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Previous work indicates that erythrocytes (RBCs) accumulate β-amyloid X-40 (Aβ40) in individuals with Alzheimer disease (AD) and to a lesser extent in healthy elderly. The toxin damages RBCs and increases their mean corpuscular volume (MCV). Furthermore, AD platelets demonstrate lower reactivity. This study investigated interactions between RBCs and platelets. Older individuals with moderate hypertension (n = 57) were classified into two groups, depending on MCV in whole blood: The MCVhigh group comprised individuals with higher MCV (n = 27; 97 ± 3(SD) fl) and MCVlow group had relatively lower MCV (n = 30; 90 ± 3(SD) fl). Flow cytometry was used to determine platelet reactivity, i.e., the surface binding of fibrinogen after provocation. Adenosine diphosphate (ADP) and a thrombin receptor-activating protein (TRAP-6) were used as agonists. Subsequently, blood cells were divided according to density into 17 subfractions. Intra-RBC Aβ40 content was analyzed and in all platelet populations surface-bound fibrinogen was determined to estimate platelet in vivo activity. We found Aβ40 inside RBCs of approximately 50% of participants, but the toxin did not affect MCV and platelet reactivity. In contrast, MCV associated inversely with platelet reactivity as judged from surface-attached fibrinogen after ADP (1.7 μmol/L) (p < 0.05) and TRAP-6 provocation (57 μmol/L (p = 0.01) and 74 μmol/L (p < 0.05)). In several density fractions (nos. 3, 4, 8, 11–13 (p < 0.05) and nos. 5–7 (p < 0.01)) MCV linked inversely with platelet-attached fibrinogen. In our community-dwelling sample, enhanced MCV associated with decreased platelet reactivity and lower in vivo platelet activity. It resembles RBCs and platelet behavior in AD-type dementia. [ABSTRACT FROM AUTHOR]

Surrogate safety measures have been employed as road safety indicators for decades; numerous measures have been developed to replicate the volume and relative severity of adverse incidents in various regions. 'Time-to-collision' (TTC) is one of the most frequently used time-based surrogate safety measures. In the current study, a new application of 'TTC' has been developed for the enhancement of road safety assessment. Values for both the rate of 'TTC' variation and the level of hazard associated with 'TTC' have been amalgamated as an approximate safety indicator. A micro-simulation model is used to validate the newly developed measure with respect to the assessment of the level of safety associated with a freeway (Interstate-80). Results suggest that the developed measure more accurately considers driver car-following behavior; consequently, detection of potentially hazardous collisions is significantly improved. The proposed technique for collision prediction is shown to provide a more accurate level of risk assessment with respect to car-following scenarios; thus, it may present an opportunity for increasing the precision associated with in-vehicle collision avoidance warning systems (IVCAWS). [ABSTRACT FROM AUTHOR]

Landscape fragmentation has threatened the landscape continuity of Ray which was maintained from prehistoric times until recent decades. From 19th century that Tehran sprawl growth affected Ray's landscape as a satellite city of Tehran, Ray experienced rapid landscape fragmentation and underwent many changes. In order to cope with the threat, the process of changes from landscape fragmentation should be studied. For this purpose, integrated approach was applied to assess landscape fragmentation. Landscape fragmentation is analyzed based on physical and quantitative evaluation using landscape metrics and perceptual and quantitative evaluation through an in-depth interview with natives. The results have cleared an image of the structural changes and also great change of people's perception during the time. Based on the results, Ray's landscape is structurally fragmented, but native do not perceive it. This is while people perceive landscape functional fragmentation. This inconsistent perception of landscape has caused the native's dissatisfaction about their living place. With the prepared image of landscape fragmentation in the City of Ray, city managers, designers, and planners will be able to deal with rapid changes and preserve landscape continuity of Ray. [ABSTRACT FROM AUTHOR]

Low temperature cracking is one of the main distresses observed in pavements made of hot mix asphalt mixtures. As a material property, the fracture toughness of asphalt pavements is a fundamental parameter for estimating the load bearing capacity and resistance of cracked pavements against crack growth. In this paper, the fracture toughness (KIc) of different and various compositions of asphalt mixtures is obtained experimentally, and the effects of asphalt characteristic specifications and its composition are investigated on the value of KIc. Several asphalt mixtures were prepared with three aggregate sizes, two aggregate types (limestone and siliceous), different air void percentages ranging from 3.5 to 8%, and two binders (60/70 and 85/100). Other similar work has only studied the influence of limited characteristic parameters on the low temperature fracture resistance of asphalt mixtures. Several Semi-Circular Bend (SCB) specimens subjected to three point bend loading were manufactured with different compositions and were then tested at -15°C. The experimental results showed the noticeable influence of characteristic specifications of asphalt mixtures on the value of KIc. Generally, the value of KIc decreases for those mixtures containing a smaller size of aggregates made of siliceous, with higher percentages of air voids and softer binder types. [ABSTRACT FROM AUTHOR]

Objective: to evaluate the incidence of genotypic resistance to NRTIs at HIV-1 infected patients from Southern Spain and with HAART. Patients and Methods: 42 patients on HAART (16 females, 26 males; mean age: 34.46 ± 8.41; risk factors: 20 IVDU, 17 heterosexual, 4 homosexual males and 1 transfusion) and with virological failure have been studied. Previous treatments and genotypic resistance (INNO LIPA HIV-1 RT) were studied. Results: 32 patients showed resistance to AZT (76.2%), 8 to 3TC (19%), 2 (4.7%) to DDI and 2 (4.7%) to DDC. Related to the number of patients/year on treatment with each NRTI, the incidence of the resistance was: 25.8 (17.59–26.85) for AZT, 19.5 (8.4–38.3) for 3TC, 6.4 (0.7–23.2) for DDC and 4.4 (0.5–16) for DDI. No influence of sex or risk factor on AZT genotype resistance was observed. After 6 months of resistance testing and therapy modification viral load was reduced as follows: 3 Logs, 11.5%; 2 Logs, 11.5%; and 1 Log, 23%. Conclusions: the highest incidence of genotype resistance to Nitres at HIV-1 infected patients from Southern Spain was for AZT, followed by 3TC. For DDI and DDC a lower incidence of genotype resistance has been observed. [ABSTRACT FROM AUTHOR]

The functionality inherent in lignin-derivable aromatics ( e.g. , polar methoxy groups) can provide a potential opportunity to improve the hydrophilicity of polysulfones (PSfs) without the need for the additional processing steps and harsh reagents/conditions that are typically used in conventional PSf modifications. As determined herein, lignin-derivable PSfs without any post-polymerization modification exhibited higher hydrophilicity than comparable petroleum-based PSfs (commercial/laboratory-synthesized) and also demonstrated similar hydrophilicity to functionalized BPA-PSfs reported in the literature. Importantly, the lignin-derivable PSfs displayed improved thermal properties relative to functionalized BPA-PSfs in the literature, and the thermal properties of these bio-derivable PSfs were close to those of common non-functionalized PSfs. In particular, the glass transition temperature ( T g ) and degradation temperature of 5% weight loss ( T d5% ) of lignin-derivable PSfs ( T g ∼165-170 °C, T d5% ∼400-425 °C) were significantly higher than those of typical functionalized BPA-PSfs in the literature ( T g ∼110-160 °C, T d5% ∼240-260 °C) and close to those of unmodified, commercial/laboratory-synthesized BPA-/bisphenol F-PSfs ( T g ∼180-185 °C, T d5% ∼420-510 °C)., Competing Interests: M. D. G. is co-founder of NuAria, LLC and owns 50% equity interest in the company. The work of this manuscript is not directly related to the activities of the company., (This journal is © The Royal Society of Chemistry.)

Background: Obesity, cardiovascular diseases, and metabolic disorders are common problems among participants with non-alcoholic fatty liver disease (NAFLD). However, the association between these problems and the healthy eating index-2015 (HEI-2015) remains unknown. Although the HEI-2015 originated from American dietary guidelines, its comprehensive evaluation of diet quality provides valuable insights for various populations, including Iranians. Therefore, the objective of this study was to investigate the association between anthropometric, hepatic, and cardio-metabolic indices with HEI-2015 scores in participants with NAFLD., Methods: We conducted a cross-sectional analysis of data from the Hoveyzeh Cohort Study, which included adults aged 35 to 70 years between 2016 and 2018. A total of 664 participant with NAFLD (452 females and 212 males) were included in the analysis. The HEI-2015 was assessed using the Food Frequency Questionnaire (FFQ). Various indices, including the body shape index (ABSI), atherogenic index of plasma (AIP), visceral adiposity index (VAI), lipid accumulation product (LAP), cardiometabolic index (CMI), lipoprotein combine index (LCI), AST/ALT ratio, ALD/NAFLD index, and hepatic steatosis index (HSI), were calculated., Results: No significant differences were observed in anthropometric, cardio-metabolic, and hepatic indices across the quartiles of HEI-2015. However, among participants with NAFLD, men had significantly higher AIP and LCI levels, while women had significantly higher BMI, ABSI, VAI, LAP, and CMI levels. Additionally, women with NAFLD exhibited higher AST/ALT and HSI levels but lower ALD/NAFLD levels compared to men with NAFLD. Linear regression analysis among men with NAFLD revealed a significant negative correlation between HEI-2015 score and HSI in both the unadjusted model (β=-0.131, SE = 0.058, p = 0.024) and the adjusted model for energy intake (β=-0.129, SE = 0.058, p = 0.028)., Conclusion: The present study demonstrated a correlation between lower HEI-2015 scores and an increased risk of steatosis in men with NAFLD. Moreover, our findings highlighted gender-related differences in NAFLD and cardio-metabolic disorders., (© 2024. The Author(s).)

Background: Alzheimer's disease (AD) is an age-related disease characterized by altered cognition, neuroinflammation, and neurodegeneration against which there is presently no effective cure. Brain-derived neurotrophic factor (BDNF) is a key neurotrophin involved in the learning and memory process, with a crucial role in synaptic plasticity and neuronal survival. Several findings support that a reduced BDNF expression in the human brain is associated with AD pathogenesis. BDNF has been proposed as a potential therapy for AD, but BDNF has low brain penetration. In this study, we used an innovative encapsulated cell biodelivery (ECB) device, containing genetically modified cells capable of releasing BDNF and characterized its feasibility and therapeutic effects in the novel App knock-in AD mouse model (App NL-G-F )., Methods: ECB's containing human ARPE-19 cells genetically modified to release BDNF (ECB-BDNF devices) were stereotactically implanted bilaterally into hippocampus of 3-month-old App NL-G-F mice. The stability of BDNF release and its effect on AD pathology were evaluated after 1, 2-, and 4-months post-implantation by immunohistochemical and biochemical analyses. Exploratory and memory performance using elevated plus maze (EPM) and Y-maze test were performed in the 4-months treatment group. Immunological reaction towards ECB-BDNF devices were studied under ex vivo and in vivo settings., Results: The surgery and the ECB-BDNF implants were well tolerated without any signs of unwanted side effects or weight loss. ECB-BDNF devices did not induce host-mediated immune response under ex vivo set-up but showed reduced immune cell attachment when explanted 4-months post-implantation. Elevated BDNF staining around ECB-BDNF device proximity was detected after 1, 2, and 4 months treatment, but the retrieved devices showed variable BDNF release. A reduction of amyloid-β (Aβ) plaque deposition was observed around ECB-BDNF device proximity after 2-months of BDNF delivery., Conclusions: The result of this study supports the use of ECB device as a promising drug-delivery approach to locally administer BBB-impermeable factors for treating neurodegenerative conditions like AD. Optimization of the mouse-sized devices to reduce variability of BDNF release is needed to employ the ECB platform in future pre-clinical research and therapy development studies., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Coenzyme Q10 is a potent antioxidant and is necessary for energy production in mitochondria. Clinical data have suggested that coenzyme Q10 (CoQ10) has some beneficial effects on liver function. However, these results are equivocal. This systematic review and meta-analysis aimed to clarify the effect of coenzyme Q10 supplementation on the serum concentration of liver function enzymes. We searched the online databases using relevant keywords up to April 2022. Randomized clinical trials (RCTs) investigating the effect of CoQ10, compared with a control group, on serum concentrations of liver enzymes were included. We found a significant reduction following supplementation with CoQ10 on serum concentrations of alanine aminotransferase (ALT) based on 15 effect sizes from 13 RCTs (weighted mean difference [WMD] = -5.33 IU/L; 95% CI: -10.63, -0.03; p  = .04), aspartate aminotransferase (AST) based on 15 effect sizes from 13 RCTs (WMD = -4.91 IU/L; 95% CI: -9.35, -0.47; p  = .03) and gamma-glutamyl transferase (GGT) based on eight effect sizes from six RCTs (WMD = -8.07 IU/L; 95% CI: -12.82, -3.32; p  = .001; I 2  = 91.6%). However, we found no significant effects of CoQ10 supplementation on alkaline phosphatase concentration (WMD = 1.10 IU/L; 95% CI: -5.98, 8.18; p  = .76). CoQ10 supplementation significantly improves circulating ALT, AST, and GGT levels; therefore, it might positively affect liver function. Further high-quality RCTs with more extended intervention periods and larger sample sizes are recommended to confirm our results., Competing Interests: Authors declared no personal or financial conflicts of interest., (© 2023 The Authors. Food Science & Nutrition published by Wiley Periodicals LLC.)

Water reclamation in spaceflight applications, such as those encountered on the International Space Station (ISS), requires complex engineering solutions to ensure maximum water recovery. Current vapor compression distillation (VCD) technologies are effective but produce highly concentrated brines and often cause scaling within a separation system. This work evaluates initial steps toward integrating pervaporation, a membrane separation process, as a brine management strategy for ISS wastewaters. Pervaporation performs separations driven by a chemical potential difference across the membrane created by either a sweep gas or a vacuum pull. Pervaporation membranes, as with most membrane processes, can be subject to scaling. Therefore, this work studies the anti-scaling properties of zwitterions (polymeric molecules with covalently tethered positive and negative ions) coated onto sulfonated pentablock terpolymer block polymer (Nexar) pervaporation membrane surfaces. We report a method for applying zwitterions to the surface of pervaporation membranes and the effect on performance parameters such as flux and scaling resistance. Membranes with zwitterions had up to 53% reduction in permeance but reduced scaling. The highest amount of scaling occurred in the samples exposed to calcium chloride, and uncoated membranes had weight percent increases as high as 1617 ± 241%, whereas zwitterion-coated membranes experienced only about 317 ± 87% weight increase in the presence of the same scalant., Competing Interests: The authors declare no competing financial interest., (© 2023 The Authors. Published by American Chemical Society.)

Cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is caused by NOTCH3 mutations. Typical CADASIL is characterised by subcortical ischemic strokes due to severe arteriopathy and fibrotic thickening of small arteries. Arteriolar vascular smooth muscle cells (VSMCs) are the key target in CADASIL, but the potential mechanisms involved in their degeneration are still unclear. Focusing on cerebral microvessels in the frontal and anterior temporal lobes and the basal ganglia, we used advanced proteomic and immunohistochemical methods to explore the extent of inflammatory and immune responses in CADASIL subjects compared to similar age normal and other disease controls. There was variable loss of VSMC in medial layers of arteries in white matter as well as the cortex, that could not be distinguished whether NOTCH3 mutations were in the epidermal growth factor (EGFr) domains 1-6 or EGFr7-34. Proteomics of isolated cerebral microvessels showed alterations in several proteins, many associated with endoplasmic reticulum (ER) stress including heat shock proteins. Cerebral vessels with sparsely populated VSMCs also attracted robust accrual of perivascular microglia/macrophages in order CD45 + > CD163 + > CD68 + cells, with > 60% of vessel walls exhibiting intercellular adhesion molecule-1 (ICAM-1) immunoreactivity. Functional VSMC cultures bearing the NOTCH3 Arg133Cys mutation showed increased gene expression of the pro-inflammatory cytokine interleukin 6 and ICAM-1 by 16- and 50-fold, respectively. We further found evidence for activation of the alternative pathway of complement. Immunolocalisation of complement Factor B, C3d and C5-9 terminal complex but not C1q was apparent in ~ 70% of cerebral vessels. Increased complement expression was corroborated in > 70% of cultured VSMCs bearing the Arg133Cys mutation independent of N3ECD immunoreactivity. Our observations suggest that ER stress and other cellular features associated with arteriolar VSMC damage instigate robust localized inflammatory and immune responses in CADASIL. Our study has important implications for immunomodulation approaches to counter the characteristic arteriopathy of CADASIL., (© 2023. The Author(s).)

Background: Estimating Fat-Free Mass (FFM) is an integral part of Body composition measurements, so obtaining an accurate estimation for evaluating FFM is critical for researchers and specialists. We aimed to develop and validate a simple equation for predicting FFM in the adult population., Methods: Participants were 1996 adults (1085 men and 911 women), and 18 to 69 years old from Ahvaz City, southern Iran. They were randomly divided into the derivation (n=1396) and the validation (n=600) groups with no significant differences from Jan 2018 to Feb 2020. FFM was measured by Bioelectrical Impedance Analyzer (BIA) (InBody 770©; Biospace, Seoul, South Korea). Based on the demographic variables retrieved from the Derivation group, 8 FFM predictive equations were developed using multiple regression; finally, the most accurate model (using the coefficient of determination (R2)) was chosen and then validated on the Validation group for more evaluation., Results: The best equation derived from demographic characteristics was: "FFM= 0.28 × Weight (kg) + 0.57×Height (cm)+7.35×Sex (M=1, F=0)+0.03×Age (years)-70.61"; where sex = 1 for male and 0 for female. R=0.94, R2=0.89, standard error of the estimate=4.04 kg., Conclusion: Our developed and cross-validated anthropometric prediction equation for fat-free mass estimation using BIA attained a high coefficient of determination, a low standard error of the estimate, and the lowermost coefficient of variation. Predictive equations may be reliable and valuable alternative methods for the clinical evaluation of fat-free mass in the adult population., Competing Interests: Conflict of interest The authors declare that there is no conflict of interests., (Copyright © 2023 Saboor et al. Published by Tehran University of Medical Sciences.)

Inflammation is implicated in the development and progression of a variety of cardiovascular diseases. We hypothesized that the Dietary Inflammatory Index (DII) is associated with anthropometric indices and metabolic parameters in Iranian atherosclerosis patients. The present cross-sectional study was conducted on 320 Iranian atherosclerosis patients. The DII was estimated using a valid and reliable 168-item food frequency questionnaire. Odds ratios and 95% confidence intervals were evaluated for anthropometric indices and metabolic parameters according to the DII score. Linear regression was used to estimate the relationship between DII scores with atherosclerosis-related dependent variables. According to the continuous score of DII, there was no significant association between DII and odds of obesity, total cholesterol/high-density lipoprotein cholesterol ratio, and aspartate aminotransferase/alanine aminotransferase ratio in all 3 models (P ≥ .05). In linear regression analysis, we found a significant association between DII score and fasting blood sugar, lipid profile (except for high-density lipoprotein cholesterol), liver enzymes (except for alkaline phosphatase), and serum sodium in adjusted models (P < .05). In this study, patients with atherosclerosis consuming a pro-inflammatory diet was positively associated with fasting blood sugar, lipid, and liver enzymes measures. Future studies with prospective and interventional designs are required to clarify the association between this dietary index and cardiovascular disease risk factors among patients with atherosclerosis., Competing Interests: Conflict of interest James R. Hebert owns controlling interest in Connecting Health Innovations LLC (CHI), a company that has licensed the right to his invention of the Dietary Inflammatory Index (DII) from the University of South Carolina to develop computer and smartphone applications for patient counselling and dietary intervention in clinical settings. Nitin Shivappa is an employee of CHI., (Copyright © 2022. Published by Elsevier Inc.)

There is no cure yet available for Alzheimer's disease (AD). We recently optimized encapsulated cell biodelivery (ECB) devices releasing human mature nerve growth factor (hmNGF), termed ECB-NGF, to the basal forebrain of AD patients. The ECB-NGF delivery resulted in increased CSF cholinergic markers, improved glucose metabolism, and positive effects on cognition in AD patients. However, some ECB-NGF implants showed altered hmNGF release post-explantation. To optimize the ECB-NGF platform for future therapeutic purposes, we initiated in-vitro optimization studies by exposing ECB-NGF devices to physiological factors present within the AD brain. We report here that microglia cells can impair hmNGF release from ECB-NGF devices in-vitro, which can be reversed by transferring the devices to fresh culture medium. Further, we exposed the hmNGF secreting human ARPE-19 cell line (NGC0211) to microglia (HMC3) conditioned medium (MCM; untreated or treated with IL-1β/IFNγ/Aβ 40 /Aβ 42 ), and evaluated biochemical stress markers (ROS, GSH, ΔΨ m , and Alamar Blue assay), cell death indicators (Annexin-V/PI), cell proliferation (CFSE retention and Ki67) and senescence markers (SA-β-gal) in NGC0211 cells. MCMs from activated microglia reduced cell proliferation and induced cell senescence in NGC0211 cells, which otherwise resist biochemical alterations and cell death. These data indicate a critical but reversible impact of activated microglia on NGC0211 cells.

The Kuwait Association of Rheumatology members met thrice in April 2020 to quickly address and support local practitioners treating rheumatic disease in Kuwait and the Gulf region during the coronavirus disease 2019 (COVID-19) pandemic. Because patients with rheumatic and musculoskeletal disease (RMD) may need treatment modifications during the COVID-19 pandemic, we voted online for the general guidance needed by local practitioners. In this review, we have addressed patients' vulnerability with rheumatic disease and issues associated with their optimum management. Our recommendations were based on the formulation of national/international guidelines and expert consensus among KAR members in the context of the Kuwaiti healthcare system for patients with RMD. The most recent reports from the World Health Organization, the Center for Disease Control, the National Institutes of Health-National Medical Library, and the COVID-19 educational website of the United Kingdom National Health Service have been incorporated. We discuss the management of RMD in various clinical scenarios: screening protocols in an infusion clinic, medication protocols for stable patients, and care for patients with suspected or confirmed COVID infection and whether they are stable, in a disease flare or newly diagnosed. Further, we outline the conditions for the hospital admission. This guidance is for the specialist and non-specialist readership and should be considered interim as the virus is relatively new, and we rely on the experience and necessity more than evidence collection. The guidance presented should be supplemented with recent scientific evidence wherever applicable., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Alzheimer's disease (AD) treatment is constrained due to the inability of peripherally administered therapeutic molecules to cross the blood-brain barrier. Encapsulated cell biodelivery (ECB) devices, a tissue-targeted approach for local drug release, was previously optimized for human mature nerve growth factor (hmNGF) delivery in AD patients but was found to have reduced hmNGF release over time. To understand the reason behind reduced ECB efficacy, we exposed hmNGF-releasing cells (NGC0211) in vitro to human cerebrospinal fluid (CSF) obtained from Subjective Cognitive Impairment (SCI), Lewy Body Dementia (LBD), and AD patients. Subsequently, we exposed NGC0211 cells directly to AD-related factors like amyloid-β peptides (Aβ 40/42 ) or activated astrocyte-conditioned medium (Aβ 40/42 /IL-1β/TNFα-treated) and evaluated biochemical stress markers, cell death indicators, cell proliferation marker (Ki67), and hmNGF release. We found that all patients' CSF significantly reduced hmNGF release from NGC0211 cells in vitro. Aβ 40/42 , inflammatory molecules, and activated astrocytes significantly affected NGC0211 cell proliferation without altering hmNGF release or other parameters important for essential functions of the NGC0211 cells. Long-term constant cell proliferation within the ECB device is critically important to maintain a steady cell population needed for stable mNGF release. These data show hampered proliferation of NGC0211 cells, which may lead to a decline of the NGC0211 cell population in ECBs, thereby reducing hmNGF release. Our study highlights the need for future studies to strengthen ECB-mediated long-term drug delivery approaches.

Background: Overweight, obesity and lack of sleep quality as inflammatory states are the common problems amongst college students and the Association of Dietary Inflammatory Index (DII) with these problems amongst this population is unknown. We aimed to evaluate the relationship of the DII with obesity and sleep quality amongst Iranian female students., Methods: The present cross-sectional study was conducted on 249 female college students. The Dietary Inflammatory Index (DII) was calculated using a valid and reliable 147-item food frequency questionnaire (FFQ). To assess sleep quality, Pittsburgh Sleep Quality Index (PSQI) was used. Odds Ratio (OR) and 95% Confidence Intervals (CIs) were estimated for anthropometric indices and sleep quality according to the DII score. Linear regression was used to estimate the relationship between DII score with sleep and anthropometric indices., Results: There was a significant association evident between DII and sleep quality (>5 is considered as poor quality of sleep); ie, the odds ratios between DII quartile 2 vs 1 (unadjusted model: OR = 0.33 (CI: 0.14-0.74), P for trend = .002; model 1: the fully adjusted OR = 0.31(CI: 0.12-0.78), P for trend = .005; model 2:OR = 0.30 (CI: 0.12-0.78), P for trend = .005) to quartile 4(unadjusted model: OR = 1.13(CI: 0.45-2.80); model 1: OR = 1.11(CI: 0.44-2.79); model 2:OR = 1.13(CI: 0.44-2.87), P for trend = .005). Also, odds ratios increased significantly from quartile 2 to quartile 4 in all models for DII and sleep quality. According to the continuous score of DII, there was a significant positive association between DII and sleep quality in all three models: unadjusted, model 1, and model 2 (OR = 1.21 (CI: 1.05-1.40), OR = 1.21 (CI: 1.03-1.43), and OR = 1.22 (CI: 1.03-1.44), respectively., Conclusions: In this study, after removing the effect of confounding factors, participants in the highest quartile of DII score had significantly higher PSQI global score., (© 2021 John Wiley & Sons Ltd.)

Background: Diabetes mellitus is a common chronic disease. Dyslipidemia and hypertension are two complications that may develop in diabetic patients if hyperglycemia, insulin resistance, and weight gain are not controlled. This study investigated the effects of melatonin supplementation on some cardiovascular disease risk factors and anthropometric indices in patients with type 2 diabetes mellitus (T2DM)., Materials and Methods: In this double-blind, randomized, placebo-controlled trial, 50 T2DM patients were randomly allocated to intervention and control groups which received two tablets of either melatonin or placebo (250 mg) once a day for 8 weeks. Systolic blood pressure (SBP), mean arterial pressure (MAP), pulse pressure (PP), the atherogenic index of plasma (AIP), weight, body mass index (BMI), waist and hip circumference (WC, HC), a body shape index (ABSI), abdominal volume index (AVI), body adiposity index (BAI), lipid accumulation product (LAP), conicity index, and waist-to-height ratio (WHtR) were evaluated in all the patients pre- and post-intervention., Results: Melatonin supplementation for 8 weeks significantly decreased the mean levels of SBP, MAP, PP, weight, BMI, WC, HC, BAI, AVI, conicity index, and WHtR post-intervention (p <  0.05). Also, the median changes of SBP, MAP, PP, weight, BMI, WC, HC BAI, AVI, and conicity index were significantly lower in the intervention group compared with the control group (p <  0.05). A significant increase (p <  0.001) was observed in the mean levels of ABSI in the intervention group. The median changes of ABSI were significantly greater in the intervention group compared with the control group (p <  0.001)., Conclusions: Consumption of melatonin supplement may be effective in controlling arterial pressure including SBP, MAP, and PP and anthropometric indices (as predictors of obesity) in T2DM patients., Trial Registration: Iranian Registry of Clinical Trials IRCT20190303042905N1 . Registered on 17 May 2019.

Age-dependent progressive neurodegeneration and associated cognitive dysfunction represent a serious concern worldwide. Currently, dementia accounts for the fifth highest cause of death, among which Alzheimer's disease (AD) represents more than 60% of the cases. AD is associated with progressive cognitive dysfunction which affects daily life of the affected individual and associated family. The cognitive dysfunctions are at least partially due to the degeneration of a specific set of neurons (cholinergic neurons) whose cell bodies are situated in the basal forebrain region (basal forebrain cholinergic neurons, BFCNs) but innervate wide areas of the brain. It has been explicitly shown that the delivery of the neurotrophic protein nerve growth factor (NGF) can rescue BFCNs and restore cognitive dysfunction, making NGF interesting as a potential therapeutic substance for AD. Unfortunately, NGF cannot pass through the blood-brain barrier (BBB) and thus peripheral administration of NGF protein is not viable therapeutically. NGF must be delivered in a way which will allow its brain penetration and availability to the BFCNs to modulate BFCN activity and viability. Over the past few decades, various methodologies have been developed to deliver NGF to the brain tissue. In this chapter, NGF delivery methods are discussed in the context of AD., (© 2021. The Author(s), under exclusive license to Springer Nature Switzerland AG.)

Typical cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is caused by mutations in the human NOTCH3 gene. Cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy is characterized by subcortical ischemic strokes due to severe arteriopathy and fibrotic thickening of small vessels. Blood regulating vascular smooth muscle cells (VSMCs) appear as the key target in CADASIL but the pathogenic mechanisms remain unclear. With the hypothesis that brain glucose metabolism is disrupted in VSMCs in CADASIL, we investigated post-mortem tissues and VSMCs derived from CADASIL patients to explore gene expression and protein immunoreactivity of glucose transporters (GLUTs), particularly GLUT4 and GLUT2 using quantitative RT-PCR and immunohistochemical techniques. In vitro cell model analysis indicated that both GLUT4 and -2 gene expression levels were down-regulated in VSMCs derived from CADASIL patients, compared to controls. In vitro studies further indicated that the down regulation of GLUT4 coincided with impaired glucose uptake in VSMCs, which could be partially rescued by insulin treatment. Our observations on reduction in GLUTs in VSMCs are consistent with previous findings of decreased cerebral blood flow and glucose uptake in CADASIL patients. That impaired ability of glucose uptake is rescued by insulin is also consistent with previously reported lower proliferation rates of VSMCs derived from CADASIL subjects. Overall, these observations are consistent with the development of severe cerebral arteriopathy in CADASIL, in which VSMCs are replaced by widespread fibrosis., (Copyright © 2020 Panahi, Rodriguez, Fereshtehnejad, Arafa, Bogdanovic, Winblad, Cedazo-Minguez, Rinne, Darreh-Shori, Hase, Kalaria, Viitanen and Behbahani.)

Background: Epidemiological studies have reported associations between elevated air pollution and autism spectrum disorders (ASD). However, we hypothesized that exposure to air pollution that mimics real world scenarios, is a potential contributor to ASD. The exact etiology and molecular mechanisms underlying ASD are not well understood. Thus, we assessed whether changes in OXTR levels may be part of the mechanism linking PM 2.5 /gaseous pollutant exposure and ASD. The current in-vivo study investigated the effect of exposure to fine particulate matter (PM 2.5 ) and gaseous pollutants on ASD using behavioral and molecular experiments. Four exposure groups of Wistar rats were included in this study: 1) particulate matter and gaseous pollutants exposed (PGE), 2) gaseous pollutants only exposed (GE), 3) autism-like model (ALM) with VPA induction, and 4) clean air exposed (CAE) as the control. Pregnant dams and male pups were exposed to air pollutants from embryonic day (E0) to postnatal day (PND21)., Results: The average ± SD concentrations of air pollutants were: PM 2.5 : 43.8 ± 21.1 μg/m 3 , CO: 13.5 ± 2.5 ppm, NO 2 : 0.341 ± 0.100 ppm, SO 2 : 0.275 ± 0.07 ppm, and O 3 : 0.135 ± 0.01 ppm. The OXTR protein level, catalase activity (CAT), and GSH concentrations in the ALM, PGE, and GE rats were lower than those in control group (CAE). However, the decrements in the GE rats were smaller than other groups. Also in behavioral assessments, the ALM, PGE, and GE rats demonstrated a repetitive /restricted behavior and poor social interaction, but the GE rats had weaker responses compared to other groups of rats. The PGE and GE rats showed similar trends in these tests compared to the VPA rats., Conclusions: This study suggested that exposure to ambient air pollution contributed to ASD and that OXTR protein may serve as part of the mechanism linking them.

OMI/HTRA2 (high-temperature requirement serine protease A2) is a mitochondrial serine protease involved in several cellular processes, including autophagy, chaperone activity, and apoptosis. Few studies on the role of OMI/HTRA2 in Alzheimer's disease (AD) are available, but none on its relationship with the cholinergic system and neurotrophic factors as well as other AD-related proteins. In this study, immunohistochemical analyses revealed that AD patients had a higher cytosolic distribution of OMI/HTRA2 protein compared to controls. Quantitative analyses on brain extracts indicated a significant increase in the active form of OMI/HTRA2 in the AD brain. Activated OMI/HTRA2 protein positively correlated with stress-associated read-through acetylcholinesterase activity. In addition, α7 nicotinic acetylcholine receptor gene expression, a receptor also known to be localized on the outer membrane of mitochondria, showed a strong correlation with OMI/HTRA2 gene expression in three different brain regions. Interestingly, the activated OMI/HTRA2 levels also correlated with the activity of the acetylcholine-biosynthesizing enzyme, choline acetyltransferase (ChAT); with levels of the neurotrophic factors, NGF and BDNF; with levels of the soluble fragments of amyloid precursor protein (APP); and with gene expression of the microtubule-associated protein tau in the examined brain regions. Overall, the results demonstrate increased levels of the mitochondrial serine protease OMI/HTRA2, and a coherent pattern of association between the activated form of OMI/HTRA2 and several key proteins involved in AD pathology. In this paper, we propose a new hypothetical model to highlight the importance and needs of further investigation on the role of OMI/HTRA2 in the mitochondrial function and AD.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder associated with abnormal protein modification, inflammation and memory impairment. Aggregated amyloid beta (Aβ) and phosphorylated tau proteins are medical diagnostic features. Loss of memory in AD has been associated with central cholinergic dysfunction in basal forebrain, from where the cholinergic circuitry projects to cerebral cortex and hippocampus. Various reports link AD progression with declining activity of cholinergic neurons in basal forebrain. The neurotrophic molecule, nerve growth factor (NGF), plays a major role in the maintenance of cholinergic neurons integrity and function, both during development and adulthood. Numerous studies have also shown that NGF contributes to the survival and regeneration of neurons during aging and in age-related diseases such as AD. Changes in neurotrophic signaling pathways are involved in the aging process and contribute to cholinergic and cognitive decline as observed in AD. Further, gradual dysregulation of neurotrophic factors like NGF and brain derived neurotrophic factor (BDNF) have been reported during AD development thus intensifying further research in targeting these factors as disease modifying therapies against AD. Today, there is no cure available for AD and the effects of the symptomatic treatment like cholinesterase inhibitors (ChEIs) and memantine are transient and moderate. Although many AD treatment studies are being carried out, there has not been any breakthrough and new therapies are thus highly needed. Long-term effective therapy for alleviating cognitive impairment is a major unmet need. Discussion and summarizing the new advancements of using NGF as a potential therapeutic implication in AD are important. In summary, the intent of this review is describing available experimental and clinical data related to AD therapy, priming to gain additional facts associated with the importance of NGF for AD treatment, and encapsulated cell biodelivery (ECB) as an efficient tool for NGF delivery.

Introduction: We recently showed that Amyloid Beta (Aβ)40 accumulates in erythrocytes and possibly causes cell damage as evidenced by an increased number of assumed injured low-density (kg/L) erythrocytes. Furthermore, we have suggested a separation technique to isolate and concentrate such damaged red blood cells for subsequent analysis., Objectives: We isolated high- and low-density erythrocytes and investigated the accumulation patterns of the Aβ peptides (Aβ40, Aβ42, and Aβ43) in Alzheimer (AD), mild cognitive impairment (MCI), and Subjective Cognitive Impairment (SCI)., Methods: Whole blood was fractionated through a density gradient, resulting in two concentrated highand presumed injured low-density erythrocyte fractions. After cell lysis, intracellular Aβ40, Aβ42, and Aβ43 were quantified by ELISA., Results: In both high- and low-density erythrocytes, Aβ40 displayed the lowest concentration in MCI, while it was equal and higher in AD and SCI. Aβ40 was detected at a 10-fold higher level than Aβ42, and in injured low-density erythrocytes, the lowest quantity of Aβ42 was found in AD and MCI. Aβ40 exhibited a 100-fold greater amount than Aβ43, and lighter erythrocytes of MCI subjects displayed less intracellular Aβ43 than SCI., Conclusion: Red blood cell accumulation patterns of Aβ40, Aβ42, and Aβ43 differ significantly between AD, MCI, and SCI. The data must be verified through larger clinical trials. It is, however, tenable that Aβ peptide distributions in erythrocyte subpopulations have the potential to be used for diagnostic purposes., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Background: Alzheimer's Disease (AD) features the accumulation of β-amyloid in erythrocytes. The subsequent red cell damage may well affect their oxygen-carrying capabilities. 2,3- diphosphoglycerate (2,3-DPG) binds to the hemoglobin thereby promoting oxygen release. It is theorized that 2,3-DPG is reduced in AD and that the resulting hypoxia triggers erythropoietin (EPO) release., Methods & Objective: To explore this theory, we analyzed red cell 2,3-DPG content and EPO in AD, mild cognitive impairment, and the control group, subjective cognitive impairment., Results: We studied (i) 2,3-DPG in red cells, and (ii) circulating EPO in AD, and both markers were unaffected by dementia. Disturbances of these oxygen-regulatory pathways do not appear to participate in brain hypoxia in AD., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a familial progressive degenerative disorder and is caused by mutations in NOTCH3 gene. Previous study reported that mutant NOTCH3 is more prone to form aggregates than wild-type NOTCH3 and the mutant aggregates are resistant to degradation. We hypothesized that aggregation or accumulation of NOTCH3 could be due to impaired lysosomal-autophagy machinery in VSMC. Here, we investigated the possible cause of accumulation/aggregation of NOTCH3 in CADASIL using cerebral VSMCs derived from control and CADASIL patients carrying NOTCH3 R133C mutation. Thioflavin-S-staining confirmed the increased accumulation of aggregated NOTCH3 in VSMC R133C compared to VSMC WT . Increased levels of the lysosomal marker, Lamp2, were detected in VSMC R133C , which also showed co-localization with NOTCH3 using double-immunohistochemistry. Increased level of LC3-II/LC3-I ratio was observed in VSMC R133C suggesting an accumulation of autophagosomes. This was coupled with the decreased co-localization of NOTCH3 with LC3, and Lamp2 and, further, increase of p62/SQSTM1 levels in VSMC R133C compared to the VSMC WT . In addition, Western blot analysis indicated phosphorylation of p-ERK, p-S6RP, and p-P70 S6K. Altogether, these results suggested a dysfunction in the autophagy-lysosomal pathway in VSMC R133C . The present study provides an interesting avenue of the research investigating the molecular mechanism of CADASIL., (Copyright © 2018 Elsevier GmbH. All rights reserved.)

Alzheimer's disease (AD) is characterized by early degeneration of cholinergic neurons and decreased levels of nerve growth factor (NGF). Thus, increasing the NGF levels by for instance encapsulated cell bio-delivery (ECB) is a potential treatment strategy. The results from our previous first-in-human studies on ECB of NGF to the basal forebrain cholinergic neurons were promising, but indicated some variability of long-term viability of the encapsulated cells and associated reduced NGF-release. Here we studied the effect of amyloid beta-peptides (Aβ), interleukin 1-beta (IL-1β), and CSF from AD, Lewy body dementia (LBD) or subjective cognitive impairment (SCI) patients on the NGF overproducing cell line NGC-0295. At physiological concentrations, neither Aβ 40 nor Aβ 42 had any major impact on cell viability or NGF-production. In contrast, IL-1β dose-dependently affected NGF-production over time. Exposure of NGF-producing cells to CSF from AD patients showed significantly reduced NGF-release as compared to CSF from LBD or SCI patients. By mass spectrometry we found 3 proteins involved in inflammatory pathways to have an altered expression in AD CSF compared to LBD and SCI. Cell survival and NGF-release were not affected by Aβ. NGF-release was affected by IL-1β, suggesting that inflammation has a negative effect on ECB cells., (Copyright © 2018 Elsevier Inc. All rights reserved.)