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Neuronal loss in Parkinson's disease (PD) is more widespread than originally thought. Among the extrastriatal sites in which significant loss of neurons has been reported is the centremedian-parafascicular (CM-PF) complex of the thalamus, which provides one of the three major afferent sources to the striatum. The functional significance of CM-PF loss in PD is unclear. Interestingly, several recent small trials have suggested that deep brain stimulation of the CM-PF improves motor function in PD. We discuss the possible transsynaptic determination of CM-PF loss secondary to nigrostriatal dopamine degeneration, and suggest that expression of the glycoprotein cerebellin1 (Cbln1) in CM-PF neurons may play an important role in striatal synaptic remodeling in parkinsonism. [ABSTRACT FROM AUTHOR]

Introduction: Engaging communities in research planning and implementation can enhance recruitment and retention (R&R) of racial and ethnic groups historically excluded and underrepresented in clinical research; however, most studies do not use community-informed approaches. This paper describes the formative research process used to design a Community-Informed Recruitment Plan Template for racial and ethnic groups historically excluded and underrepresented in clinical research., Methods: Using an existing R&R template as a starting point, we iteratively developed and refined the community-informed template through a 3-phase process to achieve cultural-appropriateness. Phase 1 included a literature review, 34 community engagement (CE) studios to review recommendations, community advisory board (CAB) review, and survey data from minority recruitment experts. Phase 2 involved integration of content into existing R&R template. Phase 3 was a final review and revision using input of the CAB and researchers' panel. Survey data collected in Phase 1 were analyzed using descriptives (i.e., frequencies and percentages). Open-ended survey responses were analyzed using inductive, qualitative thematic analysis., Results: The final 8-section template can help develop effective grant or proposal language where study R&R plans are requested. They include: 1) Recruitment Strategy; 2) A Stakeholder Communication Plan; 3) Evidence of Recruitment Feasibility; 4) Recruitment and Retention Team; 5) Recruitment and Retention Methods; 6) Recruitment and Retention Timeline; 7) Evaluation; and 8) Budget., Conclusions: Incorporating multiple perspectives into this formative research process enhances the cultural appropriateness of this community-informed R&R template to help research teams achieve R&R goals for individuals historically excluded and underrepresented in clinical research., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Use of race adjustment in estimating glomerular filtration rate (eGFR) has been challenged given concerns that it may negatively impact the clinical care of Black patients, as it results in Black patients being systematically assigned higher eGFR values than non-Black patients. We conducted a systematic review to assess how well eGFR, with and without race adjustment, estimates measured GFR (mGFR) in Black adults globally. A search across multiple databases for articles published from 1999 to May 2021 that compared eGFR to mGFR and reported outcomes by Black race was performed. We included studies that assessed eGFR using the Modification of Diet in Renal Disease (MDRD) and Chronic Kidney Disease Epidemiology Collaboration (CKD-EPICr) creatinine equations. Risk of study bias and applicability were assessed with the QUality Assessment of Diagnostic Accuracy Studies-2. Of 13,167 citations identified, 12 met the data synthesis criteria (unique patient cohorts in which eGFR was compared to mGFR with and without race adjustment). The studies included patients with and without kidney disease from Africa (n = 6), the United States (n = 3), Europe (n = 2), and Brazil (n = 1). Of 11 CKD-EPI equation studies, all assessed bias, 8 assessed accuracy, 6 assessed precision, and 5 assessed correlation/concordance. Of 7 MDRD equation studies, all assessed bias, 6 assessed accuracy, 5 assessed precision, and 3 assessed correlation/concordance. The majority of studies found that removal of race adjustment improved bias, accuracy, and precision of eGFR equations for Black adults. Risk of study bias was often unclear, but applicability concerns were low. Our systematic review supports the need for future studies to be conducted in diverse populations to assess the possibility of alternative approaches for estimating GFR. This study additionally provides systematic-level evidence for the American Society of Nephrology-National Kidney Foundation Task Force efforts to pursue other options for GFR estimation., Competing Interests: The authors have declared that no competing interests exist.

Background: Previous studies support cultural tailoring of recruitment materials as a strategy to promote the enrollment of minoritized groups in clinical trials. However, there is a lack of guidance for research teams to create culturally tailored materials, potentially contributing to low recruitment rates of minoritized groups. We describe the development and pilot testing of recruitment material guidelines used to culturally tailor clinical trial recruitment materials targeting African Americans and Latinos., Methods: The guideline development team consisted of investigators, research staff, and community leaders and members experienced in the recruitment and community engagement of minoritized groups. The recruitment material guidelines were developed using the literature, focus groups with African Americans and Latinos, the teams' research experience, and guidance from a community advisory board. To assess the effectiveness of the guidelines, a pilot study was conducted comparing advertisement click-through rates and enrollment outcomes between two institutions differing in use of culturally tailored versus non-tailored Facebook banner ads for the "Aspirin Dosing: A Patient-centric Trial Assessing Benefits and Long-Term Effectiveness" (ADAPTABLE) study., Results: Five themes emerged from focus groups: (1) employ diversity and inclusion in recruitment efforts; (2) access multiple recruitment channels to increase reach and possible participation; (3) increase your "footwork"; (4) personalize outreach and recruitment to specific groups' beliefs and values; (5) align recruitment messaging with language preferences and motivations for study participation; and (6) specify incentives for participation. Guidelines were: 1) be inclusive; 2) use all forms of media; 3) take a personalized approach; 4) align recruitment messaging with motivations for study participation; 5) specify incentives; and 6) get out into the community. Additional guidelines were developed addressing specific considerations for images and language when targeting African American and Latino populations. Pilot study results demonstrated that clicks per impression ratio (0.47 clicks per impression vs. 0.03 clicks per impression) and the percentage of African American enrollment were significantly higher when using tailored compared to non-tailored ads (12.8% vs. 8.3%, respectively)., Conclusion: The recruitment material guidelines offer practical recommendations to reach diverse populations for clinical trial participation more effectively. Our preliminary data supports use of these guidelines as a strategy to enhance recruitment of minoritized groups into clinical research studies., (© 2022. The Author(s).)

With the need to quickly advance knowledge dissemination in rapid-paced fields, and more recently in response to the urgency of the COVID-19 pandemic, prepublishing has been brought to the forefront. SPI-Hub™, a publicly available journal selection decision support tool, is being strategically enhanced to address prospective authors' critical needs in navigating and selecting the most appropriate preprint or traditional publication venue.

Clinical trials continue to face significant challenges in participant recruitment and retention. The Recruitment Innovation Center (RIC), part of the Trial Innovation Network (TIN), has been funded by the National Center for Advancing Translational Sciences of the National Institutes of Health to develop innovative strategies and technologies to enhance participant engagement in all stages of multicenter clinical trials. In collaboration with investigator teams and liaisons at Clinical and Translational Science Award institutions, the RIC is charged with the mission to design, field-test, and refine novel resources in the context of individual clinical trials. These innovations are disseminated via newsletters, publications, a virtual toolbox on the TIN website, and RIC-hosted collaboration webinars. The RIC has designed, implemented, and promised customized recruitment support for 173 studies across many diverse disease areas. This support has incorporated site feasibility assessments, community input sessions, recruitment materials recommendations, social media campaigns, and an array of study-specific suggestions. The RIC's goal is to evaluate the efficacy of these resources and provide access to all investigating teams, so that more trials can be completed on time, within budget, with diverse participation, and with enough accrual to power statistical analyses and make substantive contributions to the advancement of healthcare., Competing Interests: The authors have no conflicts of interest to declare., (© The Association for Clinical and Translational Science 2021.)

Background: Racial and ethnic minorities are often underrepresented in clinical trials, threatening the generalizability of trial results. Several factors may contribute to underrepresentation of minorities in clinical trials, including lack of training for researchers and staff on the importance of diversity in clinical trials and effective strategies for recruiting and retaining minority populations., Methods: Applying community engaged research principles, we developed a massive open online course (MOOC) to help research team members develop knowledge and skills to enhance the recruitment of minorities in clinical trials. A transdisciplinary working group, consisting of clinical researchers, community engagement specialists, minority clinical trial recruitment and retention educators and specialists, and knowledge management information scientists, was formed to develop an evidence-based curriculum. Feedback from the Recruitment Innovation Center Community Advisory Board was incorporated to help finalize the curriculum. The course was implemented in Coursera, an online learning platform offering MOOCs. A bootstrap paired sample t-test was used to compare pre- and post-assessments of knowledge, attitudes, and intentions as it relates to minority recruitment., Results: The final course, entitled Faster Together, was divided into eight 1-h modules. Each module included video presentations, reading assignments, and quizzes. After 10 months, 382 individuals enrolled in the course, 105 participants completed the pre-test, and 14 participants completed the post-test. Participants' knowledge scores were higher with an increase in the mean number of correct answers from 15.4 (95% CI:12.1-18.7) on the pre-test to 18.7 (95% CI:17.42-20.2) on the post-test. All post-test respondents (n = 14) indicated that the course improved their professional knowledge, and 71.4% of respondents indicated that they were very likely to make changes to their recruitment practices., Conclusions: Faster Together, a massive open online course, is an acceptable, accessible approach to educating research teams on minority recruitment in clinical trials. Preliminary evidence indicates the course increased knowledge on how to recruit minorities into clinical trials and could promote change in their recruitment practices.

The All of Us Research Program (All of Us) is a national effort to accelerate health research by exploring the relationship between lifestyle, environment, and genetics. It is set to become one of the largest research efforts in U.S. history, aiming to build a national resource of data from at least one million participants. All of Us aims to address the need for more diversity in research and set the stage for that diversity to be leveraged in precision medicine research to come. This paper describes how the program assessed demographic characteristics of participants who have enrolled in other U.S. biomedical research cohorts to better understand which groups are traditionally represented or underrepresented in biomedical research. We 1) reviewed the enrollment characteristics of national cohort studies like All of Us, and 2) surveyed the literature, focusing on key diversity categories essential to the program's enrollment aims. Based on these efforts, All of Us emphasizes enrollment of racial and ethnic minorities, and has formally designated the following additional groups as historically underrepresented: individuals-with inadequate access to medical care; under the age of 18 or over 65; with an annual household income at or below 200% of the federal poverty level; who have a cognitive or physical disability; have less than a high school education or equivalent; are intersex; identify as a sexual or gender minority; or live in rural or non-metropolitan areas. Research accounting for wider demographic variability is critical. Only by ensuring diversity and by addressing the very barriers that limit it, can we position All of Us to better understand and tackle health disparities., Competing Interests: The authors have declared that no competing interests exist.

Objectives: The United States transitioned to the tenth version of the International Classification of Diseases (ICD) system (ICD-10) for mortality coding in 1999 and to the International Classification of Diseases, Clinical Modification and Procedure Coding System (ICD-10-CM/PCS) on October 1, 2015. The purpose of this study was to conduct a narrative literature review to better understand the impact of the implementation of ICD-10/ICD-10-CM/PCS., Materials and Methods: We searched English-language articles in PubMed, Web of Science, and Business Source Complete and reviewed websites of relevant professional associations, government agencies, research groups, and ICD-10 news aggregators to identify literature on the impact of the ICD-10/ICD-10-CM/PCS transition. We used Google to search for additional gray literature and used handsearching of the references of the most on-target articles to help ensure comprehensiveness., Results: Impact areas reported in the literature include: productivity and staffing, costs, reimbursement, coding accuracy, mapping between ICD versions, morbidity and mortality surveillance, and patient care. With the exception of morbidity and mortality surveillance, quantitative studies describing the actual impact of the ICD-10/ICD-10-CM/PCS implementation were limited and much of the literature was based on the ICD-10-CM/PCS transition rather than the earlier conversion to ICD-10 for mortality coding., Discussion: This study revealed several gaps in the literature that limit the ability to draw reliable conclusions about the overall impact, positive or negative, of moving to ICD-10/ICD-10-CM/PCS in the United States., Conclusion: These knowledge gaps present an opportunity for future research and knowledge sharing and will be important to consider when planning for ICD-11., (© The Author(s) 2019. Published by Oxford University Press on behalf of the American Medical Informatics Association.)

All too often the quality and rigor of topic investigations is inaccurately conveyed to information professionals, resulting in a mischaracterization of the research, which, if left unchecked and published, may in turn mislead potential readers. Accurately understanding and categorizing the types of topic investigation searches that are requested of information professionals is critical to both meeting requestors' needs and reflecting their intended methodological approaches. Information professionals' expertise can be an invaluable resource to guide users through the investigative and publication process., (Copyright: © 2019, Authors.)

Background: Addressing social and behavioral determinants of health (SBDs) may help improve health outcomes of community clinic patients. This cross-sectional study explored how assessing SBDs can be used to complement health data collection strategies and provide clinicians with a more in-depth understanding of their patients., Methods: Adult patients, ages 18 and older, at an urban community health care clinic in Tennessee, U.S.A., were asked to complete a questionnaire regarding health status, health history and SBDs while waiting for their clinic appointment. The SBD component included items from the National Academy of Medicine, the Protocol for Responding to and Assessing Patient Assets, Risks, and Experiences instrument, and the Survey of Household Economics and Decisionmaking. Data collection and analysis occurred in 2017., Results: One hundred participants completed the study. The questionnaire took approximately 11 min to complete, and the response rate was 90% or higher for all items except annual household income (unanswered by 40 participants). The median number of negative SBDs was 4 (IQR 2.75-7.0), 96 participants had at least one unmet need, and the most common negative SBD was physical activity (75%; 75/100)., Conclusions: The hybrid questionnaire provided insight into a community clinic population's SBDs and allowed for a more complete understanding than a single questionnaire alone. The brief questionnaire administration time and low non-response rate support the questionnaire's feasibility in the community clinic setting, and results can be used by clinicians to further the personalization goals of precision medicine. Next steps include evaluating how to connect patients with appropriate resources for addressing their SBDs.

Introduction: Social and behavioral factors play important roles in physical and mental health; however, they are not routinely assessed in the healthcare system. A brief panel of measures of social and behavioral determinants of health (SBDs) were recommended in a National Academy of Medicine report for use in electronic health records. Initial testing of the panel established feasibility of use and robustness of the measures. This study evaluates their convergent and divergent validity in relation to self-reported physical and mental health and social desirability bias., Methods: Adults, aged ≥18 years, were recruited through Qualtrics online panel survey platform in 2015 (data analyzed in 2015-2016). Participants completed the (1) panel of SBD measures; (2) 12-Item Short Form Health Survey to assess associations with global physical and mental health; and (3) Marlowe-Crowne Social Desirability Scale short form to assess whether social desirability influenced associations between SBD measures and self-reported health., Results: The sample included 513 participants (mean age, 47.9 [SD=14.2] years; 65.5% female). Several SBD domain measures were associated with physical and mental health. Adjusting for age, poorer physical and mental health were observed among participants reporting higher levels of financial resource strain, stress, depression, physical inactivity, current tobacco use, and a positive score for intimate partner violence. These associations remained significant after adjustment for social desirability bias., Conclusions: SBD domains were associated with global measures of physical and mental health and were not impacted by social desirability bias. The panel of SBD measures should now be tested in clinical settings., (Copyright © 2017 American Journal of Preventive Medicine. Published by Elsevier Inc. All rights reserved.)

Background: Precision medicine has resulted in increasing complexity in the treatment of cancer. Web-based educational materials can help address the needs of oncology health care professionals seeking to understand up-to-date treatment strategies., Objective: This study aimed to assess learning styles of oncology health care professionals and to determine whether learning style-tailored educational materials lead to enhanced learning., Methods: In all, 21,465 oncology health care professionals were invited by email to participate in the fully automated, parallel group study. Enrollment and follow-up occurred between July 13 and September 7, 2015. Self-enrolled participants took a learning style survey and were assigned to the intervention or control arm using concealed alternating allocation. Participants in the intervention group viewed educational materials consistent with their preferences for learning (reading, listening, and/or watching); participants in the control group viewed educational materials typical of the My Cancer Genome website. Educational materials covered the topic of treatment of metastatic estrogen receptor-positive (ER+) breast cancer using cyclin-dependent kinases 4/6 (CDK4/6) inhibitors. Participant knowledge was assessed immediately before (pretest), immediately after (posttest), and 2 weeks after (follow-up test) review of the educational materials. Study statisticians were blinded to group assignment., Results: A total of 751 participants enrolled in the study. Of these, 367 (48.9%) were allocated to the intervention arm and 384 (51.1%) were allocated to the control arm. Of those allocated to the intervention arm, 256 (69.8%) completed all assessments. Of those allocated to the control arm, 296 (77.1%) completed all assessments. An additional 12 participants were deemed ineligible and one withdrew. Of the 552 participants, 438 (79.3%) self-identified as multimodal learners. The intervention arm showed greater improvement in posttest score compared to the control group (0.4 points or 4.0% more improvement on average; P=.004) and a higher follow-up test score than the control group (0.3 points or 3.3% more improvement on average; P=.02)., Conclusions: Although the study demonstrated more learning with learning style-tailored educational materials, the magnitude of increased learning and the largely multimodal learning styles preferred by the study participants lead us to conclude that future content-creation efforts should focus on multimodal educational materials rather than learning style-tailored content., (©Christine M Micheel, Ingrid A Anderson, Patricia Lee, Sheau-Chiann Chen, Katy Justiss, Nunzia B Giuse, Fei Ye, Sheila V Kusnoor, Mia A Levy. Originally published in the Journal of Medical Internet Research (http://www.jmir.org), 25.07.2017.)

Introduction: Social and behavioral factors are known to affect health but are not routinely assessed in medical practice. To date, no studies have assessed a parsimonious panel of measures of social and behavioral determinants of health (SBDs). This study evaluated the panel of SBD measures recommended by the Institute of Medicine and examined the effect of question order., Methods: Adults, aged ≥18 years, were recruited using ResearchMatch.org for this randomized, parallel design study conducted in 2015 (data analyzed in 2015-2016). Three versions of the SBD measures, sharing the same items but in different orders of presentation (Versions 1-3), were developed. Randomized to six groups, participants completed each version at least 1 week apart (Weeks 1-3). Version order was counterbalanced across each administration and randomization was stratified by gender, race, and age. Main outcomes were effect of question order, completion time, and non-response rates., Results: Of 781 participants, 624 (80%) completed the Week 1 questionnaire; median completion time for answering all SBD questions was 5 minutes, 583/624 participants answered all items, and no statistically significant differences associated with question order were observed when comparing responses across all versions. No significant differences in responses within assignment groups over time were found, with the exception of the stress measure for Group 5 (p=0.036)., Conclusion: Question order did not significantly impact participant responses. Time to complete the questionnaire was brief, and non-response rate was low. Findings support the feasibility of using the Institute of Medicine-recommended questionnaire to capture SBDs., (Copyright © 2016 American Journal of Preventive Medicine. Published by Elsevier Inc. All rights reserved.)

This study tested an innovative model for creating consumer-level content about precision medicine based on health literacy and learning style principles. "Knowledge pearl" videos, incorporating multiple learning modalities, were created to explain genetic and cancer medicine concepts. Cancer patients and caregivers (n=117) were randomized to view professional-level content directly from the My Cancer Genome (MCG) website (Group A; control), content from MCG with knowledge pearls embedded (Group B), or a consumer translation, targeted at the sixth grade level, with knowledge pearls embedded (Group C). A multivariate analysis showed that Group C, but not Group B, showed greater knowledge gains immediately after viewing the educational material than Group A. Statistically significant group differences in test performance were no longer observed three weeks later. These findings suggest that adherence to health literacy and learning style principles facilitates comprehension of precision medicine concepts and that ongoing review of the educational information is necessary.

As the role of genomics in health care grows, patients increasingly require adequate genetic literacy to fully engage in their care. This study investigated a model for delivering consumer-friendly genetic information to improve understanding of precision medicine using health literacy and learning style principles. My Cancer Genome (MCG), a freely available cancer decision support tool, was used as a testbed. MCG content on a melanoma tumor mutation, BRAF V600E, was translated to a 6th-grade reading level, incorporating multiple learning modalities. A total of 90 patients and caregivers were recruited from a melanoma clinic at an academic medical center and randomized to 3 groups. Group A (control) received an exact copy of text from MCG. Group B was given the same content with hyperlinks to videos explaining key genetic concepts, identified and labeled by the team as knowledge pearls. Group C received the translated content with the knowledge pearls embedded. Changes in knowledge were measured through pre and post questionnaires. Group C showed the greatest improvement in knowledge. The study results demonstrate that providing information based on health literacy and learning style principles can improve patients' understanding of genetic concepts, thus increasing their likelihood of taking an active role in any decision making concerning their health.

In the ventral tegmental area (VTA), a subpopulation of dopamine neurons express vesicular glutamate transporter 2 and make glutamatergic connections to nucleus accumbens (NAc) and olfactory tubercle (OT) neurons. However, their glutamatergic connections across the forebrain have not been explored systematically. To visualize dopamine neuron forebrain projections and to enable photostimulation of their axons independent of transmitter status, we virally transfected VTA neurons with channelrhodopsin-2 fused to enhanced yellow fluorescent protein (ChR2-EYFP) and used DAT(IREScre) mice to restrict expression to dopamine neurons. ChR2-EYFP-expressing neurons almost invariably stained for tyrosine hydroxylase, identifying them as dopaminergic. Dopamine neuron axons visualized by ChR2-EYFP fluorescence projected most densely to the striatum, moderately to the amygdala and entorhinal cortex (ERC), sparsely to prefrontal and cingulate cortices, and rarely to the hippocampus. Guided by ChR2-EYFP fluorescence, we recorded systematically from putative principal neurons in target areas and determined the incidence and strength of glutamatergic connections by activating all dopamine neuron terminals impinging on recorded neurons with wide-field photostimulation. This revealed strong glutamatergic connections in the NAc, OT, and ERC; moderate strength connections in the central amygdala; and weak connections in the cingulate cortex. No glutamatergic connections were found in the dorsal striatum, hippocampus, basolateral amygdala, or prefrontal cortex. These results indicate that VTA dopamine neurons elicit widespread, but regionally distinct, glutamatergic signals in the forebrain and begin to define the dopamine neuron excitatory functional connectome., Significance Statement: Dopamine neurons are important for the control of motivated behavior and are involved in the pathophysiology of several major neuropsychiatric disorders. Recent studies have shown that some ventral midbrain dopamine neurons are capable of glutamate cotransmission. With conditional expression of channelrhodopsin in dopamine neurons, we systematically explored dopamine neuron connections in the forebrain and identified regionally specific dopamine neuron excitatory connections. Establishing that only a subset of forebrain regions receive excitatory connections from dopamine neurons will help to determine the function of dopamine neuron glutamate cotransmission, which likely involves transmission of precise temporal signals and enhancement of the dynamic range of dopamine neuron signals., (Copyright © 2015 the authors 0270-6474/15/3516259-13$15.00/0.)

Objective: The study's purpose was to test the generalizability of an individualized information prescription model, which has been previously validated for educating patients about hypertension in emergency department and community health center settings. Study investigators assessed the effects of educational materials targeted to health literacy levels and learning styles on patients' diabetes knowledge in a community clinic setting., Methods: From May to August 2012, 160 patients were recruited and randomized into intervention (n = 81) and control (n = 79) groups. Inclusion criteria included 18 years or older, English or Spanish speaker, and a type 2 diabetes diagnosis. Measures included modified versions of the Diabetes Knowledge Test and Subjective Numeracy Scale, along with brief health literacy and learning style assessments. Study team members contacted both groups after 2 and 6 weeks to reassess diabetes knowledge., Results: The control group showed no significant change in diabetes knowledge at both follow-ups. In contrast, the mean number of diabetes knowledge questions answered correctly by the intervention group increased significantly after 2 weeks (Δ = 2.66, P = 0.000), which persisted at 6 weeks (Δ = 2.46, P = 0.00)., Conclusions: This study showed that patients' knowledge about diabetes increased significantly after exposure to educational materials targeted to their health literacy levels and learning style preferences and that the model is transferrable among health conditions.

Objective: This paper offers insight into the processes that have shaped the Eskind Biomedical Library's (EBL's) strategic direction and its alignment to the institution's transformative vision., Setting: The academic biomedical library has a notable track record for developing and pioneering roles for information professionals focused on a sophisticated level of information provision that draws from and fuels practice evolutions., Strategy: The medical center's overall transformative vision informs the creation of a fully aligned library strategic plan designed to effectively contribute to the execution of key organizational goals. Annual goals reflect organizational priorities and contain quantifiable and measurable deliverables. Two strategic themes, facilitating genetic literacy and preserving community history, are described in detail to illustrate the concept of goal setting., Conclusion: The strategic planning model reflects EBL's adaptation to the ever-changing needs of its organization. The paper provides a characterization of a workable model that can be replicated by other institutions.

Cerebellin precursor protein (Cbln1) is essential for synapse integrity in cerebellum through assembly into complexes that bridge pre-synaptic β-neurexins (Nrxn) to post-synaptic GluRδ2. However, GluRδ2 is largely cerebellum-specific, yet Cbln1 and its little studied family members, Cbln2 and Cbln4, are expressed throughout brain. Therefore, we investigated whether additional proteins mediate Cbln family actions. Whereas Cbln1 and Cbln2 bound to GluRδ2 and Nrxns1-3, Cbln4 bound weakly or not at all, suggesting it has distinct binding partners. In a candidate receptor-screening assay, Cbln4 (but not Cbln1 or Cbln2) bound selectively to the netrin receptor, (deleted in colorectal cancer (DCC) in a netrin-displaceable fashion. To determine whether Cbln4 had a netrin-like function, Cbln4-null mice were generated. Cbln4-null mice did not phenocopy netrin-null mice. Cbln1 and Cbln4 were likely co-localized in neurons thought to be responsible for synaptic changes in striatum of Cbln1-null mice. Furthermore, complexes containing Cbln1 and Cbln4 had greatly reduced affinity to DCC but increased affinity to Nrxns, suggesting a functional interaction. However, Cbln4-null mice lacked the striatal synaptic changes seen in Cbln null mice. Thus, Cbln family members interact with multiple receptors/signaling pathways in a subunit composition-dependent manner and have independent functions with Cbln4 potentially involved in the less well-characterized role of netrin/DCC in adult brain., (© 2012 The Authors. Journal of Neurochemistry © 2012 International Society for Neurochemistry.)

Neuronal loss in Parkinson's disease (PD) is seen in a number of brain regions in addition to the substantia nigra (SN). Among these is the thalamic parafascicular nucleus (PF), which sends glutamatergic projections to the striatum and receives GABAergic inputs from the SN. Recent data suggest that lesions of nigrostriatal dopamine axons cause a loss of PF neurons, which has been interpreted to suggest that the PF cell loss seen in PD is secondary to dopamine denervation. However, the extent of a PF dopamine innervation in the rat is unclear, and it is possible that PF cell loss in parkinsonism is independent of nigrostriatal dopamine degeneration. We characterized the dopamine innervation of the PF in the rat and determined if 6-hydroxydopamine SN lesions cause PF neuron degeneration. Dual-label immunohistochemistry revealed that almost all tyrosine hydroxylase-immunoreactive (TH-ir) axons in the PF also expressed dopamine-beta-hydroxylase and were therefore noradrenergic or adrenergic. Moreover, an antibody directed against dopamine revealed only very rare PF dopaminergic axons. Retrograde-tract tracing-immunohistochemistry did not uncover an innervation of the PF from midbrain dopamine neurons. Nigrostriatal dopamine neuron lesions did not elicit degeneration of PF cells, as reflected by a lack of FluoroJade C staining. Similarly, neither unilateral 6-OHDA lesions of nigrostriatal axons nor the dorsal noradrenergic bundle decreased the number of PF neurons or the number of PF neurons retrogradely-labeled from the striatum. These data suggest that the loss of thalamostriatal PF neurons in Parkinson's Disease is a primary event rather than secondary to nigrostriatal dopamine degeneration., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Cerebellin precursor protein 1 (Cbln1) is the prototype of a family of secreted neuronal glycoproteins (Cbln1-4) and its genetic elimination results in synaptic alterations in cerebellum (CB) and striatum. In CB, Cbln1 acts as a bi-functional ligand bridging pre-synaptic β-neurexins on granule cells to post-synaptic Grid2 on Purkinje neurons. Although much is known concerning the action of Cbln1, little is known of the function of its other family members. Here, we show that Cbln1 and Cbln2 have similar binding activities to β-neurexins and Grid2 and the targeted ectopic expression of Cbln2 to Purkinje cells in transgenic mice rescues the cerebellar deficits in Cbln1-null animals: suggesting that the two proteins have redundant function mediated by their common receptor binding properties. Cbln1 and Cbln2 are also co-expressed in the endolysosomal compartment of the thalamic neurons responsible for the synaptic alterations in striatum of Cbln1-null mice. Therefore, to determine whether the two family members have similar functions, we generated Cbln2-null mice. Cbln2-null mice do not show the synaptic alterations evident in striatum of Cbln1-null mice. Thus, Cbln2 can exhibit functional redundancy with Cbln1 in CB but it does not have the same properties as Cbln1 in thalamic neurons, implying one or both utilize different receptors/mechanisms in this brain region., (© 2011 The Authors. Journal of Neurochemistry © 2011 International Society for Neurochemistry.)

Limited patient understanding of hypertension contributes to poor health outcomes. In 2 sequential randomized studies, the authors determined the impact of administering information tailored to health literacy level alone or in combination with preferred learning style on patients' understanding of hypertension. Patients with high blood pressure were recruited in an academic emergency department. In Experiment 1 (N = 85), the control group received only the routine discharge instructions; the intervention group received discharge instructions combined with information consistent with their health literacy level as determined by the Short Test of Functional Health Literacy. In Experiment 2 (N = 87), the information provided to the intervention group was tailored to both health literacy and learning style, as indicated by the VARK™ Questionnaire. To measure learning, the authors compared scores on a hypertension assessment administered during the emergency department visit and 2 weeks after discharge. Participants who received materials tailored to both health literacy level and learning style preference showed greater gains in knowledge than did those receiving information customized for health literacy level only. This study demonstrates that personalizing health information to learning style preferences and literacy level improves patient understanding of hypertension.

Cerebellin1 (Cbln1) is a secreted glycoprotein that was originally isolated from the cerebellum and subsequently found to regulate synaptic development and stability. Cbln1 has a heterogeneous distribution in brain, but the only site in which it has been shown to have central effects is the cerebellar cortex, where loss of Cbln1 causes a reduction in granule cell-Purkinje cell synapses. Neurons of the thalamic parafascicular nucleus (PF), which provide glutamatergic projections to the striatum, also express high levels of Cbln1. We first examined Cbln1 in thalamostriatal neurons and then determined if cbln1 knockout mice exhibit structural deficits in striatal neurons. Virtually all PF neurons express Cbln1-immunoreactivity (-ir). In contrast, only rare Cbln1-ir neurons are present in the central medial complex, the other thalamic region that projects heavily to the dorsal striatum. In the striatum Cbln1-ir processes are apposed to medium spiny neuron (MSN) dendrites; ultrastructural studies revealed that Cbln1-ir axon terminals form axodendritic synapses with MSNs. Tract-tracing studies found that all PF cells retrogradely labeled from the striatum express Cbln1-ir. We then examined the dendritic structure of Golgi-impregnated MSNs in adult cbln1 knockout mice. MSN dendritic spine density was markedly increased in cbln1(-/-) mice relative to wildtype littermates, but total dendritic length was unchanged. Ultrastructural examination revealed an increase in the density of MSN axospinous synapses in cbln1(-/-) mice, with no change in postsynaptic density length. Thus, Cbln1 determines the dendritic structure of striatal MSNs, with effects distinct from those seen in the cerebellum.