Publications by authors named "David J Hill"

159 Publications

Ontology of the apelinergic system in mouse pancreas during pregnancy and relationship with β-cell mass.

Sci Rep 2021 Jul 29;11(1):15475. Epub 2021 Jul 29.

Lawson Health Research Institute, St Joseph Health Care, 268 Grosvenor St, London, ON, N6A 4V2, Canada.

The apelin receptor (Aplnr) and its ligands, Apelin and Apela, contribute to metabolic control. The insulin resistance associated with pregnancy is accommodated by an expansion of pancreatic β-cell mass (BCM) and increased insulin secretion, involving the proliferation of insulin-expressing, glucose transporter 2-low (InsGlut2) progenitor cells. We examined changes in the apelinergic system during normal mouse pregnancy and in pregnancies complicated by glucose intolerance with reduced BCM. Expression of Aplnr, Apelin and Apela was quantified in InsGlut2 cells isolated from mouse pancreata and found to be significantly higher than in mature β-cells by DNA microarray and qPCR. Apelin was localized to most β-cells by immunohistochemistry although Aplnr was predominantly associated with InsGlut2 cells. Aplnr-staining cells increased three- to four-fold during pregnancy being maximal at gestational days (GD) 9-12 but were significantly reduced in glucose intolerant mice. Apelin-13 increased β-cell proliferation in isolated mouse islets and INS1E cells, but not glucose-stimulated insulin secretion. Glucose intolerant pregnant mice had significantly elevated serum Apelin levels at GD 9 associated with an increased presence of placental IL-6. Placental expression of the apelinergic axis remained unaltered, however. Results show that the apelinergic system is highly expressed in pancreatic β-cell progenitors and may contribute to β-cell proliferation in pregnancy.
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http://dx.doi.org/10.1038/s41598-021-94725-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8322410PMC
July 2021

Impact of the exposome on the development and function of pancreatic β-cells.

Authors:
David J Hill

Mol Aspects Med 2021 May 5:100965. Epub 2021 May 5.

Department of Physiology and Pharmacology, Western University, London, ON, Canada; Department of Medicine, Western University, London, ON, Canada; Lawson Health Research Institute, St Joseph Health Care, 268 Grosvenor St, London, ON, N6A 4V2, Canada. Electronic address:

The development and plasticity of the endocrine pancreas responds to both the intrauterine and postnatal exposome in a constant attempt to predict and respond to alterations in nutritional availability and metabolic requirements. Both under- and over-nutrition in utero, or exposure to adverse environmental pollutants or maternal behaviors, can each lead to altered β-cell or function at birth, and a subsequent mismatch in pancreatic hormonal demands and secretory capacity postnatally. This can be further exacerbated by metabolic stress postnatally such as from obesity or pregnancy, resulting in an increased risk of gestational diabetes, type 2 diabetes, and even type 1 diabetes. This review will discuss evidence identifying the cellular pathways in early life whereby the plasticity of the endocrine pancreatic can become pathologically limited. By necessity, much of this evidence has been gained from animal models, although extrapolation to human fetal development is possible from the fetal growth trajectory and study of the newborn. Cellular limitations to plasticity include the balance between β-cell proliferation and apoptosis, the appearance of β-cell oxidative stress, impaired glucose-stimulated insulin secretion, and sensitivity to circulating cytokines and responsiveness to programmed death receptor-1. Evidence suggests that many of the cellular pathways responsible for limiting β-cell plasticity are related to paracrine interactions within the islets of Langerhans.
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http://dx.doi.org/10.1016/j.mam.2021.100965DOI Listing
May 2021

Increased alpha and beta cell mass during mouse pregnancy is not dependent on transdifferentiation.

Exp Biol Med (Maywood) 2021 03 24;246(5):617-628. Epub 2020 Nov 24.

Department of Physiology and Pharmacology, Western University, London, ON N6A 3K7, Canada.

Maternal pancreatic beta-cell mass (BCM) increases during pregnancy to compensate for relative insulin resistance. If BCM expansion is suboptimal, gestational diabetes mellitus can develop. Alpha-cell mass (ACM) also changes during pregnancy, but there is a lack of information about α-cell plasticity in pregnancy and whether α- to β-cell transdifferentiation can occur. To investigate this, we used a mouse model of gestational glucose intolerance induced by feeding low-protein (LP) diet from conception until weaning and compared pregnant female offspring to control diet-fed animals. Control and LP pancreata were collected for immunohistochemical analysis and serum glucagon levels were measured. In order to lineage trace α- to β-cell conversion, we utilized transgenic mice expressing yellow fluorescent protein behind the proglucagon gene promoter (Gcg-Cre/YFP) and collected pancreata for histology at various gestational timepoints. Alpha-cell proliferation increased significantly at gestational day (GD) 9.5 in control pregnancies resulting in an increased ACM at GD18.5, and this was significantly reduced in LP animals. Despite these changes, serum glucagon was higher in LP mice at GD18.5. Pregnant Gcg-Cre/YFP mice showed no increase in the abundance of insulinYFPglucagon cells (phenotypic β-cells). A second population of insulinYFPglucagon cells was identified which also did not alter during pregnancy. However, there was an altered anatomical distribution within islets with fewer insulinYFPglucagon cells but more insulinYFPglucagon cells being present in the islet mantle at GD18.5. These findings demonstrate that dynamic changes in ACM occur during normal pregnancy and were altered in glucose-intolerant pregnancies.
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http://dx.doi.org/10.1177/1535370220972686DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7934144PMC
March 2021

Performance of early pregnancy HbA for predicting gestational diabetes mellitus and adverse pregnancy outcomes in obese European women.

Diabetes Res Clin Pract 2020 Oct 21;168:108378. Epub 2020 Aug 21.

Amsterdam UMC, Vrije Universiteit Amsterdam, Department of Public and Occupational Health, Amsterdam Public Health Research Institute, Amsterdam, The Netherlands; Institute of Sport Science, University of Graz, Graz, Austria.

Aims: To investigate the performance of early pregnancy HbA for predicting gestational diabetes mellitus (GDM) and adverse pregnancy outcomes in obese women.

Methods: Post hoc analysis using data from the Vitamin D And Lifestyle Intervention for GDM prevention trials conducted across 9 European countries (2012-2014). Pregnant women (BMI ≥ 29 kg/m) underwent a baseline HbA and oral glucose tolerance tests at < 20 weeks, 24-28 weeks, and 35-37 weeks. Women with GDM were referred for treatment.

Results: Among the 869 women tested, the prevalence of GDM was 25.9% before 20 weeks, with a further 8.6% at 24-28 weeks. The areas under the curves for HbA at the two time points were 0.55 (0.50-0.59) and 0.54 (0.47-0.61), respectively. An early HbA ≥ 5.7% (39 mmol/mol) (N = 111) showed low sensitivity (18.2%) with 89.1% specificity for GDM before 20 weeks, at 24-28 weeks (sensitivity of 8.0% and specificity of 88.6% after excluding early GDM), and throughout gestation (sensitivity of 15.9% and specificity of 89.4%). The ≥ 5.7% (39 mmol/mol) threshold was significantly associated with concurrent GDM before 20 weeks (adjusted OR (aOR) 2.77(1.39-5.51)) and throughout gestation (aOR 1.72 (1.02-2.89)), but not adverse pregnancy outcomes.

Conclusions: Early pregnancy HbA is of limited use for predicting either GDM or adverse outcomes in overweight/obese European women.
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http://dx.doi.org/10.1016/j.diabres.2020.108378DOI Listing
October 2020

Less sedentary time is associated with a more favourable glucose-insulin axis in obese pregnant women-a secondary analysis of the DALI study.

Int J Obes (Lond) 2021 02 13;45(2):296-307. Epub 2020 Jul 13.

Institute of Sport Science, University of Graz, Graz, Austria.

Background/objectives: Obese pregnant women are at high risk of developing gestational diabetes mellitus (GDM), which might be reduced by sufficient physical activity (PA) and reduced sedentary time (ST). We assessed whether PA and ST are longitudinally associated with the glucose-insulin axis in obese pregnant women.

Subjects/methods: In this secondary analysis of the DALI (vitamin D And Lifestyle Intervention for gestational diabetes mellitus prevention) study, pregnant women, <20 weeks gestation, with a pre-pregnancy body mass index (BMI) ≥ 29 kg/m, without GDM on entry were included. Time spent in moderate-to-vigorous PA (MVPA) and ST were measured objectively with accelerometers at <20 weeks, 24-28 weeks and 35-37 weeks of gestation. Fasting glucose (mmol/l) and insulin (mU/l), insulin resistance (HOMA-IR) and first-phase and second-phase insulin release (Stumvoll first and second phase) were assessed at the same time. Linear mixed regression models were used to calculate between-participant differences and within-participant changes over time. Analyses were adjusted for gestational age, randomisation, pre-pregnancy BMI, education and age. MVPA, Insulin, HOMA-IR and Stumvoll first and second phase were log-transformed for analyses due to skewness.

Results: 232 women were included in the analysis. Concerning differences between participants, more ST was associated with higher fasting glucose (Estimate: 0.008; 95% CI: 0.002, 0.014), fasting insulin (0.011; 0.002, 0.019), HOMA-IR (0.012; 0.004, 0.021) and Stumvoll first and second phase (0.008; 0.001, 0.014 and 0.007; 0.001, 0.014). Participants with more MVPA had lower Stumvoll first and second phase (-0.137; -0.210, -0.064 and -0.133; -0.202, -0.063). Concerning changes over time, an increase in ST during gestation was associated with elevated Stumvoll first and second phase (0.006; 0.000, 0.011).

Conclusions: As the glucose-insulin axis is more strongly associated with ST than MVPA in our obese population, pregnant women could be advised to reduce ST in addition to increasing MVPA. Moreover, our findings suggest that behaviour change interventions aiming at GDM risk reduction should start in early or pre-pregnancy.
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http://dx.doi.org/10.1038/s41366-020-0639-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7840500PMC
February 2021

Protein adsorption to poly(tetrafluoroethylene) membranes modified with grafted poly(acrylic acid) chains.

Biointerphases 2020 06 11;15(3):031011. Epub 2020 Jun 11.

School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, QLD 4072, Australia.

Protein adsorption to biomaterial surfaces is important for the function of such materials with anchorage-dependent cell adhesion requiring the presence of adsorbed proteins. The current study evaluated five solid surfaces with poly(acrylic acid) (PAA) grafted from the surface of a poly(tetrafluoroethylene) membrane with respect to the adsorption of serum albumin (SA), lactoferrin (Lf), and lysozyme (Lys) from a phosphate buffer and NaCl solution or water for specific combinations. With the use of x-ray photoelectron spectroscopy, the relative amounts and protein layer thickness were evaluated. SA adsorption was governed by ionic repulsive forces and hydrophobic interactions as evidenced from an increase in the protein adsorption at lower pH (6.5 compared to 7.4) and a correlation with surface coverage when water (pH 6.5) was used as the medium. The adsorption of Lf and Lys followed similar trends for all samples. In general, ionic attractive forces dominated and a strong correlation of increasing protein adsorption with the PAA chain length was evident. This study concluded that all surfaces appear suitable for use in biomaterial applications where tissue ingrowth is desired and that the enhanced protein adsorption in a medium with high ionic strength (e.g., biological fluid) correlates with the PAA chain length rather than the surface coverage.
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http://dx.doi.org/10.1116/6.0000137DOI Listing
June 2020

Differential temporal and spatial post-injury alterations in cerebral cell morphology and viability.

J Comp Neurol 2021 02 28;529(2):421-433. Epub 2020 Jun 28.

Department of Pathology and Laboratory Medicine, University of Western Ontario, London, Canada.

Combination of ischemia and β-amyloid (Aβ) toxicity has been shown to simultaneously increase neuro-inflammation, endogenous Aβ deposition, and neurodegeneration. However, studies on the evolution of infarct and panorama of cellular degeneration as a synergistic or overlapping mechanism between ischemia and Aβ toxicity are lacking. Here, we compared fluorojade B (FJB) and hematoxylin and eosin (H&E) stains primarily to examine the chronology of infarct, and the viability and morphological changes in neuroglia and neurons located in different brain regions on d1, d7, and d28 post Aβ toxicity and endothelin-1 induced ischemia (ET1) in rats. We demonstrated a regional difference in cellular degeneration between cortex, corpus callosum, striatum, globus pallidus, and thalamus after cerebral injury. Glial cells in the cortex and corpus callosum underwent delayed FJB staining from d7 to d28, but neurons in cortex disappeared within the first week of cerebral injury. Striatal lesion core and globus pallidus of Aβ + ET1 rats showed extensive degeneration of neuronal cells compared with ET1 rats alone starting from d1. Differential and exacerbated expressions of cyclooxygenase-2 might be the cause of excessive neuronal demise in the striatum of Aβ + ET1 rats. Such an investigation may improve our understanding to identify and manipulate a critical therapeutic window post comorbid injury.
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http://dx.doi.org/10.1002/cne.24955DOI Listing
February 2021

The importance of maternal insulin resistance throughout pregnancy on neonatal adiposity.

Paediatr Perinat Epidemiol 2021 01 30;35(1):83-91. Epub 2020 Apr 30.

Institution of Sport Science, University of Graz, Graz, Austria.

Background: Although previous studies evaluated the association of maternal health parameters with neonatal adiposity, little is known regarding the complexity of the relationships among different maternal health parameters throughout pregnancy and its impact on neonatal adiposity.

Objectives: To evaluate the direct and indirect associations between maternal insulin resistance during pregnancy, in women with obesity, and neonatal adiposity. In addition, associations between maternal fasting glucose, triglycerides (TG), non-esterified fatty acids (NEFA), and neonatal adiposity were also assessed.

Methods: This is a longitudinal, secondary analysis of the DALI study, an international project conducted in nine European countries with pregnant women with obesity. Maternal insulin resistance (HOMA-IR), fasting glucose, TG, and NEFA were measured three times during pregnancy (<20, 24-28, and 35-37 weeks of gestation). Offspring neonatal adiposity was estimated by the sum of four skinfolds. Structural equation modelling was conducted to evaluate the direct and indirect relationships among the variables of interest.

Results: Data on 657 mother-infant pairs (50.7% boys) were analysed. Neonatal boys exhibited lower mean sum of skinfolds compared to girls (20.3 mm, 95% CI 19.7, 21.0 vs 21.5 mm, 95% CI 20.8, 22.2). In boys, maternal HOMA-IR at <20 weeks was directly associated with neonatal adiposity (β = 0.35 mm, 95% CI 0.01, 0.70). In girls, maternal HOMA-IR at 24-28 weeks was only indirectly associated with neonatal adiposity, which implies that this association was mediated via maternal HOMA-IR, glucose, triglycerides, and NEFA during pregnancy (β = 0.26 mm, 95% CI 0.08, 0.44).

Conclusions: The timing of the role of maternal insulin resistance on neonatal adiposity depends on fetal sex. Although the association was time-dependent, maternal insulin resistance was associated with neonatal adiposity in both sexes.
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http://dx.doi.org/10.1111/ppe.12682DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7891448PMC
January 2021

Ratcheting quasi-ballistic electrons in silicon geometric diodes at room temperature.

Science 2020 04;368(6487):177-180

Department of Chemistry, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.

Ratcheting effects play an important role in systems ranging from mechanical socket wrenches to biological motor proteins. The underlying principle is to convert a fluctuating, unbiased force into unidirectional motion. Here, we report the ratcheting of electrons at room temperature using a semiconductor nanowire with precisely engineered asymmetry. Modulation of the nanowire diameter creates a cylindrical sawtooth geometry with broken inversion symmetry on a nanometer-length scale. In a two-terminal device, this structure responded as a three-dimensional geometric diode that funnels electrons preferentially in one direction through specular reflection of quasi-ballistic electrons at the nanowire surface. The ratcheting effect causes charge rectification at frequencies exceeding 40 gigahertz, demonstrating the potential for applications such as high-speed data processing and long-wavelength energy harvesting.
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http://dx.doi.org/10.1126/science.aay8663DOI Listing
April 2020

Metabolic Adaptations to Pregnancy in Healthy and Gestational Diabetic Pregnancies: The Pancreas - Placenta Axis.

Curr Vasc Pharmacol 2021 ;19(2):141-153

Lawson Health Research Institute, St. Joseph's Health Care, 268 Grosvenor Street, London, Ontario N6A 4V2, Canada.

Normal pregnancy is associated with increased insulin resistance as a metabolic adaptation to the nutritional demands of the placenta and fetus, and this is amplified in obese mothers. Insulin resistance is normally compensated for by an adaptive increase in pancreatic β-cell mass together with enhanced glucose-stimulated insulin release. Placentally-derived hormones and growth factors are central to the altered pancreatic morphology and function. A failure of β-cells to undergo adaptive change after the first trimester has been linked with gestational diabetes. In the pregnant mouse, an increase in β-cell replication contributes to a 2-3-fold increase in mass peaking in late gestation, depending on the proliferation of existing β-cells, the differentiation of resident progenitor β-cells, or islet cell transdifferentiation. Using mouse models and human studies placenta- and islet of Langerhans-derived molecules have been identified that are likely to contribute to the metabolic adaptations to pregnancy and whose physiology is altered in the obese, glucose-intolerant mother. Maternal obesity during pregnancy can create a pro-inflammatory environment that can disrupt the response of the β-cells to the endocrine signals of pregnancy and limit the adaptive changes in β-cell mass and function, resulting in an increased risk of gestational diabetes.
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http://dx.doi.org/10.2174/1570161118666200320111209DOI Listing
June 2021

Altered pancreas remodeling following glucose intolerance in pregnancy in mice.

J Endocrinol 2020 05;245(2):315-326

Department of Physiology and Pharmacology, Western University, London, Ontario, Canada.

Gestational diabetes mellitus increases the risk of dysglycemia postpartum, in part, due to pancreatic β-cell dysfunction. However, no histological evidence exists comparing endocrine pancreas after healthy and glucose-intolerant pregnancies. This study sought to address this knowledge gap, in addition to exploring the contribution of an inflammatory environment to changes in endocrine pancreas after parturition. We used a previously established mouse model of gestational glucose intolerance induced by dietary low protein insult from conception until weaning. Pancreas and adipose samples were collected at 7, 30 and 90 days postpartum for histomorphometric and cytokine analyses, respectively. Glucose tolerance tests were performed prior to euthanasia and blood was collected via cardiac puncture. Pregnant female mice born to dams fed a low protein diet previously shown to develop glucose intolerance at late gestation relative to controls continued to be glucose intolerant until 1 month postpartum. However, glucose tolerance normalized by 3 months postpartum. Glucose intolerance at 7 days postpartum was associated with lower beta- and alpha-cell fractional areas and higher adipose levels of pro-inflammatory cytokine, interleukin-6. By 3 months postpartum, a compensatory increase in the number of small islets and a higher insulin to glucagon ratio likely enabled euglycemia to be attained in the previously glucose-intolerant mice. The results show that impairments in endocrine pancreas compensation in hyperglycemic pregnancy persist after parturition and contribute to prolonged glucose intolerance. These impairments may increase the susceptibility to development of future type 2 diabetes.
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http://dx.doi.org/10.1530/JOE-20-0012DOI Listing
May 2020

Temporal relationships between maternal metabolic parameters with neonatal adiposity in women with obesity differ by neonatal sex: Secondary analysis of the DALI study.

Pediatr Obes 2020 07 6;15(7):e12628. Epub 2020 Mar 6.

Institute of Sport Science, University of Graz, Graz, Austria.

Objectives: To investigate the importance of time in pregnancy and neonatal sex on the association between maternal metabolic parameters and neonatal sum of skinfolds.

Methods: This was a longitudinal, secondary analysis of the vitamin D and lifestyle intervention for gestational diabetes mellitus study, conducted in nine European countries during 2012 to 2015. Pregnant women with a pre-pregnancy body mass index (BMI) of ≥29 kg/m were invited to participate. We measured 14 maternal metabolic parameters at three times during pregnancy: <20 weeks, 24 to 28 weeks, and 35 to 37 weeks of gestation. The sum of four skinfolds assessed within 2 days after birth was the measure of neonatal adiposity.

Results: In total, 458 mother-infant pairs (50.2% female infants) were included. Insulin resistance (fasting insulin and HOMA-index of insulin resistance) in early pregnancy was an important predictor for boys' sum of skinfolds, in addition to fasting glucose and maternal adiposity (leptin, BMI and neck circumference) throughout pregnancy. In girls, maternal lipids (triglycerides and fatty acids) in the first half of pregnancy were important predictors of sum of skinfolds, as well as fasting glucose in the second half of pregnancy.

Conclusions: Associations between maternal metabolic parameters and neonatal adiposity vary between different periods during pregnancy. This time-dependency is different between sexes, suggesting different growth strategies.
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http://dx.doi.org/10.1111/ijpo.12628DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7317347PMC
July 2020

Fault Detection for a Class of Uncertain Sampled-Data Systems Using Deterministic Learning.

IEEE Trans Cybern 2020 Jan 19;PP. Epub 2020 Jan 19.

In this article, we propose a learning-based fault diagnosis approach for a class of nonlinear sampled-data systems. First, the unmodeled sampled dynamics is acquired by the using deterministic learning method. The knowledge of the sampled dynamics of the normal and fault patterns is stored in the form of constant neural networks. Second, a fault detection scheme is designed in which memories of the learned knowledge can be recalled to give a rapid response to a fault. Third, analytical results concerning the fault detection condition and detection time are derived. It is shown that the mismatch function plays an important role in the performance properties of the diagnosis scheme. To analyze the effect of mismatch function on the residual, the concept of duty ratio is developed. Moreover, by comparing the constant neural networks of the normal and fault patterns, an extraction operator is designed to capture the feature of the mismatch function. By using this method, the performance of the diagnosis scheme can be improved. A simulation study is included to demonstrate the effectiveness of the approach.
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http://dx.doi.org/10.1109/TCYB.2019.2963259DOI Listing
January 2020

The Effects of Lifestyle and/or Vitamin D Supplementation Interventions on Pregnancy Outcomes: What Have We Learned from the DALI Studies?

Curr Diab Rep 2019 12 16;19(12):162. Epub 2019 Dec 16.

Institute of Metabolic Science, Addenbrookes Hospital, Cambridge, England.

Purpose Of Review: The DALI (vitamin D and lifestyle intervention in the prevention of gestational diabetes mellitus (GDM)) study aimed to prevent GDM with lifestyle interventions or Vitamin D supplementation (1600 IU/day). This review summarizes the learnings from the DALI studies among pregnant women with a BMI ≥ 29 kg/m.

Recent Findings: Women diagnosed with GDM earlier in pregnancy had a worse metabolic profile than those diagnosed later. A combined physical activity (PA) and healthy eating (HE) lifestyle intervention improved both behaviours, limited gestational weight gain (GWG) and was cost-effective. Although GDM risk was unchanged, neonatal adiposity was reduced due to less sedentary time. Neither PA nor HE alone limited GWG or GDM risk. Fasting glucose was higher with HE only intervention, and lower with Vitamin D supplementation. Our combined intervention did not prevent GDM, but was cost-effective, limited GWG and reduced neonatal adiposity.
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http://dx.doi.org/10.1007/s11892-019-1282-7DOI Listing
December 2019

Correction to: Role of Delayed Neuroglial Activation in Impaired Cerebral Blood Flow Restoration Following Comorbid Injury.

Cell Mol Neurobiol 2020 04;40(3):381-382

Department of Pathology and Laboratory Medicine, University of Western Ontario, London, N6A 5C1, Canada.

The original version of this article contained a random order of part labels for Fig. 4. The correct caption of Fig. 4 with correct order of part labels is given below.
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http://dx.doi.org/10.1007/s10571-019-00739-8DOI Listing
April 2020

Role of Delayed Neuroglial Activation in Impaired Cerebral Blood Flow Restoration Following Comorbid Injury.

Cell Mol Neurobiol 2020 Apr 14;40(3):369-380. Epub 2019 Sep 14.

Department of Pathology and Laboratory Medicine, University of Western Ontario, London, N6A 5C1, Canada.

Besides other causes, ischemia and Alzheimer's disease pathology is also linked to decreased cerebral blood flow (CBF). There is little or no consensus about the role of neuroglial cells in maintaining CBF in various neuropathologies. This consensus becomes scarcer when it comes to clinical and experimental cases of comorbid Abeta-amyloid (Aβ) toxicity and ischemia. Here, a comorbid rat model of Aβ toxicity and endothelin-1 induced ischemia (ET1) not only demonstrated the appearance of axotomized phagocytosed pyknotic neurons (NeuN) immediately after the injury, but also showed a diversity of continuously changing neuroglia (MHC Class II/OX6, Iba1) and macrophage (Iba1/CD68) phenotypes with round, stout somas, and retracted processes. This is indicative of a response to a concomitant increase in large fluid-filled spaces due to the vascular leakage. Ironically 4 weeks after the injury despite a conclusive reduction in neurons, CBF restoration in ET1 rats was associated with a massive increase in neuroglial cell numbers, hypertrophy, ramification, and soma sizes bordering the continuously reducing lesion core and inflamed vasculature, possibly to shield their leaky phenotype. Astrocytes were also found to be releasing matrix metalloproteinase9 (MMP9), which stabilized matrix ligand β-dystroglycan (β-DG) in repaired or functional vessels. Changing neuroglia phenotypes, responses, motility, astrocytic recruitment of MMP9, and β-DG stabilization implies the role of communication between neuroglia and endothelium in recovering CBF, in the absence of neurons, in ET1 rats compared to Aβ+ET1 rats, which showed characteristics delayed neuroglial activation. Stimulation of timely neuroglial reactivity may serve as a viable strategy to compensate for the neuronal loss in restoring CBF in comorbid cases of ischemia and Aβ toxicity.
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http://dx.doi.org/10.1007/s10571-019-00735-yDOI Listing
April 2020

The effect of the source and the concentration of polymers on the release of chlorhexidine from mucoadhesive buccal tablets.

Saudi Pharm J 2019 Sep 20;27(6):756-766. Epub 2019 Apr 20.

Research Institute in Healthcare Science, Faculty of Science and Engineering, University of Wolverhampton, Wolverhampton, UK.

In the current work, two groups of chlorhexidine mucoadhesive buccal tablets were prepared, using either rod or irregularly-shaped spherical particles of hydroxypropyl methylcellulose and different ratios of poloxamer 407 (P407). The tablets were designed to release the drug over two hours. Their physicochemical properties and drug release profiles were investigated. The impact on dry granulation, the mucoadhesion, the swelling index, the morphology of swollen tablets and the drug release kinetic were investigated. Drug-polymers chemical interaction was studied using Fourier Transforms Infrared Spectroscopy (FTIR) and differential scanning calorimetry (DSC). Due to different particle shapes, the preparation of dry granules required a 40 KN force for rod-shaped particles compared to 10 KN for the irregularly-shaped spherical particles. All formulations showed at least two-hours residence time using mucoadhesion. Statistically, there was no significant difference in the swelling index, drug release nor its kinetic for both groups. However, the microscopical morphology of the swollen tablet and the size of the pores were affected by particle shape. Increasing the ratio of P407 to 62.5% resulted in a pronounced increase in drug release from around 60% to >90% after two hours. Following the FTIR and DSC analyses, no chemical interaction was noted apart from the steric hindrance effect of P407, which was observed even with the physical mixtures.
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http://dx.doi.org/10.1016/j.jsps.2019.04.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6733786PMC
September 2019

The spatial cerebral damage caused by larger infarct and β-amyloid toxicity is driven by the anatomical/functional connectivity.

J Comp Neurol 2020 01 19;528(1):48-60. Epub 2019 Jul 19.

Department of Pathology and Laboratory Medicine, University of Western Ontario, London, Ontario, Canada.

Large cerebral infarctions are major predictors of death and severe disability from stroke. Conversely, data concerning these types of infarctions and the affected adjacent brain circuits are scarce. It remains to be determined if the co-morbid concurrence of large infarct and β-amyloid (Aβ) toxicity can precipitate the early development of dementia. Here, we described a dose-dependent effect of a unilateral striatal injection of vasoconstrictive endothelin-1 (ET-1) along with Aβ toxicity on CNS pathogenesis; driven by the anatomical and functional networks within a brain circuit. After 21 days of treatment, a high dose (60 pmol) of ET-1 (E60) alone caused the greatest increase in neuroinflammation, mainly in the ipsilateral striatum and distant regions with synaptic links to the striatal lesion such as white matter (subcortical white matter, corpus callosum, internal capsule, anterior commissure), gray matter (globus pallidus, thalamus), and cortices (cingulate, motor, somatosensory, entorhinal). The combined E60 + Aβ treatment also extended perturbation in the contralateral hemisphere of these rats, such as increased deposition of amyloid precursor protein fragments associated with the appearance of degenerating cells and the leakage of laminin from the basement membrane across a compromised blood-brain barrier. However, the cerebral damage induced by the 6 pmol ET-1 (E6), Aβ and E6 + Aβ rats was not detrimental enough to injure the complete network. The appreciation of the causal interactions among distinct anatomical units in the brain after ischemia and Aβ toxicity will help in the design of effective and alternative therapeutics that may disassociate the synergistic or additive association between the infarcts and Aβ toxicity.
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http://dx.doi.org/10.1002/cne.24738DOI Listing
January 2020

A mouse model of gestational glucose intolerance through exposure to a low protein diet during fetal and neonatal development.

J Physiol 2019 08 11;597(16):4237-4250. Epub 2019 Jul 11.

Department of Physiology and Pharmacology, Western University, 1151 Richmond St., London, ON, Canada.

Key Points: Pancreatic β-cell dysfunction is hypothesized to be the significant determinant of gestational diabetes pathogenesis, however pancreatic samples from patients are scarce. This study reports a novel mouse model of gestational glucose intolerance in pregnancy, originating from previous nutrition restriction in utero, in which glucose intolerance was restricted to late gestation as is seen in human gestational diabetes. Glucose intolerance was attributed to reduced β-cell proliferation, leading to impaired gestational β-cell mass expansion in maternal endocrine pancreas, in addition to reduced glucose-stimulated insulin secretion. This model reproduces some of the features of gestational diabetes and is suitable for testing safe therapeutic interventions that increase β-cell mass during pregnancy and prevent or reverse gestational glucose intolerance.

Abstract: Gestational diabetes mellitus (GDM) is an increasingly prevalent form of diabetes that appears during pregnancy. Pathological studies link a failure to adaptively increase maternal pancreatic β-cell mass (BCM) in pregnancy to GDM. Due to the scarcity of pancreatic samples from GDM patients, we sought to develop a novel mouse model for impaired gestational glucose tolerance. Mature female C57Bl/6 mouse offspring (F1) born to dams fed either a control (C) or low-protein (LP) diet during gestation and lactation were randomly allocated into two subsequent study groups: pregnant (CP, LPP) or non-pregnant (CNP, LPNP). Glucose tolerance tests were performed at gestational day (GD) 9, 12 and 18. Subsequently, pancreata were removed for fluorescence immunohistochemistry to assess α-cell mass (ACM), BCM and β-cell proliferation. An additional group of animals was used to measure insulin secretion from isolated islets at GD18. LPP females displayed glucose intolerance compared to CP females at GD18 (P < 0.001). BCM increased threefold at GD18 in CP females. However, LPP females had reduced BCM expansion (P < 0.01) concurrent with reduced β-cell proliferation at GD12 (P < 0.05). LPP females also had reduced ACM expansion at GD18 (P < 0.01). LPP islets had impaired glucose-stimulated insulin secretion in vitro compared to CP islets (P < 0.01). Therefore, impaired glucose tolerance during pregnancy is associated with a failure to adequately adapt BCM, as a result of reduced β-cell proliferation, in addition to lower glucose-stimulated insulin secretion. This model could be used to evaluate novel interventions during pregnancy to increase BCM or function as a strategy to prevent/reverse GDM.
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http://dx.doi.org/10.1113/JP277884DOI Listing
August 2019

Assessment of environmental and occupational exposure while working with multidrug resistant (MDR) fungus in an animal facility.

J Occup Environ Hyg 2019 07 22;16(7):507-518. Epub 2019 May 22.

a Department of Biomedical Sciences , University at Albany, School of Public Health , Albany , New York.

In less than a decade since its identification in 2009, the emerging fungal pathogen has become a major public health threat due to its multidrug resistant (MDR) phenotype, high transmissibility, and high mortality. Unlike other species, has acquired high levels of resistance to an already limited arsenal of antifungals. As an emerging pathogen, there are currently a limited number of documented murine models of infection. These animal models use inoculums as high as 10-10 cells per mouse, and the environmental and occupational exposure of working with these models has not been clearly defined. Using real-time quantitative polymerase chain reaction (PCR) and culture, we monitored the animal holding room as well as the procedure room for up to 6 months while working with an intravenous model of infection. This study determined that shedding of the organism is dose-dependent, as detectable levels of were detected in the cage bedding when mice were infected with 10 and 10 cells, but not with doses of 10 and 10 cells. Autoclaving bedding in closed micro-isolator cages was found to be an effective way to minimize exposure for animal caretakers. We found that tissue necropsies of infected mice were also an important source of potential source exposure to . To mitigate these potential exposures, we implemented a rigorous "buddy system" workflow and a disinfection protocol that uses 10% bleach followed by 70% ethanol and can be used in any animal facility when using small animal models of infection.
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http://dx.doi.org/10.1080/15459624.2019.1594840DOI Listing
July 2019

The DALI vitamin D randomized controlled trial for gestational diabetes mellitus prevention: No major benefit shown besides vitamin D sufficiency.

Clin Nutr 2020 03 11;39(3):976-984. Epub 2019 Apr 11.

Amsterdam UMC, Vrije Universiteit Amsterdam, Department of Public and Occupational Health, Amsterdam Public Health Research Institute, Amsterdam, Netherlands; Institute of Sport Science, University of Graz, Graz, Austria.

Background & Aims: As vitamin D deficiency is associated with an increased risk of gestational diabetes mellitus (GDM), we aimed to test vitamin D supplementation as a strategy to reduce GDM risk (evaluated after fasting plasma glucose (FPG), insulin resistance and weight gain) in pregnant overweight/obese women.

Methods: The DALI vitamin D multicenter study enrolled women with prepregnancy body mass index (BMI) ≥ 29 kg/m, ≤19 + 6 weeks of gestation and without GDM. Participants were randomized to receive 1600 IU/day vitamin D3 or placebo (each with or without lifestyle intervention) on top of (multi)vitamins supplements. Women were assessed for vitamin D status (sufficiency defined as serum 25-hydroxyvitamin D (25(OH)D) ≥ 50 nmol/l), FPG, insulin resistance and weight at baseline, 24-28 and 35-37 weeks. Linear or logistic regression analyses were performed to assess intervention effects.

Results: Average baseline serum 25(OH)D was ≥50 nmol/l across all study sites. In the vitamin D intervention arm (n = 79), 97% of participants achieved target serum vitamin 25(OH)D (≥50 nmol/l) at 24-28 weeks and 98% at 35-37 weeks vs 74% and 78% respectively in the placebo arm (n = 75, p < 0.001). A small but significantly lower FPG (-0.14 mmol/l; CI95 -0.28, -0.00) was observed at 35-37 weeks with the vitamin D intervention without any additional difference in metabolic status, perinatal outcomes or adverse event rates.

Conclusion: In the DALI vitamin D trial, supplementation with 1600 IU vitamin D3/day achieved vitamin D sufficiency in virtually all pregnant women and a small effect in FPG at 35-37 weeks. The potential of vitamin D supplementation for GDM prevention in vitamin D sufficient populations appears to be limited.

Trial Registration Number: ISRCTN70595832.
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http://dx.doi.org/10.1016/j.clnu.2019.04.006DOI Listing
March 2020

Zero-Error Consensus Tracking With Preassignable Convergence for Nonaffine Multiagent Systems.

IEEE Trans Cybern 2021 Mar 17;51(3):1300-1310. Epub 2021 Feb 17.

In this paper, we investigate the consensus tracking control problem for networked multiagent systems (MASs) with unknown nonaffine dynamics. Our goal is to achieve asymptotic (rather than ultimately uniformly bounded) consensus tracking, which is quite challenging especially if nonvanishing/nonparametric uncertainties are involved and at the same time the control protocol is required to be fully distributed and continuous everywhere. Here, we present a conceptually new and structurally simple solution with distributed and continuous control action. The developed method is capable of ensuring zero-error tracking with a unique converging feature in that the consensus tracking error first converges to a small adjustable residual set around zero within a prescribed finite time, and then further shrinks to zero exponentially. The key technique lies in the utilization of a state transformation based on certain scaling function. Our method also prevents the restrictive requirement that all subsystems have access to the linearly parameterized information as imposed in most existing consensus tracking results for nonlinear MAS.
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http://dx.doi.org/10.1109/TCYB.2019.2893461DOI Listing
March 2021

Offspring of Mice Exposed to a Low-Protein Diet in Utero Demonstrate Changes in mTOR Signaling in Pancreatic Islets of Langerhans, Associated with Altered Glucagon and Insulin Expression and a Lower β-Cell Mass.

Nutrients 2019 Mar 12;11(3). Epub 2019 Mar 12.

Lawson Health Research Institute, London, ON N6A 4V2, Canada.

Low birth weight is a risk factor for gestational and type 2 diabetes (T2D). Since mammalian target of rapamycin (mTOR) controls pancreatic β-cell mass and hormone release, we hypothesized that nutritional insult in utero might permanently alter mTOR signaling. Mice were fed a low-protein (LP, 8%) or control (C, 20%) diet throughout pregnancy, and offspring examined until 130 days age. Mice receiving LP were born 12% smaller and β-cell mass was significantly reduced throughout life. Islet mTOR levels were lower in LP-exposed mice and localized predominantly to α-rather than β-cells. Incubation of isolated mouse islets with rapamycin significantly reduced cell proliferation while increasing apoptosis. mRNA levels for mTORC complex genes mTOR, Rictor and Raptor were elevated at 7 days in LP mice, as were the mTOR and Raptor proteins. Proglucagon gene expression was similarly increased, but not insulin or the immune/metabolic defense protein STING. In human and mouse pancreas STING was strongly associated with islet β-cells. Results support long-term changes in islet mTOR signaling in response to nutritional insult in utero, with altered expression of glucagon and insulin and a reduced β-cell mass. This may contribute to an increased risk of gestational or type 2 diabetes.
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http://dx.doi.org/10.3390/nu11030605DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6471519PMC
March 2019

Selective deletion of endothelial cell calpain in mice reduces diabetic cardiomyopathy by improving angiogenesis.

Diabetologia 2019 05 18;62(5):860-872. Epub 2019 Feb 18.

Institutes of Biology and Medical Sciences, Soochow University, Suzhou, China.

Aims/hypothesis: The role of non-cardiomyocytes in diabetic cardiomyopathy has not been fully addressed. This study investigated whether endothelial cell calpain plays a role in myocardial endothelial injury and microvascular rarefaction in diabetes, thereby contributing to diabetic cardiomyopathy.

Methods: Endothelial cell-specific Capns1-knockout (KO) mice were generated. Conditions mimicking prediabetes and type 1 and type 2 diabetes were induced in these KO mice and their wild-type littermates. Myocardial function and coronary flow reserve were assessed by echocardiography. Histological analyses were performed to determine capillary density, cardiomyocyte size and fibrosis in the heart. Isolated aortas were assayed for neovascularisation. Cultured cardiac microvascular endothelial cells were stimulated with high palmitate. Angiogenesis and apoptosis were analysed.

Results: Endothelial cell-specific deletion of Capns1 disrupted calpain 1 and calpain 2 in endothelial cells, reduced cardiac fibrosis and hypertrophy, and alleviated myocardial dysfunction in mouse models of diabetes without significantly affecting systemic metabolic variables. These protective effects of calpain disruption in endothelial cells were associated with an increase in myocardial capillary density (wild-type vs Capns1-KO 3646.14 ± 423.51 vs 4708.7 ± 417.93 capillary number/high-power field in prediabetes, 2999.36 ± 854.77 vs 4579.22 ± 672.56 capillary number/high-power field in type 2 diabetes and 2364.87 ± 249.57 vs 3014.63 ± 215.46 capillary number/high-power field in type 1 diabetes) and coronary flow reserve. Ex vivo analysis of neovascularisation revealed more endothelial cell sprouts from aortic rings of prediabetic and diabetic Capns1-KO mice compared with their wild-type littermates. In cultured cardiac microvascular endothelial cells, inhibition of calpain improved angiogenesis and prevented apoptosis under metabolic stress. Mechanistically, deletion of Capns1 elevated the protein levels of β-catenin in endothelial cells of Capns1-KO mice and constitutive activity of calpain 2 suppressed β-catenin protein expression in cultured endothelial cells. Upregulation of β-catenin promoted angiogenesis and inhibited apoptosis whereas knockdown of β-catenin offset the protective effects of calpain inhibition in endothelial cells under metabolic stress.

Conclusions/interpretation: These results delineate a primary role of calpain in inducing cardiac endothelial cell injury and impairing neovascularisation via suppression of β-catenin, thereby promoting diabetic cardiomyopathy, and indicate that calpain is a promising therapeutic target to prevent diabetic cardiac complications.
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http://dx.doi.org/10.1007/s00125-019-4828-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6702672PMC
May 2019

Solvent-Engineered Stress in Nanoscale Materials.

ACS Appl Mater Interfaces 2018 Dec 4;10(50):44183-44189. Epub 2018 Dec 4.

ARC Centre of Excellence in Exciton Science, School of Mathematics and Statistics , University of Melbourne , Parkville , Victoria 3010 , Australia.

Nanoscale materials are frequently coated with surface stabilization layers during growth that prevent flocculation in solution and facilitate processing technologies such as ink-jet device printing. Here, we show that few-nanometer-thick stabilization layers typically used swell in the presence of certain solvents and impart significant stresses to the nanomaterial that remains even after the solvent has evaporated. Solvent swelling of the surface layer dramatically enhances nanomaterial-substrate adhesion via the collapse of the stabilization layer during solvent evaporation, preventing stress relaxation. We demonstrate the stress modulation of Ag, Au, and Si nanowires functionalised with surface polymers and surfactant layers and detect strain levels between 0.1 and 0.6% using atomic force microscopy mechanical measurement and Raman spectroscopy. Dry-transferred nanowires exhibit poor adhesion and show no evidence of incorporated stress but become stressed immediately following solvent exposure. Strain engineering is demonstrated by coating nanowires with few-nanometer-thick solvent-responsive polymer layers.
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http://dx.doi.org/10.1021/acsami.8b17201DOI Listing
December 2018

Interplay of Surface Recombination and Diode Geometry for the Performance of Axial p-i-n Nanowire Solar Cells.

ACS Nano 2018 Oct 25;12(10):10554-10563. Epub 2018 Sep 25.

Department of Chemistry , University of North Carolina at Chapel Hill , Chapel Hill , North Carolina 27599-3290 , United States.

Nanowires (NWs) with axial p-i-n junctions have been widely explored as microscopic diodes for optoelectronic and solar energy applications, and their performance is strongly influenced by charge recombination at the surface. We delineate how the photovoltaic performance of these diodes is dictated not only by the surface but also by the complex and seemingly counterintuitive interplay of diode geometry, that is, radius ( R) and intrinsic length ( L), with the surface recombination velocity ( S). An analytical model to describe these relationships is developed and compared to finite-element simulations, which verify the accuracy and limitations of the model. The dependence of the dark saturation current ( I), internal quantum efficiency (IQE), short-circuit current ( I), and open-circuit voltage ( V) on both geometric and recombination parameters demonstrates that no single set of parameters produces optimal performance; instead, various trade-offs in performance are observed. For instance, longer L might be expected to produce higher I, yet at high values of S the I declines because of decreases in IQE. Moreover, longer L produces a concurrent decline in V regardless of S due to increases in I. We also find that I and V trends are radius independent, yet I is directly proportional to R, causing NWs with smaller R to display higher turn-on voltages. The analysis regarding the interplay of these parameters, verified by experimental measurements with various p-i-n geometries and surface treatments, provides clear guidance for the rational design of performance metrics for photodiode and photovoltaic devices.
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http://dx.doi.org/10.1021/acsnano.8b06577DOI Listing
October 2018

Direct comparison of the abilities of bone marrow mesenchymal versus hematopoietic stem cells to reverse hyperglycemia in diabetic NOD.SCID mice.

Islets 2018 15;10(4):137-150. Epub 2018 Aug 15.

a Lawson Health Research Institute , London , ON , Canada.

Both bone marrow-derived hematopoietic stem cells (HSC) and mesenchymal stem cells (MSC) improve glycemic control in diabetic mice, but their kinetics and associated changes in pancreatic morphology have not been directly compared. Our goal was to examine the time course of improvements in glucose tolerance and associated changes in β-cell mass and proliferation following transplantation of equivalent numbers of HSC or MSC from the same bone marrow into diabetic non-obese diabetic severe combined immune deficiency (NOD.SCID) mice. We used transgenic mice with a targeted expression of yellow fluorescent protein (YFP) driven by the Vav1 gene promoter to genetically tag HSC and progeny. HSC were separated from bone marrow by fluorescence-activated cell sorting and MSC following cell culture. Equivalent numbers of isolated HSC or MSC were transplanted directly into the pancreas of NOD.SCID mice previously made diabetic with streptozotocin. Glucose tolerance, serum insulin, β-cell mass and β-cell proliferation were examined up to 28 days following transplant. Transplantation with MSC improved glucose tolerance within 7 days and serum insulin levels increased, but with no increase in β-cell mass. Mice transplanted with HSC showed improved glucose tolerance only after 3 weeks associated with increased β-cell proliferation and mass. We conclude that single injections of either MSC or HSC transiently improved glycemic control in diabetic NOD.SCID mice, but with different time courses. However, only HSC infiltrated the islets and were associated with an expanded β-cell mass. This suggests that MSC and HSC have differing mechanisms of action.
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http://dx.doi.org/10.1080/19382014.2018.1480285DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6281365PMC
May 2019

Spatial Dynamics of Vascular and Biochemical Injury in Rat Hippocampus Following Striatal Injury and Aβ Toxicity.

Mol Neurobiol 2019 Apr 28;56(4):2714-2727. Epub 2018 Jul 28.

Department of Pathology and Laboratory Medicine, University of Western Ontario, London, N6A 5C1, Canada.

The hippocampus, a brain region vital for memory and learning, is sensitive to the damage caused by ischemic/hypoxic stroke and is one of the main regions affected by Alzheimer's disease. The pathological changes that might occur in the hippocampus and its connections, because of cerebral injury in a distant brain region, such as the striatum, have not been examined. Therefore, in the present study, we evaluated the combined effects of endothelin-1-induced ischemia (ET1) in the striatum and β-amyloid (Aβ) toxicity on hippocampal pathogenesis, dictated by the anatomical and functional intra- and inter-regional hippocampal connections to the striatum. The hippocampal pathogenesis induced by Aβ or ET1 alone was not severe enough to significantly affect the entire circuit of the hippocampal network. However, the combination of the two pathological states (ET1 + Aβ) led to an exacerbated increase in neuroinflammation, deposition of the amyloid precursor protein (APP) fragments with the associated appearance of degenerating cells, and blood-brain-barrier disruption. This was observed mainly in the hippocampal formation (CA2 and CA3 regions), the dentate gyrus as well as distinct regions with synaptic links to the hippocampus such as entorhinal cortex, thalamus, and basal forebrain. In addition, ET1 + Aβ-treated rats also demonstrated protracted loss of AQP4 depolarization, dissolution of β-dystroglycan, and basement membrane laminin with associated IgG and dysferlin leakage. Spatial dynamics of hippocampal injury in ET1 + Aβ rats may provide a valuable model to study new targets for clinical therapeutic applications, specifically when areas remotely connected to hippocampus are damaged.
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http://dx.doi.org/10.1007/s12035-018-1225-3DOI Listing
April 2019
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