Publications by authors named "Rachel Bennett"

98 Publications

Synaptic and metabolic gene expression alterations in neurons that are recipients of proteopathic tau seeds.

Acta Neuropathol Commun 2020 10 19;8(1):168. Epub 2020 Oct 19.

Alzheimer Research Unit, Department of Neurology, Massachusetts General Hospital, Building 114, Room 2009, Charlestown, MA, 02129, USA.

Recent studies suggest that misfolded tau molecules can be released, and taken up by adjacent neurons, propagating proteopathic seeds across neural systems. Yet critical to understanding whether tau propagation is relevant in pathophysiology of disease would be to learn if it alters neuronal properties. We utilized high resolution multi-color in situ hybridization technology, RNAScope, in a well-established tau transgenic animal, and found that a subset of neurons in the cortex do not appear to express the transgene, but do develop phospho-tau positive inclusions, consistent with having received tau seeds. Recipient neurons show decreases in their expression of synaptophysin, CAMKIIα, and mouse tau in both young and old animals. These results contrast with neurons that develop tau aggregates and also overexpress the transgene, which have few changes in expression of metabolic and synaptic markers. Taken together, these results strongly suggest that tau propagation impacts neuronal functional integrity.
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http://dx.doi.org/10.1186/s40478-020-01049-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7574323PMC
October 2020

Cerebrovascular Senescence Is Associated With Tau Pathology in Alzheimer's Disease.

Front Neurol 2020 16;11:575953. Epub 2020 Sep 16.

Department of Neurology, Harvard Medical School, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Charlestown, MA, United States.

Alzheimer's Disease (AD) is associated with neuropathological changes, including aggregation of tau neurofibrillary tangles (NFTs) and amyloid-beta plaques. Mounting evidence indicates that vascular dysfunction also plays a key role in the pathogenesis and progression of AD, in part through endothelial dysfunction. Based on findings in animal models that tau pathology induces vascular abnormalities and cellular senescence, we hypothesized that tau pathology in the human AD brain leads to vascular senescence. To explore this hypothesis, we isolated intact microvessels from the dorsolateral prefrontal cortex (PFC, BA9) from 16 subjects with advanced Braak stages (Braak V/VI, B3) and 12 control subjects (Braak 0/I/II, B1), and quantified expression of 42 genes associated with senescence, cell adhesion, and various endothelial cell functions. Genes associated with endothelial senescence and leukocyte adhesion, including SERPINE1 (PAI-1), CXCL8 (IL8), CXCL1, CXCL2, ICAM-2, and TIE1, were significantly upregulated in B3 microvessels after adjusting for sex and cerebrovascular pathology. In particular, the senescence-associated secretory phenotype genes SERPINE1 and CXCL8 were upregulated by more than 2-fold in B3 microvessels after adjusting for sex, cerebrovascular pathology, and age at death. Protein quantification data from longitudinal plasma samples for a subset of 13 ( = 9 B3, = 4 B1) subjects showed no significant differences in plasma senescence or adhesion-associated protein levels, suggesting that these changes were not associated with systemic vascular alterations. Future investigations of senescence biomarkers in both the peripheral and cortical vasculature could further elucidate links between tau pathology and vascular changes in human AD.
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http://dx.doi.org/10.3389/fneur.2020.575953DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7525127PMC
September 2020

Tau reduction in aged mice does not impact Microangiopathy.

Acta Neuropathol Commun 2020 08 18;8(1):137. Epub 2020 Aug 18.

Department of Neurology, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, 02129, USA.

Microangiopathy, including proliferation of small diameter capillaries, increasing vessel tortuosity, and increased capillary blockage by leukocytes, was previously observed in the aged rTg4510 mouse model. Similar gene expression changes related to angiogenesis were observed in both rTg4510 and Alzheimer's disease (AD). It is uncertain if tau is directly responsible for these vascular changes by interacting directly with microvessels, and/or if it contributes indirectly via neurodegeneration and concurrent neuronal loss and inflammation. To better understand the nature of tau-related microangiopathy in human AD and in tau mice, we isolated capillaries and observed that bioactive soluble tau protein could be readily detected in association with vasculature. To examine whether this soluble tau is directly responsible for the microangiopathic changes, we made use of the tetracycline-repressible gene expression cassette in the rTg4510 mouse model and measured vascular pathology following tau reduction. These data suggest that reduction of tau is insufficient to alter established microvascular complications including morphological alterations, enhanced expression of inflammatory genes involved in leukocyte adherence, and blood brain barrier compromise. These data imply that 1) soluble bioactive tau surprisingly accumulates at the blood brain barrier in human brain and in mouse models, and 2) the morphological and molecular phenotype of microvascular disturbance does not resolve with reduction of whole brain soluble tau. Additional consideration of vascular-directed therapies and strategies that target tau in the vascular space may be required to restore normal function in neurodegenerative disease.
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http://dx.doi.org/10.1186/s40478-020-01014-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7436970PMC
August 2020

Understanding the Experience of Cancer Pain From the Perspective of Patients and Family Caregivers to Inform Design of an In-Home Smart Health System: Multimethod Approach.

JMIR Form Res 2020 Aug 26;4(8):e20836. Epub 2020 Aug 26.

The George Washington University School of Engineering & Applied Science, Washington, DC, United States.

Background: Inadequately managed pain is a serious problem for patients with cancer and those who care for them. Smart health systems can help with remote symptom monitoring and management, but they must be designed with meaningful end-user input.

Objective: This study aims to understand the experience of managing cancer pain at home from the perspective of both patients and family caregivers to inform design of the Behavioral and Environmental Sensing and Intervention for Cancer (BESI-C) smart health system.

Methods: This was a descriptive pilot study using a multimethod approach. Dyads of patients with cancer and difficult pain and their primary family caregivers were recruited from an outpatient oncology clinic. The participant interviews consisted of (1) open-ended questions to explore the overall experience of cancer pain at home, (2) ranking of variables on a Likert-type scale (0, no impact; 5, most impact) that may influence cancer pain at home, and (3) feedback regarding BESI-C system prototypes. Qualitative data were analyzed using a descriptive approach to identity patterns and key themes. Quantitative data were analyzed using SPSS; basic descriptive statistics and independent sample t tests were run.

Results: Our sample (n=22; 10 patient-caregiver dyads and 2 patients) uniformly described the experience of managing cancer pain at home as stressful and difficult. Key themes included (1) unpredictability of pain episodes; (2) impact of pain on daily life, especially the negative impact on sleep, activity, and social interactions; and (3) concerns regarding medications. Overall, taking pain medication was rated as the category with the highest impact on a patient's pain (=4.79), followed by the categories of wellness (=3.60; sleep quality and quantity, physical activity, mood and oral intake) and interaction (=2.69; busyness of home, social or interpersonal interactions, physical closeness or proximity to others, and emotional closeness and connection to others). The category related to environmental factors (temperature, humidity, noise, and light) was rated with the lowest overall impact (=2.51). Patients and family caregivers expressed receptivity to the concept of BESI-C and reported a preference for using a wearable sensor (smart watch) to capture data related to the abrupt onset of difficult cancer pain.

Conclusions: Smart health systems to support cancer pain management should (1) account for the experience of both the patient and the caregiver, (2) prioritize passive monitoring of physiological and environmental variables to reduce burden, and (3) include functionality that can monitor and track medication intake and efficacy; wellness variables, such as sleep quality and quantity, physical activity, mood, and oral intake; and levels of social interaction and engagement. Systems must consider privacy and data sharing concerns and incorporate feasible strategies to capture and characterize rapid-onset symptoms.
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http://dx.doi.org/10.2196/20836DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7481872PMC
August 2020

Effects of intramuscular vatinoxan (MK-467), co-administered with medetomidine and butorphanol, on cardiopulmonary and anaesthetic effects of intravenous ketamine in dogs.

Vet Anaesth Analg 2020 Sep 11;47(5):604-613. Epub 2020 Jun 11.

Department of Equine and Small Animal Medicine, University of Helsinki, Helsinki, Finland.

Objective: To investigate the impact of intramuscular (IM) co-administration of the peripheral α-adrenoceptor agonist vatinoxan (MK-467) with medetomidine and butorphanol prior to intravenous (IV) ketamine on the cardiopulmonary and anaesthetic effects in dogs, followed by atipamezole reversal.

Study Design: Randomized, masked crossover study.

Animals: A total of eight purpose-bred Beagle dogs aged 3 years.

Methods: Each dog was instrumented and administered two treatments 2 weeks apart: medetomidine (20 μg kg) and butorphanol (100 μg kg) premedication with vatinoxan (500 μg kg; treatment MVB) or without vatinoxan (treatment MB) IM 20 minutes before IV ketamine (4 mg kg). Atipamezole (100 μg kg) was administered IM 60 minutes after ketamine. Heart rate (HR), mean arterial (MAP) and central venous (CVP) pressures and cardiac output (CO) were measured; cardiac (CI) and systemic vascular resistance (SVRI) indices were calculated before and 10 minutes after MVB or MB, and 10, 25, 40, 55, 70 and 100 minutes after ketamine. Data were analysed with repeated measures analysis of covariance models. A p-value <0.05 was considered statistically significant. Sedation, induction, intubation and recovery scores were assessed.

Results: At most time points, HR and CI were significantly higher, and SVRI and CVP significantly lower with MVB than with MB. With both treatments, SVRI and MAP decreased after ketamine, whereas HR and CI increased. MAP was significantly lower with MVB than with MB; mild hypotension (57-59 mmHg) was recorded in two dogs with MVB prior to atipamezole administration. Sedation, induction, intubation and recovery scores were not different between treatments, but intolerance to the endotracheal tube was observed earlier with MVB.

Conclusions And Clinical Relevance: Haemodynamic performance was improved by vatinoxan co-administration with medetomidine-butorphanol, before and after ketamine administration. However, vatinoxan was associated with mild hypotension after ketamine with the dose used in this study. Vatinoxan shortened the duration of anaesthesia.
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http://dx.doi.org/10.1016/j.vaa.2020.05.008DOI Listing
September 2020

Moral Distress, Mattering, and Secondary Traumatic Stress in Provider Burnout: A Call for Moral Community.

AACN Adv Crit Care 2020 Jun;31(2):146-157

Mary Faith Marshall is Emily Davie and Joseph S. Kornfeld Professor of Biomedical Ethics, University of Virginia School of Medicine Center for Health Humanities and Ethics; and Professor of Nursing, University of Virginia School of Nursing, Charlottesville, Virginia.

Burnout incurs significant costs to health care organizations and professionals. Mattering, moral distress, and secondary traumatic stress are personal experiences linked to burnout and are byproducts of the organizations in which we work. This article conceptualizes health care organizations as moral communities-groups of people united by a common moral purpose to promote the well-being of others. We argue that health care organizations have a fundamental obligation to mitigate and prevent the costs of caring (eg, moral distress, secondary traumatic stress) and to foster a sense of mattering. Well-functioning moral communities have strong support systems, inclusivity, fairness, open communication, and collaboration and are able to protect their members. In this article, we address mattering, moral distress, and secondary traumatic stress as they relate to burnout. We conclude that leaders of moral communities are responsible for implementing systemic changes that foster mattering among its members and attend to the problems that cause moral distress and burnout.
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http://dx.doi.org/10.4037/aacnacc2020285DOI Listing
June 2020

PTEN activation contributes to neuronal and synaptic engulfment by microglia in tauopathy.

Acta Neuropathol 2020 07 31;140(1):7-24. Epub 2020 Mar 31.

Clem Jones Centre for Ageing Dementia Research, Queensland Brain Institute, The University of Queensland, Brisbane, QLD, Australia.

Phosphatase and tensin homolog (PTEN) regulates synaptic density in development; however, whether PTEN also regulates synapse loss in a neurodegenerative disorder such as frontotemporal lobar degeneration with Tau deposition (FTLD-Tau) has not been explored. Here, we found that pathological Tau promotes early activation of PTEN, which precedes apoptotic caspase-3 cleavage in the rTg4510 mouse model of FTLD-Tau. We further demonstrate increased synaptic and neuronal exposure of the apoptotic signal phosphatidylserine that tags neuronal structures for microglial uptake, thereby linking PTEN activation to synaptic and neuronal structure elimination. By applying pharmacological inhibition of PTEN's protein phosphatase activity, we observed that microglial uptake can be decreased in Tau transgenic mice. Finally, we reveal a dichotomous relationship between PTEN activation and age in FTLD-Tau patients and healthy controls. Together, our findings suggest that in tauopathy, PTEN has a role in the synaptotoxicity of pathological Tau and promotes microglial removal of affected neuronal structures.
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http://dx.doi.org/10.1007/s00401-020-02151-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7300099PMC
July 2020

Toward Automation of the Supine Pressor Test for Preeclampsia.

J Eng Sci Med Diagn Ther 2019 Nov 19;2(4). Epub 2019 Nov 19.

Weldon School of Biomedical Engineering, Purdue Center for Cancer Research, Purdue University, 206 South Martin Jischke Drive, West Lafayette, IN 47907.

Preeclampsia leads to increased risk of morbidity and mortality for both mother and fetus. Most previous studies have largely neglected mechanical compression of the left renal vein by the gravid uterus as a potential mechanism. In this study, we first used a murine model to investigate the pathophysiology of left renal vein constriction. The results indicate that prolonged renal vein stenosis after 14 days can cause renal necrosis and an increase in blood pressure (BP) of roughly 30 mmHg. The second part of this study aimed to automate a diagnostic tool, known as the supine pressor test (SPT), to enable pregnant women to assess their preeclampsia development risk. A positive SPT has been previously defined as an increase of at least 20 mmHg in diastolic BP when switching between left lateral recumbent and supine positions. The results from this study established a baseline BP increase between the two body positions in nonpregnant women and demonstrated the feasibility of an autonomous SPT in pregnant women. Our results demonstrate that there is a baseline increase in BP of roughly 10-14 mmHg and that pregnant women can autonomously perform the SPT. Overall, this work in both rodents and humans suggests that (1) stenosis of the left renal vein in mice leads to elevation in BP and acute renal failure, (2) nonpregnant women experience a baseline increase in BP when they shift from left lateral recumbent to supine position, and (3) the SPT can be automated and used autonomously.
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http://dx.doi.org/10.1115/1.4045203DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7045991PMC
November 2019

Social Cooperativity of Bacteria during Reversible Surface Attachment in Young Biofilms: a Quantitative Comparison of Pseudomonas aeruginosa PA14 and PAO1.

mBio 2020 02 25;11(1). Epub 2020 Feb 25.

Department of Bioengineering, University of California, Los Angeles, Los Angeles, California, USA

What are bacteria doing during "reversible attachment," the period of transient surface attachment when they initially engage a surface, besides attaching themselves to the surface? Can an attaching cell help any other cell attach? If so, does it help all cells or employ a more selective strategy to help either nearby cells (spatial neighbors) or its progeny (temporal neighbors)? Using community tracking methods at the single-cell resolution, we suggest answers to these questions based on how reversible attachment progresses during surface sensing for strains PAO1 and PA14. Although PAO1 and PA14 exhibit similar trends of surface cell population increase, they show unanticipated differences when cells are considered at the lineage level and interpreted using the quantitative framework of an exactly solvable stochastic model. Reversible attachment comprises two regimes of behavior, processive and nonprocessive, corresponding to whether cells of the lineage stay on the surface long enough to divide, or not, before detaching. Stark differences between PAO1 and PA14 in the processive regime of reversible attachment suggest the existence of two surface colonization strategies. PAO1 lineages commit quickly to a surface compared to PA14 lineages, with early c-di-GMP-mediated exopolysaccharide (EPS) production that can facilitate the attachment of neighbors. PA14 lineages modulate their motility via cyclic AMP (cAMP) and retain memory of the surface so that their progeny are primed for improved subsequent surface attachment. Based on the findings of previous studies, we propose that the differences between PAO1 and PA14 are potentially rooted in downstream differences between Wsp-based and Pil-Chp-based surface-sensing systems, respectively. The initial pivotal phase of bacterial biofilm formation known as reversible attachment, where cells undergo a period of transient surface attachment, is at once universal and poorly understood. What is more, although we know that reversible attachment culminates ultimately in irreversible attachment, it is not clear how reversible attachment progresses phenotypically, as bacterial surface-sensing circuits fundamentally alter cellular behavior. We analyze diverse observed bacterial behavior one family at a time (defined as a full lineage of cells related to one another by division) using a unifying stochastic model and show that our findings lead to insights on the time evolution of reversible attachment and the social cooperative dimension of surface attachment in PAO1 and PA14 strains.
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http://dx.doi.org/10.1128/mBio.02644-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7042694PMC
February 2020

Antiretroviral therapy alone versus antiretroviral therapy with a kick and kill approach, on measures of the HIV reservoir in participants with recent HIV infection (the RIVER trial): a phase 2, randomised trial.

Lancet 2020 03 19;395(10227):888-898. Epub 2020 Feb 19.

Nuffield Department of Medicine, Oxford University, UK; Nuffield Department of Medicine, Oxford NIHR Biomedical Research Centre, Oxford, UK. Electronic address:

Background: Antiretroviral therapy (ART) cannot cure HIV infection because of a persistent reservoir of latently infected cells. Approaches that force HIV transcription from these cells, making them susceptible to killing-termed kick and kill regimens-have been explored as a strategy towards an HIV cure. RIVER is the first randomised trial to determine the effect of ART-only versus ART plus kick and kill on markers of the HIV reservoir.

Methods: This phase 2, open-label, multicentre, randomised, controlled trial was undertaken at six clinical sites in the UK. Patients aged 18-60 years who were confirmed as HIV-positive within a maximum of the past 6 months and started ART within 1 month from confirmed diagnosis were randomly assigned by a computer generated randomisation list to receive ART-only (control) or ART plus the histone deacetylase inhibitor vorinostat (the kick) and replication-deficient viral vector T-cell inducing vaccines encoding conserved HIV sequences ChAdV63. HIVconsv-prime and MVA.HIVconsv-boost (the kill; ART + V + V; intervention). The primary endpoint was total HIV DNA isolated from peripheral blood CD4 T-cells at weeks 16 and 18 after randomisation. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, NCT02336074.

Findings: Between June 14, 2015 and Jul 11, 2017, 60 men with HIV were randomly assigned to receive either an ART-only (n=30) or an ART + V + V (n=30) regimen; all 60 participants completed the study, with no loss-to-follow-up. Mean total HIV DNA at weeks 16 and 18 after randomisation was 3·02 log copies HIV DNA per 10 CD4 T-cells in the ART-only group versus 3·06 log copies HIV DNA per 10 CD4 T-cells in ART + V + V group, with no statistically significant difference between the two groups (mean difference of 0·04 log copies HIV DNA per 10 CD4 T-cells [95% CI -0·03 to 0·11; p=0·26]). There were no intervention-related serious adverse events.

Interpretation: This kick and kill approach conferred no significant benefit compared with ART alone on measures of the HIV reservoir. Although this does not disprove the efficacy kick and kill strategy, for future trials enhancement of both kick and kill agents will be required.

Funding: Medical Research Council (MR/L00528X/1).
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http://dx.doi.org/10.1016/S0140-6736(19)32990-3DOI Listing
March 2020

Web based surveys - recommendations for their design and interpretation.

Authors:
Rachel C Bennett

Vet Anaesth Analg 2020 01;47(1):1-2

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http://dx.doi.org/10.1016/j.vaa.2019.12.002DOI Listing
January 2020

Selection of an Efficient AAV Vector for Robust CNS Transgene Expression.

Mol Ther Methods Clin Dev 2019 Dec 23;15:320-332. Epub 2019 Oct 23.

Molecular Neurogenetics Unit, Department of Neurology, Massachusetts General Hospital, Charlestown, MA 02129.

Adeno-associated virus (AAV) capsid libraries have generated improved transgene delivery vectors. We designed an AAV library construct, iTransduce, that combines a peptide library on the AAV9 capsid with a Cre cassette to enable sensitive detection of transgene expression. After only two selection rounds of the library delivered intravenously in transgenic mice carrying a Cre-inducible fluorescent protein, we flow sorted fluorescent cells from brain, and DNA sequencing revealed two dominant capsids. One of the capsids, termed AAV-F, mediated transgene expression in the brain cortex more than 65-fold (astrocytes) and 171-fold (neurons) higher than the parental AAV9. High transduction efficiency was sex-independent and sustained in two mouse strains (C57BL/6 and BALB/c), making it a highly useful capsid for CNS transduction of mice. Future work in large animal models will test the translation potential of AAV-F.
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http://dx.doi.org/10.1016/j.omtm.2019.10.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6881693PMC
December 2019

2019 Awards for significant contributions to veterinary anaesthesiology.

Vet Anaesth Analg 2019 11;46(6):717-718

Wimborne, UK.

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http://dx.doi.org/10.1016/j.vaa.2019.10.002DOI Listing
November 2019

[F]-AV-1451 binding profile in chronic traumatic encephalopathy: a postmortem case series.

Acta Neuropathol Commun 2019 10 28;7(1):164. Epub 2019 Oct 28.

MassGeneral Institute for Neurodegenerative Disease, Charlestown, MA, USA.

Introduction: Chronic traumatic encephalopathy (CTE) is a tauopathy associated to repetitive head trauma. There are no validated in vivo biomarkers of CTE and a definite diagnosis can only be made at autopsy. Recent studies have shown that positron emission tomography (PET) tracer AV-1451 (Flortaucipir) exhibits high binding affinity for paired helical filament (PHF)-tau aggregates in Alzheimer (AD) brains but relatively low affinity for tau lesions in other tauopathies like temporal lobal degeneration (FTLD)-tau, progressive supranuclear palsy (PSP) or corticobasal degeneration (CBD). Little is known, however, about the binding profile of this ligand to the tau-containing lesions of CTE.

Objective: To study the binding properties of [F]-AV-1451 on pathologically confirmed CTE postmortem brain tissue samples.

Methods: We performed [F]-AV-1451 phosphor screen and high resolution autoradiography, quantitative tau measurements by immunohistochemistry and Western blot and tau seeding activity assays in brain blocks containing hippocampus, superior temporal cortex, superior frontal cortex, inferior parietal cortex and occipital cortex from 5 cases of CTE, across the stages of disease: stage II-III (n = 1), stage III (n = 3), and stage IV (n = 1). Importantly, low or no concomitant classic AD pathology was present in these brains.

Results: Despite the presence of abundant tau aggregates in multiple regions in all CTE brains, only faint or no [F]-AV-1451 binding signal could be detected by autoradiography. The only exception was the presence of a strong signal confined to the region of the choroid plexus and the meninges in two of the five cases. Tau immunostaining and Thioflavin-S staining ruled out the presence of tau aggregates in those regions. High resolution nuclear emulsion autoradiography revealed the presence of leptomeningeal melanocytes as the histologic source of this off-target binding. Levels of abnormally hyperphosphorylated tau species, as detected by Western Blotting, and tau seeding activity were both found to be lower in extracts from cases CTE when compared to AD.

Conclusion: AV-1451 may have limited utility for in vivo selective and reliable detection of tau aggregates in CTE. The existence of disease-specific tau conformations may likely explain the differential binding affinity of this tracer for tau lesions in different tauopathies.
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http://dx.doi.org/10.1186/s40478-019-0808-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6816221PMC
October 2019

Unemployment, employment precarity, and inflammation.

Brain Behav Immun 2020 01 14;83:303-308. Epub 2019 Oct 14.

Health Research Institute, Department of Psychology, University of Limerick, Ireland.

Unemployment has been associated with poorer health, but few studies have examined the biological mechanisms that confer these health decrements. Further, no studies to date have examined differences across employment groups to consider whether employment (in whatever means) is preferential in terms of health. The present study utilised secondary data from Understanding Society: The Household Longitudinal Survey during the aftermath of the recent global recession. Two markers of peripheral inflammation: C-reactive protein (CRP) and fibrinogen were assessed across employment groups (unemployed; permanent, temporary, and self-employed), controlling for individual, socio-demographic and health variables to give greater context to our understanding of how employment status influences health. After controlling for relevant confounds, unemployment was associated with higher levels of fibrinogen but not CRP. Subsequent analyses of employment subgroup revealed the temporary employed have similar levels of fibrinogen to the unemployed, and may therefore be at a similar health disadvantage. The findings confirm that unemployment is associated with increases in one marker of peripheral inflammation, but that this health protection is not conferred to those in precarious employment.
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http://dx.doi.org/10.1016/j.bbi.2019.10.013DOI Listing
January 2020

Experimental evidence for the age dependence of tau protein spread in the brain.

Sci Adv 2019 06 26;5(6):eaaw6404. Epub 2019 Jun 26.

Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.

The incidence of Alzheimer's disease (AD), which is characterized by progressive cognitive decline that correlates with the spread of tau protein aggregation in the cortical mantle, is strongly age-related. It could be that age predisposes the brain for tau misfolding and supports the propagation of tau pathology. We tested this hypothesis using an experimental setup that allowed for exploration of age-related factors of tau spread and regional vulnerability. We virally expressed human tau locally in entorhinal cortex (EC) neurons of young or old mice and monitored the cell-to-cell tau protein spread by immunolabeling. Old animals showed more tau spreading in the hippocampus and adjacent cortical areas and accumulated more misfolded tau in EC neurons. No misfolding, at any age, was observed in the striatum, a brain region mostly unaffected by tangles. Age and brain region dependent tau spreading and misfolding likely contribute to the profound age-related risk for sporadic AD.
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http://dx.doi.org/10.1126/sciadv.aaw6404DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6594764PMC
June 2019

Peer review - An editor's perspective.

Authors:
Rachel C Bennett

Vet Anaesth Analg 2019 May;46(3):257-259

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http://dx.doi.org/10.1016/j.vaa.2019.04.003DOI Listing
May 2019

Comparison of Brody's formula with respiratory gas analysis for estimating oxygen consumption in anaesthetized dogs.

Vet Anaesth Analg 2019 May 23;46(3):365-368. Epub 2019 Feb 23.

Royal (Dick) School of Veterinary Studies, University of Edinburgh, Easter Bush, Roslin, Edinburgh, Scotland, UK.

Objective: To determine agreement in oxygen consumption (V˙O) values calculated using Sykes' formula V˙O = (FiO - Fe'O) * V˙ (where Fi and Fe are the inspired and end-tidal fractional concentrations of O, respectively, and V˙ is minute volume) with values derived using Brody's formula (V˙O = 10 kg). It was hypothesized that the two methods would not yield statistically significant differences in calculated values.

Study Design: Prospective, clinical, pilot study.

Animals: A total of 22 client-owned dogs.

Methods: Dogs undergoing surgery were anaesthetized with either isoflurane or sevoflurane. The V˙, FiO and Fe'O were measured during mechanical ventilation of the lungs (tidal volume 10 mL kg; respiratory rate: 8-12 breaths minute). Oesophageal temperature was maintained between 37.0 °C and 38.5 °C. Values for V˙O derived by Sykes' and Brody's methods were compared and agreement was determined using Bland-Altman analysis.

Results: Mean V˙O values were 4.67 ± 0.51 mL kg minute and 5.32 ± 1.69 mL kg minute calculated using Brody's formula and Sykes' equation, respectively. There was greater variability in the values obtained from Sykes' equation. The Bland-Altman plot revealed a proportional error with correlation but poor agreement between values.

Conclusions And Clinical Relevance: Both methods yielded V˙O values of approximately 5 mL kgminute with no statistically significant differences between the two methods.
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http://dx.doi.org/10.1016/j.vaa.2018.11.008DOI Listing
May 2019

Parental Perspectives on Roles in End-of-Life Decision Making in the Pediatric Intensive Care Unit: An Integrative Review.

J Pediatr Nurs 2019 May - Jun;46:18-25. Epub 2019 Mar 1.

School of Nursing, University of Virginia, Charlottesville, VA, United States. Electronic address:

Problem: Little is known about how parents perceive their role or the role of health care providers (HCPs) during end-of-life decision making (EOL DM) in the context of the pediatric intensive care unit (PICU).

Eligibility Criteria: The authors searched CINAHL, PubMed, Ovid Medline, Web of Science, Social Science Database, PsycINFO, and Google scholar for English language studies performed in the United States related to parental perception of parental or HCP roles in EOL DM in the PICU since 2008.

Sample: Eleven studies of parents and health care providers (HCPs) of critically ill children in the PICU and/or receiving inpatient pediatric palliative care, and bereaved parents of PICU patients.

Results: Most parents reported belief that EOL DM is within the domain of parental role, a minority felt it was a physician's responsibility. Parental EOL DM is rooted more firmly in emotion and perception and a desire to be a 'good parent' to a child at EOL in the way they see fit than HCP recommendations or 'medical facts'. Parents need HCPs to treat them as allies, communicate well, and be trustworthy.

Conclusions: Role conflict may exist between parents and HCPs who are prioritizing different attributes of the parental role. The role of the nurse in support of parental role in the PICU is not well-elucidated in the extant literature.

Implications: Future research should focus on what parents need from HCPs, especially nurses, to support their parental role, and factors that facilitate the development of trust and good communication.
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http://dx.doi.org/10.1016/j.pedn.2019.02.029DOI Listing
December 2019

Partial reduction of microglia does not affect tau pathology in aged mice.

J Neuroinflammation 2018 Nov 9;15(1):311. Epub 2018 Nov 9.

Department of Neurology, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, 02129, USA.

Background: Activation of inflammation pathways in the brain occurs in Alzheimer's disease and may contribute to the accumulation and spread of pathological proteins including tau. The goal of this study was to identify how changes in microglia, a key inflammatory cell type, may contribute to tau protein accumulation and pathology-associated changes in immune and non-immune cell processes such as neuronal degeneration, astrocyte physiology, cytokine expression, and blood vessel morphology.

Methods: We used PLX3397 (290 mg/kg), a colony-stimulating factor receptor 1 (CSF1R) inhibitor, to reduce the number of microglia in the brains of a tau-overexpressing mouse model. Mice were fed PLX3397 in chow or a control diet for 3 months beginning at 12 months of age and then were subsequently analyzed for changes in blood vessel morphology by in vivo two-photon microscopy and tissues were collected for biochemistry and histology.

Results: PLX3397 reduced microglial numbers by 30% regardless of genotype compared to control diet-treated mice. No change in tau burden, cortical atrophy, blood vessels, or astrocyte activation was detected. All Tg4510 mice were observed to have an increased in "disease-associated" microglial gene expression, but PLX3397 treatment did not reduce expression of these genes. Surprisingly, PLX3397 treatment resulted in upregulation of CD68 and Tgf1β.

Conclusions: Manipulating microglial activity may not be an effective strategy to combat tau pathological lesions. Higher doses of PLX3397 may be required or earlier intervention in the disease course. Overall, this indicates a need for a better understanding of specific microglial changes and their relation to the disease process.
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http://dx.doi.org/10.1186/s12974-018-1348-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6230271PMC
November 2018

Tau Protein Disrupts Nucleocytoplasmic Transport in Alzheimer's Disease.

Neuron 2018 09;99(5):925-940.e7

Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA. Electronic address:

Tau is the major constituent of neurofibrillary tangles in Alzheimer's disease (AD), but the mechanism underlying tau-associated neural damage remains unclear. Here, we show that tau can directly interact with nucleoporins of the nuclear pore complex (NPC) and affect their structural and functional integrity. Pathological tau impairs nuclear import and export in tau-overexpressing transgenic mice and in human AD brain tissue. Furthermore, the nucleoporin Nup98 accumulates in the cell bodies of some tangle-bearing neurons and can facilitate tau aggregation in vitro. These data support the hypothesis that tau can directly interact with NPC components, leading to their mislocalization and consequent disruption of NPC function. This raises the possibility that NPC dysfunction contributes to tau-induced neurotoxicity in AD and tauopathies.
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http://dx.doi.org/10.1016/j.neuron.2018.07.039DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6240334PMC
September 2018

Nuclear rupture at sites of high curvature compromises retention of DNA repair factors.

J Cell Biol 2018 11 31;217(11):3796-3808. Epub 2018 Aug 31.

Physical Sciences Oncology Center at Penn, University of Pennsylvania, Philadelphia, PA

The nucleus is physically linked to the cytoskeleton, adhesions, and extracellular matrix-all of which sustain forces, but their relationships to DNA damage are obscure. We show that nuclear rupture with cytoplasmic mislocalization of multiple DNA repair factors correlates with high nuclear curvature imposed by an external probe or by cell attachment to either aligned collagen fibers or stiff matrix. Mislocalization is greatly enhanced by lamin A depletion, requires hours for nuclear reentry, and correlates with an increase in pan-nucleoplasmic foci of the DNA damage marker γH2AX. Excess DNA damage is rescued in ruptured nuclei by cooverexpression of multiple DNA repair factors as well as by soft matrix or inhibition of actomyosin tension. Increased contractility has the opposite effect, and stiff tumors with low lamin A indeed exhibit increased nuclear curvature, more frequent nuclear rupture, and excess DNA damage. Additional stresses likely play a role, but the data suggest high curvature promotes nuclear rupture, which compromises retention of DNA repair factors and favors sustained damage.
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http://dx.doi.org/10.1083/jcb.201711161DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6219729PMC
November 2018

Peripheral α-adrenoceptor antagonism affects the absorption of intramuscularly coadministered drugs.

Vet Anaesth Analg 2018 Jul 3;45(4):405-413. Epub 2018 Feb 3.

Department of Equine and Small Animal Medicine, University of Helsinki, Helsinki, Finland.

Objective: We determined the possible effects of a peripherally acting α-adrenoceptor antagonist, MK-467, on the absorption of intramuscularly (IM) coadministered medetomidine, butorphanol and midazolam.

Study Design: Randomized, experimental, blinded crossover study.

Animals: Six healthy Beagle dogs.

Methods: Two IM treatments were administered: 1) medetomidine hydrochloride (20 μg kg) + butorphanol (100 μg kg) + midazolam (200 μg kg; MBM) and 2) MBM + MK-467 hydrochloride (500 μg kg; MBM-MK), mixed in a syringe. Heart rate was recorded at regular intervals. Sedation was assessed with visual analog scales (0-100 mm). Drug concentrations in plasma were analyzed with liquid chromatography-tandem mass spectrometry, with chiral separation of dex- and levomedetomidine. Maximum drug concentrations in plasma (C) and time to C (T) were determined. Paired t-tests, with Bonferroni correction when appropriate, were used for comparisons between the treatments.

Results: Data from five dogs were analyzed. Heart rate was significantly higher from 20 to 90 minutes after MBM-MK. The T values for midazolam and levomedetomidine (mean ± standard deviation) were approximately halved with coadministration of MK-467, from 23 ± 9 to 11 ± 6 minutes (p = 0.049) for midazolam and from 32 ± 15 to 18 ± 6 minutes for levomedetomidine (p = 0.036), respectively.

Conclusions And Clinical Relevance: MK-467 accelerated the absorption of IM coadministered drugs. This is clinically relevant as it may hasten the onset of peak sedative effects.
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http://dx.doi.org/10.1016/j.vaa.2018.01.008DOI Listing
July 2018

Tau reduction in the presence of amyloid-β prevents tau pathology and neuronal death in vivo.

Brain 2018 07;141(7):2194-2212

Department of Neurology, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts, USA.

Several studies have now supported the use of a tau lowering agent as a possible therapy in the treatment of tauopathy disorders, including Alzheimer's disease. In human Alzheimer's disease, however, concurrent amyloid-β deposition appears to synergize and accelerate tau pathological changes. Thus far, tau reduction strategies that have been tested in vivo have been examined in the setting of tau pathology without confounding amyloid-β deposition. To determine whether reducing total human tau expression in a transgenic model where there is concurrent amyloid-β plaque formation can still reduce tau pathology and protect against neuronal loss, we have taken advantage of the regulatable tau transgene in APP/PS1 × rTg4510 mice. These mice develop both neurofibrillary tangles as well as amyloid-β plaques throughout the cortex and hippocampus. By suppressing human tau expression for 6 months in the APP/PS1 × rTg4510 mice using doxycycline, AT8 tau pathology, bioactivity, and astrogliosis were reduced, though importantly to a lesser extent than lowering tau in the rTg4510 alone mice. Based on non-denaturing gels and proteinase K digestions, the remaining tau aggregates in the presence of amyloid-β exhibit a longer-lived aggregate conformation. Nonetheless, lowering the expression of the human tau transgene was sufficient to equally ameliorate thioflavin-S positive tangles and prevent neuronal loss equally well in both the APP/PS1 × rTg4510 mice and the rTg4510 cohort. Together, these results suggest that, although amyloid-β stabilizes tau aggregates, lowering total tau levels is still an effective strategy for the treatment of tau pathology and neuronal loss even in the presence of amyloid-β deposition.
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http://dx.doi.org/10.1093/brain/awy117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6022692PMC
July 2018

Multigenerational memory and adaptive adhesion in early bacterial biofilm communities.

Proc Natl Acad Sci U S A 2018 04 20;115(17):4471-4476. Epub 2018 Mar 20.

Department of Bioengineering, University of California Los Angeles, CA 90095;

Using multigenerational, single-cell tracking we explore the earliest events of biofilm formation by During initial stages of surface engagement (≤20 h), the surface cell population of this microbe comprises overwhelmingly cells that attach poorly (∼95% stay <30 s, well below the ∼1-h division time) with little increase in surface population. If we harvest cells previously exposed to a surface and direct them to a virgin surface, we find that these surface-exposed cells and their descendants attach strongly and then rapidly increase the surface cell population. This "adaptive," time-delayed adhesion requires determinants we showed previously are critical for surface sensing: type IV pili (TFP) and cAMP signaling via the Pil-Chp-TFP system. We show that these surface-adapted cells exhibit damped, coupled out-of-phase oscillations of intracellular cAMP levels and associated TFP activity that persist for multiple generations, whereas surface-naïve cells show uncorrelated cAMP and TFP activity. These correlated cAMP-TFP oscillations, which effectively impart intergenerational memory to cells in a lineage, can be understood in terms of a Turing stochastic model based on the Pil-Chp-TFP framework. Importantly, these cAMP-TFP oscillations create a state characterized by a suppression of TFP motility coordinated across entire lineages and lead to a drastic increase in the number of surface-associated cells with near-zero translational motion. The appearance of this surface-adapted state, which can serve to define the historical classification of "irreversibly attached" cells, correlates with family tree architectures that facilitate exponential increases in surface cell populations necessary for biofilm formation.
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http://dx.doi.org/10.1073/pnas.1720071115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5924909PMC
April 2018

Work and family transitions and the self-rated health of young women in South Africa.

Soc Sci Med 2018 04 2;203:9-18. Epub 2018 Mar 2.

The Open University, United Kingdom. Electronic address:

Understanding the transition to adulthood has important implications for supporting young adults and understanding the roots of diversity in wellbeing later in life. In South Africa, the end of Apartheid means today's youth are experiencing their transition to adulthood in a changed social and political context which offers opportunities compared to the past but also threats. This paper presents the first national level analysis of the patterning of key transitions (completion of education, entry into the labour force, motherhood and marriage or cohabitation), and the association between the different pathways and health amongst young women. With the use of longitudinal data from the South African National Income Dynamics Study (2008-2015), this paper employs sequence analysis to identify common pathways to adulthood amongst women aged 15-17 years at baseline (n = 429) and logistic regression modelling to examine the association between these pathways and self-rated health. The sequence analysis identified five pathways: 1. 'Non-activity commonly followed by motherhood', 2. 'Pathway from school, motherhood then work', 3. 'Motherhood combined with schooling', 4. 'Motherhood after schooling', and 5. 'Schooling to non-activity'. After controlling for baseline socio-economic and demographic characteristics and health, the regression results show young women who followed pathways characterised by early motherhood and economic inactivity (1, 3 and 4) had poorer self-rated health compared to women whose pathways were characterised by combining motherhood and economic activity (2) and young women who were yet to become economically active or mothers (5). Therefore, policies should seek to prevent adolescent childbearing, support young mothers to continue their educational careers and enable mothers in work and seeking work to balance their work and care responsibilities. Further, the findings highlight the value of taking a holistic approach to health and provide further evidence for the need to consider work-family balance in the development agenda.
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http://dx.doi.org/10.1016/j.socscimed.2018.03.001DOI Listing
April 2018

Tau protein liquid-liquid phase separation can initiate tau aggregation.

EMBO J 2018 04 22;37(7). Epub 2018 Feb 22.

Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA

The transition between soluble intrinsically disordered tau protein and aggregated tau in neurofibrillary tangles in Alzheimer's disease is unknown. Here, we propose that soluble tau species can undergo liquid-liquid phase separation (LLPS) under cellular conditions and that phase-separated tau droplets can serve as an intermediate toward tau aggregate formation. We demonstrate that phosphorylated or mutant aggregation prone recombinant tau undergoes LLPS, as does high molecular weight soluble phospho-tau isolated from human Alzheimer brain. Droplet-like tau can also be observed in neurons and other cells. We found that tau droplets become gel-like in minutes, and over days start to spontaneously form thioflavin-S-positive tau aggregates that are competent of seeding cellular tau aggregation. Since analogous LLPS observations have been made for FUS, hnRNPA1, and TDP43, which aggregate in the context of amyotrophic lateral sclerosis, we suggest that LLPS represents a biophysical process with a role in multiple different neurodegenerative diseases.
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http://dx.doi.org/10.15252/embj.201798049DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5881631PMC
April 2018

A retrospective report (2003-2013) of the complications associated with the use of a one-man (head and tail) rope recovery system in horses following general anaesthesia.

Ir Vet J 2018;71. Epub 2018 Feb 13.

The Granary, Bunstead Barns, Poles Ln, Hursley, Winchester, SO21 2LL UK.

Background: The mortality rate of horses undergoing general anaesthesia is high when compared to humans or small animal patients. One of the most critical periods during equine anaesthesia is recovery, as the horse attempts to regain a standing position. This study was performed in a private equine practice in Belgium that uses a purpose-designed one-man (head and tail) rope recovery system to assist the horse during the standing process.The main purpose of the retrospective study was to report and analyse complications and the mortality rate in horses during recovery from anaesthesia using the described recovery system. Information retrieved from the medical records included patient signalment, anaesthetic protocol, duration of anaesthesia, ASA grade, type of surgery, recovery time and complications during recovery. Sedation was administered to all horses prior to recovery with the rope system. Complications were divided into major complications in which the horse was euthanized and minor complications where the horse survived. Major complications were further subdivided into those where the rope system did not contribute to the recovery complication (Group 1) and those where it was not possible to determine if the rope system was of any benefit (Group 2).

Results: Five thousand eight hundred fifty two horses recovered from general anaesthesia with rope assistance. Complications were identified in 30 (0.51%). Major complications occurred in 12 horses (0.20%) of which three (0.05%) were assigned to Group 1 and nine (0.15%) to Group 2. Three horses in Group 2 suffered musculoskeletal injuries (0.05%). Eighteen horses (0.31%) suffered minor complications, of which five (0.08%) were categorised as failures of the recovery system.

Conclusions: This study reports the major and minor complication and mortality rate during recovery from anaesthesia using a specific type of rope recovery system. Mortality associated with the rope recovery system was low. During recovery from anaesthesia this rope system may reduce the risk of lethal complications, particularly major orthopaedic injuries.
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http://dx.doi.org/10.1186/s13620-018-0117-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5810068PMC
February 2018