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PubMed2003

Can variability in corneal metabolism explain the variability in corneal swelling?

PURPOSE: To examine if the variability in hypoxic corneal swelling in non-contact lens wearing and contact lens wearing groups can be explained by the variability in corneal metabolic activity or endothelial function. METHODS: Corneal thickness was measured by Orbscan before and after 2 hr of closed-eye hydrogel lens wear. De-swelling rates (percentage recovery per hour) were determined by continued corneal thickness measurements until open-eye steady-state thickness was reached. Corneal oxygen consumption was estimated by measuring tear oxygen tension while wearing hydrogels of known oxygen transmissibility. The change in stromal pH because of hypoxia was measured by ratio fluorescence of stromal fluorescein. RESULTS: Corneal swelling was inversely correlated with open- or closed-eye tear oxygen tension while wearing the test hydrogels. Corneal swelling was directly correlated with the change in stromal pH during hypoxic lens wear. Unexpectedly, corneal swelling was also inversely correlated with the percent recovery per hour. These parameters could not explain all the swelling variability. The contact lens wearing group showed significantly less swelling and change in stromal pH with the same lenses. However, percent recovery per hour and tear oxygen tension was the same. CONCLUSION: Corneal swelling is associated with corneal metabolic activity and endothelial function; however, other factors must also be involved. Contact lens wearers do not adapt by modifying oxygen consumption but probably by using glucose more efficiently.

Adult↗

PubMed2002

Salt-sensitivity of proximal reabsorption alters macula densa salt and explains the paradoxical effect of dietary salt on glomerular filtration rate in diabetes mellitus.

GFR varies inversely with dietary NaCl in patients with early type I diabetes and in streptozotocin (STZ)-diabetic rats. To explain this paradox within the laws of physiology, it was hypothesized that it results from heightened sensitivity of the diabetic proximal tubule to dietary salt because changes in proximal reabsorption (Jprox) elicit reciprocal adjustments in GFR through the normal actions of tubuloglomerular feedback (TGF). Micropuncture was done in rats after 5 wk of moderately hyperglycemic STZ-diabetes and 1 wk of different NaCl diets. First, single-nephron GFR (SNGFR) and early distal tubular Na(+), Cl(-) and K(+) concentration (representing the TGF signal) were measured by collecting from early distal nephrons. In nondiabetics, dietary salt did not affect SNGFR or the TGF signal. In diabetics, the TGF signal varied directly with dietary salt while SNGFR varied inversely with dietary salt. Next, Jprox was measured by collecting from late proximal tubules. To control for different SNGFR, SNGFR was manipulated by perfusing Henle's loop to alter TGF activity. Controlling for SNGFR, dietary salt did not affect Jprox in nondiabetics but exerted a major inverse impact on Jprox in diabetics. In conclusion, normal rats acclimate to dietary NaCl by primarily adjusting transport downstream of the macula densa. In contrast, diabetes renders reabsorption in the proximal tubule sensitive to dietary NaCl with subsequent effects on the TGF signal. This explains the paradoxical effect of dietary NaCl on GFR in early diabetes.

Absorption↗

PubMed2005

The mediation proportion: a structural equation approach for estimating the proportion of exposure effect on outcome explained by an intermediate variable.

It is often of interest to assess how much of the effect of an exposure on a response is mediated through an intermediate variable. However, systematic approaches are lacking, other than assessment of a surrogate marker for the endpoint of a clinical trial. We review a measure of "proportion explained" in the context of observational epidemiologic studies. The measure has been much debated; we show how several of the drawbacks are alleviated when exposures, mediators, and responses are continuous and are embedded in a structural equation framework. These conditions also allow for consideration of several intermediate variables. Binary or categorical variables can be included directly through threshold models. We call this measure the mediation proportion, that is, the part of an exposure effect on outcome explained by a third, intermediate variable. Two examples illustrate the approach. The first example is a randomized clinical trial of the effects of interferon-alpha on visual acuity in patients with age-related macular degeneration. In this example, the exposure, mediator and response are all binary. The second example is a common problem in social epidemiology-to find the proportion of a social class effect on a health outcome that is mediated by psychologic variables. Both the mediator and the response are composed of several ordered categorical variables, with confounders present. Finally, we extend the example to more than one mediator.

Adult↗

PubMed2004

Can population differences explain the contrasting results of the Mwanza, Rakai, and Masaka HIV/sexually transmitted disease intervention trials?: A modeling study.

OBJECTIVE: To determine whether population differences can explain the contrasting impacts on HIV observed in the Mwanza trial of sexually transmitted disease (STD) syndromic treatment (ST), the Rakai trial of STD mass treatment (MT), and the Masaka trial of information, education, and communication (IEC) with and without ST as well as to predict the effectiveness of each intervention strategy in each population. METHODS: Stochastic modeling of the transmission of HIV and 6 STDs was used with parameters fitted to demographic, sexual behavior, and epidemiological data from the trials and general review of STD/HIV biology. RESULTS: The baseline trial populations could be simulated by assuming higher risk behavior in Uganda compared with Mwanza in the 1980s, followed by reductions in risk behavior in Uganda preceding the trials. In line with trial observations, the projected HIV impacts were larger for the ST intervention in Mwanza than for the MT intervention in Rakai or the IEC and IEC + ST interventions in Masaka. All 4 simulated intervention strategies were more effective in reducing incidence of HIV infection in Mwanza than in either Rakai or Masaka. CONCLUSIONS: Population differences in sexual behavior, curable STD rates, and HIV epidemic stage can explain most of the contrast in HIV impact observed between the 3 trials. This study supports the hypothesis that STD management is an effective HIV prevention strategy in populations with a high prevalence of curable STDs, particularly in an early HIV epidemic.

Adolescent↗

PubMed1995

'Dynamics of neuronal interactions' cannot be explained by 'neuronal transients'.

In a recent paper, Vaadia et al. demonstrated that patterns of firing correlation between single neurons in the cortex of behaving monkeys can be modified within a fraction of a second. These changes occur in relation to sensory stimuli and behavioral events, and even without modulations of the neurons' firing rates. These findings call for a revision of prevailing models of neural coding that solely rely on single neuron firing rates. In a defense of these models, Friston put forward an alternative explanation, proposing that the observed correlation dynamics emerge solely from co-modulations of the firing rates of each of the neurons, while the strength of their interaction remains constant. To test this possibility we re-examined the data, adopting Friston's 'neuronal transients' model, and the associated equations and procedures. We found that, to explain the dynamic correlation between a pair of neurons, the alternative interpretation requires that each neuron's response to a single stimulus is composed of a relatively large number of independent components, which co-vary with their counterparts in the companion neuron. This large number of components and their shapes lead us to conclude that, although in principle possible, the neuronal transients model: (i) does not provide a simpler explanation of the experimental results; and (ii) cannot explain these results without itself deviating significantly from most rate code models.

Animals↗

PubMed2002

Interspecific reciprocity explains mobbing behaviour of the breeding chaffinches, Fringilla coelebs.

When prey animals discover a predator close by, they mob it while uttering characteristic sounds that attract other prey individuals to the vicinity. Mobbing causes a predator to vacate its immediate foraging area, which gives an opportunity for prey individuals to continue their interrupted daily activity. Besides the increased benefits, mobbing behaviour also has its costs owing to injuries or death. The initiator of mobbing may be at increased risk of predation by attracting the predator's attention, especially if not joined by other neighbouring prey individuals. Communities of breeding birds have always been considered as temporal aggregations. Since an altruist could not prevent cheaters from exploiting its altruism in an anonymous community, this excluded any possibility of explaining mobbing behaviour in terms of reciprocal altruism. However, sedentary birds may have become acquainted since the previous non-breeding season. Migrant birds, forming anonymous communities at the beginning of the breeding season, may also develop closer social ties during the course of the breeding season. We tested whether a male chaffinch, a migrant bird, would initiate active harassment of a predator both at the beginning of the breeding season and a week later when it has become a member of a non-anonymous multi-species aggregation of sedentary birds. We expected that male chaffinches would be less likely to initiate a mob at the beginning of the breeding season when part of an anonymous multi-species aggregation of migratory birds. However, their mobbing activity should increase as the breeding season advances. Our results support these predictions. Cooperation among individuals belonging to different species in driving the predator away may be explained as interspecific reciprocity based on interspecific recognition and temporal stability of the breeding communities.

Aggression↗

PubMed2004

Metacommunity process rather than continental tectonic history better explains geographically structured phylogenies in legumes.

Penalized likelihood estimated ages of both densely sampled intracontinental and sparsely sampled transcontinental crown clades in the legume family show a mostly Quaternary to Neogene age distribution. The mode ages of the intracontinental crown clades range from 4-6 Myr ago, whereas those of the transcontinental crown clades range from 8-16 Myr ago. Both of these young age estimates are detected despite methodological approaches that bias results toward older ages. Hypotheses that resort to vicariance or continental history to explain continental disjunct distributions are dismissed because they require mostly Palaeogene and older tectonic events. An alternative explanation centring on dispersal that may well explain the geographical as well as the ecological phylogenetic structure of legume phylogenies is Hubbell's unified neutral theory of biodiversity and biogeography. This is the only dispersalist theory that encompasses evolutionary time and makes predictions about phylogenetic structure.

Demography↗

PubMed2006

Human development VII: a spiral fractal model of fine structure of physical energy could explain central aspects of biological information, biological organization and biological creativity.

In this paper we have made a draft of a physical fractal essence of the universe, a sketch of a new cosmology, which we believe to lay at the root of our new holistic biological paradigm. We present the fractal roomy spiraled structures and the energy-rich dancing "infinite strings" or lines of the universe that our hypothesis is based upon. The geometric language of this cosmology is symbolic and both pre-mathematical and pre-philosophical. The symbols are both text and figures, and using these we step by step explain the new model that at least to some extent is able to explain the complex informational system behind morphogenesis, ontogenesis, regeneration and healing. We suggest that it is from this highly dynamic spiraled structure that organization of cells, organs, and the wholeness of the human being including consciousness emerge. The model of "dancing fractal spirals" carries many similarities to premodern cultures descriptions of the energy of the life and universe. Examples are the Native American shamanistic descriptions of their perception of energy and the old Indian Yogis descriptions of the life-energy within the body and outside. Similar ideas of energy and matter are found in the modern superstring theories. The model of the informational system of the organism gives new meaning to Bateson's definition of information: "A difference that makes a difference", and indicates how information-directed self-organization can exist on high structural levels in living organisms, giving birth to their subjectivity and consciousness.

Biological Evolution↗

PubMed2004

Genomic regionality in rates of evolution is not explained by clustering of genes of comparable expression profile.

In mammalian genomes, linked genes show similar rates of evolution, both at fourfold degenerate synonymous sites (K4) and at nonsynonymous sites (KA). Although it has been suggested that the local similarity in the synonymous substitution rate is an artifact caused by the inclusion of disparately evolving gene pairs, we demonstrate here that this is not the case: after removal of disparately evolving genes, both (1) linked genes and (2) introns from the same gene have more similar silent substitution rates than expected by chance. What causes the local similarity in both synonymous and nonsynonymous substitution rates? One class of hypotheses argues that both may be related to the observed clustering of genes of comparable expression profile. We investigate these hypotheses using substitution rates from both human-mouse and mouse-rat comparisons, and employing three different methods to assay expression parameters. Although we confirm a negative correlation of expression breadth with both K4 and KA, we find no evidence that clustering of similarly expressed genes explains the clustering of genes of comparable substitution rates. If gene expression is not responsible, what about other causes? At least in the human-mouse comparison, the local similarity in KA can be explained by the covariation of KA and K4. As regards K4, our results appear consistent with the notion that local similarity is due to processes associated with meiotic recombination.

Animals↗

PubMed2001

Kinetic proofreading can explain the supression of supercoiling of circular DNA molecules by type-II topoisomerases.

The enzymes that pass DNA through DNA so as to remove entanglements, adenosine-triphosphate-hydrolyzing type-II topoisomerases, are able to suppress the probability of self-entanglements (knots) and mutual entanglements (links) between approximately 10 kb plasmids, well below the levels expected, given the assumption that the topoisomerases pass DNA segments at random by thermal motion. This implies that a 10-nm type-II topoisomerase can somehow sense the topology of a large DNA. We previously introduced a "kinetic proofreading" model which supposes the enzyme to require two successive collisions in order to allow exchange of DNA segments, and we showed how it could quantitatively explain the reduction in knotting and linking complexity. Here we show how the same model quantitatively explains the reduced variance of the double-helix linking number (supercoiling) distribution observed experimentally.

Binding Sites↗

PubMed2002

Extracellular stimulation window explained by a geometry-based model of the neuron-electrode contact.

Extracellular stimulation of single cultured neurons which are completely sealing a microelectrode is usually performed using anodic or biphasic currents of at least 200 nA. However, recently obtained experimental data demonstrate the possibility to stimulate a neuron using cathodic current pulses with less amplitude. Also, a stimulation window is observed. These findings can be explained by a finite-element model which permits geometry-based electrical representation of the neuron-electrode interface and can be used to explore the required conditions for extracellular stimulation in detail. Modulation of the voltage sensitive channels in the sealing part of the membrane appears to be the key to successful cathodic stimulation. Furthermore, the upper limit of the stimulation window can be explained as a normal consequence of the neuronal membrane electrophysiology.

Action Potentials↗

PubMed2002

A measure of the proportion of treatment effect explained by a surrogate marker.

Randomized clinical trials with rare primary endpoints or long duration times are costly. Because of this, there has been increasing interest in replacing the true endpoint with an earlier measured marker. However, surrogate markers must be appropriately validated. A quantitative measure for the proportion of treatment effect explained by the marker in a specific trial is a useful concept. Freedman, Graubard, and Schatzkin (1992, Statistics in Medicine 11, 167-178) suggested such a measure of surrogacy by the ratio of regression coefficients for the treatment indicator from two separate models with or without adjusting for the surrogate marker. However, it has been shown that this measure is very variable and there is no guarantee that the two models both fit. In this article, we propose alternative measures of the proportion explained that adapts an idea in Tsiatis, DeGruttola, and Wulfsohn (1995, Journal of the American Statistical Association 90, 27-37). The new measures require fewer assumptions in estimation and allow more flexibility in modeling. The estimates of these different measures are compared using data from an ophthalmology clinical trial and a series of simulation studies. The results suggest that the new measures are less variable.

Biomarkers↗

PubMed2004

How much of the variation in adaptive divergence can be explained by gene flow? An evaluation using lake-stream stickleback pairs.

How much of the variation in adaptive divergence can be explained by gene flow? The answer to this question should objectively reveal whether gene flow generally places a substantial constraint on evolutionary diversification. We studied multiple independent lake-stream population pairs of threespine stickleback (Gasterosteus aculeatus). For each pair, we quantified adaptive divergence based on morphological traits that have a genetic basis and are subject to divergent selection. We then estimated gene flow based on variation at five unlinked microsatellite loci. We found a consistent and significant pattern for morphological divergence to be positively correlated with genetic divergence and negatively correlated with gene flow. Statistical significance and the amount of variation explained varied within and among traits: 36.1-74.1% for body depth and 11.8-51.7% for gill raker number. Variation within each trait was the result of differences among methods for estimating genetic divergence and gene flow. Variation among traits likely reflects different strengths of divergent selection. We conclude that gene flow has a substantial effect on adaptive divergence in nature but that the magnitude of this effect varies among traits. An alternative explanation is that cause and effect are reversed: adaptive divergence is instead constraining gene flow. This effect seems relatively unimportant for our system because genetic divergence and gene flow were not correlated with ecologically relevant habitat features of lakes (surface area) or streams (width, depth, flow, canopy openness).

Adaptation, Biological↗

PubMed2006

Somatic symptoms explain differences in psychological distress in heart failure patients vs a comparison group.

Psychological distress is common among patients with heart failure (HF); however, somatic symptoms are also common and may confound its assessment. Understanding the contributions of symptoms to psychological distress may assist in focusing treatment. The purpose of this study was to evaluate differences between HF patients and a non-HF comparison group on psychological distress (anxiety and depression); the association of anxiety and depression with common somatic symptoms of HF (fatigue, sleep disturbance, dyspnea, and excessive daytime sleepiness); and the extent to which somatic symptoms and HF diagnosis explain psychological distress. In this cross-sectional study, 61 stable systolic HF outpatients and a comparison group of 57 persons recruited from the community completed the Centers for the Epidemiological Studies of Depression Scale, Profile of Mood States-Short Form, Hospital Anxiety and Depression Scale, Pittsburgh Sleep Quality Index, Epworth Sleepiness Scale, Multidimensional Assessment of Fatigue Scale, and the Multidimensional Assessment of Dyspnea Scale. The HF patients scored higher on depression, as measured by the Centers for the Epidemiological Studies of Depression Scale, but not on the other depression or anxiety scales. Group-related differences in depression were explained by sleep disturbance, fatigue, and excessive daytime sleepiness, after accounting for the effects of age, sex, minority status, comorbidity, and physical function.

Anxiety↗

PubMedDate not supplied

Cardiac disease in chronic uremia: can it explain the reverse epidemiology of hypertension and survival in dialysis patients?

Definitive randomized trials are rare in the dialysis literature. Treatment decisions are often based on extrapolation from trials in other populations and observational studies in dialysis patients. "Reverse epidemiology" is a term increasingly applied to classic cardiovascular risk factors in studies of dialysis patients. The term is used when outcome associations are the opposite of those seen in general population studies. Hypertension is an archetypal example, with several studies showing inverse associations with mortality. As a term, "reverse epidemiology" is intellectually unsatisfactory because validation of the real direction of an association is only possible with experimental designs. In contrast, blood pressure (BP) is associated with typical association patterns for outcomes other than death, including left ventricular hypertrophy and cardiac failure, which are dominant entities in dialysis populations. There is a strong suspicion that current analytical approaches may partly explain the paradox. For example, it is possible that unmeasured comorbidities are associated with lower BP levels. In addition, few studies use BP as a time-integrated parameter, which is problematic given the variability of this parameter. Several recent studies suggest that using pulse pressure as a BP parameter may normalize associations with mortality. BP, extracellular blood volume, residual renal function, and vasoactive medications are interlinked. Time-integrated analysis that examines all these parameters concurrently makes sense, but has rarely been attempted. A large burden of cardiac disease and insensitive analytical approaches may go a long way toward explaining the reverse epidemiology of hypertension and survival in dialysis patients.

Blood Pressure↗

PubMed2006

Severe endothelial dysfunction in young women with polycystic ovary syndrome is only partially explained by known cardiovascular risk factors.

OBJECTIVE: We aimed to assess whether metabolic abnormalities can explain endothelial dysfunction and associated cardiovascular disease risk (CVDr) in polycystic ovary syndrome (PCOS). Endothelial function, a recognized composite marker of CVDr, may be reduced in PCOS and can be precisely and noninvasively assessed by cardiovascular magnetic resonance (CMR). PATIENTS: Fourteen women with anovulatory PCOS (age [mean +/- SD] 33 +/- 4 years) and 13 controls (age: 33 +/- 6 years) with similar body mass index and regular menses. METHODS: Endothelium-dependent (flow-mediated dilatation - FMD) and -independent (glyceryl trinitrate - GTN) changes in the brachial artery area were measured using CMR in women with PCOS and controls. Arterial function was assessed twice, in the early follicular phase and mid cycle in controls and after an interval of 2 weeks in PCOS subjects. Fasting lipids, glucose, insulin and sex hormones were measured at the first visit. RESULTS: FMD was greatly reduced in women with PCOS compared to controls (-1%vs 5% and 2%vs 12%, P < 0.01) without differences in GTN responses. Risk factors were more prevalent in PCOS women and displayed significant linear relationships with FMD. PCOS status was the strongest predictor of FMD. Linear regression between PCOS and FMD remained significant after correction for all CVD risk markers linked to the metabolic syndrome. CONCLUSION: PCOS is associated with changes in CVD risk markers and pronounced endothelial dysfunction. However endothelial dysfunction with PCOS is only partly explained by recognized CVD risk markers.

Adult↗

PubMed2006

Do social information-processing models explain aggressive behaviour by children with mild intellectual disabilities in residential care?

BACKGROUND: This study aimed to examine whether the social information-processing model (SIP model) applies to aggressive behaviour by children with mild intellectual disabilities (MID). The response-decision element of SIP was expected to be unnecessary to explain aggressive behaviour in these children, and SIP was expected to mediate the relation between social schemata and aggressive behaviour. METHOD: SIP and aggressive behaviour of 130 10- to 14-year-old children with MID in residential care were assessed. The fit of various SIP models was tested with structural equation modelling. RESULTS: The response-decision process was found not to be necessary to explain aggressive behaviour. Social schemata were indirectly related to aggressive behaviour with aggressive response generation as mediating variable. CONCLUSIONS: Implications for SIP theory and intervention are discussed.

Adolescent↗

PubMed2005

Does adiponectin explain the lower insulin sensitivity and hyperinsulinemia of African-American children?

Adiponectin is an adipocytokine with antidiabetogenic properties. The present study investigated: (i) the effect of race on adiponectin levels and (ii) the relationship of adiponectin levels in children to insulin sensitivity and secretion. Fasting adiponectin levels were determined in 22 healthy prepubertal black compared with 22 white children of similar body composition. We previously reported these black children to have lower insulin sensitivity and higher first-phase insulin secretion than their white peers. Fasting adiponectin levels were lower in black children (9.9 +/- 1.0 microg/mL vs. 15.7 +/- 1.1 microg/mL, p < 0.001). Adiponectin correlated positively with insulin sensitivity (r = 0.29, p = 0.06) and negatively with first-phase insulin levels (r = -0.47, p = 0.001). In a multiple regression analysis, 48% of the variance in first-phase insulin secretion was explained by the independent effects of race (p = 0.017), adiponectin (p = 0.03), and percentage of body fat (p < 0.001). Adiponectin did not contribute significantly to the variance in insulin sensitivity. In summary, black children have approximately 35% lower adiponectin levels than their white peers. Lower adiponectin does not seem to explain the racial differences in insulin sensitivity. The relationship of hyperinsulinemia and hypoadiponectinemia needs to be further explored.

Adiponectin↗