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PubMed2002

Electrostatics explains the shift in VDAC gating with salt activity gradient.

We have analyzed voltage-dependent anion-selective channel (VDAC) gating on the assumption that the states occupied by the channel are determined mainly by their electrostatic energy. The voltage dependence of VDAC gating both in the presence and in the absence of a salt activity gradient was explained just by invoking electrostatic interactions. A model describing this energy in the main VDAC states has been developed. On the basis of the model, we have considered how external factors cause the redistribution of the channels among their conformational states. We propose that there is a difference in the electrostatic interaction between the voltage sensor and fixed charge within the channel when the former is located in the cis side of membrane as opposed to the trans. This could be the main cause of the shift in the probability curve. The theory describes satisfactorily the experimental data (Zizi et al., Biophys. J. 1998. 75:704-713) and explains some peculiarities of VDAC gating. The asymmetry of the probability curve was related to the apparent location of the VDAC voltage sensor in the open state. By analyzing published experimental data, we concluded that this apparent location is influenced by the diffusion potential. Also discussed is the possibility that VDAC gating at high voltage may be better described by assuming that the mobile charge consists of two parts that have to overcome different energetic barriers in the channel-closing process.

Biophysical Phenomena↗

PubMed1999

Differential dissociation kinetics explain the binding preference of insulin-like growth factor binding protein-6 for insulin-like growth factor-II over insulin-like growth factor-I.

Insulin-like growth factor binding protein-6 binds insulin-like growth factor-II with a marked preferential affinity over insulin-like growth factor-I. The kinetic basis of this binding preference was studied using surface plasmon resonance. Binding of insulin-like growth factor-I and insulin-like growth factor-II to immobilized insulin-like growth factor binding protein-6 fitted a two-site binding kinetic model. Insulin-like growth factor-I and insulin-like growth factor-II association rates were similar whereas the dissociation rate was approximately 60-fold lower for insulin-like growth factor-II, resulting in a higher equilibrium binding affinity for insulin-like growth factor-II. The equilibrium binding affinities of a series of insulin-like growth factor-II mutants were also explained by differential dissociation kinetics. O-glycosylation had a small effect on the association kinetics of insulin-like growth factor binding protein-6. The insulin-like growth factor binding properties of insulin-like growth factor binding protein-6 are explained by differential dissociation kinetics.

Binding, Competitive↗

PubMed2001

The -629C>A polymorphism in the CETP gene does not explain the association of TaqIB polymorphism with risk and age of myocardial infarction in Icelandic men.

The aim of this study was to examine whether the well-established effect of the common TaqIB polymorphism in intron 1 of the gene for cholesterol ester transfer protein (CETP) on high density lipoprotein cholesterol (HDL-C) concentration and increased risk of myocardial infarction (MI), could be explained by the recently identified -629C>A functional polymorphism in the promoter. Non-fatal MI cases (388 male) and a control group of 794 healthy men were recruited from the 30 year long prospective Reykjavik Study. In the healthy men the frequency of the TaqIB B2 allele was 0.47 (95% CI: 0.44-0.50) and there was a strong allelic association with the -629A allele (D=-0.21, P<0.0001), which had a frequency of 0.52 (95% CI: 0.49-0.56). B2B2 homozygotes displayed 15% higher HDL-C levels than subjects homozygous for the B1 allele (P<0.0001). Homozygotes for the -629A allele displayed 14% higher HDL-C concentrations than subjects homozygous for the -629C allele (P<0.0001). The frequencies of the alleles associated with lower HDL-C were significantly higher in cases compared with controls, 0.59 versus 0.53 (TaqIB B1) and 0.52 versus 0.48 (-629 C) respectively (P<0.05 for both). There was a significantly higher risk for MI in B1B1 homozygotes (OR=1.44, 95% CI: 1.10-1.87, P<0.01), compared to the other genotypes combined. This was not observed for the CC homozygotes (OR=1.16, 95% CI: 0.87-1.54). In addition, homozygotes for the TaqI B2 allele experienced a first MI 2 years later than men with other genotypes, 59 versus 61 years (P<0.05). This effect was not seen for the promoter polymorphism. These results strongly confirm the role of the CETP gene and the TaqIB variant as a risk factor for MI and suggest that another functional polymorphism is yet to be discovered in the CETP gene, that will explain the effect on MI associated with TaqIB observed in this study.

Aged↗

PubMed2003

Plasma fibrinogen explains much of the difference in risk of coronary heart disease between France and Northern Ireland. The PRIME study.

The incidence of coronary heart disease is higher in Northern Ireland than in France. These differences have not been adequately explained. We have investigated the associations of plasma fibrinogen concentration and factor VII activity with the incidence of coronary heart disease in a prospective cohort study involving 10600 men aged 50-59 living in four regions (Lille, Strasbourg, and Toulouse in France, Belfast in Northern Ireland). Baseline fibrinogen and factor VII were measured in 9489 men free of coronary heart disease at entry (7167 in France and 2322 in Northern Ireland). Over 5 years of follow-up, 161 participants developed myocardial infarction (MI) or coronary death (100 in France and 61 in Belfast) and 151 developed angina pectoris (94 in France and 57 in Belfast). The risk of future coronary events was 1.9 times higher in Belfast than in France (95% confidence interval: 1.5-2.4). Baseline mean levels of fibrinogen were significantly higher in Belfast than in France and they were higher in participants who experienced coronary events compared with those who did not in both countries. The age-adjusted relative risk of coronary heart disease associated with a rise of one standard deviation in fibrinogen level was 1.56 (95% confidence interval: 1.29-1.95, P<0.0001) in the whole cohort. This association remained significant after adjustment for other cardiovascular risk factors (relative risk:1.36; 95% confidence interval: 1.14-1.68; P<0.0001). There was no clear geographical variation in factor VII and no significant association between factor VII levels and the risk of coronary events was observed. Classic risk factors explained 25% of the excess risk of coronary heart disease in Belfast compared with France, while fibrinogen alone accounted for 30%. These findings add to the epidemiological evidence that elevated fibrinogen is a major risk factor for coronary heart disease.

Coronary Disease↗

PubMed2002

Models of skeletal muscle to explain the increase in passive stiffness in desmin knockout muscle.

Absence of desmin in skeletal muscle was found to induce an increase in passive stiffness. The present study aimed at developing rheological models of passive muscle to explain this stiffening. Models were elaborated by using experimental data depicting muscle viscoelastic behaviour. The experimental protocol included stepwise extension tests applied on control and desmin knockout soleus muscles from mice. Linear and non-linear models were composed of elastic and viscous elements. They were constructed with the aim at taking the presence or absence of desmin into account by simulating desmin as an elastic element. Furthermore, associated adaptation of connective tissues in absence of desmin was modelled as an additional elastic element. Differences in passive behaviour induced by absence of desmin were predicted by using a linear model and a non-linear one. The non-linear model was selected because: (1) it is able to predict experimental viscoelastic kinetics accounting for the increase in passive stiffness in muscles lacking desmin, (2) its design is consistent with morphological data, and (3) stiffness characteristics of its elements are in accordance with the literature. Finally, this modelling approach demonstrates that both absence of desmin and adaptation of connective tissue are required to explain the increase in passive stiffness in desmin knockout muscles.

Animals↗

PubMed1997

Extended Willis circle model to explain clinical observations in periorbital arterial flow.

A fluid-dynamic model of the circle of Willis and its periorbital links with the external carotid arteries has been established and tested. It is based on anatomic data and takes Doppler measurements as flow input conditions. The model explains, on fluid-dynamic grounds, the clinical observations of periorbital reverse flow and arrival pulse time delay. It also obtains the velocity and pressure pulse at any point of the studied area. This allows the comparison between the normal or healthy condition and the flow distribution when an internal carotid is externally or pathologically occluded. Several combinations of the communicating artery sizes are explored to obtain the reduced cerebral flow. The combination of the communicating diameters can lead to insufficient irrigation which can be hydrodynamically assessed. No other physiological response is included, and the results must be considered as a minimum assured. These results show the need for a common evaluation of the alternative paths and explain some paradoxes found in literature.

Algorithms↗

PubMed1998

Can marital selection explain the differences in health between married and divorced people? From a longitudinal study of a British birth cohort.

In view of the rising divorce rates, the impact of divorce on health has an increasing importance in public health. The differentials in health between the married and the divorced may be explained by 'marital selection' and 'marital protection'. Using longitudinal data from a study of the 1958 British birth cohort, factors that select people into divorce were identified from the areas of socio-economic status, health, and attractiveness, which included physical attractiveness, health-related behaviour and temperament. Evidence for both positive and adverse selection is found. The different sets of selection factors for females and males appear to be in line with gender role expectations. The health differentials between married and divorced men were weak and can be explained away by the selection factors. Having controlled for the selection effects, there were still significant associations between divorce and physical and psychological health in women. Though these unexplained differentials cannot be definitely interpreted as the consequences of marital dissolution, this interpretation remains plausible.

Adult↗

PubMed2002

On the minimum number of topologies explaining a sample of DNA sequences.

In this article I derive an alternative algorithm to Hudson and Kaplan's (Genetics 111, 147-165) algorithm that gives a lower bound to the number of recombination events in a sample's history. It is shown that the number, T(M), found by the algorithm is the least number of topologies required to explain a set of DNA sequences sampled under the infinite-site assumption. Let Tao = (T(1),...,T(r)) be a list of topologies compatible with the sequences, i.e., T(k) is compatible with an interval, I(k), of sites in the alignment. A characterization of all lists having T(M) topologies is given and it is shown that T(M) relates to specific patterns in the alignment, here called chain series. Further, a number of theorems relating general lists of topologies to the number T(M) is presented. The results are discussed in relation to the true minimum number of recombination events required to explain an alignment.

Algorithms↗

PubMed1999

Noisy templates explain area summation.

The noisy template model is a variant of an ideal detector for a signal known except for contrast. The ideal detector cross-correlates the stimulus with a normalised template which is matched to the known signal pattern. The noisy template model simply adds noise to the matched template every time it is cross-correlated with the signal. This paper outlines the predictions of the noisy template model for area summation. The noisy template model explains Piper's Law, as does the ideal-observer, but it also explains critical area phenomena and the lack of area summation for contrast discrimination.

Computer Simulation↗

PubMed2003

Responses in sediment bioassays used in the Netherlands: can observed toxicity be explained by routinely monitored priority pollutants?

In order to identify the cause of toxicity in sediments and suspended matter, a large number of samples with different degrees of contamination was taken at various locations in The Netherlands. Standard acute bioassays were carried out with the bacterium Vibrio fischeri, the rotifer Brachionus calyciflorus and the anostracan Thamnocephalus platyurus. Chronic standard tests were performed using the water flea Daphnia magna and larvae of the midge Chironomus riparius. Some novel bioassays were performed as well. Most toxic effects observed in standard bioassays with sediments from polluted sediments (class 3 and 4 on a scale of 0-4 according to the Dutch criteria) could be partly explained by toxic concentrations of known persistent priority pollutants, mainly heavy metals and occasionally polycyclic aromatic hydrocarbons. In some of the samples, ammonia toxicity was a confounding factor during testing. Suspended matter from the Meuse river at Eijsden, which may be considered as 'new' sediment (pollution class 2), was moderately to highly toxic in almost all bioassays. This could have been associated with a combination of heavy metals, PAHs and ammonia. At two locations from the Lake IJssel area with no apparent persistent pollution, moderate and strong effects were nonetheless observed in invertebrate tests. This might have been due to agricultural run-off of pesticides, which are not routinely measured in sediments. A few effects on V. fischeri in canals and a small stream could not be explained with standard chemical analysis, but seemed associated with the outlets of sewage water treatment plants and industrial effluents. Additional chemical analysis of pore water samples from five selected sediments yielded more identified substances such as phtalates, decanes, cosanes and fragrances, but it was estimated that their contribution to the effects observed on V. fischeri, D. magna and C. riparius was negligible.

Animals↗

PubMed2002

Attention-deficit/hyperactivity disorder (ADHD) behaviour explained by dysfunctioning reinforcement and extinction processes.

Inattentiveness, overactivity and impulsiveness are presently regarded as the main clinical symptoms of attention-deficit/hyperactivity disorder (ADHD). Inattention is, however, a characteristic of most psychiatric disorders. It is argued that the ADHD Inattentive subtype may have heterogeneous origins and be qualitatively different from the ADHD Hyperactive/Impulsive subtype. At the neurobiological level, ADHD symptoms may to a large extent be caused by a dysfunctioning dopamine system: A dysfunctioning meso-limbo-cortical dopamine branch will produce altered reinforcement and extinction processes, on a behavioural level giving rise to deficient sustained attention, hyperactivity, motor and cognitive impulsiveness. A dysfunctioning nigro-striatal dopamine branch will cause 'extrapyramidal' symptoms. Our model disentangles the behaviours usually explained by 'executive functions' into cognitive impulsiveness, motor impulsiveness and deficient motor control. The various dopaminergic branches may not be equally dysfunctional in all individuals with ADHD. Etiologically, dopamine dysfunctioning will probably mainly be genetically determined while sometimes be induced by environmental factors like drugs of abuse or pollutants, which may explain geographical differences in prevalence rates.

Animals↗

PubMed1998

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

Time-dependent markers, such as CD4 and viral load, are potential surrogate markers in AIDS clinical trials. A critical issue with surrogate markers is whether changes in these markers explain the beneficial effect of treatment on the real end point of the clinical trial. A statistic to measure the proportion of the treatment effect explained by the surrogate is p(FGS) = 1 - gamma/alpha, where alpha is the treatment effect coefficient in a Cox model and gamma is the treatment effect coefficient from a time-dependent Cox model adjusted for the marker. In this article we evaluate the statistical properties of p(FGS). Using a Monte Carlo study we show that the statistic is not well calibrated, because it can fall outside the range zero to one, even in very large samples. In the simulation study we consider situations where the time-dependent marker is measured with error at a fixed number of times. We show that a method of fitting a time-dependent Cox model involving smoothing the marker reduces the bias in the estimate of p(FGS) compared with the standard method of using the current or last observed marker value. We also show that the estimate of p(FGS) has considerable variability and can have wide confidence intervals. We conclude that p(FGS) is only likely to be useful in large trials with a strong treatment effect. The methods are illustrated using CD4 counts from an AIDS clinical trial of zidovidine versus placebo.

Acquired Immunodeficiency Syndrome↗

PubMed2003

[Models to explain and predict medical case-loads: their use in calculating the maximum family medicine list that allows at least ten minutes per consultation].

OBJECTIVE: To calculate the maximum family medicine list that gives at least ten minutes per consultation.Design. Transversal. SETTING: Three health centres. SUBJECTS: 45 826 inhabitants. MEASUREMENTS: We used the appointments made at three centres to calculate the annual time employed per patient and we adjusted it to allocate a minimum of ten minutes per consultation. We established a cubic regression model to predict the mean case-load per age of patient in general medicine and calculated the maximum list if 70% of the working day were dedicated to care. The results contrasted two centres with greater nursing involvement and one with less. We showed the R2 coefficients. We calculated the maximum lists for the health centres of Navarra and showed them in five clusters worked out on the basis of the percentage of patients >=65. RESULTS: Age explained 86.1% of variability in mean case-load at each age (84% in children and 93.5% in adults). According to the mean percentage of those >=65 years old, the average maximum lists for centres with more or less nursing involvement are as follows: 7.0%>=65 (2025 and 1989); 14.0% (1834 and 1715); 21.2% (1691 and 1558); 27.0% (1648 and 1460), 34.0% (1560 and 1340). CONCLUSION: To a great extent, age explains the variability in case-load and lets us calculate the maximum number of patients on the list that still ensures a minimum time for each consultation.

Adult↗

PubMed1988

Racial differences in the incidence of hypertensive end-stage renal disease (ESRD) are not entirely explained by differences in the prevalence of hypertension.

Blacks experience a disproportionate risk of end-stage renal disease (ESRD) compared with whites. The increased prevalence of hypertension in blacks has been suggested as an explanation for this increased risk. We were able to examine this possibility using hypertensive ESRD incidence rates in a population with well-characterized prevalence of hypertension and rate of its control. After adjusting rates of hypertensive ESRD for age, sex, and differences in the prevalence of hypertension by race, we found black:white (B:W) relative risk still to be increased. Prevalence estimates for moderate-severe hypertension and differences in the control of hypertension between the two race groups are of insufficient magnitude to explain the increase in adjusted relative risk. This observation provides further support for the possibility that there are racial differences in the susceptibility to renal damage from elevated BP, which may explain increased risk for hypertensive ESRD in blacks, or that hypertension is being erroneously diagnosed as the cause of ESRD in blacks when another cause is present.

Adult↗

PubMed2000

Social class and self-rated health: can the gradient be explained by differences in life style or work environment?

The purpose of the present paper is to describe differences in work environment and life style factors between social classes in Denmark and to investigate to what extent these factors can explain social class differences with regard to changes in self-rated health (SRH) over a 5 year period. We used data from a prospective study of a random sample of 5001 Danish employees, 18-59 years of age, interviewed at baseline in 1990 and again in 1995. At baseline we found higher prevalence in the lower classes of repetitive work, low skill discretion, low influence at work, high job insecurity, and ergonomic, physical, chemical, and climatic exposures. High psychological demands and conflicts at work were more prevalent in the higher classes. With regard to life style factors, we found more obese people and more smokers among the lower classes. The proportion with poor SRH increased with decreasing social class at baseline. The follow-up analyses showed a clear association between social class and worsening of SRH: The lower the social class, the higher the proportion with deterioration of SRH. There was no social gradient with regard to improved SRH over time. Approximately two thirds of the social gradient with regard to worsening of SRH could be explained by the work environment and life style factors. The largest contribution came from the work environment factors.

Adolescent↗

PubMed2003

Explaining variation in health status across space and time: implications for racial and ethnic disparities in self-rated health.

We use the Metropolitan Community Information Center-Metro Survey-a serial cross section of adults residing in the City of Chicago, USA, conducted from 1991 through 1999-in combination with 1990 census data to simultaneously examine the extent to which self-rated health varies across Chicago neighborhoods and across time. Three-level hierarchical logit models are employed to decompose individual, spatial, and temporal variance in self-rated health. Results indicate that variation in self-rated health across neighborhoods is explained, in part, by variation in the level of neighborhood affluence. Neighborhood level poverty, however, is not a significant predictor of self-rated health. Community level affluence, moreover, accounts for a substantial proportion of the residual health deficit experienced by African-Americans when compared with Whites (after controlling for individual level SES). The effects of affluence hold when controlling for spatial autocorrelation and when considered in primarily African-American neighborhoods. Findings also indicate that individuals living in the City of Chicago became significantly healthier over the decade of the 1990s, and that this improvement in health is explained largely by the increasing education and income levels of Chicago residents.

Adult↗

PubMed1999

The roles of social class of origin, achieved social class and intergenerational social mobility in explaining social-class inequalities in alcoholism among young men.

The aim of this study was to investigate the role of intergenerational health-related mobility in explaining social-class inequalities in alcoholism among young men. Data on social class of origin and on risk factors in childhood and adolescence, e.g. risk use of alcohol, were collected for 49,323 men, born 1949-51, at enlistment for compulsory military training in 1969/70. Information on achieved socioeconomic class was obtained from Sweden's 1975 census. Data on alcoholism diagnoses were collected from the national in-patient care register 1976-83. Risk indicators for alcoholism established in adolescence were found to be more common among downwardly mobile individuals, and also among stable manual workers, than among those who ended up as non-manual employees. Downwardly mobile individuals, and also stable manual workers, were also found to have an increased risk of alcoholism diagnosis. The increased relative risk could, to a considerable extent, be attributed to factors from childhood/adolescence. In this longitudinal study, it is shown that intergenerational social mobility associated with health-related factors, albeit not with illness itself, made a major contribution to explaining differences in alcoholism between social classes. Factors established in adolescence were important with regard to differences in alcoholism between social classes among young adults. But such adverse conditions did not seem to be well reflected by social class of origin.

Adult↗

PubMed1998

A comparative study of iatrogenesis, medication abuse, and psychiatric morbidity in chronic pain patients with and without medically explained symptoms.

We report a case control study comparing patients attending a pain clinic whose symptoms were not considered medically explained (cases) with those whose symptoms were considered medically explained (controls). Principal comparisons were psychiatric morbidity, medication use, and iatrogenic factors assessed by interview, and questionnaire measures of anxiety, depression, functional impairment, coping strategies and pain beliefs. Medically unexplained symptoms were associated with the presence of psychiatric morbidity (odds ratio = 3.4, 95% C.I.: 1.4,8.2), and of possible iatrogenic factors. There were no significant differences with regards to medication abuse/dependence.

Adult↗