Intranasal insulin intake and exercise improve memory function in amyloid-ß induced Alzheimer's-like disease in rats: Involvement of hippocampal BDNF-TrkB receptor.

The most prevalent type of dementia, Alzheimer's disease (AD), is a compelling illustration of the link between cognitive deficits and neurophysiological anomalies. We investigated the possible protective effect of intranasal insulin intake with exercise on amyloid-ß (Aß)-induced neuronal damage. The level of hippocampal brain-derived neurotrophic factor (BDNF) and tropomyosin-related kinase B (TrkB) were analyzed to understand the involvement of BDNF-TrkB pathway in this modulation. In this study, we induced AD-like pathology by amyloid-ß (Aß) administration. Then, we examined the impact of a 4-week pretreatment of moderate treadmill exercise and intranasal intake of insulin on working and spatial memory in male Wistar rats. We also analyzed the mechanisms of improved memory and anxiety through changes in the protein level of BDNF and TrkB. Results showed that animals received Aß had impaired working memory, increased anxiety which were accompanied by lower protein levels of BDNF and TrkB in the hippocampus. The exercise training and intranasal insulin improved working memory deficits, decreased anxiety, and increased BDNF, and TrkB levels in the hippocampus of animals received Aß. Our finding of improved memory performance after intranasal intake of insulin and exercise may be of significance for the treatment of memory impairments and anxiety-like behavior in AD.

The increment of annexin V-positive microvesicles versus annexin V-negative microvesicles in CSF of an animal model of Alzheimer's disease.

OBJECTIVE: Extracellular microvesicles (MVs) as a specific signaling molecule have received much attention in nervous system studies. Alterations in the tissue redox status in pathological conditions, such as Alzheimer's disease (AD), facilitate the translocation of cell membrane phosphatidylserine to the outer leaflet and lead to the MVs shedding. Annexin V binds with high affinity to phosphatidylserine. Some arguments exist about whether Annexin V-negative MVs should be considered in pathological conditions. MATERIAL AND METHOD: We compared the kinetics of two phenotypes of Annexin V-positive and Annexin V-negative MVs in the cerebrospinal fluid (CSF) of amyloid-ß (Aß)-treated male Wistar rats with flow cytometry technique. The Aß was injected bilaterally into the cerebral ventricles. Thioflavin T staining was used to confirm the presence of hippocampal Aß fibrils two weeks post-Aß injection. Levels of hippocampal interleukin-1ß were assessed as an inflammatory index. The CSF malondialdehyde (MDA) concentration was determined. The cognitive impairment and anxiety behaviors were assessed by object recognition and elevated plus maze tests, respectively. RESULTS: Elevation of MDA levels and a significant rise in the scoring of IL-1ß staining were found in the Aß group. The Aß induced anxiogenic behavior, impaired novel object recognition memory, and increased the CSF levels of the total number of MVs. The number of Annexin V-positive MVs was significantly higher than Annexin V-negative MVs in all groups. CONCLUSION: Data showed that Annexin V-positive MVs potentially have a significant contribution to the pathophysiology of the Aß-induced cognitive impairment. To catch a clear image of microvesicle production in pathological conditions, both phenotypes of Annexin V-positive and Annexin V-negative MVs should be analyzed and reported.

Strategies to strengthen a climate-resilient health system: a scoping review.

BACKGROUND: Climate change is a major global threat to human health and puts tremendous pressure on health systems. Therefore, a resilient health system is crucial to enhance, maintain, and restore the population's health. This study aimed to identify interventions and actions to strengthen a climate-resilient health system to deal with the adverse health effects of climate change. METHOD: This study was a scoping review. Five databases and Google Scholar search engine were searched using relevant keywords. Initially, 4945 documents were identified, and 105 were included in the review. Content thematic analysis method was applied using MAXQDA 10 software. RESULTS: Overall, 87 actions were identified for building a climate-resilient health system and were classified into six themes (i.e., governance and leadership; financing; health workforce; essential medical products and technologies; health information systems; and service delivery). The most commonly reported actions were formulating a national health and climate change adaptation plan, developing plans for essential services (electricity, heating, cooling, ventilation, and water supply), assessing the vulnerabilities and capacities of the health system, and enhancing surveillance systems targeting climate-sensitive diseases and their risk sources. CONCLUSIONS: A holistic and systemic approach is needed to build a climate-resilient health system owing to its complex adaptive nature. Strong governance and leadership, raising public awareness, strategic resource allocation, climate change mitigation, emergency preparedness, robust health services delivery, and supporting research, are essential to building a climate-resilient health system.

Evaluation of hippocampal arylalkylamine N-acetyltransferase activity in amyloid-ß neurotoxicity.

Arylalkylamine N-acetyltransferase (AANAT), a rate-limiting enzyme in melatonin synthesis, is present in extra-pineal tissues such as the hippocampus. The hippocampal AANAT activity in amyloid ß (Aß) neurotoxicity has not been exactly defined. Adult male rats received bilateral intra-CA1 Aß administration. The hippocampus tissue sampling was performed 2, 12, and 24 h after Aß injection in the morning and night. The inflammation was monitored using tumor necrosis factor-alpha (TNF-α) immunohistochemistry. The AANAT enzyme activity and melatonin levels were measured using western blotting and high-performance liquid chromatography. The sampling in the morning vs night showed no significant differences in the AANAT activity. The Aß increased the area of TNF-α positive staining 24 h after injection, which indicated the induction of an inflammatory context. It was accompanied by a significant reduction in AANAT activity and hippocampal melatonin. A reverse correlation was also detected between TNF-α and AANAT activity in the 24-h group. The TNF-α positive area was significantly increased in the 24-h group as compared to the 12-h group. Data showed that inflammatory processes began 12 h after the Aß injection and augmented 24 h later. In the second experiment, the impact of Aß injection on hippocampus AANAT activity was examined in the pinealectomized (PIN×) animals. The PIN× per se did not affect the hippocampal AANAT and melatonin levels. However, there was a significant decrease in hippocampal melatonin in the PIN×+Aß group. The findings suggest the accompanying hippocampal inflammatory context and AANAT enzyme activity reduction in early stages after Aß administration. Understanding the underlying mechanism of the decreased AANAT activity may suggest new treatment strategies.

A surgical modification in the technique of rat pinealectomy.

BACKGROUND: Several experimental intents require pineal gland removal. The main challenge of the pinealectomy surgical procedure is the hemorrhage due to the transverse sinus torn. The study aimed to modify the rat pinealectomy surgical procedure to reduce the risk of bleeding and the mortality rate. METHODS: Adult male rats experienced pinealectomy surgery. A mini-drill was used to remove a small skull area in the junction of the lambda and sagittal sutures. The pineal gland was removed using a curved-head hook. Animals experienced intensive post-surgical care. Locomotion, cerebellar motor function, working memory, and anxiety were evaluated 2 weeks after pinealectomy by the open field, rotarod, Y maze, and the elevated plus maze, respectively. RESULTS: Surgical modification reduced the bleeding risk and animal mortality rate. No significant alteration was found in locomotion and working memory. However, the pinealectomy was anxiogenic and decreased entry to the open arm. The cerebellar motor performance did not change in the rotarod test. Hematoxylin-Eosin staining of removed tissue confirmed the histology of the pineal gland. CONCLUSION: Advantages of this technique were removing a small skull area, modifying the hook insertion point to prevent damaging the brain veins, reducing the bleeding risk and the mortality rate. Surgery modification was associated with a decreased final number of animals used. Regardless of the melatonin shortage, pinealectomy affects different organs, which should be considered in the research study design.

Increment of CSF fractalkine-positive microvesicles preceded the spatial memory impairment in amyloid beta neurotoxicity.

BACKGROUND: Fractalkine (CX3CL1) is a key chemokine, affects neuronal cell communication and involves in Alzheimer's disease pathogenesis. Microvesicles (MVs) participate in neuronal cells' cross-talk in physiological and pathological states. Microvesicles released in cerebrospinal fluid (CSF) may provide a valuable footprint of brain changes. Little information is available regarding the release of fractalkine-positive MVs (CX3CL1+ -MVs) in the nervous system. METHODS: We induced cognitive impairment by bilateral injection of amyloid-beta (Aß) into the cerebral ventricles. We analyzed the CSF by flow cytometry in two experiments (trained and untrained) to elucidate the presence of CX3CL1+ -MVs. The hippocampal TNF-α as an inflammatory factor was assessed by immunohistochemistry. RESULTS: The Aß induced spatial memory impairment after two weeks, verified by a decrease in the escape latency in Morris water maze test. It caused an increase in the anxiety-like behaviors demonstrated by a decrease in entries into the open arms of elevated plus maze test. The Aß increased the percent of the positive area for TNF-α staining. Histological evaluation of the hippocampus confirmed the tissue injuries. The CSF levels of CX3CL1+ -MVs, increased 2 and 7 days after Aß injection. The Aß increased the TNF-α staining and provided an inflammatory context to facilitate the MVs release. The rise of CX3CL1+ -MVs was transient and subsided after two weeks. Both trained and untrained experiments showed a similar rise pattern of CX3CL1+ -MVs. CONCLUSION: Increase of fractalkine-positive microvesicles preceded the cognitive impairment, more studies are required to approve the CX3CL1+ -MVs as a potential biomarker in the early diagnosis of Alzheimer's disease.

Assessment of lipophilic fluorescence products in ß-amyloid-induced cognitive decline: A parallel track in hippocampus, CSF, plasma and erythrocytes.

BACKGROUND: Oxidative stress implicates in Alzheimer's disease (AD) pathophysiology, and associates with the creation of end products of free radical reactions, are known as lipophilic fluorescent products (LFPs). This study aimed to evaluate the probable parallel alterations in the spectral properties of the LFPs in the hippocampus tissues, cerebrospinal fluid (CSF), plasma, and erythrocytes during AD model induction by intra-cerebroventricular (ICV) amyloid ß-protein fragment 25-35 (Aß) injection. METHODS: Male rats received an intra-ICV injection of Aß. Hippocampus, CSF, plasma, and erythrocytes were harvested at 5, 14, and 21 days after Aß injection. The fluorescent intensity of LFPs was assessed by spectrofluorimetry using synchronous fluorescence spectra 25 (SYN 25) and 50 (SYN 50) in the range of 250-500 nm. Hippocampal tissue malondialdehyde (MDA) and superoxide dismutase (SOD) were also measured. Cognitive alterations were evaluated using Morris water maze (MWM) test. RESULTS: The parallel significant rise in the fluorescence intensity of LFPs was detected in the hippocampus, CSF, plasma, and erythrocytes, 14, and 21 days after ICV-Aß injection. These alterations were found in both types of synchronous spectra 25, and 50, and were coincided with hippocampal cognitive decline, the MDA rise, and decrease of SOD activity. There was a positive correlation between hippocampus homogenate, and plasma or CSF rise in fluorescence intensity. CONCLUSION: Data showed that the Aß increased hippocampal MDA, and decreased SOD activity, led to a higher rate of oxidative products and subsequently resulted in an increase in LFPs fluorescence intensity during the development of cognitive decline. LFPs' alterations reflect a comprehensive view of tissue redox status. The fluorescence properties of LFPs indicate their composition, which may pave the way to trace the different pathological states.

Inhibition of brain 17ß-estradiol synthesis by letrozole induces cognitive decline in male and female rats.

BACKGROUND: Hippocampal aromatase is responsible for local synthesis of 17ß-estradiol (E2) that has much higher concentrations than serum levels in males and females. Letrozole, an aromatase inhibitor, passes through the brain barriers, distributes to the brain, and affects local E2 synthesis. Here, the effects of intra-cerebroventricular (ICV) letrozole administration in the presence and absence of gonads were examined on the cognitive abilities of male and female rats. METHOD: Animals received intra-ICV injection of letrozole or vehicle for 14 consecutive days. Spatial working memory, novel object recognition memory, and anxiety-related behavior, were evaluated using Y-maze, object recognition test, and elevated plus maze, respectively. The E2 levels in the serum and hippocampal tissue were measured by the ELISA technique. RT-PCR was performed to assess the hippocampal estrogen receptors (ER) expression. Moreover, letrozole effect on neuronal activity of CA1 pyramidal neurons was studied by in vivo single-unit recording. RESULTS: Letrozole (0.2, 0.4, and 0.8 µg) significantly decreased the hippocampal E2 levels compared to the vehicle group. Letrozole caused cognitive impairments in a dose-dependent manner in male and female rats in the presence or absence of gonads. Dose-response analysis revealed that the minimum effective dose of letrozole on the behavioral measures was 0.4 µg. Letrozole also caused an up-regulation of ERα and ERß and a down-regulation of GPR30 gene expression. The firing rate of pyramidal neurons was reduced by letrozole in gonadal-intact animals. CONCLUSION: The detrimental effects of letrozole treatment on cognitive abilities in the presence and absence of gonads indicate that local E2 synthesis in the hippocampus is a crucial factor in normal cognitive performance. The suppressive effect of letrozole on hippocampal neuronal firing might alter synaptic plasticity that is critical for memory formation. These data potentially suggest that memory deficits following letrozole administration should be monitored.

GnRH protective effects against amyloid ß-induced cognitive decline: A potential role of the 17ß-estradiol.

INTRODUCTION: The 17ß-estradiol (E2) enhances hippocampal dendritic spine synapses, facilitates learning processes, and exerts neuroprotection. Brain estrogen decline has been reported in Alzheimer's disease. The role of GnRH in modulating steroid biosynthesis convinced us to examine whether hippocampal GnRH administration could enhance the local E2 levels and overcome the development of cognition decline in amyloid ß (Aß) neurotoxicity. To explore if GnRH acts through regulating E2 synthesis, letrozole, an aromatase inhibitor, has been applied in combination with GnRH. METHODS: Female rats received an intracerebroventricular injection of Aß. The GnRH and, or letrozole were injected into the CA1 for 14 consecutive days. Working memory, novel object recognition memory, and anxiety-like behavior were evaluated. Serum and hippocampal E2 levels were measured. Hippocampal mRNA expression of GnRH (GnRH-R) and E2 (ERα and ERß) receptors was assessed. GnRH effect on the excitability of pyramidal cells was studied by in vivo single-unit recording. RESULTS: GnRH increased hippocampal E2 levels, evoked an increase in the spontaneous firing of pyramidal neurons, and caused mRNA overexpression of hippocampal GnRH receptors. GnRH prevented the adverse effects of Aß on working memory, NOR index, and anxiogenic behavior. Letrozole did not reverse GnRH modulatory effects on hippocampal E2 levels and neuroprotection. CONCLUSION: GnRH prevented the Aß-induced memory deficit, which may be mediated through hippocampal E2 levels enhancement. The electrophysiological analysis revealed the enhanced neuronal excitability in the CA1 region. All these data suggest that GnRH might be a promising candidate that reduces anxiety and improves memory indices in the context of Aß neurotoxicity.

Anxiolytic impact of Apelin-13 in a rat model of Alzheimer's disease: Involvement of glucocorticoid receptor and FKBP5.

Apelin-13 is known to be one of the predominant neuropeptides with marked protective role in circuits involved in mood disturbances. The most putative hypothesis in pathophysiology of Alzheimer's disease (AD) is Amyloid beta (Aß) aggregation which interrupt proper function of hypothalamic-pituitary-adrenal (HPA) axis and are associated with anxiety. Here, we assessed the potential anxiolytic effect of Apelin-13 in a rodent cognitive impairment model induced by intrahippocampal Aß 25-35 administration. We evaluated the memory impairment and anxiogenic behavior using shuttle box and Elevated plus maze apparatuses. We also measured the glucocorticoid receptor (GR) and FK506 binding protein 51 (FKBP5) expression as important markers showing the proper feedback mechanism within the HPA axis. Our findings showed that Aß 25-35 administration induced memory impairment and anxiety behaviors. Apelin-13 exerted the anxiolytic effects and provided protection against Aß 25-35 -induced passive avoidance memory impairment. Moreover, Apelin-13 caused an increase in GR and a decrease in FKBP5 expression levels in Aß 25-35 treated animals. Taken together, these findings showed the anxiolytic effect of Apelin-13. This effect at least in part, may be mediated through the regulation of GR and FKBP5 expression levels which have a pivotal role in the appropriate negative feedback mechanism within the HPA axis. These data suggest that Apelin-13 might be considered as a potential neuropeptide defense that reduces anxiety along with neuroprotective effect against the Aß 25-35 -induced injury.

Melatonin protective effect against amyloid ß-induced neurotoxicity mediated by mitochondrial biogenesis; involvement of hippocampal Sirtuin-1 signaling pathway.

Melatonin has a potential therapeutic value in Alzheimer's disease (AD), a disease that is associated with a dramatic decline in memory and cognitive abilities. The aggregation of the amyloid ß (Aß) peptide, a hallmark of AD, deactivates mitochondrial biogenesis and antioxidant defenses. Melatonin as an endogenous antioxidant, decreases in plasma and cerebrospinal fluid of AD patients. Even though several experimental studies have demonstrated the melatonin neuroprotection in AD, clinical trials of melatonin therapy have not yet confirmed outstanding results in AD patients. Better understanding of the molecular mechanisms involved in melatonin neuroprotective effects may pave the way for an efficient therapy. Hence, we investigated the involvement of silent information regulator 1 (SIRT1) signaling and mitochondrial biogenesis in melatonin neuroprotection in a rat model of cognitive impairment induced by intra-hippocampal Aß injection. Animals assigned to melatonin treatment in the presence or absence of SIRT1 inhibitor (EX527), for 14 consecutive days. Spatial working memory and anxiety level were examined with Y-maze and elevated plus maze tests respectively. Hippocampal SIRT1, transcription factor-A mitochondrial (TFAM) and mitochondrial DNA (mtDNA) copy number were measured. We observed a decrease in hippocampal SIRT1, which accompanied with reduction in TFAM and mtDNA copy number in the Aß-injected rats. Melatonin treatment increased hippocampal SIRT1 and TFAM expression and enhanced mtDNA copy number in the hippocampus. It also improved memory, ameliorated the anxiety, and attenuated hippocampal cell damage in the Aß-injected animals. These effects were blocked by EX527 administration, suggesting SIRT1 signaling involvement in melatonin neuroprotective effect. This mechanism may introduce a new promising strategy in battle against AD.

Simvastatin Attenuates Hippocampal MMP-9 Expression in the Streptozotocin-Induced Cognitive Impairment

Background: Matrix metalloproteinase-9 (MMP-9) expression has been implicated in molecular mechanisms of neurodegenerative disorders, and its abnormal level has been reported in Alzheimer's disease (AD). Some protective mechanisms of statins against neurodegeneration might be mediated by the inhibition of MMP-9 expression. Here, we investigated the effect of simvastatin on the hippocampal MMP-9 expression in the context of AD. Methods: We examined the influence of three-week simvastatin (5 mg/kg) administration on hippocampal MMP-9 expression in a rat model of cognitive decline induced by streptozotocin (STZ). Spatial long-term memory and MMP-9 expression were assessed by Morris water maze (MWM) test and quantitative polymerase chain reaction, respectively. Results: The results showed a decline in the learning and memory in STZ group when compared with the control group. The MMP-9 up-regulated (1.41 ± 0.2 vs. 0.980 ± 0.02, p < 0.05), and cresyl violet staining showed hippocampal cell damage in STZ group compared with the control group. Simvastatin prevented the up-regulation of MMP-9 (1.05 ± 0.05 vs. 1.41 ± 0.2, p < 0.05), improved spatial memory impairment and attenuated hippocampal cell damage. Furthermore, we found a negative correlation (r = 0.77) between MMP-9 expression and cognitive function. Conclusion: Our findings suggest that the neuroprotective influence of simvastatin in battle to cognitive impairment is mediated in part by the modulation of MMP-9 expression. The reduction of MMP-9 expression in simvastatin-treated animals is in correlation with the improvement of cognitive functions. Understanding the protective mechanism of simvastatin will shed light on more efficient therapeutic modalities in AD.

Protective role of Apelin-13 on amyloid ß25-35-induced memory deficit; Involvement of autophagy and apoptosis process.

Alzheimer's disease (AD) by progressive neurodegenerative pattern is associated with autophagy stress which is suggested as a potential cause of amyloid ß (Aß) aggregation and neural loss. Apelin-13, a neuropeptide with modulatory effect on autophagy, has been shown the beneficial effects on neural cell injuries. We investigated the effect of Apelin-13 on Aß-induced memory deficit as well as autophagy and apoptosis processes. We performed bilateral intra-CA1 injection of Aß25-35 alone or in combination with Apelin-13. Spatial reference and working memory was evaluated using the Morris water maze (MWM) and Y-maze tests. Hippocampus was harvested on 2, 5, 10 and 21 days after Aß injection. The light chain 3 (LC3II/I) ratio, histone deacetylase 6 (HDAC6) level, Caspase-3 cleavage, and mTOR phosphorylation were assessed using western blot technique. Intra-CA1 injection of Aß caused impairment of working and spatial memory. We observed higher LC3II/I ratio, cleaved caspase-3 and lower HDAC6, and p-mTOR/mTOR ratio in Aß-treated animals. Apelin-13 provided significant protection against the destructive effects of Aß on working and spatial memory. Apelin-13 prevented the increase of LC3II/I ratio and cleaved caspase-3 on days 10 and 21 after injection of Aß. It also limited the Aß-induced reduction in HDAC6 expression. This implies that Apelin-13 has suppressed both autophagy and apoptosis. Our findings suggested that the neuroprotection of Apelin-13 may be in part related to autophagy and apoptosis inhibition via the mTOR signaling pathway. Apelin-13 may be a promising approach to improve memory impairment and potentially pave the way for new therapeutic plans in AD.

Opioid Use Disorder Induces Oxidative Stress and Inflammation: The Attenuating Effect of Methadone Maintenance Treatment.

Objective: Frequent use of opioids produces reactive oxygen species, upregulates inflammatory factors, and contributes to opiate dependence. In this study, we examined perturbations of plasma oxidative and inflammatory markers in patients with opioid use disorder in two phases. In the first phase, we compared the oxidative status in patients with opioid use disorders and in healthy controls; and in the second phase, we examined oxidative changes before and after methadone maintenance treatment. Method: To explore whether oxidative changes were associated with opioid use disorder, we compared plasma oxidative and inflammatory markers in patients with opioid use disorder and in smoking and non-smoking healthy participants. All participants completed measures of catalase (CAT), glutathione (GSH), malondialdehyde (MDA), superoxide dismutase (SOD), matrix metalloproteinase (MMP-9), and TNF-α at baseline. Baseline measures were compared using Kruskal-Wallis test. In the second phase, to explore oxidative changes during transition from opium use to methadone, blood and urine samples of patients with opioid use disorder were re-evaluated on Days 3, 7, and 14 after methadone therapy. Repeated measures analysis was used to determine the relative contribution of intervention to changes in CAT, GSH, MDA, SOD, MMP-9, and TNF-α level over time. Results: We observed lower SOD and catalase activities, and higher TNF-α and MMP-9 level in patients compared to the two comparison groups. Opioids exacerbated the oxidative imbalance and superimposed the underlying oxidative injury in smoker comparison group. Methadone therapy was associated with lower MMP-9 and TNF-α level, and higher SOD and catalase activities two weeks after therapy; showing an improvement in oxidative profile. Conclusion: This was an investigation indicating an oxidative imbalance before methadone therapy and during early days of transition from opium use to methadone. Being aware of redox status is crucial for determining an appropriate antioxidant therapy in opioid use disorder.

Effect of methamphetamine exposure on the plasma levels of endothelial-derived microparticles.

BACKGROUND: Methamphetamine (Meth), a neurotoxin, induces inflammation, oxidative stress, and triggers endothelial dysfunction and cardiovascular disease which is the second cause of death among individuals with Meth-use disorder. Oxidative stress and inflammation trigger the microparticle (MP) release. These are extracellular vesicles extracted from cell surface and identified in biological fluids. MP levels alter during pathological conditions, suggesting its potential biomarker role. In this respect, we designed the present experiment to investigate the effects of Meth on the plasma level of the endothelial-derived microparticle (EMP). METHODS: Animals received Meth (4 mg/kg i.p.) for 1, 7 and 14 days and then, the plasma level of EMPs was evaluated, using cell surface markers, including AnnexinV, CD144, CD31, CD41a antigens with the flow cytometry method. The biochemical indices and locomotor activity were also assessed in a rat model. RESULTS: Meth increased locomotor activity (Meth-1, 277.12 ±â€¯20.17; Meth-7, 262.25 ±â€¯11.95; Meth-14, 265.75 ±â€¯14.75), inflammatory and oxidative indices as evidenced by rising of the C-reactive protein (Meth-7, 39.4 ±â€¯1.24; Meth-14, 38.58 ±â€¯2.19, vs 8.65 ±â€¯0.45, mg/L) and malondialdehyde (Meth-7, 9.74 ±â€¯1.38; Meth-14, 14.6 ±â€¯1.45, vs 4.43 ±â€¯0.32 nmol/L) plasma levels. We also found that Meth triggered endothelial injury, as demonstrated by elevated levels of EMP (Meth-7, 4.77 ±â€¯0.22; Meth-14, 5.91 ±â€¯0.34, % total events/mL) compared with control group. CONCLUSION: Our data showed that Meth exposure stimulates inflammatory and oxidative pathways and facilitates the EMPs shedding. Measuring the level of EMPs might be applied as a potential diagnostic index to monitor the endothelial dysfunction in substance-use disorders.

The comparison of hospitals' performance indicators before and after the Iran's hospital care transformations plan.

INTRODUCTION: Hospital care transformation plan (HCTP) was implemented, in 2014, with the aim of ensuring all Iranians have fair access to hospital care, mainly in the public sector. It was assumed that HCTP would lead to increased quality and effectiveness of health care in public hospitals. To explore whether HCTP has achieved its aim, this study has investigated the impact of this plan on performance indicators (PIs) of the public hospitals. MATERIALS AND METHODS: This cross-sectional descriptive study was conducted in 2016. The study population included all hospitals in the Isfahan City. Data (10 selected PIs) were collected through formal reports which were available at the Isfahan University of Medical Sciences and analyzed using Statistical Package for Social Sciences (version 17). The statistical significant level analysis was 0.05. RESULTS: After HCTP, it was shown an increase of (1) Bed occupancy, bed turnover, occupied bed-days, inpatients visits, and number of surgeries in all types of hospitals, (2) Outpatients' visits in all hospitals except private ones, (3) Emergency visits in public and social security hospitals, and (4) Natural deliveries in public and semi-public hospitals. Furthermore, the average length of stay and hospital mortality rate has decreased in all types of hospitals after HCTP implementation. DISCUSSION AND CONCLUSION: Although, improving PIs of hospitals were not directly stated and known objectives of HCTP implementation, it seems HCTP could improve the performance of all hospitals, including involved and noninvolved ones.

Impact of opioids on oxidative status and related signaling pathways: An integrated view.

BACKGROUND: Opioids produce reactive oxygen species (ROS) which are highly reactive molecules that damage cells and tissues, and are suggested to contribute to the opioid use disorders. Thus, antioxidant supplementation might improve the disturbance in redox (oxidation-reduction) homeostasis. However, randomized trials on antioxidant therapy have not shown beneficial effects. OBJECTIVES: The purpose of this review is to shed lights on the oxidative changes resulting from opioid use and to highlight the unanswered questions regarding oxidative profile in an effort to provide a comprehensive view of different aspects of an efficient antioxidant therapy in clinical settings. METHODS: The studies were identified and gathered from the PubMed database over the past 16 years (2000-2016). Our search results were limited to articles in English, both animals and human and in vitro and in vivo studies. A total of 50 full text articles were reviewed and summarized. RESULTS: Opioids elevate the level of ROS and decrease the function of enzymatic antioxidants such as superoxide dismutase, catalase, and glutathione peroxidase. They increase the risk of vitamin deficiency and modify gene expression of target cells through ROS production. The effects of opioids on their target cells are exerted through different way and various mechanisms. CONCLUSION: Opioids modulate the redox homeostasis; therefore, understanding the profile of oxidative changes in individuals with opioid use disorder could be of significant benefits in the clinical setting, to help with selection of an efficient antioxidant therapy and diminishing oxidative damage.

Simvastatin enhances the hippocampal klotho in a rat model of streptozotocin-induced cognitive decline.

Brain oxidative status is a crucial factor in the development of sporadic Alzheimer's disease (AD). Klotho, an anti-aging protein, diminishes oxidative stress by the induction of manganese superoxide dismutase (MnSOD). Thus, the substances that increase klotho expression could be considered as a potential treatment for Alzheimer's disease when the oxidative imbalance is present. Statins are suggested to up-regulate klotho expression. We examined the effect of simvastatin (5mg/kg, daily for 3weeks) on hippocampal klotho and MnSOD expression in the cognitive declined animal model induced by intracerebroventricular (ICV)-streptozotocin (STZ) administration. Cognitive assessment was performed by the Morris Water Maze (MWM) test. The results indicated that mean escape latency and distance were prolonged in the ICV-STZ group compared with the control group. The expression of klotho and MnSOD were also down regulated in the hippocampus. Furthermore, improved spatial performance was observed in simvastatin-treated animals. This effect could be related to increase in oxidative stress tolerance as evidenced by klotho and MnSOD up-regulation. Our current study indicates that klotho upregulation may be a neuroprotective mechanism of simvastatin against cognitive decline in AD.

Decentralisation, Decision Space and Directions for Future Research Comment on "Decentralisation of Health Services in Fiji: A Decision Space Analysis".

Decentralisation continues to re-appear in health system reform across the world. Evaluation of these reforms reveals how research on decentralisation continues to evolve. In this paper, we examine the theoretical foundations and empirical references which underpin current approaches to studying decentralisation in health systems.