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PubMed1990

A bivariate negative binomial model to explain traffic accident migration.

The phenomenon of "regression to the mean" is now widely known in the study of the effectiveness of remedial treatment of traffic accident blackspots. What happens is that the criterion used for selection of sites at which treatment is to be applied gives rise to bias in the estimate of the effectiveness: the conditional expectation of the after frequency is less than the true mean, even if the treatment is totally ineffective. It has been reported in some previous studies that accident "migration" has been observed. This is the phenomenon whereby the accident rate apparently rises at sites that are untreated but that are neighbours to treated sites. If this were a genuine effect, it would have serious implications for the assessment of remedial treatments. This paper aims to explain this migration effect in purely probabilistic terms, without recourse to the concept of physical migration. The model used is a new bivariate negative binomial distribution, incorporating spatial correlation between the true mean site accident rates. As with the regression to mean effect, the migration effect can then be explained in terms of the conditioning implicit in the selection process.

Accidents, Traffic↗

PubMed1984

Distribution of adrenergic receptors does not explain regional differences in blood flow in the pregnant rabbit uterus.

The increase in uterine blood flow during pregnancy is maximal at the placental implantation site, but the mechanisms of this increase are poorly understood. Adrenergic receptor activation may influence blood flow both directly and indirectly. We therefore asked whether distribution of myometrial adrenergic receptors within the rabbit uterus could explain the increased blood flow to smooth muscle under the placenta. alpha-Adrenergic and beta-adrenergic receptor concentrations and affinities were measured in myometrium from under the placenta and compared to myometrium between placentas and distant from the placentas. There were no differences in receptor concentrations or affinities in different parts of the uterus. We therefore conclude that the distribution of adrenergic receptors in the pregnant rabbit uterus cannot explain the preferential blood flow to myometrium at the placental implantation site.

Animals↗

PubMed1978

A tunnelling model to explain the reduction of ferricytochrome c by H and OH radicals.

The kinetics of the reaction of OH radicals with ferricytochrome c was studied in the time range 1 microsecond to 1 s by means of pulse radiolysis. The OH radicals reduce ferricytochrome c by 40% +/- 10%. The time course of the reduction is explained by a mechanism whereby a radical formed after hydrogen has been abstracted from the outer surface of the protein reduces the iron by electron tunnelling. We have calculated that the reducing electron in the radical is bound with an energy of at least 1.75 eV and that the frequency factor of the tunnelling process is v=10(11.5)s-1. This model accounts for the observed absorbance change in time range 5 . 10(-6)--10(-1)s. The time course of the reduction of ferricytochrome c by H radicals (Lichtin, N.N., Shafferman A. and Stein, G. (1974) Biochim. Biophys. Acta 357, 386--398) is explained by the same model.

Calorimetry↗

PubMed1986

The receptor binding properties of the 20K variant of human growth hormone explain its discrepant insulin-like and growth promoting activities.

The 20K variant of native (22K) hGH is a full agonist for the growth promoting and lactogenic properties of the hormone in vivo but has been reported to have weak or absent insulin-like properties. To explore if these differences may be explained at the receptor level, we compared the ability of 22K and 20K hGH to inhibit the binding of 125I-22K hGH to receptors in isolated rat adipocytes, a target for the insulin-like effects of the hormone and in IM-9 cultured human lymphocytes, more specific for growth effects. Our data show that while 20K hGH is a potent agonist of native 22K hGH in the IM-9 lymphocyte assay, its potency in the rat adipocyte binding assay is only 3%, even when both cells are incubated together in identical conditions. Thus, the receptors for hGH appear to be different on various target cells, explaining why the 20K variant has different relative biological potencies at different sites of action.

Adipose Tissue↗

PubMed1995

Stoichiometry of K+/H+ antiport helps to explain extracellular pH 11 in a model epithelium.

The stoichiometry of K+/H+ antiport was measured fluorometrically by the static head method in highly purified vesicles from goblet cell apical membranes of larval lepidopteran midgut. The measured stoichiometry of 1 K+/2 H+ explains how the antiport results in electrophoretic exchange of extracellular H+ for intracellular K+, driven by the voltage component of the proton-motive force of an H+ translocating V-ATPase that is located in the same membrane. In turn, the exchange of K+ for H+ helps to explain how the midgut contents are alkalinized to a pH of 11.

Animals↗

PubMed1995

Abnormal intestinal motor patterns explain enteric colonization with gram-negative bacilli in late radiation enteropathy.

BACKGROUND & AIMS: Bacterial overgrowth and intestinal pseudo-obstruction may succeed abdominal radiotherapy, and absence of intestinal migrating motor complex (MMC) has been reported in bacterial overgrowth. The aims of this study were to address the relationship between intestinal patterns of motility and gastrointestinal microflora and to elucidate the pathogenesis of late radiation enteropathy. METHODS: Forty-one consecutive female patients with symptoms of late radiation enteropathy were examined by prolonged ambulatory manometry, culture of gastric and duodenal samples with quantification of gram-negative bacilli (GNB) by the glucose gas test, the [14C]D-xylose breath test, and determination of pH and short-chain fatty acids in gastric juice. RESULTS: The intensity of MMC explained 61% (P < 0.001) and 71% (P < 0.001) of the variability of GNB in the stomach and duodenum, respectively, corresponding to the severity of disease. Abnormal MMC index and presence of irregular bursts were the best predictors of GNB (86%; P < 0.001, multiple regression). Fasting gastric pH explained gastric bacterial counts (63%; P < 0.001) but did not predict GNB. CONCLUSIONS: Impaired motility emerges as a causal factor for gastrointestinal colonization with GNB, whereas hypochlorhydria facilitates unspecific gastric colonization. Abnormal motility and GNB in the proximal small intestine are essential factors in the pathogenesis of severe late radiation enteropathy.

Adult↗

PubMed1989

DNA B to D transition can be explained in terms of hydration economy of the minor groove atoms.

Adjacent phosphate oxygen atoms in A and Z-DNA are located much closer together than in the B form and can be hydrated more economically due to the formation of water bridges between them, whereas in the B form phosphates are hydrated individually. This principle of hydration economy of phosphate groups discovered by Saenger and colleagues could not be applied to the B-D transition, which, like the B-A and B-Z transitions, occurs in a situation of water deficiency, because the distances between adjacent phosphates of individual polynucleotide chains in the D form are not much different from B-DNA. It follows from our calculations of B and D-DNA accessibility to solvent performed by the method of Lee & Richards, and from a simulation of solvent structure near DNA, that there is an economy of hydration only for the minor groove atoms. This feature and some experimental data can explain why only a limited range of sequences consisting of A.T or I.C pairs undergo the transition to the D form. The conformational transition in DNAs with such sequences to a poly[d(A]).poly[d(T])-like conformation (Bh-DNA), which is accompanied by a narrowing of the minor groove, can be explained in the same way. Calculations suggest that in the D-form minor groove of different A-T or I-C DNAs there is a double-layer hydration spine similar to that observed by Drew & Dickerson in the A-T tract of the d(C-G-C-G-A-A-T-T-C-G-C-G) dodecamer. The B-D and B-Bh transitions in A + T-rich DNAs can have biological implications, e.g. they can facilitate DNA bending upon the interaction with proteins.

DNA↗

PubMed1989

The effects of althesin on luteinizing hormone release cannot be explained by actions of the GABAA receptor alone.

Althesin and pentobarbitone are anaesthetics which act by prolonging the open time of the chloride channels of the GABA(A) receptor. To explain why luteinizing hormone (LH) release is less depressed by Althesin anaesthesia than by pentobarbitone anaesthesia we suggest that either Althesin is a less potent anaesthetic in the preoptic area or that Althesin as well as stimulating GABA(A) receptors has some other action, perhaps stimulation of GABA(B) receptors, which may facilitate LH release. To investigate the relative potency of the anaesthetics in the preoptic area nine cats were anaesthetised, six with Althesin and three with pentobarbitone, mounted in a stereotaxic frame and prepared for extracellular recording and stimulation of spontaneously active units in the preoptic region. When cats anaesthetised with Althesin were compared with cats anaesthetised with pentobarbitone there were significantly fewer of these units for the number of tracks made. These units also had a significantly lower frequency and a distribution significantly skewed toward lower frequencies. Electrical stimulation of the fornix and of sites in the medial basal hypothalamus and medial forebrain bundle inhibited about 50% of the units and the median duration of the inhibitory pause was significantly longer following stimulation at all three sites in cats anaesthetised with Althesin. We conclude that Althesin is a more potent anaesthetic than pentobarbitone in the preoptic region and that its effects on LH release cannot be explained by its effects on the GABA(A) receptor alone.

Action Potentials↗

PubMed1995

Photoreceptor sensitivity changes explain color appearance shifts induced by large uniform backgrounds in dichoptic matching.

Photoreceptor sensitivity changes explained the effect of large uniform backgrounds on the color appearance of small targets in a dichoptic asymmetric color matching experiment. Subjects viewed in each eye a target superimposed on a large background. The backgrounds presented to the two eyes had different spectral compositions. Subjects adjusted the target seen by the right eye to match the appearance of the target seen by the left eye. Receptor sensitivity changes explained the effect of numerous adapting backgrounds on the color appearance of many targets with high precision. Post-receptoral sensitivity changes provided a poorer account of the data. The apparent sensitivity of each receptor class varied inversely with changes in background light absorbed by that receptor class, but did not depend on background light absorbed by the other two receptor classes.

Adaptation, Ocular↗

PubMed1998

Hormone replacement therapy and body size: how much does lifestyle explain?

OBJECTIVE: Our purpose was to assess the association of hormone replacement therapy with body size. STUDY DESIGN: A total of 1658 randomly selected women aged 45 to 64 years in four regions (two provinces in eastern Finland, one southwestern province, and the capital area) were studied in a 1992 population survey. Linear regression analysis was used to assess the use of hormone replacement therapy as a determinant of body size, measured with the body mass index, the waist/hip ratio, and the body fat percentage and adjusted by sociodemographic (area and education) and lifestyle (diet, smoking, physical activity, and alcohol use) factors. The regression coefficients of hormone replacement therapy use obtained from the model when including sociodemographic and lifestyle variables (beta 1a[Hormone replacement therapy use] = -0.98) were compared with the coefficients obtained when these variables were excluded (beta 1b[Hormone replacement therapy use] = -1.36). The percentage of change (beta 1b-beta 1a/beta 1b%) in the regression coefficients denoted the variability explained by sociodemographic and lifestyle characteristics. RESULTS: Hormone replacement therapy users (28%, n = 463) had higher education, were more often from the capital area, had a significantly higher healthy diet factor score, and were leaner than nonusers. Use of hormone replacement therapy remained a significant determinant of body mass index, waist/hip ratio, and body fat percentage after adjusting for sociodemographic and lifestyle factors. Of the difference in body mass index between hormone replacement therapy users and non-users, 28% were explained by lifestyle and sociodemographic risk factors, respectively, 31% of the difference by use of the waist/hip ratio and 42% by use of the body fat percentage. CONCLUSIONS: The difference in body size between hormone replacement users and nonusers may not be the result of self-selection. The use of hormone replacement therapy was inversely associated with body size in menopause.

Body Composition↗

PubMed2000

Isoform-specific lidocaine block of sodium channels explained by differences in gating.

When depolarized from typical resting membrane potentials (V(rest) approximately -90 mV), cardiac sodium (Na) currents are more sensitive to local anesthetics than brain or skeletal muscle Na currents. When expressed in Xenopus oocytes, lidocaine block of hH1 (human cardiac) Na current greatly exceeded that of mu1 (rat skeletal muscle) at membrane potentials near V(rest), whereas hyperpolarization to -140 mV equalized block of the two isoforms. Because the isoform-specific tonic block roughly parallels the drug-free voltage dependence of channel availability, isoform differences in the voltage dependence of fast inactivation could underlie the differences in block. However, after a brief (50 ms) depolarizing pulse, recovery from lidocaine block is similar for the two isoforms despite marked kinetic differences in drug-free recovery, suggesting that differences in fast inactivation cannot entirely explain the isoform difference in lidocaine action. Given the strong coupling between fast inactivation and other gating processes linked to depolarization (activation, slow inactivation), we considered the possibility that isoform differences in lidocaine block are explained by differences in these other gating processes. In whole-cell recordings from HEK-293 cells, the voltage dependence of hH1 current activation was approximately 20 mV more negative than that of mu1. Because activation and closed-state inactivation are positively coupled, these differences in activation were sufficient to shift hH1 availability to more negative membrane potentials. A mutant channel with enhanced closed-state inactivation gating (mu1-R1441C) exhibited increased lidocaine sensitivity, emphasizing the importance of closed-state inactivation in lidocaine action. Moreover, when the depolarization was prolonged to 1 s, recovery from a "slow" inactivated state with intermediate kinetics (I(M)) was fourfold longer in hH1 than in mu1, and recovery from lidocaine block in hH1 was similarly delayed relative to mu1. We propose that gating processes coupled to fast inactivation (activation and slow inactivation) are the key determinants of isoform-specific local anesthetic action.

Animals↗

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↗

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↗

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↗

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↗

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↗