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Transurothelial drug delivery continues to be an attractive treatment option for a range of urological conditions; however, dosing regimens remain largely empirical. Recently, intravesical delivery of the nonsteroidal anti-inflammatory ketorolac has been shown to significantly reduce ureteral stent-related pain. While this latest development provides an opportunity for advancing the management of stent-related pain, clinical translation will undoubtedly require an understanding of the rate and extent of delivery of ketorolac into the bladder wall. Using an ex vivo porcine model, we evaluate the urothelial permeability and bladder wall distribution of ketorolac. The subsequent application of a pharmacokinetic (PK) model enables prediction of concentrations achieved in vivo. Ketorolac was applied to the urothelium and a transurothelial permeability coefficient (Kp) calculated. Relative drug distribution into the bladder wall after 90 min was determined. Ketorolac was able to permeate the urothelium (Kp = 2.63 × 10(-6) cm s(-1)), and after 90 min average concentrations of 400, 141 and 21 μg g(-1) were achieved in the urothelium, lamina propria and detrusor respectively. An average concentration of 87 μg g(-1) was achieved across the whole bladder wall. PK simulations (STELLA) were then carried out, using ex vivo values for Kp and muscle/saline partition coefficient (providing an estimation of vascular clearance), to predict 90 min in vivo ketorolac tissue concentrations. When dilution of the drug solution with urine and vascular clearance were taken into account, a reduced ketorolac concentration of 37 μg g(-1) across the whole bladder wall was predicted. These studies reveal crucial information about the urothelium's permeability to agents such as ketorolac and the concentrations achievable in the bladder wall. It would appear that levels of ketorolac delivered to the bladder wall intravesically would be sufficient to provide an anti-inflammatory effect. The combination of such ex vivo data and PK modeling provides an insight into the likelihood of achieving clinically relevant concentrations of drug following intravesical administration.

Objective: Pediatric psychologists are often interested in finding patterns in heterogeneous longitudinal data. Latent variable mixture modeling is an emerging statistical approach that models such heterogeneity by classifying individuals into unobserved groupings (latent classes) with similar (more homogenous) patterns. The purpose of the second of a 2-article set is to offer a nontechnical introduction to longitudinal latent variable mixture modeling., Methods: 3 latent variable approaches to modeling longitudinal data are reviewed and distinguished., Results: Step-by-step pediatric psychology examples of latent growth curve modeling, latent class growth analysis, and growth mixture modeling are provided using the Early Childhood Longitudinal Study-Kindergarten Class of 1998-1999 data file., Conclusions: Latent variable mixture modeling is a technique that is useful to pediatric psychologists who wish to find groupings of individuals who share similar longitudinal data patterns to determine the extent to which these patterns may relate to variables of interest.

Objective: Pediatric psychologists are often interested in finding patterns in heterogeneous cross-sectional data. Latent variable mixture modeling is an emerging person-centered statistical approach that models heterogeneity by classifying individuals into unobserved groupings (latent classes) with similar (more homogenous) patterns. The purpose of this article is to offer a nontechnical introduction to cross-sectional mixture modeling., Method: An overview of latent variable mixture modeling is provided and 2 cross-sectional examples are reviewed and distinguished., Results: Step-by-step pediatric psychology examples of latent class and latent profile analyses are provided using the Early Childhood Longitudinal Study-Kindergarten Class of 1998-1999 data file., Conclusions: Latent variable mixture modeling is a technique that is useful to pediatric psychologists who wish to find groupings of individuals who share similar data patterns to determine the extent to which these patterns may relate to variables of interest.

E. coli O111 strains are responsible for outbreaks of blood diarrhea and hemolytic uremic syndrome throughout the world. Because of their phenotypic variability, the development of a vaccine against these strains which targets an antigen that is common to all of them is quite a challenge. Previous results have indicated, however, that O111 LPS is such a candidate, but its toxicity makes LPS forbidden for human use. To overcome this problem, O111 polysaccharides were conjugated either to cytochrome C or to EtxB (a recombinant B subunit of LT) as carrier proteins. The O111-cytochrome C conjugate was incorporated in silica SBA-15 nanoparticles and administered subcutaneously in rabbits, while the O111-EtxB conjugate was incorporated in Vaxcine(TM), an oil-based delivery system, and administered orally in mice. The results showed that one year post-vaccination, the conjugate incorporated in silica SBA-15 generated antibodies in rabbits able to inhibit the adhesion of all categories of O111 E. coli to epithelial cells. Importantly, mice immunized orally with the O111-EtxB conjugate in Vaxcine(TM) generated systemic and mucosal humoral responses against all categories of O111 E. coli as well as antibodies able to inhibit the toxic effect of LT in vitro. In summary, the results obtained by using 2 different approaches indicate that a vaccine that targets the O111 antigen has the potential to prevent diarrhea induced by O111 E. coli strains regardless their mechanism of virulence. They also suggest that a conjugated vaccine that uses EtxB as a carrier protein has potential to combat diarrhea induced by ETEC.

The polysaccharides (PS) surrounding encapsulated bacteria are generally unable to activate T cells and hence do not induce B cell memory (BMEM). PS conjugate vaccines recruit CD4(+) T cells via a carrier protein, such as tetanus toxoid (TT), resulting in the induction of PS-specific BMEM. However, the requirement for T cells in the subsequent activation of the BMEM at the time of bacterial encounter is poorly understood, despite having critical implications for protection. We demonstrate that the PS-specific BMEM induced in humans by a meningococcal serogroup C PS (Men C)-TT conjugate vaccine conform to the isotype-switched (IgG(+)CD27(+)) rather than the IgM memory (IgM(+)CD27(+)) phenotype. Both Men C and TT-specific BMEM require CD4(+) T cells to differentiate into plasma cells. However, noncognate bystander T cells provide such signals to PS-specific BMEM with comparable effect to the cognate T cells available to TT-specific BMEM. The interaction between the two populations is contact-dependent and is mediated in part through CD40. Meningococci drive the differentiation of the Men C-specific BMEM through the activation of bystander T cells by bacterial proteins, although these signals are enhanced by T cell-independent innate signals. An effect of the TT-specific T cells activated by the vaccine on unrelated BMEM in vivo is also demonstrated. These data highlight that any protection conferred by PS-specific BMEM at the time of bacterial encounter will depend on the effectiveness with which bacterial proteins are able to activate bystander T cells. Priming for T cell memory against bacterial proteins through their inclusion in vaccine preparations must continue to be pursued.

Pneumococcal disease is associated with a particularly high morbidity and mortality amongst adults in HIV endemic countries. Our previous findings implicating a B-cell defect in HIV-infected children from the same population led us to comprehensively characterize B-cell subsets in minimally symptomatic HIV-infected Malawian adults and investigate the isotype-switched IgG memory B-cell immune response to the pneumococcus. We show that similar to vertically acquired HIV-infected Malawian children, horizontally acquired HIV infection in these adults is associated with IgM memory B-cell (CD19(+) CD27(+) IgM(+) IgD(+)) depletion, B-cell activation and impairment of specific IgG B-cell memory to a range of pneumococcal proteins. Our data suggest that HIV infection affects both T-cell independent and T-cell dependent B-cell maturation, potentially leading to impairment of humoral responses to extracellular pathogens such as the pneumococcus, and thus leaving this population susceptible to invasive disease.

Objective: To determine whether there is an association between body mass index (BMI) and body esteem in young overweight and obese urban children, and to test peer relationship difficulties and perceived physical health as mediators of this relationship., Methods: Child self-reported body esteem, and parent-reported child peer relationship difficulties (being bullied by peers and peer rejection) and physical health perceptions were obtained from 218 overweight and obese children aged 5-7 years (81% racial/ethnic minority, M BMI = 25.3) and their primary caregivers., Results: Higher BMI was associated with lower body esteem for both girls and boys. This relation was mediated by poor physical health for boys but not for girls. Peer relationship difficulties did not mediate the observed association between BMI and body esteem in either group; however, girls with higher BMI experienced more bullying and being bullied by peers was associated with lower body esteem in girls., Conclusions: Intervening with perceptions of physical health may buffer overweight and obese boys from developing low body esteem in early childhood., (© 2012 John Wiley & Sons Ltd.)

The B subunit of E. coli heat-labile enterotoxin (EtxB) protects against the development of T helper type 1 (Th1)-mediated autoimmune pathologies in mice. Protection was transferable with splenic CD4(+) T cells and was less effective following CD25 depletion; implying a T regulatory cell (Treg)-mediated process. We hypothesized that if this were the case, then EtxB would also control a Th2-mediated disorder. We tested the effect of EtxB treatment on asthma development in ovalbumin (OVA)-sensitized mice. EtxB treatment diminished eosinophilia in bronchoalveolar lavage samples, reduced OVA-specific immunoglobulin E and interleukin 4 production locally and systemically, and reduced airway hyper-reactivity. EtxB induced a dose-dependent increase in Foxp3(+)CD4(+) T cells, and adoptive transfer of splenic CD4(+) T cells partially suppressed lung pathology. Importantly, EtxB treatment increased OVA-specific CD4(+)Foxp3(+) T cells in the lung and systemically. These data demonstrate that EtxB modulates the differentiation of allergen-specific T cells causing inducible Treg induction and preventing disease.

Colonization of the nasopharyngeal mucosa by meningococcus and other polysaccharide (PS)-encapsulated bacteria precedes invasion. PS-conjugate vaccines induce PS-specific B-cell memory (B(MEM)) and also prevent colonization, thus blocking person-to-person transmission, generating herd protection. However, in isolation the B(MEM) are unable to sustain immunity. Furthermore, the duration of herd protection the vaccines induce appears limited. We demonstrate that, despite the persistence of PS-specific B(MEM), the population is not maintained within the nasopharynx. Although booster immunization results in the transient appearance of PS-specific B(MEM) within the mucosa, this reflects the re-circulation of systemic B(MEM) through the site rather than the generation of resident mucosal B(MEM). The induction of sustained PS-specific B(MEM) in the nasopharynx would allow the population to be activated by colonization, thus inhibiting subsequent invasion. It would also be expected to boost local mucosal immunity, thus extending herd protection. Strategies to generate PS-specific B(MEM) in the mucosa warrant further investigation.

Background: African adults infected with human immunodeficiency virus (HIV) have high rates of pneumococcal colonization and invasive disease. Here we have investigated the possibility that HIV disrupts the normal balance of pneumococcal-specific helper T cell (Th) 1/Th17 immunity to colonization, resulting in a more permissive nasopharyngeal niche., Methods: One hundred thirty-six HIV-infected and -uninfected Malawian adults were enrolled in the study. Changes in rates and composition of nasopharyngeal pneumococcal colonization were analyzed using microarray. The underlying pneumococcal-specific Th1/Th17 responses associated with altered pneumococcal colonization were investigated using flow cytometry., Results: We find that pneumococcal carriage is only modestly increased in asymptomatic HIV-infected Malawian adults but that colonization rates rise dramatically during symptomatic disease (HIV(neg) 13%, HIV(asy) 19%, and HIV(sym) 38%). These rates remain high in subjects established on antiretroviral therapy (ART): 33% (at 6-12 months) and 52% (at 18 months), with HIV-infected individuals carrying a broader range of invasive and noninvasive serotypes compared with HIV-negative controls. The frequency of multiple serotype carriage (>1 serotype HIV(neg) 26%, HIV(asy) 30%, HIV(sym) 31%, HIV(ART) 31%) is not affected. These changes in colonization are associated with generalized CD4 T-cell depletion, impaired antigen-specific proliferation, and a defect in pneumococcal-specific T-cell interferon-γ but not interleukin 17 production., Conclusions: These data reveal the persistently poor control of pneumococcal colonization in HIV-infected adults following immune ART-mediated reconstitution, highlighting a potential reservoir for person-to-person spread and vaccine escape. Novel approaches to control colonization either through vaccination or through improvements in the quality of immune reconstitution are required.

There are few effective obesity interventions directed towards younger children, particularly young minority children. This paper describes the design, intervention, recruitment methods, and baseline data of the ongoing Positive Lifestyles for Active Youngsters (Team PLAY) study. This randomized controlled trial is designed to test the efficacy of a 6-month, moderately intense, primary care feasible, family-based behavioral intervention, targeting both young children and their parent, in promoting healthy weight change. Participants are 270 overweight and obese children (ages 4 to 7 years) and their parents, who were recruited from a primarily African American urban population. Parents and children were instructed in proven cognitive behavioral techniques (e.g. goal setting, self-talk, stimulus control and reinforcement) designed to encourage healthier food choices (more whole grains, fruits and vegetables, and less concentrated fats and sugar), reduce portion sizes, decrease sweetened beverages and increase moderate to vigorous physical activity engagement. The main outcome of this study is change in BMI at two year post enrollment. Recruitment using reactive methods (mailings, TV ads, pamphlets) was found to be more successful than using only a proactive approach (referral through physicians). At baseline, most children were very obese with an average BMI z-score of 2.6. Reported intake of fruits and vegetables and minutes of moderate to vigorous physical activity engagement did not meet national recommendations. If efficacious, Team PLAY would offer a model for obesity treatment directed at families with young children that could be tested and translated to both community and primary care settings., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Much of the developing world, particularly sub-Saharan Africa, has high levels of morbidity and mortality associated with infectious diseases. The greatest risk of invasive disease is in the young, the malnourished and HIV-infected individuals. In many regions in Africa these vulnerable groups and the wider general population are under constant immune pressure from a range of environmental factors, under-nutrition and multiple concurrent infections from birth through to adulthood. Intermittent microbial exposure during childhood is required for the generation of naturally acquired immunity capable of protection against a range of infectious diseases in adult life. However, in the context of a resource-poor setting, the heavy burden of malarial, diarrhoeal and respiratory infections in childhood may subvert or suppress immune responses rather than protect, resulting in sub-optimal immunity. This review will explore how poor maternal health, HIV exposure, socio-economic and seasonal factors conspire to weaken childhood immune defences to disease and discuss the hypothesis that recurrent infections may drive immune dysregulation, leading to relative immune senescence and premature immunological aging., (© 2011 The Authors. Immunology © 2011 Blackwell Publishing Ltd.)

Context: To aid translation of childhood obesity interventions evidence into practice, research studies must report results in a way that better supports pragmatic decision making. The current review evaluated the extent to which information on key external validity dimensions, participants, settings, interventions, outcomes, and maintenance of effects, was included in research studies on behavioral treatments for childhood obesity., Evidence Acquisition: Peer-reviewed studies of behavioral childhood obesity treatments published between 1980 and 2008 were identified from (1) electronic searches of social science and medical databases; (2) research reviews of childhood obesity interventions; and (3) reference lists cited in these reviews. Included studies reported on a controlled obesity intervention trial, targeted overweight or obese children aged 2-18 years, included a primary or secondary anthropometric outcome, and targeted change in dietary intake or physical activity behaviors., Evidence Synthesis: 1071 publications were identified and 77 met selection criteria. Studies were coded on established review criteria for external validity elements. All studies lacked full reporting of generalizability elements. Across criteria, the average reporting was 23.9% (range=0%-100%). Infrequently reported were setting-level selection criteria and representativeness, characteristics regarding intervention staff, implementation of the intervention content, costs, and program sustainability., Conclusions: Enhanced reporting of relevant and pragmatic information in behavioral investigations of childhood obesity interventions is needed to improve the ability to evaluate the applicability of results to practice implementation. Such evidence would improve translation of research to practice, provide additional explanation for variability in intervention outcomes, and provide insights into successful adaptations of interventions to local conditions., (Copyright © 2012 American Journal of Preventive Medicine. Published by Elsevier Inc. All rights reserved.)

Background: Seasonal influenza has been associated with greater morbidity and mortality in AIDS patients. Highly-active antiretroviral therapy (HAART) has led to some reduction in influenza-related complications but the nature of naturally-acquired T-cell immunity to influenza virus in an African setting, and how this changes with immune reconstitution following HAART is unknown. We measured influenza-specific CD4(+) T-cell immunity in unimmunized HIV-infected Malawian adults and then investigated immune reconstitution following HAART., Methods: Peripheral blood mononuclear cells were isolated from HIV-infected and HIV-uninfected Malawian adults. CFSE proliferation and CD154 expression flow cytometry-based assays were used to measure influenza-specific CD4(+) T-cell immunity., Results: We found lower naturally-acquired proliferative influenza-specific CD4(+) T-cell responses in AIDS patients that was also present in asymptomatic HIV-infected adults with relatively high CD4 counts (>350 cells/µl). Influenza-specific CD4(+) T-cell immune reconstitution in HIV-infected patients on HAART for 12 months was poor despite a marked reduction in viral load and an increase in CD4 count. This poor immune reconstitution was characterised by a low influenza-specific proliferative CD4(+) T-cell response and reduced proportions of CD154-expressing influenza-specific CD4(+) T-cells in peripheral blood., Conclusion: Our data suggest that asymptomatic HIV-infected adults may also be at risk of influenza-related complications and that HAART alone may not circumvent this risk in AIDS patients. This study highlights the need to identify possible interventions early in HIV infection to reduce the risk of influenza and to intensify influenza surveillance in these susceptible African populations.

Worldwide, invasive pneumococcal disease caused by Streptococcus pneumoniae is most common in young children. In adults, disease rates decline following intermittent colonization and the acquisition of naturally acquired immunity. We characterized mucosal and systemic pneumococcal-specific T-cell responses in African children and adults who contend with intense rates of colonization, up to 100% and 60% respectively. We find most Malawian children have high pneumococcal-specific T-cell responses in tonsil tissue and peripheral blood. In addition, frequent commensalism generates CD25(hi) (Tregs) which modulate mucosal pneumococcal-specific T-cell responses in some children and ≥50% of adults. We propose that immune regulation may prolong pneumococcal colonization and predispose vulnerable individuals to disease.

The upper respiratory tract mucosa is the location for commensal Streptococcus (S.) pneumoniae colonization and therefore represents a major site of contact between host and bacteria. The CD4(+) T cell response to pneumococcus is increasingly recognised as an important mediator of immunity that protects against invasive disease, with data suggesting a critical role for Th17 cells in mucosal clearance. By assessing CD4 T cell proliferative responses we demonstrate age-related sequestration of Th1 and Th17 CD4(+) T cells reactive to pneumococcal protein antigens within mucosal lymphoid tissue. CD25(hi) T cell depletion and utilisation of pneumococcal specific MHCII tetramers revealed the presence of antigen specific Tregs that utilised CTLA-4 and PDL-1 surface molecules to suppress these responses. The balance between mucosal effector and regulatory CD4(+) T cell immunity is likely to be critical to pneumococcal commensalism and the prevention of unwanted pathology associated with carriage. However, if dysregulated, such responses may render the host more susceptible to invasive pneumococcal infection and adversely affect the successful implementation of both polysaccharide-conjugate and novel protein-based pneumococcal vaccines.

Repressive adaptation has been conceptualized as one pathway to psychological resilience in children with cancer, but the physiological costs of maintaining a repressive adaptive style are currently unknown. The goal of this study was to examine physiological functioning as a function of adaptive style in children with cancer (N = 120) and healthy controls (N = 120). Children completed self-report measures of state anxiety and defensiveness prior to participating in three verbal stress tasks while monitoring blood pressure, electrocardiogram, and electrodermal response, and rated their anxiety following each task. Findings indicated no consistent differences in baseline indices and physiological reactivity as a function of adaptive style or health status (cancer vs. control). In addition, children identified as having a repressive adaptive style did not exhibit greater verbal-autonomic discrepancy than low-anxious children. In contrast to findings with adults, children with a repressive adaptive style do not appear to experience adverse effects of this coping style in terms of physiological reactivity.

Understanding the processes by which certain mucosal pathogens and their products induce regulatory T cells (Tregs) is important in determining mechanisms of pathogenicity and may point toward their use in treating immunological disorders. Accordingly, we have studied the events that follow mucosal administration of the B subunit of E. coli heat-labile enterotoxin (EtxB). EtxB modulates the response to co-administered antigens and can prevent autoimmune disease. Our data show that EtxB translocates across the nasal epithelium, modulating the expression of interleukin-10 (IL-10) and transforming growth factor-β(1) (TGF-β(1)). The modulated microenvironment drives an increase in Forkhead box P3 (Foxp3)-positive T cells, predominantly in the CD4(+)CD25(-) subset. Adoptive transfer experiments showed that enhanced Foxp3 expression was particularly evident in recently activated T cells by concomitant unrelated antigen challenge, and was both TGF-β(1) and IL-10 dependent. This ability to alter T-cell differentiation pathways following mucosal delivery explains how EtxB may modify mucosal immune environments and prevent unwanted pathologies.

Objective: Invasive pneumococcal disease (IPD) is a leading cause of morbidity and mortality in HIV-infected African adults. CD4 T cell depletion may partially explain this high disease burden but those with relatively preserved T cell numbers are still at increased risk of IPD. This study evaluated the extent of pneumococcal-specific T cell memory dysfunction in asymptomatic HIV infection early on in the evolution of the disease., Methods: Peripheral blood mononuclear cells were isolated from asymptomatic HIV-infected and HIV-uninfected Malawian adults and stained to characterize the underlying degree of CD4 T cell immune activation, senescence and regulation. Pneumococcal-specific T cell proliferation, IFN-γ, IL-17 production and CD154 expression was assessed using flow cytometry and ELISpot., Results: We find that in asymptomatic HIV-infected Malawian adults, there is considerable immune disruption with an increase in activated and senescent CD4+CD38+PD-1+ and CD4+CD25(high)Foxp3+ Treg cells. In the context of high pneumococcal exposure and therefore immune stimulation, show a failure in pneumococcal-specific memory T cell proliferation, skewing of T cell cytokine production with preservation of interleukin-17 but decreased interferon-gamma responses, and failure of activated T cells to express the co-stimulatory molecule CD154., Conclusion: Asymptomatic HIV-infected Malawian adults show early signs of pneumococcal- specific immune dysregulation with a shift in the balance of CD4 memory, T helper 17 cells and Treg. Together these data offer a mechanistic understanding of how antigen-specific T cell dysfunction occurs prior to T cell depletion and may explain the early susceptibility to IPD in those with relatively preserved CD4 T cell numbers.

According to established theories of attention (e.g., Mackintosh, 1975; Sutherland & Mackintosh, 1971), simple discriminations of the form AX+ BX- result in an increase in attention to stimuli A and B, which are relevant to the outcome that follows them, at the expense of X, which is irrelevant. Experiments that have apparently shown such changes in attention have failed to determine whether attention is enhanced to both A and B, which signal reinforcement and nonreinforcement, respectively, or just to A. In Experiments 1 and 2, pigeons were trained with a number of discriminations of the kind AX+ BX-, before compounds that had been consistently nonreinforced were involved in a subsequent discrimination. Both experiments provided support for theories that propose that more attention is paid to stimuli that consistently signal nonreinforcement than to irrelevant stimuli in simple discriminations.

In many developing countries, populations are under considerable pressure from high bacterial exposure on mucosal surfaces. Immune dysregulation in this setting is multifactorial and is driven by a range of environmental factors, undernutrition and coinfections such as measles, malaria and HIV. Disruption or subversion of respiratory-tract and intestinal epithelial barriers leads to increased invasion by mucosal pathogens and a high frequency of life-threatening bacterial disease. It is our opinion that a process of epithelial barrier dysfunction and immune dysregulation at these mucosal surfaces leads to the much higher rates of pneumonia, meningitis and severe sepsis seen in resource-limited countries., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

Objectives: To assess the relative protective effect of commercial mouthrinses containing 0-450 ppm fluoride on erosion progression in enamel using a simulated 5-day in vitro cycling model with concurrent monitoring of surface microhardness (SMH) and bulk tissue loss., Methods: Specimens were randomly assigned to six treatment groups (n=6). The model mimicked morning and evening use with rinse times (30 or 60 s) reflecting those prescribed on pack, interspersed with three cycles of demineralisation/remineralisation per simulated day. The latter comprised 1.0% citric acid monohydrate pH 3.2 for 300 s, with subsequent remineralisation in mucin-free artificial saliva pH7.0 for 120 min. SMH was determined by Vickers microindentation and bulk tissue loss using white-light interferometry., Results: From the end of day 1, fluoride-containing mouthrinses conferred statistically significant reductions in bulk tissue loss versus fluoride-free rinses (p<0.05), with lesion depth inversely proportional to fluoride concentration. From day 3, the mean lesion depth of specimens treated with the 450 ppm rinse were statistically significantly lower than all comparator treatment groups (p<0.05). Two distinct trends were apparent when comparing SMH changes in groups treated with fluoride-free versus fluoride-containing mouthrinses. In the latter, SMH levelled out over the final three simulated days in contrast to the former whose SMH continued to fall; differences were statistically significant at day 5 (p< 0.05)., Conclusions: Bulk tissue loss is inversely proportional to fluoride concentration in this cycling model. The plateau in SMH reflects stabilisation of mineral density as the study progresses and the number of fluoride binding sites and consequently uptake increases, in turn leading to enhanced lesion remineralisation., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

Neisseria lactamica is a commensal bacteria that colonizes the human upper respiratory tract mucosa during early childhood. In contrast to the closely related opportunistic pathogen Neisseria meningitidis, there is an absence of adaptive cell-mediated immunity to N. lactamica during the peak age of carriage. Instead, outer membrane vesicles derived from N. lactamica mediate a B cell-dependent proliferative response in mucosal mononuclear cells that is associated with the production of polyclonal IgM. We demonstrate in this study that this is a mitogenic human B cell response that occurs independently of T cell help and any other accessory cell population. The ability to drive B cell proliferation is a highly conserved property and is present in N. lactamica strains derived from diverse clonal complexes. CFSE staining of purified human tonsillar B cells demonstrated that naive IgD(+) and CD27(-) B cells are selectively induced to proliferate by outer membrane vesicles, including the innate CD5(+) subset. Neither purified lipooligosaccharide nor PorB from N. lactamica is likely to be responsible for this activity. Prior treatment of B cells with pronase to remove cell-surface Ig or treatment with BCR-specific Abs abrogated the proliferative response to N. lactamica outer membrane vesicles, suggesting that this mitogenic response is dependent upon the BCR.

Objective: To test the measurement equivalence of the Youth Life Orientation Test (YLOT) in children with cancer (N = 199) and healthy controls (N = 108), and to examine optimism and pessimism as predictors of children's health-related quality of life (HRQL)., Methods: Confirmatory factor analysis (CFA) was conducted to establish the two factor structure of the YLOT and to test for metric invariance., Results: A two-factor structure for the YLOT was confirmed and found to be stable across our study groups. There were no differences in mean levels of optimism and pessimism between cancer patients and controls after controlling for race/ethnicity. Higher optimism was associated with lower self-reports of pain and better emotional/behavioral functioning, whereas pessimism was related to poorer mental health and general behavior, and greater impact on the family., Conclusions: Optimism and pessimism appear to be differentially related to certain aspects of children's HRQL, and should be investigated separately in relation to these outcomes.

This article reviews the normal development of sleep in infants, children, and adolescents, with specific focus on both the subjective and objective aspects of sleep. Notably, sleep duration decreases substantially from infancy through adolescence with increased consolidation of sleep to the nighttime period only. Sleep architecture exhibits developmental changes with decreases in slow-wave sleep and increases in stage 2 sleep from childhood through adolescence. Although the development of sleep is a dramatic and relatively rapid process during the first decades of life, changes in sleep continue across the life span.

Metastatic malignant melanoma remains a highly aggressive form of skin cancer for which no reliable methods for treatment exist. Given the increasing incidence of this cancer, considerable attention has focused on the development of new and improved methods for tackling this disease. Within this article, methods for treating melanoma are reviewed and discussed with particular attention focusing on prodrugs that are activated by the tyrosinase enzyme. This enzyme is up-regulated and is of elevated activity within malignant melanomas compared with healthy melanocytes, providing an ideal in-situ tool for the activation of melanoma prodrugs. By way of background to the prodrug strategies discussed within this review, the causes of melanoma, the enzymology of tyrosinase, and the chemistry of the biosynthetic pathways associated with melanogenesis are presented. Aspects of the design, mode of action, and biological profiles of key prodrugs that are activated by tyrosinase, and that show potential for the treatment of melanoma, are then presented and compared.

Background: Streptococcus pneumoniae is a leading cause of vaccine-preventable disease worldwide. Pneumococcal protein antigens are currently under study as components of potential vaccines that offer protection against multiple serotypes. We have therefore characterized T cell pneumococcal immunity acquired through asymptomatic carriage., Methods: Peripheral blood mononuclear cells from 40 healthy Gambian adults were stimulated with supernatants derived from S. pneumoniae strain (D39), 2 isogenic mutant strains lacking either pneumolysin or choline binding protein A, and recombinant pneumolysin. Immune responses were measured by cellular proliferation and by interleukin-10 (IL-10) and interferon-gamma (IFN-gamma) enzyme-linked immunosorbent spot and bioplex cytokine assays. Nasopharyngeal swabs were cultured to determine carriage rates., Results: S. pneumoniae nasopharyngeal carriage was detected in 60% of individuals. Both effector and resting (or central) CD4(+) T cell memory were frequently present to a range of pneumococcal antigens. However, the level of the effector memory response did not relate to current nasopharyngeal carriage. Pneumolysin was not immunodominant in these T cell responses but induced a distinct proinflammatory profile (high IFN-gamma, IL-12[p40], and L-17 levels and low IL-10 and IL-13 levels)., Conclusions: In this population, T cell-mediated immunological memory potentially capable of pathogen clearance and immune surveillance is common but is not associated with the absolute interruption of pneumococcal carriage. How this naturally acquired immune memory influences pneumococcal vaccine efficacy remains to be determined.

Background: Food allergy affects up to 8% of children and is increasingly common. Although adult caregivers initially assume the primary role in children's daily allergy management activities, as children approach school age they assume greater responsibility for the prevention of allergic exposures. The ways that parents prepare children for this transition are likely to influence children's subsequent risk for allergic exposures, yet few studies have examined parent behaviors in the context of pediatric food allergy., Objective: To develop a brief measure to evaluate specific parenting practices related to caring for a child with food allergy., Methods: A total of 292 primary caregivers of food-allergic children completed an Internet-based survey that included the Parenting Children with Food Allergy (PCFA) questionnaire., Results: Factor analysis of the PCFA items suggested 3 factors that accounted for 98% of the variance: autonomy support, protection/monitoring, and emergency education. Internal consistencies for the 3 scales were acceptable (alpha = .79, .73, and .82, respectively). Child age and medical variables (history of emergency epinephrine use, perceived severity of worst allergic reaction, and number of different food allergies) were associated with parenting practices., Conclusion: Although additional psychometric data for the PCFA are needed, preliminary findings suggest that this measure may be useful in evaluating parenting within the context of pediatric food allergy.

Objective: The present study used a case-crossover design to investigate the association of caregiver alcohol consumption and supervision to children's injury occurrence and severity., Method: A community sample of 170 mothers of toddlers was interviewed biweekly about their children's daily injuries for a period of 6 months., Results: Proximal caregiver-reported alcohol use predicted higher likelihood of injury occurrence and higher injury severity, whereas caregiver-reported supervision predicted lower likelihood of injury occurrence and lower injury severity., Conclusion: Even at low levels, proximal caregiver alcohol use may contribute to higher risk for childhood injuries and more severe injuries. The combined effect of supervision and drinking on injury likelihood warrants further exploration.

Despite high carriage rates of Neisseria meningitidis, incidence of meningococcal disease remains low, partially due to development of natural immunity. We have previously demonstrated an inverse relationship between salivary anti-meningococcal IgA and disease incidence, but little is known about the contribution of IgA to immunity at mucosal surfaces. Here we show strong immunoreactivity by human salivary IgA against the meningococcal outer membrane porin, PorA. Monomeric anti-PorA IgA1 (humanized chimeric antibodies) but not IgG increased the association of unencapsulated serogroup B N. meningitidis (H44/76) with Chang (conjunctival) but not with either Detroit (pharyngeal) cells or with A549 (alveolar) epithelial cells. Association of encapsulated N. meningitidis was not increased. Epithelial binding of IgA was Fc fragment dependent and not inhibited by IgM. Together these data suggest the presence of a specific epithelial IgA receptor that could influence the effect of both naturally acquired and vaccine induced IgA antibodies at the epithelial surface.

The importance of T cells in the generation of antigen-specific B-cell immunity has been extensively described, but the role B cells play in shaping T-cell memory is uncertain. In healthy controls, exposure to Neisseria meningitidis in the upper respiratory tract is associated with the generation of memory T cells in the mucosal and systemic compartments. However, we demonstrate that in B cell-deficient subjects with X-linked agammaglobulinemia (XLA), naturally acquired T-cell memory responses to meningococcal antigens are reduced compared with healthy control patients. This difference is not found in T-cell memory to an obligate respiratory pathogen, influenza virus. Accordingly, we show that meningococcal antigens up-regulate major histocompatibility complex (MHC) class II, CD40, CD86/80 expression on mucosal and systemic associated B cells and that antigen presentation stimulates T-cell proliferation. A similar reduction in N meningitidis but not influenza antigen-specific T-cell memory was observed in subjects with X-linked hyper IgM syndrome (X-HIM), implicating the interaction of CD40-CD40L in this process. Together, these data implicate B cells in the induction and maintenance of T-cell memory to mucosal colonizing bacteria such as N meningitidis and highlight the importance of B cells beyond antibody production but as a target for immune reconstitution.

The normal flora that colonizes the mucosal epithelia has evolved diverse strategies to evade, modulate, or suppress the immune system and avoid clearance. Neisseria lactamica and Neisseria meningitidis are closely related obligate inhabitants of the human upper respiratory tract. N. lactamica is a commensal but N. meningitidis is an opportunistic pathogen that occasionally causes invasive disease such as meningitis and septicemia. We demonstrate that unlike N. meningitidis, N. lactamica does not prime the development of mucosal T or B cell memory during the peak period of colonization. This cannot be explained by the induction of peripheral tolerance or regulatory CD4(+)CD25(+) T cell activity. Instead, N. lactamica mediates a B cell-dependent mitogenic proliferative response that is absent to N. meningitidis. This mitogenic response is associated with the production of T cell-independent polyclonal IgM that we propose functions by shielding colonizing N. lactamica from the adaptive immune system, maintaining immunological ignorance in the host. We conclude that, in contrast to N. meningitidis, N. lactamica maintains a commensal relationship with the host in the absence of an adaptive immune response. This may prolong the period of susceptibility to colonization by both pathogenic and nonpathogenic Neisseria species.

Bacterial toxins are the causative agent at pathology in a variety of diseases. Although not always the primary target of these toxins, many have been shown to have potent immunomodulatory effects, for example, inducing immune responses to co-administered antigens and suppressing activation of immune cells. These abilities of bacterial toxins can be harnessed and used in a therapeutic manner, such as in vaccination or the treatment of autoimmune diseases. Furthermore, the ability of toxins to gain entry to cells can be used in novel bacterial toxin based immuno-therapies in order to deliver antigens into MHC Class I processing pathways. Whether the immunomodulatory properties of these toxins arose in order to enhance bacterial survival within hosts, to aid spread within the population or is pure serendipity, it is interesting to think that these same toxins potentially hold the key to preventing or treating human disease.

Previously we have described studies on in vitro pentamer assembly of Escherichia coli (E. coli) derived heat-labile enterotoxin B subunit (EtxB) using conventional monoclonal antibodies (Amin et al., JBC 1995: 270, 20143-50 and Chung et al., JBC 2006: 281, 39465-70). To extend these studies further we have used phage-display to select single-chain Fragment variable (scFv) antibodies against different forms of the B-subunit. Two clones exhibiting strong and differential binding were chosen for detailed characterization. A comprehensive sequence analysis was performed to assign the framework and complementary-determining regions and a nonsense mutation present in one of these (scFv-B1.3.9) was corrected. Binding analysis showed that scFv-B1.3.9 bound in ELISA to both heat-denatured monomeric B-subunits (EtxB1) and also displayed cross-reactivity towards pentameric EtxB (EtxB5), although there was no reactivity towards monoganglioside (GM1) captured EtxB5. Another antibody (scFv-B5.2.14) had a different reactivity profile and, in ELISA, bound only to EtxB5 but not to EtxB1 or to EtxB5 captured via GM1. Surprisingly, in competition experiments, the assembled pentameric B-subunit inhibited binding of scFv-B5.2.14 to immobilized EtxB5 only weakly, whereas reduced, but not oxidized, monomeric EtxB1 was an efficient competitor. These results clearly demonstrate that B1.3.9 and B5.2.14 have different specificities for cryptic epitopes not accessible in the fully assembled GM1 bound pentameric form of EtxB. Taken together our results show that we were able to successfully isolate and characterize recombinant scFvs that differentially recognize diverse denatured forms or assembly intermediates of the heat-labile enterotoxin B subunit of E. coli.

Boron-containing complexes that have the potential to irreversibly accumulate in melanoma cells have been prepared by reaction of amino acids with 9-methoxy-9-borabicyclo[3.3.1]nonane. The ability of each complex to act as a substrate for tyrosinase has been probed by oximetry. Increased uptake of the lead candidate in a tyrosinase-rich cell line, compared with a tyrosinase-absent cell line, is reported, with results correlating well with that for a drug currently approved for BNCT.

Background: Nasopharyngeal carriage of meningococcus or related species leads to protective immunity in adolescence or early adulthood. This natural immunity is associated with mucosal and systemic T cell memory. Whether parenteral Neisseria meningitidis serogroup B (MenB) vaccination influences natural mucosal immunity is unknown., Objectives: To determine whether parenteral MenB vaccination affects mucosal immunity in young adults and whether this immunity differs from that induced in the blood., Methods: Otherwise healthy volunteers were immunized with MenB outer membrane vesicle vaccine before and after routine tonsillectomy. Mucosal and systemic immunity were assessed in 9 vaccinees and 12 unvaccinated control subjects by measuring mononuclear cell proliferation, cytokine production, Th1/Th2 surface marker expression, and antibody to MenB antigens., Results: Parenteral vaccination induced a marked increase in systemic T cell immunity against MenB and a Th1 bias. In contrast, although mucosal T cell proliferation in response to MenB neither increased nor decreased following vaccination, mononuclear cell interferon gamma, interleukin (IL)-5, and IL-10 production increased, and the Th1/Th2 profile lost its Th1 bias., Conclusions: Parenteral MenB vaccination selectively reprograms preexisting naturally acquired mucosal immunity. As new-generation protein-based MenB vaccine candidates undergo evaluation, the impact of these vaccines on mucosal immunity in both adults and children will need to be addressed.

Purpose: To investigate the efficacy of the B subunit of Escherichia coli heat-labile enterotoxin (EtxB) in the treatment of ocular autoimmune disease. Murine experimental autoimmune uveoretinitis (EAU) is an animal model of autoimmune posterior uveitis initiated by retinal antigen-specific Th1 and Th17 CD4(+) T cells, which activate myeloid cells, inducing retinal damage. EtxB is a potent immune modulator that ameliorates other Th1-mediated autoimmune diseases, enhancing regulatory T-cell activity., Methods: EAU was induced in B10.RIII mice by immunization with peptide hIRBP(161-180). Disease severity was measured by clinical and histologic assessment, and functional responses of macrophages (Mphis) and T cells were assessed, both in vivo and in cocultures in vitro. EtxB was administered intranasally daily for 4 days, starting either 3 days before or 3 days after EAU induction., Results: Preimmunization treatment with EtxB protected mice from EAU, limiting both the number and the activation status of retinal infiltrating immune cells. Treatment after EAU induction did not alter the disease course, despite suppression of IFN-gamma. Although EtxB treatment of in vitro cocultures of T cells and Mphis increased IL-10 production, EtxB treatment in vivo increased the proportion and number of IL-17-producing CD4(+) cells infiltrating the eye., Conclusions: EtxB preimmunization protects mice from EAU induction by inhibiting Th1 responses, but the resultant reduction in IFN-gamma responses by EtxB does not effect infiltration or structural damage in established EAU, where Th17 responses predominate. These data highlight the critical importance of the dynamics of T-cell phenotype and infiltration during EAU when considering immunomodulatory therapy.

A major problem in generating effective antitumor CTL responses is that most tumors express self-antigens to which the immune system is rendered unresponsive due to mechanisms of self-tolerance induction. CTL precursors (CTLp) expressing high-affinity T-cell receptors (TCR) are often functionally deleted from the repertoire, leaving a residual repertoire of CTLp having only low-affinity TCR. Furthermore, even when unique antigens are expressed, their presentation by dendritic cells (DC) may predispose to peripheral tolerance induction rather than the establishment of CTL responses that kill tumor cells. In this study, we examined both high-avidity (CL4) and low-avidity (CL1) CD8(+) T-cell responses to a murine renal carcinoma expressing, as a neoantigen, high and low levels of the hemagglutinin (HA) protein from influenza virus A/PR/8 H1N1 (PR8; RencaHA(high) and RencaHA(low)). Our data show that, following encounter with K(d)HA epitopes cross-presented by bone marrow-derived DC, low-avidity CL1 cells become tolerized within tumor-draining lymph nodes (TDLN), and in mice bearing either RencaHA(high) or RencaHA(low) tumors, very few form tumor-infiltrating lymphocytes (TIL). In marked contrast, high-avidity CL4 cells differentiate into effector CTL within the TDLN of mice bearing either RencaHA(high) or RencaHA(low) tumors, and although they form TIL in both tumors, they lose CTL effector function. Critically, these results show that anticancer therapies involving either adoptive transfer of high-avidity tumor-specific CTL populations or targeting of preexisting tumor antigen-specific memory CD8(+) T cells could fail due to the fact that CTL effector function is lost following tumor infiltration.

Neisseria meningitidis is commonly carried asymptomatically in the upper respiratory tract and only occasionally invades the bloodstream and meninges to cause disease. Naturally acquired immunity appears protective but the nature of the cellular immune response within the mucosa is uncertain. We show that following in vitro stimulation with N. meningitidis serogroup B (MenB) antigens, approximately 66% of the dividing mucosal CD4(+)CD45RO(+) memory population express the Th1-associated IL18-R while the remainder express CRTH2, a Th2-associated marker. The pro-inflammatory bias of this anti-MenB response is not evident in blood, demonstrating compartmentalization at the induction site; and occurs in the presence or absence of lipopolysacharide indicating that these responses are already fully committed. Depletion of CD25(+) cells reveals suppression of the effector CD4(+) T cell response restricted to the mucosa and most marked in children (i.e. those at greatest risk of disease). Mucosal T-regulatory cell (Treg) activity is partially overcome by blocking the human glucocorticoid-induced TNF receptor (GITR) and is not seen following stimulation with antigens from another mucosal pathogen, influenza virus. Pro-inflammatory, antimeningococcal T cell responses may limit invasive disease at the mucosa but Treg induction while reducing immunopathological damage, may also restrict the effectiveness of the protective response, particularly in children.

Escherichia coli heat-labile enterotoxin (Etx) is an oral adjuvant in mice. We show that this is also true for rats. To understand this adjuvant activity we examined lymph dendritic cells (DC) migrating from the intestine to mesenteric lymph nodes (MLN) in animals fed Etx. These DC can prime antigen-specific antibody responses. We show that in rats the small intestine contains 7-24 million DC and 8 x 10(5 )of these migrate to MLN each day. Surprisingly, Etx does not stimulate increased migration of lymph DC. However, oral Etx affects the activation, antigen transport and localization of migratory DC. Specifically, expression of CD25 increases on the CD172a(high) subset of lymph DC. Oral Etx also increases the number of CD172a(high) lymph DC containing co-administered ovalbumin. CD172a(high) lymph DC treated with Etx in vitro, or purified from the lymph of animals fed Etx, stimulate stronger proliferative responses from primed T cells. Etx also directs more of the CD172a(high) lymph DC into the central region of the MLN T cell areas. This change in DC localization is associated with an increase in the expression of CCR7. These data help advance our understanding of the role of DC in initiating mucosal immune responses in vivo.

The addition of isocyanides to pyridinium salts is studied. The process takes place efficiently when a carboxamido group is present in the 3 position of the pyridine ring. The outcome of the reaction involves the stabilization of the nitrilium intermediate by the amide, which suffers a mild dehydration, leading regioselectively to beta-cyano-gamma-carbamoyl-1,4-dihydropyridines. In this way, a variety of nicotinamide derivatives were carbamoylated. Extension to quinolinium, isoquinolinium, and N-acylpyridinium salts is also reported. [reaction: see text]

It has been argued that cerebral asymmetry (the "torque") is the characteristic that defines the human brain and that morphological findings in psychosis are consistent with a deviation in this sex-dependent dimension of brain growth. Evidence from sex chromosome aneuploidies and an association within families between sex and handedness is consistent with the presence of a determinant of cerebral asymmetry (a possible correlate of language) on the X and the Y chromosomes. During hominid evolution a 3.5 Mb translocation occurred from the ancestral X chromosome to the Y chromosome, resulting in duplication of the Protocadherin11X gene, such that it is represented on the X and Y chromosomes in man, whereas there is a single X-linked gene in other mammals. We re-date the duplicative translocation to 6 million years ago, that is, close to the chimpanzee-hominid bifurcation. Sequence comparisons with the chimpanzee, bonobo, gorilla, and orangutan indicate that in contrast to earlier purifying selection there has been accelerated change in the Protocadherin11X ectodomain as well as the Protocadherin11Y sequence in the hominid lineage since the duplication. The evolutionary sequence of events together with the prior case for an X-Y homologous gene suggests that this gene-pair is a candidate for the evolution of hominid-specific characteristics including the sexual dimorphism of cerebral asymmetry, a putative correlate of language.

Candidate Neisseria meningitidis serogroup B vaccines that are based on outer-membrane vesicles induce protective immunity in adults but provide neither crossprotection for infants nor long-lasting immunity. We suggest that this lack of vaccine efficacy is not solely because the best antigens are yet to be identified but also results from inappropriate programming of the immune response. Natural carriage of N. meningitidis and related bacteria leads to the development of protective immunity both at the mucosal surface and in the circulation. We propose that vaccine strategies that mimic this natural immunization process would better-optimize vaccine-induced protective immunity. Thus, mucosal immunization before a systemic booster vaccination could provide the solution and reduce the necessity for multiple injections to achieve immunity.

Autoimmune diabetes in the non-obese diabetic (NOD) mouse is associated with development of inflammation around the islets at around 4-5 weeks of age, which may be prolonged until frank diabetes begins to occur around 12 weeks of age. Although many interventions can halt disease progression if administration coincides with the beginning of the anti-beta cell response, very few are able to prevent diabetes development once insulitis is established. Here we describe a strategy which blocks cellular infiltration of islets and prevents diabetes. Intranasal treatment with the B-subunit of Escherichia coli heat labile enterotoxin (EtxB), a protein that binds GM1 ganglioside (as well as GD1b, asialo-GM1 and lactosylceramide with lower affinities), protected NOD mice from developing diabetes in a receptor-binding dependent manner. Protection was associated with a significant reduction in the number of macrophages, CD4(+) T cells, B cells, major histocompatibility complex class II(+) cells infiltrating the islets. Despite this, treated mice showed increased number of interleukin-10(+) cells in the pancreas, and a decrease in both T helper 1 (Th1) and Th2 cytokine production in the pancreatic lymph node. Disease protection was also transferred with CD4(+) splenocytes from treated mice. Taken together, these results demonstrated that EtxB is a potent immune modulator capable of blocking diabetes.

Two novel tyrosinase mediated drug delivery pathways have been investigated for the selective delivery of cytotoxic units to melanocytes from urea and thiourea prodrugs. The synthesis of these prodrugs is reported, as well as oximetry data that illustrate that the targets are substrates for tyrosinase. The stability of each of the prodrugs in (i) phosphate buffer and (ii) bovine serum is discussed, and the urea prodrugs are identified as lead candidates for further studies. Finally, HPLC studies and preliminary cytotoxicity studies in a melanotic and an amelanotic cell line, that illustrate the feasibility of the approach, are presented.

Objective: To examine how maternal and child characteristics interact to moderate injury rate and injury severity for young children., Methods: In this study, 149 mothers reported their toddlers' injuries over a 6-month period during biweekly interviews. Mothers completed questionnaires assessing parenting behaviors, psychological characteristics, and their children's injury-relevant behaviors., Results: Maternal locus of control was found to moderate the association between children's risky behavior and child injury rate. Specifically, an external locus of control was associated with increased child injury rate for high-risk but not for low-risk children., Conclusion: These findings illuminate the potential importance of parental locus of control in moderating high-risk injury-relevant behavior.

The activation of naive CD4+ T cells requires both TCR engagement and a second costimulatory signal mediated by the interaction of CD28 with CD80/CD86 expressed on professional APC. However, the situation for naive CD8+ T cells is less clear. Although evidence indicates that induction of CD8+ T cell responses is also dependent on professional APC, the ability of some tumors, which do not express CD80/CD86, to induce CTL suggests that other pathways of costimulation exist for the activation of CD8+ T cells. We examined the ability of tumor cells expressing different levels of a tumor-specific Ag to directly prime CD8+ T cells. We demonstrate that CD8+ T cells are directly activated by tumor cells in a CD80/CD86-CD28 independent manner. In this system, costimulation requires ICAM-1/LFA-1 interaction. This results in the generation of CTL capable of inhibiting tumor growth in vivo, and maintaining long-term survival.

Pathological alcohol use is a complex and costly problem. This chapter focuses on recent developments in the etiology of alcohol use disorders. Literature is reviewed from the fields of epidemiology, genetics, personality, neuropsychology, parenting, and social influences. In addition, theoretical models that describe pathways to the development of alcohol use disorders are presented. Particular emphasis is given to ways in which genetic, environmental, psychopharmacological, and personological literatures can inform one another.