scholarly journals The impact of chronic mild hypoxia on cerebrovascular remodelling; uncoupling of angiogenesis and vascular breakdown

2021 ◽  
Vol 18 (1) ◽  
Author(s):  
Sebok K. Halder ◽  
Richard Milner
Keyword(s):  
Blood Vessels ◽  
Side Effect ◽  
Vascular Perfusion ◽  
Vascular Leak ◽  
Unwanted Side Effect ◽  
Endothelial Proliferation ◽  
Junction Protein ◽  
Temporary Closure ◽  
The Impact ◽  
Mild Hypoxia

Abstract Background Chronic mild hypoxia (CMH, 8% O2) stimulates robust vascular remodelling in the brain, but it also triggers transient vascular disruption. This raises the fundamental question: is the vascular leak an unwanted side-effect of angiogenic remodelling or is it a pathological response, unrelated to endothelial proliferation, in which declining oxygen levels trigger endothelial dysfunction? Methods To answer this question, mice were exposed to CMH (8% O2) for periods up to 14 days, after which, brain tissue was examined by immunofluorescence (IF) to determine which type of blood vessel (arteriole, capillary or venule) was most commonly associated with endothelial proliferation and vascular leak and how this correlated with tight junction protein expression. Vascular perfusion was examined using DiI. Data were analysed using one-way analysis of variance (ANOVA) followed by Tukey’s multiple comparison post-hoc test. Results The following was observed: (1) most endothelial proliferation and extravascular fibrinogen leak occurred in capillaries and to a lesser degree in venules, (2) much to our surprise, endothelial proliferation and extravascular fibrinogen leak never colocalized, (3) interestingly however, endothelial proliferation was strongly associated with an intravascular fibrinogen staining pattern not seen in stable blood vessels, (4) DiI perfusion studies revealed that angiogenic vessels were adequately perfused, suggesting that fibrinogen retention in angiogenic vessels is not due to temporary closure of the vessel, but more likely because fibrinogen is retained within the vessel wall, (5) bromodeoxyuridine (BrdU) labelling as a means to more permanently label proliferating endothelial cells, confirmed lack of any connection between endothelial proliferation and extravascular fibrinogen leak, while (6) in contrast, proliferating microglia were detected within extravascular leaks. Conclusions Taken together, our findings support the concept that in the short-term, hypoxia-induced endothelial proliferation triggers transient fibrinogen deposition within the walls of angiogenic blood vessels, but no overt vascular leak occurs in these vessels. Importantly, endothelial proliferation and extravascular fibrinogen leaks never co-localize, demonstrating that extravascular leak is not an unwanted side-effect of angiogenic endothelial proliferation, but rather a dysfunctional vascular response to hypoxia that occurs in a distinct group of non-angiogenic blood vessels.

scholarly journals Mild hypoxia triggers transient blood–brain barrier disruption: a fundamental protective role for microglia

2020 ◽  
Vol 8 (1) ◽  
Author(s):  
Sebok K. Halder ◽  
Richard Milner
Keyword(s):  
Spinal Cord ◽  
Blood Vessels ◽  
Blood Brain Barrier ◽  
Protective Role ◽  
Neurological Dysfunction ◽  
Brain Barrier ◽  
Vascular Leak ◽  
Vascular Integrity ◽  
Blood Brain ◽  
Mild Hypoxia

Abstract We recently demonstrated that when mice are exposed to chronic mild hypoxia (CMH, 8% O2), blood vessels in the spinal cord show transient vascular leak that is associated with clustering and activation of microglia around disrupted vessels. Importantly, microglial depletion profoundly increased hypoxia-induced vascular leak, implying that microglia play a critical role maintaining vascular integrity in the hypoxic spinal cord. The goal of the current study was to examine if microglia play a similar vasculo-protective function in the brain. Employing extravascular fibrinogen leak as an index of blood–brain barrier (BBB) disruption, we found that CMH provoked transient vascular leak in cerebral blood vessels that was associated with activation and aggregation of Mac-1-positive microglia around leaky vessels. Interestingly, CMH-induced vascular leak showed regional selectivity, being much more prevalent in the brainstem and olfactory bulb than the cerebral cortex and cerebellum. Pharmacological depletion of microglia with the colony stimulating factor-1 receptor inhibitor PLX5622, had no effect under normoxic conditions, but markedly increased hypoxia-induced cerebrovascular leak in all regions examined. As in the spinal cord, this was associated with endothelial induction of MECA-32, a marker of leaky CNS endothelium, and greater loss of endothelial tight junction proteins. Brain regions displaying the highest levels of hypoxic-induced vascular leak also showed the greatest levels of angiogenic remodeling, suggesting that transient BBB disruption may be an unwanted side-effect of hypoxic-induced angiogenic remodeling. As hypoxia is common to a multitude of human diseases including obstructive sleep apnea, lung disease, and age-related pulmonary, cardiac and cerebrovascular dysfunction, our findings have important translational implications. First, they point to a potential pathogenic role of chronic hypoxia in triggering BBB disruption and subsequent neurological dysfunction, and second, they demonstrate an important protective role for microglia in maintaining vascular integrity in the hypoxic brain.

scholarly journals A critical role for microglia in maintaining vascular integrity in the hypoxic spinal cord

2019 ◽  
Vol 116 (51) ◽  
pp. 26029-26037 ◽  
Author(s):  
Sebok K. Halder ◽  
Richard Milner
Keyword(s):  
Spinal Cord ◽  
Cord Blood ◽  
Blood Vessels ◽  
Critical Role ◽  
Barrier Properties ◽  
Vascular Leak ◽  
Vascular Integrity ◽  
Age Related ◽  
Obstructive Sleep ◽  
The Impact

Hypoxic preconditioning reduces disease severity in a mouse model of multiple sclerosis (MS), in part by enhancing the barrier properties of spinal cord blood vessels. Because other studies have shown that similar levels of hypoxia transiently increase permeability of central nervous system (CNS) blood vessels, the goal of this study was to define the impact of chronic mild hypoxia (CMH, 8% O2) on the integrity of spinal cord blood vessels and the responses of neighboring glial cells. Using extravascular fibrinogen as a marker of vascular disruption, we found that CMH triggered transient vascular leak in spinal cord blood vessels, particularly in white matter, which was associated with clustering and activation of Mac-1–positive microglia around disrupted vessels. Microglial depletion with the colony stimulating factor-1 receptor (CSF-1R) inhibitor PLX5622, while having no effect under normoxic conditions, profoundly increased vascular leak in both white and gray matter during CMH, and this was associated with disruption of astrocyte-vascular coupling and enhanced loss of tight junction proteins. Microglial repair of leaky blood vessels was blocked by a peptide that inhibits the interaction between fibrinogen and its Mac-1 integrin receptor. These findings highlight an important role for microglia in maintaining vascular integrity in the hypoxic spinal cord and suggest that a fibrinogen–Mac-1 interaction underpins this response. As relative hypoxia is experienced in many situations including high altitude, lung disease, obstructive sleep apnea, and age-related CNS ischemia/hypoxia, our findings have important implications regarding the critical role of microglia in maintaining vascular integrity in the CNS.

scholarly journals Gut-Ex-Vivo system as a model to study gluten response in celiac disease

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Mara Gagliardi ◽  
Nausicaa Clemente ◽  
Romina Monzani ◽  
Luca Fusaro ◽  
Eleonora Ferrari ◽  
...  
Keyword(s):  
Celiac Disease ◽  
Intestinal Epithelium ◽  
Complex Disease ◽  
Ex Vivo ◽  
Dynamic Condition ◽  
Model Systems ◽  
In Vivo Models ◽  
Effective Manner ◽  
Junction Protein ◽  
The Impact

AbstractCeliac disease (CD) is a complex immune-mediated chronic disease characterized by a consistent inflammation of the gastrointestinal tract induced by gluten intake in genetically predisposed individuals. Although initiated by the interaction between digestion-derived gliadin, a gluten component, peptides, and the intestinal epithelium, the disorder is highly complex and involving other components of the intestine, such as the immune system. Therefore, conventional model systems, mainly based on two- or three-dimension cell cultures and co-cultures, cannot fully recapitulate such a complex disease. The development of mouse models has facilitated the study of different interacting cell types involved in the disorder, together with the impact of environmental factors. However, such in vivo models are often expensive and time consuming. Here we propose an organ ex vivo culture (gut-ex-vivo system) based on small intestines from gluten-sensitive mice cultivated in a dynamic condition, able to fully recapitulate the biochemical and morphological features of the mouse model exposed to gliadin (4 weeks), in 16 h. Indeed, upon gliadin exposure, we observed: i) a down-regulation of cystic fibrosis transmembrane regulator (CFTR) and an up-regulation of transglutaminase 2 (TG2) at both mRNA and protein levels; ii) increased intestinal permeability associated with deregulated tight junction protein expression; iii) induction and production of pro-inflammatory cytokines such as interleukin (IL)-15, IL-17 and interferon gamma (IFNγ); and iv) consistent alteration of intestinal epithelium/villi morphology. Altogether, these data indicate that the proposed model can be efficiently used to study the pathogenesis of CD, test new or repurposed molecules to accelerate the search for new treatments, and to study the impact of the microbiome and derived metabolites, in a time- and cost- effective manner.

scholarly journals Combination of µCT and light microscopy for generation-specific stereological analysis of pulmonary arterial branches: a proof-of-concept study

2020 ◽  
Author(s):  
Roman Grothausmann ◽  
Jonas Labode ◽  
Pablo Hernandez-Cerdan ◽  
David Haberthür ◽  
Ruslan Hlushchuk ◽  
...  
Keyword(s):  
Blood Vessels ◽  
Volume Fraction ◽  
Pulmonary Vasculature ◽  
Chronic Obstructive ◽  
Micro Computed Tomography ◽  
Vascular Perfusion ◽  
Arterial Tree ◽  
Color Code ◽  
Rabbit Lung ◽  
Stereological Analysis

AbstractVarious lung diseases, including pulmonary hypertension, chronic obstructive pulmonary disease or bronchopulmonary dysplasia, are associated with structural and architectural alterations of the pulmonary vasculature. The light microscopic (LM) analysis of the blood vessels is limited by the fact that it is impossible to identify which generation of the arterial tree an arterial profile within a LM microscopic section belongs to. Therefore, we established a workflow that allows for the generation-specific quantitative (stereological) analysis of pulmonary blood vessels. A whole left rabbit lung was fixed by vascular perfusion, embedded in glycol methacrylate and imaged by micro-computed tomography (µCT). The lung was then exhaustively sectioned and 20 consecutive sections were collected every 100 µm to obtain a systematic uniform random sample of the whole lung. The digital processing involved segmentation of the arterial tree, generation analysis, registration of LM sections with the µCT data as well as registration of the segmentation and the LM images. The present study demonstrates that it is feasible to identify arterial profiles according to their generation based on a generation-specific color code. Stereological analysis for the first three arterial generations of the monopodial branching of the vasculature included volume fraction, total volume, lumen-to-wall ratio and wall thickness for each arterial generation. In conclusion, the correlative image analysis of µCT and LM-based datasets is an innovative method to assess the pulmonary vasculature quantitatively.

GENETIC SUSCEPTIBILITY TO IBD OPERATES VIA CONTROL OF APICAL JUNCTIONAL COMPLEXES

2021 ◽  
Vol 27 (Supplement_1) ◽  
pp. S30-S30
Author(s):  
Isabelle Hébert-Milette ◽  
Chloé Lévesque ◽  
Guy Charron ◽  
John Rioux
Keyword(s):  
Tight Junction ◽  
Tight Junctions ◽  
Intestinal Inflammation ◽  
Protein Localization ◽  
Junctional Complex ◽  
Epithelial Permeability ◽  
3D Cultures ◽  
Apical Junctional Complex ◽  
Junction Protein ◽  
The Impact

Abstract Introduction Intestinal permeability is increased in unaffected 1st degree relatives of patients with inflammatory bowel disease (IBD), and is considered a risk factor for the development of IBD, likely increasing the interactions between intestinal microorganisms and the immune system. We recently reported that C1orf106, a gene located within a genomic region associated with IBD, regulates epithelial permeability. We further demonstrated that a rare coding variant within C1orf106 (p.Y333F) decreases protein stability and that lower levels of C1orf106 protein leads altered stability of adherens junctions (AJ) and to an increase in epithelial permeability. Hypothesis In addition to altering AJ, we believe that C1orf106 is also involved in the regulation of tight junction (TJ) formation, which also impacts epithelial permeability. Objectives The objectives of the project are to (a) validate the impact of C1orf106 on tight junctions and (b) verify the impact of C1orf106 IBD-associated variants on intestinal barrier integrity. Results We observed that knocking down the expression of C1orf106 in Caco-2 cells leads to a number of phenotypes in human epithelial monolayer (2D) and spheroid (3D) cultures that are associated with alterations in TJs. Specifically, when studying the dynamic reformation of TJ in 2D cultures after transient withdrawal of calcium, which is required for TJ stability, we observed that lower levels of C1orf106 resulted in (1) decreased recovery of barrier function as measured by transepithelial electrical resistance (TEER); (2) an alteration of tight junction protein localization; and (3) thickening of the circumferential actin belt. Moreover, in 3D cultures, we observed an altered spheroid formation associated with impaired epithelial polarization. In addition, our preliminary studies of human induced pluripotent stem cell (hiPSC)-derived epithelial cultures support that Y333F heterozygotes also have altered structure and function of their tight junctions. Conclusion Our observations indicate an important role of C1orf106 in apical junctional complex (AJC) formation likely mediated by a regulation of the circumferential actin belt. This can affect other functions of AJC, like the establishment of cell polarity. AJC formation is important for epithelial repair after an injury and its dysregulation impairs the formation of an impermeable epithelial barrier, which likely facilitates the passage of microorganisms and the induction and maintenance of intestinal inflammation.

scholarly journals The Fairness of Solidarity Bills under the Solidarity Value of Nowak and Radzik

Game Theory ◽  
2015 ◽  
Vol 2015 ◽  
pp. 1-12
Author(s):  
Lawrence Diffo Lambo ◽  
Pierre Wambo
Keyword(s):  
Shapley Value ◽  
Real World ◽  
Side Effect ◽  
Tu Games ◽  
Unwanted Side Effect ◽  
The Disabled ◽  
Threshold Position ◽  
To Receive

The solidarity value is a variant of the well-known Shapley value in which some sense of solidarity between the players is implemented allowing the disabled to receive help from the fortunate ones. We investigate on how fairly solidarity expenses are shared. We discuss the unwanted side effect of someone paying undue solidarity contributions as far as reversing his condition from a privileged to a needy person. A deeper case study is conducted for two classes of TU games that we obtain by modeling two real world business contexts. Here, we trace all player to player transfers of funds that arise when solidarity actions are processed, and we answer the question of who settles the solidarity bills. Also, we obtain the threshold position of a player below which he gets solidarity help, but above which he instead pays out donation.

Editorial

2012 ◽  
Vol 11 (1) ◽  
Author(s):  
Chris Roseveare ◽  
Keyword(s):  
Patient Safety ◽  
Young Male ◽  
Final Diagnosis ◽  
Mass Casualty ◽  
Major Incident ◽  
Spare Capacity ◽  
Acute Medical Unit ◽  
Infected Urine ◽  
Temporary Closure ◽  
The Impact

The snow and freezing temperatures will hopefully have passed by the time this edition reaches you; the sight of daffodils may be asignal that the relief of spring is not far off. Winter frequently stretches AMU resources to the limit – in recent years we have had epidemics of seasonal and swine f lu, but this year Norovirus seems to have been the bigger challenge. Ward closures from diarrhoea outbreaks have traditionally been more of a ‘downstream’ problem (no pun intended), but the impact of closure of the AMU would be substantial.At the time of writing this has still, thankfully, been avoided in my own hospital; however it remains a circumstance for which we have to be prepared. This edition’s ‘Viewpoint’ article describes how temporary closure of the AMU was managed in a London hospital. The use of an empty ‘winter pressures ward’ eased the burden in this case, enabling the AMU service to be maintained. Even with the luxury of this spare capacity, there was clearly significant disruption, requiring close collaboration between a variety of departments, which is well described by the authors. Many hospitals have become highly dependent on a functioning AMU to provide timely, safe and effective care for medical emergencies. Major incident plans are in place to deal with mass casualty incidents; we need to consider similar contingencies to deal with AMU closure if patient safety is going to be maintained. This article is a timely reminder of the need for forward planning. Maintaining patient safety is a mantra which will be familiar to acute physicians, particularly those who attended any of the recent SAM meetings, where this theme has been well rehearsed. An acute medical unit can provide significant safety benefits by concentrating resources in a single area. However, for the 60% who cannot go directly home from the AMU, this model creates the need for care to be transferred at some point. It is well recognised that transfer is a time at which patient safety can become compromised; so if safety is our mantra, acute physicians and nurses have a responsibility to manage this process effectively. The article by David Hindmash and Liz Lees provides an important addition to the limited literature in this area. Structured checklists are becoming an increasing part of medical practice; this paper highlights how a checklist can be used to improve the quality of handover from AMU. The authors emphasise the need to keep the form simple, and the importance of regular reinforcement to ensure that it is used. What skills and attributes does an acute physician require? With interview season approaching it’s a question that many prospective trainees will be contemplating – remaining calm under pressure, communication skills and teamworking are some of the standard responses; but what about a good sense of smell? Most of us recognise the characteristic odour of melaena , or the whiff of infected urine. But the absence of body odour might be equally revealing. Luther and Yap noted their patient to be ‘remarkably clean’ – unusual, perhaps, for a young male patient on the AMU; along with his persistent demands to use the showering facilities, this was a clue to the final diagnosis of Cannabis Hyperemesis Syndrome.It’s a case worth reading and highlights the importance of lateral thinking, particularly when patients repeatedly attend – as well as having a ‘good nose’ to sniff out something unusual!

COVID-19 AND SOUNDSCAPE CHANGES DUE TO THE LOCKDOWN. THE CASE OF LIMA, PERU

Akustika ◽  
2021 ◽  
Author(s):  
walter Montano ◽  
Elena Gushiken
Keyword(s):  
Leisure Activities ◽  
Way Of Life ◽  
Environmental Sound ◽  
Educational Activities ◽  
Industrial Activities ◽  
Sound Levels ◽  
Temporary Closure ◽  
The Impact ◽  
The Way

The COVID-19 pandemic has changed the way of life of the world’s population, and initially all non-essential commercial and industrial activities in all countries were suspended, as well as the temporary closure of major airports and educational activities. As never before, environmental sound levels were reduced as a result of the quarantine, as the authorities ordered people to remain confined in their homes in order to reduce and prevent the SARS-CoV-2 transmission. Cities became silent and in some cases birds and wildlife “took over” this situation. This change in the soundscape led to sounds that were previously masked, now being heard, i.e. HVAC and other noises. This article presents the case of Lima, Peru, in which the impact and annoyance produced by aircrafts overflights are analyzed (during 2020); as well as the healthy soundscape levels achieved ‘thanks’ to the commercial lockdown and leisure activities.

Fatigue

2019 ◽  
pp. 132-139
Author(s):  
Edith O’Neil-Page ◽  
Grace E. Dean ◽  
Paula R. Anderson
Keyword(s):  
End Of Life ◽  
Side Effect ◽  
Healthcare Providers ◽  
Self Care ◽  
Significant Others ◽  
Daily Activities ◽  
Course Of Disease ◽  
Cancer Related Fatigue ◽  
Care Requirements ◽  
The Impact

Individuals suffering from chronic or malignant disease may experience overwhelming and debilitating symptoms of extensive tiredness or sleepiness or an inability to meet daily self-care requirements and maintain personal interaction with significant others. However, they may be unable to verbalize the impact of fatigue on their daily activities. Fatigue is both personal and communal, affecting all aspects of life. Fatigue is often unrecognized by family and healthcare providers or is accepted as a “side effect” of disease and treatment. Cancer-related fatigue affects all aspects of life, at all ages, and may remain unacknowledged by healthcare providers. Yet with recognition and intervention, fatigue can be successfully managed throughout the course of disease, recovery, or through end of life.

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