Age and Periodontal Health - Immunological View.

PURPOSE OF THE REVIEW: Aging clearly impacts a wide array of systems, in particular the breadth of the immune system leading to immunosenescence, altered immunoactivation, and coincident inflammaging processes. The net result of these changes leads to increased susceptibility to infections, increased neoplastic occurrences, and elevated frequency of autoimmune diseases with aging. However, as the bacteria in the oral microbiome that contribute to the chronic infection of periodontitis is acquired earlier in life, the characteristics of the innate and adaptive immune systems to regulate these members of the autochthonous microbiota across the lifespan remains ill defined. RECENT FINDINGS: Clear data demonstrate that both cells and molecules of the innate and adaptive immune response are adversely impacted by aging, including in the oral cavity, yielding a reasonable tenet that the increased periodontitis noted in aging populations is reflective of the age-associated immune dysregulation. Additionally, this facet of host-microbe interactions and disease needs to accommodate the population variation in disease onset and progression, which may also reflect an accumulation of environmental stressors and/or decreased protective nutrients that could function at the gene level (ie. epigenetic) or translational level for production and secretion of immune system molecules. SUMMARY: Finally, the majority of studies of aging and periodontitis have emphasized the increased prevalence/severity of disease with aging, all based upon chronological age. However, evolving areas of study focusing on "biological aging" to help account for population variation in disease expression, may suggest that chronic periodontitis represents a co-morbidity that contributes to "gerovulnerability" within the population.

Evaluation of consistency for multiple experiments of a single combination in the time-dependence mixture toxicity assay.

Test-to-test consistency was evaluated for a single binary combination of organic chemicals using an assay that examined toxicity over multiple exposure times. Six experiments were conducted. The toxicities of 3-chloro-2-butanone (3C2B), methyl crotonate (MC) and the mixture of both (MX) were evaluated in each experiment at 15, 30 and 45 min of exposure using the Microtox® system. Concentration-response (x/y) curves were generated via the five-parameter logistic minus one-parameter (5PL - 1P) curve-fitting function and were used to develop predicted x/y curves for the dose-addition (DA) and independence (I) models of combined effect. A variety of toxicity (e.g. effective concentration, EC50) and time-dependent toxicity (TDT) endpoints, 5PL - 1P parameters and various combined-effects metrics (e.g. MX/DA) were calculated. Test-to-test consistency was evaluated via the coefficient of variation (CV) or, for TDT, the standard deviation of mean values. In the study, CVs obtained for single-chemical and mixture toxicity endpoints (EC25, EC50 and EC75) at each exposure time were <20, as were those for the predicted DA and I curves. For the MX/DA metric, mixture toxicity was consistent with that predicted for DA at each exposure time in each experiment with CVs <6, despite some substantial variation in TDT for MC-alone at the EC25 and for the 30-45 min time-interval. There was a lower variation in TDT for 3C2B and MX. Mean and CV values for 5PL - 1P-derived slope and asymmetry parameters were also assessed to provide bases for comparisons in future reports.

Mixture toxicity of SN2-reactive soft electrophiles: 3. Evaluation of ethyl α-halogenated acetates with α-halogenated acetonitriles.

Mixture toxicity for each of four ethyl α-halogenated acetates with each of three α-halogenated acetonitriles (xANs) was assessed. Inhibition of bioluminescence in Vibrio fischeri was measured after 15, 30, and 45 min of exposure. Concentration-response curves were developed for each chemical at each exposure duration and used to develop predicted concentration-response curves for the dose-addition and independence models of combined effect. Concentration-response curves for each mixture and each exposure duration were then evaluated against the predicted curves using three metrics per model: (1) EC50-based additivity quotient (AQ) or independence quotient (IQ) values; (2) mean AQ (mAQ) or mean IQ (mIQ) values, which were calculated by averaging the EC25, EC50, and EC75 AQ or IQ values; and (3) deviation values from additivity (DV-A) or independence (DV-I). Mixture toxicity for ethyl iodoacetate was dose-additive with each of the xANs at all exposure durations and was also often consistent with independence. The same was true for mixture toxicity of ethyl bromoacetate with each xAN. However, for the two more slowly reactive chemicals, ethyl chloroacetate (ECAC) and ethyl fluoroacetate (EFAC), mixture toxicity with each xAN only became consistent with dose-addition on increasing exposure duration. Consistency with independence for both ECAC and EFAC with the xANs was essentially limited to the EC50-IQ metric, thereby showing the utility of calculating the mean quotient (mAQ, mIQ) and deviation value (DV-A, DV-I) metrics. On review of these findings with those from the first two studies in the series, the results suggest that instances in which mixture toxicity was not consistent with dose-addition relate (1) to differences in the capability of the chemicals to form strong H-bonds with water; and (2) to differences in relative reactivity and time-dependent toxicity levels of the chemicals.

Genetic diversity and population structure in contemporary house sparrow populations along an urbanization gradient.

House sparrow (Passer domesticus) populations have suffered major declines in urban as well as rural areas, while remaining relatively stable in suburban ones. Yet, to date no exhaustive attempt has been made to examine how, and to what extent, spatial variation in population demography is reflected in genetic population structuring along contemporary urbanization gradients. Here we use putatively neutral microsatellite loci to study if and how genetic variation can be partitioned in a hierarchical way among different urbanization classes. Principal coordinate analyses did not support the hypothesis that urban/suburban and rural populations comprise two distinct genetic clusters. Comparison of FST values at different hierarchical scales revealed drift as an important force of population differentiation. Redundancy analyses revealed that genetic structure was strongly affected by both spatial variation and level of urbanization. The results shown here can be used as baseline information for future genetic monitoring programmes and provide additional insights into contemporary house sparrow dynamics along urbanization gradients.

Antisocial behavioral syndromes and 3-year quality-of-life outcomes in United States adults.

OBJECTIVE: To examine 3-year quality-of-life (QOL) outcomes among United States adults with Diagnostic and Statistical Manual of Mental Disorders - Fourth Edition (DSM-IV) antisocial personality disorder (ASPD), syndromal adult antisocial behavior without conduct disorder (CD) before age 15 [adulthood antisocial behavioral syndrome (AABS), not a DSM-IV diagnosis], or no antisocial behavioral syndrome at baseline. METHOD: Face-to-face interviews (n = 34 653). Psychiatric disorders were assessed using the Alcohol Use Disorder and Associated Disabilities Interview Schedule - DSM-IV Version. Health-related QOL was assessed using the Short-Form 12-Item Health Survey, version 2 (SF-12v2). Other outcomes included past-year Perceived Stress Scale-4 (PSS-4) scores, employment, receipt of Supplemental Security Income (SSI), welfare, and food stamps, and participation in social relationships. RESULTS: Antisocial personality disorder and AABS predicted poorer employment, financial dependency, social relationship, and physical health outcomes. Relationships of antisociality to SSI and food stamp receipt and physical health scales were modified by baseline age. Both antisocial syndromes predicted higher PSS-4, AABS predicted lower SF-12v2 Vitality, and ASPD predicted lower SF-12v2 Social Functioning scores in women. CONCLUSION: Similar prediction of QOL by ASPD and AABS suggests limited utility of requiring CD before age 15 to diagnose ASPD. Findings underscore the need to improve prevention and treatment of antisocial syndromes.

Maternal effects and heritability of annual productivity.

Within-individual consistency and among-individual heterogeneity in fitness are prerequisites for selection to take place. Within-individual variation in productivity between years, however, can vary considerably, especially when organisms become older and more experienced. We examine individual consistency in annual productivity, the covariation between survival and annual productivity, and the sources of variation in annual productivity, while accounting for advancing age, to test the individual-quality and resource-allocation life-history theory hypotheses. We use long-term data from a pedigreed, wild population of house sparrows. Within-individual annual productivity first increased and later decreased with age, but there were no selective mortality due to individual quality and no correlation between lifespan and productivity. Individuals were consistent in their annual productivity (C = 0.49). Narrow-sense heritability was low (h(2) = 0.09), but maternal effects explained much of the variation (M = 0.33). Such effects can influence evolutionary processes and are of major importance for our understanding of how variation in fitness can be maintained.

Mixture toxicity of S(N)2-reactive soft electrophiles: 2-evaluation of mixtures containing ethyl α-halogenated acetates.

Four ethyl α-halogenated acetates were tested in (1) sham and (2) nonsham combinations and (3) with a nonreactive nonpolar narcotic. Ethyl iodoacetate (EIAC), ethyl bromoacetate (EBAC), ethyl chloroacetate (ECAC), and ethyl fluoroacetate (EFAC), each considered to be an SN2-H-polar soft electrophile, were selected for testing based on their differences in electro(nucleo)philic reactivity and time-dependent toxicity (TDT). Agent reactivity was assessed using the model nucleophile glutathione, with EIAC and EBAC showing rapid reactivity, ECAC being less reactive, and EFAC lacking reactivity at ≤250 mM. The model nonpolar narcotic, 3-methyl-2-butanone (3M2B), was not reactive. Toxicity of the agents alone and in mixture was assessed using the Microtox acute toxicity test at three exposure durations: 15, 30 and 45 min. Two of the agents alone (EIAC and EBAC) had TDT values >100%. In contrast, ECAC (74 to 99%) and EFAC (9 to 12%) had partial TDT, whereas 3M2B completely lacked TDT (<0%). In mixture testing, sham combinations of each agent showed a combined effect consistent with predicted effects for dose-addition at each time point, as judged by EC(50) dose-addition quotient values. Mixture toxicity results for nonsham ethyl acetate combinations were variable, with some mixtures being inconsistent with the predicted effects for dose-addition and/or independence. The ethyl acetate-3M2B combinations were somewhat more toxic than predicted for dose-addition, a finding differing from that observed previously for α-halogenated acetonitriles with 3M2B.

Mixture toxicity of SN2-reactive soft electrophiles: 1. Evaluation of mixtures containing α-halogenated acetonitriles.

The concept of multiple modes of toxic action denotes that an individual chemical can induce two or more toxic effects within the same series of concentrations, for example, reactive toxicity and narcosis. It appears that such toxicity confounds the ability to develop precise predictions of mixture toxicity and makes it more difficult to clearly link a dose-additive combined effect to agents in the mixture having a single common mechanism of toxic action. This initial study of a three-part series begins to examine this issue in greater detail by testing three α-halogenated acetonitriles: (1) in sham combinations, (2) in true combinations, and (3) with a nonreactive nonpolar narcotic. Iodo-, bromo-, and chloro-derivatives of acetonitrile were selected for testing based on their electro(nucleo)philic reactivity, via the S(N)2 mechanism, and their time-dependent toxicity individually. Reactivity of each agent was assessed in tests with the model nucleophile glutathione (GSH). Each acetonitrile was reactive with GSH, but the nonpolar narcotic 3-methyl-2-butanone was not. In addition, toxicity of the agents alone and in mixtures was assessed using the Microtox(®) acute toxicity test at three time points: 15, 30, and 45 min of exposure. Each of the three agents alone had time-dependent toxicity values of about 100%, making it likely that most of the toxicity of these agents, at these times, was due to reactivity. In contrast, the nonpolar narcotic agent lacked time-dependent toxicity. In mixture testing, sham combinations of each acetonitrile showed a combined effect consistent with predicted effects for dose-addition at each time point, as did the sham combination of the nonpolar narcotic. Mixture toxicity results for true acetonitrile combinations were also consistent with dose-addition, but the acetonitrile-nonpolar narcotic combinations were generally not consistent with either the dose-addition or independence models of combined effect. Based on current understanding of mixture toxicity, these results were expected and provide a foundation for the second and third studies in the series.

Avian genome evolution: insights from a linkage map of the blue tit (Cyanistes caeruleus).

We provide a first-generation linkage map of the blue tit (Cyanistes caeruleus), a passerine within the previously genetically uncharacterized family Paridae, which includes 91 orthologous loci with a single anchored position in the chicken (Gallus gallus) sequence assembly. The map consists of 18 linkage groups and covers 935 cM. There was highly conserved synteny between blue tit and chicken with the exception of a split on chromosome 1, potential splits on chromosome 4 and the translocation of two markers from chromosome 2 and 3, respectively, to chromosome 5. Gene order was very well conserved for the majority of chromosomes, an exception being chromosome 1 where multiple rearrangements were detected. Similar results were obtained in a comparison to the zebra finch (Taeniopygia guttata) genome assembly. The recombination rate in females was slightly higher than in males, implying a moderate degree of heterochiasmy in the blue tit. The map distance of the blue tit was approximately 78% of that of the Wageningen chicken broiler population, and very similar to the Uppsala chicken mapping population, over homologous genome regions. Apart from providing insights into avian recombination and genome evolution, our blue tit linkage map forms a valuable genetic resource for ecological and evolutionary research in Paridae.

Sociodemographic and psychopathologic predictors of first incidence of DSM-IV substance use, mood and anxiety disorders: results from the Wave 2 National Epidemiologic Survey on Alcohol and Related Conditions.

The objective of this study was to present nationally representative findings on sociodemographic and psychopathologic predictors of first incidence of Diagnostic and Statistical Manual of Mental Disorders, 4th edn (DSM-IV) substance, mood and anxiety disorders using the Wave 2 National Epidemiologic Survey on Alcohol and Related Conditions. One-year incidence rates of DSM-IV substance, mood and anxiety disorders were highest for alcohol abuse (1.02), alcohol dependence (1.70), major depressive disorder (MDD; 1.51) and generalized anxiety disorder (GAD; 1.12). Incidence rates were significantly greater (P<0.01) among men for substance use disorders and greater among women for mood and anxiety disorders except bipolar disorders and social phobia. Age was inversely related to all disorders. Black individuals were at decreased risk of incident alcohol abuse and Hispanic individuals were at decreased risk of GAD. Anxiety disorders at baseline more often predicted incidence of other anxiety disorders than mood disorders. Reciprocal temporal relationships were found between alcohol abuse and dependence, MDD and GAD, and GAD and panic disorder. Borderline and schizotypal personality disorders predicted most incident disorders. Incidence rates of substance, mood and anxiety disorders were comparable to or greater than rates of lung cancer, stroke and cardiovascular disease. The greater incidence of all disorders in the youngest cohort underscores the need for increased vigilance in identifying and treating these disorders among young adults. Strong common factors and unique factors appear to underlie associations between alcohol abuse and dependence, MDD and GAD, and GAD and panic disorder. The major results of this study are discussed with regard to prevention and treatment implications.

Isolation of sixteen autosomal loci and a sex-linked polymorphic microsatellite locus from the Milne-Edwards' sportive lemur (Lepilemur edwardsi).

We isolated 21 microsatellites from the Milne-Edwards' sportive lemur, Lepilemur edwardsi. Eighteen microsatellite sequences possessed sufficient flanking DNA for primer design. Seventeen loci amplified and were found to be polymorphic displaying two to 17 alleles in 32 unrelated individuals from a population from the National Park of Ankarafantsika in northwest Madagascar. One locus (Led-12) was found to be sex linked located on the X chromosome and can be used to sex-type 40% of female L. edwardsi lemurs. These 17 loci were characterized to investigate family structure and the phylogeography of L. edwardsi.

Microsatellite flanking region similarities among different loci within insect species.

Although microsatellites are ubiquitous in eukaryota, the number of available markers varies strongly among taxa. This meta-analysis was conducted on 32 insect species. Sequences were obtained from two assembled whole genomes, whole genome shotgun (WGS) sequences from 10 species and screening partial genomic libraries for microsatellites from 23 species. We have demonstrated: (1) strong differences in the abundance of microsatellites among species; (2) that microsatellites within species are often grouped into families based on similarities in their flanking sequences; (3) that the proportion of microsatellites grouped into families varies strongly among taxa; and (4) that microsatellite families were significantly more often associated with transposable elements - or their remnants - than unique microsatellite sequences.

Time dependence in mixture toxicity with soft electrophiles: 1. Combined effects of selected SN2- and SNAr-reactive agents with a nonpolar narcotic.

Frequently the toxicity of an organic chemical mixture is close to dose-additive, even when the agents are thought to induce toxicity at different molecular sites of action. These findings appear to conflict with the hypothesis that a strictly dose-additive combined effect will be observed for agents sharing a single molecular site of toxic action within the organism. In this study, several SN2-reactive (alpha-halogen) or S(N)Ar-reactive (halogenated dinitrobenzene) soft electrophiles were tested with a model nonpolar narcotic (NPN) to determine the toxicity of the combinations. A sham combination of the model NPN (3-methyl-2-butanone) was also tested as a positive control. The study design incorporated time-dependent toxicity (TDT) determinations at 15, 30, and 45 minutes using a Microtox (Vibrio fischeri) protocol that included testing seven duplicated concentrations for each single agent and mixture per combination. Additionally, in chemico reactivity was determined for each compound using thiol in glutathione as a model nucleophile. The model NPN alone lacked reactivity and TDT. The SN2-reactive agents individually showed varying levels of both reactivity and TDT alone, while the SNAr-reactive chemicals alone were reactive and had toxicity that was fully time-dependent between 15 and 45 minutes of exposure. Data analyses indicated that the sham combination was dose additive, as expected, whereas three of four SN2:NPN combinations showed effects close to that predicted for dose addition but with some differences. The fourth SN2:NPN combination, which included an alpha-halogen with full TDT, showed a less-than-dose-additive combined effect as did both of the SNAr:NPN pairings. By incorporating TDT values, shapes of the dose-response curves, chemical reactivity data with thiol, reactive mechanisms for the soft electrophiles, and quantitative structure activity relationship information on whether the toxicity of the individual soft electrophiles did or did not exceeded that predicted for baseline narcosis, the results suggested that the alpha-halogens elicited two toxic effects at the concentrations tested (reactivity and narcotizing effects), whereas toxicity induced by the halogenated dinitrobenzenes was essentially limited to reactive effects. Collectively, these results provide experimental evidence consistent with previous explanations as to why binary mixtures of industrial organic chemicals often show combined effects that are close to dose additive, even when the chemicals are thought to induce toxicity at different molecular sites of action.

Screening for high- and moderate-risk drinking during pregnancy: a comparison of several TWEAK-based screeners.

PURPOSE: This study investigated the use of the TWEAK and nine alternative screeners for predicting high-risk and moderate-risk drinking during pregnancy. METHOD: The analysis was based on self-reports from 404 lifetime drinkers who presented for an initial visit at nine prenatal clinics in Washington, DC. Data were collected anonymously by having women directly enter their responses onto an audio, computer-assisted interview that was programmed onto a laptop computer. Pregnancy risk drinking status was based on both average daily volume of intake and frequency of drinking 3+ drinks in a day. Each of the alternative screeners was constructed by adding one additional risk indicator to the TWEAK, and three different scoring options were explored. RESULTS: Using thresholds of 2 points for high-risk drinking and 1 point for moderate-risk drinking, the TWEAK demonstrated a sensitivity and specificity of 70.6% and 73.2% for high-risk drinking and a sensitivity and specificity of 65.6% and 63.7% for any (high- or moderate-) risk drinking during pregnancy. None of the alternative screeners resulted in significant improvement, but the addition of current smoking status showed enough promise to warrant further testing in larger samples. CONCLUSIONS: Despite some loss in sensitivity and specificity, the TWEAK, in its original or a modified form, can be extended to measures of high-risk drinking that incorporate infrequent heavy intake and can be used to test for moderate- as well as high-risk drinking. Because identification of moderate-risk drinkers substantially increases the pool of women targeted for intervention, cost implications must be considered in designing appropriate interventions.

A comparative assessment of the efficacy and side-effect liability of neuroprotective compounds in experimental stroke.

There are many examples of compounds showing neuroprotective efficacy in animal models of stroke but not in clinical trials. It is possible that some or all of these compounds possess poor therapeutic ratios, which results in the administration of sub-efficacious doses in order to avoid the emergence of side-effects. In order to explore this possibility, this study compared the therapeutic ratios of a number of neuroprotective agents that have undergone clinical trials. Neuroprotective efficacy was established using the mouse permanent (24 h) middle cerebral artery occlusion model. Side-effect liability was determined by assessment of motor coordination using the rotarod test. The therapeutic ratio was calculated as the ratio between the minimum effective dose (MED) for significant impairment in rotarod performance and the MED for significant neuroprotection. Compounds were administered i.p. 30 min prior to rotarod testing or onset of ischemia. Drugs such as Ifenprodil, Cerestat and Selfotel, that have failed in clinical trials, were found to have very low therapeutic ratios of < or = 1, whereas compounds with more tolerable clinical side-effect profiles were found to have higher therapeutic ratios (2, 10 and 10 for Sipatrigine, Remacemide and sPBN, respectively). It is concluded that the lack of efficacy of a number of neuroprotectants in clinical trials may well be a consequence of their poor therapeutic ratios.

Alcohol and mortality from external causes.

OBJECTIVE: The aim of this study was to examine the relationship between alcohol consumption, considering both volume of intake and drinking pattern, and the risk of death from external causes. METHOD: A prospective study of mortality from external causes was conducted using data from the 1988 National Health Interview Survey linked with the National Death Index for 1988 through 1995. During the 7.5-year follow-up interval, there were 155 deaths from external causes among the 42,910 adults 18 years of age and over included in the sample. Proportional hazards models were used to adjust for censoring due to competing causes of death and for the effects of potentially confounding background variables including age, gender, marital status, education, smoking and poor health at baseline. RESULTS: Relative to lifetime abstainers and infrequent drinkers, the risk of death from external causes increased directly with volume of intake, exhibiting a logarithmic-shaped risk curve. There was no evidence of reduced risk among light or moderate drinkers. When usual quantity and frequency were examined, the only drinkers at significantly increased risk were those who drank less than once a month but usually drank 5+ drinks (or, to a lesser extent, 3+ drinks) and those who drank at least twice a week and usually drank 2+ drinks. Former drinkers also were at increased risk. Age strongly affected the drinking pattern parameters. CONCLUSIONS: Quantity and frequency of drinking are proxies for in-the-event risks associated with alcohol intake and their cumulative effect on mortality risk. The results are discussed with particular attention to the role of factors that may affect the association between usual quantity of drinks consumed and the in-the-event risk of mortality from external causes.

Analysis of the combined osteolathyritic effects of beta-aminopropionitrile and diethyldithiocarbamate on xenopus development.

In order to examine the mechanistic basis between combined effects and mechanisms of action, two osteolathyrogens, beta-aminopropionitrile (betaAPN) and diethyldithiocarbamate (DTC), were tested together on Xenopus embryos. In a separate test, DTC was also tested with copper sulfate to determine the importance of copper in DTC-induced osteolathyrism. Frog embryos (Xenopus laevis) were exposed for 96 h, with daily solution removal and replacement. Preserved tadpoles were evaluated for osteolathyritic lesions. For the betaAPN:DTC test, a 1.2-factor matrix design was used, producing two single chemical and seven mixture-response curves. The chi(2) goodness-of-fit test was used to compare the experimental mixture-response curves with theoretical effects for two combined effects models, dose-addition and independence. All seven mixture curves were consistent with expected results for dose-addition, but the correlations were generally not high. For the DTC:copper test, the three mixture-response curves generated showed that added copper increased the DTC-alone EC(50), but there was no corresponding right shift at the top of the response curves, as observed previously with betaAPN and copper. In the betaAPN:DTC and DTC:copper tests, DTC alone showed a biphasic concentration-osteolathyrism curve, and the slope of the response curve for DTC alone in each test was statistically different than the slope for the betaAPN alone response curve. Taken together, the results suggest the potential for a second osteolathyritic effect of DTC that affected the combined toxicity enough to produce a dose-addition correlation without the chemicals necessarily having the same mechanism.