Ascorbate insufficiency disrupts glutamatergic signaling and alters electroencephalogram phenotypes in a mouse model of Alzheimer's disease.

Clinical studies have reported that increased epileptiform and subclinical epileptiform activity can be detected in many patients with an Alzheimer's disease (AD) diagnosis using electroencephalogram (EEG) and this may correlate with poorer cognition. Ascorbate may have a specific role as a neuromodulator in AD as it is released concomitantly with glutamate reuptake following excitatory neurotransmission. Insufficiency may therefore result in an exacerbated excitatory/inhibitory imbalance in neuronal signaling. Using a mouse model of AD that requires dietary ascorbate (Gulo-/-APPswe/PSEN1dE9), EEG was recorded at baseline and during 4 weeks of ascorbate depletion in young (5-month-old) and aged (20-month-old) animals. Data were scored for changes in quantity of spike trains, individual spikes, sleep-wake rhythms, sleep fragmentation, and brainwave power bands during light periods each week. We found an early increase in neuronal spike discharges with age and following ascorbate depletion in AD model mice and not controls, which did not correlate with brain amyloid load. Our data also show more sleep fragmentation with age and with ascorbate depletion. Additionally, changes in brain wave activity were observed within different vigilance states in both young and aged mice, where Gulo-/-APPswe/PSEN1dE9 mice had shifts towards higher frequency bands (alpha, beta, and gamma) and ascorbate depletion resulted in shifts towards lower frequency bands (delta and theta). Microarray data supported ascorbate insufficiency altering glutamatergic transmission through the decreased expression of glutamate related genes, however no changes in protein expression of glutamate reuptake transporters were observed. These data suggest that maintaining optimal brain ascorbate levels may support normal brain electrical activity and sleep patterns, particularly in AD patient populations where disruptions are observed.

Enhancing face validity of mouse models of Alzheimer's disease with natural genetic variation.

Classical laboratory strains show limited genetic diversity and do not harness natural genetic variation. Mouse models relevant to Alzheimer's disease (AD) have largely been developed using these classical laboratory strains, such as C57BL/6J (B6), and this has likely contributed to the failure of translation of findings from mice to the clinic. Therefore, here we test the potential for natural genetic variation to enhance the translatability of AD mouse models. Two widely used AD-relevant transgenes, APPswe and PS1de9 (APP/PS1), were backcrossed from B6 to three wild-derived strains CAST/EiJ, WSB/EiJ, PWK/PhJ, representative of three Mus musculus subspecies. These new AD strains were characterized using metabolic, functional, neuropathological and transcriptional assays. Strain-, sex- and genotype-specific differences were observed in cognitive ability, neurodegeneration, plaque load, cerebrovascular health and cerebral amyloid angiopathy. Analyses of brain transcriptional data showed strain was the greatest driver of variation. We identified significant variation in myeloid cell numbers in wild type mice of different strains as well as significant differences in plaque-associated myeloid responses in APP/PS1 mice between the strains. Collectively, these data support the use of wild-derived strains to better model the complexity of human AD.

Early immune responses are independent of RGC dysfunction in glaucoma with complement component C3 being protective.

Various immune response pathways are altered during early, predegenerative stages of glaucoma; however, whether the early immune responses occur secondarily to or independently of neuronal dysfunction is unclear. To investigate this relationship, we used the Wlds allele, which protects from axon dysfunction. We demonstrate that DBA/2J.Wlds mice develop high intraocular pressure (IOP) but are protected from retinal ganglion cell (RGC) dysfunction and neuroglial changes that otherwise occur early in DBA/2J glaucoma. Despite this, immune pathways are still altered in DBA/2J.Wlds mice. This suggests that immune changes are not secondary to RGC dysfunction or altered neuroglial interactions, but may be directly induced by the increased strain imposed by high IOP. One early immune response following IOP elevation is up-regulation of complement C3 in astrocytes of DBA/2J and DBA/2J.Wlds mice. Unexpectedly, because the disruption of other complement components, such as C1Q, is protective in glaucoma, C3 deficiency significantly increased the number of DBA/2J eyes with nerve damage and RGC loss at an early time point after IOP elevation. Transcriptional profiling of C3-deficient cultured astrocytes implicated EGFR signaling as a hub in C3-dependent responses. Treatment with AG1478, an EGFR inhibitor, also significantly increased the number of DBA/2J eyes with glaucoma at the same early time point. These findings suggest that C3 protects from early glaucomatous damage, a process that may involve EGFR signaling and other immune responses in the optic nerve head. Therefore, therapies that target specific components of the complement cascade, rather than global inhibition, may be more applicable for treating human glaucoma.

Acute manganese exposure impairs glutamatergic function in a young mouse model of Alzheimer's disease.

Manganese (Mn) is an essential metal that serves as a cofactor for metalloenzymes important in moderating oxidative stress and the glutamate/glutamine cycle. Mn is typically obtained through the diet, but toxic overexposure can occur through other environmental or occupational exposure routes such as inhalation. Mn is known to accumulate in the brain following exposure and may contribute to the etiology of neurodegenerative disorders such as Alzheimer's disease (AD) even in the absence of acute neurotoxicity. In the present study, we used in vitro primary cell culture, ex vivo slice electrophysiology and in vivo behavioral approaches to determine if Mn-induced changes in glutamatergic signaling may be altered by genetic risk factors for AD neuropathology. Primary cortical astrocytes incubated with Mn exhibited early rapid clearance of glutamate compared to saline treated astrocytes but decreased clearance over longer time periods, with no effect of the AD genotype. Further, we found that in vivo exposure to a subcutaneous subacute, high dose of Mn as manganese chloride tetrahydrate (3 ×50 mg/kg MnCl2·4(H2O) over 7 days) resulted in increased expression of cortical GLAST protein regardless of genotype, with no changes in GLT-1. Hippocampal long-term potentiation was not altered in APP/PSEN1 mice at this age and neither was it disrupted following Mn exposure. Mn exposure did increase sensitivity to seizure onset following treatment with the excitatory agonist kainic acid, with differing responses between APP/PSEN1 and control mice. These results highlight the sensitivity of the glutamatergic system to Mn exposure. Experiments were performed in young adult APP/PSEN1 mice, prior to cognitive decline or accumulation of hallmark amyloid plaque pathology and following subacute exposure to Mn. The data support a role of Mn in pathophysiology of AD in early stages of the disease and support the need to better understand neurological consequences of Mn exposure in vulnerable populations.

Woman-centered research on access to safe abortion services and implications for behavioral change communication interventions: a cross-sectional study of women in Bihar and Jharkhand, India.

BACKGROUND: Unsafe abortion in India leads to significant morbidity and mortality. Abortion has been legal in India since 1971, and the availability of safe abortion services has increased. However, service availability has not led to a significant reduction in unsafe abortion. This study aimed to understand the gap between safe abortion availability and use of services in Bihar and Jharkhand, India by examining accessibility from the perspective of rural, Indian women. METHODS: Two-stage stratified random sampling was used to identify and enroll 1411 married women of reproductive age in four rural districts in Bihar and Jharkhand, India. Data were collected on women's socio-demographic characteristics; exposure to mass media and other information sources; and abortion-related knowledge, perceptions and practices. Multiple linear regression models were used to explore the association between knowledge and perceptions about abortion. RESULTS: Most women were poor, had never attended school, and had limited exposure to mass media. Instead, they relied on community health workers, family and friends for health information. Women who had knowledge about abortion, such as knowing an abortion method, were more likely to perceive that services are available (ß = 0.079; p < 0.05) and have positive attitudes toward abortion (ß = 0.070; p < 0.05). In addition, women who reported exposure to abortion messages were more likely to have favorable attitudes toward abortion (ß = 0.182; p < 0.05). CONCLUSIONS: Behavior change communication (BCC) interventions, which address negative perceptions by improving community knowledge about abortion and support local availability of safe abortion services, are needed to increase enabling resources for women and improve potential access to services. Implementing BCC interventions is challenging in settings such as Bihar and Jharkhand where women may be difficult to reach directly, but interventions can target individuals in the community to transfer information to the women who need this information most. Interpersonal approaches that engage community leaders and influencers may also counteract negative social norms regarding abortion and associated stigma. Collaborative actions of government, NGOs and private partners should capitalize on this potential power of communities to reduce the impact of unsafe abortion on rural women.

Strength in Numbers: The Promise of Community-Based Participatory Research in Rural Education.

Montana is a state that is ravaged by a suicide epidemic and mental health crisis, particularly among its youth. In an area in which harsh climates, geographic challenges, and distance to rural healthcare providers are significant barriers to mental healthcare accessibility, educators are faced with the acute social and emotional challenges of their students on a daily basis. This article documents the process and promise of utilizing novel and innovative community-based participatory research to support rural schools. By integrating a trauma-informed intervention in the school setting, while mobilizing local community resources, this interdisciplinary approach shows the ability to address the needs of adolescents while supporting rural educators.

Trauma-Informed Yoga: Investigating an Intervention for Mitigating Adverse Childhood Experiences in Rural Contexts.

In a state ravaged by suicide and a mental health crisis, this study sought to mitigate impacts of adverse childhood experiences (ACEs) and depressive and anxiety symptomology in high school students in a rural Montana community. Through a seven-week, twice weekly intervention of trauma-informed yoga, participants experienced statistically significant reductions in anxiety (GAD-7) and increases in Strengths and Difficulties (SDQ-11) overall scores and some subscales; noteworthy improvements were also present in depressive symptomatology (PHQ-A), salivary cortisol levels, and sleep duration. Importantly, participant qualitative feedback indicated significant benefits in focus, relaxation, and overall well-being. Further research is needed to imply generalizability and should include a larger, more diverse sample as well as utilization of control groups and an examination of academic and behavioral impacts at the school level.

Meox2 Haploinsufficiency Accelerates Axonal Degeneration in DBA/2J Glaucoma.

Purpose: Glaucoma is a complex disease with major risk factors including advancing age and increased intraocular pressure (IOP). Dissecting these earliest events will likely identify new avenues for therapeutics. Previously, we performed transcriptional profiling in DBA/2J (D2) mice, a widely used mouse model relevant to glaucoma. Here, we use these data to identify and test regulators of early gene expression changes in DBA/2J glaucoma. Methods: Upstream regulator analysis (URA) in Ingenuity Pathway Analysis was performed to identify potential master regulators of differentially expressed genes. The function of one putative regulator, mesenchyme homeobox 2 (Meox2), was tested using a combination of genetic, biochemical, and immunofluorescence approaches. Results: URA identified Meox2 as a potential regulator of early gene expression changes in the optic nerve head (ONH) of DBA/2J mice. Meox2 haploinsufficiency did not affect the characteristic diseases of the iris or IOP elevation seen in DBA/2J mice but did cause a significant increase in the numbers of eyes with axon damage compared to controls. While young mice appeared normal, aged Meox2 haploinsufficient DBA/2J mice showed a 44% reduction in MEOX2 protein levels. This correlated with modulation of age- and disease-specific vascular and myeloid alterations. Conclusions: Our data support a model whereby Meox2 controls IOP-dependent vascular remodeling and neuroinflammation to promote axon survival. Promoting these earliest responses prior to IOP elevation may be a viable neuroprotective strategy to delay or prevent human glaucoma.

Assessing state substance abuse prevention infrastructure through the lens of CSAP's Strategic Prevention Framework.

Although the organizational structures and operating procedures of state substance abuse prevention systems vary substantially across states, there is scant empirical research regarding approaches for rigorous assessment of system attributes and which attributes are most conducive to overall effectiveness. As one component of the national cross-site evaluation of the SPF State Incentive Grant Program (SPF SIG), an instrument was developed to assess state substance abuse prevention system infrastructure in order to measure infrastructure change and examine the role of state infrastructure in achieving prevention-related outcomes. In this paper we describe the development of this instrument and summarize findings from its baseline administration. As expected, states and territories were found to vary substantially with respect seven key characteristics, or domains, of state prevention infrastructure. Across the six domains that were assessed using numeric ratings, states scored highest on data systems and lowest on strategic planning. Positive intercorrelations were observed among these domains, indicating that states with high capacity on one domain generally have relatively high capacity on other domains as well. The findings also suggest that state prevention infrastructure development is linked to both funding from state government and the presence of a state interagency coordinating body with decision-making authority. The methodology and baseline findings presented will be used to inform the ongoing national cross-site evaluation of the SPF SIG and may provide useful information to guide further research on state substance abuse prevention infrastructure.

Who are the defendants in domestic violence protection order cases?

Domestic violence protective orders (DVPOs) are the nation's most widely used intimate partner violence (IPV)-related legal intervention, and there is emerging evidence that DVPOs are effective. However, little is known about DVPO defendants. We examined a population-based sample of male DVPO defendants. Most had previous IPV-related offenses, mental health issues, and alcohol and drug-use histories. Court personnel should be aware of the severity of violence plaintiffs are likely experiencing, and the potential danger posed by defendants, and ensure that expedited and appropriate protection is awarded. Concurrent treatment for substance abuse and mental health may enhance the effectiveness of DVPOs.

A tale of two cities: replication of a study on the acculturation and adaptation of immigrant adolescents from the former Soviet Union in a different community context.

While a great deal of research has been conducted to understand acculturation and its relationship to adaptation in the new country, surprisingly little attention has been paid to the ways in which the characteristics of the local community impact these processes. The present study addresses this gap in the literature by exploring the potential role of community differences in the acculturation and adaptation processes of 269 refugee and immigrant adolescents from the former Soviet Union who resettled in two different community contexts. Specifically, a prior study on acculturation and adjustment among high school students (D. Birman, E. J. Trickett, & A. Vinokurov, 2002) was replicated with the same émigré population in a contrasting community within the same state. The contrast between these communities allowed us to test hypotheses emerging from an ecological perspective concerning (1) patterns of acculturation, (2) levels of discrimination and its effect on acculturative outcomes, and (3) community differences in the relationship between acculturation and outcomes. In addition to the focus on community differences, the study also employs a multidimensional measure of acculturation and assesses acculturation to both American and Russian culture. Furthermore, adaptation is assessed across different life domains; including peer relationships, family relationships, school adaptation, and psychological adaptation. Findings support the general ecological perspective, suggesting the importance of studying acculturation and adaptation as a reflexive process in which culture and context are very much intertwined.