Search

Cardiovascular disease (CVD) is a significant health concern influenced by various determinants. Stigma and resilience have emerged as factors in CVD development and management. Women with HIV (WWH) have higher CVD rates than women without HIV. To improve cardiovascular health for WWH, a comprehensive understanding of how these factors interact, the understanding about individual awareness and willingness to engage in risk-reduction interventions are needed. Methods: As part of a study examining CVD risk among WWH aged >35 years old, 90-min focus groups were conducted (May 2022) in the English language. Focus groups aimed to elicit participants' CVD risk knowledge and potential prevention strategies. Transcripts underwent a qualitative analysis. Results: Nineteen WWH participated in three focus groups. Participants experienced the following: (a) enacted stigma related to their HIV diagnosis (e.g., family, church member, healthcare staff); (b) a recent event (e.g., hospitalization of self/family, death in family, chest pain) triggered both heart health-promoting lifestyle changes and suboptimal health behaviors (e.g., COVID-19 pandemic: unhealthy snacking). Participants wanted to obtain more knowledge ("on a mission") about CVD risk. In total, 100% expressed willingness to take medication or embark on other lifestyle changes to prevent future CVD events. Although participants identified preventative heart health behaviors (e.g., eating healthy foods; exercising; limiting stress, substances, and smoking), misconceptions were also identified (e.g., "catching" heart disease). Conclusions: Understanding the interplay of the different factors related to heart health is needed both at the provider and the patient level to inform interventions that reduce CVD risk amongst racial/ethnic minoritized women with HIV, living in the Southern region of the US.

Objective: People living with HIV have an increased risk of heart failure (HF). There are different subtypes of HF. Knowledge about the factors differentiating HF subtypes in people with HIV is limited but necessary to guide preventive measures and treatment., Methods: A retrospective review of medical records was undertaken in people with HIV aged ≥18 years who received care at the University of Miami/Jackson Memorial HIV Clinic between January 2017 and November 2019 (N = 1166). Patients with an echocardiogram available for review (n = 305) were included. HF was defined as a documented diagnosis of any HF subtype (n = 52). We stratified those with HF by their ejection fraction (EF) into HF with preserved EF (HFpEF), HF with borderline EF, or HF with reduced EF (HFrEF)., Results: The prevalence of HF was 4.5%. The cohort included 46.2% females and 75% self-identified African Americans. Those with HF had a higher prevalence of hypertension, prior myocardial infarction, angina, coronary artery disease, percutaneous coronary intervention, coronary artery bypass grafting, diastolic dysfunction, and left ventricle hypertrophy. People with HIV with HF with borderline EF exhibited more coronary artery disease than those with HFpEF., Conclusions: We characterize HF in people with HIV in South Florida and report the prevalence of HF and HF subtypes. Only a small percentage of patients had echocardiograms performed, suggesting an ongoing need for recognition of the increased risk of HF in people living with HIV, and raising the concern about lack of awareness contributing to underdiagnosis and missed treatment opportunities in this population., (© 2024 British HIV Association.)

Introduction: Implementation science (IS) offers methods to systematically achieve the Ending the HIV Epidemic goals in the United States, as well as the global UNAIDS targets. Federal funders such as the National Institutes of Mental Health (NIMH) have invested in implementation research to achieve these goals, including supporting the AIDS Research Centres (ARCs), which focus on high-impact science in HIV and mental health (MH). To facilitate capacity building for the HIV/MH research workforce in IS, "grey areas," or areas of IS that are confusing, particularly for new investigators, should be addressed in the context of HIV/MH research., Discussion: A group of IS experts affiliated with NIMH-funded ARCs convened to identify common and challenging grey areas. The group generated a preliminary list of 19 grey areas in HIV/MH-related IS. From the list, the authors developed a survey which was distributed to all ARCs to prioritize grey areas to address in this paper. ARC members across the United States (N = 60) identified priority grey areas requiring clarification. This commentary discusses topics with 40% or more endorsement. The top grey areas that ARC members identified were: (1) Differentiating implementation strategies from interventions; (2) Determining when an intervention has sufficient evidence for adaptation; (3) Integrating recipient perspectives into HIV/MH implementation research; (4) Evaluating whether an implementation strategy is evidence-based; (5) Identifying rigorous approaches for evaluating the impact of implementation strategies in the absence of a control group or randomization; and (6) Addressing innovation in HIV/MH IS grants. The commentary addresses each grey area by drawing from the existing literature (when available), providing expert guidance on addressing each in the context of HIV/MH research, and providing domestic and global HIV and HIV/MH case examples that address these grey areas., Conclusions: HIV/MH IS is key to achieving domestic and international goals for ending HIV transmission and mitigating its impact. Guidance offered in this paper can help to overcome challenges to rigorous and high-impact HIV/MH implementation research., (© 2024 The Author(s). Journal of the International AIDS Society published by John Wiley & Sons Ltd on behalf of International AIDS Society.)

The syndemic theoretical framework has been used in health disparities research to explain several co-occurring epidemics, particularly in populations facing disparate health conditions. A prominent example of this is seen in Singer's Substance Abuse, Violence and HIV/AIDS (SAVA) syndemic theory. However, even though numerous studies support some of the theoretical underpinnings of the SAVA syndemic, the empirical applications of the theory remain methodologically underdeveloped. The current review was guided by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extension for Scoping Review (PRISMA-ScR), to present the state of the science of methodologies examining SAVA constructs using the syndemic framework. Seven bibliographic databases were searched with no language or date restrictions. Studies were synthesized by author, year of publication, study location, total sample size, study population, SAVA outcomes, analytic method of SAVA measurement, intervention type, level of influence, disease interaction and concentration, main findings of the study, and possible future areas of research. Our search yielded a total of 967 articles, and 123 were included in the review. Methodologic and statistical innovation is needed to elevate the impact of syndemic theory for elucidating the synergistic effects of determinants leading to health disparities.

The current cross-sectional study examined the effect of coronavirus disease 2019 (COVID-19) household isolation on household conflict and cohesion in one-, two-, and three-generation households with older adults (aged ≥65 years). Participants were 757 adults (aged ≥18 years) with at least one older adult in their household. Respondents were from 51 countries. Study variables were measured with the COVID-19 Household Environmental Scale. Non-parametric tests were used to assess differences between groups. Most participants ( n = 437, 57.7%) lived in three-generation homes. Three-generation homes reported greater increases in conflict ( p < 0.001) and cohesion ( p < 0.001) during household isolation compared to oneand two-generation homes. Findings suggest that older adults living in multigenerational households experienced more cohesive and conflictive household environments as a function of the COVID-19 pandemic. Further research should explore how family or health care interventions could better support older adults and families as a unit of care to avoid adverse outcomes and boost resilience. [ Journal of Gerontological Nursing, 49 (4), 47-56.].

Introduction: The COVID-19 pandemic has dramatically altered the functioning of households. Because of the vulnerability of high-risk groups, such as older adults and people with compromised immune systems, households caring for these vulnerable adults may be facing elevated levels of caregiving-related stress and burden. The current study sought to examine the impact of the pandemic on conflict and cohesion in households with adults requiring caregiving versus noncaregiving households. Methods: Respondent demographic, household level, and family functioning data were collected anonymously from an international sample ( N = 4,241). Responses were examined using descriptive and bivariate analyses. Results: Overall, respondents in caregiving households ( n = 667) reported a significantly greater negative impact of social distancing on their family functioning, with greater increase in conflict than nonadult caregiving households ( n = 3,574). Significantly more caregiving households also reported that someone had stopped working due to the pandemic. No differences were observed for cohesion between the two groups, with both reporting a little bit more cohesion when compared with the period before social distancing. Conclusions: Our findings add to a body of literature demonstrating that caregiving families experience greater disruption and strain during disaster situations such as the COVID-19 pandemic. Future research is needed to establish the causality of the collected proximal factors, such as job loss and education, with pandemic related family functioning among homes caring for adults, and examining the impact of contextual factors, such as level of caregiving need and caregiving support. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Objectives: Most transitional care initiatives to reduce rehospitalization have focused on the transition that occurs between a patient's hospital discharge and return home. However, many patients are discharged from a skilled nursing facility (SNF) to their homes. The goal was to evaluate the effectiveness of the Mayo Clinic Care Transitions (MCCT) program (hereafter called program) among patients discharged from SNFs to their homes., Design: Propensity-matched control-intervention trial., Intervention: Patients in the intervention group received care management following nursing stay (a home visit and nursing phone calls)., Setting and Participants: Patients enrolled after discharge from an SNF to home were matched to patients who did not receive intervention because of refusal, program capacity, or distance. Patients were aged ≥60 years, at high risk for hospitalization, and discharged from an SNF., Methods: Program enrollees were matched through propensity score to nonenrollees on the basis of age, sex, comorbid health burden, and mortality risk score. Conditional logistic regression analysis examined 30-day hospitalization and emergency department (ED) use; Cox proportional hazards analyses examined 180-day hospital stay and ED use., Results: Each group comprised 160 patients [mean (standard deviation) age, 85.4 (7.4) years]. Thirty-day hospitalization and ED rates were 4.4% and 10.0% in the program group and 3.8% and 10.0% in the group with usual care (P = .76 for hospitalization; P > .99 for ED). At 180 days, hospitalization and ED rates were 30.6% and 46.3% for program patients compared with 11.3% and 25.0% in the comparison group (P < .001)., Conclusions and Implications: We found no evidence of reduced hospitalization or ED visits by program patients vs the comparison group. Such findings are crucial because they illustrate how aggressive stabilization care within the SNF may mitigate the program role. Furthermore, we found higher ED and hospitalization rates at 180 days in program patients than the comparison group., (Copyright © 2021 AMDA – The Society for Post-Acute and Long-Term Care Medicine. Published by Elsevier Inc. All rights reserved.)

The COVID-19 pandemic is a worldwide event that has exacerbated stress and caused significant disruptions in the day-to-day living of families. Of particular concern are socially vulnerable families, which have felt the impacts of the pandemic most acutely. Because stress can alter family dynamics, it is important to understand which stressors impact families the most, and what resources can be leveraged to strengthen family functioning. The current study examined the impacts of COVID-19 on the conflict and cohesion of households with children compared to households without children. Additionally, we sought to assess how conflict and cohesion are related to social vulnerabilities in the context of the pandemic. Using an international sample, we analyzed responses to the COVID-19 Household Environment Scale (N = 4122) using descriptive and bivariate analyses. Latent class analysis was used to identify patterns of family functioning in households with and without children. We found that social vulnerability was associated with more disrupted family functioning, and that households with children (n = 2666) reported less disrupted family functioning when compared to households without children (n = 1456), despite having higher social vulnerability scores. Our exploratory latent class analysis identified a 5-class model among both subgroups. Conflict, cohesion, family functioning and social vulnerability varied significantly by subgroup and class membership. Our findings add to a body of evidence that argues that despite facing greater vulnerability, households with children have many strengths to draw from. Family interventions that help to promote family cohesion and conflict resolution can foster resilience in stressful circumstances.

Background and Purpose: Artificial intelligence decision support systems are a rapidly growing class of tools to help manage ever-increasing imaging volumes. The aim of this study was to evaluate the performance of an artificial intelligence decision support system, Aidoc, for the detection of cervical spinal fractures on noncontrast cervical spine CT scans and to conduct a failure mode analysis to identify areas of poor performance., Materials and Methods: This retrospective study included 1904 emergent noncontrast cervical spine CT scans of adult patients (60 [SD, 22] years, 50.3% men). The presence of cervical spinal fracture was determined by Aidoc and an attending neuroradiologist; discrepancies were independently adjudicated. Algorithm performance was assessed by calculation of the diagnostic accuracy, and a failure mode analysis was performed., Results: Aidoc and the neuroradiologist's interpretation were concordant in 91.5% of cases. Aidoc correctly identified 67 of 122 fractures (54.9%) with 106 false-positive flagged studies. Diagnostic performance was calculated as the following: sensitivity, 54.9% (95% CI, 45.7%-63.9%); specificity, 94.1% (95% CI, 92.9%-95.1%); positive predictive value, 38.7% (95% CI, 33.1%-44.7%); and negative predictive value, 96.8% (95% CI, 96.2%-97.4%). Worsened performance was observed in the detection of chronic fractures; differences in diagnostic performance were not altered by study indication or patient characteristics., Conclusions: We observed poor diagnostic accuracy of an artificial intelligence decision support system for the detection of cervical spine fractures. Many similar algorithms have also received little or no external validation, and this study raises concerns about their generalizability, utility, and rapid pace of deployment. Further rigorous evaluations are needed to understand the weaknesses of these tools before widespread implementation., (© 2021 by American Journal of Neuroradiology.)

Background: Intralipid (ILP), a lipid emulsion, protects organs against ischemia/reperfusion (IR) injury. We hypothesized that ILP activates endothelial nitric oxide synthase (eNOS) and increases NO release from endothelial cells (ECs) through a fatty-acid translocase cluster of differentiation (CD36) mediated endocytotic mechanism, acting as a potentially protective paracrine signal during oxidative stress., Methods: Human umbilical-vein ECs were exposed to 1% ILP for 2 hours followed by oxidative stress with 0.2-mM hydrogen peroxide for 2 hours. Western blots were conducted with anti-CD36, dynamin-2, src-kinase-1, eNOS, and phospho-eNOS; equal protein loading was confirmed with β-actin. CD36 immunoprecipitation was probed for caveolin-1 to determine if CD36 and caveolin-1 were complexed on the cell membrane. NO was measured by fluorescence of ECs., Results: ILP caused a 227% increase in CD36 expression vs controls. Immunoprecipitation indicated a CD36/caveolin-1 complex on ECs' membrane with exposure to ILP. Dynamin-2 increased 52% and src-kinase-1 340% after ILP treatment vs control cells. eNOS phosphorylation was confirmed by a 63% increase in the phospho-eNOS/eNOS ratio in ILP-treated cells, and NO fluorescence increased 102%., Conclusion: ILP enters ECs via endocytosis by a CD36/caveolin-1 cell membrane receptor complex, which in turn is pulled into the cell by dynamin-2 activity. Upregulation of src-kinase-1 and eNOS phosphorylation suggest downstream mediators. Subsequent NO release from ECs serve as a paracrine signal to neighboring cells for protection against IR injury. Student t-test was utilized for single comparisons and analysis of variance with Bonferroni-Dunn post hoc modification for multiple comparisons; P < .05 was considered statistically significant., (© 2020 American Society for Parenteral and Enteral Nutrition.)

Purpose: To compare the rates of colorectal and extracolonic findings at CT colonography (CTC) screening between patients with and without a personal prior history of other., Methods: Over a 160-month interval, 349 adults (mean age, 60.3 years; 67% female) with a positive history of extracolonic cancer [Ca(+)], excluding 271 patients with isolated non-melanoma skin cancers, underwent CTC screening. This study cohort was compared against 8859 controls (mean age, 57.0 years; 53% female) without a prior cancer history [Ca(-)]. Primary outcome measures included the rates of relevant colorectal (C-RADS C2-C4) and extracolonic (C-RADS E3-E4) findings at CTC. Wilcoxon rank sum test was used to test for statistical significance with post-hoc analysis by relative rate (RR)., Results: Both colorectal (C2-C4) and extracolonic (E3-E4) findings were significantly increased in the Ca(+) group versus Ca(-) control group (p = 0.0283 and 0.0236, respectively). Positive colorectal findings were most notably increased among survivors of non-small cell lung cancer (RR 3.1), head/neck cancers (RR, 3.4), and bladder cancers (RR 2.2). The proportion of C2-C4 patients undergoing intervention in the Ca(+) cohort was not significantly different than the Ca(-). Potentially relevant extracolonic findings (E3) were increased in survivors of hematogenous malignancies (RR 2.0), while likely important extracolonic findings (E4) were increased in survivors of female gynecological malignancies (RR 3.4)., Conclusions: Relevant colorectal and extracolonic findings at CTC screening are increased in patients with a previous extracolonic cancer history, particularly among certain cancer subsets. These results may have important implications for choice of colorectal test in these patients.

Anaphase in epithelia typically does not ensue until after spindles have achieved a characteristic position and orientation, but how or even if cells link spindle position to anaphase onset is unknown. Here, we show that myosin-10 (Myo10), a motor protein involved in epithelial spindle dynamics, binds to Wee1, a conserved regulator of cyclin-dependent kinase 1 (Cdk1). Wee1 inhibition accelerates progression through metaphase and disrupts normal spindle dynamics, whereas perturbing Myo10 function delays anaphase onset in a Wee1-dependent manner. Moreover, Myo10 perturbation increases Wee1-mediated inhibitory phosphorylation on Cdk1, which, unexpectedly, concentrates at cell-cell junctions. Based on these and other results, we propose a model in which the Myo10-Wee1 interaction coordinates attainment of spindle position and orientation with anaphase onset., (© 2018 Sandquist et al.)

Background/aims: There is a paucity of population-based studies on the association between inflammatory bowel disease (IBD) and depression in the U.S. population. We sought to study this association using the National Health and Nutrition Examination Survey (NHANES) database., Methods: We used NHANES data from 2009 to 2010. Our study included 190,269,933 U.S. adults without IBD and 2,325,226 with IBD. We sought to determine whether IBD is an independent risk factor for depressive symptoms (DS) in the U.S. population and studied the independent predictors of DS in IBD population., Results: DS was present in 49% of the IBD population versus 23% of the non-IBD population (p<0.001). During the multivariate analysis, we found that IBD was independently associated with DS in the U.S. population (p=0.002). The independent predictors of DS in the IBD population were older age (p=0.048) and divorced/separated/widowed status (p=0.005). There was nonsignificant increase in suicidal risk in IBD population with DS versus that in non-IBD population with DS (27% vs 12%, respectively, p=0.080). Only 36% of IBD individuals with DS visited mental health professional or psychiatrist within the past year., Conclusions: IBD is independently associated with DS in the U.S. population. Further research is warranted on risk stratification, screening and management of those with IBD who are at risk of depression.

Mounting evidence indicates that soluble oligomeric forms of amyloid proteins linked to neurodegenerative disorders, such as amyloid-β (Aβ), tau, or α-synuclein (αSyn) might be the major deleterious species for neuronal function in these diseases. Here, we found an abnormal accumulation of oligomeric αSyn species in AD brains by custom ELISA, size-exclusion chromatography, and nondenaturing/denaturing immunoblotting techniques. Importantly, the abundance of αSyn oligomers in human brain tissue correlated with cognitive impairment and reductions in synapsin expression. By overexpressing WT human αSyn in an AD mouse model, we artificially enhanced αSyn oligomerization. These bigenic mice displayed exacerbated Aβ-induced cognitive deficits and a selective decrease in synapsins. Following isolation of various soluble αSyn assemblies from transgenic mice, we found that in vitro delivery of exogenous oligomeric αSyn but not monomeric αSyn was causing a lowering in synapsin-I/II protein abundance. For a particular αSyn oligomer, these changes were either dependent or independent on endogenous αSyn expression. Finally, at a molecular level, the expression of synapsin genes SYN1 and SYN2 was down-regulated in vivo and in vitro by αSyn oligomers, which decreased two transcription factors, cAMP response element binding and Nurr1, controlling synapsin gene promoter activity. Overall, our results demonstrate that endogenous αSyn oligomers can impair memory by selectively lowering synapsin expression., Competing Interests: The authors declare no conflict of interest.

Proper spindle positioning at anaphase onset is essential for normal tissue organization and function. Here we develop automated spindle-tracking software and apply it to characterize mitotic spindle dynamics in the Xenopus laevis embryonic epithelium. We find that metaphase spindles first undergo a sustained rotation that brings them on-axis with their final orientation. This sustained rotation is followed by a set of striking stereotyped rotational oscillations that bring the spindle into near contact with the cortex and then move it rapidly away from the cortex. These oscillations begin to subside soon before anaphase onset. Metrics extracted from the automatically tracked spindles indicate that final spindle position is determined largely by cell morphology and that spindles consistently center themselves in the XY -plane before anaphase onset. Finally, analysis of the relationship between spindle oscillations and spindle position relative to the cortex reveals an association between cortical contact and anaphase onset. We conclude that metaphase spindles in epithelia engage in a stereotyped "dance," that this dance culminates in proper spindle positioning and orientation, and that completion of the dance is linked to anaphase onset., (© 2017 Larson and Bement. This article is distributed by The American Society for Cell Biology under license from the author(s). Two months after publication it is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License (http://creativecommons.org/licenses/by-nc-sa/3.0).)

Background and Purpose: It is critical to accurately represent strengths interventions to improve data and enable intervention effectiveness research from a strengths perspective. However, it is challenging to understand strengths interventions from the multiple perspectives of computerized knowledge representation, evidence-based practice guidelines, and practice-based evidence narratives. Intervention phrases abstracted from nurse care coordinator practice narratives described strengths interventions with community-dwelling elders. This project aims were to (a) compare nurse care coordinator use of evidence-based interventions as described in the two guidelines (what to do and how to do it), (b) analyze nurse care coordinator intervention tailoring (individualized care), and (c) evaluate the usefulness of the Omaha System for comparison of narrative phrases to evidence-based guidelines., Methods: Phrases from expert nurse care coordinators were mapped to the Omaha System for comparison with the guidelines interventions and were analyzed using descriptive statistics. Venn diagrams were used to visually depict intervention overlap between the guidelines and the phrases., Results: Empirical evaluation of 66 intervention phrases mapped to 14 problems using 3 category terms and 19 target terms showed alignment between guidelines and the phrases, with the most overlap across two guidelines and the phrases in categories, and the most diversity in care descriptions., Conclusion: These findings demonstrate the value in having both standardized guidelines and expert clinicians who see the whole person and can synthesize and apply guidelines in tailored ways. There is potential to create a feedback loop between practice-based evidence and evidence-based practice by expanding this approach to use of practice-generated Omaha System data as practice-based evidence. Further research is needed to refine and advance the use of these methods with additional practices and guidelines.

A comprehensive description of starch biosynthesis and granule assembly remains undefined despite the central nature of starch as an energy storage molecule in plants and as a fundamental calorie source for many animals. Multiple theories regarding the starch synthase (SS)-catalyzed assembly of (α1-4)-linked d-glucose molecules into maltodextrins generally agree that elongation occurs at the non-reducing terminus based on the degradation of radiolabeled maltodextrins, although recent reports challenge this hypothesis. Surprisingly, a direct analysis of the SS catalytic product has not been reported, to our knowledge. We expressed and characterized recombinant Zea mays SSIIa and prepared pure ADP-[ 13 C U ]glucose in a one-pot enzymatic synthesis to address the polarity of maltodextrin chain elongation. We synthesized maltoheptaose (degree of polymerization 7) using ADP-[ 13 C U ]glucose, maltohexaose (degree of polymerization 6), and SSIIa. Product analysis by ESI-MS revealed that the [ 13 C U ]glucose unit was added to the non-reducing end of the growing chain, and SSIIa demonstrated a >7,850-fold preference for addition to the non-reducing end versus the reducing end. Independent analysis of [ 13 C U ]glucose added to maltohexaose by SSIIa using solution NMR spectroscopy confirmed the polarity of maltodextrin chain elongation., (© 2016 by The American Society for Biochemistry and Molecular Biology, Inc.)

Unlabelled: Despite the demonstration that amyloid-β (Aβ) can trigger increased tau phosphorylation and neurofibrillary tangle (NFT) formation in vivo, the molecular link associating Aβ and tau pathologies remains ill defined. Here, we observed that exposure of cultured primary neurons to Aβ trimers isolated from brain tissue of subjects with Alzheimer's disease led to a specific conformational change of tau detected by the antibody Alz50. A similar association was supported by postmortem human brain analyses. To study the role of Aβ trimers in vivo, we created a novel bigenic Tg-Aβ+Tau mouse line by crossing Tg2576 (Tg-Aβ) and rTg4510 (Tg-Tau) mice. Before neurodegeneration and amyloidosis, apparent Aβ trimers were increased by ∼2-fold in 3-month-old Tg-Aβ and Tg-Aβ+Tau mice compared with younger mice, whereas soluble monomeric Aβ levels were unchanged. Under these conditions, the expression of soluble Alz50-tau conformers rose by ∼2.2-fold in the forebrains of Tg-Aβ+Tau mice compared with nontransgenic littermates. In parallel, APP accumulated intracellularly, suggestive of a putative dysfunction of anterograde axonal transport. We found that the protein abundance of the kinesin-1 light chain (KLC1) was reduced selectively in vivo and in vitro when soluble Aβ trimers/Alz50-tau were present. Importantly, the reduction in KLC1 was prevented by the intraneuronal delivery of Alz50 antibodies. Collectively, our findings reveal that specific soluble conformers of Aβ and tau cooperatively disrupt axonal transport independently from plaques and tangles. Finally, these results suggest that not all endogenous Aβ oligomers trigger the same deleterious changes and that the role of each assembly should be considered separately., Significance Statement: The mechanistic link between amyloid-β (Aβ) and tau, the two major proteins composing the neuropathological lesions detected in brain tissue of Alzheimer's disease subjects, remains unclear. Here, we report that the trimeric Aβ species induce a pathological modification of tau in cultured neurons and in bigenic mice expressing Aβ and human tau. This linkage was also observed in postmortem brain tissue from subjects with mild cognitive impairment, when Aβ trimers are abundant. Further, this modification of tau was associated with the intracellular accumulation of the precursor protein of Aβ, APP, as a result of the selective decrease in kinesin light chain 1 expression. Our findings suggest that Aβ trimers might cause axonal transport deficits in AD., (Copyright © 2016 the authors 0270-6474/16/369647-12$15.00/0.)

The iconic bipolar structure of the mitotic spindle is of extreme importance to proper spindle function. At best, spindle abnormalities result in a delayed mitosis, while worse outcomes include cell death or disease. Recent work has uncovered an important role for the actin-based motor protein myosin-10 in the regulation of spindle structure and function. Here we examine the contribution of the myosin tail homology 4 (MyTH4) domain of the myosin-10 tail to the protein's spindle functions. The MyTH4 domain is known to mediate binding to microtubules and we verify the suspicion that this domain contributes to myosin-10's close association with the spindle. More surprisingly, our data demonstrate that some but not all of myosin-10's spindle functions require microtubule binding. In particular, myosin-10's contribution to spindle pole integrity requires microtubule binding, whereas its contribution to normal mitotic progression does not. This is demonstrated by the observation that dominant negative expression of the wild-type MyTH4 domain produces multipolar spindles and an increased mitotic index, whereas overexpression of a version of the MyTH4 domain harboring point mutations that abrogate microtubule binding results in only the mitotic index phenotype. Our data suggest that myosin-10 helps to control the metaphase to anaphase transition in cells independent of microtubule binding. © 2016 Wiley Periodicals, Inc., Competing Interests: The authors declare no conflict of interest in this work., (© 2016 Wiley Periodicals, Inc.)

Animal cell cytokinesis results from patterned activation of the small GTPase Rho, which directs assembly of actomyosin in the equatorial cortex. Cytokinesis is restricted to a portion of the cell cycle following anaphase onset in which the cortex is responsive to signals from the spindle. We show that shortly after anaphase onset oocytes and embryonic cells of frogs and echinoderms exhibit cortical waves of Rho activity and F-actin polymerization. The waves are modulated by cyclin-dependent kinase 1 (Cdk1) activity and require the Rho GEF (guanine nucleotide exchange factor), Ect2. Surprisingly, during wave propagation, although Rho activity elicits F-actin assembly, F-actin subsequently inactivates Rho. Experimental and modelling results show that waves represent excitable dynamics of a reaction-diffusion system with Rho as the activator and F-actin the inhibitor. We propose that cortical excitability explains fundamental features of cytokinesis including its cell cycle regulation.

Objective: To use urine drug testing (UDT) results and other covariates to develop a model for the assessment of opioid medication prescription adherence., Design: Retrospective study., Setting: The Pain Management Clinic at one center of a large, private, multispecialty healthcare system (consisting of 52 regional centers) in northcentral and western Wisconsin., Participants: Seven hundred thirty-three Pain Management Clinic patients with an opioid prescription and UDT between June 1, 2007 and May 17, 2010. UDT results were available for 2,615 individual drug screens from 2,364 urine samples., Intervention: Patient characteristics, drug dosage, quantitative urine creatinine and drug/analyte levels, and reported adherence/nonadherence were abstracted from the electronic medical record., Main Outcome Measures: Adherence was categorized for all UDT results using an objective set of criteria. Drug adherence was modeled excluding samples for clinically observed adherence issues, detection of illicit substances, diagnosed addictive disorders, and/or metabolic reasons., Results: Considerable variability was observed for primary urine analytes, even among those prescribed the same dose and believed to be adherent and free of confounding medical issues. For all medications evaluated, only urine creatinine contributed significantly (p < 0.0001) to predictive models of adherence based on dose alone. Simulated underuse and review of identified overuse and underuse suggest that this model could provide useful adherence information., Conclusion: Predictive models based on urine analyte levels and clinical covariates, particularly urine creatinine, may be clinically useful for assessing opioid adherence. Future work should evaluate whether genetics or other factors can improve predictive accuracy of these models.

An unresolved debate in Alzheimer's disease (AD) is whether amyloid plaques are pathogenic, causing overt physical disruption of neural circuits, or protective, sequestering soluble forms of amyloid-β (Aβ) that initiate synaptic damage and cognitive decline. Few animal models of AD have been capable of isolating the relative contribution made by soluble and insoluble forms of Aβ to the behavioral symptoms and biochemical consequences of the disease. Here we use a controllable transgenic mouse model expressing a mutant form of amyloid precursor protein (APP) to distinguish the impact of soluble Aβ from that of deposited amyloid on cognitive function and synaptic structure. Rapid inhibition of transgenic APP modulated the production of Aβ without affecting pre-existing amyloid deposits and restored cognitive performance to the level of healthy controls in Morris water maze, radial arm water maze, and fear conditioning. Selective reduction of Aβ with a γ-secretase inhibitor provided similar improvement, suggesting that transgene suppression restored cognition, at least in part by lowering Aβ. Cognitive improvement coincided with reduced levels of synaptotoxic Aβ oligomers, greater synaptic density surrounding amyloid plaques, and increased expression of presynaptic and postsynaptic markers. Together these findings indicate that transient Aβ species underlie much of the cognitive and synaptic deficits observed in this model and demonstrate that significant functional and structural recovery can be attained without removing deposited amyloid., (Copyright © 2014 the authors 0270-6474/14/347871-15$15.00/0.)

Recent evidence has emphasized soluble species of amyloid-β (Aβ) and tau as pathogenic effectors in Alzheimer's disease (AD). Despite the fact that Aβ, tau, and α-synuclein (αSyn) can promote each other's aggregation, the potential contribution of soluble αSyn to AD pathogenesis is unknown. Here, we found an approximate twofold increase over controls in soluble αSyn levels in AD brains in the absence of Lewy body cytopathology. Importantly, soluble αSyn levels were a quantitatively stronger correlate of cognitive impairment than soluble Aβ and tau levels. To examine a putative role for αSyn in modulating cognitive function, we used the Barnes circular maze to assess spatial reference memory in transgenic mice overexpressing human wild-type αSyn. The results revealed that an approximate threefold elevation of αSyn in vivo induced memory deficits similar to those observed in AD mouse models. The neurobiological changes associated with this elevation of soluble αSyn included decreases in selected synaptic vesicle proteins and an alteration of the protein composition of synaptic vesicles. Finally, a synergism between Aβ/APP and human tau seems to be responsible for the abnormal elevation of soluble αSyn in transgenic mice. Altogether, our data reveal an unexpected role for soluble, intraneuronal αSyn in AD pathophysiology.

For nearly 100 years following the first description of this neurological disorder by Dr Alois Alzheimer, amyloid plaques and neurofibrillary tangles have been hypothesized to cause neuronal loss. With evidence that the extent of insoluble, deposited amyloid poorly correlated with cognitive impairment, research efforts focused on soluble forms of Aβ, also referred as Aβ oligomers. Following a decade of studies, soluble oligomeric forms of Aβ are now believed to induce the deleterious cascade(s) involved in the pathophysiology of Alzheimer's disease. In this review, we will discuss our current understanding about endogenous oligomeric Aβ production, their relative toxicity in vivo and in vitro, and explore the potential future directions needed for the field., (© 2011 The Authors. Journal of Neurochemistry © 2011 International Society for Neurochemistry.)

The mitotic spindle is a structure that forms during mitosis to help ensure that each daughter cell receives a full complement of genetic material. In metaphase, the spindle contains microtubules that nucleate inward from two opposing poles. Chromosomes are attached to plus-ends of these microtubules via protein structures called kinetochores. The centromere is the specific region of kinetochore attachment on the chromosome. Chromatin surrounding the centromere (pericentric chromatin) is subject to microtubule-based forces and is commonly modeled as a linear spring, where the force that it exerts is proportional to the distance that it is stretched. We have incorporated physically based models of chromatin to create more accurate and predictive models of the spindle. In addition, using fluorescence microscopy and motion analysis of fluorescently labeled chromatin spots we discovered that pericentric chromatin is restrained relative to free diffusive motion. The characterization of chromatin is crucial to understand mitotic spindle stability and to understand the cell cycle checkpoint regulating anaphase onset., (Copyright © 2010 Elsevier Masson SAS. All rights reserved.)

Objective: To investigate the possibility of utilizing the ratio of the methadone metabolite, 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP), to urine creatinine to develop a regression model that would predict drug adherence in patients prescribed methadone for either pain management or drug addiction., Design: Retrospective study., Setting: Marshfield Clinic-Lakeland Center, one of 41 regional centers that make up Marshfield Clinic, a large, private, multi-specialty healthcare institution in central Wisconsin., Participants: Patients receiving methadone treatment for substance abuse or chronic pain. Group 1 was an initial pilot group consisting of 7 patients who were followed for a 4-month period. Group 2 consisted of 33 patients who were followed over a 28-month period., Methods: Age, gender, weight, height, methadone dosage, quantitative urine creatinine and EDDP levels, reported compliance/non-compliance, and relevant clinical cofactors were retrospectively abstracted from the patients' medical records. Log-log regression analyses were used to model EDDP and the EDDP/creatinine ratio from urine screening results as functions of methadone dose, and in the larger cohort (group 2), body size, gender and age. The coefficient of determination adjusted for the number of predictor terms (R(adj)(2)) was reported as a measure of model fit., Results: For group 1 data, there was a significant positive relation (P<0.001) but also substantial variability (R(adj)(2) = 0.49). Adjustment for creatinine through the EDDP/creatinine ratio provided a tighter relation (R(adj)(2) = 0.95). Similarly, for group 2 data, there was a significant positive relation (P=0.001) and substantial variability (R(adj)(2) = 0.53). Adjustment for creatinine through EDDP/creatinine ratios provided a substantially stronger relation (R(adj)(2) = 0.73). Gender and age showed no evidence of association with the EDDP/creatinine ratio (P=0.60 and P=0.51, respectively). Body size was significant in the model, both when measured by body surface area and by lean body weight, and improved the prediction when added to our model (R(adj)(2) = 0.80)., Conclusion: For the first time, urine analyses may be used to monitor methadone over- or under-use in a clinical setting, regardless of the state of patient hydration or the manipulation of a sample by addition of another substance, such as bleach, soap, or even methadone, which could render an appropriate sample inappropriate or an inappropriate sample appropriate. A similar approach may prove useful for other drug treatments, allowing for more accurate monitoring of commonly abused prescription medications.

The use of combined positive and negative contingencies markedly reduced ruminative behavior in a severely mentally retarded, blind 20-year-old male residing in a residential treatment facility. A 95.4% decrease in rumination events occurred from baseline to follow-up. This procedure is offered as an effective and convenient treatment for chronic rumination.

A 110-kDa Borrelia burgdorferi fusion protein, Escherichia coli expressing the fusion protein, transformed E. coli lacking the fusion protein insert, and lyophilized whole B. burgdorferi bacteria were compared for immunogenicity in C3H/He mice. Immunized mice were challenged with a variety of isolates from the United States or the European isolate P/Gau 3 weeks following the last inoculation. An average of 76.7% of the mice immunized with 25 micrograms of lyophilized whole B. burgdorferi cells were protected from infection, while 60% of the mice immunized with the 110-kDa fusion protein were protected. Whole E. coli bacteria expressing the fusion protein protected 57.7% of immunized mice against experimental challenge. Lower levels of protection occurred in mice challenged with the European isolate than in those challenged with isolates originating from the United States. These results demonstrate the potential of the 110-kDa fusion protein for use as a component of a subunit vaccine for prevention of Lyme borreliosis.

Early detection of swine influenza A outbreaks is essential to understand the true cause and effect relationship that exists between this disease and other serious respiratory or herd health problems. Enzyme-linked immunosorbent assays (ELISAs) for the early detection of H1N1 subtype specific serum IgM, IgG and secretory IgA were compared to direct virus detection in in embryonated eggs. Elevated levels of H1 hemagglutinin (HA) specific IgM and IgG were detected as early as 3 days post experimental infection with a field strain of swine influenza A (H1N1). Influenza specific IgA in nasal mucous samples was detected on day 4 post infection (PI). This compared favorably with egg inoculation methods which detected virus 2-4 days PI. Identification of elevated H1 HA specific IgM in test herds could signify a recent influenza outbreak. Alternatively, ELISA analysis of nasal mucous samples for H1 HA specific IgA could provide a noninvasive method of obtaining similar information on the influenza specific immune status of the herd.

To evaluate the role of excessive polyol pathway activity in the pathogenesis of nerve disorders in diabetes mellitus, nerve conduction velocity was measured in motor nerves of diabetic dogs given an aldose reductase inhibitor (Sorbinil) or placebo, and also in non-diabetic dogs made experimentally galactosaemic. The nerve conduction velocity slowly declined in the diabetic placebo group, becoming significantly less than normal by the fifth year of the study, and the decline was prevented by administration of the aldose reductase inhibitor. Non-diabetic dogs made galactosaemic by consuming a 30% galactose diet developed erythrocyte and nerve polyol concentrations many times greater than that of diabetic or normal animals, but the nerve conduction velocity remained normal throughout 5 years of study. These results in dogs suggest that aldose reductase inhibitors may prevent defective nerve conduction in long-term diabetes, and raise the possibility that excessive accumulation of polyol itself is not sufficient to produce the nerve defect in the absence of excessive polyol utilization.

To evaluate the role of hyperglycemia and excessive polyol pathway activity in the pathogenesis of nerve disorders in diabetes, motor nerve conduction velocity (MNCV) was measured in dogs alloxan diabetic or experimentally galactosemic for 5 years. Diabetic dogs in poor glycemic control showed a progressive decline of MNCV from baseline values. Diabetic dogs that had been randomly assigned to good glycemic control retained normal MNCV. Nondiabetic dogs made galactosemic by a 30% galactose diet developed erythrocyte polyol concentrations many-fold greater than in diabetic animals, but the MNCV remained unchanged and comparable to that of normal dogs. Nerve polyol levels, when compared in short-term diabetic dogs or dogs galactose-fed 2 to 4 months, were elevated at least as much by the galactose-rich diet as by diabetes. Thus, in dogs, excessive tissue polyol accumulation is associated with subnormal MNCV in diabetes, but not in experimental galactosemia.