield that is attainable for each of the eight proteins examined, under a selected chemical environment. Although the correlations must be tested with a far larger set of protein sequences, this work represents a significant move beyond empirical approaches for optimizing renaturation conditions. The approach moves toward the ideal of predicting maximum refolding yield using simple bioinformatic metrics that can be estimated from the gene sequence. Such a capability could potentially "screen," in silico, those sequences suitable for expression in bacteria from those that must be expressed in more complex hosts.

Chromatography, High Pressure Liquid↗
PubMed2006

Energetic bicyclic azolium salts.

Bicyclic azoles, 2-methyl-5-(imidazol-1-yl)-2H-tetrazole (1), 2-methyl-5-(1,2,4-triazol-1-yl)-2H-tetrazole (4), 1-methyl-5-(imidazol-1-yl)-1H-tetrazole (7), 1-methyl-5-(1,2,4-triazol-1-yl)-1H-tetrazole (10), 1-methyl-4-nitro-2-(imidazol-1-yl)-1H-imidazole (13), and 1-methyl-4-nitro-2-(1,2,4-triazol-1-yl)-1H-imidazole (16) were prepared. Their thermally stable azolium salts, 3, 6, 9, 12, 15, and 18-21, with densities ranging between 1.519-1.674 g cm-3, were synthesized by quaternization with nitric or perchloric acid or with iodomethane followed by metathesis reactions with silver nitrate and silver perchlorate. The structures of 12 b and 21 b were confirmed by single-crystal X-ray analysis. The standard enthalpies of formation for some of the new salts were calculated by using the computationally feasible DFT(B3LYP) and MP2 methods in conjunction with an empirical approach based on densities of salts. The calculated values range from DeltaHdegreef=209.9 (21 a) to 412.3 (12 b) kJ mol-1 in which the experimental densities are >1.515 g cm-3.

Journal Article↗
PubMed1986

Video analysis of chemotactic locomotion of stored human polymorphonuclear leukocytes.

Previous studies of the storage of polymorphonuclear leukocytes (PMNs) have used an empirical approach to define "optimal" conditions. To date, no storage conditions have been described which satisfactorily preserve the chemotactic function of PMNs beyond 24 h. In an effort to define the precise nature of the storage lesion, we studied the chemotactic locomotion of freshly isolated PMNs and PMNs which had been suspended in citrate-phosphate-dextrose-adenine (CPD-A1) plasma and stored in PVC bags, at 20-22 degrees C for 24 h. We used time-lapse video recording and computer image analysis to quantitate the motion of PMNs migrating under agarose. The positions of individual motile cells were traced at 1-min intervals for 5 min. The following parameters were used to quantitate migration: speed (distance/min), persistence of locomotion index (velocity/speed), orientation angle (the angle of the vector describing the next displacement of a cell relative to a direct line toward the chemoattractant), and chemotropic index (cosine of the orientation angle). After 24 h of storage, the following changes were observed: fewer cells migrated, the speed of migrating cells was reduced by 25%, the persistence of locomotion index decreased by 7%, which indicates that migrating cells made slightly more/wider turns, and the chemotropic index was decreased by 30%, which indicates that migrating cells were less accurate in their orientation toward the chemoattractant. Apparently, the storage of PMNs selectively impairs the ability of some cells to orient accurately in a chemotactic gradient and changes the distribution of these locomotor parameters within the population.

Blood Preservation↗
PubMed1994

Optimized separation of seven corticosteroids by micellar electrokinetic chromatography.

The corticosteroids studied can be effectively separated by employing micellar electrokinetic capillary chromatography (MECC). The effect of pH, borate concentration and the sodium dodecyl sulfate (SDS) concentration on both the resolution and the selectivity was studied under 15 different experimental conditions. The experimental design was similar to the central composite design approach. Empirical quadratic regression models were derived for analyte migration time, band broadening and analyte velocity. Satisfactory regression fits and coefficients of determination for prediction were obtained with cross-validated models. The models for analyte migration time and analyte velocity were in good agreement with theory. Modeling of the band broadening seemed to be somewhat more complicated. Optimum conditions for resolution and selectivity were different. This is due to the fact that selectivity studies ignore the electroosmotic and band broadening properties of different electrolyte solutions. However, the study of the selectivity yielded good information about the suitability of the electrolyte systems for the particular separation problem. Although a high solubilizing power of SDS caused the corticosteroids to partition strongly into the SDS micelles, a good separation could be achieved at low SDS concentrations.

Adrenal Cortex Hormones↗
PubMed2004

Tag SNP selection for association studies.

This report describes current methods for selection of informative single nucleotide polymorphisms (SNPs) using data from a dense network of SNPs that have been genotyped in a relatively small panel of subjects. We discuss the following issues: (1) Optimal selection of SNPs based upon maximizing either the predictability of unmeasured SNPs or the predictability of SNP haplotypes as selection criteria. (2) The dependence of the performance of tag SNP selection methods upon the density of SNP markers genotyped for the purpose of haplotype discovery and tag SNP selection. (3) The likely power of case-control studies to detect the influence upon disease risk of common disease-causing variants in candidate genes in a haplotype-based analysis. We propose a quasi-empirical approach towards evaluating the power of large studies with this calculation based upon the SNP genotype and haplotype frequencies estimated in a haplotype discovery panel. In this calculation, each common SNP in turn is treated as a potential unmeasured causal variant and subjected to a correlation analysis using the remaining SNPs. We use a small portion of the HapMap ENCODE data (488 common SNPs genotyped over approximately a 500 kb region of chromosome 2) as an illustrative example of this approach towards power evaluation.

Chromosome Mapping↗
PubMed2005

The innovation triad: an EvoDevo agenda.

This article introduces a special issue on evolutionary innovation and morphological novelty, two interrelated themes that have received a remarkable increase of attention over the past few years. We begin with a discussion of the question of whether innovation and novelty represent distinct evolutionary problems that require a distinct conceptualization. We argue that the mechanisms of innovation and their phenotypic results--novelty--can only be properly addressed if they are distinguished from the standard evolutionary themes of variation and adaptation, and we present arguments for making such a distinction. We propose that origination, the first formation of biological structures, is another distinct problem of morphological evolution, and that together with innovation and novelty it constitutes a conceptual complex we call the innovation triad. We define a problem agenda of the triad, which separates the analysis of the initiating conditions from the mechanistic realization of innovation, and we discuss the theoretical problems that arise from treating innovation as distinct from variation. Further, we categorize the empirical approaches that address themes of the innovation triad in recognizing four major strands of research: the morphology and systematics program, the gene regulation program, the epigenetic program, and the theoretical biology program. We provide examples of each program, giving priority to contributions in the present issue. In conclusion, we observe that the innovation triad is one of the defining topics of EvoDevo research and may represent its most pertinent contribution to evolutionary theory. We point out that an inclusion of developmental systems properties into evolutionary theory represents a shift of explanatory emphasis from the external factors of natural selection to the internal dynamics of developmental systems, complementing adaptation with emergence, and contingency with inherency.

Adaptation, Physiological↗
PubMed2003

Physiologically based pharmacokinetic (PBPK) modeling of disposition of epiroprim in humans.

The objective of this study was to use in synergy physiologically based and empirical approaches to estimate the drug-specific input parameters of PBPK models of disposition to simulate the plasma concentration-time profile of epiroprim in human. The estimated input parameters were the tissue:plasma partition coefficients (Pt:p) for distribution and the blood clearance (CL) for the in vivo conditions. Epiroprim represents a challenge for such methods, because it shows large interspecies differences in its pharmacokinetic properties. Two approaches were used to predict the human Pt:p values: the tissue composition model (TCM) and the "Arundel approach" based on the volume of distribution at steady state (Vdss) determined in vivo in the rat. CL in human was predicted by (1) conventional allometric scaling of in vivo animal clearances (CAS), (2) physiologically based direct scaling up of in vitro hepatocyte data (DSU), and (3) allometric scaling of animal intrinsic in vivo blood CL normalized by the ratios of animal:human intrinsic clearances determined in vitro with hepatocytes (NAS). The performance of prediction was assessed by comparing separately the above pharmacokinetic parameters (Vdss estimated from the Pt:p values and blood CL) with the corresponding in vivo data obtained from the plasma kinetic profiles. These input parameters were used in PBPK models, and the resulting plasma concentration-time profiles of epiroprim were compared with those observed in rat and human. Previously to the construction of the human PBPK model, a model for the rat was also developed to gain more confidence on the model structure and assumptions. Overall, using the TCM and the NAS for the parameterization of the distribution and clearance, respectively, the PBPK model gave the more accurate predictions of epiroprim's disposition in human. This study represents therefore an attractive approach, which may potentially help the clinical candidate selection.

Animals↗
PubMed1985

Prediction of solubility in nonideal multicomponent systems using the UNIFAC group contribution model.

There is a need to identify suitable blends of solvents to dissolve drugs. Empirical approaches, such as trial-and-error and response surface, require several solubility measurements. In this study the UNIFAC method was used to predict solubility in highly nonideal multicomponent systems in which only the solute enthalpy of fusion and melting point must by measured. UNIFAC combines a group contribution approach with the UNIQUAC model for activity coefficients. Parameters characterizing interactions among constituent groups of a molecule have been previously determined from binary vapor pressure data. These tabulated group parameters are used to predict activity coefficients for newly synthesized compounds. These coefficients, together with the ideal solubility, permit a prediction of solubility. The solubility of 4-hexylresorcinol in ethyl acetate, ethyl myristate, and hexane mixtures was both measured and calculated using UNIFAC. The predicted solubilities were within 10% of the experimental solubilities for all but 3 of 21 mixtures. Since the method accounted for positive and negative deviations from ideality in a hydrogen-bonding system of molecules having different sizes, it shows great potential for use in pharmacy.

Acetates↗