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PubMed1985

Some nonsteroidal antiinflammatory drugs inhibit the generation of superoxide anions by activated polymorphs by blocking ligand-receptor interactions.

Representatives of the major classes of nonsteroidal antiinflammatory drugs (NSAID) were assessed for their effects on superoxide anion (O2-.) production by human polymorphonuclear leukocytes stimulated with phorbol myristate acetate or N-formyl methionyl-leucyl phenylalanine (fMLP). Three levels of effects were studied: (1) overall inhibition of O2-. production, (2) the inhibition of interaction between fMLP and specific receptors at the cell surface, and (3) intermediate proenzyme and enzyme effects. Some, but not all drugs inhibited O2-. production. In general, drugs that inhibited O2-. production inhibited fMLP-receptor interactions in a consistent dose dependent fashion, showing noncompetitive kinetics. Drugs that failed to inhibit O2-. production showed weak and variable effects on receptor binding and on the intermediate enzymes. Clinical observations suggest that inflammation in diseases such as gout respond differently to NSAID than diseases such as rheumatoid arthritis; studies of drug effects may help to clarify the differences in pathogenesis of these inflammatory diseases.

Anions↗
PubMed1993

Light variability in the modern neonatal nursery: chronobiologic issues.

The role that nursery light variability may play in modulating infant biological rhythms is being studied in Stanford Medical Center's Neonatal Intensive Care (NICU) and Intermediate Care (IN) Nurseries. In this investigation, spatial and temporal variability in illuminance was determined at 20 sites within each nursery over a 5-day period. The analysis of 240 measurements at 30 min intervals from each site revealed marked variability in illumination with respect to both time and position in the nursery. These aperiodic lighting patterns differed greatly from the published characterization of NICUs as having 'constant' illumination. Light pulses of variable frequency, intensity, and duration were common at each of the 40 bedsites studied. Given the powerful impact of light on circadian rhythmicity and sleep in adults, the results from this study suggest that modern NICU lighting, while implemented to facilitate intensive care, may have adverse effects on infant development. Future studies on the influence of light on biological rhythmicity and sleep are essential to provide a framework for clinical and environmental interventions, which may play a significant role in improving developmental outcome in hospitalized preterm or term infants.

California↗
PubMed1999

Differentiating between septic arthritis and transient synovitis of the hip in children: an evidence-based clinical prediction algorithm.

BACKGROUND: A child who has an acutely irritable hip can pose a diagnostic challenge. The purposes of this study were to determine the diagnostic value of presenting variables for differentiating between septic arthritis and transient synovitis of the hip in children and to develop an evidence-based clinical prediction algorithm for this differentiation. METHODS: We retrospectively reviewed the cases of children who were evaluated at a major tertiary-care children's hospital between 1979 and 1996 because of an acutely irritable hip. Diagnoses of true septic arthritis, presumed septic arthritis, and transient synovitis were explicitly defined on the basis of the white blood-cell count in the joint fluid, the results of cultures of joint fluid and blood, and the clinical course. Univariate analysis and multiple logistic regression analysis were used to compare groups. A probability algorithm for differentiation between septic arthritis and transient synovitis on the basis of independent multivariate predictors was constructed and tested. RESULTS: Patients who had septic arthritis differed significantly (p < 0.05) from those who had transient synovitis with regard to the erythrocyte sedimentation rate, serum white blood-cell count and differential, weight-bearing status, history of fever, temperature, evidence of effusion on radiographs, history of chills, history of recent antibiotic use, hematocrit, and gender. Patients who had true septic arthritis differed significantly (p < 0.05) from those who had presumed septic arthritis with regard to history of recent antibiotic use, history of chills, temperature, erythrocyte sedimentation rate, history of fever, gender, and serum white blood-cell differential. Four independent multivariate clinical predictors were identified to differentiate between septic arthritis and transient synovitis: history of fever, non-weight-bearing, erythrocyte sedimentation rate of at least forty millimeters per hour, and serum white blood-cell count of more than 12,000 cells per cubic millimeter (12.0 x 10(9) cells per liter). The predicted probability of septic arthritis was determined for all sixteen combinations of these four predictors and is summarized as less than 0.2 percent for zero predictors, 3.0 percent for one predictor, 40.0 percent for two predictors, 93.1 percent for three predictors, and 99.6 percent for four predictors. The chi-square test for trend and the area under the receiver operating characteristic curve indicated excellent diagnostic performance of this group of multivariate predictors in identifying septic arthritis. CONCLUSIONS: Although several variables differed significantly between the group that had septic arthritis and the group that had transient synovitis, substantial overlap in the intermediate ranges made differentiation difficult on the basis of individual variables alone. However, by combining variables, we were able to construct a set of independent multivariate predictors that, together, had excellent diagnostic performance in differentiating between septic arthritis and transient synovitis of the hip in children.

Acute Disease↗
PubMed1994

P nucleotide insertions and the resolution of hairpin DNA structures in mammalian cells.

Two lines of evidence point to a hairpin DNA intermediate in V(D)J joining (V, variable; D, diversity; J, joining) [Lieber, M.R. (1991) FASEB J. 4, 2934-2944]. One is the presence of P nucleotide insertions (short inverted-repeat sequence) in V(D)J junctions [Lafaille, J. J., DeCloux, A., Bonneville, M., Takagaki, Y. & Tonegawa, S. (1989) Cell 59, 859-870]; a second is the detection of site-specifically broken DNA molecules with covalently closed (hairpin) termini in thymus DNA [Roth, D. B., Menetski, J. P., Nakajima, P., Bosma, M. J. & Gellert, M. (1989) Cell 70, 983-991]. However, P nucleotide insertions could be generated in ways not involving a hairpin structure, and because physical evidence for hairpin-ended DNA fragments has been obtained only with mutant mice, there is some uncertainty regarding the role of hairpin molecules in the normal V(D)J joining pathway. To determine whether mammalian cells are capable of metabolizing this odd type of DNA terminus and whether, in doing so, junctions with P insertions are in fact created, a linear DNA molecule with a hairpin closure at each end was transfected into several murine cell lines. The hairpin-ended molecules were recircularized, and the junctions exhibited P insertions at a high frequency. This result directly links the presence of P insertions to a hairpin precursor, providing strong evidence for the notion that a hairpin DNA intermediate exists in V(D)J recombination. A comparison of hairpin end joining in various cells, including those derived from mice with the severe combined immunodeficiency (scid) mutation, is presented.

3T3 Cells↗
PubMed1999

Decision training: the effects of complex instruction, variable practice and reduced delayed feedback on the acquisition and transfer of a motor skill.

Novice, intermediate and advanced baseball hitters followed a 7-week training programme, in which they received either behavioural training or decision training. Participants in the behavioural training group received simple-to-complex instruction, variable practice and an abundance of feedback throughout the acquisition period; the decision training group received complex instruction, variable practice and reduced delayed feedback. As predicted, the intermediate and advanced hitters who received decision training hit at a lower level (%) during acquisition but at a higher level during a transfer test in week 7. Novices in the behavioural training group were better than novices in the decision training group over both acquisition and transfer trials.

Adolescent↗
PubMed1994

Predictors of nursing home placement and mortality of residents in intermediate care.

Assessments of sensorimotor function, cognitive status and health measures were made in 95 intermediate-care (hostel) residents (mean age 82.7 years). The residents were then followed up for 3 years to determine which measures were associated with nursing-home placement and/or death. Information on the outcome of 92 participants was available at the end of the 3-year period. At this time, 53 residents (58%) were still residing at the hostel, seven (8%) had been transferred to nursing homes and 32 residents (35%) had died. Sixteen of the 32 subjects who had died had been transferred to nursing homes. Discriminant function analysis identified tactile sensitivity, ankle dorsiflexion strength, reaction time, sway with eyes open on a compliant (foam rubber) surface and cognitive impairment as the variables that significantly discriminated between subjects who were still in intermediate care and subjects who had been transferred to nursing homes. This procedure correctly classified 88% of subjects into intermediate care or nursing home groups. These variables, with the exception of ankle dorsiflexion strength, were also included in the final discriminant model when predicting mortality, correctly classifying 71% of the subjects. The findings indicate that cognitive impairment and reduced functioning in a number of sensorimotor factors are strongly related to poor outcomes for residents in hostel care.

Accidental Falls↗
PubMed2005

Pharmacokinetic and glucodynamic variability: assessment of insulin glargine, NPH insulin and insulin ultralente in healthy volunteers using a euglycaemic clamp technique.

AIMS/HYPOTHESIS: This single-dose, double-blind, randomised, parallel-group study evaluated the reproducibility in systemic exposure and glucodynamic effect of insulin glargine, NPH insulin (NPH) and insulin ultralente (ultralente) using the manually adjusted euglycaemic clamp technique. METHODS: In total, 36 healthy volunteers received two consecutive s.c. injections (0.4 IU/kg) of glargine, NPH or ultralente with a wash-out period of 7 days between treatments. RESULTS: In healthy volunteers, glargine presented well-reproduced flat concentration profiles and no pronounced peaks in activity. NPH, by contrast, showed well-defined peaks in concentration and glucose disposal, while ultralente had highly variable profiles. Within-subject variability (ANOVA) for insulin exposure over 24 h was 15% for glargine and 19% for NPH, compared with 67% for ultralente (p<0.05, glargine and NPH vs ultralente). The 49% within-subject variability in total glucose disposal (glucose infusion rate [GIR]-AUC0-24 h) with ultralente was about twice as large as the 22% with NPH (p<0.05), but was intermediate with glargine at 31% (p=NS). By contrast, variability in the diurnal time-action profile (SD of diurnal day-to-day differences in GIR) for glargine was 30% (p<0.05) and 50% (p<0.05) less than with NPH and ultralente, respectively. No serious adverse events were reported. CONCLUSIONS/INTERPRETATION: Although representing insulins of different profiles, glargine and NPH showed a high and similar reproducibility of total absorption and glucodynamic effect, whereas ultralente proved to have poor reproducibility. However, while NPH yields peaks in concentration and activity, glargine shows flat and non-fluctuating profiles resulting in less variation in day-to-day 24-h activity.

Adolescent↗
PubMed2006

Variability of indicator bacteria at different time scales in the Upper Hoosic River watershed.

Accurately evaluating whether a water body is meeting water quality criteria for indicator bacteria requires an understanding of the spatial and temporal variability in concentrations of these indicators. We have collected data on concentrations of Escherichia coli at 12 sites within the upper Hoosic River Basin, spanning a range of land uses and levels of development. Sampling was conducted with the goal of assessing the variation in E. coli levels over different time scales: seasonal, storm-related, and diurnal. General linear models were constructed to describe the factors contributing to E. coli concentrations at a given location and time. We found that bacterial levels were higher in more developed watersheds; in summer rather than winter; in storms rather than baseflow; and in the early morning rather than afternoon. Seasonal and storm sampling captured different portions of the range of E. coli concentrations, but the levels of variability at these two scales were similar. Diurnal sampling produced concentrations intermediate between seasonal and storm sampling. Compared to a pristine stream, a more urbanized stream exhibited greater diurnal variability, but less variation from baseflow to stormflow. We recommend collecting both seasonal and storm data, but not necessarily diurnal data, in assessment of stream bacterial quality.

Environmental Monitoring↗
PubMed1973

Comparisons between variable-interval and fixed-interval schedules of electric shock delivery.

Responding maintained in rats under a variable-interval 35-sec food schedule was suppressed more by 60-sec and 240-sec fixed-interval schedules of shock delivery than by 60-sec and 240-sec variable-interval schedules of shock delivery. When the delivery of shock was preceded by a 5-sec visual stimulus, little overall response suppression was found with either fixed-interval or variable-interval schedules. In a third experiment, the percentage of occasions on which a cue preceded each shock delivery was varied from 0% to 100%. For the fixed-interval shock condition, the most suppression occurred with the 0% treatment, the least with 100%, and an intermediate amount with the 50% treatment. For the variable-interval groups, the most suppression occurred in the 50% condition, the least in the 100% group, and an intermediate amount with 0%.

Journal Article↗
PubMed1987

Somatic mutation in anti-phosphorylcholine antibodies.

A detailed analysis of the genes and proteins that participate in the murine immune response to PC has provided key insights at the structural level into the phenomenon of somatic mutation in B cells. Most anti-PC antibodies are encoded by 1 VH gene of the S107 subfamily, and 3 VK genes, VKT15 of the VK22 subfamily, VKM3 from the VK8 subfamily, and VK167 from the VK24 subfamily. No mutation was detected in these genes until the 2nd wk after immunization, indicating that mutation is under developmental control. The protein sequences of 73 heavy and light chains derived from the secondary response support the concept of developmental activation of mutation after antigen stimulation. No mutation was found in the IgM antibodies, whereas half of the IgG and IgA antibodies had mutation. Most of the mutated antibodies had higher affinity for antigen than their germline counterparts, which suggests that the major role of somatic mutation is to increase affinity rather than to create new specificities. Nucleotide sequencing established two hallmarks of mutation in immunoglobulin genes: mutations are targeted to a 1 kilobase region surrounding and including the rearranged variable gene, and they occur at an extraordinary frequency of 10(-2) nucleotide substitutions. Mutation is probably caused by DNA repair, and may occur during error-prone repair of nicked DNA around the variable gene or during mismatch repair of misaligned structural intermediates. The elucidation of this remarkable mechanism clearly requires studies of a more dynamic character. Two major questions that need to be answered are: what targets mutation to the variable gene, and what enzymes are involved?

Animals↗
PubMed2000

In search of the wage-labour/service contract: new evidence on the validity of the Goldthorpe class schema.

In this paper we examine new empirical evidence on the coherence and magnitude of the main classes in the Goldthorpe class schema. Particular attention is paid to issues that have recently been a source of academic dispute: the coherence and size of the service class and the distinction between the service class and intermediate classes. Using recently available British data collected by the Office for National Statistics we examine: (i) the extent to which measures of class-relevant job characteristics are empirically discriminated by the categories of the schema; (ii) the structure of a 'contract type' dimension of employment relations conceived of as a categorical latent variable; and (iii) the association between this latent variable and both the Goldthorpe class schema and a related measure socio-economic group (SEG). We find that the data are consistent with the existence of a three category latent 'contract type' variable largely corresponding to the notions of service, intermediate and wage-labour contracts explicit in discussions of the theoretical rationale for the Goldthorpe schema. We further find a substantial degree of fit between the latent 'contract types' and the schema. However, the service class fault line appears to lie within class I and II of the schema rather than between them and the intermediate classes which suggests a revised, smaller service class would better capture the reality of the contemporary British occupational structure.

Adolescent↗
PubMed1975

Characteristics of ventricular extrasystoles and their prognostic importance: a reappraisal of their method of classification.

The concept of two different types of extrasystoles, parasystolic and coupled, depends upon two distinguishing characteristics of these beats. The characteristics of the parasystolic extrasystoles are the invariability of the ectopic cycle together with their independence from the basic rhythm. Coupled extrasystoles demonstrate a dependence upon the basic rhythm although they may express some degree of ectopic variability. The degree of variation of the interectopic interval or its common denominator measures the irregularity of the ectopic parasystolic rhythm. The variation of coupling intervals describes the dependence of the ectopic beat upon the basic rhythm. In a study of 719 electrocardiograms with ventricular extrasystoles, about one-third of the extrasystoles appeared intermediate between these types since they had both variable coupling intervals and variable interectopic intervals. Some of these had total variability of coupling intervals and of the interectopic intervals (random non-parasystolic coupling), and others had limited variation of coupling intervals when expressed in relationship to the total duration of electrical diastole (approximate non-parasystolic coupling). Both these ectopic types appeared to be associated with cardiac disease, and repetitive ventricular extrasystoles. Left bundle branch type extra-with fixed coupling. There were no obvious relationships between the contour and the type of coupling of ventricular extrasystoles. Left bundle branch type extrasystoles with vertical or right axis were the most frequent, particularly in normal subjects, but in the presence of cardiac disease there were more electrocardiograms with right bundle branch type extrasystoles. Extrasystoles in the presence of underlying conduction defects were usually of opposite configuration to this defect. The contour of uniform extrasystoles did not appear to predispose to serious ventricular arrhythmias but multiformity of extrasystoles was an important prognostic indicator. It is suggested that variability of contour and coupling are important signs of inhomogenous conduction and may precede the onset of severe ventricular arrhythmias. Random nonparasystolic coupling and marked multiformity indicate a more sinister arrhythmic state.

Bundle of His↗
PubMed2006

Shrinkage estimation method for mapping multiple quantitative trait loci.

In this article, shrinkage estimation method for multiple-marker analysis and for mapping multiple quantitative trait loci (QTL) was reviewed. For multiple-marker analysis, Xu (Genetics, 2003, 163:789-801) developed a Bayesian shrinkage estimation (BSE) method. The key to the success of this method is to allow each marker effect have its own variance parameter, which in turn has its own prior distribution so that the variance can be estimated from the data. Under this hierarchical model, a large number of markers can be handled although most of them may have negligible effects. Under epistatic genetic model, however, the running time is very long. To overcome this problem, a novel method of incorporating the idea described above into maximum likelihood, known as penalized likelihood method, was proposed. A simulated study showed that this method can handle a model with multiple effects, which are ten times larger than the sample size. For multiple QTL analysis, two modified versions for the BSE method were introduced: one is the fixed-interval method and another is the variable-interval method. The former deals with markers with intermediate density, and the latter can handle markers with extremely high density as well as model with epistatic effects. For the detection of epistatic effects, penalized likelihood method and the variable-interval approach of the BSE method are available.

Bayes Theorem↗
PubMed1988

Relationship between Mayer-Rokitansky-Küster (MRK) anomaly and hereditary renal adysplasia (HRA).

We report the results of a study performed in a sample of women with the Mayer-Rokitansky-Küster (MRK) anomaly and in their first-degree relatives. Our results are compatible with a traditional model of multifactorial determination; however, we cannot exclude the hypothesis of autosomal dominant inheritance, with an intermediate degree of penetrance and a highly variable expressivity of a single mutant gene. In this sense, our data seem to support the idea expressed recently by Opitz [1987].

Abnormalities, Multiple↗
PubMed1998

Expression of the intermediate filament keratin gene, K15, in the basal cell layers of epithelia and the hair follicle.

The intermediate filament keratin, K15, is present in variable abundance in stratified epithelia. In this study we have isolated and characterized the sheep K15 gene, focusing on its expression in the follicles of sheep and mice. We show that K15 is expressed throughout the hair cycle in the basal layer of the outer root sheath that envelops the follicle. Strikingly, however, in large medullated wool follicles, a small group of basal outer root sheath cells located in the region thought to contain hair follicle stem cells are K15-negative. In the follicle bulb K15 is expressed in cells situated next to the dermal papilla but not in the inner bulb cells. Elsewhere, K15 is expressed at a low, variable level in the basal layer of the epidermis and sebaceous gland, often in a punctate pattern. In the esophagus of the sheep K15 expression is restricted to the basal layer, in contrast to human esophagus where it is expressed throughout the epithelium. Transgenic mouse lines established with a 15-kb sheep K15 gene construct exhibited faithful expression and showed no phenotypic consequences of K15 overexpression. An investigation of transgene expression showed that K15 is continuously expressed in outer root sheath cells during the hair cycle. Given its expression in the mitotically active basal cell layers of diverse epithelia and the follicle, K15 expression appears to signal an early stage in the pathway of keratinocyte differentiation that precedes the decision of a cell to become epidermal or hair-like.

Amino Acid Sequence↗
PubMed1981

Correlations between relatives for acrocentric association frequency.

Acrocentric association was investigated in peripheral blood lymphocytes of twins (10 female monozygotic and 11 females dizygotic pairs), newborns and both parents (30 families), and spouses (51 pairs). Seventy two hour cultures were G-banded and scored for both absolute and relative acrocentric association frequency, except in the case of the spouse pairs where only the absolute frequency was measured. Both relative and absolute parameters of acrocentric association show positive correlations between relatives with the values being highest and most consistent in monozygotic twins, intermediate in parent and offspring, and most variable in dizygotic twins. Husband and wife pairs from our family collections show a positive correlation for the absolute parameter but not for relative parameters. The environmental factors responsible have not been identified. A rough estimate of broad sense heritability (0.81) has been made for the relative parameters. It probably contains a large component due to genetic dominance. Heritability of the absolute parameters is probably lower than for the relative parameters though estimation of its value is complicated by inconsistent results. A model is proposed to account for the variation in satellite association frequency which contains two elements: (i) The genotype determines the ratio of one chromosome type to another in the population of associated chromosomes (ii) All other environmental factors influence the absolute frequency of association without altering this basic ratio.

Adult↗
PubMed1989

Benign partial epilepsy and related conditions: multifactorial pathogenesis with hereditary impairment of brain maturation.

The main clinical and bioelectrical features of the benign partial epilepsies and related conditions are described. Based on highly selected groups, the definition of these suggested syndromes disregards the considerable overlap between borderline and intermediate cases. To understand the great phenotypic variability of these epilepsies, the complexity of causal especially genetic factors must be considered. Different genetic traits, expressed in certain EEG patterns, determine the level of cerebral excitability. These hereditary variables are widespread in the general population. Most are polygenic, focal sharp waves possibly autosomal dominant. In individuals, the coincidence of different traits with little or no clinical significance, results in additive effects lowering the seizure threshold and raising the risk of clinical manifestation. The complexity of causal factors, which, potentially include organic brain lesions, account for the wide spectrum of epileptic and non-epileptic conditions ranging from mild selective performance deficits to complex psychomental retardation, and from simple rolandic epilepsy to severe epilepsies with minor seizures or bioelectrical status. These conditions are not "syndromes" in the stricter sense, but sets of variably weighted symptoms of a complex pathogenetic background. A genetic disposition to focal pathogenetic background. A genetic disposition to focal anomalies of brain function is of decisive importance. The biological background is as of yet unknown. The marked age-dependency of symptoms and almost regular disappearance of seizures and EEG abnormalities at puberty justify the assumption of an hereditary impairment of brain maturation. The hypothesis of autosomal dominant inheritance awaits appraisal by studies of larger populations and quantitative genetic approaches.

Adolescent↗