Epigenetic Effects in HPA Axis Genes Associated with Cortical Thickness, ERP Components and SUD Outcome.

Association between familial loading for alcohol use disorders (AUD) and event-related potentials (ERPs) suggests a genetic basis for these oscillations though much less is known about epigenetic pathways influenced by environmental variation. Early life adversity (ELA) influences negative outcomes much later in life. The stress-activated neuropeptide corticotropin-releasing hormone (CRH) contributes to the deleterious effects of ELA on brain structure and function in animals. Accordingly, we hypothesized that ELA would be related to cortical thickness and electrophysiological characteristics through an epigenetic effect on CRH receptor type-1 (CRHR1) methylation. A total of 217 adolescent and young adult participants from either multiplex alcohol dependence or control families were scanned using magnetic resonance imaging (MRI) at 3T and cortical thickness was determined. Longitudinal follow-up across childhood, adolescence, and young adulthood provided developmental ERP data and measures of adversity. Blood samples for genetic and epigenetic analyses were obtained in childhood. Cortical thickness and visual ERP components were analyzed for their association and tested for familial risk group differences. Visual P300 amplitude at Pz and cortical thickness of the left lateral orbitofrontal region (LOFC), were significantly related to risk group status. LOFC cortical thickness showed a negative correlation with CRHR1 methylation status and with childhood total stress scores from the Life Stressors and Social Resources Inventory (LISRES). Stress scores were also significantly related to P300 amplitude recorded in childhood. The present results suggest that early life adversity reflected in greater total LISRES stress scores in childhood can impact the methylation of the CRHR1 gene with implications for brain development as seen in cortical thickness and electrophysiological signals emanating from particular brain regions.

Factors influencing COVID-19 Infection in older individuals: History of Alcohol Use Disorder, Major Depressive illness, genetic variation and current use of alcohol.

Introduction: The Coronavirus Disease 2019 (COVID-19) pandemic continues to be a major public health problem. Vulnerable populations include older individuals with presumed weakening of the immune response. Identification of factors influencing COVID-19 infection could provide an additional means for protecting such individuals. Methods: Members of a family study previously interviewed as middle aged individuals were re-contacted and asked to participate in extended phone interview (2-3 hours) covering past and current mental health issues, physical health diagnoses, use of alcohol and drugs, and exposure to anyone with COVID-19. The average follow-up period was 32 years. Detailed medication use was collected to confirm medical diagnoses and to reveal possible protective effects of particular drug classes currently prescribed for the participant by their physician. Serology was available for red cell antigens (ABO, Kell, Duffy, Kidd, Rhesus) and HLA subtypes. Analyses were conducted to contrast COVID-19 + and COVID-19 - individuals for physical and mental health diagnoses, use of alcohol and drugs, and red cell and HLA serology. Additionally, analyses were conducted to contrast these groups with a group reporting known exposure but absence of COVID-19 symptoms or diagnosis by a health professional. Results: Interviews were completed between September 2020 and November 2021. A total of 42 of the 90 individuals interviewed had been vaccinated at the time of interview. At the time of interview, 11.1% reported having developed COVID-19.Using quantity per occasion (QPO) and quantity by frequency (QXF) totals in the past month by type of alcohol consumed, we found a significant association between QPO for liquor (p=0.017) and marginal effects for QXF for liquor consumption (p=0.06). Exposed individuals who were COVID-19 negative tended to drink more liquor than those who were positive, an average of about one drink per day. Beer and wine consumption were not statistically significant. A diagnosis of alcohol use disorder at baseline evaluation was not a significant predictor of being COVID positive or negative.Self-reported current depression or depression in the past only was not a predictor of COVID-19 status based on a single question "Are you depressed currently or only in the past?". In contrast, completion of a clinical interview designed to elicit depressed mood and concurrent symptoms for determination of the lifetime presence or absence of a depressive episode did reveal a significant effect. Comparison of responses at baseline to follow-up showed those most resilient to developing COVID-19 were those without evidence of a depressive episode by lifetime history at both points in time.Physical health issues were analyzed for those that were frequently occurring in our sample such as hypertension but not found to be significant. BMI was analyzed and found to be statistically non-significant.Analysis of HLA variation across the whole sample did not reveal a significant association but among males two variants, A1 and B8, did show significant variation associated with COVID-19+ and COVID-19- status. Analyses of the red cell antigens revealed one significant red cell effect; Kidd genotypic variation was associated with COVID-19 status. Interpretation: We tentatively conclude that use of specific types of alcohol, namely liquor, is associated with reduced frequency of COVID-19. However, the amount is low, averaging about 1 drink per day. Enlarged samples are needed to confirm these results. The finding that past history of alcohol use disorder does not increase likelihood of developing COVID-19 is important. It should be noted that the 34 individuals diagnosed with AUD at baseline had survived an average of 32 years in order to participate in the current interview suggesting they may be especially resilient to adverse health conditions. The finding that a single question designed to elicit the presence or absence of depressed mood either currently or in the past was not a risk factor for COVID-19 in contrast to report of a clinically significant past history of a depressive episode based on more extensive examination using DSM criteria is important. Results for the KIDD blood group are novel and warrant further investigation.

Optical and mechanical factors in the temporal development of tooth-composite bond.

OBJECTIVES: To obtain an accurate picture of the temporal development of bond strength between resin composites and tooth structures during cure for assessing debonding at the tooth-composite interface. METHODS: An assembly of uncured composite sandwiched between a glass block and a dentin slab with a layer of pre-cured adhesive was used in this study. A conventional composite was compared against a bulk-fill composite. The rate of bond formation was determined by measuring the tensile bond strength of specimens of different thicknesses at different time points during cure. The changing light irradiance exiting the composite as it cured was also recorded. Mode of fracture was analyzed by examining the fracture surfaces. RESULTS: Photo-bleaching occurred in both resin composites. The development of the dentin-composite bond strength was initially dictated by the developing cohesive strength of the resin composite, and its final value was capped by the strength of the preformed dentin-adhesive bond. The higher interfacial irradiance in the bulk-fill composite did not lead to faster development of the overall bond strength. This was caused by its slower rate of cohesive strength development as reflected in the longer time for its interfacial irradiance to plateau and the greater proportion of cohesive failure seen in the initial stage of polymerization. The law of reciprocity did not hold for the development of dentin bond strength. SIGNIFICANCE: The results from this study, when compared with the development of shrinkage stress, can be used as a basis for ensuring the integrity of the dentin-composite interface during cure.

Accuracy of self-reported hypertension: Effect of age, gender, and history of alcohol dependence.

Patient awareness of medical conditions may influence treatment seeking and monitoring of these conditions. Accurate awareness of hypertension reported to clinicians evaluating patients for whom clinical history is limited, such as in emergency care, can aid in diagnosis by revealing whether measured hypertension is typical or atypical. Measurement of blood pressure in a laboratory study was assessed at rest, immediately before phlebotomy, and within 10 minutes after. The resting measure was used to determine the accuracy of self-reported hypertension in 283 adults. Parametric analyses were conducted to identify potential variables influencing accuracy of self-reported hypertension. Sensitivity, specificity, and the kappa coefficient of agreement were calculated to determine the influence of alcohol dependence (AD), sex, age, and cigarette smoking on hypertension awareness. Self-report was mildly sensitive, correctly identifying individuals with hypertension in approximately 37% of the cases, but was highly specific (95%) in identifying individuals without hypertension. Similar sensitivities were found in analyses separated by sex. Sensitivity was greater in those over age 55 (53%) in comparison with those <54, as well as in those who were not smoking. Comparison of those with and without a history of AD revealed that both groups show similar accuracy in reporting hypertension. Absence of hypertension can be accurately determined with self-report data in those without hypertension. A significant proportion of those with measured hypertension report an absence of hypertension.

Influence of curing modes on the degree of conversion and mechanical parameters of dual-cured luting agents.

PURPOSE: To investigate the effects of different curing modes, including tack cure, on the degree of conversion (DC) and mechanical parameters of dual-cured luting agents for all-ceramic restorations. METHODS: Immediate light curing, intermittent light curing (2-s tack cure and a 1-min interval before the main cure), delayed light cuing (2-min delay) and chemical or no light curing were used to cure two dual-cured luting agents, RelyX Unicem and PermaCem 2.0, through a 1.5-mm thick lithium disilicate ceramic slide. DC (n=3), micro-hardness (n=5), shrinkage strain (n=4) and shrinkage stress (n=3) were measured under the aforementioned curing modes. The data were analyzed using two-way ANOVA and post-hoc Tukey HSD test, with the level of significance set at α=0.05. RESULTS: For both luting agents, all the light-curing modes produced similar final DC, but using chemical cure only could significantly reduce the DC. The mechanical parameters followed a similar pattern. There were positive but nonlinear correlations between DC and the other mechanical parameters, with the increase in these parameters with DC being slower initially. CONCLUSIONS: Provided adequate light curing is applied to a dual-cured luting agent, delaying the light curing or using a tack cure first to facilitate seating of a restoration may not have a significant impact on the luting agent's final degree of conversion. However, using chemical cure only may result in inadequate cure of the luting agent and is recommended only for highly opaque restorations.

Effects of Molecular Weight and Concentration of Poly(Acrylic Acid) on Biomimetic Mineralization of Collagen.

Inspired by nature, poly(acrylic acid) (PAA) and other polyelectrolytes have been used as noncollagenous proteins (NCPs) surrogates for biomimetic intrafibrillar mineralization of collagen fibrils and thus, to model the ultrastructure of bone, to study the mechanism of bone mineralization and, more scarcely to fabricate scaffolds for hard tissue engineering. The objective of this study was to systematically investigate the effect of the molecular weight (MW) and the concentration of PAA on the rate and pattern of biomineralization of collagen matrices. Densified type I collagen films were mineralized in supersaturated PAA-stabilized amorphous calcium-phosphate (PAA-ACP) solutions containing increasing MW (2 kDa, 50 kDA, 450 kDa) and concentrations (10, 25, 50 mg/L) of PAA up to 7 days. The stability and physical properties of collagen-free PAA-ACP solutions were also investigated. In our system, lowering PAA MW and increasing PAA concentration resulted in solutions with increasing stability. Over stable PAA-ACP solutions that fully inhibited mineralization of the collagen matrices were achieved using PAA 2k-50. Conversely, unstable solutions were obtained using high PAA MW at low concentrations. Nucleation and growth of significant amount of extrafibrillar minerals on the collagen fibrils was obtained using these solutions. In a wide range of combined MW and concentration of PAA we obtained intrafibrillar mineralization of collagen with hydroxyapatite crystals aligned parallel to the collagen fibril as in natural tissues. Intrafibrillar mineralization was correlated with PAA-ACP stability and growth of the PAA-ACP particles in solution. Our results support using PAA to surrogate NCPs function as selective inhibitors or promoters of biological mineralization and provide parameters to manufacture new biomimetic scaffolds and constructs for bone and dentin tissue engineering.

Determining the temporal development of dentin-composite bond strength during curing.

OBJECTIVES: As composite restorations cure a competition develops between bond formation and shrinkage stress at the composite-dentin interface. Thus, understanding the temporal development of tooth-composite bond strength should enable better assessment of tooth-composite debonding. METHODS: In this study, bond strengths of composite-dentin specimens obtained from tensile test at different curing times were used to determine the bond formation rate. By varying the composite thickness and output from the curing light, their effects on the rate of bond formation for two different materials (a conventional and a bulk-fill composite) were also investigated. The proportions of cohesive and adhesive failure were determined by analysis of electron micrographs of the fractured surfaces. RESULTS: The development of dentin-composite bond strength (S) with time (t) can be described by the equation: S=Smax(1-exp(-αt)), where Smax is the final bond strength (∼12MPa for both composites) and α the rate of bond formation. Using bulk-fill and thinner specimens gave faster bond formation. In fact, the higher the irradiance at the interface, the higher the rate of bond formation. However, α had a maximum value of ∼0.6s(-1) and the rule of reciprocity did not hold. A minimum dose of ∼2J/cm(2) was required to achieve adequate bond strength. The predominant failure mode changed from cohesive in the composite and adhesive to interfacial at the adhesive-dentin interface, indicating the latter to be the weakest link in the cured dentin-composite assemblies considered. SIGNIFICANCE: When combined with the temporal development of shrinkage stress, the current results will help determine the likelihood of tooth-composite debonding.

Familial risk for alcohol dependence and developmental changes in BMI: the moderating influence of addiction and obesity genes.

AIM: Familial loading for alcohol dependence (AD) and variation in genes reported to be associated with AD or BMI were tested in a longitudinal study. MATERIALS & METHODS: Growth curve analyses of BMI data collected at approximately yearly intervals and obesity status (BMI > 30) were examined. RESULTS: High-risk males were found to have higher BMI than low-risk males, beginning at age 15 years (2.0 kg/m(2) difference; p = 0.046), persisting through age 19 years (3.3 kg/m(2) difference; p = 0.005). CHRM2 genotypic variance predicted longitudinal BMI and obesity status. Interactions with risk status and sex were also observed for DRD2 and FTO gene variation. CONCLUSION: Variation at loci implicated in addiction may be influential in determining susceptibility to increased BMI in childhood and adolescence.

Cholinergic receptor gene (CHRM2) variation and familial loading for alcohol dependence predict childhood developmental trajectories of P300.

P300 amplitude in childhood predicts substance use disorders by young adulthood. Trajectories of visual P300 amplitude show an association between low amplitude P300 and familial risk for alcohol dependence (AD). Variation in the cholinergic muscarinic receptor gene (CHRM2) has previously been associated with P300 amplitude and AD. The present study used group based trajectory modeling of auditory P300 data collected longitudinally from offspring in families with and without familial loading for AD to determine if specific trajectories would be associated with familial risk and CHRM2 variation. Trajectory modeling confirms previous reports of an association between the low visual P300 trajectory with high familial risk in male offspring. This association was detected in offspring in the 8-12 age range, but not in 13-18 or 19-29 year olds or in high-risk female offspring. CHRM2 association analysis with P300 finds 8-12 year olds who are homozygous for the T allele of rs1824024 are 2.6 times more likely to follow a P300 trajectory characterized by lower and slower change regardless of familial loading. Combining the odds for being male and having a TT genotype results in odds of 6.5 that individuals will follow the low P300 trajectory.

Cerebellum volume in high-risk offspring from multiplex alcohol dependence families: association with allelic variation in GABRA2 and BDNF.

Offspring from families with multiple cases of alcohol dependence have a greater likelihood of developing alcohol dependence (AD) and related substance use disorders. Greater susceptibility for developing these disorders may be related to structural differences in brain circuits that influence the salience of rewards or modify the efficiency of information processing and AD susceptibility. We examined the cerebellum of 71 adolescent/young adult high-risk (HR) offspring from families with multiple cases of alcohol dependence (multiplex families), and 60 low-risk (LR) controls with no family history of alcohol or drug dependence who were matched for age, gender, socioeconomic status and IQ, with attention given to possible effects of personal use of substances and maternal use during pregnancy. Magnetic resonance images were acquired on a General Electric 1.5-Tesla scanner and manually traced (BRAINS2) blind to clinical information. GABRA2 and BDNF variation were tested for their association with cerebellar volumes. High-risk offspring from multiplex AD families showed greater total volume of the cerebellum and total gray matter (GM), in comparison with LR controls. An interaction between allelic variation in GABRA2 and BDNF genes was associated with GM volumes, suggesting that inherited variation in these genes may promote early developmental differences in neuronal proliferation of the cerebellum.

Disruption of orbitofrontal cortex laterality in offspring from multiplex alcohol dependence families.

BACKGROUND: Increased susceptibility for developing alcohol dependence (AD) might be related to structural differences in brain circuits that influence the salience of rewards and/or modify the efficiency of information processing. The role of the orbitofrontal cortex (OFC) in regulating emotional processing is increasingly being recognized along with its association with impulsive behavior. METHODS: Magnetic resonance imaging was used to measure the OFC in 107 high- and low-risk offspring (mean age 17.6 +/- 4.69 years) from either multiplex AD families or control families. Region of interest measures including segmented values were obtained by reliable raters using BRAINS2 software. Statistical analyses were adjusted for intracranial volume, age, socioeconomic status (SES), IQ, and handedness. The Multidimensional Personality Questionnaire (MPQ) was administered to determine scale scores for Control. Genotyping was performed for the serotonin transporter (5-HTT) gene and the brain-derived neurotrophic factor (BDNF) gene. RESULTS: High-risk offspring from multiplex for AD families showed decreased right/left OFC volumes in comparison with control subjects. Smaller volume in the right hemisphere was significantly associated with variation in the 5-HTT and BDNF genes. White matter (WM) ratios showed a positive correlation with MPQ Control scale scores, indicating that reduced OFC WM is related to greater impulsivity. CONCLUSIONS: Offspring from multiplex families for AD manifest genetic susceptibility by exhibiting disruption in the laterality of the OFC volume that is related to greater impulsivity (lower Control scale scores). This disruption in OFC laterality is related to variation in genes associated with neuronal growth.

fMRI BOLD response to the eyes task in offspring from multiplex alcohol dependence families.

BACKGROUND: Increased susceptibility for developing alcohol dependence (AD) may be related to structural and functional differences in brain circuits that influence social cognition and more specifically, theory of mind (ToM). Alcohol dependent individuals have a greater likelihood of having deficits in social skills and greater social alienation. These characteristics may be related to inherited differences in the neuroanatomical network that comprises the social brain. METHODS: Adolescent/young adult participants from multiplex AD families and controls (n = 16) were matched for gender, age, IQ, education, and handedness and administered the Eyes Task of Baron-Cohen during functional magnetic resonance imaging (fMRI). RESULTS: High-risk (HR) subjects showed significantly diminished blood oxygen level dependent (BOLD) response in comparison with low-risk control young adults in the right middle temporal gyrus (RMTG) and the left inferior frontal gyrus (LIFG), areas that have previously been implicated in ToM tasks. CONCLUSIONS: Offspring from multiplex families for AD may manifest one aspect of their genetic susceptibility by having a diminished BOLD response in brain regions associated with performance of ToM tasks. These results suggest that those at risk for developing AD may have reduced ability to empathize with others' state of mind, possibly resulting in diminished social skill.

No evidence of persistent Yersina pestis infection at prairie dog colonies in north-central Montana.

Sylvatic plague is a flea-borne zoonotic disease caused by the bacterium Yersinia pestis, which can cause extensive mortality among prairie dogs (Cynomys) in western North America. It is unclear whether the plague organism persists locally among resistant host species or elsewhere following epizootics. From June to August 2002 and 2003 we collected blood and flea samples from small mammals at prairie dog colonies with a history of plague, at prairie dog colonies with no history of plague, and from off-colony sites where plague history was unknown. Blood was screened for antibody to Y. pestis by means of enzyme-linked immunosorbent assay or passive hemagglutination assay and fleas were screened for Y. pestis DNA by polymerase chain reaction. All material was negative for Y. pestis including 156 blood samples and 553 fleas from colonies with a known history of plague. This and other studies provide evidence that Y. pestis may not persist at prairie dog colonies following an epizootic.

An application of nanotechnology in advanced dental materials.

BACKGROUND: This article reports the authors' development of nanofillers and a resulting nanocomposite. They measured the nanocomposite's properties in vitro in comparison with those of several existing composites (hybrids, microhybrids and microfill). METHODS: The authors developed two types of nanofillers: nanomeric particles and nanoclusters. They used optimal combinations of these nanofillers in a proprietary resin matrix to prepare the nanocomposite system with a wide range of shades and opacities. The properties they studied were compressive, diametral tensile and flexural strengths; in vitro three-body wear; fracture resistance; polish retention; and surface morphology after toothbrush abrasion. They performed statistical analysis using analysis of variance/Tukey-Kramer paired analysis at a 95 percent confidence interval. RESULTS: The compressive and diametral strengths and the fracture resistance of the nanocomposite were equivalent to or higher than those of the other commercial composites tested. The three-body wear results of the nanocomposite system were statistically better than those of all other composites tested. The nanocomposite showed better polish retention than the hybrids and microhybrids tested at the extended brushing periods. After extended toothbrush abrasion, the dentin, body and enamel shades showed polish retention equivalent to that of the microfill tested, while translucent shades showed better polish retention than the microfill. CONCLUSIONS: The dental nanocomposite system studied showed high translucency, high polish and polish retention similar to those of microfills while maintaining physical properties and wear resistance equivalent to those of several hybrid composites. CLINICAL IMPLICATIONS: The strength and esthetic properties of the resin-based nanocomposite tested should allow the clinician to use it for both anterior and posterior restorations.

1,2,4,5-tetrakis(2-vinylpyridyl)-benzene-dichloromethane (1/2).

The title compound, C(34)H(26)N(4) x 2CH(2)Cl(2), lies about an inversion center. The solvent molecules interact with the benzene molecule both through C-H...N hydrogen bonding to span pyridine N atoms of adjacent vinyl groups, possibly stabilizing the rotational conformation observed, and through a pi interaction between a dichloromethane Cl atom and a pyridyl ring C-C bond of a c-glide-related molecule. The benzene molecules form stacks along the a axis such that two of the four olefin groups are properly oriented for photoreactivity (2+2 cyclodimerization).

2,6-Diiodopyridine.

The title compound, C(5)H(3)I(2)N, crystallizes in the polar space group Fmm2, with crystallographic mm2 symmetry imposed on the molecule. Molecules are linked through C-H...N hydrogen bonding to form chains which are, in turn, joined through weak I...I halogen-bonding interactions to form layers. The pyridine ring lies parallel to the polar z axis and has the N atom pointing in the +z direction. The layers stack in a polar fashion normal to the a axis and the absolute structure has been determined.