Familial Linkage between Neuropsychiatric Disorders and Intellectual Interests

From personality to neuropsychiatric disorders, individual differences in brain function are known to have a strong heritable component. Here we report that between close relatives, a variety of neuropsychiatric disorders covary strongly with intellectual interests. We surveyed an entire class of high-functioning young adults at an elite university for prospective major, familial incidence of neuropsychiatric disorders, and demographic and attitudinal questions. Students aspiring to technical majors (science/mathematics/engineering) were more likely than other students to report a sibling with an autism spectrum disorder (p = 0.037). Conversely, students interested in the humanities were more likely to report a family member with major depressive disorder (p = 8.8×10−4), bipolar disorder (p = 0.027), or substance abuse problems (p = 1.9×10−6). A combined PREdisposition for Subject MattEr (PRESUME) score based on these disorders was strongly predictive of subject matter interests (p = 9.6×10−8). Our results suggest that shared genetic (and perhaps environmental) factors may both predispose for heritable neuropsychiatric disorders and influence the development of intellectual interests

Urban women's socioeconomic status, health service needs and utilization in the four weeks after postpartum hospital discharge: findings of a Canadian cross-sectional survey

<p>Abstract</p> <p>Background</p> <p>Postpartum women who experience socioeconomic disadvantage are at higher risk for poor health outcomes than more advantaged postpartum women, and may benefit from access to community based postpartum health services. This study examined socioeconomically disadvantaged (SED) postpartum women's health, and health service needs and utilization patterns in the first four weeks post hospital discharge, and compared them to more socioeconomically advantaged (SEA) postpartum women's health, health service needs and utilization patterns.</p> <p>Methods</p> <p>Data collected as part of a large Ontario cross-sectional mother-infant survey were analyzed. Women (N = 1000) who had uncomplicated vaginal births of single 'at-term' infants at four hospitals in two large southern Ontario, Canada cities were stratified into SED and SEA groups based on income, social support and a universally administered hospital postpartum risk screen. Participants completed a self-administered questionnaire before hospital discharge and a telephone interview four weeks after discharge. Main outcome measures were self-reported health status, symptoms of postpartum depression, postpartum service needs and health service use.</p> <p>Results</p> <p>When compared to the SEA women, the SED women were more likely to be discharged from hospital within the first 24 hours after giving birth [OR 1.49, 95% CI (1.01–2.18)], less likely to report very good or excellent health [OR 0.48, 95% CI (0.35–0.67)], and had higher rates of symptoms of postpartum depression [OR 2.7, 95% CI(1.64–4.4)]. No differences were found between groups in relation to self reported need for and ability to access services for physical and mental health needs, or in use of physicians, walk-in clinics and emergency departments. The SED group were more likely to accept public health nurse home visits [OR 2.24, 95% CI(1.47–3.40)].</p> <p>Conclusion</p> <p>Although SED women experienced poorer mental and overall health they reported similar health service needs and utilization patterns to more SEA women. The results can assist policy makers, health service planners and providers to develop and implement necessary and accessible services. Further research is needed to evaluate SED postpartum women's health service needs and barriers to service use.</p

Ethical and Scientific Considerations Regarding Animal Testing and Research

In 1959, William Russell and Rex Burch published the seminal book, The Principles of Humane Experimental Technique, which emphasized reduction, refinement, and replacement of animal use, principles which have since been referred to as the ‘‘3 Rs’’. These principles encouraged researchers to work to reduce the number of animals used in experiments to the minimum considered necessary, refine or limit the pain and distress to which animals are exposed, and replace the use of animals with non-animal alternatives when possible. Despite the attention brought to this issue by Russell and Burch and since, the number of animals used in research and testing has continued to increase, raising serious ethical and scientific issues. Further, while the ‘‘3 Rs’’ capture crucially important concepts, they do not adequately reflect the substantial developments in our new knowledge about the cognitive and emotional capabilities of animals, the individual interests of animals, or an updated understanding of potential harms associated with animal research. This Overview provides a brief summary of the ethical and scientific considerations regarding the use of animals in research and testing, and accompanies a Collection entitled Animals, Research, and Alternatives: Measuring Progress 50 Years Later, which aims to spur ethical and scientific advancement

Program for expectant and new mothers: a population-based study of participation

<p>Abstract</p> <p>Background</p> <p>The Manitoba Healthy Baby Program is aimed at promoting pre- and perinatal health and includes two components: 1) prenatal income supplement; 2) community support programs. The goal of this research was to determine the uptake of these components by target groups.</p> <p>Methods</p> <p>Data on participation in each of the two program components were linked to data on all hospital births in Manitoba between 2004/05 through 2007/08. Descriptive analyses of participation by maternal characteristics were produced. Logistic regression analyses were conducted to identify factors associated with participation in the two programs. Separate regressions were run for two groups of women giving birth during the study period: 1) total population; 2) those receiving provincial income assistance during the prenatal period.</p> <p>Results</p> <p>Almost 30% of women giving birth in Manitoba received the Healthy Baby prenatal income supplement, whereas only 12.6% participated in any community support programs. Over one quarter (26.4%) of pregnant women on income assistance did not apply for and receive the prenatal income supplement, despite all being eligible for it. Furthermore, 77.8% of women on income assistance did not participate in community support programs. Factors associated with both receipt of the prenatal benefit and participation in community support programs included lower SES, receipt of income assistance, obtaining adequate prenatal care, having completed high school and having depressive symptoms. Having more previous births was associated with higher odds of receiving the prenatal benefit, but lower odds of attending community support programs. Being married was associated with lower odds of receiving the prenatal benefit but higher odds of participating in community support programs.</p> <p>Conclusions</p> <p>Although uptake of the Healthy Baby program in Manitoba is greater for women in groups at risk for poorer perinatal outcomes, a substantial number of women eligible for this program are not receiving it; efforts to reach these women should be enhanced.</p

Structure of S. aureus HPPK and the Discovery of a New Substrate Site Inhibitor

The first structural and biophysical data on the folate biosynthesis pathway enzyme and drug target, 6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase (SaHPPK), from the pathogen Staphylococcus aureus is presented. HPPK is the second essential enzyme in the pathway catalysing the pyrophosphoryl transfer from cofactor (ATP) to the substrate (6-hydroxymethyl-7,8-dihydropterin, HMDP). In-silico screening identified 8-mercaptoguanine which was shown to bind with an equilibrium dissociation constant, Kd, of ∼13 µM as measured by isothermal titration calorimetry (ITC) and surface plasmon resonance (SPR). An IC50 of ∼41 µM was determined by means of a luminescent kinase assay. In contrast to the biological substrate, the inhibitor has no requirement for magnesium or the ATP cofactor for competitive binding to the substrate site. The 1.65 Å resolution crystal structure of the inhibited complex showed that it binds in the pterin site and shares many of the key intermolecular interactions of the substrate. Chemical shift and 15N heteronuclear NMR measurements reveal that the fast motion of the pterin-binding loop (L2) is partially dampened in the SaHPPK/HMDP/α,β-methylene adenosine 5′-triphosphate (AMPCPP) ternary complex, but the ATP loop (L3) remains mobile on the µs-ms timescale. In contrast, for the SaHPPK/8-mercaptoguanine/AMPCPP ternary complex, the loop L2 becomes rigid on the fast timescale and the L3 loop also becomes more ordered – an observation that correlates with the large entropic penalty associated with inhibitor binding as revealed by ITC. NMR data, including 15N-1H residual dipolar coupling measurements, indicate that the sulfur atom in the inhibitor is important for stabilizing and restricting important motions of the L2 and L3 catalytic loops in the inhibited ternary complex. This work describes a comprehensive analysis of a new HPPK inhibitor, and may provide a foundation for the development of novel antimicrobials targeting the folate biosynthetic pathway

Engaging diverse underserved communities to bridge the mammography divide

<p>Abstract</p> <p>Background</p> <p>Breast cancer screening continues to be underutilized by the population in general, but is particularly underutilized by traditionally underserved minority populations. Two of the most at risk female minority groups are American Indians/Alaska Natives (AI/AN) and Latinas. American Indian women have the poorest recorded 5-year cancer survival rates of any ethnic group while breast cancer is the number one cause of cancer mortality among Latina women. Breast cancer screening rates for both minority groups are near or at the lowest among all racial/ethnic groups. As with other health screening behaviors, women may intend to get a mammogram but their intentions may not result in initiation or follow through of the examination process. An accumulating body of research, however, demonstrates the efficacy of developing 'implementation intentions' that define when, where, and how a specific behavior will be performed. The formulation of intended steps in addition to addressing potential barriers to test completion can increase a person's self-efficacy, operationalize and strengthen their intention to act, and close gaps between behavioral intention and completion. To date, an evaluation of the formulation of implementation intentions for breast cancer screening has not been conducted with minority populations.</p> <p>Methods/Design</p> <p>In the proposed program, community health workers will meet with rural-dwelling Latina and American Indian women one-on-one to educate them about breast cancer and screening and guide them through a computerized and culturally tailored "implementation intentions" program, called <it>Healthy Living Kansas - Breast Health</it>, to promote breast cancer screening utilization. We will target Latina and AI/AN women from two distinct rural Kansas communities. Women attending community events will be invited by CHWs to participate and be randomized to either a mammography "implementation intentions" (<b>MI</b>^<b>2</b>) intervention or a comparison general breast cancer prevention informational intervention (<b>C</b>). CHWs will be armed with notebook computers loaded with our Healthy Living Kansas - Breast Health program and guide their peers through the program. Women in the <b>MI</b>^{<b>2 </b>}condition will receive assistance with operationalizing their screening intentions and identifying and addressing their stated screening barriers with the goal of guiding them toward accessing screening services near their community. Outcomes will be evaluated at 120-days post randomization via self-report and will include mammography utilization status, barriers, and movement along a behavioral stages of readiness to screen model.</p> <p>Discussion</p> <p>This highly innovative project will be guided and initiated by AI/AN and Latina community members and will test the practical application of emerging behavioral theory among minority persons living in rural communities.</p> <p>Trial Registration</p> <p>ClinicalTrials (NCT): <a href="http://www.clinicaltrials.gov/ct2/show/NCT01267110">NCT01267110</a></p

Aberrant DNA Methylation Is Associated with Disease Progression, Resistance to Imatinib and Shortened Survival in Chronic Myelogenous Leukemia

The epigenetic impact of DNA methylation in chronic myelogenous leukemia (CML) is not completely understood. To elucidate its role we analyzed 120 patients with CML for methylation of promoter-associated CpG islands of 10 genes. Five genes were identified by DNA methylation screening in the K562 cell line and 3 genes in patients with myeloproliferative neoplasms. The CDKN2B gene was selected for its frequent methylation in myeloid malignancies and ABL1 as the target of BCR-ABL translocation. Thirty patients were imatinib-naïve (mostly treated by interferon-alpha before the imatinib era), 30 were imatinib-responsive, 50 were imatinib-resistant, and 10 were imatinib-intolerant. We quantified DNA methylation by bisulfite pyrosequencing. The average number of methylated genes was 4.5 per patient in the chronic phase, increasing significantly to 6.2 in the accelerated and 6.4 in the blastic phase. Higher numbers of methylated genes were also observed in patients resistant or intolerant to imatinib. These patients also showed almost exclusive methylation of a putative transporter OSCP1. Abnormal methylation of a Src suppressor gene PDLIM4 was associated with shortened survival independently of CML stage and imatinib responsiveness. We conclude that aberrant DNA methylation is associated with CML progression and that DNA methylation could be a marker associated with imatinib resistance. Finally, DNA methylation of PDLIM4 may help identify a subset of CML patients that would benefit from treatment with Src/Abl inhibitors

Alzheimer disease models and human neuropathology: similarities and differences

Animal models aim to replicate the symptoms, the lesions or the cause(s) of Alzheimer disease. Numerous mouse transgenic lines have now succeeded in partially reproducing its lesions: the extracellular deposits of Aβ peptide and the intracellular accumulation of tau protein. Mutated human APP transgenes result in the deposition of Aβ peptide, similar but not identical to the Aβ peptide of human senile plaque. Amyloid angiopathy is common. Besides the deposition of Aβ, axon dystrophy and alteration of dendrites have been observed. All of the mutations cause an increase in Aβ 42 levels, except for the Arctic mutation, which alters the Aβ sequence itself. Overexpressing wild-type APP alone (as in the murine models of human trisomy 21) causes no Aβ deposition in most mouse lines. Doubly (APP × mutated PS1) transgenic mice develop the lesions earlier. Transgenic mice in which BACE1 has been knocked out or overexpressed have been produced, as well as lines with altered expression of neprilysin, the main degrading enzyme of Aβ. The APP transgenic mice have raised new questions concerning the mechanisms of neuronal loss, the accumulation of Aβ in the cell body of the neurons, inflammation and gliosis, and the dendritic alterations. They have allowed some insight to be gained into the kinetics of the changes. The connection between the symptoms, the lesions and the increase in Aβ oligomers has been found to be difficult to unravel. Neurofibrillary tangles are only found in mouse lines that overexpress mutated tau or human tau on a murine tau −/− background. A triply transgenic model (mutated APP, PS1 and tau) recapitulates the alterations seen in AD but its physiological relevance may be discussed. A number of modulators of Aβ or of tau accumulation have been tested. A transgenic model may be analyzed at three levels at least (symptoms, lesions, cause of the disease), and a reading key is proposed to summarize this analysis