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Fluctuations and correlations in crystalline protein dynamics: a simulation analysis of staphylococcal nuclease.

Understanding collective motions in protein crystals is likely to furnish insight into functional protein dynamics and will improve models for refinement against diffraction data. Here, four 10 ns molecular dynamics simulations of crystalline Staphylococcal nuclease are reported and analyzed in terms of fluctuations and correlations in atomic motion. The simulation-derived fluctuations strongly correlate with, but are slightly higher than, the values derived from the experimental B-factors. Approximately 70% of the atomic fluctuations are due to internal protein motion. For 65% of the protein atoms the internal fluctuations converge on the nanosecond timescale. Convergence is much slower for the elements of the interatomic displacement correlation matrix--of these, >80% converge within 1 ns for interatomic distances less, approximately <6 A, but only 10% for separations approximately =12 A. Those collective motions that converged on the nanosecond timescale involve mostly correlations within the beta-barrel or between alpha-helices of the protein. The R-factor with the experimental x-ray diffuse scattering for the crystal, which is determined by the displacement variance-covariance matrix, decreases to 8% after 10 ns simulation. Both the number of converged correlation matrix elements and the R-factor depend logarithmically on time, consistent with a model in which the number of energy minima sampled depends exponentially on the maximum energy barrier crossed. The logarithmic dependence is also extrapolated to predict a convergence time for the whole variance-covariance matrix of approximately 1 micros.

Biophysics↗

Estimation of repeatability of blood constituents in gestating beef cattle on protein- and energy-restricted diets.

Repeatabilities of blood constituents were calculated for 104 Angus heifers on two separate experiments fed adequate, protein-deficient, energy-deficient, or both protein- and energy-deficient diets. Four statistical methodologies were compared including analysis of variance, principal component (structural) analysis based on the sample covariance and sample correlation matrix, and maximum likelihood. Of 12 blood constituents tested only seven were considered sufficiently important to be included in the analysis. These blood constituents included blood urea nitrogen (BUN), creatinine (Creat), alkaline phosphatase (Alk Phos), total protein (T Prot), total bilirubin (T Bil), cholesterol (Chol) and Iron (Fe). If the standard linear model assumptions were met for heifers on the adequate diet, the estimators appeared to be quite similar for both years except when the correlation coefficient was relatively small. If the assumption of homogeneity of the variance-covariance matrix (compound symmetry) was relaxed, the structural analysis method based on the sample correlation matrix appeared preferable. However, when combining all diets, the maximum likelihood methodology was preferred. Among the specific blood constituents, Alk Phos had the highest repeatability, not only for the heifers on the adequate diet, but also for heifers on other treatments in both years. Repeatabilities for T Prot appeared to be the most consistent over all rations in both years. Repeatability estimates for Fe were high and relative rankings were consistent for both years, while repeatabilities for the other variables were either low and(or) inconsistent.

Animals↗

Doubting these doubts--a reply to Collet.

In reply to Collet (1989) it is argued that principal component analysis (PCA) of event-related potentials is not invalidated or disproved by the arguments of his comment. The main points of this reply are as follows. First, since Collet's analysis was based on the correlation matrix only, it cannot disprove assumptions of PCA which do not constrain the correlation (or covariance) matrix. Second, his model utilizes results of PCA which invalidate the comparison and parameter count. Third, his model does not allow specific predictions and does not lead to real data reduction, which reverses Collet's argument based on the principle of parsimony. Fourth, his model is less general than PCA, as it could apply (if at all) to slow brain potentials only.

Evoked Potentials↗

Expression of membrane-type matrix metalloproteinase in rabbit neointimal tissue and its correlation with matrix-metalloproteinase-2 activation.

Smooth muscle cell (SMC) phenotypic alteration, followed by migration and proliferation, is a prominent feature of atherogenesis and vascular neointimal formation. Despite extensive research, mechanism(s) responsible for this alteration remain unclear. Recently, matrix metalloproteinases (MMP), a family of potent proteinases, have been implicated in vascular diseases by way of extracellular matrix degradation. Of particular interest is that expression of a 72-kD MMP (MMP-2) is elevated in neointima, and inhibition of this MMP results in reduced SMC migration and proliferation, suggesting a role for MMP-2 in neointimal development. However, MMP-2 needs activation before digesting protein; the mechanism of this activation in the arterial wall is largely unexplored. A novel membrane-type MMP termed MT-MMP-1 has recently been identified, and its expression in tumor cells is concomitant with MMP-2 activation. Transfection of this MMP cDNA into mammalian cells results in activation of MMP-2. However, the importance of this MMP in various pathological situations is not clear. The present study was designed to explore the relationship between MT-MMP- 1 expression and MMP-2 activation during rabbit neointimal development. Using polymerase chain reaction, we isolated a rabbit cDNA from arterial SMC; sequence analysis indicated that it is a rabbit form ofMT-MMP-1. A segment of this cDNA was subcloned into pGEM-3 and employed to synthesize a DIG-labeled RNA probe. This probe was then used in the Northern blot analysis for MT-MMP-1 mRNA expression both in aortic tissue and in neointimal tissues developed 3, 7, 14 and 21 days after balloon catheter de-endothelialization. The results show low-level expression ofMT-MMP-1 in the normal aortic wall; expression is significantly increased in the neointimal tissues, with peak expression observed in tissues 3 days after injury. Expression of active MMP-2 was also determined using gel zymography. A close temporal expression pattern was observed between MT-MMP-1 and active MMP-2. These data verify the expression of MT-MMP-1 in arterial SMC and suggest its importance in MMP-2 activation after balloon catheter de-endothelialization.

Amino Acid Sequence↗

Functional holography of recorded neuronal networks activity.

We present a new approach for analyzing multi-channel recordings, such as ECoG (electrocorticograph) recordings of cortical brain activity and of individual neuron dynamics, in cultured networks. The latter are used here to illustrate the method and its ability to discover hidden functional connectivity motifs in the recorded activity. The cultured networks are formed from dissociated mixtures of cortical neurons and glia-cells that are homogeneously spread over multi-electrode array for recording of the neuronal activity. Rich, spontaneous dynamical behavior is detected, marked by the formation of temporal sequences of synchronized bursting events (SBEs), partitioned into statistically distinguishable subgroups, each with its own characteristic spatio-temporal pattern of activity.In analogy with coherence connectivity networks for multi-location cortical recordings, we evaluated the inter-neuron correlation-matrix for each subgroup. Ordinarily such matrices are mapped onto a connectivity network between neuron positions in real space. In our functional holography, the correlations are normalized by the correlation distances Euclidian distances between the matrix columns. Then, we project the N-dimensional (for N channels) space spanned by the matrix of the normalized correlations, or correlation affinities, onto a corresponding 3D manifold (3D Cartesian space constructed by the three leading principal vectors of the principal component algorithm). The neurons are located by their principal eigenvalues and linked by their original (not normalized) correlations. By looking at these holograms, hidden causal motifs are revealed: each SBEs subgroup generates its characteristic connectivity diagram (network) in the 3D manifold, where the neuron locations and their links form simple structures. Moreover, the computed temporal ordering of neuron activity, when projected onto the connectivity diagrams, also exhibits simple patterns of causal propagation. We show that the method can expose functional connectivity motifs like the co-existence of subneuronal functional networks in the space of affinities. The method can be directly utilized to construct similar causal holograms for recorded brain activity. We expect that by doing so, hidden functional connectivity motifs with relevance to the understanding of brain activity might be discovered.

Animals↗

Multicollinearity in prognostic factor analyses using the EORTC QLQ-C30: identification and impact on model selection.

Clinical and quality of life (QL) variables from an EORTC clinical trial of first line chemotherapy in advanced breast cancer were used in a prognostic factor analysis of survival and response to chemotherapy. For response, different final multivariate models were obtained from forward and backward selection methods, suggesting a disconcerting instability. Quality of life was measured using the EORTC QLQ-C30 questionnaire completed by patients. Subscales on the questionnaire are known to be highly correlated, and therefore it was hypothesized that multicollinearity contributed to model instability. A correlation matrix indicated that global QL was highly correlated with 7 out of 11 variables. In a first attempt to explore multicollinearity, we used global QL as dependent variable in a regression model with other QL subscales as predictors. Afterwards, standard diagnostic tests for multicollinearity were performed. An exploratory principal components analysis and factor analysis of the QL subscales identified at most three important components and indicated that inclusion of global QL made minimal difference to the loadings on each component, suggesting that it is redundant in the model. In a second approach, we advocate a bootstrap technique to assess the stability of the models. Based on these analyses and since global QL exacerbates problems of multicollinearity, we therefore recommend that global QL be excluded from prognostic factor analyses using the QLQ-C30. The prognostic factor analysis was rerun without global QL in the model, and selected the same significant prognostic factors as before.

Antineoplastic Agents↗

Ciclosporin metabolite pattern in blood and urine of liver graft recipients. I. Association of ciclosporin metabolites with nephrotoxicity.

Blood ciclosporin (Cs) metabolite pattern in 58 liver grafted patients was routinely monitored by HPLC from the first Cs dose after transplantation until discharge from hospital. Eighteen patients with normal kidney function were allocated to Group I and 14 patients in Group II suffered Cs nephrotoxicity during their clinical course. There were no significant differences between both groups in blood Cs level, kidney function before transplantation, liver function or co-administration of other potentially nephrotoxic drugs. A correlation matrix involving both groups showed a significant correlation between the blood concentration of metabolite M1c9 and serum creatinine and urea, and an inverse correlation with creatinine clearance. During a nephrotoxic episode the blood concentrations of metabolites M1c9 and M1A were significantly elevated in patients in Group II. Analysis of the time course revealed significantly higher blood levels of M19 and M1c9 in Group II patients compared with those in Group I for the first 10 days after transplantation. Serum creatinine and urea concentrations remained significantly elevated, the creatinine clearance being significantly reduced throughout the period of observation. The elevated blood concentrations of ciclosporin metabolites M1c9 and M19 during nephrotoxic episodes suggest that these metabolites are associated with ciclosporin nephrotoxicity. It could not be decided if the elevated metabolite concentrations were the result of and/or the reason for impaired kidney function.

Adult↗

Brain weights correlate with behavioral parameters in individual inbred mice housed in a common and enriched environment.

Fifty 8-week-old Balb/c mice were individually identified and housed together in a large and enriched environment for 5 months. Maze and open field exploration, response to an aversive noise, swimming, and induced grooming tests were applied to each mouse in an initial search for possible relationships between brain morphology and spontaneous behavior in isogenic individuals living in a complex social and physical environment. The tasks generated 39 quantitative behavioral indices which include locomotion, rearing, still, and grooming bout frequencies, latencies, total, and mean bout durations. At the end of the tests, the 7-month-old mice were sacrificed and the fresh weights of their whole brain, cerebellum, brain stem, diencephalon, telencephalon, and prosencephalon were rapidly obtained. Behavioral data have wide variations and do not adjust to normal population distributions. Means of the same parameter differ between tests. A Spearman correlation matrix of all data yielded many significant correlations between indices of the same task which can be interpreted in terms of time budget and sequence probability. Significant correlations between indices of different tests suggest diverse emotionalities, exploratory strategies, and motor skills. The correlations between body and brain weights and among separate brain regions were not significant. There were several low but significant correlations between brain weights and behavioral indices. Such correlations, the resulting factors, and significant behavioral differences between mice with large and small brains suggest that mice displaying low motor activity in novel environments have larger brains and forebrain/hindbrain ratios than mice with high activity, and that animals with high scores of some specific behaviors have larger brain areas physiologically related to such behaviors.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

On power and efficiency robust linkage tests for affected sibs.

For diseases that do not follow a clear Mendelian pattern of inheritance nonparametric tests applied to affected sibs have been shown to be robust to the inherent uncertainty about the precise underlying genetic model. It is known that the weights optimizing the power of tests using IBD alleles shared by affected sib pairs or triples depend on the underlying model. We show how efficiency robustness techniques, used in other areas of statistics, provide a systematic approach for constructing a robust linear combination of the statistics that are optimal for the individual members of a family of plausible genetic models. The method depends on the correlation matrix of the optimal tests as these correlations reflect how different the models are. When the minimal correlation is less than 0.5, an alternate robust procedure is proposed. The methods apply to combining data from sibships of different sizes.

Automation↗

Aggressive hydration during continuous positive-pressure ventilation restores atrial transmural pressure, plasma atrial natriuretic peptide concentrations, and renal function.

BACKGROUND AND METHODS: The correlations between continuous positive-pressure ventilation-induced antidiuresis/antinatriuresis, atrial transmural pressure, and atrial natriuretic peptide concentrations have not been clarified. The purpose of the present study was to use aggressive hydration to restore atrial transmural pressure during continuous positive-pressure ventilation and to test for correlations of atrial transmural pressure, atrial natriuretic peptide concentration, diuresis, and natriuresis during this intervention. An intrapleural catheter was used to measure atrial transmural pressure in three ways: a) right atrial pressure minus intrapleural pressure, b) left ventricular end-diastolic pressure minus intrapleural pressure, and c) pulmonary artery occlusion pressure minus intrapleural pressure. Hemodynamic, atrial natriuretic peptide concentrations, and renal measurements were made in 12 anesthetized closed-chest dogs during baseline (intermittent positive-pressure ventilation), during continuous positive-pressure ventilation), during continuous positive-pressure ventilation with 10 cm H2O end-expiratory pressure, and during continuous positive-pressure ventilation plus aggressive hydration (approximately 60 mL/kg lactated Ringer's solution). Pearson's correlation matrix was used to generate all possible correlation coefficients between the three atrial transmural pressures, atrial natriuretic peptide concentrations, urine output, and urine sodium excretion. RESULTS: Application of continuous positive-pressure ventilation resulted in a 60% decrease in right atrial transmural pressure (p less than .05), a 51% decrease in left ventricular end-diastolic transmural pressure (p less than .05), and a 26% decrease in pulmonary artery occlusion transmural pressure (p less than .05) from baseline. Plasma atrial natriuretic peptide concentration decreased from 80 +/- 12 (SEM) pg/mL at baseline to 49 +/- 8 pg/mL during continuous positive-pressure ventilation (p less than .05). Both urine output and sodium excretion decreased by 81% (p less than .05). After aggressive hydration with lactated Ringer's solution during continuous positive-pressure ventilation, to restore atrial transmural pressure to baseline, plasma atrial natriuretic peptide concentration returned to baseline values (81 +/- 12 pg/mL) as did urine output and sodium excretion. Correlation indices (r2 values) between transmural pressure, atrial natriuretic peptide concentration, urine output, and sodium excretion ranged from .835 to .994. Multivariate analysis of covariance demonstrated significant (p less than .05) temporal dependence between the three transmural pressures, atrial natriuretic peptide concentration, urine output, and sodium excretion. CONCLUSIONS: The results demonstrate that aggressive hydration during continuous positive-pressure ventilation will restore diuresis and natriuresis and that this response correlates significantly with atrial transmural filling pressure and plasma atrial natriuretic peptide concentration.

Animals↗

Changes in genetic architecture during relaxation in Drosophila melanogaster selected on divergent virgin life span.

Artificial selection experiments often confer important information on the genetic correlations constraining the evolution of life history. After artificial selection has ceased however, selection pressures in the culture environment can change the correlation matrix again. Here, we reinvestigate direct and correlated responses in a set of lines of Drosophila melanogaster that were selected on virgin life span and for which selection has been relaxed for 10 years. The decrease in progeny production in long-lived lines, a strong indication of antagonistic pleiotropy, had disappeared during relaxation. This was associated with a higher cost of reproduction to long-lived flies in mated, but not in virgin life span. These data strongly suggest that genetic mechanisms of mated and virgin life span determination are partly independent. Furthermore, data on body weight, developmental time and viability indicated deleterious effects of longevity selection in either direction, giving rise to a nonlinear relationship with life span for these characters. In order to reclaim original patterns, we founded a new set of derived lines by resuming selection in mixed replicate lines of the original set. Although selection was successful, most patterns in correlated characters remained, showing that these new patterns are resistant to new episodes of selection.

Animals↗

Lithium RBC/plasma ratio in subgroups of patients with affective disorders.

The lithium RBC/plasma ratio was determined in 59 patients during prophylactic lithium therapy -- 10 cycloid psychotics, 28 unipolars and 21 bipolars -- as well as in 20 patients during lithium therapy in phase of illness -- 8 cycloid psychotics, 5 unipolars and 7 bipolars. The lithium ratio was found to be normally distributed both among patients in phase of remission and those in phase of illness. No differences in lithium ratio were found between patients in phase of remission and phase of illness, respectively. During prophylactic lithium therapy, no differences were found in the lithium ratio between patients in different diagnostic subgroups. In a correlation matrix, the lithium ratio was found to correlate to lithium in RBC but not to age, sex, type of illness, weight, lithium dosage, duration of treatment or level of lithium in plasma. The lithium level in RBC was determined only by the lithium level in plasma. Thus, the lithium RBC/plasma ratio does not seem to be of diagnostic value in affective disorders.

Adult↗

Angiotensin-converting enzyme gene polymorphism, lipids, and apolipoproteins in menopausal women on hormone replacement therapy.

This study investigated the frequency of angiotensin-converting enzyme (ACE) genotypes, concentrations of total cholesterol (T-C), triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), lipoprotein Lp (a), Established Risk Factor (ERF) ratio (total cholesterol/HDL-C), apolipoproteins A-I, A-II, apoBand apoE in 134 menopausal women aged 49.62 +/- 4.83 on oral hormone replacement therapy (HRT) (2 mg 17 beta estradiol plus 1 mg norethisterone acetate/day), during (mean +/- SD) 15.77 +/- 9.94 months. ACE genotypes of 134 menopausal women showed DD genotype in 48 (36%), ID genotype in 59 (44%), and II genotype in 27 (20%) women, with the mean body mass index (BMI) (kg/m2) of 26.34 +/- 4.02, systolic blood pressure (mm Hg) of 145.71 +/- 23.32, diastolic blood pressure of 95.28 +/- 12.88, pulse rate of 77.76 +/- 13.81, positive family history of myocardial infarction (MI) (23%) and stroke (22%); 26% were smokers and 6% consumed alcohol regularly. The mean levels of TC (mmol/l) were 5.72 +/- 1.25, TG (mmol/L) 1.63 +/- 0.82, HDL-C (mmol/L) 1.15 +/- 0.29, LDL-C (mmol/L) 3.98 +/- 1.31, lipoprotein Lp(a) (g/L) 0.16 +/- 0.24, ERF ratio 5.35 +/- 1.90, apolipoproteins (g/L): A-I 1.83 +/- 0.39, A-II 0.57 +/- 0.12, apoB 0.92 +/- 0.31, and apoE 0.08 +/- 0.04. The highest mean levels of T-C 5.89 +/- 1.40, TG 1.67 +/- 0.96, LDL-C 4.15 +/- 1.60, lipoprotein Lp(a) 0.19 +/- 0.25) apoB 0.95 +/- 0.32 and ERF ratio 5.46 +/- 2.24 were found in ID genotype, while in DD genotype HDL-C 1.11 +/- 0.28 and apo A-I 1.78 +/- 0.34 were lowest. In II genotype, the levels of apo A-II 0.56 +/- 0.11 were lowest and of apoE 0.09 +/- 0.05 highest. According to DD, ID and II genotypes and lipid, lipoprotein Lp(a), ERF ratio and apolipoprotein concentrations, there were no statistically significant differences between groups. ERF ratio in DD genotype showed a positive correlation with TG (r = 0.59) and LDL-C (r = 0.57), a slight positive correlation with apoB (r = 0.40), and a strong negative correlation with HDL-C (r = -0.73). ERF in ID genotype showed a strong negative correlation with HDL-C (r = -0.73), strong positive correlation with TG (r = 0.70), and T-C (r = 0.58), and slight positive correlation with LDL-C (r = 0.36) and alcohol abuse (r = 0.34). In II genotype, ERF ratio showed a strong positive correlation with LDL-C (r = 0.73), T-C (r = 0.70) and apoE (r = 0.58), slight positive correlation with apoB (r = 0.46) and TG (r = 0.36), and negative correlation with HDL-C (r = -0.54). Matrix correlation of DD genotypes showed the highest positive correlation between T-C and LDL-C (r = 0.91) and apoE (r = 0.45), and negative correlation between HDL-C and ERF ratio (r = 77), and LDL-C and ERF ratio (r = 0.55). In ID genotype, T-C showed a strong positive correlation between LDL-C (r = 0.75) and ERF ratio (r = 0.63), TG and ERF ratio (r = 0.73), and negative with HDL-C (r = 0.53). In genotype II, T-C showed a strong positive correlation between LDL-C (r = 0.96), ERF ratio (r = 0.71), apoB (r = 0.66) and apoE (r = 0.46). LDL-C correlated positively with ERF ratio (r = 0.72), apoB (r = 0.61) and apoE (r = 0.48). These findings indicated the frequency of ACE genotypes to differ within the group of menopausal women. Analysis of ACE genotypes showed ID genotype to be most common among menopausal women. This result indicated their intermediate risk of coronary heart disease (CHD) and myocardial infarction (MI). It has been well established that an increased risk of MI is associated with high frequency of DD genotype, and a low risk with high frequencies of II genotype. In addition to ACE polymorphism analysis, assessment of lipid, apolipoprotein, and lipoprotein Lp(a) concentrations, and of ERF ratio provides further important parameters for better understanding of the risk factors for CDH in women. In the present study, assessment of the genetic, metabolic and environmental markers pointed to an intermediate risk of CHD in menopausal women on HRT, although the mechanism underlying the disease is not clear and well understood yet.

Apolipoproteins↗

[Characterization of changes in the epidemiological tuberculosis situation in Russia on the basis of integral estimates].

The paper substantiates and provides evidence for that it is necessary to use summarized estimates to characterize the tuberculosis endemic situation. Some individual epidemiological indices are inadequately estimated to give a correct idea of epidemiological well-being. By using his own method for deriving an integral estimates, the author has analyzed the dynamics of the tuberculosis situation in Russia in 1985 to 2003. Two turning points have been established in the dynamics of the epidemic situation: 1) improvement up to 1991 inclusive and 2) a subsequent deterioration up to 2002, thereafter the epidemic situation had tended to improve. A correlation matrix has been derived, which reflects a correlation of integral estimates with individual epidemiological indices.

Data Interpretation, Statistical↗

Role of parathyroid hormone in the anemia of chronic terminal renal dysfunction in dogs.

Terminal renal dysfunction (TRD) was induced in 2 groups of dogs by partial surgical ablation of the kidney. Dogs of a control group and of 1 of the TRD groups were maintained on a diet containing normal phosphorus concentration, whereas dogs of the other TRD group were maintained on a low-phosphorus diet. Mild anemia developed in dogs of both TRD groups and could not be attributed to iron deficiency, increased erythrocyte concentration of 2,3-diphosphoglycerate, or absolute deficiency of erythropoietin (EP). Subsequently, all dogs were acutely depleted of approximately 25% of their blood volume. Erythropoietin concentration in dogs of the TRD groups was lower than that of controls, however, erythroid regenerative capacity was comparable with that of control dogs when plasma parathyroid hormone (PTH) concentration was lowered by reduced dietary intake of phosphorus. The PCV in dogs of the chronic TRD groups had a slight positive correlation with serum EP concentration, and a significant (P less than 0.05) negative correlation with plasma PTH and serum phosphorus and creatinine concentrations, using a correlation matrix. There was no longer a significant correlation between plasma PTH concentration and PCV after controlling for serum creatinine concentration by use of a multiple linear regression analysis. A significant (P less than 0.05) negative correlation also was observed between plasma PTH and serum EP concentrations, but not between serum EP and phosphorus or creatinine concentrations. Significance of the EP and PTH association was reduced when analyzed, using a multiple linear regression analysis that included serum creatinine values.(ABSTRACT TRUNCATED AT 250 WORDS)

Anemia↗

[The alteration of the motility rate of human spermatozoa and relationship to morphological quality].

On the ejaculate of 715 patients with fertility disorders (one spermatogram) as well as on 90 patients (two spermatograms) the alteration of the motility rate comparing the morphological quality of the spermatozoa has been carried out. In some norm orientated subgroups a statistical evaluation (correlation analysis, covariance selection) were determined. We found a positive correlation between increased percentage of pathological spermatozoa and increased motility rate. A special graphic allows more information about the correlative structure of the correlation matrix: this confirms the results of the correlation analysis. On the different malformations of the spermatozoa the intraindividual fluctuation was in the least, but very high on the sperm density. The fluctuation of the fructose content (detailed observed) was very little.

Humans↗

Multiple alpha-2 adrenergic receptor subtypes. II. Evidence for a role of rat R alpha-2A adrenergic receptors in the control of nociception, motor behavior and hippocampal synthesis of noradrenaline.

In this study, we attempted to identify of the subtype(s) of alpha-2 adrenergic receptor (AR) involved in the control of motor behavior, nociception and the hippocampal synthesis of noradrenaline (NA) in the rat. The high efficacy alpha-2 AR agonists, xylazine and UK 14,304 [5-bromo-6-[2-imidazolin-2-yl-amino]quinoxaline], inhibited striatal accumulation of L-dopa in rats pretreated with NSD 1015 (an inhibitor of aromatic amino acid-decarboxylase), elicited a loss of the righting reflex in rats, provoked ataxia in the rotarod test in mice and elicited antinociception in the writhing and hot-plate tests in mice. Guanfacine and guanabenz, agonists acting preferentially at rat alpha-2A (R alpha-2A)/human alpha-2A (H alpha-2A) AR, mimicked the antinociceptive and motor actions of xylazine and UK 14,304 and likewise inhibited NA synthesis. The preferential R alpha-2A/H alpha-2A AR antagonist, [2-(2H-(1-methyl-1, 3-dihydroisoindole)methyl)-4, 5-dihydro-imidazole (BRL 44408), enhanced hippocampal synthesis of NA and blocked the antinociceptive and motor effects of UK 14,304, xylazine, guanfacine and guanabenz. Similarly, fluparoxan and des-fluorofluparoxan, preferential antagonists at R alpha-2A AR as compared to H alpha-2A AR, were highly active. In contrast, the preferential alpha-2B/alpha-2C AR antagonists, ARC 239 [2-(2-(4-o-methoxyphenyl)piperazine-1-yl)-ethyl)-4,4-dimethyl-1,3- (2H,4H)-isoquinolinedione] prazosin, corynanthine, spiroxatrine and [1,2-dimethyl-2,3,9,13-betetrahydro-1H-dibenzo(c,f)- imidazo(1,5-a)azepine (BRL 41992)], as well as the preferential H alpha-2A AR antagonist, [2-(2,6-dimethoxyphenoxyethyl)- aminomethyl-1,4-benzodioxane] (WB 4101), were only weakly active. Based on the actions of a total of 16, structurally diverse alpha-2 AR antagonists, a correlation matrix was constructed. This revealed a strong correlation among the tests (median r = 0.82) and allowed for a comparison between drug potency in inhibiting these alpha-2 AR-mediated actions and affinity at various populations of alpha-2 AR subtypes (see companion paper). Correlations for potency in the two motor tests were pronounced with R alpha-2A sites (0.85), modest with H alpha-2A sites (0.60) and alpha-2B sites (0.58) and poor with alpha-2C sites (0.35). For the two antinociceptive tests, correlations were likewise pronounced with R alpha-2A sites (0.80) but less marked with H alpha-2A sites (0.73), alpha-2B sites (0.62) and alpha-2C sites (0.62).(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

Changes in periodontal status of children and young adolescents: a one year longitudinal study.

The purpose of the present study was to describe longitudinal changes in accumulation of dental plaque and gingival inflammation, and their effect on changes in sulcus depth of children and young adolescents. Forty one boys and 37 girls aged 1-12 years living in a rural community in Israel were included in the study. At baseline and 12 months later, Loe's Plaque Index (PlI) and Gingival Index (GI), and sulcus depth were examined. Boys' mean age was significantly lower than girls' mean age (6.04 + 2.76 years, and 7.68 + 2.84 years respectively). PlI, GI and sulcus depth were higher in the 12-month examination compared to baseline. PlI was slightly higher in boys, while GI was slightly higher in girls. These differences however, were not statistically significant. At baseline, sulcus depth was significantly greater in girls than in boys, while at 12 months the difference was not significant. The children were grouped by age as follows: 1-5 years, 6-9 years and 10-12 years. PlI and GI mean scores were significantly higher among the 6-9-year-old individuals. Mean sulcus depth for the 10-12-year-old children was greater than that of the 6-9-year-olds at baseline and after 12 months. The effect of age, PlI and GI on the outcome variable (sulcus depth) was examined using a correlation matrix. At baseline, age showed the highest correlation (r = 0.659) followed by GI (r = 0.364) and PlI (r = 0.123). The same pattern was also observed at the 12 months examination.(ABSTRACT TRUNCATED AT 250 WORDS)

Age Distribution↗