Transforming growth factor-ß1 induces cerebrovascular dysfunction and astrogliosis through angiotensin II type 1 receptor-mediated signaling pathways.

Transgenic mice constitutively overexpressing the cytokine transforming growth factor-ß1 (TGF-ß1) (TGF mice) display cerebrovascular alterations as seen in Alzheimer's disease (AD) and vascular cognitive impairment and dementia (VCID), but no or only subtle cognitive deficits. TGF-ß1 may exert part of its deleterious effects through interactions with angiotensin II (AngII) type 1 receptor (AT1R) signaling pathways. We test such interactions in the brain and cerebral vessels of TGF mice by measuring cerebrovascular reactivity, levels of protein markers of vascular fibrosis, nitric oxide synthase activity, astrogliosis, and mnemonic performance in mice treated (6 months) with the AT1R blocker losartan (10 mg/kg per day) or the angiotensin converting enzyme inhibitor enalapril (3 mg/kg per day). Both treatments restored the severely impaired cerebrovascular reactivity to acetylcholine, calcitonin gene-related peptide, endothelin-1, and the baseline availability of nitric oxide in aged TGF mice. Losartan, but not enalapril, significantly reduced astrogliosis and cerebrovascular levels of profibrotic protein connective tissue growth factor while raising levels of antifibrotic enzyme matrix metallopeptidase-9. Memory was unaffected by aging and treatments. The results suggest a pivotal role for AngII in TGF-ß1-induced cerebrovascular dysfunction and neuroinflammation through AT1R-mediated mechanisms. Further, they suggest that AngII blockers could be appropriate against vasculopathies and astrogliosis associated with AD and VCID.

Relations between work and upper extremity musculoskeletal problems (UEMSP) and the moderating role of psychosocial work factors on the relation between computer work and UEMSP.

PURPOSE: Computer work has been identified as a risk factor for upper extremity musculoskeletal problems (UEMSP). But few studies have investigated how psychosocial and organizational work factors affect this relation. Nor have gender differences in the relation between UEMSP and these work factors  been studied. We sought to estimate: (1) the association between UEMSP and a range of physical, psychosocial and organizational work exposures, including the duration of computer work, and (2) the moderating effect of psychosocial work exposures on the relation between computer work and UEMSP. METHODS: Using 2007-2008 Québec survey data on 2478 workers, we carried out gender-stratified multivariable logistic regression modeling and two-way interaction analyses. RESULTS: In both genders, odds of UEMSP were higher with exposure to high physical work demands and emotionally demanding work. Additionally among women, UEMSP were associated with duration of occupational computer exposure, sexual harassment, tense situations when dealing with clients, high quantitative demands and lack of prospects for promotion, and among men, with low coworker support, episodes of unemployment, low job security and contradictory work demands. Among women, the effect of computer work on UEMSP was considerably increased in the presence of emotionally demanding work, and may also be moderated by low recognition at work, contradictory work demands, and low supervisor support. CONCLUSIONS: These results suggest that the relations between UEMSP and computer work are moderated by psychosocial work exposures and that the relations between working conditions and UEMSP are somewhat different for each gender, highlighting the complexity of these relations and the importance of considering gender.

Economic evaluations of ergonomic interventions preventing work-related musculoskeletal disorders: a systematic review of organizational-level interventions.

BACKGROUND: Work-related musculoskeletal disorders (WMSD) represent a major public health problem and economic burden to employers, workers and health insurance systems. This systematic review had two objectives: (1) to analyze the cost-benefit results of organizational-level ergonomic workplace-based interventions aimed at preventing WMSD, (2) to explore factors related to the implementation process of these interventions (obstacles and facilitating factors) in order to identify whether economic results may be due to a successful or unsuccessful implementation. METHODS: Systematic review. Studies were searched in eight electronic databases and in reference lists of included studies. Companion papers were identified through backward and forward citation tracking. A quality assessment tool was developed following guidelines available in the literature. An integration of quantitative economic results and qualitative implementation data was conducted following an explanatory sequential design. RESULTS: Out of 189 records, nine studies met selection criteria and were included in our review. Out of nine included studies, grouped into four types of interventions, seven yielded positive economic results, one produced a negative result and one mixed results (negative cost-effectiveness and positive net benefit). However, the level of evidence was limited for the four types of interventions given the quality and the limited number of studies identified. Our review shows that among the nine included studies, negative and mixed economic results were observed when the dose delivered and received by participants was low, when the support from top and/or middle management was limited either due to limited participation of supervisors in training sessions or a lack of financial resources and when adequacy of intervention to workers' needs was low. In studies where economic results were positive, implementation data showed strong support from supervisors and a high rate of employee participation. CONCLUSION: Studies investigating the determinants of financial outcomes of prevention related to implementation process are very seldom. We recommend that in future research economic evaluation should include information on the implementation process in order to permit the interpretation of economic results and enhance the generalizability of results. This is also necessary for knowledge transfer and utilization of research results for prevention-oriented decision-making in occupational health and safety.

Angiotensin II type 1 receptor blocker losartan prevents and rescues cerebrovascular, neuropathological and cognitive deficits in an Alzheimer's disease model.

Angiotensin II (AngII) receptor blockers that bind selectively AngII type 1 (AT1) receptors may protect from Alzheimer's disease (AD). We studied the ability of the AT1 receptor antagonist losartan to cure or prevent AD hallmarks in aged (~18months at endpoint, 3months treatment) or adult (~12months at endpoint, 10months treatment) human amyloid precursor protein (APP) transgenic mice. We tested learning and memory with the Morris water maze, and evaluated neurometabolic and neurovascular coupling using [(18)F]fluoro-2-deoxy-D-glucose-PET and laser Doppler flowmetry responses to whisker stimulation. Cerebrovascular reactivity was assessed with on-line videomicroscopy. We measured protein levels of oxidative stress enzymes (superoxide dismutases SOD1, SOD2 and NADPH oxidase subunit p67phox), and quantified soluble and deposited amyloid-ß (Aß) peptide, glial fibrillary acidic protein (GFAP), AngII receptors AT1 and AT2, angiotensin IV receptor AT4, and cortical cholinergic innervation. In aged APP mice, losartan did not improve learning but it consolidated memory acquisition and recall, and rescued neurovascular and neurometabolic coupling and cerebrovascular dilatory capacity. Losartan normalized cerebrovascular p67phox and SOD2 protein levels and up-regulated those of SOD1. Losartan attenuated astrogliosis, normalized AT1 and AT4 receptor levels, but failed to rescue the cholinergic deficit and the Aß pathology. Given preventively, losartan protected cognitive function, cerebrovascular reactivity, and AT4 receptor levels. Like in aged APP mice, these benefits occurred without a decrease in soluble Aß species or plaque load. We conclude that losartan exerts potent preventive and restorative effects on AD hallmarks, possibly by mitigating AT1-initiated oxidative stress and normalizing memory-related AT4 receptors.

Underreporting work absences for nontraumatic work-related musculoskeletal disorders to workers' compensation: results of a 2007-2008 survey of the Québec working population.

OBJECTIVES: We examined underestimation of nontraumatic work-related musculoskeletal disorders (WMSDs) stemming from underreporting to workers' compensation (WC). METHODS: In data from the 2007 to 2008 Québec Survey on Working and Employment Conditions and Occupational Health and Safety we estimated, among nonmanagement salaried employees (NMSEs) (1) the prevalence of WMSDs and resulting work absence, (2) the proportion with WMSD-associated work absence who filed a WC claim, and (3) among those who did not file a claim, the proportion who received no replacement income. We modeled factors associated with not filing with multivariate logistic regression. RESULTS: Eighteen percent of NMSEs reported a WMSD, among whom 22.3% were absent from work. More than 80% of those absent did not file a WC claim, and 31.4% had no replacement income. Factors associated with not filing were higher personal income, higher seniority, shorter work absence, and not being unionized. CONCLUSIONS: The high level of WMSD underreporting highlights the limits of WC data for surveillance and prevention. Without WC benefits, injured workers may have reduced job protection and access to rehabilitation.

Psychosocial Risks among Quebec Healthcare Workers during the COVID-19 Pandemic: A Social Media Analysis.

During the COVID-19 pandemic, healthcare workers (HCWs) were at high risk of exposure to the SARS-CoV-2 virus and to work-related psychosocial risks, such as high psychological demands, low social support at work and low recognition. Because these factors are known to be detrimental to health, their detection and mitigation was essential to protect the healthcare workforce during the pandemic, when this study was initiated. Therefore, using Facebook monitoring, this study aims to identify the psychosocial risk factors to which HCWs in Quebec, Canada reported being exposed at work during the first and second pandemic waves. In this study, HCWs mainly refer to nurses, respiratory therapists, beneficiary attendants and technicians (doctors, managers and heads of healthcare establishments were deemed to be less likely to have expressed work-related concerns on the social media platforms explored). A qualitative exploratory research based on passive analysis of Facebook pages from three different unions was conducted. For each Facebook page, automatic data extraction was followed by and completed through manual extraction. Posts and comments were submitted to undergo thematic content analysis allowing main coded themes to emerge based on known theoretical frameworks of the psychosocial work environment. In total, 3796 Facebook posts and comments were analyzed. HCWs reported a variety of psychosocial work exposures, the most recurrent of which were high workload (including high emotional demands), lack of recognition and perceived injustice, followed by low workplace social support and work-life conflicts. Social media monitoring was a useful approach for documenting the psychosocial work environment during the COVID-19 crisis and could be a useful means of identifying potential targets for preventive interventions in future sanitary crises or in a context of major reforms or restructuring.

Are Organizational Interventions Effective in Protecting Healthcare Worker Mental Health during Epidemics/Pandemics? A Systematic Literature Review.

It is unclear how to effectively protect healthcare workers' mental health during infectious disease epidemics. Targeting the occupational determinants of stress may hold more promise than individual stress management, which has received more focus. Through a systematic review of the 2000-2021 English- and French-language scientific literature, we evaluated the effectiveness of organizational and psychosocial work environment interventions to protect healthcare workers' mental health in an epidemic/pandemic context. Evidence from medium- and high-quality studies was synthesized using GRADE. Among 1604 unique search results, 41 studies were deemed relevant, yielding 34 low-quality and seven medium-quality studies. The latter reported on promising multi-component prevention programs that combined staffing adjustments, work shift arrangements, enhanced infection prevention and control, recognition of workers' efforts, psychological and/or logistic support during lockdowns (e.g., accommodation). Our confidence in the effectiveness of reviewed interventions is low to very low, however, owing to methodological limitations. We highlight gaps in the reporting of intervention process and context elements and discuss theory and implementation failure as possible explanations for results. We conclude by urging authors of future studies to include and document detailed risk assessments of the work environment, involve workers in solution design and implementation and consider how this process can be adapted during an emergency.

Transgenic mice overexpressing APP and transforming growth factor-beta1 feature cognitive and vascular hallmarks of Alzheimer's disease.

High brain levels of amyloid-ß (Aß) and transforming growth factor-ß1 (TGF-ß1) have been implicated in the cognitive and cerebrovascular alterations of Alzheimer's disease (AD). We sought to investigate the impact of combined increases in Aß and TGF-ß1 on cerebrovascular, neuronal, and mnemonic function using transgenic mice overproducing these peptides (A/T mice). In particular, we measured cerebrovascular reactivity, evoked cerebral blood flow and glucose uptake during brain activation, cholinergic status, and spatial memory, along with cerebrovascular fibrosis, amyloidosis, and astrogliosis, and their evolution with age. An assessment of perfusion and metabolic responses was considered timely, given ongoing efforts for their validation as AD biomarkers. Relative to wild-type littermates, A/T mice displayed an early progressive decline in cerebrovascular dilatory ability, preserved contractility, and reduction in constitutive nitric oxide synthesis that establishes resting vessel tone. Altered levels of vasodilator-synthesizing enzymes and fibrotic proteins, resistance to antioxidant treatment, and unchanged levels of the antioxidant enzyme, superoxide dismutase-2, accompanied these impairments. A/T mice featured deficient neurovascular and neurometabolic coupling to whisker stimulation, cholinergic denervation, cerebral and cerebrovascular Aß deposition, astrocyte activation, and impaired Morris water maze performance, which gained severity with age. The combined Aß- and TGF-ß1-driven pathology recapitulates salient cerebrovascular, neuronal, and cognitive AD landmarks and yields a versatile model toward highly anticipated diagnostic and therapeutic tools for patients featuring Aß and TGF-ß1 increments.

Complete rescue of cerebrovascular function in aged Alzheimer's disease transgenic mice by antioxidants and pioglitazone, a peroxisome proliferator-activated receptor gamma agonist.

Accumulating evidence suggests that cerebrovascular dysfunction is an important factor in the pathogenesis of Alzheimer's disease (AD). Using aged ( approximately 16 months) amyloid precursor protein (APP) transgenic mice that exhibit increased production of the amyloid-beta (Abeta) peptide and severe cerebrovascular and memory deficits, we examined the capacity of in vivo treatments with the antioxidants N-acetyl-L-cysteine (NAC) and tempol, or the peroxisome proliferator-activated receptor gamma agonist pioglitazone to rescue cerebrovascular function and selected markers of AD neuropathology. Additionally, we tested the ability of pioglitazone to normalize the impaired increases in cerebral blood flow (CBF) and glucose uptake (CGU) induced by whisker stimulation, and to reverse spatial memory deficits in the Morris water maze. All compounds fully restored cerebrovascular reactivity of isolated cerebral arteries concomitantly with changes in proteins regulating oxidative stress, without reducing brain Abeta levels or Abeta plaque load. Pioglitazone, but not NAC, significantly attenuated astroglial activation and improved, albeit nonsignificantly, the reduced cortical cholinergic innervation. Furthermore, pioglitazone completely normalized the CBF and CGU responses to increased neuronal activity, but it failed to improve spatial memory. Our results are the first to demonstrate that late pharmacological intervention with pioglitazone not only overcomes cerebrovascular dysfunction and altered neurometabolic coupling in aged APP mice, but also counteracts cerebral oxidative stress, glial activation, and, partly, cholinergic denervation. Although early or combined therapy may be warranted to improve cognition, these findings unequivocally point to pioglitazone as a most promising strategy for restoring cerebrovascular function and counteracting several AD markers detrimental to neuronal function.

Simvastatin improves cerebrovascular function and counters soluble amyloid-beta, inflammation and oxidative stress in aged APP mice.

Cerebrovascular dysfunctions appear to contribute to Alzheimer's disease (AD) pathogenesis and the associated cognitive decline. Recently, it has been suggested that statins could be beneficial to AD patients independently from their cholesterol-lowering effects. Using 10 month-old amyloid precursor protein transgenic mice (APP mice), we sought to reverse cerebrovascular, neuronal and memory impairments with simvastatin (20 mg/kg/day, 8 weeks). Simvastatin improved reactivity of cerebral arteries, rescued the blood flow response to neuronal activation, attenuated oxidative stress and inflammation, and reduced cortical soluble amyloid-beta (Abeta) levels and the number of Abeta plaque-related dystrophic neurites. However, at such an advanced stage of the pathology, it failed to reduce Abeta plaque load and normalize cholinergic and memory deficits. These findings demonstrate that low-dose simvastatin treatment in aged APP mice largely salvages cerebrovascular function and has benefits on several AD landmarks, which could explain some of the positive effects of statins reported in AD patients.

Are work organization interventions effective in preventing or reducing work-related musculoskeletal disorders? A systematic review of the literature.

Objectives We sought to determine whether interventions that target work organization or the psychosocial work environment are effective in preventing or reducing work-related musculoskeletal disorders (WMSD) compared to usual work. Methods We systematically reviewed the 2000-2015 English- and French-language scientific literature, including studies evaluating the effectiveness of an organizational or psychosocial work intervention on incidence, prevalence or intensity of work-related musculoskeletal pain or disorders in the neck, shoulders, upper limbs and/or back or of work absence due to such problems, among non-sick-listed workers. We excluded rehabilitation and individual-level behavioral interventions and studies with >50% attrition. We analyzed medium- and high-quality studies and synthesized the evidence using the Grading of Recommendations Assessment, Development & Evaluation (GRADE) approach. An analysis of key workplace intervention elements supplemented the interpretation of results. Results We identified 884 articles; 28 met selection criteria, yielding 2 high-quality, 10 medium-quality and 16 low-quality studies. There was moderate evidence that supplementary breaks, compared to conventional break schedules, are effective in reducing symptom intensity in various body regions. Evidence was low-to-very-low quality for other interventions, primarily due to risk of bias related to study design, high attrition rates, co-interventions, and insensitive indicators. Most interventions lacked key intervention elements, such as work activity analysis and ergonomist guidance during implementation, but the relation of these elements to intervention effectiveness or ineffectiveness remains to be demonstrated. Conclusions Targeting work-rest cycles may reduce WMSD. Better quality studies are needed to allow definitive conclusions to be drawn on the effectiveness of other work organizational or psychosocial interventions to prevent or reduce WMSD.

Vascular remodeling versus amyloid beta-induced oxidative stress in the cerebrovascular dysfunctions associated with Alzheimer's disease.

The roles of oxidative stress and structural alterations in the cerebrovascular dysfunctions associated with Alzheimer's disease (AD) were investigated in transgenic mice overexpressing amyloid precusor protein (APP+) or transforming growth factor-beta1 (TGF+). Age-related impairments and their in vitro reversibility were evaluated, and underlying pathogenic mechanisms were assessed and compared with those seen in AD brains. Vasoconstrictions to 5-HT and endothelin-1 were preserved, except in the oldest (18-21 months of age) TGF+ mice. Despite unaltered relaxations to sodium nitroprusside, acetylcholine (ACh) and calcitonin gene-related peptide-mediated dilatations were impaired, and there was an age-related deficit in the basal availability of nitric oxide (NO) that progressed more gradually in TGF+ mice. The expression and progression of these deficits were unrelated to the onset or extent of thioflavin-S-positive vessels. Manganese superoxide dismutase (SOD2) was upregulated in pial vessels and around brain microvessels of APP+ mice, pointing to a role of superoxide in the dysfunctions elicited by amyloidosis. In contrast, vascular wall remodeling associated with decreased levels of endothelial NO synthase and cyclooxygenase-2 and increased contents of vascular endothelial growth factor and collagen-I and -IV characterized TGF+ mice. Exogenous SOD or catalase normalized ACh dilatations and NO availability in vessels from aged APP+ mice but had no effect in those of TGF+ mice. Increased perivascular oxidative stress was not evidenced in AD brains, but vascular wall alterations compared well with those seen in TGF+ mice. We conclude that brain vessel remodeling and associated alterations in levels of vasoactive signaling molecules are key contributors to AD cerebrovascular dysfunctions.

Enalapril Alone or Co-Administered with Losartan Rescues Cerebrovascular Dysfunction, but not Mnemonic Deficits or Amyloidosis in a Mouse Model of Alzheimer's Disease.

The co-administration of angiotensin converting enzyme inhibitors (ACEi) and angiotensin II (AngII) receptor blockers (ARB) that bind angiotensin type 1 receptors (AT1R) may protect from Alzheimer's disease (AD) better than each treatment taken alone. We tested the curative potential of the non brain-penetrant ACEi enalapril (3 mg/kg/day) administered for 3 months either alone or in combination with the brain penetrant ARB losartan (10 mg/kg/day) in aged (∼15 months) transgenic mice overexpressing a mutated form of the human amyloid-ß protein precursor (AßPP, thereafter APP mice). We studied cerebrovascular function, protein levels of oxidative stress markers (superoxide dismutases SOD1, SOD2 and the NADPH oxidase subunit p67phox), amyloid-ß (Aß) pathology, astrogliosis, cholinergic innervation, AT1R and angiotensin IV receptor (AT4R) levels, together with cognitive performance. Both treatments normalized cerebrovascular reactivity and p67phox protein levels, but they did not reduce the cerebrovascular levels of SOD1. Combined treatment normalized cerebrovascular SOD2 levels, significantly attenuated astrogliosis, but did not reduce the increased levels of cerebrovascular AT1R. Yet, combined therapy enhanced thioflavin-S labeled Aß plaque burden, a tendency not significant when Aß1 - 42 plaque load was considered. None of the treatments rescued cognitive deficits, cortical AT4R or cholinergic innervation. We conclude that both treatments normalized cerebrovascular function by inhibiting the AngII-induced oxidative stress cascade, and that the positive effects of the combined therapy on astrogliosis were likely due to the ability of losartan to enter brain parenchyma. However, enalapril did not potentiate, and may even dampen, the reported cognitive benefits of losartan, raising caution when selecting the most appropriate antihypertensive therapy in AD patients.

Neurovascular function in Alzheimer's disease patients and experimental models.

The ability of the brain to locally augment glucose delivery and blood flow during neuronal activation, termed neurometabolic and neurovascular coupling, respectively, is compromised in Alzheimer's disease (AD). Since perfusion deficits may hasten clinical deterioration and have been correlated with negative treatment outcome, strategies to improve the cerebral circulation should form an integral element of AD therapeutic efforts. These efforts have yielded several experimental models, some of which constitute AD models proper, others which specifically recapture the AD cerebrovascular pathology, characterized by anatomical alterations in brain vessel structure, as well as molecular changes within vascular smooth muscle cells and endothelial cells forming the blood-brain barrier. The following paper will present the elements of AD neurovascular dysfunction and review the in vitro and in vivo model systems that have served to deepen our understanding of it. It will also critically evaluate selected groups of compounds, the FDA-approved cholinesterase inhibitors and thiazolidinediones, for their ability to correct neurovascular dysfunction in AD patients and models. These and several others are emerging as compounds with pleiotropic actions that may positively impact dysfunctional cerebrovascular, glial, and neuronal networks in AD.

Intact memory in TGF-ß1 transgenic mice featuring chronic cerebrovascular deficit: recovery with pioglitazone.

The roles of chronic brain hypoperfusion and transforming growth factor-beta 1 (TGF-ß1) in Alzheimer's disease (AD) are unresolved. We investigated the interplay between TGF-ß1, cerebrovascular function, and cognition using transgenic TGF mice featuring astrocytic TGF-ß1 overexpression. We further assessed the impact of short, late therapy in elderly animals with the antioxidant N-acetyl-L-cysteine (NAC) or the peroxisome proliferator-activated receptor-γ agonist pioglitazone. The latter was also administered to pups as a prophylactic 1-year treatment. Elderly TGF mice featured cerebrovascular dysfunction that was not remedied with NAC. In contrast, pioglitazone prevented or reversed this deficit, and rescued the impaired neurovascular coupling response to whisker stimulation, although it failed to normalize the vascular structure. In aged TGF mice, neuronal and cognitive indices--the stimulus-evoked neurometabolic response, cortical cholinergic innervation, and spatial memory in the Morris water maze--were intact. Our findings show that impaired brain hemodynamics and cerebrovascular function are not accompanied by memory impairment in this model. Conceivably in AD, they constitute aggravating factors against a background of aging and underlying pathology. Our data further highlight the ability of pioglitazone to protect the cerebrovasculature marked by TGF-ß1 increase, aging, fibrosis, and antioxidant resistance, thus of high relevance for AD patients.

The Nuclear Receptor PPARgamma as a Therapeutic Target for Cerebrovascular and Brain Dysfunction in Alzheimer's Disease.

Peroxisome proliferator-activated receptors (PPARs) are ligand-activated nuclear transcription factors that regulate peripheral lipid and glucose metabolism. Three subtypes make up the PPAR family (alpha, gamma, beta/delta), and synthetic ligands for PPARalpha (fibrates) and PPARgamma (Thiazolidinediones, TZDs) are currently prescribed for the respective management of dyslipidemia and type 2 diabetes. In contrast to the well characterized action of PPARs in the periphery, little was known about the presence or function of these receptors in the brain and cerebral vasculature until fairly recently. Indeed, research in the last decade has uncovered these receptors in most brain cell types, and has shown that their activation, particularly that of PPARgamma, is implicated in normal brain and cerebrovascular physiology, and confers protection under pathological conditions. Notably, accumulating evidence has highlighted the therapeutic potential of PPARgamma ligands in the treatment of brain disorders such as Alzheimer's disease (AD), leading to the testing of the TZDs pioglitazone and rosiglitazone in AD clinical trials. This review will focus on the benefits of PPARgamma agonists for vascular, neuronal and glial networks, and assess the value of these compounds as future AD therapeutics in light of evidence from transgenic mouse models and recent clinical trials.